Macrocyclic compounds and pharmaceutical compositions thereof for the treatment of proliferative diseases

Abstract

The present invention discloses compounds according to Formula (I), wherein R1a, R1b, R2a, R2b, R4a, R4b, X, Y, Cy, W, L, A, 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 DISEASESFIELD 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 TP 53 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 (NCT04585750 2020).

[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:Xi is CR3a- or N, X2 is CR3bor N, and X3 is CR3cor N;Each Zi and Z2 is independently selected from C and N;A is selected from N, or CH;W is absent or is O, -NHC(=O)-, or -C(=O)NH-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;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 =0;Each Rla, Rlb, R2a, and R2bis independently selected from:- H,- halo,- CN,- =0 (Rlatogether with Rlb, and / or R2atogether with R2b),- -T1-G1,- C1-6 alkyl, optionally substituted with one or more independently selected R6,- C1-6 alkoxy, optionally substituted with one or more independently selected R6,- C37 cycloalkyl, optionally substituted with one or more independently selected R6,- C5-12 membered fused, spiro or bridged polycyclic cycloalkyl, optionally substituted with one or more independently selected R6,- 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 R6, 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 R6; orRlaand R2a, together with the atoms to which they are attached together may form:- C3-7 membered monocyclic cycloalkyl ring, optionally substituted with one or more independently selected R6,- 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 R6, 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 R6;Each R3a, R3b, R3cis independently selected from:- H,- halo,- -OH,- -CN,- -NR9aR9b,- Ci-4 alkyl optionally substituted with one or more independently selected halo,- Ci-4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and- 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;Each R4aand R4bis independently selected from H, or C1-4 alkyl optionally substituted with one or more independently selected halo;X is absent, -CH2-, -O-, or -NH-;Each R6is independently selected from: halo,- CN, oxo,- G2A,- -T2-G2B,Cy is a phenyl or naphthyl, each of which is optionally substituted with one or more independently selected R8,5-6 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, or8-10 membered bicyclic 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,- G3A,- -T3-G3B,Each Ti, T2and T3is independently -CH2-, -CH2CH2-, -CH=CH-, -C=C-, -NG4-, -CH2NG4-, -O-, -S-, - S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -CH2C(=O)O-, -C(=O)OCH2-, -C(=O)NG4-, -C(=O)NHS(O)2G4-, - CH2C(=O)NG4-, -C(=O)NG4CH2-, -OC(=O)NG4-, -S(=O)2NG4-, -S(=O)2NG4CH2-, -OC(=O)-, -CH2NG4C(=O)-, -NG4C(=O)-, -NG4C(=O)CH2-, -NG4S(=O)2-,-S(=O)=NG4-, or -P(=O)G4-;Each G1, G2A, G2B, G3A, G3B, G4is independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, =0, CN, or Ci .4 alkoxy, monocyclic C3-7 cycloalkyl optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, Ci -4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, B, P, O, or S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, OH, =0, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo, phenyl optionally substituted with one or more independently selected halo, OH, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo, and5 or 6 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 halo, OH, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo.Y is -NR7-;R7is H, C1-6 alkyl, C3-6 cycloalkyl, -C(=0)Ci-6 alkyl, -C(=0)C3-e cycloalkyl, or -C(=0)Ci-6 alkoxy; and each R9aand R9bis independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl.

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

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

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

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

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

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

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

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

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

[0021] When describing inter alia 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.

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

[0023] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2-CH2-CH2-CH3), tert-butyl (-CH2-C(CH3)3), sec-butyl (-CH2-CH(CH3)2), n-pentyl (-CH2-CH2-CH2-CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CHCH3)-C(CH3)H2-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.

[0024] ‘Alkenyl’ refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 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 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2) and the like.

[0025] ‘Alkylene’ refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.

[0026] ‘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-.

[0027] ‘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-Ci e alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. 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.

[0028] ‘ Amino’ refers to the radical -NH2.

[0029] ‘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.

[0030] ‘Cycloalkyl’ refers to non-aromatic fully or partially saturated ring structure, monocyclic, fused polycyclic, spirocyclic or bridged polycyclic, 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. When partially saturated, the cycloalkyl may contain one or two double bonds, and more particularly one double bond. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Such polycyclic and / or partially saturated cycloalkyl groups include, by way of example:

[0031] ‘Cyano’ refers to the radical -CN.

[0032] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0033] ‘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 nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above 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.

[0034] ‘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 canbe, 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, sulphur 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.

[0035] “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- dihydro-benzo[l,4]dioxinyl, benzo[l,3]dioxolyl, 2,2-dioxo-l,3-dihydro-2-benzothienyl, 4, 5,6,7- tetrahydrobenzofuranyl, indolinyl, 1 ,2,3,4-tetrahydro- 1 ,8-naphthyridinyl,1.2.3.4-tctrahydropyrido|2.3- / > |pyrazinyl and 3.4-dihydro-2 / / -pyrido|3.2- / ? || l,4]oxazinyl.

[0036] 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.

[0037] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] Examples of representative heteroaryls include the following:wherein each Y is selected from >C=O, NH, O and S.

[0042] ‘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, B, 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, boron, 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.

[0043] 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-.

[0044] 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-.

[0045] 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.

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

[0047] 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.

[0048] ‘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.

[0049] ‘Hydroxyl’ refers to the radical -OH.

[0050] ‘ Oxo’ refers to the radical =0.

[0051] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0052] ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as -SO3H.

[0053] ‘ Thiol’ refers to the group -SH.

[0054] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.

[0055] ‘Thioalkoxy’ refers to the group -S-alkyl where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -S-C1-6 alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, secthiobutoxy, n-thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0056] 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 the heteroatoms. Ingeneral, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0057] ‘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.

[0058] ‘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.

[0059] In some embodiments the compound of the invention is in the form of a pharmaceutically acceptable salt. In some embodiments the compound of the invention is in the free acid / free base form.

[0060] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0061] ‘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.

[0062] ‘ 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.

[0063] In some embodiments the compound of the invention is in the form of a solvate. In some embodiments the compound of the invention is a solvate of a pharmaceutically acceptable salt of a compound according to any of formulae (I) to (Vlllf).

[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 (z. 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 (z. 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 celltypes (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, Waldenstrom 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, Sezary 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 the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[0073] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, 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 Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci4 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 (nC), 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 (36C1), chlorine-37 (37C1), 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 halflife 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 as nC,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 7i 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):whereinXi is CR3a- or N, X2 is CR3bor N, and X3 is CR3cor N;Each Zi and Z2 is independently selected from C and N;A is selected from N, or CH;W is absent or is O, -NHC(=O)-, or -C(=O)NH-;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;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 =0;Each Rla, Rlb, R2a, and R2bis independently selected from:- H,- halo,- CN,- =0 (Rlatogether with Rlb, and / or R2atogether with R2b),- -Ti-G1,- Ci-6 alkyl, optionally substituted with one or more independently selected R6,- Ci-6 alkoxy, optionally substituted with one or more independently selected R6,- Cs 7 cycloalkyl, optionally substituted with one or more independently selected R6,- C5-12 membered fused, spiro or bridged polycyclic cycloalkyl, optionally substituted with one or more independently selected R6,- 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 R6, 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 R6; orRlaand R2a, together with the atoms to which they are attached together may form:- C3-7 membered monocyclic cycloalkyl ring, optionally substituted with one or more independently selected R6,- 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 R6, 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 R6;Each R3a, R3b, R3cis independently selected from:- H,- halo,- -OH,- -CN,- -NR9aR9b,- C1-4 alkyl optionally substituted with one or more independently selected halo,- C1-4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and- 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;Each R4aand R4bis independently selected from H, or C1-4 alkyl optionally substituted with one or more independently selected halo;X is absent, -CH2-, -O-, or -NH-;Each R6is independently selected from: halo,- CN, oxo,- G2A,- -T2-G2B,Cy is a phenyl or naphthyl, each of which is optionally substituted with one or more independently selected R8,5-6 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, or8-10 membered bicyclic 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,- G3A,- -T3-G3B,Each Ti, T2and T3is independently -CH2-, -CH2CH2-, -CH=CH-, -C=C-, -NG4-, -CH2NG4-, -O-, -S-, - S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -CH2C(=O)O-, -C(=O)OCH2-, -C(=0)NG4-, -C(=O)NHS(O)2G4-, - CH2C(=O)NG4-, -C(=O)NG4CH2-, -0C(=0)NG4-, -S(=O)2NG4-, -S(=O)2NG4CH2-, -OC(=O)-, -CH2NG4C(=O)-, -NG4C(=0)-, -NG4C(=O)CH2-, -NG4S(=O)2-,-S(=O)=NG4-, or -P(=O)G4-;Each G1, G2A, G2B, G3A, G3B, G4is independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, =0, CN, or Ci- 4 alkoxy, monocyclic Ck? cycloalkyl optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, Ci .4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, B, P, O, or S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, OH, =0, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo,phenyl optionally substituted with one or more independently selected halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo, and5 or 6 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 halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo.Y is -NR7-;R7is H, Ci-6 alkyl, C3-6 cycloalkyl, -C(=O)Ci-6 alkyl, -C(=O)C3-e cycloalkyl, or -C(=O)Ci-6 alkoxy; and each R9aand R9bis independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl.Accordingly, another aspect of the invention, the compounds of the invention are provided having a Formula (I) whereinXi is CR3a- or N, X2 is CR3bor N, and X3 is CR3cor N;Each Zi and Z2 is independently selected from C and N;A is selected from N, or CH;W is absent or is O, -NHC(=O)-, or -C(=O)NH-;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;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 =0;Each Rla, Rlb, R2a, and R2bis independently selected from:- H,- halo,- CN,- =0 (Rlatogether with Rlb, and / or R2atogether with R2b),- -T1-G1,- C1-6 alkyl, optionally substituted with one or more independently selected R6,- C1-6 alkoxy, optionally substituted with one or more independently selected R6,- C37 cycloalkyl, optionally substituted with one or more independently selected R6,- C5-12 membered fused, spiro or bridged polycyclic cycloalkyl, optionally substituted with one or more independently selected R6,- 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 R6, 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 R6; orRlaand R2a, together with the atoms to which they are attached together may form:- C3-7 membered monocyclic cycloalkyl ring, optionally substituted with one or more independently selected R6,- 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 R6, 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 R6;Each R3a, R3b, R3cis independently selected from:- H,- halo,- -OH,- -CN,- -NR9aR9b,- C1-4 alkyl optionally substituted with one or more independently selected halo,- C1-4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and- 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;Each R4aand R4bis independently selected from H, or C1-4 alkyl optionally substituted with one or more independently selected halo;X is absent, -CH2-, -O-, or -NH-;Each R6is independently selected from: halo,- CN, oxo,- G2A,- -T2-G2B,Cy is aphenyl or naphthyl, each of which is optionally substituted with one or more independently selected R8,5-6 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, or8-10 membered bicyclic 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,- G3A,- -T3-G3B,Each Ti, T2and T3is independently -CH2-, -CH2CH2-, -CH=CH-, -C=C-, -NG4-, -CH2NG4-, -O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -CH2C(=O)O-, -C(=O)NG4-, -CH2C(=O)NG4-, -OC(=O)NG4-, - S(=O)2NG4-, -OC(=O)-, -CH2NG4C(=O)-, -NG4C(=O)-, -NG4S(=O)2-,-S(=O)=NG4-, or -P(=O)G4-;Each G1, G2A, G2B, G3A, G3B, G4is independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, =0, CN, or Ci-4 alkoxy, monocyclic Ck? cycloalkyl optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, Ci .4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, B, P, O, or S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, OH, =0, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo, phenyl optionally substituted with one or more independently selected halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo, and5 or 6 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 halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo.Y is -NR7-;R7is H, Ci-6 alkyl, C3.e cycloalkyl, -C(=O)Ci-6 alkyl, -C(=O)C3.6 cycloalkyl, or -C(=O)Ci-6 alkoxy; and each R9aand R9bis independently selected from H, Ci-6 alkyl, and C3.e cycloalkyl.

[0087] Accordingly, in a second embodiment, the compounds of the invention are provided having aFormula II:wherein Rla, Rlb, R2a, R2b, R4a, R4b, R5, X, Y, Cy, W, L, Zi, Z2, and A are as defined for Formula I.

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

[0089] Accordingly, in a second embodiment, the compounds of the invention are provided having aFormula III:wherein Rla, Rlb, R2a, R2b, R4a, R4b, R5, Y, Cy, W, L, Zi, Z2, and A are as defined for Formula I.

[0090] In one embodiment, the compound of the invention is according to any one of Formula I-III, wherein Y is -NR7-. In a particular embodiment, R7is H, CH,. or cyclopropyl. In a more particular embodiment, R7is H.

[0091] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula IV :wherein Rla, Rlb, R2a, R2b, R4a, R4b, R5, Cy, W, L, Zi, Z2, and A are as defined for Formula I.

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

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

[0094] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula V:wherein Rla, Rlb, R2a, R2b, R5, Cy, W, L, Zi, Z2, and A are as defined for Formula I.

[0095] In one embodiment, the compound of the invention is according to any one of Formula I-V, wherein W is absent or is O, -NHC(=O)-, or -C(=O)NH-. In a particular embodiment, W is O, -NHC(=O)-, or -C(=O)NH-. In a particular embodiment, W is O, - or -C(=O)NH-.

[0096] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula Via or VIb:wherein Rla, Rlb, R2a, R2b, R5, Cy, L, Zi, Z2, and A are as defined for Formula I.

[0097] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein Zi is C, Z2 is N, and A is N.

[0098] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein Zi is C, Z2 is N, and A is CH.

[0099] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein Zi is N, Z2 is C, and A is CH.

[0100] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, 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 ormore 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.

[0101] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula Vic:Vic

[0102] wherein Rla, Rlb, R2a, R2b, R5, Cy, L, Zi, Z2, and A are as defined for Formula I.

[0103] In one embodiment, the compound of the invention is according to Formula Vic, wherein Zi is C, Z2 is N, and A is N.

[0104] In one embodiment, the compound of the invention is according to Formula Vic, wherein Zi is C, Z2 is N, and A is CH.

[0105] In one embodiment, the compound of the invention is according to Formula Vic, wherein Zi is N, Z2 is C, and A is CH.

[0106] In one embodiment, the compound of the invention is according to Formula Vic, wherein Zi is N, Z2 is C, and A is N.

[0107] In one embodiment, the compound of the invention is according to Formula Vic, wherein R5is Ci- 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 heteroatomsindependently 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, R5isS"CF3*^CF3, wherein * represents the attachment point.

[0108] Accordingly, in a further or another embodiment, the compounds of the invention are provided having a Formula Vila, Vllb, Vile, Vlld, Vile or Vllf.Vile VlldVile Vllf wherein Rla, Rlb, R2a, R2b, Cy, and L are as defined for Formula I.

[0109] Accordingly, in a further or another embodiment, the compounds of the invention are provided having a Formula Vllg or Vllh:Vllg Vllh wherein Rla, Rlb, R2a, R2b, Cy, and L are as defined for Formula I.

[0110] Accordingly, in a further or another embodiment, the compounds of the invention are provided having a Formula Villa, Vlllb, VIIIc, Vllld, Ville, Vlllf, Vlllg or Vlllh:Villa VUIbwherein Rla, Rlb, R2a, R2b, Cy, and L are as defined for Formula I.[oni] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Cy is phenyl or naphthyl. In a particular embodiment, Cy is phenyl.

[0112] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Cy is phenyl substituted with one or more independently selected R8. in a particular embodiment, Cy is phenyl substituted with one or two independently selected R8. In a more particular embodiment, Cy is phenyl substituted with one R8.

[0113] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Cy is a 5-6 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, thiadiazolyl, pyridinyl, pyrazinyl, or pyrimidinyl.

[0114] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Cy is a 5-6 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 5-6 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 5-6 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 5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, which heteroaryl is optionally substituted with one R8.

[0115] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Cy is pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, or pyrimidinyl , 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, thiadiazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, 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, thiadiazolyl, pyridinyl, pyrazinyl, or pyrimidinyl , 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, thiadiazolyl, pyridinyl, pyrazinyl, or pyrimidinyl , each of which is optionally substituted with one R8.

[0116] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Cy is phenyl or pyridinyl, each of which is optionally substituted with one or more independently selected R8.

[0117] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Cy is:Wherein * is the attachment to Y, and * * is the attachment to W as defined for Formula I; andEach R8a, R8b, R8c, R8d, and R8e, is independently selected from: halo,- -CN,- G3A, and- -T3-G3B

[0118] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis halo. In a particular embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis F, or Cl.

[0119] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis CN.

[0120] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Awherein G3Ais H.

[0121] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Awherein G3Ais Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, =0, CN, or Ci-4 alkoxy. In a particular embodiment, G3Ais CH ,. CH2CH3, each of which is optionally substituted with one or more independently selected halo, OH, =0, CN, or C1-4 alkoxy. In a more particular embodiment, G3Ais CH3, CH2CH3, each of which is optionally substituted with one or more independently selected F, Cl, OH, =0, CN, or OCH3.

[0122] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Awherein G3Ais monocyclic C3-7 cycloalkyl optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, Ci- 4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G3Ais cyclopropyl, or cyclobutyl, each of which is optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, G3Ais cyclopropyl, or cyclobutyl, each of which is optionally substituted with one or more independently selected F, Cl, OH, NH2, =0, CN, CH3, CH2CH3, CF3, OCH3, OCH2CH3, or OCF3.

[0123] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Awherein G3Ais 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, B, P, O, or S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, OH, =0, CN, C1.4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G3Ais oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, each of which is optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, G3Ais oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, each of which is optionally substituted with one or more independently selected F, Cl, OH, NH2, =0, CN, CH3, CH2CH3, CF3, 0CH3, OCH2CH3, or OCF3.

[0124] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Awherein G3Ais phenyl optionally substituted with one or more independently selected halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G3Ais phenyl optionally substituted with one or more independently selected F, Cl, OH, CN, C H ,. CH2CH3, CF3, OCH3, OCH2CH3, or OCF3.

[0125] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Awherein G3Ais 5 or 6 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 halo, OH, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G3Ais imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, each of which is optionally substituted with one or more independently selected halo, OH, CN, C1.4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G3Ais imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, each of which is optionally substituted with one or more independently selected F, Cl, OH, CN, CH3, CH2CH3, CF3, OCH3, OCH2CH3, or OCF3.

[0126] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3A. in a particular embodiment, -T3-G3B. In a particular embodiment, T3 is -O-, -NH-, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)NHCH3-,-S(=O)2NH-, -S(=O)2-, -P(=O)CH3-, or -S(=O)2NH-. In another particular embodiment, T3 is T3 is -O-, -NH-, -C(=O)-, -C(=O)O-, -C(=O)NH-, -C(=O)NHS(O)2-, - C(=O)NHCH2-, -C(=O)NHCH3-,-S(=O)2NH-, -S(=O)2-, -P(=O)CH3-, or -S(=O)2NH-.

[0127] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Awherein G3Bis H.

[0128] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Awherein G3Bis C1.4 alkyl optionally substituted with one or more independently selected halo, OH, =0, CN, or C1.4 alkoxy. In a particular embodiment, G3Ais CH3, CH2CH3, each of which is optionally substituted with one or more independently selected halo, OH, =0, CN, or C1-4 alkoxy. In a more particular embodiment, G3Ais CH3, CH2CH3, each of which is optionally substituted with one or more independently selected F, Cl, OH, =0, CN, or OCH3.

[0129] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Awherein G3Bis monocyclic C3-7 cycloalkyl optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, Cn 4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G3Ais cyclopropyl, or cyclobutyl, each of which is optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, G3Ais cyclopropyl, or cyclobutyl, each of which is optionallysubstituted with one or more independently selected F, Cl, OH, NH2, =0, CN, CH3, CH2CH3, CF3, OCH3, OCH2CH3, or OCF3.

[0130] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Awherein G3Bis 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, B, P, O, or S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, OH, =0, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G3Ais oxetanyl, furanyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, Ci- 4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, G3Ais oxetanyl, furanyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is optionally substituted with one or more independently selected F, Cl, OH, NH2, =0, CN, CH3, CH2CH3, CF3, 0CH3, OCH2CH3, or 0CF3.

[0131] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Bwherein G3Bis phenyl optionally substituted with one or more independently selected halo, OH, CN, C1.4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G3Bis phenyl optionally substituted with one or more independently selected F, Cl, OH, CN, CH3, CH2CH3, CF3, OCH3, OCH2CH3, or OCF3.

[0132] In one embodiment, one or more independently selected R8a, R8b, R8c, R8d, and R8eis G3Bwherein G3Bis 5 or 6 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 halo, OH, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G3Bis imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, each of which is optionally substituted with one or more independently selected halo, OH, CN, C1.4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G3Bis imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, each of which is optionally substituted with one or more independently selected F, Cl, OH, CN, CH3, CH2CH3, CF3, OCH3, OCH2CH3, or OCF3.

[0133] In one embodiment, each R8a, R8b, R8c, R8d, and R8eis independently selected from H, F, Cl, CN, - CH3, -0CH3, -CF3, -C(=0)NH2, -C(=O)NHCH3, -C(=O)NHCH2CF3, -C(=O)OH, -C(=O)OCH3, o C(=O)NHoxetanyl,,-C(=O)morpholinyl, -S(=O)2NH2, -S(=O)2CH3, -S(=O)CH3, -P(=O)(CH3)2, -S(=O)(=NH)CH3, and - S(=O)2CH3.

[0134] In one embodiment, each R8a, R8b, R8c, R8d, and R8eis independently selected from H, F, Cl, CN, - CH3, -OCHs, -CFs, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHCH2CF3, -C(=O)OH, -C(=O)OCH3, C(=O)NHoxetanyl, -C(=O)morpholinyl, -C(=O)NHS(O)2CH3, -S(=O)2NH2, -S(=O)2CH3, -S(=O)CH3, - P(=O)(CH3)2, -S(=O)(=NH)CH3, and - S(=O)2CH3.In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Cy is:wherein * is attached to Y, and ** attached to L in Formula I.

[0135] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Cy is:

[0136] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Cy is:wherein * is atached to Y, and ** atached to L in Formula I.

[0137] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, 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 Ci-4 alkyl, Ci-4 alkoxyl, -OH, or =0.

[0138] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, 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 Ci-4 alkyl, Ci-4 alkoxyl, -OH, or =0.

[0139] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein L iswherein # is atached to W and ## is atached to -CR2aR2b- of Formula I.

[0140] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Rlais H.

[0141] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Rlbis H.

[0142] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Rlais Ci-6 alkyl, optionally substituted with one or more independently selected R6and R6is as described for Formula I. In a particular embodiment, Rlais -CHs, -CH2CH3, -CH2CH2CH3, each of which is optionally substituted with one or more independently selected R6. In a more particular embodiment, R6is halo, -NH2, -N(CHs)2. In a more particular embodiment Rlais -CH2-NH2, -CH2- N(CH3)2, -CH2CH2-NH2, or -CH2CH2-N(CH3)2.

[0143] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Rlais C1-6 alkyl, optionally substituted with one or more independently selected R6and R6is apreviously described. In a particular embodiment, Rlais -CH,. -CH2CH3, -CH2CH2CH3, each of which is optionally substituted with one or more independently selected R6. In a more particular embodiment, R6is halo, -NH2, -N(CHs)2. In a more particular embodiment Rlais -CH2-NH2, -CH2-N(CH3)2, - CH2CH2-NH2, or -CH2CH2-N(CH3)2.

[0144] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein R2ais H.

[0145] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein R2bis H.

[0146] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein R2ais C1-6 alkyl, optionally substituted with one or more independently selected R6and R6is a previously described. In a particular embodiment, R2ais -CH3, -CH2CH3, -CH2CH2CH3, each of which is optionally substituted with one or more independently selected R6. In a more particular embodiment, R6is halo, -NH2, -N(CHs)2. In a more particular embodiment R2ais -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-VIIIf, wherein R2bis C1-6 alkyl, optionally substituted with one or more independently selected R6and R6is a previously described. In a particular embodiment, R2ais -CH3, -CH2CH3, -CH2CH2CH3, each of which is optionally substituted with one or more independently selected R6. In a more particular embodiment, R6is halo, -NH2, -N(CHs)2. In a more particular embodiment R2ais -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-VIIIf, wherein R2aand R2btogether is =0.

[0149] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein R2aand R2btogether is =0.

[0150] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Rlaand 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 R6. In a particular embodiment, Rlaand R2a, together with the atoms to which they are attached together may form cyclopentyl or cyclohexyl, each of which is optionally substituted with one or more independently selected R6.

[0151] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, wherein Rlaand 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 R6. In a particular embodiment, Rlaand R2a, together with the atoms to which they are attached together may form pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, each of which is optionally substituted with one or more independently selected R6.

[0152] In one embodiment, one or more independently selected R6is halo. In a particular embodiment, one or more independently selected R6is F or Cl.

[0153] In one embodiment, one or more independently selected R6is CN.

[0154] In one embodiment, one or more independently selected R6is oxo.

[0155] In one embodiment, one or more independently selected R6is G2A, wherein G2Ais C1.4 alkyl optionally substituted with one or more independently selected halo, OH, =0, CN, or C1-4 alkoxy. In a particular embodiment, G2Ais -CH3, -CH2CH3, or -CF3.

[0156] In one embodiment, one or more independently selected R6is G2A, wherein G2Ais monocyclic C3- 7 cycloalkyl optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, C1.4 alkyl optionally substituted with one or more independently selected halo, C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G2Ais cyclopropyl, or cyclobutyl, optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, C1.4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo.

[0157] In one embodiment, one or more independently selected R6is G2A, wherein G2Ais 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, B, P, O, or S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, OH, =0, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo . In a particular embodiment, G2Ais pyrrolidinyl, tetrahydrofuranyl, piperazinyl; piperidinyl, morpholinyl, thiomorpholinyl, each of which is optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo.

[0158] In one embodiment, one or more independently selected R6is G2A, wherein G2Ais 5 or 6 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 halo, OH, CN, C1-4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G2Ais pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with one or more independently selected halo, OH, CN, C1.4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo.

[0159] In one embodiment, one or more independently selected R6is -T2-G2B, wherein T2 is -O-, -NH-, - NCH3-, -S(=O)2-, -C(=O)-, -C(=O)O-, or -C(=0)NH-.

[0160] In one embodiment, one or more independently selected R6is -T2-G2B, wherein G2Bis monocyclic C3-7 cycloalkyl optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, C1.4 alkyl optionally substituted with one or more independently selected halo, C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G2Biscyclopropyl, or cyclobutyl, optionally substituted with one or more independently selected halo, OH, NH2, =0, CN,Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo.

[0161] In one embodiment, one or more independently selected R6is -T2-G2B, wherein G2Bis 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, B, P, O, or S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, OH, =0, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G2Bis pyrrolidinyl, tetrahydrofuranyl, piperazinyl; piperidinyl, morpholinyl, thiomorpholinyl, each of which is optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci- 4 alkoxy optionally substituted with one or more independently selected halo.

[0162] In one embodiment, one or more independently selected R6is -T2-G2B, wherein G2Bis 5 or 6 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 halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, G2Bis pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with one or more independently selected halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo.

[0163] In one embodiment, each R6is independently selected from =0, halo, C 1.4 alkyl optionally substituted with one or more independently selected halo, -NH2, -NHRl lh, and -NRllhRlh. In a more particular embodiment, each R6is independently selected from is =0, -CH3, F, Cl, -NH2, and -N(CH3)2.

[0164] In one embodiment, the compound of the invention is according to any one of Formula I-VIIIf, p2a tR2bR1bwherein * R1ais selected from:Wherein Rlband R2bis as described for Formula I.

[0165] In a particular embodiment, Rlband R2bare both H.

[0166] Accordingly, in another aspect of the invention, the compounds of the invention are provided having a Formula (la) wherein a compound, or a pharmaceutically acceptable salt, solvate, salt of a solvate thereof, according to Formula I:whereinXi is CR3a- or N, X2 is CR3bor N, and X3 is CR3cor N;Each Zi and Z2 is independently selected from C and N;A is selected from N, or CR11;W is absent or is O, -NR10C(=O)-, or -C(=O)NR10-, -S(=O)2NR10C(=O) or -C(=O)NR10S(=O)2-;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;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 =0;Each Rla, Rlb, R2a, and R2bis independently selected from:- H,- halo,- CN,- =0 (Rlatogether with Rlb, and / or R2atogether with R2b),- -Ti-G1,- Ci-6 alkyl, optionally substituted with one or more independently selected R6,- Ci-6 alkoxy, optionally substituted with one or more independently selected R6,- Cs 7 cycloalkyl, optionally substituted with one or more independently selected R6,- C5-12 membered fused, spiro or bridged polycyclic cycloalkyl, optionally substituted with one or more independently selected R6,- 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 R6, 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 R6; orRlaand 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 R6,- 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 R6, 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 R6;Each R3a, R3b, R3cis independently selected from:- H- halo,- -OH,- -CN,- -NR9aR9b,- C1-4 alkyl optionally substituted with one or more independently selected halo,- C1-4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and- 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;Each R4aand R4bis independently selected from H, or Ci-4 alkyl optionally substituted with one or more independently selected halo;X is absent, -CH2-, -O-, or -NH-;Each R6is independently selected from: halo,- CN, oxo,- G2A,- -T2-G2B,Cy is a phenyl or naphthyl, each of which is optionally substituted with one or more independently selected R8,5-6 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, or8-10 membered bicyclic 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,- G3A,- -T3-G3B,Each Ti, T2and T3is independently -CH2-, -CH2CH2-, -CH=CH-, -C=C-, -NG4-, -CH2NG4-, -O-, -S-, - S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -CH2C(=O)O-, -C(=O)OCH2-, -C(=O)NG4-, -C(=O)NS(O)2G4-, - CH2C(=O)NG4-, -C(=O)NG4CH2-, -OC(=O)NG4-, -S(=O)2NG4-, -S(=O)2NG4CH2-, -OC(=O)-, -CH2NG4C(=O)-, -NG4C(=O)-, -NG4C(=O)CH2-, -NG4S(=O)2-,-S(=O)=NG4-, or -P(=O)G4-;Each G1, G2A, G2BG3A, G3B, G4is independently selected from:- H,C1-4 alkyl optionally substituted with one or more independently selected halo, OH, =0, CN, or Ci- 4 alkoxy, monocyclic Ck? cycloalkyl optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, Ci -4 alkyl optionally substituted with one or more independently selected halo, C1-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, B, P, O, or S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, OH, =0, CN, C1-4 alkyl optionally substituted with one or moreindependently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo, phenyl optionally substituted with one or more independently selected halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo, and5 or 6 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 halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo.Y is O or -NR7-;R7is H, Ci-6 alkyl, C3-6 cycloalkyl, -C(=O)Ci-6 alkyl, -C(=O)C3-e cycloalkyl, or -C(=O)Ci-6 alkoxy; and each R9aand R9bis independently selected from H, C1-6 alkyl, and C3-6 cycloalkylEach R10is independently selected from:- H- C1.4 alkyl optionally substituted with one or more independently selected halo, OH, CN- C1.4 alkoxy optionally substituted with one or more independently selected halo, OH, CN- C3-7 cycloalkyl optionally substituted with one or more independently selected halo, OH, CN 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 OH, CN.R11is independently selected from:- H- halo,- -OH,- -CN,- -NR12aR12b,- C1.4 alkyl optionally substituted with one or more independently selected halo,- C1.4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and- 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;- each R12aand R12bis independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl

[0167] Wherein in an alternative embodiment of the invention W is -NR10C(=O)-, or -C(=O)NR10-, - S(=O)2NR10C(=O) or -C(=O)NR10S(=O)2-; In an further embodiment of the invention W is - NR10C(=O)-. In another alternative embodiment of the invention -C(=O)NR10-. In another alternativeembodiment of the invention W is -S(=O)2NR10C(=O). In an alternative embodiment of the invention W is -C(=O)NR10S(=O)2-.

[0168] In an alternative embodiment of the invention W is -C(=O)NH-.

[0169] In an alternative embodiment of the invention W is -C(=O)N(C 1-4 alkyl) In another alternative embodiment W is -C(=O)N(CI-4 alkyl) - wherein C1-4 alkyl is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0170] In an alternative embodiment of the invention W is -C(=O)N(CI-4 alkoxy) In another alternative embodiment W is -C(=O)N(CI-4 alkoxy) - wherein C1-4 alkoxy is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0171] In an alternative embodiment of the invention W is -C(=O)N(C3-7cycloalkyl) In another alternative embodiment W is -C(=O)N(C3-7cycloalkyl) - wherein C3-7cycloalkyl is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0172] In an alternative embodiment of the invention W is -C(=O)N(4-8 membered monocyclic heterocycloalkyl) -.Wherein the 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. Wherein halo is selected from F, Cl, Br or I.

[0173] In an alternative embodiment of the invention W is -HNC(=O)-.

[0174] In an alternative embodiment of the invention W is -(Ci-4 alkyl)NC(=O) -. In another alternative embodiment W is -N(CI-4 alkyl)C(=O) - wherein C1.4 alkyl is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0175] In an alternative embodiment of the invention W is -N(CI-4 alkoxy)C(=O) -. In another alternative embodiment W is -N(CI-4 alkoxy)C(=O)- wherein C1.4 alkoxy is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0176] In an alternative embodiment of the invention W is -(C3-7 cycloalkyl)NC(=O) -. In another alternative embodiment W is -N(Cs-7 cycloalkyl)C(=O) - wherein C3-7 cycloalkyl is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0177] In an alternative embodiment of the invention W is -N(4-8 membered monocyclic heterocycloalkyl)C(=O)N -. Wherein the 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. Wherein halo is selected from F, Cl, Br or I.

[0178] In an alternative embodiment of the invention W is -S(=O)2NHC(=O)

[0179] In an alternative embodiment of the invention W is - S(=O)2N(CI-4 alkyl)C(=O). In another alternative embodiment W is -S(=O)2N(Ci-4alkyl)C(=O) - wherein C1.4 alkyl is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0180] In an alternative embodiment of the invention W is -S(=O)2N(CI-4 alkoxy)C(=O)-. In another alternative embodiment W is -S(=O)2N(Ci-4alkoxy)C(=O)- wherein Ci-4 alkoxy is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0181] In an alternative embodiment of the invention W is -S(=O)2N(C3-7 cycloalkyl)C(=O)-. In another alternative embodiment W is -S(=O)2N(C3-7 cycloalkyl)C(=O) - wherein C3-7 cycloalkyl is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0182] In an alternative embodiment of the invention W is -S(=O)2N(4-8 membered monocyclic heterocycloalkyl)C(=O)-. Wherein the 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. Wherein halo is selected from F, Cl, Br or I.

[0183] In an alternative embodiment of the invention W is -C(=O)NHS(=O)2-;

[0184] In an alternative embodiment of the invention W is -C(=O)N(Ci-4 alkyl)S(=O)2-; In another alternative embodiment W is -C(=O)N(Ci-4 alkyl)S(=O)2— wherein C1-4 alkyl is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0185] In an alternative embodiment of the invention W is -C(=O)N(Ci-4 alkoxy)S(=O)2-. In another alternative embodiment W is -C(=O)N(Ci-4alkoxy)S(=O)2- wherein C1-4 alkoxy is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0186] In an alternative embodiment of the invention W is -C(=O)N(C3-7 cycloalkyl)S(=O)2-; In another alternative embodiment W is -C(=O)N(C3-7cycloalkyl)S(=O)2— wherein C3-7 cycloalkyl is substituted with one or more independently selected halo, OH, CN. Wherein halo is selected from F, Cl, Br or I.

[0187] In an alternative embodiment of the invention W is -C(=O)(4-8 membered monocyclic heterocycloalkyl)NS(=O)2-. Wherein the 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. Wherein halo is selected from F, Cl, Br or I.

[0188] In a further embodiment A is CR11. In an even further embodiment A is CH.

[0189] In an even further embodiment A is CR11and Rn-halo. In an even further embodiment R11is F, I, Cl or Br.

[0190] In an even further embodiment R11is OH.

[0191] In a further embodiment R11is CN.

[0192] In an alternative embodiment R11is NR12aR12b. In an even further alternative embodiment R11is - NH2. In an alternative embodiment R11is -NHCi-ealkyl. In a further embodiment R11is -N(Ci-6alkyl)2. In a further embodiment R11is -NHC3-6 cycloalkyl. In a further embodiment R11is -N(Ci-6cycloalky)2

[0193] In an alternative embodiment of the invention R11is -C1-4 alkyl optionally substituted with one or more independently selected halo.

[0194] In an even further embodiment of the invention R11is -C1.4 alkoxy optionally substituted with one or more independently selected halo,

[0195] In an even further embodiment R11is -C3-7 cycloalkyl optionally substituted with one or more independently selected halo.

[0196] In an alternative embodiment of the invention R11is 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;

[0197] Accordingly, in an embodiment, the compounds of the invention are provided having a Formula IVa:IVawherein Rla, Rlb, R2a, R2b, R4a, R4b, R5, Cy, W, L, Zi, Z2, and A are as defined for Formula Ia.

[0198] The features, embodiments and / or combinations disclosed with respect to the preceding aspect are also applicable to the present aspect.

[0199] In one embodiment, a compound of the invention is selected from the illustrative compounds of Table IV.

[0200] In one embodiment, a compound of the invention is provided in a natural isotopic form.

[0201] 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 (z. 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.

[0202] 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.

[0203] 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.

[0204] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0205] 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.

[0206] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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, A-alkylmorpholine esters and the like.

[0212] 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 Ci to Cs alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.PHARMACEUTICAL COMPOSITIONS

[0213] 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 inthe 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.

[0214] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent.

[0215] 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.

[0216] 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, 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, Waldenstrom 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 malignantpotential 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, Sezary 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.

[0217] 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 blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0218] 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.

[0219] 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.

[0220] 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 asstarch or lactose, a disintegrating agent such as alginic acid, Primogel, or com 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.

[0221] 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.

[0222] 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 additional ingredients 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.

[0223] 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.

[0224] 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.

[0225] 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).

[0226] 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

[0227] 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

[0228] 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 fdled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).Formulation 3 - Liquid

[0229] 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

[0230] 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

[0231] 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

[0232] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75 °C 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

[0233] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine .

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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, Waldenstrom 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 malignantpotential 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, Sezary 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.

[0238] 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, Waldenstrom 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 malignantpotential 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, Sezary 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.

[0239] 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, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukaemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma ofbone, 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, Sezary 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.

[0240] 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).

[0241] 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).

[0242] 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).

[0243] 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.

[0244] Lor 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 patientconvenience 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.

[0245] 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.

[0246] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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 singlepharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.CHEMICAL SYNTHETIC PROCEDURESGeneral

[0252] 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.

[0253] 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).

[0254] 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.

[0255] 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 pm) 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. ’H 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 (5) for ’H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (5 0.00) or the appropriate residual solvent peak, e.g. CHCL (5 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 methodsTable I. Description of LC-MS methodThe analysis below is performed on a Shimadzu LCMS-2020GAL-378-EP-EPA 56GAL-378-EP-EPA 57GAL-378-EP-EPA 58GAL-378-EP-EPA 59Additional method name:

[0256] Method 25a

[0257] Apparatus: Waters ACQUITY UPLC I-Class PLUS System with Waters SQ Detector 2

[0258] Column: Acquitv UPLC BEH C 18 1.7 pm (2.1 x 100 mm), column no. 186002352, internal column no. Pur CC - WatOOl

[0259] Reagents:- - Formic acid 98-100% for analysis EMSURE® ACS,Reag. Ph Eur, Merck- - Acetonitrile gradient grade for liquid chromatography LiChrosolv® Reag. Ph Eur., Merck - - pQ-water for LCMS.GAL-378-EP-EPA 60

[0260] UPLC conditions:- - Wavelength range: 200 - 400 nm- - Flow: 0.5 ml / min- - Column temperature: 40 °C - - Autosampler temperature: room temperature- - Analysis time: 3.0 min- - Elution: gradient

[0261] For compound 1 and 2 alternative route:

[0262] Preparative HPLC is performed on a Waters AutoPurification System with UV and MS detection using Gemini NX-C18, 00G-4454-P0-AX, 250x21.2 mm, 5pm / 110A Phenomenex column and ACN / H2O gradients with acidic (0,1% FA in both mobile phases).Table IE List of abbreviations used in the experimental section:GAL-378-EP-EPA 61SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION Example 1. Overview for the preparation of illustrative compounds of the invention1.1. Scheme 1:GAL-378-EP-EPA 621.2. Scheme 2:PG= protecting groupExample 2. Methods for the preparation of intermediates of illustrative compounds of the invention2.1. Intermediates Int-1: 3-(2,2-dimethyl-3,3-diphenyl-4, 7,10-trioxa-3-siladodecan-12-yl)-l- methylpiperidin-4-onelnt-12.1.1. Step 1: 4-(2,2-dimethylhydrazineylidene)-l-methylpiperidine

[0263] To a solution of l-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).

[0264] LCMS(ESI-MS) m / z = 156.0 [M+H]+

[0265] Rt 0.355 min; Method 22GAL-378-EP-EPA 632.1.2. Step 2: 12-bromo-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecane

[0266] 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, fdtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (8% - 10%) to afford the title compound (18.3 g, 69%).

[0267] LCMS(ESI-MS) m / z = 473.0, 475.0 [M+Na]+

[0268] Rt 1.175 min; Method 1

[0269] 1H NMR (400 MHz, DMSO) 5 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).2.1.3. Step 3: 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-l- methylpiperidin-4-one

[0270] To a stirred mixture of 4-(2,2-dimethylhydrazineylidene)-l -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, fdtered 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 NaHCOs 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, fdtered 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; Wavelength: 220 nm; 5% - 6% B fractions were collected to afford the title compound (5.2 g, 43%).

[0271] LCMS(ESI-MS) m / z = 484.4 [M+H]+

[0272] Rt: 1.071 min; Method 20GAL-378-EP-EPA 642.2. Intermediates Int-2: 3-(2,2-dimethyl-3,3-diphenyl-4, 7,10-trioxa-3-siladodecan-12-yl)-l- methylpiperidin-4-amine

[0273] To a stirred mixture of Int-8 (20.0 g, 4E3 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 NaBHsCN (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, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase (Column:C18 column, 350 g, Mobile Phase A: Water(0.05% PA), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 0% B to 50% B in 40 min; Wavelength: 220 nm; 35% - 40% B fractions were collected) to provide the title compound (10.0 g , 44.0% yield).

[0274] LCMS(ESI-MS) m / z = 485.3 [M+H]+

[0275] Rt: 0.542 min; Method 22.3. Intermediates Int-3: 8-bromo-2-iodo-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridine2.3.1. Step 1: ethyl 8-bromo-3-thiocyanatoimidazo[l,2-a]pyridine-2-carboxylate

[0276] To a stirred mixture of ethyl 8-bromoimidazo[l,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 room temperature 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% NH4CI (50 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure to afford crude product. The residue was triturated with MTBE (100 mL) at 25 °C for 1 h and filtered to provide title compound (4.3 g, 79% yield).

[0277] LCMS(ESI-MS) m / z = 327.9 [M+H]+

[0278] Rt: 0.599 min; Method 25GAL-378-EP-EPA 652.3.2. Step 2: ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridine-2-carboxylate

[0279] To a stirred mixture of ethyl 8-bromo-3-thiocyanatoimidazo[l,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 Na2SC>4 and fdtered. The crude product was dissolved by DCM (700 mL) and fdtered through silica gel. The filtrate was concentrated in vacuo to provide the title compound (13 g, 43% yield).

[0280] LCMS(ESI-MS) m / z = 369.0 [M+H]+

[0281] Rt: 0.794 min; Method 62.3.3. Step 3: 8-bromo-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridine-2-carboxylic acid

[0282] To a stirred mixture of ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[l,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 room temperature. The mixture was adjusted to pH = 3 with hydrochloric acid (2 M) and filtered. Then the filter cake was washed with MeOH (100 mL) to provide the crude title compound (10 g, 74%). The crude product was used for next step directly.

[0283] LCMS(ESI-MS) m / z = 342.9 [M+H]+

[0284] Rt: 0.512 min; Method 182.3.4. Step 4: Int-3: 8-bromo-2-iodo-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridine

[0285] To a stirred mixture of 8-bromo-3-((trifhioromethyl)thio)imidazo[l,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 room temperature and filtered. The filter cake was collected and re- dissolve with EtOAc (200 mL). The organic layer was washed with saturated NaHCO; (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%).

[0286] LCMS(ESI-MS) m / z = 422.9 [M+H]+Rt: 0.833 min; Method 62.4. Int-4: 12-iodo-2,2-dimethyl-3,3-diphenyl-4, 7,10-trioxa-3-siladodecane step 1 step 2HO^°^O^OH- " HO^°^O~OTBDPS- ►| / ^O^O^OTBDPS int-4GAL-378-EP-EPA 662.4.1. Step 1: 2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-ol

[0287] To a solution of triethylene glycol (500 mL, 7.1 equiv) and py (74.8 g, 945 mmol, 2.0 equiv) was added TBDPSC1 (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 HC1 (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; Plow 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 title product 2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecan-12-ol (150 g, 73% yield). LCMS(ESI-MS) m / z = 411.0 [M+Na]+. Rt: 0.822 min (Method 2).2.4.2. Step 2: 12-iodo-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecane

[0288] 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 NaHSOs (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 title product 12-iodo- 2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecane (150 g, 70% yield) . LCMS(ESI-MS) m / z = 521.0 [M+Na]+. Rt: 0.939 min (Method 2).GAL-378-EP-EPA 672.5. Int-5: (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4, 7,10-trioxa-3-siladodecan-12-yl)-l- methylpiperidin-4-amine2.5.1. Step 1: (lR)-N-(l-methylpiperidin-4-ylidene)-l-phenylethanamine

[0289] A solution of l-methylpiperidin-4-one (20.0 g, 177 mmol, 1.0 equiv) and D-a-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)-l-phenylethanamine (40 g, crude) .2.5.2. Step 2: (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-l- methyl-N-( (R)-l -ph enylethy piperidin -4-amin e

[0290] To a solution of (lR)-N-(l-methylpiperidin-4-ylidene)-l-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 (title 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 title product (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-GAL-378-EP-EPA 6812-yl)-l-methyl-N-((R)-l-phenylethyl)piperidin-4-amine (3.5 g, 16% yield) . LCMS(ESI-MS) m / z = 589.4 [M+H]+. Rt: 0.687 min (Method 2).2.5.3. Step 3: (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-l- methylpiperidin-4-amine

[0291] To a solution of 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-l-methyl-N- [(lR)-l-phenylethyl]piperidin-4-amine (10.0 g, 17.0 mmol, 1.0 equiv) and HO Ac (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 fdtered 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 title product (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- siladodecan-12-yl)-l-methylpiperidin-4-amine (3.0 g, 32% yield) . LCMS(ESI-MS) m / z = 485.3 [M+H]+. Rt: 0.605 min (Method 2).2.6. Intermediates Int-6: tert-butyl 4-amino-3-(2,2-dimethyl-3,3-diphenyl-4, 7, 10-trioxa-3- siladodecan-12-yl)piperidin e-1 -carboxylate2.6.1. Step 1: tert-butyl 4-(2,2-dimethylhydrazin-l-ylidene)piperidine-l-carboxylate

[0292] To a solution of tert-butyl 4-oxopiperidine-l -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 fdtration. The heptane fdtrate was concentrated under reduced pressure to afford the crude title compound (6.00 g, 89%) , used in the next steps without further purification.

[0293] LCMS(ESI-MS) m / z = 242.2 [M+H]+

[0294] Rt 0.228 min; Method 1

[0295] 1H NMR (400 MHz, DMSO) 5 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).GAL-378-EP-EPA 692.6.2. Step 2: tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-4- oxopiperidin e-1 -carboxylate

[0296] To a solution of tert-butyl 4-(2,2-dimethylhydrazin-l-ylidene)piperidine-l -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, fdtered 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, fdtered 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%) .

[0297] LCMS(ESI-MS) m / z = 592.4 [M+H]+

[0298] Rt 0.915 min; Method 22.6.3. Step 3:tert-butyl 4-amino-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12- yl)piperidin e-1 -carboxylate

[0299] To a solution of tcrt-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-tnoxa-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%) .

[0300] LCMS(ESI-MS) m / z = 571.4 [M+H]+

[0301] Rt 0.703 min; Method 22.6.4. Step 4: int-6: rac-tert-butyl (3S,4S)-4-amino-3-(2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecan-12-yl)piperidine-l-carboxylate

[0302] Tert-butyl 4-amino-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-l- carboxylate (10.0 g, 17.5 mmol, 1.0 equiv) was separated by prep-Achiral SFC (Column: GreenSepGAL-378-EP-EPA 70Basic 3* 15 cm, 5 gm; Mobile Phase A: CO2, Mobile Phase B: MeOH(l%-2M-NH3-MeOH); Flow rate: 70 mL / min; Gradient (B%): isocratic 20% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 9.95; RT2(min): 11.85; Sample Solvent: MeOH+DCM; Injection Volume: 1.5 mb). Purification resulted in isomer 1 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 (3.5 g, 33 %y ield) (RT=9.95 min) . LCMS (ESI-MS) m / z = 571.3 [M+H]+. Rt: 0.720 min (Method 2). And isomer 2 rac- tert-butyl (3S,4R)-4-amino-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12- yl)piperidine-l -carboxylate (5.1 g, 48%yield) (RT=11.85 min) . LCMS (ESI-MS) m / z = 571.3 [M+H]+. Rt: 0.705 min (Method 2).2. 7. Int-7: methyl 4-methoxy-3-(prop-2-yn-l-ylamino)benzoate

[0303] To a solution of methyl 3-amino-4-methoxybenzoate (5.00 g, 27.6 mmol, 1.00 equiv) in DMF (50 mL) was added propargyl bromide (4.92 g, 41.4 mmol, 1.50 equiv) and K2CO3 (11.4 g, 82.8 mmol, 3.00 equiv) stirred at room temperature. The reaction mixture was stirred overnight at 70 °C and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL) and the organic layers were combined, washed with brine (3 xl50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column (Column: 350 g, 20-35 pm, Mobile Phase A: water (0.05% TFA), Mobile Phase B: CH3CN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; Wave Length: 220 / 254 nm; 45% B fractions were collected), the fraction was concentrated under reduced pressure to provide the title product methyl 4-methoxy-3-(prop-2-yn-l-ylamino)benzoate (4.6 g, 69% yield). LCMS(ESI- MS) m / z = 220.2 [M+H]+. Rt: 0.763 min (Method 6).2.8. Int-8: methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-l-yl)amino]-3-methoxybenzoate2.8.1. Step 1: methyl 4-[(tert-butoxycarbonyl)amino]-3-methoxybenzoate

[0304] To a methyl 4-amino-3 -methoxybenzoate (25.0 g, 138 mmol, 1.0 equiv) was added (Boc^O (250 mL) stirred at room temperature. The reaction mixture was stirred overnight at 110 °C and quenched with water (300 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were combined, washed with brine (4 x 500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The residue was purified by triturationGAL-378-EP-EPA 71 with PE (500 mL) and filtered. The filter cake was washed with PE (100 mL x 2) to provide the title product methyl 4-[(tert-butoxycarbonyl)amino]-3-methoxybenzoate (35 g, 81% yield,). LCMS(ESI- MS) m / z = 223.0 [M-Boc+ACN]+. Rt: 0.948 min (Method 5).2.8.2. Step 2: methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-l-yl)amino]-3-methoxybenzoate

[0305] To a solution of methyl 4-[(tert-butoxycarbonyl)amino]-3-methoxybenzoate (15.0 g, 53.3 mmol, 1.0 equiv) in DMF (150 mL) was added propargyl bromide (19.0 g, 1660 mmol, 3.0 equiv) and CS2CO3 (43.4 g, 133.3 mmol, 2.5 equiv) stirred at room temperature. The reaction mixture was stirred for 4 h at room temperature. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (3 x 300 mL). The filtrate was quenched with water (250 mL), 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: PE, Mobile Phase B: EA; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; Wave Length: 220 nm; 19% - 21% B fractions were collected) to provide the title product methyl 4-[(tert- butoxycarbonyl)(prop-2-yn-l-yl)amino] -3 -methoxybenzoate (15 g, 79%yield). LCMS(ESI-MS) m / z = 220.0 [M-Boc+H]+. Rt: 0.897 min (Method 5).2.9. Int-9: tert-butyl (3-bromo-5-hydroxyphenyl)(prop-2-yn-l-yl)carbamate2.9.1. Step 1: 3-bromo-5-methoxy-N-[3-(trimethylsilyl)prop-2-yn-l-yl]aniline

[0306] To a solution of 3 -bromo-5 -methoxyaniline (20.0 g, 99.0 mmol, 1.0 equiv) in DCM (300 mL) was added 3-(trimethylsilyl)prop-2-ynal (12.5 g, 99.0 mmol, 1.0 equiv), acetic acid (30 mL) and 4A molecular sieve (10.0 g) at -10 °C. The mixture was stirred for 1 h at -10 °C. Then sodium triacetoxyborohydride (83.9 g, 396 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 2 h at 0 °C and quenched with water (1000 mL). The resulting mixture was extracted with dichloromethane (3 x 1000 mL) and the organic layers were combined, washed with brine (2 x 1000 mL), dried over anhydrous sodium sulfate, fdtered 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 30% B in 40 min; Wave Length: 220nm nm; Collected fractions: 13% - 18% B), the fraction was concentrated under reduced pressure to provide the title product 3-bromo-5-GAL-378-EP-EPA 72 methoxy-N-[3-(trimethylsilyl)prop-2-yn-l-yl]aniline (26.2 g, 72% yield). LCMS (ESI-MS) m / z = 312.1 [M+H]+. Rt: 1.111 min (Method 7).2.9.2. Step 2: 3-bromo-5-(prop-2-yn -1 -y lamin o)ph en ol

[0307] To a solution of 3-bromo-5-methoxy-N-[3-(trimethylsilyl)prop-2-yn-l-yl]aniline (20.0 g x 3, 192 mmol, 1.0 equiv) in DCM (200 mL x 3) was added Boron tribromide (192 mL x 3, IM solution in methylene chloride) slowly at 0 °C. The reaction mixture was stirred overnight at room temperature and quenched with saturated aqueous sodium bicarbonate (2000 mL). The resulting mixture was extracted with dichloromethane (3 x 2000 mL) and the organic layers were combined, washed with brine (2 x 2000 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g x 4, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Plow rate: 80 mL / min; Gradient: 0% B to 50% B in 40 min; Wave Length: 254 nm; Collected fractions: 30% - 35% B), the fraction was concentrated under reduced pressure to provide the title product 3- bromo-5 -(prop-2 -yn-l-ylamino)phenol (25.0 g, 57% yield) . LCMS(ESI-MS) m / z = 226.0 [M+H]+. Rt: 0.669 min (Method 6).2.9.3. Step 3: 3-bromo-N-(prop-2-yn-l-yl)-5-[(triisopropylsilyl)oxy]aniline

[0308] To a solution of 3 -bromo-5 -(prop-2 -yn-l-ylamino)phenol (25.0 g, 111 mmol, 1.0 equiv) in DMF (300 mL) was added IH-imidazole (37.6 g, 553 mmol, 5.0 equiv) and chlorotris(propan-2-yl)silane (64.0 g, 332 mmol, 3.0 equiv). The reaction mixture was stirred for 2 h at room temperature and quenched with water (300 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were combined, washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford the crude product. The crude product was chromatographed on a silica gel column (Column: 330 g x 4, 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: 7% - 13% B), the fraction was concentrated under reduced pressure to provide the title product 3-bromo-N-(prop-2-yn-l-yl)-5-[(triisopropylsilyl)oxy]aniline (61.0 g, crude) . LCMS(ESI-MS) m / z = 382.1 [M+H]+. Rt: 1.220 min (Method 6).2.9.4. Step 4: tert-butyl (3-bromo-5-((tert-butoxycarbonyl)oxy)phenyl)(prop-2-yn-l- ytcarbamate

[0309] To a solution of 3-bromo-5-[(triisopropylsilyl)oxy]-N-[3-(trimethylsilyl)prop-2-yn-l-yl]aniline (10.0 g x 6, 132 mmol, 1.0 equiv) was added di -tert-butyl dicarbonate (7.5 mL x 6). The reaction mixture was stirred overnight at 90 °C and quenched with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 700 mL) and the organic layers were combined, washed with brine (2 x 700 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g x 4,GAL-378-EP-EPA 73100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 80 mL / min; Gradient: 0% B to 30% B in 30 min; Wave Length: 254 nm; Collected fractions: 12% - 16% B), the fraction was concentrated under reduced pressure to provide the title product tert-butyl (3- bromo-5-((tert-butoxycarbonyl)oxy)phenyl)(prop-2-yn-l-yl)carbamate (44.0 g, crude) . LCMS(ESI- MS) m / z = 426.1 [M+H]+. Rt: 1.088 min (Method 2).2.9.5. Step 5: tert-butyl (3-bromo-5-hydroxyphenyl)(prop-2-yn-l-yl)carbamate

[0310] To a solution of 3-bromo-5-[(tert-butoxycarbonyl)(prop-2-yn-l-yl)amino]phenyl tert-butyl carbonate (10.0 g x 4, 93.8 mmol, 1.0 equiv) in MeOH (100 mL x 4) was added potassium carbonate (6.5 g x 4, 206 mmol, 2.0 equiv). The reaction mixture was stirred for 1 h at room temperature and quenched with water (500 mL). The resulting mixture was extracted with dichloromethane (3 x 500 mL) and the organic layers were combined, washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g x 4, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Plow rate: 80 mL / min; Gradient: 0% B to 50% B in 40 min; Wave Length: 254 nm; Collected fractions: 25% - 30% B), the fraction was concentrated under reduced pressure to provide the title product tert-butyl (3-bromo-5- hydroxyphenyl)(prop-2-yn-l-yl)carbamate (15.2 g, 42% yield).

[0311] LCMS(ESI-MS) m / z = 270.0 [M+H-56]+.

[0312] Rt: 0.697 min (Method 2).2.10. Int-10: methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-l-yl)amino]-5-methoxypyridine-2- carboxylate2.10.1. Step 1: tert-butyl N-(2-bromo-5-methoxypyridin-4-yl)-N-(tert- butoxycarbonytcarbamate

[0313] To a solution of 2-bromo-5-methoxypyridin-4-amine (5.00 g, 24.6 mmol, 1.0 equiv) in DCM (50 mL) was added di-tert-butyl dicarbonate (13.4 g, 61.6 mmol, 2.5 equiv), N,N-dimethylpyridin-4-amine (1.50 g, 12.3 mmol, 0.5 equiv) and trimethylamine (7.48 g, 73.9 mmol, 3.0 equiv). The reaction mixture was stirred for 2 h at room temperature and quenched with water (100 mL). The resulting mixture was extracted with dichloromethane (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product tert-butyl N-(2-bromo-5-methoxypyridin-4-yl)-N-(tert- butoxycarbonyl)carbamate (8.00 g, crude).

[0314] LCMS (ESI-MS) m / z = 402.9 / 404.9 [M+H]+.GAL-378-EP-EPA 74

[0315] Rt: 0.911 min (Method 16).2.10.2. Step 2: tert-butyl N-(2-bromo-5-methoxypyridin-4-yl)carbamate

[0316] To a solution of tert-butyl N-(2-bromo-5-methoxypyridin-4-yl)-N-(tert-butoxycarbonyl)carbamate (8.00 g, 19.8 mmol, 1.0 equiv) in methanol (80 mb) was added potassium carbonate (8.22 g, 59.5 mmol, 3.0 equiv). The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was fdtered 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: 100 mL / min; Gradient: 0% B to 60% B in 40 min; Wave Length: 254nm; Collected fractions: 25% - 32% B), the fraction was concentrated under reduced pressure to afford the title product tert-butyl N-(2-bromo-5-methoxypyridin-4-yl)carbamate (5.00 g, 70% yield). LCMS (ESI-MS) m / z = 303.0 305.0 [M+H]+. Rt: 1.053 min (Method 26).2.10.3. Step 3: methyl 4-[(tert-butoxycarbonyl)amino]-5-methoxypyridine-2-carboxylate

[0317] To a solution of tert-butyl N-(2-bromo-5-methoxypyridin-4-yl)carbamate (1.50 g, 4.95 mmol, 1.0 equiv) in methanol (20 mb) was added [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (404 mg, 0.495 mmol, 0.1 equiv) and triethylamine (1.50 g, 14.9 mmol, 3.0 equiv). The reaction mixture was stirred overnight at 80 °C under 10 atm carbon monoxide. The resulting mixture was 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: 70 mL / min; Gradient: 0% B to 100% B in 40 min; Wave Length: 254nm; Collected fractions: 60% - 70% B), the fraction was concentrated under reduced pressure to afford the title product methyl 4-[(tert-butoxycarbonyl)amino]-5-methoxypyridine-2 -carboxylate (800 mg, 50% yield). LCMS (ESI-MS) m / z = 283.1 [M+H]+. Rt: 0.713 min (Method 34).2.10.4. Step 4: methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-l-yl)amino]-5-methoxypyridine-2- carboxylate

[0318] To a solution of methyl 4-[(tert-butoxycarbonyl)amino]-5-methoxypyridine-2-carboxylate (800 mg, 2.83 mmol, 1.0 equiv) in N,N -dimethylformamide (16 mL) was added sodium hydride (136 mg, 3.40 mmol, 1.2 equiv, 60% in oil). After stirred for 1 h at 0 °C, propargyl bromide (438 mg, 3.68 mmol, 1.3 equiv) was added. The reaction mixture was stirred for 2 h at room temperature and quenched with saturated aqueous ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 80 mL) and the organic layers were combined, washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 130 g, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 70 mL / min; Gradient: 0% B to 100% B in 30 min; Wave Length: 254 nm; Collected fractions: 40% - 50% B) to provide the title product methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-l-yl)amino]-5-methoxypyridine-2 -carboxylate (700 mg, 79% yield). LCMS (ESI-MS) m / z = 320.8 [M+H]+. Rt: 0.912 min (Method 22).GAL-378-EP-EPA 752.11. Int-11: methyl 3-[(tert-butoxycarbonyl)(prop-2-yn-l-yl)amino]-5-[(tert- butyldimethylsilyl)oxy]benzoate

[0319] A stirred mixture of methyl 3-[(tert-butyldimethylsilyl)oxy]-5-(prop-2-yn-l-ylamino)benzoate (1.2 g, 3.75 mmol, 1.0 equiv) in BOC2O (12 mL) was stirred overnight at 90 °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, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse purification C18 (Column: 20 - 35 pm, 100 A, 220 g; Mobile Phase A: Water (0.05% NH4HCO3), Mobile Phase B: ACN; Plow rate: 80 mL / min; Gradient: 0% B to 100% B in 40 min; Wave Length: 220nm nm; Collected fractions: 88 % B) to provide the title product methyl 3-[(tert- butoxycarbonyl)(prop-2-yn-l-yl)amino]-5-[(tert-butyldimethylsilyl)oxy]benzoate (1.0 g, 57% yield). LCMS(ESI-MS) m / z = 364.1[M+H-56]+. Rt: 0.871 min (Method 18).2.12. Int-12:3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-5-fluoro-l- methylpiperidin-4-amine2.12.1. Step 1: tert-butyl N-(3-bromo-5-fluoropyridin-4-yl)carbamate

[0320] To a solution of 3-bromo-5-fhioropyridin-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, fdtered and concentrated under reduced pressure to afford crude product tert-butyl N-(3-bromo-5-fluoropyridin-4-yl)carbamate (47 g). To a solution ofGAL-378-EP-EPA 76 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 fdtered through a celite pad and washed with DCM (3 x 200 mL). The fdtrate was dried over anhydrous sodium sulfate, fdtered 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 title product tert-butyl N-(3-bromo-5-fluoropyridin-4- yl)carbamate (32 g, 82%yield).

[0321] LCMS(ESI-MS) m / z = 291.0, 293.0 [M+H]+.

[0322] Rt: 0.569 min (Method 18).2.12.2. Step 2: tert-butyl N-[3-(2,2-dimethyl-3,3-diphenyl-4, 7,10-trioxa-3-siladodecan-12-yl)-5- fluoropyridin-4-y I / carbamate

[0323] 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), Nal (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 (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were combined, washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate, fdtered 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 title 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).

[0324] LCMS(ESI-MS) m / z = 583.3 [M+H] +.

[0325] Rt: 1.071 min (Method 6).2.12.3. Step 3: 4-[(tert-butoxycarbonyl)amino]-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- siladodecan-12-yl)-5-fluoro-l -methylpyridin -1 -ium iodide

[0326] 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 Mel (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 fdtered. 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-GAL-378-EP-EPA 7712-yl)-5 -fluoro- 1-methylpyridin-l-ium iodide (1.12 g). LCMS(ESI-MS) m / z = 597.4 [M-I ]+. Rt: 0.895 min (Method 6).2.12.4. Step 4: tert-butyl N-[3-(2,2-dimethyl-3,3-diphenyl-4, 7,10-trioxa-3-siladodecan-12-yl)-5- fluoro-l-methyl-3,6-dihydro-2H-pyridin-4-yl]carbamate

[0327] 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-l-ium iodide (5.25 g, 7.24 mmol, 1.0 equiv) in DCM (36 mb) and methanol (36 mb) was added Cerium(III) chloride heptahydrate (2.70 g, 7.24 mmol, 1.0 equiv), followed by addition of NaBH (5.48 g, 145 mmol, 20 equiv) in batches at 0°C. The mixture was stirred at 0 C for 30 min and HO Ac (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 mb) at 0 °C. The resulting mixture was extracted with EtOAc (4 x 150 mb) and the organic layers were combined, washed with brine (200 mb), 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; Plow rate: 60 mb / min; Gradient: 0% B to 80% B in 30 min; Wave Eength: 254 nm) 55% - 62% B fractions were collected to provide the title product tert-butyl N-[3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecan-12-yl)-5-fluoro-l-methyl-3,6-dihydro-2H-pyridin-4-yl]carbamate (1.71 g, 35 %yield) .

[0328] ECMS(ESI-MS) m / z = 601.2 [M+H]+.

[0329] Rt: 2.061 min (Method 50).2.12.5. Step 5: tert-butyl N-[(4R,5S)-3-(2, 2-dimethyl-3,3-diphenyl-4, 7, 10-trioxa-3-siladodecan- 12-yl)-5-fluoro-l-methylpiperidin-4-yl]carbamate

[0330] To a solution of tert-butyl N-[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-5- fluoro-l-methyl-3,6-dihydro-2H-pyridin-4-yl]carbamate (1.86 g, 3.10 mmol, 1.0 equiv) in methanol (140 mb) was added [((R)-BINAP)RuC12](p-cymene) (0.720 g, 0.774 mmol, 0.25 equiv) at room temperature. The reaction mixture was stirred at 80 °C for 16 h under hydrogen atmosphere (20 atm). Then the mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase purification (C18 spherical, 20 - 30 urn, 100 A, 220 g; Mobile Phase A: water (0.05% TFA), Mobile Phase B: MeCN; Flow rate: 60 mb / min; Gradient: 0% B to 0% B in 5 min, 0% B to 95% B in 30 min; Detector: UV 210 nm; 60% B fractions were collected) to provide the title product tert-butyl N-[(4R,5S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-5- fluoro-l-methylpiperidin-4-yl]carbamate (1.8 g, 73% yield).

[0331] ECMS(ESI-MS) m / z = 603.4 [M+H]+.

[0332] Rt: 0.884 min (Method 6).GAL-378-EP-EPA 782.12.6. Step 6: 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-5-fluoro-l- methylpiperidin-4-amine

[0333] To a solution of tert-butyl N-[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-5- fluoro-l-methylpiperidin-4-yl]carbamate (1.60 g, 2.65 mmol, 1.0 equiv) in DCM (31 mL) was added TFA (3. 1 mL) stirred at room temperature. The reaction mixture was stirred for 4 h at room temperature and adjusted the pH to 8 with saturated potassium carbonate solution, dilute with water (50 mL). The resulting mixture was extracted with DCM (3 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 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-5- fluoro- l-methylpiperidin-4-amine (1.58 g, crude) as a brown semi-solid.

[0334] LCMS(ESI-MS) m / z = 503.3 [M+H]+.

[0335] Rt: 0.648 min (Method 6).Example 3. Preparation of illustrative compounds of the invention

[0336] Stereocentres marked with * are arbitrarily assigned as absolute stereochemistry was not determined. For examplemeans that the compound is eitherGAL-378-EP-EPA 793.1. Compound 1: N,18-dimethyl-35-(ti-ifluoi-omethylsulfanyl)-23,26,29-trioxa-2, 7,9,14,18- pentazapentacyclo[28.3.1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen-4- yn e-32-carboxamide3.1.1. Step 1 : methyl 3-amino-5-((tert-butyldimethylsilyl)oxy)benzoate

[0337] To a solution of methyl 3 -amino-5 -hydroxybenzoate (CAS# 67973-80-2; 5.00 g, 29.9 mmol, 1.00 equiv) in THF (50 mL) was added TBDMSC1 (5.41 g, 35.9 mmol, 1.2 equiv) and Imidazole (8.15 g, 119 mmol, 4.0 equiv) stirred at RT. The reaction mixture was stirred for 2 h at RT and quenched with water (70 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, fdtered 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: PE, Mobile Phase B: EtOAc; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; Wavelength: 220 nm; 24% - 26% B fractions were collected) to provide title compound (7.9 g, 84% yield).

[0338] LCMS(ESI-MS) m / z = 282.3 [M+H]+

[0339] Rt: 0.693 min; Method 2GAL-378-EP-EPA 803.1.2. Step 2: methyl 3-((tert-butyldimethylsilyl)oxy)-5-(prop-2-yn-l-ylamino)benzoate

[0340] To a solution of methyl 3-amino-5-((tert-butyldimethylsilyl)oxy)benzoate (8.50 g, 30.2 mmol, 1.0 equiv) in DMF (85 mL) was added propargyl bromide (3.95 g, 33.2 mmol, 1.1 equiv) and K2CO3 (6.26 g, 45.3 mmol, 1.5 equiv) stirred at RT. The reaction mixture was stirred overnight at RT and quenched with water (150 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL) and the organic layers were combined, washed with brine (3 x 200 mL), dried over anhydrous sodium sulfate, fdtered 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: PE, Mobile Phase B: EtOAc; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; Wavelength: 220 nm; 23% - 25% B fractions were collected) to provide the title compound (4.2 g, 39% yield).

[0341] LCMS(ESI-MS) m / z = 320.2 [M+H]+

[0342] Rt: 0.766 min; Method 183.1.3. Step 3: methyl 3-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2- yl)prop-2-yn-l-yl)amino)-5-((tert-butyldimethylsilyl)oxy)benzoate

[0343] To a solution of methyl methyl 3-((tert-butyldimethylsilyl)oxy)-5-(prop-2-yn- 1 -ylamino)benzoate (1.50 g, 4.69 mmol, 1.0 equiv) in DMSO (15 mL) was added 8-bromo-2-iodo-3- ((trifluoromethyl)thio)imidazo[l,2-a]pyridine (Int 3, CAS# 3036279-54-3; 2.09 g, 4.93 mmol, 1.05 equiv), Pd(PPh3)2C12 (CAS# 13965-03-2; 329 mg, 0.470 mmol, 0.1 equiv), Cui (179 mg, 0.939 mmol, 0.200 equiv) and TEA (2.61 mL, 18.8 mmol, 4.0 equiv) stirred at RT under nitrogen. The reaction mixture was stirred for 4 h at RT under nitrogen and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 25 mL) and the organic layers were combined, washed with brine (3 x 25 mL), dried over anhydrous sodium sulfate, fdtered 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: PE, Mobile Phase B: EtOAc; Flow rate: 65 mL / min; Gradient: 0% B to 100% B in 30 min; Wavelength: 220 nm; 15% - 17% B fractions were collected) to provide the title compound (2.2 g, 61% yield).

[0344] LCMS(ESI-MS) m / z = 616.2 [M+H]+

[0345] Rt: 0.871 min; Method 23.1.4. Step 4: methyl 3-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2- yl)prop-2-yn-l-yl)(tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)benzoate

[0346] To a solution of methyl 3-((3-(8-bromo-3-((trifluoromcthyl)thio)imidazo| l .2-«|pyridin-2-yl)prop- 2-yn-l-yl)amino)-5-((tert-butyldimethylsilyl)oxy)benzoate (2.50 g, 4.07 mmol, 1.0 equiv) was added BOC2O (7.5 mL) stirred at RT. The reaction mixture was stirred for 4 h at 90 °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 purified by Cl 8 column (Column: 350 g, 20-35 pm, Mobile Phase A: water (0.05% FA), Mobile Phase B: CH3CN;GAL-378-EP-EPA 81Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; Wavelength: 220 / 254 nm; 100% B fractions were collected), the fraction was concentrated under reduced pressure to provide the title compound (2.4 g, 74% yield).

[0347] LCMS(ESI-MS) m / z = 1\62 [M+H]+

[0348] Rt: 1.204 min; Method 63.1.5. Step 5: methyl 3-((tert-butoxycarbonyl)(3-(8-((3-(2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecan-12-yl)-l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[l,2- a]pyridin-2-yl)prop-2-yn-l-yl)amino)-5-hydroxybenzoate

[0349] To a solution of methyl 3-((3-(8-bromo-3-((trifhioromethyl)thio)imidazo[ 1 ,2-a]pyridin-2-yl)prop- 2-yn-l-yl)(tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)benzoate (360 mg, 0.504 mmol, 1.0 equiv) in dioxane (11 mb) was added Int-2 (244 mg, 0.504 mmol, 1.0 equiv), CS2CO3 (410 mg, 1.26 mmol, 2.5 equiv) and Pd-PEPPSI-IHept-Cl (CAS# 1814936-54-3; 98.1 mg, 0.101 mmol, 0.2 equiv) stirred at RT under nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen and quenched with water (20 mb). The resulting mixture was extracted with EtOAc (3 x 25 mb) and the organic layers were combined, washed with brine (3 x 25 mb), dried over anhydrous sodium sulfate, fdtered 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: 80 mb / min; Gradient: 0% B to 15% B in 30 min; Wavelength: 220 nm; 10% - 12% B fractions were collected) to provide the title compound (290 mg, 51% yield).

[0350] ECMS(ESI-MS) m / z = 1004.5 [M+H]+

[0351] Rt: 0.850 min; Method 23.1.6. Step 6: methyl 3-((tert-butoxycarbonyl)(3-(8-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)- l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l- yl)amino)-5-hydroxybenzoate

[0352] To a solution of methyl 3-((tert-butoxycarbonyl)(3-(8-((3-(2,2-dimethyl-3,3-diphenyl-4,7, 10- trioxa-3 -siladodecan- 12-yl)- 1 -methylpiperidin-4-yl)amino)-3 -((trifhioromethyl)thio)imidazo [1,2- « | pyridin-2-y I )prop-2-yn- 1 -y I )amino)-5 -hydroxybenzoate (1.60 g, 1.59 mmol, 1.0 equiv) in THF (16 mb) was added TBAF (2.39 mb, 2.39 mmol, 1.5 equiv) stirred at RT. The reaction mixture was stirred for 1 h at RT and quenched with water (30 mb). The resulting mixture was extracted with EtOAc (3 x 40 mb) and the organic layers were combined, washed with brine (2 x 40 mb), dried over anhydrous sodium sulfate, fdtered 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: DCM, Mobile Phase B: MeOH; Flow rate: 50 mb / min; Gradient: 0% B to 15% B in 30 min; Wavelength: 220 nm; 12% - 14% B fractions were collected) to provide the title product. The crude product was purified by C18 column (Column: 130 g, 20-35 pm, Mobile Phase A: water (0.05% NH4HCO3), Mobile Phase B: CH3CN; Flow rate: 50 mb / min; Gradient: 0% B to 100% B in 30 min;GAL-378-EP-EPA 82Wavelength: 220 / 254 nm; 69% B fractions were collected), the fraction was concentrated under reduced pressure to provide the title compound (640 mg, 47% yield).

[0353] LCMS(ESI-MS) m / z = 766.3 [M+H]+

[0354] Rt: 0.688 min; Method 23.1.7. Step 7: O2-tert-butyl O32-methyl 18-methyl-35-(trifluoromethylsulfanyl)-23, 26,29- trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,32-dicarboxylate

[0355] To a solution of methyl 3-((tert-butoxycarbonyl)(3-(8-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)- 1 -methylpiperidin-4-yl)amino)-3 -((trifluoromethyl)thio)imidazo [ 1 ,2-a ] py ridin-2-y 1 )prop-2-yn- 1 - yl)amino)-5 -hydroxybenzoate (500 mg, 0.653 mmol, 1.0 equiv) in toluene (15 mb) was added CMBP (945 mg, 3.92 mmol, 6.0 equiv) stirred at RT. The reaction mixture was stirred for 2 h at 90 °C and quenched with water (30 mb). The resulting mixture was extracted with EtOAc (3 x 40 mb) and the organic layers were combined, washed with brine (2 x 40 mb), dried over anhydrous sodium sulfate, fdtered 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: DCM, Mobile Phase B: MeOH; Plow rate: 50 mb / min; Gradient: 0% B to 20% B in 30 min; Wavelength: 220 nm; 20% B fractions were collected) to provide the title product. The crude product was purified by C18 column (Column: 130 g, 20-35 pm, Mobile Phase A: water (0.05% NH4HCC>3), Mobile Phase B: CH3CN; Flow rate: 50 mb / min; Gradient: 0% B to 100% B in 30 min; Wavelength: 220 / 254 nm; 100% B fractions were collected), the fraction was concentrated under reduced pressure to provide the title compound (310 mg, 57% yield).

[0356] ECMS(ESI-MS) m / z = 692.2 [M-56]+

[0357] Rt: 1. 163 min; Method 213.1.8. Step 8: methyl 18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta-l (33), 6(35), 7, 10, 12, 30(34), 31- h eptaen-4-yn e-32-carboxylate

[0358] To a solution of 02-tert-butyl 032-methyl 18-methyl-35-(trifluoromethylsulfanyl)-23,26,29- trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12, 30(34),31-heptaen-4-yne-2,32-dicarboxylate (290 mg, 0.388 mmol, 1.00 equiv) in dioxane (2.9 mb) was added hydrogen chloride (5.8 mb, 4.0 M in 1,4-dioxane) stirred at RT. The reaction mixture was stirred 1 h at RT and concentrated under reduced pressure to afford the crude title compound (250 mg, crude).

[0359] ECMS(ESI-MS) m / z = 648.5 [M+H]+

[0360] Rt: 0.578 min; Method 2GAL-378-EP-EPA 833.1.9. Step 9: 18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta-l (33), 6(35), 7, 10, 12, 30(34), Silt eptaen-4-yn e-32-carboxylic acid

[0361] To a solution of methyl 18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4- yne-32-carboxylate (250 mg, 0.386 mmol, 1.00 equiv) in MeOH (7 mL) was added NaOH (61.7 mg, 1.54 mmol, 4.00 equiv, in H2O (7 mL)) stirred at RT. The reaction mixture was stirred overnight at 50 °C and diluted with water (7 mL). The resulting mixture was extracted with EtOAc (10 x 25 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (240 mg, crude).

[0362] LCMS(ESI-MS) m / z = 634.5 [M+H]+

[0363] Rt: 0.525 min; Method 23.1.10. Step 10: Compound Cpd 1 N,18-dimethyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide

[0364] To a solution of 18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4- yne-32-carboxylic acid (240 mg, 0.379 mmol, 1.0 equiv) in DML (8 mL) was added HATU (172 mg, 0.455 mmol, 1.2 equiv), Methylamine hydrochloride (63.9 mg, 0.948 mmol, 2.5 equiv) and DIPEA (244 mg, 1.89 mmol, 5.0 equiv) stirred at 0 °C. The reaction mixture was stirred at RT for 1 h and quenched with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (3 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: Kinetex EVO C18, 30* 150 mm, 5 pm; Mobile Phase A: Water(0. 1% PA), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient (B%): 12% B to 33 % B in 15 min; Wavelength: 254 nm / 220 nm; Rtl(min): 13.99) to provide the title compound (95 mg, 37% yield).

[0365] LCMS(ESI-MS) m / z = 647.6 [M+H]+

[0366] Rtl: 1.397 and Rt2: 1.444 min; Method 12GAL-378-EP-EPA 843.2. Compound 1A: (15R,20R)-N,18-dimethyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31- h eptaen-4-yn e-32-carboxamide *Compound IB: (15S,20S)-N,18-dimethyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen-4- yn e-32-carboxamide *Compound 1C: (15R,20S)-N,18-dimethyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen-4- yn e-32-carboxamide *Compound ID: (15S,20R)-N,18-dimethyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen-4- yn e-32-carboxamide *

[0367] Compound 1 (89 mg) was separated by Chiral-HPLC column (Column: CHIRALPAK IM, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1: 1- -HPLC; Flow rate: 20 ML / MIN mL / min; Gradient (B%): isocratic 30; Wavelength: 254 / 220 nm nm; Rtl(min): 11.193; Rt2(min): 15.18; Rt3(min): 19.328 Sample Solvent: EtOH--HPLC; Injection Volume: 0.8 mb; Number Of Runs: 4). Purification resulted in isomer 1 with Rtl(min): 11.193, isomer 2 with Rt2(min): 15.18 and mixture 3.

[0368] Compound 1A with Rt 11.193 min (17.7 mg, 7% yield).

[0369] 1H NMR (400 MHz, DMSO) 58.27 - 8.20 (m, 1H), 7.76 (d, J = 6.6 Hz, 1H), 6.97 (dd, J = 7.7, 6.7 Hz, 1H), 6.81 - 6.76 (m, 1H), 6.66 - 6.60 (m, 1H), 6.46 (t, J = 6.3 Hz, 1H), 6.41 (d, J = 7.8 Hz, 1H), 6.38 - 6.36 (m, 1H), 6.04 (d, J = 9.3 Hz, 1H), 4.32 - 4.15 (m, 2H), 4.15 - 4.04 (m, 2H), 3.81 - 3.68 (m, 2H), 3.67 - 3.58 (m, 1H), 3.57 - 3.44 (m, 3H), 3.43 - 3.29 (m, 2H), 3.07 - 2.96 (m, 1H), 2.96 - 2.89 (m, 1H), 2.82 - 2.70 (m, 4H), 2.18 (s, 3H), 2.07 - 1.89 (m, 4H), 1.67 - 1.45 (m, 2H), 1.10 - 0.99 (m, 1H).

[0370] LCMS(ESI-MS) m / z = 647.5 [M+H]+

[0371] Rt: 1.448 min; Method 12

[0372] Compound IB with Rt 15.18 min (17.6 mg, 7% yield).

[0373] 1H NMR (400 MHz, DMSO) 58.27 - 8.20 (m, 1H), 7.76 (d, J = 6.6 Hz, 1H), 6.97 (dd, J = 7.7, 6.6 Hz, 1H), 6.81 - 6.76 (m, 1H), 6.66 - 6.60 (m, 1H), 6.46 (t, J = 6.2 Hz, 1H), 6.41 (d, J = 7.7 Hz, 1H), 6.38 - 6.36 (m, 1H), 6.04 (d, J = 9.3 Hz, 1H), 4.32 - 4.15 (m, 2H), 4.15 - 4.04 (m, 2H), 3.80 - 3.68 (m, 2H), 3.68 - 3.58 (m, 1H), 3.57 - 3.43 (m, 3H), 3.43 - 3.29 (m, 2H), 3.07 - 2.95 (m, 1H), 2.95 - 2.88 (m, 1H), 2.81 - 2.70 (m, 4H), 2.18 (s, 3H), 2.06 - 1.89 (m, 4H), 1.66 - 1.45 (m, 2H), 1.10 - 0.98 (m, 1H).

[0374] LCMS(ESI-MS) m / z = 647.6 [M+H]+GAL-378-EP-EPA 85

[0375] Rt: 1.452 min; Method 12

[0376] The mixture 3 (37 mg) was separated by Chiral-HPLC column (Column: CHIRALPAK IK 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1:1- HPLC; Flow rate: 20 ML / MIN mL / min; Gradient (B%): isocratic 40; Wavelength: 254 / 220 nm nm; Rtl(min): 6.85; Rt2(min): 8.608; Sample Solvent: EtOH— HPLC; Injection Volume: 0.9 mL; Number Of Runs: 3). Purification resulted in compound 1C and ID.

[0377] Compound 1C with Rt 6.85 min (13.6 mg, 5% yield).

[0378] 1H NMR (400 MHz, DMSO) 58.27 - 8.19 (m, 1H), 7.80 (d, J = 6.6 Hz, 1H), 7.00 (dd, J = 7.7, 6.7 Hz, 1H), 6.82 - 6.77 (m, 1H), 6.64 - 6.59 (m, 1H), 6.51 (d, J = 7.7 Hz, 1H), 6.45 (t, J = 6.3 Hz, 1H), 6.40 - 6.34 (m, 1H), 5.81 (d, J = 8.9 Hz, 1H), 4.25 (d, J = 6.2 Hz, 2H), 4.08 - 4.02 (m, 2H), 3.76 - 3.58 (m, 3H), 3.56 - 3.28 (m, 5H), 3.18 - 3.09 (m, 1H), 2.77 - 2.65 (m, 4H), 2.61 - 2.54 (m, 1H), 2.15 (s, 3H), 2.13 - 2.06 (m, 1H), 2.04 - 1.97 (m, 1H), 1.95 - 1.81 (m, 3H), 1.68 - 1.49 (m, 2H).

[0379] LCMS(ESI-MS) m / z = 647.6 [M+H]+

[0380] Rt: 0.704 min; Method 7

[0381] Compound ID with Rt 8.608 min (13.2 mg, 5% yield ).

[0382] 1H NMR (400 MHz, DMSO) 58.27 - 8.20 (m, 1H), 7.80 (d, J = 6.6 Hz, 1H), 7.00 (dd, J = 7.7, 6.7 Hz, 1H), 6.82 - 6.77 (m, 1H), 6.64 - 6.59 (m, 1H), 6.51 (d, J = 7.7 Hz, 1H), 6.45 (t, J = 6.3 Hz, 1H), 6.40 - 6.34 (m, 1H), 5.81 (d, J = 9.4 Hz, 1H), 4.25 (d, J = 6.2 Hz, 2H), 4.08 - 4.02 (m, 2H), 3.76 - 3.57 (m, 3H), 3.56 - 3.30 (m, 5H), 3.18 - 3.08 (m, 1H), 2.77 - 2.65 (m, 4H), 2.61 - 2.54 (m, 1H), 2.16 (s, 3H), 2.13 - 2.06 (m, 1H), 2.06 - 1.96 (m, 1H), 1.95 - 1.80 (m, 3H), 1.66 - 1.50 (m, 2H).

[0383] LCMS(ESI-MS) m / z = 647.6 [M+H]+

[0384] Rt: 0.705 min; Method 73.3. Compound 2GAL-378-EP-EPA 863.4. Compoun d 2

[0385] Compound may be prepared using the above synthetic route starting from methyl 3 -aminobenzoate(CAS# 4518-10-9)3.5. Compound 3: 34-meth oxy-18-methyl-36-(ti-ifluoromethylsulfanyl)-23,26-dioxa-2, 7,9, 14, 18,29- hexazapentacyclo[29.3.1.1 ''[6,9'.0''[8,13'.0''[l 5,20} ]hexatriaconta-l(35),6(36),7,10,12,31 ,33-heptaen- 4-yn-30-one

[0386] Compound may be prepared using the same synthetic route as for Compound 2 starting from methyl 3-amino-4-methoxybenzoate (CAS# 24812-90-6).3.5.1. Step 1: methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2- yl}prop-2-yn-l-yl)amino]-4-methoxybenzoate

[0387] To a solution of methyl 4-methoxy-3-(prop-2-yn-l-ylamino)benzoate (500 mg, 2.28 mmol, 1.0 equiv) in DMSO (10 mb) was added 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2- a]pyridine (964 mg, 2.28 mmol, 1.0 equiv), Pd phs^Ch (160 mg, 0.228 mmol, 0.1 equiv), Cui (86.9 mg, 0.456 mmol, 0.2 equiv) and TEA (1.27 mb, 9.12 mmol, 4.0 equiv) stirred under nitrogen at room temperature. The reaction mixture was stirred for 4 h at room temperature under nitrogen and quenched with water (30 mb). The resulting mixture was extracted with EtOAc (3 x 40 mb) and the organic layers were combined, washed with brine (2 x 40 mb), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column (Column: 130 g, 20-35 pm, Mobile Phase A: water (0.05% NH4HCC>3), Mobile Phase B: CH3CN; Plow rate: 50 mb / min; Gradient: 0% B to 100% B in 30 min; Wave Eength: 220 / 254 nm; 70% B fractions were collected), the fraction was concentrated under reduced pressure to provide the title product methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l- yl)amino]-4-methoxybenzoate (0.7 g, 53% yield).

[0388] ECMS(ESI-MS) m / z = 515.9 [M+H]+.

[0389] Rt: 0.695 min (Method 2).GAL-378-EP-EPA 873.5.2. Step 2: methyl 3-{[3-(8-{[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12- yl)-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2- yn-l-yl]amino}-4-methoxybenzoate

[0390] To a solution of methyl 3-[(3-{8-bromo-3-[(trifhioromethyl)sulfanyl]imidazo[l,2-a]pyridin-2- yl}prop-2-yn-l-yl)amino]-4-methoxybenzoate (500 mg, 0.972 mmol, 1.0 equiv) in dioxane (12.5 mL) was added 3 -(2,2-dimethyl-3 ,3 -diphenyl -4, 7, 10-trioxa-3 -siladodecan- 12-yl)- 1 -methylpiperidin-4- amine (471 mg, 0.972 mmol, 1.0 equiv), CS2CO3 (792 mg, 2.43 mmol, 2.5 equiv) and 3 -chloropyridine; { l,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-lH-imidazol-2-yl}dichloropalladium (189 mg, 0. 194 mmol, 0.2 equiv) at room temperature under nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen and quenched with water (30 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, fdtered 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; Plow rate: 45 mL / min; Gradient: 0% B to 15% B in 30 min; Wave Length: 220 nm; 5% - 7% B fractions were collected) to provide the title product methyl 3-{[3-(8-{[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l- yl]amino}-4-methoxybenzoate (625 mg, 63% yield).

[0391] LCMS(ESI-MS) m / z = 460. 1 [1 / 2M+H]+.

[0392] Rt: 0.788 min (Method 2).3.5.3. Step 3: methyl 3-[(3-{8-[(3-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l-yl)amino]-4- methoxybenzoate

[0393] To a solution of methyl 3-{[3-(8-{[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12- yl)-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2- yn-l-yl]amino}-4-methoxybenzoate (1.50 g, 1.63 mmol, 1.0 equiv) in THF (15 mL) was added Tetra- n-butylammonium fluoride (2.45 mL, 2.45 mmol, 1.5 equiv, 1 M in THF) stirred at room temperature. The reaction mixture was stirred for 1 h at room temperature and quenched with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL) and the organic layers were combined, washed with brine (5 x 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column (Column: 220 g, 20- 35 pm, Mobile Phase A: water (0.05% NH4HCO3), Mobile Phase B: CH3CN; Flow rate: 70 mL / min; Gradient: 0% B to 100% B in 30 min; Wave Length: 220 / 254 nm; 60% B fractions were collected), the fraction was concentrated under reduced pressure to provide the title product methyl 3-[(3-{8-[(3-{2- [2-(2-hydroxyethoxy)ethoxy]ethyl } - 1 -methylpiperidin-4-yl)amino] -3 - [(trifhioromethyl)sulfanyl]imidazo [ 1 ,2-a]pyridin-2-yl }prop-2-yn- 1 -yl)amino] -4-methoxybenzoate (800 mg, 64% yield).

[0394] LCMS(ESI-MS) m / z = 680. 1 [M+H]+.GAL-378-EP-EPA 88

[0395] Rt: 0.574 min (Method 2).3.5.4. Step 4: methyl 3-[(3-{8-[(3-{2-[2-(2-azidoethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l-yl)amino]-4- methoxybenzoate

[0396] To a solution of methyl 3-[(3-{8-[(3-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l-yl)amino]-4- methoxybenzoate (400 mg, 0.588 mmol, 1.0 equiv) in THF (10 mL) was added DPPA (647 mg, 2.35 mmol, 4.0 equiv) and DBU (358 mg, 2.35 mmol, 4.0 equiv) stirred at 0 °C. The reaction mixture was stirred overnight at room temperature first. Then the reaction mixture was stirred for 24 h at 70 °C and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product methyl 3-[(3-{8-[(3-{2-[2-(2-azidoethoxy)ethoxy]ethyl}-l- methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l- yl)amino] -4-methoxy benzoate (400 mg, crude).

[0397] LCMS(ESI-MS) m / z = 705.6 [M+H]+.

[0398] Rt: 0.621 min (Method 2).3.5.5. Step 5: methyl 3-[(3-{8-[(3-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l-yl)amino]-4- methoxybenzoate

[0399] To a solution of methyl 3-[(3-{8-[(3-{2-[2-(2-azidoethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l-yl)amino]-4- methoxybenzoate (410 mg, 0.582 mmol, 1.0 equiv) in THF (18 mL) was added PPhs (228 mg, 0.873 mmol, 1.5 equiv) stirred at room temperature. The reaction mixture was stirred for 3 h at room temperature. And then H2O (6 mL) was added and the reaction mixture stirred overnight at 80 °C. The mixture was acidified to pH 3~4 with 2 M HC1. The resulting mixture was extracted with EtOAc (3 x 50 mL) and the aqueous phase were basified to pH 8~9 with saturated potassium carbonate solution. The resulting mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product methyl 3-[(3-{8-[(3-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-l-methylpiperidin-4-yl)amino]-3- [(trifluoromethyl)sulfanyl]imidazo [l,2-a]pyridin-2-yl}prop-2-yn-l-yl)amino]-4-methoxybenzoate (206 mg, crude).

[0400] LCMS(ESI-MS) m / z = 679.5 [M+H]+.

[0401] Rt: 0.518 min (Method 2).GAL-378-EP-EPA 893.5.6. Step 6: 3-[(3-{8-[(3-{2-[2-(2-aminoethoxy)ethoxy]ethyl]-l-methylpiperidin-4-yl)amino]- 3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l-yl)amino]-4-methoxybenzoic acid

[0402] To a solution of methyl 3-[(3-{8-[(3-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l-yl)amino]-4- methoxybenzoate (180 mg, 0.265 mmol, 1.0 equiv) in MeOH (1.8 mL) was added NaOH (63.6 mg, 1.59 mmol, 6.0 equiv, in H2O (1.8 mL)) stirred at room temperature. The reaction mixture was stirred overnight at 50 °C 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, 5 pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 5 % B to 25 % B in 10 min; Wave Length: 254 nm / 220 nm nm; RTl(min): 8.26) to provide the title product 3-[(3-{8-[(3-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl)amino] -3 - [(trifluoromethyl) sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l-yl)amino]-4-methoxybenzoic acid (75 mg, 38% yield).

[0403] LCMS(ESI-MS) m / z = 333.4 [1 / 2M+H]+.

[0404] Rt: 0.485 min (Method 2).3.5.7. Step 7: 34-methoxy-18-methyl-36-(trifluoromethylsulfanyl)-23,26-dioxa-2,7,9,14,18,29- hexazapentacyclo[29.3.1.1f'{6,9}.0f'{8,13}.0f'{15,20}]hexatriaconta-l(35),6(36),7,10,12,31,33- heptaen-4-yn-30-one

[0405] To a solution of 3-[(3-{8-[(3-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-l-methylpiperidin-4-yl)amino]- 3-[(trifhioromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l-yl)amino]-4-methoxybenzoic acid (50.0 mg, 0.0750 mmol, 1.0 equiv) in DMF (2.5 mL) was added HATU (31.4 mg, 0.0830 mmol, 1. 1 equiv) and DIEA (97.2 mg, 0.750 mmol, 10 equiv) stirred at 0 °C. The reaction mixture was stirred for 1 h at 0 °C 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 (3 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: (DCM / MeOH) =11: 1; Rf= 0.3; detection: UV) to provide the title crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5 pm; Mobile Phase A: Water(10 mmol / LNFLHCOs). Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 34 % B to 64 % B in 10 min; Wave Length: 254 nm / 220 nm nm) to provide the title product 34-methoxy-18-methyl-36-[(trifluoromethyl)sulfanyl]- 23,26-dioxa-2,7,9,14,18,29-hexaazapentacyclo[29.3.1.1A{6,9}.0A{8,13}.0A{ 15,20}]hexatriaconta- l(35),6(36),7,10,12,31,33-heptaen-4-yn-30-one (12.8 mg, 25% yield).

[0406] LCMS(ESI-MS) m / z = 669.3 [M+Na]+.

[0407] Rtl: 1.330 min; Rt2: 1.357 min (Method 28).GAL-378-EP-EPA 903.6. Compound 4: (15S,20S)-33-methoxy-18-methyl-36-(trifluoromethylsulfanyl)-23,26-dioxa- 2,7,9,14,18,29-hexazapentacyclo[29.2.2.16,9.08,13.015,20]hexatriaconta-l(33),6(36),7,10,12,31 ,34- heptaen-4-yn-30-one3.6.1. Step 1: methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2- yl}prop-2-yn-l-yl)(tert-butoxycarbonyl)amino]-3-methoxybenzoate

[0408] To a solution of methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-l-yl)amino]-3-methoxybenzoate (500 mg, 1.56 mmol, 1.0 equiv) in DMSO (10 mL) was added 8-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine (662 mg, 1.56 mmol, 1.0 equiv), Pd phs^CE (109 mg, 0.157 mmol, 0.1 equiv), Cui (59.6 mg, 0.313 mmol, 0.2 equiv) and TEA (633 mg, 6.26 mmol, 4.0 equiv) stirred at room temperature. The reaction mixture was stirred for 2 h at room temperature under nitrogen and quenched with water (30 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, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column (Column: 130 g, 20-35 pm, Mobile Phase A: water (0.05% NH4HCO3), Mobile Phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; Wave Length: 220 / 254 nm; 70% B fractions were collected), the fraction was concentrated under reduced pressure to provide the title product methyl 4-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}prop-2-yn-l-yl)(tert-butoxycar bonyl)amino] -3 -methoxybenzoate (725 mg, 67% yield).

[0409] LCMS(ESI-MS) m / z = 559.8 [M+H-56]+.

[0410] Rt: 0.810 min (Method 2).GAL-378-EP-EPA 913.6.2. Step 2: methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4, 7, 10-trioxa-3-siladodecan-l 2-yl)-l -methylpiperidin -4-yl]amin o'-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-3-methoxybenzoate

[0411] To a solution of methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2- yl}prop-2-yn-l-yl)(tert-butoxycarbonyl)amino]-3-methoxybenzoate (800 mg, 1.30 mmol, 1.0 equiv) in dioxane (20 mL) was added (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)- l-methylpiperidin-4-amine (631 mg, 1.30 mmol, 1.0 equiv), CS2CO3 (1.06 g, 3.25 mmol, 2.5 equiv) and 3 -chloropyridine; { l,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-lH-imidazol-2- yl} dichloro palladium (253 mg, 0.260 mmol, 0.2 equiv) stirred at room temperature under nitrogen. The reaction mixture was stirred for 3 h at 90 °C under nitrogen and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 70 mL) and the organic layers were combined, washed with brine (3 x 70 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column (Column: 220 g, 20- 35 pm, Mobile Phase A: water (0.05% TLA), Mobile Phase B: CH3CN; Plow rate: 65 mL / min; Gradient: 0% B to 100% B in 30 min; Wave Length: 220 / 254 nm; 60% B fractions were collected), the fraction was concentrated under reduced pressure to provide the title product methyl 4-[(tert- butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-l- methylpiperidin-4-yl] amino } -3 - [(trifluoromethyl) sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-3-methoxybenzoate (730 mg, 49% yield,).

[0412] LCMS(ESI-MS) m / z = 1018.4 [M+H]+.

[0413] Rt: 0.816 min (Method 2).3.6.3. Step 3: methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2- hydroxyeth oxy)eth oxy]ethyl}-l -methylpiperidin -4-yl]amin o'-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-3-methoxybenzoate

[0414] To a solution of methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3 -siladodecan- 12-yl)- 1 -methylpiperidin -4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -3 -methoxybenzoate (730 mg, 0.717 mmol, 1.0 equiv) in THF (7.3 mL) was added Tetra-n-butylammonium fluoride(1.0M in THF) (1.08 mL, 1.07 mmol, 1.5 equiv) stirred at room temperature. The reaction mixture was stirred for 1 h at room temperature 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 (4 x 20 mL), dried over anhydrous sodium sulfate, fdtered 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: DCM, Mobile Phase B: MeOH; Flow rate: 50 mL / min; Gradient: 0% B to 20% B in 30 min; Wave Length: 220 nm; 15% - 17% B fractions were collected) to provide the title product methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-l-GAL-378-EP-EPA 92 methylpiperidin-4-yl] amino } -3 - [(trifluoromethyl) sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-3-methoxybenzoate (450 mg, 72% yield).

[0415] LCMS(ESI-MS) m / z = 724.3 [M+H-56]+.

[0416] Rt: 0.965 min (Method 21).3.6.4. Step 4: 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-azidoethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl](tert- butoxycarbonyl)amino}-3-methoxybenzoate

[0417] To a solution of methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2- hydroxyethoxy)ethoxy] ethyl } - 1 -methylpiperidin-4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -3 -methoxybenzoate (450 mg, 0.577 mmol, 1.0 equiv) in THF (12 mb) was added DPPA (635 mg, 2.30 mmol, 4.0 equiv) and DBU (351 mg, 2.30 mmol, 4.0 equiv) stirred at 0 °C. The reaction mixture was stirred for 2 h at room temperature. And then the reaction mixture was stirred overnight at 70 °C and quenched with water (30 mb). The resulting mixture was extracted with EtOAc (3 x 50 mb) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product methyl 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-azidoethoxy)ethoxy]ethyl}-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l- yl](tert-butoxycarbonyl)amino} -3 -methoxybenzoate (400 mg, crude).

[0418] ECMS(ESI-MS) m / z = 805.3 [M+H]+.

[0419] Rt: 0.668 min (Method 2).3.6.5. Step 5: methyl 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l- yl](tert-butoxycarbonyl)amino}-3-methoxybenzoate

[0420] To a solution of methyl 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-azidoethoxy)ethoxy]ethyl}-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l- yl](tert-butoxycarbonyl)amino} -3 -methoxybenzoate (450 mg, 0.559 mmol, 1.0 equiv) in THE (15 mb) was added PPhs (219 mg, 0.839 mmol, 1.5 equiv) stirred at room temperature. The reaction mixture was stirred for 3 h at room temperature. And then H2O (4 mb) was added, the reaction mixture was stirred overnight at 80 °C and quenched with water (30 mb). The resulting mixture was extracted with EtOAc (3 x 50 mb) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product methyl 4-{[3-(8-{[(3S,4S)-3-{2-[2- (2-aminoethoxy)ethoxy]ethyl } - 1 -methylpiperidin-4-yl]amino } -3 - [(trifluoromethyl)sulfanyl]imidazo [ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl] (tert-butoxycarbonyl)amino } -3 - methoxybenzoate (400 mg, crude).

[0421] ECMS(ESI-MS) m / z = 779.3 [M+H]+.

[0422] Rt: 0.563 min (Method 2).GAL-378-EP-EPA 933.6.6. Step 6: methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-[2-(2-{2-[(tert- butoxycarbonyl)amino]ethoxy}ethoxy)ethyl]-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-3-methoxybenzoate

[0423] To a solution of methyl 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l- yl](tert-butoxycarbonyl)amino} -3 -methoxybenzoate (400 mg, 0.514 mmol, 1.0 equiv) in DCM (6 mb) was added BOC2O (168 mg, 0.770 mmol, 1.5 equiv) and TEA (103 mg, 1.02 mmol, 2.0 equiv) stirred at 0 °C. The reaction mixture was stirred for 2 h at room temperature and quenched with water (10 mb). The resulting mixture was extracted with DCM (3 x 15 mb) 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 TLC (Mobile phase: (DCM / MeOH) =7: 1; Rf = 0.4; detection: UV) to provide the title product methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-[2-(2-{2- [(tert-butoxycarbonyl)amino] ethoxy } ethoxy)ethyl] - 1 -methylpiperidin-4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -3 -methoxybenzoate (189 mg, 35% yield).

[0424] LCMS(ESI-MS) m / z = 879.3 [M+H]+.

[0425] Rt: 0.684 min (Method 2).3.6.7. Step 7: 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-[2-(2-{2-[(tert-butoxycar bonyl)amino]ethoxy}ethoxy)ethyl]-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-3-methoxybenzoic acid

[0426] To a solution of methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-[2-(2-{2-[(tert- butoxycarbonyl)amino] ethoxy } ethoxy)ethyl] - 1 -methylpiperidin-4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -3 -methoxybenzoate (180 mg, 0.205 mmol, 1.0 equiv) in MeOH (2 mb) was added NaOH (49.1 mg, 1.23 mmol, 6.0 equiv, in H2O (2 mb)) stirred at room temperature. The reaction mixture was stirred for 2 h at 50 °C and diluted with water (10 mb). The resulting mixture was extracted with EA (3 x 15 mb) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-[2-(2-{2-[(tert- butoxycarbonyl)amino] ethoxy } ethoxy) ethyl] - 1 -methylpiperidin-4-yl]amino } -3 - [(trifluoromethyl)sulfanyl]imidazo [ 1 ,2-a]pyridin-2-yl)prop- 2-yn-l-yl]amino]-3-methoxybenzoic acid (180 mg, crude).

[0427] ECMS(ESI-MS) m / z = 865.3 [M+H]+.

[0428] Rt: 0.622 min (Method 2).GAL-378-EP-EPA 943.6.8. Step 8: 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-aminoethoxy)ethoxy]ethyl]-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino}-3- methoxybenzoic acid

[0429] To a solution of 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-[2-(2-{2-[(tert- butoxycarbonyl)amino] ethoxy } ethoxy)ethyl] - 1 -methylpiperidin-4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -3 -methoxybenzoic acid (180 mg, 0.208 mmol, 1.0 equiv) in DCM (3 mb) was added DIEA (161 mg, 1.24 mmol, 6.0 equiv) and TMSOTf (231 mg, 1.04 mmol, 5.0 equiv) stirred at 0 °C. The reaction mixture was stirred for 1 h at room temperature and quenched with water (10 mb). The resulting mixture was extracted with DCM (3 x 15 mb) and the organic layers were combined, dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2- aminoethoxy)ethoxy] ethyl } - 1 -methylpiperidin-4-yl] amino } -3 - [(trifluoromethyl) sulfanyl] imidazo [1,2- a]pyridin-2-yl)prop-2-yn- 1 -yl] amino} -3 -methoxybenzoic acid (130 mg, crude).

[0430] LCMS(ESI-MS) m / z = 333.2 [1 / 2M+H]+.

[0431] Rt: 0.478 min (Method 2).3.6.9. Step 9: (15S,20S)-33-methoxy-18-methyl-36-(trifluoromethylsulfanyl)-23,26-dioxa-2, 7, 9,14,18,29-hexazapentacyclo[29.2.2.16, 9.08,13.015,20]hexatriaconta- l(33),6(36),7,10,12,31,34-heptaen-4-yn-30-one

[0432] To a solution of 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino}-3- methoxybenzoic acid (130 mg, 0.196 mmol, 1.0 equiv) in DCM (2 mb) was added HOBT (29.0 mg, 0.216 mmol, 1.1 equiv), EDCI (36.4 mg, 0.235 mmol, 1.2 equiv) and NMM (59.3 mg, 0.588 mmol, 3.0 equiv) stirred at 0 °C. The reaction mixture was stirred for 1 h at 0 °C and quenched with water (5 mb). The resulting mixture was extracted with DCM (3 x 7 mb) and the organic layers were combined, dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TEC (Mobile phase: (DCM / MeOH) =5: 1; Rf = 0.4; detection: UV) to provide the title product. The crude product was purified by preparative HPEC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5 pm; Mobile Phase A: Water(10 mmol / E NH4HCO3), Mobile Phase B: ACN; Plow rate: 60 mb / min mb / min; Gradient (B%): 34% B to 64 % B in 10 min; Wave Eength: 254 nm / 220 nm nm; RTl(min): 7.08 ) to provide the title product (15S,20S)- 33-methoxy-18-methyl-36-(trifluoromethylsulfanyl)-23,26-dioxa-2,7,9, 14, 18,29- hexazapentacyclo [29.2.2.16,9.08,13.015,20]hexatriaconta-l(33),6(36),7,10,12,31,34-heptaen-4-yn-30-one (14.6 mg, 11% yield).

[0433] ’H NMR (400 MHz, DMSO-de) 5 8.15 - 8.35 (m, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.45 - 7.59 (m, 1H), 7.29 - 7.40 (m, 1H), 6.96 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 7.6 Hz, 1H), 6.15 (d, J = 9.6 Hz, 1H), 6.10 (t, J = 6.8 Hz, 1H), 4.36 (d, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.41 - 3.62 (m, 7H), 3.32 - 3.39 (m, 1H), 3.29 - 3.31 (m, 1H), 3.19 - 3.28 (m, 1H), 2.90 - 3.02 (m, 1H), 2.79 - 2.89 (m,GAL-378-EP-EPA 951H), 2.69 - 2.78 (m, 1H), 2.15 (s, 3H), 1.71 - 2.06 (m, 4H), 1.50 - 1.63 (m, 1H), 1.35 - 1.49 (m, 1H), 0.94 - 1.11 (m, 1H). LCMS(ESI-MS) m / z = 647.3 [M+H]+. Rt: 1.481 (Method 12).3.7. Compound 5: (15S,20S)-32-dimethylphosphoryl-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne3.7.1. Step 1: tert-butyl (3-bromo-5-((triisopropylsilyl)oxy)phenyl)(prop-2-yn-l-yl)carbamate

[0434] To a solution of tert-butyl (3-bromo-5-hydroxyphenyl)(prop-2-yn-l-yl)carbamate (3.00 g, 9.20 mmol, 1.0 equiv) in DMF (30 mL) was added chlorotris(propan-2-yl)silane (2.66 g, 13.8 mmol, 1.5 equiv) and IH-imidazole (1.57 g, 23.0 mmol, 2.5 equiv). The reaction mixture was stirred for 2 h at room temperature and quenched with water (150 mL). The resulting mixture was extracted with ethyl acetate (3 x 150 mL) and the organic layers were combined, washed with brine (2 x 150 mL), dried over anhydrous sodium sulfate, fdtered 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: 100 mL / min; Gradient: 0% B to 30% B in 40 min; Wave Length: 254nm; Collected fractions: 15% - 20% B), the fraction was concentrated under reduced pressure to afford the title product tert-butyl (3-bromo-5- ((triisopropylsilyl)oxy)phenyl)(prop-2-yn-l-yl)carbamate (4.40 g, 89% yield).

[0435] LCMS (ESI-MS) m / z = 426.0, 428.0 [M+H-56]+.

[0436] Rt: 1.070 min (Method 2).GAL-378-EP-EPA 963.7.2. Step 2: tert-butyl (3-(dimethylphosphoryl)-5-((triisopropylsilyl)oxy)phenyl)(prop-2-yn-1-yl)carbamate

[0437] To a solution of tert-butyl (3-bromo-5-((triisopropylsilyl)oxy)phenyl)(prop-2-yn-l-yl)carbamate (1.00 g, 2.07 mmol, 1.0 equiv) in 1,4-dioxane (20 mL) was added dimethylphosphine oxide (242 mg, 3.11 mmol, 1.5 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (120 mg, 0.207 mmol, 0.1 equiv), palladium(II) acetate (46.5 mg, 0.207 mmol, 0.1 equiv) and potassium phosphate (660 mg, 3.11 mmol, 1.5 equiv) at room temperature under nitrogen. The reaction mixture was stirred for 4 h at 95 °C under nitrogen and quenched with water (120 mL). The resulting mixture was extracted with Ethyl acetate (3 x 120 mL) and the organic layers were combined, washed with brine (2 x 120 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g, 100 - 200 mesh; Mobile Phase A: dichloromethane, Mobile Phase B: methanol; Flow rate: 60 mL / min; Gradient: 0% B to 20% B in 30 min; Wave Length: 220 nm; Collected fractions: 10% - 15% B), the fraction was concentrated under reduced pressure to provide the title product tert-butyl (3- (dimethylphosphoryl)-5-((triisopropylsilyl)oxy)phenyl)(prop-2-yn-l-yl)carbamate (637 mg, 57% yield).

[0438] LCMS (ESI-MS) m / z = 480.3 [M+H]+.

[0439] Rt: 0.808 min (Method 2).3.7.3. Step 3: tert-butyl (3-(8-bromo-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl)(3-(dimethylphosphoryl)-5-((triisopropylsilyl)oxy)phenyl)carbamate

[0440] To a solution of 8-bromo-2-iodo-3-((trifhioromethyl)thio)imidazo[l,2-a]pyridine (750 mg, 1.77 mmol, 1.0 equiv) in DMSO (15 mL) was added tert-butyl (3-(dimethylphosphoryl)-5- ((triisopropylsilyl)oxy)phenyl)(prop-2-yn-l-yl)carbamate (1.53 g, 3.19 mmol, 1.8 equiv), cuprous iodide (101 mg, 0.532 mmol, 0.3 equiv), trimethylamine (718 mg, 7.09 mmol, 4.0 equiv) and dichlorobis(triphenylphosphine)palladium(II) (187 mg, 0.266 mmol, 0.15 equiv). The reaction mixture was stirred for 1 h at room temperature under nitrogen and quenched with water (100 mL). The resulting mixture was extracted with Ethyl acetate (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g, 100 - 200 mesh; Mobile Phase A: dichloromethane, Mobile Phase B: methanol; Flow rate: 60 mL / min; Gradient: 0% B to 20% B in 30 min; Wave Length: 220 nm; Collected fractions: 8% - 13% B) to afford the title product tert-butyl (3-(8-bromo-3-((trifluoromethyl)thio)imidazo[l,2- a]pyridin-2-yl)prop-2-yn-l-yl)(3-(dimethylphosphoryl)-5-((triisopropylsilyl)oxy)phenyl)carbamate (1.00 g, 65% yield).

[0441] LCMS(ESI-MS) m / z = 774.0, 776.0 [M+H]+.

[0442] Rt: 0.897 min (Method 2).GAL-378-EP-EPA 973.7.4. Step 4: tert-butyl (3-(8-(((3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4, 7,10-trioxa-3- siladodecan-12-yl)-l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin- 2-yl)prop-2-yn-l-yl)(3-(dimethylphosphoryl)-5-hydroxyphenyl)carbamate

[0443] To a solution of tert-butyl (3-(8-bromo-3-((trifhioromethyl)thio)imidazo[l,2-a]pyridin-2-yl)prop- 2-yn-l-yl)(3-(dimethylphosphoryl)-5-((triisopropylsilyl)oxy)phenyl)carbamate (799 mg, 1.03 mmol, 1.0 equiv) in 1,4-dioxane (18 mL) was added (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- siladodecan-12-yl)-l-methylpiperidin-4-amine (500 mg, 1.03 mmol, 1.0 equiv), cesium carbonate (840 mg, 2.58 mmol, 2.5 equiv) and 3 -chloropyridine; { l,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro- 2,3-dihydro-lH-imidazol-2-yl}dichloropalladium (100 mg, 0.103 mmol, 0.1 equiv). The reaction mixture was stirred overnight at 90 °C under nitrogen and quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, fdtered 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: dichloromethane, Mobile Phase B: methanol; Plow rate: 60 mL / min; Gradient: 0% B to 20% B in 30 min; Wave Length: 220 nm; Collected fractions: 9% - 12% B) to afford the title product tert-butyl (3-(8-(((3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3 -siladodecan- 12-yl)- 1 -methylpiperidin-4-yl)amino)-3 -((trifhioromethyl)thio)imidazo [1,2- a]pyridin-2-yl)prop-2-yn-l-yl)(3-(dimethylphosphoryl)-5-hydroxyphenyl)carbamate (350 mg, crude).

[0444] LCMS(ESI-MS) m / z = 511.8 [1 / 2M+H]+.

[0445] Rt: 0.741 min (Method 2).3.7.5. Step 5: tert-butyl (3-(dimethylphosphoryl)-5-hydroxyphenyl)(3-(8-(((3S,4S)-3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[l,2- a]pyridin-2-yl)prop-2-yn-l-yl)carbamate

[0446] To a solution of tert-butyl (3-(8-(((3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- siladodecan- 12-yl)- 1 -methylpiperidin-4-yl)amino)-3 -((trifluoromethyl)thio)imidazo [ 1 ,2-a]pyridin-2- yl)prop-2-yn-l-yl)(3-(dimethylphosphoryl)-5-hydroxyphenyl)carbamaterbamate (500 mg, 0.489 mmol, 1.0 equiv) in THF (10 mL) was added tetrabutylammonium fluoride (0.74 mL, 0.734 mmol, 1.5 equiv, 1 M in THF) at 0 °C. The reaction mixture was stirred for 1 h at room temperature and quenched with water (100 mL). The resulting mixture was extracted with Ethyl acetate (3 x 150 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: dichloromethane / methanol=5 / l; Rf = 0.4; detection: UV) to afford the title product tert-butyl (3-(dimethylphosphoryl)-5-hydroxyphenyl)(3-(8-(((3S,4S)-3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[l,2- a]pyridin-2-yl)prop-2-yn-l-yl)carbamate (260 mg, 61% yield).

[0447] LCMS(ESI-MS) m / z = 784.3 [M+H]+.

[0448] Rt: 0.531 min (Method 2).GAL-378-EP-EPA 983. 7.6. Step 6: tert-butyl (15S,20S)-32-dimethylphosphoryl-18-methyl-35-(trifluoro methylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20] pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2-carboxylate

[0449] To a solution of tert-butyl (3-(dimethylphosphoryl)-5-hydroxyphenyl)(3-(8-(((3S,4S)-3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[l,2- a]pyridin-2-yl)prop-2-yn-l-yl)carbamate (240 mg, 0.306 mmol, 1.0 equiv) in toluene (48 mL) was added 2-(tributylphosphoranylidene)acetonitrile (443 mg, 1.84 mmol, 6.0 equiv) at 0 °C under nitrogen. 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 Ethyl acetate (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: methanol / dichloromethane =1:5; Rf = 0.5; detection: UV) to afford the title product (120 mg, 46% yield).

[0450] LCMS(ESI-MS) m / z = 766.3 [M+H]+.

[0451] Rt: 0.706 min (Method 6).3.7.7. Step 7: (15S,20S)-32-dimethylphosphoryl-18-methyl-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne

[0452] To a stirred mixture of tert-butyl (15S,20S)-32-dimethylphosphoryl-18-methyl-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9, 14, 18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4- yne-2-carboxylate (120 mg, 0.157 mmol, 1.0 equiv) in 1,4-dioxane (1.2 mL) was added hydrogen chloride (3.6 mL, 1.0 M in 1,4-dioxane). The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(10nmol / L NH4HCO3), Mobile Phase B: ACN; Plow rate: 60 mL / min mL / min; Gradient (B%): 29% B to 59 % B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 9. 11) to provide the title product (59.3 mg, 55% yield).

[0453] ’H NMR (400 MHz, DMSO-6) 5 7.76 (d, J= 8.0 Hz, 1H), 6.98 (t, J= 7.2 Hz, 1H), 6.67 - 6.74 (m, 1 H), 6.56 (t, J= 6.0 Hz, 1 H), 6.47 - 6.52 (m, 1H), 6.36 - 6.44 (m, 2H), 6.00 (d, J= 9..2 Hz, 1H), 4.19 - 4.34 (m, 2H), 4.04 - 4.16 (m, 2H), 3.67 - 3.78 (m, 2H), 3.58 - 3.67 (m, 1H), 3.44 - 3.55 (m, 3H), 3.35 - 3.43 (m, 2H), 2.95 - 3.02 (m, 1H), 2.87 - 2.95 (m, 1H), 2.72 - 2.82 (m, 1 H), 2.17 (s, 3 H), 1.88 - 2.05 (m, 4H), 1.47 - 1.65 (m, 8H), 0.99 - 1.11 (m, 1H). LCMS(ESI-MS) m / z = 666.3 [M+H]+. Rt: 1.441 min (Method 12)GAL-378-EP-EPA 993.8. Compound 6: (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen-4- yne-32-carboxylic acid3.8.1. Step 1: methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4, 7, 10-trioxa-3-siladodecan-l 2-yl)-l -methylpiperidin -4-yl]amin o'-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5-hydroxybenzoate

[0454] To a solution of methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2- yl }prop-2-yn- 1 -yl)(tert-butoxycarbonyl)amino] -5 -[(tert-butyldimethylsilyl)oxy]benzoate (12 g, 16.7 mmol, 1.0 equiv) in dioxane (360 mL) was added (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa- 3-siladodecan-12-yl)-l-methylpiperidin-4-amine (8.14 g, 16.7 mmol, 1.0 equiv), CS2CO3 (13.6 g, 41.9 mmol, 2.5 equiv), 3 -chloropyridine; { l,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro- lH-imidazol-2-yl}dichloropalladium (3.27 g, 3.35 mmol, 0.2 equiv) stirred at room temperature. The reaction mixture was stirred at 90 °C overnight under nitrogen and quenched with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 700 mL) and the organic layers were combined, washed with brine (3 x 700 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product The crude product was chromatographed on a silica gel column (Column: 350 * 2 g, 100 - 200 mesh, Mobile Phase A: DCM, Mobile Phase B: MeOH; Plow rate: 80 mL / min; Gradient: 0% B to 15% B in 30 min; Wave Length: 220 nm; 10% - 12% B fractions were collected) to provide the title product methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2- dimethyl-3 ,3 -diphenyl -4, 7, 10-trioxa-3 -siladodecan- 12-yl)- 1 -methylpiperidin -4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -5 -hydroxybenzoate (crude). The crude product was used in the next step directly without further purification.

[0455] LCMS(ESI-MS) m / z = 503.0 [1 / 2M+H]+.

[0456] Rt: 0.797 min (Method 2).GAL-378-EP-EPA 1003.8.2. Step 2: methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2- hydroxyeth oxy)eth oxy]ethyl}-l -methylpiperidin -4-yl]amin o'-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5-hydroxybenzoate

[0457] To a solution of methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3 -siladodecan- 12-yl)- 1 -methylpiperidin -4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -5 -hydroxybenzoate (27 g, 26.8 mmol, 1.0 equiv) in THF (270 mb) was added Tetra-n-butylammonium fluoride(1.0M in THF) (40.3 mb, 40.3 mmol, 1.5 equiv) stirred at room temperature. The reaction mixture was stirred for 1 h at room temperature and quenched with water (400 mb). The resulting mixture was extracted with EtOAc (3 x 500 mb) and the organic layers were combined, washed with brine (5 x 500 mb), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column (Column: 350 g, 20-35 pm, Mobile Phase A: water (0.05% NH4HCO3), Mobile Phase B: CH3CN; Flow rate: 80 mb / min; Gradient: 0% B to 100% B in 30 min; Wave Eength: 220 / 254 nm; 47% B fractions were collected), the fraction was concentrated under reduced pressure to provide the title product methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3- {2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5-hydroxybenzoate (9.5 g, 39% yield).

[0458] ECMS(ESI-MS) m / z = 766.4 [M+H]+.

[0459] Rt: 0.593 min (Method 2).3.8.3. Step 3: O2-tert-butyl O32-methyl (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,32-dicarboxylate

[0460] To a solution of methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2- hydroxyethoxy)ethoxy] ethyl } - 1 -methylpiperidin -4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5-hydroxybenzoate (6.5 g, 8.48 mmol, 1.0 equiv) in toluene (195 mb) was added CMBP (12.2 g, 50.9 mmol, 6.0 equiv) stirred at room temperature. The reaction mixture was stirred for 2 h at 90 °C and quenched with water (300 mb). The resulting mixture was extracted with EtOAc (3 x 500 mb) and the organic layers were combined, washed with brine (3 x 500 mb), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by Cl 8 column (Column: 350 g, 20-35 pm, Mobile Phase A: water (0.05% NH4HCO3), Mobile Phase B: CH3CN; Flow rate: 80 mb / min; Gradient: 0% B to 100% B in 30 min; Wave Eength: 220 / 254 nm; 88% B fractions were collected), the fraction was concentrated under reduced pressure to provide the title product (4.7 g, 66% yield).

[0461] ECMS(ESI-MS) m / z = 748.2 [M+H]+.

[0462] Rt: 0.647 min (Method 2).GAL-378-EP-EPA 1013.8.4. Step 4: methyl ( 15S,20S)-l 8-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylate

[0463] To a solution of 02-tert-butyl 032-methyl (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,32-dicarboxylate (2.5 g, 3.34 mmol, 1.0 equiv) in dioxane (25 mL) was added hydrogen chloride ((25 mb, 4.0 M in 1,4-dioxane) stirred at room temperature. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to afford the crude product (2.2 g, crude).

[0464] LCMS(ESI-MS) m / z = 648.3 [M+H]+.

[0465] Rt: 0.582 min (Method 18).3.8.5. Step 5: ( 15S,20S)-l 8-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18- pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta-l (33), 6(35), 7, 10, 12, 30(34), 31- h eptaen-4-yn e-32-carboxylic acid

[0466] To a solution of methyl (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylate (70.0 mg, 0.108 mmol, 1.0 equiv) in MeOH (1 mL) was added NaOH (17.3 mg, 0.432 mmol, 4 equiv, in H2O (0.5 mL)). The reaction mixture was stirred overnight at 50 °C. The mixture was adjusted to PH = 6 with hydrochloric acid (2 M). The resulting mixture was extracted with EtOAc (4 x 20 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 preparative HPLC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5 pm; Mobile Phase A: Water(10 nmol / LbTLJTCOs), Mobile Phase B: ACN; Plow rate: 60 mL / min mL / min; Gradient (B%): 28% B to 41% B in 9 min; Wave Length: 254 nm / 220 nm nm; RTl(min): 8.18) to provide the title product (15S,20S)-18-methyl-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid (51 mg, 74% yield).

[0467] LCMS(ESI-MS) m / z = 634.3 [M+H]+.

[0468] Rt: 0.747 min (Method 7).3.9. Alternative synthesis of compound IB: (15S,20S)-N,18-dimethyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamideGAL-378-EP-EPA 1023.9.1. Step 1: (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 7,9,14,18- pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta-l (33), 6(35), 7, 10, 12, 30(34), Silt eptaen-4-yn e-32-carboxylic acid

[0469] To a solution of methyl (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylate (2.2 g, 3.39 mmol, 1.0 equiv) in MeOH (22 mL) and THF (22 mL) was added NaOH (0.54 g, 13.5 mmol, 4.0 equiv, in H2O (22 mL)) stirred at room temperature. The reaction mixture was stirred overnight at 50 °C and diluted with water (50 mL). The mixture was adjusted to PH = 6 with hydrochloric acid (2 M). The resulting mixture was extracted with EtOAc (10 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product (15S,20S)-18-methyl-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9, 14, 18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12, 30(34),31-heptaen-4-yne-32-carboxylic acid (1.95 g, crude) . The crude product was used in the next step directly without further purification.

[0470] LCMS(ESI-MS) m / z = 634.2 [M+H]+.

[0471] Rt: 0.544 min (Method 2).3.9.2. Step 2: ( 15S,20S)-N, 18-dimethyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide

[0472] To a solution of (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4- yne-32-carboxylic acid (1.7 g, 2.68 mmol, 1.0 equiv) in DMF (57 mL) was added HATU (1.22 g, 3.22 mmol, 1.2 equiv), Methylamine hydrochloride (0.45 g, 6.70 mmol, 2.5 equiv) and DIEA (1.73 g, 13.4 mmol, 5.0 equiv) stirred at 0 °C. The reaction mixture was stirred at room temperature for 1 h and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL) and the organic layers were combined, washed with brine (3 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: WelFlash C18, Regular C18 20-40 pm, 330 g; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Wave Length: 254 nm / 220 nm nm; RTl(min): 25.5) to provide the title product (15S,20S)-N,18-dimethyl- 35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9, 14, 18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4- yne-32-carboxamide (570 mg, 97.9% purity). The crude product was triturated with ethyl acetate / n- hexane (20 mL / 20 mL ) to provide the title product (420.5 mg, 24% yield, 99.7% purity).

[0473] LCMS(ESI-MS) m / z = 647.3 [M+H]+.

[0474] Rt: 0.704 min (Method 7).GAL-378-EP-EPA 1033.10. Compound 7: (15S,20S)-N-[(l-hydroxycyclopropyl)methyl]-18-methyl-35-(trifluoro methylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]penta triaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide

[0475] To a stirred mixture of (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid (170 mg, 0.268 mmol, 1 equiv) and HATU (112 mg, 0.295 mmol, 1.1 equiv) in DMF (5 mL) was added DIEA (208 mg, 1.61 mmol, 6.0 equiv) at 0 °C. After stirred for 10 min at 0°C, l-(aminomethyl)cyclopropan-l-ol (25.7 mg, 0.295 mmol, 1.1 equiv) was added. The reaction mixture was stirred for 1 h at room temperature and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water Onmol / LNFLHCOs), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 43% B to61% B in8min; Wave Length: 254nm / 220nm nm; RTl(min): 5.77) to provide the title product ( 15 S,20S)-N-[( 1 -hydroxycyclopropyl)methyl] - 18-methyl-35-(trifluoromethylsulfanyl)-23,26,29- trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20] pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (59.7 mg, 31% yield).

[0476] ’H NMR (400 MHz, DMSO-6) 5 8.33 - 8.09 (m, 1H), 7.76 (d, J= 6.8 Hz, 1H), 6.97 (t, J= 7.2 Hz, 1H), 6.75 - 6.87 (m, 1H), 6.65 - 6.74 (m, 1H), 6.32 - 6.55 (m, 3H), 6.03 (d, J= 9.6 Hz, 1H), 5.41 (s, 1H), 4.20 - 4.35 (m, 2H), 4.02 - 4.19 (m, 2H), 3.70 - 3.82 (m, 2H), 3.61 - 3.69 (m, 1H), 3.45 - 3.60 (m, 3H), 3.35 -3.43 (m, 4H), 2.96 - 3.07 (m, 1H), 2.88 - 2.95 (m, 1H), 2.69 - 2.82 (m, 1H), 2.17 (s, 3H), 1.78 - 2.06 (m, 4H), 1.43 - 1.66 (m, 2H), 0.94 - 1.12 (m, 1H), 0.53 (s, 4H).

[0477] LCMS(ESI-MS) m / z = 703.3 [M+H]+.

[0478] Rt: 1.481 min (Method 12).GAL-378-EP-EPA 1043.11. Compound 8: (15S,20S)-18-methyl-N-(oxetan-3-yl)-35-(trifluoromethylsulfanyl)-23, 26,29- trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide

[0479] To a stirred mixture of (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid (170 mg, 0.268 mmol, 1.0 equiv) and HATU (112 mg, 0.295 mmol, 1.1 equiv) in DMF (5 mL) was added DIEA (208 mg, 1.61 mmol, 6.0 equiv). After stirred for 10 min at 0 °C, oxetan-3-amine (21.5 mg, 0.295 mmol, 1.1 equiv) was added. The reaction mixture was stirred for 1 h at room temperature and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water Onmol / LNFLHCOs), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 43% B to 61% B in8min; Wave Length: 254nm / 220nm nm; RTl(min): 5.68) to provide the title product (15S,20S)-18-methyl-N-(oxetan-3-yl)-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (77.6 mg, 41% yield).

[0480] ’H NMR (400 MHz, DMS0-6) 5 8.92 (d, J = 6.8 Hz, 1H), 7.76 (d, J= 6.4 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 6.75 - 6.90 (m, 1H), 6.55 - 6.71 (m, 1H), 6.44 - 6.53 (m, 1H), 6.36 - 6.43 (m, 2H), 6.03 (d, J= 9.2 Hz, 1H), 4.86 - 5.07 (m, 1H), 4.66 - 4.83 (m, 2H), 4.44 - 4.63 (m, 2H), 4.22 - 4.34 (m, 2H), 4.03- 4.21 (m, 2H), 3.67 - 3.83 (m, 2H), 3.57 - 3.67 (m, 1H), 3.42 - 3.56 (m, 3H), 3.34 - 3.43 (m, 2H), 2.94- 3.07 (m, 1H), 2.84 - 2.93 (m, 1H), 2.70 - 2.82 (m, 1H), 2.17 (s, 3H), 1.86 - 2.10 (m, 4H), 1.54 - 1.67 (m, 1H), 1.40 - 1.53 (m, 1H), 0.94 - 1.12 (m, 1H).

[0481] LCMS(ESI-MS) m / z = 689.3 [M+H]+.

[0482] Rt: 0.708 min (Method 7).GAL-378-EP-EPA 1053.12. Compound 9: (15S,20S)-18-methyl-N-methylsulfonyl-35-(trifluoromethylsulfanyl)-23, 26,29- trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide3.12.1. Step 1: (15S,20S)-2-tert-butoxycarbonyl-18-methyl-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid

[0483] A mixture of 02-tert-butyl 032-methyl (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,32-dicarboxylate (200 mg, 0.267 mmol, 1.0 equiv) in THF (2.0 mL) and MeOH (2.0 mL) was added NaOH (53.5 mg, 1.34 mmol, 5.0 equiv, in H2O (2.0 mL) ), then the mixture was stirred for 2 h at 50°C. The reaction mixture was diluted with water (20 mL) and acidified to PH=4 with hydrochloric acid (2M in H2O). The resulting mixture was extracted with ethyl acetate (3 x 50 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 (15S,20S)-2-tert-butoxycarbonyl-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9, 14, 18 -pentazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid (200 mg).

[0484] LCMS(ESI-MS) m / z = 734.3 [M+H]+.

[0485] Rt: 0.633 min. (Method 3).3.12.2. Step 2: (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta-l (33), 6(35), 7, 10, 12, 30(34), 31- h eptaen-4-yn e-32-carboxylic acid

[0486] A mixture of (15S,20S)-2-tert-butoxycarbonyl-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29- trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid (180 mg, 0.245 mmol, 1.0 equiv) inGAL-378-EP-EPA 106HC1 (g) (5.0 mL, 4.0 M in 1,4-dioxane) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford crude product ((15S,20S)-18-methyl-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20] pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid (crude).

[0487] LCMS(ESI-MS) m / z = 634.2 [M+H]+.

[0488] Rt: 0.557 min. (Method 2).3.12.3. Step 3: (15S,20S)-18-methyl-N-methylsulfonyl-35-(trifluoromethylsulfanyl)-23, 26,29- trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide

[0489] To a solution of ((15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4- yne-32-carboxylic acid (86.0 mg, 0.136 mmol, 1.0 equiv) in DCM (2.5 mL) was added methanesulfonamide (16.8 mg, 0.177 mmol, 1.3 equiv), DIEA (43.9 mg, 0.340 mmol, 2.5 equiv), DMAP (16.6 mg, 0.136 mmol, 1.0 equiv) and EDCI.HC1 (42.1 mg, 0.272 mmol, 2.0 equiv). The reaction mixture was stirred for 1 h at room temperature and quenched with H2O (60 mL) and the resulting mixture was extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 33% B to 43% B in 7min; Wave Length: 220nm; RTl(min): 6.37) to provide the title product (15S,20S)-18-methyl-N-methylsulfonyl-35- (trifluoromethylsulfanyl)-23 ,26, 29-trioxa-2, 7,9, 14, 18 -pentazapentacyclo[28.3. 1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen-4-yne-32- carboxamide (31.3 mg, 32 % yield).

[0490] LCMS(ESI-MS) m / z = 711.3 [M+H]+.

[0491] Rt: 1.541 min. (Method 12).GAL-378-EP-EPA 1073.13. Compound 10: (15S,20S)-N,18-dimethyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 9,14,18-tetrazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta-l (33), 6(35), 7, 10, 12, 30(34), 31- h eptaen-4-yn e-32-carboxamide3.13.1. Step 1: methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-l- yl)amino]-5-[(tert-butyldimethylsilyl)oxy]benzoate

[0492] To a stirred mixture of 8 -bromo-2-(3 -bromoprop- l-yn-l-yl)-3- [(trifhioromethyl)sulfanyl]indolizine (2.5 g, 6.05 mmol, 1.0 equiv, CAS3036280-30-2) and methyl 3- amino-5-[(tert-butyldimethylsilyl)oxy]benzoate (2.04 g, 7.26 mmol, 1.2 equiv) in DMF (40 mL) was added K2CO3 (2.51 g, 18.1 mmol, 3.0 equiv). The reaction mixture was stirred for 2 h at 70 °C and quenched with water (300 mL). The resulting mixture was quenched with EtOAc (3 x 300 mL) and the organic layers were combined, washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate, fdtered 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: 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; 11% B fractions were collected) to provide the title product methyl 3-[(3-{8-bromo- 3-[(trifhroromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-l-yl)amino]-5-[(tert- butyldimethylsilyl)oxy]benzoate (1.8 g, 43% yield).

[0493] LCMS(ESI-MS) m / z = 613.1, 615.1 [M+H]+.

[0494] Rt: 1. 194 min (Method 6).3.13.2. Step 2: methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-l- yl)(tert-butoxycarbonyl)amino]-5-[(tert-butyldimethylsilyl)oxy]benzoate

[0495] A stirred mixture of methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-l-yl)amino]-5-[(tert-butyldimethylsilyl)oxy]benzoate (1.8 g, 2.93 mmol, 1.0 equiv) in BOC2O (20 mL) was stirred overnight at 90 °C. The reaction mixture was quenched with water (100 mb) and extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100GAL-378-EP-EPA 108 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse purification C18 (Column: 20 - 35 pm, 100 A, 350 g; Mobile Phase A: Water (0.05% NH4HCO3), Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 40 min; Wave Length: 220nm nm; Collected fractions: 100 % B) to provide the title product methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2- yn-l-yl)(tert-butoxycarbonyl)amino]-5-[(tert-butyldimethylsilyl)oxy]benzoate (1.65 g, 71% yield).

[0496] LCMS(ESI-MS) m / z = 657.0 [M+H-56]+.

[0497] Rt: 1.105 min (Method 2).3.13.3. Step 3: methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecan-12-yl)-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)prop-2-yn-l-yl]amino]-5-[(tert-butyldimethylsilyl)oxy]benzoate and methyl 3-((tert- butoxycarbonyl)(3-(8-(((3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)- l-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-5- hydroxybenzoate (mixture)

[0498] A mixture of methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-l- yl)(tert-butoxycarbonyl)amino]-5-[(tert-butyldimethylsilyl)oxy]benzoate (1.0 g, 1.40 mmol, 1.0 equiv) and (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-l-methylpiperidin-4- amine (680 mg, 1.40 mmol, 1.0 equiv), 3 -chloropyridine; { l,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5- dichloro-2,3-dihydro-lH-imidazol-2-yl}dichloropalladium(140 mg, 0.140 mmol, 0.1 equiv), CS2CO3 (1.14 g, 3.50 mmol, 2.5 equiv) in dioxane (25 mL) was stirred overnight at 90 °C under nitrogen. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (3 x 200 mL). The organic layers were combined, washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product methyl 3 -[(tertbutoxy carbonyl)[3-(8-{[(3S,4S)-3-(2,2-dimethyl-3, 3-diphenyl -4,7,10-trioxa-3-siladodecan-12-yl)-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-l-yl]amino]-5- [(tert-butyldimethylsilyl)oxy]benzoate and methyl 3-((tert-butoxycarbonyl)(3-(8-(((3S,4S)-3-(2,2- dimethyl-3 ,3 -diphenyl -4, 7, 10-trioxa-3 -siladodecan- 12-yl)- 1 -methylpiperidin-4-yl)amino)-3 - ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-5-hydroxybenzoate (mixture) (1 g, crude).

[0499] LCMS(ESI-MS) m / z = 1117.4 [M+H]+.

[0500] Rt: 0.934 min (Method 2).3.13.4. Step 4: methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2- hydroxyeth oxy)eth oxy]ethyl}-l -methylpiperidin -4-yl]amin o'-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn-l-yl]amino]-5-hydroxybenzoate

[0501] To a stirred mixture of methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2-dimethyl-3,3- diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)prop-2-yn- 1 -yl]amino] -5 - [(tert-GAL-378-EP-EPA 109 butyldimethylsilyl)oxy]benzoate and methyl 3-((tert-butoxycarbonyl)(3-(8-(((3S,4S)-3-(2,2-dimethyl- 3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-l-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-l-yl)amino)-5-hydroxybenzoate (mixture) (1.0 g, 0.895 mmol, 1.0 equiv) in THF (20 mL) was added TBAF (1.8 mL, 2.0 equiv, IM in THF). The reaction mixture was stirred for 1 h at room temperature and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (6 x 100 mL), dried over anhydrous sodium sulfate, fdtered 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 30 min; Wave Length: 220 run; 7% B fractions were collected) to provide the title product methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2- hydroxyethoxy)ethoxy]ethyl}-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin- 2-yl)prop-2-yn-l-yl]amino]-5-hydroxybenzoate (600 mg, 90% pure).

[0502] LCMS(ESI-MS) m / z = 765.2 [M+H]+.

[0503] Rt: 0.612 min (Method 2).3.13.5. Step 5: O2-tert-butyl O32-methyl (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)~ 23,26,29-trioxa-2, 9,14,18-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,32-dicarboxylate

[0504] To a stirred mixture of methyl 3-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2- hydroxyethoxy)ethoxy]ethyl}-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin- 2-yl)prop-2-yn-l-yl]amino]-5-hydroxybenzoate (600 mg, 0.784 mmol, 1.0 equiv) in toluene (12 mL) was added CMBP (1.14 g, 4.70 mmol, 6.0 equiv). The reaction mixture was stirred for 1 h at 100 °C and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column with CH3CN / Water(0.05% NH4HCO3), the fraction was concentrated under reduced pressure to provide the title product 02 -tert-butyl 032-methyl (15S,20S)-18-methyl-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,9, 14, 18- tetrazapentacyclo [28.3.1.16,9.08,13.015 ,20]pentatria conta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,32-dicarboxylate (260 mg, 44% yield).

[0505] LCMS(ESI-MS) m / z = 747.3 [M+H]+.

[0506] Rt: 0.694 min (Method 2).3.13.6. Step 6: methyl (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 9,14,18-tetrazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylate

[0507] To a stirred mixture of 02-tert-butyl 032-methyl (15S,20S)-18-methyl-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,9, 14, 18-GAL-378-EP-EPA 110 tetrazapentacyclo [28.3.1.16,9.08,13.015 ,20]pentatria conta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,32-dicarboxylate (210 mg, 0.281 mmol, 1.0 equiv) in dioxane (3 mL) was added hydrogen chloride (3 mL, 4.0 M in 1,4-dioxane ). The reaction mixture was stirred for 1 h at room temperature and concentrated under reduced pressure to afford the crude product methyl (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,9,14,18- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4- yne-32-carboxylate (180 mg, crude).

[0508] LCMS(ESI-MS) m / z = 647.2 [M+H]+.

[0509] Rt: 0.743 min (Method 6).3.13.7. Step 7: (15S,2()S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,9,14,18- tetrazapentacyclo[28.3.1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen- 4-yne-32-carboxylic acid

[0510] To a stirred mixture of methyl (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,9,14,18-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31- heptaen-4-yne-32-carboxylate (180 mg, 0.278 mmol, 1.0 equiv) in THF (2 mL), methanol (2 mL) was added NaOH (44 mg, 1.11 mmol, 4.0 equiv, in H2O (2 mL) ). The reaction mixture was stirred for 4 h at 50 °C. The reaction mixture was adjusted to PH=2 with IM HC1 and diluted 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, fdtered and concentrated under reduced pressure to afford crude product (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,9,14,18-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31- heptaen-4-yne-32-carboxylic acid (170 mg, crude).

[0511] LCMS(ESI-MS) m / z = 633.3 [M+H]+.

[0512] Rt: 0.721 min (Method 6).3.13.8. Step 8: (15S,20S)-N,18-dimethyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 9,14,18-tetrazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide

[0513] To a stirred mixture of (15S,20S)-18-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,9,14,18-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31- heptaen-4-yne-32-carboxylic acid (130 mg, 0.205 mmol, 1.0 equiv) and Methylamine hydrochloride (41 mg, 0.615 mmol, 3.0 equiv) in DML (3 mL) was added DIEA (185 mg, 1.43 mmol, 7.0 equiv) dropwise at 0 °C. The reaction mixture was stirred for 1 h at 0 °C and quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, fdtered 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, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Plow rate: 60 mL / min mL / min; Gradient (B%):GAL-378-EP-EPA 11142% B to 72% B in 8min; Wave Length: 254nm / 220nm nm; RTl(min): 7.18 to provide the title product (15S,20S)-N,18-dimethyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,9,14,18- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12, 30(34),31-heptaen-4-yne-32-carboxamide (74.8 mg, 55% yield).

[0514] ’H NMR (400 MHz, DMSO-6) 5 8.22 (d, J= 4.4 Hz, 1H), 7.70 (d, J= 6.8 Hz, 1H), 7.08 (s, 1H),6.78 - 6.82 (m, 1H), 6.70 - 6.77 (m, 1H), 6.62 (s, 1H), 6.42 (s, 2H), 6.01 (d, J= 7.6 Hz, 1H), 5.78 (d, J = 9.2 Hz, 1H), 4.15-4.25 (m, 2H), 4.00-4.15 (m, 2H), 3.65 - 3.83 (m, 2H), 3.50 - 3.64 (m, 3H), 3.35- 3.49 (m, 3H), 2.68 - 3.00 (m, 6H), 2.17 (s, 3H), 1.91 - 2.00 (m, 2H), 1.75- 1.90 (m, 2H), 1.55- 1.68 (m, 1H), 1.38 - 1.54 (m, 1H), 0.98 - 1.12 (m, 1H).

[0515] LCMS(ESI-MS) m / z = 646.3 [M+H]+.

[0516] Rt: 0.759 min (Method 7).3.14. Compound 11A and 11B: (15S,20S)-N-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31- heptaen-4-yne-32-carboxamide and (15R,20R)-N-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31- h eptaen-4-yn e-32-carboxamideGAL-378-EP-EPA 1123.14.1. Step 1: rac-tert-butyl (3S,4S)-4-((2-(3-((tert-butoxycarbonyl)(3-((tert-butyldimethyl silyl)oxy)-5-(methoxycarbonyl)phenyl)amino)prop-l-yn-l-yl)-3-((trifluoromethyl)thio)imidazo [l,2-a]pyridin-8-yl)amino)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)pipe ridine-l-carboxylate (mixture with rac-tert-butyl (3S,4S)-4-((2-(3-((tert-butoxycarbonyl)(3-hydro xy-5-(methoxycarbonyl)phenyl)amino)prop-l-yn-l-yl)-3-((trifluoromethyl)thio)imidazo[l,2- a]pyridin-8-yl)amino)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate)

[0517] To a mixture of methyl 3-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl)(tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)benzoate (2.0 g, 2.80 mmol,1.0 equiv), rac-tert-butyl (3S,4S)-4-amino-3-(2,2-dimethyl-3,3-diphenyl-4,7, 10-trioxa-3-siladodecan- 12-yl)piperidine-l -carboxylate (1.76 g, 3.08 mmol, 1.1 equiv), 3 -chloropyridine; { l,3-bis[2,6- bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-lH-imidazol-2-yl}dichloropalladium (273 mg, 0.280 mmol, 0.1 equiv) and CS2CO3 (2.28 g, 7.00 mmol, 2.5 equiv) in Dioxane (110 mb) was stirred overnight at 90°C under nitrogen and quenched with water (100 mb). The resulting mixture was extracted with ethyl acetate (3 x 100 mb) and the organic layers were combined, washed with brine (2 x 60 mb), dried over anhydrous sodium sulfate, fdtered 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: PE, Mobile Phase B: EtOAc; Plow rate: 60 mb / min; Gradient: 0% B to 100% B in 30 min; Wave Eength: 220 nm; 50% B fractions were collected) to provide the title product rac-tert-butyl (3S,4S)-4-((2-(3-((tert-butoxycarbonyl)(3-((tert-butyldimethylsilyl)oxy)-5- (methoxycarbonyl)phenyl)amino)prop- 1 -yn- 1 -yl)-3-((trifluoromethyl)thio)imidazo[ 1 ,2-a]pyridin-8- yl)amino)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-l-carboxylate (mixture with rac-tert-butyl (3 S, 4 S)-4-((2-(3-((tert-butoxycarbonyl)(3 -hydroxy-5 -(methoxy carbonyl)phenyl)amino)prop- 1 -yn- 1 -yl) -3 -((trifluoromethyl) thio)imidazo[l,2-a]pyridin-8-yl)amino)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan- 12-yl)piperidine-l -carboxylate) (2.8 g, crude).

[0518] ECMS(ESI-MS) m / z = 1204.5 [M+H]+.

[0519] Rt: 1.367 min (Method 2).3.14.2. Step 2: rac-tert-butyl (3S,4S)-4-((2-(3-((tert-butoxycarbonyl)(3-hydroxy-5- (methoxycarbonyl)phenyl)amino)prop-l-yn-l-yl)-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin- 8-yl)amino)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine-l-carboxylate

[0520] To a solution of rac-tert-butyl (3S,4S)-4-((2-(3-((tert-butoxycarbonyl)(3-((tert- butyldimethylsilyl)oxy)-5 -(methoxy carbonyl)phenyl)amino)prop- 1 -yn- 1 -y 1) -3 - ((trifhioromethyl)thio)imidazo[l,2-a]pyridin-8-yl)amino)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3 -siladodecan-12-yl)piperidine-l -carboxylate (mixture with rac-tert-butyl (3S,4S)-4-((2-(3-((tert- butoxycarbonyl)(3 -hydroxy-5 -(methoxy carbonyl)phenyl)amino)prop- 1 -yn- 1 -y 1) -3 - ((trifluoromethyl)thio) imidazo[l,2-a]pyridin-8-yl)amino)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)GAL-378-EP-EPA 113 piperidine- 1 -carboxylate) (2.8 g, 2.33 mmol, 1.0 equiv) in THF (28.0 mL) was added TBAF (3.5 mL, 3.49 mmol, 1.5 equiv) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL), the organic layers were combined, washed with brine (60 mL), dried over anhydrous sodium sulfate, fdtered 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: PE, Mobile Phase B: EtOAc; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; Wave Length: 220 nm; 100% B fractions were collected) to provide the title product rac-tert-butyl (3S,4S)- 4-((2-(3 -((tert-butoxycarbonyl)(3 -hydroxy-5 -(methoxy carbonyl)phenyl)amino)prop- 1 -yn- 1 -y 1) -3 - ((trifluoromethyl)thio)imidazo [ 1 ,2-a]py ridin-8-yl)amino)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine-l-carboxylate (610 mg, 90% pure).

[0521] LCMS(ESI-MS) m / z = 852.3 [M+H]+.

[0522] Rt: 0.758 min (Method 2).3.14.3. Step 3: 02,018-ditert-butyl O32-methyl rac-(15S,20S)-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,18,32-tricarboxylate

[0523] To a solution of rac-tert-butyl (3S,4S)-4-((2-(3-((tert-butoxycarbonyl)(3-hydroxy-5- (methoxycarbonyl)phenyl)amino)prop- 1 -yn- 1 -yl)-3-((trifluoromethyl)thio)imidazo[ 1 ,2-a]pyridin-8- yl)amino)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine-l-carboxylate (1.0 g, 1.17 mmol, 1.0 equiv) in toluene (30 mL) was added CMBP (1.69 g, 7.02 mmol, 6.0 equiv) at room temperature under nitrogen. The reaction mixture was stirred for 2 h at 90 °C under nitrogen and quenched with water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 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: 120 g, 100 - 200 mesh, Mobile Phase A: PE, Mobile Phase B: EtOAc; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; Wave Length: 220 nm; 28% B fractions were collected) to provide the title product 02,018-ditert-butyl 032-methyl rac-(15S,20S)-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]penta triaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,18,32-tricarboxylate (600 mg, 55% yield).

[0524] LCMS(ESI-MS) m / z = 834.4 [M+H]+.

[0525] Rt: 0.911 min (Method 2).GAL-378-EP-EPA 1143.14.4. Step 4: rac-( 15S,20S)-2, 18-bis(tert-butoxycarbonyl)-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid

[0526] To a stirred mixture of 02,018-ditert-butyl 032-methyl rac-(15S,20S)-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20] pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,18,32-tricarboxylate (600 mg, 0.719 mmol, 1.0 equiv) in THF (6 mL) and MeOH (2 mL) was added NaOH (57.6 mg, 1.44 mmol, 2.0 equiv, in H2O (2 mL)) and stirred for 2 h at 50°C. The reaction mixture was diluted with water (50 mL) and acidified to PH=4 with hydrochloric acid (2M). The resulting mixture was extracted with ethyl acetate (3 x 100 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 rac-( 15 S,20S)-2, 18-bis(tert-butoxycarbonyl)-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2.7.9.14.18 -pentazapentacyclo [28.3. 1.16, 9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid (600 mg, crude).

[0527] LCMS(ESI-MS) m / z = 820.2 [M+H]+.

[0528] Rt: 0.819 min (Method 2).3.14.5. Step 5: ditert-butyl rac-(15S,20S)-32-(methylcarbamoyl)-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,18-dicarboxylate

[0529] To a solution of rac-(15S,20S)-2,18-bis(tert-butoxycarbonyl)-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35), 7,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid (600 mg, 0.732 mmol, 1.0 equiv) in DMF (14.4 mL) were added HATU (334 mg, 0.878 mmol, 1.2 equiv), Methylamine hydrochloride (79.1 mg, 1.17 mmol, 1.6 equiv) and DIEA (568 mg, 4.39 mmol, 6.0 equiv) at 0°C. The reaction mixture was stirred for 1 h at room temperature and quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 80 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (EtOAc =100; Rf = 0.3; detection: UV) to provide the title product ditert-butyl rac-(15S, 20S)-32-(methylcarbamoyl)-35-(trifluoromethylsulfanyl)-23, 26,29- trioxa-2,7,9,14.18-entazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31- heptaen-4-yne-2,18-dicarboxylate (300 mg, 44% yield).

[0530] LCMS(ESI-MS) m / z = 833.3 [M+H]+.

[0531] Rt: .834 min (Method 2).GAL-378-EP-EPA 1153.14.6. Step 6: (15S,20S)-N-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta-l (33), 6(35), 7, 10, 12, 30(34), 31- heptaen-4-yne-32-carboxamide and (15R,20R)-N-methyl-35-(trifluoromethylsulfanyl)-23, 26,29- trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide

[0532] To a solution of ditert-butyl rac-(15S,20S)-32-(methylcarbamoyl)-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2,7,9,14,18-entazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-2,18-dicarboxylate (50.0 mg, 0.060 mmol, 1.0 equiv) in HC1 (g, 1.0 mL, 4.0 M in 1,4-dioxane) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford crude product rac-(15S,20S)-N-methyl-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20] pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (30 mg) . Then the racemic product (30 mg) was separated by Chiral HPLC (Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.3% IPAmine)-HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 25; Wave Length: 220 nm; RTl(min): 17.617; RT2(min): 20.96) to provide the title product (15S,20S)-N-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (13 mg).

[0533] The product (13 mg) was further purified by preparative HPLC (Column: Xselect CSH Prep C18 OBD Column, 30* 150 mm, 5pm; Mobile Phase A: Water(0. 1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 15% B to 35% B in 5 min; Wave Length: 220nm; RTl(min): 4.6) to provide the title compound 11A (2.7 mg, 7% yield).

[0534] ’H NMR (400 MHz, DMSO-6) 5 8.39 (br, 1H), 8. 15 - 8.29 (m, 1H), 7.78 (d, J= 6.4 Hz, 1H), 6.99 (t, J= 7.2 Hz, 1H), 6.79 (s, 1H), 6.63 (s, 1H), 6.40 - 6.50 (m, 2H), 6.35 - 6.39 (m, 1H), 6.15 - 6.30 (m,1H), 4.20 - 4.30 (m, 2H), 4.05 - 4.15 (m, 2H), 3.70 - 3.80 (m, 2H), 3.60 - 3.69 (m, 1H), 3.45 - 3.59 (m,3H), 3.30 - 3.40 (m, 2H), 3.20 - 3.29 (m, 2H), 3.00 - 3.10 (m, 1H), 2.70 - 2.90 (m, 4H), 2.35 - 2.45 (m,1H), 1.80 - 2.10 (m, 3H), 1.40 - 1.60 (m, 1H), 1.00 - 1.20 (m, 1H).

[0535] LCMS(ESI-MS) m / z = 633.3 [M+H]+.

[0536] Rt: 0.709 min. (Method 7).

[0537] And (15R,20R)-N-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4- yne-32-carboxamide((12 mg). The product (12 mg) was purified by preparative HPLC (Column: Xselect CSH Prep C18 OBD Column, 30* 150 mm, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 15% B to 35% B in 5 min; Wave Length: 220nm; RTl(min): 4.6) to provide the title product title compound 1 IB (4.7 mg, 12% yield).

[0538] LCMS(ESI-MS) m / z = 633.3 [M+H]+.

[0539] Rt: 0.708 min. (Method 7).GAL-378-EP-EPA 1163.15. Compound 12: (15S,20S)-34-methoxy-18-methyl-36-(trifluoromethylsulfanyl)-23,26-dioxa- 2,7,9,14,18,29,32-heptazapentacyclo[29.3.1.16,9.08,13.015,20]hexatriaconta-l(35),6(36),7,10,12,31 ,33- heptaen-4-yn-30-one3.15.1. Step 1: methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2- yl}prop-2-yn-l-yl)(tert-butoxycarbonyl)amino]-5-methoxypyridine-2-carboxylate

[0540] To a solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine (640 mg, 1.51 mmol, 1.0 equiv) in DMSO (12 mL) was added methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-l- yl)amino] -5 -methoxypyridine-2 -carboxylate (727 mg, 2.27 mmol, 1.5 equiv), cuprous iodide (86.5 mg, 0.454 mmol, 0.3 equiv), trimethylamine (612 mg, 6.05 mmol, 4.0 equiv) and Bis(triphenylphosphine)palladium(II) chloride (159 mg, 0.227 mmol, 0.15 equiv). The reaction mixture was stirred for 2 h at room temperature under nitrogen and quenched with water (30 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, fdtered and concentrated under reduced pressure to afford the 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; Plow rate: 60 mL / min; Gradient: 0% B to 100% B in 40 min; Wave Length: 254nm; Collected fractions: 45% - 52% B) to afford the title product methyl 4-[(3-{8-bromo-3-[(trifhroromethyl)sulfanyl]imidazo [ 1 ,2-a]pyridin-2-yl }prop-2-yn- 1 -yl)(tert-butoxycarbonyl)amino] -5 - methoxypyridine-2 -carboxylate (900 mg, 86% yield).

[0541] LCMS(ESI-MS) m / z = 615.1, 617.1 [M+H]+.

[0542] Rt: 0.851 min (Method 6).GAL-378-EP-EPA 1173.15.2. Step 2: methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2-dimethyl-3,3-diphenyl- 4, 7, 10-trioxa-3-siladodecan-l 2-yl)-l -methylpiperidin -4-yl]amin o'-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5-methoxypyridine- 2-carboxylate

[0543] To a solution of methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2- yl}prop-2-yn-l-yl)(tert-butoxycarbonyl)amino]-5-methoxypyridine-2-carboxylate (381 mg, 0.619 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) was added (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecan-l 2-yl)- 1 -methylpiperidin -4-amine (300 mg, 0.619 mmol, 1.0 equiv), cesium carbonate (504 mg, 1.55 mmol, 2.5 equiv) and 3 -chloropyridine; { l,3-bis[2,6-bis(heptan-4-yl)phenyl]- 4,5-dichloro-2,3-dihydro-lH-imidazol-2-yl}dichloropalladium (151 mg, 0.155 mmol, 0.25 equiv). The reaction mixture was stirred overnight at 90°C under nitrogen and quenched with water (30 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, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: methanol / dichloromethane =1: 10; Rf = 0.4; detection: UV), the fraction was concentrated under reduced pressure to afford the title product methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2- dimethyl-3 ,3 -diphenyl -4, 7, 10-trioxa-3 -siladodecan- 12-yl)- 1 -methylpiperidin -4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -5-methoxypyridine-2- carboxylate (500 mg, 63% yield).

[0544] LCMS(ESI-MS) m / z = 1019.4 [M+H]+.

[0545] Rt: 0.795 min (Method 2).3.15.3. Step 3: methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2- hydroxyeth oxy)eth oxy]ethyl}-l -methylpiperidin -4-yl]amin o'-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5-methoxypyridine- 2-carboxylate

[0546] To a solution of methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3 -siladodecan- 12-yl)- 1 -methylpiperidin -4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -5-methoxypyridine-2- carboxylate (650 mg, 0.638 mmol, 1.0 equiv) in THE (6.5 mL) was added tetrabutylammonium fluoride (0.96 mL, 0.957 mmol, 1.2 equiv, 1 M in THF). The reaction mixture was stirred for 1 h at room temperature and quenched with water (30 mL). The resulting mixture was extracted with EA (3 x 30 mL) and the organic layers were combined, washed with brine (5 x 30 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: dichloromethane / methanol=10 / l; Rf = 0.4; detection: UV), the fraction was concentrated under reduced pressure to provide the title product methyl 4-[(tert- butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5- methoxypyridine-2 -carboxylate (300 mg, 54% yield).GAL-378-EP-EPA 118

[0547] LCMS (ESI-MS) m / z = 781.3 [M+H]+.

[0548] Rt: 0.572 min (Method 18).3.15.4. Step 4: methyl 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-a doethoxy)ethoxy]ethyl}-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l- yl](tert-butoxycarbonyl)amino}-5-methoxypyridine-2-carboxylate

[0549] To a solution of methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-{2-[2-(2- hydroxyethoxy)ethoxy] ethyl } - 1 -methylpiperidin-4-yl] amino } -3 - [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -5-methoxypyridine-2- carboxylate (330 mg, 0.423 mmol, 1.0 equiv) in THF (15 mb) was added diphenylphosphoryl azide (465 mg, 1.69 mmol, 4.0 equiv) and l,8-Diazabicyclo[5.4.0]undec-7-ene (257 mg, 1.69 mmol, 4.0 equiv) at 0 °C. After stirred for 24 h at room temperature, the reaction mixture was warmed to 70 °C and stirred overnight. The reaction mixture was quenched with water (30 mb). The resulting mixture was extracted with EtOAc (3 x 50 mb) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product methyl 4-{ [3- (8-{[(3S,4S)-3-{2-[2-(2-azidoethoxy)ethoxy]ethyl}-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[ 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl] (tert-butoxycarbonyl)amino}-5-methoxypyridine-2-carboxylate (400 mg, crude).

[0550] ECMS (ESI-MS) m / z = 806.4 [M+H]+.

[0551] Rt: 0.623 min (Method 2).3.15.5. Step 5: methyl 4-((3-(8-(((3S,4S)-3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-l- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l- yl)(tert-butoxycarbonyl)amin o)-5-meth oxypicolin ate

[0552] To a solution of methyl 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-azidoethoxy)ethoxy]ethyl}-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl] (tert-butoxycarbonyl)amino}-5-methoxypyridine-2-carboxylate (289 mg, 0.371 mmol, 1.0 equiv) in THF (6 mb) was added triphenylphosphine (146 mg, 0.556 mmol, 1.5 equiv). After stirred for 3 h at room temperature, H2O (2 mb) was added and the mixture was stirred overnight at 80 °C to afford the crude product methyl 4-((3-(8-(((3S,4S)-3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-l-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl)(tert- butoxy carbonyl)amino)-5 -methoxypicolinate .

[0553] ECMS (ESI-MS) m / z = 780.4 [M+H]+.

[0554] Rt: 0.448 min (Method 51).GAL-378-EP-EPA 1193.15.6. Step 6: methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-[2-(2-{2-[(tert- butoxycarbonyl)amino]ethoxy}ethoxy)ethyl]-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5-methoxypyridine- 2-carboxylate

[0555] To a mixture of methyl 4-((3-(8-(((3S,4S)-3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-l- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l- yl)(tert-butoxycarbonyl)amino)-5-methoxypicolinate (245 mg, 0.314 mmol, 1.0 equiv) in THF (7 mL) was added di-tert-butyl dicarbonate (103 mg, 0.471 mmol, 1.5 equiv) and trimethylamine (63.6 mg, 0.628 mmol, 2.0 equiv). The reaction mixture was stirred for 2 h at room temperature and quenched with water (30 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 TLC (Mobile phase: dichloromethane / methanol=10 / l; Rf = 0.5; detection: UV), the fraction was concentrated under reduced pressure to provide the title product methyl 4-[(tert-butoxycarbonyl)[3-(8- {[(3S,4S)-3-[2-(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethoxy)ethyl]-l-methylpiperidin-4- yl] amino } -3 - [(trifluoromethyl) sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5-methoxypyridine-2 -carboxylate (50 mg, 16% yield).

[0556] LCMS(ESI-MS) m / z = 902.3 [M+Na]+.

[0557] Rt: 0.643 min (Method 2).3.15.7. Step 7: 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-[2-(2-{2-[(tert- butoxycarbonyl)amino]ethoxy}ethoxy)ethyl]-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5-methoxypyridine- 2-carboxylic acid

[0558] To a mixture of methyl 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-[2-(2-{2-[(tert- butoxycarbonyl)amino] ethoxy } ethoxy)ethyl] - 1 -methylpiperidin-4-yl] amino } -3 - [(trifluoromethyl) sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino]-5-methoxypyridine-2 -carboxylate (40.0 mg, 0.045 mmol, 1.0 equiv) in MeOH (0.4 mL) and THE (0.4 mL) was added sodium hydroxide (9.07 mg, 0.225 mmol, 5.0 equiv, in 0.4 mL H2O). The reaction mixture was stirred for 1 h at room temperature and diluted with water (2 mL). 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 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)- 3-[2-(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethoxy)ethyl]-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl] imidazof 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -5 -methoxypyridine -2 -carboxylic acid(40.0 mg, crude).

[0559] LCMS(ESI-MS) m / z = 866.4 [M+H]+.

[0560] Rt: 0.751 min (Method 6).GAL-378-EP-EPA 1203.15.8. Step 8: 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-aminoethoxy)ethoxy]ethyl]-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino}-5- meth oxypyridin e-2-carboxylic acid

[0561] To a solution of 4-[(tert-butoxycarbonyl)[3-(8-{[(3S,4S)-3-[2-(2-{2-[(tert- butoxycarbonyl)amino] ethoxy } ethoxy)ethyl] - 1 -methylpiperidin-4-yl] amino } -3 - [(trifluoromethyl) sulfanyl] imidazof 1 ,2-a]pyridin-2-yl)prop-2-yn- 1 -yl]amino] -5 -methoxypyridine -2 -carboxylic acid(40.0 mg, 0.046 mmol, 1.0 equiv) in dichloromethane (0.9 mb) was added trifluoroacetic acid (0.3 mb). The reaction mixture was stirred for 1 h at room temperature and concentrated under reduced pressure to afford crude product 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-l-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino}-5- methoxypyridine-2 -carboxylic acid (30.8 mg, crude).

[0562] LCMS(ESI-MS) m / z = 666.3 [M+H]+.

[0563] Rt: 0.503 min (Method 6).3.15.9. Step 9: (15S,20S)-34-methoxy-18-methyl-36-(trifluoromethylsulfanyl)-23,26-dioxa- 2,7,9,14,18,29,32-heptazapentacyclo[29.3.1.16,9.08,13.015,20]hexatriaconta-l(35),6(36),7, 10,12,31,33-h eptaen -4-yn -30-on e

[0564] To a mixture of 4-{[3-(8-{[(3S,4S)-3-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)prop-2-yn-l-yl]amino}-5- methoxy pyridine-2 -carboxylic acid (30.8 mg, 0.046 mmol, 1.0 equiv) and o-(7-azabenzotriazol-l-yl)- N,N,N',N'-te-tramethyluronium hexafluorophosphate (21.1 mg, 0.055 mmol, 1.2 equiv) in N,N- dimethylformamide (2 mb) was added dropwise N,N -diisopropylethylamine (29.9 mg, 0.230 mmol, 5.0 equiv) at 0 °C. The reaction mixture was stirred for 1 h at room temperature and quenched with water (10 mb). The resulting mixture was extracted with EtOAc (3 x 30 mb) and the organic layers were combined, washed with brine (2 x 20 mb), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPEC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Wate^lOnmol / ENlEHCOs), Mobile Phase B: ACN; Plow rate: 60 mb / min mb / min; Gradient (B%): 38% B to51% B in9 min; Wave Eength: 254nm / 220nm nm; RTl(min): 8.23) to afford the title product (15S,20S)-34-methoxy-18-methyl-36-(trifluoromethylsulfanyl)-23,26-dioxa-2,7,9,14,18,29,32- heptazapentacyclo [29.3.1.16,9.08,13.015,20] hexatriaconta-l(35),6(36),7,10,12,31,33-heptaen-4-yn-30-one (2.1 mg, 6% yield).

[0565] ECMS(ESI-MS) m / z = 648.3 [M+H]+.

[0566] Rt: 0.589 min (Method 7).GAL-378-EP-EPA 1213.16. Compound 13A and 13B: (15R,20R)-18-(cyanomethyl)-N-methyl-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide and (15S,20S)-18-(cyanomethyl)-N- methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18- pentazapentacyclo[28.3.1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen-4- yn e-32-carboxamide

[0567] To a solution of rac-(15S,20S)-N-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (53 mg, 0.084 mmol, 1.0 equiv) in THF (2.65 mL) was added 2-bromoacetonitrile (11.1 mg, 0.092 mmol, 1.1 equiv) and triethylamine (9.32 mg, 0.092 mmol, 1.1 equiv) at room temperature. The reaction mixture was stirred for 2 h at 50°C under N2 and quenched with H2O (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 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 (MeOH / DCM = 1 / 6, Rf= 0.4; detection: UV), the fraction was concentrated under reduced pressure to provide the title crude product (25 mg, 83% pure). The crude product was further purified by Chiral HPLC (Column: CHIRALPAK IM, 2*25 cm, 5 pm; 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 50; Wave Length: 254 / 220 nm; RTl(min): 7.404; RT2(min): 9.481) to provide the isomer 1 (RTl(min): 7.404): (15R,20R)-18-(cyanomethyl)-N-methyl-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2,7,9, 14, 18 -pentazapentacyclo[28.3. 1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen-4-yne-32- carboxamide (1.7 mg, 2% yield).

[0568] LCMS(ESI-MS) m / z = 672.3

[0569] [M+H]+. Rt: 0.812 min. (Method 7).

[0570] And another isomer 2 (RT2(min): 9.481): (15S,20S)-18-(cyanomethyl)-N-methyl-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20] pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (1.4 mg, 2% yield).

[0571] ’H NMR (400 MHz, DMSO-d6) 5 8.10 - 8.40 (m, 1H), 7.76 (d, J = 6.4 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.78 (s, 1H), 6.63 (s, 1H), 6.40 - 6.50 (m, 2H), 6.30 - 6.39 (m, 1H), 6.11 (d, J = 9.6 Hz, 1H),4.20 - 4.30 (m, 2H), 4.00 - 4.15 (m, 2H), 3.70 - 3.80 (m, 4H), 3.60 - 3.69 (m, 1H), 3.45 - 3.59 (m, 3H),3.40 - 3.44 (m, 2H), 3.00 - 3.15 (m, 1H), 2.90 - 2.99 (m, 1H), 2.80 - 2.88 (m, 1H), 2.70 - 2.79 (m, 3H),2.35 - 2.40 (m, 1H), 2.00 - 2.10 (m, 1H), 1.90 - 1.99 (m, 3H), 1.50 - 1.60 (m, 1H), 1.00 - 1.10 (m, 1H).

[0572] LCMS(ESI-MS) m / z = 672.3 [M+H]+.GAL-378-EP-EPA 122

[0573] Rt: 0.818 min. (Method 7).3.17. Compound 14A and 14B: (15R,20R)-N-methyl-18-(2,2,2-trifluoroethyl)-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18- pentazapentacyclo[28.3.1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen-4- yne-32-carboxamide and (15S,20S)-N-methyl-18-(2,2,2-trifluoroethyl)-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide

[0574] To a solution of rac-(15S,20S)-N-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (76.0 mg, 0.120 mmol, 1.0 equiv) in ACN (7.6 mL) was added 2,2, 2 -trifluoroethyl trifluoromethanesulfonate (105 mg, 0.450 mmol, 3.75 equiv) and CS2CO3 (176 mg, 0.540 mmol, 4.5 equiv). The reaction mixture was stirred overnight at room temperature and quenched with water (50 mL) and the resulting mixture was extracted with EtOAc (3 x 80 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was further purified by Chiral HPLC (Column: CHIRALPAK IM 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1- HPLC; Plow rate: 20 mL / min; Gradient (B%): isocratic 40; Wave Length: 220 nm; RTl(min): 8.565; RT2(min): 11.556) to provide the title isomer 1 / RT1: (15R,20R)-N-methyl-18-(2,2,2-trifluoroethyl)- 35-(trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9, 14, 18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4- yne-32-carboxamide (13.7 mg, 15% yield).

[0575] LCMS(ESI-MS) m / z = 715.3 [M+H]+.

[0576] Rt: 0.866 min. (Method 7).

[0577] (15S,20S)-N-methyl-18-(2,2,2-trifluoroethyl)-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (11.3 mg, 13% yield).

[0578] LCMS(ESI-MS) m / z = 715.3 [M+H]+.

[0579] Rt: 0.869 min. (Method 7).GAL-378-EP-EPA 1233.18. Compound 15A and 15B: (15R,20R)-N-methyl-18-(trideuteriomethyl)-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2, 7, 9,14,18- pentazapentacyclo[28.3.1.16, 9.08, 13.015, 20]pentatriaconta-l(33), 6(35), 7, 10, 12, 30(34), 31-heptaen-4- yne-32-carboxamide and (15S,20S)-N-methyl-18-(trideuteriomethyl)-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide

[0580] To a solution of rac-(15S,20S)-N-methyl-35-(trifluoromethylsulfanyl)-23,26,29-trioxa- 2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (75.0 mg, 0.119 mmol, 1.0 equiv) in deuterated methanol (3.75 mL) was added Formaldehyde-d2 (15.2 mg, 0.095 mmol, 0.8 equiv, (20% in D2O)), acetic-d3 acid-d (15.2 mg, 0.238 mmol, 2.0 equiv) and sodium tetrahydroborate- d4 (7.44 mg, 0.178 mmol, 1.5 equiv) at 0°C. The reaction mixture was stirred for 2 h at room temperature and quenched with H2O (50 mL) and the resulting mixture was extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (MeOH / DCM = 1 / 6, Rf = 0.4; detection: UV), the fraction was concentrated under reduced pressure to provide the title crude product (30 mg, 85% pure). The crude product was further purified by Chiral HPLC (Column: CHIRALPAK IM, 2*25 cm, 5 pm; 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 40; Wave Length: 220 nm; RTl(min): 8.181; RT2(min): 10.812) to provide the title isomer 1 (RTl(min): 8.181): (15R,20R)-N-methyl-18-(trideuteriomethyl)-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9,14,18-pentazapentacyclo[28.3.1.16,9.08,13.015,20] pentatriaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (1.5 mg, 1% yield).

[0581] LCMS(ESI-MS) m / z = 650.3 [M+H]+.

[0582] Rt: 1.444 min. (Method 12).

[0583] And another isomer 2 (RT2(min): 10.812): (15S,20S)-N-methyl-18-(trideuteriomethyl)-35- (trifluoromethylsulfanyl)-23,26,29-trioxa-2,7,9, 14, 18- pentazapentacyclo[28.3.1.16,9.08,13.015,20]penta triaconta-l(33),6(35),7,10,12,30(34),31-heptaen-4-yne-32-carboxamide (1.1 mg, 1% yield).

[0584] LCMS(ESI-MS) m / z = 650.3 [M+H]+.

[0585] Rt: 1.457 min. (Method 12).GAL-378-EP-EPA 1243.19. Compound 16A and 16B: (15S,20S)-N-methyl-18-(oxetan-3-yl)-35-(trifluoromethylsulfanyl)- 23,26,29-trioxa-2, 7, 9,14,18-pentazapentacyclo[28.3.1.16, 9.08,13.015,20]pent...

Claims

GAL-378-EP-EPA 178CLAIMS1. A compound, or a pharmaceutically acceptable salt, solvate, salt of a solvate thereof, according to Formula I:I whereinXi is CR3a- or N, X2 is CR3bor N, and X3 is CR3cor N;Each Zi and Z2 is independently selected from C and N;A is selected from N, or CH;W is absent or is O, -NHC(=O)-, or -C(=O)NH-;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;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 =0;Each Rla, Rlb, R2a, and R2bis independently selected from:- H,- halo,- CN,- =0 (Rlatogether with Rlb, and / or R2atogether with R2b),- -T1-G1,- C1-6 alkyl, optionally substituted with one or more independently selected R6,- C1-6 alkoxy, optionally substituted with one or more independently selected R6,- C37 cycloalkyl, optionally substituted with one or more independently selected R6,GAL-378-EP-EPA 179- C5-12 membered fused, spiro or bridged polycyclic cycloalkyl, optionally substituted with one or more independently selected R6,- 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 R6, 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 R6; orRlaand 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 R6,- 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 R6, 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 R6;Each R3a, R3b, R3cis independently selected from:- H- halo,- -OH,- -CN,- -NR9aR9b,- C1-4 alkyl optionally substituted with one or more independently selected halo,- C1-4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and- 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;Each R4aand R4bis independently selected from H, or C1-4 alkyl optionally substituted with one or more independently selected halo;X is absent, -CH2-, -O-, or -NH-;Each R6is independently selected from: halo,- CN, oxo,- G2A,- -T2-G2B,Cy is aGAL-378-EP-EPA 180 phenyl or naphthyl, each of which is optionally substituted with one or more independently selected R8,5-6 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, or8-10 membered bicyclic 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,- G3A,- -T3-G3B,Each Ti, T2and T3is independently -CH2-, -CH2CH2-, -CH=CH-, -C=C-, -NG4-, -CH2NG4-, -O-, -S-, - S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -CH2C(=O)O-, -C(=O)OCH2-, -C(=O)NG4-, -C(=O)NHS(O)2G4-, - CH2C(=O)NG4-, -C(=O)NG4CH2-, -OC(=O)NG4-, -S(=O)2NG4-, -S(=O)2NG4CH2-, -OC(=O)-, -CH2NG4C(=O)-, -NG4C(=O)-, -NG4C(=O)CH2-, -NG4S(=O)2-,-S(=O)=NG4-, or -P(=O)G4-;Each G1, G2A, G2BG3A, G3B, G4is independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, =0, CN, or Ci-4 alkoxy, monocyclic Ck? cycloalkyl optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, Ci .4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, B, P, O, or S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, OH, =0, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo, phenyl optionally substituted with one or more independently selected halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo, and5 or 6 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 halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo.Y is -NR7-;R7is H, Ci-6 alkyl, C3.e cycloalkyl, -C(=O)Ci-6 alkyl, -C(=O)C3.6 cycloalkyl, or -C(=O)Ci-6 alkoxy; andGAL-378-EP-EPA 181- each R9aand R9bis independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl.

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 Zi is C, Z2 is N, A is N.

4. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein Zi is C, Z2 is N, A is CH.

5. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein Zi is N, Z2 is C, A is N.

6. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R is,or, wherein * represents the attachment point.

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

8. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein Cy is Cy is phenyl or pyridinyl, each of which is optionally substituted with one or more independently selected R8.

9. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein Cy isGAL-378-EP-EPA 182wherein * is attached to Y, and ** attached to L in Formula I.

10. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein Cy is11. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein L isGAL-378-EP-EPA 183wherein # is attached to W and ## is attached to -CR2aR2b- of 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, whereinselected from:

13. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to claim 12, wherein Rlband R2bare both H.

14. 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 1-13.

15. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1 - 13 , or a pharmaceutical composition according to claim 14 for use in medicine.

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 - 13 , or a pharmaceutical composition according to claim 14 for use in the prophylaxis and / or treatment of proliferative diseases.

17. A compound, or a pharmaceutically acceptable salt, solvate, salt of a solvate thereof, according to Formula la:GAL-378-EP-EPA 184whereinXi is CR3a- or N, X2 is CR3bor N, and X3 is CR3cor N;Each Zi and Z2 is independently selected from C and N;A is selected from N, or CR11;W is absent or is O, -NR10C(=O)-, or -C(=O)NR10-, -S(=O)2NR10C(=O) or -C(=O)NR10S(=O)2-;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;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 =0;Each Rla, Rlb, R2a, and R2bis independently selected from:- H,- halo,- CN,- =0 (Rlatogether with Rlb, and / or R2atogether with R2b),- -T1-G1,- C1-6 alkyl, optionally substituted with one or more independently selected R6,- C1-6 alkoxy, optionally substituted with one or more independently selected R6,- C37 cycloalkyl, optionally substituted with one or more independently selected R6,- C5-12 membered fused, spiro or bridged polycyclic cycloalkyl, optionally substituted with one or more independently selected R6,GAL-378-EP-EPA 185- 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 R6, 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 R6; orRlaand 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 R6,- 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 R6, 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 R6;Each R3a, R3b, R3c, R11is independently selected from:- H- halo,- -OH,- -CN,- -NR9aR9b,- C1-4 alkyl optionally substituted with one or more independently selected halo,- C1-4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and- 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;Each R4aand R4bis independently selected from H, or C1-4 alkyl optionally substituted with one or more independently selected halo;X is absent, -CH2-, -O-, or -NH-;Each R6is independently selected from: halo,- CN, oxo,- G2A,- -T2-G2B,Cy is a phenyl or naphthyl, each of which is optionally substituted with one or more independently selectedGAL-378-EP-EPA 1865-6 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, or8-10 membered bicyclic 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,- G3A,- -T3-G3B,Each Ti, T2and T3is independently -CH2-, -CH2CH2-, -CH=CH-, -C=C-, -NG4-, -CH2NG4-, -O-, -S-, - S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -CH2C(=O)O-, -C(=O)OCH2-, -C(=O)NG4-, -C(=O)NS(O)2G4-, - CH2C(=O)NG4-, -C(=O)NG4CH2-, -OC(=O)NG4-, -S(=O)2NG4-, -S(=O)2NG4CH2-, -OC(=O)-, -CH2NG4C(=O)-, -NG4C(=O)-, -NG4C(=O)CH2-, -NG4S(=O)2-,-S(=O)=NG4-, or -P(=O)G4-;Each G1, G2A, G2BG3A, G3B, G4is independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, =0, CN, or Ci-4 alkoxy, monocyclic Ck? cycloalkyl optionally substituted with one or more independently selected halo, OH, NH2, =0, CN, Ci .4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, B, P, O, or S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, OH, =0, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo, phenyl optionally substituted with one or more independently selected halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo, and5 or 6 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 halo, OH, CN, Ci-4 alkyl optionally substituted with one or more independently selected halo, Ci-4 alkoxy optionally substituted with one or more independently selected halo.Y is O or -NR7-;R7is H, Ci-6 alkyl, C3.e cycloalkyl, -C(=0)Ci-6 alkyl, -C(=O)C3.6 cycloalkyl, or -C(=0)Ci-6 alkoxy; and each R9aand R9bis independently selected from H, Ci-6 alkyl, and C3.e cycloalkylEach R10is independently selected from:GAL-378-EP-EPA 187- H;- Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, CN;- Ci-4 alkoxy optionally substituted with one or more independently selected halo, OH, CN ;- C3-7 cycloalkyl optionally substituted with one or more independently selected halo, OH, CN; 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 OH, CN.R11is independently selected from:- H- halo,- -OH,- -CN,- -NR12aR12b,- C1.4 alkyl optionally substituted with one or more independently selected halo,- C1.4 alkoxy optionally substituted with one or more independently selected halo,- C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and- 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;- each R12aand R12bis independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl

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