Protac compounds binding keap1 ubiquitin ligase for targeted protein degradation

Abstract

The present disclosure relates to methods of co-administering PROTAC (proteolysis targeting chimera) compounds that can promote ubiquitination and degradation of a target protein. The present disclosure also relates to antibody drug conjugates of PROTAC compounds Also disclosed herein are pharmaceutical compositions that can include a compound of Formula (V), the use and preparation thereof.

Description

PROTAC COMPOUNDS BINDING KEAP1 UBIQUITIN UIGASE FOR TARGETED PROTEIN DEGRADATIONINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 592095, filed October 20, 2023 and 63 / 614863, filed December 26, 2023.FIELD

[0002] The present disclosure relates generally to the fields of chemistry and medicine. More specifically, the present disclosure relates to the field of heterobifunctional compounds for the treatment of cancer.BACKGROUND

[0003] PROTACs (proteolysis targeting chimera) are hetero-bifunctional molecules that comprise a moiety for binding a protein of interest linked to a ligand for binding an E3 ligase. The PROTAC interacts with both the target protein and the E3 ligase to induce proximity between the target protein and E3 ligase to form a ternary complex, wherein the target protein is ubiquitinated and subsequently degraded by the proteasome. Because PROTACs possess more than one binding moiety, binding may result in formation of ineffective binary complexes. At high concentrations, formation of binary complexes can become competitive with formation of ternary complexes necessary for protein degradation, slowing PROTAC-mediated degradation of the protein of interest.SUMMARY

[0004] Some embodiments herein relate to a method of treating cancer that can include co-administering to a patient in need thereof a first PROTAC compound that can bind to a first ubiquitin ligase and can promote degradation of a target protein and a second PROTAC compound that can bind to a second different ubiquitin ligase and can promote degradation of the target protein.

[0005] In some embodiments, the method of treating cancer includes administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the target protein can be Kras. In other embodiments, the target protein can be AR (androgen receptor).

[0007] In some embodiments, the ubiquitin ligase can be Keapl . In other embodiments, the ubiquitin ligase can be VHL (von-Hippcl Lindau).

[0008] In some embodiments, the method comprises co-administering the first PROTAC compound at a first concentration and the second PROTAC compound at second concentration, wherein the degradation efficacy of the co-administration is greater than the degradation efficacy of the first PROTAC compound administered alone at the first concentration or the degradation efficacy of the second PROTAC compound administered alone at the second concentration.

[0009] In some embodiments, the first and second concentrations are each at least 10 pM. In other embodiments, the first and second concentrations are each at least 5 pM. In other embodiments, the first and second concentrations are each at least 2.5 pM. In other embodiments, the first and second concentrations are each at least 1 pM.

[0010] Some embodiments described herein relate to a method of treating cancer that can include co-administering to a subject identified as suffering from the cancer an effective amount of a first compound, or pharmaceutically acceptable salt thereof, as described herein and an effective amount of a second compound, or pharmaceutically salt thereof, as described herein, wherein the first compound can be a first PROTAC compound that can bind to a first ubiquitin ligase and the second compound can be a second PROTAC compound that binds to a second different ubiquitin ligase.

[0011] Some embodiments described herein relate to a compound of Formula (V).

[0012] Some embodiments disclosed herein relate to a pharmaceutical composition that contains an effective amount of a compound of Formula (V).

[0013] Some embodiments described herein relate to a method of treating cancer that can include administering to a subject identified as suffering from the cancer an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating cancer, including pancreatic and colorectal cancers. Still other embodiments described herein relate to theuse of a compound, or a pharmaceutically acceptable salt thereof, as described herein, in the preparation of a medicament for treating cancer, including pancreatic and colorectal cancers.

[0014] There are other embodiments described in greater detail below.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 depicts the promotion of KEAP1 and KRAS interaction by Compound P-7 and Compound P-9 as measured by a lanthanide chelate excite (LANCE) time-resolved fluorescence-Forster Resonance Energy Transfer (TR-FRET) assay.

[0016] FIG. 2 depicts dose-dependent screening of compounds for KRAS G12D potency at 0.1, 1, 5 and 10 pM concentrations in HiBiT-KRasG12D cells as assessed by luminescence monitoring.

[0017] FIG. 3 depicts rescuing downregulation of KRAS G12D induced by Compound P-1 or P-9 by pre-treatment of AsPCl HiBiT-KrasG12D cells.

[0018] FIG. 4 depicts a western blot showing compound C-l shows enhanced KRAS G12D degradation compared to Compound P-1 or Compound P-9.

[0019] FIG. 5 shows that cell fractionation indicates that the majority of KRAS G12D downregulation induced by Compounds P-1 or P-9 occurs at the plasma membrane.

[0020] FIGs. 6A and 6B show that the combination of Compound C-l and P-9 demonstrates a synergistic effect in promoting KRAS G12D degradation without a hook effect .

[0021] FIGs. 7 A and 7B depicts a western blot showing that the treatment of KRAS G12D lysates with a combination of Compound C-l and Compound P-9 increased poly ubiquitination .

[0022] FIGs. 8A and 8B show that colony numbers of HiBiT-KRasG12D cells are substantially reduced by the co-administration of Compound C-l with Compound P-9.

[0023] FIGs. 9A and 9B show that the co-administration of Compound P-16 with ARCC-4 synergistically improves the degradation of AR in comparison to Compound P-16 or ARCC-4 alone.

[0024] FIG. 10 shows that the co-administration of Compound P-16 with ARCC-4 synergistically in vivo reduces cell growth.

[0025] FIGs. 11 A-H show the synergistic degradation of AR without a hook effect by various KEAPl-based PROTACs in combination with ARCC-4 and ARV-110.DETAILED DESCRIPTIONAs provided herein, ternary complexes can be formed when a PROTAC compound binds a protein of interest and an E3 ligase, inducing proximity between the protein and E3 ligase. Ternary complex formation drives ubiquitination of the target protein and subsequent proteasomal degradation. High concentrations of PROTACs, however, can lead to formation of unproductive dimers, inhibiting ternary complex formation, slowing degradation rates and producing a “hook effect”. Therefore, a need exists for novel approaches for targeting proteins associated with cancer for degradation. The present disclosure provides a method for treating, ameliorating, or preventing cancer in a subject in need thereof including co-administering combination of PROTAC compounds, wherein a first PROTAC compound that binds a first ubiquitin ligase and promotes degradation of a target protein and a second PROTAC compound that binds a second different ubiquitin ligase and promotes degradation of the target protein.Definitions

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0027] The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable salts can also be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, bases that contain sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. In some embodiments, treatment of the compounds disclosed herein with an inorganic base results in loss of a labile hydrogen from the compound to afford the salt form including an inorganic cation such as Li+, Na+, K+, Mg2+and Ca2+and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).

[0028] As used herein, “Cato Cb” or “Ca-b” in which “a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “Ci to C4 alkyl” or “C1-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CTEhCH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, (CH3)2CHCH2-, and (CCH3)3)-.

[0029] The term “halogen” or “halo,” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0030] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be designated as “C1-4 alkyl” or similar designations. By way of example only, “C1-4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0031] As used herein, “alkoxy” refers to the formula -OR wherein R is an alkyl as is defined above, such as “C1-9 alkoxy”, including but not limited to methoxy, ethoxy, n-propoxy, 1- methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.

[0032] As used herein, “alkylthio” refers to the formula -SR wherein R is an alkyl as is defined above, such as “C1-9 alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1 -methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, and the like.

[0033] As used herein, “alkenyl” refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. The alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group may be designated as “C2-4 alkenyl” or similar designations. By way of example only, “C2-4 alkenyl” indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen- 1-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-l-yl, 2-methyl-propen-l-yl, 1- ethyl-ethen-l-yl, 2-methyl-propen-3-yl, buta- 1,3-dienyl, buta- 1,2, -dienyl, and buta-l,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.

[0034] As used herein, “alkynyl” refers to a straight or branched hydrocarbon chain containing one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. The alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group may be designated as “C2-4 alkynyl” or similar’ designations. By way of example only, “C2-4 alkynyl” indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-l-yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.

[0035] As used herein, “heteroalkyl” refers to a straight or branched hydrocarbon chain containing one or more hctcroatoms, that is, an clement other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atom, although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group may be designated as “C1-4 heteroalkyl” or similar’ designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, “C1-4 heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0036] As used herein, “alkylene” means a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogen that is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl). The alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated. The alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms. The alkylene group could also be a lower alkylene having 1 to 4 carbon atoms. The alkylene group may be designated as “C1-4 alkylene” or similar designations. By way of example only, “C1-4 alkylene” indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan- 1,1 -diyl, propylene, propan- 1,1 -diyl, propan-2, 2-diyl, 1-methyl-ethylene, butylene, butan- 1,1 -diyl, butan-2, 2-diyl, 2-methyl-propan- 1,1 -diyl, 1-methyl-propylene, 2- methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

[0037] As used herein, “alkenylene” means a straight or branched chain di-radical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond that is attached to the rest of the molecule via two points of attachment. The alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated. The alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms. The alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms. The alkenylene group may be designated as “C2-4 alkenylene” or similar’ designations. By way of example only, “C2-4 alkenylene” indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selectedfrom the group consisting of ethenylene, ethen- 1 ,1 -diyl, propenylene, propen- 1 ,1 -diyl, prop-2-en-1.1 -diyl, 1-mcthyl-cthcnylcnc, but-1-cnylcnc, but-2-cnylcnc, but-l,3-dicnylcnc, butcn- 1,1 -diyl, but- 1,3-dien- 1,1 -diyl, but-2-en- 1,1 -diyl, but-3-en- 1,1 -diyl, l-methyl-prop-2-en- 1,1 -diyl, 2- methyl-prop-2-en- 1 , 1 -diyl, 1 -ethyl-etheny lene, 1 ,2-dimethyl-ethenylene, 1 -methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propen- 1,1 -diyl, and 2,2-dimethyl-ethen-1.1 -diyl.

[0038] The term “aromatic” refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.

[0039] As used herein, “aryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term “aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as “C6-10 aryl,” “C6 or C10 aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0040] As used herein, “aryloxy” and “arylthio” refers to RO- and RS-, in which R is an aryl as is defined above, such as “C6-10 aryloxy” or “C6-10 arylthio” and the like, including but not limited to phenyloxy.

[0041] An “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such as “C7-14 aralkyl” and the like, including but not limited to benzyl, 2- phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4 alkylene group).

[0042] As used herein, “heteroaryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also coversthe occurrence of the term “heteroaryl” where no numerical range is designated. In some embodiments, the hetero aryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similar designations. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0043] A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4 alkylene group).

[0044] As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term “carbocyclyl” where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as “C3-6 carbocyclyl” or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0045] A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as “C4-10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.

[0046] As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] As used herein, “cycloalkenyl” means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0048] As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heterocyclyl” where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as “3-6 membered heterocyclyl” or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1 ,4-oxathiinyl, 1,4-oxathianyl, 277-1,2- oxazinyl, trioxanyl, hexahydro- 1, 3, 5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3- dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindo linyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro- 1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0049] A “(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0050] As used herein, “acyl” refers to -C(=O)R, wherein R is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0051] An “O-carboxy” group refers to a “-OC(=O)R” group in which R is selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0052] A “C-carboxy” group refers to a “-C(=O)OR” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., -C(=O)OH).

[0053] A “cyano” group refers to a “-CN” group.

[0054] A “cyanato” group refers to an “-OCN” group.

[0055] An “isocyanato” group refers to a “-NCO” group.

[0056] A “thiocyanato” group refers to a “-SCN” group.

[0057] An “isothiocyanato” group refers to an “ -NCS” group.

[0058] A “sulfinyl” group refers to an “-S(=O)R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0059] A “sulfonyl” group refers to an “-SO2R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0060] An “S-sulfonamido” group refers to a “-SO2NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0061] An “N- sulfonamide” group refers to a “-N(RA)SO2RB” group in which RA and Rb are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0062] An “O-carbamyl” group refers to a “-OC(=O)NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7carbocyclyl, C6-10 aryl, 5- 10 membered heteroaryl, and 3- 10 membered heterocyclyl, as defined herein.

[0063] An “N-carbamyl” group refers to an “-N(RA)C(=O)ORB” group in which RA and RB are each independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0064] An “O-thiocarbamyl” group refers to a “-OC(=S)NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0065] An “N-thiocarbamyl” group refers to an “-N(RA)C(=S)ORB” group in which RA and RB are each independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0066] A “C-amido” group refers to a “-C(=O)NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0067] An “N-amido” group refers to a “-N(RA)C(=O)RB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0068] An “amino” group refers to a “-NRARB” group in which RA and RB are each independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce- 10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. A non- limiting example includes free amino (i.e., -NH2).

[0069] An “aminoalkyl” group refers to an amino group connected via an alkylene group.

[0070] An “alkoxyalkyl” group refers to an alkoxy group connected via an alkylene group, such as a “C2-8 alkoxyalkyl” and the like.

[0071] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom orgroup. Unless otherwise indicated, when a group is deemed to be “substituted,” it is meant that the group is substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), Ca-Cv-carbocyclyl-Ci- Ce-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and§ C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N- sulfonamide, C-carboxy, O- carboxy, acyl, cyanato, isocyanato, thiocyanate, isothiocyanato, sulfinyl, sulfonyl, and oxo (=0). Unless otherwise indicated, wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0072] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di- radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene” or “alkenylene.”

[0073] When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) “together with the atom to which they are attached,” it is meant that the collective unit of the atom and the two R groups are the recited ring. The ring is not otherwiselimited by the definition of each R group when taken individually. For example, when the following substructure is present:and R1and R2are defined as selected from the group consisting of hydrogen and alkyl, or R1and R2together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R1and R2can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:where ring A is a heterocyclyl ring containing the depicted nitrogen.

[0074] Similarly, when two “adjacent” R groups are said to form a ring “together with the atoms to which they are attached,” it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring. For example, when the following substructure is present:and R1and R2are defined as selected from the group consisting of hydrogen and alkyl, or R1and R2together with the atoms to which they are attached form an aryl or carbocyclyl, it is meant that R1and R2can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:where A is an aryl ring or a carbocyclyl containing the depicted double bond.

[0075] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. Thus, for example, a substituentdepicted as -AE- orincludes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.

[0076] As used herein, "isosteres" of a chemical group are other chemical groups that exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isostcrcs contemplated include -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, -CONHNHSO2R, -COHNSO2R, and -CONRCN, where R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. In addition, carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH2, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions. The following structures are non-limiting examples of carbocyclic and heterocyclic isosteres contemplated. The atoms of said ring structure may be optionally substituted at one or more positions with R as defined above.

[0077] It is also contemplated that when chemical substituents are added to a carboxylic isostere, the compound retains the properties of a carboxylic isostere. It is contemplated that when a carboxylic isostere is optionally substituted with one or more moieties selected from R as defined above, then the substitution and substitution position is selected such that it does not eliminate the carboxylic acid isosteric properties of the compound. Similarly, it is alsocontemplated that the placement of one or more R substituents upon a carbocyclic or heterocyclic carboxylic acid isostcrc is not a substitution at one or more atom(s) that maintain(s) or is / arc integral to the carboxylic acid isosteric properties of the compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the compound.

[0078] Other carboxylic acid isosteres not specifically exemplified in this specification are also contemplated.

[0079] As used herein, a “conjugate” is a compound that comprises two or more substances (such as an antibody, a linker moiety and / or a drug moiety) joined together by chemical bonds. Examples of conjugates include antibody-drug conjugates (which may optionally include a linker moiety), drug-linker conjugates, and antibody-linker conjugates. An “immunoconjugate” is a conjugate that comprise an immunological substance such as an antibody.

[0080] As used herein, an “antibody” (Ab) is a protein made by the immune system, or a synthetic variant thereof, that binds to specific sites on cells or tissues. An “antigen-binding fragment” is a portion of an antibody that binds to a specific antigen, including Fab and scFv.

[0081] “Subject” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0082] The term “mammal” is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.

[0083] An “effective amount” or a “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. “Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).

[0084] ‘Treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particulardisease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease or condition.Compounds

[0085] Some embodiments disclosed herein include compounds that bind to ubiquitin ligases. In some embodiments, the ubiquitin ligase bound by a compound disclosed herein can be KEAP1. In other embodiments, the ubiquitin ligase bound by a compound disclosed herein Von Hippel-Lindau (VHL). Some embodiments disclosed herein include compounds that can degrade a target protein. In some embodiments, the target protein can be Kras. In other embodiments, the target protein can be androgen receptor (AR).

[0086] Some embodiments disclosed herein include a compound of Formula (I):

[0087] or a pharmaceutically acceptable salt thereof, wherein:

[0088] A can be a KEAP1 binder of Formula (II) having the structure:unsubstituted C1-4 alkoxy and R1can be, or R4can be a substituted or unsubstituted Cm alkoxy and R1can

[0090] R2can be hydrogen (H) or a substituted or unsubstituted C1-4 alkyl, R3can be is -CH2CO2R6; R5can be hydrogen (H) or a substituted or unsubstituted C1-4 alkyl; R6can be hydrogen (H) or a substituted or unsubstituted C1-4 alkyl; B can be selected from Formula (III- A):can be halogen; R9can be -OR15; R10can be halogen or C1-4 haloalkyl; R11can be cyano; R13cancan be hydrogen (H) or a substituted or unsubstituted C1-4 alkyl; R15can be hydrogen (H) or a substituted or unsubstituted C1-4 alkyl; R16can be hydrogen (H) or a substituted or unsubstituted C1-4 alkyl;a single bond attachment to L; andL can be a chemical linker.

[0091] Compounds of Formula (I), or a pharmaceutically salt thereof, can include one or more chiral centers. As provided herein, if an absolute stereochemistry is not expressly indicated, then each center may independently be of (R)-configuration or (S) -configuration or a mixture thereof. Those skilled in the art recognize that the carbon to which Rlaand R2are attached can be a chiral center.I

[0092] In some embodiments, R can beand R can be a C1-4 alkoxy, such as methoxy, such that A can be a KEAP1 binder that can have the structure of Formula (II- A):that can have the structure of Formula (II-B):R4can be a C1-4 alkoxy, such as methoxy, and R1can be ~

[0093] In some embodiments, R7can be ? . In other embodiments, R can be

[0094] In some embodiments, R12can

[0095] In some embodiments, R7can be -OR13and R13can

[0096] In some embodiments, L can be a chemical linker that can have the structure ofFormula (IV):[-X’-X^-X^-X^-X8-] (IV), wherein

[0097] X1can be -(CH2)m-, wherein m can be an integer from 1 to 4; X2can be oxygen (O) or can be absent; X3can be -(CH2)n-, wherein n can be an integer from 0 to 4; X4can be oxygen (O) or can be absent; X5can be -(CH2)P-, wherein p can be an integer from 0 to 4; X6canbe absent or can be selected from -NH-,andcan to 4; and X8can be selected fromr can be absent.

[0098] In some embodiments, X1can be -(CH2)m-. In some embodiments, m can be 0, such that X1can be absent. In some embodiments, m can be 1, such that X1can be -CH2-. In other embodiments, m can be 2, such that X1can be -CH2CH2-. In still other embodiments, m can be 3, such that X1can be -CH2CH2CH2-. In yet still other embodiments, m can be 4, such that X1can be -CH2CH2CH2CH2-.

[0099] In some embodiments, X2can be oxygen (O). In other embodiments, X2can be absent.

[0100] In some embodiments, X3can be -(CH2)n- In some embodiments, n can be 0, such that X3can be absent. In some embodiments, n can be 1, such that X3can be -CH2-. In other embodiments, n can be 2, such that X3can be -CH2CH2-. In still other embodiments, n can be 3, such that X3can be -CH2CH2CH2-. In yet still other embodiments, n can be 4, such that X3can be -CH2CH2CH2CH2-.

[0101] In some embodiments, X4can be oxygen (O). In other embodiments, X4can be absent.

[0102] In some embodiments, X5can be -(CH2)P-. In some embodiments, p can be 0, such that X5can be absent. In some embodiments, p can be 1, such that X5can be -CH2-. In otherembodiments, p can be 2, such that X5can be -CH2CH2-. In still other embodiments, p can be 3, such that X5can be -CH2CH2CH2-. In yet still other embodiments, p can be 4, such that X5can be -CH2CH2CH2CH2-.

[0103] In some embodiments X6can be -NH-. In other embodiments, X6can beIn still other embodiments, X6can beIn yet still other embodiments, X6can

[0104] In some embodiments, X7can be -C(=O)-. In other embodiments, X7can be - (CH2)q-, wherein q can be an integer from 0 to 4. In some embodiments, q can be 0, such that X7can be absent. In some embodiments, q can be 1, such that X7can be -CH2-. In other embodiments, q can be 2, such that X7can be -CH2CH2-. In still other embodiments, q can be 3, such that X7can be -CH2CH2CH2-. In yet still other embodiments, q can be 4, such that X7can be -CH2CH2CH2CH2-.

[0105] In some embodiments, X8canother embodiments, X8In still other embodiments, X8canIn some embodiments, X8can

[0106] In some embodiments, X6can be absent, provided that X8cannot be absent. In other embodiments, X8can be absent, provided that X8cannot be absent. In some embodiments,if X8is absent, X6can be selected fromandIn other embodiments, L canIn other embodiments, L can be,

[0108] In some embodiments, B can have the structure of Formula (III-A):. In other embodiments, B can have the structure of Formulastill other embodiments,B can have the structure of Formula (III-C):

[0109] In some embodiments, R2can be hydrogen. In other embodiments, R2can be an unsubstituted C1-4 alkyl. Examples of unsubstituted C1-4 alkyls are described herein, including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl. In some embodiments, R2can be methyl. In some embodiments, R2can be a substituted C1-4 alkyl. When R2is substituted, R2can be substituted with one or more substituents (such as 1, 2 or 3 substituents) independently selected from halogen (such as F or Cl), an unsubstituted C1-4 alkoxy, cycloalkyl, aryl, or heteroaryl.

[0110] In some embodiments, R3can be -CH2CO2R6and R6can be H, such that R3can be -CH2CO2H. In other embodiments, R3can be -CH2CO2R6and R6can be an unsubstitutedor substituted C1-4 alkyl. Examples of unsubstituted C1-4 alkyls are described herein, including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tcrt-butyl. In some embodiments, R6can be ethyl, such that R3can be -CH2CO2CH2CH3. In some embodiments, R6can be a substituted C1-4 alkyl. When R6is substituted, R6can be substituted with one or more substituents (such as 1, 2 or 3 substituents) independently selected from halogen (such as F or Cl), an unsubstituted C1-4 alkoxy, cycloalkyl, aryl, or heteroaryl.

[0111] In some embodiments, R5can be hydrogen. In other embodiments, R5can be an unsubstituted C1-4 alkyl. Examples of unsubstituted C1-4 alkyls are described herein, including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl. In some embodiments, R5can be methyl. In some embodiments, R5can be a substituted C1-4 alkyl. When R5is substituted, R5can be substituted with one or more substituents (such as 1, 2 or 3 substituents) independently selected from halogen (such as F or Cl), an unsubstituted C1-4 alkoxy, cycloalkyl, aryl, or heteroaryl.

[0112] In some embodiments R8can be halogen, such as fluoro or chloro. In some embodiments, R10can be halogen, such as fluoro or chloro. In some embodiments, R8and R10can each be fluoro. In other embodiments, R8and R10can each be chloro. . In some embodiments, R10can be a C1-4 haloalkyl (such as -CF3, -CCI3, -CHF2, -C(CH3)F2, -CHCh, -CH2F, - CH(CH3)F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and -CH2CH2CH2CI).

[0113] In some embodiments, R14can be hydrogen (H). In other embodiments, R14can be an unsubstituted C1-4 alkyl. Examples of unsubstituted C1-4 alkyls are described herein, including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl. In some embodiments, R5can be methyl. In some embodiments, R5can be a substituted C1-4 alkyl. When R14is substituted, R5can be substituted with one or more substituents (such as 1, 2 or 3 substituents) independently selected from halogen (such as F or Cl), an unsubstituted C1-4 alkoxy, cycloalkyl, aryl, or heteroaryl.

[0114] In some embodiments, R15can be hydrogen (H). In other embodiments, R15can be an unsubstituted C1-4 alkyl. Examples of unsubstituted C1-4 alkyls are described herein, including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl. In some embodiments, R5can be methyl. In some embodiments, R15can be a substituted C1-4 alkyl. When R15is substituted, R15can be substituted with one or more substituents (such as 1, 2 or 3substituents) independently selected from halogen (such as F or Cl), an unsubstituted C1-4 alkoxy, cycloalkyl, aryl, or hctcroaryl.

[0115] In some embodiments, R16can be hydrogen (H). In other embodiments, R16can be an unsubstituted C1-4 alkyl. Examples of unsubstituted C1-4 alkyls are described herein, including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl. In some embodiments, R5can be methyl. In some embodiments, R16can be a substituted C1-4 alkyl. When R16is substituted, R16can be substituted with one or more substituents (such as 1, 2 or 3 substituents) independently selected from halogen (such as F or Cl), an unsubstituted C1-4 alkoxy, cycloalkyl, aryl, or heteroaryl.

[0116] In some embodiments, a compound of Formula (I) can be selected from:pharmaceutically acceptable salt of any of the foregoing.F0117] In some embodiments, a compound of Formula (I) can be selected from:pharmaceutically acceptable salt of any of the foregoing.

[0118] In some embodiments, compounds disclosed herein can include, which is described inInternational Application Publication No. WO2022 / 148422, incorporated herein by reference in its entirety. In other embodiments, the compounds disclosed herein can include ARCC-4, which has the structure. In other embodiments, the compounds disclosed herein can include ARV- 110 (bavdegalutamide), which has the structureAntibody-Drug Conjugates

[0119] Some embodiments provide for an antibody-drug conjugate (ADC) ofFormula (V):(V), wherein:Ab can be an antibody or antigen-binding fragment thereof;M can be a moiety coupled to an amino acid residue of Ab;La, Lei, LC2, Lpi, and LP2 each can be chemical linkers;Lb can be a branched group with bifunctional moieties that selectively couple Lcior LC2;Di can be a first PROTAC compound;D2 can be a second different PROTAC compound; and subscript n can be an integer from 1 to 10.

[0120] In some embodiments, the antibody may be of any class (e.g., IgA, IgD, IgE, IgG, and IgM) or subclass (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2).

[0121] In some embodiments, the antibody can target VEGF, PD-1, EGFR, CD38, GD2, PD-L1, SLAMF7, CTLA-4, CCR4, CD20, PDGFRa, HER2, HER3, cMET, TIM-3, LAG- 3, KIR, NK2DA, CD47, CD3, CD19, CD22, CD33, CD47, CD123, NKG2D, TROP2, 5T4, GPC3, Mesothelin, WT1, NY-ESO, NKp46, or ESO. In some embodiments, the antibody can be, but is not limited to, atezolizumab, avelumab, bevacizumab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumabelotuzumab, ipilimumab, isatuximab, mogamulizumab, or necitumumab as described in Zahavi, D. and Weiner L., “Monoclonal Antibodies in Cancer Therapy”, Antibodies (Basel), 9(3), 34 (2020), incorporated herein by reference in its entirety.

[0122] In some embodiments, M canwhereinrepresents a single bond attachment to La and * represents an attachment point between M and Ab.

[0123] In some embodiments, La canwherein represents a single bond attachment to M and * represents a single bond attachment to Lb.

[0124] In some embodiments, Lb can bewherein represents a single bond— it attachment to La, represents a single bond attachment to Lci, andrepresents a single bond attachment to LC2.

[0125] In some embodiments, Lcican be, represents a single bond attachment toLb and * represents a single bond attachment to Lpi.

[0126] In some embodiments, LC2 can berepresents a single bond attachment to Lb, and * represents a single bond attachment to LP2.

[0127] In some embodiments, Lp1and LP2 each can be a cleavable chemical linker, e.g., an acid-clcavablc, cnzymc-clcavablc or reducible linker. In other embodiments, Lp1and Lp2 each can be a non-cleavable linker, including, but not limited to, thioether or maleimidocaproyl. Lp1and LP2 can include linkers described in Sheyi et al., “Linkers: An Assurance for ControlledDelivery of Antibody-Drug Conjugates” Pharmaceutics, 14, 396 (2022), incorporated herein in its entirety. In some embodiments, Lp1and LP2 can each be:

[0128] In some embodiments, Di and D2 bind to a different ubiquitin ligase but promote ubiquitization of the same target protein. In some embodiments, Di is a PROTAC that binds KEAP1. In some embodiments, D2 is a PROTAC that binds to VHL. In some embodiments, the target protein for both Di and D2 is Kras. In other embodiments, the target protein for both Di and D2 is AR.

[0129] Di can be a PROTAC compound of Formula (I’) having the structure:wherein:A can be a KEAP1 binder of Formula (IF) having the structure:R can be H and R can be ? , R can be a substituted or unsubstituted C1-4 alkoxy andR1can be , or R4can be a substituted or unsubstituted C1-4 alkoxy and R1 can be ~ ;R2can be H or a substituted or unsubstituted C1-4 alkyl;R3can be -CH2CO2R6;R5can be H or a substituted or unsubstituted C1-4 alkyl;R6can be H, a substituted or unsubstituted C1-4 alkyl, orB can be selected from Formulas (III-A’), (III-B’), and (III-C’):R8can be halogen;R9can be -OR15;R10can be halogen or C1-4 haloalkyl;R11can be cyano;R14can be H or a substituted or unsubstituted C1-4 alkyl;R15can be H, a substituted or unsubstituted C1-4 alkyl, or;R16can be H or a substituted or unsubstituted C1-4 alkyl; in Di represents a single bond attachment to Lpi;represents a single bond attachment to L; and L can be a chemical linker.

[0130] In some embodiments, A can be a KEAP1 binder of Formula (II-A’):other embodiments, A can be aKEAP1 binder of Formula (II-B ’ ) :

[0131] In some embodiments, R7can be. In other embodiments, R7can be

[0132] In some embodiments, R12canother embodiments, R12wherein * represents a single bond attachment to Lp1. In still other embodiments, R7can be -OR13and R13can

[0133] In some embodiments, L can be a chemical linker having the structure of Formula (IV’):wherein:X1is -(CH2)m-, wherein m can be an integer from 1 to 4;X2can be O (oxygen) or can be absent;X3can be -(CH2)n-, wherein n can be an integer from 0 to 4;X4can be O (oxygen) or can be absent;X5can be -(CH2)P-, wherein p can be an integer from 0 to 4;X6can be absent or can be selected from:X7can be -C(=0)- or -(CH2)q-, wherein q can be an integer from 0 to 4; and

[0134] In some embodiments, L can be selected from:of attachment to the rest of the compound and * represents a single bond attachment to Lp1.n o er em o mens, can beIn other embodiments, L can beIn some

[0136] In some embodiments, at least one * containing group is present in Di.

[0137] In some embodiments, B can have the structure of Formula (III-A’):. In other embodiments, B can have the structure ofFormula (III-B’):In yet other embodiments, B can have the structure of Formula (III-C’):

[0138] In some embodiments, Di can be a radical or cation of a compound selectedpharmaceutically acceptable salt of any of the foregoing.

[0139] In some embodiments, Di can be a radical or cation of a compound selected from:

[0140] In some embodiments, D2 can be a radical or cation of, wherein * represents a single bond attachment to LP2. In some embodiments, D2 has therepresents a single bond attachment to LP2.Administration and Pharmaceutical Compositions

[0141] The compounds arc administered at a therapeutically effective dosage. While human dosage levels have yet to be optimized for the compounds described herein, generally, a daily dose may be from about 0.0125 mg / kg to about 120 mg / kg or more of body weight, from about 0.025 mg / kg or less to about 70 mg / kg, from about 0.05 mg / kg to about 50 mg / kg of body weight, or from about 0.075 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 0.88 mg per day to about 8000 mg per day, from about 1.8 mg per day or less to about 7000 mg per day or more, from about 3.6 mg per day to about 6000 mg per day, from about 5.3 mg per day to about 5000 mg per day, or from about 11 mg to about 3000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.

[0142] Administration of the compounds disclosed herein, or the pharmaceutically acceptable salts thereof, can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments. Co-administration of the PROTACs described herein can be by the same route of administration or different routes of administration.

[0143] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated herein by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. In some embodiments, the combination of PROTACs described herein are combined in the same pharmaceutical formulation. In other embodiments, the PROTACs are administered in separate pharmaceutical formulations.

[0144] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0145] Some examples of substances, which can serve as pharmaceutically-acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0146] The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

[0147] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan willrecognize that the formulation does not specifically contemplate the entire course of therapy and such decisions arc left for those skilled in the art of treatment rather than formulation.

[0148] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically- active materials may be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0149] Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0150] The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the ail. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate,sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintcgrants such as starch, alginic acid and croscarmclosc; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.

[0151] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

[0152] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

[0153] Compositions described herein may optionally include other drug actives.

[0154] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0155] A liquid composition, which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye. The comfort may be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid may be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid may either be packaged for single use or contain a preservative to prevent contamination over multiple uses.

[0156] For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions may preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0157] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

[0158] Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.

[0159] Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

[0160] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

[0161] Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.

[0162] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein arc employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co- solvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0163] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0164] The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.

[0165] The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. In some embodiments, a daily dose may be from about0.25 mg / kg to about 120 mg / kg or more of body weight, from about 0.5 mg / kg or less to about 70 mg / kg, from about 1.0 mg / kg to about 50 mg / kg of body weight, or from about 1.5 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day.Methods of Preparation

[0166] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

[0167] All variables shown in the schemes are defined as mentioned herein, unless otherwise is indicated or is clear from the context.Methods of Use

[0168] Some embodiments described herein relate to a method of treating cancer that can include co-administering to a subject identified as suffering from the cancer an effective amount of a first PROTAC compound that binds to a first ubiquitin ligase and promotes degradation of a target protein and an effective amount of a second PROTAC compound that binds to a second different ubiquitin ligase and promotes degradation of the target protein. In some embodiments, the target protein can be Kras. In some embodiments, the Kras is Kras G12D. In other embodiments, the target protein can be AR (androgen receptor). In some embodiments, the ubiquitin ligase can be KEAP1. In other embodiments, the ubiquitin ligase can be VHL.

[0169] By ‘ ‘co-administration” or “co-administering,” it is meant that the two or more agents may be found in the patient’s bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one being administered orally and another being administered i.v.

[0170] Some embodiments described herein relate to a method for inhibiting cell proliferation, such as inhibiting cell proliferation of a cancer cell, that can include co-administering to a subject identified as suffering from a disease wherein inhibiting cell proliferation is desirable an effective amount of a first PROTAC compound and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes effective amount of a first PROTAC compound and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein. Other embodiments described herein relate to the use of an effective amount of a first PROTAC compound and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a first PROTAC compound and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for inhibiting cell proliferation, such as inhibiting cell proliferation of a cancer cell. Still other embodiments described herein relate to an effective amount of a first PROTAC compound and a second PROTAC compound, or a pharmaceutically acceptable saltthereof, described herein, or a pharmaceutical composition that includes an effective amount of a first PROTAC compound and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein for the use in inhibiting cell proliferation, such as inhibiting cell proliferation of a cancer cell.

[0171] Some embodiments described herein relate to a method for inhibiting replication of a cancer cell that can include contacting the cancer cell with an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein. Other embodiments described herein relate to the use of an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for inhibiting replication of a cancer cell. Still other embodiments described herein relate to an effective amount of a combination of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a combination of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein for use in inhibiting replication of a cancer cell.

[0172] Some embodiments described herein relate to a method of inducing apoptosis of a cell (for example, a cancer cell) that can include contacting the cell with an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a first PROTAC and a second PROTAC compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for inducing apoptosis of a cell, such as a cancer cell. Still other embodiments described herein relate to the use of an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable saltthereof, as described herein or a pharmaceutical composition that includes an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, as described herein for use in inducing apoptosis of a cell, such as a cancer cell.

[0173] Some embodiments described herein relate to a method of decreasing the viability of a cell (for example, a cancer cell) that can include contacting the cell with an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for decreasing the viability of a cell, such as a cancer cell or cell infected with a virus. Still other embodiments described herein relate to the use of an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes an effective amount of a first PROTAC and a second PROTAC compound, or a pharmaceutically acceptable salt thereof, as described herein for use in decreasing the viability of a cell, such as a cancer cell.

[0174] In some embodiments, the second PROTAC compound can be:In other embodiments, the secondPROTAC compound can

[0175] In some embodiments, the method of administering one or more of the compounds disclosed herein results in the polyubiquitination and degradation of a KRas protein. In some embodiments, the method of administering one or more of the compounds disclosed herein results in the polyubiquitination and degradation of KRas G12D. In some embodiments, the method of administering one or more of the compounds disclosed herein results in the polyubiquitination and degradation of AR.

[0176] In some embodiments, the method of administering one or more compounds disclosed herein can include co-administering a first PROTAC compound at a first concentration and a second PROTAC compound at a second concentration. In some embodiments, the degradation efficacy of the co-administration of the first PROTAC compound and the secondPROTAC compound is greater than the degradation efficacy of the first PROTAC compound administered alone at the first concentration or the degradation efficacy of the second PROTAC compound administered alone at the second concentration. In some embodiments, the first and second concentrations can each independently be at least 1 pM, at least 2.5 pM, at least 5 pM, or at least 10 pM. For example, the first and second concentrations can each be at least 1, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.5, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8 or 10 pM.

[0177] In some embodiments, the method can include co-administeringas the second PROTAC compound. In other embodiments, the first PROTAC compound can be

[0178] In some embodiments, the method can include administering the first and second PROTAC compounds by administering an antibody-drug conjugate that can include the first and second PROTAC compounds.

[0179] In some embodiments, the subject is a human.

[0180] Some embodiments further include administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

[0181] Examples of cancers that can be treated with methods described herein include, but are not limited to, pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, appendiceal cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer,head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, gastroesophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0182] Some embodiments herein relate to a method of treating a neurodegenerative disease that can include administering to a subject identified as suffering from the neurodegenerative disease an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating a neurodegenerative disease. Still other embodiments described herein relate to a use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, in the preparation of a medicament for treating a neurodegenerative disease.

[0183] Some embodiments herein relate to a method of treating an inflammatory condition that can include administering to a subject identified as suffering from the inflammatory condition an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating an inflammatory condition. Still other embodiments described herein relate to a use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, in the preparation of a medicament for treating an inflammatory condition.

[0184] Some embodiments herein relate to a method of treating a dermatological condition that can include administering to a subject identified as suffering from the dermatological condition an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof,as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating a dermatological condition. Still other embodiments described herein relate to a use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, in the preparation of a medicament for treating a dermatological condition.

[0185] Some embodiments herein relate to a method of treating a renal condition that can include administering to a subject identified as suffering from the renal condition an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating a renal condition. Still other embodiments described herein relate to a use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, in the preparation of a medicament for treating a renal condition.

[0186] Some embodiments herein relate to a method of treating a liver condition that can include administering to a subject identified as suffering from the liver condition an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating a liver condition. Still other embodiments described herein relate to a use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, in the preparation of a medicament for treating a liver condition.

[0187] Some embodiments herein relate to a method of treating cardiovascular disease that can include administering to a subject identified as suffering from the cardiovascular disease an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or apharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating cardiovascular disease. Still other embodiments described herein relate to a use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, in the preparation of a medicament for treating cardiovascular disease.

[0188] The terms “treating,” “treatment,” “therapeutic,” or “therapy” as used herein has its ordinary meaning as understood in light of the specification, and do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and / or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well- being or appearance.

[0189] Compounds, and pharmaceutically acceptable salts thereof, disclosed herein can be evaluated for efficacy and toxicity using known methods. A non-limiting list of potential advantages of a compound, or a pharmaceutically acceptable salt thereof, described herein include improved stability, increased safety profile, increased efficacy, increased binding to the target, increased specificity for the target (for example, a cancer cell).EXAMPLES

[0190] Some aspects of the embodiments discussed above are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the present disclosure. Those in the art will appreciate that many other embodiments also fall within the scope of the invention, as it is described herein above and in the claims.

[0191] The following abbreviations have the indicated meanings: 1HNMR = proton nuclear magnetic resonanceAcCl = acetyl chlorideAcOH = acetic acidBINAP = (2,2’-bis(diphenylphosphino)-l,l’-binapthylBOC = tert-butoxycarbonylDCM = dichloromethaneDIEA = MA-diisopropylcthylamincDIPEA = / V, / V-di isopropylethylamineDMAP = 4-dimethylaminopyridineDMF = dimethylformamideDMP = Dess-Martin periodinaneDMSO = dimethyl sulfoxideESI = electrospray ionizationEt = ethyl eq = equivalent(s) h = hour(s)HATU = hexafluorophosphate azabeznotriazole tetramethyl uroniumHO Ac = acetic acidLDA = lithium diisopropylamideM = molar min = minute(s)MeCN = acetonitrileMeOH = methanolMOM = methoxymethyletherMS = mass spectrometryMW = microwaveNBS = N-bromosuccinimideNaBh(OAc)a = sodium triacetoxyborohydrideNaOAc = sodium acetateNaOMe = sodium methanolate or sodium methoxideOTB S = tert-butyl-dimethyl- silanePd / C = palladium on carbonPd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0) psi = pounds per square inchRf = retention factor[Rh(C0D)Cl]2 = cyclooctadiene rhodium chloride dimerRh(0Ac)2 = rhodium(II) acetate t-Amyl-OH = 2-methylbutan-2-ol r-BuOK = potassiumtert-butoxidcTEA = triethylamineTfoO = trifluormethanesulfonic anhydrideTHF = tetrahydrofuranTLC = thin-layer chromatographyTsCl = 4-toluenesulfonyl chlorideXantPhos Pd G3 = [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-l,l'- biphenyl)]palladium(II) methanesulfonateExample 1 , Preparation of Compound 5 A1A 2A

[0192] To a solution of (3R,7aS)-3-(trichloromethyl)tetrahydropyrrolo[l,2-c]oxazol- l(3H)-one (15.0 g, 61.4 mmol, 1.00 eq) in tetrahydrofuran (80.0 mL) was added lithium diisopropylamide (2 M, 46.0 mL, 1.50 eq) at -78 C under N2. The mixture was stirred at -78 °C for 1 h. A solution of ((chloromethoxy)methyl)benzene (16.3 g, 104 mmol, 14.4 mL, 1.70 eq) in tetrahydrofuran (50.0 mL) was added to the mixture at -78 °C, the resulting mixture was stirred at -30°C for 2 h. The mixture was quenched with water (50.0 mL). The resulting mixture was extracted with ethyl acetate (100 mLx3). The separated organic layer was washed with brine (50 mLx2), dried over NaiSCL and concentrated in vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100:1 to 10:1). (3R,7aR)-la-((benzyloxy)methyl)-3-(trichloromethyl)tetrahydropyrrolo[l,2-c]oxazol-l(3H)-one (17.3 g, 47.4 mmol, 77% yield) was obtained as a yellow oil. NMR (400 MHz, CHLOROFORM-d) δ = 7.27 - 7.15 (m, 5H), 5.00 - 4.87 (m, 1H), 4.63 - 4.50 (m, 2H), 3.75 - 3.61 (m, 2H), 3.33 - 3.12 (m, 2H), 2.32 - 2.18 (m, 1H), 2.12 - 2.02 (m, 1H), 2.00 - 1.88 (m, 1H), 1.72 - 1.59 (m, 1H).Example 1 ,2: Synthesis of Compound 3A

[0193] To a solution of (T / ?,7a / ?)-7a-((benzyloxy)methyl)-3- (trichloromethyl)tetrahydropyrrolo[l,2-c]oxazol-l(3 / / )-one (17.0 g, 46.6 mmol, 1.00 eq) in methanol (100 mL) was added sodium ;methanol ate (2.27 g, 42.0 mmol, 0.900 eq) at 20°C. The mixture was stirred at 20 °C for 3 h. Then the mixture was cooled to 0°C, acetyl chloride (54.9 g, 699 mmol, 49.9 mL, 15.0 eq) was added into the mixture at 0°C. The mixture was stirred at 70°C for 17 h. The mixture was diluted with water (50 mL), quenched with sodium bicarbonate (100 mL) and extracted with dichloromethane (150 mL x 3). The combined organic layer was washed with brine (50 mLx2), dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography (ethyl acetate / dichloromethane = 100:1 to 10:1). (R)-methyl 2-((benzyloxy)methyl)pyrrolidine-2-carboxylate (9.50 g, 38.1 mmol, 82% yield) was obtained as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d ) δ = 7.36 - 7.28 (m, 5H), 4.78 (d, J= 12.0 Hz, 1H), 4.57 (d, J= 12.0 Hz, 1H), 4.20 (d, J= 9.6 Hz, 1H), 3.98 (d, J= 9.6 Hz, 1H), 3.85 (s, 3H), 3.73 - 3.63 (m, 1H), 3.54 - 3.50 (m, 1H), 2.28 - 2.21 (m, 1H), 2.20 - 2.11 (m, 2H), 2.00 - 1.90 (m, 1H).Example 1 ,3: Synthesis of Compound 4 AF0194] To a solution of (R)-methyl 2-((benzyloxy)methyl)pyrrolidine-2-carboxylate (9.00 g, 36.1 mmol, 1.00 eq) in dichloromethane (35 mL) was added formaldehyde (11.7 g, 144 mmol, 10.8 mL, 37% purity, 4.00 eq) at 20 °C. The mixture was stirred at 20 °C for 0.5 h. Sodium triacetoxyhydroborate (23.0 g, 108 mmol, 3.00 eq) was added into the mixture at 20 °C. Themixture was stirred at 20°C for 12 h. The mixture was poured into water (50 mL), extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (30.0 mL), dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate =100:1 to 1:1). (R)-methyl 2- ((benzyloxy)methyl)-l-methylpyrrolidine-2-carboxylate (5.90 g, 22.41 mmol, 62.06% yield) was obtained as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ =7.39 - 7.29 (m, 5H), 4.58 (s, 2H), 3.73 (s, 4H), 3.59 (br d, J = 9.2 Hz, 1H), 3.02 (br d, J = 4.4 Hz, 1H), 2.84 (br d, J = 7.6 Hz, 1H), 2.45 (br s, 3H), 2.31 - 2.18 (m, 1H), 2.06 - 1.97 (m, 1H), 1.91 - 1.80 (m, 2H).Example 1.4: Synthesis of Compound 5A

[0195] To a solution of methyl (R)-2-((benzyloxy)methyl)-l-methylpyrrolidine-2- carboxylate (2.50 g, 9.49 mmol, 1.00 eq) in methanol (20.0 mL) was added acetic acid (1.05 g,17.5 mmol, 1.00 mL, 1.84 eq) and Hydroxide palladium (500 mg, 9.49 mmol, 20% purity, 1.00 eq) at 20°C. The mixture was stirred at 50°C for 120 h under hydrogen (50 Psi). The mixture was filtered. The filter cake was washed with methanol (3 x 30.0 mL). The combined filtrate was concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether / ethyl acetate =100: 1 to 1:1. Methyl (R )-2-(hydroxymethyl)- 1-methy Ipyrrolidine- 2-carboxylate (654 mg, 3.78 mmol, 40% yield) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 3.88 - 3.71 (m, 5H), 3.29 (br s, 1H), 3.04 (q, J = 8.5 Hz, 1H), 2.59 - 2.45 (m, 3H), 2.25 - 2.14 (m, 2H), 1.96 (br d, J = 5.9 Hz, 2H).Example 2,1: Synthesis of Compound 76 7

[0196] To a solution of 2-methoxy-6-nitro-aniline (10.0 g, 59.4 mmol, 10.0 mL, 1.00 eq) in dichloromethane (300 mL) was added / V-Bromosuccinimidc (13.8 g, 77.3 mmol, 1.30 eq) at 20 °C, the mixture was stirred at 20 °C for 16 h under nitrogen. The mixture was concentrated in vacuum to give a residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1 to 10:1). 4-bromo-2-methoxy-6-nitroaniline (12.0 g, 48.6 mmol, 81.68% yield) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 3.93 (s, 3 H) 6.46 (br s, 2 H) 6.94 (d, 7=1.9 Hz, 1 H) 7.90 (d, 7=2.0 Hz, 1 H).Example 2,2: Synthesis of Compound 87 8

[0197] To a solution of 4-bromo-2-methoxy-6-nitro-aniline (12.0 g, 48.6 mmol, 1.00 eq) in dimethylformamide (120 mL) was added sodium hydride (2.33 g, 58.3 mmol, 60% purity, 1.20 eq) at 0 °C, the mixture was stirred at 0 °C for 30 min, and then added iodomethane (6.89 g, 48.6 mmol, 3.02 mL, 1.00 eq) at 0 °C, the mixture was stirred at 0 °C for 10 min. The mixture was poured into water (200 mL), filtered, the filter cake was concentrated in vacuum to give a residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1 to 5:1). 4-bromo-2-methoxy-A^-methyl-6-nitro-aniline (10 g, crude) was obtained as a yellow solid. MS (ESI) m / z 261.0. [M+H]+.Example 2,3: Synthesis of Compound 98 9

[0198] To a solution of 4-bromo-2-methoxy-N-methyl-6-nitro-aniline (2.70 g, 10.34 mmol, 1.00 eq) in acetic acid (60 mL) was added zinc powder (3.38 g, 51.7 mmol, 5.00 eq) at 20°C, the mixture was stirred at 20 °C for 20 min. The mixture was filtered. The filtrate was concentrated in vacuum to give a residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1 to 10:1). 5-bromo-3-methoxy-nitrogen- methyl-benzene-l,2-diamine (2.3 g, 9.95 mmol, 96.24% yield) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.00 (s, 3 H) 4.45 (s, 3 H) 6.86 (d, J= 0.8 Hz, 1 H) 7.76 (d, J= 1.2 Hz, 1 H).Example 2,4: Synthesis of Compound 10DMF, 95 C, 4 h

[0199] To a solution of 5-bromo-7-methoxy-l-methyl-benzotriazole (2.20 g, 9.09 mmol, 1.00 eq) and ethyl prop-2-enoate (4.55 g, 45.4 mmol, 4.94 mL, 5.00 eq) in dimethylformamide (40 mL) was added palladium acetate (204 mg, 909 μmol, 0.10 eq), tris(2- methoxyphenyl)phosphane (1.60 g, 4.55 mmol, 0.50 eq) and DIEA (2.94 g, 22.7 mmol, 3.96 mL, 2.50 eq) at 20 °C, the mixture was stirred at 100 °C for 4 h under nitrogen. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuum to give a residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100: 1 to 10: 1). Ethyl (E)-3-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)acrylate (1.1 g, 4.21 mmol, 46.32% yield) was obtained as a yellow solid.{H NMR (400 MHz, CHLOROFORM-7) δ ppm 1.35 (t, 7=7.1 Hz, 3 H) 4.02 (s, 3 H) 4.28 (q, 7=7.1 Hz, 2 H) 4.45 (s, 3 H) 6.44 (d, 7=15.9 Hz, 1 H) 6.92 (s, 1 H) 7.69 - 7.81 (m, 2 H).Example 2,5: Synthesis of Compound 11

[0200] To a solution of ethyl (£’)-3-(7-methoxy-l-methyl-benzotriazol-5-yl)prop-2- enoate (500 mg, 1.91 mmol, 1.00 eq) in dioxane (10 mL) and water (5.00 mL) was added triethylamine(290 mg, 2.87 mmol, 399 pL, 1.50 eq) [3-(hydroxymethyl)-4-methyl-phenyl]boronic acid (476 mg, 2.87 mmol, 1.50 eq) , chlororhodium;(lZ,5Z)-cycloocta- 1,5 -diene (18.8 mg, 38.2 μmol, 0.02 eq) and [l-(2-diphenylphosphanyl-l-naphthyl)-2-naphthyl]-diphenyLphosphane (47.6 mg, 76.5μmol, 0.04 eq) at 20 °C, the mixture was stirred at 95 °C for 16 h. The mixture wasdiluted with water (30 mL). And then extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuum to give a residue. The crude product was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate=100:l to 1:1. Ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-l- methyl-177-benzo[d][l,2,3]triazol-5-yl)propanoate (250 mg, 651.99 μmol, 34.07% yield) was obtained as a white oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (t, 7=7.1 Hz, 3 H) 2.31 (s, 3 H) 3.01 - 3.21 (m, 2 H) 3.92 (s, 3 H) 4.06 (q, 7=7.1 Hz, 2 H) 4.42 (s, 3 H) 4.62 - 4.69 (m, 3 H) 6.61 (s, 1 H) 7.11 (s, 2 H) 7.28 (s, 1 H) 7.50 (s, 1 H).Example 3: Preparation of Compound 19Example 3.1 : Synthesis of Compound 1312 13

[0201] To a solution of l-fluoro-3-methoxybenzene (5.00 g, 39.6 mmol, 4.55 mL, 1.00 eq) in dichloromethane (45.0 mL) was added chloro sulfonic acid (18.5 g, 158 mmol, 10.6 mL, 4.00 eq) at 0°C. The mixture was stirred at 20°C for 2 h (4 batches). The mixture was poured into ice-water (120 mL), extracted with dichloromethane (3 x 150 mL). The organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuum. 2-Fluoro-4- methoxybenzenesulfonyl chloride (14.7 g, crude) was obtained as a yellow oil.Example 3.2: Synthesis of Compound 14

[0202] To a solution of 2-fluoro-4-methoxybenzenesulfonyl chloride (12.0 g, 53.4 mmol, 1.00 eq) in tetrahydrofuran (32.0 mL) and water (8.00 mL) was added potassium carbonate (7.38 g, 53.4 mmol, 1.00 eq) and (R )-l-aminopropan-2-ol (4.01 g, 53.4 mmol, 4.21 mL, 1.00 eq) at 20°C. The mixture was stirred at 20°C for 1 h. The mixture was poured into water (50.0 mL), and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 50.0 mL), dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether / ethyl acetate=100: 1 to 10:1. (R )-2-fluoro-N -(2-hydroxypropyl)-4-methoxybenzenesulfonamide (10.5 g, 39.9 mmol, 75% yield) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.69 (t, J - 8.8 Hz, 1H), 7.62 (br t, J = 5.8 Hz, 1H), 7.04 (dd, J = 2.4, 12.4 Hz, 1H), 6.94 - 6.89 (m, 1H), 4.68 - 4.63 (m, 1H), 3.94 - 3.79 (m, 3H), 3.64 - 3.52 (m, 1H), 2.81 - 2.72 (m, 1H), 2.67 (td, J= 6.4, 13.3 Hz,1H), 1.02 - 0.94 (m, 3H).Example 3.3: Synthesis of Compound 15methoxybenzenesulfonamide (8.00 g, 30.4 mmol, 1.00 eq) in dimethylsulfoxide (50.0 mL) was added potassium tert-butoxide (10.2 g, 91.2 mmol, 3.00 eq) at 20°C. The mixture was stirred at 100°C for 1 hr. The mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine (30 mL), dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether / ethyl acetate = 100:1 to 10:1. (R)-7-methoxy-4- methyl-3,4-dihydro-2 / / -benzo[&][l,4,5]oxathiazepine 1,1-dioxide (4.50 g, 18.5 mmol, 61% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ - 7.67 (br s, 1H), 7.62 (d, J - 8.8 Hz, 1H), 6.82 (dd, J= 2.4, 8.8 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 4.08 - 3.92 (m, 1H), 3.81 (s,3H), 3.30 (br s, 2H), 1.29 (d, J = 6.4 Hz, 3H).Example 3.4: Synthesis of Compound 1615 16

[0204] To a solution of (R)-7-methoxy-4-methyl-3,4-dihydro-277- benzo[b ][l,4,5]oxathiazepine 1,1-dioxide (2.20 g, 9.04 mmol, 1.00 eq) in dimethylformamide (15.0 mL) was added ethylsulfanylsodium (3.80 g, 45.2 mmol, 5.00 eq) at 20°C. The mixture was stirred at 150 °C for 3.5 h. The mixture was stirred at 140 °C for 15 h. The mixture was poured into water (50.0 mL), extracted with dichloromethane (50.0 mL x 3). The combined organic layer was washed with brine(30 ml), dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether / ethyl acetate =100: 1 to 5:1. (R)-7-hydroxy-4-methyl-3,4-dihydro-2H-benzo[&][ 1,4,5 ]oxathiazepine 1,1- dioxide (1.20 g, 5.23 mmol, 58% yield) was obtained as a yellow solid.!H NMR (400 MHz,DMSO- d6) δ = 10.40 (s, 1H), 7.61 - 7.49 (m, 2H), 6.62 (dd, J= 2.2, 8.6 Hz, 1H), 6.51 (d, J = 2.1 Hz, 1H), 4.00 - 3.90 (m, 1H), 3.27 (hr dd, J = 3.7, 7.8 Hz, 2H), 1.27 (d, J = 6.4 Hz, 3H).Example 3.5: Synthesis of Compound 17

[0205] To a solution of (R)-7-hydroxy-4-methyl-3,4-dihydro-2H- benzo[b][l,4,5]oxathiazepine 1,1-dioxide (500 mg, 2.18 mmol, 1.00 eq) and tert-butyl (2-(2- bromoethoxy)ethyl)carbamate (585 mg, 2.18 mmol, 1.00 eq) in dimethylformamide (20.0 mL) was added potassium carbonate (603 mg, 4.36 mmol, 2.00 eq) at 20°C, the mixture was stirred at 20°C for 16 h. The mixture was diluted with water (40.0 mL). And then extracted with ethyl acetate (2 x 40.0 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuum to give a residue. The crude product was purified by reversed-phase HPLC(0.1% FA condition). Tert-butyl (R)-(2-(2-((4-methyl-l,l-dioxido-3,4-dihydro-2H- benzo[b][l,4,5]oxathiazepin-7-yl)oxy)ethoxy)ethyl)carbamate (1.00 g, 2.40 mmol, 55% yield) was obtained as a yellow oil. MS (ESI) m / z 317.0 [M-100]+.Example 3.6: Synthesis of Compound 18

[0206] To a solution of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-l- methyl-lH-benzo[rf][l,2,3]triazol-5-yl)propanoate (500 mg, 1.30 mmol, 1.00 eq) in dichloromethane (4.00 mL) was added thionyl chloride (821 mg, 6.90 mmol, 500 μL. 5.29 eq) at 20°C, the mixture was stirred at 20°C for 30 min. The mixture was concentrated in vacuum to give a residue. It was not purified and used for the next step. Ethyl 3-(3-(((R )-7-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)-4-methyl- 1 , 1 -dioxido-3,4-dihydro-2H- bcnzo[&] [ 1 ,4,5]oxathiazcpin-2-yl)mcthyl)-4-mcthylphcnyl)-3-(7-mcthoxy- 1 -methyl- 177- benzo[t / ][l,2,3]-triazol-5-yl)propanoate (500 mg, 1.24 mmol, 95.41% yield) was obtained as a yellow oil. To a solution of tert-butyl (R )-(2-(2-((4-methyl-l,l-dioxido-3,4-dihydro-2H- benzo[Z?][l,4,5]oxathiazepin-7-yl)oxy)ethoxy)-ethyl)carbamate (500 mg, 1.20 mmol, 1 eq) and ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7 -methoxy- l-methyl-benzotriazol-5- yl)propanoate (482 mg, 1.20 mmol, 1.00 eq) in acetonitrile (10.0 mL) was added potassium carbonate (332 mg, 2.40 mmol, 2.00 eq) at 20°C, the mixture was stirred at 90°C for 3 h. The mixture was diluted with water (50.0 mL). And then extracted with ethyl acetate (60.0 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuum to give a residue. The crude product was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate=100 : 1 to 1 : 1. ethyl 3-(3-(((R )-7-(2-(2-((tert- butoxycarbonyl)amino)ethoxy)ethoxy)-4-methyl-l,l-dioxido-3,4-dihydro-277- benzo[&][l,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy-l-methyl-177- benzo[c?][l,2,3]triazol-5-yl)propanoate (560 mg, 680 μmol, 57% yield, 95% purity) was obtained as a yellow solid. MS (ESI) m / z 782.8 [M+H]+.Example 3.7: Synthesis of Compound 19

[0207] To a solution of ethyl 3-(3-(((R )-7-(2-(2-aminoethoxy)ethoxy)-4-methyl-l,l- dioxido-3,4-dihydro-277-benzo[b ][ 1 ,4,5 ]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7- mcthoxy- 1 -methyl- 177-bcnzo|<b | l,2,3]-triazol-5-yl)propanoate (550 mg, 703 jimol, 1.00 eq) in dichloromethane (10.0 mL) was added hydrochloric acid / dioxane (4 M, 4.00 mL, 22.8 eq) at 20°C. The mixture was stirred at 20°C for 10 min. The mixture concentrated in vacuum. It was not purified and used for the next step. Ethyl 3-(3-(((R )-7-(2-(2-aminoethoxy)ethoxy)-4-methy 1-1,1 - dioxido-3,4-dihydro-277-benzo[&][ 1 ,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy- 1 -methyl- l H-benzo[d][l , 2, 3]triazol-5-yl)propanoate (480 mg, 668 μmol, 95% yield, hydrochloric acid) was obtained as a white solid.Example 4: Preparation of Compound P-124A 25A

[0208] To a solution of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2, 4(177, 3 / 7)-dionc(5.00 g, 23.2 mmol, 1.00 eq) in toluene (50.0 mL) was added phosphorus oxychloride (10.7 g, 69.6 mmol, 6.47 mL, 3.00 eq) and MAMiisopropylethylamine (8.99 g, 69.6 mmol, 12.1 mL, 3.00 eq) at 0°C. The mixture was stirred at 20°C for 10 min, and then stirred at 110°C for 16 h. The mixture was concentrated in vacuum to give a residue. The residue was dissolved with ethyl acetate (400 mL), and then washed with water (2 x 100 mL), brine (2 x 50.0 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. It was not purified and used for the next step. 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.00 g, 15.8 mmol, 68% yield) was obtained as a yellow solid.Example 4,2: Synthesis of Compound 2221 22

[0209] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.00 g, 3.96 mmol, crude purity, 1.00 eq) in dichloromethane (20.0 mL) was added tert-butyl (17 ,55)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (841 mg, 3.96 mmol, 1.00 eq) and N,N- diisopropylethylamine (1.02 g, 7.92 mmol, 1.38 mL, 2.00 eq) at -40°C. The mixture was stirred at -40°C for 10 min. The mixture was poured into water (200 mL), and then extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuum to give a residue. The residue was triturated with ethyl acetate (10.0 mL), and then filtered. The filter cake was dried in vacuum (760 mg). The filtrate was concentrated in vacuum to give a residue (700 mg). The residue was triturated with ethyl acetate (5.00 mL), and then filtered. The filter cake was dried in vacuum (500 mg). Tert-butyl (17?,5S')-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.26 g, 2.94 mmol, 74% yield) was obtained as a yellow solid. NMR (400 MHz, DMSO-d6) δ = 9.06 (s, 1H), 4.57 - 4.38 (m, 2H), 4.26 (s, 2H), 3.77 - 3.58 (m, 2H), 1.87 - 1.73 (m, 2H), 1.67 - 1.55 (m, 2H), 1.46 (s, 9H).Example 4,3: Synthesis of Compound 23

[0210] To a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3- e / ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.63 mmol, 1.00 eq) andmethyl (R )-2-(hydroxymethyl)-1 -methylpyrrolidine-2-carboxylate (340 mg, 1.96 mmol, 1.20 eq) in dioxane (20.0 mL) was added cesium carbonate (1.07 g, 3.27 mmol, 2.00 eq) at 20°C. The mixture was stirred at 95°C for 16 h. The mixture was concentrated in vacuum to give a residue. The residue was diluted with ethyl acetate (30 mL), and then filtered. The filtrate was concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =5:1-1:1). Tert-butyl (1R ,55)-3-(7-chloro-8-fluoro-2-(((A)-2- (methoxycarbonyl)-l-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-rf]pyrimidin-4-yl)-3,8- diazabicyclo-[3.2.1]octane-8-carboxylate (640 mg, 1.13 mmol, 69% yield) was obtained as a yellow solid.JH NMR (400 MHz, CHLOROFORM-d) δ = 8.72 (s, 1H), 4.72 (d, J= 10.8 Hz, 1H), 4.57 - 4.42 (m, 2H), 4.41 - 4.29 (m, 1H), 3.67 - 3.58 (m, 3H), 3.15 - 3.01 (m, 2H), 2.91 (q, J= 8.8 Hz, 1H), 2.81 (q, J = 8.0 Hz, 1H), 2.44 - 2.35 (m, 2H), 2.32 (s, 3H), 2.20 - 2.04 (m, 4H), 1.99 - 1.78 (m, 5H), 1.76 - 1.66 (m, 2H), 1.52 (s, 6H).Example 4,4: Synthesis of Compound 24solution of tert-butyl (1R ,55)-3-(7-chloro-8-fluoro-2-(((R)-2-(methoxycarbonyl)- l-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-(7]pyrimidin-4-yl)-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 531 1.0μ0mo elq, ) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl)ethynyl)triisopropylsilane (408 mg, 796 1.50e q ) in, tetrahydrofuran (6.00 mL) was added di( 1 -adamantyl)-butylphosphine-2-(2’ -amin- 1,1’ -biphenyl)]palladium(II) methanesulfonate (38.7 mg, 53.1 μmo 0l,.100 eq) and potassium phosphate (1.5 M, 1.06 mL, 3.00 eq) at 20°C. The mixture was stirred at 65 °C for 16 h. The mixture was concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =10:1-1:1). Tert-butyl (lR,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)cthynyl)naphthalcn-l-yl)-2-(((R)-2-(mcthoxycarbonyl)-l-mcthylpyrrolidin-2- yl)methoxy)pyrido[4,3-7]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (378 mg, 413 μmol, 78% yield) was obtained as a yellow solid.JH NMR (400 MHz, CHLOROFORM-d) <5 = 9.06 (s, 1H), 7.79 (dd, J = 5.6, 9.2 Hz, 1H), 7.51 (d, 7= 2.4 Hz, 1H), 7.33 - 7.27 (m, 2H), 5.36 - 5.24 (m, 2H), 4.88 - 4.65 (m, 2H), 4.53 - 4.32 (m, 3H), 4.20 (d, J= 12.4 Hz, 1H), 3.87 - 3.60 (m, 5H), 3.01 - 2.74 (m, 2H), 2.49 - 2.39 (m, 4H), 2.19 - 2.07 (m, 2H), 2.01 (dd, 7= 4.0, 9.2 Hz, 6H), 1.53 (s, 9H), 0.87 (t, 7 = 6.4 Hz, 18H), 0.60 - 0.50 (m, 3H).(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((R )-2-(methoxycarbonyl)- l-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-<7]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (278 mg, 304 μ 1m.0o0l, eq) in tetrahydrofuran (2.00 mL), methanol (2.00 mL) and Water (0.500 mL) was added Lithium hydroxide monohydrate (51.0 mg, 1.22 mmol, 4.00 eq) at 20°C. The mixture was stirred at 20°C for 3 h. The mixture was poured into water (20.0 mL), and then extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=l: 1-0:1- dichloromethane / methanol=10:l). (R)-2-(((4-((lR,55)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo [3.2.1 ] -octan-3-yl)- 8-fluoro-7-(7 -fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido-[4,3-< / ]pyrimidin-2-yl)oxy)methyl)-l- methylpyrrolidine-2-carboxylic acid (160 mg, 178 58% μ yimelodl,, 100% purity) was obtainedas a yellow solid. H NMR (400 MHz, CHLOROFORM-^) δ = 9.11 (s, 1 H), 7.80 (dd, J = 6.0, 8.8 Hz, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.31 (d, J = 6.0 Hz, 2H), 5.36 - 5.24 (m, 2H), 5.23 - 5.08 (m, 1H), 4.76 (t, J = 13.2 Hz, 1H), 4.55 - 4.37 (m, 2H), 4.35 - 4.22 (m, 1H), 4.02 - 3.78 (m, 2H), 3.56 - 3.47 (m, 4H), 3.40 - 3.23 (m, 1H), 3.01 (d, J = 7.2 Hz, 3H), 2.65 - 2.51 (m, 2H), 2.11 (s, 2H), 2.04 (d, J = 9.6 Hz, 4H), 1.92 - 1.85 (m, 2H), 1.53 (s, 9H), 0.91 - 0.82 (m, 18H), 0.63 - 0.48 (m, 3H).Example 4,6: Synthesis of Compound 2625A 26A

[0213] To a solution of (R)-2-(((4-((17?,55')-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((ti’iisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l- methylpyrrolidine-2-carboxylic acid (80.0 mg, 88.8 1.00 eμqm) o anl,d ethyl 3-(3-(((R)-7-(2-(2- aminoethoxy)ethoxy)-4-methyl- 1 , 1 -dioxido-3,4-dihydro-2H-benzo[&][ 1 ,4,5 ]oxathiazepin-2- yl)methyl)-4-methylphenyl)-3-(7-methoxy-l-methyl-lH-benzo[<i][l,2,3]triazol-5-yl)propanoate (76.5 mg, 106 μmo 1l.,20 eq, hydrochloric acid) in dimethylformamide (2.00 mL) was added O- (7-azabenzotriazol-l-yl)-A(MA(AMetramethyluroniumhexafluorophosphate (50.6 mg, 133 μmol, 1.50 eq) and A(iV-diisopropylethylamine (34.4 mg, 266 46.4 μμLm, o 3l.0, 0 eq) at 20°C. The mixture was stirred at 20°C for 3 h. The mixture was poured into water (50.0 mL), and then extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum to give a residue. The residue was purified silica gel chromatography (petroleum ether / ethyl acetate =1:1-1:3). Tert-butyl (17?,5S)-3-(2-(((27?)-2-((2- (2-(((4R)-2-(5-(3-ethoxy- 1 -(7-methoxy- 1 -methyl- 1 rt-bcnzo|<7|| 1 ,2,3 ]triazol-5-yl)-3-oxopropyl)- 2-methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[Z?][l,4,5]oxathiazepin-7- yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-<7]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (130 mg, 83.1 93% yielμdm) o wl,as obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM) δ = 9.16 - 9.05 (m, 1H), 8.05 - 7.98 (m, 1H), 7.84 - 7.76 (m, 1H), 7.73 - 7.66 (m, 1H), 7.55 - 7.48 (m, 1H), 7.45 - 7.41 (m, 1H), 7.33 - 7.29 (m, 2H), 7.16 - 7.10 (m, 2H), 7.07 - 7.03 (m, 1H), 6.77 - 6.64 (m, 2H), 6.59 - 6.54 (m, 1H), 5.34 - 5.26 (m, 5H), 4.63 - 4.56 (m, 2H), 4.50 (dd, J= 3.6, 14.1 Hz, 2H), 4.08 - 4.03 (m, 2H), 3.85 (d, J= 2.0 Hz, 2H), 3.74 - 3.64 (m, 5H), 3.15 - 2.99 (m, 4H), 2.96 (s, 4H), 2.89 (s, 3H), 2.87 - 2.78 (m, 4H), 2.38 (t, J= 8.0 Hz, 2H), 2.31 (s, 3H), 2.07 - 1.99 (m, 6H), 1.53 (s, 9H), 1.30 - 1.24 (m, 4H), 1.22 - 1.19 (m, 2H), 1.17 - 1.10 (m, 5H), 0.91 - 0.82 (m, 21H), 0.61 - 0.53 (m, 3H).Example 4,7: Synthesis of Compound P-126A P-1

[0214] To a solution of Tert-butyl (lR,5S)-3-(2-(((2R)-2-((2-(2-(((4R)-2-(5-(3-ethoxy- l-(7-methoxy- 1-methyl- l / Tbcnzo|<7|| l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4- methyl-l,l-dioxido-3,4-dihydro-2 / / -benzo[ / ?][l,4,5]oxathiazepin-7- yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-<i]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 83.1 1.00 eq) iμnm dioml,ethylformamide (2.00 mL) was added cesium fluoride (126 mg, 831 30.6 μLμ,m 10o.l0, eq) at 20°C. The mixture was stirred at 20°C for 30 min. The mixture was poured into water (20.0 mL), and then filtered. The filtrate was dissolved in ethyl acetate (50.0 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum. It was not purified and used for the next step. Tert- butyl (lA,5S)-3-(2-(((27?)-2-((2-(2-(((4R)-2-(5-(3-ethoxy-l-(7-methoxy-l-methyl-lH- benzo[<7][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro- 2H-benzo[&][l,4,5]oxathiazepin-7-yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2- yl)methoxy)-7-(8-ethynyl-7-fhroro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoropyrido[4,3-<7]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, crude) was obtained as a yellow solid. MS (ESI) m / z 1409.6 [M+H]+.

[0215] To a solution of tert-butyl (17?,5S)-3-(2-(((27?)-2-((2-(2-(((47?)-2-(5-(3-ethoxy-1-(7-methoxy-l-methyl-l / / -benzo[6?][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4- methyl- 1 , 1 -dioxido-3,4-dihydro-277-benzo[Z>] [ 1 ,4,5]oxathiazepin-7 - yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoropyrido[4,3-t / ]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 85.2 1.00 eq)μ imno dli,chloromethane (2.00 mL) was added hydrochloric acid / dioxane (4 M, 0.500 mL, 23.5 eq) at 20°C. The mixture was stirred at 20°C for 10 min. The mixture was concentrated in vacuum. It was not purified and used for the next step, ethyl 3-(3-((( / ?)-7-(2-(2-((R )-2-(((4-((17?,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)-l-methylpyrrolidine-2-carboxamido)ethoxy)ethoxy)-4-methyl-l,l-dioxido-3,4- dihydro-2H-benzo[&][l,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy-l-methyl- 17 / -benzo[<7][l,2,3]triazol-5-yl)propanoate (110 mg, 84.6 99% yield,μ hmydorlo,chloric acid) was obtained as a yellow oil.

[0216] To a solution of ethyl 3-(3-(((R )-7-(2-(2-((R )-2-(((4-((l / ?,55)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fluoropyrido[4,3-t / ]pyrimidin-2-yl)oxy)methyl)-l-methylpyrrolidine-2- carboxamido)ethoxy)ethoxy)-4-methyl-l,l-dioxido-3,4-dihydro-2H- benzo[&][ 1 ,4,5 ]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy- 1 -methyl- 1 H- benzo[t / ][l,2,3]triazol-5-yl)propanoate (110 mg, 87.0 1.00 eqμ) imno tel,trahydrofuran (2.00 mL) and methanol (2.00 mL) was added a mixture of Lithium hydroxide monohydrate (14.6 mg, 348 μmol, 4.00 eq) in Water (0.200 mL) at 20°C. The mixture was stirred at 20°C for 2 h. The mixture was concentrated in vacuum to give a residue. The residue was dissolved in dimethylformamide (2.00 mL), and then acidified by hydrochloric acid (1 M) adjust to pH-7. The resulting mixture was filtered. The filtrate was purified by / ucp-HPLC (column: Phenomenex luna Cl 8 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 17%-47%,10min). 3-(3-(((Z?)-7-(2-(2- ((l?)-2-(((4-((ll?,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l-methylpyiTolidine-2-carboxamido)ethoxy)ethoxy)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[ / ?] [1 ,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy- 1 -methyl- 177- bcnzo[7][l,2,3]triazol-5-yl)propanoic acid (10.99 mg, 8.40 9.65%μ ymieoldl,, 98% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1236.6 [M+H]+.JH NMR (400 MHz, DMSO-76) 3 = 9.03 (s, 1H), 8.15 - 8.06 (m, 1H), 8.01 - 7.92 (m, 1H), 7.67 - 7.58 (m, 1H), 7.50 - 7.30 (m, 4H), 7.29 - 7.22 (m, 1H), 7.18 (d, 7= 2.4 Hz, 1H), 7.10 (d, 7 = 8.0 Hz, 1H), 6.94 - 6.82 (m, 3H), 4.70 - 4.54 (m, 2H), 4.52 - 4.44 (m, 2H), 4.43 - 4.26 (m, 7H), 4.20 (s, 2H), 3.95 - 3.90 (m, 4H), 3.77 (s, 2H), 3.73 (d, 7= 7.2 Hz, 1H), 3.67 - 3.63 (m, 2H), 3.57 (s, 2H), 3.54 (s, 2H), 3.31 - 3.30 (m, 2H), 3.08 - 3.04 (m, 2H), 3.02 - 2.96 (m, 2H), 2.83 - 2.72 (m, 2H), 2.39 (d, 7 = 4.0 Hz, 3H), 2.22 (d, 7 = 1.6 Hz, 3H), 2.02 - 1.93 (m, 2H), 1.77 - 1.62 (m, 6H), 1.19 - 1.05 (m, 3H).Example 5: Preparation of Compound 28,27 28 29

[0217] To a solution of l-(tert-butoxycarbonyl)piperidine-3-carboxylic acid was added potassium carbonate (1.2 eq) and iodomethane (1 .4 eq) at 20 °C. The mixture was stirred for 2h. To a solution of l-(tcrt-butyl) 3-mcthyl piperidine- 1,3-dicarboxylatc (1.60 g, 6.58 mmol, 1.00 eq) in dichloromethane (10 mL) was added HCl / dioxane (4 M, 16 mL, 9.73 eq) at 20 °C. The mixture was stirred at 20°C for 1 h. The solvent was removed to give the residue. The residue was not purified and used for next step. Methyl piperidine-3-carboxylate (1.17 g, 6.51 mmol, 99.04% yield, HC1) was obtained as a white solid.Example 6: Preparation of Compound P-233Example 6.1 : Synthesis of Compound 3021 30

[0218] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.50 g, 5.94 mmol, 1.00 eq) in dichloromethane (15 mL) was added a solution of N,N-d i i sopropy let hy 1 am i ne (1.54 g, 11.9 mmol, 2.07 mL, 2.00 eq) and methyl pipcridinc-3-carboxylatc (851 mg, 4.74 mmol, 7.97e-1eq, HC1) dropwise at -40°C under N2. The reaction mixture was warmed to -40°C for 10 min. The mixture was diluted with water (150 mL), extracted with dichloromethane (50 mLx3).The combined organic layer was washed with brine (50 mL), dried over with sodium sulphate and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-35% Ethyl acetate / Petroleum ether gradient @ 60 mL / min). Methyl l-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxylate (1.40 g, 3.90 mmol, 65.6% yield) was obtained as a yellow solid.XH NMR (400 MHz, DMSO-Je) δ = 9.04 (s, 1H), 4.51 (dd, J= 3.6, 13.2 Hz, 1H), 4.32 - 4.15 (m, 1H), 3.75 (dd, J= 9.2, 13.2 Hz, 1H), 3.69 - 3.64 (m, 1H), 3.63 (s, 3H), 2.94 - 2.82 (m, 1H), 2.12 - 2.03 (m, 1H), 1.88 - 1.66 (m, 3H).Example 6.2: Synthesis of Compound 31

[0219] To a solution of methyl l-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)piperidine-3-carboxylate (1.40 g, 3.90 mmol, 1.00 eq) in dioxane (14 mL) was added cesium carbonate (2.54 g, 7.80 mmol, 2.00 eq) and ( (2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methanol (807 mg, 5.07 mmol, 1.30 eq) at 25 °C. The mixture was stirred at 95°C for 10 h. The mixture was poured into watcr(100 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layer was dried over with sodium sulphate and concentrated in vacuum. TLC (PE:EA=0:l) showed a main spot (Rf=0.4) detected. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=O / l to 3 / 4). Methyl l-(7-chloro-8-fluoro- 2-(((2S,7aR)-2-fluorotetrahydro-lH-pyrrolizin-7a(5 / / )-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-3-carboxylate (0.600 g, 1.07 mmol, 27.5% yield, 86% purity) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-tfc) δ = 8.90 (s, 1H), 4.22 - 4.10 (m, 2H), 3.71 - 3.48 (m, 5H), 3.16 - 2.96 (m, 4H), 2.91 - 2.78 (m, 2H), 2.21 - 2.01 (m, 4H), 1.93 - 1.64 (m, 8H).Example 6.3: Synthesis of Compound 32

[0220] To a solution of methyl l-(7-chloro-8-fhroro-2-(((2S,7aR)-2-fluorotetrahydro- l / 7-pyrrolizin-7a(5 / 7)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate (400 mg, 830 μmol 1,.00 eq) in tetrahydrofuran (5 mL) was added Ad2nBuP Pd G3(cataCXium® A Pd G3 ) (60.5 mg, 83.0 μm 0.o10l,0 eq), potassium phosphate (1.5 M, 553 μL, 1.00 eq) and ((2-fluoro- 6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl)ethynyl)triisopropylsilane (638 mg, 1.25 mmol, 1.50 eq) at 20°C under N2. The mixture was stirred at 70°C for 16 h. LCMS showed the starting material remained, and the mixture was stirred at 70°C for 4 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layer was dried over with sodium sulphate and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-55% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Methyl l-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-2-(((2S,7a / ?)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate (300 mg, 361 43.4μ%myoiel,ld) was obtained as a yellow solid.{H NMR (400 MHz, DMSO-d6) δ = 9.09 (d, J= 12.4 Hz, 1H), 8.18 - 8.05 (m, 1H), 7.75 (s, 1H), 7.57 (t, J = 8.8 Hz, 1H), 7.36 (s, 1H), 5.37 (s, 2H), 5.23 (s, 1H), 4.56 - 4.39 (m, 1H), 4.38 - 4.15 (m, 1H), 4.25 - 3.90 (m, 3H), 3.75 - 3.51 (m, 6H), 3.43 (s, 3H), 3.10 (s, 2H), 2.92 - 2.76 (m, 2H), 2.24 - 2.01 (m, 5H), 1.95 - 1.79 (m, 5H), 0.87 - 0.75 (m, 18H), 0.55 - 0.42 (m, 3H).Example 6.4: Synthesis of Compound 3332 33

[0221] To a solution of methyl l-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl) naphthalen- 1 -yl)-2-(((2S,7a / ?)-2-fluorotetrahydro- 1 H-pyrrolizin-7a(577)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate (300 mg, 361 μmol, 1.00 eq) in tetrahydrofuran (9 mL) was added lithium hydroxide;hydrate (75.7 mg, 1.80 mmol, 5.00 eq) in water (3 mL) and methanol (3 mL) at 20 °C. The mixture was stirred at 20 °C for 2 h. The mixture was poured into water(10 mL) and extracted with ethyl acetate (20 mLx3). The combined organic layer was dried over with sodium sulphate and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with dichloromethane: methanol =100: 1 to 10:1. l-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen- l-yl)-2-(((2S,7a / ?)-2- fluorotetrahydro- 17 / -pyrrolizin-7a(5H)-yl)methoxy)pyrido[4, 3- d]pyrimidin-4-yl)piperidine-3-carboxylic acid (80.0 mg, 97.8 27.12%μ ymieolld,, 100% purity) was obtained as a yellow solid.Example 6.5: Synthesis of Compound 34

[0222] To a solution of ethyl 3-[3-[[(47?)-7-[2-(2-aminoethoxy)ethoxy]-4-methyl-l,l- dioxo-3,4-dihydro-5,lX6,2-bcnzoxathiazcpin-2-yl]mcthyl]-4-mcthyl-phcnyl]-3-(7-mcthoxy-l- methyl-benzotriazol-5-yl)propanoate (80.0 mg, 111 1.00 μ emq,o cl,oncentrated hydrochloric acid) and l-[8-fluoro-2-[[(2S,4S,87?)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3- d]pyrimidin-4-yl]piperidine-3-carboxylic acid (95.1 mg, 116 μmol, 1.04 eq) in dimethylformamide (4 mL) was added N,N-diisopropylethylamine (72.0 mg, 557 97.0 μL, μmol, 5.00 eq) and O-(7-azabenzotriazol-l-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (63.5 mg, 167 μmol 1, .50 eq) at 20 °C, the mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (30 mL). And then extracted with ethyl acetate (2 x 30 mL). The combined organiclayers were dried over sodium sulfate and concentrated in vacuum to give a residue. It was not purified and used for the next step. Ethyl 3-[3-[[(47?)-7-[2-[2-[[l-[8-fhioro-2-[[(2S,4S,87?)-2- fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,lX6,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (160 mg, 107.98 μmol, 96.94% yield) was obtained as a yellow oil. MS (ESI) m / z 1483.1. [M+H]+.Example 6.6: Synthesis of Compound P-2P-2

[0223] To a solution of ethyl 3-[3-[[(4R)-7-[2-[2-[[l-[8-fluoro-2-[[(2S,4S,8R)-2- fluoro-l,2,3,5,6,7-hexahydropyiTolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,lX6,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (70.0 mg,47.2 μmol, 1 eq) in dimethylformamide (1 .00 mL) was added cesium fluoride (71 .7 mg, 472 pmol, 17.4 μL, 10.0 eq) at 20 °C ,thc mixture was stirred at 20 °C for 30 min under nitrogen. The mixture was diluted with water (20 mL). And then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuum to give a residue. It was not purified and used for the next step. Ethyl 3-[3-[[(4R)-7-[2-[2-[[l-[7-[8-ethynyl-7-fluoro- 3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-L2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,lX6,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (62 mg, 46.78 μmol, 99.02% yield) was obtained as a yellow solid.

[0224] To a solution of ethyl 3-[3-[[(4R)-7-[2-[2-[[l-[7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,lX6,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (62.0 mg, 46.7 μmol, 1.00 eq) in dioxane (1.00 mL) was added concentrated hydrochloric acid / dioxane (4 M, 233 μL, 20.0 eq) at 20°C. The mixture was stirred at 20°C for 15 min. The mixture was concentrated in vacuum to give a crude product. It was not purified and used for the next step. Ethyl 3-[3-[[(4R)-7-[2-[2-[[l-[7-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]piperidine-3-carbonyl]amino]ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,lX6,2- benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7 -methoxy- 1-methy 1-benzo triazol- 5- yl)propanoate (59 mg, 44.77 9μ5m.7o1l,% yield, concentrated hydrochloric acid) was obtained as a yellow solid.

[0225] To a solution of ethyl 3-[3-[[(4R)-7-[2-[2-[[l-[7-(8-ethynyl-7-fluoro-3- hydroxy-l-naphthyl)-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3-carbonyl]amino]ethoxy]ethoxy]-4-methyl- l,l-dioxo-3,4-dihydro-5,lX6,2-benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7-methoxy- l-methyl-benzotriazoL5-yl)propanoate (59.0 mg, 46.0 1.00 μ eqm)o iln, tetrahydrofuran (1.00 mL) was added water (1.00 mL) and methanol (0.200 mL) and lithium hydroxide (19.3 mg, 460 pmol, 10.0 eq) at 20 °C, the mixture was stirred at 40 °C for 2 h. The mixture was concentratedin vacuum to give a crude product. The crude product was purified by Prep-HPLC(column: Phcnomcncx luna C18 150*25mm* 10um;mobilc phase: [watcr(FA)-ACN];B%: 26%- 56%,10min). The desired product was lyophilized. 3-[3-[[(4R)-7-[2-[2-[[l-[7-(8-ethynyl-7- fluoro-3-hydroxy-l-naphthyl)-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3-carbonyl]amino]ethoxy]ethoxy]-4- methy 1- 1 , 1 -dioxo-3 ,4-dihydro-5 , 1 X6,2-benzoxathiazepin-2-y 1] methyl] -4-methy 1-phenyl] -3 - (7- methoxy-l-methyl-benzotriazol-5-yl)propanoic acid (8.21 mg, 6.42 13.94%μ ymieolld,, 98% purity) was obtained as a yellow solid. MS (ESI) m / z 1254.2. [M+H]+. (401H0 M NMHzR, DMSO-d6) δ ppm 1.01 - 1.19 (m, 3 H) 1.70 - 1.90 (m, 6 H) 1.96 - 2.13 (m, 4 H) 2.22 (d, J=3.5 Hz, 3 H) 2.69 - 2.88 (m, 3 H) 2.99 - 3.13 (m, 6 H) 3.46 - 3.52 (m, 3 H) 3.55 - 3.64 (m, 2 H) 3.71 - 3.79 (m, 3 H) 3.91 (d, J=4.5 Hz, 3 H) 3.96 - 4.06 (m, 2 H) 4.07 - 4.21 (m, 3 H) 4.29 - 4.40 (m, 6 H) 4.43 - 4.55 (m, 2 H) 5.14 - 5.39 (m, 1 H) 6.80 - 6.92 (m, 3 H) 7.07 - 7.22 (m, 2 H) 7.26 (br t, J=7.1 Hz, 1 H) 7.31 - 7.47 (m, 4 H) 7.58 - 7.66 (m, 1 H) 7.95 (br t, J=6.4 Hz, 1 H) 8.03 - 8.16 (m, 1 H) 9.01 (d, J=1.9 Hz, 1 H).P-3Example 7, 1 : Synth35 36

[0226] To a solution of 2-fluorobenzenesulfonyl chloride (5.00 g, 25.6 mmol, 3.40 mL, 1.00 eq) in tetrahydrofuran (16 mL) and water (4 mL) was added potassium carbonate (3.55 g, 25.6 mmol, 1.00 eq) and (R)-l-aminopropan-2-ol (2.12 g, 28.2 mmol, 2.22 mL, 1.10 eq) at 20 °C. The mixture was stirred at 20 °C for 1 h. The mixture was poured into water (50 mL), and then extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate=100:l to 10:1. (TLC (petroleum ether: ethyl acetate=3:l); Rf(Rl)=0.4; Rf (Pl)=0.2). (R)-2-fluoro-N-(2- hydroxypropyl)benzenesulfonamide (4.87 g, 20.88 mmol, 81.27% yield) was obtained as a colorless oil. 'l l NMR (400 MHz, DMSO-(Z6) 3 = 7.93 - 7.64 (m, 3H), 7.50 - 7.32 (m, 2H), 4.68 (d, 7= 4.8 Hz, 1H), 3.60 (td, 7= 5.9, 11.6 Hz, 1H), 2.89 - 2.68 (m, 2H), 0.99 (d, 7 = 6.3 Hz, 3H).Example 7.2: Synthesis of Compound 3736 37

[0227] To a solution of (R)-2-fluoro-N-(2-hydroxypropyl)benzenesulfonamide (4.85 g, 20.7 mmol, 1.00 eq) in dimethylsulfoxide (25 mL) was added potassium tert-butoxide (7.00 g, 62.3 mmol, 3.00 eq) at 20 °C. The mixture was stirred at 100 °C for 0.5 hr. The mixture was poured into water (50 mL), and then extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate=100: 1 to 10:1 (TLC (petroleum ether:ethyl acetate=3:l) ; Rf(Rl)=0.2; Rf (Pl)=0.3). (R)-4-methyl-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepine 1, 1 -dioxide (3.2 g, 15.01 mmol, 72.17% yield) was obtained as a white solid. NMR (400 MHz, DMSO-76) δ = 7.88 (brs, 1H), 7.78 (dd, 7= 1.1 , 7.8 Hz, 1H), 7.65 - 7.57 (m, 1H), 7.33 (t, 7= 7.6 Hz, 1H), 7.26 (d, 7= 8.0 Hz, 1H), 4.13 - 3.95 (m, 1H), 3.35 (br s, 2H), 1.34 (d, 7 = 6.5 Hz, 3H).Example 7,3: Synthesis of Compound 38

[0228] To a solution of (R)-4-methyl-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepine 1,1-dioxide (100 mg, 468 μmol 1,.00 eq) in acetonitrile (5 mL) was added ethyl 3-(3- (chloromethyl)-4-methylphenyl)-3-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5- yl)propanoate (188 mg, 468 1μ.0m0o elq,) and potassium carbonate (129 mg, 937 2.00 eq) μmol, at 20 °C. The mixture was stirred at 100 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate=100: 1 to 10:1 (TLC (petroleum ether: ethyl acetate=l:l); Rf(Rl)=0.4; Rf(Pl)=0.2). ethyl 3-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-(4- methyl-3-(((R)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoate (157 mg, 271.31 57.86%μm yioell,d) was obtained as a white solid. H NMR (400 MHz, DMSO-76) δ = 7.78 (br d, J = 7.5 Hz, 1H), 7.66 (br t, 7 = 7.7 Hz, 1H), 7.46 (s, 1H), 7.36 (br s, 2H), 7.33 - 7.23 (m, 2H), 7.14 - 7.08 (m, 1H), 6.93 (br d, J= 10.3 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.46 - 4.29 (m, 5H), 3.98 - 3.89 (m, 5H), 3.81 (br d, J = 14.3 Hz, 1H), 3.68 - 3.57 (m, 1H), 3.24 - 3.14 (m, 2H), 2.87 - 2.71 (m, 1H), 2.24 (br s, 3H), 1.18 - 1.09 (m, 3H), 1.05 (t, J = 6.9 Hz, 3H).Example 7,4: Synthesis of Compound 3938 39

[0229] To a solution of ethyl 3-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)- 3-(4-methyl-3-(((R)-4-methyl- 1 , 1 -dioxido-3,4-dihydro-2H-benzo[b] [ 1 ,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoate (145 mg, 250 μm 1o.l0,0 eq) in (2 mL) was added ethylsulfanylsodium (105 mg, 1.25 mmol, 5.00 eq) at 20 °C. The mixture was stirred at 150 °C for 2 h. The mixture was diluted with water (5 mL), extracted with dichloromethane(15 mLx3). The combined organic layer was washed with brine (5 mL), dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate=100:l to 5:1 (TLC (petroleum ether:ethyl acctatc=O: l ) ; Rf (Rl)=0.4; Rf (Pl)=0.2). 3-(7-hydroxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-(4-methyl-3- (((R)-4-methyL 1 , 1 -dioxido-3,4-dihydro-2H-benzo[b] [ 1 ,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoic acid (120 mg, 223.63 89.25%μm yioell,d) was obtained as a yellow solid. ‘H NMR (400 MHz, DMSO-d6) δ = 12.22 - 12.06 (m, 1H), 10.53 (d, 7= 3.1 Hz, 1H), 7.82 - 7.73 (m, 1H), 7.68 - 7.62 (m, 1H), 7.41 - 7.10 (m, 6H), 6.60 (d, J = 4.9 Hz, 1H), 4.45 - 4.38 (m, 2H), 4.34 (d, 7 = 2.5 Hz, 3H), 3.80 (br d, 7 = 14.1 Hz, 1H), 3.68 - 3.55 (m, 1H), 1.17 (d, 7 = 7.1 Hz, 3H).Example 7,5: Synthesis of Compound 4039 40

[0230] To a solution of 3-(7-hydroxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-(4- methyl-3-(((R)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoic acid (100 mg, 186 1.0μ0m eoql), in ethanol (2 mL) was added sulfuric acid (1.83 mg, 18.6 0μ.m10o0l, eq) at 20 °C. The mixture was stirred at 75 °C for 1.5 h. The mixture was concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate=100:l to 5:1 (TLC (petroleum ether: ethyl acetate=O:l); Rf (Rl)=0.2; Rf (Pl)=0.4). ethyl 3-(7-hydroxy-l-methyl-lH- benzo[d][l,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-4-methyl-l,l-dioxido-3,4-dihydro-2H- benzo[b][l,4,5]oxathiazepin-2-yl)methyl) phenyl)propanoate (85 mg, 150.54 80.78% yield)μmol, was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ =10.52 (br s, 1H), 7.77 (ddd, J = 1.6, 3.3, 7.8 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.40 - 7.09 (m, 6H), 6.58 (d, J= 4.3 Hz, 1H), 4.40 (br d, J= 13.0 Hz, 2H), 4.33 (d, 7 = 2.4 Hz, 3H), 3.95 (q, 7 = 7.1 Hz, 2H), 3.80 (d, 7 = 14.1 Hz, 1H), 3.69 - 3.60 (m, 2H), 3.18 - 3.00 (m, 2H), 2.84 - 2.73 (m, 1H), 2.24 (s, 3H), 1.25 - 1.15 (m, 3H), 1.04 (dt, 7= 1.2, 7.1 Hz, 3H).Example 7,6: Synthesis of Compound 41solution of ethyl 3-(7-hydroxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-4-methyl-l ,l-dioxido-3,4-dihydro-2H-benzo[b][l ,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoate (80.0 mg, 141 1.00μ emqo)l, in dimethylformamide (1 mL) was added potassium carbonate (58.7 mg, 425 μmol 3, .00 eq) and tert-butyl N-[2-(2- bromoethoxy)ethyl]carbamate (45.5 mg, 170 1.20 eqμ)m aotl 2, 0 °C. The mixture was stirred at 80 °C for 2 h. The mixture was poured into water (5 mL) and extracted with ethyl acetate (15 mL). The organic layer was dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate=100: 1 to 5:1 (TLC (petroleum ether: ethyl acetate=l:l); Rf (Rl)=0.1; Rf (Pl)=0.3). ethyl 3-(7-(2-(2-((tert-butoxycarbonyl)amino) ethoxy)ethoxy)-l-methyl-lH-benzo[d][l,2,3]triazol-5- yl)-3-(4-methyl-3-(((R)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoate (75 mg, 99.75 70.40%μm yoiell,d) was obtained as a colorless gum.NMR (400 MHz, DMSO-d6 ) δ ==.78 (td, J = 1.8, 7.8 Hz, 1H), 7.70 - 7.63 (m, 1H), 7.47 (s,1H), 7.40 - 7.24 (m, 4H), 7.11 (d, J= 7.8 Hz, 1H), 6.95 (d, J= 12.0 Hz, 1H), 6.77 (br s, 1H), 4.56- 4.48 (m, 1H), 4.47 - 4.38 (m, 2H), 4.35 (d, J = 2.4 Hz, 3H), 4.26 (br d, J = 3.9 Hz, 2H), 3.99 -3.90 (m, 2H), 3.81 (br dd, J = 4.6, 8.9 Hz, 3H), 3.62 (ddd, J = 6.0, 9.9, 15.4 Hz, 1H), 3.53 - 3.44 (m, 2H), 3.22 - 3.14 (m, 2H), 3.09 (br d, J= 5.3 Hz, 2H), 2.87 - 2.70 (m, 1H), 2.24 (d, J= 2.6 Hz, 3H), 1.34 (s, 9H), 1.23 (br d, J = 17.5 Hz, 3H), 1.04 (t, J = 6.9 Hz, 3H).Example 7,7: Synthesis of Compound 42 A

[0232] To a solution of ethyl 3-(7-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)- l-methyl-lH-benzo[d][l,2,3] triazol-5-yl)-3-(4-methyl-3-(((R)-4-methyl-l,l-dioxido-3,4- dihydro-2H-benzo[b][l,4,5]oxathiazepin-2-yl) methyl)phenyl)propanoate (72.0 mg, 95.7 pmol, 1.00 eq) in dichloromethane (2 mL) was added hydrochloric acid / dioxane (4 M, 0.5 mL, 20.89 eq) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated in vacuum, ethyl 3-(7-(2-(2-aminoethoxy)ethoxy)-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-(4-methyl-3- (((R)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2-yl)methyl) phenyl)propanoate (64 mg, crude, hydrochloric acid) was obtained as a white solid.

[0233] To a solution of ethyl 3-(7-(2-(2-aminoethoxy)ethoxy)-l-methyl-lH- benzo[d][l,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-4-methyl-l,l-dioxido-3,4-dihydro-2H- benzo[b][l,4,5]oxathiazepin-2-yl)methyl)phenyl) propanoate (63.00 mg, 91.54 1 eq, μmol, hydrochloric acid) in dimethylformamide (3 mL) was added / V.AMiisopropylcthylaminc (59.1 mg, 457 μmol, 79.7 μL, 5.00 eq), 6L(7-azabcnzo(nazol- l -yl)-MA7 / VjV- tetramethyluroniumhexafluorophosphate (52.2 mg, 137 1.50 eq) anμdm (oRl,)-2-(((4-((lR,5S)-8- (tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)-l-methylpyrrolidine-2-carboxylic acid (82.4 mg, 91.5 1.00 eq)μm ato 2l0, °C. The mixture was stirred at 20 °C 0.5 h. The mixture was poured into water (5 mL), then the mixture was filtered, and filter cake was collected. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate= 100:1 to 1:1 (TLC (petroleum ether: ethyl acetate=O:l); Rf (Rl)=0.4; Rf (Pl)=0.2). Tert-butyl (lR,5S)-3-(2-(((2R)-2-((2-(2-((5-(3- ethoxy- 1 -(4-methyl-3-(((R)-4- methyl- 1 , 1 -dioxido-3,4-dihydro-2H-benzo [b] [ 1 ,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-oxopropyl)- 1 -methyl- 1 H-benzo[d][ 1 ,2,3]triazol-7- yl)oxy)cthoxy)cthyl)carbamoyl)-l-mcthylpyrrolidin-2-yl)mcthoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (79 mg, 51.47 56.23% yμiemldo)l, was obtained as a white solid.Example 7,8: Synthesis of Compound P-3

[0234] To a solution of tert-butyl (lR,5S)-3-(2-(((2R)-2-((2-(2-((5-(3-ethoxy-l-(4- methyl-3-(((R)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2- yl)methyl)phenyl)-3-oxopropyl)- 1-methyl- lH-benzo[d] [1 ,2,3]triazol-7 - yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (57.0 mg, 37.1 1.00 eq) inμ dmimole,thylformamide (0.5 mL) was added CsF (5.64 mg, 37.1 1.37μ μmLo,l, 1.00 eq) at 25 °C. The mixture was stirred at 25 °C for 20 min. The mixture was poured into water (10 mL), then filtered and the filter cake was collected. tert-butyl (lR,5S)-3-(2-(((2R)-2-((2-(2-((5-(3-ethoxy-l-(4-methyl-3-(((R)-4- methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2-yl)methyl)phenyl)-3- oxopropyl)-l-methyl-lH-benzo[d][l,2,3]triazol-7-yl)oxy)ethoxy)ethyl)carbamoyl)-l- methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (51 mg, crude) was obtained as a yellow solid.

[0235] To a solution of tert-butyl (lR,5S)-3-(2-(((2R)-2-((2-(2-((5-(3-ethoxy-l-(4- mcthyl-3-(((R)-4-mcthyl-l,l-dioxido-3,4-dihydro-2H-bcnzo[b][l,4,5]oxathiazcpin-2- yl)methyl)phenyl)-3-oxopropyl)-l-methyl-lH-benzo[d][l,2,3]triazol-7- yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 36.2 1.00 eq) iμnm dioclh,loromethane (2 mL) was added hydrochloric acid / dioxane (4 M, 0.5 mL, 55.1 eq) at 25 °C. The mixture was stirred at 25 °C for 15 min. The mixture was concentrated in vacuum. Ethyl 3-(7-(2-(2-((R)-2-(((4- ((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fhioropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l-methylpyrrolidine-2- carboxamido)ethoxy)ethoxy)-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-4- methyl- l,l-dioxido-3,4-dihydro-2H-benzo[b][l, 4, 5]oxathiazepin-2-yl)methyl)phenyl)propanoate (46 mg, crude, hydrochloric acid) was obtained as a yellow solid.

[0236] To a solution of ethyl 3-(7-(2-(2-((R)-2-(((4-((lR,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fhioropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l-methylpyrrolidine-2- carboxamido)ethoxy)ethoxy)-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-4- methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (46.0 mg, 36.2 μmo 1.l0,0 eq, hydrochloric acid) in tetrahydrofuran (3 mL) was added solution of Lithium hydroxide hydrate (6.08 mg, 144 4.00μ emqo) l i,n water (1 mL) and methanol (1 mL) at 20 °C. The mixture was stirred at 40 °C for 3 h. The mixture was concentrated in vacuum. The residual was dissolved in dimethylformamide (1 mL) and acidified with IN aq. hydrochloric acid to pH=7. The mixture was purified by prep-HPLC(column: Phenomenex luna Cl 8 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 18%-48%,8min). The desired fraction was lyophilized. 3-(7-(2-(2-((R)-2-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l- methylpyrrolidine-2-carboxamido)ethoxy)ethoxy)-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3- (4-methyl-3-(((R)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoic acid (4.96 mg, 3.92 10μ.8m3o%l, yield, 99% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1207.0 / 120707 [M+H]+.NMR (400 MHz, DMSO- d6) 5 = 9.04 - 8.97 (m, 1H), 8.06 (br d, J = 3.8 Hz, 1H), 7.96 (dd, J = 6.4, 8.1 Hz, 1H), 7.76 (d, J =7.8 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.50 - 7.42 (m, 2H), 7.40 - 7.27 (m, 4H), 7.26 - 7.16 (m, 2H), 7.11 - 7.03 (m, 1H), 6.93 (br d, J = 11.4 Hz, 1H), 4.63 - 4.20 (m, 14H), 3.98 - 3.76 (m, 6H), 3.55 (br d, J = 4.5 Hz, 4H), 3.04 (br d, J = 7.9 Hz, 2H), 2.82 (br s, 2H), 2.79 - 2.72 (m, 1H), 2.72 - 2.65 (m, 2H), 2.32 - 2.28 (m, 3H), 2.22 (br d, J = 3.4 Hz, 3H), 1.88 (br d, J = 5.1 Hz, 2H), 1.68 - 1.54 (m, 6H), 1.19 - 1.06 (m, 3H).Example 8: Preparation of Compound P-4Example 8.1 : Synthesis of Compound 4433 44

[0237] To a solution of l-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen- 1 -yl)-2-(((2S,7a7?)-2-fluorotetrahydro- 1 / / -pyrrol izin- 7a(5 / / )-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid (80.0 mg, 97.8 μmol, 1.00 eq) in dimethylformamide (1 mL) was added <9-(7-azabcnzotriazol- l -yl)-MAf,M. / V- tetramethyluroniumhexafluorophosphate (74.4 mg, 196 μmol 2, .00 eq), N,N- diisopropylethylamine (63.2 mg, 489 μmo 8l5,.2 μL, 5.00 eq) and ethyl 3-(7-(2-(2- aminocthoxy)cthoxy)-l -methyl- 17 / -bcnzo[d][ 1,2, 3]triazol-5-yl)-3-(4-mcthyl-3-(((R)-4-mcthyl- 1 , 1 -dioxido-3 ,4-dihydro-2 / / -benzo [b] [1 ,4,5] oxathiazepin-2-yl)methyl)phenyl)propanoate (67.3 mg, 97.8 μmol 1,.00 eq, HC1) at 25 °C. The mixture was stirred at 25 °C 1.5 h. The mixture was poured into water (5 mL), then the mixture was filtered, and the filter cake was collected. The crude product was purified by silica gel chromatography eluted with dichloromethane: methanol =100:1 tol0:l (TLC (dichloromethane: methanol — 10: 1) Rf (Pl)=0.5). LCMS showed desired mass was detected. Ethyl 3-(7-(2-(2-(l-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((25,7a7?)-2-fluorotetrahydro-l / / -pyrrolizin- 7a(5 / / )-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamido)ethoxy)ethoxy)-l- methyl-l / / -benzo[d][l,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-4-methyl-l,l-dioxido-3,4-dihydro- 2Z / -benzo[b][l,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (125 mg, 86.1 88.0% μmol, yield) was obtained as a yellow solid.Example 8.2: Synthesis of Compound P-4(methoxymethoxy)-8-((triisopropylsilyl) ethynyl)naphthalen- 1 -y l)-2-(((2S,7 a7?)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- cai’boxamido)ethoxy)ethoxy)- 1 -methyl- lH-benzo[d][ l,2,3]triazol-5-yl)-3-(4-methyl-3-(((R )-4- methyl-l,l-dioxido-3,4-dihydro-27 / -benzo[b][l,4,5]oxathiazepin-2-yl)methyl)phenyl) propanoate (120 mg, 82.7 1μ.0m0o elq,) in dimethylformamide ( 1 mL) was added cesium fluoride (37.7 mg, 248μmol, 9.14 μL, 3.00 eq) at 25°C. The mixture was stirred at 25°C for 30 min. The mixture was poured into water (10 mL), then filtered and the filter cake was collected, ethyl 3-[7- [2-[2-[[l-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2-[[(25,41S',8A)-2- fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-l-methyl-benzotriazol-5-yl]-3-[4-methyl-3-[[(47?)-4-methyl-l,l- dioxo-3,4-dihydro-5,lk6,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (105 mg, crude) was obtained as a yellow solid.

[0239] To a solution of ethyl 3-[7-[2-[2-[[l-[7-[8-cthynyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-2-[[(25,45,87?)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-l-methylbenzotriazol-5-yl]-3-[4-methyl-3-[[(4A)-4-methyl-l,l- dioxo-3,4-dihydro-5,lk6,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (102 mg, 78.7 μmol, 1.00 eq) in dichloromethane (3 mL) was added HCl / dioxane (4 M, 500 μL, 25.4 eq)at 25 °C. The mixture was stirred at 25 °C for 15 min. The mixture was concentrated in vacuum, ethyl 3-[7-[2-[2-[[l-[7-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-2-[[(2S,4S,87?)-2-fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy] pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-l-methylbenzotriazol-5-yl]-3-[4-methyl-3-[[(4A)-4-methyl-l,l-dioxo-3,4-dihydro-5,lX6,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (97 mg, crude) was obtained as a yellow solid.

[0240] To a solution of ethyl 3-[7-[2-[2-[[l-[7-(8-ethynyl-7-fluoro-3-hydroxy-l- naphthy 1)- 8 -fluoro -2- [ [(2S,4S, 87?) -2-fluoro - 1 ,2,3 , 5 , 6 ,7 -hexahydropy rrolizin- 8 - yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3-carbonyl] amino]ethoxy]ethoxy]-l- methy lbenzotriazol-5-yl] -3- [4-methy 1-3 -[ [(47?)-4-methyl- 1 , 1 -dioxo-3 ,4-dihydro-5 , 1 X6.2- benzoxathiazepin-2-yl]methyl]phenyl]propanoate (97.0 mg, 77.5 1μ.0m0ol, eq) in tetrahydrofuran (6 mL) was added lithium hydroxide monohydrate (32.5 mg, 775 10.0 eq)in μmol, water (2 mL) and methanol (2 mL) at 25 °C. The mixture was stirred at 40 °C for 1 h. The mixture was concentrated in vacuum. The mixture was purified by prep-HPLC (column: Phenomenex lunaC18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 25%-55%,10min). Thedesired fraction was lyophilized. 3-(7-(2-(2-(l-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fluoro-2-(((25,7a7?)-2-fluorotetrahydro-177-pyrrolizin-7a(577)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxamido)ethoxy)ethoxy)-l-methyl-177-benzo[d][l,2,3]triazol- 5-yl)-3-(4-methyl-3-(((R )-4-methyl-l,l-dioxido-3,4-dihydro-277-benzo[b][l,4,5] oxathiazepin-2- yl)methyl)phenyl)propanoic acid (7.77 mg, 6.22μmol, 8.03% yield, 98% purity) was obtained as a yellow solid. ‘H NMR (400 MHz, DMSO-d6 ) δ = 12.90 - 11.43 (m, 1H), 10.60 - 9.79 (m, 1H), 9.00 (s, 1H), 8.12 - 8.00 (m, 1H), 8.00 - 7.89 (m, 1H), 7.77 (br d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.50 - 7.16 (m, 8H), 7.10 (d, J = 8.0 Hz, 1H), 6.97 - 6.84 (m, 1H), 5.50 - 5.01 (m, 1H), 4.58 - 4.15 (m, 10H), 4.13 - 3.96 (m, 3H), 3.87 - 3.73 (m, 3H), 3.69 - 3.37 (m, 6H), 3.17 - 2.96 (m, 5H), 2.86 - 2.60 (m, 4H), 2.23 (d, J= 3.56 Hz, 3H), 2.15 - 1.91 (m, 4H), 1.89 - 1.53 (m, 6H), 1.25 - 1.04 (m, 3H).Example 9: Preparation of Compound P-5Example 9.1 : Synthesis of Compound 45

[0241] To a solution of (47?)-4-methyl-l,l-dioxo-3,4-dihydro-2H-5,lX6,2- benzoxathiazepin-7-ol (600 mg, 2.62 mmol, 1.00 eq) in dimethylformamide (5 mL) was added potassium carbonate (361 mg, 2.62 mmol, 1.00 eq) and tert-butyl A-(2-bromoethyl)carbamate (586 mg, 2.62 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 25 °C for 19 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over with sodium sulfate and concentrated in vacuum. The mixture was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 21%-51%,10min). The desired fraction was lyophilized. Tert-butyl (R )-(2-((4-methyl- 1 , 1 -dioxido-3,4-dihydro-2H- benzo[b][l,4,5]oxathiazepin-7-yl)oxy)ethyl)carbamate (350 mg, 939.76 35.91% yieldμ)m woal,s obtained as a white solid.

[0242] To a solution of ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-l- methyl-benzotriazol-5-yl)propanoate (215 mg, 537 1.00 μ eqm)o iln, acetonitrile (4 mL) was added / c / 7-butyl (R )-(2-((4-methyl-l,l-dioxido-3,4-dihydro-2 / / -benzo[b][L4,5]oxathiazepin-7- yl)oxy)ethyl)carbamate (200 mg, 537 1.μ0m0 o elq,) and potassium carbonate (148 mg, 1.07 mmol, 2.00 eq) at 20°C, the mixture was stirred at 90°C for 3 h. The mixture was diluted with water (20 mL). And then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuum to give a residue. Ethyl 3-(3-(((2?)-7- (2-((tert-butoxycarbonyl)amino)ethoxy)-4-methyl-l,l-dioxido-3,4-dihydro-2H- benzo[b][l,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy-l-methyl-l.f / -benzo[d][l ,2,3]triazol-5-yl)propanoate (300 mg, crude) was obtained a yellow solid. MS (ESI)

[0243] To a solution of ethyl 3-(3-(((R )-7-(2-((tert-butoxycarbonyl)amino)ethoxy)-4- methyl-1 , l -dioxido-3.4-dihydro-2 / / -bcnzo| / ?|| l,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)- 3-(7-methoxy-l-methyl-l / / -benzo[7][l,2,3]triazol-5-yl)propanoate (300 mg, 406 1.00 eq) μmol, in dioxane (10 mL) was added hydrochloric acid (4 M, 101.65 μL, 1.00 eq) at 0°C,the mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuum to give a residue. Ethyl 3-(3- (((R )-7 -(2-aminoethoxy)-4-methyl- 1 , 1 -dioxido-3,4-dihydro-277-benzo[b] [ 1 ,4,5]oxathiazepin-2- yl)methyl)-4-methylphenyl)-3-(7-methoxy-l-methyl-177-benzo[d][l,2,3]triazol-5-yl)propanoate (259 mg, 384.16 μm 9o4l.,48% yield, HC1 salt) was obtained as a yellow solid.Example 9.2: Synthesis of Compound 46

[0244] To a solution of (27?)-2-[[4-[(lS,57?)-8-tert-butoxycarbonyl-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(mcthoxymcthoxy)-8-(2- triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l-methyl- pyrrolidine-2-carboxylic acid (200 mg, 222 μmo 1l.,00 eq) and ethyl 3-(3-((( / ?)-7-(2- aminoethoxy)-4-methyl- 1 , 1 -dioxido-3,4-dihydro-2H-benzo[&][ 1 ,4,5 ]oxathiazepin-2-yl)methyl)- 4-methylphenyl)-3-(7 -methoxy- 1 - methyl- 1 / / -benzol <r / | [ 1 ,2,3] triazol-5-yl)propanoate (149 mg, 222 μmol, 1.00 eq, concentrated hydrochloric acid) in dimethylformamide (4 mL) was added N,N- diisopropylethylamine (114 mg, 888 1μ5m4o μl,L, 4.00 eq) and O-(7-azabenzotriazol-l-yl)- A,A,A,A-tetramethyluroniumhexafluorophosphate (126 mg, 333 1.50 eq)μm atol 2,0 °C, the mixture was stirred at 20 °C for 16 h. The mixture was diluted with water (20 mL). And then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuum to give a residue. The crude product was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = 100:1 to 1:1. Tert-butyl (l / ?,5S)-3-(2-(((27?)-2-((2-(((47?)-2-(5-(3-ethoxy-l-(7-methoxy-l-methyl-l / / - benzo[c?][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro- 2 / / -bcnzo| / ?|| 1 ,4,5 ]oxathiazepin-7-yl)oxy)ethyl)carbamoyl)- 1 -methylpyrrolidin-2-yl)methoxy)- 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (337 mg, 221.59 μmol, 99.84% yield) was obtained as a yellow solid. MS (ESI) m / z 761.1 [M+H]+.Example 9.3: Synthesis of Compound P-5

[0245] To a solution of tert-butyl (lT,5S)-3-(2-(((27?)-2-((2-(((4 / ?)-2-(5-(3-cthoxy-l- (7-methoxy-l -methyl- 1 t / -bcnzo|d|[ l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl- 1 , 1 -dioxido-3 ,4-dihydro-277-benzo [ / ? | [ 1 ,4,5 ]oxathiazepin-7 -yl)oxy )ethy l)carbamoyl)- 1 - methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octanc-8-carboxylatc (337 mg, 221 1.00 eqμ)m inol d, imethylformamide (4 mL) was added cesium formic (336 mg, 2.22 mmol, 81.7 μL, 10.0 eq) at 20 °C, the mixture was stirred at 20 °C for 30 min. The mixture was poured into water (10 mL), and then filtered, the filter cake was concentrated in vacuum to give a residue. It was not purified and used for the next step. Tert-butyl (17?,5S)-3-(2-(((2T)-2-((2-(((4T)-2-(5-(3-ethoxy-l-(7-methoxy-l-methyl-lH- benzo[d][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro- 2H-benzo[b][l,4,5]oxathiazepin-7-yl)oxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)- 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 219.86 99.22%μm yoile,ld) was obtained as a yellow solid. MS (ESI) m / z 683.3 [M+H]+.

[0246] To a solution of tert-butyl (17?,5S)-3-(2-(((27?)-2-((2-(((47?)-2-(5-(3-ethoxy-l- (7 -methoxy- 1 -methyl- 1 / / -benzo [d] [ 1 ,2,3] triazol-5 -yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl- 1 , 1 -dioxido-3 ,4-dihydro-2 / / -benzo | / ? | [ 1 ,4,5 ]oxathiazepin-7-yl)oxy )ethy l)carbamoyl)- 1 - methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8- fhioropyrido[4,3-t / ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 220 μmol, 1.00 eq) in dichloromethane (4 mL) was added hydrochloric acid (4 M, 55.0 μL, 1.00 eq) at 20 °C, the mixture was stirred at 20 °C for 30 min. The mixture was concentrated in vacuum to give a crude product. Ethyl 3-(3-(((R )-7-(2-((R )-2-(((4-((17?,55')-3,8-diazabicyclo[3.2.1]octan-3- yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy )methyl)- 1 -methylpyrrolidine-2-carboxamido)ethoxy )-4-methyl- 1 , 1 -dioxido-3 ,4-dihydro- 2H-benzo[b][ 1 ,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy- 1-methyl- 1H- benzo[d][l,2,3]triazol-5-yl)propanoate (268 mg, 213.24 96.99%μm yioell,d, HC1) was obtained as a yellow solid. MS (ESI) m / z 610.9 [M+H]+.

[0247] To a solution of ethyl 3-(3-((( / ?)-7-(2-((T)-2-(((4-((17?,55)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fhioropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l-methylpyrrolidine-2-carboxamido)ethoxy)-4- methyl- 1, l-dioxido-3,4-dihydro-2Z / -benzo[b] [1,4, 5]oxathiazepin-2-yl)methyl)-4-methylphenyl)- 3-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazoL5-yl)propanoate (268 mg, 219 1.00 eq) μmol, in tetrahydrofuran (4 mL) was added methanol (1 mL) , water (2 mL) and lithium hydroxide (46.0 mg, 1.10 mmol, 5.00 eq) at 20 °C, the mixture was stirred at 40 °C for 1 h. The mixture wasconcentrated in vacuum to give a crude product. The crude product was purified by Prep- HPLC(column: Phcnomcncx luna C18 150*25mm* 10um;mobilc phase: [watcr(FA)-ACN];B%: 14%-44%,10min). The desired product was lyophilized. 3-(3-(((R )-7-(2-((R)-2-(((4-((17?,55)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l-methylpyrrolidine-2-carboxamido)ethoxy)-4- methyl-1 , l -dioxido-3.4-dihydro-2 / / -bcnzo|b|| 1 ,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)- 3-(7-methoxy- 1 -methyl- 1 H-benzo[d][ 1 ,2,3 ]triazol-5-yl)propanoic acid (32.7 mg, 27.15 p mol. 12.36% yield, 99% purity) was obtained as a yellow solid. MS (ESI) m / z 1192.7 [M+H]+.rH NMR (400 MHz, DMSO-d6) δ = 9.03 (s, 1H), 8.29 (br t, J = 6.0 Hz, 1H), 7.96 (dd, J = 6.0, 9.2 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.49 - 7.30 (m, 4H), 7.29 - 7.23 (m, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.94 - 6.84 (m, 3H), 4.74 - 4.62 (m, 1H), 4.60 - 4.54 (m, 1H), 4.50 (dt, J = 3.2, 7.4 Hz, 2H), 4.42 - 4.27 (m, 6H), 4.15 (br t, J = 5.4 Hz, 2H), 3.94 (s, 1H), 3.91 (d, J = 4.4 Hz, 3H), 3.79 - 3.72 (m, 2H), 3.59 (br s, 4H), 3.10 - 2.97 (m, 5H), 2.85 - 2.66 (m, 3H), 2.42 - 2.40 (m, 3H), 2.22 (br d, 7= 4.0 Hz, 3H), 2.03 - 1.92 (m, 2H), 1.81 - 1.59 (m, 6H), 1.19 - 1.04 (m, 3H).Example 10: Preparation of Compound P-616 49

[0248] To a solution of (R )-7-hydroxy-4-methyl-3,4-dihydro-2H- benzo[Z?][l,4,5]oxathiazepine 1,1 -dioxide (500 mg, 2.18 mmol, 1.00 eq) in dimethylformamide (5 mL) was added potassium carbonate (301 mg, 2.18 mmol, 1.00 eq) and tert-butyl (2-(2-(2- bromoethoxy)ethoxy)ethyl)carbamate (681 mg, 2.18 mmol, 1.00 eq) at 25°C. The mixture was stirred at 25°C for 19 h. The mixture was poured into water (50.0 ml) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (50.0 mL), dried over with sodium sulfate and concentrated in vacuum. The mixture was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 21%-51 %,10min). The desired fraction was lyophilized. Tert-butyl (R)-(2-(2-(2-((4-methyl-l ,1 - dioxido-3,4-dihydro-2H-bcnzo[Z?][l,4,5]oxathiazcpin-7-yl)oxy)cthoxy)cthoxy)cthyl)carbamatc (350 mg, 760 μmo 3l5, % yield) was obtained as a colorless oil. (400 M1HH Nz,M DRMSO-rfe) 8 = 7.67-7.64 (m, 1H), 7.61 (d, J = 8.8 Hz, 1H), 6.82 - 6.70 (m, 2H), 4.16 (m, 2H), 3.98 (m, 1H), 3.74 (m, 2H), 3.58 (m, 4H), 3.40 (m, 2H), 3.22 - 3.15 (m, 2H), 3.08 (q, J = 6.0 Hz, 2H), 1.37 (s, 9H), 1.21 - 1.15 (m, 3H).Example 10.2: Synthesis of Compound 50

[0249] To a solution of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-l- methyl- lH-benzo[<i][ l,2,3]triazol-5-yl)propanoate (500 mg, 1.30 mmol, 1.00 eq) in dichloromethane (4.00 mL) was added thionyl chloride (821 mg, 6.90 mmol, 500 μL, 5.29 eq) at20°C, the mixture was stirred at 20°C for 30 min. The mixture was concentrated in vacuum to give a residue. It was not purified and used for the next step, ethyl 3-(3-(chloromethyl)-4- methylphenyl)-3-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-propanoate (524 mg, 1.30 mmol, 100% yield) was obtained as a yellow oil.

[0250] To a solution of tert-butyl (R )-(2-(2-(2-((4-methyl-l,l-dioxido-3,4-dihydro- 2H-benzo[&][ 1 ,4,5 ]oxathiazepin-7-yl)oxy)ethoxy)ethoxy )ethyl)carbamate (200 mg, 434 pmol, 1.00 eq) in acetonitrile (4.00 mL) was added ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7- methoxy-l-methyl-benzotriazol-5-yl)propanoate (174 mg, 434 1.00 eqμ)m aonl,d potassium carbonate (120 mg, 868 μ 2m.0o0l, eq) at 20°C, the mixture was stirred at 90°C for 3 h. The mixture was diluted with water (20.0 mL). And then extracted with ethyl acetate (20mLx2). The combined organic layers were dried over sodium sulfate and concentrated in vacuum to give a residue. Ethyl 3-(3-(((R)-7-((2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13-yl)oxy)-4- methyl-1 , l -dioxido-3.4-dihydro-2 / / -bcnzo| / ?|| 1 ,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)- 3-(7-methoxy-l-methyl-lH-benzo[6?][l,2,3]triazol-5-yl)propanoate (300 mg, crude) was as a obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6 ) δ = 7.66 (dd, J = 2.8, 8.8 Hz, 1H),7.46 (s, 1H), 7.35 (s, 1H), 7.31 - 7.24 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.98 - 6.84 (m, 3H), 6.82 - 6.70 (m, 1H), 4.60 - 4.49 (m, 1H), 4.47 - 4.30 (m, 5H), 4.20 (s, 2H), 3.99 - 3.90 (m, 5H), 3.83 - 3.72 (m, 3H), 3.65 - 3.50 (m, 5H), 3.40 (t, J = 6.0 Hz, 2H), 3.22 - 3.15 (m, 2H), 3.08 (q, J = 6.0 Hz, 2H), 2.82 - 2.64 (m, 1H), 2.23 (d, 7= 2.4 Hz, 3H), 1.37 (s, 9H), 1.21 - 1.15 (m, 3H), 1.05 (t, J = 7.2 Hz, 3H).Example 10,3: Synthesis of Compound 51

[0251] To a solution of ethyl 3-[3-[[(47?)-7-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]-4-methyl- 1, l-dioxo-3,4-dihydro-5, 1X6,2- benzoxathiazepin-2-yl] methyl] -4-methy l-phenyl]-3-(7 -methoxy- 1-methy 1-benzo triazol- 5- yl)propanoate (300 mg, 363 μ 1m.0o0l, eq) in dioxane (10.0 mL) was added hydrochloric acid / dioxane (4 M, 90.8 μL, 1 .00 eq) at 0°C, the mixture was stirred at 20°C for 1 h. The mixture was concentrated in vacuum to give a residue. It was not purified and used for the next step, ethyl 3- [3-[[(4R)-7-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,lX6,2- benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7 -methoxy- 1-methyl-benzo triazol- 5- yl)propanoate (263 mg, 345 9μ4m%o yl,ield, HC1)M was obtained as a yellow solid.

[0252] To a solution of (2R)-2-[[4-[(lS,5R)-8-tert-butoxycarbonyl-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l-methyl- pyrrolidine-2-carboxylic acid (200 mg, 222 1μ.0m0ol e,q) and ethyl 3-[3-[[(4R)-7-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,126,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (169 mg, 222 pmol, 1.00 eq, HC1) in dimethylformamide (6.00 mL) was added <9-(7-azabenzotriazol-l-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (169 mg, 444 2.00 μ eqm)ol a,nd N,N- diisopropylethylamine (86.0 mg, 666 116μm μLo,l, 3.00 eq) at 20°C. The mixture was stirred at 20°C for 16 h. The mixture was poured into water (30.0 mL), and then extracted with ethyl acetate (30.0 mLx3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =1: 1-0: 1). Tert-butyl (lR,55')-3-(2-(((27?)-2-((2-(2-(2-(((47?)-2-(5- (3-ethoxy- 1 -(7-methoxy- 1 -methyl- 1 H-benzo[t / ][ 1 ,2,3 ]triazol-5-yl)-3-oxopropyl)-2- methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[Z?][l,4,5]oxathiazepin-7- yl)oxy)ethoxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-T|pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 218 98% yieμldm)o wl,as obtained as a yellow oil. MS (ESI) m / z 805.5. [1 / 2M+H]+.Example 10.4: Synthesis of Compound P-6cthoxy-l-(7-mcthoxy-l-mcthyl-bcnzotriazol-5-yl)-3-oxo-propyl]-2-mcthyl-phcnyl]mcthyl]-4- methyl- l,l-dioxo-3,4-dihydro-5, 126, 2-benzoxathiazepin-7- yl]oxy]ethoxy]ethoxy]ethylcarbamoyl]-l-methyl-pyrrolidin-2-yl]methoxy]-8-fluoro-7-[7-fluoro- 3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 218 1.00 eq) μ inm doilm, ethylformamide (4.00 mL) was added cesium fluoride (330 mg, 2.18 mmol, 80.2 μL, 10.0 eq) at 20°C. The mixture was stirred at 20°C for 20 min. The mixture was poured into water (10.0 mL), and then filtered. The filter cake was dissolved in ethyl acetate (20.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuum. It was not purified and used for the next step. Tert- butyl (lS,57?)-3-[2-[[(2A)-2-[2-[2-[2-[[(47?)-2-[[5-[3-ethoxy-l-(7-methoxy-l-methyl- benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl-l,l-dioxo-3,4-dihydro-5,126,2-benzoxathiazepin-7-yl]oxy]ethoxy]ethoxy]ethylcarbamoyl]-l-methyl-pyrrolidin-2- yl]mcthoxy]-7-[8-cthynyl-7-fluoro-3-(mcthoxymcthoxy)-l-naphthyl]-8-fluoro-pyrido[4,3- d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 186 85% yield)μmol, was obtained as a yellow solid. MS (ESI) m / z 727.0 [1 / 2M+H]+.

[0254] To a solution of tert-butyl (15,57?)-3-[2-[[(27?)-2-[2-[2-[2-[[(47?)-2-[[5-[3- ethoxy-l-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4- methyl- 1 , 1 -dioxo-3 ,4-dihydro-5 , 126,2-benzoxathiazepin-7 - yl]oxy]ethoxy]ethoxy]ethylcarbamoyl]-l-methyl-pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7- fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-pyrido[4,3-t / ]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 186 1.00 eqμ)m inol d,ichloromethane (6.00 mL) was added hydrochloric acid / dioxane (4 M, 2.00 mL, 43.0 eq) at 20°C. The mixture was stirred at 20°C for 20 min. The mixture was concentrated in vacuum. It was not purified and used for the next step. Ethyl 3-[3-[[(4R)-7-[2-[2-[2-[[(2R)-2-[[4-[(lS,5R)-3,8- diazabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro- pyrido [4,3-d]pyrimidin-2-yl] oxymethyl] - 1 -methyl-pyrrolidine-2-carbonyl] amino]- ethoxy]ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,lX6,2-benzoxathiazepin-2-yl]methyl]- 4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (260 mg, crude, HC1) was obtained as a yellow solid.

[0255] To a solution of ethyl 3-[3-[[(4A)-7-[2-[2-[2-[[(27?)-2-[[4-[(15,57?)-3,8- diazabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro- pyrido[4,3-t7]pyrimidin-2-yl]oxymethyl]-l-methyl-pyrrolidine-2- carbonyl]amino]ethoxy]ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,126,2- benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7 -methoxy- 1-methyl-benzo triazol- 5- yl)propanoate (260 mg, 199 1μ.0m0o elq, ) in methanol (4.00 mL) and tetrahydrofuran (4.00 mL) was added a mixture of Lithium hydroxide monohydrate (83.4 mg, 1.99 mmol, 10.0 eq) in Water (2.00 mL) at 20°C. The mixture was stirred at 40°C for 30 min. The mixture was concentrated in vacuum to give a residue. The residue was diluted with dimethylformamide (4.00 mL), and then acidified by 1 M hydrochloric acid adjusted to pH=5. Yellow precipitate was formed. The resulting mixture was filtered. The filter cake was dissolved in dimethylformamide (5.00 mL), and then purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 18%-48%,10min). 3-(112-benzo[<7][l,2,3]triazol-5-yl)-3-(3-(((R )-7-(2-(2-(2-((R )-2-(((4-((17?,55)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalcn-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)mcthyl)-l-mcthylpyrrolidinc- 2-carboxamido)ethoxy)ethoxy)ethoxy)-4-methyl-l,l-dioxido-3,4-dihydro-2H- benzo[Z>][l,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid (16.76 mg, 13.09 μmol, 6.59% yield, 100% purity) was obtained as off-white solid. MS (ESI) m / z 1280.7 [M+H]+.NMR (400 MHz, DMSO-d6 ) δ = 9.02 (s, 1H), 8.08 (t, J = 6.0 Hz, 1H), 7.96 (dd, J = 6.0, 9.2 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.49 - 7.30 (m, 4H), 7.29 - 7.23 (m, 1H), 7.18 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.93 - 6.83 (m, 3H), 4.68 - 4.47 (m, 4H), 4.43 - 4.26 (m, 6H), 4.19 (s, 2H), 3.95 - 3.89 (m, 4H), 3.78 - 3.71 (m, 4H), 3.60 ( d, J = 4.4 Hz, 7H), 3.48 - 3.46 (m, 2H), 3.28 (d, J = 6.0 Hz, 2H), 3.10 - 2.96 (m, 4H), 2.82 - 2.67 (m, 2H), 2.40 (s, 3H), 2.21 (br d, J= 4.4 Hz, 3H), 2.02 - 1.92 (m, 2H), 1.79 - 1.60 (m, 6H), 1.19 - 1.03 (m, 3H).Example 11 : Preparation of Compound 5B4B 5BExample 11.1 : Synthesis of Compound IB1 1 B

[0256] A mixture of (27?)-pyrrolidine-2-carboxylic acid (40.0 g, 347 mmol, 1.00 eq), 2,2,2-trichloroethane-l,l-diol (100 g, 604 mmol, 78.7 mL, 1.74 eq) in chloroform (1.00 L) was heated to 80°C for 16 h and remove water by Dean-Stark trap. The mixture was poured into brine (200 mL), and then extracted with dichloromethane (100 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum to give a residue. The residue was triturated with ice- ethanol (200 mL), and then filtered. The filter cake was dried in vacuum. (3S,7a / ?)-3-(trichloromethyl)tetrahydro-l / 7,3H-pyrrolo[l,2-c]oxazol-l-one (55.0 g, 225 mmol, 65% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6 ) δ = 5.83 (s, 1H), 4.10 (dd, J = 4.4, 8.8 Hz, 1H), 3.31 - 3.27 (m, 1H), 3.16 (ddd, J= 6.0, 8.4, 10.8 Hz, 1H), 2.14 (dtd, J = 6.8, 8.8, 12.8 Hz, 1H), 1.98 - 1.89 (m, 1H), 1.85 - 1.73 (m, 1H), 1.67 - 1.55 (m, 1H).Example 11,2: Synthesis of Compound 2B1B 2B

[0257] To a solution of (3S,7aZ?)-3-(trichloromethyl)-5,6,7,7a-tetrahydro-3H- pyrrolo[l,2-c]oxazol-l-one (30.0 g, 123 mmol, 1.00 eq) in tetrahydrofuran (750 mL) was added lithium diisopropylamide (2 M, 92.0 mL, 1.50 eq) at -78°C. The mixture was stirred at -78°C for 30 min. Chloromethoxymethylbenzene (23.1 g, 147 mmol, 20.4 mL, 1.20 eq) was added to the mixture at -78°C. The mixture was stirred at -40°C for 2 h. The mixture was poured into ice- water (600 mL), and then extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =100:1-10:1). (3S,7aS)-7a-((benzyloxy)methyl)-3-(trichloromethyl)tetrahydro-lH,3H-pyrrolo[l ,2-c]oxazol-l-one (27.0 g, 74.0 mmol, 60% yield) was obtained as a yellow oil. (4001H M NHMz,R DMSO-cfc) 5 = 7.37 - 7.29 (m, 5H), 5.60 (s, 1H), 4.56 (s, 2H), 3.70 - 3.60 (m, 2H), 3.35 (s, 1H), 3.13 (ddd, J = 6.0, 9.6, 11.7 Hz, 1H), 2.14 - 2.00 (m, 2H), 1.91 - 1.69 (m, 2H).Example 11.3: Synthesis of Compound 3B(3S,7aS)-7a-(benzyloxymethyl)-3-(trichloromethyl)-3, 5,6,7- tetrahydropyrrolo[l,2-c]oxazol-l-one (37.0 g, 102 mmol, 1.00 eq) in hydrochloric acid / methanol(4 M, 111 mL, 4.38 eq) was stirred at 60°C for 16 h. The mixture was concentrated in vacuum, and then diluted with water (100 mL), and then extracted with ethyl acetate (100 mL x 3). The aqueous phase was basified by sodium bicarbonate adjust to pH=9, and then extracted with 50.0 mL x 3 (methanol: dichloromethane =10: 1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum. It was not purified and used for the next step. Methyl (S)-2-((benzyloxy)methyl)pyrrolidine-2-carboxylate (16.8 g, 67.4 mmol, 66% yield) was obtained as a yellow oil. ‘H NMR (400 MHz, DMSO-d6) δ = 7.38 - 7.31 (m, 2H), 7.30 - 7.24 (m, 3H), 4.55 - 4.39 (m, 2H), 3.62 (s, 3H), 3.58 - 3.55 (m, 1H), 3.39 (d, J = 8.8 Hz, 1H), 2.89 - 2.77 (m, 2H),1.99 - 1.94 (m, 1H), 1.69 - 1.52 (m, 3H).Example 11,4: Synthesis of Compound 4B

[0259] To a solution of methyl (25)-2-(benzyloxymethyl)pyrrolidine-2-carboxylate (16.8 g, 67.4 mmol, 1.00 eq) in dichloromethane (200 mL) was added formaldehyde (10.9 g, 135 mmol, 10.0 mL, 37% purity, 2.00 eq) and sodium triacetoxyhydroborate (28.6 g, 135 mmol, 2.00eq) at 20°C. The mixture was stirred at 20°C for 16 h. The mixture was poured into sat. sodium bicarbonate (300 mL), and then extracted with dichloromcthanc (300 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =l:l-0:l). Methyl (S)-2-((benzyloxy)methyl)-l-methylpyrrolidine-2-carboxylate (10.0 g, 38.0 mmol, 56% yield) was obtained as a yellow oil. ’H NMR (400 MHz, DMSO-t / e) d = 7.39 - 7.22 (m, 5H), 4.48 (s, 2H), 3.68 (d, J - 9.2 Hz, 1H), 3.61 (s, 3H), 3.44 (s, 1H), 2.85 (td, 7 - 6.0, 8.4 Hz, 1H), 2.65 - 2.56 (m, 1H), 2.28 (s, 3H), 2.18 - 2.08 (m, 1H), 1.88 - 1.79 (m, 1H), 1.76 - 1.65 (m, 2H).Example 11,5: Synthesis of Compound 5B4B 5B

[0260] To a solution of methyl (2S)-2-(benzyloxymethyl)-l-methyl-pyrrolidine-2- carboxylate (8.00 g, 30.4 mmol, 1.00 eq) in methanol (160 mL) was added Pd(OH)2 (1.00 g, 1.42 mmol, 20% purity, 4.69e-2 eq) and acetic acid (4.20 g, 69.9 mmol, 4.00 mL, 2.30 eq) at 30°C. The mixture was stirred at 30°C for 48 h under H2 (20 Psi). The mixture was filtered. The filter cake was washed with methanol (5% ammonium hydroxide) (100 mL x 3). The combined filtrate was concentrated in vacuum to give a residue. The residue was triturated with ethyl acetate (20 mL), and then filtered. The filter cake was washed with ethyl acetate (5.00 mL x 2). The combined filtrate was purified by silica gel chromatography (petroleum ether / ethyl acetate =l:l-O:l). Methyl (S)-2-(hydroxymethyl)-l-methylpyrrolidine-2-carboxylate (3.40 g, 18.6 mmol, 61% yield, 95% purity) was obtained as a colorless oil.rH NMR (400 MHz, CHLOROFORM) δ = 3.72 (s, 3H), 3.71 - 3.62 (m, 2H), 3.16 - 3.07 (m, 1H), 2.92 (q, J = 8.8 Hz, 1H), 2.36 (s, 3H), 2.17 - 2.07 (m, 2H), 1.91 - 1.78 (m, 2H)Example 12: Preparation of Compound 25B

[0261] To a solution of methyl (2.S')-2-(hydroxy methyl )- 1 - methyl -pyrrol idinc-2- carboxylatc (500 mg, 2.89 mmol, 1.00 eq) and tert-butyl (15,5R)-3-(2,7-dichloro-8-fluoro- pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (1.24 g, 2.89 mmol, 1.00 eq) in dioxane (20.0 mb) was added cesium carbonate (2.82 g, 8.66 mmol, 3.00 eq) at 20°C. The mixture was stirred at 95 °C for 16 h. The mixture was filtered. The filtrate was concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =10:1-5:1). Tert-butyl (15',5R)-3-[7-chloro-8-fluoro-2-[[(21S')-2- methoxycarbonyl-l-methyl-pyrrolidin-2-yl]methoxy]pyrido[4,3-6?]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 708 24% yielμdm) wola,s obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM) δ = 8.73 (s, 1H), 4.73 (d, J = 10.8 Hz, 1H), 4.57 - 4.42 (m, 3H), 4.40 - 4.33 (m, 1H), 3.73 (s, 3H), 3.14 - 3.01 (m, 2H), 2.97 - 2.89 (m, 2H), 2.45 - 2.36 (m, 3H), 2.19 - 2.07 (m, 4H), 1.98 - 1.92 (m, 2H), 1.74 - 1.68 (m, 2H), 1.55 - 1.50 (m, 9H).

[0262] To a solution of tert-butyl (15,5R)-3-[7-chloro-8-fluoro-2-[[(21S')-2- methoxycarbonyl- l-methyl-pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3, 8-diazabicyclo[3.2.1 ]octane-8-carboxylate (400 mg, 708 1.0μ0m eoql,) and 2-[2-fluoro-6- (mcthoxymcthoxy)-8-(4,4,5,5-tctramcthyl-l,3,2-dioxaborolan-2-yl)-l-naphthyl]cthynyl- triisopropyl- silane (544 mg, 1.06 mmol, 1.50 eq) in tetrahydrofuran (10.0 mL) was added [2-(2- aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl-phosphane;methanesulfonate (51.6 mg, 70.8 μmo 0l,.100 eq) and potassium phosphate (1.5 M, 1.42 mL, 3.00 eq) at 20°C. The mixture was stirred at 65°C for 16 h. The mixture was poured into water (50.0 mL), and then extracted with ethyl acetate (50.0 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =10:1-3:1). Tert-butyl (lS,5A)-3-[8-fluoro-7-[7- fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]-2-[[(2S)-2- methoxycarbonyl-l-methyl-pyrrolidin-2-yl]methoxy]pyrido[4,3-t / ]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (380 mg, 399 56% yieldμ,m 9o6l%, purity) was obtained24B 25B

[0263] To a solution of tert-butyl (lS,57?)-3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]-2-[[(25)-2-methoxycarbonyl-l- methyl-pyrrolidin-2-yl]methoxy]pyrido[4,3-(7]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (380 mg, 415 μ 1m.0o0l, eq) in tetrahydrofuran (5.00 mL) and methanol (5.00 mL) was added a mixture of Lithium hydroxide monohydrate (87.1 mg, 2.08 mmol, 5.00 eq) in Water(1.00 mL) at 20°C. The resulting mixture was stirred at 40°C for 1 h. The mixture was poured into water (50 mL), and then extracted with ethyl acetate (50.0 mLx3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum. It was not purified and used for the next step. (2S)-2-[[4-[(lS,57?)-8-tert-butoxycarbonyl-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l-methyl- pyrrolidine-2-carboxylic acid (320 mg, 355 85%μm yioell,d) was obtained as a yellow oil. MS (ESI) m / z 901.5. [M+H]+.Example 13: Preparation of Compound P-7Example 13.1 : Synthesis of Compound 26B25B 26B

[0264] To a solution of (25)-2-[[4-[(lS,5R)-8-tert-butoxycarbonyl-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l-methyl- pyrrolidinc-2-carboxylic acid (150 mg, 166 μm 1.0o0l, eq) and ethyl 3-[3-[[(47?)-7-[2-(2- aminoethoxy)ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,126,2-benzoxathiazepin-2-yl]methyl]-4- methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (120 mg, 166 1.00 μmol, eq, HC1) in dimethylformamide (4.00 mL) was added O-(7-azabenzotriazol-l-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (127 mg, 333 μm 2.o0l0, eq) and N,N- diisopropylethylamine (64.5 mg, 499 87.0μm μLol,, 3.00 eq) at 20°C. The mixture was stirred at 20°C for 4 h. The mixture was poured into water (20.0 mL), and then filtered. The filter cake was dried in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =1:1-1:10). Tert-butyl (lS,5R)-3-[2-[[(25)-2-[2-[2-[[(4R)-2-[[5-[3- ethoxy-l-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4- methy 1- 1 , 1 -dioxo-3 ,4-dihydro-5 , 1 A,6,2-benzoxathiazepin-7 -y 1] oxy ]ethoxy] ethylcarbamoyl] - 1 - methyl-pyrrolidin-2-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (200 mg, 120 μ 7m2%ol, yield, 94% purity) was obtained as a yellow solid. ’ H NMR (400 MHz, CHLOROFORM) δ = 9.06 (s, 1H), 8.19 - 8.11 (m, 1H), 7.81 - 7.71 (m, 2H), 7.51 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.33 - 7.27 (m, 3H), 7.16 - 7.03 (m, 3H), 6.78 - 6.68 (m, 2H), 6.57 (d, J = 3.6 Hz, 1H), 5.33 - 5.24 (m, 2H), 4.86 - 4.69 (m, 3H), 4.65 - 4.58 (m, 1H), 4.54 - 4.49 (m, 1H), 4.46 - 4.37 (m, 5H), 4.24 - 4.18 (m, 2H), 4.07 - 4.02 (m, 2H), 3.92 - 3.85 (m, 6H), 3.71 - 3.64 (m, 4H), 3.54 - 3.44 (m, 6H), 3.03 (s, 4H), 2.57 - 2.48 (m, 3H), 2.30 (s, 3H), 2.02 - 1.98 (m, 2H), 1.52 (s, 9H), 1.28 - 1.25 (m, 2H), 1.17 - 1.12 (m, 5H), 0.96 - 0.90 (m, 3H), 0.89 - 0.81 (m, 20H), 0.55 (quin, J = 7.6 Hz, 3H).Example 13.2: Synthesis of Compound P-7P-7

[0265] To a solution of tert-butyl (lS,57?)-3-[2-[[(2S)-2-[2-[2-[[(4T)-2-[[5-[3-ethoxy- l-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl- 1 , 1 -dioxo-3 ,4-dihydro-5 , 1 X6,2-benzoxathiazepin-7 -yl]oxy] ethoxy ] ethylcarbamoyl] - 1 -methyl- pyrrolidin-2-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2. l]octane- 8-carboxylatc (190 mg, 121 μ 1m.00ol e, q) in dimethylformamide (4.00 mL) was added cesium fluoride (184 mg, 1.21 mmol, 44.8 μL, 10.0 eq) at 20 °C, the mixture was stirred at 20 °C for 30 min. The mixture was diluted with water (20 mL). And then extracted with ethyl acetate (20.0 mLx2). The combined organic layers were dried over sodium sulfate and concentrated in vacuum to give a residue. It was not purified and used for the next step. Tert-butyl (lS,57?)-3-[2-[[(25)-2- [2-[2-[[(47?)-2-[[5-[3-ethoxy-l-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl- phenyl] methyl] -4-methyl- 1 , 1 -dioxo-3 ,4-dihydro-5 , 1 X6,2-benzoxathiazepin-7- yl]oxy]ethoxy]ethylcarbamoyl]-l-methyl-pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (171 mg, crude) was obtained as a yellow solid. MS (ESI) m / z 1409.8 [M+H]+.

[0266] To a solution of tert-butyl (lS,57?)-3-[2-[[(2S)-2-[2-[2-[[(4R)-2-[[5-[3-ethoxy- l-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl-1.1-dioxo-3,4-dihydro-5,126,2-benzoxathiazepin-7-yl]oxy]ethoxy]ethylcarbamoyl]-l-methyl- pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro- pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (171 mg, 121 pmol, 1.00 eq) in dichloromethane (2.00 mL) was added hydrochloric acid / dioxane (4 M, 2.00 mL, 65.9 eq) at 0°C, the mixture was stirred at 20 °C for 10 min. The mixture was concentrated in vacuum to give a crude product. It was not purified and used for the next step, ethyl 3-[3-[[(47?)-7-[2-[2- [[(25)-2-[[4-[(15,57?)-8-azabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-l- naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l-methyl-pyrrolidine-2- carbonyl]amino]ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,126,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (155 mg, crude, HC1) was obtained as a yellow solid.

[0267] To a solution of ethyl 3-[3-[[(4R)-7-[2-[2-[[(2S)-2-[[4-[(15,5R)-8- azabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]-l-methyl-pyrrolidine-2-carbonyl]amino]ethoxy]ethoxy]-4-methyl-1.1-dioxo-3,4-dihydro-5, 126, 2-benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7 -methoxy- l-methyl-benzotriazol-5-yl)propanoate (155 mg, 123 1.00 eqμ)m ino tle,trahydrofuran (4.00 mL) was added Lithium hydroxide monohydrate (25.7 mg, 613 5.00 eq)μ,m woalt,er (4.42 mg, 245 μmol, 4.42 μL, 2.00 eq) and Lithium hydroxide monohydrate (3.93 mg, 123 4.96 μL, 1.0μ0mol, eq) at 20°C, the mixture was stirred at 40°C for 30 min. The mixture was concentrated in vacuum to give a crude product. The mixture was purified by Prep-l IPLC(column: Phenomenex luna Cl 8 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 15%-45%,15min).The desired fraction was lyophilized. 3-[3-[[(47?)-7-[2-[2-[[(2S)-2-[[4-[(lS,57?)-8-azabicyclo[3.2.1]octan-3-yl]-7-(8- ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-l- methyl-pyrrolidine-2-carbonyl]amino]ethoxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,126,2- benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7 -methoxy- 1 -methy 1-benzo triazol- 5- yl)propanoic acid (26.22 mg, 20.16 1μ6m.44o%l, yield, 95% purity) was obtained as a yellow solid. MS (ESI) m / z 1236.6 [M+H]+. ’H NMR (400 MHz, DMSO-d6) δ = 9.11 - 8.96 (m, 1H),8.12 (t, J= 5.6 Hz, 1H), 8.01 - 7.93 (m, 1H), 7.67 - 7.61 (m, 1H), 7.51 - 7.31 (m, 4H), 7.30 - 7.23 (m, 1H), 7.18 (d, J = 1.2 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.95 - 6.81 (m, 3H), 4.70 - 4.46 (m, 4H), 4.45 - 4.25 (m, 7H), 4.24 - 4.16 (m, 2H), 3.97 - 3.89 (m, 4H), 3.82 - 3.72 (m, 4H), 3.66 (d, J = 12.4 Hz, 2H), 3.54 (t, J = 5.6 Hz, 3H), 3.34 - 3.29 (m, 3H), 3.07 (dd, J= 4.0, 6.8 Hz, 2H), 3.03 - 2.98 (m, 1H), 2.85 - 2.77 (m, 2H), 2.41 (s, 3H), 2.22 (d, J = 4.0 Hz, 3H), 2.01 - 1.94 (m, 2H), 1.79 - 1.59 (m, 6H), 1.19 - 1.04 (m, 3H).Example 14: Preparation of Compound P-8Example 14.1 : Synthesis of Compound 42B

[0268] To a solution of ethyl 3-(7-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)- l-methyl-lH-benzo[6?][l,2,3]triazol-5-yl)-3-(4-methyl-3-(((R )-4-methyl-l,l-dioxido-3,4- dihydro-2 / Lbciizo| / ?|| l,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (155 mg, 206 μmol, 1.00 eq) in dichloromethane (2 mL) was added hydrochloric acid / dioxane (4 M, 2 mb, 38.8 eq) at25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuum. Ethyl3-(7-(2-(2-aminoethoxy)ethoxy)-l-methyl-177-benzo[J][l,2,3]triazol-5-yl)-3-(4-methyl-3-(((R )-4-methyl- 1 , 1 -dioxido-3 ,4-di hydro-2 / 7-bcnzo [Z>] [ 1 ,4,5] oxathiazepin-2- yl)methyl)phenyl)propanoate (140 mg, crude, hydrochloric acid) was obtained as a yellow solid.

[0269] To a solution of ethyl 3-(7-(2-(2-aminoethoxy)ethoxy)-l-methyl-177- bcnzo| <7| [ 1 ,2,3]triazol-5-yl)-3-(4-methyl-3-(((R )-4-methyl- 1 , 1 -dioxido-3,4-dihydro-2H- benzo[7>][l,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (140 mg, 203 1.2 eqμ, mol, hydrochloric acid) in dimethylformamide (2 mL) was added M / V-di isopropyl ethyl am inc (43.82 mg, 339.03 μmol, 59.05 μL, 2 eq), O-(7-azabenzotriazol-l-yl)-AkNJV,. / V- tetramethyluroniumhexafluorophosphate (96.6 mg, 254 1.50 eq) aμnmdo (Sl,)-2-(((4-((77?,5S)-8- (tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-<7]pyrimidin-2- yl)oxy)methyl)-l-methylpyrrolidine-2-carboxylic acid (152 mg, 169 1 .00 eq) atμ 2m5o °lC, . The mixture was stirred at 25 °C 15 h. The mixture was poured into water (10 mL), the mixture was filtered, and the filter cake was collected. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate = 100: 1 to 1:1. Tert-butyl (17?,5S)-3- (2-(((2S)-2-((2-(2-((5-(3-ethoxy-l-(4-methyl-3-(((R )-4-methyl-l,l-dioxido-3,4-dihydro-27L benzo[7>] [ 1 ,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-oxopropyl)- 1 -methyl- 1 H-benzo[<7][l ,2,3]triazol-7-yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-8- fluoro-7-(7-fluoro-3-(mcthoxymcthoxy)-8-((triisopropylsilyl)cthynyl)naphthalcn-l- yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 90.9 μmol, 53.6% yield, 93% purity) was obtained as a yellow solid. MS (ESI) m / z 768.4 [1 / 2M+H]+.NMR (400 MHz, DMSO-76) d = 9.17 (s, 1H), 8.14 - 8.03 (m, 2H), 7.82 - 7.71 (m, 2H), 7.70 - 7.52 (m, 3H), 7.47 (d, J = 2.5 Hz, 1H), 7.39 - 7.22 (m, 5H), 7.13 - 7.05 (m, 1H), 7.00 - 6.90 (m, 1H), 5.37 (s, 2H), 4.77 - 4.64 (m, 2H), 4.61 - 4.47 (m, 3H), 4.46 - 4.38 (m, 3H), 4.38 - 4.31 (m, 4H), 4.30 - 4.20 (m, 5H), 3.98 - 3.89 (m, 4H), 3.88 - 3.82 (m, 4H), 3.82 - 3.67 (m, 11H), 2.30 (br s, 4H), 2.24 - 2.20 (m, 4H), 1.45 (br d, J= 1.2 Hz, 9H), 1.28 - 1.22 (m, 6H), 1.19 (br d, J= 7.0 Hz, 3H), 1.03 (t, J= 70 Hz, 3H), 0.80 (dt, 7= 3.8, 8.0 Hz, 18H).

[0270] To a solution of ferZ-butyl (17?,5S)-3-(2-(((2S)-2-((2-(2-((5-(3-ethoxy-l-(4- methyl-3-(((R )-4-methyl- 1 , 1 -dioxido-3,4-dihydro-2H-benzo[&][ 1 ,4,5 ]oxathiazepin-2- yl)methyl)phenyl)-3-oxopropyl)- 1 -methyl- 1 H-benzo[t / ] [ 1 ,2,3]triazol-7 - yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 78.1 1.00 eq) iμnm dioml,ethylformamide (2 mL) was added cesium fluoride (23.7 mg, 156 2.00 eqμ)m ato 2l,5 °C. The mixture was stirred at 25 °C for 0.2 h. The mixture was poured into water (10 mL), the mixture was filtered, and the filter cake was collected. TerLbutyl (17?,55)-3-(2-(((2S)-2-((2-(2-((5-(3-ethoxy-l-(4-methyl-3- (((R )-4-methyl- 1 , 1 -dioxido-3,4-dihydro-2H-benzo[b][ 1 ,4,5 ]oxathiazepin-2-yl)methyl)phenyl)-3- oxopropyl)-l-methyl-lH-benzo[d][l,2,3]triazol-7-yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l -yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octanc-8-carboxylatc (105 mg, crude) was obtained as a yellow solid.

[0271] To a solution of tert-butyl (17?,5S,)-3-(2-(((2S)-2-((2-(2-((5-(3-ethoxy-l-(4- methyl-3-(((R )-4-methyl- 1 , 1 -dioxido-3,4-dihydro-2H-benzo[&][ 1,4,5 ]oxathiazepin-2- yl)methyl)phenyl)-3-oxopropyl)- 1 -methyl- 1 / 7-bcnzo| <7| [ 1 ,2,3]triazol-7 - yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 76.1 1.00 eq) iμnm doiclh, loromethane (2 mL) was added hydrochloric acid / dioxane (4 M, 2 mL, 105 eq) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated in vacuum. Ethyl 3-(7-(2-(2-((5)-2-(((4-((17?,55)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fluoropyrido[4,3-i / ]pyrimidin-2-yl)oxy)methyl)-l-methylpyrrolidine-2- carboxamido)ethoxy)ethoxy)- 1 -methyl- 17 / -bcnzo|<7|| 1 ,2,3]triazol-5-yl)-3-(4-methyl-3-(((R )-4- methyl-1, l-dioxido-3,4-dihydro-2H-benzo[&][ 1 ,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (95 mg, crude, hydrochloric acid) was obtained as a yellow solid.

[0272] To a solution of ethyl 3-(7-(2-(2-((5)-2-(((4-((H?,55)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fhioropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l-methylpyrrolidine-2- carboxamido)ethoxy)ethoxy)- 1 -methyl- lH-benzo[d][ 1,2, 3]triazol-5-yl)-3-(4-methyl-3-(((R )-4- methyl-1, l-dioxido-3,4-dihydro-2H-benzo[&][ 1 ,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (95.0 mg, 74.7 μmo 1l.0, 0 eq, hydrochloric acid) in tetrahydro furan (6 mL) and methanol (2 mL) was added a mixture of Lithium hydroxide hydrate (15.6 mg, 373 5.00 eq) in μ wmatoelr, (2 mL) at 25 °C. The mixture was stirred at 40 °C for 1 h. The mixture was concentrated in vacuum, then diluted with dimethylformamide (2 mL) and acidified with 3 N aq. hydrochloric acid to pH = 5. The residual was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 15%-45%,15min). The desired fraction was lyophilized. 3-(7-(2-(2-((5,)-2-(((4-((lR,5S')-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l- methylpyrrolidine-2-carboxamido)ethoxy)ethoxy)-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid (10.02 mg, 8.14 10.9%μm yioell,d, 98% purity) was obtained as a yellow solid. LCMS (ESI) m / z 1206.6 / 1207.5 [M+H]+.JH NMR (400 MHz, DMSO-d6) d = 9.06 - 8.93 (m, 1H), 8.12 - 8.03 (m, 1H), 8.01 - 7.90 (m, 1H), 7.81 - 7.72 (m, 1H), 7.68 - 7.58 (m, 1H), 7.50 - 7.41 (m, 2H), 7.39 - 7.15 (m, 6H), 7.11 - 7.02 (m, 1H), 6.97 - 6.88 (m, 1H), 4.64 - 4.18 (m, 14H), 3.96 - 3.92 (m, 1H), 3.88 - 3.74 (m, 5H), 3.29 (br t, J = 17.2 Hz, 4H), 3.07 - 3.00 (m, 2H), 2.83 - 2.65 (m, 5H), 2.30 (br s, 3H), 2.21 (br d, J = 2.8 Hz, 3H), 1.88 (br d, J = 3.2 Hz, 2H), 1.69 - 1.50 (m, 6H), 1.20 - 1.05 (m, 3H).P-9

[0273] To a solution of tert-butyl (17?,5S)-3-(2-(((2R)-2-((2-(2-(((47?)-2-(5-(3-ethoxy- l-(7-methoxy- 1-methyl- lH-benzo[d][ l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4- methyl- 1 ,1 -dioxido-3,4-dihydro-2H-benzo[b][ 1 ,4,5]oxathiazepin-7- yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octanc-8-carboxylatc (110 mg, 70.3 1.00 eq) iμnm doiml,ethylformamide (2 mL) was added cesium fluoride (106 mg, 703 25.9 μμLm, o 10l,.0 eq) at 20°C,the mixture was stirred at 20°C for 30 min. The mixture was diluted with water (20 mL). And then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuum to give a residue. It was not purified and used for the next step. Tert- butyl (lS,57?)-3-[2-[[(27?)-2-[2-[2-[[(4R)-2-[[5-[3-ethoxy-l-(7-methoxy-l-methyl-benzotriazol-5- yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl-l,l-dioxo-3,4-dihydro-5,l?c6,2- benzoxathiazepin-7 -yl] oxy ] ethoxy ]ethylcarbamoyl] - 1 -methy l-pyrrolidin-2-yl] methoxy ] -7- [8- ethynyL7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (99 mg, 70.28 99.99%μm yioelld, ) was obtained as a white solid. MS (ESI) m / z 1409.4 [M+H]+.

[0274] To a mixture was tert-butyl (17?,5S)-3-(2-(((27?)-2-((2-(2-(((47?)-2-(5-(3- ethoxy-l-(7-methoxy-l-methyl-17Tbenzo[d][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)- 4-methyL 1 , 1 -dioxido-3,4-dihydro-2H-benzo[b] [ 1 ,4,5]oxathiazepin-7 - yl)oxy)ethoxy)ethyl)carbamoyl)-l-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (99.0 mg, 70.2 1.00 eq) iμnm dioclh,loromethane (2 mL) was added hydrochloric acid (4 M, 1 mL, 56.9 eq) at 20°C,the mixture was stirred at 20 °C for 10 min. The mixture was concentrated in vacuum to give a crude product. The mixture was purified by Prep-HPLC(column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)- ACN];B%: 15%-45%,8min). The desired fraction was lyophilized. Ethyl 3-(3-(((R )-7-(2-(2-((R )- 2-(((4-((17?,5S,)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen- l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l-methylpyrrolidine-2- carboxamido)ethoxy)ethoxy)-4-methyl-l,l-dioxido-3,4-dihydro-2H- benzo[b] [ 1 ,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy- 1 -methyl- 177- benzo[d][l,2,3]triazol-5-yl)propanoate (33.83 mg, 25.56 36.36%μm yoiel,ld, 99% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1286.4 [M+H]+.JH NMR (400 MHz, DMSO-d6) δ ppm 1.00 - 1.06 (m, 3 H) 1.07 - 1.19 (m, 3 H) 1.61 - 1.77 (m, 6 H) 1.93 - 2.02 (m, 2 H) 2.22 (d, 1=2.6 Hz, 3 H) 2.41 (s, 3 H) 2.66 - 2.85 (m, 3 H) 2.98 - 3.04 (m, 1 H) 3.13 - 3.20 (m, 3 H) 3.31 - 3.34 (m, 3 H) 3.54 (br s, 2 H) 3.60 (br d, 1=4.4 Hz, 2 H) 3.74 (br d, 1=2.5 Hz, 1 H) 3.78 (br d,1=3.0 Hz, 3 H) 3.92 - 3.96 (m, 5 H) 4.21 (br s, 2 H) 4.26 - 4.43 (m, 7 H) 4.50 - 4.69 (m, 4 H) 6.83 - 6.96 (m, 3 H) 7.11 (d, 1=7.8 Hz, 1 H) 7.18 (d, 1=2.0 Hz, 1 H) 7.23 - 7.30 (m, 1 H) 7.33 (br s, 1 H) 7.39 (d, 1=2.4 Hz, 1 H) 7.42 - 7.50 (m, 2 H) 7.65 (dt, 1=8.8, 2.6 Hz, 1 H) 7.97 (dd, 1=9.2, 6.0 Hz, 1 H) 8.11 (br t, 1=6.0 Hz, 1 H) 9.04 (s, 1 H).Example 16: Preparation of Compound 54Example 16.1 : Synthesis of Compound 5222 52

[0275] Compound 22 was prepared according to the method of Example 4.2 as described herein. To a mixture of (S)-pyrrolidin-2-ylmethanol (5.00 g, 49.4 mmol, 4.81 mL, 1.00 eq) and triethylamine (5.25 g, 51.9 mmol, 7.22 mL, 1.05 eq) in methanol (22 mL) was added dropwise ethyl 2,2,2-trifluoroacetate (10.6 g, 74.6 mmol, 10.3 mL, 1.51 eq). The mixture was stirred at 25 °C for 16 hr. The mixture was diluted with 2M hydrochloric acid (70 ml) and extracted with ethyl acetate (50 mL*3). The aqueous phase was saturated with solid sodium chloride and extracted with ethyl acetate (50 mL*3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. TLC (ethyl acetate: methanol=10: 1) showed a main spot. The residue was purified by silica gel chromatography (ethyl acetate / methanol=95 / 5). (S)-2,2,2-trifluoro-l-(2-(hydroxymethyl)pyrrolidin-l-yl)ethan-l-one (6 g, 30.43 mmol, 61.56% yield) was obtained as a yellow oil.

[0276] To a solution of tert-butyl (lR,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3- <f|pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.40 mmol, 1.00 eq) and (S)-2,2,2-trifluoro-l-(2-(hydroxymethyl)pyrrolidin-l-yl)ethan-l-one (331 mg, 1.68 mmol, 1.20 eq) in dioxane (10 mL) was added cesium carbonate (912 mg, 2.80 mmol, 2.00 eq) at 20°C. The mixture was stirred at 95 °C for 10 h. The mixture was poured into water (10 mL) and extracted with dichloromethane (30 mL x 2). The combined organic layer was concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate=100: 1 to 1 :1. Tert-butyl (lR,5S)-3-(7-chloro-8-fluoro-2-(((S)-l -(2,2,2- trifluoroacctyl)pyrrolidin-2-yl)mcthoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 564 40.3%μm yoile,ld, 95% purity) was obtained as a white solid^H NMR (400 MHz, CDC13) δ = 8.70 - 8.62 (m, 1H), 4.67 - 4.18 (m, 7H), 3.74 - 3.50 (m, 4H), 2.17 - 1.83 (m, 6H), 1.62 (br d, J= 7.6 Hz, 2H), 1.45 (s, 9H).Example 16.2: Synthesis of Compound 53- trifluoroacetyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 560 1.00 eq)μm ino tle,trahydrofuran (5 mL) was added ((2-fhioro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl)ethynyl)triisopropylsilane (344 mg, 672 1.20 eq)μ, smoolult,ion of potassium phosphate (237 mg, 1.12 mmol, 2.00 eq) in water (0.5 mL) and AdonBuP Pd-G3(cataCXium® A Pd G3) (40.8 mg, 56.0 μm 0o.1l0, 0 eq) at 25 °C. The mixture was stirred at 60 °C for 2 h. The mixture was poured into water (15 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layer was dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate= 100: 1 to 5 : 1. Tert-butyl (lR,5S)-3-(8-fhioro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((S)-l-(2,2,2-trifluoroacetyl)pyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (450 mg, 446 μmol, 79.5% yield, 93% purity) was obtained as a yellow solid. 1H NMR (400 MHz, CDC13) 6 = 9.10 - 9.05 (m, 1H), 7.83 - 7.76 (m, 1H), 7.52 (br d, J = 2.0 Hz, 1H), 7.31 (br dd, J = 1.6, 8.8Hz, 2H), 5.34 - 5.27 (m, 2H), 4.89 - 4.35 (m, 6H), 4.26 - 4.19 (m, 1H), 4.17 - 4.09 (m, 2H), 3.82 - 3.71 (m, 2H), 3.55 - 3.49 (m, 3H), 2.28 - 2.15 (m, 2H), 2.01 (br s, 2H), 1.27 (br s, 4H), 1.25 (d, J = 1.2 Hz, 9H), 0.91 - 0.83 (m, 18H), 0.61 - 0.49 (m, 3H).Example 16.3: Synthesis of Compound 5453 54

[0277] To a solution of tert-butyl (17?,5S)-3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((5)-l-(2,2,2- trifluoroacetyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-t / ]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 425 1.00 eμqm) o inl, water (0.1 mL) and methanol (0.5 mL) was added NaOH (17.0 mg, 425 1.00 μ eqm)o alt, 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (15 mL) and extracted with dichloromethane (50 mLx3). The combined organic layer was concentrated in vacuum. The mixture was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate= 100 / 1 to 2 / 1). Tert-butyl (17?,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)cthynyl)naphthalcn-l-yl)-2-(((S)-pyrrolidin-2-yl)mcthoxy)pyrido[4,3- <7]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 390.23 jimol, 91.62% yield, 94% purity) was obtained as a yellow solid. LCMS (ESI) m / z 843.6 [M+H]+.1H NMR (400 MHz, DMSO-t / 6) 3 = 8.94 - 8.83 (m, 1H), 8.12 - 8.03 (m, 1H), 7.71 (s, 1H), 7.54 (t, J = 8.8 Hz, 1H), 7.36 - 7.26 (m, 1H), 5.36 (s, 2H), 5.26 (br t, J= 4.8 Hz, 1H), 4.88 (br t, J = 5.6 Hz, 1H), 4.78 - 4.59 (m, 1H), 4.36 - 4.09 (m, 4H), 3.93 (s, 1H), 3.83 - 3.46 (m, 5H), 3.43 (s, 3H), 1.97 - 1.57 (m, 8H), 1.46 (s, 9H), 0.86 - 0.78 (m, 18H), 0.59 - 0.42 (m, 3H).Example 17 : Preparation of Compound P- 10

[0278] To a solution of tert-butyl 3-(2-bromoethoxy)propanoate (500 mg, 1.98 mmol, 1.00 eq) in dimethylformamide (5 mL) was added potassium carbonate (272 mg, 1.98 mmol, 1.00 eq) and (T)-7-hydroxy-4-methyl-3,4-dihydro-2H-benzo[Z>][l,4,5]oxathiazepine 1,1-dioxide (452 mg, 1.98 mmol, 1.00 eq) at 20 °C. The mixture was stirred at 20 °C for 20 h. The mixture was poured into water (30 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layer was dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether / ethyl acetate=100: 1 to 1 : 1. Tert-butyl (R )-3-(2-((4-methyLl,l-dioxido-3,4-dihydro-2H-benzo[&][l,4,5]oxathiazepin-7- yl)oxy)ethoxy)propanoate (270 mg, 659 33μ.m4%ol, yield, 98% purity) was obtained as a colorless gum.Example 17.2: Synthesis of Compound 57

[0279] To a solution of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy- 1- methyl-lH-benzo[d][l,2,3]triazol-5-yl)propanoate (200 mg, 521 μm 1o.0l,0 eq) in dichloromethane (2 mL) was added thionyl chloride (310.27 mg, 2.61 mmol, 189 μL, 5 eq) at 20°C. The mixture was stirred at 20°C for Ih. The mixture was concentrated in vacuum. Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-methoxy-l-methyl-lH-benzo[6?][l,2,3]triazol-5- yl)propanoate (210 mg, crude) was obtained as a yellow oil, which was used for the next step directly.

[0280] To a solution of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-methoxy-l- methyl-lH-benzo[d][l,2,3]triazol-5-yl)propanoate (210 mg, 522 1.00 eq)μ imn o acl,etonitrile (5 mL) was added potassium carbonate (144 mg, 1.05 mmol, 2.00 eq) and tert-butyl (7?)-3-(2-((4- methyl-l,l-dioxido-3,4-dihydro-2H-benzo[&][l,4,5]oxathiazepin-7-yl)oxy)ethoxy)propanoate (251 mg, 627 μmo 1l.,20 eq) at 20°C. The mixture was stirred at 90°C for Ih. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). Ethyl 3-(3-(((A)-7-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)-4-methyl- 1 , 1 -dioxido-3 ,4-dihydro-2H-benzo [ / ? | [ 1 ,4,5 ]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7 - methoxy- 1 -methyl- 1 / / -bcnzo[c / | [ 1,2,3 ]triazol-5-yl)propanoate (380 mg, 496 94.8% yield) μmol, was obtained as a colorless oil.Example 17.3: Synthesis of Compound 58

[0281] To a solution of ethyl 3-(3-(((R )-7-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)-4-methyl- 1 , l -dioxido-3.4-dihydro-2 / / -bcnzo| / ?|[ l,4,5]oxathiazepin-2-yl)methyl)-4- methylphenyl)-3-(7-methoxy- 1 -methyl- 1 H-benzo[<7][ 1 ,2,3]triazol-5-yl)propanoate (300 mg, 391 μmol, 1.00 eq) in dichloromethane (1 mL) was added 2,2,2-trifluoroacetaldehyde (4.62 g, 40.5 mmol, 3.00 mL, 103 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. 3-(2-(((4Z?)-2-(5-(3- ethoxy-l-(7-methoxy-l-methyl-17 / -benzo[d][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)- 4-methyl- l,l-dioxido-3,4-dihydro-2H-benzo[b][l, 4, 5]oxathiazepin-7-yl)oxy)ethoxy (propanoic acid (320 mg, crude) was obtained as a yellow gum.

[0282] To a solution of 3-(2-(((47?)-2-(5-(3-ethoxy-l-(7-methoxy-l-methyl-lH- benzo[<7][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[&][l,4,5]oxathiazepin-7-yl)oxy)ethoxy)propanoic acid (100 mg, 140 1.00 eq) in μmol, dichloromethane (0.5 mL) was added dimethylformamide (10.2 mg, 140 10.8 μL, 1.00μm eqo)l, and oxalyl dichloride (53.5 mg, 422 36μ.9m μolL,, 3.00 eq) at 0 °C. The mixture was stirred at25 °C for 15 min. The mixture was concentrated in vacuum. Ethyl 3-(3-(((R )-7-(2-(3-chloro-3- oxopropoxy)cthoxy)-4-mcthyl-l,l-dioxido-3,4-dihydro-277-bcnzo[&][l,4,5]oxathiazcpin-2- yl)methyl)-4-methylphenyl)-3-(7-methoxy-l-methyl-lH-benzo[7][l,2,3]triazol-5-yl)propanoate (101 mg, crude) was obtained as a yellow solid.

[0283] To a solution of tert-butyl (17?,5S)-3-(8-fhioro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((S)-pyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (115 mg, 137 μmol, 1.00 eq) and triethylamine (13.8 mg, 137 19.0 μLμ,m 1o.0l,0 eq) in dichloromethane (3 mL) was added ethyl 3-(3-(((R)-7-(2-(3-chloro-3-oxopropoxy)ethoxy)-4-methyl-l,l-dioxido- 3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy-l- methyl-lH-benzo[d][l,2,3]triazol-5-yl)propanoate (100 mg, 137 μm 1o.0l,0 eq) in dichloromethane (2 mL) at 0 °C. The mixture was stirred at 25 °C for 30 min. The mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was dried over with sodium sulfate and concentrated in vacuum. The mixture was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=100 / l to 2 / 1. Tert-butyl ( lR,5S)-3-(2-(((2S)- 1 -(3-(2-(((47?)-2-(5-(3-ethoxy- l-(7-methoxy- 1-methyl- 1H- benzo[d][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro- 277-benzo[&][l,4,5]oxathiazepin-7-yl)oxy)ethoxy)propanoyl)pyrrolidin-2-yl)methoxy)-8-lluoro- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 83.99 61.25% μmol, yield, 86% purity) was obtained as a yellow solid. MS (ESI) m / z 1536.0 [M+H]+. (4001H NMR MHz, DMSO-76) d = 8.93 - 8.88 (m, 1H), 8.07 (dd, J= 6.0, 9.2 Hz, 1H), 7.70 (d, J= 1.6 Hz, 1H), 7.62 (ddd, J= 3.2, 5.2, 8.4 Hz, 1H), 7.53 (t, J= 8.8 Hz, 1H), 7.45 (s, 1H), 7.34 - 7.23 (m, 3H), 7.10 (d, 7 = 7.6 Hz, 1H), 6.93 - 6.81 (m, 3H), 5.35 (d, 7 = 1.6 Hz, 2H), 4.62 - 4.48 (m, 2H), 4.45 - 4.11 (m, 13H), 4.03 (q, 7 = 7.2 Hz, 2H), 3.98 - 3.87 (m, 6H), 3.80 - 3.53 (m, 10H), 3.44 - 3.38 (m, 3H), 3.26 - 3.11 (m, 3H), 2.69 - 2.58 (m, 2H), 2.24 - 2.20 (m, 3H), 1.96 - 1.85 (m, 4H), 1.45 (s, 9H), 1.20 - 1.16 (m, 3H), 1.08 - 1.02 (m, 4H), 0.80 (q, 7 = 7.2 Hz, 18H), 0.49 (br s, 3H).59 P-10

[0284] To a solution of tert-butyl (lR,5S)-3-(2-(((2S)-l-(3-(2-(((4R)-2-(5-(3-ethoxy- l-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4- methyl- l,l-dioxido-3, 4-dihydro-2H-benzo[b] [1,4, 5]oxathiazepin-7- yl)oxy)ethoxy)propanoyl)pyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 78.1 1.00 eq)μ imno dli,methylformamide (2 mL) was added cesium fluoride (59.3 mg, 390 14.4 μμLm, o 5l.0, 0 eq) at 25 °C. The mixture was stirred at 25 °C for 20 min. The mixture was poured into water (20 mL) and filtered. The filter cake was washed with water (10 mL) and collected, tert-butyl (lR,5S)-3-(2-(((2S)-l-(3-(2-(((4R)- 2-(5-(3-ethoxy-l-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-oxopropyl)-2- methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo|b][l,4,5Joxathiazepin-7- yl)oxy)ethoxy)propanoyl)pyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate (90 mg, crude) was obtained as a yellow solid.

[0285] To a solution of tert-butyl (lR,5S)-3-(2-(((2S)-l-(3-(2-(((4R)-2-(5-(3-ethoxy- l-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4- methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-7- yl)oxy)ethoxy)propanoyl)pyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 65.2 1.00 eq) iμnm dioclh,loromethane (1 mL) was added hydrochloric acid / dioxane (4 M, 16.31 μL, 1.00 eq) at 25 °C. The mixture was stirred 25 °C for 2.5 h. The mixture was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)- ACN];B%: 30%-60%,10min).The desired fraction was lyophilized, ethyl 3-(3-(((R)-7-(2-(3-((S)-2-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1 ]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen- l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)mcthyl)pyrrolidin-l-yl)-3-oxopropoxy)cthoxy)-4- methyl- l,l-dioxido-3, 4-dihydro-2H-benzo[b] [1,4, 5]oxathiazepin-2-yl)methyl)-4-methy Iphenyl)-3-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)propanoate (6.92 mg, 5.13 7.86% μmol, yield, 95% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1235.7 / 1236.8 [M+H]+.!H NMR (400 MHz, DMSO-d 6) δ = 10.24 - 9.99 (m, 1H), 8.84 - 8.75 (m, 1H), 7.95 (dd, J = 6.3, 8.9 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.49 - 7.40 (m, 2H), 7.38 - 7.31 (m, 2H), 7.30 - 7.24 (m, 1H), 7.18 - 7.08 (m, 2H), 6.96 - 6.81 (m, 3H), 4.59 - 4.09 (m, 13H), 4.02 - 3.87 (m, 6H), 3.80 - 3.52 (m, 12H), 3.21 - 3.15 (m, 2H), 2.81 - 2.60 (m, 3H), 2.22 (br s, 3H), 2.08 - 1.85 (m, 4H), 1.82 - 1.61 (m, 4H), 1.20 - 1.00 (m, 6H).

[0286] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-t / ]pyrimidine (3.00 g, 11.9 mmol, 1.00 eq) in dichloromethane (60.0 mL) was added ethyldiisopropylamine (3.07 g, 23.8 mmol, 4.14 mL, 2.00 eq) and tert-butyl (lA^^-S^-diazabicycloES^. l]octane-8-carboxylate (2.52 g, 11.9 mmol, 1.00 eq) at -40 °C. The mixture was stirred at 0 °C for 10 min. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 10 / 1 at 20 °C for 30 min. tert-butyl (17?,55)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (4.66 g, 10.1 mmol, 85.15% yield, 93% purity) was obtained as a yellow solid. MS (ESI) m / z 428.2 [M+H]+.Example 18.2: Preparation of Compound 6022 60

[0287] To a solution of tert-butyl (lA,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.10 g, 2.57 mmol, 1.00 eq) in dimethyl sulfoxide (40.0 mL) was added potassium fluoride (1.49 g, 25.7 mmol, 602 μL, 10.0 eq). The mixture was stirred at 120 °C for 1 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 10 / 1 at 20 °C for 30 min. tert-butyl (17?,5S)-3-(7- chloro-2,8-difluoropyrido[4,3-c?]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (870 mg, 1.84 mmol, 71.56% yield, 87% purity) was obtained as a yellow solid. MS (ESI) m / z 412.0 [M+H]+.Example 18.3: Preparation of Compound 6160 61

[0288] To a solution of tert-butyl (17R,55,)-3-(7-chloro-2,8-difluoropyrido[4,3- r / ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octanc-8-carboxylatc (770 mg, 1.87 mmol, 1.00 eq) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- naphthyl]ethynyl-triisopropyl-silane (1.15 g, 2.24 mmol, 1.20 eq) in tetrahydrofuran (7.00 mL) and water (1.40 mL) was added [2-(2-aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)- butyl-phosphane;methanesulfonate (136 mg, 187 0.100 eμqm) aonld, potassium phosphate (794 mg, 3.74 mmol, 2.00 eq). The mixture was stirred at 60 °C for 3h. The mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl (lR,5S)-3-(2,8-difhioro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 919 49.14% μ yimelodl), as a yellow oil.NMR (400 MHz, DMSO-d6) δ = 9.37 (s, 1H), 8.12 (dd, J = 6.0, 9.2 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.58 (t, J = 8.8 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 5.37 (s, 2H), 4.76 (br d, J = 12.0 Hz, 1H), 4.45 - 4.24 (m, 3H), 3.43 (s, 3H), 1.96 - 1.80 (m, 2H), 1.79 - 1.60 (m, 2H), 1.47 (s, 9H), 1.07 (s, 5H), 0.81 (dd, J = 5.2, 7.2 Hz, 18H).Example 19: Preparation of Compound 69Example 19.1: Synthesis of Compound 6362 63

[0289] To a solution of 2-(benzyloxy)ethan-l-ol (10.0 g, 65.7 mmol, 9.35 mL, 1.00 eq) in dichloromethane (100 mL) was added triethylamine (13.3 g, 131 mmol, 18.2 mL, 2.00 eq) and 4-methylbenzenesulfonyl chloride (15.0 g, 78.8 mmol, 1.20 eq) at 0 °C. The mixture was stirredat 20 °C for 2 h. The mixture was poured into water (100 mL), extracted with dichloromethane (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). 2-(benzyloxy)ethyl 4- methylbenzenesulfonate (18 g, 58.75 mmol, 89.41 % yield) was obtained as a yellow oil, which was used for the next step directly.Example 19.2: Synthesis of Compound 64

[0290] To a solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (1.00 g, 4.97 mmol, 1.00 eq) in dimethylformamide (10.0 mL) was added potassium tert-butoxide (1.12 g, 9.94 mmol, 2.00 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. 2-(benzyloxy)ethyl 4- methylbenzenesulfonate (2.28 g, 7.45 mmol, 1.50 eq) was added to the mixture at 0 °C. The mixture was stirred at 80 °C for 16 h.Example 19.3: Synthesis of Compound 65

[0291] To a solution of palladium / carbon (500 mg, 10% purity) in tetrahydrofuran (30.0 mL) was added tert-butyl 4-(2-(benzyloxy)ethoxy)piperidine-l -carboxylate (3.50 g, 10.4 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 30 °C for 16 h under hydrogen (21.0 mg, 10.4 mmol, 1.00 eq) (50 Psi). The mixture was filtered and washed with tetrahydrofuran (200 mL). The filtrate was concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether / ethyl acetate =100:1 to 1:1. tert-butyl 4-(2-hydroxyethoxy )piperidine-l -carboxylate (2.2 g, 8.97 mmol, 85.95% yield) was obtained as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) J = 3.82 - 3.71 (m, 4H), 3.64 - 3.55 (m, 2H), 3.50 (td, J= 4.4, 8.0 Hz, 1H), 3.08 (ddd, J= 3.6, 9.6, 13.2 Hz, 2H), 1.89 - 1.84 (m, 2H), 1.59 - 1.49 (m, 2H), 1.46 (s, 9H).Example 19.4: Synthesis of Compound 6665 66

[0292] To a solution of tert-butyl 4-(2-hydroxyethoxy)piperidine- 1 -carboxylate (980 mg, 3.99 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added triethylamine (808 mg, 7.99 mmol, 1.11 mL, 2.00 eq) and 4-methylbenzenesulfonyl chloride (1.14 g, 5.99 mmol, 1.50 eq). The mixture was stirred at 20 °C for 16 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiCF. petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-l-carboxylate (1.40 g, 3.50 mmol, 87.72% yield) as a yellow oil. ’ H NMR (400 MHz, CHLOROFORM-^ / ) δ = 7.81 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.21 - 4.12 (m, 2H), 3.71 - 3.58 (m, 4H), 3.43 (qd, J= 4.0, 8.0 Hz, 1H), 3.16 - 3.03 (m, 2H), 2.46 (s, 3H), 1.73 (tdd, J= 3.6, 6.4, 9.2 Hz, 2H), 1.46 (s, 10H).Example 19.5: Synthesis of Compound 67

[0293] To a solution of (4R)-4-methyl-1 ,l -dioxo-3,4-dihydro-2H-5,1 ,2- benzoxathiazepin-7-ol (800 mg, 3.49 mmol, 1.00 eq) in dimethylformamide (20.0 mL) was added potassium carbonate (965 mg, 6.98 mmol, 2.00 eq) and tert-butyl 4-[2-(p- tolylsulfonyloxy)ethoxy]piperidine-l -carboxylate (1.39 g, 3.49 mmol, 1.00 eq). The mixture was stirred at 20 °C for 16 h. The mixture was poured into water (100 mL) and extracted withdichloromethane / isopropanol = 3 / 1 (50.0 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 3 / 1) to give tert- butyl 4- [2- [ [(4R)-4-methyl- 1 , 1 -dioxo-3 ,4-di hydro-2 / / - 5 , 1 ,2-benzoxathiazepin-7 - yl]oxy]ethoxy]piperidine-l-carboxylate (1.20 g, 2.34 mmol, 67.04% yield, 89% purity) as a brown oil. ’H NMR (400 MHz, CHLOROFORM-d) δ = 8.00 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 6.73 - 6.64 (m, 2H), 4.19 - 4.11 (m, 4H), 3.81 (t, J= 4.8 Hz, 2H), 3.73 (td, J = 3.2, 10.0 Hz, 2H), 3.67 - 3.50 (m, 2H), 3.17 - 3.03 (m, 2H), 1.90 - 1.77 (m, 2H), 1.54 (qd, J = 4.4, 12.8 Hz, 2H), 1.45 (s, 9H), 1.38 (d, J = 6.4 Hz, 3H).Example 19.6: Synthesis of Compound 68

[0294] To a solution of ethyl 3-[3-(hydroxymethyl)-4-methyl-phenyl]-3-(7-methoxy- l-methyl-benzotriazol-5-yl)propanoate (1.00 g, 2.61 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added sulfurous dichloride (1.55 g, 13.0 mmol, 947 μL, 5.00 eq). The mixture was stirred at 20 °C for 0.5 h . The mixture was concentrated under vacuum to give a yellow solid. The yellow solid and tert-butyl 4-[2-[[(4R)-4-methyl-l,l-dioxo-3,4-dihydro-2 / / -5,l,2-benzoxathiazepin-7- yl]oxy]ethoxy]piperidine-l-carboxylate (1.20 g, 2.10 mmol, 1.00 eq) in acetonitrile (20.0 mL) added potassium carbonate (872 mg, 6.31 mmol, 3.00 eq) and stirred at 90 °C for 3 h. The mixture was filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl 4-[2-[[(4R)-2-[[5-[3- ethoxy-l-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4- methyl-l,l-dioxo-3,4-dihydro-5,l,2-benzoxathiazepin-7-yl]oxy]ethoxy]piperidine-l-carboxylate (550 mg, 669.12 μm 3o1l.,82% yield) as a yellow oil. ’H NMR (400 MHz, CHLOROFORM-t / ) 3 = 7.75 (dd, J = 1.6, 8.8 Hz, 1H), 7.46 (s, 1H), 7.16 (s, 1H), 7.10 - 6.96 (m, 2H), 6.82 - 6.66 (m, 2H), 6.60 (s, 1H), 4.81 - 4.68 (m, 1H), 4.40 (s, 3H), 4.24 - 4.11 (m, 4H), 4.04 (q, J = 7.2 Hz, 2H),3.90 (s, 3H), 3.80 (t, J = 4.8 Hz, 2H), 3.62 (td, J = 9.2, 15.2 Hz, 1H), 3.49 - 3.33 (m, 4H), 3.16 - 3.04 (m, 2H), 2.68 (dd, J= 2.0, 5.2 Hz, 2H), 2.29 (s, 3H), 2.11 (t, J= 9.6 Hz, 2H), 1.85 (d, J= 7.6 Hz, 2H), 1.57 (s, 9H), 1.40 (d, J = 6.4 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H).Exa68 69

[0295] A mixture of tert-butyl 4-[2-[[(4R)-2-[[5-[3-ethoxy-l-(7-methoxy-l-methyl- benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl-l,l-dioxo-3,4-dihydro- 5, l,2-benzoxathiazepin-7-yl]oxy]ethoxy]piperidine-l -carboxylate (530 mg, 645 1.00 eq) in μmol, hydrochloride / dioxane (4 M, 5.00 mL, 31.0 eq) was stirred at 20 °C for 1 h under nitrogen atmosphere. The mixture was concentrated under vacuum to give a crude product (500mg, hydrochloric acid salt). The mixture was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*25mm* 10um;mobile phase: [water(FA)-ACN] gradient: 18%-48% B over 2 min) to give ethyl 3-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-[4-methyl-3-[[(47?)-4-methyl-l,l-dioxo-7-[2- (4-piperidyloxy)ethoxy]-3,4-dihydro-5,l,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (500 mg, 623.39 μm 9o6l.,68% yield, 90% purity) as a yellow solid.1H NMR (400 MHz, DMSO- d6) δ = 8.16 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 5.2, 8.4 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.23 (s, 1H), 7.18 - 7.13 (m, 1H), 7.04 (d, J= 8.0 Hz, 1H), 6.91 (s, 1H), 6.82 (dd, J= 2.5, 8.8 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 4.54 (t, J = 8.0 Hz, 1H), 4.34 (s, 3H), 4.15 (d, J = 2.4 Hz, 2H), 4.05 - 3.87 (m, 6H), 3.73 (d, J = 4.4 Hz, 2H), 3.18 (d, J = 8.0 Hz, 4H), 2.66 - 2.57 (m, 3H), 2.23 (s, 3H), 2.12 - 2.01 (m, 2H), 1.86 - 1.72 (m, 2H), 1.46 - 1.31 (m, 2H), 1.29 (d, J = 6.4 Hz, 3H), 1.05 (t, J = 12 Hz, 3H).Example 20: Synthesis of Compound P-11 /

[0296] To a solution of tert-butyl (15,57?)-3-[2,8-difluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-rf]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 131 1.00 eq)μ imno dli,oxane (2.00 mL) was added cesium carbonate (128 mg, 394 μ 3m.0o0l, eq) and ethyl 3-(7-methoxy-l-methyl- benzotriazol-5-yl)-3-[4-methyl-3-[[(47?)-4-methyl-l,l-dioxo-7-[2-(4-piperidyloxy)ethoxy]-3,4- dihydro-5,l,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (119 mg, 165 1.26 eq). μmol, The mixture was stirred at 100 °C for 1 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2. petroleum ether / ethyl acetate = 0 / 1) to give tert-butyl (15,57?)-3-[2-[4-[2-[[(47?)-2-[[5-[3-ethoxy-l-(7-methoxy-l-methyl- benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl-l,l-dioxo-3,4-dihydro- 5,l,2-benzoxathiazepin-7-yl]oxy]ethoxy]-l-piperidyl]-8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 99.47 75.79%μ ymieolld,, 91% purity) as a yellow solid. MS (ESI) m / z 1464.4 [M+H]+.

[0297] To a solution of tert-butyl (lS,5 / ?)-3-[2-[4-[2-[[(47?)-2-[[5-[3-ethoxy-l -(7- mcthoxy-l-mcthyl-bcnzotriazol-5-yl)-3-oxo-propyl]-2-mcthyl-phcnyl]mcthyl]-4-mcthyl-l,l- dioxo-3,4-dihydro-5,l,2-benzoxathiazepin-7-yl]oxy]ethoxy]-l-piperidyl]-8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-rf]pyrimidin-4-yl]-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (160 mg, 109 1.00 eq) iμnm doiml,ethylformamide (1.60 mL) was added cesium fluoride (166 mg, 1.09 mmol, 40.4 μL, 10.0 eq). The mixture was stirred at 20 °C for 0.5 h. The mixture was poured into water (20.0 mL) and filtered. The filter cake was concentrated under vacuum to give a yellow solid. The yellow solid was dissolved in hydrochloride / dioxane (2.00 mL) and stirred at 20 °C for 0.5 h under nitrogen atmosphere. The mixture was concentrated under vacuum to give a residue. The residue was purified by prep- HPLC (column: Welch ultimate C18 150*25mm* 7um;mobile phase: [water(FA)- ACN];gradient:18%-48% B over 10 min) and lyophilized to afford ethyl 3-[3-[[(47?)-7-[2-[[l-[4-[(lS,5 / ?)-3,8-diazabicyclo[3.2.1 ]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8- fluoro-pyrido[4,3-d]pyrimidin-2-yl]-4-pipcridyl]oxy]cthoxy]-4-mcthyl-l,l-dioxo-3,4-dihydro- 5, l,2-benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7 -methoxy- l-methyl-benzotriazol-5- yl)propanoate (48.40 mg, 41.31 38μ.5m8o%l, yield, 99.29% purity) as a yellow solid. MS (ESI) m / z 207.1 [M+H]+. NMR (400 MHz, DMSO-d6) δ = 9.02 (s, 1H), 8.19 (s, 1H), 7.97 (dd, 7 = 6.0, 9.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.38 (s, 1H), 7.21 (s, 1H), 7.16 - 7.09 (m, 2H), 7.03 (d, 7 = 7.6 Hz, 1H), 6.93 (dd, 7 = 2.4, 8.8 Hz, 1H), 6.89 (s, 1H), 6.79 (dd, 7 = 2.4, 4.4 Hz, 1H), 4.72 - 4.47 (m, 2H), 4.45 - 4.25 (m, 5H), 4.22 - 4.04 (m, 3H), 4.00 - 3.84 (m, 6H), 3.71 (s, 3H), 3.52 (s, 4H), 3.32 (s, 5H), 3.16 (d, 7 = 8.0 Hz, 3H), 2.57 (d, 7 = 2.4 Hz, 2H), 2.21 (s, 3H), 2.04 (t, 7 = 9.2 Hz, 2H), 1.76 (d, 7 = 9.2 Hz, 2H), 1.50 (s, 2H), 1.42 - 1.24 (m, 6H), 1.03 (t, 7 = 7.2 Hz, 3H).

[0298] To a solution of 2-methyloxirane (1.66 g, 28.5 mmol, 2.00 mL, 114 eq) in ethanol (1.00 mL) was added diisopropylethylamine (371 mg, 2.87 mmol, 0.500 mL, 11.5 eq) and ethyl 3-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-[4-methyl-3-[[(47?)-4-methyl-l,l-dioxo-7-[2- (4-piperidyloxy)ethoxy]-3,4-dihydro-5,l,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (180 mg, 249 μmo 1l.0, 0 eq), the mixture at 20 °C for 16 h. The mixture was concentrated under vacuum to give a residue. The residue was diluted with ethyl acetate (10.0 mL), poured into water (10.0 mL) and extracted with ethyl acetate (10.0 mL x 2). The organic layer was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiCh, ethyl acetate) to give ethyl 3-[3-[[(47?)-7-[2-[[l-(2-hydroxypropyl)-4-piperidyl]oxy]ethoxy]-4-methyl- l ,l-dioxo-3,4-dihydro-5,l ,2-benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-l - mcthyl-bcnzotriazol-5-yl)propanoatc (140 mg, 179.50 71.99%μm yoiel,ld) as a white oil. ’H NMR (400 MHz, CDCh) d = 7.75 (dd, J= 1.6, 8.8 Hz, 1H), 7.46 (s, 1H), 7.16 (s, 1H), 7.10 - 6.96 (m, 2H), 6.82 - 6.66 (m, 2H), 6.60 (s, 1H), 4.81 - 4.68 (m, 1H), 4.40 (s, 3H), 4.24 - 4.11 (m, 4H), 4.04 (q, 7- 7.2 Hz, 2H), 3.90 (s, 3H), 3.80 (t, 7 = 4.8 Hz, 2H), 3.62 (td, 7= 9.2, 15.2 Hz, 1H), 3.49 - 3.33 (m, 4H), 3.16 - 3.04 (m, 2H), 2.68 (dd, J = 1.6, 5.2 Hz, 2H), 2.29 (s, 3H), 2.11 (t, J = 9.6 Hz, 2H), 1.85 (d, J - 7.6 Hz, 2H), 1.57 (s, 9H), 1.40 (d, J - 6.4 Hz, 3H), 1.14 (t, 7 - 7.2 Hz, 3H).Example 21 ,2: Synthesis of Compound 72

[0299] To a solution of ethyl 3-[3-[[(4 / ?)-7-[2-[[l-(2-hydroxypropyl)-4- piperidyl]oxy]ethoxy]-4-methyl-l,l-dioxo-3,4-dihydro-5,l,2-benzoxathiazepin-2-yl]methyl]-4- methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (140 mg, 179 1.00 μmol, eq) in tetrahydrofuran (2.00 mL) was added sodium hydride (14.4 mg, 359 60% purity, 2.0μ0mol, eq). The mixture was stirred at 20 °C for 5 min. Then tert-butyl (lS,57?)-3-[2,8-difluoro-7-[7- fhioro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-4- yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (178 mg, 2338 1.30 eq) inμ tmetoral,hydrofuran (0.500 mL) was added and stirred at 20 °C for 16 h. The mixture was poured into saturated ammonium chloride (20.0 mL) and extracted ethyl acetate (20.0 mL x 2). The organic layer was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 0 / 1) to give tert-butyl (15,57?)-3-[2-[2-[4-[2-[[(4A)-2-[[5- [3-ethoxy-l-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4- methyl- 1 , 1 -dioxo-3 ,4-dihydro-5 , 1 ,2-benzoxathiazepin-7 -yl] oxy ]ethoxy ] - 1 -piperidyl] - 1 -methyl- etho xy]-8-fhioro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 106.12 μmol 5, 9.12% yield, 95% purity) as a yellow solid.MS (ESI) m / z 1522.3 [M+H]+.Example 21.3: Synthesis of Compound P-12

[0300] To a solution of tert-butyl (lS,57?)-3-[2-[2-[4-[2-[[(47?)-2-[[5-[3-ethoxy-l-(7- methoxy- l-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl- 1,1- dioxo-3,4-dihydro-5,l,2-benzoxathiazepin-7-yl]oxy]ethoxy]-l-piperidyl]-l-methyl-ethoxy]-8- fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]pyrido[4,3- d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 112 1.00 eq) inμmol, dimethylformamide (1.70 mL) was added cesium fluoride (169 mg, 1.12 mmol, 41.2 p.L, 10.0 eq). The mixture was stirred at 20 °C for 0.5 h. The mixture was poured into water (10.0 mL) and filtered. The filter cake was concentrated under vacuum to give a yellow solid. The yellow solid was dissolved in hydrochloride / dioxane (4 M, 3.00 mL, 96.4 eq) and stirred at 20 °C for 0.5 h. The mixture was concentrated under vacuum to give a residue (210 mg, hydrochloric acid salt ). The residue(100 mg, crude) was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:l l%-41% B over 10 min) andlyophilized to afford ethyl 3- [3-[[(47?)-7-[2-[[ 1 - [2- [4- [( 1 S,57?)-3,8-diazabicyclo[3.2.1 ]octan-3-yl]- 7-(8-cthynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxypropyl]- 4-piperidyl]oxy] ethoxy ] -4-methyl- 1 , 1 -dioxo-3 ,4-dihydro-5 , 1 ,2-benzoxathiazepin-2-yl] methyl] - 4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (10.05 mg, 7.91 μmol, 6.35% yield, 99.7% purity, FA) as a yellow solid. MS (ESI) m / z 1222.1 [M+H]+. (4001H NMR MHz, DMSO-de) & = 9.02 (d, J = 1.2 Hz, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.56 (dd, J = 8.8, 14.1 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.39 (s, 1H), 7.24 - 7.16 (m, 2H), 7.13 (br d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 6.83 - 6.72 (m, 1H), 6.70 - 6.64 (m, 1H), 5.49 - 5.31 (m, 1H), 4.58 - 4.38 (m, 2H), 4.37 - 4.19 (m, 5H), 4.16 - 4.00 (m, 2H), 3.98 - 3.85 (m, 6H), 3.83 - 3.73 (m, 1H), 3.69 (br d, J = 3.2 Hz, 3H), 3.62 - 3.45 (m, 7H), 3.16 (d, J = 8.0 Hz, 5H), 2.57 (s, 3H), 2.21 (s, 3H), 2.11 - 1.94 (m, 2H), 1.76 (d, J= 6.4 Hz, 2H), 1.67 (s, 4H), 1.45 - 1.17 (m, 8H), 1.03 (t, J = 7.1 Hz, 3H).P-13

[0301] To a solution of ethyl 3-[3-[[(4R)-7-[2-[[l -[2-[4-[( 1 S,5R)-3,8- diazabicyclo[3.2.1]octan-3-yl]-7-(8-cthynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro- pyrido[4,3-d]pyrimidin-2-yl]oxypropyl]-4-piperidyl]oxy]ethoxy]-4-methyl-l,l-dioxo-3,4- dihydro-5 , 1 ,2-benzoxathiazepin-2-yl] methyl] -4-methyl-phenyl] -3-(7 -methoxy- 1 -methyl- benzotriazol-5-yl)propanoate (100 mg, 79.5 1.00 eμqm, o hly,drochloride salt) in tetrahydrofuran (1.00 mL) and water (0.200 mL) was added lithium hydroxide monohydrate (10.0 mg, 239 pmol, 3.00 eq). The mixture was stirred at 40 °C for 1 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column; Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN] gradient: 11%-41% B over 10 min) and lyophilized to afford 3-[3-[[(4R)-7-[2-[[l-[2-[4-[(lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(8- ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxypropyl]-4- piperidyl] oxy Jethoxy] -4-methyl- 1 , 1 -dioxo-3 ,4-dihydro-5 , 1 ,2-benzoxathiazepin-2-yl] methyl] -4- methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoic acid (5.57 mg, 4.39 pmol, 5.52% yield, 97.6% purity, FA) as a yellow solid. MS (ESI) m / z 384.2 [M+H]+.JH NMR (400 MHz, DMSO-d6 ) δ = 9.11 - 8.92 (m, 1H), 8.06 - 7.90 (m, 1H), 7.63 - 7.51 (m, 1H), 7.49 - 7.43 (m, 1H), 7.41 (s, 1H), 7.39 (s, 1H), 7.21 (br s, 1H), 7.20 (s, 1H), 7.12 (d, J - 12 Hz, 1H), 7.02 (d, 7 = 8.0 Hz, 1H), 6.86 (s, 1H), 6.83 - 6.71 (m, 1H), 6.71 - 6.62 (m, 1H), 5.51 - 5.27 (m, 1H), 4.55 - 4.37 (m, 2H), 4.35 - 4.19 (m, 4H), 4.17 - 4.05 (m, 2H), 4.00 - 3.86 (m, 4H), 3.81 - 3.75 (m, 1H), 3.67 (d, J = 12.0 Hz, 3H), 3.63 - 3.48 (m, 9H), 3.04 (d, 7 = 7.6 Hz, 5H), 2.57 (d, 7 = 2.4 Hz, 3H), 2.20 (s, 3H), 2.05 (d, 7 = 9.2 Hz, 2H), 1.83 - 1.56 (m, 6H), 1.45 - 1.13 (m, 8H).Example 22: Preparation of Compound P-14P-14Example 22.1 : Synthesis of Compound 7373

[0302] To a solution of (R )-2-(((4-((17?,5S)-8-(ter / -butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l- methylpyrrolidine-2-carboxylic acid (210 mg, 233 1.00μm eqo)l, and ethyl 3-(7-methoxy-1 - methyl- 1 / / -benzol d|| 1 ,2,3 ]triazol-5-yl)-3-(4-methyl-3-(((R )-4-methyl- 1 , 1 -dioxido-7-(2- (piperidin-4-yloxy)ethoxy)-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoate (176 mg, 233 p.mol, 1.00 eq, hydrochloric acid) in dimethylformamide (5.00 mL) was added O-(7-azabcnzotriazol- l -yl)-MMM. / V- tetramethyluroniumhexafluorophosphate (132 mg, 349 μm 1o.5l, eq) and N,N- diisopropylethylamine (60.2 mg, 466 81μ.1m po.Ll,, 2.00 eq) at 16 °C. The mixture was stirred at 20 °C for 16 h. The mixture was poured into water (20.0 mL) and extracted with ethyl acetate(30.0 mL x 3). The combined organic layer was washed with water (10.0 mL), brine (10.0 mL), and dried over with sodium sulfate. The mixture was concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate=100: 1 to 0: 1. Tert-butyl (17?,5S,)-3-(2-(((27?)-2-(4-(2-(((4T)-2-(5-(3-ethoxy-l-(7-methoxy-l-methyl-17 / - benzo[d][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro- 2 / L benzo [b][ 1,4, 5 ]oxathiazepin-7-yl)oxy)ethoxy)piperidine-l -carbonyl)- l-methylpyrrolidin-2- yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- l-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (145 mg, 74.99 μmol, 32.18% yield, 83% purity) was obtained as a yellow solid.Example 22,2: Synthesis of Compound P-14

[0303] To a solution of tert-butyl (17?,5S)-3-(2-(((2 / ?)-2-(4-(2-(((47?)-2-(5-(3-ethoxy- 1 -(7-mcthoxy- 1 -methyl- 1 H-bcnzo[d][ 1 ,2,3 ]triazol-5-yl)-3-oxopropyl)-2-mcthylbcnzyl)-4- methyl-1 , l-dioxido-3,4-dihydro-2H-benzo[b][ 1 ,4,5]oxathiazepin-7-yl)oxy)ethoxy)piperidine- 1- carbonyl)-l-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 72.4 1.00 eμqm) o inl, dimethylformamide (1.50 mL) was added cesium fluoride (54.9 mg, 362 13.3 μL,μ 5m.0o0l, eq) at 16 °C. The mixture was stirred at 16 °C for 15 min. The mixture was poured into water (10.0 mL) and filtered. The filter cake was washed with water (10.0 mL) and collected. Tert-butyl (lR,55)-3-(2-(((27?)-2-(4- (2-(((47?)-2-(5-(3-ethoxy-l-(7-methoxy-l-methyl-17Lbenzo[d][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-7- yl)oxy)ethoxy)piperidine-l-carbonyl)-l-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (95 mg, crude) was obtained as a yellow solid.

[0304] To a solution of tert-butyl (17?,5>S,)-3-(2-(((27?)-2-(4-(2-(((47?)-2-(5-(3-ethoxy-l- (7 -methoxy- 1 -methyl- 1 / / -benzo [d] [ 1 ,2,3] triazol-5 -yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl- 1 , 1 -dioxido-3 ,4-di hydro-2 / 7-bcnzo [b] [ 1 ,4,5 ]oxathiazepin-7-yl)oxy )ethoxy )piperidine- 1 - carbonyl)-l-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 54.0 1.00 eq)μ inm doilc,hloromethane (1.00 mL) was added hydrochloric acid / dioxane (4 M, 870 μL, 64.3 eq) at 16 °C. The mixture was stirred at 16 °C for 0.5 h. The mixture was concentrated in vacuum. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:19%-49% B over 10 min ). Ethyl 3-(3-(((R )-7-(2-((l-((R )-2- (((4-((17?,55)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l- yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l-methylpyrrolidine-2-carbonyl)piperidin-4-yl)oxy)ethoxy )-4-methyl- 1 , 1 -dioxido-3, 4-dihydro-27 / -benzo[b] [ 1 ,4,5]oxathiazepin-2- yl)methyl)-4-methylphenyl)-3-(7-methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)propanoate (18.40 mg, 13.49 μm 2o4l.,96% yield, 99% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1304.5 [M+H]+. ’H NMR (400 MHz, DMSO-d6) δ = 10.52 - 9.82 (m, 1H), 9.03 (s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.65 (dd, J = 3.2, 8.4 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.39 (d, J = 2.4 Hz,1H), 7.33 (s, 1H), 7.30 - 7.23 (m, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.94 -6.83 (m, 3H), 4.73 - 4.59 (m, 2H), 4.56 - 4.44 (m, 2H), 4.43 - 4.26 (m, 6H), 4.20 (s, 2H), 4.16 -4.06 (m, 1H), 4.00 - 3.87 (m, 6H), 3.83 - 3.72 (m, 3H), 3.68 - 3.48 (m, 7H), 3.30 (s, 2H), 3.22 -3.11 (m, 3H), 3.09 - 3.01 (m, 1H), 3.01 - 2.91 (m, 1H), 2.80 - 2.65 (m, 1H), 2.36 (s, 3H), 2.22 (d,J = 2.4 Hz, 3H), 2.15 (dd, J = 1.2, 6.0 Hz, 2H), 2.00 - 1.79 (m, 4H), 1.66 (s, 3H), 1.49 - 1.32 (m, 2H), 1.20 - 1.07 (m, 3H), 1.03 (t, J = 7.2 Hz, 3H).Example 23: Preparation of Compound P-15P-15Example 23.1: Synthesis of Compound 75274 DCM,0-20°C, 16 h 75

[0305] To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (3.00 g, 13.8 mmol, 1.00 eq) and Rhodium acetate (30.5 mg, 138 μmol, 0.0100 eq) in dichloromethane (30.0 mL) was added a solution of ethyl 2-diazoacetate (6.30 g, 55.2 mmol, 5.81 mL, 4.00 eq) in dichloromethane (30.0 mL) dropwise at 0 °C under nitrogen. The mixture was stirred at 25 °C for 48 h. The mixture was poured into water (1000 mL), separated the organic phase and the aqueous phase was extracted with dichloromethane (500 mL x 3). The organic layers were combined and washed with brine (200 mL), dried over anhydrous sodium sulphate and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). Tert-butyl 2-((2-cthoxy-2-oxocthoxy)mcthyl)morpholinc-4-carboxylatc (2.00 g, 6.59 mmol, 47.75% yield) was obtained as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 4.24 (d, J = 7.2 Hz, 2H), 4.16 (s, 2H), 4.01 - 3.81 (m, 3H), 3.72 - 3.47 (m, 4H), 3.09 - 2.60 (m, 2H), 1.49 (s, 9H), 1.31 (t, 7 = 7.2 Hz, 3H).Example 23.2: Synthesis of Compound 7675 76

[0306] To a solution of tert-butyl 2-((2-ethoxy-2-oxoethoxy)methyl)morpholine-4- carboxylate (1.00 g, 3.30 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was added lithium aluminum hydride (2.50 M, 1.58 mL, 1.20 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (1.00 mL) slowly. Then to the mixture was added 10% aq. sodium hydroxide (1.00 mL) and water (3.00 mL). The mixture was filtered, and the filter cake was washed with tetrahydrofuran (100 mL). The crude compound was used into the next step without further purification. Tert-butyl 2-((2-hydroxyethoxy)methyl)morpholine-4-carboxylate (800 mg, crude) was obtained as a white oil.Example 23.3: Synthesis of Compound 77Boc, , 6 h BocOTs76 77

[0307] To a solution of tert-butyl 2-((2-hydroxyethoxy)methyl)morpholine-4- carboxylate (800 mg, 3.06 mmol, 1.00 eq) in dichloromethane (8.00 mL) was added triethylamine (620 mg, 6.12 mmol, 852 μL. 2.00 eq) at 25 °C. P-toluensulfonyl chloride (876 mg, 4.59 mmol, 1.50 eq) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was poured into water (30.0 mL), separated the organic phase and the aqueous phase was extracted with dichloromethane (20.0 mL x 3). The organic layers were combined and washed with brine (20.0 mL), dried over anhydrous sodium sulphate and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). Tert-butyl 2-((2- (tosyloxy)ethoxy)methyl)morpholine-4-carboxylate (730 mg, 1.70 mmol, 55.67% yield, 97% purity) was obtained as a white oil.1H (40 N0M MRHz, DMSO-d6 ) δ = 7.79 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 4.16 - 4.10 (m, 3H), 3.83 - 3.66 (m, 6H), 3.61 - 3.55 (m, 4H), 1.42 (s, 12H).Example 23.4: Synthesis of Compound 7877 78

[0308] To a solution of tert-butyl 2-((2-(tosyloxy)ethoxy)methyl)morpholine-4- carboxylate (300 mg, 722 1μ.0m0o elq, ) in dimethylformamide (3 mL) was added (R)-7-hydroxy- 4-methyl-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepine 1,1 -dioxide (248 mg, 1.08 mmol, 1.50 eq) and potassium carbonate (100 mg, 722 1.00 μ eqm)o alt, 25 °C. The mixture was stirred at 80 °C for 6 h. The mixture was poured into water (20.0 mL), separated the organic phase and the aqueous phase was extracted with dimethylformamide (20.0 mL x 3). The organic layers were combined and washed with brine (20.0 mL), dried over anhydrous sodium sulphate and concentrated to give a residue. EC3875-561 was combined to this page to purify. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). Tert-butyl 2-((2-(((R)-4-methyl-l,l-dioxido-3,4- dihydro-2H-benzo[b][l,4,5]oxathiazepin-7-yl)oxy)ethoxy)methyl)morpholine-4-carboxylate (430 mg, crude) was obtained as a white oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.76 (d, J = 8.8 Hz, 1H), 6.81 - 6.61 (m, 2H), 4.91 - 4.65 (m, 1H), 4.25 - 4.09 (m, 3H), 3.97 - 3.79 (m, 5H), 3.71 - 3.50 (m, 5H), 3.41 (br d, J = 14.4 Hz, 1H), 3.04 - 2.88 (m, 1H), 2.80 - 2.62 (m, 1H),1.48 (s, 9H), 1.41 (d, J = 6.4 Hz, 3H).Example 23.5: Synthesis of Compound 79

[0309] To a solution of ethyl 3-[3-(hydroxymethyl)-4-methyl-phenyl]-3-(7-methoxy- l-methyl-benzotriazol-5-yl)propanoate (350 mg, 913 1.00 μ emq)o iln, dichloromethane (3.50mL) was added thionyl chloride (434 mg, 3.65 mmol, 265 μL, 4.00 eq) at 15 °C. The mixture was stirred at 20 °C for 30 min. Remove the solvent on a rotary evaporator. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 50 mL / min). Ethyl 3-[3-(chloromethyl)-4- methyl-phenyl]-3-(7 -methoxy- l-methyl-benzotriazol-5-yl)propanoate (160 mg, 398 43.6% μmol, yield) was obtained as a white solid.

[0310] To a solution of ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-l- methyl-benzotriazol-5-yl)propanoate (150 mg, 373 1.00 eqμ)m inol a,cetonitrile (3.00 mL) was added tert-butyl 2-[2-[[(4R)-4-methyl-l,l-dioxo-3,4-dihydro-2H-5,l,2-benzoxathiazepin-7- yl]oxy]ethoxymethyl]morpholine-4-carboxylate (176 mg, 373 1.00 eμqm) o anl,d potassium carbonate (103 mg, 747 μ 2m.0o0l, eq) at 25 °C. The mixture was stirred at 90 °C for 3 h. The mixture was poured into water (20.0 mL), separated the organic phase and the aqueous phase was extracted with ethyl acetate (10.0 mL x 3). The organic layers were combined and washed with brine (20.0 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Tert-butyl 2- ((2-(((4R)-2-(5-(3-ethoxy-l-(7-methoxy-l -methyl- lH-benzo[d][ 1,2, 3]triazoL5-yl)-3-oxopropyl)- 2-methylbenzyl)-4-methyl- 1 , l-dioxido-3,4-dihydro-2H-benzo[b] [ 1 ,4,5]oxathiazepin-7 - yl)oxy)ethoxy)methyl)morpholine-4-carboxylate (250 mg, 298 79.9% yieμlmd)o wl,as obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.66 (dd, J = 2.8, 8.8 Hz, 1H), 7.46 (s, 1H), 7.35 (s, 1H), 7.30 - 7.25 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.97 - 6.83 (m, 3H), 4.53 (t, J= 7.6 Hz, 1H), 4.46 - 4.29 (m, 5H), 4.21 (s, 2H), 3.99 - 3.89 (m, 5H), 3.87 - 3.67 (m, 6H), 3.65 - 3.45 (m, 5H), 3.45 - 3.33 (m, 2H), 3.24 - 3.13 (m, 2H), 2.68 (s, 1H), 2.23 (d, J= 2.0 Hz, 3H), 1.40 (s, 9H), 1.22 - 1.12 (m, 3H), 1.10 - 1.03 (m, 3H).Example 23.6: Synthesis of Compound 80

[0311] To a solution of tert-butyl 2-((2-(((47?)-2-(5-(3-ethoxy- 1 -(7-methoxy- 1 -methyl-1 H-bcnzo[d][ 1 ,2,3 ]triazol-5-yl)-3-oxopropyl)-2-mcthylbcnzyl)-4-mcthyl- 1 , 1 -dioxido-3,4- dihydro-2H-benzo[b] [ 1 ,4,5]oxathiazepin-7-yl)oxy)ethoxy)methyl)morpholine-4-carboxylate (250 mg, 298 μmo 1l.0, 0 eq) in dichloromethane (1.00 mL) was added concentrated hydrochloric acid hydrochloric acid (4 M in dioxane) (4 M, 224 μL, 3.00 eq) at 16 °C. The mixture was stirred at 25 °C for 2 h. Remove the solvent on a rotary evaporator. The crude compound was used into the next step without further purification. Ethyl 3-(7-methoxy-l-methyl-177- benzo[d][l,2,3]triazol-5-yl)-3-(4-methyl-3-(((4E)-4-methyl-7-(2-(morpholin-2- ylmethoxy)ethoxy)- 1 , 1 -dioxido-3,4-dihydro-2H-benzo[b] [ 1 ,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoate (230 mg, 297 99.6μ%m yoile,ld, hydrochloric acid) was obtained as a white solid.Example 23.7: Synthesis of Compound 81

[0312] To a solution of ethyl 3-(7-methoxy-1 -methyl-l77-benzo[d][l ,2,3]triazol-5-yl)- 3-(4-mcthyl-3-(((47?)-4-mcthyl-7-(2-(morpholin-2-ylmcthoxy)cthoxy)-l,l-dioxido-3,4-dihydro- 2H-benzo[b][ 1,4,5 ]oxathiazepin-2-yl)methyl)phenyl)propanoate (172 mg, 222 1.00 eq, μmol, hydrochloric acid) in dimethylformamide (5.00 mL) was added (R )-2-(((4-((17?,5S)-8-(tert- butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-l- methylpyrrolidine-2-carboxylic acid (200 mg, 222 1.00μ emqo),l, O-(7-azabenzotriazol-l-yl)- / V.MA^-lctranicthyluroniumhcxanuorophosphatc (127 mg, 333 1.50μm eqo)l, and N,N- diisopropylethylamine (86.0 mg, 666 116μm μLo,l, 3.00 eq) at 20°C. The mixture was stirred at 20 °C for 16 h. The mixture was poured into water (20.0 mL), separated the organic phase and the aqueous phase was extracted with ethyl acetate (10.0 mL x 3). The organic layers were combined and washed with brine (10.0 mL), dried over anhydrous sodium sulphate, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-80% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Tert-butyl (lT,5S)-3-(2-(((27?)-2-(2-((2-(((4T)-2-(5-(3-ethoxy-l-(7-methoxy-l-methyl-17T benzo[d][l,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl-l,l-dioxido-3,4-dihydro- 27 / -bcnzo[b| [1,4,5 ]oxathiazepin-7-yl)oxy)ethoxy)methyl)morpholine-4-carbonyl)-l- methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (260 mg, 160 72.3% yieμlmd)o wl,as obtained as a white solid.1H NMR (400 MHz, DMSO-de) δ = 9.17 (s, 1H), 8.10 (dd, J= 5.6, 8.8 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 2.8, 8.4 Hz, 1H), 7.56 (t, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.34 (s, 2H), 7.29 - 7.23 (m, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.95 - 6.84 (m, 3H), 5.36 (s, 2H), 4.78 - 4.55 (m, 4H), 4.45 - 4.18 (m, 11H), 3.98 - 3.74 (m, 10H), 3.65 - 3.56 (m, 2H), 3.33 (s, 16H), 3.23 - 3.13 (m, 2H), 3.03 - 2.92 (m, 2H), 2.38 (s, 3H), 2.22 (d, 7= 2.4 Hz, 3H), 1.96 - 1.77 (m, 5H), 1.45 (s, 9H), 1.20 - 1.15 (m, 4H), 0.80 (t, 7 - 7.2 Hz, 18H), 0.57 - 0.40 (m, 3H).Example 23.8: Synthesis of Compound P- 15P-15

[0313] To a solution of tert-butyl (17?,5S)-3-(2-(((27?)-2-(2-((2-(((47?)-2-(5-(3-ethoxy-1 -(7-methoxy- 1 -methyl- 1H-benzo[d][l , 2, 3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4- methyl-l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-7- yl)oxy)ethoxy)methyl)morpholine-4-carbonyl)-l-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 154 1.00 eq) inμmol, dimethylformamide (2.00 mL) was added cesium fluoride (234 mg, 1.54 mmol, 56.9 μL, 10.0 eq) at 16 °C. The mixture was stirred at 20 °C for 30 min. The mixture was poured into water (10.0 mL), the white solid was filtered with suction and washed with 50.0 mL of ethyl acetate. The crude compound was used into the next step without further purification. Tert-butyl ( lS,57?)-3- [2- [[(27?)-2-[2-[2-[[(47?)-2-[[5-[3-ethoxy-l-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methy 1] -4-methyl- 1 , 1 -dioxo-3 ,4-dihy dro-5 , 1 ,2-benzoxathiazepin-7 - yl]oxy]ethoxymethyl]morpholine-4-carbonyl]-l-methyl-pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)- l-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octanc-8-carboxylatc (225 mg, crude) was obtained as a yellow solid.

[0314] To a solution of tert-butyl (lS,5R)-3-[2-[[(2R)-2-[2-[2-[[(4E)-2-[[5-[3-ethoxy- l-(7-methoxy-l-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl- l,l-dioxo-3,4-dihydro-5,l,2-benzoxathiazepin-7-yl]oxy]ethoxymethyl]morpholine-4-carbonyl]- l-methyl-pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8- fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 150 μmol, 1.00 eq) in dichloromethane (1.00 mL) was added hydrochloric acid (4 M in dioxane) (4 M, 0.500 mL, 13.3 eq) at 16 °C. The mixture was stirred at 16 °C for 30 min. Remove the solvent on a rotary evaporator. The residue was purified by prep-HPLC (Column: Welch ultimate Cl 8 150*25mm* 7um; Condition: water(FA)-ACN; B%: 20%-50%; FlowRate(ml / min): 25.) to give desired compound. Ethyl 3-(3-(((4R)-7-(2-((4-((E)-2-(((4-((17?,55)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)-l-methylpyrrolidine-2-carbonyl)morpholin-2-yl)methoxy)ethoxy)-4-methyl-l,l- dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7- methoxy-l-methyl-lH-benzo[d][l,2,3]triazol-5-yl)propanoate (103 mg, 77.3 51.44% yieμldm, ol, 99% purity) was obtained as a white solid. MS (ESI) m / z 1321 [M+H]+.1H NMR (400 MHz, DMSO-ifc) δ = 10.57 - 9.87 (m, 1H), 9.04 (s, 1H), 8.16 (s, 1H), 7.97 (dd, J= 5.8, 9.2 Hz, 1H), 7.65 (dd, J = 3.2, 8.4 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.39 (d, J = 2.4 Hz, 1H), 7.33 (s, 1H), 7.29 - 7.23 (m, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.94 - 6.85 (m, 3H), 4.73 - 4.62 (m, 2H), 4.55 - 4.48 (m, 2H), 4.37 (d, J = 13.6 Hz, 2H), 4.32 (d, J = 2.4 Hz, 3H), 4.20 (s, 2H), 3.97 - 3.89 (m, 6H), 3.88 - 3.82 (m, 1H), 3.78 (s, 3H), 3.73 (d, J= 9.2 Hz, 3H), 3.68 - 3.49 (m, 8H), 3.20 - 3.14 (m, 3H), 3.05 - 2.91 (m, 3H), 2.82 - 2.66 (m, 2H), 2.36 (s, 3H), 2.21 (d, J = 2.4 Hz, 3H), 2.20 - 2.11 (m, 2H), 1.98 - 1.88 (m, 2H), 1.73 (s, 4H), 1.19 - 1.06 (m, 3H), 1.03 (t, J = 7.2 Hz, 3H).Example 24: Preparation of Compound 87Example 24,1: Synthesis of Compound 83

[0315] To a solution of 4-bromo-2-fluoro-benzenesulfonyl chloride (10.0 g, 36.6 mmol, 1.00 eq) in tetrahydrofuran (80.0 mL) and water (20.0 mL) was added potassium (5.05 g, 36.6 mmol, 1.00 eq) and (27?)-l-aminopropan-2-ol (2.75 g, 36.6 mmol, 2.88 mL, 1.00 eq) at 20°C. The mixture was stirred at 20°C for 1 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified bycolumn chromatography (silicon dioxide, petroleum ether / ethyl acetate = 3 / 1 ) to give (R )-4- bromo-2-fluoro-7V-(2-hydroxypropyl)bcnzcncsulfonamidc (10.8 g, 34.60 mmol, 94.63% yield) as a white solid. (400 MHz, DMSO-rfe)= 7.98 (br s, 1H), 7.84 (dd, 7= 2.0, 9.6 Hz, 1H), 7.77 - 7.66 (m, 1H), 7.62 (dd, 7 = 1.6, 8.4 Hz, 1H), 4.68 (d, 7 = 4.8 Hz, 1H), 3.68 - 3.49 (m, 1H), 2.91 - 2.68 (m, 2H), 0.98 (d, 7 = 6.2 Hz, 3H).Example 24,2: Synthesis of Compound 84

[0316] To a solution of (R )-4-bromo-2-fluoro-Ar-(2- hydroxypropyl)benzenesulfonamide (4.50 g, 14.4 mmol, 1.00 eq) in dimethylsulfoxide (60.0 mL) was added potassium terLbutoxide (4.85 g, 43.3 mmol, 3.00 eq). The mixture was stirred at 100°C for 1 h. The mixture was poured into water (300 mL) and extracted with ethyl acetate (100 mLx3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 3 / 1) to give (R )-7-bromo-4-methyL3,4-dihydro-277- benzo[Z?][l,4,5]oxathiazepine 1,1-dioxide (1.70 g, 5.82 mmol, 40% yield) as a yellow solid. MS (ESI) m / z 293.8 [M+H]+.Example 24,3: Synthesis of Compound 85

[0317] To a solution of (R)-7-bromo-4-methyl-3,4-dihydro-277- benzo[£>][l,4,5]oxathiazepine 1,1-dioxide (520 mg, 1.78 mmol, 1.00 eq) in 2-methylbutan-2-ol (10.0 mL) was added XantPhos Pd G3 (169 mg, 178 μmol, 0.100 eq), sodium tert-butoxide (513mg, 5.34 mmol, 3.00 eq) and tert-butyl piperazine- 1 -carboxylate (497 mg, 2.67 mmol, 1.50 eq). The mixture was stirred at 90°C for 16h. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (50.0 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl (R )-4-(4-methyl-l,l-dioxido-3,4-dihydro-2 / / -benzo[&][l,4,5]oxathiazepin-7- yl)piperazine- 1 -carboxylate (400 mg, 996. 56% yμimelodl,, 99% purity) as a yellow solid. MS (ESI) m / z 397.9 [M+H]+.Example 24,4: Synthesis of Compound 86

[0318] To a solution of ethyl 3-[3-(hydroxymethyl)-4-methyl-phenylJ-3-(7-methoxy- l-methyl-benzotriazol-5-yl)propanoate (340 mg, 887 pmol. 1.00 eq) in dichloromethane (10.0 mL) was added SOC12 (527 mg, 4.43 mmol, 322 μL, 5.00 eq). The mixture was stirred at 20°C for 0.5 h. The mixture was quenched by adding sat. sodium carbonate (50.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic layer was concentrated under vacuum to give ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate as a yellow oil. To a solution of tert-butyl (R )-4-(4-methyl-l,l-dioxido-3,4-dihydro-2 / / - benzo[&][l, 4, 5]oxathiazepin-7-yl)piperazine-l -carboxylate (110 mg, 277 1.00 eq)μ imnol, acetonitrile (1.00 mL) was added potassium carbonate (115 mg, 830 3.00 eq) andμ emthoyl,l 3- [3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (133 mg, 332 μmol, 1.20 eq). The mixture was stirred at 80°C for 3 h. The mixture was filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl 4-((47?)-2-(5-(3-ethoxy-l- (7 -methoxy- 1 -methyl- 1 / / -benzo [d] [ 1 ,2,3] triazol-5 -yl)-3-oxopropyl)-2-methy lbenzyl)-4-methyl-1 ,1 -dioxido-3,4-dihydro-277-benzo[ / ?][ 1 ,4,5]oxathiazepin-7-yl)piperazine-l -carboxylate (170 mg,223 μmol, 80% yield) as a yellow oil. MS (ESI) m / z 763.5 [M+H]+.Example 24.5: Synthesis of Compound 87of tert-butyl 4-((4A)-2-(5-(3-ethoxy-l-(7-methoxy-l-methyl-lH- benzo[<7] [ 1 ,2, 3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4- methyl- 1 , 1 -dioxido-3,4-dihydro- 2 / / -bcnzo| / 7|| 1 ,4,5 |oxathiazcpin-7-yl)pipcrazinc- 1 -carboxylate (160 mg, 209 1.00 eq) in μmol, hydrochloric acid / dioxane (4.00 mL) was stirred at 20°C for 1 h. The mixture was concentrated under vacuum to give ethyl 3-(7-methoxy-l-methyl-177-benzo[<7][l,2,3]triazol-5-yl)-3-(4-methyl- 3-(((A)-4-methyl- 1 , 1 -dioxido-7 -(piperazin- 1 -yl)-3 ,4-dihydro-2 / 7-bcnzo| / ? | [ 1 ,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoate (140 mg, 196 93%μ ymieoldl,, 98% purity, hydrochloric acid salt) as a yellow solid. MS (ESI) m / z 663.2 [M+H]+.Example 25 : Preparation of Compounds P- 16 and P- 17

[0320] To a solution of methyl 6-chloropyridazine-3-carboxylate (4.50 g, 26.1 mmol, 1.00 eq) in dioxane (60.0 mL) was added ethyldiisopropylamine (6.74 g, 52.2 mmol, 9.08 mL, 2.00 eq) and 4-piperidylmethanol (6.01 g, 52.2 mmol, 2.00 eq). The mixture was stirred at 110°Cfor 16 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum cthcr / cthyl acetate = 0 / 1) to give methyl 6-(4-(hydroxymethyl)piperidin-l-yl)pyridazine-3-carboxylate (4.3 g, 17.11 mmol, 65.62% yield) as a white solid.1H NMR (400 MHz, DMSO-< / 6) S = 7.79 (d, J = 9.6 Hz, 1H), 7.27 (d, J = 9.6 Hz, 1H), 4.61 - 4.34 (m, 3H), 3.86 (s, 3H), 3.28 (t, J = 5.6 Hz, 2H), 3.09 - 2.90 (m, 2H), 1.86 - 1.62 (m, 3H), 1.27 - 0.99 (m, 2H).Example 25.2: Synthesis of Compound 90F0321] To a solution of 6-(4-(hydroxymethyl)piperidin-l-yl)pyridazine-3-carboxylate (2.00 g, 7.96 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL)and methanol (10.0 mL) was added dropwise lithium hydroxide monohydrate (668 mg, 15.9 mmol, 2.00 e< / )and in water (6.00 mL). The mixture was stirred at 20°C for 1 h. The mixture was concentrated. The pH of solution was adjusted to 3 with 2 M hydrochloric acid solution. The final solution was concentrated to give a residue. The residue was triturated with methanol (20.0 mL) at 20°C for 1 h. 6-(4- (hydroxymethyl)piperidin-l-yl)pyridazine-3-carboxylic acid (1.1 g, 4.64 mmol, 58.25% yield, 100% purity) was obtained as a white solid.1H NMR (400 MHz, DMSO-de) δ = 7.78 (d, J = 9.6 Hz, 1H), 7.27 (d, J = 9.6 Hz, 1H), 4.52 (br d, J = 13.2 Hz, 2H), 3.27 (br d, J = 5.6 Hz, 2H), 3.07 - 2.87 (m, 2H), 1.90 - 1.54 (m, 3H), 1.32 - 0.82 (m, 2H).Example 25.3: Synthesis of Compound 91cyano- phenoxy )cyclohexyl]carbamate (1.00 g, 2.85 mmol, 1.00 eq) in hydrochloric acid / dioxane (10 mL)was stirred at 20°C for 1 h under nitrogen atmosphere. The mixture was filtered. 4-(((l r,4r)-4- aminocyclohcxyl)oxy)-2-chlorobcnzonitrilc (880 mg, 2.54 mmol, 89.23% yield, 83% purity, hydrochloric acid salt) was obtained as a white solid. ’ H NMR (400 MHz, DMSO-tfc) δ = 8.25 (br d, J = 14.4 Hz, 3H), 7.84 (dd, J= 1.6, 8.8 Hz, 1H), 7.40 (s, 1H), 7.13 (dd, J = 2.0, 8.8 Hz, 1H),4.61 - 4.40 (m, 1H), 3.04 (br d, J = 4.4 Hz, 1H), 2.20 - 1.91 (m, 4H), 1.68 - 1.26 (m, 4H).

[0323] To a solution of 6-(4-(hydroxymethyl)piperidin-l-yl)pyridazine-3-carboxylic acid (500 mg, 2.11 mmol, 1.00 eq) in N,N- Di methyl formam ide (10.0 mL) was added O-(J- azabenzotriazol-l-yl)-MMM^V-tetramethyluroniumhexafluorophosphate (1.20 g, 3.16 mmol, 1.50 eq), ethyldiisopropylamine (817 mg, 6.32 mmol, 1.10 mL, 3.00 eq) and 4-(4-aminocyclohexoxy)- 2-chloro-benzonitrile (545 mg, 1.90 mmol, 0.900 eq, hydrochloric acid salt). The mixture was stirred at 20°C for 1 h. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (silicon dioxide, ethyl acetate) to give 2V-((lr,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-l-yl)pyridazine-3-carboxamide (950 mg, 2.02 mmol, 96% yield) as a yellow solid.1H NMR (400 MHz, DMSO-rid) δ = 8.57 (d, J = 8.0 Hz, 1H), 7.92 - 7.66 (m, 2H), 7.47 - 7.23 (m, 2H), 7.13 (dd, J= 2.4, 8.8 Hz, 1H), 4.52 - 4.46 (m, 3H), 3.94 - 3.76 (m, 1H), 3.27 (br t, J = 5.6 Hz, 2H), 2.98 (br t, J = 12.0 Hz, 2H), 2.10 (br d, J = 10.4 Hz, 2H), 1.90 (br d, J = 10.4 Hz, 2H), 1.81 - 1.70 (m, 3H), 1.64 (br d, J = 13.2 Hz, 2H), 1.51 (br d, J= 12A Hz, 2H), 1.22 - 1.03 (m, 3H).Example 25.4: Synthesis of Compound 92

[0324] To a solution of jV-((l r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4- (hydroxymcthyl)pipcridin-l-yl)pyridazinc-3-carboxamidc (500 mg, 1.06 mmol, 1.00 eq} in dichloromethane (10.0 mL) was added Dess-Martin periodinane (903 mg, 2.13 mmol, 659 μL, 2.00 eq} at 0°C. The mixture was stirred at 20°C for 1.5 h. The mixture was quenched by adding sat. sodium sulfite (10.0 mL) and extracted with dichloromethane (50 mL x 2). The organic layer was concentrated to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 3 / 1) to give 7V-((lr,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-l-yl)pyridazine-3-carboxamide (350 mg, 748 μmol, 70.30% yield) as a yellow solid.1H NMR (400 MHz, DMSO-rfc) δ = 9.62 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 9.2, 15.2 Hz, 2H), 7.49 - 7.29 (m, 2H), 7.13 (dd, J = 2.4, 8.8 Hz, 1H), 4.62 - 4.44 (m, 1H), 3.93 - 3.77 (m, 1H), 3.31 - 3.20 (m, 4H), 2.72 - 2.64 (m, 1H), 2.10 (br d, J= 10.4 Hz, 2H), 1.96 - 1.86 (m, 4H), 1.64 (br d, J= 13.2 Hz, 2H), 1.57 - 1.46 (m, 4H).Example 25.5: Synthesis of Compound P-16

[0325] To a solution of 2V-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4- formylpiperidin-l-yl)pyridazine-3 -carboxamide (85 mg, 181.64 1 eq)μ amnodl, ethyl 3-(7- methoxy-1 -methyl- l / 7-benzo[t / || 1 ,2,3]triazol-5-yl)-3-(4-methyl-3-(((R )-4-methyl- 1 ,l-dioxido-7- (piperazin-l-yl)-3,4-dihydro-2H-benzo[Z?][l,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (127 mg, 182 μmol 1, .00 eq, hydrochloric acid salt) in tetrahydrofuran (2.00 mL) was added sodium acetate (44.7 mg, 545 3.μ0m0 o elq,} and acetic acid (32.7 mg, 545 31.2 μL, 3.00 μmol, eq}. The mixture was stirred at 20°C for 30 min. Then sodium triacetoxyhydroborate (77.0 mg,363 μmol, 2.00 eq) was added and stirred at 20°C for 1.5 h. The mixture was filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:33%-63% B over 10 min) and lyophilized to afford ethyl 3-(3-(((R )-7-(4-((l-(6-(((lr,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazin-l-yl)-4- methyl-1 , l -dioxido-3.4-dihydro-2 / / -bcnzo| / ?|| 1 ,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)- 3-(7-methoxy- 1 -methyl- 1 A / - benzol <71| 1 ,2,3 ]triazol-5-yl)propanoate (60 mg, 52.8 μmol, 29 % yield, 98% purity) as a white solid. MS (ESI) m / z 1114.3 [M+H]+. ’H NMR (400 MHz, DMSO- d&) d = 8.60 (d, J = 8.4 Hz, 1H), 7.91 - 7.73 (m, 2H), 7.51 (dd, 7 = 3.2, 8.8 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.30 - 7.23 (m, 1H), 7.18 - 7.06 (m, 2H), 6.92 (d, J = 10.8 Hz, 1H), 6.84 - 6.76 (m, 1H), 6.74 (s, 1H), 4.61 - 4.44 (m, 4H), 4.41 - 4.25 (m, 5H), 4.02 - 3.89 (m, 5H), 3.89 - 3.80 (m, 1H), 3.71 (br d, J = 13.8 Hz, 1H), 3.62 - 3.47 (m, 2H), 3.27 - 3.13 (m, 4H), 3.03 (br t, J= 12.0 Hz, 2H), 2.74 - 2.60 (m, 1H), 2.49 - 2.44 (m, 4H), 2.30 - 2.17 (m, 5H), 2.10 (br d, J = 10.4 Hz, 2H), 2.00 - 1.78 (m, 5H), 1.64 (br d, J = 12.8 Hz, 2H), 1.51 (br d, J = 12.0 Hz, 2H), 1.29 - 0.99 (m, 9H).

[0326] To a solution of ethyl 3-(3-(((R )-7-(4-((l-(6-(((l r,4r)-4-(3-chloro-4- cyanophcnoxy)cyclohcxyl)carbamoyl)pyridazin-3-yl)pipcridin-4-yl)mcthyl)pipcrazin-l-yl)-4- methyl-1, l -dioxido-3.4-dihydro-2 / / -bcnzo| / ?|| l,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)- 3-(7-methoxy-l-methyl-l / / -benzo[d][l,2,3]triazol-5-yl)propanoate (40.0 mg, 35.9 1.00 eq) μmol, in water (0.400 mL) and tetrahydrofuran (2.00 mL) was added lithium hydroxide monohydrate (4.52 mg, 108 μmo 3l.,00 eq). The mixture was stirred at 40°C for 1 h. The pH of mixture was adjusted to 3. The mixture was extracted with ethyl acetate (5.00 mL). The organic layer was concentrated under vacuum to give a residue. The residue was purified by p / cp-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:25%-55% B over 8 min) and lyophilized to afford 3-(3-(((R )-7-(4-((l-(6-(((lr,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazin-l-yl)-4- methyl- 1 , 1 -dioxido-3,4-dihydro-27 / -benzo[Z>] [ 1 ,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)- 3-(7-methoxy-l-methyl-177-benzo[7][l,2,3]triazol-5-yl)propanoic acid (28.64 mg, 25.85 μmol, 72.05% yield, 98.1% purity) as a white solid. MS (ESI) m / z 1086.4 [M+H]+.1H NMR (400 MHz, DMSO-76) δ = 12.36 - 11.81 (m, 1H), 8.60 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 9.2, 19.8 Hz, 2H), 7.51 (dd, 7 = 2.0, 8.8 Hz, 1H), 7.45 (d, 7 = 4.0 Hz, 1H), 7.39 (d, 7 = 2.0 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.27 (br t, 7 = 6.8 Hz, 1H), 7.17 - 7.06 (m, 2H), 6.91 (d, 7 = 9.8 Hz, 1H), 6.80 (br d, 7 = 8.8 Hz, 1H), 6.75 (br s, 1H), 4.61 - 4.45 (m, 4H), 4.44 - 4.25 (m, 5H), 3.92 (d, 7 = 4.4 Hz, 3H), 3.88 - 3.80 (m, 1H), 3.71 (br d, 7 = 13.6 Hz, 1H), 3.61 - 3.47 (m, 2H), 3.19 - 2.89 (m, 5H), 2.81 - 2.57 (m, 2H), 2.50 (br s, 4H), 2.23 (br d, 7= 3.6 Hz, 5H), 2.13 - 2.04 (m, 2H), 2.02 - 1.78 (m, 5H), 1.72 - 1.43 (m, 4H), 1.26 - 0.98 (m, 6H).Example 26: Preparation of Compound 96Example 26.1: Synthesis of Compound 9316 93

[0327] To a solution of (R )-7-hydroxy-4-methyl-3,4-dihydro-2H- benzo[£>][l,4,5]oxathiazepine 1,1-dioxide (600 mg, 2.62 mmol, 1.00 eq) in dimethylformamide (10.0 mL) was added 4-bromobutoxy-tert-butyl-dimethyl-silane (560 mg, 2.09 mmol, 0.800 eq) and potassium carbonate (723 mg, 5.23 mmol, 2.00 eq) at 30°C. The mixture was stirred at 30°C for 16 h. The mixture was poured into water (100 mL), separated the organic phase and the aqueous phase was extracted with ethyl acetate (50.0 mLx3). The organic layers were combined and washed with brine (20.0 mL), dried over anhydrous sodium sulphate and concentrated to givea residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-12% Ethyl acctatc / Pctrolcum ether gradient @ 40 mL / min). ( / ?)- 7-(4-((tert-butyldimethylsilyl)oxy)butoxy)-4-methyl-3,4-dihydro-2H- benzo[Z>][l,4,5]oxathiazepine 1,1 -dioxide (480 mg, 1.11 mmol, 42% yield, 96% purity) was obtained as a white oil.Example 26.2: Synthesis of Compound 94

[0328] To a solution of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-l- methyl- lH-benzo[d][ l,2,3]triazol-5-yl)propanoate (300 mg, 782 μmol, 1.00 eq) in dichloromethane (3.00 mL) was added thionyl chloride (465 mg, 3.91 mmol, 284 μL, 5.00 eq) at 0°C under N2. The mixture was stirred at 25°C for 10 min. The mixture was poured into ice. sodium bicarbonate (50.0 mL) to adjusted to PH=3, separated the organic phase and the aqueous phase was extracted with ethyl acetate (30.0 mLx3). The organic layers were combined and washed with brine (20.0 mL), dried over anhydrous sodium sulphate and concentrated to give a residue. The crude compound was used into the next step without further purification. Ethyl 3- [3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-l-methyl-benzotriazol-5-yl)propanoate (300 mg, crude) was obtained as a yellow oil.

[0329] To a solution of ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-l- methyl-benzotriazol-5-yl)propanoate (300 mg, 747 μ 1.m00ol, eq) and (R )-7-(4-((tert- butyldimethylsilyl)oxy)butoxy)-4-methyl-3,4-dihydro-2H-benzo[ / j][ 1,4,5 ]oxathiazepine 1,1- dioxide (310 mg, 746 μm 1o.0l,0 eq) in acetonitrile (6.00 mL) was added potassium carbonate (206 mg, 1.49 mmol, 2.00 eq) at 25°C. The mixture was stirred at 40°C for 16 h. The mixture was poured into water (100 mL), separated the organic phase and the aqueous phase was extracted with ethyl acetate (50.0 mLx3). The organic layers were combined and washed with brine (50.0 mL), dried over anhydrous sodium sulphate and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-13% Ethyl acctatc / Pctrolcum ether gradient @ 40 mL / min). Ethyl 3-(3-(((E)-7-(4-((tcrt- butyldimethylsilyl)oxy)butoxy)-4-methyl-l,l-dioxido-3,4-dihydro-2H- benzo[Z>][l,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy-l-methyl-lH- benzo[d][l,2,3]triazol-5-yl)propanoate (400 mg, 512.14 68.61%μm yoiell,d) was obtained as a white oil.

[0330] To a solution of Ethyl 3-(3-(((E)-7-(4-((tert-butyldimethylsilyl)oxy)butoxy)-4- methyl-1 , l -dioxido-3.4-dihydro-2 / / -bcnzo| / ?|| 1 ,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)- 3-(7-methoxy- 1 -methyl- 1 H-benzo[ri][ 1 ,2,3 ]triazol-5-yl)propanoate (300 mg, 384 1.00 eq) μmol, in dichloromethane (3.00 mL) was added concentrated hydrochloric acid hydrochloric acid (2 M in dioxane) (2 M, 900 μL, 4.69 eq) at 25°C. The mixture was stirred at 25 °C for 15 min. The mixture was poured into water (40.0 mL), separated the organic phase and the aqueous phase was extracted with dichloromethane (20.0 mLx3). The organic layers were combined and washed with brine (20.0 mL), dried over anhydrous sodium sulphate and concentrated to give a residue. The crude compound was used into the next step without further purification. Ethyl 3-(3-(((E)-7-(4- hydroxybutoxy )-4-methyl- 1 , 1 -dioxido-3,4-dihydro-2H-benzo[ b ] [ 1 ,4,5]oxathiazepin-2- yl)methyl)-4-methylphenyl)-3-(7-methoxy- 1 -methyl- 1 H-benzo[d][ 1 ,2,3 ]triazol-5-yl)propanoate (250 mg, crude) was obtained as a yellow oil.Example 26.4: Synthesis of Compound 9695 96

[0331] To a solution of ethyl 3-(3-(((R )-7-(4-hydroxybutoxy)-4-methyl-l,l-dioxido-3.4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy-l- methyl- lH-benzo[d][ l,2,3]triazol-5-yl)propanoate (250 mg, 375 μ 1m.0o0l, eq) in dichloromethane (4.00 mL) was added 4-methylbenzenesulfonyl chloride (143 mg, 750 pmol, 2.00 eq), triethylamine (114 mg, 1.12 mmol, 157 μL, 3.00 eq) and 4-dimethylaminopyridine (2.29 mg, 18.8 μmol, 0.0500 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was poured into water (50.0 mL), separated the organic phase and the aqueous phase was extracted with ethyl acetate (20.0 mLx3). The organic layers were combined and washed with brine (20.0 mL), dried over anhydrous sodium sulphate and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ether gradient @ 20 mL / min). Ethyl 3-(7-methoxy-l-methyl-lH- benzo[d][L2,3]triazol-5-yl)-3-(4-methyl-3-(((R )-4-methyl-l,l-dioxido-7-(4-(tosyloxy)butoxy)-3.4-dihydro-2H-benzo[Z>][l,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (200 mg, 244 pmol, 64.9% yield) was obtained as a white oil.1H NMR (400 MHz, DMSO-de) d - 7.81 (d, J— 8.0 Hz, 2H), 7.65 (dd, J = 2.8, 8.8 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.39 - 7.22 (m, 2H), 7.11 (d, J = 7.6 Hz, 1H), 7.01 - 6.77 (m, 3H), 4.62 - 4.25 (m, 6H), 4.17 - 3.86 (m, 9H), 3.76 (d, J= 14.0 Hz, 1H), 3.66 - 3.54 (m, 1H), 3.22 - 3.13 (m, 2H), 2.68 (s, 1H), 2.42 (s, 2H), 2.23 (d, J = 1.6 Hz, 2H), 1.99 (s, 2H), 1.73 (s, 4H), 1.24 - 0.99 (m, 7H).Example 27 : Preparation of Compounds P- 18 and P- 19

[0332] To a solution of 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-l-yl)-2-(trifluoromcthyl)bcnzo nitrile (1.00 g, 2.47 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added Tf-acid anhydride (835 mg, 2.96 mmol, 488 μL, 1.2 Qeq) and triethylamine (739 mg, 7.30 mmol, 1.02 mL, 2.96 eq) at 0°C under N2. The mixture was stirred at 0°C for 1 h under N2. The mixture was poured into water (100 mL), separated the organic phase and the aqueous phase was extracted with dichloromethane (50.0 mLx3). The organic layers were combined and washed with brine (50.0 mL), dried over anhydrous sodium sulphate and concentrated to give a residue. The crude compound was used into the next step without further purification. 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)phenyl trifluoromethanesulfonate (1.6 g, crude) was obtained as a red solid.98 99

[0333] To a solution of 4-(3-(4-cyano-3-(trifhioromcthyl)phcnyl)-5,5-dimcthyl-4-oxo- 2-thioxoimidazolidin-l-yl)phenyl trifluoromethanesulfonate (500 mg, 930 1.00 eqμ) m inol, dioxane (10.0 mL) was added (4-hydroxyphenyl)boronic acid (192 mg, 1.40 mmol, 1.50 eq), tetrakis[triphenylphosphine]palladium(0) (86.0 mg, 74.4 0.08μ0m0ol e,q) and potassium phosphate (584 mg, 2.75 mmol, 2.96 eq) at 25°C under N2. The reaction vessel was sealed and heated in microwave at 90 °C for 1 h. The mixture was poured into water (100 mL), separated the organic phase and the aqueous phase was extracted with ethyl acetate (50.0 mLx3). The organic layers were combined and washed with brine (20.0 mL), dried over anhydrous sodium sulphate and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ethergradient @ 40 mL / min). 4-(3-(4'-hydroxy-[l,l'-biphenyl]-4-yl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-l-yl)-2-(trifluoromethyl)benzo nitrile (180 mg, 373.84 40.18% yμimeldo)l, was obtained as a red solid. ’H NMR (400 MHz, DMSO-de) δ = 9.65 (s, 1H), 8.40 (d, J = 8.4 Hz,1H), 8.32 (d, J= 1.6 Hz, 1H), 8.1 1 (dd, J= 1.6, 8.4 Hz, 1H), 7.77 (d, 7= 8.4 Hz, 2H), 7.58 (d, J = 8.8Hz, 2H), 7.41 (d, J= 8.4 Hz, 2H), 6.91 - 6.86 (m, 2H), 1.55 (s, 6H).Example 27,3: Synthesis of Compound P-18P-18

[0334] To a solution of 4-(3-(4'-hydroxy-[l,T-biphenyl]-4-yl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-l-yl)-2-(trifluoromethyl)benzo nitrile (35.2 mg, 73.1 1.50 μ emqo) l, in dimethylformamide (1.00 mL) was added ethyl 3-(7-methoxy-l-methyl-lH- benzo[t / ] [ 1 ,2,3]triazol-5-yl)-3-(4-methyl-3-(((R )-4-methyl- 1 , 1 -dioxido-7 -(4-( tosyloxy)butoxy )- 3,4-dihydro-2H-benzo[Z?][l,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (40.0 mg, 48.7 μmol, 1.00 eq) and potassium carbonate (13.5 mg, 97.5 μmol, 2.00 eq) at 25°C. The mixture was stirred at 60°C for 16 h. The mixture was poured into water (100 mL), separated the organic phaseand the aqueous phase was extracted with ethyl acetate (50.0 mLx3). The organic layers were combined and washed with brine (50.0 mL), dried over anhydrous sodium sulphate, and concentrated to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex luna C18 150*25mm* lOum; Condition: water(FA)-ACN; B%: 31%-61%; FlowRate(ml / min): 25.) to give desired compound. Ethyl 3-(3-(((R)-7-(4-((4'-(3-(4-cyano-3-(trifhioromethyl)phenyl)- 5,5-dimethyl-4-oxo-2-thioxoimidazolidin- 1 -yl)-[ 1 , 1 '-biphenyl] -4-yl)oxy )butoxy)-4-methyl- 1,1- dioxido-3,4-dihydro-2H-benzo[Z>][ 1 ,4,5 ]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7- methoxy- 1 -inethyl- 17 / -bciizo[<7|[ l,2,3]triazol-5-yl)propanoate (12.99 mg, 11.26 23.12% μmol, yield, 98% purity) was obtained as an off-white solid. MS (ESI) m / z 1130.5 [M+H]+.NMR (400 MHz, DMSO-de) δ = 8.41 (d, J= 8.4 Hz, 1H), 8.33 (d, J= 1.6 Hz, 1H), 8.11 (dd, J= 1.6, 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.75 - 7.63 (m, 3H), 7.50 - 7.41 (m, 3H), 7.35 (d, J = 2.4 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.15 - 7.04 (m, 3H), 6.97 - 6.84 (m, 3H), 4.53 (s, 1H), 4.47 - 4.28 (m, 5H), 4.15 (d, J= 16.8 Hz, 4H), 4.02 - 3.88 (m, 5H), 3.77 (d, J= 14.0 Hz, 1H), 3.69 - 3.52 (m, 1H), 3.26 - 3.10 (m, 2H), 2.82 - 2.65 (m, 1H), 2.23 (d, J = 2.4 Hz, 3H), 1.93 (s, 4H), 1.55 (s, 6H), 1.28 - 1.16 (m, 2H), 1.11 - 1.01 (m, 4H).Example 27.4: Synthesis of Compound P- 19P-19

[0335] To a solution of ethyl 3-(3-(((R )-7-(4-((4'-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-[l,T-biphenyl]-4- yl)oxy)butoxy)-4-methyl-l ,l-dioxido-3,4-dihydro-2H-benzo[b][ 1 ,4,5]oxathiazepin-2-yl)methyl)- 4-methylphenyl)-3-(7 -methoxy- l-methyl-l / / -benzo[d] [1,2, 3]triazol-5-yl)propanoate (40.0 mg, 35.4 μmol, 1.00 eq) in water (0.4 mL), tetrahydrofuran (1.20 mL) and methanol (0.4 mL) was added lithium hydroxide monohydratc (4.46 mg, 106 3.00 eqμ)m aotl 2, 0°C. The mixture was stirred at 30°C for 4 h. The mixture was poured into water (10.0 mL) and adjusted to PH=3 with hydrochloric acid, separated the organic phase and the aqueous phase was extracted with ethyl acetate (10.0 mLx3). The organic layers were combined and washed with brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by prep-HPLC (ColummPhenomenex luna C18 150*25mm* lOum; Condition: water(FA)-ACN;B%: 65%-95%; FlowRate(ml / min): 25.) to give desired compound. 3-(3-(((R)-7-(4-((4'-(3-(4- cyano-3-(trifluoromcthyl)phcnyl)-5,5-dimcthyl-4-oxo-2-thioxoimidazolidin-l-yl)-[l,r- biphenyl]-4-yl)oxy)butoxy)-4-methyl-l,l-dioxido-3,4-dihydro-2H-benzo[Z>][l,4,5]oxathiazepin- 2-yl)methyl)-4-methylphenyl)-3-(7-methoxy-l-methyl-l / / -benzo[7][l,2,3]triazol-5-yl)propanoic acid (22.68 mg, 18.96 μ 5m3o.5l,8% yield, 96% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1102.4 [M+H]+. ‘H NMR (400 MHz, DMSO-d6) d = 12.38 - 11.95 (m, 1H), 8.46 - 8.25 (m, 2H), 8.10 (dd, 7= 1.6, 8.4 Hz, 1H), 7.84 - 7.64 (m, 5H), 7.45 - 7.24 (m, 5H), 7.14 - 7.05 (m, 3H), 6.94 - 6.85 (m, 3H), 4.53 - 4.31 (m, 6H), 4.14 (d, J = 16.8 Hz, 4H), 3.92 (d, J = 5.2 Hz, 3H), 3.76 (d, J= 14.0 Hz, 1H), 3.67 - 3.47 (m, 1H), 3.09 (dd, J = 4.4, 7.6 Hz, 2H), 2.89 (s, 1H), 2.80 - 2.64 (m, 2H), 1.92 (s, 4H), 1.54 (s, 6H), 1.17 (d, J= 6.4 Hz, 2H), 1.07 (d, J= 6.4 Hz, 2H).Example 28: TR-FRET Assay

[0336] Compounds were screened to determine compounds that can promote interactions between two non-interacting proteins (Biotinylated-Keapl and His-tagged KRAS). Compounds were dissolved in DMSO to prepare 10 mM stock concentrations. Compounds were diluted and 200 nL of the compounds were transferred to a 384- well plate to be assayed. An assay buffer (25 mM HEPES, 100 mM NaCl, 0.05% BS A0.1 % Tween20) was prepared. For the assay, equal volumes of 5x His-KRAS (200 nM) and 5x Biotin-Keapl (40 nM) were mixed and 4 μL of the resulting mixture were transferred each well in the 384- well plate. An additional 2 μL of buffer was added to make the total volume 6 μL. The plate was incubated at room temperature (~ 25°C) for Ih. lOOx Streptavidin-Eu cryptate (Eu) and lOOx Mab Anti 6HIS-d2 (d2) were diluted to 5x using assay buffer. Equal volumes of 5x d2 and 5x EU were mixed and 4 μL was dispensed to the entire plate. The plate was incubated room temperature (~ 25°C) for Ih and the plates were read. The results are shown in Table 1.Table 1

[0337] An additional assay was performed to assess the effect of compounds in promoting interactions between Biotinylated-KEAPl and His-tagged-KRAS (His6-KRas). In an assay buffer containing 20 mM HEPES, 140 mM KC1 and LANCE® Detection Buffer (Revvity), 50 nM of biotinylated KEAP1 and 50 nM of His6-KRAS were mixed. After dispensing the assay mixture (12 μL volume), increasing concentrations of the compounds were dispensed in a 384- well microplate using a ThermoFisher Pico Digital Dispenser normalized to 1 % DMSO. The plate was incubated in the dark at room temperature for Ih and then mixed with 2 nM Eu-anti-his6 and 20 nM of Streptavidin labeled with ULight™ dye. The reactions were incubated for Ih at room temperature before TR-FRET measurements were conducted. After excitation of europium fluorescence, emission at 615 nm (europium) and 665 nm (ULight™ dye) were recorded with a 50 ps delay over 400 ps to reduce background fluorescence using an EnVision® 2105 microplate reader (Perkin Elmer). The TR-FRET signal of each data point was extracted by calculating the 665 nm / 615 nm ratio. Data was calculated as an average of three replicates.

[0338] The concentration-dependent response curve for compounds P-7 and P-9 is shown in Figure 1. As can be seen in Figure 1, both compounds P-7 and P-9 demonstrated an increase in FRET signal at concentrations above 1 pM indicating that P-7 and P-9 both promote the interaction of KE API and KRAS.Example 29: KRAS G12D Potency

[0339] Compounds were screened in HiBiT-KRasG12D cells in a dose dependent manner. 5000 AsPCl HiBiT KRASG12D cells (Promega) were seeded in a 96-well plate. The next day, the cells were treated with different concentrations (0.1 , 1, 5 and 10 pM) of compoundsfor six hours. Next, 1 pl Vivazine was added, and the plate was read after 2h using TEC AN at 445- 485 nm. The dose dependent response is depicted in Figure 2.Example 30: KRAS G12D Downregulation Rescue

[0340] KRAS G12D downregulation induced by Compound P-1 or its ester, Compound P-9, was rescued by pre-treatment of AsPCl HiBiT-KRasG12D cells with MLN4924 as assessed by luminescence monitoring. 5000 AsPCl HiBiTKRASG12D cells (Promega) were seeded in a 96- well plate. The next day, the cells were pre-treated with MLN4924 (5 p.M) for 211 and then with lOuM of compounds for six hours. Next, 1 ul Vivazine was added, and the plate read after 2h using TEC AN at 445-485 ran. The results are depicted in Figure 3 compared to the control (DMSO).

[0341] In an additional study, 500,000 cells / ml AsPCl HiBiT KRASG12D cells were seeded in 6 well plate. The next day, the cells were pre-treated with MLN4924 for 2h and then with lOuM of compounds for six hours. The cells were then collected and lysed in RIPA buffer, centrifuged and supernatants were collected. Cell lysates were probed for the indicated antibodies. The western blot is depicted in Figure 4 and showed that comparative Compound C-l, a compound sharing similar KRAS G12D warheads as in Compound P- l , but having a VHL recruitment module, showed enhanced KRAS G12D degradation as opposed to Compound P-l or its ester, Compound P-9. The structure of Compound C-l is:which is described in International Application Publication No. WO2022 / 148422, incorporated herein by reference in its entirety.Example 31 : Cell Fractionation

[0342] Cell fractionation of AsPCl HiBiT-KRasG12D revealed that most of KRASG12D downregulation induced by Compound P-1 or its ester, Compound P-9, is at the plasma membrane. 500,000 cells / ml AsPCl HiBiT KRASG12D cells were seeded in 10 cm dish. The next day, the cells were treated with lOuM of compounds for six hours. The cells were then collected and fractionated using Mem-PER™ Plus Membrane Protein Extraction Kit (thermofisher.com). Cytoplasm and membrane fractions were probed for the indicated antibodies. The results are depicted in Figure 5.Example 32: PROTAC Combinations

[0343] Additional studies were performed to assess the effect of a combination of PROTAC compounds described herein. In a 10 cm dish, 500,000 AsPCl HiBiT KrasG12D cells were seeded. The next day, cells were treated with different concentrations of compounds (0 pM, 1 pM, 2.5 pM, and 5 pM). The cells were then collected and fractionated using Mem-PER™ Plus Membrane Protein Extraction Kit (thermofisher.com) and membrane fractions were probed for the indicated antibodies. The results are indicated in Figure 6A. While Compound P-9 had a modest effect in inducing KRAS G12D degradation, Compound C-l, effectively promoted KRAS G12D degradation at a 1 pM concentration. Furthermore, a hook-effect for Compound C-l was observed at concentrations of 2.5 pM and 5 pM. Co-treatment of AsPCl HiBIT-KRAS G12D cells with Compound C-l and P-9 revealed a synergistic effect in promoting KRAS G12D degradation with no hook-effect detected.

[0344] In an additional study, 500,000 cells / mL of AsPCl HiBiT KRAS G12D cells were seeded in a 10 cm dish. The next day, the cells were incubated with Compound C-l for 0 pM, 1 pM and 5 pM for sixteen hours. In one set, Compound C-l was washed out, but kept in the other set. Both sets where then treated with 5 pM Compound P-9 for 4h, 8h or 16h. The cells were then collected and fractionated using Mem-PER™ Plus Membrane Protein Extraction Kit (thermofisher.com). Membrane fractions were probed for the indicated antibodies. The results are depicted in Figure 6B. The results are consistent with the above data in that co-treatment of AsPCl HiBiT-KRAS G12D cells with Compound C-l and Compound P-9 demonstrated a synergistic effect in promoting KRAS G12D degradation without a hook effect.Example 33: FLAG Immunoprecipitation

[0345] Lysate ubiquitylation of endogenous KRAS G12D was performed by incubating AsPCl HiBiT-KRAS G12D lysates with recombinant FLAG-Ubiquitin, along with El (UBE1), E2 (equal molar amount of Ubch3, Ubch5 and Ubch7) and ATP for 2h at 30 °C. Cell lysates were treated compounds at 10 pM and 100 pM. Reactions were stopped with 1% SDS and further immunoprecipitated via FLAG. Western blot analysis with anti-KRAS or Ubiquitin antibodies, as shown in Figure 7A, showed polyubiquitination increased when KRAS G12D lysates were treated with a combination of Compound C-l and Compound P-9.

[0346] In an additional study, cell lysates were treated with compounds at 10 pM and individual KRAS and Keap 1 binders were tested in combination with Compound C- 1. The results indicated that the combinatorial effect of Compound C-l and Compound P-9 in inducing KRAS G12D ubiquitylation is not due to some off target effect of the individual warheads. The results are shown in Figure 7B. Lysates from cells knocked out for VHL or KEAP1 showed no KRAS G12D ubiquitylation upon treatment.Example 34: Monitoring of Cell Populations in Pancreatic Cancer Cells

[0347] In a 10 cm dish, AsPCl HiBiT KrasG12D cells were seeded. The next day, cells were treated with different concentrations of Compound P-9 (0 pM, 0.5 pM, 1 pM, and 5 pM) and Compound C-l (0 pM, 0.5 pM, and 1 pM). Cell populations were measured every three days. As seen in Figure 8A, cell growth was substantially reduced by the combination of Compound P-9 and Compound C-L Figure 8B depicts the percentage decrease in colony numbers relative to the control.Example 35: AR Combination Potency

[0348] To address whether a KEAP1-PROTAC could alleviate the hook effect on a different target, additional studies were done using ARCC-4. ARCC-4 is a low-nanomolar androgen receptor (AR) PROTAC degrader based on VHL and employing enzalutamide as a recruiting warhead for AR. ARCC-4 is highly effective in inducing AR degradation at a concentration of 1 pM, but fails to degrade AR at doses of 0.1 pM. At higher concentrations of ARCC-4 of 20 pM, AR degradation was impaired indicating a hook effect. As seen in Figure 9A,both Compound P-16 and ARCC-4 exhibit moderate potency against AR compared to ARV-1 10 (bavdcgalutamidc).

[0349] Significantly, low dose combinations of Compound P-16 and ARCC-4 exhibit a synergistic effect for the degradation of AR without a hook effect as shown in Figure 9B demonstrating that the synergy between KEAP1 and VHL can be harnessed for targets beyond KRAS G12D. The combination of P-16 and ARCC-4 also demonstrated a synergistic effect in reducing cell growth in vivo as shown in Figure 10. Other KEAPl-based PROTACs linked to enzalutamide, such as Compounds P-17, P-18 and P-19, exhibited a similar synergistic effect in degrading AR as shown in Figure 11 A-F. In addition, Figures 11G and 11H show the synergistic effect in degrading AR of Compound P-16 with ARV- 110 (bavdegalutamide) in human prostate carcinoma epithelial cells (22RV1).

Claims

What is claimed is:

1. A method of treating cancer, comprising co-administcring to a patient in need thereof a first PROTAC compound that binds to a first ubiquitin ligase and promotes degradation of a target protein and a second PROTAC compound that binds to a second different ubiquitin ligase and promotes degradation of the target protein.

2. The method of Claim 1, wherein the target protein is Kras.

3. The method of Claim 1, wherein the target protein is AR.

4. The method of any one of Claims 1-3, wherein the first ubiquitin ligase is KEAP1.

5. The method of any one of Claims 1-4, wherein the first PROTAC Compound has the structure of Formula (I):wherein:A is a KEAP1 binder of Formula (II) having the structure:R1is H and R4isor R4is a substituted or unsubstituted C1-4 alkoxy and R1isor R4is a substituted or unsubstituted C1-4 alkoxy and R1is LR2is H or a substituted or unsubstituted C1-4 alkyl;R3is -CH2CO2R6;R5is H or a substituted or unsubstituted CIM alkyl;R6is H or a substituted or unsubstituted C1-4 alkyl;B is selected from the group consisting of Formulas (III-A), (III-B), and (III-C):R8is halogen;R9is -OR15;R10is halogen or C1-4 haloalkyl;R11is cyano;R14is H or a substituted or unsubstituted C1-4 alkyl;R15is H or a substituted or unsubstituted C1-4 alkyl;R16is H or a substituted or unsubstituted C1-4 alkyl; represents a single bond attachment to L; andL is a chemical linker, or a pharmaceu tic ally acceptable salt thereof.

6. The method of any one of Claims 1 to 5, wherein A is a KEAP1 binder of Formula (11-A):

7. The method of any one of Claims 1 to 5, wherein A is a KEAP1 binder of Formula (II-B):

8. The method of any one of Claims 1 to 7, wherein R7is9. The method of any one of Claims 1 to 7, wherein R7is12. The method of any one of Claims to 1 to 11, wherein L is a chemical linker having the structure of Formula (IV):(IV), wherein:X1is -(CH2)m-, wherein m is an integer from 1 to 4;X2is O (oxygen) or is absent;X3is - (CHi)n- , wherein n is an integer from 0 to 4;X4is O (oxygen) or is absent;X5is -(CH2)P-, wherein p is an integer from 0 to 4;X6is absent or is selected from the group consisting of:X7is -C(=O)-, or -(CH2)q-, wherein q is an integer from 0 to 4; andX8is selected from the group consisting of:

13. The method of any one of Claims 1 to 8, wherein L is selected from the group consisting of:, represents points of attachment to the rest of the compound.

14. The method of Claim 13, wherein16. The method of Claim 13, wherein17. The method of Claim 13, wherein18. The method of Claim 13, wherein20. The method of Claim 13, wherein L21. The method of Claim 13, wherein22. The method of Claim 13, wherein23. The method of Claim 13, wherein24. The method of Claim 13, wherein25. The method of any one of Claims 1-24, wherein B has the structure of Formula (III- A):

26. The method of any one of Claims 1-24, wherein B has the structure of Formula (III-B):

27. The method of any one of Claims 1-24, wherein B has the structure of Formula (III-C):

28. The method of Claim 1, wherein the first PROTAC compound is selected from thepharmaceutically acceptable salt of any of the foregoing.

29. The method of Claim 1, wherein the first PROTAC compound is selected from the group consisting of:

30. The method of any one of Claims 1-29, wherein the second ubiquitin ligase is VHL.31 . The method of Claim 30, wherein the second PROTAC compound is32. The method of Claim 30, wherein the second PROTAC compound is33. The method of any one of Claims 1-32, comprising co-administering the first PROTAC compound at a first concentration and the second PROTAC compound at a second concentration, wherein the degradation efficacy of the co-administration is greater than the degradation efficacy of the first PROTAC compound administered alone at the first concentration or the degradation efficacy of the second PROTAC compound administered alone at the second concentration.

34. The method of Claim 33, wherein the first and second concentrations are each at least pM.

35. The method of Claim 33, wherein the first and second concentrations are each at least pM.

36. The method of Claim 33, wherein the first and second concentrations are each at least5 pM.

37. The method of Claim 33, wherein the first and second concentrations are each at least pM.

38. The method of Claim 33, wherein the first PROTAC compound is39. The method of Claim 33, wherein the first PROTAC compound is40. The method of any one of Claims 1-39, wherein the first and second PROTAC compounds arc administered by administering an antibody-drug conjugate (ADC) that comprises the first and second PROTAC compounds.

41. An antibody-drug conjugate (ADC) of Formula (V):(V), wherein:Ab is an antibody or antigen-binding fragment thereof;M is a moiety coupled to an amino acid residue of Ab;La, Lei, LC2, Lpi, and LP2 are chemical linkers;Lb is a branched group with bifunctional moieties that selectively couple Lcior LC2;Di is a first PROTAC compound;D2 is a second different PROTAC compound; and subscript n is an integer from 1 to 10.

42. The compound of Claim 41, whereinwhereinrepresents a single bond attachment to Laand * represents an attachment point between M and Ab.

43. The compound of Claim 41 or 42, whereinwherein represents a single bond attachment to M and * represents a single bond attachment to Lb.

44. The compound of any one of Claims 41-43, wherein Lb isrepresents a single bond attachment / / — i to La, represents a single bond attachment to Lci, and ? represents a single bond attachment tO LC2-45. The compound of any one of Claims 41-44, wherein Lciisrepresents a single bond attachment to Lb and * represents a single bond attachment to Lp1.

46. The compound of any one of Claims 41-45, wherein LC2 isrepresents a single bond attachment to Lb, and * represents a single bond attachment to LP2.

47. The compound of any one of Claims 41-46, wherein Lpi and LP2 are each:, wherein * represents a single bond attachment to Lci or LC2 andrepresents a single bond attachment to Di or D2.

48. The compound of any one of Claims 41-47, wherein Di is a PROTAC compound of Formula (I’) having the structure:wherein:A is a KEAP1 binder of Formula (II’) having the structure:wherein:R4is a substituted or unsubstituted C1-4 alkoxy and R1is, orR4is a substituted or unsubstituted C1-4 alkoxy;R2is H or a substituted or unsubstituted C1-4 alkyl;R3is -CH2CO2R6;R5is H or a substituted or unsubstituted C1-4 alkyl;R6is H, a substituted or unsubstituted C1-4 alkyl, or * ;B is selected from the group consisting of Formulas (III-A’), (III-B’), and (III-C’):R8is halogen;R9is -OR15;R10is halogen or C1-4 haloalkyl;R14is H or a substituted or unsubstituted C1-4 alkyl;R15is H, a substituted or unsubstituted C1-4 alkyl, or * ;R16is H or a substituted or unsubstituted C1-4 alkyl;* in Di represents a single bond attachment to Lpi;represents a single bond attachment to L; andL is a chemical linker.

49. The compound of Claim 48, wherein A is a KEAP1 binder of Formula (II- A’):

50. The compound of Claim 48, wherein A is a KEAP1 binder of Formula (II-B’):

51. The compound of any one of Claims 48-50, wherein R7is52. The compound of any one of Claims 48-50, wherein R7is,55. The compound of any one of Claims 48-52, wherein R7is -OR13and R13is56. The compound of any one of Claims 48-55, wherein L is a chemical linker having the structure of Formula (IV’):[-X^X^-XM^-X^-X8-](IV’),wherein:X1is -(CH2)m-, wherein m is an integer from 1 to 4;X2is O (oxygen) or is absent;X3is - (CH2)U- , wherein n is an integer from 0 to 4;X4is O (oxygen) or is absent;X5is -(CHi)p-, wherein p is an integer from 0 to 4;X6is absent or is selected from the group consisting of:X7is -C(=O)- or -(CH2)q-, wherein q is an integer from 0 to 4; and57. The compound of any one of Claims 48-56, wherein L is selected from the group consisting of:, represents points of attachment to the rest of the compound and * represents a single bond attachment to Lpi.

58. The compound of Claim 57, wherein62. The compound of Claim 57, wherein63. The compound of Claim 57, wherein69. The compound of Claim 57, wherein70. The compound of Claim 57, whereinL is72. The compound of Claim 57, wherein73. The compound of Claim 57, wherein74. The compound of any one of Claims 48-73, wherein B has the structure of Formula75. The compound of any one of Claims 48-73, wherein B has the structure of Formula (III-B’):

76. The compound of any one of Claims 48-73, wherein B has the structure of Formula77. The compound of any one of Claims 41-76, wherein Di is a radical or cation of a compound selected from the group consisting of:pharmaceutically acceptable salt of any of the foregoing.

78. The compound of any one of Claims 41-76, wherein Di is a radical or cation of a compound selected from the group consisting of:

79. The compound of any one of Claims 41-78, wherein D2 is a radical or cation of80. The compound of any one of Claims 41-78, wherein D? is a radical or cation of81. The compound of any one of Claims 41-78, wherein D2 is a radical or cation of82. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-81 and an excipient.

83. A method of treating cancer in a subject comprising administering to a subject in need thereof an effective amount of a compound of any one of Claims 1-81.

84. A compound of any one of Claims 1-81 for use in treating cancer.

85. The compound of Claim 84, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, appendiceal cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acutemyeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, gastroesophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

86. Use of a compound of any one of Claims 1-81 in the preparation of a medicament for use in treating cancer.

87. The use of Claim 86, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, appendiceal cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, gastroesophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

Images