Protac compounds binding KEAP1 ubiquitin ligase for targeted protein degradation

Abstract

The present disclosure relates to PROTAC (proteolysis targeting chimera) compounds that bind to Keapl ubiquitin ligase and can promote ubiquitination and degradation of a target protein, particularly Kirsten rat sarcoma (KRAS) and androgen receptor (AR). Also disclosed herein are pharmaceutical compositions that can include a compound of Formula (I), the use and preparation thereof.

Description

PROTAC COMPOUNDS BINDING KEAP1 UBIQUITIN LIGASE FOR TARGETED PROTEIN DEGRADATION INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No.63 / 592088, filed October 20, 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] Nrf2 is a transcription factor that regulates cellular defense against toxic and oxidative stress, but in the absence of such conditions, is regulated by Keap1, which serves as an adaptor protein for the Cul3 E3 ligase complex, to promote ubiquitination and rapid degradation of Nrf2. Proteolysis-targeting chimera (PROTACs) can effectively inhibit biological function of a target protein via proteasomal degradation. PROTACS link two different chemical moieties via a linker. These bifunctional compounds simultaneously bind a target protein and an E3 ligase, forming a ternary complex, facilitating polyubiquitination of the target protein and subsequent proteasome-mediated degradation.

[0004] Kirsten rat sarcoma (KRAS) is an oncogene that encodes KRas, a GTPase signal transduction protein involved in regulating cell division. KRAS has the highest mutation rate among all cancers and many known gain-of-function mutations result in mutant forms, such as KRAS G12D, that remain active even in the absence of growth signals resulting in uncontrolled cell growth. The KRAS G12D mutation is present in more than one in three pancreatic cancers, one in ten colorectal cancers and numerous other types of cancers.

[0005] Androgen receptor (AR) translocates to the nucleus and binds to numerous sites throughout the human genome, regulating transcription of many genes controlling functions such as growth and proliferation. Like KRAS, overexpression of AR is related to uncontrolled cell growth and cancer, in particular, prostate cancer.SUMMARY

[0006] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0007] Some embodiments disclosed herein relate to a pharmaceutical composition that contains an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0008] 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 the use 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.

[0009] Some embodiments disclosed herein relate to a method of modulating cellular expression of KRas or AR that can include contacting a cell with 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 modulating cellular expression of KRas or AR. 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 modulating cellular expression of KRas or AR.

[0010] There are other embodiments described in greater detail below.DETAILED DESCRIPTION

[0011] As provided herein, gain-of-function mutations of the KRAS gene and AR are common and frequently associated with a variety of human cancers. Overexpression and aggregation of KRas and AR is associated with a poor prognosis, increased resistance to therapies and refractory disease. Modulation of cellular expression of KRas and AR has the potential for multiple anti-tumor effects including inhibition of cell cycle progression, metabolic starvation and immune reactivation. However, KRas and AR have often been viewed as “undruggable” targets. Therefore, a need exists for novel compounds that can target and modulate the cellular expression of KRas and AR for the treatment of cancer. Definitions

[0012] 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.

[0013] 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. Pharmaceutically acceptable 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. Insome 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).

[0014] As used herein, “Ca to 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 “C1to C4alkyl” or “C1-4alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, (CH3)2CHCH2-, and (CH3)3C-.

[0015] 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.

[0016] 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 “C1-4alkyl” or similar designations. By way of example only, “C1-4alkyl” 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.

[0017] 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.

[0018] 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.

[0019] 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-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1- ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.

[0020] 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-1-yl, propyn-2-yl, butyn-1-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.

[0021] As used herein, “heteroalkyl” refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limitedto, 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 “C1-4heteroalkyl” or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, “C1-4heteroalkyl” 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.

[0022] 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 “C1-4alkylene” or similar designations. By way of example only, “C1-4alkylene” 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.

[0023] 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 selected from the group consisting of ethenylene, ethen-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-en- 1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, buten-1,1-diyl,but-1,3-dien-1,1-diyl, but-2-en-1,1-diyl, but-3-en-1,1-diyl, 1-methyl-prop-2-en-1,1-diyl, 2- methyl-prop-2-en-1,1-diyl, 1-ethyl-ethenylene, 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.

[0024] 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.

[0025] 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 “C6-10aryl,” “C6or C10aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0026] As used herein, “aryloxy” and “arylthio” refers to RO- and RS-, in which R is an aryl as is defined above, such as “C6-10aryloxy” or “C6-10arylthio” and the like, including but not limited to phenyloxy.

[0027] An “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such as “C7-14aralkyl” 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 C1-4alkylene group).

[0028] 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 covers the occurrence of the term “heteroaryl” where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. Theheteroaryl 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.

[0029] 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, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4alkylene group).

[0030] 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 “C3-6carbocyclyl” 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.

[0031] 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.

[0032] As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0033] 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.

[0034] 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, 2H-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, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0035] 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.

[0036] As used herein, “acyl” refers to –C(=O)R, wherein R is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 3-10membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0037] An “O-carboxy” group refers to a “-OC(=O)R” group in which R is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0038] A “C-carboxy” group refers to a “-C(=O)OR” group in which R is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., -C(=O)OH).

[0039] A “cyano” group refers to a “-CN” group.

[0040] A “cyanato” group refers to an “-OCN” group.

[0041] An “isocyanato” group refers to a “-NCO” group.

[0042] A “thiocyanato” group refers to a “-SCN” group.

[0043] An “isothiocyanato” group refers to an “ -NCS” group.

[0044] 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, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0045] 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, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0046] An “S-sulfonamido” group refers to a “-SO2NRARB” group in which RAand RBare each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0047] An “N-sulfonamido” 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, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0048] An “O-carbamyl” group refers to a “-OC(=O)NRARB” group in which RA and RBare each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0049] An “N-carbamyl” group refers to an “-N(RA)C(=O)ORB” group in which RA and RBare each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0050] An “O-thiocarbamyl” group refers to a “-OC(=S)NRARB” group in which RAand RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0051] An “N-thiocarbamyl” group refers to an “-N(RA)C(=S)ORB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0052] 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, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0053] 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, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0054] An “amino” group refers to a “-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, C6-10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. A non- limiting example includes free amino (i.e., -NH2).

[0055] An “aminoalkyl” group refers to an amino group connected via an alkylene group.

[0056] An “alkoxyalkyl” group refers to an alkoxy group connected via an alkylene group, such as a “C2-8 alkoxyalkyl” and the like.

[0057] 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-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), C3-C7-carbocyclyl-C1- C6-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-C6haloalkyl, and C1-C6haloalkoxy), 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-C6haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 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-C6haloalkoxy), halo, cyano, hydroxy, C1-C6alkoxy, C1-C6alkoxy(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-sulfonamido, C-carboxy, O- carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Unless otherwise indicated, wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0058] 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.”

[0059] 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.

[0060] 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.

[0061] 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– or includes the substituent being oriented such that the A isattached 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.

[0062] 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 isosteres contemplated include -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, - CONHNHSO2R, -COHNSO2R, and –CONRCN, where R is selected from hydrogen, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10aryl, 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.

[0063] 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 isostere is not a substitution at one or more atom(s) that maintain(s) or is / are integral to the carboxylic acid isosteric properties of the compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the compound.

[0064] Other carboxylic acid isosteres not specifically exemplified in this specification are also contemplated.

[0065] “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.

[0066] 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.

[0067] 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).

[0068] “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 particular disease 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

[0069] Some embodiments disclosed herein include a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein:

[0070] A can be a KEAP1 binder of Formula (II) having the structure:, wherein

[0071] R1can be hydrogen (H) and R4can be4, R can be a substituted or unsubstituted C1-4alkoxy and R1can be, or R4can be a substituted or unsubstituted C1-4alkoxy and R1can be;

[0072] R2can be hydrogen (H) or a substituted or unsubstituted C1-4alkyl, R3can be –CH2CO2R6; R5can be hydrogen (H) or a substituted or unsubstituted C1-4alkyl; R6can be hydrogen (H) or a substituted or unsubstituted C1-4alkyl; B can be selected from Formula (III-A):; R8can be halogen; R9can be –OR15; R10can be halogen or C1-4haloalkyl ; R11can be cyano; R13can be; R14can be hydrogen (H) or a substituted or unsubstituted C1-4alkyl; R15can be hydrogen (H) or a substituted or unsubstituted C1-4alkyl; R16can be hydrogen (H) or a substituted or unsubstituted C1-4alkyl;represents a single bond attachment to L; and Lcan be a chemical linker.

[0073] 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 R3is attached can be a chiral center.

[0074] In some embodiments, R1can beand R4can be a C1-4alkoxy, such as methoxy, such that A can be a KEAP1 binder that can have the structure of Formula (II-A):In other embodiments, R1can be hydrogen (H) and R4can be , such that A can be a KEAP 1 binder that can have the structure of Formula (II-B):. In other embodiments,R4can be a C1-4alkoxy, such as methoxy, and R1can be

[0075] In some embodiments, R7can be7In other embodiments, R can be .

[0076] In some embodiments, R12can be

[0077] In some embodiments, R7can be –OR13and R13can be12and R can be.

[0078] In some embodiments, L can be a chemical linker that can have the structure of Formula (IV): [–X1–X2–X3–X4–X5–X6–X7–X8–] (IV), wherein

[0079] 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–, , and; X7can be –C(=O)– or –(CH2)q–, wherein q is an integer from 0 to 4; and X8can be selected from andor can be absent.

[0080] 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–.

[0081] In some embodiments, X2can be oxygen (O). In other embodiments, X2can be absent.

[0082] 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–.

[0083] In some embodiments, X4can be oxygen (O). In other embodiments, X4can be absent.

[0084] 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–.

[0085] In some embodiments X6can be –NH–. In other embodiments, X6can be. In still other embodiments, X6can be . In yet still otherembodiments, X6can be.

[0086] 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–.

[0087] In some embodiments, X8can be. In other embodiments, X8can be. In still other embodiments, X8can be. In some embodiments, X8can be

[0088] 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 from , and

[0089] In some embodiments, L can be. In otherembodiments, L can be . In other embodiments, L can be In still other embodiments, L can be In yet still other embodiments, L can be In some embodiments, L can beIn other embodiments, L can beIn still other embodiments, L can be. In yet still other embodiments, L can be. In other embodiments, L can be. In still other embodiments, L can be .

[0090] In some embodiments, B can have the structure of Formula (III-A):. In other embodiments, B can have the structure of Formula (III-B):. In still other embodiments, B can have the structure of Formula (III-C):

[0091] In some embodiments, R2can be hydrogen. In other embodiments, R2can be an unsubstituted C1-4alkyl. Examples of unsubstituted C1-4alkyls 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 C1-4alkyl. 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 C1-4alkoxy, cycloalkyl, aryl, or heteroaryl.

[0092] In some embodiments, R3can be –CH2CO2R6and R6can be H, such that R3can be –CH2CO2H. In other embodiments, R3can be –CH2CO2R6and R6can be an unsubstituted or substituted C1-4alkyl. Examples of unsubstituted C1-4alkyls are described herein, includingmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl. In some embodiments, R6can be ethyl, such that R3can be –CH2CO2CH2CH3. In some embodiments, R6can be a substituted C1-4alkyl. 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 C1-4alkoxy, cycloalkyl, aryl, or heteroaryl.

[0093] In some embodiments, R5can be hydrogen. In other embodiments, R5can be an unsubstituted C1-4alkyl. Examples of unsubstituted C1-4alkyls 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 C1-4alkyl. 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 C1-4alkoxy, cycloalkyl, aryl, or heteroaryl.

[0094] 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 C1-4haloalkyl (such as –CF3, –CCl3, –CHF2, –C(CH3)F2, –CHCl2, –CH2F, –CH(CH3)F, –CH2CF3, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F and –CH2CH2CH2Cl).

[0095] In some embodiments, R14can be hydrogen (H). In other embodiments, R14can be an unsubstituted C1-4alkyl. Examples of unsubstituted C1-4alkyls are described herein, including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl. In some embodiments, R14can be methyl. In some embodiments, R5can be a substituted C1-4alkyl. When R14is substituted, R14can 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 C1-4alkoxy, cycloalkyl, aryl, or heteroaryl.

[0096] In some embodiments, R15can be hydrogen (H). In other embodiments, R15can be an unsubstituted C1-4alkyl. Examples of unsubstituted C1-4alkyls 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 C1-4alkyl. When R15is substituted, R15can 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 C1-4alkoxy, cycloalkyl, aryl, or heteroaryl.

[0097] In some embodiments, R16can be hydrogen (H). In other embodiments, R16can be an unsubstituted C1-4alkyl. Examples of unsubstituted C1-4alkyls 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 C1-4alkyl. 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 C1-4alkoxy, cycloalkyl, aryl, or heteroaryl.

[0098] In some embodiments, a compound of Formula (I) can be selected from:and, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a compound of Formula (I) can be selected from:, and In some embodiments,the compound can be or a pharmaceutically acceptable salt thereof. In other embodiments, the compound can be, or a pharmaceutically acceptable salt thereof. Administration and Pharmaceutical Compositions

[0099] The compounds are 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, bedependent 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.

[0100] 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.

[0101] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions. 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.

[0102] 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.

[0103] 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 corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solidlubricants, 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.

[0104] 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.

[0105] 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 will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.

[0106] 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).

[0107] 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.

[0108] The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. 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; disintegrants such as starch, alginic acid and croscarmelose; 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.

[0109] 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, sodiumcarboxymethyl 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.

[0110] 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.

[0111] Compositions described herein may optionally include other drug actives.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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, Tween80. 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.

[0116] 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.

[0117] 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.

[0118] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

[0119] 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.

[0120] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0121] 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, HCl, 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.

[0122] 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.

[0123] 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 about 0.25 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

[0124] 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.

[0125] All variables shown in the schemes are defined as mentioned herein, unless otherwise is indicated or is clear from the context. Methods of Use

[0126] 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. 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 cancer.

[0127] Some embodiments described herein relate to a method for inhibiting cell proliferation, such as inhibiting cell proliferation of a cancer cell, that can include administering to a subject identified as suffering from a disease wherein inhibiting cell proliferation is desirable an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein. Other embodiments described hereinrelate to the use of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a 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 compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a 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.

[0128] 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 compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein. Other embodiments described herein relate to the use of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a 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 compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein for use in inhibiting replication of a cancer cell.

[0129] 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 compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a 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 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, described herein in the manufacture of a medicament for inducing apoptosis of a cell, such as a cancer cell. Still other embodimentsdescribed herein relate to the use of 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 for use in inducing apoptosis of a cell, such as a cancer cell.

[0130] 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 compound, or a pharmaceutically acceptable salt thereof, 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 using a 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 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 use in decreasing the viability of a cell, such as a cancer cell.

[0131] 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 other embodiments, the method of administering one or more of the compounds disclosed herein results in the polyubiquitination and degradation of AR. In some embodiments, the method of administering one or more of the compounds disclosed herein results in the polyubiquitination and degradation of KRas G12D.

[0132] 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 acompound, or a pharmaceutically acceptable salt thereof, as described herein, in the preparation of a medicament for treating a neurodegenerative disease.

[0133] 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.

[0134] 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.

[0135] 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 apharmaceutically 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.

[0136] 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.

[0137] 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 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 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.

[0138] In some embodiments, the subject is a human.

[0139] Further embodiments include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, or pharmaceutical composition described herein with an additional medicament.

[0140] Some embodiments include co-administering a compound, composition, and / or pharmaceutical composition described herein, with an additional medicament. By “co- administration,” 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.

[0141] Some embodiments further include administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

[0142] 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.

[0138] 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.

[0143] 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

[0144] 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.

[0145] The following abbreviations have the indicated meanings: 1H NMR = proton nuclear magnetic resonance AcCl = acetyl chloride AcOH = acetic acid BINAP = (2,2’-bis(diphenylphosphino)-1,1’-binapthyl BOC = tert-butoxycarbonyl DCM = dichloromethane DIEA = N,N-diisopropylethylamine DIPEA = N,N-diisopropylethylamine DMAP = 4-dimethylaminopyridine DMF = dimethylformamide DMP = Dess-Martin periodinane DMSO = dimethyl sulfoxide ESI = electrospray ionization Et = ethyl eq = equivalent(s) h = hour(s) HATU = hexafluorophosphate azabeznotriazole tetramethyl uronium HOAc = acetic acid LDA = lithium diisopropylamide M = molar min = minute(s) MeCN = acetonitrile MeOH = methanol MOM = methoxymethylether MS = mass spectrometry MW = microwave NBS = N-bromosuccinimide NaBh(OAc)3 = sodium triacetoxyborohydride NaOAc = sodium acetate NaOMe = sodium methanolate or sodium methoxide OTBS = tert-butyl-dimethyl-silane Pd / C = palladium on carbon Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0) psi = pounds per square inch Rf = retention factor [Rh(COD)Cl]2= cyclooctadiene rhodium chloride dimer Rh(OAc)2= rhodium(II) acetatet-Amyl-OH = 2-methylbutan-2-ol t-BuOK = potassium tert-butoxide TEA = triethylamine Tf2O = trifluormethanesulfonic anhydride THF = tetrahydrofuran TLC = thin-layer chromatography TsCl = 4-toluenesulfonyl chloride XantPhos Pd G3 = [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate Example 1. Preparation of Compound 5AExample 1.1: Synthesis of Compound 2A

[0146] To a solution of (3R,7aS)-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol- 1(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 mL×3). The separated organic layer was washed with brine (50mL×2), dried over Na2SO4and concentrated in vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100:1 to 10:1). (3R,7aR)-7a- ((benzyloxy)methyl)-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (17.3 g, 47.4 mmol, 77% yield) was obtained as a yellow oil.1H 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

[0147] To a solution of (3R,7aR)-7a-((benzyloxy)methyl)-3- (trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (17.0 g, 46.6 mmol, 1.00 eq) in methanol (100 mL) was added sodium;methanolate (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 × 3). The combined organic layer was washed with brine (50 mL×2), 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 4A

[0148] 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. The mixture was stirred at 20°C for 12 h. The mixture was poured into water (50 mL), extracted with ethyl acetate (100 mL × 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)-1-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

[0149] To a solution of methyl (R)-2-((benzyloxy)methyl)-1-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 × 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-methylpyrrolidine-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).

[0150] 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 N-Bromosuccinimide (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) δ ppm 3.93 (s, 3 H) 6.46 (br s, 2 H) 6.94 (d, J=1.9 Hz, 1 H) 7.90 (d, J=2.0 Hz, 1 H).

[0151] 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-N-methyl-6-nitro-aniline (10 g, crude) was obtained as a yellow solid. MS (ESI) m / z 261.0. [M+H]+.

[0152] 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-1,2-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).

[0153] To a solution of 5-bromo-7-methoxy-1-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 × 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-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (1.1 g, 4.21 mmol, 46.32% yield) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.1 Hz, 3 H) 4.02 (s, 3 H) 4.28 (q, J=7.1 Hz, 2 H) 4.45 (s, 3 H) 6.44 (d, J=15.9 Hz, 1 H) 6.92 (s, 1 H) 7.69 - 7.81 (m, 2 H).

[0154] To a solution of ethyl (E)-3-(7-methoxy-1-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 µL, 1.50 eq) [3-(hydroxymethyl)-4-methyl-phenyl]boronic acid (476 mg, 2.87 mmol, 1.50 eq) , chlororhodium;(1Z,5Z)-cycloocta-1,5-diene (18.8 mg, 38.2 µmol, 0.02 eq) and [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane (47.6 mg, 76.5 µmol, 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 × 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-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-1- methyl-1H-benzo[d][1,2,3]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, J=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, J=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).

[0155] To a solution of 1-fluoro-3-methoxybenzene (5.00 g, 39.6 mmol, 4.55 mL, 1.00 eq) in dichloromethane (45.0 mL) was added chlorosulfonic 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 × 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.

[0156] 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)-1-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 × 100 mL). The combined organic layers were washed with brine (2 × 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).

[0157] To a solution of (R)-2-fluoro-N-(2-hydroxypropyl)-4- methoxybenzenesulfonamide (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 × 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-2H-benzo[b][1,4,5]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).

[0158] To a solution of (R)-7-methoxy-4-methyl-3,4-dihydro-2H- benzo[b][1,4,5]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 × 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[b][1,4,5]oxathiazepine 1,1- dioxide (1.20 g, 5.23 mmol, 58% yield) was obtained as a yellow solid.1H 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 (br dd, J = 3.7, 7.8 Hz, 2H), 1.27 (d, J = 6.4 Hz, 3H).

[0159] To a solution of (R)-7-hydroxy-4-methyl-3,4-dihydro-2H- benzo[b][1,4,5]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 × 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-1,1-dioxido-3,4-dihydro-2H- benzo[b][1,4,5]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]+.

[0160] To a solution of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-1- methyl-1H-benzo[d][1,2,3]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- benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7-methoxy-1-methyl-1H- benzo[d][1,2,3]-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-1,1-dioxido-3,4-dihydro-2H- benzo[b][1,4,5]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-1-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 × 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-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][1,2,3]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

[0161] To a solution of ethyl 3-(3-(((R)-7-(2-(2-aminoethoxy)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][1,2,3]-triazol-5-yl)propanoate (550 mg, 703 µmol, 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-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][1,2,3]triazol-5-yl)propanoate (480 mg, 668 µmol, 95% yield, hydrochloric acid) was obtained as a white solid.

[0162] To a solution of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (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 N,N-diisopropylethylamine (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 × 100 mL), brine (2 × 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.

[0163] 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 (1R,5S)-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 × 100 mL). The combined organic layers were washed with brine (2 × 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 (1R,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.1H 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).

[0164] To a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3- d]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,5S)-3-(7-chloro-8-fluoro-2-(((R)-2- (methoxycarbonyl)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]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.1H 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 24

[0165] To a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((R)-2- (methoxycarbonyl)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 531 µmol, 1.00 eq) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (408 mg, 796 µmol, 1.50 eq) 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 µmol, 0.100 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. Theresidue was purified by silica gel chromatography (petroleum ether / ethyl acetate =10:1-1:1). Tert- butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((R)-2-(methoxycarbonyl)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (378 mg, 413 µmol, 78% yield) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 9.06 (s, 1H), 7.79 (dd, J = 5.6, 9.2 Hz, 1H), 7.51 (d, J = 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, J = 4.0, 9.2 Hz, 6H), 1.53 (s, 9H), 0.87 (t, J = 6.4 Hz, 18H), 0.60 - 0.50 (m, 3H).

[0166] To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((R)-2-(methoxycarbonyl)- 1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (278 mg, 304 µmol, 1.00 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 × 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=1:1-0:1- dichloromethane / methanol=10:1). (R)-2-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]-octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido-[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-2-carboxylic acid (160 mg, 178 µmol, 58% yield, 100% purity) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 9.11 (s, 1H), 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).

[0167] To a solution of (R)-2-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1- methylpyrrolidine-2-carboxylic acid (80.0 mg, 88.8 µmol, 1.00 eq) and ethyl 3-(3-(((R)-7-(2-(2- aminoethoxy)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][1,2,3]triazol-5-yl)propanoate (76.5 mg, 106 µmol, 1.20 eq, hydrochloric acid) in dimethylformamide (2.00 mL) was added O- (7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (50.6 mg, 133 µmol, 1.50 eq) and N,N-diisopropylethylamine (34.4 mg, 266 µmol, 46.4 µL, 3.00 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 × 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 (1R,5S)-3-(2-(((2R)-2-((2- (2-(((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 83.1 µmol, 93% yield) was 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).

[0168] To a solution of Tert-butyl (1R,5S)-3-(2-(((2R)-2-((2-(2-(((4R)-2-(5-(3-ethoxy- 1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 83.1 µmol, 1.00 eq) in dimethylformamide (2.00 mL) was added cesium fluoride (126 mg, 831 µmol, 30.6 µL, 10.0 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 (1R,5S)-3-(2-(((2R)-2-((2-(2-(((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H- benzo[d][1,2,3]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)-1-methylpyrrolidin-2- yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]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]+.

[0169] To a solution of tert-butyl (1R,5S)-3-(2-(((2R)-2-((2-(2-(((4R)-2-(5-(3-ethoxy- 1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 85.2 µmol, 1.00 eq) in dichloromethane (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-(((R)-7-(2-(2-((R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)-1-methylpyrrolidine-2-carboxamido)ethoxy)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][1,2,3]triazol-5-yl)propanoate (110 mg, 84.6 µmol, 99% yield, hydrochloric acid) was obtained as a yellow oil.

[0170] To a solution of ethyl 3-(3-(((R)-7-(2-(2-((R)-2-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-2- carboxamido)ethoxy)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][1,2,3]triazol-5-yl)propanoate (110 mg, 87.0 µmol, 1.00 eq) in tetrahydrofuran (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 prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 17%-47%,10min). 3-(3-(((R)-7-(2-(2- ((R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine- 2-carboxamido)ethoxy)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][1,2,3]triazol-5-yl)propanoic acid (10.99 mg, 8.40 µmol, 9.65% yield, 98% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1236.6 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 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, J = 2.4 Hz, 1H), 7.10 (d, J = 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, J = 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, J = 4.0 Hz, 3H), 2.22 (d, J = 1.6 Hz, 3H), 2.02 - 1.93 (m, 2H), 1.77 - 1.62 (m, 6H), 1.19 - 1.05 (m, 3H).

[0171] To a solution of 1-(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 1-(tert-butyl) 3-methyl piperidine-1,3-dicarboxylate (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, HCl) was obtained as a white solid.Example 6: Preparation of Compound P-2E

[0172] 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-diisopropylethylamine (1.54 g, 11.9 mmol, 2.07 mL, 2.00 eq) and methyl piperidine-3-carboxylate (851 mg, 4.74 mmol, 7.97e-1eq, HCl) 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 mL×3). 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 1-(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.1H NMR (400 MHz, DMSO-d6) 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).

[0173] To a solution of methyl 1-(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-1H-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 water(100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was dried over with sodium sulphate and concentrated in vacuum. TLC (PE:EA=0:1) showed a main spot (Rf=0.4) detected. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=0 / 1 to 3 / 4). Methyl 1-(7-chloro-8-fluoro- 2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-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-d6) 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).

[0174] To a solution of methyl 1-(7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-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 µmol, 0.100 eq), potassium phosphate (1.5 M, 553 µL, 1.00 eq) and ((2-fluoro- 6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- 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 mL×3). 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 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate (300 mg, 361 µmol, 43.4%yield) was obtained as a yellow solid.1H 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).

[0175] To a solution of methyl 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl) naphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-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 mL×3). 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. 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxylic acid (80.0 mg, 97.8 µmol, 27.12% yield, 100% purity) was obtained as a yellow solid.

[0176] To a solution of ethyl 3-[3-[[(4R)-7-[2-(2-aminoethoxy)ethoxy]-4-methyl-1,1- dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1- methyl-benzotriazol-5-yl)propanoate (80.0 mg, 111 µmol, 1.00 eq, concentrated hydrochloric acid) and 1-[8-fluoro-2-[[(2S,4S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-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 µmol, 97.0 µL, 5.00 eq) and O-(7-azabenzotriazol-1-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 × 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-[[(4R)-7-[2-[2-[[1-[8-fluoro-2-[[(2S,4S,8R)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-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]+.

[0177] To a solution of ethyl 3-[3-[[(4R)-7-[2-[2-[[1-[8-fluoro-2-[[(2S,4S,8R)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-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 µmol, 17.4 µL, 10.0 eq) at 20 °C ,the 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 × 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-[[1-[7-[8-ethynyl-7-fluoro- 3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5-yl)propanoate (62 mg, 46.78 µmol, 99.02% yield) was obtained as a yellow solid.

[0178] To a solution of ethyl 3-[3-[[(4R)-7-[2-[2-[[1-[7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-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-[[1-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2S,4S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]piperidine-3-carbonyl]amino]ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2- benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5- yl)propanoate (59 mg, 44.77 µmol, 95.71% yield, concentrated hydrochloric acid) was obtained as a yellow solid.

[0179] To a solution of ethyl 3-[3-[[(4R)-7-[2-[2-[[1-[7-(8-ethynyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3-carbonyl]amino]ethoxy]ethoxy]-4-methyl- 1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7-methoxy- 1-methyl-benzotriazol-5-yl)propanoate (59.0 mg, 46.0 µmol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added water (1.00 mL) and methanol (0.200 mL) and lithium hydroxide (19.3 mg, 460 µmol, 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: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 26%- 56%,10min). The desired product was lyophilized. 3-[3-[[(4R)-7-[2-[2-[[1-[7-(8-ethynyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3-carbonyl]amino]ethoxy]ethoxy]-4- methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7- methoxy-1-methyl-benzotriazol-5-yl)propanoic acid (8.21 mg, 6.42 µmol, 13.94% yield, 98% purity) was obtained as a yellow solid. MS (ESI) m / z 1254.2. [M+H]+.1H NMR (400 MHz, 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).

[0180] 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)-1-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 mL×3). The combined organic layers were washed with brine (50 mL×2), 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=3:1); Rf(R1)=0.4; Rf (P1)=0.2). (R)-2-fluoro-N-(2- hydroxypropyl)benzenesulfonamide (4.87 g, 20.88 mmol, 81.27% yield) was obtained as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 7.93 - 7.64 (m, 3H), 7.50 - 7.32 (m, 2H), 4.68 (d, J = 4.8 Hz, 1H), 3.60 (td, J = 5.9, 11.6 Hz, 1H), 2.89 - 2.68 (m, 2H), 0.99 (d, J = 6.3 Hz, 3H).

[0181] 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 mL×3). The combined organic layers were washed with brine (50 mL×2), 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=3:1) ; Rf(R1)=0.2; Rf (P1)=0.3). (R)-4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (3.2 g, 15.01 mmol, 72.17% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.88 (brs, 1H), 7.78 (dd, J = 1.1, 7.8 Hz, 1H), 7.65 - 7.57 (m, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 4.13 - 3.95 (m, 1H), 3.35 (br s, 2H), 1.34 (d, J = 6.5 Hz, 3H).

[0182] To a solution of (R)-4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]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-1-methyl-1H-benzo[d][1,2,3]triazol-5- yl)propanoate (188 mg, 468 µmol, 1.00 eq) and potassium carbonate (129 mg, 937 µmol, 2.00 eq) 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=1:1); Rf(R1)=0.4; Rf(P1)=0.2). ethyl 3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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 (157 mg, 271.31 µmol, 57.86% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.78 (br d, J = 7.5 Hz, 1H), 7.66 (br t, J = 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).

[0183] To a solution of ethyl 3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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 µmol, 1.00 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 mL×3). 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=100:1 to 5:1 (TLC (petroleum ether:ethyl acetate=0:1) ; Rf (R1)=0.4; Rf (P1)=0.2). 3-(7-hydroxy-1-methyl-1H-benzo[d][1,2,3]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 µmol, 89.25% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 12.22 - 12.06 (m, 1H), 10.53 (d, J = 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, J = 2.5 Hz, 3H), 3.80 (br d, J = 14.1 Hz, 1H), 3.68 - 3.55 (m, 1H), 1.17 (d, J = 7.1 Hz, 3H).

[0184] To a solution of 3-(7-hydroxy-1-methyl-1H-benzo[d][1,2,3]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 (100 mg, 186 µmol, 1.00 eq) in ethanol (2 mL) was added sulfuric acid (1.83 mg, 18.6 µmol, 0.100 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=100:1 to 5:1 (TLC (petroleum ether: ethyl acetate=0:1); Rf (R1)=0.2; Rf (P1)=0.4). ethyl 3-(7-hydroxy-1-methyl-1H- benzo[d][1,2,3]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 (85 mg, 150.54 µmol, 80.78% yield) 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, J = 2.4 Hz, 3H), 3.95 (q, J = 7.1 Hz, 2H), 3.80 (d, J = 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, J = 1.2, 7.1 Hz, 3H).

[0185] To a solution of ethyl 3-(7-hydroxy-1-methyl-1H-benzo[d][1,2,3]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 (80.0 mg, 141 µmol, 1.00 eq) 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 µmol, 1.20 eq) at 20 °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=1:1); Rf (R1)=0.1; Rf (P1)=0.3). ethyl 3-(7-(2-(2-((tert-butoxycarbonyl)amino) ethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (75 mg, 99.75 µmol, 70.40% yield) was obtained as a colorless gum. 1H NMR (400 MHz, DMSO-d6) δ =7.78 (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).

[0186] To a solution of ethyl 3-(7-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)- 1-methyl-1H-benzo[d][1,2,3] 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 (72.0 mg, 95.7 µmol, 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)-1-methyl-1H-benzo[d][1,2,3]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 (64 mg, crude, hydrochloric acid) was obtained as a white solid.

[0187] To a solution of ethyl 3-(7-(2-(2-aminoethoxy)ethoxy)-1-methyl-1H- benzo[d][1,2,3]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 (63.00 mg, 91.54 µmol, 1 eq, hydrochloric acid) in dimethylformamide (3 mL) was added N,N-diisopropylethylamine (59.1 mg, 457 µmol, 79.7 µL, 5.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (52.2 mg, 137 µmol, 1.50 eq) and (R)-2-(((4-((1R,5S)-8- (tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)-1-methylpyrrolidine-2-carboxylic acid (82.4 mg, 91.5 µmol, 1.00 eq) at 20 °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=0:1); Rf (R1)=0.4; Rf (P1)=0.2). Tert-butyl (1R,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-1H-benzo[d][1,2,3]triazol-7- yl)oxy)ethoxy)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (79 mg, 51.47 µmol, 56.23% yield) was obtained as a white solid.

[0188] To a solution of tert-butyl (1R,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-1H-benzo[d][1,2,3]triazol-7- yl)oxy)ethoxy)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (57.0 mg, 37.1 µmol, 1.00 eq) in dimethylformamide (0.5 mL) was added CsF (5.64 mg, 37.1 µmol, 1.37 µL, 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 (1R,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-1H-benzo[d][1,2,3]triazol-7-yl)oxy)ethoxy)ethyl)carbamoyl)-1- methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-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.

[0189] To a solution of tert-butyl (1R,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-1H-benzo[d][1,2,3]triazol-7- yl)oxy)ethoxy)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 36.2 µmol, 1.00 eq) in dichloromethane (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- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-2- carboxamido)ethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (46 mg, crude, hydrochloric acid) was obtained as a yellow solid.

[0190] To a solution of ethyl 3-(7-(2-(2-((R)-2-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-2- carboxamido)ethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (46.0 mg, 36.2 µmol, 1.00 eq, hydrochloric acid) in tetrahydrofuran (3 mL) was added solution of Lithium hydroxide hydrate (6.08 mg, 144 µmol, 4.00 eq) in 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 1N aq. hydrochloric acid to pH=7. The mixture was purified by prep-HPLC(column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 18%-48%,8min). The desired fraction was lyophilized. 3-(7-(2-(2-((R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1- methylpyrrolidine-2-carboxamido)ethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (4.96 mg, 3.92 µmol, 10.83% yield, 99% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1207.0 / 120707 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ = 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).

[0191] To a solution of 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-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 O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (74.4 mg, 196 µmol, 2.00 eq), N,N- diisopropylethylamine (63.2 mg, 489 µmol, 85.2 µL, 5.00 eq) and ethyl 3-(7-(2-(2- aminoethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (67.3 mg, 97.8 µmol, 1.00 eq, HCl) 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 to10:1 (TLC (dichloromethane: methanol =10:1) Rf (P1)=0.5). LCMS showed desired mass was detected. Ethyl 3-(7-(2-(2-(1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamido)ethoxy)ethoxy)-1- methyl-1H-benzo[d][1,2,3]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 (125 mg, 86.1 µmol, 88.0% yield) was obtained as a yellow solid.

[0192] To a solution of ethyl 3-(7-(2-(2-(1-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl) ethynyl)naphthalen-1-yl)-2-(((2S,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxamido)ethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (120 mg, 82.7 µmol, 1.00 eq) 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-[[1-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2S,4S,8R)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-1-methyl-benzotriazol-5-yl]-3-[4-methyl-3-[[(4R)-4-methyl-1,1- dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (105 mg, crude) was obtained as a yellow solid.

[0193] To a solution of ethyl 3-[7-[2-[2-[[1-[7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-1-methylbenzotriazol-5-yl]-3-[4-methyl-3-[[(4R)-4-methyl-1,1- dioxo-3,4-dihydro-5,1λ6,2-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-[[1-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S,4S,8R)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy] pyrido[4,3-d]pyrimidin-4-yl]piperidine-3- carbonyl]amino]ethoxy]ethoxy]-1-methylbenzotriazol-5-yl]-3-[4-methyl-3-[[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (97 mg, crude) was obtained as a yellow solid.

[0194] To a solution of ethyl 3-[7-[2-[2-[[1-[7-(8-ethynyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2S,4S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidine-3-carbonyl] amino]ethoxy]ethoxy]-1- methylbenzotriazol-5-yl]-3-[4-methyl-3-[[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2- benzoxathiazepin-2-yl]methyl]phenyl]propanoate (97.0 mg, 77.5 µmol, 1.00 eq) in tetrahydrofuran (6 mL) was added lithium hydroxide monohydrate (32.5 mg, 775 µmol, 10.0 eq)in 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 luna C18150*25mm* 10um;mobile phase:[water(FA)-ACN];B%: 25%-55%,10min). The desired fraction was lyophilized. 3-(7-(2-(2-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxamido)ethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (7.77 mg, 6.22µmol, 8.03% yield, 98% purity) was obtained as a yellow solid.1H 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).

[0195] To a solution of (4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1λ6,2- 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 N-(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 × 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][1,4,5]oxathiazepin-7-yl)oxy)ethyl)carbamate (350 mg, 939.76 µmol, 35.91% yield) was obtained as a white solid.

[0196] To a solution of ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-1- methyl-benzotriazol-5-yl)propanoate (215 mg, 537 µmol, 1.00 eq) in acetonitrile (4 mL) was added tert-butyl (R)-(2-((4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7- yl)oxy)ethyl)carbamate (200 mg, 537 µmol, 1.00 eq) 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 × 20 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue. Ethyl 3-(3-(((R)-7- (2-((tert-butoxycarbonyl)amino)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][1,2,3]triazol-5-yl)propanoate (300 mg, crude) was obtained a yellow solid. MS (ESI) m / z 738.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 7.65 (dd, J = 3.2, 8.6 Hz, 1H), 7.46 (s, 1H), 7.34 (br d, J = 2.4 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.05 (br t, J = 5.4 Hz, 1H), 6.96 - 6.81 (m, 3H), 4.53 (br t, J = 7.6 Hz, 1H), 4.43 - 4.34 (m, 2H), 4.33 (d, J = 2.4 Hz, 3H), 4.06 (br t, J = 5.4 Hz, 2H), 4.04 (br s, 1H), 3.98 - 3.88 (m, 6H), 3.76 (br d, J = 14.0 Hz, 1H), 3.59 (ddd, J = 6.8, 9.2, 15.6 Hz, 1H), 3.22 - 3.14 (m, 2H), 2.82 - 2.64 (m, 1H), 2.23 (d, J = 2.4 Hz, 3H), 1.39 (s, 9H), 1.22 - 1.13 (m, 3H), 1.04 (t, J = 7.2 Hz, 3H).

[0197] To a solution of ethyl 3-(3-(((R)-7-(2-((tert-butoxycarbonyl)amino)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][1,2,3]triazol-5-yl)propanoate (300 mg, 406 µmol, 1.00 eq) 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-2H-benzo[b][1,4,5]oxathiazepin-2- yl)methyl)-4-methylphenyl)-3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (259 mg, 384.16 µmol, 94.48% yield, HCl salt) was obtained as a yellow solid.

[0198] To a solution of (2R)-2-[[4-[(1S,5R)-8-tert-butoxycarbonyl-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl- pyrrolidine-2-carboxylic acid (200 mg, 222 µmol, 1.00 eq) and ethyl 3-(3-(((R)-7-(2- aminoethoxy)-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][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 µmol, 154 µL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (126 mg, 333 µmol, 1.50 eq) at 20 °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 × 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 (1R,5S)-3-(2-(((2R)-2-((2-(((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H- benzo[d][1,2,3]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)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)- 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- 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]+.

[0199] To a solution of tert-butyl (1R,5S)-3-(2-(((2R)-2-((2-(((4R)-2-(5-(3-ethoxy-1- (7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (337 mg, 221 µmol, 1.00 eq) in dimethylformamide (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 (1R,5S)-3-(2-(((2R)-2-((2-(((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H- benzo[d][1,2,3]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)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)- 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 219.86 µmol, 99.22% yield) was obtained as a yellow solid. MS (ESI) m / z 683.3 [M+H]+.

[0200] To a solution of tert-butyl (1R,5S)-3-(2-(((2R)-2-((2-(((4R)-2-(5-(3-ethoxy-1- (7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)ethyl)carbamoyl)-1- methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoropyrido[4,3-d]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-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-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][1,2,3]triazol-5-yl)propanoate (268 mg, 213.24 µmol, 96.99% yield, HCl) was obtained as a yellow solid. MS (ESI) m / z 610.9 [M+H]+.

[0201] To a solution of ethyl 3-(3-(((R)-7-(2-((R)-2-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-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][1,2,3]triazol-5-yl)propanoate (268 mg, 219 µmol, 1.00 eq) in tetrahydrofuran (4 mL) was added methanol (1 mL) ,water (2 mL) and lithium hydroxide (46.0mg, 1.10 mmol, 5.00 eq) at 20 °C, the mixture was stirred at 40 °C for 1 h. The mixture was concentrated in vacuum to give a crude product. The crude product was purified by Prep- HPLC(column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 14%-44%,10min). The desired product was lyophilized. 3-(3-(((R)-7-(2-((R)-2-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-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][1,2,3]triazol-5-yl)propanoic acid (32.7 mg, 27.15 µmol, 12.36% yield, 99% purity) was obtained as a yellow solid. MS (ESI) m / z 1192.7 [M+H]+.1H 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, J = 4.0 Hz, 3H), 2.03 - 1.92 (m, 2H), 1.81 - 1.59 (m, 6H), 1.19 - 1.04 (m, 3H).

[0202] To a solution of (R)-7-hydroxy-4-methyl-3,4-dihydro-2H- benzo[b][1,4,5]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 × 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 C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 21%-51%,10min). The desired fraction was lyophilized. Tert-butyl (R)-(2-(2-(2-((4-methyl-1,1- dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (350 mg, 760 µmol, 35% yield) was obtained as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 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).

[0203] To a solution of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-1- methyl-1H-benzo[d][1,2,3]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-(chloromethyl)-4- methylphenyl)-3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-propanoate (524 mg, 1.30 mmol, 100% yield) was obtained as a yellow oil.

[0204] To a solution of tert-butyl (R)-(2-(2-(2-((4-methyl-1,1-dioxido-3,4-dihydro- 2H-benzo[b][1,4,5]oxathiazepin-7-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (200 mg, 434 µmol, 1.00 eq) in acetonitrile (4.00 mL) was added ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7- methoxy-1-methyl-benzotriazol-5-yl)propanoate (174 mg, 434 µmol, 1.00 eq) and potassium carbonate (120 mg, 868 µmol, 2.00 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 (20mL×2). 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-3,8,11-trioxa-5-azatridecan-13-yl)oxy)-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][1,2,3]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, J = 2.4 Hz, 3H), 1.37 (s, 9H), 1.21 - 1.15 (m, 3H), 1.05 (t, J = 7.2 Hz, 3H).

[0205] To a solution of ethyl 3-[3-[[(4R)-7-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5- yl)propanoate (300 mg, 363 µmol, 1.00 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-1,1-dioxo-3,4-dihydro-5,1λ6,2- benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5- yl)propanoate (263 mg, 345 µmol, 94% yield, HCl)M was obtained as a yellow solid.

[0206] To a solution of (2R)-2-[[4-[(1S,5R)-8-tert-butoxycarbonyl-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl- pyrrolidine-2-carboxylic acid (200 mg, 222 µmol, 1.00 eq) and ethyl 3-[3-[[(4R)-7-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5-yl)propanoate (169 mg, 222 µmol, 1.00 eq, HCl) in dimethylformamide (6.00 mL) was added O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (169 mg, 444 µmol, 2.00 eq) and N,N- diisopropylethylamine (86.0 mg, 666 µmol, 116 µL, 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 mL×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 =1:1-0:1). Tert-butyl (1R,5S)-3-(2-(((2R)-2-((2-(2-(2-(((4R)-2-(5- (3-ethoxy-1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)ethoxy)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 218 µmol, 98% yield) was obtained as a yellow oil. MS (ESI) m / z 805.5. [1 / 2M+H]+.

[0207] To a solution of tert-butyl (1S,5R)-3-[2-[[(2R)-2-[2-[2-[2-[[(4R)-2-[[5-[3- ethoxy-1-(7-methoxy-1-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4- methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-7- yl]oxy]ethoxy]ethoxy]ethylcarbamoyl]-1-methyl-pyrrolidin-2-yl]methoxy]-8-fluoro-7-[7-fluoro- 3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 218 µmol, 1.00 eq) in dimethylformamide (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 (1S,5R)-3-[2-[[(2R)-2-[2-[2-[2-[[(4R)-2-[[5-[3-ethoxy-1-(7-methoxy-1-methyl- benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-7-yl]oxy]ethoxy]ethoxy]ethylcarbamoyl]-1-methyl-pyrrolidin-2- yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3- d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 186 µmol, 85% yield) was obtained as a yellow solid. MS (ESI) m / z 727.0 [1 / 2M+H]+.

[0208] To a solution of tert-butyl (1S,5R)-3-[2-[[(2R)-2-[2-[2-[2-[[(4R)-2-[[5-[3- ethoxy-1-(7-methoxy-1-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4- methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-7- yl]oxy]ethoxy]ethoxy]ethylcarbamoyl]-1-methyl-pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 186 µmol, 1.00 eq) in dichloromethane (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-[(1S,5R)-3,8- diazabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl-pyrrolidine-2-carbonyl]amino]- ethoxy]ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2-yl]methyl]- 4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5-yl)propanoate (260 mg, crude, HCl) was obtained as a yellow solid.

[0209] To a solution of ethyl 3-[3-[[(4R)-7-[2-[2-[2-[[(2R)-2-[[4-[(1S,5R)-3,8- diazabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl-pyrrolidine-2- carbonyl]amino]ethoxy]ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2- benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5- yl)propanoate (260 mg, 199 µmol, 1.00 eq) 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-(1l2-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-7-(2-(2-(2-((R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine- 2-carboxamido)ethoxy)ethoxy)ethoxy)-4-methyl-1,1-dioxido-3,4-dihydro-2H- benzo[b][1,4,5]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]+. 1H 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).

[0210] A mixture of (2R)-pyrrolidine-2-carboxylic acid (40.0 g, 347 mmol, 1.00 eq), 2,2,2-trichloroethane-1,1-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 × 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,7aR)-3-(trichloromethyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-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).

[0211] To a solution of (3S,7aR)-3-(trichloromethyl)-5,6,7,7a-tetrahydro-3H- pyrrolo[1,2-c]oxazol-1-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 × 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-1H,3H-pyrrolo[1,2-c]oxazol-1-one (27.0 g, 74.0 mmol, 60% yield) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 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).

[0212] A mixture of (3S,7aS)-7a-(benzyloxymethyl)-3-(trichloromethyl)-3,5,6,7- tetrahydropyrrolo[1,2-c]oxazol-1-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 × 3). The aqueous phase was basified by sodium bicarbonate adjust to pH=9, and then extracted with 50.0 mL × 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.1H 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).

[0213] To a solution of methyl (2S)-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 dichloromethane (300 mL × 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 =1:1-0:1). Methyl (S)-2-((benzyloxy)methyl)-1-methylpyrrolidine-2-carboxylate (10.0 g, 38.0 mmol, 56% yield) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 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, J = 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).

[0214] To a solution of methyl (2S)-2-(benzyloxymethyl)-1-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 × 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 × 2). The combined filtrate was purified by silica gel chromatography (petroleum ether / ethyl acetate =1:1-0:1). Methyl (S)-2-(hydroxymethyl)-1-methylpyrrolidine-2-carboxylate (3.40 g, 18.6 mmol, 61% yield, 95% purity) was obtained as a colorless oil.1H 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)

[0215] To a solution of methyl (2S)-2-(hydroxymethyl)-1-methyl-pyrrolidine-2- carboxylate (500 mg, 2.89 mmol, 1.00 eq) and tert-butyl (1S,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 mL) 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 (1S,5R)-3-[7-chloro-8-fluoro-2-[[(2S)-2- methoxycarbonyl-1-methyl-pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 708 µmol, 24% yield) was 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).

[0216] To a solution of tert-butyl (1S,5R)-3-[7-chloro-8-fluoro-2-[[(2S)-2- methoxycarbonyl-1-methyl-pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 708 µmol, 1.00 eq) and 2-[2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl- triisopropyl-silane (544 mg, 1.06 mmol, 1.50 eq) in tetrahydrofuran (10.0 mL) was added [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane;methanesulfonate (51.6 mg, 70.8 µmol, 0.100 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 × 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 (1S,5R)-3-[8-fluoro-7-[7- fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[(2S)-2- methoxycarbonyl-1-methyl-pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (380 mg, 399 µmol, 56% yield, 96% purity) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM) δ = 9.06 (s, 1H), 7.79 (dd, J = 5.6, 9.2 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 5.33 - 5.26 (m, 2H), 4.81 - 4.66 (m, 2H), 4.57 - 4.36 (m, 3H), 4.20 (d, J = 12.8 Hz, 1H), 3.73 (s, 3H), 3.51 (s, 3H), 3.18 - 3.01 (m, 2H), 2.95 - 2.73 (m, 2H), 2.48 - 2.42 (m, 3H), 2.19 - 2.10 (m, 2H), 2.01 - 1.85 (m, 6H), 1.53 (s, 9H), 0.87 (t, J = 6.4 Hz, 18H), 0.60 - 0.50 (m, 3H).

[0217] To a solution of tert-butyl (1S,5R)-3-[8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[(2S)-2-methoxycarbonyl-1- methyl-pyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (380 mg, 415 µmol, 1.00 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 mL×3). 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-[(1S,5R)-8-tert-butoxycarbonyl-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl- pyrrolidine-2-carboxylic acid (320 mg, 355 µmol, 85% yield) was obtained as a yellow oil. MS (ESI) m / z 901.5. [M+H]+.

[0218] To a solution of (2S)-2-[[4-[(1S,5R)-8-tert-butoxycarbonyl-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl- pyrrolidine-2-carboxylic acid (150 mg, 166 µmol, 1.00 eq) and ethyl 3-[3-[[(4R)-7-[2-(2- aminoethoxy)ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2-yl]methyl]-4- methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5-yl)propanoate (120 mg, 166 µmol, 1.00 eq, HCl) in dimethylformamide (4.00 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (127 mg, 333 µmol, 2.00 eq) and N,N- diisopropylethylamine (64.5 mg, 499 µmol, 87.0 µL, 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 (1S,5R)-3-[2-[[(2S)-2-[2-[2-[[(4R)-2-[[5-[3- ethoxy-1-(7-methoxy-1-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4- methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-7-yl]oxy]ethoxy]ethylcarbamoyl]-1- methyl-pyrrolidin-2-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (200 mg, 120 µmol, 72% yield, 94% purity) was obtained as a yellow solid.1H 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).

[0219] To a solution of tert-butyl (1S,5R)-3-[2-[[(2S)-2-[2-[2-[[(4R)-2-[[5-[3-ethoxy- 1-(7-methoxy-1-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl- 1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-7-yl]oxy]ethoxy]ethylcarbamoyl]-1-methyl- pyrrolidin-2-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (190 mg, 121 µmol, 1.00 eq) 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 mL×2). 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 (1S,5R)-3-[2-[[(2S)-2- [2-[2-[[(4R)-2-[[5-[3-ethoxy-1-(7-methoxy-1-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl- phenyl]methyl]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-7- yl]oxy]ethoxy]ethylcarbamoyl]-1-methyl-pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-1-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]+.

[0220] To a solution of tert-butyl (1S,5R)-3-[2-[[(2S)-2-[2-[2-[[(4R)-2-[[5-[3-ethoxy- 1-(7-methoxy-1-methyl-benzotriazol-5-yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl- 1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-7-yl]oxy]ethoxy]ethylcarbamoyl]-1-methyl- pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro- pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (171 mg, 121 µmol, 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-[[(4R)-7-[2-[2- [[(2S)-2-[[4-[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl-pyrrolidine-2- carbonyl]amino]ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2- yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5-yl)propanoate (155 mg, crude, HCl) was obtained as a yellow solid.

[0221] To a solution of ethyl 3-[3-[[(4R)-7-[2-[2-[[(2S)-2-[[4-[(1S,5R)-8- azabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]-1-methyl-pyrrolidine-2-carbonyl]amino]ethoxy]ethoxy]-4-methyl- 1,1-dioxo-3,4-dihydro-5,1λ6,2-benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7-methoxy- 1-methyl-benzotriazol-5-yl)propanoate (155 mg, 123 µmol, 1.00 eq) in tetrahydrofuran (4.00 mL) was added Lithium hydroxide monohydrate (25.7 mg, 613 µmol, 5.00 eq), water (4.42 mg, 245 µmol, 4.42 µL, 2.00 eq) and Lithium hydroxide monohydrate (3.93 mg, 123 µmol, 4.96 µL, 1.00 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-HPLC(column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 15%-45%,15min).The desired fraction was lyophilized. 3-[3-[[(4R)-7-[2-[2-[[(2S)-2-[[4-[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]-7-(8- ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1- methyl-pyrrolidine-2-carbonyl]amino]ethoxy]ethoxy]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2- benzoxathiazepin-2-yl]methyl]-4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5- yl)propanoic acid (26.22 mg, 20.16 µmol, 16.44% yield, 95% purity) was obtained as a yellow solid. MS (ESI) m / z 1236.6 [M+H]+.1H 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).

[0222] To a solution of ethyl 3-(7-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)- 1-methyl-1H-benzo[d][1,2,3]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 (155 mg, 206 µmol, 1.00 eq) in dichloromethane (2 mL) was added hydrochloric acid / dioxane (4 M, 2 mL, 38.8 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuum. Ethyl 3-(7-(2-(2-aminoethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (140 mg, crude, hydrochloric acid) was obtained as a yellow solid.

[0223] To a solution of ethyl 3-(7-(2-(2-aminoethoxy)ethoxy)-1-methyl-1H- benzo[d][1,2,3]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 (140 mg, 203 µmol, 1.2 eq, hydrochloric acid) in dimethylformamide (2 mL) was added N,N-diisopropylethylamine (43.82 mg, 339.03 µmol, 59.05 µL, 2 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (96.6 mg, 254 µmol, 1.50 eq) and (S)-2-(((4-((1R,5S)-8- (tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)-1-methylpyrrolidine-2-carboxylic acid (152 mg, 169 µmol, 1.00 eq) at 25 °C. 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 (1R,5S)-3- (2-(((2S)-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-1H-benzo[d][1,2,3]triazol-7-yl)oxy)ethoxy)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- 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]+. 1H NMR (400 MHz, DMSO-d6) δ = 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, J = 3.8, 8.0 Hz, 18H).

[0224] To a solution of tert-butyl (1R,5S)-3-(2-(((2S)-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-1H-benzo[d][1,2,3]triazol-7- yl)oxy)ethoxy)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 78.1 µmol, 1.00 eq) in dimethylformamide (2 mL) was added cesium fluoride (23.7 mg, 156 µmol, 2.00 eq) at 25 °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. Tert-butyl (1R,5S)-3-(2-(((2S)-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-1H-benzo[d][1,2,3]triazol-7-yl)oxy)ethoxy)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, crude) was obtained as a yellow solid.

[0225] To a solution of tert-butyl (1R,5S)-3-(2-(((2S)-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-1H-benzo[d][1,2,3]triazol-7- yl)oxy)ethoxy)ethyl)carbamoyl)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 76.1 µmol, 1.00 eq) in dichloromethane (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-((S)-2-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-2- carboxamido)ethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (95 mg, crude, hydrochloric acid) was obtained as a yellow solid.

[0226] To a solution of ethyl 3-(7-(2-(2-((S)-2-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-2- carboxamido)ethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (95.0 mg, 74.7 µmol, 1.00 eq, hydrochloric acid) in tetrahydrofuran (6 mL) and methanol (2 mL) was added a mixture of Lithium hydroxide hydrate (15.6 mg, 373 µmol, 5.00 eq) in water (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-((S)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1- methylpyrrolidine-2-carboxamido)ethoxy)ethoxy)-1-methyl-1H-benzo[d][1,2,3]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 (10.02 mg, 8.14 µmol, 10.9% yield, 98% purity) was obtained as a yellow solid. LCMS (ESI) m / z 1206.6 / 1207.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 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).

[0227] To a solution of tert-butyl (1R,5S)-3-(2-(((2R)-2-((2-(2-(((4R)-2-(5-(3-ethoxy- 1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 70.3 µmol, 1.00 eq) in dimethylformamide (2 mL) was added cesium fluoride (106 mg, 703 µmol, 25.9 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 (2 × 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 (1S,5R)-3-[2-[[(2R)-2-[2-[2-[[(4R)-2-[[5-[3-ethoxy-1-(7-methoxy-1-methyl-benzotriazol-5- yl)-3-oxo-propyl]-2-methyl-phenyl]methyl]-4-methyl-1,1-dioxo-3,4-dihydro-5,1λ6,2- benzoxathiazepin-7-yl]oxy]ethoxy]ethylcarbamoyl]-1-methyl-pyrrolidin-2-yl]methoxy]-7-[8- ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (99 mg, 70.28 µmol, 99.99% yield) was obtained as a white solid. MS (ESI) m / z 1409.4 [M+H]+.

[0228] To a mixture was tert-butyl (1R,5S)-3-(2-(((2R)-2-((2-(2-(((4R)-2-(5-(3- ethoxy-1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (99.0 mg, 70.2 µmol, 1.00 eq) in dichloromethane (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-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-2- carboxamido)ethoxy)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][1,2,3]triazol-5-yl)propanoate (33.83 mg, 25.56 µmol, 36.36% yield, 99% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1286.4 [M+H]+.1H 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, J=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, J=4.4 Hz, 2 H) 3.74 (br d, J=2.5 Hz, 1 H) 3.78 (br d,J=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, J=7.8 Hz, 1 H) 7.18 (d, J=2.0 Hz, 1 H) 7.23 - 7.30 (m, 1 H) 7.33 (br s, 1 H) 7.39 (d, J=2.4 Hz, 1 H) 7.42 - 7.50 (m, 2 H) 7.65 (dt, J=8.8, 2.6 Hz, 1 H) 7.97 (dd, J=9.2, 6.0 Hz, 1 H) 8.11 (br t, J=6.0 Hz, 1 H) 9.04 (s, 1 H).

[0229] 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-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one (6 g, 30.43 mmol, 61.56% yield) was obtained as a yellow oil.

[0230] To a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3- d]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-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-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 × 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 (1R,5S)-3-(7-chloro-8-fluoro-2-(((S)-1-(2,2,2- trifluoroacetyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 564 µmol, 40.3% yield, 95% purity) wasobtained as a white solid.1H NMR (400 MHz, CDCl3) 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).To a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((S)-1-(2,2,2- trifluoroacetyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 560 µmol, 1.00 eq) in tetrahydrofuran (5 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilane (344 mg, 672 µmol, 1.20 eq), solution of potassium phosphate (237 mg, 1.12 mmol, 2.00 eq) in water (0.5 mL) and Ad2nBuP Pd-G3(cataCXium® A Pd G3) (40.8 mg, 56.0 µmol, 0.100 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 mL×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 5:1. Tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-(2,2,2-trifluoroacetyl)pyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 446 µmol, 79.5% yield, 93% purity) was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ = 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, 8.8 Hz, 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).

[0231] To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-(2,2,2- trifluoroacetyl)pyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 425 µmol, 1.00 eq) in water (0.1 mL) and methanol (0.5 mL) was added NaOH (17.0 mg, 425 µmol, 1.00 eq) at 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 mL×3). The combined organic layer was concentrated in vacuum. The mixture was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 2 / 1). Tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 390.23 µmol, 91.62% yield, 94% purity) was obtained as a yellow solid. LCMS (ESI) m / z 843.6 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 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).

[0232] 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 (R)-7-hydroxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]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 × 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-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7- yl)oxy)ethoxy)propanoate (270 mg, 659 µmol, 33.4% yield, 98% purity) was obtained as a colorless gum.

[0233] To a solution of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-1- methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (200 mg, 521 µmol, 1.00 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 1h. The mixture was concentrated in vacuum. Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5- yl)propanoate (210 mg, crude) was obtained as a yellow oil, which was used for the next step directly.

[0234] To a solution of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-methoxy-1- methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (210 mg, 522 µmol, 1.00 eq) in acetonitrile (5 mL) was added potassium carbonate (144 mg, 1.05 mmol, 2.00 eq) and tert-butyl (R)-3-(2-((4- methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7-yl)oxy)ethoxy)propanoate (251 mg, 627 µmol, 1.20 eq) at 20°C. The mixture was stirred at 90°C for 1h. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 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-(((R)-7-(2-(3-(tert-butoxy)-3-oxopropoxy)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][1,2,3]triazol-5-yl)propanoate (380 mg, 496 µmol, 94.8% yield) was obtained as a colorless oil.

[0235] To a solution of ethyl 3-(3-(((R)-7-(2-(3-(tert-butoxy)-3-oxopropoxy)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][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-(((4R)-2-(5-(3- ethoxy-1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)propanoic acid (320 mg, crude) was obtained as a yellow gum.

[0236] To a solution of 3-(2-(((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H- benzo[d][1,2,3]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)propanoic acid (100 mg, 140 µmol, 1.00 eq) in dichloromethane (0.5 mL) was added dimethylformamide (10.2 mg, 140 µmol, 10.8 µL, 1.00 eq) and oxalyl dichloride (53.5 mg, 422 µmol, 36.9 µL, 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)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][1,2,3]triazol-5-yl)propanoate (101 mg, crude) was obtained as a yellow solid.

[0237] To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-pyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (115 mg, 137 µmol, 1.00 eq) and triethylamine (13.8 mg, 137 µmol, 19.0 µL, 1.00 eq) in dichloromethane (3 mL) was added ethyl 3-(3-(((R)-7-(2-(3-chloro-3-oxopropoxy)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][1,2,3]triazol-5-yl)propanoate (100 mg, 137 µmol, 1.00 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 × 3). The combined organic layer was dried over with sodium sulfate and concentrated in vacuum. The mixture was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 2 / 1. Tert-butyl (1R,5S)-3-(2-(((2S)-1-(3-(2-(((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H- benzo[d][1,2,3]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)propanoyl)pyrrolidin-2-yl)methoxy)-8-fluoro- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 83.99 µmol, 61.25% yield, 86% purity) was obtained as a yellow solid. MS (ESI) m / z 1536.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 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, J = 7.6 Hz, 1H), 6.93 - 6.81 (m, 3H), 5.35 (d, J = 1.6 Hz, 2H), 4.62 - 4.48 (m, 2H), 4.45 - 4.11 (m, 13H), 4.03 (q, J = 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, J = 7.2 Hz, 18H), 0.49 (br s, 3H).

[0238] To a solution of tert-butyl (1R,5S)-3-(2-(((2S)-1-(3-(2-(((4R)-2-(5-(3-ethoxy- 1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)propanoyl)pyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 78.1 µmol, 1.00 eq) in dimethylformamide (2 mL) was added cesium fluoride (59.3 mg, 390 µmol, 14.4 µL, 5.00 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 (1R,5S)-3-(2-(((2S)-1-(3-(2-(((4R)- 2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)propanoyl)pyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-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.

[0239] To a solution of tert-butyl (1R,5S)-3-(2-(((2S)-1-(3-(2-(((4R)-2-(5-(3-ethoxy- 1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)propanoyl)pyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 65.2 µmol, 1.00 eq) in dichloromethane (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-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)-3-oxopropoxy)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][1,2,3]triazol-5-yl)propanoate (6.92 mg, 5.13 μmol, 7.86% yield, 95% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1235.7 / 1236.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) 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).

[0240] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]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 (1R,5S)-3,8-diazabicyclo[3.2.1]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 × 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 (1R,5S)-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]+.

[0241] To a solution of tert-butyl (1R,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 × 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 (1R,5S)-3-(7- chloro-2,8-difluoropyrido[4,3-d]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]+.

[0242] To a solution of tert-butyl (1R,5S)-3-(7-chloro-2,8-difluoropyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (770 mg, 1.87 mmol, 1.00 eq) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- 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(1+);bis(1-adamantyl)- butyl-phosphane;methanesulfonate (136 mg, 187 μmol, 0.100 eq) and 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 (1R,5S)-3-(2,8-difluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 919 μmol, 49.14% yield) as a yellow oil.1H 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).

[0243] To a solution of 2-(benzyloxy)ethan-1-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 × 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.

[0244] To a solution of tert-butyl 4-hydroxypiperidine-1-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.

[0245] To a solution of palladium / carbon (500 mg, 10% purity) in tetrahydrofuran (30.0 mL) was added tert-butyl 4-(2-(benzyloxy)ethoxy)piperidine-1-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-1-carboxylate (2.2 g, 8.97 mmol, 85.95% yield) was obtained as acolorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 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).

[0246] 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 (SiO2, petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (1.40 g, 3.50 mmol, 87.72% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) 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).

[0247] To a solution of (4R)-4-methyl-1,1-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-1-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 with dichloromethane / isopropanol = 3 / 1 (50.0 mL × 3). The combined organic layer was dried overanhydrous sodium sulfate, filtered, and 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 4-[2-[[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7- yl]oxy]ethoxy]piperidine-1-carboxylate (1.20 g, 2.34 mmol, 67.04% yield, 89% purity) as a brown oil.1H 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).

[0248] To a solution of ethyl 3-[3-(hydroxymethyl)-4-methyl-phenyl]-3-(7-methoxy- 1-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-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7- yl]oxy]ethoxy]piperidine-1-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 (SiO2, petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl 4-[2-[[(4R)-2-[[5-[3- ethoxy-1-(7-methoxy-1-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]piperidine-1-carboxylate (550 mg, 669.12 μmol, 31.82% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 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).

[0249] A mixture of tert-butyl 4-[2-[[(4R)-2-[[5-[3-ethoxy-1-(7-methoxy-1-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]piperidine-1-carboxylate (530 mg, 645 μmol, 1.00 eq) in 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 C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:18%-48% B over 2 min) to give ethyl 3-(7-methoxy-1-methyl-benzotriazol-5-yl)-3-[4-methyl-3-[[(4R)-4-methyl-1,1-dioxo-7-[2- (4-piperidyloxy)ethoxy]-3,4-dihydro-5,1,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (500 mg, 623.39 μmol, 96.68% 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 = 7.2 Hz, 3H).

[0250] To a solution of tert-butyl (1S,5R)-3-[2,8-difluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 131 μmol, 1.00 eq) in dioxane (2.00 mL) was added cesium carbonate (128 mg, 394 μmol, 3.00 eq) and ethyl 3-(7-methoxy-1-methyl- benzotriazol-5-yl)-3-[4-methyl-3-[[(4R)-4-methyl-1,1-dioxo-7-[2-(4-piperidyloxy)ethoxy]-3,4- dihydro-5,1,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (119 mg, 165 μmol, 1.26 eq). 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 (1S,5R)-3-[2-[4-[2-[[(4R)-2-[[5-[3-ethoxy-1-(7-methoxy-1-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]-8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 99.47 μmol, 75.79% yield, 91% purity) as a yellow solid. MS (ESI) m / z 1464.4 [M+H]+.

[0251] To a solution of tert-butyl (1S,5R)-3-[2-[4-[2-[[(4R)-2-[[5-[3-ethoxy-1-(7- methoxy-1-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]-8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 109 μmol, 1.00 eq) in dimethylformamide (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-[[(4R)-7-[2-[[1-[4-[(1S,5R)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-pyrido[4,3-d]pyrimidin-2-yl]-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-1-methyl-benzotriazol-5- yl)propanoate (48.40 mg, 41.31 μmol, 38.58% yield, 99.29% purity) as a yellow solid. MS (ESI) m / z 207.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.02 (s, 1H), 8.19 (s, 1H), 7.97 (dd, J = 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, J = 7.6 Hz, 1H), 6.93 (dd, J = 2.4, 8.8 Hz, 1H), 6.89 (s, 1H), 6.79 (dd, J = 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, J = 8.0 Hz, 3H), 2.57 (d, J = 2.4 Hz, 2H), 2.21 (s, 3H), 2.04 (t, J = 9.2 Hz, 2H), 1.76 (d, J = 9.2 Hz, 2H), 1.50 (s, 2H), 1.42 - 1.24 (m, 6H), 1.03 (t, J = 7.2 Hz, 3H).

[0252] 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-1-methyl-benzotriazol-5-yl)-3-[4-methyl-3-[[(4R)-4-methyl-1,1-dioxo-7-[2- (4-piperidyloxy)ethoxy]-3,4-dihydro-5,1,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoate (180 mg, 249 μmol, 1.00 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 × 2). The organic layer was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, ethyl acetate) to give ethyl 3-[3-[[(4R)-7-[2-[[1-(2-hydroxypropyl)-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-1- methyl-benzotriazol-5-yl)propanoate (140 mg, 179.50 μmol, 71.99% yield) as a white oil.1H NMR (400 MHz, CDCl3) δ = 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 = 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, J = 7.2 Hz, 3H).

[0253] To a solution of ethyl 3-[3-[[(4R)-7-[2-[[1-(2-hydroxypropyl)-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-1-methyl-benzotriazol-5-yl)propanoate (140 mg, 179 μmol, 1.00 eq) in tetrahydrofuran (2.00 mL) was added sodium hydride (14.4 mg, 359 μmol, 60% purity, 2.00 eq). The mixture was stirred at 20 °C for 5 min. Then tert-butyl (1S,5R)-3-[2,8-difluoro-7-[7- fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4- yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (178 mg, 2338 μmol, 1.30 eq) in tetrahydrofuran (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 × 2). The organic layer 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 (1S,5R)-3-[2-[2-[4-[2-[[(4R)-2-[[5- [3-ethoxy-1-(7-methoxy-1-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- ethoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 106.12 μmol, 59.12% yield, 95% purity) as a yellow solid.MS (ESI) m / z 1522.3 [M+H]+.

[0254] To a solution of tert-butyl (1S,5R)-3-[2-[2-[4-[2-[[(4R)-2-[[5-[3-ethoxy-1-(7- methoxy-1-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-ethoxy]-8- fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3- d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 112 μmol, 1.00 eq) in dimethylformamide (1.70 mL) was added cesium fluoride (169 mg, 1.12 mmol, 41.2 μL, 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:11%-41% B over 10 min) andlyophilized to afford ethyl 3-[3-[[(4R)-7-[2-[[1-[2-[4-[(1S,5R)-3,8-diazabicyclo[3.2.1]octan-3-yl]- 7-(8-ethynyl-7-fluoro-3-hydroxy-1-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-1-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]+.1H NMR (400 MHz, DMSO-d6) δ = 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).

[0255] To a solution of ethyl 3-[3-[[(4R)-7-[2-[[1-[2-[4-[(1S,5R)-3,8- diazabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-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-1-methyl- benzotriazol-5-yl)propanoate (100 mg, 79.5 μmol, 1.00 eq, hydrochloride salt) in tetrahydrofuran (1.00 mL) and water (0.200 mL) was added lithium hydroxide monohydrate (10.0 mg, 239 μmol, 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-[[1-[2-[4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(8- ethynyl-7-fluoro-3-hydroxy-1-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-1-methyl-benzotriazol-5-yl)propanoic acid (5.57 mg, 4.39 μmol, 5.52% yield, 97.6% purity, FA) as a yellow solid. MS (ESI) m / z 384.2 [M+H]+.1H 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 = 7.2 Hz, 1H), 7.02 (d, J = 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, J = 7.6 Hz, 5H), 2.57 (d, J = 2.4 Hz, 3H), 2.20 (s, 3H), 2.05 (d, J = 9.2 Hz, 2H), 1.83 - 1.56 (m, 6H), 1.45 - 1.13 (m, 8H).

[0256] To a solution of (R)-2-(((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1- methylpyrrolidine-2-carboxylic acid (210 mg, 233 μmol, 1.00 eq) and ethyl 3-(7-methoxy-1- methyl-1H-benzo[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][1,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoate (176 mg, 233 μmol, 1.00 eq, hydrochloric acid) in dimethylformamide (5.00 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (132 mg, 349 μmol, 1.5 eq) and N,N- diisopropylethylamine (60.2 mg, 466 μmol, 81.1 μL, 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 × 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 (1R,5S)-3-(2-(((2R)-2-(4-(2-(((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H- benzo[d][1,2,3]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)piperidine-1-carbonyl)-1-methylpyrrolidin-2- yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- 1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (145 mg, 74.99 μmol, 32.18% yield, 83% purity) was obtained as a yellow solid.

[0257] To a solution of tert-butyl (1R,5S)-3-(2-(((2R)-2-(4-(2-(((4R)-2-(5-(3-ethoxy- 1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)piperidine-1- carbonyl)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 72.4 μmol, 1.00 eq) in dimethylformamide (1.50 mL) was added cesium fluoride (54.9 mg, 362 μmol, 13.3 μL, 5.00 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 (1R,5S)-3-(2-(((2R)-2-(4- (2-(((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)piperidine-1-carbonyl)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-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.

[0258] To a solution of tert-butyl (1R,5S)-3-(2-(((2R)-2-(4-(2-(((4R)-2-(5-(3-ethoxy-1- (7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)piperidine-1- carbonyl)-1-methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 54.0 μmol, 1.00 eq) in dichloromethane (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-((1-((R)-2- (((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-2-carbonyl)piperidin- 4-yl)oxy)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][1,2,3]triazol-5-yl)propanoate (18.40 mg, 13.49 μmol, 24.96% yield, 99% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1304.5 [M+H]+.1H 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).

[0259] 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 × 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-ethoxy-2-oxoethoxy)methyl)morpholine-4-carboxylate (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, J = 7.2 Hz, 3H).

[0260] 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.

[0261] 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 × 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 NMR (400 MHz, 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).

[0262] To a solution of tert-butyl 2-((2-(tosyloxy)ethoxy)methyl)morpholine-4- carboxylate (300 mg, 722 μmol, 1.00 eq) in dimethylformamide (3 mL) was added (R)-7-hydroxy- 4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (248 mg, 1.08 mmol, 1.50 eq) and potassium carbonate (100 mg, 722 μmol, 1.00 eq) at 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 × 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-1,1-dioxido-3,4- dihydro-2H-benzo[b][1,4,5]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).

[0263] To a solution of ethyl 3-[3-(hydroxymethyl)-4-methyl-phenyl]-3-(7-methoxy- 1-methyl-benzotriazol-5-yl)propanoate (350 mg, 913 μmol, 1.00 eq) in 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-1-methyl-benzotriazol-5-yl)propanoate (160 mg, 398 μmol, 43.6% yield) was obtained as a white solid.

[0264] To a solution of ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-1- methyl-benzotriazol-5-yl)propanoate (150 mg, 373 μmol, 1.00 eq) in acetonitrile (3.00 mL) was added tert-butyl 2-[2-[[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7- yl]oxy]ethoxymethyl]morpholine-4-carboxylate (176 mg, 373 μmol, 1.00 eq) and potassium carbonate (103 mg, 747 μmol, 2.00 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 × 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-1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)methyl)morpholine-4-carboxylate (250 mg, 298 μmol, 79.9% yield) was 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).

[0265] To a solution of tert-butyl 2-((2-(((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl- 1H-benzo[d][1,2,3]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)methyl)morpholine-4-carboxylate (250 mg, 298 μmol, 1.00 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-1-methyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((4R)-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 μmol, 99.6% yield, hydrochloric acid) was obtained as a white solid.

[0266] To a solution of ethyl 3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)- 3-(4-methyl-3-(((4R)-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 (172 mg, 222 μmol, 1.00 eq, hydrochloric acid) in dimethylformamide (5.00 mL) was added (R)-2-(((4-((1R,5S)-8-(tert- butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1- methylpyrrolidine-2-carboxylic acid (200 mg, 222 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (127 mg, 333 μmol, 1.50 eq) and N,N- diisopropylethylamine (86.0 mg, 666 μmol, 116 μL, 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 × 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 (1R,5S)-3-(2-(((2R)-2-(2-((2-(((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H- benzo[d][1,2,3]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)methyl)morpholine-4-carbonyl)-1- methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (260 mg, 160 μmol, 72.3% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 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, J = 2.4 Hz, 3H), 1.96 - 1.77 (m, 5H), 1.45 (s, 9H), 1.20 - 1.15 (m, 4H), 0.80 (t, J = 7.2 Hz, 18H), 0.57 - 0.40 (m, 3H).

[0267] To a solution of tert-butyl (1R,5S)-3-(2-(((2R)-2-(2-((2-(((4R)-2-(5-(3-ethoxy- 1-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]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)methyl)morpholine-4-carbonyl)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 154 μmol, 1.00 eq) in 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 (1S,5R)-3-[2- [[(2R)-2-[2-[2-[[(4R)-2-[[5-[3-ethoxy-1-(7-methoxy-1-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]ethoxymethyl]morpholine-4-carbonyl]-1-methyl-pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (225 mg, crude) was obtained as a yellow solid.

[0268] To a solution of tert-butyl (1S,5R)-3-[2-[[(2R)-2-[2-[2-[[(4R)-2-[[5-[3-ethoxy- 1-(7-methoxy-1-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]ethoxymethyl]morpholine-4-carbonyl]- 1-methyl-pyrrolidin-2-yl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-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 C18 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-((R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)-1-methylpyrrolidine-2-carbonyl)morpholin-2-yl)methoxy)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][1,2,3]triazol-5-yl)propanoate (103 mg, 77.3 μmol, 51.44% yield, 99% purity) was obtained as a white solid. MS (ESI) m / z 1321 [M+H]+.1H NMR (400 MHz, DMSO-d6) 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).

[0269] 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 (2R)-1-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 × 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-N-(2-hydroxypropyl)benzenesulfonamide (10.8 g, 34.60 mmol, 94.63% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.98 (br s, 1H), 7.84 (dd, J = 2.0, 9.6 Hz, 1H), 7.77 - 7.66 (m, 1H), 7.62 (dd, J = 1.6, 8.4 Hz, 1H), 4.68 (d, J = 4.8 Hz, 1H), 3.68 - 3.49 (m, 1H), 2.91 - 2.68 (m, 2H), 0.98 (d, J = 6.2 Hz, 3H).

[0270] To a solution of (R)-4-bromo-2-fluoro-N-(2- hydroxypropyl)benzenesulfonamide (4.50 g, 14.4 mmol, 1.00 eq) in dimethylsulfoxide (60.0 mL) was added potassium tert-butoxide (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 mL×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 (R)-7-bromo-4-methyl-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepine 1,1-dioxide (1.70 g, 5.82 mmol, 40% yield) as a yellow solid. MS (ESI) m / z 293.8 [M+H]+.

[0271] To a solution of (R)-7-bromo-4-methyl-3,4-dihydro-2H- benzo[b][1,4,5]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 × 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-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7- yl)piperazine-1-carboxylate (400 mg, 996. μmol, 56% yield, 99% purity) as a yellow solid. MS (ESI) m / z 397.9 [M+H]+.

[0272] To a solution of ethyl 3-[3-(hydroxymethyl)-4-methyl-phenyl]-3-(7-methoxy- 1-methyl-benzotriazol-5-yl)propanoate (340 mg, 887 μmol, 1.00 eq) in dichloromethane (10.0 mL) was added SOCl2 (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 × 3). The organic layer was concentrated under vacuum to give ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5-yl)propanoate as a yellow oil. To a solution of tert-butyl (R)-4-(4-methyl-1,1-dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin-7-yl)piperazine-1-carboxylate (110 mg, 277 μmol, 1.00 eq) in acetonitrile (1.00 mL) was added potassium carbonate (115 mg, 830 μmol, 3.00 eq) and ethyl 3- [3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-1-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-((4R)-2-(5-(3-ethoxy-1- (7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-7-yl)piperazine-1-carboxylate (170 mg, 223 μmol, 80% yield) as a yellow oil. MS (ESI) m / z 763.5 [M+H]+.

[0273] A mixture of tert-butyl 4-((4R)-2-(5-(3-ethoxy-1-(7-methoxy-1-methyl-1H- benzo[d][1,2,3]triazol-5-yl)-3-oxopropyl)-2-methylbenzyl)-4-methyl-1,1-dioxido-3,4-dihydro- 2H-benzo[b][1,4,5]oxathiazepin-7-yl)piperazine-1-carboxylate (160 mg, 209 μmol, 1.00 eq) in 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-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl- 3-(((R)-4-methyl-1,1-dioxido-7-(piperazin-1-yl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoate (140 mg, 196 μmol, 93% yield, 98% purity, hydrochloric acid salt) as a yellow solid. MS (ESI) m / z 663.2 [M+H]+.

[0274] 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°C for 16 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 0 / 1) to give methyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate (4.3 g, 17.11 mmol, 65.62% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 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).

[0275] To a solution of 6-(4-(hydroxymethyl)piperidin-1-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 eq)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-1-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-d6) 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).

[0276] A mixture of tert-butyl N-[4-(3-chloro-4-cyano- 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-(((1r,4r)-4- aminocyclohexyl)oxy)-2-chlorobenzonitrile (880 mg, 2.54 mmol, 89.23% yield, 83% purity, hydrochloric acid salt) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 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).

[0277] To a solution of 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (500 mg, 2.11 mmol, 1.00 eq) in N,N-Dimethylformamide (10.0 mL) was added O-(7- azabenzotriazol-1-yl)-N,N,N,N-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 × 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 N-((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (950 mg, 2.02 mmol, 96% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 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 = 12.4 Hz, 2H), 1.22 - 1.03 (m, 3H).

[0278] To a solution of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4- (hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (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 × 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 N-((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (350 mg, 748 μmol, 70.30% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 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).

[0279] To a solution of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4- formylpiperidin-1-yl)pyridazine-3-carboxamide (85 mg, 181.64 μmol, 1 eq) and ethyl 3-(7- methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-7- (piperazin-1-yl)-3,4-dihydro-2H-benzo[b][1,4,5]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 μmol, 3.00 eq) and acetic acid (32.7 mg, 545 μmol, 31.2 μL, 3.00 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 C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:33%-63% B over 10 min) and lyophilized to afford ethyl 3-(3-(((R)-7-(4-((1-(6-(((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)-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][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]+.1H NMR (400 MHz, DMSO- d6) δ = 8.60 (d, J = 8.4 Hz, 1H), 7.91 - 7.73 (m, 2H), 7.51 (dd, J = 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).

[0280] To a solution of ethyl 3-(3-(((R)-7-(4-((1-(6-(((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)-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][1,2,3]triazol-5-yl)propanoate (40.0 mg, 35.9 μmol, 1.00 eq) in water (0.400 mL) and tetrahydrofuran (2.00 mL) was added lithium hydroxide monohydrate (4.52 mg, 108 μmol, 3.00 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 prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:25%-55% B over 8 min) and lyophilized to afford 3-(3-(((R)-7-(4-((1-(6-(((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)-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][1,2,3]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-d6) 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, J = 2.0, 8.8 Hz, 1H), 7.45 (d, J = 4.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.27 (br t, J = 6.8 Hz, 1H), 7.17 - 7.06 (m, 2H), 6.91 (d, J = 9.8 Hz, 1H), 6.80 (br d, J = 8.8 Hz, 1H), 6.75 (br s, 1H), 4.61 - 4.45 (m, 4H), 4.44 - 4.25 (m, 5H), 3.92 (d, J = 4.4 Hz, 3H), 3.88 - 3.80 (m, 1H), 3.71 (br d, J = 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, J = 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). E l 26 P i f C d 96

[0281] To a solution of (R)-7-hydroxy-4-methyl-3,4-dihydro-2H- benzo[b][1,4,5]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 mL×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®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~12% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). (R)- 7-(4-((tert-butyldimethylsilyl)oxy)butoxy)-4-methyl-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepine 1,1-dioxide (480 mg, 1.11 mmol, 42% yield, 96% purity) was obtained as a white oil.

[0282] To a solution of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(7-methoxy-1- methyl-1H-benzo[d][1,2,3]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 mL×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 crude compound was used into the next step without further purification. Ethyl 3- [3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-1-methyl-benzotriazol-5-yl)propanoate (300 mg, crude) was obtained as a yellow oil.

[0283] To a solution of ethyl 3-[3-(chloromethyl)-4-methyl-phenyl]-3-(7-methoxy-1- methyl-benzotriazol-5-yl)propanoate (300 mg, 747 μmol, 1.00 eq) and (R)-7-(4-((tert- butyldimethylsilyl)oxy)butoxy)-4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1- dioxide (310 mg, 746 μmol, 1.00 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 mL×3). 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 flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~13% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Ethyl 3-(3-(((R)-7-(4-((tert- butyldimethylsilyl)oxy)butoxy)-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][1,2,3]triazol-5-yl)propanoate (400 mg, 512.14 μmol, 68.61% yield) was obtained as a white oil.

[0284] To a solution of Ethyl 3-(3-(((R)-7-(4-((tert-butyldimethylsilyl)oxy)butoxy)-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][1,2,3]triazol-5-yl)propanoate (300 mg, 384 μmol, 1.00 eq) 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 mL×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 crude compound was used into the next step without further purification. Ethyl 3-(3-(((R)-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-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (250 mg, crude) was obtained as a yellow oil.

[0285] To a solution of ethyl 3-(3-(((R)-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-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (250 mg, 375 μmol, 1.00 eq) in dichloromethane (4.00 mL) was added 4-methylbenzenesulfonyl chloride (143 mg, 750 μmol, 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 mL×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®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate / Petroleum ether gradient @ 20 mL / min). Ethyl 3-(7-methoxy-1-methyl-1H- benzo[d][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[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (200 mg, 244 μmol, 64.9% yield) was obtained as a white oil.1H NMR (400 MHz, DMSO-d6) δ = 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).

[0286] To a solution of 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (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, 1.20eq) 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 mL×3). 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-1-yl)phenyl trifluoromethanesulfonate (1.6 g, crude) was obtained as a red solid.

[0287] To a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1-yl)phenyl trifluoromethanesulfonate (500 mg, 930 μmol, 1.00 eq) in 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 μmol, 0.0800 eq) 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 mL×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®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). 4-(3-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (180 mg, 373.84 μmol, 40.18% yield) was obtained as a red solid.1H NMR (400 MHz, DMSO-d6) δ = 9.65 (s, 1H), 8.40 (d, J = 8.4 Hz,1H), 8.32 (d, J = 1.6 Hz, 1H), 8.11 (dd, J = 1.6, 8.4 Hz, 1H), 7.77 (d, J = 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). E l 273 S th i f C d P 18

[0288] To a solution of 4-(3-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (35.2 mg, 73.1 μmol, 1.50 eq) in dimethylformamide (1.00 mL) was added ethyl 3-(7-methoxy-1-methyl-1H- benzo[d][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[b][1,4,5]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 mL×3). 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* 10um; 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-(trifluoromethyl)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[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(7- methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (12.99 mg, 11.26 μmol, 23.12% yield, 98% purity) was obtained as an off-white solid. MS (ESI) m / z 1130.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) 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).

[0289] To a solution of ethyl 3-(3-(((R)-7-(4-((4'-(3-(4-cyano-3- (trifluoromethyl)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[b][1,4,5]oxathiazepin-2-yl)methyl)- 4-methylphenyl)-3-(7-methoxy-1-methyl-1H-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 monohydrate (4.46 mg, 106 μmol, 3.00 eq) at 20°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 mL×3). 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 byprep-HPLC (Column:Phenomenex luna C18 150*25mm* 10um; 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-(trifluoromethyl)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[b][1,4,5]oxathiazepin- 2-yl)methyl)-4-methylphenyl)-3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid (22.68 mg, 18.96 μmol, 53.58% yield, 96% purity, FA) was obtained as a yellow solid. MS (ESI) m / z 1102.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 12.38 - 11.95 (m, 1H), 8.46 - 8.25 (m, 2H), 8.10 (dd, J = 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

[0290] Compounds were screened to determine compounds that can promote interactions between two non-interacting proteins (Biotinylated-Keap1 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% BSA0.1% Tween20) was prepared. For the assay, equal volumes of 5x His-KRAS (200 nM) and 5x Biotin-Keap1 (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 1h. 100x Streptavidin-Eu cryptate (Eu) and 100x 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 1h and the plates were read. The results are shown in Table 1.T

Claims

What is claimed is:

1. A compound, having the structure of Formula (I): , wherein:A is a KEAP1 binder of Formula (II) having the structure:wherein: R1is H and R4is , R4is a substituted or unsubstituted C1-4alkoxy and R1is, or R4is a substituted or unsubstituted C1-4alkoxy and R1 is; R2is H or a substituted or unsubstituted C1-4alkyl; R3is –CH2CO2R6; R5is H or a substituted or unsubstituted C1-4alkyl; R6is H or a substituted or unsubstituted C1-4alkyl; B is selected from the group consisting of Formulas (III-A), (III-B), and (III-C):R7is or and R12is , or R7i13 12s –OR and R isR8is halogen; R9is –OR15; R10is halogen or C1-4haloalkyl; R11is cyano; R13is; R14is H or a substituted or unsubstituted C1-4alkyl; R15is H or a substituted or unsubstituted C1-4alkyl; R16is H or a substituted or unsubstituted C1-4alkyl; represents a single bond attachment to L; and L is a chemical linker, or a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1, wherein A is a KEAP1 binder of Formula (II-A):

3. The compound of Claim 1, wherein A is a KEAP1 binder of Formula (II-B):

4. The compound of any one of Claims 1 to 3, wherein R7is 5. The compound of any one of Claims 1 to 3, wherein R7is6. The compound of any one of Claims 1 to 5, wherein R12is7. The compound of any one of Claims 1 to 5, wherein R7is –OR13and R13isand R12is.

8. The compound of any one of Claims 1 to 7, wherein L is a chemical linker having the structure of Formula (IV): [–X1–X2–X3–X4–X5–X6–X7–X8–] (IV), wherein: X1is –(CH2)m–, wherein m is an integer from 1 to 4; X2is O (oxygen) or is absent; X3is –(CH2)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; and X8is selected from the group consisting of:, or is absent.

9. The compound of any one of Claims 1-8, wherein X1is –(CH2)m– and m is 2.

10. The compound of any one of Claims 1-9, wherein X2is O (oxygen).

11. The compound of any one of Claims 1-9, wherein X2is absent.

12. The compound of any one of Claims 1-11, wherein X3is –(CH2)n– and n is 0.

13. The compound of any one of Claims 1-11, wherein X3is –(CH2)n– and n is 1.

14. The compound of any one of Claims 1-11, wherein X3is –(CH2)n– and n is 2.

15. The compound of any one of Claims 1-14, wherein X4is O (oxygen).

16. The compound of any one of Claims 1-14, wherein X4is absent.

17. The compound of any one of Claims 1-16, wherein X5is –(CH2)p– and p is 0.

18. The compound of any one of Claims 1-16, wherein X5is –(CH2)p– and p is 2.

19. The compound of any one of Claims 1-18, wherein X6is –NH–.

20. The compound of any one of Claims 1-18, wherein X6is 21. The compound of any one of Claims 1-18, wherein X6is.

22. The compound of any one of Claims 1-18, wherein X6is23. The compound of any one of Claims 1-22, wherein X7is –C(=O)–.

24. The compound of any one of Claims 1-22, wherein X7is –(CH2)q– and q is 0.

25. The compound of any one of Claims 1-24, wherein X8is 26. The compound of any one of Claims 1-24, wherein X8is 27. The compound of any one of Claims 1-24, wherein X8is 28. The compound of any one of Claims 1-24, wherein X8is29. The compound of any one of Claims 1-28, wherein X6is absent, provided that X8is not absent; or wherein X8is absent, provided that X6is not absent.

30. The compound of Claim 29, wherein if X8is absent, X6is31. The compound of any one of Claims 1-4, wherein L is selected from the group consisting of:, and, whereinrepresents points of attachment to the rest of the compound.

32. The compound of Claim 31, wherein L is 33. The compound of Claim 31, wherein L is 34. The compound of Claim 31, wherein L is35. The compound of Claim 31, wherein L is 36. The compound of Claim 31, wherein L is 37. The compound of Claim 31, wherein L is 38. The compound of Claim 31, wherein L is 39. The compound of Claim 31, wherein L is40. The compound of Claim 31, wherein L is41. The compound of Claim 31, wherein L is42. The compound of Claim 31, wherein L is 43. The compound of any one of Claims 1-42,wherein B has the structure of Formula (III-44. The compound of any one of Claims 1-42, wherein B has the structure of Formula (III-45. The compound of any one of Claims 1-42, wherein B has the structure of Formula (III-C): R .

46. The compound of any one of Claims 1-45, wherein R2is –CH3.

47. The compound of any one of Claims 1-46, wherein R3is –CH2CO2R6and R6is H.

48. The compound of any one of Claims 1-47, wherein R3is –CH2CO2R6and R6is –CH2CH3.

49. The compound of any one of Claims 1-48, wherein R5is –CH3.

50. The compound of any one of Claims 1-43, wherein R8is fluoro.

51. The compound of any one of Claims 1-43, wherein R9is H.

52. The compound of any one of Claims 1-51, wherein R10is fluoro.

53. The compound of any one of Claims 1-51, wherein R10is chloro.

54. The compound of any one of Claims 1-51, wherein R10is –CF3.

55. The compound of any one of Claims 1-54, wherein R14is H.

56. The compound of Claim 45, wherein R16is H.

57. The compound of Claim 1, wherein the compound is selected from the group consistingor a pharmaceutically acceptable salt of any of the foregoing.

58. The compound of Claim 1, wherein the compound is selected from the group consistingor apharmaceutically acceptable salt of any of the foregoing.

59. The compound of Claim 1, wherein the compound is or, or a pharmaceutically acceptable salt of any of the foregoing.

60. The compound of Claim 1, wherein the compound is or, or a pharmaceutically acceptable salt of any of the foregoing.

61. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-60 and an excipient.

62. 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 1-60.

63. A compound of any one of Claims 1-60 for use in treating cancer.

64. The compound of Claim 63, 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.

65. Use of a compound of any one of Claims 1-60 in the preparation of a medicament for use in treating cancer.

66. The use of Claim 65, 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.

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