Ras inhibitors and methods of use thereof

Abstract

The disclosure provides compounds, e.g., compounds of Formulae (I)-(III), and their use in treating medical diseases or disorders, such as cancer. Pharmaceutical compositions and methods of making various indene compounds are provided. The compounds are contemplated to be modulators of Ras (e.g., K-Ras).

Description

Attorney Docket No. KEST-004WO RAS INHIBITORS AND METHODS OF USE THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 607,618, filed on December 8, 2022; the content of which is hereby incorporated by reference herein in its entirety. BACKGROUND

[0002] Ras proteins (e.g., K-Ras, H-Ras and N-Ras) play an important role in various human cancers and represent attractive targets for anticancer therapy. Dysregulation of Ras proteins by activating mutations, overexpression or upstream activation is commonly observed in human tumor cells, and activating mutations in Ras are often observed in human cancers. For example, activating mutations at codon 12 in Ras proteins function by inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly altering the population of Ras mutant proteins to the "on" (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. Ras proteins show a strong affinity for GTP, thereby allowing Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61K) of Ras are also responsible for oncogenic activity in some cancers.

[0003] For example, oncogenic K-Ras mutations that stabilize GTP binding and lead to constitutive activation of K-Ras and downstream signaling have been reported in various types of cancers. K-Ras mutations at codons 12, 13, 61 and other positions of the K-Ras primary amino acid sequence have been observed in patient with pancreatic, colorectal, non-small cell lung, and small cell lung adenocarcinomas.

[0004] Despite extensive research and discovery efforts by the pharmaceutical industry to develop inhibitors of Ras (e.g., K-Ras) for treating cancer, no such inhibitor has yet demonstrated sufficient safety and / or efficacy to obtain regulatory approval. Thus, an unmet need exists to develop new pan-Ras inhibitors, for example inhibitors of activating Ras mutants. that show safety and efficacy profiles necessary for treating Ras-mediated cancers and other conditions that are affected by, associated with, or would benefit from inhibition of Ras. 1 IPTS / 125370156.1Attorney Docket No. KEST-004WO SUMMARY

[0005] The disclosure is directed, in part, to compounds that inhibit Ras, for example, multiple mutated forms of Ras, for example, K-Ras. Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a method of treating a disease or disorder characterized by aberrant Ras activity due to a Ras mutation (e.g., aberrant K-Ras activity due to a K-Ras mutation). In some embodiments, the disease or disorder is a cancer.

[0006] For example, disclosed herein is a compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; Ring B is a 5-10 membered heterocyclyl containing at least one ring nitrogen; RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; X is selected from the group consisting of -C(RX1RX2)-, -O-, -NRa-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -NRaC(O)-, and -C(O)NRa-; 2 IPTS / 125370156.1Attorney Docket No. KEST-004WO RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, - NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; L is a linker moiety comprising: two to five bivalent units each represented by -(CR1R2)-; and one or two additional units each independently selected from the group consisting of -O-, -NRa-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, - OC(O)NRa-, -NRaC(O)NRb-, and -CH=CH-; R1and R2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, -NRaRb, C1-C3alkyl, and C1-C3alkoxy; R3is selected from the group consisting of hydrogen, deuterium, halogen, and C1- C3alkyl; R4, R5, and R6are each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; R7, R8, R9, and R10are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, - O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, - O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1- C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each 3 IPTS / 125370156.1Attorney Docket No. KEST-004WO independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; or R7and R8are joined together to form oxo; or or R9and R10are joined together to form oxo; R11and R12are each independently selected from the group consisting of hydrogen, deuterium, and C1-C3alkyl; Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1- C6alkyl, and C1-C6alkoxy; m is 1 and n is 2 or 1; or m is 2 and n is 1 or 0; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and t is 0, 1, or 2.

[0007] Also disclosed herein is a compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl; 4 IPTS / 125370156.1Attorney Docket No. KEST-004WO RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NH2, -C(O)NH2,C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, and C3-C6cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens; X is selected from the group consisting of -C(RX1RX2)-, -O-, and -N(Ra); RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; L is selected from the group consisting of -(CH2)2-5-O-, -(CH2)2-5-C(O)-O-, -(CH2)2-5-O- C(O)-, -(CH2)2-5-C(O)-NRa-, -(CH2)2-5-NRa-C(O)-, -(CH2)2-5-S-, -(CH2)2-5-S(O)-, -(CH2)-2-5- S(O)2-, -O-(CH2)2-5-O-, -(CH2)1-2-O-(CH2)2-3-O-, and -CH=CH-(CH2)2-5-O-; R1and R2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy, or R1and R2are joined together to form oxo; R3and R4are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy, or R1and R2are joined together to form oxo; R5is selected from the group consisting of halogen and hydrogen; Ring B is selected from the group consistingRaand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl; and q is 1, 2, or 3.

[0008] Further disclosed herein is a compound represented by Formula III:5 IPTS / 125370156.1Attorney Docket No. KEST-004WO or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein A, B, L, RA, RB,R1, R2, p, and q are as defined herein.

[0009] Also disclosed herein are pharmaceutical compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions comprise at least one additional therapeutic agent.

[0010] Further disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from inhibition of Ras (e.g., K-Ras), comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0011] For example, disclosed herein are methods of treating a Ras protein-related (e.g., a K-Ras protein-related) disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. For example, in some embodiments, the compounds and compositions disclosed herein may be used to treat a cancer having one or more Ras mutations (e.g., a K-Ras mutation). In some embodiments, the methods described herein may be useful to treat cancers including, but not limited to, pancreatic cancer, colorectal cancer, multiple myeloma, lung adenocarcinoma, melanoma, endometrial cancer, uterine cancer, thyroid, acute myelocytic leukemia, bladder carcinoma, gastric cancer, cervical cancer, and head and neck squamous cell carcinoma.

[0012] Also disclosed herein are methods of inhibiting a Ras protein (e.g., a K-Ras protein) in a cell or tissue, comprising contacting the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. DETAILED DESCRIPTION

[0013] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. 6 IPTS / 125370156.1Attorney Docket No. KEST-004WO Definitions

[0014] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0015] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-6alkyl, C1-4alkyl, and C1-3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0016] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C1-C5alkenyl, C2-C6alkenyl, and C3-C4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0017] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and C3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0018] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C1-C5alkoxy, C1-C6alkoxy, and C2- C6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[0019] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems 7 IPTS / 125370156.1Attorney Docket No. KEST-004WO wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from C1-C8alkyl, C1-C8haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60and R61are each independently hydrogen, C1-C8alkyl, C1-C4haloalkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, substituted C6-C10aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0020] The term “carbonyl” as used herein refers to the radical -C(O)-.

[0021] The term “cyano” as used herein refers to the radical -CN.

[0022] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3-C10cycloalkyl, C3-6cycloalkyl or C4-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0023] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

[0024] The terms “haloalkyl” as used herein refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not 8 IPTS / 125370156.1Attorney Docket No. KEST-004WO limited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e., Cl, F, Br and I), referred to herein as C1-6haloalkyl, C1-4haloalkyl, and C1-3haloalkyl, respectively.

[0025] The term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0026] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.

[0027] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 3-12 membered ring structures, for example, 4-10 membered ring structures, for example, 4-8 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur, wherein the sulfur atom may be oxidized to SO or SO2.. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. Further examples include Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, 9 IPTS / 125370156.1Attorney Docket No. KEST-004WO oxazolidinonyl, decahydroquinolinyi, piperidonyl, 4-piperidinonyl, quinudidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro- 1 H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro- 1 Ή,3Ή- spiro [cyclopropane- 1 ,2'-pyrrolizine] , hexahydro- 1 H-pyrroliziny 1, hexahy dro- 1 H-pyrrolo [2,1- c][1]oxazinyI, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyI 1 -oxide and tetrahydro-2H-thiopyranyl 1,1 -dioxide. In some embodiments, the heterocycle is a spiro heterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro-1H-4,7- methanoisoindole). "Spiro heterocyclyl," or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is an integer of 0 to 2) as ring atoms.

[0028] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH.

[0029] The term “oxo” as used herein refers to the radical =O.

[0030] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0031] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0032] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0033] “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the 10 IPTS / 125370156.1Attorney Docket No. KEST-004WO disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). “Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and / or partial agonism.

[0034] In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0035] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2- hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. 11 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0036] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(- ),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0037] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0038] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans,” where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0039] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of 12 IPTS / 125370156.1Attorney Docket No. KEST-004WO resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0040] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0041] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0042] Certain isotopically labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. 13 IPTS / 125370156.1Attorney Docket No. KEST-004WO Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0043] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C1-8)alkyl, (C2-12)alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-2)alkylamino(C2-3)alkyl (such as β- dimethylaminoethyl), carbamoyl-(C1-2)alkyl, N,N-di(C1-2)alkylcarbamoyl-(C1-2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyl.

[0044] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-6)alkylcarbonyloxymethyl, 1-((C1-6)alkylcarbonyloxy)ethyl, 1-methyl-1-((C1-6)alkylcarbonyloxy)ethyl (C1-6)alkoxycarbonyloxymethyl, N-(C1-6)alkoxycarbonylaminomethyl, succinoyl, (C1-6)alkylcarbonyl, α-amino(C1-4)alkylcarbonyl, arylalkylcarbonyl and α- aminoalkylcarbonyl, or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl, where each α - aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-6)alkyl)2or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0045] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In 14 IPTS / 125370156.1Attorney Docket No. KEST-004WO addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplício, et al., Molecules 2008, 13, 519 and references therein. I. Compounds

[0046] The disclosure is directed, in part, to compounds that inhibit Ras, for example, multiple mutated forms of Ras, for example, K-Ras. In some embodiments, the present disclosure provides a method of treating a disease or disorder characterized by aberrant Ras activity due to a Ras mutant (e.g., aberrant K-Ras activity due to a K-Ras mutant). In some embodiments, the disease or disorder is a cancer.

[0047] For example, disclosed herein is a compound represented by Formula I: compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; Ring B is a 5-10 membered heterocyclyl containing at least one ring nitrogen; 15 IPTS / 125370156.1Attorney Docket No. KEST-004WO RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; X is selected from the group consisting of -C(RX1RX2)-, -O-, -NRa-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -NRaC(O)-, and -C(O)NRa-; RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, - NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; L is a linker moiety comprising: two to five bivalent units each represented by -(CR1R2)-; and one or two additional units each independently selected from the group consisting of -O-, -NRa-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, - OC(O)NRa-, -NRaC(O)NRb-, and -CH=CH-; R1and R2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, -NRaRb, C1-C3alkyl, and C1-C3alkoxy; R3is selected from the group consisting of hydrogen, deuterium, halogen, and C1- C3alkyl; R4, R5, and R6are each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; R7, R8, R9, and R10are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, - 16 IPTS / 125370156.1Attorney Docket No. KEST-004WO O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, - O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1- C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; or R7and R8are joined together to form oxo; or or R9and R10are joined together to form oxo; R11and R12are each independently selected from the group consisting of hydrogen, deuterium, and C1-C3alkyl; Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1- C6alkyl, and C1-C6alkoxy; m is 1 and n is 2 or 1; or m is 2 and n is 1 or 0; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and t is 0, 1, or 2.

[0048] In some embodiments, R4, R5, and R6are each, for example, hydrogen. In other embodiments, t is 1. In further embodiments, R11and R12are each hydrogen. For example, in some embodiment a compound of the present disclosure may be represented by: 17 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0049] For example, is some embodiments ring m is 1 and n is 2. For example, in some embodiments a compound of the present disclosure may be represented by:

[0050] In some embodiments, X is selected from the group consisting of, for example, - C(RX1RX2)-, -O-, and -N(Ra). In other embodiments, RX1and RX2are each independently selected from the group consisting of, for example, hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy. In further embodiments, RX1is hydrogen and RX2is selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1- C6alkoxy. In certain embodiments, RX1and RX2are each hydrogen.

[0051] In some embodiments, R7and R8are each independently selected from the group consisting of, for example, hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1- C6alkoxy, or R7and R8are joined together to form oxo. In other embodiments, R7is hydrogen and R8is selected from the group consisting of, for example, hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy. In further embodiments, R7and R8are each hydrogen. In additional embodiments, R7and R8are joined together to form oxo.

[0052] In some embodiments, R9and R10are each independently selected from the group consisting of, for example, hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1- C6alkoxy, or R9and R10are joined together to form oxo. In other embodiments, R9is hydrogen and R10is selected from the group consisting of, for example, hydrogen, halogen, hydroxyl, - CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy. In further embodiments, R9and R10are each hydrogen. In additional embodiments, R9and R10are joined together to form oxo. 18 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0053] In some embodiments, for example, R1and R2are for each occurrence hydrogen. In other embodiments, L is selected from the group consisting of, for example, -(CH2)2-5-O-, - (CH2)2-5-C(O)-O-, -(CH2)2-5-O-C(O)-, -(CH2)2-5-C(O)-NRa-, -(CH2)2-5-NRa-C(O)-, -(CH2)2-5-S-, -(CH2)2-5-S(O)-, -(CH2)-2-5-S(O)2-, -O-(CH2)2-5-O-, -(CH2)1-2-O-(CH2)2-3-O-, and -CH=CH- (CH2)2-5-O-. In additional embodiments, L is selected from the group consisting of, for example, -CH2-CH2-CH2-O-, -CH2-CH2-CH2-CH2-O-, -CH2-CH2-CH2-CH2-CH2-O-, -CH2-O- CH2-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, -O-CH2- CH2-CH2-CH2-O-, and -CH=CH-CH2-CH2-CH2-O-.

[0054] In other embodiments, ring A is selected from the group consisting of, for example, phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl. In still other embodiments, RAis independently selected for each occurrence from the group consisting of, for example, halogen, hydroxyl, cyano, -NH2, -C(O)NH2,C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, and C3- C6cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens or -CN. In certain embodiments, for example, RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, and C1-C4alkyl. In further embodiments, q is, for example, 1, 2, or 3. In additional embodiments, ring A is selected from the group consisting of, for example,wherein * denotes the point of attachment to L.

[0055] In some embodiments, R3is selected from the group consisting of, for example, hydrogen, halogen, and -CH3. For example, in certain embodiments R3is fluoro. In other embodiments, p is 1 or 2. In further embodiments, RBis independently selected for each occurrence from the group consisting of, for example, halogen, hydroxyl, C1-C6alkyl, and C1- C6alkoxy. In still other embodiments, RBis halogen or C1-C6alkyl. In some embodiments RBis fluoro or -CH3. In other embodiments, ring B is selected from the group consisting of19 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0056] Also disclosed herein is a compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, -C(O)NH2,C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, and C3-C6cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens; X is selected from the group consisting of -C(RX1RX2)-, -O-, and -N(Ra); RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; L is selected from the group consisting of -(CH2)2-5-O-, -(CH2)2-5-C(O)-O-, -(CH2)2-5-O- C(O)-, -(CH2)2-5-C(O)-NRa-, -(CH2)2-5-NRa-C(O)-, -(CH2)2-5-S-, -(CH2)2-5-S(O)-, -(CH2)-2-5- S(O)2-, -O-(CH2)2-5-O-, -(CH2)1-2-O-(CH2)2-3-O-, and -CH=CH-(CH2)2-5-O-; R1and R2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy, or R1and R2are joined together to form oxo; R3and R4are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy, or R1and R2are joined together to form oxo; R5is selected from the group consisting of halogen and hydrogen; Ring B is selected from the group consisting20 IPTS / 125370156.1Attorney Docket No. KEST-004WO Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl; and q is 1, 2, or 3.

[0057] In some embodiments, RAis independently selected for each occurrence from the group consisting of, for example, halogen, hydroxyl, cyano, -NH2, and C1-C4alkyl. In other embodiments, for example, L is selected from the group consisting of: -CH2-CH2-CH2-O-, - CH2-CH2-CH2-CH2-O-, -CH2-CH2-CH2-CH2-CH2-O-, -CH2-O-CH2-CH2-CH2-O-, -CH2-CH2- O-CH2-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, -O-CH2-CH2-CH2-CH2-O-, and - CH=CH-CH2-CH2-CH2-O-. In still other embodiments, R5is, for example, fluoro. In further embodiments, R1and R2are each hydrogen.

[0058] Further disclosed herein is a compound represented by Formula III:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; Ring B is a 5-10 membered heterocyclyl containing at least one ring nitrogen; RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; 21 IPTS / 125370156.1Attorney Docket No. KEST-004WO L is a linker moiety comprising: three to eight bivalent units each represented by -(CR1R2)-; and one or two additional units each independently selected from the group consisting of -O-, -NRa-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, - OC(O)NRa-, -NRaC(O)NRb-, and -CH=CH-; R1is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl; wherein C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl; R2is selected from the group consisting of hydrogen, deuterium, halogen, and C1- C3alkyl; Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1- C6alkyl, and C1-C6alkoxy; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4. 22 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0059] For example, in some embodiments a compound of the present disclosure may be represented by Formula IIIA:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of phenyl, naphthyl, quinolinyl, and isoquinolinyl; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, -C(O)NH2,C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, and C3-C6cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens; L is selected from the group consisting of -(CH2)3-6-O-(CH2)2-3, -(CH2)3-6-O-C(O)- (CH2)2-3, -(CH2)3-6-C(O)-O-(CH2)2-3, -(CH2)3-6-NRa-C(O)-(CH2)2-3, and -(CH2)3-6-C(O)-NRa- (CH2)2-3; R1is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl; wherein C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -CN, -NRaRb, and C1-C4alkoxy; R2is halogen or hydrogen; Ring B is selected from the group consistingRaand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl; and q is 1, 2, or 3. 23 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0060] In some embodiments, for example, ring A is selected from the group consisting ofwherein * denotes the point of attachment to L.

[0061] In other embodiments, L is selected from the group consisting of, for example, - CH2-CH2-CH2-CH2-CH2-O-CH2-CH2- and- CH2-CH2-O-(C(O)- CH2-CH2. In some embodiments, R1is C1-C6alkyl optionally substituted by hydroxyl. In further embodiments, R2is fluoro.

[0062] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds.24 IPTS / 125370156.1Attorney Docket No. KEST-004WO25 IPTS / 125370156.1Attorney Docket No. KEST-004WOIPTS / 125370156.1Attorney Docket No. KEST-004WO

[0063] Procedures for making compounds described herein are provided in the examples below. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds as disclosed herein. Starting materials used in the following scheme can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0064] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify disclosed compounds or any preceding intermediates by modifying, introducing or removing appropriate functional groups.

[0065] Where it is desired to obtain a particular enantiomer of a disclosed compound, this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, diastereomeric derivatives (such as salts) can be produced by reaction of a mixture of enantiomers of a disclosed compound (such a racemate) and an appropriate chiral compound (such as a chiral base). The diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000). 27 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0066] In another resolution process a racemate of disclosed compounds can be separated using chiral High Performance Liquid Chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.

[0067] In an alternative embodiment, disclosed compounds may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or 15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound. II. Methods

[0001] Further disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from inhibition of Ras (e.g., K-Ras), comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. For example, disclosed herein are methods of treating a Ras protein-related (e.g., a K-Ras protein-related) disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0002] In some embodiments, the present disclosure provides a method of treating a disease or disorder characterized by aberrant Ras activity due to a Ras mutant (e.g., aberrant K- Ras activity due to a K-Ras mutation). In some embodiments, for example, the compounds and compositions disclosed herein may be used to treat a cancer having one or more Ras mutations (e.g., a K-Ras mutation).

[0003] For example, the methods described herein may be useful to treat cancers including, but not limited to, lung, prostate, breast, brain, skin, cervical carcinomas, and testicular carcinomas. For example, in some embodiments, the cancers that may be treated by the compounds, compositions and methods disclosed herein are, but are not limited to, tumor types 28 IPTS / 125370156.1Attorney Docket No. KEST-004WO such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.

[0004] In certain embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, related to the cardiovascular system. Non- limiting examples contemplated herein include, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma.

[0005] In further embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the lung. Non-limiting examples contemplated herein include, e.g., bronchogenic carcinoma (for example, squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (for example, bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, and mesothelioma.

[0006] In some embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the gastrointestinal system. Non-limiting examples contemplated herein include, e.g., esophageal cancer (for example, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach cancer (for example, carcinoma, lymphoma, and leiomyosarcoma), pancreatic cancer (for example, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel cancer (for example, adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), and large bowel cancer (for example, adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma).

[0007] In other embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the genitourinary tract. Non-limiting examples contemplated herein include, e.g., kidney cancer (for example, adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (for example, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (for example, adenocarcinoma, sarcoma), and testicular cancer (for example, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

[0008] In still other embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the liver. Non-limiting examples contemplated herein include, e.g., hepatoma (for example, hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma. 29 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0009] In further embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the biliary tract. Non-limiting examples contemplated herein include, e.g., gall bladder carcinoma, ampullary carcinoma, and cholangiocarcinoma.

[0010] In certain embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the bone. Non-limiting examples contemplated herein include, e.g., osteogenic sarcoma (for example, osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (for example, reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (for example, osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.

[0011] In some embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the nervous system. Non-limiting examples contemplated herein include, e.g., cancer and / or tumors of the skull (for example, osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), cancer and / or tumors of the meninges (for example, meningioma, meningiosarcoma, gliomatosis), brain cancer (for example, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and cancer and / or tumors of the spinal cord (for example, neurofibroma, meningioma, glioma, sarcoma).

[0012] In other embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the gynecological system. Non-limiting examples contemplated herein include, e.g., cancers and / or tumors of the uterus (for example, endometrial carcinoma), cancers and / or tumors of the cervix (for example, cervical carcinoma, pre-tumor cervical dysplasia), cancers and / or tumors of the ovaries (for example, ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), cancers and / or tumors of the vulva (for example, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), cancers and / or tumors of the vagina (for example, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and cancers and / or tumors of the fallopian tubes (carcinoma).

[0013] In further embodiments, the compounds, compositions and methods disclosed herein can be used to treat hematologic cancers, including tumors. Non-limiting examples contemplated herein include, e.g., cancers and / or tumors of the blood (for example, myeloid 30 IPTS / 125370156.1Attorney Docket No. KEST-004WO leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, and non-Hodgkin's lymphoma (malignant lymphoma).

[0014] In certain embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the skin. Non-limiting examples contemplated herein include, e.g., malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and psoriasis. In some embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the adrenal glands, e.g., neuroblastoma.

[0015] In some embodiments, the methods described herein may be useful to treat cancers including, but not limited to, pancreatic cancer, colorectal cancer, multiple myeloma, lung adenocarcinoma, melanoma, endometrial cancer, uterine cancer, thyroid, acute myelocytic leukemia, bladder carcinoma, gastric cancer, cervical cancer, and head and neck squamous cell carcinoma.

[0016] In particular, in certain embodiments, the disclosure provides a method of treating the medical indications contemplated herein comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.

[0017] In some embodiments, the Ras protein is wild-type (Raswt). Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Raswt(e.g., K-Raswt, H-Raswtor N-Raswt). In some embodiments, the Ras protein is Ras amplification (e.g., K-Rasamp)_ Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Rasamp(K-Rasamp, H-Rasampor N-Rasamp).

[0018] In some embodiments, the cancer comprises a Ras mutation, such as a Ras mutation described herein. In some embodiments, the mutation is selected from a K-Ras mutation (for example, G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof); a H-Ras mutation (for example, Q61 R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof); and a N-Ras mutation (for example, Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof); or a combination of any thereof. 31 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0019] In some embodiments, the cancer comprises a K-Ras mutation selected from the group consisting of, for example, G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K and Q61L. In other embodiments, the cancer comprises an N-Ras mutation selected from the group consisting of, for example, G12C, Q61H, Q61K, Q61L, Q61P and Q61R. In still other embodiments, the cancer comprises an H-Ras mutation selected from the group consisting of, for example, Q61H and Q61L. In further embodiments, the cancer comprises a Ras mutation selected from the group consisting of, for example, G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. In certain embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of, for example, G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V.

[0020] In some embodiments, a compound disclosed herein may inhibit more than one Ras mutant. For example, in some embodiments a disclosed compound may inhibit both K-Ras G12C and K-Ras G13C. In other embodiments, disclosed compound may inhibit both N-Ras G12C and K-Ras G12C. In still other embodiments, a disclosed compound may inhibit both N- Ras G12C and K-Ras G12C. In further embodiments, a disclosed compound may inhibit both K-Ras G12C and K-Ras G12D. In certain embodiments, a disclosed compound may inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, a disclosed compound may inhibit both K-Ras G12V and K-Ras G12S.

[0021] In some embodiments, a compound disclosed herein inhibits Raswtin addition to one or more additional Ras mutations (e.g., K, H or N-Raswtand K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61 K, L 19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K, H, or N-Raswtand H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61 H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H, or N-Raswtand N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T).

[0022] In some embodiments, a compound disclosed herein inhibits Rasampin addition to one or more additional Ras mutations (e.g., K-, H- or N-Rasampand K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K-, H- or N-Rasampand H- Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D,G12C, K117N, A59T, G12V, G13C, Q61H ,G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or 32 IPTS / 125370156.1Attorney Docket No. KEST-004WO K-, H- or N-Rasampand N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T).

[0023] In some embodiments, a cancer comprises a Ras mutation and an STK11LOF, a KEAP1, an EPHA5 or an NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation. In other embodiments, the cancer is non- small cell lung cancer and comprises a K-Ras G12C mutation and an STK11LOFmutation. In other embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and an STK11LOFmutation. In further embodiments, a cancer comprises a K-Ras G13C Ras mutation and an STK11LOF, a KEAP1, an EPHA5 or an NF1 mutation. In certain embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12V mutation. In further embodiments, the cancer is colorectal cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12D mutation. In other embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12V mutation. In still other embodiments, the cancer is endometrial cancer and comprises a K-Ras G12C mutation. In certain embodiments, the cancer is lung cancer, colorectal cancer, or pancreatic cancer and comprises a K-Ras G12D mutation. In further embodiments, the cancer is lung cancer or pancreatic cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is colorectal cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is gastric cancer and comprises a K-Ras G12C mutation. In addition, a disclosed compound may inhibit Raswt(e.g., K-, H- or N-Raswt) or Rasamp(e.g., K-, H- or N- Rasamp).

[0024] Also disclosed herein are methods of inhibiting a Ras protein (e.g., a K-Ras protein) in a cell or tissue, comprising contacting the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the Ras protein is a mutated Ras protein. Further disclosed herein are methods of inhibiting a Ras protein (e.g., a K-Ras protein) in a patient, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. 33 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0025] The compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a disclosed compound and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a disclosed compound and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, a disclosed compound and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.

[0026] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc. 34 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0027] In some embodiments, the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence or severity of side effects of treatment). For example, in some embodiments, the compounds of the present invention can also be used in combination with a therapeutic agent that treats nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0028] In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies includes a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). In other embodiments, the one or more additional therapies includes two therapeutic agents. In still other embodiments, the one or more additional therapies includes three therapeutic agents. In some embodiments, the one or more additional therapies includes four or more therapeutic agents.

[0029] Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and T cell adoptive transfer (ACT) therapy. In some embodiments, the compounds of the invention may be used as an adjuvant therapy after surgery. In some embodiments, the compounds of the invention may be used as a neo-adjuvant therapy prior to surgery.

[0030] A therapeutic agent may be a compound used in the treatment of cancer or symptoms associated with cancer. For example, a therapeutic agent may be a steroid. Non- limiting examples contemplated herein include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, 35 IPTS / 125370156.1Attorney Docket No. KEST-004WO paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0031] In further embodiments, a therapeutic agent contemplated herein may be a biologic (e.g., cytokine (e.g., interferon or an interleukin such as IL-2)) used in treatment of cancer or symptoms associated therewith. In some embodiments, the biologic is an immunoglobulin- based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fe fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer. Also contemplated herein are antibody-drug conjugates.

[0032] In other embodiments, a therapeutic agent contemplated herein may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fe-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with the ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L 1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fe fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / lg fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, ipilimumab, tremelimumab, or lirilumab. In other embodiments, a therapeutic agent may be an anti-TIGIT antibody, such as etigilimab.

[0033] In some embodiments, a therapeutic agent contemplated herein may be an anti- cancer agent. Non-limiting examples contemplated herein include, but are not limited to, 36 IPTS / 125370156.1Attorney Docket No. KEST-004WO mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Further anti-cancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, the one or more additional therapies includes two or more anti-cancer agents, for example, to be administered in combination or administered separately.

[0034] Other non-limiting examples of anti-cancer agents include, e.g., imatinib mesylate, carfilzornib, bortezornib, bicalutarnide, gefitinib, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, and meturedopa; uredopaethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); camptothecin and synthetic analogues (e.g., topotecan); bryostatin; callystatin; adozelesin; carzelesin; bizelesin; cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin and synthetic analogues; eleutherobin; pancratistatin; sarcodictyin A; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, such as calicheamicin gammall and calicheamicin omegall; dynemicin such as dynemicin A; bisphosphonates such as clodronate; an esperamicin; neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- 37 IPTS / 125370156.1Attorney Docket No. KEST-004WO FU); folic acid analogues such as denopterin, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"- trichlorotriethylamine; trichothecenes such as T-2 toxin, verracurin A, roridin A and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside; cyclophosphamide; thiotepa; toxoids (e.g., paclitaxel and doxetaxel; chloranbucil; tamoxifen; raloxifene; aromatase inhibiting 4(5)-irnidazoles; 4- tiydroxytamoxifen; trioxifene; keoxifene; onapristone; torernifene; flutamide, nilutarnide, bicalutarnide, leuprnlide, goserelin; chlorarnbucil; gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan; topoisomerase inhibitors; difluoromethylornithine; retinoids such as retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts of any of the aforementioned agents.

[0035] Additional non-limiting examples of anti-cancer agents include trastuzumab, bevacizumab, cetuximab, rituximab, avicine, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3- aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastics (e.g., cell-cycle nonspecific antineoplastic agents, and other antineoplastics described herein), antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, biricodar, brostallicin, bryostatin, buthionine sulfoximine, calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, 38 IPTS / 125370156.1Attorney Docket No. KEST-004WO resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, and zosuquidar.

[0036] Further non-limiting examples of anti-cancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., abemaciclib, ribociclib, palbociclib; seliciclib, dinaciclib), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine and analogs, and streptozocin), trazenes-dacarbazinine, antiproliferative / antimitotic antimetabolites such as folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, romidepsin, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors, DNA binding agents, Pl3K delta and gamma inhibitors, copanlisib, alpelisib and idelalisib; multi-kinase inhibitors (e.g., sorafenib), hormones (e.g., estrogen), goserelin, leuprolide, triptorelin, IKK inhibitors, p38MAPK inhibitors, anti-lL-6, telomerase inhibitors, aurora kinase inhibitors, cell surface monoclonal antibodies, elotuzumab, HSP90 inhibitors, P13K / Akt inhibitors, Akt inhibitors, PKC inhibitors (e.g., enzastaurin), Torcl / 2 specific kinase inhibitors, ER / UPR targeting agents, cFMS inhibitors, JAK1 / 2 inhibitors, PARP inhibitors (e.g., olaparib and veliparib), and BCL-2 antagonists. In some embodiments, a contemplated anti-cancer agent is selected from, for example, mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, sorafenib, or any analog or derivative variant of the foregoing.

[0037] In some embodiments, the anti-cancer agent is a HER2 inhibitor, for example, monoclonal antibody such as trastuzumab and pertuzumab; or a small molecule tyrosine kinase inhibitor such as gefitinib, erlotinib, pilitinib, canertinib, or lapatinib. In other embodiments, a contemplated anti-cancer agent is an ALK inhibitor, for example, ceritinib, crizotinib, alectinib, brigatinib, entrectinib, ensartinib, or lorlatinib. In other embodiments, a contemplated anti- 39 IPTS / 125370156.1Attorney Docket No. KEST-004WO cancer agent is a SHP2 inhibitor an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a Pl3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., mTORC1 inhibitor or mTORC2 inhibitor).

[0038] In some embodiments, a contemplated anti-cancer agent is an additional Ras inhibitor or a Ras vaccine, or another therapeutic modality designed to directly or indirectly decrease the oncogenic activity of Ras. For example, in some embodiments a contemplated anti-cancer agent is an additional Ras inhibitor. In some embodiments, the Ras inhibitor targets Ras in its active, or GTP-bound state (Ras(ON)). In some embodiments, the Ras inhibitor targets Ras in its inactive, or GDP-bound state. In some embodiments, the Ras inhibitor is an inhibitor of K-Ras G12C. In other embodiments, the Ras inhibitor is an inhibitor of K-Ras G12C. In other embodiments, the Ras inhibitor is a K-Ras G12V inhibitor.

[0039] In certain embodiments, the methods described herein further comprises administering to the patient one or more additional therapeutic agents that treats a disease or disorder that is affected by, associated with, or would benefit from inhibition of Ras protein (e.g., K-Ras).

[0040] The methods described herein include administering to the patient a therapeutically effective amount of at least one compound as described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the patient an additional therapeutic agent that treats a cancer, or that treats a disease or disorder that is affected by, associated with, or would benefit from inhibition of Ras, e.g., K-Ras.

[0041] In some embodiments, administering the compound(s) described herein to the patient allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating, ameliorating, and / or preventing cancer, or in treating, ameliorating, and / or preventing a disease or disorder that is affected by, associated with, or would benefit from inhibition of Ras (e.g., K-Ras) in the patient. For example, in certain embodiments, the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect. 40 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0042] In particular, in certain embodiments, the disclosure provides a method of treating the above medical indications comprising administering a subject in need thereof a therapeutically effective amount of a compound described herein. III. Pharmaceutical Compositions and Kits

[0043] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral or subcutaneous administration.

[0044] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0045] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. 41 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0046] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0047] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0048] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, 42 IPTS / 125370156.1Attorney Docket No. KEST-004WO olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0049] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0050] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0051] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0052] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0053] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0054] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, 43 IPTS / 125370156.1Attorney Docket No. KEST-004WO or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0055] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0056] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0057] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose 44 IPTS / 125370156.1Attorney Docket No. KEST-004WO acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure.

[0058] The disclosure also provides kits for use by a e.g., a consumer in need of treatment of a disease or disorder described herein. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0059] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . 45 IPTS / 125370156.1Attorney Docket No. KEST-004WO . etc. . . . Second Week, Monday, Tuesday, . . . “ etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this. EXAMPLES

[0060] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

[0061] HPLC conditions: Method A: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Method B: Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Method C: Column: Xselect CSH C18 OBD Column 19*250mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 30 mL / min. Synthesis of Intermediates: Synthesis of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3-d]pyrimidine (Intermediate 1)46 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 1: Synthesis of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine

[0062] To a solution of compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (40 g, 158 mmol, 1 eq) in dioxane (400 mL) was added DIEA (61.4 g, 475 mmol, 82.7 mL, 3 eq) and BnOH (18.8 g, 174 mmol, 18.0 mL, 1.1 eq). The mixture was stirred at 80 °C for 3 h under N2. The reaction mixture was a brown solution. Cooled the reaction to room temperature. The suspension was filtered, and the filtrate was concentrated under pressure to give residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g Sepa Flash® Silica Flash Column, Eluent of 0~4% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (22.5 g, 84.5 mmol, 53.5% yield) as a white solid . LCMS m / z = 324.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (s, 1 H) 7.61 (br d, J=6.88 Hz, 2 H) 7.40 - 7.48 (m, 3 H) 5.72 (s, 2 H). Step 2: 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidine

[0063] To a solution of compound 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidine (21 g, 64.7 mmol, 1 eq) in dioxane (250 mL) was added DIEA (33.4 g, 258 mmol, 45.1 mL, 4.00 eq) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (11.3 g, 71.2 mmol, 1.1 eq). The mixture was stirred at 80 °C for 1 h under N2. The reaction mixture was a brown solution. The solution was filtered, and the filtrate was concentrated under pressure to give a residue. The crude product was triturated with MTBE (150 mL) at 25oC for 5 h and filtered to isolate the solid. Compound 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (15 g, 34.4 mmol, 69.1% yield) was obtained as a white solid. LCMS m / z = 447.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (s, 1 H) 7.59 (d, J=7.13 Hz, 2 H) 7.36 - 7.47 (m, 3 H) 5.67 (s, 2 H) 5.13 - 5.39 (m, 1 H) 4.13 - 4.27 (m, 2 H) 3.05 - 3.14 (m, 2 H) 2.99 - 3.05 (m, 1 H) 2.83 (br d, J=6.25 Hz, 1 H) 2.05 - 2.18 (m, 2 H) 1.98 - 2.05 (m, 1 H) 1.74 - 1.91 (m, 3 H). 47 IPTS / 125370156.1Attorney Docket No. KEST-004WO Synthesis of 2-(2-bromo-4-(methoxymethoxy)-6-methylphenyl)ethan-1-ol (Intermediate 2)Step 1: Synthesis of 1-bromo-2-iodo-5-(methoxymethoxy)-3-methylbenzene

[0064] To a solution of 3-bromo-4-iodo-5-methyl-phenol (10 g, 31.9 mmol) and DIPEA (12.3 g, 95.8 mmol) in DCM (100 mL) was added MOMCl (3.86 g, 47.9 mmol) at 0°C. The reaction mixture was stirred at 20°C for 1 h, then poured into water (100 mL) and extracted with EtOAc (50 mLx3). The organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0) to give the title compound (10 g, 87%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.22 (d, 1H), 6.90 (d, 1H), 5.14 (s, 2H), 3.47 (s, 3H), 2.53 (s, 3H). Step 2: Synthesis of 1-bromo-5-(methoxymethoxy)-3-methyl-2-vinylbenzene

[0065] To a solution of the title compound of Step 1 (5 g, 14.0 mmol) in dioxane (100 mL) and H2O (25 mL) was added potassium trifluoro(vinyl)borate (1.88 g, 14.0 mmol), Pd(dppf)Cl2•DCM (1.14 g, 1.40 mmol) and Cs2CO3(9.13 g, 28.0 mmol). The reaction mixture was stirred at 100°C for 16 h under N2, then diluted with water (40 mL) and extracted with EtOAc (25 mLx3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE) to give the title compound (2 g, 55%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.15 (d, 1H), 6.94 (d, 1H), 6.69 - 6.54 (m, 1H), 5.65 - 5.50 (m, 1H), 5.44 - 5.32 (m, 1H), 5.27 - 5.13 (m, 2H), 3.36 (s, 3H), 2.32 (s, 3H). Step 3: Synthesis of 2-(2-bromo-4-(methoxymethoxy)-6-methylphenyl)ethan-1-ol

[0066] To a solution of the title compound of Step 2 (2.64 g, 10.2 mmol) in THF (30 mL) was added BH3•THF (1 M, 12.3 mL) at 0°C. The reaction mixture was stirred at 20°C for 1 h under N2. H2O (10 mL) was added at 0°C followed by NaOH (3 M, 34.2 mL) and H2O2(16.3 g, 143 mmol). The reaction mixture was stirred at 30°C for 15 h, then quenched with aq. sodium sulfite (100 mL) and extracted with EtOAc (50 mLx3). The combined organic phase was dried 48 IPTS / 125370156.1Attorney Docket No. KEST-004WO over anhydrous Na2SO4, filtered and concentratedunder reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 4:1) to give the title compound (1 g, 35%) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.08 (d, 1H), 6.86 (d, 1H), 5.15 (s, 2H), 4.76 (t, 1H), 3.53 - 3.42 (m, 2H), 3.35 (s, 3H), 2.85 (t, 2H), 2.34 (s, 3H). Synthesis of 1-bromo-3-chloro-2-iodo-5-(methoxymethoxy)benzene (Intermediate 3)Step 1: Synthesis of 2-(3-bromo-5-chloro-4-iodophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane

[0067] To a solution of 1-bromo-3-chloro-2-iodobenzene (9 g, 28.4 mmol) in hexane (150 mL) were added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24.0 g, 187 mmol) , 4,4′-di-tert-butyl- 2,2′-dipyridyl (0.99 g, 3.69 mmol) and [Ir(OMe)(1,5-cod)]2(1.88 g, 2.84 mmol) at rt. The reaction mixture was stirred for 8 h at 80°C under N2, then concentrated under reduced pressure to afford the title compound (16 g, crude) as a yellow oil. The crude was used in the next step directly without further purification. Step 2: Synthesis of 3-bromo-5-chloro-4-iodophenol

[0068] To a solution of the title compound of Step 1 (8.0 g, 18.0 mmol) in THF (100 mL) and water (40 mL), was added AcOH (100 mL) at 0°C. The reaction mixture was stirred for 30 min at 0°C before addition of H2O2(75 mL) at 0°C. The reaction mixture was stirred for 3 min at 0°C, then quenched with water (100 mL) at 0°C and extracted with EtOAc (100 mLx2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 8%) to afford the title compound (7.9 g) as a white solid. LCMS: m / z = 333 [M+H]+. Step 3: Synthesis of 1-bromo-3-chloro-2-iodo-5-(methoxymethoxy)benzene

[0069] To a solution of the title compound of Step 2 (4.8 g, 14.4 mmol) and DIPEA (3.72 g, 28.8 mmol) in DCM (50 mL) was added bromo(methoxy)methane (1.80 g, 14.4 mmol) at 0°C under N2. The reaction mixture was stirred for 1 h at rt, then quenched with water (100 mL) at 0°C and extracted with EtOAc (50 mLx3). The combined organic layers were washedwith brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced49 IPTS / 125370156.1Attorney Docket No. KEST-004WO pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 5:1) to give the title compound (4 g, 73.6%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.20 (d, 1H), 7.07 (d, 1H), 5.08 (s, 2H), 4.37 (s, 3H). Synthesis of 8-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (Intermediate 4)Step 1: Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

[0070] To a solution of 7-fluoronaphthalene-1,3-diol (15 g, 84 mmol), (bromoethynyl)triisopropylsilane (26.4 g, 101 mmol) and KOAc (16.53 g, 168 mmol) in dioxane (150 mL) was added [Ru(p-cymene)Cl2]2(5.16 g, 8.42 mmol) at rt under N2. The reaction mixture was refluxed at 110°C for 2 h, then poured into water (500 mL) and extracted with EtOAc (300 mLx3). The combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography (SiO2, EtOAc / n-hexane 0% to 8%) to afford the title compound (25 g, 80%) as a brown solid. LCMS: m / z = 359 [M+H]+. Step 2: Synthesis of ((2-fluoro-6,8-bis(methoxymethoxy)naphthalen-1- yl)ethynyl)triisopropylsilane

[0071] To a solution of the title compound of Step 1 (25 g, 69.7 mmol) in DCM (200 mL) were added DIPEA (125 mL, 697 mmol) and chloromethyl methyl ether (28.1 g, 349 mmol) at rt under N2. The reaction mixture was refluxed at 45°C for 4 h, then poured into water (200 mL) and extracted with DCM (150 mLx3). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford a 50 IPTS / 125370156.1Attorney Docket No. KEST-004WO crude which was purified by column chromatography (SiO2, EtOAc / n-hexane 0% to 2%) to afford the title compound (16.8 g, 52.1%) as a brown liquid.1H NMR (400 MHz, DMSO-d6): δ 7.88 (dd, 1H), 7.44 (t, 1H), 7.19 (d, 1H), 6.97 (d, 1H), 5.34 (s, 2H), 5.29 (s, 2H), 3.43 (s, 3H), 3.44 (s, 3H), 1.14 (s, 21H). Step 3: Synthesis of 1-ethynyl-2-fluoro-6,8-bis(methoxymethoxy)naphthalene

[0072] To a solution of the title compound of Step 2 (10 g, 22.4 mmol) in DMF (100 mL) was added cesium fluoride (6.80 g, 44.8 mmol) at rt under N2. The reaction mixture was stirred at 80°C for 6 h, then concentrated under reduced pressure to give a residue which was diluted with cold water (250 mL) and extracted with EtOAc (200 mLx3). The combined organic layer was washed with brine solution (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, EtOAc / n-hexane 0% to 18%) to afford the title compound (6 g, 88%) as a brown solid. LCMS: m / z = 291 [M+H]+. Step 4: Synthesis of 2-fluoro-6,8-bis(methoxymethoxy)-1-vinylnaphthalene

[0073] To a solution of the title compound of Step 3 (6 g, 20.7 mmol) in EtOH (120 mL) was added Lindlar catalyst (Pd / CaCO3) (200 mg, 0.463 mmol) at rt under N2. The reaction mixture was hydrogenated under a balloon of H2for 2 h, then filtered through a pad of Celite®. The pad was washed with MeOH (30x3 mL). The filtrate was concentrated under reduced pressure to get a residue which was purified by column chromatography (SiO2, EtOAc / n- hexane 0% to 15%) to afford the title compound (5 g, 62.1%) as a brown liquid.1H NMR (400 MHz, DMSO-d6): δ 7.76 (dd, 1H), 7.39 (t, 1H), 7.27 (dd, 1H), 7.13 (d, 1H), 6.86 (d, 1H), 5.53 (dd, 1H), 5.29 (s, 2H), 5.28 (s, 2H), 3.44 (s, 3H), 3.42 (s, 3H). Step 5: Synthesis of 2-(2-fluoro-6,8-bis(methoxymethoxy)naphthalen-1-yl)ethan-1-ol

[0074] To a solution of the title compound of Step 4 (4.1 g, 14.0 mmol) in anhydrous THF (40 mL) was added BH3•THF (21.0 mL, 21.0 mmol) at 0°C under N2. The reaction mixture was stirred at rt for 2 h. EtOH (8 mL) was added dropwise at 0°C followed by NaOH (1.68 g, 42.1 mmol) in water (5 mL) and H2O2(4.77 g, 42.1 mmol) at 0°C. The reaction mixture was stirred for 30 min at rt, then poured into water (100 mL) and extracted with EtOAc (100 mLx3). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc / n-hexane 0% to 35%) to afford the title compound (2.1 g, 45.7%) as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 7.68 (dd, 1H), 7.32 (t, 1H), 51 IPTS / 125370156.1Attorney Docket No. KEST-004WO 7.10 (d, 1H), 6.87 (d, 1H), 5.39 (s, 2H), 5.27 (s, 2H), 4.67 (t, 1H), 3.66-3.61 (m, 2H), 3.49 (s, 3H), 3.46-3.42 (m, 5H). Step 6: Synthesis of tert-butyl(2-(2-fluoro-6,8-bis(methoxymethoxy)naphthalen-1- yl)ethoxy)diphenylsilane

[0075] To solution of the title compound of Step 5 (2.1 g, 6.77 mmol) in DCM (20 mL) were added imidazole (1.38 g, 20.3 mmol) and TBDPS-Cl (1.74 mL, 6.77 mmol) at 0°C under N2. The reaction mixture was stirred at rt for 4 h, poured into water (30 mL) and extracted with DCM (30 mLx3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc / n-hexane 0% to 5%) to afford the title compound (3.2 g, 81%) as a colorless liquid. LCMS: m / z = 549 [M+H]+. Step 7: Synthesis of 8-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-3- (methoxymethoxy)naphthalen-1-ol

[0076] To a solution of the title compound of Step 6 (3.2 g, 5.83 mmol) in DCM (200 mL) was added TFA (3.32 g, 29.2 mmol) in DCM (20 mL) at 0°C under N2. The reaction mixture was stirred for 2 h, then poured into cold water (100 mL) and extracted with DCM (50 mLx3). The combined organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc / n-hexane 0% to 15%) to yield the title compound (1.44 g, 33.8%) as a light pink gum. LCMS: m / z = 505 [M+H]+. Step 8: Synthesis of 8-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate

[0077] To a solution of the title compound of Step 7 (1.4 g, 2.77 mmol) in DCM (30 mL) were added DIPEA (1.40 g, 13.9 mmol) and a solution of Tf2O (1.96 g, 6.94 mmol) in DCM (5 mL) at 0°C under N2. The reaction mixture was stirred at 0°C for 1 h, poured into cold water (50 mL) and extracted with DCM (25 mLx3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc / n-hexane 0% to 5%) to afford the title compound (1.05 g, 57.5%) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.01 (dd, 1H), 7.76 (d, 1H), 7.56 (t, 1H), 7.40-7.36 (m, 2H), 7.31 (d, 1H), 7.27-7.24 (m, 8H), 5.38 (s, 2H), 3.82 (d, 2H), 3.51 (d, 2H), 3.45 (s, 3H), 0.75 (s, 9H). 52 IPTS / 125370156.1Attorney Docket No. KEST-004WO Synthesis of 8-(benzyloxy)-1-(3-bromoprop-1-yn-1-yl)-2-fluoro-6- (methoxymethoxy)naphthalene (Intermediate 5)Step 1: Synthesis of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol

[0078] The title compound (30.0 g, crude, yellow oil) was obtained using a similar method to the one described in Step 1 of Intermediate 2, from the title compound of Intermediate 4, Step 1. LCMS: m / z = 403 [M+H]+. Step 2: ((8-(benzyloxy)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane

[0079] To a solution of the title compound of Step 1 (40 g, 99.4 mmol) and benzyl alcohol (21.5 g, 199 mmol) in THF (800 mL) was added PPh3(52.1 g, 199 mmol) and DIAD (40.2 g, 199 mmol) in THF (80 mL) at 0°C under N2. The reaction mixture was stirred at 50°C for 3 h, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 50 / 1) to give the title compound (40.0 g, 81.7%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.53 - 7.49 (m, 1H), 7.42 - 7.40 (m, 2H), 7.27 - 7.25 (m, 2H), 7.24 (s, 1H), 7.19 - 7.13 (m, 1H), 6.83 (s, 1H), 6.49 (s, 1H), 5.29 (s, 2H), 5.08 (s, 2H), 3.36 (s, 3H), 1.07 (s, 21H). Step 3: 8-(benzyloxy)-1-ethynyl-2-fluoro-6-(methoxymethoxy)naphthalene

[0080] To a solution of the title compound of Step 2 (40.0 g, 81.2 mmol) in THF (200 mL) was added TBAF (1 M in THF, 200 mL). The reaction mixture was stirred at 25°C for 10 min, then poured into sat. NH4Cl solution (200 mL) and extracted with EtOAc (300 mLx3). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 10 / 1) to give the title compound (27.0 g, 98.9%) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.65 - 7.56 (m, 1H), 7.52 - 7.48 (m, 2H), 7.32 - 7.26 (m, 3H), 7.17 - 7.15 (m, 1H), 6.90 (d, 1H), 6.67 (d, 1H), 5.17 (s, 2H), 5.15 (s, 2H), 3.43 (s, 3H), 3.24 (s, 1H). 53 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 4: 3-(8-(benzyloxy)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)prop-2-yn-1-ol

[0081] To a solution of the title compound of Step 3 (10.0 g, 29.7 mmol) in THF (100 mL) was added n-BuLi (2.5 M, 17.8 mL) dropwise at -78°C under N2. The reaction mixture was stirred at -78°C for 1 h, then paraformaldehyde (3.57 g, 119 mmol) was added portion wise at - 78°C. The reaction mixture was stirred at 25°C for 1 h, then quenched by Na2SO4•10H2O (2.00 g), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / DCM 10 / 1 to 1 / 1) to give the title compound (7.47 g, 68.6%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.63 - 7.61 (m, 3H), 7.49 - 7.46 (m, 3H), 7.25 - 7.23 (m, 1H), 7.02 (d, 1H), 6.80 (d, 1H), 5.30 (s, 2H), 5.17 (s, 2H), 4.03 (s, 2H), 3.55 (s, 3H). Step 5: 8-(benzyloxy)-1-(3-bromoprop-1-yn-1-yl)-2-fluoro-6-(methoxymethoxy)naphthalene

[0082] To a mixture of the title compound of Step 4 (800 mg, 2.18 mmol) in DCM (20 mL) was added PPh3(859 mg, 3.28 mmol) and CBr4(1.45 g, 4.37 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 h under N2, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 33 / 1) to give the title compound (500 mg, 50%) as a light yellow solid. LCMS: m / z = 429 [M+H]+. Synthesis of ((4-(benzyloxy)-5-bromo-6-fluoronaphthalen-2-yl)oxy)triisopropylsilane (Intermediate 6)Step 1: Synthesis of 8-bromo-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-ol

[0083] To a solution of 8-bromo-7-fluoronaphthalene-1,3-diol (39 g, 106 mmol) in DCM (400 mL) was added DIPEA (41.1 g, 318 mmol) and TIPSCl (18.4 g, 95.5 mmol). The reaction mixture was stirred at 0°C for 0.5 h, then diluted with water (500 mL) and extracted with EtOAc (200 mLx3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE) to give the title compound (22.7 g, 41.3%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.65 - 7.55 (m, 1H), 7.24 - 7.14 (m, 1H), 6.85 (d, 1H), 6.79 (d, 1H), 1.33 - 1.25 (m, 3H), 1.13 (d, 18H). Step 2: Synthesis of ((4-(benzyloxy)-5-bromo-6-fluoronaphthalen-2-yl)oxy)triisopropylsilane

[0084] The title compound (820 mg, 90%, colorless oil) was obtained using a similar method to the one described in Step 2 of Intermediate 5, from the title compound of Step 1 and benzyl alcohol.1H NMR (400 MHz, CDCl3) δ = 7.60 - 7.50 (m, 3H), 7.42 - 7.36 (m, 2H), 7.35 - 54 IPTS / 125370156.1Attorney Docket No. KEST-004WO 7.32 (m, 1H), 7.20 (t, 1H), 6.83 (d, 1H), 6.64 (d, 1H), 5.25 (s, 2H), 1.26 - 1.18 (m, 3H), 1.08 (d, 18H). Synthesis of 6-(benzyloxy)-8-bromo-2-fluoronaphthalen-1-ol (Intermediate 7)Step 1: Synthesis of 6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime

[0085] A solution of 6-benzyloxytetralin-1-one (90.0 g, 356 mmol), O-methyl hydroxylamine hydrochloride (35.7 g, 428 mmol) and pyridine (33.8 g, 428 mmol) in EtOH (900 mL) was stirred at 25°C for 16 h, then concentrated under reduced pressure. The residue was poured into sat. NH4Cl (500 mL) and extracted with EtOAc (500 mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 10 / 1) to give the title compound (98.0 g, 97%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.84 (d, 1H), 7.41 - 7.20 (m, 5H), 6.81 - 6.70 (m, 1H), 6.64 (d, 1H), 4.98 (s, 2H), 3.88 (s, 3H), 2.78 - 2.51 (m, 4H), 1.83 - 1.66 (m, 2H). Step 2: Synthesis of 6-(benzyloxy)-8-bromo-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime

[0086] A solution of the title compound of Step 1 (106 g, 376 mmol), NBS (67.1 g, 376 mmol) and Pd(OAc)2(4.22 g, 18.8 mmol) in AcOH (500 mL) was stirred at 80°C for 1 h under N2, then concentrated under reduced pressure. The residue was poured into water (400 mL) and extracted with EtOAc (300 mLx3). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 50 / 1) to give the title compound (115 g, 85%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.42 - 7.23 (m, 5H), 7.10 (d, 1H), 6.65 (d, 1H), 4.98 (s, 2H), 3.94 (s, 3H), 2.72 - 2.63 (m, 2H), 2.55 - 2.46 (m, 2H), 1.73 - 1.60 (m, 2H). 55 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 3: Synthesis of 6-(benzyloxy)-8-bromo-3,4-dihydronaphthalen-1(2H)-one

[0087] A solution of the title compound of Step 2 (105 g, 291 mmol) in 12 M aq. HCl (400 mL) and dioxane (600 mL) was stirred at 100°C for 1 h before 6N NaOH solution was added to pH 7 at 0°C. The mixture was extracted with EtOAc (500 mLx2), the organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with EtOAc (150 mL) and MeOH (100 mL) then filtered. The filtrate was purified by reversed-phaseHPLC (column: 150mm*H400mm YMC-Triart Prep C1815 m 120A; mobile phase: [water(FA)-ACN]; gradient:30%-50% B over 45 min) to give the title compound (48.0 g, 49%) as white solid.1H NMR (400 MHz, DMSO-d6) δ 7.56 - 7.31 (m, 5H), 7.23 (d, 1H), 7.04 (d, 1H), 5.21 (s, 2H), 2.93 (t, 2H), 2.59 - 2.53 (m, 2H), 2.04 - 1.82 (m, 2H). Step 4: Synthesis of 6-(benzyloxy)-8-bromo-2-fluoro-3,4-dihydronaphthalen-1(2H)-one

[0088] To a solution of the title compound of Step 3 (28.0 g, 84.4 mmol) and Selectfluor (44.8 g, 126 mmol) in MeOH (280 mL) was added H2SO4(676 mg, 6.89 mmol) under N2. The reaction mixture was stirred at 50°C for 5 h, then poured into water (200 mL). Sat. NaHCO3solution (30 mL) was added, the solution was filtered, and the filter cake was washed with water (100 mL) and EtOAc / MeOH (1:1, 100 mL) to give the title compound (27.0 g, 91%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.34 (m, 6H), 7.13 - 6.98 (m, 1H), 5.46 - 5.25 (m, 1H), 5.25 - 5.19 (m, 2H), 3.23 - 3.02 (m, 2H), 2.45 - 2.34 (m, 1H), 2.28 - 2.08 (m, 1H). Step 5: Synthesis of 6-(benzyloxy)-2,8-dibromo-2-fluoro-3,4-dihydronaphthalen-1(2H)-one

[0089] To a solution of the title compound of Step 4 (26.0 g, 74.5 mmol) in MeCN (260 mL) was added pyridinium tribromide (26.2 g, 81.9 mmol). The reaction mixture was stirred at 60°C for 0.5 h under N2, then poured into sat. NaHCO3solution (500 mL) at rt and filtered. The filter cake was washed with EtOAc (20 mL) and MeOH (10 mL) to give the title compound (27.0 g, 84%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.55 - 7.31 (m, 6H), 7.13 (d, 1H), 5.25 (s, 2H), 3.26 - 3.05 (m, 2H), 2.89 - 2.69 (m, 2H). Step 6: Synthesis of 6-(benzyloxy)-8-bromo-2-fluoronaphthalen-1-ol

[0090] To a solution of the title compound of Step 5 (22.0 g, 51.3 mmol) in DMF (220 mL) was added LiBr (8.93 g, 102 mmol). The reaction mixture was stirred at 100°C for 1 h under N2, then cooled to rt and poured into water (500 mL). The mixture was extracted with EtOAc (300 mLx3). The organic layer was washed with brine (500 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with EtOAc (100 mL) to 56 IPTS / 125370156.1Attorney Docket No. KEST-004WO give the title compound (14.1 g, 70%) as a white solid.1H NMR (400 MHz, CDCl3) δ 6.86 - 6.68 (m, 6H), 6.65 - 6.51 (m, 2H), 6.51 - 6.43 (m, 2H), 4.50 (s, 2H). Synthesis of 4-chloro-3-fluoroquinoline-5,7-diol (Intermediate 8)Step 1: Synthesis of 2,4-dichloro-3-fluoro-5,7-dimethoxyquinoline

[0091] A suspension of 2-fluoromalonic acid (4.78 g, 39.2 mmol) in POCl3(20 mL) was heated at 80°C.3,5-Dimethoxyaniline (6.00 g, 39.2 mmol) was added dropwise at 60°C. The reaction mixture was refluxed at 100°C for 16 h, then concentrated under vacuum and cooled to 0~10°C. The reaction mixture was added to water and stirred, then sat. sodium carbonate solution was slowly added until pH ~ 9. The solution was diluted with H2O (100 mL) and extracted with DCM (150 mLx2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc / DCM 100 / 1 / 0 to 5 / 1 / 5) to give the title compound (4.60 g, 36%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 6.96 (d, 1H), 6.62 (d, 1H), 3.95 (s, 3H), 3.92 (s, 3H). Step 2: Synthesis of 4-chloro-3-fluoro-5,7-dimethoxyquinoline

[0092] A mixture of the title compound of Step 1 (1.50 g, 4.46 mmol), Pd(OAc)2(100 mg, 445 μmol), PPh3(117 mg, 445 μmol), TEA (2.70 g, 26.7 mmol) and formic acid (410 mg, 8.91 mmol) in DMF (25 mL) was stirred at 90°C for 2 h under N2. The reaction was diluted with H2O (50 mL) and extracted with EtOAc (50 mLx2). The combined organic layers were washed with brine (50 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 50 / 1 to 10 / 1) to give the title compound (900 mg, 67%) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.04 (d, 1H), 6.63 (s, 1H), 3.98 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H). 57 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 3: Synthesis of 4-chloro-3-fluoroquinoline-5,7-diol

[0093] To a solution of the title compound of Step 2 (1.65 g, 5.46 mmol) in DCM (5 mL) was added BBr3(2 M in DCM, 27.3 mL) dropwise at 0°C. The reaction mixture was stirred at 25°C for 16 h, then quenched with ice-cold MeOH (60 mL) and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (column: SANTAI, SW-5222-040- SP, Spherical C 18, 20-45μm, 100Å; mobile phase: water (0.1% FA) – ACN; gradient:15%- 30% B over 20 min) to give the title compound (1.10 g, 92%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.19 (s, 1H), 8.74 (s, 1H), 6.81 (d, 1H), 6.66 (d, 1H). Synthesis of (R)-4-(benzyloxy)-7-chloro-8-fluoro-2-((1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate 9)Step 1: Synthesis of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine

[0094] To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (10.0 g, 39.6 mmol) in dioxane (150 mL) was added BnOH (4.71 g, 43.5 mmol), DIPEA (15.3 g, 118 mmol) and 4Å MS (1 g). The reaction mixture was stirred at 60°C for 4 h, then concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 10 / 1) to give the title compound (9.50 g, 73.9%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 7.57 - 7.52 (m, 2H), 7.44 (s, 2H), 7.37 - 7.35 (m, 1H), 5.72 (s, 2H). Step 2: Synthesis of (R)-4-(benzyloxy)-7-chloro-8-fluoro-2-((1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidine

[0095] To a solution of the title compound of Step 1 (200 mg, 61 μmol) in dioxane (3 mL) was added DIPEA (239 mg, 1.85 mmol) and (R)-(1-methylpyrrolidin-2-yl)methanol (71.0 mg, 617 μmol). The reaction mixture was stirred at 80°C for 3 h, then concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE / EtOAc 10 / 1 to 0 / 1, DCM / MeOH 10: 1) to give the title compound (100 mg, 38.6%) as a yellow solid. LCMS: m / z = 403 [M+H]+. 58 IPTS / 125370156.1Attorney Docket No. KEST-004WO Synthesis of 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(trimethylstannyl)pyrido[4,3-d]pyrimidine (Intermediate 10)

[0096] A mixture of Intermediate 1 (2 g, 4.48 mmol), 1,1,1,2,2,2-hexamethyldistannane (2.20 g, 6.71 mmol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) 200 mg, 307 μmol) in toluene (100 mL) was stirred at 100°C for 1 h under N2, then quenched with water (120 mL) and extracted with EtOAc (110 mLx3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (4 g, crude) as a black solid. LCMS: m / z = 577 [M+H]+. Synthesis of tert-butyl (S)-6-(2-hydroxyethoxy)-1,4-oxazepane-4-carboxylate (Intermediate 11)Step 1: Synthesis of tert-butyl (S)-6-(2-(benzyloxy)ethoxy)-1,4-oxazepane-4-carboxylate

[0097] A solution of tert-butyl (S)-6-hydroxy-1,4-oxazepane-4-carboxylate (1.00 g, 4.60 mmol), TBAB (297 mg, 921 μmol) and ((2-bromoethoxy)methyl)benzene (4.95 g, 23.0 mmol) in hexane (20 mL) and NaOH (10 mL) was stirred at 80°C for 16 h, then quenched with water (50 mL) and extracted with EtOAc (50 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 83:17) to yield the title compound (1.31 g, 77%) as colorless oil.1H NMR (400 MHz, CDCl3) δ 7.38 - 7.27 (m, 5H), 4.57 (s, 2H), 4.16 - 3.89 (m, 2H), 3.86 - 3.48 (m, 9H), 3.33 - 3.10 (m, 2H), 1.46 (s, 9H). Step 2: Synthesis of tert-butyl (S)-6-(2-(benzyloxy)ethoxy)-1,4-oxazepane-4-carboxylate

[0098] To a solution of the title compound of Step 1 (1.31 g, 3.73 mmol) in MeOH (30 mL) was added Pd(OH)2(300 mg, 2.14 mmol) and Pd / C (300 mg, 282 μmol, 10% purity) under N2. The reaction mixture was stirred under H2(50 psi) at 30°C for 16 h, then filtered and concentrated under reduced pressure to give the title compound (890 mg, 87%) as colorless oil.1H NMR (400 MHz, CDCl3) δ 4.01 - 3.21 (m, 13H), 1.46 (s, 9H). 59 IPTS / 125370156.1Attorney Docket No. KEST-004WO Synthesis of tert-butyl (S)-6-(2-iodoethoxy)-1,4-oxazepane-4-carboxylate (Intermediate 12)

[0099] To a solution of Intermediate 11 (1.80 g, 6.89 mmol) in toluene (36 mL) was added PPh3(2.17 g, 8.27 mmol) and imidazole (1.41 g, 20.7 mmol). The reaction mixture was stirred at 25°C for 3 min before I2(2.27 g, 8.95 mmol) was added. After stirring at 90°C for 3 h under N2the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 5:1) to give the title compound (620 mg, 23%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 4.08 - 3.53 (m, 9H), 3.34 - 3.13 (m, 4H), 1.48 (d, 9H). Synthesis of tert-butyl (R)-3-(allyloxy)azepane-1-carboxylate (Intermediate 13)

[0100] A solution of tert-butyl (R)-3-hydroxyazepane-1-carboxylate (5.00 g, 23.2 mmol) and NaH (1.11 g, 27.8 mmol, 60% purity) in THF (50 mL) was stirred at 0°C for 0.5 h under N2then allyl bromide (4.21 g, 34.8 mmol) was added. The reaction mixture was stirred at 20°C for 2.5 h under N2, then quenched with water (100 mL) and extracted with EtOAc (100 mLx3). The combined organic layers were washed with sat. brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (4.60 g, 77%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 5.96 - 5.88 (m, 1H), 5.30 - 5.26 (d, 1H), 5.19 - 5.14 (t, 1H), 4.10 - 3.80 (m, 3H), 3.80 - 3.45 (m, 2H), 3.10 - 2.95 (m, 1H), 2.93 - 2.78 (m, 1H), 1.95 - 1.66 (m, 4H), 1.65 - 1.57 (m, 1H), 1.45 - 1.40 (m, 9H), 1.32 - 1.14 (m, 1H). Synthesis of tert-butyl 3-(pent-4-en-1-yloxy)azepane-1-carboxylate (Intermediate 14)60 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0101] To a solution of tert-butyl 3-hydroxyazepane-1-carboxylate (4 g, 18.6 mmol) in DMF (50 mL) was added NaH (1.34 g, 55.7 mmol) at 0°C under N2. The reaction mixture was stirred at 0oC for 15 min then 5-bromopent-1-ene (2.77 g, 18.6 mmol) was added at 0°C. The reaction mixture was stirred for 1.5 h at rt under N2, then quenched with ice-water (50 mL) at 0°C. The mixture was extracted with EtOAc (3x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 5:1) to afford the title compound (1.9 g, 36.1%) as a colorless oil. LCMS: m / z = 284 [M+H]+. Synthesis of tert-butyl (R)-3-(pent-4-en-1-yloxy)azepane-1-carboxylate (Intermediate 15)

[0102] The title compound (6.1 g, 41.7%, colorless oil) was prepared following a similar method to the one described for Intermediate 14, from tert-butyl (R)-3-hydroxyazepane-1-carboxylate. LCMS: m / z = 284 [M+H]+.Synthesis of tert-butyl (R)-6-(allyloxy)-3-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-1,4- diazepane-1-carboxylate (Intermediate 16)Step 1: Synthesis of tert-butyl (R)-(2-hydroxy-3-((4-methoxybenzyl)amino)propyl)carbamate

[0103] To a solution of tert-butyl (S)-(oxiran-2-ylmethyl)carbamate (25.0 g, 144 mmol) in i-PrOH (250 mL) was added PMBNH2(19.8 g, 144 mmol). The reaction mixture was stirred at 50°C for 16 h, then concentrated under reduced pressure to give the title compound (44.0 g, crude) as a light yellow oil. LCMS: m / z = 311 [M+H]+. 61 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 2: Synthesis of tert-butyl (R)-(2-((tert-butyldimethylsilyl)oxy)-3-((4- methoxybenzyl)amino)propyl)carbamate

[0104] To a solution of the title compound of Step 1 (44.0 g, 141 mmol) in DCE (440 mL) was added TEA (43.0 g, 425 mmol) and TBSCl (64.1 g, 425 mmol). The reaction mixture was stirred at 40°C for 16 h, then washed with brine (300 mLx2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 2 / 1) to give the title compound (30.6 g, 50%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, 2H), 6.91 - 6.79 (m, 2H), 6.69 (t, 1H), 3.74 (d, 1H), 3.72 (s, 3H), 3.61 (s, 2H), 3.04 - 2.86 (m, 2H), 2.47 - 2.38 (m, 1H), 1.80 (d, 1H), 1.36 (s, 9H), 0.83 (s, 9H), 0.02 (d, 6H). Step 3: Synthesis of tert-butyl (S)-(2-((tert-butyldimethylsilyl)oxy)-3-(2-chloro-N-(4- methoxybenzyl)acetamido)propyl)carbamate

[0105] To a solution of the title compound of Step 2 (30.6 g, 72.1 mmol) in DCM (300 mL) was added DIPEA (18.6 g, 144 mmol) and 2-chloroacetyl chloride (10.6 g, 93.7 mmol) at 0°C and the reaction mixture was stirred at 25°C for 1 h. The mixture was diluted with EtOAc (400 mL) and washed with brine (200 mLx3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (40.0 g, crude) as a brown oil. LCMS m / z = 501 [M+H]+. Step 4: Synthesis of tert-butyl (R)-6-((tert-butyldimethylsilyl)oxy)-4-(4-methoxybenzyl)-3-oxo- 1,4-diazepane-1-carboxylate

[0106] To a solution of the title compound of Step 3 (40.0 g, 79.8 mmol) in DMF (300 mL) was added NaH (3.19 g, 79.8 mmol, 60% purity) at 0°C under N2. The reaction mixture was stirred at 25°C for 1 h under N2, then quenched with sat. NH4Cl (50 mL) solution, washed with water (150 mL) and extracted with EtOAc (300 mLx2). The combined organic layers were washed with brine (200 mLx2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 2 / 1) to give the title compound (24.8 g, 59%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 7.15 - 7.04 (m, 2H), 6.86 (d, 2H), 5.07 - 4.85 (m, 1H), 4.20 - 3.93 (m, 2H), 3.92 - 3.74 (m, 2H), 3.72 (s, 3H), 3.60 - 3.46 (m, 1H), 3.32 - 3.24 (m, 1H), 3.15 - 3.03 (m, 1H), 2.94 (dd, 1H), 1.40 (s, 9H), 0.76 (s, 9H), -0.14 (dd, 6H). 62 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 5: Synthesis of tert-butyl (R)-6-hydroxy-4-(4-methoxybenzyl)-3-oxo-1,4-diazepane-1- carboxylate

[0107] To a solution of the title compound of Step 4 (19.8 g, 42.6 mmol) in MeOH (200 mL) was added HOAc (2.56 g, 42.6 mmol) and KF (7.43 g, 127 mmol). The reaction mixture was stirred at 80°C for 16 h, then concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL), filtered and concentrated under reduced pressure to give the title compound (18.5 g, crude) as a brown oil. LCMS: m / z = 351 [M+Na]+. Step 6: Synthesis of tert-butyl (R)-6-(allyloxy)-4-(4-methoxybenzyl)-3-oxo-1,4-diazepane-1- carboxylate

[0108] To a solution of the title compound of Step 5 (7.50 g, 21.4 mmol) in hexane (75 mL) was added 3-bromoprop-1-ene (12.9 g, 107 mmol), TBAB (1.38 g, 4.28 mmol) and NaOH (1.71 g, 21.4 mmol, 35 mL, 50% purity). The reaction mixture was stirred at 80°C for 16 h, then diluted with water (100 mL) and extracted with EtOAc (100 mLx2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 5 / 1) to give the title compound (6.00 g, 70%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 2H), 6.86 (d, 2H), 5.81 - 5.71 (m, 1H), 5.18 - 5.00 (m, 2H), 4.82 (t, 1H), 4.18 - 3.96 (m, 3H), 3.84 (s, 2H), 3.73 (s, 3H), 3.67 - 3.38 (m, 3H), 3.34 - 3.10 (m, 2H), 1.38 (s, 9H). Step 7: Synthesis of tert-butyl (R)-6-(allyloxy)-3-oxo-1,4-diazepane-1-carboxylate

[0109] To a solution of the title compound of Step 6 (7.20 g, 18.4 mmol) in ACN (70 mL) was added ceric ammonium nitrate (30.3 g, 55.3 mmol) in water (35 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 h, then diluted with water (100 mL) and extracted with EtOAc (100 mLx3). The combined organic layers were washed with brine (70 mLx3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (column: SANTAI, SW-5222-330-SP, Spherical C 18, 20- 45μm, 100Å; mobile phase: water (0.1% FA) – ACN; gradient:20%-40% B over 45 min) to give the title compound (2.20 g, 42%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.41 (t, 1H), 5.98 - 5.76 (m, 1H), 5.26 (d, 1H), 5.14 (t, 1H), 4.00 (d, 2H), 3.97 - 3.82 (m, 2H), 3.76 - 3.41 (m, 3H), 3.25 - 3.12 (m, 2H), 1.38 (d, 9H). 63 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 8: Synthesis of tert-butyl (R)-6-(allyloxy)-3-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-1,4- diazepane-1-carboxylate

[0110] To a solution of the title compound of Step 7 (2.20 g, 8.14 mmol) in DMF (22 mL) was added NaH (390 mg, 9.77 mmol, 60% purity) at 0°C. The reaction mixture was stirred at 25°C for 0.5 h under N2then SEM-Cl (2.04 g, 12.2 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 1 h, then quenched with sat. NH4Cl solution (50 mL) and extracted with EtOAc (50 mLx2). The combined organic layers were washed with brine (40 mLx2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 5 / 1) to give the title compound (1.84 g, 50%) as yellow oil. LCMS: m / z = 401 [M+H]+. Synthesis of tert-butyl (R)-3-(but-3-yn-1-yloxy)azepane-1-carboxylate (Intermediate 17)Step 1: Synthesis of tert-butyl (R)-3-(3-(benzyloxy)propoxy)azepane-1-carboxylate

[0111] The title compound (3.62 g, 18.3%, yellow oil) was obtained following a similar method to that described in Intermediate 13, from tert-butyl (3R)-3-hydroxyazepane-1- carboxylate and using DMF as solvent. LCMS: m / z = 363 [M+H]+. Step 2: Synthesis of tert-butyl (R)-3-(3-hydroxypropoxy)azepane-1-carboxylate

[0112] A solution of the title compound of Step 1 (500 mg, 1.38 mmol) and Pd / C (293 mg, 2.75 mmol) in MeOH (20 mL) was stirred at rt for 4 h under H2. The reaction mixture was filtered, the filter cake was washed with MeOH (2x20 mL) and the filtrate was concentrated under reduced pressure to yield the title compound (320 mg, 68.9%) as a yellow oil. LCMS: m / z = 273 [M+H]+. Step 3: Synthesis of tert-butyl (R)-3-(3-oxopropoxy)azepane-1-carboxylate

[0113] To a solution of the title compound of Step 2 (50 mg, 0.183 mmol) in DCM (1 mL) was added Dess Martin periodane (1.74 g, 4.12 mmol) at 0°C under N2. The reaction mixture 64 IPTS / 125370156.1Attorney Docket No. KEST-004WO was stirred at rt for 5 h, then filtered. The filter cake was washed with DCM (30 mLx2). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, PE / EtOAc 3:1) to afford the title compound (450 mg, 60.4%) as an off- white solid. LCMS: m / z = 271 [M+H]+. Step 4: Synthesis of tert-butyl (R)-3-(but-3-yn-1-yloxy)azepane-1-carboxylate

[0114] To a solution of the title compound of Step 3 (100 mg, 0.037 mmol) and K2CO3(100 mg, 0.074 mmol) in MeOH (10 mL) was added dimethyl (1-diazo-2- oxopropyl)phosphonate (151 mg, 0.081 mmol) at 0°C under N2. The reaction mixture was stirred at rt overnight under N2, then quenched with HCl (1mL) at 0°C and extracted with EtOAc (30 mLx2). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH 10:1) to afford the title compound (70 mg, 49.3%) as a yellow solid. LCMS: m / z = 267 [M+H]+. Synthesis of 2-(pent-4-yn-1-yloxy)acetaldehyde (Intermediate 18)Step 1: Synthesis of 5-(2,2-dimethoxyethoxy)pent-1-yne

[0115] To a solution of pent-4-yn-1-ol (15.0 g, 178 mmol) in THF (200 mL) was added NaH (7.13 g, 178 mmol, 60% purity) at 0°C under N2. The reaction mixture was heated to 40°C and stirred for 0.5 h, then cooled to 15°C and 2-bromo-1,1-dimethoxy-ethane (30.1 g, 178 mmol) was added. The reaction mixture was stirred at 40°C for 16 h, then quenched by HCl solution (1 M, 30 mL) at 0°C. The mixture was poured into water (200 mL) and extracted with EtOAc (200 mLx3). The organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 8 / 1) to give the title compound (12.2 g, 39%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 4.51 (t, 1H), 3.59 (t, 2H), 3.50 (d, 2H), 3.40 (s, 6H), 2.32-2.70 (m, 2H), 1.95 (t, 1H), 1.83 - 1.79 (m, 2H). Step 2: Synthesis of 2-(pent-4-yn-1-yloxy)acetaldehyde

[0116] To a solution of the title compound of Step 1 (12.0 g, 69.7 mmol) in DCM (72 mL) was added formic acid (58.5 g, 1.27 mol). The reaction mixture was stirred at 15°C for 24 h, then diluted with DCM (150 mL) and water (150 mL). The mixture was adjusted to pH 7~8 65 IPTS / 125370156.1Attorney Docket No. KEST-004WO with K2CO3. The layers were separated and the aqueous layer was extracted with DCM (100 mLx4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (11.5 g, crude) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 4.09 (s, 2H), 3.71 - 3.64 (m, 2H), 2.36 - 2.34 (m, 2H), 1.98 - 1.96 (m, 1H), 1.90 - 1.83 (m, 2H). Synthesis of 3-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)propanoic acid (Intermediate 19)

[0117] The title compound (750 mg, 52.3 %, off white solid) was obtained following a similar method to that described in Step 6 of Intermediate 4, from 3-((2- hydroxyethyl)amino)propanoic acid and using DMF as solvent.1H NMR (400 MHz, DMSO- d6): δ 7.75 - 7.73 (m, 1H), 7.67 - 7.65 (m, 4H), 7.45 - 7.28 (m, 5H), 7.10 (br s, 1H), 3.88 (t, 2H), 3.09 - 2.99 (m, 4H), 2.55 (t, 2H), 1.08 (s, 9H). Example 1: Synthesis of 28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)- benzenacyclononaphan-35-ol (Compound 101) 66 IPTS / 125370156.1Attorney Docket No. KEST-004WOStep 1: tert-butyl 3-{[(4E)-5-[2-bromo-4-(methoxymethoxy)-6-methyl phenyl]pent-4- en-1- yl]oxy}azepane-1-carboxylate

[0118] In to a 50 ml flask purged and maintained in a nitrogen atmosphere, was placed a solution of 1-bromo-2-iodo-5-(methoxymethoxy)-3-methylbenzene (1 g, 2.801 mmol, 1 eq), tert-butyl 3-(pent-4-en-1-yloxy)azepane-1-carboxylate (952.69 mg, 3.361 mmol, 1.2 eq), Pd(OAc)2(157.23 mg, 0.700 mmol, 0.25 eq) and P(o-Tol)3(341.05 mg, 1.120 mmol, 0.4 eq) in ACN (20 mL), DIEA (1086.15 mg, 8.403 mmol, 3 eq) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional 2h at 100 °C under nitrogen atmosphere. The reaction was diluted with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (3x7 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 12:1) to afford tert-butyl 3-{[(4E)-5-[2-bromo-4-(methoxymethoxy)-6- methylphenyl]pent-4-en-1-yl]oxy}azepane-1-carboxylate (940 mg, 65.48%) as a brown oil LCMS m / z = 536 [M+H+Na]+67 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 2: tert-butyl 3-{[(4E)-5-[4-(methoxymethoxy)-2-methyl-6-(4,4,5,5-tetramethyl -1,3,2- dioxaborolan-2-yl)phenyl]pent-4-en-1-yl]oxy}azepane-1-carboxylate

[0119] Into a 50 ml flask purged and maintained in a nitrogen atmosphere, was placed a solution of tert-butyl 3-{[(4E)-5-[2-bromo-4-(methoxymethoxy)-6-me thylphenyl]pent-4-en-1- yl]oxy}azepane-1-carboxylate (720 mg, 1.405 mmol, 1 eq), bis(pinacolato)diboron (535.15 mg, 2.107 mmol, 1.5 eq), Pd(dppf)Cl2.CH2Cl2(114.45 mg, 0.141 mmol, 0.1 eq) and KOAc (413.64 mg, 4.215 mmol, 3 eq) in dioxane (15 mL). The resulting mixture was stirred for an additional 2h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 8:1) to afford tert-butyl 3-{[(4E)-5- [4-(methoxymethoxy)-2-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pent-4- en-1-yl]oxy}azepane-1-carboxylate (300 mg, 38.16%) as a brown oil. LCMS m / z = 582 [M+H+Na]+Step 3: tert-butyl 3-{[(4E)-5-[2-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]met hoxy}-4- (benzyloxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6-methylphenyl]pent-4- en-1-yl]oxy}azepane-1-carboxylate

[0120] Into a 25 ml flask purged and maintained in a nitrogen atmosphere, was placed a solution of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-Intermediate 1 (240 mg, 0.537 mmol, 1 eq), tert- butyl 3-{[(4E)-5-[4-(methoxymethoxy)-2-methyl-6-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]pent-4-en-1-yl]oxy}azepane-1-carboxylate (360.61 mg, 0.644 mmol, 1.2 eq), K3PO4(342.00 mg, 1.611 mmol, 3 eq) and cataCXium A-Pd-G3 (39.10 mg, 0.054 mmol, 0.1 eq) in dioxane (8 mL) / H2O (1 mL). The resulting mixture was stirred for 1 hour at 80°C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (3x7 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 12:1) to afford tert-butyl 3-{[(4E)-5-[2-(2-{[(2R,7aS)-2-fluoro-hexahy dropyrrolizin-7a- yl]met hoxy}-4-(benzyloxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4- (methoxymethoxy)-6- methylphenyl]pent-4-en-1-yl]oxy}azepane-1-carboxylate (240 mg, 52.95%) as a colorless oilLCMS m / z = 844 [M+H]+68 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 4: tert-butyl 3-({5-[2-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]m ethoxy}-8- fluoro-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6- methylphenyl]pentyl}oxy)azepane-1-carboxylate

[0121] Into a 50 ml flask under a nitrogen atmosphere was placed a solution of tert-butyl 3- {[(4E)-5-[2-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4-(benzyloxy)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6-methylphenyl]pent-4-en-1- yl]oxy}azepane-1-carboxylate (120 mg, 0.142 mmol, 1 eq) in MeOH (18.61 mL). Then Pd / C (224.99 mg, 2.112 mmol, 14.87 eq) was added carefully at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional 20h at room temperature under H2. The catalyst was filtered out, the filter cake was washed with MeOH (2x15 mL). The filtrate was concentrated under reduced pressure to afford tert- butyl 3-({5-[2-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-4-hyd roxypyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6-methylphenyl]pentyl}oxy)azepane-1- carboxylate (86 mg, 80.02%) as a brown solid. The crude was used directly without further purification. LCMS m / z = 756 [M+H]+Step 5: 7-(2-(5-(azepan-3-yloxy)pentyl)-5-hydroxy-3-methylphenyl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol

[0122] Into a 25ml flask was placed a solution of tert-butyl 3-({5-[2-(2-{[(2R,7aS)-2- fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-4- (methoxymethoxy)-6-methylphenyl]pentyl}oxy)azepane-1-carboxylate (30 mg, 0.040 mmol, 1 eq) in DCM (6.00 mL). TFA (1.50 mL) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional 30min at room temperature. The resulting mixture was concentrated under reduced pressure to afford 7-(2-(5-(azepan-3-yloxy)pentyl)-5-hydroxy-3-methylphenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (20 mg, 76.84%) as a brown oil. The crude was used directly without further purification. LCMS m / z = 612 [M+H]+Step 6: 28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33- methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)-benzenacyclononaphan- 35-ol

[0123] Into a 25 ml flask was placed a solution of 7-(2-(5-(azepan-3-yloxy)pentyl)-5- hydroxy-3-methylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (30 mg, 0.046 mmol, 1 eq) and PyBOP (35.71 mg, 69 IPTS / 125370156.1Attorney Docket No. KEST-004WO 0.069 mmol, 1.5 eq) in DCM (5 mL). TEA (46.29 mg, 0.460 mmol, 10 eq) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional 2h at room temperature. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (3x7 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 41% B to 68% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 6.95) to afford 28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)- benzenacyclononaphan-35-ol (0.9 mg, 8.03%) as a white solid. MS (ESI): m / z [M+H]+=594.1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.32 (s, 1H), 6.68 (dd, J = 16.2, 2.6 Hz, 2H), 5.35 (s, 1H), 5.18 (d, J = 23.9 Hz, 2H), 4.36 (s, 1H), 4.18 – 3.99 (m, 3H), 3.05 (d, J = 30.7 Hz, 7H), 2.90 (s, 5H), 2.26 (s, 4H), 2.17 – 1.93 (m, 7H), 1.81 (d, J = 34.7 Hz, 9H), 1.41 (s, 5H), 1.24 (s, 4H), 1.14 (s, 3H), 1.04 – 0.68 (m, 7H). Example 2: 28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-33-methyl-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)- benzenacycloheptaphan-35-ol (Compound 102) 70 IPTS / 125370156.1Attorney Docket No. KEST-004WOStep 1: tert-butyl 3-{[(2E)-3-[2-bromo-4-(methoxymethoxy)-6-methylphenyl]prop-2-en-1- yl]oxy}azepane-1-carboxylate

[0124] Into a 50 ml flask under a nitrogen atmosphere was placed a solution of 1-bromo-2- iodo-5-(methoxymethoxy)-3-methylbenzene (500 mg, 1.401 mmol, 1 eq) ,tert-butyl 3-(pent-4- en-1-yloxy)azepane-1-carboxylate (238.17 mg, 0.840 mmol, 1.2 eq), Pd(OAc)2(39.31 mg, 0.175 mmol, 0.25 eq) and P(o-Tol)3(170.52 mg, 0.560 mmol, 0.4 eq) in ACN (10 mL). Then DIEA (543.08 mg, 4.203 mmol, 3 eq) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional 2h at 100°C. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (1x7 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 8:1) to afford tert-butyl 3-{[(2E)-3-[2-bromo- 4-(methoxymethoxy)-6-methylphenyl]prop-2-en-1-yl]oxy}azepane-1-carboxylate (600 mg, 88.43%) as a brown oil. LCMS m / z = 484 [M+H]+Step 2: tert-butyl 3-{[(2E)-3-[4-(methoxymethoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]prop-2-en-1-yl]oxy}azepane-1-carboxylate

[0125] Into a 25 ml flask in a nitrogen atmosphere, was placed a solution of tert-butyl 3- {[(2E)-3-[2-bromo-4-(methoxymethoxy)-6-methylphenyl]prop-2-en-1-yl]oxy}azepane-1- carboxylate (700 mg, 1.445 mmol, 1 eq) ,bis(pinacolato)diboron (733.88 mg, 2.890 mmol, 2 71 IPTS / 125370156.1Attorney Docket No. KEST-004WO eq), KOAc (425.44 mg, 4.335 mmol, 3 eq) and Pd(dppf)Cl2CH2Cl2 (235.42 mg, 0.289 mmol, 0.2 eq) in dioxane (20 mL). The resulting mixture was stirred for an additional 2h at 100°C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2 (3x10 mL). The combined organic layers were washed with brine (3x7 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 8:1) to afford tert-butyl 3-{[(2E)-3-[4-(methoxymethoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]prop-2-en-1-yl]oxy}azepane-1-carboxylate (750 mg, 97.65%) as a colorless oil. LCMS m / z = 554 [M+H]+Step 3: tert-butyl 3-{[(2E)-3-[2-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4- (benzyloxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6-methylphenyl]prop-2- en-1-yl]oxy}azepane-1-carboxylate

[0126] Into a 50 ml flask in a nitrogen atmosphere, was placed a solution of 4-(benzyloxy)- 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidine-Intermediate 1(360 mg, 0.806 mmol, 1 eq) ,tert-butyl 3- {[(4E)-5-[4-(methoxymethoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]pent-4-en-1-yl]oxy}azepane-1-carboxylate (360.61 mg, 0.644 mmol, 1.2 eq), K3PO4 (512.99 mg, 2.418 mmol, 3 eq) and cataCXium A-Pd-G3 (58.65 mg, 0.081 mmol, 0.1 eq) in dioxane (16 mL) / H2O (2 mL). The resulting mixture was stirred for an additional 1h at 80°C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2 (3x10 mL). The combined organic layers were washed with brine (1x7 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) to afford tert-butyl 3-{[(2E)-3-[2-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-4-(benzyloxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6- methylphenyl]prop-2-en-1-yl]oxy}azepane-1-carboxylate (550 mg, 83.67%) as a colorless oil. LCMS m / z = 816 [M+H]+Step 4: tert-butyl 3-{3-[2-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro- 4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6-methylphenyl]propoxy}azepane- 1-carboxylate

[0127] Into a 50 ml flask was placed a solution of tert-butyl 3-{[(2E)-3-[2-(2-{[(2R,7aS)-2- fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4-(benzyloxy)-8-fluoropyrido[4,3-d]pyrimidin-7- yl)-4-(methoxymethoxy)-6-methylphenyl]prop-2-en-1-yl]oxy}azepane-1-carboxylate (350 mg, 72 IPTS / 125370156.1Attorney Docket No. KEST-004WO 0.429 mmol, 1 eq) in MeOH (5 mL). Pd / C (699.78 mg, 6.577 mmol, 15.33 eq) was added carefully under nitrogen atmosphere. The mixture was stirred at room temperature overnight under hydrogen atmosphere. The catalyst was filtered out and the filter cake was washed with MeOH (2x15 mL). The filtrate was concentrated under reduced pressure to afford tert- butyl3-{3-[2-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-4- hydroxypyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6-methylphenyl]propoxy}azepane- 1-carboxylate (160 mg, 51.25%) as a white solid. The crude was used directly for the next step without further purification. LCMS m / z = 728 [M+H]+Step 5: 2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-{2-[3-(azepan-3- yloxy)propyl]-5-hydroxy-3-methylphenyl}-8-fluoropyrido[4,3-d]pyrimidin-4-ol

[0128] Into a 25 ml flask was placed a solution of tert-butyl 3-{3-[2-(2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl] methoxy}-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-4- (methoxymethoxy)-6-methylphenyl]propoxy}azepane-1-carboxylate (150 mg, 0.206 mmol, 1 eq) in DCM (2 mL). Then TFA (0.4 mL) was added at rt. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl] methoxy}-7-{2- [3-(azepan-3-yloxy)propyl]-5-hydroxy-3-methylphenyl}-8-fluoropyrido[4,3-d]pyrimidin-4-ol (110 mg, 91.45%) as a yellow oil. The crude was used directly for the next step without further purification. LCMS m / z = 584 [M+H]+Step 6: 28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33- methyl-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)-benzenacycloheptaphan- 35-ol

[0129] Into a 25 ml flask was placed a solution of 2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-7-{2-[3-(azepan-3-yloxy)propyl]-5-hydroxy-3- methylphenyl}-8-fluoropyrido[4,3-d]pyrimidin-4-ol (100 mg, 0.171 mmol, 1 eq) and PyBOP (133.74 mg, 0.257 mmol, 1.5 eq) in DCM (1 mL). TEA (86.69 mg, 0.855 mmol, 5 eq) was added at rt. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (1x7 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 73 IPTS / 125370156.1Attorney Docket No. KEST-004WO mL / min mL / min; Gradient: 44% B to 69% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.38) to afford 28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 33-methyl-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)- benzenacycloheptaphan-35-ol (1.2 mg, 1.24%) as a white solid. LCMS m / z = 566 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 6.71 (d, J = 2.6 Hz, 1H), 6.50 (d, J = 2.7 Hz, 1H), 5.23 (d, J = 54.5 Hz, 1H), 3.88 (s, 2H), 3.15 – 2.87 (m, 3H), 2.79 (s, 1H), 2.30 (s, 4H), 1.86 (dd, J = 77.4, 23.6 Hz, 5H), 1.61 – 1.26 (m, 4H), 1.13 (s, 1H). Example 3: (13R,Z)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacyclononaphan-4-en-33-ol (Compound 103)Step 1: 4-amino-6-chloro-5-fluoropyridine-3-carboxylic acid

[0130] Into a 500 ml flask was placed a solution of ethyl 4-amino-6-chloro-5- fluoropyridine-3-carboxylate (20 g, 91.487 mmol, 1 eq) in THF (200 mL) / H2O (40 ml). NaOH (14.64 g, 365.948 mmol, 4 eq) was added at 0°C. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The solvent was removed under reduced pressure and diluted with water (400 mL). The pH was adjusted to pH=5-6 with 2N HCl solution. The aqueous layer was extracted with EtOAc (6x200 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Column: C18 Column, Mobile Phase A: WaterMobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 41% B to 68% B in 7min; Wavelength: 74 IPTS / 125370156.1Attorney Docket No. KEST-004WO 254nm / 220nm nm;) to afford 4-amino-6-chloro-5-fluoropyridine-3-carboxylic acid (15 g, 86.04%) as a yellow solid. LCMS m / z = 190 [M+H]+. Step 2: 7-chloro-8-fluoro-4-hydroxy-1H-pyrido[4,3-d]pyrimidine-2-thione

[0131] Into a 250 ml flask was placed a solution of 4-amino-6-chloro-5-fluoropyridine-3- carboxylic acid (14 g, 73.468 mmol, 1 eq) in POCl3(140 mL). The mixture was stirred for 4h at 90°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was dissolved in anhydrous THF (140 mL), which was followed by the addition of a solution of NH4SCN (11.18 g, 146.936 mmol, 2 eq) in THF dropwise at room temperature under nitrogen atmosphere. The mixture was stirred for 16h at room temperature under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x100 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Column: C18 Column, Mobile Phase A: Water Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Wave Length: 254nm / 220nm nm;) to afford 7- chloro-8-fluoro-4-hydroxy-1H-pyrido[4,3-d]pyrimidine-2-thione (10.5 g, 61.70%) as a yellow solid. LCMS m / z = 232 [M+H]+. Step 3: 7-chloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidin-4-ol

[0132] Into a 500 ml flask was placed a solution of 7-chloro-8-fluoro-4-hydroxy-1H- pyrido[4,3-d]pyrimidine-2-thione (10.4 g, 44.899 mmol, 1 eq) in MeOH (104 mL). Then NaOH (104.17 mL, 104.166 mmol, 2.32 eq) in H2O (104 mL) and CH3I (104.01 mL, 1670.692 mmol, 37.21 eq) was added at 0oC. The mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x100 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Column: C18 Column, Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Wave Length: 254nm / 220nm nm;) to afford 7- chloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidin-4-ol (5.8 g, 52.58%) as a white solid. LCMS m / z = 246 [M+H]+. 75 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 4: 1-[7-chloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidin-4-yl]-3-(pent-4-en-1- yloxy)azepane

[0133] Into a 100 ml flask in a nitrogen atmosphere, was placed a solution of 7-chloro-8- fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidin-4-ol (1.4 g, 5.699 mmol, 1 eq), PyBOP (4.45 g, 8.549 mmol, 1.5 eq) and TEA (1.73 g, 17.097 mmol, 3 eq) in DMF (20 mL). The mixture was stirred for 15 min at room temperature under nitrogen atmosphere. Then, 3-(pent-4-en-1- yloxy)azepane (1.04 g, 5.699 mmol, 1 eq) was added. The resulting mixture was stirred for 16h at room temperature under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (1x7 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 1-[7-chloro-8-fluoro- 2-(methylsulfanyl)pyrido[4,3-d]pyrimidin-4-yl]-3-(pent-4-en-1-yloxy)azepane (1 g, 42.70%) as a colorless oil. LCMS m / z = 411 [M+H]+. Step 5: 1-{7-[8-ethenyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2- (methylsulfanyl)pyrido[4,3-d]pyrimidin-4-yl}-3-(pent-4-en-1-yloxy)azepane

[0134] Into a 50 flask purged and maintained in a nitrogen atmosphere, was placed a solution of 1-[7-chloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidin-4-yl]-3-(pent-4-en- 1-yloxy)azepane (1 g, 2.433 mmol, 0.87 eq),2-[8-ethenyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 2.792 mmol, 1.00 eq) ,{1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2- yl}dichloro(2-methyl-1lambda4-pyridin-1-yl)palladium (0.47 g, 0.558 mmol, 0.2 eq) and K2CO3(0.77 g, 5.584 mmol, 2 eq) in 1,4-dioxane (10 mL) and H2O (1 mL). The resulting mixture was stirred overnight at 90°C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x30 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC / silica gel column chromatography, eluted with PE / EA (1:1) to afford 1-{7-[8- ethenyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-(methylsulfanyl)pyrido[4,3- d]pyrimidin-4-yl}-3-(pent-4-en-1-yloxy)azepane (800 mg, 47.23%) as a red oil. LCMS m / z = 607 [M+H]+. 76 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 6: (Z)-28,37-difluoro-33-(methoxymethoxy)-22-(methylthio)-9-oxa-2(4,7)-pyrido[4,3- d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacyclononaphan-4-ene

[0135] Into a 250 ml flask was placed a solution of 1-{7-[8-ethenyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidin-4-yl}- 3-(pent-4-en-1-yloxy)azepane (800 mg, 1.319 mmol, 1 eq) and [1,3-bis(2,4,6- trimethylphenyl)imidazolidin-2-ylidene]dichloro{[2-(propan-2- yloxy)phenyl]methylidene}ruthenium (413.11 mg, 0.659 mmol, 0.5 eq) in DCE (134 mL). The mixture was stirred for 5h at 60°C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x30 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford (Z)-28,37-difluoro-33-(methoxymethoxy)- 22-(methylthio)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacyclononaphan-4-ene (100 mg, 13.11%) as a brown solid. LCMS m / z = 579 [M+H]+. Step 7: (Z)-28,37-difluoro-33-(methoxymethoxy)-22-(methylsulfinyl)-9-oxa-2(4,7)-pyrido[4,3- d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacyclononaphan-4-ene

[0136] Into a 25 ml flask was placed a solution of (Z)-28,37-difluoro-33-(methoxymethoxy)- 22-(methylthio)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacyclononaphan-4-ene (50 mg, 0.086 mmol, 1 eq) in DCM (5 mL) under nitrogen atmosphere. m-CPBA (16.40 mg, 0.095 mmol, 1.1 eq) was added -15°C. The resulting mixture was stirred for 1 h at -15°C under nitrogen atmosphere. The reaction was quenched with ice- water at 0°C. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (1x7 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (Z)-28,37-difluoro-33- (methoxymethoxy)-22-(methylsulfinyl)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana- 3(1,8)-naphthalenacyclononaphan-4-ene (45 mg, 87.58%) as a yellow solid. The crude was used directly for the next step without further purification. LCMS m / z = 595 [M+H]+. 77 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 8: (13R,Z)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-33-(methoxymethoxy)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana- 3(1,8)-naphthalenacyclononaphan-4-ene

[0137] Into a 25 ml flask was placed a solution of (Z)-28,37-difluoro-33-(methoxymethoxy)- 22-(methylsulfinyl)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacyclononaphan-4-ene (48 mg, 0.081 mmol, 1 eq) and [(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methanol (38.55 mg, 0.243 mmol, 3 eq) in Toluene (2 mL). The mixture was stirred for 30 min at 25°C under nitrogen atmosphere. Then, tBuONa (24.33 mg, 0.243 mmol, 3 eq) was added at 0°C. The resulting mixture was stirred for 10 min at 0°C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (3x1 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) to afford (13R,Z)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-33-(methoxymethoxy)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana- 3(1,8)-naphthalenacyclononaphan-4-ene (30 mg, 53.88%) as a yellow oil. . LCMS m / z = 690 [M+H]+. Step 9: (13R,Z)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacyclononaphan-4-en-33-ol

[0138] Into a 25 ml flask was placed a solution of (13R,Z)-28,37-difluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-(methoxymethoxy)-9-oxa-2(4,7)- pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacyclononaphan-4-ene (25 mg, 0.036 mmol, 1 eq) in DCM (2 mL). TFA (0.4 mL) was added at rt. The resulting mixture was stirred for 30 min at room temperature under air atmosphere. The solvent was removed under reduced pressure. The crude product (15 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 19*250mm 5μm; Mobile Phase A: Water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 33% B to 69% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.13; Number Of Runs: 3) to afford (13R,Z)- 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-oxa- 2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacyclononaphan-4-en-33-ol; trifluoroacetic acid (3.2 mg, 11.62%) as a yellow solid. LCMS m / z = 646 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 10.16 (s, 1H), 9.27 (d, J = 18.1 Hz, 1H), 7.84 (dd, J = 78 IPTS / 125370156.1Attorney Docket No. KEST-004WO 9.1, 5.7 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.15 (dd, J = 10.7, 4.9 Hz, 1H), 5.94 (dd, J = 17.9, 11.6 Hz, 1H), 5.50 (s, 2H), 5.08 – 4.98 (m, 1H), 4.79 (s, 4H), 4.57 (s, 4H), 2.31 (s, 4H), 2.24 – 2.13 (m, 4H), 2.06 (d, J = 13.0 Hz, 3H), 1.93 (s, 3H), 1.81 (d, J = 27.9 Hz, 2H), 1.58 (s, 2H), 1.34 (s, 1H) Example 4: 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacycloheptaphan-33-ol (Compound 104)Step 1 tert-butyl 3-{[(2E)-3-[8-(benzyloxy)-2-fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1-yl]prop -2-en-1-yl]oxy}azepane-1-carboxylate

[0139] Into a 50 ml flask in a nitrogen atmosphere, was placed a solution of {[4- (benzyloxy)-6-fluoro-5-iodonaphthalen-2-yl]oxy}triisopropylsilane (1.5 g, 1.635 mmol, 1 eq, 60%), tert-butyl 3-(prop-2-en-1-yloxy)azepane-1-carboxylate (417.46 mg, 1.635 mmol, 1 eq), Pd(AcO)2(73.41 mg, 0.327 mmol, 0.2 eq) and Tri(o-tolyl)phosphine (199.03 mg, 0.654 mmol, 0.4 eq) in ACN (30 mL). Then DIEA (633.88 mg, 4.905 mmol, 3 eq) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional 2h at 100°C. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x20 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 12:1) to afford tert-butyl 3-{[(2E)-3-[8-(benzyloxy)-2-fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1- 79 IPTS / 125370156.1Attorney Docket No. KEST-004WO yl]prop -2-en-1-yl]oxy}azepane-1-carboxylate (600 mg, 54.13%) as a yellow oil. LCMS m / z = 678 [M+H]+.Step 2 tert-butyl 3-(3-{2-fluoro-8-hydroxy-6-[(triisopropylsilyl)oxy]naphthalen-1-yl}propoxy)a zepane-1-carboxylate

[0140] Into a 100 ml flask in a nitrogen atmosphere, was placed a solution of tert-butyl 3- {[(2E)-3-[8-(benzyloxy)-2-fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1-yl]prop-2-en-1- yl]oxy}azepane-1-carboxylate (466 mg, 0.687 mmol, 1 eq) in MeOH (50 mL). Pd / C (970.66 mg, 9.116 mmol, 13.27 eq) was added carefully at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional 2h at room temperature under H2. The catalyst was filtered out, the filter cake was washed with MeOH (2x50 mL). The filtrate was concentrated under reduced pressure to afford tert- butyl 3-(3-{2-fluoro-8-hydroxy-6-[(triisopropylsilyl)oxy]naphthalen-1-yl}propoxy)azepane-1- carboxylate (284 mg, 70.05%) as a brown oil. LCMS m / z = 590 [M+H]+.Step 3 tert-butyl 3-{3-[2-fluoro-8-(trifluoromethanesulfonyloxy)-6-[(triisopropylsilyl)oxy]naphtha alen-1-yl]propoxy}azepane-1-carboxylate

[0141] Into a 50 ml flask was placed a solution of tert-butyl 3-(3-{2-fluoro-8-hydroxy-6- [(triisopropylsilyl)oxy]naphthale n-1-yl}propoxy)azepane-1-carboxylate (200 mg, 0.339 mmol, 1 eq) and DIEA (131.47 mg, 1.017 mmol, 3 eq) in DCM (10 mL). Triflic anhydride (143.49 mg, 0.509 mmol, 1.5 eq) was added dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for an additional 1h at rt. The reaction was quenched by the addition of water (5mL) at 0°C. The resulting mixture was extracted with CH2Cl2(2 x 20mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl3-{3-[2-fluoro-8-(trifluoromethanesulfonyloxy)-6- [(triisopropylsilyl)oxy]naphthalen-1-yl]propoxy}azepane-1-carboxylate (230 mg, 93.96%) as a brown oil. The crude was used directly for the next without further purification. LCMS m / z = 744 [M+H]+.Step 4 tert-butyl 3-{3-[2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-[(triisopropylsilyl)oxy]n aphthalen-1-yl]propoxy}azepane-1-carboxylate

[0142] Into a 25 ml flask in a nitrogen atmosphere, was placed a solution of tert-butyl 3-{3- [2-fluoro-8-(trifluoromethanesulfonyloxy)-6-[(triisopropylsilyl)oxy]naphthalen-1- yl]propoxy}azepane-1-carboxylate (340 mg, 0.471 mmol, 1 eq), bis(pinacolato)diboron (239.19 mg, 0.942 mmol, 2 eq), KOAc (138.66 mg, 1.413 mmol, 3 eq) and Pd(dppf)Cl2CH2Cl2(38.37 80 IPTS / 125370156.1Attorney Docket No. KEST-004WO mg, 0.047 mmol, 0.1 eq) in dioxane (8 mL). The resulting mixture was stirred for an additional 12h at 100°C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 6:1) to afford tert-butyl 3-{3-[2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-6- [(triisopropylsilyl)oxy]naphthalen-1-yl]propoxy}azepane-1-carboxylate (40 mg, 12.14%) as a colorless oil. . LCMS m / z = 722 [M+H]+.Step 5 tert-butyl 3-{3-[8-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4-(benzyloxy)-8-f luoropyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6- [(triisopropylsilyl)oxy]naphthalen-1-yl]propoxy}azepane-1-carboxylate

[0143] Into a 25 ml flask in a nitrogen atmosphere, was placed a solution of tert-butyl 3-{3- [2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-[(triisopropylsilyl)oxy]naphthalen- 1-yl]propoxy}azepane-1-carboxylate (90 mg, 0.129 mmol, 1 eq), 4-(benzyloxy)-7-chloro-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine-Intermediate 1 (57.47 mg, 0.129 mmol, 1 eq), cataCXium A Pd G3(9.36 mg, 0.013 mmol, 0.1 eq) and K3PO4(81.89 mg, 0.387 mmol, 3 eq) in 1,4-dioxane (4 mL) / H2O (0.5 mL). The resulting mixture was stirred for an additional 1h at 80°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 18:1) to afford tert-butyl 3-{3-[8-(2-{[(2R,7aS)-2-fl uoro- hexahydropyrrolizin-7a-yl]methoxy}-4-(benzyloxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2- fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1-yl]propoxy}azepane-1-carboxylate (60 mg, 47.40%) as a yellow solid. LCMS m / z = 985 [M+H]+.Step 6 tert-butyl 3-{3-[8-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-4-hydro xypyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1- yl]propoxy}azepane-1-carboxylate

[0144] Into a 100 ml flask in a nitrogen atmosphere, was placed a solution of tert-butyl 3- {3-[8-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4-(benzyloxy)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1- yl]propoxy}azepane-1-carboxylate (50 mg, 0.051 mmol, 1 eq) in MeOH (25.00 mL). Pd / C 81 IPTS / 125370156.1Attorney Docket No. KEST-004WO (100.01 mg, 0.943 mmol, 18.50 eq) was added carefully at room temperature under N2. The resulting mixture was stirred for an additional 2h at room temperature hydrogen atmosphere. The catalyst was filtered out, the filter cake was washed with MeOH (2x15 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 3-{3-[8-(2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl] methoxy}-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-2- fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1-yl]propoxy}azepane-1-carboxylate (45 mg,99.07%) as a colorless oil The crude was used directly for the next step without furtherpurification. LCMS m / z = 894 [M+H]+. Step 7: 2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-{8-[3-(azepan-3- yloxy)propyl]-7-fluoro-3-[(triisopropylsilyl)oxy]naphthalen-1-yl}-8-fluoropyrido[4,3- d]pyrimidin-4-ol

[0145] Into a 25 ml flask was placed a solution of tert-butyl 3-{3-[8-(2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-2-fluoro- 6-[(triisopropylsilyl)oxy]naphthalen-1-yl]propoxy}azepane-1-carboxylate (40 mg, 0.045 mmol, 1 eq) in DCM (8 mL). Then TFA (3 mL) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional 30min at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-{8-[3-(azepan-3- yloxy)propyl]-7-fluoro-3-[(triisopropylsilyl)oxy]naphthalen-1-yl}-8-fluoropyrido[4,3- d]pyrimidin-4-ol (30 mg, 84.46%) as a yellow oil. The crude was used directly for the next step without further purification. LCMS m / z = 794 [M+H]+.Step 8 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-((triisopropylsilyl)oxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacycloheptaphane

[0146] Into a 25 ml flask was placed a solution of 2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-7-{8-[3-(azepan-3-yloxy)propyl]-7-fluoro-3- [(triisopropylsilyl)oxy]naphthalen-1-yl}-8-fluoropyrido[4,3-d]pyrimidin-4-ol (40 mg, 0.050 mmol, 1 eq), PyBOP (39.32 mg, 0.075 mmol, 1.5 eq) and TEA (50.98 mg, 0.500 mmol, 10 eq) in DCM (7 mL). The resulting mixture was stirred for an additional 2h at room temperature. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) to afford 28,37- 82 IPTS / 125370156.1Attorney Docket No. KEST-004WO difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33- ((triisopropylsilyl)oxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacycloheptaphane (20 mg, 51.16%) as a colorless solid. LCMS m / z = 776 [M+H]+.Step 9 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacycloheptaphan-33-ol

[0147] Into a 10 ml flask was placed a solution of 28,37-difluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-((triisopropylsilyl)oxy)-7-oxa-2(4,7)- pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacycloheptaphane (15 mg, 0.019 mmol, 1 eq) in DMF (2 mL). CsF (58.72 mg, 0.380 mmol, 20 eq) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional h at room temperature. The resulting mixture was filtered. The filtrate was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 40% B to 67% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 7.87) to afford 28,37-difluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina- 1(1,3)-azepana-3(1,8)-naphthalenacycloheptaphan-33-ol (1.7 mg, 14.05%) as a white solid. LCMS m / z = 620 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.46 (s, 1H), 7.76 (dd, J = 9.1, 6.0 Hz, 1H), 7.37 – 7.24 (m, 2H), 7.16 (d, J = 2.2 Hz, 1H), 5.22 (s, 1H), 4.72 (d, J = 12.0 Hz, 1H), 4.11 (dd, J = 10.3, 4.9 Hz, 1H), 4.02 (dd, J = 10.3, 6.4 Hz, 1H), 3.75 (d, J = 15.6 Hz, 1H), 3.56 (s, 1H), 3.25 (s, 1H), 3.18 – 3.05 (m, 3H), 2.99 (d, J = 11.6 Hz, 2H), 2.82 (d, J = 7.3 Hz, 1H), 2.12 (s, 1H), 2.07 – 1.94 (m, 4H), 1.79 (dd, J = 23.8, 11.1 Hz, 5H), 1.53 (s, 2H), 1.37 (d, J = 12.5 Hz, 1H), 1.24 (s, 3H), 0.88 – 0.70 (m, 2H). Example 5: 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacyclononaphan-33-ol (Compound 105) 83 IPTS / 125370156.1Attorney Docket No. KEST-004WOStep 1: tert-butyl 3-{[(4Z)-5-[8-(benzyloxy)-2-fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1- yl]pent-4-en-1-yl]oxy}azepane-1-carboxylate

[0148] Into a 50 ml flask in a nitrogen atmosphere, was placed a solution of {[4- (benzyloxy)-6-fluoro-5-iodonaphthalen-2-yl]oxy}triisopropylsilane (1.7 g, 3.088 mmol, 1 eq),tert-butyl 3-(pent-4-en-1-yloxy)azepane-1-carboxylate (0.88 g, 3.088 mmol, 1 eq) , Palladium acetate (0.17 g, 0.772 mmol, 0.25 eq) ,tris(2-methylphenyl)phosphane (0.38 g, 1.235 mmol, 0.4 eq) and DIEA (1.20 g, 9.264 mmol, 3 eq) in ACN (20 mL). The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 10:1) to afford tert-butyl 3-{[(4Z)-5-[8-(benzyloxy)-2-fluoro-6- [(triisopropylsilyl)oxy]naphthalene-1-yl]pent-4-en-1-yl]oxy}azepane-1-carboxylate (1.2 g, 55.04%) as a yellow oil. LCMS m / z = 728 [M+Na]+. Step 2: tert-butyl 3-[(5-{2-fluoro-8-hydroxy-6-[(triisopropylsilyl)oxy]naphthalen-1- yl}pentyl)oxy]azepane-1-carboxylate

[0149] Into a 50 ml flask was placed a solution of tert-butyl 3-{[(4Z)-5-[8-(benzyloxy)-2- fluoro-6-[(triisopropylsilyl)oxy]naphthalene-1-yl]pent-4-en-1-yl]oxy}azepane-1-carboxylate (1.2 g, 1.700 mmol, 1 eq) in MeOH (50 mL). Pd / C (2.40 g, 22.559 mmol, 13.27 eq) was added 84 IPTS / 125370156.1Attorney Docket No. KEST-004WO carefully under nitrogen atmosphere. The mixture was stirred at room temperature overnight under hydrogen atmosphere. The catalyst was filtered out and the filter cake was washed with MeOH (3x100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 10:1) to afford tert-butyl 3-[(5-{2-fluoro-8-hydroxy-6- [(triisopropylsilyl)oxy]naphthalen-1-yl}pentyl)oxy]azepane-1-carboxylate (1 g, 95.22%) as a brown oil. LCMS m / z = 640 [M+Na]+. Step 3: tert-butyl 3-({5-[2-fluoro-8-(trifluoromethanesulfonyloxy)-6- [(triisopropylsilyl)oxy]naphthalen-1-yl]pentyl}oxy)azepane-1-carboxylate

[0150] Into a 100 ml flask in a nitrogen atmosphere, was placed a solution of tert-butyl 3- [(5-{2-fluoro-8-hydroxy-6-[(triisopropylsilyl)oxy]naphthalen-1-yl}pentyl)oxy]azepane-1- carboxylate (1.0 g, 1.618 mmol, 1 eq) and pyridine (0.38 g, 4.854 mmol, 3 eq) in DCM (20 mL). Then Tf2O (0.91 g, 3.236 mmol, 2 eq) was added dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with ice-water. The aqueous layer was extracted with CH2Cl2(3x20 mL). The combined organic layers were washed with brine (1x20mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 10:1) to afford tert-butyl 3-({5-[2-fluoro-8- (trifluoromethanesulfonyloxy)-6-[(triisopropylsilyl)oxy]naphthalen-1-yl]pentyl}oxy)azepane-1- carboxylate (600 mg, 49.44%) as a yellow oil. LCMS m / z = 772 [M+Na]+. Step 4: tert-butyl 3-({5-[2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6- [(triisopropylsilyl)oxy]naphthalen-1-yl]pentyl}oxy)azepane-1-carboxylate

[0151] Into a 50 ml flask in a nitrogen atmosphere, was placed a solution of tert-butyl 3- ({5-[2-fluoro-8-(trifluoromethanesulfonyloxy)-6-[(triisopropylsilyl)oxy]naphthalen-1- yl]pentyl}oxy)azepane-1-carboxylate (600 mg, 0.800 mmol, 1 eq) ,4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (609.48 mg, 2.400 mmol, 3 eq), KOAc (157.03 mg, 1.600 mmol, 2 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium (II (65.17 mg, 0.080 mmol, 0.1 eq) in dioxane (10 mL). The mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x15 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 10:1) to afford tert-butyl 3-({5-[2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6- 85 IPTS / 125370156.1Attorney Docket No. KEST-004WO [(triisopropylsilyl)oxy]naphthalen-1-yl]pentyl}oxy)azepane-1-carboxylate (240 mg, 41.21%) as a white solid. LCMS m / z = 750 [M+Na]+. Step 5: tert-butyl 3-({5-[8-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4- (benzyloxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6- [(triisopropylsilyl)oxy]naphthalen-1-yl]pentyl}oxy)azepane-1-carboxylate

[0152] Into a 25 ml flask in a nitrogen atmosphere, was placed a solution of tert-butyl 3- ({5-[2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6- [(triisopropylsilyl)oxy]naphthalen-1-yl]pentyl}oxy)azepane-1-carboxylate (160 mg, 0.220 mmol, 1 eq), 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-Intermediate 1 (98.23 mg, 0.220 mmol, 1 eq), K3PO4(139.98 mg, 0.660 mmol, 3 eq) and cataCXium-A-Pd-G3(32.02 mg, 0.044 mmol, 0.2 eq) in 1,4-dioxane (2 mL) / H2O (0.4 mL). The mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) to afford tert-butyl 3-({5-[8-(2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-4-(benzyloxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2- fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1-yl]pentyl}oxy)azepane-1-carboxylate (35 mg, 15.73%) as a brown oil. LCMS m / z = 1013 [M+H]+. Step 6: tert-butyl 3-({5-[8-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8- fluoro-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1- yl]pentyl}oxy)azepane-1-carboxylate

[0153] Into a 25 ml flask was placed a solution of tert-butyl 3-({5-[8-(2-{[(2R,7aS)-2- fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4-(benzyloxy)-8-fluoropyrido[4,3-d]pyrimidin-7- yl)-2-fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1-yl]pentyl}oxy)azepane-1-carboxylate (30 mg, 0.030 mmol, 1 eq) in MeOH (4 mL). Pd / C (60.01 mg, 0.571 mmol, 19.03 eq) was added carefully under nitrogen atmosphere. The mixture was stirred at room temperature overnight under hydrogen atmosphere. The catalyst was filtered out, the filter cake was washed with MeOH (3x100 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 3- ({5-[8-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-4- hydroxypyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1- 86 IPTS / 125370156.1Attorney Docket No. KEST-004WO yl]pentyl}oxy)azepane-1-carboxylate (26 mg, 95.14%) as a white oil. LCMS m / z = 923 [M+H]+. Step 7: 2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-{8-[5-(azepan-3- yloxy)pentyl]-7-fluoro-3-[(triisopropylsilyl)oxy]naphthalen-1-yl}-8-fluoropyrido[4,3- d]pyrimidin-4-ol

[0154] Into a 10 ml flask was placed a solution of tert-butyl 3-({5-[8-(2-{[(2R,7aS)-2- fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-2- fluoro-6-[(triisopropylsilyl)oxy]naphthalen-1-yl]pentyl}oxy)azepane-1-carboxylate (30 mg, 0.033 mmol, 1 eq) in DCM (2 mL). TFA (0.4 ml) was added at rt. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-7-{8-[5-(azepan-3-yloxy)pentyl]-7-fluoro-3-[(triisopropylsilyl)oxy]naphthalen-1- yl}-8-fluoropyrido[4,3-d]pyrimidin-4-ol (25 mg, 93.48%) as a brown oil. The crude was used directly for the next step without further purification. LCMS m / z = 822 [M+H]+. Step 8: 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33- ((triisopropylsilyl)oxy)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacyclononaphane

[0155] Into a 10 ml flask was placed a solution of 2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-7-{8-[5-(azepan-3-yloxy)pentyl]-7-fluoro-3- [(triisopropylsilyl)oxy]naphthalen-1-yl}-8-fluoropyrido[4,3-d]pyrimidin-4-ol (30 mg, 0.036 mmol, 1 eq) in DCM (2 mL). TEA (36.93 mg, 0.360 mmol, 10 eq) and PyBOP (28.49 mg, 0.054 mmol, 1.5 eq) was added at rt. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with CH2Cl2(3x10 mL). The combined organic layers were washed with brine (1x7 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) to afford 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-33-((triisopropylsilyl)oxy)-9-oxa-2(4,7)-pyrido[4,3- d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacyclononaphane (10 mg, 34.08%) as a brown oil. LCMS m / z = 804 [M+H]+. Step 9: 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9- oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacyclononaphan-33-ol 87 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0156] Into a 10 ml flask was placed a solution of 28,37-difluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-((triisopropylsilyl)oxy)-9-oxa-2(4,7)- pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacyclononaphane (10 mg, 0.012 mmol, 1 eq) in DMF (2 mL). CsF (18.89 mg, 0.120 mmol, 10 eq) was added at rt. The mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was filtered. The filtrate was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 40% B to 67% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 7.87)to afford 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacyclononaphan-33-ol (0.8 mg, 9.93%) as a white solid. LCMS m / z = 648 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.79 – 7.74 (m, 1H), 7.35 – 7.31 (m, 2H), 7.03 (d, J = 2.6 Hz, 1H), 5.15 (d, J = 16.4 Hz, 2H), 4.50 (s, 1H), 4.06 (s, 2H), 3.84 (s, 2H), 3.72 (s, 1H), 1.73 (s, 9H), 1.54 (s, 4H), 1.29 (d, J = 44.5 Hz, 13H), 0.85 (s, 2H). Example 6: Synthesis of 28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-32-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(4,3)- pyridinacyclononaphan-36-amine (Compound 106)88 IPTS / 125370156.1Attorney Docket No. KEST-004WOStep 1 4-bromo-5-iodo-6-methylpyridin-2-amine

[0157] Into a 500 ml flask was placed a solution of 4-bromo-6-methylpyridin-2-amine (9.36 g, 50.043 mmol, 1 eq) in DMF (150mL), NIS (11.82 g, 52.545 mmol, 1.05 eq) was added portion wise at 0oC. The resulting mixture was stirred for 16h at room temperature. The reaction was quenched by the addition of water (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 4-bromo-5-iodo-6-methylpyridin-2-amine (14 g, 89.40%) as a light yellow solid. LCMS m / z = 313 [M+Na]+. Step 2: tert-butyl N-(4-bromo-5-iodo-6-methylpyridin-2-yl)-N-(tert-butoxycarbonyl)carbamate

[0158] Into a 250 ml flask was placed a solution of 4-bromo-5-iodo-6-methylpyridin-2- amine (5.0 g, 15.978 mmol, 1 eq), DMAP (1.95 g, 15.978 mmol, 1.0 eq) and TEA (4.85 g, 47.934 mmol, 3.0 eq) in CH2Cl2(50 mL). A solution of di-tert-butyl dicarbonate (10.46 g, 47.934 mmol, 3.0 eq) in DCM (20 mL) was added dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 500mL). The combined organic layers were washed with brine (100mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl N-(4-bromo-5-iodo-6-methylpyridin-2-yl)-N-(tert-butoxycarbonyl)carbamate (7.5 g, 91.47%) as a brown solid. LCMS m / z = 513 [M+Na]+. Step 3: tert-butyl 3-{[(4E)-5-{6-[bis(tert-butoxycarbonyl)amino]-4-bromo-2-methylpyridin-3- yl}pent-4-en-1-yl]oxy}azepane-1-carboxylate

[0159] Into a 50 ml flask purged and maintained in a nitrogen atmosphere, was placed a solution of tert-butyl N-(4-bromo-5-iodo-6-methylpyridin-2-yl)-N-(tert- butoxycarbonyl)carbamate (1 g, 1.949 mmol, 1 eq), tert-butyl 3-(pent-4-en-1-yloxy)azepane-1- carboxylate (662.73 mg, 2.339 mmol, 1.2 eq), 3-tert-butyl-4-(2,6-dimethoxyphenyl)-2,3- dihydro-1,3-benzoxaphosphole (128.75 mg, 0.390 mmol, 0.2 eq) and Pd2(dba)3(178.45 mg, 0.195 mmol, 0.1 eq) in toluene (10 mL). DIEA (754.26 mg, 5.847 mmol, 3 eq) was added under nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under nitrogen atmosphere. The reaction was cooled to rt and quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20mL). The combined 89 IPTS / 125370156.1Attorney Docket No. KEST-004WO organic layers were washed with brine (100mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 2:1) to afford tert-butyl 3-{[(4E)-5-{6-[bis(tert-butoxycarbonyl)amino]-4-bromo-2- methylpyridin-3-yl}pent-4-en-1-yl]oxy}azepane-1-carboxylate (600 mg, 46.05%) as a yellow oil. LCMS m / z = 668 [M+Na]+. Step 4: tert-butyl 3-{[(4E)-5-{6-[bis(tert-butoxycarbonyl)amino]-2-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl}pent-4-en-1-yl]oxy}azepane-1-carboxylate

[0160] Into a 25 ml flask was placed a solution of tert-butyl 3-{[(4E)-5-{6-[bis(tert- butoxycarbonyl)amino]-4-bromo-2-methylpyridin-3-yl}pent-4-en-1-yl]oxy}azepane-1- carboxylate (600 mg, 0.897 mmol, 1 eq), bis(pinacolato)diboron (683.58 mg, 2.691 mmol, 3 eq), Pd(dppf)Cl2(146.57 mg, 0.179 mmol, 0.2 eq) and KOAC (176.13 mg, 1.794 mmol, 2 eq) in dioxane (8 mL) in a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction was diluted by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 10mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 3:1) to afford tert-butyl 3-{[(4E)-5-{6-[bis(tert-butoxycarbonyl)amino]-2-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl}pent-4-en-1-yl]oxy}azepane-1-carboxylate (200 mg, 31.14%) as a yellow oil. LCMS m / z = 716 [M+Na]+. Step 5: tert-butyl 3-{[(4E)-5-[4-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4- (benzyloxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-[(tert-butoxycarbonyl)amino]-2- methylpyridin-3-yl]pent-4-en-1-yl]oxy}azepane-1-carboxylate

[0161] Into a 25 ml flask in a nitrogen atmosphere, was placed a solution of tert-butyl 3- {[(4E)-5-{6-[bis(tert-butoxycarbonyl)amino]-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-3-yl}pent-4-en-1-yl]oxy}azepane-1-carboxylate (180 mg, 0.251 mmol, 1 eq), 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-Intermediate 1 (134.86 mg, 0.301 mmol, 1.2 eq), cataCXium-A-Pd-G3 (18.32 mg, 0.025 mmol, 0.1 eq) and K3PO4(160.15 mg, 0.753 mmol, 3 eq) in 1,4-dioxane (2 mL) and H2O (0.4 mL) under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 10mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The 90 IPTS / 125370156.1Attorney Docket No. KEST-004WO crude product was purified by reverse phase flash with the following conditions (C18 Column, Mobile Phase A: Water(10mmol / L NH4HCO3) Mobile Phase B: ACN; Flow rate: 60 mL / min Gradient: 31% B to 58% B Wave Length: 254nm / 220nm nm;) to afford tert-butyl 3-{[(4E)-5- [4-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4-(benzyloxy)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)-6-[(tert-butoxycarbonyl)amino]-2-methylpyridin-3-yl]pent- 4-en-1-yl]oxy}azepane-1-carboxylate (55 mg, 24.30%) as a yellow solid. LCMS m / z = 1001 [M+H]+. Step 6: tert-butyl 3-({5-[4-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8- fluoro-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-6-[(tert-butoxycarbonyl)amino]-2-methylpyridin- 3-yl]pentyl}oxy)azepane-1-carboxylate

[0162] Into a 25 ml flask in a nitrogen atmosphere, was placed a solution of tert-butyl 3- {[(4E)-5-[4-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4-(benzyloxy)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)-6-[(tert-butoxycarbonyl)amino]-2-methylpyridin-3-yl]pent- 4-en-1-yl]oxy}azepane-1-carboxylate (50 mg, 0.056 mmol, 1 eq) in MeOH (5 mL). Then Pd / C (100.03 mg, 0.948 mmol, 16.92 eq) was added carefully under nitrogen atmosphere. The mixture was stirred at room temperature for 3h under hydrogen atmosphere. The catalyst was filtered out, the filter cake was washed with MeOH (3x20 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 3-({5-[4-(2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-6-[(tert- butoxycarbonyl)amino]-2-methylpyridin-3-yl]pentyl}oxy)azepane-1-carboxylate (40 mg, 88.68%) as a yellow oil. The crude used directly for the next step without further purification. LCMS m / z = 912 [M+H]+. Step 7: 2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-{6-amino-3-[5-(azepan-3- yloxy)pentyl]-2-methylpyridin-4-yl}-8-fluoropyrido[4,3-d]pyrimidin-4-ol

[0163] Into a 25 ml flask was placed a solution of tert-butyl 3-({5-[4-(2-{[(2R,7aS)-2- fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-6- [bis(tert-butoxycarbonyl)amino]-2-methylpyridin-3-yl]pentyl}oxy)azepane-1-carboxylate (40 mg, 0.044 mmol, 1 eq) in DCM (2 mL), then TFA (0.4 mL) was added at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 2- {[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-{6-amino-3-[5-(azepan-3- yloxy)pentyl]-2-methylpyridin-4-yl}-8-fluoropyrido[4,3-d]pyrimidin-4-ol (25 mg, 93.19%) as a 91 IPTS / 125370156.1Attorney Docket No. KEST-004WO brown oil. The crude was used directly for the next step without further purification. LCMS m / z = 612 [M+H]+. Step 8: 28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-32- methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(4,3)-pyridinacyclononaphan- 36-amine

[0164] Into a 25 ml flask was placed a solution of 2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-7-{6-amino-3-[5-(azepan-3-yloxy)pentyl]-2- methylpyridin-4-yl}-8-fluoropyrido[4,3-d]pyrimidin-4-ol (20 mg, 0.033 mmol, 1 eq) in DCM (2 mL, 31.461 mmol, 962.30 eq) under a nitrogen atmosphere. TEA (9.93 mg, 0.099 mmol, 3 eq) and PyBOP (25.52 mg, 0.050 mmol, 1.5 eq) were added at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 10mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 31% B to 58% B in 7min; Wave Length: 254nm / 220nm nm; RT1(min): 7.13) to afford 28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-32- methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(4,3)-pyridinacyclononaphan-36- amine (1.9 mg, 9.79%) as a white solid. LCMS m / z = 594 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 58.1 Hz, 1H), 6.43 (d, J = 50.5 Hz, 1H), 5.89 (d, J = 79.7 Hz, 2H), 5.41 – 4.75 (m, 3H), 4.37 (d, J = 10.6 Hz, 1H), 4.21 – 3.96 (m, 2H), 3.56 (s, 2H), 3.22 – 2.95 (m, 3H), 2.94 – 2.67 (m, 2H), 2.43 – 1.94 (m, 6H), 1.81 (d, J = 35.2 Hz, 4H), 1.54 – 0.68 (m, 7H). Example 7: Synthesis of (13R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-33-methyl-6,9-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana- 3(1,2)-benzenacyclononaphan-35-ol (Compound 111) 92 IPTS / 125370156.1Attorney Docket No. KEST-004WOStep 1: Synthesis of tert-butyl (R)-3-(2-(benzyloxy)ethoxy)azepane-1-carboxylate

[0165] The title compound (7.8 g, 67.2%, yellow oil) was obtained following a similar method to the one described in Step 1 of Intermediate 11, from tert-butyl (3R)-3- hydroxyazepane-1-carboxylate.1H NMR (400 MHz, CDCl3) δ 7.35 (d, 5H), 4.58 (s, 2H), 4.10 - 3.84 (m, 1H), 3.81 - 3.71 (m, 1H), 3.69 (s, 1H), 3.67 (s, 1H), 3.61 - 3.48 (m, 3H), 3.09 - 2.97 (m, 1H), 2.95 - 2.82 (m, 1H), 1.87 - 1.67 (m, 3H), 1.67 - 1.56 (m, 2H), 1.47 (s, 9H), 1.43 - 1.30 (m, 1H). Step 2: Synthesis of tert-butyl (R)-3-(2-hydroxyethoxy)azepane-1-carboxylate

[0166] The title compound (4.77 g, crude, yellow oil) was obtained following a similar method to the one described in Step 2 of Intermediate 11, from the title compound of Step 1.1H NMR (400 MHz, CDCl3) δ 3.89 - 3.75 (m, 2H), 3.74 - 3.67 (m, 2H), 3.63 - 3.56 (m, 2H), 3.55 - 3.27 (m, 2H), 3.13 - 2.91 (m, 1H), 1.90 - 1.70 (m, 3H), 1.68 - 1.55 (m, 2H), 1.52 - 1.44 (m, 9H), 1.43 - 1.32 (m, 1H). Step 3: Synthesis of tert-butyl (R)-3-(2-iodoethoxy)azepane-1-carboxylate

[0167] The title compound (2.27 g, 35%, yellow oil) was obtained following a similar method to the one described for Intermediate 12.1H NMR (400 MHz, CDCl3) δ 4.06 - 3.81 (m, 1H), 3.80 - 3.48 (m, 4H), 3.32 - 3.17 (m, 2H), 3.12 - 2.97 (m, 1H), 2.97 - 2.82 (m, 1H), 1.89 - 1.61 (m, 4H), 1.47 (m, 11H). 93 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 4: Synthesis of tert-butyl (R)-3-(2-(2-bromo-4-(methoxymethoxy)-6- methylphenethoxy)ethoxy)azepane-1-carboxylate

[0168] To a solution of Intermediate 2 (400 mg, 1.45 mmol) in DMF (10 mL) was added NaH (87.2 mg, 2.18 mmol) at 0°C. The reaction mixture was stirred at 20°C for 1 h under N2then the title compound of Step 3 (1.07 g, 2.91 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 16 h under N2, then quenched with NH4Cl (100 mL) and extracted with EtOAc (50 mLx3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water (FA)-ACN]; gradient: 65%-95% B over 10 min) to give the title compound (190 mg, 24%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 6.80 (s, 1H), 5.12 (s, 2H), 4.10 - 3.82 (m, 1H), 3.80 - 3.49 (m, 8H), 3.47 (s, 3H), 3.10 - 2.95 (m, 3H), 2.93 - 2.78 (m, 1H), 2.38 (s, 3H), 1.91 - 1.61 (m, 4H), 1.58 - 1.53 (m, 1H), 1.47 (d, 9H), 1.42 - 1.29 (m, 1H). Step 5: Synthesis of tert-butyl (R)-3-(2-(4-(methoxymethoxy)-2-methyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenethoxy)ethoxy)azepane-1-carboxylate

[0169] To a solution of the title compound of Step 4 (150 mg, 290 μmol) in dioxane (5 mL) was added bis(pinacolato)diboron (368 mg, 1.45 mmol), Pd2(dba)3(26.6 mg, 29.0 μmol), KOAc (85.5 mg, 871 μmol) and XPhos (27.6 mg, 58.1 μmol). The reaction mixture was stirred at 80°C for 16 h under N2, then diluted with water (40 mL) and extracted with EtOAc (25 mLx3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 1:2) to give the title compound (200 mg, 97%) as yellow gum.1H NMR (400 MHz, CDCl3) δ 7.33 - 7.27 (m, 1H), 6.93 (s, 1H), 5.16 (s, 2H), 4.10 - 3.83 (m, 1H), 3.81 - 3.52 (m, 8H), 3.48 (s, 3H), 3.23 - 2.78 (m, 4H), 2.05 (s, 3H), 1.90 - 1.60 (m, 5H), 1.54 (d, 1H), 1.34 (s, 9H), 1.29 - 1.24 (m, 12H). Step 6: Synthesis of tert-butyl (R)-3-(2-(2-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4- (methoxymethoxy)-6-methylphenethoxy)ethoxy)azepane-1-carboxylate

[0170] To a solution of Intermediate 1 (140 mg, 313 μmol) in dioxane (4 mL) and H2O (1 mL) was added the title compound of Step 5 (176 mg, 313 μmol), cataCXium A Pd 3 (22.8 mg, 31.3 μmol) and K3PO4(199 mg, 939 μmol). The mixture was stirred at 80°C for 1 h under N2, then quenched with water (5 mL) and extracted with EtOAc (5 mLx3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 0:1) to give the title 94 IPTS / 125370156.1Attorney Docket No. KEST-004WO compound (160 mg, 53%) as a yellow gum.1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 7.54 (d, 2H), 7.47 - 7.41 (m, 3H), 6.97 (s, 1H), 5.70 (s, 2H), 5.15 (s, 2H), 4.43 - 4.27 (m, 2H), 4.04 - 3.67 (m, 2H), 3.59 - 3.48 (m, 3H), 3.46 (s, 3H), 3.43 - 3.37 (m, 4H), 3.34 - 3.25 (m, 2H), 3.23 - 3.18 (m, 1H), 3.04 - 2.93 (m, 2H), 2.87 - 2.72 (m, 3H), 2.42 (s, 3H), 2.29 (d, 1H), 2.20 - 2.16 (m, 1H), 2.03 - 1.88 (m, 4H), 1.79 - 1.71 (m, 4H), 1.67 (d, 1H), 1.60 - 1.50 (m, 2H), 1.44 (d, 9H), 1.36 - 1.29 (m, 1H). Step 7: Synthesis of 7-(2-(2-(2-(((R)-azepan-3-yl)oxy)ethoxy)ethyl)-5-hydroxy-3-methylphenyl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-ol

[0171] To a solution of the title compound of Step 6 (150 mg, 176 μmol) in DCM (1 mL) was added BCl3(1 M, 1.06 mL). The reaction mixture was stirred at 20°C for 5 h, then quenched with water (10 mL) and extracted with EtOAc (5 mLx3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 2%-32% B over 10 min) to give the title compound (35 mg, 29%) as a yellow solid. LCMS: m / z = 614 [M+H]+. Step 8: Synthesis of (13R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-33-methyl-6,9-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)- benzenacyclononaphan-35-ol

[0172] To a solution of the title compound of Step 7 (40 mg, 65.1 μmol) in DCM (5 mL) was added TEA (65.9 mg, 651 μmol) and PyBOP (50.8 mg, 97.7 μmol) at 0°C. The reaction mixture was stirred at 20°C for 3 h, then concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient:12%-42% B over 10 min), prep-HPLC (column: Waters Xbridge 150*25mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 33%-63% B over 10 min) and prep-HPLC (column: Phenomenex Luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 10%-40% B over 10 min) to give the title compound (0.6 mg, 1.4%, FA salt) as a yellow solid. LCMS: m / z = 594 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.44 - 9.29 (m, 2H), 8.21 (s, 1H), 6.76 - 6.68 (m, 2H), 5.39 - 5.19 (m, 1H), 5.18 - 5.06 (m, 1H), 4.45 - 4.33 (m, 1H), 4.14 - 4.04 (m, 2H), 3.68 - 3.62 (m, 1H), 3.52 - 3.45 (m, 3H), 3.17 (s, 1H), 3.08 (d, 2H), 3.03 - 3.00 (m, 2H), 2.82 (d, 1H), 2.66 - 2.60 (m, 2H), 2.55 (s, 1H), 2.23 (s, 3H), 2.20 - 2.10 (m, 2H), 2.08 - 2.04 (m, 1H), 2.01 - 1.96 (m, 1H), 1.90 - 1.68 (m, 6H), 1.57 - 1.51 (m, 1H), 1.42 - 1.34 (m, 1H), 1.25 (d, 2H). 95 IPTS / 125370156.1Attorney Docket No. KEST-004WO Example 8: Synthesis of (13R,15R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- azepana-3(1,2)-benzenacyclononaphane-15,35-diol (Compound 112) and (13S,15S)-28- fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9- oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)-benzenacyclononaphane-15,35- diol (Compound 113) or (13S,15R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- azepana-3(1,2)-benzenacyclononaphane-15,35-diol (Compound 114) and (13R,15S)-28- fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9- oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)-benzenacyclononaphane-15,35- diol (Compound 115)96 IPTS / 125370156.1Attorney Docket No. KEST-004WO97 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 1: Synthesis of tert-butyl 5-(benzyloxy)-3-oxoazepane-1-carboxylate

[0173] To a solution of tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (6 g, 28.40 mmol) in BnOH (30.7 g, 284 mmol) was added t-BuOK (319 mg, 2.84 mmol). The reaction mixture was stirred at 25°C for 12 h, then quenched with water (400 mL) and extracted with EtOAc (200 mLx3). The combined organic layers were washed with sat. brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (33 g, crude) as a brown oil. LCMS: m / z = 220 [M-Boc+H]+. Step 2: Synthesis of tert-butyl rel-(3R,5R)-5-(benzyloxy)-3-hydroxyazepane-1-carboxylate and tert-butyl rel-(3R,5S)-5-(benzyloxy)-3-hydroxyazepane-1-carboxylate

[0174] To a solution of the title compound of Step 1 (34.4 g, 108 mmol) in EtOH (250 mL) was added NaBH4(4.06 g, 107 mmol). The reaction mixture was stirred at 15°C for 2 h, then quenched with water (500 mL), and extracted with EtOAc (200 mLx3). The combined organic layers were washed with sat. brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 30%-60% B over 20 min) and lyophilized to give Peak 1, tert-butyl rel-(3R,5R)-5-(benzyloxy)- 3-hydroxyazepane-1-carboxylate or tert-butyl rel-(3R,5S)-5-(benzyloxy)-3-hydroxyazepane-1- carboxylate (2.6 g, 7.68 mmol, 7.1%) as a yellow oil:1H NMR (400 MHz, CDCl3) δ 7.40 - 7.28 (m, 5H), 4.66 - 4.44 (m, 2H), 4.12 - 4.00 (m, 1H), 3.96 - 3.87 (m, 1H), 3.81 - 3.41 (m, 3H), 3.29 - 3.12 (m, 1H), 2.88 (br s, 1H), 2.25 - 2.14 (m, 1H), 2.05 - 1.80 (m, 3H), 1.46 (s, 9H);

[0175] And Peak 2, tert-butyl rel-(3R,5S)-5-(benzyloxy)-3-hydroxyazepane-1-carboxylate or tert-butyl rel-(3R,5R)-5-(benzyloxy)-3-hydroxyazepane-1-carboxylate (2.6 g, 7.68 mmol, 7.1%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.39 - 7.28 (m, 5H), 4.63 - 4.43 (m, 2H), 4.22 - 4.08 (m, 1H), 4.01 - 3.80 (m, 2H), 3.77 - 3.26 (m, 3H), 3.14-3.07 (m, 1H), 2.29 - 2.15 (m, 1H), 1.99 - 1.80 (m, 3H), 1.50 - 1.44 (m, 9H). Step 3: Synthesis of tert-butyl rel-(3R,5R)-5-(benzyloxy)-3-(pent-4-yn-1-yloxy)azepane-1- carboxylate or tert-butyl rel-(3S,5R)-5-(benzyloxy)-3-(pent-4-yn-1-yloxy)azepane-1-carboxylate

[0176] To a solution of the title compound of Peak 1 from Step 2 (2.25 g, 7.00 mmol) in hexane (32 mL) and NaOH (16 mL) was added TBAB (451 mg, 1.40 mmol) and 5-iodopent-1- yne (6.79 g, 35.0 mmol). The reaction mixture was stirred at 80°C for 32 h, then quenched with water (100 mL) and extracted with EtOAc (50 mLx3). The combined organic layers were washed with sat. brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 98 IPTS / 125370156.1Attorney Docket No. KEST-004WO 4:1) to give the title compound (1.37 g, 47%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.40 - 7.27 (m, 5H), 4.54 (d, 2H), 4.11 - 3.79 (m, 1H), 3.73 - 3.33 (m, 5H), 3.30 - 3.14 (m, 1H), 3.04 - 2.82 (m, 1H), 2.41 - 2.11 (m, 4H), 1.95 (s, 1H), 1.87 - 1.68 (m, 4H), 1.46 (d, 9H). Step 4: Synthesis of tert-butyl rel-(3R,5R)-5-(benzyloxy)-3-((5-(2-bromo-4-(methoxymethoxy)-6- methylphenyl)pent-4-yn-1-yl)oxy)azepane-1-carboxylate or tert-butyl rel-(3S,5R)-5-(benzyloxy)- 3-((5-(2-bromo-4-(methoxymethoxy)-6-methylphenyl)pent-4-yn-1-yl)oxy)azepane-1-carboxylate

[0177] To a solution of the title compound of Step 3 (1.05 g, 2.94 mmol) and the title compound of Intermediate 2, Step 1 (1.14 g, 2.94 mmol) in DMF (15 mL) and TEA (30 mL) was added CuI (112 mg, 588 μmol) and Pd(PPh3)4(340 mg, 294 μmol). The reaction mixture was stirred at 80°C for 2 h under N2, then quenched with water (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were washed with sat. brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 100:0 to 90:10) followed by prep-HPLC (column: Phenomenex Luna C18150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 70%-100% B over 10 min). The fractions were lyophilized to give the title compound (680 mg, 36%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.37 - 7.28 (m, 5H), 7.12 (s, 1H), 6.82 (s, 1H), 5.13 (s, 2H), 4.63 - 4.43 (m, 2H), 4.08 - 3.84 (m, 1H), 3.75 - 3.41 (m, 3H), 3.54 - 3.41 (m, 5H), 3.30 - 3.17 (m, 1H), 3.04 - 2.85 (m, 1H), 2.60 (d, 2H), 2.42 (s, 3H), 2.39 - 2.31 (m, 1H), 2.17 (s, 1H), 1.93 - 1.73 (m, 4H), 1.44 (s, 9H). Step 5: Synthesis of tert-butyl rel-(3R,5R)-5-(benzyloxy)-3-((5-(4-(methoxymethoxy)-2-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pent-4-yn-1-yl)oxy)azepane-1-carboxylate or tert-butyl rel-(3S,5R)-5-(benzyloxy)-3-((5-(4-(methoxymethoxy)-2-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pent-4-yn-1-yl)oxy)azepane-1-carboxylate

[0178] To a solution of the title compound of Step 4 (630 mg, 1.02 mmol) and bis(pinacolato)diboron (1.30 g, 5.11 mmol) in dioxane (30 mL) was added Pd2(dba)3(93.6 mg, 102 μmol), KOAc (301 mg, 3.07 mmol) and XPhos (97.4 mg, 204 μmol). The reaction mixture was stirred at 100°C for 16 h under N2, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 100:0 to 4:1) to give the title compound (440 mg, 52%) as a yellow oil. LCMS: m / z = 686 [M+Na]+. Step 6: Synthesis of tert-butyl rel-(3R,5R)-5-hydroxy-3-((5-(4-(methoxymethoxy)-2-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentyl)oxy)azepane-1-carboxylate or tert- butyl rel-(3S,5R)-5-hydroxy-3-((5-(4-(methoxymethoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)pentyl)oxy)azepane-1-carboxylate 99 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0179] To a solution of the title compound of Step 5 (440 mg, 663 μmol) in MeOH (20 mL) was added Pd / C (40 mg, 37.6 μmol, 10% purity) and Pd(OH)2(40 mg, 285 μmol). The mixture was stirred at 30°C for 4 h under H2atmosphere (50 psi), then filtered and concentrated under reduced pressure to give the title compound (377 mg, crude) as a colorless oil. LCMS: m / z = 578 [M+H]+. Step 7: Synthesis of tert-butyl rel-(3R,5R)-3-((5-(2-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4- (methoxymethoxy)-6-methylphenyl)pentyl)oxy)-5-hydroxyazepane-1-carboxylate or tert-butyl rel-(3S,5R)-3-((5-(2-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6- methylphenyl)pentyl)oxy)-5-hydroxyazepane-1-carboxylate

[0180] The title compound (0.2 g, 77%, yellow oil) was prepared using a method similar to the one described in Step 6 of Example 7, from the title compound of Step 6 and Intermediate 1.1H NMR (400 MHz, CD3OD) δ 9.17 (d, 1H), 7.59 (d, 2H), 7.50 - 7.36 (m, 3H), 7.01 (d, 1H), 6.82 (d, 1H), 5.74 (s, 2H), 5.41 - 5.24 (m, 1H), 5.16 (s, 2H), 4.45 - 4.33 (m, 2H), 3.68 - 3.43 (m, 6H), 3.30 - 3.23 (m, 4H), 3.09 - 2.94 (m, 2H), 2.47 (d, 2H), 2.39 (s, 3H), 2.36 - 2.28 (m, 1H), 2.26 - 2.21 (m, 1H), 2.19 - 2.14 (m, 1H), 2.09 - 2.03 (m, 2H), 2.00 - 1.91 (m, 2H), 1.75 - 1.55 (m, 2H), 1.51 - 1.38 (m, 10H), 1.37 - 1.24 (m, 7H), 1.18 - 1.10 (m, 2H). Step 8: Synthesis of tert-butyl rel-(3R,5R)-3-((5-(2-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-4- (methoxymethoxy)-6-methylphenyl)pentyl)oxy)-5-hydroxyazepane-1-carboxylate or tert-butyl rel-(3S,5R)-3-((5-(2-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6- methylphenyl)pentyl)oxy)-5-hydroxyazepane-1-carboxylate

[0181] To a solution of the title compound of Step 7 (170 mg, 197 μmol) in MeOH (10 mL) was added Pd / C (20.0 mg, 18.8μmol, 10% purity). The mixture was stirred at 30°C for 4 h under H2(30 psi), then filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (column: SANTAI, SW-5222-040-SP, Spherical C 18, 20- 45μm, 100A; mobile phase: water (0.1% FA) – ACN; gradient:15%-35% B over 15 min) and lyophilized to give the title compound (50 mg, 30%) as a white solid. LCMS: m / z = 772 [M+H]+. 100 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 9: Synthesis of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5-hydroxy-2-(5-(((3R,5R)-5-hydroxyazepan-3-yl)oxy)pentyl)-3- methylphenyl)pyrido[4,3-d]pyrimidin-4-ol and 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5-hydroxy-2-(5-(((3S,5S)-5-hydroxyazepan-3-yl)oxy)pentyl)- 3-methylphenyl)pyrido[4,3-d]pyrimidin-4-ol or 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5-hydroxy-2-(5-(((3S,5R)-5-hydroxyazepan-3-yl)oxy)pentyl)- 3-methylphenyl)pyrido[4,3-d]pyrimidin-4-ol and 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(5-hydroxy-2-(5-(((3R,5S)-5-hydroxyazepan-3-yl)oxy)pentyl)- 3-methylphenyl)pyrido[4,3-d]pyrimidin-4-ol

[0182] To a solution of the title compound of Step 8 (45 mg, 58.3 μmol) in MeCN (2.7 mL) was added 2-(2-pyridyl)pyridine (54.6 mg, 350 μmol) and TMSOTf (51.8 mg, 233 μmol) at 0°C. The reaction mixture was stirred at 20°C for 5 h, then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 23%-43% B over 8 min) and lyophilized to give the title compound (22 mg, 55%) as a pink solid. LCMS: m / z = 628 [M+H]+. Step 10: Synthesis of (13R,15R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)- benzenacyclononaphane-15,35-diol and (13S,15S)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- azepana-3(1,2)-benzenacyclononaphane-15,35-diol or (13S,15R)-28-fluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3- d]pyrimidina-1(1,3)-azepana-3(1,2)-benzenacyclononaphane-15,35-diol and (13R,15S)-28- fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa- 2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)-benzenacyclononaphane-15,35-diol

[0183] The title compound (14 mg, 36%, FA salt, white solid) was obtained using a method similar to the one described in Step 8 of Example 7, from the title compound of Step 9.

[0184] The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm*10μm; mobile phase: [water (FA)-ACN]; gradient:13%-43% B over 10 min). LCMS: m / z = 610 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.40 - 9.23 (m, 2H), 8.19 (s, 1H), 6.69 (d, 1H), 6.63 (d, 1H), 5.38 - 5.16 (m, 1H), 5.15 - 4.96 (m, 1H), 4.76 - 4.49 (m, 1H), 4.39 - 4.22 (m, 1H), 4.19 - 3.99 (m, 2H), 3.77 - 3.68 (m, 1H), 3.13 - 2.98 (m, 4H), 2.93 - 2.80 (m, 3H), 2.48 - 2.39 (m, 2H), 2.29 - 2.23 (m, 3H), 2.21 - 2.09 (m, 3H), 2.08 - 1.95 (m, 4H), 1.90 - 1.68 (m, 4H), 101 IPTS / 125370156.1Attorney Docket No. KEST-004WO 1.29 - 1.12 (m, 3H), 1.05 - 0.95 (m, 1H), 0.91 - 0.81 (m, 1H), 0.79 - 0.69 (m, 1H), 0.34 - 0.16 (m, 1H). Example 9: Synthesis of (13R,15R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- azepana-3(1,2)-benzenacyclononaphane-15,35-diol (Compound 112) or (13R,15S)-28-fluoro- 22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa- 2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)-benzenacyclononaphane-15,35-diol (Compound 115) and (13S,15S)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana- 3(1,2)-benzenacyclononaphane-15,35-diol (Compound 113) or (13S,15R)-28-fluoro-22- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)- pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)-benzenacyclononaphane-15,35-diol (Compound 114)

[0185] The title compound of Example 8, Step 10 was purified by SFC (column: DAICEL CHIRALCEL OD 250*30mm*10μm; mobile phase: [CO2-EtOH (0.1% NH3.H2O)]; B%: 50% isocratic) and lyophilized to give (13R,15R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- azepana-3(1,2)-benzenacyclononaphane-15,35-diol or (13R,15S)-28-fluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3- d]pyrimidina-1(1,3)-azepana-3(1,2)-benzenacyclononaphane-15,35-diol (6.61 mg, 48%, FA salt) as a white solid: LCMS: m / z = 610 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.43 - 9.17 (m, 2H), 8.16 (s, 1H), 6.70 (d, 1H), 6.64 (d, 1H), 5.41 - 5.18 (m, 1H), 5.12 - 4.98 (m, 1H), 4.66 (d, 102 IPTS / 125370156.1Attorney Docket No. KEST-004WO 1H), 4.29 (d, 1H), 4.16 - 4.03 (m, 2H), 3.71 (t, 1H), 3.17 - 3.02 (m, 4H), 2.93 - 2.81 (m, 3H), 2.43 (dd, 2H), 2.26 (s, 3H), 2.24 - 2.12 (m, 3H), 2.10 - 1.94 (m, 5H), 1.89 - 1.76 (m, 3H), 1.24 - 1.17 (m, 3H), 1.05 - 0.94 (m, 1H), 0.89 - 0.82 (m, 1H), 0.79 - 0.68 (m, 1H), 0.26 (d, 1H);

[0186] and (13S,15S)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,2)- benzenacyclononaphane-15,35-diol or (13S,15R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-33-methyl-9-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- azepana-3(1,2)-benzenacyclononaphane-15,35-diol (6.16 mg, 47%, FA salt) as a white solid: LCMS: m / z = 610 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.43 - 9.20 (m, 2H), 8.16 (s, 1H), 6.70 (d, 1H), 6.64 (d, 1H), 5.39 - 5.18 (m, 1H), 5.05 (d, 1H), 4.80 - 4.55 (m, 1H), 4.30 (d, 1H), 4.20 - 4.03 (m, 2H), 3.71 (t, 1H), 3.20 - 3.03 (m, 4H), 2.95 - 2.81 (m, 3H), 2.48 - 2.38 (m, 2H), 2.26 (s, 3H), 2.22 - 2.11 (m, 3H), 2.10 - 1.91 (m, 5H), 1.88 - 1.75 (m, 3H), 1.23 - 1.13 (m, 3H), 1.04 - 0.95 (m, 1H), 0.84 (d, 1H), 0.75 (d, 1H), 0.26 (d, 1H). Example 10: Synthesis of 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-33-hydroxy-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana- 3(1,8)-naphthalenacycloheptaphane-15-carbonitrile (Compound 116)103 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 1: Synthesis of tert-butyl 5-cyano-3-oxoazepane-1-carboxylate

[0187] To a solution of tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (2.00 g, 9.47 mmol) in DMF (20 mL) and H2O (8 mL) was added NH4Cl (557 mg, 10.4 mmol) and NaCN (510 mg, 10.4 mmol) and the reaction mixture was stirred at 70°C for 1 h. The mixture was diluted with water (50 mL) and sat. Na2CO3solution to adjust to pH ~ 9 and extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine (30 mLx2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 4 / 1) to give the title compound (1.50 g, 66%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 4.17 - 3.92 (m, 2H), 3.77 - 3.41 (m, 2H), 3.12 - 2.94 (m, 1H), 2.91 - 2.75 (m, 2H), 2.27 - 2.09 (m, 2H), 1.56 - 1.40 (m, 9H). Step 2: Synthesis of tert-butyl 5-cyano-3-hydroxyazepane-1-carboxylate

[0188] The title compound (870 mg, 45%, light yellow oil) was obtained following a similar method to the one described in Step 2 of Example 8, using the title compound of Step 1.1H NMR (400 MHz, DMSO-d6) δ 5.07 (dd, 1H), 3.97 - 3.83 (m, 1H), 3.75 - 3.55 (m, 2H), 3.28 - 3.01 (m, 2H), 2.96 - 2.82 (m, 1H), 1.97 - 1.68 (m, 4H), 1.39 (s, 9H). Step 3: Synthesis of tert-butyl 3-((3-(8-(benzyloxy)-2-fluoro-6-(methoxymethoxy)naphthalen-1- yl)prop-2-yn-1-yl)oxy)-5-cyanoazepane-1-carboxylate

[0189] To a solution of the title compound of Step 2 (320 mg, 1.33 mmol) in DMF (4 mL) was added NaH (63.9 mg, 1.60 mmol, 60% purity) at 0°C. The reaction mixture was stirred at 25°C for 0.5 h under N2, then Intermediate 5 (500 mg, 1.16 mmol) in DMF (5 mL) was added at 0°C. The reaction mixture was stirred at 25°C for 1 h under N2, then quenched by sat. NH4Cl solution (50 mL) and extracted with EtOAc (50 mLx2). The combined organic layers were washed with brine (30 mLx3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 7 / 1) to give the title compound (334 mg, 40%) as a yellow oil. LCMS: m / z = 589 [M+H]+. Step 4: Synthesis of tert-butyl 5-cyano-3-(3-(2-fluoro-8-hydroxy-6- (methoxymethoxy)naphthalen-1-yl)propoxy)azepane-1-carboxylate

[0190] To a solution of the title compound of Step 3 (334 mg, 567 μmol) in MeOH (8 mL) was added Pd / C (120 mg, 113 μmol, 10% purity). The reaction mixture was stirred at 30°C for 16 h under H2(50 Psi), then filtered and concentrated under reduced pressure to give the title compound (250 mg, crude) as a yellow oil. LCMS: m / z = 503 [M+H]+. 104 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 5: Synthesis of tert-butyl 5-cyano-3-(3-(2-fluoro-6-(methoxymethoxy)-8- (((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)propoxy)azepane-1-carboxylate

[0191] To a solution of the title compound of Step 4 (230 mg, 458 μmol) in DCM (5 mL) was added DMAP (279 mg, 2.29 mmol) and 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl)methanesulfonamide (490 mg, 1.37 mmol) at 0°C. The reaction mixture was stirred at 25°C for 2 h, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 6 / 1) to give the title compound (240 mg, 80%) as a light yellow oil. LCMS: m / z = 657 [M+Na]+. Step 6: Synthesis of tert-butyl 3-(3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6- (methoxymethoxy)naphthalen-1-yl)propoxy)-5-cyanoazepane-1-carboxylate

[0192] To a mixture of the title compound of Step 5 (50.0 mg, 78.8 μmol) in dioxane (1 mL) was added Intermediate 10 (159 mg, 276 μmol), CuI (3.00 mg, 15.8 μmol), CsF (12.0 mg, 78.8 μmol) and Pd(PPh3)4(18.2 mg, 15.8 μmol). The reaction mixture was stirred at 80°C for 2 h under N2, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 1:1) to give the title compound (120 mg, 85%) as a yellow oil. LCMS: m / z = 897 [M+H]+. Step 7: Synthesis of 6-(3-(2-fluoro-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-6-hydroxynaphthalen-1- yl)propoxy)azepane-4-carbonitrile

[0193] To a solution of the title compound of Step 6 (100 mg, 55.7 μmol) in DCM (3 mL) was added TFA (461 mg, 4.04 mmol). The reaction mixture was stirred at 25°C for 2 h, then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10μm; mobile phase: [water (TFA)-ACN]; gradient: 13%- 43% B over 10 min) to give the title compound (35 mg, 94%) as a white solid. LCMS: m / z = 663 [M+H]+. Step 8: Synthesis of 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-33-hydroxy-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacycloheptaphane-15-carbonitrile

[0194] The title compound (5.31 mg, 17%, brown solid) was obtained using a method similar to the one described in Step 8 of Example 7, from the title compound of Step 7. The crude was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: 105 IPTS / 125370156.1Attorney Docket No. KEST-004WO [water (NH4HCO3)-ACN]; gradient: 35%-65% B over 10 min). LCMS: m / z = 645 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.50 (s, 1H), 7.76 (dd, 8.8 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.21 - 7.14 (m, 1H), 5.50 – 5.25 (m, 2H), 4.76 - 4.68 (m, 1H), 3.78 - 3.63 (m, 4H), - - - - - -2-106 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 1: Synthesis of tert-butyl rel-(3S,6R)-3-((tert-butyldimethylsilyl)oxy)-6-hydroxy-2,3,6,7- tetrahydro-1H-azepine-1-carboxylate

[0195] To a solution of tert-butyl (3R,6S)-3,6-dihydroxy-2,3,6,7-tetrahydro-1H-azepine-1- carboxylate (1.7 g, 7.41 mmol) in THF (40 mL) was added NaH (356 mg, 8.90 mmol, 60% purity) followed by a solution of TBSCl (1.34 g, 8.90 mmol) in THF (5 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 h, then quenched with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 1:1) to give the title compound (1.8 g, 67%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 5.77 - 5.57 (m, 2H), 4.43 - 4.23 (m, 2H), 4.00- 3.71 (m, 2H), 3.25 - 2.89 (m, 2H), 1.49 (s, 9H), 0.91 (s, 9H), 0.11 (s, 6H). Step 2: Synthesis of tert-butyl rel-(3R,6S)-3-(allyloxy)-6-((tert-butyldimethylsilyl)oxy)-2,3,6,7- tetrahydro-1H-azepine-1-carboxylate

[0196] To a solution of the title compound of Step 1 (1.8 g, 5.24 mmol) in DMF (30 mL) was added NaH (251 mg, 6.29 mmol, 60% purity) at 0°C. The reaction mixture was stirred at 0°C for 0.5 h, then allyl bromide (951 mg, 7.86 mmol) and NaI (157 mg, 1.05 mmol) were added. The mixture was stirred at 20°C for 2 h under N2, then quenched with water (50 mL) and extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 9:1) to give the title compound (1.75 g, 87%) as colorless oil.1H NMR (400 MHz, CDCl3) δ 5.98 - 5.84 (m, 1H), 5.77 - 5.60 (m, 2H), 5.37 - 5.09 (m, 2H), 4.34 - 3.90 (m, 6H), 2.89 - 2.62 (m, 2H), 1.50 (s, 9H), 0.91 (s, 9H), 0.15 - 0.07 (m, 6H). Step 3: Synthesis of tert-butyl rel-(3R,6S)-3-(((E)-3-(8-(benzyloxy)-2-fluoro-6- ((triisopropylsilyl)oxy)naphthalen-1-yl)allyl)oxy)-6-((tert-butyldimethylsilyl)oxy)-2,3,6,7- tetrahydro-1H-azepine-1-carboxylate

[0197] To a solution of the title compound of Step 2 (620 mg, 1.62 mmol) and Intermediate 6 (814 mg, 1.62 mmol) in toluene (40 mL) was added Pd2(dba)3(148 mg, 162 μmol), DIPEA (627 mg, 4.85 mmol) and (R)-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3- dihydrobenzo[d][1,3]oxaphosphole (107 mg, 323 μmol). The reaction mixture was stirred at 100°C for 16 h under N2, then concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under 107 IPTS / 125370156.1Attorney Docket No. KEST-004WO reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 9:1) to give the title compound (970 mg, 67%) as a yellow oil. LCMS: m / z = 828 [M+Na]+. Step 4: Synthesis of tert-butyl rel-(3S,6R)-3-((tert-butyldimethylsilyl)oxy)-6-(3-(2-fluoro-8- hydroxy-6-((triisopropylsilyl)oxy)naphthalen-1-yl)propoxy)azepane-1-carboxylate

[0198] The title compound (640 mg, 72%, yellow oil) was obtained following a similar method to the one described in Step 6 of Example 8, from the title compound of Step 3. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 9:1).1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 7.40 (dd, 1H), 7.15 - 7.04 (m, 1H), 6.73 (d, 1H), 6.58 (d, 1H), 4.30 (dd, 1H), 4.08 - 3.99 (m, 2H), 3.96 - 3.79 (m, 2H), 3.77 - 3.62 (m, 2H), 3.57 - 3.35 (m, 1H), 2.95 (dt, 1H), 2.77 - 2.65 (m, 2H), 2.41 - 2.27 (m, 1H), 1.87 - 1.72 (m, 3H), 1.54 (s, 9H), 1.34 - 1.25 (m, 4H), 1.13 (d, 18H), 0.92 - 0.89 (m, 9H), 0.07 (s, 6H). Step 5: Synthesis of tert-butyl rel-(3S,6R)-3-((tert-butyldimethylsilyl)oxy)-6-(3-(2-fluoro-8- (((trifluoromethyl)sulfonyl)oxy)-6-((triisopropylsilyl)oxy)naphthalen-1-yl)propoxy)azepane-1- carboxylate

[0199] The title compound (590 mg, 80%, yellow oil) was obtained following a similar method to the one described in Step 5 of Example 10, from the title compound of Step 4. LCMS: m / z = 852 [M+H]+. Step 6: Synthesis of tert-butyl rel-(3R,6S)-3-(3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6- ((triisopropylsilyl)oxy)naphthalen-1-yl)propoxy)-6-((tert-butyldimethylsilyl)oxy)azepane-1- carboxylate

[0200] To a solution of the title compound of Step 5 (370 mg, 382 μmol) and Intermediate 10 (439 mg, 764 μmol) in dioxane (30 mL) and DMF (3 mL) was added Pd(PPh3)4(44.1 mg, 38.2 μmol) and CuBr (11.0 mg, 76.4 μmol). The reaction mixture was stirred at 120°C for 2 h under N2, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 3 / 2) to give the title compound (360 mg, 42%) as a brown oil. LCMS: m / z = 1114 [M+H]+. Step 7: Synthesis of 8-fluoro-7-(7-fluoro-8-(3-(((3R,6S)-6-hydroxyazepan-3-yl)oxy)propyl)-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol and 8-fluoro-7-(7-fluoro-8-(3-(((3S,6R)-6- hydroxyazepan-3-yl)oxy)propyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol 108 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0201] The title compound (42 mg, 14%, white solid) was obtained using a similar method to the one described in Step 7 of Example 10, from the title compound of Step 6. The crude was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 62%-82% B over 8 min). LCMS: m / z = 810 [M+H]+. Step 8: Synthesis of (13R,16S)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-33-((triisopropylsilyl)oxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- azepana-3(1,8)-naphthalenacycloheptaphan-16-ol and (13S,16R)-28,37-difluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-((triisopropylsilyl)oxy)-7-oxa-2(4,7)- pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacycloheptaphan-16-ol

[0202] The title compound (8 mg, 44%, green oil) was obtained using a method similar to the one described in Step 8 of Example 7, from the title compound of Step 7. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm*10 um; mobile phase: [water (FA)-ACN]; gradient: 41%-71% B over 10 min). LCMS: m / z = 792 [M+H]+. Step 9: Synthesis of (13R,16S)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacycloheptaphane-16,33-diol and (13S,16R)-28,37-difluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina- 1(1,3)-azepana-3(1,8)-naphthalenacycloheptaphane-16,33-diol

[0203] To a solution of the title compound of Step 8 (8 mg, 10.1 μmol) in MeCN (0.2 mL) and H2O (0.01 mL) was added CsF (3.07 mg, 20.2 μmol). The reaction mixture was stirred at 50°C for 1 h, then concentrated under reduced pressure. The residue was purified by prep- HPLC (column: Phenomenex Luna C18150*25 mm*10 μm; mobile phase: [water (FA) - ACN]; gradient: 19%-49% B over 10 min) and lyophilized to give the title compound (1.33 mg, 20%, FA salt) as a light yellow solid. LCMS: m / z 636 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.26 (s, 1H), 7.75 (dd, 1H), 7.37 - 7.26 (m, 2H), 7.19 (t, 1H), 5.37 - 5.14 (m, 2H), 4.71 (dd, 1H), 4.25 - 3.99 (m, 3H), 3.70 – 3.60 (m, 2H), 3.35 – 3.25 (m, 2H), 3.10 - 3.05 (m, 2H), 3.00 (s, 1H), 2.90 (t, 1H), 2.81 (d, 1H), 2.41 - 2.25 (m, 2H), 2.11 - 1.73 (m, 7H), 1.63 - 1.38 (m, 5H), 1.07 - 0.90 (m, 1H). 109 IPTS / 125370156.1Attorney Docket No. KEST-004WO Examples 12 and 13: Chiral separation of (13R,16S)-28,37-difluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3- d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacycloheptaphane-16,33-diol (Compound 117) and (13S,16R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacycloheptaphane-16,33-diol (Compound 118)

[0204] The title compound of Example 11, was purified by SFC (column: DAICEL CHIRALPAK AS 250*30mm,10um); mobile phase: [CO2-i-PrOH (0.1% NH3.H2O)]; B: 50% isocratic) and lyophilized to give Peak 1, (13R,16S)-28,37-difluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina- 1(1,3)-azepana-3(1,8)-naphthalenacycloheptaphane-16,33-diol or (13S,16R)-28,37-difluoro-22- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3- d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacycloheptaphane-16,33-diol (5.99 mg, 38%, Rt1=1.458 min) as an off-white solid: LCMS: m / z = 636 [M+H]+;1H NMR (400 MHz, DMSO- d6) δ 9.47 (s, 1H), 7.76 (dd, 1H), 7.44 - 7.26 (m, 3H), 7.19 (d, 1H), 5.36 - 5.18 (m, 2H), 4.73 (d, 1H), 4.19 - 4.00 (m, 3H), 3.65 (d, 2H), 3.28 (d, 2H), 3.14 - 3.10 (m, 2H), 2.94 - 2.79 (m, 3H), 2.38 - 2.27 (m, 2H), 2.09 - 1.77 (m, 7H), 1.58 - 1.39 (m, 5H), 1.07 - 0.97 (m, 1H);

[0205] And Peak 2, (13S,16R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacycloheptaphane-16,33-diol or (13R,16S)-28,37-difluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina- 1(1,3)-azepana-3(1,8)-naphthalenacycloheptaphane-16,33-diol (4.93 mg, 32%, Rt1=1.732 min) as an off-white solid: LCMS: m / z = 636 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.47 (s, 1H), 7.76 (dd, 1H), 7.36 - 7.26 (m, 2H), 7.20 (d, 1H), 5.44 - 5.07 (m, 3H), 4.71 (d, 1H), 4.15 – 3.95 (m, 2H), 3.67 - 3.52 (m, 2H), 3.25 - 2.98 (m, 5H), 2.93 - 2.79 (m, 2H), 2.33 (t, 2H), 2.09 - 1.77 (m, 7H), 1.61 - 1.42 (m, 5H), 1.05 - 0.95 (m, 1H). 110 IPTS / 125370156.1Attorney Docket No. KEST-004WO Example 14: Synthesis of (13R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4,8-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana- 3(1,8)-naphthalenacyclooctaphan-33-ol (Compound 119)Step 1: Synthesis of tert-butyl (R)-3-(3-((methylsulfonyl)oxy)propoxy)azepane-1-carboxylate

[0206] To a solution of the title compound of Intermediate 17, Step 2 (200 mg, 731 μmol) in DCM (2 mL) was added TEA (222 mg, 2.19 mmol) and methanesulfonic anhydride (254 mg, 1.46 mmol). The reaction mixture was stirred at 0°C for 0.5 h, then poured into water (5 mL) and extracted with DCM (5 mLx3). The organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 1) to give the title compound (200 mg, 77%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 4.32 - 4.21 (m, 2H), 3.93 - 3.63 (m, 2H), 3.61 - 3.45 (m, 3H), 3.42 - 2.98 (m, 1H), 2.94 (d, 3H), 2.89 - 2.74 (m, 1H), 1.95 - 1.84 (m, 2H), 1.81 - 1.46 (m, 6H), 1.39 (d, 9H). Step 2: Synthesis of tert-butyl (R)-3-(3-((6-(benzyloxy)-8-bromo-2-fluoronaphthalen-1- yl)oxy)propoxy)azepane-1-carboxylate

[0207] To a solution of the title compound of Step 1 (200 mg, 569 μmol) and Intermediate 7 (197 mg, 569 μmol) in DMF (1 mL) was added Cs2CO3(370 mg, 1.14 mmol) and TBAI (630 111 IPTS / 125370156.1Attorney Docket No. KEST-004WO mg, 1.71 mmol). The reaction mixture was stirred at 50°C for 1 h, then poured into water (20 mL) and extracted with EtOAc (20 mLx3). The organic layers were washed with brine (30 mLx3), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 100 / 1 to 10 / 1) to give the title compound (300 mg, 87%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.42 - 7.20 (m, 7H), 7.07 (s, 1H), 5.07 (s, 2H), 4.14 (t, 2H), 4.03 - 3.79 (m, 1H), 3.75 - 3.38 (m, 4H), 3.02 - 2.72 (m, 2H), 2.15 - 2.04 (m, 2H), 1.85 - 1.54 (m, 4H), 1.39 (d, 9H), 1.36 - 1.16 (m, 2H). Step 3: Synthesis of tert-butyl (R)-3-(3-((6-(benzyloxy)-8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2- fluoronaphthalen-1-yl)oxy)propoxy)azepane-1-carboxylate

[0208] The title compound (84 mg, 23%, black oil) was obtained following a similar method to the one described in Step 6 of Example 11, from the title compound of Step 2 and Intermediate 10 as starting material. Purification by reversed-phase HPLC (column: SANTAI, SW-5222-040-SP, Spherical C 18, 20-45μm, 100A; mobile phase: water (0.1% FA) – ACN; gradient: 45%-65% B over 15 min). LCMS: m / z = 934 [M+H]+. Step 4: Synthesis of tert-butyl (R)-3-(3-((6-(benzyloxy)-2-fluoro-8-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7- yl)naphthalen-1-yl)oxy)propoxy)azepane-1-carboxylate

[0209] The title compound (75.0 mg, crude, yellow solid) was obtained following a similar method to the one described in Step 8 of Example 8, from the title compound of Step 3. LCMS: m / z = 844 [M+H]+. Step 5: Synthesis of 7-(8-(3-(((R)-azepan-3-yl)oxy)propoxy)-3-(benzyloxy)-7-fluoronaphthalen- 1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-ol

[0210] The title compound (30 mg, 45%, white solid) was obtained using a similar method to the one described in Step 7 of Example 10, from the title compound of Step 4. The crude was purified by prep-HPLC (column: SANTAI, SW-5222-040-SP, Spherical C 18, 20-45μm, 100A; mobile phase: water (0.1% FA) – ACN; gradient: 22%-42% B over 15 min). LCMS: m / z = 744 [M+H]+. 112 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 6: Synthesis of (13R)-33-(benzyloxy)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4,8-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana- 3(1,8)-naphthalenacyclooctaphane

[0211] To a solution of the title compound of Step 5 (30.0 mg, 40.3 μmol) in CHCl3(3 mL) was added BOP-Cl (12.3 mg, 48.4 μmol) and DIPEA (10.4 mg, 80.6 μmol). The reaction mixture was stirred at 70°C for 1 h, then concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (column: SANTAI, SW-5222-040-SP, Spherical C18, 20- 45μm, 100Å; mobile phase: water (0.1% FA) – ACN; gradient: 20%-40% B over 15 min) to give the title compound (25.0 mg, 85%) as white solid. LCMS: m / z = 726 [M+H]+. Step 7: Synthesis of (13R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4,8-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacyclooctaphan-33-ol

[0212] The title compound (8.87 mg, 39%, FA salt, yellow solid) was obtained using a similar method to the one described in Step 7 of Example 7, from the title compound of Step 6. The crude was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm* 10μm; mobile phase: [water (FA)-ACN]; gradient: 18%-48% B over 10 min). LCMS: m / z = 636 [M+H]+;1H NMR (400 MHz, CD3OD) δ 9.24 (s, 1H), 7.58 - 7.44 (m, 1H), 7.35 - 7.26 (m, 2H), 7.16 (d, 1H), 5.53 - 5.28 (m, 2H), 4.60 (s, 1H), 4.51 - 4.34 (m, 2H), 4.16 - 3.92 (m, 1H), 3.68 - 3.36 (m, 7H), 3.24 - 3.13 (m, 3H), 2.63 - 2.30 (m, 3H), 2.27 - 2.19 (m, 1H), 2.18 - 2.08 (m, 2H), 2.07 - 1.93 (m, 1H), 1.90 - 1.78 (m, 2H), 1.76 - 1.60 (m, 3H), 1.58 - 1.46 (m, 1H), 0.85 - 0.70 (m, 1H). Example 15: Synthesis of (13R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4,7-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana- 3(1,8)-naphthalenacycloheptaphan-33-ol (Compound 120) 113 IPTS / 125370156.1Attorney Docket No. KEST-004WOStep 1: Synthesis of tert-butyl (R)-3-(2-((6-(benzyloxy)-8-bromo-2-fluoronaphthalen-1- yl)oxy)ethoxy)azepane-1-carboxylate

[0213] To a solution of the title compound of Example 7, Step 3 (320 mg, 866 μmol) and Intermediate 7 (300 mg, 864 μmol) in DMF (5 mL) was added Cs2CO3(563 mg, 1.73 mmol). The reaction mixture was stirred at 55°C for 1 h, then poured into water (50 mL) and extracted with EtOAc (30 mLx3). The organic layers were washed with brine (50 mLx3), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 100 / 1 to 10 / 1) to give the title compound (900 mg, 88%) as colorless oil.1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.46 - 7.27 (m, 6H), 7.26 - 7.20 (m, 1H), 7.06 (br d, 1H), 5.07 (s, 2H), 4.23 - 4.20 (m, 2H), 4.03 - 3.96 (m, 1H), 3.96 - 3.86 (m, 2H), 3.84 - 3.78 (m, 1H), 3.71 - 3.53 (m, 2H), 3.02 - 2.87 (m, 1H), 2.85 - 2.75 (m, 1H), 1.81 - 1.53 (m, 5H), 1.39 (d, 9H), 1.34 - 1.24 (m, 1H). Step 2: Synthesis of tert-butyl (R)-3-(2-((6-(benzyloxy)-8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2- fluoronaphthalen-1-yl)oxy)ethoxy)azepane-1-carboxylate

[0214] The title compound (400 mg, 63%, white solid) was obtained following a similar method to the one described in Step 6 of Example 11, from the title compound of Step 1 and 114 IPTS / 125370156.1Attorney Docket No. KEST-004WO Intermediate 10. Purification by column chromatography (SiO2, PE / EtOAc 1:1 to 0:1) followed by reversed-phase HPLC (column: SANTAI, SW-5222-040-SP, Spherical C18, 20-45μm, 100Å; mobile phase: water (0.1% FA) – ACN; gradient: 45%-65% B over 15 min). LCMS: m / z = 920 [M+H]+. Steps 3 to 6: Synthesis of (13R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4,7-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacycloheptaphan-33-ol

[0215] The title compound (16.4 mg, FA salt, white solid) was obtained following a similar sequence to the one described in Steps 4 to 7 of Example 14, from the title compound of Step 2 and was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 15%-45% B over 10 min). LCMS: m / z = 622 [M+H]+;1H NMR (400 MHz, CD3OD) δ 9.30 (s, 1H), 8.48 (s, 2H), 7.60 - 7.45 (m, 1H), 7.37 - 7.17 (m, 3H), 5.57 - 5.29 (m, 2H), 4.59 - 4.36 (m, 2H), 3.87 - 3.48 (m, 8H), 3.39 (d, 2H), 3.29 - 3.20 (m, 2H), 2.63 - 2.34 (m, 2H), 2.32 - 2.12 (m, 4H), 2.09 - 1.93 (m, 2H), 1.90 - 1.57 (m, 2H), 1.54 - 1.38 (m, 1H), 1.17 - 0.96 (m, 1H). Example 16: Synthesis of (33R)-17,28-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-oxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(1,8)-isoquinolina- 3(1,3)-azepanacycloheptaphan-13-amine (Compound 121)115 IPTS / 125370156.1Attorney Docket No. KEST-004WOStep 1: Synthesis of tert-butyl 2-cyano-2-(2-cyano-4-fluoro-3-iodophenyl)acetate

[0216] A solution of 3,6-difluoro-2-iodobenzonitrile (15.0 g, 56.6 mmol), tert-butyl 2- cyanoacetate (8.79 g, 62.2 mmol) and Cs2CO3(27.6 g, 84.9 mmol) in DMSO (150 mL) was stirred at 100°C for 2 h. The reaction mixture was diluted with water (750 ml) and extracted with EtOAc (750 mLx3). The organic layer was washed with sat. brine (200 mLx2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 5:1) to give the title compound (14.8 g, 67%) as a brown oil.1H NMR (400 MHz, CDCl3) δ 7.82 - 7.63 (m, 1H), 7.37 (dd, 1H), 5.10 (s, 1H), 1.52 (s, 9H). Step 2: Synthesis of 6-(cyanomethyl)-3-fluoro-2-iodobenzonitrile

[0217] A solution of the title compound of Step 1 (14.8 g, 38.3 mmol) in DCE (150 mL) and TFA (13.1 g, 114 mmol) was stirred at 80°C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 7:1) to give the title compound (5.00 g, 45%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.65 (dd, 1H), 7.35 (dd, 1H), 4.03 (s, 2H). Step 3: Synthesis of N-(1-bromo-7-fluoro-8-iodoisoquinolin-3-yl)acetamide

[0218] The title compound of Step 2 (5.0 g, 17.4 mmol) was added to a solution of HBr / AcOH (17.4 mmol, 50 mL, 33% purity) at 0°C. The reaction mixture was stirred at 15°C for 1 h, then diluted with ice-water (100 mL) and adjusted to pH 7~8 with sat. Na2CO3. The mixture was extracted with EtOAc (500 mLx2) and the organic layer was concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 4:1) to give the title compound (2.90 g, 40%) as a yellow solid. LCMS: m / z = 410 [M+H]+. 116 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 4: Synthesis of N-(1-(benzyloxy)-7-fluoro-8-iodoisoquinolin-3-yl)acetamide

[0219] To a solution of BnOH (1.35 g, 12.4 mmol) in DMF (17 mL) was added NaH (498 mg, 12.4 mmol, 60% purity) at 0°C under N2. The reaction mixture was stirred at 0°C for 0.5 h then a solution of the title compound of Step 3 (1.70 g, 4.16 mmol) in DMF (10 mL) was added. The mixture was stirred for 0.5 h, then quenched with NH4Cl (30 mL), diluted with water (30 mL) and extracted with EtOAc (100 mLx2). The organic layer was washed with sat. brine (30 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Ultimate XB-NH2250*50*10μm; mobile phase: [Hexane-EtOH 0.1% NH3.H2O]; gradient: 10%-50% B over 15 min) to give the title compound (0.80 g, 44%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.08 (s, 1H), 7.88 (dd, 1H), 7.64 (d, 2H), 7.57 - 7.52 (m, 1H), 7.42 - 7.38 (m, 2H), 7.35 - 7.32 (m, 1H), 5.65 (s, 2H), 2.14 (s, 3H). Step 5: Synthesis of 1-(benzyloxy)-7-fluoro-8-iodoisoquinolin-3-amine

[0220] To a solution of the title compound of Step 4 (0.70 g, 1.60 mmol) in EtOH (7 mL) was added NaOH (377 mg, 1.60 mmol). The reaction mixture was stirred at 50°C for 12 h, then concentrated. The residue was diluted with water (40 mL), extracted with EtOAc (80 mLx2) and the combined organic layers were concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 5:1) to give the title compound (0.55 g, 87%) as a brown solid. LCMS: m / z = 395 [M+H]+. Step 6: Synthesis of tert-butyl (1-(benzyloxy)-7-fluoro-8-iodoisoquinolin-3-yl)carbamate

[0221] To a solution of the title compound of Step 5 (0.50 g, 1.27 mmol) in t-BuOH (10 mL) was added Boc2O (830 mg, 3.81 mmol). The reaction mixture was stirred at 50°C for 14 h, then concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 10:1) to give the title compound (1.22 g, 97%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.66 - 7.54 (m, 3H), 7.43 - 7.37 (m, 2H), 7.34 (d, 1H), 6.97 (s, 1H), 5.55 (s, 2H), 1.56 (s, 9H). Step 7: Synthesis of tert-butyl (R,E)-3-((3-(1-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-7- fluoroisoquinolin-8-yl)allyl)oxy)azepane-1-carboxylate

[0222] The title compound (1.00 g, 66%, brown solid) was obtained following a similar method to the one described in Step 3 of Example 11, from the title compound of Step 6 and Intermediate 13. Purification by column chromatography (SiO2, PE / EtOAc 1:0 to 10:1). LCMS: m / z = 622 [M+H]+. 117 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 8: Synthesis of tert-butyl (R)-3-(3-(3-((tert-butoxycarbonyl)amino)-7-fluoro-1- hydroxyisoquinolin-8-yl)propoxy)azepane-1-carboxylate

[0223] To a mixture of the title compound of Step 7 (900 mg, 1.45 mmol) in MeOH (10 mL) was added Pd / C (500 mg, 469 μmol, 10% purity) and the reaction mixture was stirred at 30°C for 16 h under H2atmosphere (50 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (710 mg, crude) as a yellow solid. LCMS: m / z = 534 [M+H]+. Step 9: Synthesis of tert-butyl (R)-3-(3-(3-((tert-butoxycarbonyl)amino)-7-fluoro-1- (((trifluoromethyl)sulfonyl)oxy)isoquinolin-8-yl)propoxy)azepane-1-carboxylate

[0224] To a mixture of the title compound of Step 8 (560 mg, 1.05 mmol) in DCM (8 mL) was added DIPEA (406 mg, 3.15 mmol) and Tf2O (444 mg, 1.57 mmol) at 0°C. The reaction mixture was stirred at 20°C for 1 h under N2, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 12 / 1) to give the title compound (540 mg, 72%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.28 (s, 1H), 8.02 (dd, 1H), 7.72 (t, 1H), 3.75 - 3.60 (m, 1H), 3.54 - 3.42 (m, 4H), 3.14 (t, 2H), 3.06 - 2.95 (m, 1H), 2.93 - 2.81 (m, 1H), 1.84 - 1.73 (m, 2H), 1.58 (s, 4H), 1.51 (s, 9H), 1.36 (d, 9H), 1.20 (d, 1H), 0.88 - 0.76 (m, 1H). Step 10: Synthesis of tert-butyl (R)-3-(3-(1-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-3-((tert- butoxycarbonyl)amino)-7-fluoroisoquinolin-8-yl)propoxy)azepane-1-carboxylate

[0225] To a mixture of the title compound of Step 9 (100 mg, 150 μmol) in dioxane (3 mL) was added Intermediate 10 (172 mg, 300 μmol), CuI (5.72 mg, 30.0 μmol), CsF (22.8 mg, 150 μmol) and Pd(PPh3)4(17.3 mg, 15.0 μmol). The reaction mixture was stirred at 60°C for 2 h under N2, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 1:1) to give the title compound (120 mg, 73%) as a yellow oil. LCMS: m / z = 928 [M+H]+. Steps 11 and 12: Synthesis of (33R)-17,28-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-oxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(1,8)-isoquinolina- 3(1,3)-azepanacycloheptaphan-13-amine

[0226] The title compound (6.15 mg, 9% over two steps, FA salt, yellow solid) was obtained following a similar sequence to the one described in Steps 7 and 8 of Example 7, from the title compound of Step 10. Purification by prep-HPLC (column: Phenomenex Luna C18 118 IPTS / 125370156.1Attorney Docket No. KEST-004WO 150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 21%-51% B over 10 min). LCMS: m / z = 620 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.29 (s, 1H), 7.61 (dd, 1H), 7.37 (t, 1H), 6.83 (s, 1H), 6.08 (s, 2H), 5.38 - 5.25 (m, 1H), 5.25 - 5.17 (m, 1H), 4.78 - 4.64 (m, 1H), 4.13 (d, 1H), 4.02 (d, 1H), 3.74 (dd, 1H), 3.60 - 3.54 (m, 1H), 3.10 - 2.94 (m, 5H), 2.86 - 2.78 (m, 1H), 2.35 - 2.28 (m, 1H), 2.13 - 1.94 (m, 5H), 1.87 - 1.66 (m, 6H), 1.60 - 1.51 (m, 2H), 1.41 - 1.32 (m, 1H), 1.23 - 1.11 (m, 1H), 0.83 - 0.69 (m, 1H). Example 17: Synthesis of (33R)-13,28-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-oxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(5,4)-quinolina- 3(1,3)-azepanacycloheptaphan-17-ol (Compound 122)Step 1: Synthesis of 4-bromo-3-fluoroquinoline-5,7-diol

[0227] A solution of Intermediate 8 (1.40 g, 6.55 mmol) in MeCN (30 mL) and TMSBr (11.8 g, 77.3 mmol) was stirred at 85°C for 4 days under N2, then concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (column: SANTAI, SW- 5222-120-SP, Spherical C 18, 20-45μm, 100Å; mobile phase: water (0.1% FA) – ACN; 119 IPTS / 125370156.1Attorney Docket No. KEST-004WO gradient: 18%-48% B over 30 min) and then re-purified by prep-HPLC (column: Phenomenex Luna C18250*70mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 15%-45% B over 21 min) to give the title compound (1.20 g, 71%) as a yellow solid.1H NMR (400 MHz, DMSO- d6) δ 10.63 (s, 1H), 10.15 (s, 1H), 8.65 (s, 1H), 6.83 (d, 1H), 6.67 (d, 1H). Step 2: Synthesis of 4-bromo-3-fluoro-5,7-bis((triisopropylsilyl)oxy)quinoline

[0228] To a solution of the title compound of Step 1 (1.10 g, 4.26 mmol) in DCM (10 mL) was added TIPSCl (3.29 g, 17.0 mmol) and DIPEA (3.31 g, 25.5 mmol). The reaction mixture was stirred at 0°C for 2 h, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 10:1) to give the title compound (2.40 g, 99% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.16 (d, 1H), 6.68 (d, 1H), 1.54 - 1.42 (m, 3H), 1.36 - 1.29 (m, 3H), 1.18 (d, 18H), 1.12 (d, 18H). Step 3: Synthesis of tert-butyl (R,E)-3-((3-(3-fluoro-5,7-bis((triisopropylsilyl)oxy)quinolin-4- yl)allyl)oxy)azepane-1-carboxylate

[0229] The title compound (2.00 g, 56%, yellow solid) was obtained following a similar method to the one described in Step 3 of Example 11, from the title compound of Step 2 and Intermediate 13. Purification by column chromatography (SiO2, PE / EtOAc 10:0 to 5:1).1H NMR (400 MHz, DMSO-d6) δ 8.76 - 8.63 (m, 1H), 7.36 (d, 2H), 7.02 (d, 1H), 6.56 (s, 1H), 5.13 - 4.40 (m, 1H), 3.94 - 3.69 (m, 4H), 3.05 - 2.97 (m, 2H), 1.39 - 1.35 (m, 9H), 1.32 - 1.22 (m, 12H), 1.13 - 1.06 (m, 36H). Step 4: Synthesis of tert-butyl (R)-3-(3-(3-fluoro-5,7-bis((triisopropylsilyl)oxy)quinolin-4- yl)propoxy)azepane-1-carboxylate

[0230] A solution of the title compound of Step 3 (2.00 g, 2.68 mmol) and PtO2(50.0 mg, 220 μmol) in MeOH (20 mL) was stirred at 25°C for 12 h under H2(30 psi), then filtered and concentrated under reduced pressure to give the title compound (2.00 g, crude) as a yellow solid. LCMS: m / z = 747 [M+H]+. Step 5: Synthesis of tert-butyl (R)-3-(3-(3-fluoro-5,7-dihydroxyquinolin-4-yl)propoxy)azepane- 1-carboxylate

[0231] To a solution of the title compound of Step 4 (2.00 g, 2.68 mmol) in THF (20 mL) was added triethylamine trishydrofluoride (2.59 g, 16.0 mmol). The reaction mixture was stirred at 25°C for 1 h, then concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (column: SANTAI, SW-5222-120-SP, Spherical C18, 20-45μm, 100Å; mobile phase: water (0.1% FA) – ACN; gradient: 25%-45% B over 30 min) to give the title 120 IPTS / 125370156.1Attorney Docket No. KEST-004WO compound (1.00 g, 78%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.88 (s, 1H), 8.56 (s, 1H), 6.76 (d, 1H), 6.59 (s, 1H), 3.90 - 3.75 (m, 4H), 3.32 - 3.22 (m, 2H), 3.05 - 2.98 (m, 1H), 2.95 - 2.82 (m, 1H), 1.92 - 1.75 (m, 2H), 1.72 - 1.43 (m, 6H), 1.37 (d, 9H), 1.30 - 1.20 (m, 1H). Step 6: Synthesis of tert-butyl (R)-3-(3-(3-fluoro-5-hydroxy-7-((triisopropylsilyl)oxy)quinolin-4- yl)propoxy)azepane-1-carboxylate

[0232] The title compound (1.00 g, 75%, yellow solid) was obtained following a similar method to the one described in Step 2, from the title compound of Step 5 and using 1.5 equivalents of TIPSCl. Purification by column chromatography (SiO2, PE / EtOAc 1:0 to 5:1). LCMS: m / z = 591 [M+H]+. Step 7: Synthesis of tert-butyl (R)-3-(3-(3-fluoro-5-(((trifluoromethyl)sulfonyl)oxy)-7- ((triisopropylsilyl)oxy)quinolin-4-yl)propoxy)azepane-1-carboxylate

[0233] The title compound (950 mg, 78%, yellow solid) was obtained following a similar method to the one described in Step 5 of Example 10, from the title compound of Step 6. Purification by column chromatography (SiO2, PE / EtOAc 1:0 to 10:1). LCMS: m / z = 723 [M+H]+. Step 8: Synthesis of tert-butyl (R)-3-(3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-7-((triisopropylsilyl)oxy)quinolin-4-yl)propoxy)azepane-1-carboxylate

[0234] A mixture of the title compound of Step 7 (200 mg, 277 μmol), bis(pinacolato)diboron (351 mg, 1.38 mmol), Pd(dppf)Cl2(20.2 mg, 27.7 μmol), K3PO4(88.1 mg, 415 μmol) in dioxane (10 mL) was stirred at 70°C for 12 h under N2, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 10 / 1 to 5 / 1) to give the title compound (150 mg, 67%) as a yellow solid. LCMS: m / z = 701 [M+H]+. Step 9: Synthesis of tert-butyl (R)-3-(3-(5-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-3-fluoro-7- ((triisopropylsilyl)oxy)quinolin-4-yl)propoxy)azepane-1-carboxylate

[0235] The title compound (15.0 mg, 8.9%, yellow solid) was prepared using a method similar to the one described in Step 6 of Example 7, from the title compound of Step 8 and Intermediate 1. Purification by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 50%-80% B over 10 min). LCMS: m / z = 985 [M+H]+. 121 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 10: Synthesis of 7-(4-(3-(((R)-azepan-3-yl)oxy)propyl)-3-fluoro-7- ((triisopropylsilyl)oxy)quinolin-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol

[0236] The title compound (10.0 mg, 69%, yellow oil) was obtained using a similar method to the one described in Step 7 of Example 10 from the title compound of Step 9. The crude was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 58%-88% B over 9 min). LCMS: m / z = 795 [M+H]+. Step 11: Synthesis of (33R)-13,28-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-17-((triisopropylsilyl)oxy)-4-oxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(5,4)- quinolina-3(1,3)-azepanacycloheptaphane

[0237] The title compound (9.0 mg, crude, yellow oil) was obtained using a method similar to the one described in Step 8 of Example 7, from the title compound of Step 10. LCMS: m / z = 777 [M+H]+. Step 12: Synthesis of (33R)-13,28-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-oxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(5,4)-quinolina-3(1,3)- azepanacycloheptaphan-17-ol

[0238] The title compound (1.42 mg, 19%, FA salt, off-white solid) was obtained using a similar method to the one described in Step 5, from the title compound of Step 11. Purification by prep-HPLC (column: Phenomenex Luna C18150*25mm*10μm; mobile phase: [water (FA)- ACN]; gradient: 15%-45% B over 10 min). LCMS: m / z = 621 [M+H]+;1H NMR (400 MHz, MeOD) δ 9.40 (s, 1H), 8.55 (d, 1H), 7.43 - 7.34 (m, 2H), 7.28 - 7.22 (m, 2H), 5.43 - 5.25 (m, 1H), 4.58 (s, 2H), 3.98 - 3.87 (m, 1H), 3.83 - 3.75 (m, 3H), 3.60 - 3.55 (m, 1H), 3.36 - 3.32 (m, 1H), 3.16 - 3.10 (m, 1H), 3.04 - 3.00 (m, 1H), 2.71 - 2.58 (m, 1H), 2.55 - 2.48 (m, 1H), 2.35 - 2.19 (m, 4H), 2.11 - 1.99 (m, 4H), 1.96 - 1.90 (m, 1H), 1.82 - 1.73 (m, 2H), 1.65 - 1.57 (m, 2H), 1.54 - 1.47 (m, 1H), 1.42 - 1.32 (m, 2H), 0.85 - 0.80 (m, 1H). Example 18: Synthesis of 11-((S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-18-fluoro- 12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-23-methyl-8-oxa-11- aza-1(7,4)-pyrido[4,3-d]pyrimidina-2(1,2)-benzenacycloundecaphan-25-ol (Compound 123) 122 IPTS / 125370156.1Attorney Docket No. KEST-004WOStep 1: Synthesis of (S)-1-((tert-butyldiphenylsilyl)oxy)-N-(2-(pent-4-yn-1-yloxy)ethyl)propan-2- amine

[0239] To a mixture of (S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-amine (11.0 g, 35.1 mmol) and Intermediate 18 (5.31 g, 42.1 mmol) in MeOH (110 mL) was added 4Å MS (5.5 g) and Na2SO4(2.49 g, 17.5 mmol). The reaction mixture was stirred at 15°C for 16 h then NaBH3CN (3.31 g, 52.6 mmol) and HOAc (1.05 g, 17.5 mmol) were added at 0°C. After 1 h at 40 °C the mixture was filtered, the filtrate was diluted with water (200 mL) and extracted with EtOAc (200 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography 123 IPTS / 125370156.1Attorney Docket No. KEST-004WO (SiO2, PE / EtOAc 1:0 to 2:3) to give the title compound (10.0 g, 47%) as a yellow oil. LCMS: m / z = 424 [M+H]+. Step 2: Synthesis of tert-butyl (S)-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)(2-(pent-4-yn-1- yloxy)ethyl)carbamate

[0240] To a mixture of the title compound of Step 2 (10.0 g, 23.6 mmol) in DCM (100 mL) was added TEA (7.17 g, 70.8 mmol) and Boc2O (7.73 g, 35.4 mmol) at 0°C. The reaction mixture was stirred at 15°C for 16 h, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 10:1) to give the title compound (6.70 g, 47%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, 4H), 7.53 - 7.33 (m, 6H), 4.23 - 3.79 (m, 1H), 3.75 - 3.61 (m, 1H), 3.56 (s, 1H), 3.41 (s, 4H), 3.32 - 3.11 (m, 2H), 2.74 (s, 1H), 2.18 - 2.14 (m, 2H), 1.63 - 1.60 (m, 2H), 1.45 - 1.24 (m, 9H), 1.32 - 1.02 (m, 3H), 0.98 (s, 9H). Step 3: Synthesis of tert-butyl (S)-(2-((5-(2-bromo-4-(methoxymethoxy)-6-methylphenyl)pent-4- yn-1-yl)oxy)ethyl)(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)carbamate

[0241] To a mixture of the title compound of Intermediate 2, Step 1 (2.39 g, 6.68 mmol), the title compound of Step 2 (3.50 g, 6.68 mmol), CuI (254 mg, 1.34 mmol) and Pd(PPh3)2Cl2(469 mg, 668 μmol) in DMF (40 mL) was added TEA (6.76 g, 66.8 mmol, 9.30 mL). The reaction mixture was stirred at 90°C for 1 h under N2, then diluted with water (60 mL) and extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine (50 mLx2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1:0 to 13:1) to give the title compound (1.56 g, 31%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.70 - 7.60 (m, 4H), 7.53 - 7.43 (m, 6H), 7.19 (d, 1H), 6.99 (d, 1H), 5.24 (s, 2H), 4.24 - 3.89 (m, 1H), 3.78 - 3.66 (m, 1H), 3.65 - 3.42 (m, 6H), 3.40 (s, 3H), 3.34 - 3.17 (m, 2H), 2.38 (s, 3H), 1.80 - 1.76 (m, 2H), 1.46 - 1.32 (m, 9H), 1.07 (d, 4H), 1.01 (s, 9H). Step 4: Synthesis of tert-butyl (S)-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)(2-((5-(4- (methoxymethoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pent-4-yn- 1-yl)oxy)ethyl)carbamate

[0242] The title compound (60.0 mg, 26%, yellow oil) was obtained using a method similar to the one described in Step 8 of Example 17, from the title compound of Step 3. Purification by column chromatography (SiO2, PE / EtOAc 1:0 to 10:1).1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, 4H), 7.47 - 7.39 (m, 6H), 6.98 (s, 2H), 5.17 (s, 2H), 4.20 - 4.05 (m, 1H), 3.69 - 3.65 (m, 1H), 124 IPTS / 125370156.1Attorney Docket No. KEST-004WO 3.51 (s, 4H), 3.35 (s, 3H), 3.31 (s, 2H), 2.29 (s, 3H), 1.75 (d, 2H), 1.38 - 1.30 (m, 9H), 1.26 (s, 12H), 1.07 - 1.01 (m, 4H), 0.97 (s, 9H). Steps 5-7: Synthesis of tert-butyl ((S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)(2-((5-(2-(8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- hydroxypyrido[4,3-d]pyrimidin-7-yl)-4-(methoxymethoxy)-6- methylphenyl)pentyl)oxy)ethyl)carbamate

[0243] The title compound (25.0 mg, yellow oil) was obtained following a sequence similar to the one described in Steps 6 to 8 of Example 8, from the title compound of Step 4. LCMS: m / z = 998 [M+H]+. Steps 8 and 9: Synthesis of 11-((S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-18-fluoro-12- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-23-methyl-8-oxa-11-aza- 1(7,4)-pyrido[4,3-d]pyrimidina-2(1,2)-benzenacycloundecaphan-25-ol

[0244] The title compound (10.0 mg, 61% over two steps, yellow solid) was obtained following a sequence similar to the one described in Steps 10 and 11 of Example 17 from the title compound of Step 7. LCMS: m / z = 836 [M+H]+. Step 10: Synthesis of 11-((S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-18-fluoro-12- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-23-methyl-8-oxa-11-aza- 1(7,4)-pyrido[4,3-d]pyrimidina-2(1,2)-benzenacycloundecaphan-25-ol

[0245] A mixture of the title compound of Step 9 (10.0 mg, 11.9 μmol) and TBAF (1 M, 0.2 mL) in DCM (0.2 mL) was stirred at 20°C for 8 h, then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 4%-34% B over 10 min) to give the title compound (0.26 mg, 3%, FA salt) as a brown solid. LCMS: m / z = 598 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 6.70 (d, 1H), 6.63 (d, 1H), 6.54 (s, 1H), 5.37 - 5.33 (m, 1H), 5.24 - 5.20 (m, 1H), 4.94 (dd, 1H), 4.80 - 4.75 (m, 1H), 4.48 - 4.39 (m, 2H), 3.03 - 2.99 (m, 6H), 2.84 (d, 8H), 2.27 (s, 3H), 1.86 - 1.75 (m, 5H), 1.87 - 1.75 (m, 1H), 1.13 (s, 3H), 0.94 - 0.81 (m, 4H), 0.83 (d, 2H). Example 19: Synthesis of (16R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-33-hydroxy-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,6)- diazepana-3(1,8)-naphthalenacycloheptaphan-13-one (Compound 124) 125 IPTS / 125370156.1Attorney Docket No. KEST-004WOStep 1: Synthesis of tert-butyl (R,E)-6-((3-(8-(benzyloxy)-2-fluoro-6- ((triisopropylsilyl)oxy)naphthalen-1-yl)allyl)oxy)-3-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)- 1,4-diazepane-1-carboxylate

[0246] The title compound (3.00 g, 77%, yellow oil) was obtained following a similar method to that described in Step 3 of Example 11, from Intermediate 16 and Intermediate 6.1H NMR (400 MHz, DMSO-d6) δ 7.64 (td, 1H), 7.52 - 7.46 (m, 2H), 7.44 - 7.24 (m, 5H), 6.87 (t, 1H), 6.62 - 6.55 (m, 1H), 6.18 - 6.02 (m, 1H), 5.28 (s, 2H), 4.98 - 4.83 (m, 1H), 4.39 - 4.27 (m, 1H), 4.14 - 4.03 (m, 2H), 3.97 - 3.91 (m, 1H), 3.83 (d, 1H), 3.38 (s, 6H), 3.33 - 3.21 (m, 2H), 1.35 (s, 9H), 1.18 (s, 2H), 1.05 - 1.00 (m, 18H), 0.87 - 0.76 (m, 2H), 0.05 -0.09 (m, 9H). 126 IPTS / 125370156.1Attorney Docket No. KEST-004WO Steps 2 and 3: Synthesis of tert-butyl (R)-6-(3-(2-fluoro-8-(((trifluoromethyl)sulfonyl)oxy)-6- ((triisopropylsilyl)oxy)naphthalen-1-yl)propoxy)-3-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-1,4- diazepane-1-carboxylate

[0247] The title compound (1.26 g, yellow oil) was obtained following a similar sequence to the one described in Steps 4 and 5 of Example 10. Purification by column chromatography (SiO2, PE / EtOAc 1 / 0 to 5 / 1). LCMS: m / z = 889 [M+Na]+. Step 4: Synthesis of tert-butyl (R)-6-(3-(8-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-6- ((triisopropylsilyl)oxy)naphthalen-1-yl)propoxy)-3-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-1,4- diazepane-1-carboxylate

[0248] To a solution of the title compound of Step 3 (1.26 g, 1.45 mmol) in dioxane (15 mL) was added bis(neopentyl glycolato)diboron (1.64 g, 7.27 mmol), Pd(dppf)Cl2(106 mg, 145 μmol) and KOAc (427 mg, 4.36 mmol). The reaction mixture was stirred at 100°C for 16 h under N2, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc 1 / 0 to 5 / 1) to give the title compound (1.20 g, 94%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.70 (m, 1H), 7.34 - 7.28 (m, 2H), 7.15 (d, 1H), 5.74 (s, 2H), 5.02 - 4.86 (m, 1H), 3.06 - 2.92 (m, 2H), 1.81 (s, 2H), 1.35 (s, 9H), 1.31 - 1.20 (m, 4H), 1.08 (d, 18H), 0.75 (s, 6H), -0.05 (s, 9H). Step 5: Synthesis of tert-butyl (R)-6-(3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6- ((triisopropylsilyl)oxy)naphthalen-1-yl)propoxy)-3-oxo-4-((2-(trimethylsilyl)ethoxy)methyl)-1,4- diazepane-1-carboxylate

[0249] The title compound (340 mg, 41%, yellow solid) was prepared using a method similar to the one described in Step 6 of Example 7, from the title compound of Step 4 and Intermediate 1. Purification by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 58%-88% B over 10 min) and reversed-phase HPLC (column: SANTAI, SW-5222-040-SP, Spherical C 18, 20-45μm, 100A; mobile phase: water (0.1% FA) – ACN; gradient: 35%-50% B over 30 min). LCMS: m / z = 1129 [M+H]+. 127 IPTS / 125370156.1Attorney Docket No. KEST-004WO Steps 6 and 7: Synthesis of (16S)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-14-(hydroxymethyl)-33-((triisopropylsilyl)oxy)-7-oxa-2(4,7)- pyrido[4,3-d]pyrimidina-1(1,6)-diazepana-3(1,8)-naphthalenacycloheptaphan-13-one

[0250] The title compound (10.0 mg, off-white solid) was obtained following a sequence similar to the one described in Steps 10 and 11 of Example 17, from the title compound of Step 5. LCMS: m / z = 821 [M+H]+. Step 8: Synthesis of (16R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-33-((triisopropylsilyl)oxy)-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,6)- diazepana-3(1,8)-naphthalenacycloheptaphan-13-one

[0251] A solution of the title compound of Step 7 (10.0 mg, 12.1 μmol) and NH3•H2O (182.mg, 1.56 mmol, 30% purity) in MeOH (0.5 mL) was stirred at 25°C for 0.5 h. The mixture was concentrated under reduced pressure to give the title compound (10.0 mg, crude) as a yellow oil. LCMS: m / z = 791 [M+H]+. Step 9: Synthesis of (16R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-33-hydroxy-7-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,6)-diazepana-3(1,8)- naphthalenacycloheptaphan-13-one

[0252] The title compound (2.55 mg, 31%, yellow solid) was obtained using a method similar to the one described in Step 5 of Example 17, from the title compound of Step 8. Purification by prep-HPLC (column: Waters Xbridge 150*25mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30%-50% B over 8 min). LCMS: m / z = 635 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.09 - 9.76 (m, 1H), 9.45 (s, 1H), 7.76 (dd, 1H), 7.37 (t, 1H), 7.34 - 7.28 (m, 2H), 7.20 (d, 1H), 5.37 - 5.18 (m, 2H), 5.08 (d, 1H), 4.25 (d, 1H), 4.12 (d, 1H), 4.00 (d, 1H), 3.89 (d, 1H), 3.65 (dd, 1H), 3.21 (td, 1H), 3.12 - 3.04 (m, 2H), 3.03 - 2.97 (m, 2H), 2.86 - 2.79 (m, 1H), 2.76 - 2.66 (m, 1H), 2.35 - 2.22 (m, 2H), 2.16 - 2.09 (m, 1H), 2.04 (s, 1H), 1.99 - 1.88 (m, 2H), 1.84 - 1.73 (m, 3H), 1.59 - 1.48 (m, 1H), 1.04 - 0.88 (m, 1H). Examples 20 and 21: Synthesis of (33R)-13,28-difluoro-22-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-4,7-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(5,4)- quinolina-3(1,3)-azepanacycloheptaphan-17-ol (atropisomers) (Compounds 125 and 126) 128 IPTS / 125370156.1Attorney Docket No. KEST-004WOyl)oxy)ethoxy)azepane-1-carboxylate

[0253] The title compound (900 mg, 38%, yellow solid) was obtained following a similar method to the one described in Step 4 of Example 7, from Intermediate 8 and the title compound of Example 7, Step 2 and using THF as solvent.1H NMR (400 MHz, CDCl3) δ 8.87 (d, 1H), 8.51 (dd, 1H), 6.93 (dd, 1H), 6.54 (dd, 1H), 4.75 - 4.60 (m, 2H), 4.04 - 3.86 (m, 3H), 3.83 - 3.59 (m, 2H), 3.13 - 2.91 (m, 2H), 1.75 - 1.64 (m, 5H), 1.46 (s, 9H), 1.44 - 1.37 (m, 1H). Steps 2-6: Synthesis of (33R)-13,28-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-17-((triisopropylsilyl)oxy)-4,7-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina- 1(5,4)-quinolina-3(1,3)-azepanacycloheptaphane formate

[0254] The title compound (80 mg, yellow solid) was obtained following a sequence similar to the one described in Steps 6-10 of Example 17, from the title compound of Step 1. Purification by reversed-phase HPLC (column: SANTAI, SW-5222-040-SP, Spherical C 18, 20-45μm, 100Å; mobile phase: water (0.1% FA) – ACN; gradient: 25%-45% B over 15 min.1H 129 IPTS / 125370156.1Attorney Docket No. KEST-004WO NMR (400 MHz, CD3OD) δ 8.98 (d, 1H), 8.73 (d, 1H), 7.54 (d, 1H), 7.20 (t, 1H), 5.43 - 5.23 (m, 1H), 4.36 - 4.21 (m, 4H), 3.47 - 3.36 (m, 2H), 3.26 - 3.20 (m, 1H), 3.15 - 2.99 (m, 7H), 2.43 - 2.30 (m, 1H), 2.29 - 2.09 (m, 3H), 2.03 - 1.99 (m, 1H), 1.95 - 1.87 (m, 1H), 1.79 - 1.63 (m, 3H), 1.59 - 1.52 (m, 2H), 1.45 - 1.32 (m, 5H), 1.17 (d, 18H). Step 7: Synthesis of (33R)-13,28-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-17-((triisopropylsilyl)oxy)-4,7-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina- 1(5,4)-quinolina-3(1,3)-azepanacycloheptaphane

[0255] The title compound (35 mg, crude, yellow solid) was obtained following a similar method to the one described in Step 6 of Example 14, from the title compound of Step 6. LCMS: m / z = 779 [M+H]+. Step 8: Synthesis of (33R)-13,28-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4,7-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(5,4)-quinolina-3(1,3)- azepanacycloheptaphan-17-ol (atropisomers)

[0256] The title compound (35.0 mg, yellow solid) was obtained as a mixture of atropisomers following a similar method to the one described in Step 12 of Example 17, from the title compound of Step 7. It was further purified and separated into atropisomers by prep- HPLC (column: Phenomenex Luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 5%-35% B over 10 min) to give Isomer P1 (3.27 mg, 11%) and mixture of Isomers P1 and P2 (5.54 mg, 11%). The mixture of Isomers P1 and P2 was re-purified by SFC (column: DAICEL CHIRALPAK IC 250mm*30mm*10μm); mobile phase: [CO2-ACN / i-PrOH (0.1% NH3.H2O)]; B: 45% isocratic) to give Isomer P2 (1.65 mg, 30%) and Isomer P1 (2.32 mg, 42%):

[0257] Isomer P1 (Example 20) LCMS: m / z = 623 [M+H]+;1H NMR (400 MHz, CD3OD) δ 9.34 (s, 1H), 8.64 (d, 1H), 7.41 (d, 1H), 7.29 (d, 1H), 5.40 - 5.35 (m, 1H), 4.83 - 4.74 (m, 2H), 4.44 - 4.37 (m, 1H), 4.30 (d, 1H), 4.28 - 4.21 (m, 1H), 4.16 - 4.06 (m, 1H), 3.72 - 3.56 (m, 3H), 3.50 - 3.36 (m, 1H), 3.28 (s, 2H), 3.13 - 3.07 (m, 1H), 2.41 - 2.17 (m, 4H), 2.08 - 2.01 (m, 4H), 1.96 - 1.89 (m, 1H), 1.87 - 1.78 (m, 1H), 1.77 - 1.68 (m, 1H), 1.65 - 1.55 (m, 1H), 1.53 - 1.42 (m, 1H), 1.10 - 1.01 (m, 1H).

[0258] Isomer P2 (Example 21): LCMS: m / z = 623 [M+H]+;1H NMR (400 MHz, CD3OD) δ 9.29 (s, 1H), 8.67 (d, 1H), 7.44 - 7.41 (m, 1H), 7.39 (s, 1H), 5.46 - 5.34 (m, 1H), 4.82 (d, 2H), 4.37 (s, 2H), 4.26 - 4.16 (m, 1H), 4.16 - 4.05 (m, 1H), 3.96 - 3.87 (m, 1H), 3.74 - 3.60 (m, 1H), 3.37 (s, 1H), 3.18 - 3.02 (m, 3H), 2.79 - 2.66 (m, 1H), 2.45 - 2.16 (m, 4H), 2.11 - 1.73 (m, 9H), 1.70 - 1.54 (m, 1H). 130 IPTS / 125370156.1Attorney Docket No. KEST-004WO Example 22: Synthesis of (33R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-oxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(5,4)-quinolina-3(1,3)- azepanacycloheptaphan-17-ol (Compound 127)

[0259] The title compound (5.00 g, 71%, white solid) was obtained following a similar method to that described in Step 1 of Example 17, from 4-chloro-5,7-dimethoxyquinoline. Purification by column chromatography (SiO2, PE / EtOAc 1:0 to 65:35). LCMS: m / z = 270 [M+H]+. Step 2: Synthesis of 4-bromoquinoline-5,7-diol

[0260] The title compound (3.70 g, 82.5%, FA salt, yellow solid) was obtained following a similar method to the one described in Step 3 of Intermediate 8, from the title compound of Step 1. Purification by prep-HPLC (column: Phenomenex Luna C18250*80 mm*10 μm; mobile 131 IPTS / 125370156.1Attorney Docket No. KEST-004WO phase: [water (FA)-ACN]; gradient: 2%-22% B over 20 min).1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 10.14 (s, 1H), 8.34 (d, 1H), 8.13 (s, 1H), 7.43 (d, 1H), 6.78 (d, 1H), 6.61 (d, 1H). Steps 3-10: Synthesis of tert-butyl (R)-3-(3-(5-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-7- hydroxyquinolin-4-yl)propoxy)azepane-1-carboxylate

[0261] The title compound (40.0 mg, white solid) was obtained following a sequence similar to the one described in Steps 2-9 of Example 17, from the title compound of Step 2. LCMS: m / z 811 [M+H]+. Step 11: Synthesis of tert-butyl (R)-3-(3-(5-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-7- ((triisopropylsilyl)oxy)quinolin-4-yl)propoxy)azepane-1-carboxylate

[0262] The title compound (47.0 mg, crude, colorless oil) was obtained following a similar method to the one described in Step 2 of Example 17, from the title compound of Step 10. LCMS: m / z = 967 [M+H]+. Steps 12-14: Synthesis of (33R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-oxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(5,4)-quinolina-3(1,3)- azepanacycloheptaphan-17-ol

[0263] The title compound (2.93 mg, FA salt. yellow solid) was obtained following a sequence similar to the one described in Steps 10-12 of Example 17, from the title compound of Step 11. Purification by prep-HPLC (column: Phenomenex Luna C18150*25mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 5%-35% B over 10 min). LCMS: m / z = 603 [M+H]+;1H NMR (400 MHz, CD3OD) δ 9.57 - 9.44 (m, 1H), 8.76 - 8.57 (m, 1H), 7.53 - 7.47 (m, 1H), 7.41 - 7.31 (m, 2H), 5.70 - 5.48 (m, 1H), 3.98 - 3.79 (m, 3H), 3.72 - 3.62 (m, 1H), 3.50 - 3.45 (m, 1H), 3.14 (d, 1H), 2.86 - 2.52 (m, 4H), 2.45 - 2.28 (m, 4H), 2.23 - 2.01 (m, 6H), 1.90 - 1.65 (m, 4H), 1.57 - 1.27 (m, 4H), 0.95 - 0.81 (m, 1H). Examples 23 and 24: Synthesis of (16S)-28,33-difluoro-22-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-4,7-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3- d]pyrimidina-3(5,4)-quinolinacycloheptaphan-37-ol (atropisomers) (Compounds 128 and 129) 132 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0264] The title compound (780 mg, 38%, yellow solid) was obtained using a similar method to the one described in Step 2 of Intermediate 5, starting with the title compound of Intermediate 8.1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.53 (dd, 4H), 7.45 - 7.34 (m, 6H), 7.20 (d, 1H), 7.05 (d, 1H), 5.32 (s, 2H), 5.26 (s, 2H). Step 2: Synthesis of tert-butyl (S)-6-(2-((5,7-bis(benzyloxy)-3-fluoroquinolin-4-yl)oxy)ethoxy)- 1,4-oxazepane-4-carboxylate

[0265] The title compound (500 mg, 47%, yellow oil) was obtained following a similar method to the one described in Step 1 of Example 20, starting with Intermediate 11 and the title compound of Step 1, and using DMF as solvent. LCMS: m / z = 619 [M+H]+. 133 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 3: Synthesis of tert-butyl (S)-6-(2-((3-fluoro-5,7-dihydroxyquinolin-4-yl)oxy)ethoxy)-1,4- oxazepane-4-carboxylate

[0266] To a solution of the title compound of Step 2 (500 mg, 808 μmol) in MeOH (20 mL) was added Pd(OH)2(36.4 mg, 25.9 μmol, 10% purity) under N2. The mixture was stirred under H2(15 psi) at 20°C for 3 h, then filtered and concentrated under reduced pressure to give the title compound (350 mg, crude) as a yellow oil. LCMS: m / z = 439 [M+H]+. Steps 4 and 5: Synthesis of tert-butyl (S)-6-(2-((3-fluoro-5-(((trifluoromethyl)sulfonyl)oxy)-7- ((triisopropylsilyl)oxy)quinolin-4-yl)oxy)ethoxy)-1,4-oxazepane-4-carboxylate

[0267] The title compound (320 mg, colorless oil) was obtained following a sequence similar to the one described in Steps 6 and 7 of Example 17, from the title compound of Step 3. LCMS: m / z = 727 [M+H]+. Steps 6 and 7: Synthesis of tert-butyl (S)-6-(2-((5-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-3-fluoro-7- hydroxyquinolin-4-yl)oxy)ethoxy)-1,4-oxazepane-4-carboxylate

[0268] The title compound (47.0 mg, yellow oil) was obtained following a sequence similar to the one described in Steps 4 and 5 of Example 19, from the title compound of Step 5. Purification by prep-HPLC (column: Phenomenex Luna C18150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 22%-52% B over 10 min). LCMS: m / z = 833 [M+H]+. Steps 8 to 10: Synthesis of (16S)-28,33-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-37-((triisopropylsilyl)oxy)-4,7-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3- d]pyrimidina-3(5,4)-quinolinacycloheptaphane

[0269] The title compound (6.00 mg, white solid) was obtained as a mixture of atropisomers following a sequence similar to the one described in Steps 11 to 13 of Example 22, from the title compound of Step 7. Purification by prep-HPLC (column: Phenomenex Luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 31%-61% B over 10 min). LCMS: m / z = 781 [M+H]+. Step 11: Synthesis of (16S)-28,33-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4,7-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(5,4)- quinolinacycloheptaphan-37-ol (atropisomers)

[0270] The title compound (2.93 mg, 50%, yellow solid) was obtained as a mixture of atropisomers following a sequence similar to the one described in Step 8 of Example 20, from the title compound of Step 10. Purification and separation into atropisomers by prep-HPLC 134 IPTS / 125370156.1Attorney Docket No. KEST-004WO (column: Phenomenex Luna C18150*25 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 26%-56% B over 10 min) gave Isomer P1 (270 μg, 4.9%) as white solid and Isomer P2 (550 μg, 11%) as off-white solid:

[0271] Isomer P1 (Example 23): LCMS: m / z = 625 [M+H]+;1H NMR (400 MHz, CD3OD) δ 9.39 (s, 1H), 8.63 - 8.54 (m, 1H), 7.45 - 7.41 (m, 2H), 7.29 - 7.24 (m, 1H), 5.35 (s, 2H), 4.34 - 4.19 (m, 2H), 4.08 (dd, 2H), 3.82 - 3.74 (m, 2H), 3.35 (s, 2H), 3.30 - 3.10 (m, 6H), 2.90 (dd, 1H), 2.80 - 2.70 (m, 1H), 2.48 - 1.72 (m, 6H), 1.29 (s, 2H).

[0272] Isomer P2 (Example 24): LCMS: m / z = 625 [M+H]+;1H NMR (400 MHz, CD3OD) δ 9.37 (s, 1H), 8.73 - 8.62 (m, 1H), 7.53 - 7.33 (m, 3H), 5.49 - 5.17 (m, 2H), 4.29 - 4.06 (m, 4H), 4.00 - 3.95 (m, 2H), 3.86 - 3.78 (m, 2H), 3.44 (s, 2H), 3.21 - 3.00 (m, 4H), 2.48 - 1.84 (m, 8H), 1.39 - 1.29 (m, 2H). Example 25: Synthesis of (13R)-28,37-difluoro-22-(((R)-1-methylpyrrolidin-2-yl)methoxy)- 4,7-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacycloheptaphan-33-ol (Compound 130)yl)methoxy)-4,7-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)- naphthalenacycloheptaphane

[0273] The title compound (18.0 mg, yellow oil) was obtained following a sequence similar to the one described in Steps 4 to 7 of Example 19, from the title compound of Example 15, Step 2. LCMS: m / z = 668 [M+H]+. Step 5: Synthesis of (13R)-28,37-difluoro-22-(((R)-1-methylpyrrolidin-2-yl)methoxy)-4,7-dioxa- 2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-azepana-3(1,8)-naphthalenacycloheptaphan-33-ol 135 IPTS / 125370156.1Attorney Docket No. KEST-004WO

[0274] The title compound (1.69 mg, 12.3%, gray solid) was obtained using a similar method to the one described in Step 7 of Example 7, from the title compound of Step 4. The crude was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient:12%-42% B over 10 min) and prep-HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 38%-68% B over 9 min). LCMS: m / z = 578 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.56 - 7.50 (m, 1H), 7.40 - 7.33 (m, 1H), 7.28 (d, 1H), 7.19 (d, 1H), 5.24 (d, 1H), 4.64 - 4.53 (m, 1H), 4.44 - 4.37 (m, 1H), 4.22 - 4.12 (m, 1H), 3.79 - 3.68 (m, 1H), 3.67 - 3.57 (m, 2H), 3.55 - 3.50 (m, 1H), 2.98 - 2.91 (m, 1H), 2.35 (s, 3H), 2.23 - 2.09 (m, 2H), 2.03 - 1.87 (m, 4H), 1.77 - 1.63 (m, 3H), 1.62 - 1.50 (m, 2H), 1.48 - 1.34 (m, 2H), 0.93 - 0.80 (m, 2H). Example 26: Synthesis of 18,27-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-23-hydroxy-9-(2-hydroxyethyl)-5-oxa-9-aza-1(7,4)-pyrido[4,3- d]pyrimidina-2(1,8)-naphthalenacyclononaphan-6-one (Compound 131)Step 1: Synthesis of 4-(benzyloxy)-7-(8-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0275] The title compound (600 mg, 30.4%, off-white foam) was obtained following a similar method to the one described in Step 6 of Example 10, using Intermediate 10 and Intermediate 4 as starting materials. LCMS: m / z = 899 [M+H]+. 136 IPTS / 125370156.1Attorney Docket No. KEST-004WO Step 2: Synthesis of 8-fluoro-7-(7-fluoro-8-(2-hydroxyethyl)-3-(methoxymethoxy)naphthalen-1- yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-ol

[0276] The title compound (300 mg, 76%, brown solid) was obtained following a similar method to the one described in Step 3 of Intermediate 5, from the title compound of Step 1. LCMS: m / z = 571 [M+H]+. Step 3: Synthesis of 3-((2-((tert-butyldiphenylsilyl)oxy)ethyl)(8-fluoro-7-(7-fluoro-8-(2- hydroxyethyl)-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)propanoic acid

[0277] To a solution of the title compound of Step 2 (200 mg, 0.35 mmol) in DMA (2 mL) were added DIPEA (227 mg, 1.75 mmol) and HATU (200 mg, 0.53 mmol) at rt under N2, and the reaction mixture was stirred for 2 h. Intermediate 19 (195 mg, 0.53 mmol) was added and the reaction mixture was stirred for 16 h, then concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (column: RediSep Gold® C18,100 g, mobile phase A: 10 mM NH4HCO3in water; mobile phase B: ACN: flow rate: 15 mL / min) and lyophilized to afford the title compound (70 mg, 20.6%) as an off-white solid. LCMS: m / z = 571 [M+H]+. Step 4: Synthesis of 9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-18,27-difluoro-12-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-23-(methoxymethoxy)-5-oxa-9-aza-1(7,4)- pyrido[4,3-d]pyrimidina-2(1,8)-naphthalenacyclononaphan-6-one

[0278] To a solution of the title compound of Step 3 (70 mg, 0.076 mmol) in CHCl3(1 mL) were added DMAP (13.9 mg, 0.12 mmol) and EDC (18.1 mg, 0.09 mmol) at 0°C under N2. The reaction mixture was stirred at rt for 1 h, then poured into water (5 mL) and extracted with DCM (10 mLx2). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered a...

Claims

Attorney Docket No. KEST-004WO CLAIMS What is claimed is:

1. A compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; Ring B is a 5-10 membered heterocyclyl containing at least one ring nitrogen; RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; X is selected from the group consisting of -C(RX1RX2)-, -O-, -NRa-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -NRaC(O)-, and -C(O)NRa-; RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, - NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and 158 IPTS / 125370156.1Attorney Docket No. KEST-004WO -NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; L is a linker moiety comprising: two to five bivalent units each represented by -(CR1R2)-; and one or two additional units each independently selected from the group consisting of -O-, -NRa-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, - OC(O)NRa-, -NRaC(O)NRb-, and -CH=CH-; R1and R2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, -NRaRb, C1-C3alkyl, and C1-C3alkoxy; R3is selected from the group consisting of hydrogen, deuterium, halogen, and C1- C3alkyl; R4, R5, and R6are each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; R7, R8, R9, and R10are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, - O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, - O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1- C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; or R7and R8are joined together to form oxo; or or R9and R10are joined together to form oxo; 159 IPTS / 125370156.1Attorney Docket No. KEST-004WO R11and R12are each independently selected from the group consisting of hydrogen, deuterium, and C1-C3alkyl; Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1- C6alkyl, and C1-C6alkoxy; m is 1 and n is 2 or 1; or m is 2 and n is 1 or 0; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and t is 0, 1, or 2.

2. The compound of claim 1, wherein R4, R5, and R6are each hydrogen.

3. The compound of claim 1 or 2, wherein t is 1.

4. The compound of any one of claims 1-3, wherein R11and R12are each hydrogen.

5. The compound of any one of claims 1-4, wherein the compound is represented by:

6. The compound of any one of claims 1-5, wherein ring m is 1 and n is 2.

7. The compound of any one of claims 1-6, wherein the compound is represented by: 160 IPTS / 125370156.1Attorney Docket No. KEST-004WO8. The compound of any one of claims 1-7, wherein X is selected from the group consisting of - C(RX1RX2)-, -O-, and -N(Ra).

9. The compound of any one of claims 1-8, wherein RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy.

10. The compound of any one of claims 1-9, wherein RX1is hydrogen and RX2is selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1- C6alkoxy.

11. The compound of any one of claims 1-10, wherein RX1and RX2are each hydrogen.

12. The compound of any one of claims 1-11, wherein R7and R8are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy, or R7and R8are joined together to form oxo.

13. The compound of any one of claims 1-12, wherein R7is hydrogen and R8is selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1- C6alkoxy.

14. The compound of any one of claims 1-13, wherein R7and R8are each hydrogen.

15. The compound of any one of claims 1-12, wherein R7and R8are joined together to form oxo.

16. The compound of any one of claims 1-15, wherein R9and R10are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy, or R9and R10are joined together to form oxo.

17. The compound of any one of claims 1-16, wherein R9is hydrogen and R10is selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1- C6alkoxy. 161 IPTS / 125370156.1Attorney Docket No. KEST-004WO 18. The compound of any one of claims 1-17, wherein R9and R10are each hydrogen.

19. The compound of any one of claims 1-15, wherein R9and R10are joined together to form oxo.

20. The compound of any one of claims 1-19, wherein R1and R2are for each occurrence hydrogen.

21. The compound of any one of claims 1-20, wherein L is selected from the group consisting of: -(CH2)2-5-O-, -(CH2)2-5-C(O)-O-, -(CH2)2-5-O-C(O)-, -(CH2)2-5-C(O)-NRa-, -(CH2)2-5-NRa- C(O)-, -(CH2)2-5-S-, -(CH2)2-5-S(O)-, -(CH2)-2-5-S(O)2-, -O-(CH2)2-5-O-, -(CH2)1-2-O-(CH2)2-3-O-, and -CH=CH-(CH2)2-5-O-.

22. The compound of any one of claims 1-21, wherein L is selected from the group consisting of: -CH2-CH2-CH2-O-, -CH2-CH2-CH2-CH2-O-, -CH2-CH2-CH2-CH2-CH2-O-, -CH2-O-CH2- CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, -O-CH2-CH2- CH2-CH2-O-, and -CH=CH-CH2-CH2-CH2-O-.

23. The compound of any one of claims 1-22, wherein ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl.

24. The compound of any one of claims 1-23, wherein RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, -C(O)NH2,C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, and C3-C6cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens or -CN.

25. The compound of any one of claims 1-24, wherein RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, and C1-C4alkyl.

26. The compound of any one of claims 1-25, wherein q is 1, 2, or 3.

27. The compound of any one of claims 1-26, wherein ring A is selected from the group consisting of:wherein * denotes the point of attachment to L. 162 IPTS / 125370156.1Attorney Docket No. KEST-004WO 28. The compound of any one of claims 1-27, wherein R3is selected from the group consisting of hydrogen, halogen, and -CH3.

29. The compound of any one of claims 1-28, wherein R3is fluoro.

30. The compound of any one of claims 1-29, wherein p is 1 or 2.

31. The compound of any one of claims 1-30, wherein RBis independently selected for each occurrence from the group consisting of halogen, hydroxyl, C1-C6alkyl, and C1-C6alkoxy.

32. The compound of any one of claims 1-31, wherein RBis halogen or C1-C6alkyl.

33. The compound of any one of claims 1-32, wherein RBis fluoro or -CH3.

34. The compound of any one of claims 1-33, wherein ring B is selected from the group consisting of35. A compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, -C(O)NH2,C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, and C3-C6cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens; X is selected from the group consisting of -C(RX1RX2)-, -O-, and -N(Ra); RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; 163 IPTS / 125370156.1Attorney Docket No. KEST-004WO L is selected from the group consisting of -(CH2)2-5-O-, -(CH2)2-5-C(O)-O-, -(CH2)2-5-O- C(O)-, -(CH2)2-5-C(O)-NRa-, -(CH2)2-5-NRa-C(O)-, -(CH2)2-5-S-, -(CH2)2-5-S(O)-, -(CH2)-2-5- S(O)2-, -O-(CH2)2-5-O-, -(CH2)1-2-O-(CH2)2-3-O-, and -CH=CH-(CH2)2-5-O-; R1and R2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy, or R1and R2are joined together to form oxo; R3and R4are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy, or R1and R2are joined together to form oxo; R5is selected from the group consisting of halogen and hydrogen; Ring B is selected from the group consistingRaand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl; and q is 1, 2, or 3.

36. The compound of claim 35, wherein RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, and C1-C4alkyl.

37. The compound of claim 35 or 36, wherein L is selected from the group consisting of: -CH2- CH2-CH2-O-, -CH2-CH2-CH2-CH2-O-, -CH2-CH2-CH2-CH2-CH2-O-, -CH2-O-CH2-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, -O-CH2-CH2-CH2-CH2-O-, and -CH=CH-CH2-CH2-CH2-O-.

38. The compound of any one of claims 35-37, wherein R5is fluoro.

39. The compound of any one of claims 35-38, wherein R1and R2are each hydrogen.

40. A compound represented by Formula III:164 IPTS / 125370156.1Attorney Docket No. KEST-004WO or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; Ring B is a 5-10 membered heterocyclyl containing at least one ring nitrogen; RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; L is a linker moiety comprising: three to eight bivalent units each represented by -(CR1R2)-; and one or two additional units each independently selected from the group consisting of -O-, -NRa-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, - OC(O)NRa-, -NRaC(O)NRb-, and -CH=CH-; R1is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl; wherein C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl; R2is selected from the group consisting of hydrogen, deuterium, halogen, and C1- C3alkyl; Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each 165 IPTS / 125370156.1Attorney Docket No. KEST-004WO independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1- C6alkyl, and C1-C6alkoxy; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

41. The compound of claim 40, wherein the compound is represented by Formula IIIA:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of phenyl, naphthyl, quinolinyl, and isoquinolinyl; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, -C(O)NH2,C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, and C3-C6cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens; L is selected from the group consisting of -(CH2)3-6-O-(CH2)2-3, -(CH2)3-6-O-C(O)- (CH2)2-3, -(CH2)3-6-C(O)-O-(CH2)2-3, -(CH2)3-6-NRa-C(O)-(CH2)2-3, and -(CH2)3-6-C(O)-NRa- (CH2)2-3; R1is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl; wherein C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -CN, -NRaRb, and C1-C4alkoxy; R2is halogen or hydrogen; 166 IPTS / 125370156.1Attorney Docket No. KEST-004WO Ring B is selected from the group consistingRaand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl; and q is 1, 2, or 3.

42. The compound of claim 41 or 42, wherein ring A is selected from the group consisting ofwherein * denotes the point of attachment to L.

43. The compound of any one of claims 40-42, wherein L is selected from the group consistingof -CH2-CH2-CH2-CH2-CH2-O-CH2-CH2- and- CH2-CH2-O-(C(O)- CH2-CH2.

44. The compound of any one of claims 40-43, wherein R1is C1-C6alkyl optionally substituted by hydroxyl.

45. The compound of any one of claims 40-44, wherein R2is fluoro.

46. A compound selected from the group consisting of:, 167 IPTS / 125370156.1Attorney Docket No. KEST-004WO168 IPTS / 125370156.1Attorney Docket No. KEST-004WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

47. A pharmaceutical composition comprising a compound of any one of claims 1-46, or a pharmaceutically acceptable salt and / or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

48. A method of treating a Ras-related disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-46.

49. The method of claim 48, wherein the disease or disorder is characterized by aberrant Ras activity in the patient due to a Ras mutation. 169 IPTS / 125370156.1Attorney Docket No. KEST-004WO 50. The method of claim 48 or 49, wherein the Ras mutation is a K-Ras mutation, a H-Ras mutation, or a N-Ras mutation.

51. The method of any one of claims 48-50, wherein the disease or disorder is a cancer.

52. A method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-46.

53. The method of claim 52, wherein the cancer is a Ras-mutated cancer.

54. The method of claim 52, wherein the cancer is a KRas-mutated cancer. 170 IPTS / 125370156.1

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