Quinazoline compounds and uses thereof

Abstract

Provided herein are quinazoline compounds useful in the treatment of cancers.

Description

QUINAZOLINE COMPOUNDS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of International Patent Application No. PCT / CN2025 / 075816 filed on February 5, 2025, which is hereby expressly incorporated by refenrece in its entirety.FIELD OF INVENTION

[0002] Provided herein are quinazoline compounds useful in the treatment of cancers comprising a KRas mutation, compositions of such compounds, and methods of treating cancers comprising a KRas mutation.BACKGROUND

[0003] Ras is a small GTP-binding protein that functions as a nucleotidedependent switch for central growth signaling pathways. In response to extracellular signals, Ras is converted from a GDP-bound (RasGDP) to a GTP-bound (RasGTP) state, as catalyzed by guanine nucleotide exchange factors (GEFs), notably the SOS1 protein. Active RasGTPmediates its diverse growth-stimulating functions through its direct interactions with effectors including Raf, PI3K, and Rai guanine nucleotide dissociation stimulator. The intrinsic GTPase activity of Ras then hydrolyzes GTP to GDP to terminate Ras signaling. The Ras GTPase activity can be further accelerated by its interactions with GTPase-activating proteins (GAPs), including the neurofibromin 1 tumor suppressor.

[0004] Mutant Ras has a reduced GTPase activity, which prolongs its activated state, thereby promoting Ras-dependent signaling and cancer cell survival or growth. Mutation in Ras that affects its ability to interact with GAP or to convert GTP back to GDP will result in a prolonged activation of the protein and consequently a prolonged signal to the cell telling it to continue to grow and divide. Because these signals result in cell growth and division, overactive RAS signaling may ultimately lead to cancer. Mutations in any one of the three main isoforms of RAS (HRas, NRas, or KRas) genes are common events in human tumorigenesis. Among the three Ras isoforms (K, N, and H), KRas is most frequently mutated.

[0005] The most common KRas mutations are found at residue G12 and G13 in the P-loop and at residue Q61. Mutations of Ras in cancer are associated with poorprognosis. Inactivation of oncogenic Ras in mice results in tumor shrinkage. Thus, Ras is widely considered an oncology target of exceptional importance.

[0006] Accordingly, there is a pressing need for therapies for mutant KRas mediated cancers.SUMMARY

[0007] Provided herein are solutions to the problems above and other problems in the art.

[0008] In a first aspect provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein.

[0009] In another aspect provided herein is a compound of formula (II), (Ila), or (lib), or a pharmaceutically acceptable salt thereof as described herein.

[0010] In another aspect provided herein is a compound of formula (III), (Illa), or (I I lb), or a pharmaceutically acceptable salt thereof as described herein.

[0011] In another aspect provided herein is a compound or pharmaceutically acceptable salt thereof as set forth in Table 1.

[0012] In another aspect provided herein is a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof as described herein.

[0013] In another aspect provided herein is a method of treating a cancer comprising a KRas mutation, the method comprising administering to a patient having such cancer, a compound, or a pharmaceutically acceptable salt thereof as described herein.

[0014] In another aspect provided herein is a method for regulating activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound, or a pharmaceutically acceptable salt thereof as described herein.

[0015] In another aspect provided herein is a method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound, or a pharmaceutically acceptable salt thereof as described herein.

[0016] In another aspect provided herein is a method for inhibiting tumor metastasis comprising administering to an individual in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof asdescribed herein or a pharmaceutical composition as described herein to a subject in need thereof.

[0017] In another aspect provided herein is method for preparing a labeled KRas mutant protein, the method comprising reacting a KRas mutant protein with a labeled compound or a pharmaceutically acceptable salt thereof, as described here to result in the labeled KRas mutant protein.

[0018] In another aspect provided herein is a process for synthesizing a compound or a pharmaceutically acceptable salt thereof as set forth herein.DEFINITIONS

[0019] Disclosed herein are heterocyclic quinazoline compounds as described herein or pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof that, in certain embodiments, are inhibitors or modulators of mutant KRas. In certain instances, such compounds and compositions are inhibitors or modulators of mutant KRasG12Vas provided herein. In certain instances, such compounds and compositions are inhibitors or modulators of mutant KRas (i.e. pan-KRas inhibitors) as provided herein. The compounds and compositions described herein are useful in treating diseases and disorders mediated by mutant KRas.

[0020] While the disclosure herein provides enumerated embodiments, it is understood that they are not intended to limit the compounds and methods described herein to those embodiments. On the contrary, the disclosure is intended to cover all alternatives, modifications, and equivalents that can be included within the scope of the present disclosure as defined by the claims.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The nomenclature used in this Application is based on IUPAC systematic nomenclature, unless indicated otherwise. In instances where structure may disagree with nomenclature, the structure controls.

[0022] The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references referred to herein are incorporated by reference in their entirety.

[0023] The terms “halogen” and “halo” are used interchangeably and refer to F, Cl, Br or I. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl, polyhaloalkyl, and perhaloalkyl.

[0024] The term "alkyl" refers to a saturated linear or branched-chain monovalent hydrocarbon radical. In one example, the alkyl radical is one to eighteen carbon atoms (C1-18). In other examples, the alkyl radical is C1-12, C1-10, C1-8, C1-6, C1-5, C1-4, or C1-3. Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1 -propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1 -pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), 1 -hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1 -heptyl and 1 -octyl.

[0025] The term “oxo” refers to =0.

[0026] The term "alkoxy" refers to -O-alkyl.

[0027] The terms “cyano” or “nitrile” refers to -C=N or -CN.

[0028] The term "haloalkoxy" refers to -O-haloalkyl.

[0029] The terms "hydroxy" and “hydroxyl” refer to -OH.

[0030] The term "alkenyl" refers to linear or branched-chain monovalent hydrocarbon radical with at least one carbon-carbon double bond, and includes radicals having "cis" and "trans" orientations, or alternatively, " E" and " Z" orientations. In one example, the alkenyl radical is two to eighteen carbon atoms (C2-18). In other examples, the alkenyl radical is C2-12, C2-10, C2-8, C2-6, or C2-3. Examples include, but are not limited to, ethenyl or vinyl (-CH=CH2), prop-1 -enyl (-CH=CHCHs), prop-2-enyl (-CH2CH=CH2), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1, 3-dienyl, 2-methylbuta-1,3-diene, hex-1 -enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1, 3-dienyl.

[0031] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon, triple bond. In one example, the alkynyl radical is two to eighteen carbon atoms (C2-18). In other examples, the alkynyl radical is C2-12, C2-10, C2-8, C2-6, or C2-3. Examples include, but are not limited to, ethynyl (-C^CH), prop-1-ynyl (–C≡CCH3), prop-2-ynyl (propargyl, –CH2C≡CH), but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0032] The term "alkylene” refers to a saturated, branched, or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. In one example, the divalent alkylene group is one to eighteen carbon atoms (C1-18). In other examples, the divalent alkylene group is C1-12, C1-10, C1-8, C1-6, C1-5, C1-4, or C1-3. Example alkylene groups include methylene (-CH2-), 1,1 -ethyl (-CH(CHs)-), (1,2-ethyl (-CH2CH2-), 1,1 -propyl (-CH(CH2CH3)-), 2,2-propyl (-C(CH3)2-), 1,2-propyl (-CH(CH3)CH2-), 1,3-propyl (-CH2CH2CH2-), 1,1-dimethyleth-1,2-yl (–C(CH3)2CH2–), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0033] The term “cycloalkyl” refers to a saturated hydrocarbon ring group. Cycloalkyl encompasses mono-, bi-, tricyclic, spiro and bridged, saturated hydrocarbon ring systems. In one example, the cycloalkyl group is 3 to 12 carbon atoms (C3-12). In other examples, cycloalkyl is C3-4, C3-5, C3-7, C3-8, C3-10, or C5-10. In other examples, the cycloalkyl group, as a monocycle, is C3-4, C3-8, C3-6, or C5-6. In another example, the cycloalkyl group, as a bicycle, is C7-C12. In another example, the cycloalkyl group, as a spiro system, is C5-12. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of spirocycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.

[0034] “Heterocycloalkyl” as used herein refers to any mono-, bi-, tricyclic, spiro or bridged, unsaturated ring system copmrising at least one annular heteroatom. In some embodiments, each annular heteroatom is independnetly selected from nitrogen, sulfur, and oxygen. If any ring atom of such a saturated ring system is a heteroatom,that system is a heterocycloalkyl, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocycloalkyl includes 3-10 ring atoms (“members”) and includes monocycles, bicycles, tricycles, spiro, and bridged ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In other examples, heterocycloalkyl includes 3-6, 5-9, 4-10 or 5-10 ring atoms. In one example, heterocycloalkyl includes 1 to 4 heteroatoms. In one example, heterocycloalkyl includes 1 to 3 heteroatoms. In another example, heterocycloalkyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocycloalkyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocycloalkyl includes 8, 9, or 10 membered bicycles. In such examples, the heterocycloalkyl group can be 4,5-, 5,5-, 4,6-, 5,6-, or 6,6- fused ring system, and may include one ring comprising a heteratom fused to a ring without any annular heteroatom In some embodiments, a heterocycloalkyl includes at least one nitrogen. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4]+CI_, [NR4]+OH_). Examples of heterocycloalkyl include, but are not limited to, morphlinyl, dioxanyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, azetidinyl, oxetanyl, and tetrahydrofuranyl.

[0035] “Aryl” as used herein refers to a monocylic or polycyclic group comprising at least one aromatic hydrocarbon ring, and wherein the aryl is a polycyclic system, no aromatic ring heteroatoms are present. An aryl group may have a single ring (e.g., phenyl) or multiple fused or spiro rings (e.g., naphthyl or anthryl) which fused or spiro rings can or can not be aromatic. In certain embodiments, aryl includes groups with an aromatic hydrocarbon ring fused to a non-aromatic ring, wherein the non-aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of nitrogen, oxygen, and sulfur. Particular aryl groups are those having from 6 to 14 annular (i.e., ring) carbon atoms (a “Ce-14 aryl”). Preferred aryl groups include those having 5 to 6 ring carbons. An aryl group having more than one ring where at least one ring is non-aromatic can be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

[0036] “Hydroxyalkyl”, “alkoxy-alkyl”, “cyano-alkyl”, and “aryl-alkyl” refer to an alkyl group substituted by one or more hydroxy, alkoxy, cyano, and aryl groups, respectively. In some embodiments, the alkyl is substituted by one hydroxy, alkoxy, cyano, or aryl group.

[0037] The term “heteroaryl” refers to any mono- or polycyclic aromatic ring system, wherein at least one aromatic ring of the system contains an annular heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl ring system contains from 1 to 8 ring heteroatoms selected from nitrogen, oxygen, and sulfur, which heteroatoms may be present in more than one ring if the heteroaryl is polycyclic. In an example embodiment, at least one heteroatom is nitrogen. Heteroaryl may also include polycyclic groups with at least one aromatic ring comprising at least one ring heteroatom, fused to a non-aromatic hydrocarbon ring. A heteroaryl group can have a single ring (e.g., pyridyl, furyl) or multiple fused or spiro rings (e.g., indolizinyl, benzothienyl) which fused or spiro rings can or can not be aromatic. In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indazolyl and indolyl.

[0038] The term “carbocycle” or “carbocyclyl” includes any monocyclic or polycyclic ring system wherein all ring atoms are carbon. This includes cycloalkyl groups, but also aryl groups which are not fused to a non-aromatic heterocycle. Carbocycle includes spiro or bridged, saturated, partially saturated, and aromatic hydrocarbon ring systems.

[0039] The term “heterocycle” or “heterocyclyl” includes any monocyclic or polycyclic ring system wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. This includes heterocycloalkyl and heteroaryl, but also includes aryl groups wherein an aromatic hydrocarbon ring is fused to a non-aromatic ring, wherein the non-aromatic ring comprises at least one ring heteroatom. Heterocycle includes spiro or bridged, saturated, partially saturated, and aromatic ring systems wherein at least one ring comprises a heteroatom. Any nitrogen or sulfur heteroatommay optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4]+CI_, [NR4]+OH_). In some embodiments, heterocycle is a 4- to 12-membered ring system comprising from 1 to 5 annular heteroatoms, independently selected from O, N, and S. In some embodiments, heterocycle comprises between 1 to 4 heteroatoms, and at least one heteroatom is N.

[0040] The term “amino” as used herein refers to -NR’R”, wherein each R’ and R” are independently selected from the group consisting of H and alkyl. In some embodiments, R’ and R” are independnetly selected from the group consisting of H and Ci-ealkyl. In some embodiments, both R’ and R” are H.

[0041] “Fused” refers to any ring structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with an existing ring structure in the compounds described herein.

[0042] The term “haloalkyl” refers to an alkyl chain in which one or more hydrogen atoms has been replaced by a halogen, wherein each halogen is independently selected from Cl, I, Br, and F. Examples of haloalkyls are trifluoromethyl, difluoromethyl, and fluoromethyl. A substituted haloalkyl refers to a haloalkyl having a moiety other than a halogen.

[0043] As used herein a wavy linethat intersects a bond in a chemical structure indicate the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule.

[0044] The term “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.

[0045] Compounds described herein may be in the form of a salt, such as a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” include both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvicacid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0046] The term “pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particular base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particular organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0047] The term “stereoisomers” refer to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, atropisomers, conformers and the like.

[0048] The term “chiral” refers to molecules that have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

[0049] The term “diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0050] The term “enantiomers” refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0051] The term “atropisomers” refers to two conformers resulting from hindered rotation about a single bond where the steric strain barrier to rotation can be high enough to allow for the isolation of the each conformer.

[0052] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and I or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0053] The term “tautomer” or “tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0054] Certain compounds described herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. A “solvate” refers to an association or complex of one or more solvent molecules and a compound described herein. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.

[0055] The compounds and pharmaceutically acceptable salts thereof described herein also embrace isotopically-labeled compounds that are identical to those recitedherein, but for the fact 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. All isotopes of any particular atom or element as specified are contemplated herein, and their uses. Exemplary isotopes that can be incorporated into compounds and pharmaceutically acceptable salts thereof described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N,15N,150,170,180,32P,33P,35S,18F,36CI,123l, and125I Certain isotopically-labeled compounds or pharmaceutical acceptable salts thereof described herein (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful 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. Positron emitting isotopes such as15O,13N,11C and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds or pharmaceutical acceptable salts thereof described herein can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0056] Compounds and pharmaceutically acceptable salts thereof described herein may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers, atropisomers, or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers, enantiomers, or atropisomers as starting materials or as intermediates. Mixtures of particular diastereomeric compounds may be separated, or enriched in one or more particular diastereomers, by chromatographic or crystallization methods. Similarly, enantiomeric and / or atropisomeric mixtures may be separated, or enantiomerically or atropisomerically enriched, using the same techniques or others known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration and both of these configurations are contemplated herein. Those skilled in the art will recognize if a stereocenter exists in the compounds disclosed herein. In some embodiments, compounds of the disclosure can exist as enantiomeric or diastereomeric stereoisomers. Accordingly, the present disclosure includes both possiblestereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. If the chirality of a particular stereocenter is not defined, all possible stereoisomers (including atropisomers, if they exist) are included.

[0057] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included (including atropisomers). Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended.

[0058] Likewise, it is understood that a compound or salt may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the subject matter disclosed herein.

[0059] A “subject,” “individual,” or “patient” are used interchangeably herein, and refer to a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits and horses), primates, mice and rats. In certain embodiments, the subject, individual, or patient is a human. In embodiments comprising administration of a compound to a patient, the patient is typically in need thereof.

[0060] The terms “inhibiting” and “reducing,” or any variation of these terms, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of activity compared to normal. In a particular embodiment, the decrease is at least 10%, or at least 5%.

[0061] The term “treatment” refers to clinical intervention designed to alter the natural course of the patient or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For example, a patient is successfully “treated” if one or more symptoms associated with a disorder (such as cancer) described herein are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells,decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and / or prolonging survival of patients.

[0062] The term “delaying progression” of a disease refers to deferring, hindering, slowing, retarding, stabilizing, and / or postponing development of a cancer described herein. This delay can be of varying lengths of time, depending on the history of the cancer and / or patient being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the patient does not develop cancer or relapse.

[0063] A “mutant KRas mediated disease” and the like refer to a disease described herein (e.g. a cancer described herein) having symptoms or requiring treatment as set forth herein that is / are wholly or partly associated with, a result of, a function of, or otherwise correlated to mutant KRas activity as described herein. In one such embodiment, the mutant KRas is KRasG12V. In another embodiment, the mutant KRas is any G12 mutant (i.e. a pan-KRas inhibitor).

[0064] An “effective amount” or “therapeutically effective amount” is at least the minimum amount required to effect a measurable improvement or prevention of a cancer described herein. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the agent to elicit a desired response in the patient. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. Beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, delaying the onset of the disease (including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease), decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and / or prolonging survival. In some embodiments, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow or stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow or stop) tumor metastasis; inhibiting (i.e., slow or stop) tumor growth; and / or relieving one or more of the symptomsassociated with the disorder. An effective amount can be administered in one or more administrations.

[0065] The terms “cancer” and “cancerous”, “neoplasm”, and “tumor” and related terms are used interchangeably herein and refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer) and lung cancer including small-cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung. Other cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral), lip, tongue, mouth, salivary gland, esophageal, larynx, hepatocellular, gastric, stomach, gastrointestinal, small intestine, large intestine, pancreatic, cervical, ovarian, liver, bladder, hepatoma, breast, colon, rectal, colorectal, genitourinary, biliary passage, thyroid, papillary, hepatic, endometrial, uterine, salivary gland, kidney or renal, prostate, testis, vulval, peritoneum, anal, penile, bone, multiple myeloma, B-cell lymphoma, diffuse large B-Cell lymphoma (DLBCL), central nervous system, brain, head and neck, Hodgkin’s, and associated metastases. Other examples of neoplastic disorders include myeloproliferative disorders, such as polycythemia vera, essential thrombocytosis, myelofibrosis, such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

[0066] It is specifically contemplated that any limitation discussed with respect to one embodiment provided herein may apply to any other embodiment provided herein. Furthermore, any compound and pharmaceutically acceptable salts thereof described herein or composition described herein may be used in any method provided herein, and any method provided herein may be used to produce or to utilize any compound and pharmaceutically acceptable salts thereof described herein or composition described herein.

[0067] Throughout this application, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.COMPOUNDS

[0068] Provided herein are compounds of formula (I):or a pharmaceutically acceptable salt thereof,wherein;R1is halogen, cyclopropyl, halocyclopropyl, C1-3haloalkyl, or C1-3alkyl;R2is hydrogen and R3is hydrogen, methyl, or halomethyl; or R2and R3come together to form -OCHR4-;R4is H, methyl, or halomethyl;X1is N or CR°, wherein R° is H, halogen, C1-3alkyl, C1-3haloalkyl, cyclopropyl, or halocyclopropyl;Q1is a carbocycle or heterocycle;m is an integer from 0 to 7;each R8is independently selected from the group consisting of halogen, C1-6alkyl, C3-6cycloalkyl, C2-6alkynyl, -CN, -OH, amino, and C1-3haloalkyl; and two R8on adjacent carbon atoms may come together to form a cycloalkyl or heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from Ci-ealkyl, halo, and haloalkyl;Z is H, -OCRZ2-Q2, or Q2; wherein each Rzis independently H or halo;Q2is a heterocycle or carbocycle; wherein Q2is unsubstituted or substituted with 1 to 6 R9groups;each R9is independently selected from the group consisting of halogen, alkyl, amino, and C2-C4alkenyl, wherein each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, amino, -OH, alkoxy, haloalkoxy, and heterocycloalkyl;R10is cyano, alkyl, haloalkyl, hydroxyalkyl, heteroaryl, alkyl-R11, alkyl-R12, or alkyl-O-R12, wherein the heteroaryl is unsubstituted or substituted with aryl-al kyl;R11is selected from the group consisting of -N(R14)S(=O)2R15, -N(R14)S(=O)2N(R15)2, -N(R14)C(=O)R15, -N(R14)C(=O)N(R15)2, -N=S(=O)(R14)(R16), and NR14-S(=O)(=NH)R15; R14is H, alkyl, or cycloalkyl; each R15is independently H, alkyl,or cycloalkyl, or two R15attached to the same nitrogen form a cycle; and R16is H, alkyl, cycloalkyl, or heteroaryl;R12is a heterocycle group unsubstituted or substituted with one or more R13; andeach R13is independently oxo, cyano, cyano-alkyl, halo, alkyl, haloalkyl, alkoxy, alkoxy-alkyl, -S(O)2R13b, cycloalkyl, halocycloalkyl, heterocycloalkyl, or -N(R13a)C(=O)R13b, wherein the heterocycloalkyl is unsubstituted or substituted with oxo or hydroxyalkyl.

[0069] In embodiments of Formula (I) wherein R2and R3come together to form -OCHR4-, the carbon atom is bonded to the azetidine group of the core structure.

[0070] In one embodiment, the compound of Formula (I) is a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein R1, R4, X1, Q1, m, R8, Z, Q2, R10, R11, R12and R13are as described herein

[0071] In one embodiment, the compound of Formula (II) is a compound of Formula (Ila):or a pharmaceutically acceptable salt thereof, wherein R1, R4, Q1, m, R8, Z, Q2, R10, R11, R12and R13are as described herein.

[0072] In one embodiment, the compound of Formula (II) is a compound of Formula (lib):or a pharmaceutically acceptable salt thereof, wherein R1, R4, R°, Q1, m, R8, Z, Q2, R10, R11, R12and R13are as described herein.

[0073] In one embodiment, the compound of Formula (I) is a compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein R1, R3, X1, Q1, m, R8, Z, Q2, R10, R11, R12and R13are as described herein.

[0074] In one embodiment, the compound of Formula (III) is a compound of Formula (Illa):or a pharmaceutically acceptable salt thereof, wherein R1, R3, Q1, m, R8, Z, Q2, R10, R11, R12and R13are as described herein.

[0075] In one embodiment, the compound of Formula (III) is a compound of Formula (I lib):R3O R1«H NZ(lllb)or a pharmaceutically acceptable salt thereof, wherein R1, R3, R°, Q1, m, R8, Z, Q2, R10, R11, R12and R13are as described herein.

[0076] In some embodiments of the compound of Formula (I) (including (II), (III), (Illa), (lllb)), Q1is a C6-C10carbocycle, or 5-10-membered heterocycle comprising one to four annular heteratoms. In some embodiments, the heteroatom is selected from the group consisting of O, N, and S. In some embodiments, Q1is a C6-C10aryl, or 5-10-membered heteroaryl comprising one to four annular heteratoms selected from the group consisting of O, N, and S. In particular embodiments, Q1is phenyl, pyridinyl, naphthyl, quinoline, or isoquinoline, each of which may be unsubstituted or substituted with R8. In some embodiments, Q1is:wherein n1 is an integer from 0-3; n2 is an integer from 0-4; n3 is an integer from 0-7; and n4 is an integer from 0-7; wherein each R8is independently selected from the group consisting of halogen, Ci-ealkyl, C3-6cycloalkyl, C2-6alkynyl, -CN, -OH, amino, and C1-3haloalkyl. In some embodiments, each R8is independently selected from the group consisting of halogen, C1-3alkyl, C2-3alkynyl, -CN, -OH, -NH2, and C1-3haloalkyl. In some embodiments, each R8is independently selected from the group consisting of F, Cl, methyl, ethyl, -C≡CH, -CN, -OH, -NH2, -CHF2, and –CF3.

[0077] In some embodiments of the compound of Formula (I) (including (II), (III), (Illa), (lllb)), R10is alkyl-R12. In some embodiments, R12is a 5-12 membered heteroaryl or a 5-12 membered heterocycloalkyl, comprising 1-5 annular heteroatoms independently selected from O, N, and S. In some embodiments, R12is a 5-12 membered heteroaryl comprising 1-4 annular heteratoms independently selected fromO, N, and S. In some embodiments, R12is a 5-12 membered heteroaryl comprising 1-3 annular N atoms; and optionally 1-2 additional heteroatoms independently selected from O and S. In some embodiments, R12is a 5-12 membered heterocycloalkyl comprising 1-3 annular N atoms; and optionally 1-2 additional heteroatoms independently selected from O and S. In certain embodiments, R12is substituted with at least one R13which is oxo, and further unsubstituted or substituted with one or more R13independendently selected from the group consisting of oxo, cyano, cyano-alkyl, halo, alkyl, haloalkyl, alkoxy, alkoxy-alkyl, -S(O)2R13b, cycloalkyl, halocycloalkyl, heterocycloalkyl, and -N(R13a)C(=O)R13b, wherein the heterocycloalkyl is unsubstituted or substituted with oxo or hydroxyalkyl. In still further embodiments, R12is a 5-12 membered heteroaryl or a 5-12 membered heterocycloalkyl, comprising 1-5 annular heteroatoms independently selected from O, N, and S (e.g., R12is a 5-12 membered heteroaryl comprising 1-3 annular N atoms, and optionally 1-2 additional heteroatoms independently selected from O and S; or R12is a 5-12 membered heterocycloalkyl comprising 1-3 annular N atoms, and optionally 1-2 additional heteroatoms independently selected from O and S) and the R12is substituted with at least one R13which is oxo, and further unsubstituted or substituted with one or more R13. In some embodiments, the further one or more R13is each independently selected from the group consisting of halo, C1-C3alkyl, C1-C6haloalkyl, C1-C6alkoxy, alkoxy- C1-C6alkyl, C3-C5cycloalkyl, and 3-to-5-membered heterocycloalkyl.

[0078] In one such embodiment, Q1is an aryl or heteroaryl, and Z is H, -OCH2-Q2, or Q2.

[0079] In one such embodiment, R1is halogen; X1is N or CR°, wherein R° is H or halogen; and Q1is a C6-C10aryl or 5-10-membered heteroaryl comprising at least one annular N.

[0080] In one such embodiment, R1is fluoro; X1is N or CR°, wherein R° is chloro; and Q1is phenyl, naphthyl, pyridine, isoquinoline, or pyrazole.

[0081] In one such embodiment, m is an integer from 0 to 4; and each R8is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, C3-6cycloalkyl, -C≡CH, -CN, -OH, -NH2, -NHCH3, and CF3; and, independently, two R8on adjacent carbon atoms may come together to form a 6-membered ring unsubstituted or substituted with one or two methyl.33988-981 (P39387-WO-1)PCT

[0082] In one such embodiment, X1is N.

[0083] In one such embodiment, X1is CR°.

[0087] In one such embodiment, Q2is ∿∿∿ , ∿∿∿ , In one embodiment, Q2is substituted by one or more R9selected from halogen, alkyl, hydroxyalkyl, haloalkyl, and dialkylaminoalkyl.

[0088] In one such embodiment, R10is -CH2-R11; R11is -N(R14)S(=O)2R15, -N(R14)S(=O)2N(R15)2, -N(R14)C(=O)R15, -N(R14)C(=O)N(R15)2, and -N=S(=O)(R14)(R16), or -NR14-S(=O)(=NH)R15; R14is H, methyl, or cyclopropyl; each R15is independently H, methyl, or cyclopropyl, or two R15attached to the same nitrogen come together to form a 5-6 membered heterocycloalkyl; and R16is 6-membered heteroaryl.

[0089] In one such embodiment, R10is cyano, methyl, ethyl, halomethyl, hydroxymethyl, or 5-membered heteroaryl substituted with phenyl-methyl.

[0090] In one such embodiment, R10is CH2-R12, or CH2-O-R12, R12is a 5-10-membered heteroaryl or 5-10-membered heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl comprises 1-3 annular heteroatoms independently selected from N, O, S, SO2, and -N+O_and is substituted with one to five R13; and each R13is independently oxo, cyano, cyano-CH2-, halo, C1-C3alkyl, C1-C3haloalkyl, -O-C1-C3alkyl, -CH2-O-CH3, -S(O)2R13b, cyclopropyl, halocyclopropyl, 4-5 membered heterocycloalkyl, N(R13a)C(=O)R13b, or S(O)2R13b; wherein R13aand R13bare independently C-i-Csalkyl; and wherein the heterocycloalkyl is unsubstituted or substituted with oxo or hydroxyC1-C3alkyl. In one embodiment, R10is -CH2-R12.In one such embodiment, R10 is -CH2-R12and R12, unsubstituted orwherein the R12may be further substituted by one or more R13groups.

[0091] In one such embodiment, R12is not further substituted or is further substituted by 1 to 5 additional R13groups, wherein each R13is independently selected from oxo, cyano, cyano-CH2-, halo, C1-C3alkyl, C1-C3haloalkyl, -O-C1-C3alkyl, -CH2-O-CH3, -S(O)2R13b, cyclopropyl, halocyclopropyl, 4-5 membered heterocycloalkyl, -N(R13a)C(=O)R13b, and S(O)2R13b; wherein R13aand R13bare independently C-i-Csalkyl; and wherein the heterocycloalkyl is unsubstituted or substituted with oxo or hydroxyC1-C3alkyl.

[0092] In one embodiment, the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof is a compound of Table 1.

[0093] It should be understood that individual enantiomers and diastereomers are included in the tables below by Compound Name, and their corresponding structures can be readily determined therefrom. Compounds isolated as racemic mixtures are provided with chirality not specified, if such chiral center was present as a mixture of compounds. In some instances, the enantiomers or diastereomers are identified by their respective properties, for example, retention times on a chiral HPLC or its biological activities (e.g., as described further in the Examples), and the absolute stereo configurations of one or more chiral centers are arbitrarily assigned (e.g., stereochemistry of all chiral centers is arbitrarily assigned, or stereochemistry of one chiral center is known and remaining chiral centers arbitrarily assigned, etc.). In some instances, the absolute stereo configuration of one or more chiral centers is assigned based on biological activity.

[0094] Table 1Compound # Structure\ ON1 FH2N r il l r / kA F < jN. < >— ' 0N2 FI F\ o\3 N0tF!NM| F'F' —1F33988-981 (P39387-WO-1)PCT< >— o N4o X 5\ o?=I I N> N> z zI z\ \ / o / o _ _ / x N— Ai— ' o N6Yr\ HFw?#n°W | TF1X 0zS^- c F ^ Iz (O> z\ / N7“nA HFH2NW JT1" / ~F NF ' —8933988-981 (P39387-WO-1)PCTX- < >— / 0 N10“rrh H tlY'NT / ^F1FX LL XXoXT < " 11 \ / L- oX N N <> zI 2E F\ / o _^n-n —< X-70 12 N / SA °\ Qx CHjF F / F< z\ / H o 13 NXX^ XNT ^F14Ox / \< >— / NX 0FN1533988-981 (P39387-WO-1)PCT< N >— ' 0 16H2NYN>C^IY; XV r\^ JL^ X ZYo " \ J ^Y> Y 17\ / ^oIz zT*\ / o _18YLb o^19N20C'YV\ J XXF? GNT TFN'< >— 0 21 N ^Y^YS rYHANYNXYN°Y YY F^F—33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1)PCTyy / CN N38c,rAH2NL A / ZNA TAz i Z2 \ O? T C A L CL <X39u.A ■ A) “- jC Oj OTI MM C z z XC *zz T 40 O r- o41 — / l o N42H2NOIXXA AXcZNA T AF\ / —0N43c,rr\ LA / I FF4633988-981 (P39387-WO-1)PCTN47H2NYNSYc'rAAiN\A0 / "-A TZFx? e 48 yy y □. -zI*N NO49H2NYNyc'rAAiXNAo / v^x H F / N-Z T ZFN NO50H2Nc,x / li ZFN NO51H2N “X / A LX / FTZFOH\ 7^ 0 52 N33988-981 (P39387-WO-1)PCT NC53 < >-^ 0 Nz\< >—J0 54 / NJN jl J Jf r\ W0GN>OH< / \ >— ' w 0 N55HF17?n°'6 OH / \< >— ' o 56 N rrlriS H YJ JN^(Y OH■- < >—< o N57y jN 0n OH33988-981 (P39387-WO-1)PCTFF— o / \NV < >— 0 58 NOTN 0GN>OH< >— ' 0 N59yTN 0GN>OH\ 0< >— * 0 60 NATy jN O^N;OHxA?61NC; / fYl x X H y jN° (y OHJ J F N62HFYy jn° (y OH33988-981 (P39387-WO-1)PCT< >— ' o 63 F N iQ jNOHF N64IJ JN° O OH, J3 F N65H y jON 0G HN>< / \ >—7 N~^ 0 66 F | NCi JOCS H IT;ON 0C HN>\ 7^ 0 67 / NU 1 1 J 1 r \ y fNOH33988-981 (P39387-WO-1)PCTE Fej i ' 68 V / Nli 1 1 1 A r\ Yy?n° <y OH< >—Jo F N69Vj jN°^YN>OHA70F / NAA^A^ f L1 JL A A r\ y jN° GN>OHF N71HFXT;N° GN>OH< >— ' 0 1N72 rf'^A N'^A^N f LXxA A r\ y jN 0< J OH33988-981 (P39387-WO-1)PCT,, J4 < >— o F i N73f l H z Y XJ fNOH\ Y 7^ 0 F i N74OHA < >— ' 0 F N75y FN 0GN>OH0^— * 0 F | N76eV H y TN 0GN>OHyx < >— / NA o F | N77ry H XJ JNOH33988-981 (P39387-WO-1)PCT0-^.NA\ < >— ' 0 78 F | Nt l A X A H OHF. F— ' 0 79 F N rSXxX X XX JN°'XN>OH F FA80 F i N Az N'A'^A / LXxA A r\ y jN 0XN>OH< y~* o F I N81C l AXA X y jN 0GN>OH F F< A o 82 F I N A / N" A''A J QAA A r\ YX iN° XN>OH33988-981 (P39387-WO-1)33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1)PCT94X OHF. F< >—J0 95F / N|l 1 jl J T YYAN°'"'O OH t0)< A ' 'l 0 F I N960,9? ^+ OH VF97 < 1 / X XNNJ L l i A A r\ y rN° <y OHA98 0 NH2N-X^NCI^Y hfAl?''''.'' ' • r — i 'FLXA AT r33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1)PCT116<3 / " \00 N117a T N> zCIIYI XH2Nv3N ^ \ / o / _ I^NAO / U )X?p t,. / " \ / Qfx 0 0 N117bClib6., HF<3 / " < z\ >— ' 0 O N118JH; N Nv«ykN^. J-A VM?FFo / '" O^--AbPk0H 119 Cix^X / L. FH2NtIT^033F33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1)PCT129aE F129b O NX I N> N> z z “YX r( ™TNT' JN“"(V \ / o _ / \ -130 / "" / 0 0 N131a< Jt O N131bh l V / — ( H2NYNrYNV> Q vXFTF33988-981 (P39387-WO-1)PCTA o3 / "■< o O N132a\ _ / 1TFyri <~ <9 / " < >— o O _ 7 L LL N 132bC(= \IoYMN y K2NI N>zM C zI1\ / o _ TFFt’. 133 \C U \.LCX ° Az134■50 N 135aCli6 Z XI J o T TF33988-981 (P39387-WO-1)PCT0 N135bH*NYNT>JN136X N> z / \ - F F" -. / FZ\NV / " \ z~“ ' o 137 O NCIY^YS _ / \vF / T fFF Fy / " \ 0 138a 0 N “Wy xH2" TNT\JN° (JF F / *\ z " ■ 0 138b O Nc'Vxtl r\H2NYNV JN33988-981 (P39387-WO-1)PCT\ / . N-S=O / " \zo O N139C,YYX HFH2NrrTN° oF FJ. ’ 140 O NCl / F UJ OI 7F / '"< >—Jo 0 N141H2NTNrc'i55TNH"6'0 N142c,:65 H X TIJ oFo V143HiNxY^"(?F33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1)PCTZ" \0O N163H2Nc,iYxw -■\ NH / " < Zf\HN^ o O N164CIYS5 X LXJ OT >FF F165a O N “lYx HFHiNYNrXN a<j FxF, _■ 0 / " \6 b N 7^1 5“lYi HFH> NTN'jGJN O" GN>16633988-981 (P39387-WO-1)PCT167 / '"\ <3^ 0 0 N168a I I M N> z -n z H I2 N> NCL- J H ) zF\ / Q _■ / — \?=-\, - ■■■ ■ 5m°^xy- V R (-.Ft-, \ 168b Qx Q^<yx o OFFt °,169 / " X < >— ' 0 170a 0 Nc,yx HFVk? P 01FF33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1)PCT186oV Vf" "W ' 187I N> y\= oz z I N> ho z zM C zi ^zI ^ ^=\z / \ - / o _= / \ - ’’< K'°M-'' 8 > H18 $><1 oI OX? XX ° V 1 0 „, / \ / =N Q N189C|XXM F X 1 5, H XXFf CNT TF19033988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1)PCT / " < / o O N221axxx o O T TF / i \ L<oii >w^4.< t.y %- \ _ / u_ u_u221b^ 6 \— ~I N> ( \= OzI IJ CN z < zX X'2 / \ - t O 222Qzx CKfV / "■< >— ' 0 0 N223clXrS JH2NxXyZow T YF22433988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1)PCT\ \ NH N-S=O O N245HFH2NTNX\JN°Wz246 I z N> N> N Z> z z\ \ / Q / o _ _X \ ' # TI m _I I o O \-,.\ F tvI i V I o- I / ~^ / , l O" H Y Yz°>\>» 247 / O2480ZN249C'^5 YFXXpfo T TF33988-981 (P39387-WO-1)PCT250aI o \ o V250bH2c,y°ksI I A o / N> N YNY / YS^ / ,'Y\X z z r JIFFXN < z^ y Tz / \ / — \ - - Fyy ’z N^I < y / " < >—7o O Ry y<> N251 CiXX,, \ F XXA.. r\ XXFJOT y25225333988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1)PCT. N-S=O O N269 FXLF NAN / NH2OZN As- F 270 \\\ / N / N^ J\ F ( ' —1\ " < >— ^ 0 0 N271FYFN^Y^N_ z IT F GNNH2 / "■G— b- O N272 FGF NAA / NH20.e NJi0F273NGANna° A33988-981 (P39387-WO-1)PCT / " < 7 >— * o F O N 4 274a 7 |l^717 J^jl 1 7 J r~~\ YX JNOHF O N274bOHNA / x A 275FAFv NA^'AvN7FNH27" <O < N3? O 276FAFNAVAN_ TNH20Z' 277 N-^A^N J ^ ■V7.-6> FT33988-981 (P39387-WO-1)PCTOZFXF NIA / 278FJ TNA NH2NA / \NA / " \ o O N279 FXLFNJANNH2NA / x Q V'V’' 280FAFNJANFUA ^ I? NH2AU / " \ z " O O N281 F-XF N JJN 7Fv V " JNH2ry-3 z\ jH O N282FJF N'Jf'J / T AA A r \ I I F GNNH233988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1) PCT33988-981 (P39387-WO-1)PCToz298 N'V'^N / FozFAFN\ANF299NH2F < G300 A I Ay^A"°'A A NH2NOZ' / A / " NAA J 301 [ A G A / .AAAN° A rK / \ XJ G OHF / "■ A< 0 302 O N AA^ N AAN / f A TAA lAA^N A / . A AM2 TJ G OHGz\ / N0ZN303FA NG N f G? Gy NH233988-981 (P39387-WO-1)PCT NA ) <' jXNv / " < >— ' o O N304 N4> AN_ z x y F G NH2305I N>z -n\ / y I _\z=jG " HO, m J.4 >" ■ < y— * o O N306aFXF_ z T A AG > A \ r\ X T f F t G NH2XX^ O-n\,^. z^Q Z" \ >— ■fo O N F V 1FF306b x|^F / FX iTGNNH230733988-981 (P39387-WO-1)PCTOZ' 308OH / 1" / \\ z-W 0 0 N309FXLFN'^Y'^N _ / ;ijr- NH2 / \ / NOZ310FXFN" V^N / NH2\ z" \ 7~~^ 0 0 N311FXLF N^MN / NH2J / / "■< >— ' o 0 N312NH233988-981 (P39387-WO-1)PCT< / \_ / 0H0ZNF A NZ / N313A?NA°W NH2A\ z\ A A O N314 FXFNZAN / A VNAOA NH2 / X N-Z OZhF ^ ° 315FNAXN_ Z A o / 'JT )FXJCJ W I FF\ Z\^NA O N316FXF NZAN / Fxr?z°w NH2\ N— Z'" \0 N0317 NAANJH2NN AA> C / Ar 633988-981 (P39387-WO-1)PCToz318FXFf A A A NH2F O N319 (XX' NAJAN / L X / kA A r\ W yn° CN>OHNAFOZ 0320NH2( / O <y>^ / NA 321NH2 / < / y^ o ^Ny 322NH2SYNTHESIS OF COMPOUNDS

[0095] Compounds or or pharmaceutically acceptable salts thereof as described herein of the present disclosure can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vol. 1-40. The synthetic reaction schemes provided herein are merely illustrative of some methods by which the compounds or pharmaceutical acceptable salts thereof described herein can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained herein.

[0096] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing compounds described herein and necessary reagents and intermediates include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0097] The Examples provide exemplary methods for preparing compounds or pharmaceutically acceptable salts thereof as described herein. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds or pharmaceutically acceptable salts thereof as described herein described herein. Although specific starting materials and reagents are depicted and discussed in the Examples, other starting materials and reagents can be substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry.

[0098] In preparing compounds or pharmaceutically acceptable salts thereof as described herein protection of remote functionality (e.g., primary or secondary amine) of intermediates can be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection can be readily determined. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0099] In the methods of preparing compounds or pharmaceutically acceptable salts thereof as described herein, it can be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps is separated and / or purified to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.

[0100] Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in thecase of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid / liquid ion extraction reagents (LIX), or the like. Selection of appropriate methods of separation depends on the nature of the materials involved, such as, boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like.

[0101] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds or pharmaceutically acceptable salts thereof as described herein described herein can be atropisomers (e.g., substituted biaryls). Enantiomers can also be separated by use of a chiral HPLC column.

[0102] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer can be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds or pharmaceutically acceptable salts thereof described herein can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: “Drug Stereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

[0103] Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. Thediastereomeric salts can be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.

[0104] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem. (1982) 47:4165), of the racemic mixture, and analyzing the1H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthylisoquinolines (WO 96 / 15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (“Chiral Liquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[0105] The chemical reactions described herein may be readily adapted to prepare other compounds and pharmaceutically acceptable salts thereof described herein. For example, the synthesis of non-exemplified compounds and pharmaceutically acceptable salts thereof described herein may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds and pharmaceutically acceptable salts thereof described herein.PHARMACEUTICAL FORMULATIONS

[0106] Also provided herein are pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable excipients.

[0107] Compounds or pharmaceutically acceptable salts thereof as described herein can be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Thus, further provided herein is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described herein as described herein and one or more pharmaceutically acceptable excipients.

[0108] A typical formulation is prepared by mixing a compound or pharmaceutically acceptable salt thereof as described herein and an excipient. Suitable carriers, diluents and excipients include, but are not limited to, materials such as carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular excipient used will depend upon the means and purpose for which the compound or pharmaceutically acceptable salt thereof as described herein is being applied. Solvents are generally selected based on solvents recognized as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0109] The formulations can be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound or pharmaceutically acceptable salt thereof as described herein or stabilized form thereof (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients describedabove. The compound or a pharmaceutically acceptable salt thereof as described herein is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.

[0110] The pharmaceutical composition (or formulation) for application can be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container can also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label can also include appropriate warnings.

[0111] Pharmaceutical formulations of the compound or a pharmaceutically acceptable salt thereof as described herein can be prepared for various routes and types of administration. For example, a compound or a pharmaceutically acceptable salt thereof having the desired degree of purity can optionally be mixed with one or more pharmaceutically acceptable excipients (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation can be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but can range from about 3 to about 8. For example, formulation in an acetate buffer at pH 5 can be a suitable embodiment.

[0112] The pharmaceutical composition ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.

[0113] The pharmaceutical compositions described herein can be formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the schedulingof administration, and other factors known to medical practitioners. The effective amount of the compound or a pharmaceutically acceptable salt thereof to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, or treat the hyperproliferative disorder.

[0114] As a general proposition, the initial pharmaceutically effective amount of the compound or a pharmaceutically acceptable salt thereof administered parenterally per dose will be in the range of about 0.01-100 mg / kg, namely about 0.1 to 20 mg / kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg / kg / day. In another embodiment, a pharmaceutical composition described herein comprises an effective amount of a compound or a pharmaceutically acceptable salt thereof described herein in an amount of about: 1mg-10mg; 10mg-25mg; 20mg-50mg; 50mg-75mg; 70mg-100mg;100mg-150mg; 100mg-200mg; 100mg-500mg; 200mg-500mg; 250mg-500mg; 500mg-1000mg; or 750mg-1000mg.

[0115] Acceptable pharmaceutically acceptable excipients are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The active pharmaceutical ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0116] The formulations include those suitable for the administration routes detailed herein. The formulations can conveniently be presented in unit dosage form and can be prepared by any methods. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0117] Formulations of a compound or a pharmaceutically acceptable salt thereof as described herein suitable for oral administration can be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of such compound or a pharmaceutically acceptable salt thereof. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs can be prepared for oral use. Formulations of compounds or pharmaceutically acceptable salts thereof as described herein intended for oral use can be prepared according to any method for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients can be, for example, inert diluents; granulating and disintegrating agents; and lubricating agents. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.METHODS OF ADMINISTRATION

[0118] Compounds or pharmaceutically acceptable salts thereof described herein can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. Where the compound or a pharmaceutically acceptable salt thereof is administered orally, it can be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient. Where the compound or a pharmaceutically acceptable salt thereof is administered parenterally, it can be formulated with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below.

[0119] Thus, in one aspect provided herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable excipients. In one embodiment, compounds or pharmaceutically acceptable salts thereof described herein are administered as pharmaceutical compositions capable of being administered to a subject orally or parenterally. The compounds or pharmaceutically acceptable salts thereof described herein can be formulated for topical or parenteral use where the compound or pharmaceutically acceptable salt thereof is dissolved or otherwise suspended in a solution suitable for injections, suspensions, syrups, creams, ointments, gels, sprays, solutions and emulsions.

[0120] Oral administration can promote patient compliance in taking the compound (e.g. formulated as a pharmaceutical composition), thereby increasing compliance and efficacy. Oral pharmaceutical compositions comprising a compound described herein include, but are not limited to, tablets (e.g. coated, non-coated and chewable) and capsules (e.g. hard gelatin capsules, soft gelatin capsules, enteric coated capsules, and sustained release capsules). Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Oral pharmaceutical compositions comprising a compound described herein can be formulated for delayed or prolonged release.

[0121] A dose to treat human patients can range from about 10 mg to about 1000 mg of a compound described herein. A typical dose can be about 100 mg to about 300mg of the compound. A dose can be administered once a day (QID), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. Administration as used herein refers to the frequency of dosing and not, for example, the number of individual units a patient described herein must take for a dose. Thus, in some embodiments, a patient may take two or more dosage units (e.g. two or more pills / tablets / capsules) QD. In addition, toxicity factors can influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet can be ingested daily or less frequently for a specified period of time. The regimen can be repeated for a number of cycles of therapy.METHODS OF TREATING AND USES

[0122] The compounds or or pharmaceutically acceptable salts thereof described herein are useful as Ras inhibitors. In one aspect, the compounds or pharmaceutically acceptable salts thereof described herein are useful as KRas inhibitors. In another embodiment, the compounds or pharmaceutically acceptable salts thereof described herein are useful as KRasG12V inhibitors. In such embodiments, such compounds are useful in the methods described herein where such cancer or disease is mediated by KRasG12V.

[0123] Provided herein are methods of contacting a cell, such as an ex vivo cell, with a compound or a pharmaceutically acceptable salt thereof described herein, to inhibit KRas activity in the cell. In another embodiment, the activity is mutant KRasG12V activity. In another embodiment, the activity is mutant KRas activity (e.g. mutant pan-KRas activity).

[0124] As used herein, inhibition of the activity of more than one KRas mutant is referred to as pan-KRas inhibition. In such instances, a compound or pharmaceutically acceptable salt thereof as described herein inhibits the activity of more than one mutant KRas protein. In certain instances, such compounds or pharmaceutically acceptable salts thereof selectively inhibit more than one mutant KRas protein relative to the wildtype (WT) KRas protein activity. In one such embodiment, a pan-KRas inhibitor as described herein and used in the methods provided herein inhibits more than one mutant KRas protein at least 5x, 8x, 10x, 12x, 15x, 20x, 24x, 27x, 50x, 100x, 500x, 700x, 1000x, 1300x, 1700x, 2000x, 5000x, or more greater than WT KRas protein. In one embodiment, such a KRas mutation is in the SWII domain. In one embodiment, such aKRas mutation corresponds to a change in the natural amino acid at the position corresponding to G12, G13, Q61, or A146. In some embodiments, the mutation corresponds to G12A, G12C, G12D, G12R, G12S, G12V, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V, or A146T.

[0125] Further provided herein are methods of treating a cancer comprising a KRas mutation, the method comprising administering to a patient having such cancer, an effective amount of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein. In one embodiment, the KRas mutation is a KRasG12Vmutation. In still another embodiment, the mutation is a known KRas mutation (e.g. treating with a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein that demonstrates pan-KRas inhibition).

[0126] In one embodiment, the methods further comprise testing a sample (e.g. as set forth herein) from the patient before administration of a compound of pharmaceutically acceptable salt thereof described herein for the absence or presence of a KRasG12Vmutation. In one such embodiment, a compound or a pharmaceutically acceptable salt thereof or pharmaceutical composition described herein is administered to the patient after the patient sample is determined to be positive for (e.g. the presence of) a KRas mutation. In one embodiment, the methods further comprise testing a sample (e.g. as set forth herein) from the patient before administration of a compound of pharmaceutically acceptable salt thereof described herein for the absence or presence of a KRas mutation, wherein the compound or pharmaceutically acceptable salt thereof or pharmaceutical composition described herein is administered to the patient after the patient sample is determined to be positive for (e.g. the presence of) such KRas mutation.

[0127] The methods of treating a cancer described herein relate to the treatment of cancer such as acute myeloid leukemia, cancer in adolescents, childhood adrenocortical carcinoma, AIDS-related cancers (e.g. lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, nonsmall cell lung cancer (NSCLC), oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancer.

[0128] In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendicial cancer, or pancreatic cancer. In one embodiment, the cancer is pancreatic cancer, lung cancer, or colon cancer. The lung cancer can be adenocarcinoma, non-small cell lung cancer (NSCLC), or small cell lung cancer (SCLC). In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is lung adenocarcinoma.

[0129] The methods provided herein can also comprise testing a sample from the patient before administration of a compound or a pharmaceutically acceptable salt thereof described herein for the absence or presence of a KRas mutation corresponding to the 12 position of KRas (e.g. Gly12). In one embodiment, a compound, or a pharmaceutically acceptable salt thereof or pharmaceutical composition is administered to the patient after the patient sample shows the presence of a KRas mutation corresponding to the 12 position of KRas (e.g. Gly 12). In one embodiment, a compound or a pharmaceutically acceptable salt thereof described herein is not administered unless a patient sample comprises a KRas mutation corresponding to the 12 position of KRas (e.g. Gly12).

[0130] The methods provided herein can also comprise testing a sample from the patient before administration of a compound or a pharmaceutically acceptable salt thereof described herein for the absence or presence of a KRasG12Vmutation. In one embodiment, a compound, or a pharmaceutically acceptable salt thereof or pharmaceutical composition is administered to the patient after the patient sample shows the presence of a KRasG12Vmutation. In one embodiment, a compound or a pharmaceutically acceptable salt thereof described herein is not administered unless a patient sample comprises a KRasG12Vmutation.

[0131] The methods provided herein can further comprise testing a sample from the patient before administration of a compound or a pharmaceutically acceptable salt thereof described herein for the absence or presence of a KRas mutation, where the compound or a pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition. In one embodiment, a compound, or a pharmaceutically acceptable salt thereof or pharmaceutical composition is administered to the patient after the patient sample shows the presence of a KRas mutation, where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition. In one embodiment, a compound or a pharmaceutically acceptable salt thereof described herein is not administered unless a patient sample comprises a KRas mutation, where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition.

[0132] In one embodiment, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In another embodiment, the pancreatic cancer, lung cancer, or colorectal cancer comprises a KRasG12Vmutation. In still another embodiment, the cancer is tissue agnostic but comprises a KRasG12Vmutation.

[0133] In another embodiment, the pancreatic cancer, lung cancer, or colorectal cancer comprises a KRas mutation. In one such embodiment, the cancer is tissue agnostic but comprises a KRas mutation. In such embodiments, the cancer can be treated as described herein with a compound or a pharmaceutically acceptable salt thereof described herein having pan-KRas inhibition.

[0134] In one embodiment of the methods of Ag1, Ag2, and Ag3, the patient is diagnosed with a cancer described herein. In another embodiment of the methods of Ag1, Ag2, and Ag3, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is taken before administration of any therapy. In another such embodiment, the sample is taken before administration of a compound or a pharmaceutically acceptable salt thereof described herein and after administration of another chemotherapeutic agent. In another embodiment of the methods of Ag1, Ag2, and Ag3, the compound or pharmaceutically acceptable salt thereof described herein is administered as provided herein (e.g. orally).

[0135] Also provided herein is a compound or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance. In another such embodiment, the compound or pharmaceutically acceptable salt thereof can be for the therapeutic treatment of a cancer comprising a KRasG12Vmutation. In still another such embodiment, the compound or pharmaceutically acceptable salt thereof can be for the therapeutic treatment of a cancer comprising a KRas mutation (e.g. corresponding to position Gly12) where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition.

[0136] Further provided herein is a compound or a pharmaceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of a cancer comprising a KRasG12Vmutation. Still further provided herein is a compound or a pharmaceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of a cancer comprising a KRas mutation (e.g. corresponding to position Gly12) where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition.

[0137] In one embodiment, a compound or a pharmaceutically acceptable salt thereof described herein is used in the preparation of a medicament for the therapeutic treatment of a cancer comprising a KRasG12Vmutation. In one embodiment, a compound or a pharmaceutically acceptable salt thereof described herein is used in the preparationof a medicament for the therapeutic treatment of a cancer comprising a KRas mutation (e.g. corresponding to position Gly12) where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition.

[0138] Still further provided herein are uses of a compound or a pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for inhibiting tumor metastasis.

[0139] Further provided herein are methods for inhibiting tumor metastasis, the method comprising administering to a patient having a tumor a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described herein. In one embodiment, the inhibition is of a tumor comprising a KRasG12Vmutation. In one embodiment, the inhibition is of a tumor comprising a KRas mutation (e.g. corresponding to position Gly12) where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition. In another embodiment, inhibiting tumor metastasis in a patient described herein results in reduction of tumor size. In another embodiment, inhibiting tumor metastasis in a patient described herein results in stabilizing (e.g. no further growth) of tumor size. In another embodiment, inhibiting tumor metastasis in a patient described herein results in remission of the cancer and / or its symptoms.

[0140] Further provided herein are methods for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound or a pharmaceutically acceptable salt thereof described herein. In one embodiment, the cell population is in a human patient. In another embodiment, the cell population comprises a KRasG12Vmutation. In another embodiment, the cell population comprises a KRas mutation (e.g. corresponding to position Gly12) where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition.

[0141] Further provided herein are methods of inhibiting KRas in a patient in need of therapy, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described herein. In one embodiment, the KRas inhibited is KRasG12V. In one embodiment, the KRas inhibited is a mutant KRas protein (e.g. corresponding to position Gly12) where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition. In another embodiment, inhibiting KRas results in decreased tumor size. Inanother embodiment, inhibiting KRas results in remission of the cancer and / or its symptoms.

[0142] Further provided herein are methods for regulating activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound or a pharmaceutically acceptable salt thereof described herein. In one embodiment, the mutant protein comprises a KRasG12Vmutation. In one embodiment, the mutant protein comprises a KRas mutation where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition. In one embodiment, the activity of KRas is decreased after contacting with a compound or a pharmaceutically acceptable salt thereof described herein. In another embodiment, the downregulation of activity of the KRas mutant protein treats a cancer described herein in a patient described herein. In another embodiment, the downregulation of activity of the KRas mutant protein results in decreased tumor size. In another embodiment, the downregulation of activity of the KRas mutant protein results in remission of a cancer described herein and / or its symptoms.

[0143] In some embodiments, the methods provided herein comprise inhibiting KRasG12Vactivity in a cell by contacting said cell with an amount of a compound or a pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRasG12Vin said cell. In some embodiments, the methods provided herein comprise inhibiting KRasG12Vactivity in a tissue by contacting said tissue with an amount of a compound or a pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRasG12Vin said tissue. In some embodiments, the methods provided herein comprise inhibiting KRasG12Vactivity in a patient described herein by contacting said patient with an amount of a compound or a pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRasG12Vin said patient.

[0144] In some embodiments, the methods provided herein comprise inhibiting mutant KRas (e.g. mutation at Gly12) activity in a cell by contacting said cell with an amount of a compound or a pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of mutant KRas (e.g. mutation at Gly12) in said cell. In some embodiments, the methods provided herein comprise inhibiting mutant KRas (e.g. mutation at Gly12) activity in a tissue by contacting said tissue with an amount of a compound or a pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of mutant KRas (e.g. mutation at Gly12) in said tissue. In some embodiments, the methods provided herein comprise inhibiting mutant KRas (e.g.mutation at Gly12) activity in a patient described herein by contacting said patient with an amount of a compound or a pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of mutant KRas (e.g. mutation at Gly12) in said patient. In such embodiments, it is understood that the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition.

[0145] Further provided herein are methods for preparing a labeled KRasG12Vmutant protein, the method comprising reacting a KRasG12Vmutant protein with a labeled compound or a pharmaceutically acceptable salt thereof described herein to result in the labeled KRasG12Vmutant protein. In one embodiment, the label is an imaging agent. In one embodiment, the labeled KRasG12Vcan be used to detect the absence or presence of KRasG12Vmutant protein in a patient sample, thereby detecting the presence or absence of a cancer mediated by mutant KRas.

[0146] Further provided herein are methods for preparing a labeled KRas mutant protein (e.g. mutation at Gly12), the method comprising reacting a KRas mutant protein with a labeled compound or a pharmaceutically acceptable salt thereof described herein, where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition, to result in the labeled KRas mutant protein. In one embodiment, the label is an imaging agent. In one embodiment, the labeled mutant KRas protein can be used to detect the absence or presence of mutant KRas in a patient sample, thereby detecting the presence or absence of a cancer mediated by mutant KRas.

[0147] Still further provided herein are methods of inhibiting Ras-mediated cell signaling. In one embodiment, the methods comprise contacting a cell with an effective amount of one or more compounds or pharmaceutically acceptable salts thereof disclosed herein thereof. Inhibition of Ras-mediated signal transduction can be assessed and demonstrated by a wide variety of ways known in the art. Non-limiting examples include a showing of (a) a decrease in GTPase activity of Ras; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in K off of GTP or a decrease in K off of GDP; (d) a decrease in the levels of signaling transduction molecules downstream in the Ras pathway, such as a decrease in pMEK level; and / or (e) a decrease in binding of Ras complex to downstream signaling molecules including but not limited to Raf. Kits and commercially available assays can be utilized for determining one or more of the above.

[0148] KRas mutations have also been identified in hematological malignancies (e.g., cancers that affect blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments are directed to administration of a disclosed compound or pharmaceutically acceptable salt thereof (e.g., in the form of a pharmaceutical composition) as described herein to a patient in need of treatment of a hematological malignancy. Such malignancies include, but are not limited to leukemias and lymphomas. For example, the presently disclosed compounds can be used for treatment of diseases such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL) and / or other leukemias. In other embodiments, the compounds or a pharmaceutically acceptable salt thereof described herein are useful for treatment of lymphomas such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0149] Determining whether a tumor or cancer comprises a KRas mutation as described here can be undertaken by assessing the nucleotide sequence encoding the KRas protein, by assessing the amino acid sequence of the KRas protein, or by assessing the characteristics of a putative KRas mutant protein. The sequence of wildtype human KRas (e.g. Accession No. NP203524) is known in the art.

[0150] Methods for detecting a mutation in a KRas nucleotide sequence are known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some embodiments, samples are evaluated for KRas mutations described herein by real-time PCR. In real-time PCR, fluorescent probes specific for the KRas mutation are used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRas mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and / or exon 3) in the KRas gene. This technique will identify all possible mutations in the region sequenced.

[0151] Methods for determining whether a tumor or cancer comprises a KRas mutation described herein can use a variety of samples. In some embodiments, thesample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA.

[0152] Further provided herein are uses of a compound or a pharmaceutically acceptable salt thereof described herein, in the manufacture of a medicament for treating cancer. In some embodiments, the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for injection. In some embodiments, the cancer comprises a KRasG12Vmutation. In some embodiments, the cancer comprises a KRas mutation (e.g. mutation at Gly 12) where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In some embodiments, are uses of a compound or a pharmaceutically acceptable salt thereof described herein, in the manufacture of a medicament for inhibiting tumor metastasis.

[0153] Further provided herein is a compound or a pharmaceutically acceptable salt thereof described herein, for use in a method of treating cancer. In one embodiment, the cancer comprises a KRasG12Vmutation. In one embodiment, the cancer comprises a KRas mutation (e.g. mutation at Gly12) where the compound or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibition In one such embodiment, the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer. In one such embodiment, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In one such embodiment, the cancer is colorectal cancer. In one such embodiment, the cancer is pancreatic cancer. In one such embodiment, the cancer is lung adenocarcinoma.ARTICLES OF MANUFACTURE

[0154] Also provided herein are articles of manufacture, or "kit", containing materials useful for the treatment of a cancer provided herein. In one embodiment, the kit comprises a container comprising a compound or a pharmaceutically acceptable salt thereof described herein. The kit may further comprise a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials,syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound or a pharmaceutically acceptable salt thereof described herein or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound or a pharmaceutically acceptable salt thereof described herein. Alternatively, or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution or dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0155] In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound or a pharmaceutically acceptable salt thereof described herein, such as tablets or capsules. Such a kit can include a number of unit dosages. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.EXAMPLES

[0156] For the NMR peak lists provided, some proton peaks may be missing due to overlapping with solvent peaks.

[0157] Cross Scaffold Intermediates

[0158] Intermediate IHO-*,step a TBSO-Ostep bTBSO-'yyP”step cJi-I - ► A-l - ► N— I - ►Boc Boc BocTBSO — > stepdTBSO __,s'Fstep e HO \R ZNJ- OBocBoczBocz

[0159] Intermediate I. tert-butyl (2R,3R)-3-fluoro-2-(hydroxymethyl)azetidine-1-carboxylate.

[0160] Step a: tert-butyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]azetidine-1-carboxylate

[0161] To a dry 100 ml_ round-bottom flask equipped with a magnetic stirring rod was added tert-butyl (2S)-2-(hydroxymethyl)azetidine-1 -carboxylate (2.03 g, 10.8 mmol) and imidazole (1.77 g, 26.0 mmol), which was then dissolved in DCM (35 mL). To this solution was added tert-butyldimethylchlorosilane (3.35 g, 21.6 mmol) and then the reaction mixture was allowed to stir at room temperature for 20 h. After this time, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (30 mL) and water (30 mL), and diluted with DCM (30 mL). The aqueous layer was separated from the organics and washed with DCM (2 x 30 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash silica gel chromatography (gradient 0-30% IPrOAc in heptane) afforded tert-butyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]azetidine-1 -carboxylate (3.481 g, 11.55 mmol, 106% yield) as a colorless oil.1H NMR (400 MHz, CDCl3, ppm) 6 4.21 (s, 1H), 3.92 (br s, 1H), 3.77 (t, J = 8.0 Hz, 2H), 3.65 (d, J = 10.9 Hz, 1H), 2.17 (q, J = 7.4 Hz), 1.43 (s, 9H), 0.90 (s, 9H), 0.06 (s, 6 H).

[0162] Step b: tert-butyl (2R,3S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-hydroxy-azetidine-1 -carboxylate

[0163] To a dry 2-dram vial equipped with a stirbar was added bis(1,5-cyclooctadiene)dimethoxydiiridium (113 mg, 0.167 mmol), 2-methyl-1,10-phenanthroline (67.6 mg, 0.331 mmol), tert-butyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]azetidine-1 -carboxylate (1.10 ml_, 3.23 mmol), and bis(pinacolato)diboron (2.74 g, 10.5 mmol). T o this mixture was added freshly degassed cyclooctane (5 mL). The reaction mixture was allowed to stir at 100 °C for 64 h. After this time, the reaction mixture was allowed to cool to room temperature and then diluted with Et2O (30 mL). The reaction mixture was cooled to 0 °C and treated dropwise with 1:1 v / v 15% aq NaOH and 30% aq H2O2(40 mL). The mixture was then allowed to stir at 0 °C for 0.5 h. After this time, the reaction mixture was diluted with water (50 mL), brine, (50 mL), sodium thiosulfate (50 mL) and Et2O (50 mL). The aqueous layer was separated from the organic layer and washed with Et2O (2 x 30 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash silica gel chromatography (gradient 0-100% IPrOAc in heptane) afforded tert-butyl (2R,3S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-hydroxy-azetidine-1 -carboxylate (539 mg, 1.70 mmol, 52.6% yield) as a pale yellow oil. LC-MS: (ESI, m / z): [M+H]+= 317.95.

[0164] Step c: (2R,3S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3- (trifluoromethylsulfonyloxy)azetidine-1-carboxylate

[0165] To a dry 2-dram vial equipped with a stirbar was added tert-butyl (2R,3S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-hydroxy-azetidine-1 -carboxylate (500 mg, 1.57 mmol), which was dissolved in DCM (5 mL). 2,6-lutidine (0.370 ml_, 3.15 mmol) was then added to this solution. This solution was then cooled to -40°C (dry ice I MeCN bath) and then treated dropwise with trifluoromethanesulfonic anhydride (0.290 ml_, 1.73 mmol). The solution was allowed to stir at -40°C for 1 h. After this time, the reaction mixture was diluted with Et2O (50 mL) and then washed with 1 M aq HCl (2 x 20 mL) and water (20 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash silica gel chromatography (gradient 0-30% IPrOAc in heptane) afforded fert-butyl (2R,3S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(trifluoromethylsulfonyloxy)azetidine-1 -carboxylate (632 mg, 1.41 mmol, 89.3% yield) as a colorless oil. LC-MS: (ESI, m / z): [M+H]+= 450.0.

[0166] Step d: tert-butyl (2R,3R)-3-fluoro-2-(hydroxymethyl)azetidine-1-carboxylate

[0167] To a dry 8-dram vial equipped with a stirbar was added tert-butyl (2R,3S)- 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(trifluoromethylsulfonyloxy)azetidine-1-carboxylate (301 mg, 0.670 mmol), which was then dissolved in THF (5 mL). This solution was cooled to 0 °C and then tetrabutylammonium fluoride (2.5 ml_, 2.5 mmol, 1 M in THF) was added. The reaction mixture was allowed to warm to room temperature and allowed to stir for 2.5 h. After this time, the reaction mixture was filtered through a plug of silica gel eluting with 7:3 IPrOAc: heptane (10 mL) and then concentrated under reduced pressure. Purification by flash silica gel chromatography (gradient 0-70% IPrOAc in heptane) afforded tert-butyl (2R,3R)-3-fluoro-2-(hydroxymethyl)azetidine-1-carboxylate (87.8 mg, 0.428 mmol, 63.9% yield) as a colorless oil. LC-MS: (ESI, m / z):[M+H]+= 206.0.

[0168] Step e: tert-butyl (2R,3R)-3-fluoro-2-(hydroxymethyl)azetidine-1-carboxylate.

[0169] To a dry 2-dram vial equipped with a stirbar was added tert-butyl (2R,3R)- 3-fluoro-2-(hydroxymethyl)azetidine-1 -carboxylate (132 mg, 0.643 mmol), which was then dissolved in THF (3 mL). The reaction mixture was cooled to 0 °C and then treated dropwise with lithium aluminum hydride (0.640 mL, 1.29 mmol, 2 M in THF). Thereaction mixture was allowed to stir at 0 °C for 10 min, and then allowed to warm to room temperature and stir for 1 h. After this time, the reaction mixture was cooled to 0 °C and diluted with Et2O (10 mL). The reaction mixture was treated successively with water (50 pL), 15% aq NaOH (50 pL), and water (150 pL) and then the mixture was allowed to warm to room temperature and stir for 15 min. After this time, the reaction mixture was dried over magnesium sulfate, filtered, and cautiously concentrated under reduced pressure. The crude product [(2R,3R)-3-fluoro-1-methyl-azetidin-2-yl]methanol was used directly in the next step without further purification.

[0170] Intermediate 2_pPMBXOPMBstep a step bstep c

[0171] Intermediate 2: ((3S)-3-((4-methoxybenzyl)oxy)-1-azabicyclo[3.2.0]heptan-5-yl)methanol

[0172] Step a: 1 -(tert-Butyl) 2-methyl (2S,4S)-4-((4-methoxybenzyl)oxy)pyrrolidine-1,2-dicarboxylate

[0173] To a solution of 01-tert-butyl O2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (20.0 g, 81.5 mmol) in A / , A / -dimethylformamide (40 mL) was added sodium hydride (4.90 g, 122.5 mmol) at 0 °C. The reaction mixture was stirred for 30 min at the same temperature. Then alpha-chloro-4-methoxytoluene (16.5 g, 105.4 mmol) was added at 0 °C and stirred for 1 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layers were combined. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (68:32) to afford the title compound (25.00 g, 83.9 % yield) as a yellow oil. LCMS (ESI): [M+H]+= 366.0.

[0174] Step b: 1 -(terf-Butyl) 2-methyl (2R,4S)-2-(2-chloroethyl)-4-((4-methoxybenzyl)oxy)pyrrolidine-1,2-dicarboxylate

[0175] Under nitrogen, to a solution of 01-tert-Butyl O2-methyl (2S,4S)-4-((4-methoxyphenyl)methoxy)pyrrolidine-1,2-dicarboxylate (12.2 g, 33.4 mmol) in THF (100mL) was added 2 M LDA in THF (100 ml_, 200 mmol), and the reaction mixture was stirred for 1 h at -78 °C. Then 1-bromo-2-chloroethane (20.8 ml_, 250.3 mmol) and HMPA (59.8 g, 333.7 mmol) were added and stirred for 6 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (20 - 40%) to afford the title compound (4.4 g, 30.8% yield) as a yellow oil. LCMS (ESI): [M+H]+= 450.0.

[0176] Step c: Methyl (2R,4S)-2-(2-chloroethyl)-4-((4-methoxybenzyl)oxy)pyrrolidine-2-carboxylate

[0177] A solution of 01-terf-butyl O2-methyl (2R,4S)-2-(2-chloroethyl)-4-((4-methoxyphenyl)methoxy)pyrrolidine-1,2-dicarboxylate (1.60 g, 3.70 mmol), 2,6-di-tert-butylpyridine (2.46 ml_, 11 mmol) and trimethylsilyl trifluoromethanesulfonate (0.88 ml_, 4.86 mmol) in dichloromethane (20 mL) was stirred for 1 h at room temperature. The organic layer was quenched with water and concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (910 mg, 74.2% yield) as a yellow oil. LCMS (ESI): [M+H]+= 328.1.

[0178] Step d: Methyl (3S,5S)-3-((4-methoxybenzyl)oxy)-1-azabicyclo(3.2.0)heptane-5-carboxylate

[0179] A solution of methyl (2R,4S)-2-(2-chloroethyl)-4-((4-methoxyphenyl)methoxy)pyrrolidine-2-carboxylate (900 mg, 2.75 mmol) and potassium carbonate (1.10 g, 8.14 mmol) in acetonitrile (12 mL) was stirred at 85 °C for 1 h. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10-15%) to afford the title compound (700 mg, 87.5% yield) as a yellow oil. LCMS (ESI): [M+H]+= 292.1.

[0180] Step e: ((3S)-3-((4-Methoxybenzyl)oxy)-1-azabicyclo(3.2.0)heptan-5-yl)methanol

[0181] A solution of methyl (3S)-3-((4-methoxyphenyl)methoxy)-1-azabicyclo(3.2.0)heptane-5-carboxylate (700 mg, 2.40 mmol) and aluminum lithium hydride (1.9 mL, 4.75 mmol) in THF (15 mL) was stirred for 1 h at 0 °C. The reaction mixture was quenched with sodium sulfate decahydrate. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (500 mg, 79 % yield)as a yellow oil. The crude product was directly used in the next step without purification. LCMS (ESI): [M+H]+= 264.0.

[0182] Intermediate IIIMe Me Me MeOH

[0183] Intermediate III. (5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid.

[0184] Step a: 5-bromo-2-fluoro-3-methylbenzoic acid

[0185] 4-bromo-1-fluoro-2-methylbenzene (2 kg, 10.5 mol) was dissolved in THF (6L), under N2, and cooled to – 78 °C before the dropwise addition of LDA (2.0M in THF, 10.5L, 21 mol). The reaction mixture was stirred for 1h. A second vessel was charged with THF (6L) before the addition of solid CO2. Upon complete dissolution of CO2, the solution of the first reaction vessel was added dropwise and the mixture stirred for 2h before being quenched with saturated NH4CI. The pH was adjusted to <7 with 2 M HCI and the reaction mixture was concentrated under vacuum. The mixture was filtered and washed with petroleum ether / dichloromethane (95%:5%) to provide the title compound as a white solid (10.5 kg, 42.3%) LCMS (ESI): [M+H]+=188.0.

[0186] Step b: tert-butyl (5-bromo-2-fluoro-3-methylphenyl)carbamate

[0187] A reaction vessel was charged with 5-bromo-2-fluoro-3-methylbenzoic acid (950g, 4.1 mol) dissolved in toluene (4.75 L). To the mixture was added t-BuOH (3039g, 41 mol) and triethylamine (1242g, 12.3 mol). The reaction mixture was warmed to 80 °C before DPPA (1300g, 4.72 mol) in toluene (1 L) was added slowly at 85 °C. The reaction mixture was stirred for 1 h, cooled to room temperature, and concentrated to dryness. Ethyl acetate was then added. The crude reaction mixture was washed with saturated sodium bicarbonate three times. The aqueous layer was removed, and the organic layer was concentrated to yield 960 g of a yellow solid that was used without further purification. LCMS (ESI): [M+H]+=305.2.

[0188] Step c: 5-bromo-2-fluoro-3-methylbenzenaminium chloride

[0189] Tert-butyl (5-bromo-2-fluoro-3-methylphenyl)carbamate (1.9 kg, 6.24 mol) was dissolved in a solution of HCI in dioxane (4M, 19L). The reaction mixture was stirred for 24h at room temperature, filtered, and dried under vacuo to yield 1.03 kg of a white solid that was used in the next step without further purification. LCMS (ESI):[M+H]+=241.5.

[0190] Step d: 5-bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-3-methylaniline

[0191] 5-bromo-2-fluoro-3-methylbenzenaminium chloride (800 g, 3.3 mol) and PMBCI (1302 g, 8.25 mol) were dissolved in DMF (8L) and cooled to -10 °C. To the reaction mixture was added solid t-BuOK (1493 g, 13.2 mol) at the same temperature, and the reaction mixture was allowed to warm to 0 °C and stir for 1 h. Ethyl acetate was added at room temperature and the organic layer was washed with water three times. The combined organic layer was concentrated to dryness and EtOH was added at 0 °C. The resulting precipitate was filtered and dried to yield 720 g of a white solid that was used without further purification. LCMS (ESI): [M+H]+=445.3.

[0192] Step e: 5-bromo-2-fluoro-4-iodo-N, N-bis(4-methoxybenzyl)-3-methylaniline

[0193] 5-bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-3-methylaniline (1.1 kg, 2.47 mol) and N-iodosuccinimide (836 g, 3.7 mol) were dissolved in EtOH (5.5L). The reaction mixture was cooled to -10 °C before the addition of TsOH (43 g, 0.247 mol). The reaction mixture was stirred for 1h at -10 °C, after which it was warmed to room temperature, and quenched with saturated sodium thiosulfate (2.2L). The reaction mixture was filtered before the addition of water (5.5L). The reaction mixture was again filtered and a solution of EtOH / Ethyl Acetate (10:1, 5.5L) was added before the resulting suspension was filtered and dried to yield 1.19 kg of a white solid that was used without further purification. LCMS (ESI): [M+H]+=571.2.

[0194] Step f: 5-bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-3-methyl-4- (trifluoromethyl)aniline

[0195] 5-bromo-2-fluoro-4-iodo-N, N-bis(4-methoxybenzyl)-3-methylaniline (1.33 kg 2.33 mol) and Cui (889 g, 4.66 mol) were dissolved in DMF (6.7L, 5V) before the addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.1 kg, 16.3 mol). The reaction mixture was warmed to 70 °C. After stirring for 10h, the reaction mixture was cooled to room temperature, and MTBE (13.3L) was added. The reaction mixture was washed with NH4OH (6.7L, 12% w / w) two times and brine (4L) three times. The organic layerwas concentrated and purified by silica gel chromatography (ethyl acetate: n-heptane=50: 1 ) to give the final product as a solid (1.02g, 81.3%). LCMS (ESI): [M+H]+=513.3.

[0196] Step g: (5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2- (trifluoromethyl)phenyl)boronic acid

[0197] Under nitrogen, to a solution of 5-bromo-2-fluoro-A / , A / -bis(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)aniline (5.0 g, 9.76 mmol) in tetrahydrofuran (60 mL) was added 2.5 M n-butyl lithium in hexane (5.07 ml_, 12.66 mmol) at -78 °C. The reaction mixture was stirred for 30 min at the same temperature. Then triisopropyl borate (3.38 ml_, 14.64 mmol) was added and the mixture was stirred at -78 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride and extracted with dichloromethane. The organic layers were combined, and the solvent was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (0-30%), to afford the title compound (4 g, 85.9% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 478.2.

[0198] Untethered Quinazolines

[0199] Intermediates I and IIIntermediate I Intermediate II

[0200] Step a: tert-butyl (S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1 -carboxylate

[0201] A reactor was charged with tert-butyl (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1 -carboxylate (42g, 0.09 mol) and purged with argon for 15 min. THF (200 mL) was added and the reaction mixture was cooled to -70 °C before the addition of isopropylmagensium chloride lithium chloride complexsolution (1.14M in THF, 80 ml_, 0.90 mol), which was stirred. After 30 min, zinc chloride (50g, 0.09 mol) was added at -70 °C via syringe pump over 1h with stirring to give a reddish brown suspension. After complete addition, the suspension was warmed to 10 °C over 80 min to give a brown solution. Sodium trifluoroacetate (32.6g, 0.24 mol) was added as a solid in 5-6 portions over a period of 45min-1h, and after addition was complete, the brown suspension was heated to 50 °C over 40 min. A separate reaction vessel was charged with 6-bromo-N, N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (39.6g, 0.08 mol) and flushed with argon for 15 min before the addition of THF (72 mL). This solution was transferred via cannula into the reactor and the transfer vessel was rinsed with additional THF (8 mL). The reaction mixture was stirred for 5-15 min at 50 °C. A third reaction vessel was charged with palladium (-cinnamyl) chloride dimer (210 mg, 0.4 mmol) and (R, R)-chiraphite (772 mg, 0.88 mmol) and purged with argon for 15 minutes before the addition of THF (16 mL). The resulting yellow solution was transferred into the reactor via syringe. The solution was stirred at 50 °C until consumption of starting material, at which point the solution was cooled to 20 °C and added to a solution of trisodium citrate dehydrate solution (20% w / w, 600g) and toluene (710 mL). After stirring for 15 min at ambient temperature, the aqueous phase was removed and additional trisodium citrate dehydrate solution (20% w / w, 300g) was added. The reaction mixture was stirred and the aqueous phase was removed. Water (100 mL) was added and the aqueous phase was removed. The reaction mixture was concentrated under vacuum to a volume of 300 ml_ before the remaining water and THF was replaced by distillation at a constant volume under vacuum with tolulene (200 mL). The vacuum distillation was stopped and the organic phase drained into a Schott bottle. The reactor was rinsed with toluene (20 ml) and the resulting solution was filtered over charcoal (Zetacarbon R55SP, 2.6g) over 1 h at 50 °C, rinsing with toluene (40 mL). The resulting solution was heated to 50 °C and concentrated to 150 ml_ under vacuum. After cooling to ambient temperature, product seeding crystals (80 mg) and n-heptane (440 mL) were added, and the mixture stirred for 1h. Additional n-heptane (440 mL) was added over 2h and the suspension was stirred for 12h. The resulting crystals were filtered and washed with n-heptane / toluene (1:1, 100 mL) three times before the crude product was dried at room temperature under vacuum. The resulting filter cake was dissolved in toluene (250 mL) and placed in a reactor that was heated to 50 °C. The solution was concentrated to 150 ml_ under vacuum and cooled to ambient temperature. Over a period of 10 min, n-heptane (25 mL) and product seeding crystals (40 mg) were added, and the mixture was stirred for1h. Additional n-heptane (275 mL) was added over 2h and the suspension was stirred overnight at ambient temperature. The resulting crystals were filtered and washed with n-heptane / toluene (1:1, 100 mL) three times, and dried under vacuum at 50 °C to provide the title compound as yellow to light brown crystals (50.1g, 66.8% yield, >99:1 d.r.). LCMS (ESI): [M+H]+=813.4.

[0202] Step b: tert-butyl (S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1 -carboxylate

[0203] To a solution of ((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methanol (660 mg, 4.15 mmol) in THF (20 mL) was added NaH (330 mg, 8.25 mmol) at 0 °C under nitrogen. The resulting mixture was stirred at 0 °C for 10 min. Then tertbutyl (3S)-4-(7-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-6-chloro-2,8-difluoro-quinazolin-4-yl)-3-methyl-piperazine-1 -carboxylate (2.2 g, 2.71 mmol) was added and the reaction mixture as stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NH4CI. The resulting solution was extracted with ethyl acetate (3 × 50 mL). The organic layers were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (83:17) to provide the title compound (1.87 g, 72.6% yield) as a yellow solid. LCMS (ESI): [M+H]+=952.5.

[0204] Intermediate I: (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one

[0205] To a mixture of tert-butyl (3S)-4-(7-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-6-chloro-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy)quinazolin-4-yl)-3-methyl-piperazine-1 -carboxylate (2.2 g, 2.3 mmol) in dimethyl sulfoxide (20 mL) was added sodium hydroxide (1.0 g, 24.4 mmol) in water (4 mL). The mixture was stirred for 1h at 60 °C. LC-MS showed the product formed and SM was consumed. The reaction mixture was quenched with water (50 mL). The resulting solution was extracted with ethyl acetate (3 x50 mL). The organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase eluting with acetonitrile / 10 mmol NH4HCO3in water (1:1). This resulted in (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin- 4(3H)-one (1.05 g, 59% yield) as a yellow solid. LCMS (ESI): [M+H]+= 770.2.

[0206] Intermediate II: (R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one

[0207] A solution of (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (2.9 g, 3.77 mmol) in trifluoroacetic acid (20 mL) was stirred at 60 °C for 2h. After completion, the solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography eluting with aceton itrile / water (1:10) to afford the title compound (1.7 g, 85.2% yield) as a white solid.

[0208] Intermediate IIIstep bIntermediate III

[0209] Intermediate III. (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-ol

[0210] Step a: 7-bromo-6-chloroquinazoline-2,4(1H,3H)-dione

[0211] A reaction vessel was charged with 2-amino-4-bromo-5-chlorobenzoic acid (200g, 798 mmol) and urea (719.3g, 12 mmol, 642 mL) and heated to 200 °C for 1h. The reaction mixture was cooled to 90° C and hot H2O (1L) was added to the mixture. The reaction mixture was then stirred for 30 min at 90 °C. The reaction mixture was filtered at 90 °C and the cake washed with hot water (800 ml_ x 4) at the same temperature. Following trituration with MeOH (2L) at room temperature for 30 min, themixture was filtered, and the crude product triturated with 1 M NaOH (18.7L) and filtered. After the filter cake was adjusted to pH 7 with 6 M HCI (300 mL), the mixture was filtered and the cake triturated with MeOH (10L). The mixture was filtered and the filter cake was dried in vacuum to give the title compound as a pale yellow solid (460 g, 83.7% yield). LC-MS: (ESI, m / z): [M+H] = 274.0.

[0212] Step b: 7-bromo-2,4,6-trichloroquinazoline

[0213] To a reaction vessel with POCl3(1580 mL) was added 7-bromo-6-chloroquinazoline-2,4(1 H,3H)-dione (316 g, 1.15 mmol). A / , A / -dimethylaniline (417 g, 3.44 mol) was added drop-wise at 10-30 °C and the resulting mixture was stirred at 105 °C for 5h. The reaction mixture was concentrated and the residue was poured onto ice water (2L) slowly with stirring. The mixture was filtered, the filter cake dissolved in 2 L of dichloromethane, and the organic layer was washed with brine (500 ml_ x 2) and dried over Na2SO4. The organic layer was concentrated to give the title compound as a brown solid (408g, 67.8% yield, 69% purity). LC-MS: (ESI, m / z): [M+H] = 310.7.

[0214] Step c: 7-bromo-2,6-dichloro-N, N-dimethylquinazolin-4-amine

[0215] 7-bromo-2,4,6-trichloroquinazoline (408g, 1.31 mol) was dissolved in THF (2.5 L) followed by NMe2(2M, 522 mL) and DIPEA (337.6g, 455 mL) and the reaction mixture was stirred at room temperature for 1h. The reaction mixture was filtered and the filter cake rinsed with THF (1L). The filter cake was triturated with H2O (2 L) and MeCN (1 L) and filtered. The filter cake was dried under vacuum to give the title compound as a yellow solid (222 g, 53% yield). LC-MS: (ESI, m / z): [M+H] = 319.9.

[0216] Step d: 7-bromo-6-chloro-2-fluoro-N, N-dimethylquinazolin-4-amine

[0217] 7-bromo-2,6-dichloro-N, N-dimethylquinazolin-4-amine (152 g, 473 mmol) and dimethyl amine (912 mL) were placed in a reaction vessel and CsF (143.86g, 947 mmol, 34.92 mL) was added. The reaction mixture was stirred at 110 °C for 26 h, poured into ice-water (2 L) and stirred at room temperature for 30 min. The reaction mixture was filtered and the filter cake triturated with MeCN (1 L), filtered and dried to give the title compound as a yellow solid (122g, 84.6% yield). LC-MS: (ESI, m / z): [M+H] = 303.9.

[0218] Step e: (S)-7-bromo-6-chloro-N, N-dimethyl-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-amine

[0219] (S)-(1-methylpyrrolidin-2-yl)methanol (44.3g, 384 mmol) was dissolved in THF (900 mL) under nitrogen gas. NaH (17.7g, 443.3 mmol, 60% w / w) was added at 0°C. The resulting mixture was stirred for 30 min at room temperature before the addition of 7-bromo-6-chloro-2-fluoro-N, N-dimethylquinazolin-4-amine (90g, 295.5 mmol) at 0 °C. The mixture was stirred at 40 °C for 3h before being poured into ice-water (2 L) and stirred for 5 min. The aqueous phase was extracted with EtOAc (2 L x 3) and the combined organic layers were washed with brine (1.5 L), dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was triturated with EtOAc and filtered, and the filter cake was concentrated in vacuum to provide the title compound as a yellow solid (100g, 84.7% yield). LC-MS: (ESI, m / z): [M+H] = 399.0.

[0220] Step f: (S)-6-chloro-N, N-dimethyl-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine

[0221] (S)-7-bromo-6-chloro-N, N-dimethyl-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-amine (100g, 250 mmol) was added to a reaction flask and Pin2B2(95.3g, 375.3 mmol), KOAc (98.2, 1 mol) and Pd(dppf)Cl2 (18.3g, 25 mmol) were added in dioxane (1 L). The reaction mixture was stirred at 100 °C for 12h, after which it was filtered and concentrated under vacuum to provide the title compound as a brown oil (170g crude). LC-MS: (ESI, m / z): [M+H of boronic acid] = 365.1.

[0222] Step g: (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-N, N-dimethyl-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-amine

[0223] To a reaction flask under nitrogen was added (S)-6-chloro-N, N-dimethyl-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (63.5 g, 174.2 mmol), Pd(PPh3)2Cl2(12.2 g, 17.4 mmol) and KF (15.18g, 261.2 mmol) in MeCN (477 mL) and H2O (96 mL). 6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine (35.53g, 193.3 mmol) was added and the reaction stirred at 80 °C for 2 h. The reaction mixture was then filtered, concentrated under vacuum and purified by silica gel chromatography (DCM / MeOH = 50 / 1, 5 / 1) to provide the title compound as a yellow solid (61.1g, 35% yield). LC-MS: (ESI, m / z): [M+H] = 495.2.

[0224] Step h: (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-ol

[0225] (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-N, N-dimethyl-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-amine (54 g, 109.1 mmol) and NaOH (43.6 g, 1.09 mmol) were dissolved in MeOH (315 mL) and H2O (63 mL). The reaction mixture was stirred at 80 °C for 2 h after which the reaction mixture wascooled to room temperature, filtered, concentrated, and purified (C18, water with 0.05% NH3H2O-ACN 20-41%) to provide the title compound as a pale yellow solid (22.7g, 36.9% yield). LC-MS: (ESI, m / z): [M+H] = 468.1.

[0226] Synthetic Routes to Final Compounds

[0227] Route A

[0228] Example 1. 1-(((S)-1-((R)-7-(6-Amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahydro-1 / 7-pyrrolizin-7a(5 / 7)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (Compound 1)

[0229] Step a: tert-Butyl 2-((2-oxopyridin-1(2H)-yl)methyl)azetidine-1-carboxylate

[0230] A solution of 1H-pyridin-2-one (253.0 mg, 2.66 mmol), tert-butyl 2-(bromomethyl)azetidine-1-carboxylate (998 mg, 3.99 mmol) and potassium carbonate (1103 mg, 7.98 mmol) in A / , A / -dimethylacetamide (3 mL) was stirred at 100 °C for 4h. After completion, the resulting residue was purified by reverse phase chromatography (acetonitrile 58% / 0.1 % ammonium bicarbonate in water) to afford the title compound (580 mg, 77.5% yield) as a yellow solid. LCMS: [M+H]+(ESI, m / z)= 265.1.

[0231] Step b: 1-(Azetidin-2-ylmethyl)pyridin-2(1H)-one

[0232] A solution of tert-butyl 2-((2-oxopyridin-1(2H)-yl)methyl)azetidine-1-carboxylate (225 mg, 0.85 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (0.4 mL) was stirred at 25 °C for 2h. After completion, the resulting solution was concentrated under vacuum to afford the title compound (215 mg, crude) as a black solid. LCMS: (ESI, m / z) [M+H]+=165.1.

[0233] Step c: 1-(((S)-1-((R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0234] A solution of (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (300 mg, 0.57 mmol), 1-(azetidin-2-ylmethyl)pyridin-2-one (139.4 mg, crude), A / , A / -diisopropylethylamine (0.3 ml_, 1.70 mmol) and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (441 mg, 0.85 mmol) in dichloromethane (3 mL) was stirred at 25 °C for 2h. After completion, the resulting solution was concentrated under vacuum. The crude product was purified directly by Prep-HPLC and Chiral HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol / L Ammonium bicarbonate), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 62% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5. Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: Hex: Dichloromethane=3: 1(0.5% 2M NHs-MeOH)- HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220 / 254 nm; RT1(min): 12.74; RT2(min): 16.21; Sample Solvent: EtOH: Dichloromethane=1: 1--HPLC; Injection Volume: 0.5 mL; Number Of Runs: 24. The stereochemistry of the isomers was arbitrarily assigned. This resulted in the title compounds (34.1 mg, 8.9% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+=676.0. tR = 2.83 min (CHIRALPAK IE-3, 4.6*50mm,3um, (Hex: Dichloromethane=3:1)(0.1%DEA): EtOH=80:20, 1 mL / min).

[0235] Route B

[0236] Examples 2a and 2b. 1 -(((S)-1 -(( / ?)-7-(6-Amino-5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)-4-(trifluoromethyl)pyridin-2(1H)-one (Compound 32a) & 1-(((S)-1-(( / ?)-7-(6-amino-5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)-4-(trifluoromethyl)pyridin-2(1H)-one (Compound 32b)

[0237] Step a: (S)-(4-(4-(terf-Butoxycarbonyl)-2-methylpiperazin-1-yl)-6-chloro-2,8-difluoroquinazolin-7-yl)zinc(ll) chloride

[0238] Under nitrogen, to a solution of fert-butyl (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1 -carboxylate (2.0 g, 4.2 mmol) in tetrahydrofuran (20 mL) was added 1.3 M isopropylmagnesium chloride lithium chloride complex in tetra hydrofuran (4.8 mL, 6.24 mmol) at -78 °C. The resulting solution was stirred for 1h at -78 °C. Then 2M zinc chloride in tetra hydrofuran (6.32 mL, 12.64 mmol) was added and stirred at room temperature for 1h. The reaction mixture was directly used in the next step without purification.

[0239] Step b: tert-Butyl (3S)-4-(7-(6-(Bis(4-methoxybenzyl)amino)-5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1 -carboxylate

[0240] Under nitrogen, to a solution of 6-bromo-3-fluoro-A / , A / -bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (2.16 g, 4.2 mmol), tris(dibenzylideneacetone)dipalladium (384 mg, 0.42 mmol) and tri(2-furyl)phosphine (190 mg, 0.8 mmol) in A / , A / -dimethylformamide (20 mL) was added the above solution at room temperature slowly by syringe. The resulting solution was stirred for 1h at 70 °C. The reaction mixture was quenched with saturated ammonium chloride solution. The reaction mixture was diluted with ethyl acetate and washed with brine. The reaction mixture was dissolved in A / , A / -dimethylformamide and purified by a reverse-phase chromatography to afford the title compound (1.25 g, 24% yield) as a brown solid. LCMS: (ESI, m / z), [M+H]+=831.10.

[0241] Step c: tert-Butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1 -carboxylate

[0242] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (326 mg, 2.05 mmol) in tetrahydrofuran (17 mL) was added sodium hydride (246 mg, 6.15 mmol) at 0 °C. The resulting solution was stirred for 30 minutes at 0 °C.Then tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (1.7 g, 2.05 mmol) was added and stirred at room temperature for 1h. The reaction mixture was quenched with saturated ammonium chloride solution. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in A / , A / -dimethylformamide and purified by reverse-phase chromatography directly to afford the title compound (720 mg, 36.3% yield) as a brown solid. LCMS: (ESI, m / z): [M+H]+= 970.65.

[0243] Step d: 7-(6-(Bis(4-methoxybenzyl)amino)-5-fluoro-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol

[0244] A solution of tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1 -carboxylate (670 mg, 0.69 mmol) and sodium hydroxide (280 mg, 7.0 mmol) in dimethyl sulfoxide (7.5 mL) and water (1.5 mL) was stirred at 60 °C for 1 h. The reaction mixture was adjusted to pH 7 with citric acid solution. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in N, N-dimethylformamide and purified by reverse-phase chromatography to afford the title compound (320 mg, 58.8% yield) as a yellow solid. LCMS: (ESI, m / z): [M+H]+= 788.55.

[0245] Step e: 7-(6-Amino-5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol

[0246] A solution of 7-(6-(bis(4-methoxybenzyl)amino)-5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol (310 mg, 0.39 mmol) in trifluoroacetic acid (1 mL) was stirred at 60 °C for 2h. The reaction mixture was concentrated under vacuum. The reaction mixture was diluted with dichloromethane. The reaction mixture was adjusted to pH 8 with A / , A / -diisopropylethylamine. The reaction mixture was concentrated under vacuum. The residue was dissolved in A / , A / -dimethylformamide andpurified by reverse-phase chromatography to afford the title compound (130 mg, 60.3% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+= 548.25.

[0247] Step f: 1-(((S)-1-((R)-7-(6-Amino-5-fluoro-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)-4-(trifluoromethyl)pyridin-2(1 H)-one & 1 -(((S)-1 -((R)-7-(6-amino-5-fluoro-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0248] To a solution of (S)-1-(azetidin-2-ylmethyl)-4-(trifluoromethyl)pyridin-2(1H)-one (44 mg, 0.19 mmol) in dichloromethane (4 mL) was added N, N-diisopropylethylamine (0.05 ml_, 0.28 mmol) at room temperature. Then benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (240 mg, 0.46 mmol) was added at room temperature. Then 7-(6-amino-5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol (100 mg, 0.18 mmol) was added and stirred at room temperature for 1h. The reaction mixture was concentrated under vacuum. The residue was dissolved in N, N-dimethylformamide and purified by reversephase chromatography to afford the crude product. Then the solid was dissolved with dichloromethane and washed with saturated sodium bicarbonate aqueous solution. Then the organic layer was concentrated under vacuum. The residue was further purified by Chiral-Prep-HPLC with following condition. Column: CHIRALPAK IC-3; Mobile Phase A: (Hex: Dichloromethane=1: 1)(0.1%DEA): EtOH=90: 10; Flow rate: 1ml_ / min; Temperature: 25 °C) to afford the title compounds. The stereo chemistry of the title compounds was arbitrarily assigned. 1-(((S)-1-((R)-7-(6-Amino-5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)- 4-(trifluoromethyl)pyridin-2(1 H)-one (21 mg, 15.1% yield) as a white solid. LCMS: (ESI, m / z): [M+H]+ = 762.30. tR = 0.949 min (CHIRALPAK IC-3, 4.6*100mm 3um, (Hex: Dichloromethane=1: 1)(0.1%DEA): EtOH=90: 10; 1mL / min). 1-(((S)-1-((R)-7-(6-Amino- 5-fluoro-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)-4-(trifluoromethyl)pyridin-2(1 H)-one (19.5mg, 14% yield) as a white solid. LCMS: (ESI,m / z): [M+H]+= 762.30. tR = 1.156 min (CHIRALPAK IC-3, 4.6*100mm 3um, (Hex: Dichloromethane=1: 1)(0.1%DEA): EtOH=90: 10; 1ml_ / min).

[0249] Route C

[0250] Examples 3a and 3b. 1-(((S)-1-(6-Chloro-7-((S)-8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2 -(((2 / ?, 7aS)-2 -fluorotetrahydro-1 H-pyrrolizin-7a(5 / 7)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyrazin-2(1 H)-one (Compound 33a) & 1-(((S)-1-(6-chloro-7-(( / ?)-8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyrazin-2(1H)-one (Compound 33b)

[0251] Step a: terf-Butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1 -carboxylate

[0252] To a mixture of ((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methanol (1500 mg, 9.42 mmol) in tetrahydrofuran (10 mL) was add sodium hydride (753 mg, 18.84 mmol) and the mixture was stirred for 0.5h at 0 °C. Then tert-butyl (3S)-4-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)-3-methyl-piperazine-1 -carboxylate (3000 mg, 6.28 mmol) was added and the mixture was stirred for 2h at room temperature. The reaction mixture was quenched with brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleumether / ethyl acetate (68%) to afford the title compound (2000 mg, 52% yield) as a white solid. LCMS (ESI, m / z): [M+H]+= 616.1.

[0253] Step b: 7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one

[0254] To a mixture of tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2 -fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1 -carboxylate (2000 mg, 3.24 mmol) in dimethyl sulfoxide (3 mL) was added sodium hydroxide (260 mg, 6.5 mmol) in water (1 mL), and the mixture was stirred for 2 h at 60 °C. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase chromatography to afford the title compound (1.2 g, 85% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+ = 434.1.

[0255] Step c: 1-(((S)-1-(7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyrazin-2(1 H)-one

[0256] To a mixture of 7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (1000 mg, 2.3 mmol) in 1,2-dichlorobenzene (3 mL) was added 1-(((2S)-azetidin-2-yl)methyl)pyrazin-2-one (380 mg, 2.3 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1795 mg, 3.45mmol), and A / , A / -diisopropylethylamine (1177 mg, 9.2mmol), and the mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase chromatography to afford the title compound (650 mg, 48% yield) as a yellow solid. LCMS (ESI, m / z):[M+H]+ = 581.2.

[0257] Step d: 1-(((2S)-1-(6-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)azetidin-2-yl)methyl)pyrazin-2(1H)-one

[0258] Under nitrogen, a mixture of 1-(((S)-1-(7-bromo-6-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyrazin-2(1H)-one (100 mg, 0.17 mmol), tri isopropyl ((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (101 mg,0.20 mmol), cataCXium A Pd G3 (12 mg, 0.017 mmol), potassium phosphate tribasic (108 mg, 0.51 mmol) in tetrahydrofuran (2 mL) and water (0.4 mL) was stirred for 1h at 60 °C. The solvent was removed. The residue was purified by silica gel column chromatography eluting with dichloromethane / methanol (5 / 1) to afford the title compound (140 mg, 94% yield). LCMS (ESI, m / z): [M+H]+= 869.3.

[0259] Step e: 1-(((S)-1-(6-Chloro-7-((S)-8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyrazin-2(1 H)-one & 1 -(((S)-1 -(6-chloro-7-((R)-8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyrazin-2(1 H)-one

[0260] To a solution of 1-(((2S)-1-(6-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)azetidin-2-yl)methyl)pyrazin-2(1H)-one (140 mg, 0.16 mmol) in A / , A / -dimethylacetamide (1 mL) was add caesium fluoride (52 mg, 0.35 mmol), and the mixture was stirred for 2h at room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The solvent was removed. The residue was dissolved in dichloromethane (1 mL) and 4M HCI in dioxane (0.1 mL). The solution was stirred for 0.5h at room temperature. The solvent was removed. The residue was purified by reverse phase chromatography, Prep-HPLC and Chiral HPLC. The stereochemistry of the isomers was arbitrarily assigned. 1 -(((S)-1 -(6-Chloro-7-((S)-8-ethynyl-3-hydroxynaphthalen-1 -yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyrazin-2(1 H)-one (6.6 mg, 5.7% yield) as a white solid. LCMS (ESI, m / z):[M+H]+=669.2. tR = 2.60 min (CHIRALPAK IG-3, 4.6*100mm 3um, (Hex / Dichloromethane 3:1, 0.1%DEA): EtCH=80:20, 1mL / min). 1-(((S)-1-(6-Chloro-7-((R)-8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyrazin-2(1H)-one (6.5 mg, 5.7% yield) as a white solid. LCMS (ESI, m / z): [M+H]+= 669.2. tR = 4.06 min, (CHIRALPAK IG-3, 4.6*100mm 3um, (Hex / Dichloromethane 3:1, 0.1%DEA): EtCH=80:20, 1mL / min).

[0261] Route D

[0262] Examples 4a, 4b, 4c and 4d. 1-(((S)-1-(7-(( / ?)-6-Amino-4-methyl-3-(trifluoromethylJpyridin^-ylJ-e-chloro^-^IR a'SJ^^-difluorodihydro-TH. S'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5' / 7)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (Compound 35a) & 1-((( / ?)-1-(7-(( / ?)-6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1 / ?,7a'S)-2,2-difluorodihydro-TH. S'H-spiroIcyclopropane-l^'-pyrrolizinJ^aXS'HJ-ylJmethoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 / 7)-one (Compound 35b) & 1-(((S)-1-(7-((S)-6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((IR a'SJ^^-difluorodihydro-TH. S'H-spiroIcyclopropane-l^'-pyrrolizin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (Compound 35c) & 1-((( / ?)-1-(7-((S)-6-amino-4-methyl-3- (trifluoromethylJpyridin^-ylJ-e-chloro^-^IR a'SJ^^-difluorodihydro-TH. S'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5' / 7)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (Compound 35d)

[0263] Step a: A / , A / -bis(4-methoxybenzyl)-4-methyl-6-(2,4,6-trichloro-8-fluoroquinazolin-7-yl)-5-(trifluoromethyl)pyridin-2-amine

[0264] A solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazoline-2,4-diol (2 g, 3.18 mmol) and A / , A / -diisopropylethylamine (1.23 g, 9.54 mmol) in phosphorus oxychloride (20 mL) was stirred at 65 °C for 3h. The solvent was concentrated under vacuum. The reaction mixture was quenched with water / ice (30 mL). The reaction mixture was diluted with dichloromethane (50 mL). The resulting solution was extracted with dichloromethane (3 x 50 mL) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (90 / 10)to afford the title compound (550 mg, 26% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+=665.1.

[0265] Step b: 1-((1-(7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-2,6-dichloro-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 H)-one

[0266] A solution of 1-(azetidin-2-ylmethyl)pyridin-2(1H)-one hydrogen chloride (230 mg, crude) and A / , A / -diisopropylethylamine (345 mg, 2.68 mmol) in N, N-dimethylformamide (5 mL) was stirred at 25 °C for 5 min. Then A / , A / -bis(4-methoxybenzyl)-4-methyl-6-(2,4,6-trichloro-8-fluoroquinazolin-7-yl)-5-(trifluoromethyl)pyridin-2-amine (550 mg, 0.826 mmol) was added and stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (7 / 3) to afford the title compound (490 mg, 74.6% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+=793.2.

[0267] Step c: 1-((1-(7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,7a'S)-2,2-difluorodihydro-TH,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0268] Under nitrogen, to a solution of ((1R,7a'S)-2,2-difluorodihydro-TH,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methanol (147 mg, 0.73 mmol) in N, N-dimethylformamide (3 mL) was added sodium hydride (120 mg, 3 mmol) at 0 °C. The resulting solution was stirred for 10 min at 0 °C. Then 1-((1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 / - / )-one (480 mg, 0.60 mmol) was added and stirred at 0 °C for 1.5h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on C18 silica gel eluting to afford the title compound (280 mg, 48.2% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+=960.35.

[0269] Step d: 1-(((S)-1-(7-((R)-6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1 R,7a'S)-2,2-difluorodihydro-1 'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 H)-one & 1 -(((R)-1 -(7-((R)-6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1 R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5' / - / )-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 H)-one & 1 -(((S)-1-(7-((S)-6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 H)-one & 1 -(((R)-1 -(7-((S)-6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0270] A solution of 1-((1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,7a'S)-2,2-difluorodihydro-TH,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (280 mg, 0.29 mmol) in trifluoroacetic acid (8 mL) was stirred at 50 °C for 2h. The solvent was concentrated under vacuum. The reaction mixture was quenched with saturated ammonium chloride aqueous solution. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography, Prep-HPLC and Chiral HPLC. The stereochemistry of the isomers was arbitrarily assigned. 1-(((S)-1-((R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,7a'S)-2,2-difluorodihydro- 1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (16.8 mg, 10.0 % yield) as an off-white solid. LCMS: (ESI, m / z) [M+H]+=720.3. tR = 2.915 min (CHIRALPAK IA-34.6*50 mm 3um; Hex(0.1%DEA): EtOH=80:20; 1mL / min).1-(((R)-1-((R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,7a'S)-2,2-difluorodihydro-1 H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (19.2 mg, 11.4 % yield) as an off-white solid. LCMS: (ESI, m / z) [M+H]+= 720.3. tR = 4.20 min (CHIRALPAK IA-34.6*50 mm 3um; Hex(0.1%DEA): EtOH=80:20; 1mL / min). 1-(((S)-1 -((S)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (23.2 mg, 13.8 % yield) as an off-white solid. LCMS: (ESI, m / z): 720.3 [M+H]+. tR = 4.01 min (CHIRALPAK IC-3 4.6*50 mm 3um; Hex(0.1%DEA): EtOH=80:20; 1mL / min). 1-(((R)-1-((S)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,7a'S)-2,2-difluorodihydro-TH, 3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (30.1 mg, 17.9 % yield) as an off-white solid. LCMS: (ESI, m / z): 720.3 [M+H]+. tR = 5.20 min (CHIRALPAK IC-3 4.6*50 mm 3um; Hex(0.1%DEA): EtOH=80:20; 1mL / min).

[0271] Route ECl step a ci■CF3■CF3

[0272] Example 5. 1-((1-(7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 / - / )-one (Compound 42)

[0273] Step a: 1-((1-(7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 H)-one

[0274] A solution of (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4(3H)-one (180 mg, 0.38 mmol), 1-(azetidin-2-ylmethyl)pyridin-2-one (126 mg, 0.77 mmol) (Intermediate III), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (300 mg, 0.58 mmol) and A / , A / -diisopropylethylamine (0.2 ml_, 1.15 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 0.5h. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC to afford the title compound (24.3 mg, 10.2% yield) as a white solid. LC-MS: (ESI, m / z) [M+H]+=614.1.

[0275] Route F

[0276] Example 6. 2-(4-((1-(7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyridin-3-yl)acetonitrile (Compound 51)

[0277] Step a: 4-Bromo-3-(chloromethyl)pyridine

[0278] A solution of (4-bromopyridin-3-yl)methanol (1.50 g, 7.98 mmol) in thionyl chloride (12 mL) was stirred at 50 °C for 2h. After completion, the reaction solution was diluted with water, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate to afford the title compound (1.80 g, 52.4% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+=205.9.

[0279] Step b: 2-(4-Bromopyridin-3-yl)acetonitrile

[0280] To a solution of 4-bromo-3-(chloromethyl)pyridine (1.50 g, 7.26 mmol) in A / , A / -dimethylformamide (15 mL) was added triethylamine (1.47 g, 14.5 mmol), trimethylsilyl cyanide (1.10 g, 10.90 mmol) and potassium carbonate (2.00 g, 14.5 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1h. After completion, the reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate to afford the title compound (1.20 g, 83.8% yield) as a yellow solid. LCMS: (ESI, m / z [M+H]+=197.0.

[0281] Step c: tert-Butyl 2-((3-(cyanomethyl)pyridin-4-yl)methyl)azetidine-1-carboxylate

[0282] Under nitrogen, to a solution of tert-butyl 2-(bromomethyl)azetidine-1-carboxylate (500 mg, 2.00 mmol) in 1,2-dimethoxyethane (9.6 mL) was added (4,4'-di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(ll I) hexafluorophosphate (22 mg, 0.02 mmol), tris(trimethylsilyl)silane (0.62 ml_, 2.00 mmol), sodium carbonate (423 mg, 4.00 mmol) and 2-(4-bromopyridin-3-yl)acetonitrile (393 mg, 2.00 mmol) at 25 °C. Then to the resulting solution was added a solution of 4,4'-di-tert-butyl-2,2'-bipyridine (3 mg, 0.01 mmol) and nickel chloride, dimethoxyethane adduct (3 mg, 0.01 mmol) in 1,2-dimethoxyethane (1 mL). The resulting mixture was stirred for 6h at 25°C under blue LEDs. After completion, the reaction solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate to afford the title compound (350 mg, 60.9% yield) as yellow solid. LCMS: (ESI, m / z) [M+H]+=288.2.

[0283] Step d: 2-(4-(Azetidin-2-ylmethyl)pyridin-3-yl)acetonitrile

[0284] To a solution of tert-butyl 2-((3-(cyanomethyl)pyridin-4-yl)methyl)azetidine-1 -carboxylate (123 mg, 0.43 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at 25 °C for 1h. After completion, the reaction mixture was concentrated under vacuum, diluted with ethyl acetate, adjusted to pH >7 with sodium bicarbonate saturated solution, extracted with ethyl acetate, and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by solid-phase extraction to afford the title compound (100 mg, 99.8% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+=188.1.

[0285] Step e: 2-(4-((1-(7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)pyridin-3-yl)acetonitrile

[0286] A solution of (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4(3H)-one (100 mg, 0.21 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (70 mg, 0.28 mmol) and N, N-diisopropylethylamine (82 mg, 0.64 mmol) in chloroform (5 mL) was stirred at 70 °C for 1h. Then 2-(4-(azetidin-2-ylmethyl)pyridin-3-yl)acetonitrile (80 mg, 0.43 mmol) was added and stirred at 70°C for 2 hours. After completion, the reaction mixture was diluted with ethyl acetate, washed with water, and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Theproduct was purified by Prep-HPLC to afford the title compound (44.3 mg, 32.5% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+=637.4.

[0287] Route G

[0288] Example 7. 2 -(((S) -1 -((R)-7-(6-Amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)-6-methylpyridine 1 -oxide (Compound 18)

[0289] Step a: tert-Butyl (S)-2-((6-methylpyridin-2-yl)methyl)azetidine-1-carboxylate

[0290] To a mixture of fert-butyl (2S)-2-(bromomethyl)azetidine-1-carboxylate (500 mg, 2 mmol) in 1,2-dimethoxyethane (3.0 mL) was added 2-bromo-6-methylpyridine (3 mg, 0.02 mmol), bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridinyl)phenyl)ruthenium hexafluorophosphate-4,4'-bis(2-methyl-2-propanyl)-2,2'-bipyridine (2242 mg, 2.00 mmol), tris(trimethylsilyl)silane (994 mg, 4 mmol), sodium carbonate (1 mg, 0.01 mmol), nickel chloride dimethoxyethane adduct (2 mg, 0.01 mmol), 4,4'-dimethoxy-2,2'-bipyridine (432 mg, 2.00 mmol), and 2-bromo-6-methylpyridine (3 mg, 0.02 mmol). The reaction mixture was irradiated with purple light for 12h at 25 °C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was backwashed with water and dried with anhydrous sodium sulfate, and the organic layers were combined. The organic phase was mixed with silica gel. The organic layer was concentrated under vacuum and purified by flash chromatography with petroleum ether / ethyl acetate to afford the title compound (86 mg, 16.4% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 263.2.

[0291] Step b: (S)-2-((1-(tert-Butoxycarbonyl)azetidin-2-yl)methyl)-6-methylpyridine 1 -oxide

[0292] To a mixture of tert-butyl (2S)-2-((6-methyl-2-pyridyl)methyl)azetidine-1-carboxylate (130 mg, 0.5 mmol) in dichloromethane (5 mL) was added 3-chloroperoxybenzoic acid (204 mg, 1.19 mmol) at 25 °C, and the mixture was stirred for2h at 25 °C. The solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile 60-70% / 10mmol / L ammonium bicarbonate in water) to afford the title compound (74 mg, 53.7% yield) as a white oil. LCMS (ESI, m / z): [M+H]+= 279.2.

[0293] Step c: (S)-2-(Azetidin-2-ylmethyl)-6-methylpyridine 1 -oxide

[0294] To a mixture of tert-butyl (2S)-2-((6-methyl-1-oxido-pyridin-1-ium-2-yl)methyl)azetidine-1 -carboxylate (10 mg, 0.04 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred for 2h at 25 °C. The solvent was removed under vacuum to afford the title compound (158 mg) as a white solid and as crude product. LCMS (ESI, m / z): [M+H]+= 179.1.

[0295] Step d: 2-(((S)-1-((R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azetidin-2-yl)methyl)-6-methylpyridine 1 -oxide

[0296] Step d proceeded as in Step c of Route A to provide the title compound (15 mg, 10.5% yield) as a white solid. LCMS (ESI, m / z): [M+H]+= 690.2.

[0297] Route H

[0298] Example 8. 6-(( / ?)-6-Chloro-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-(pyridin-2-ylmethyl)azetidin-1-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Compound 7)

[0299] Step a: tert-Butyl (S)-2-(pyridin-2-ylmethyl)azetidine-1 -carboxylate

[0300] To a mixture of tert-butyl (2S)-2-(bromomethyl)azetidine-1-carboxylate (500 mg, 2 mmol) in 1,2-dimethoxyethane (5 mL) was added bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridinyl)phenyl)ruthenium hexafluorophosphate-4,4'-bis(2-methyl-2-propanyl)-2,2'-bipyridine (22 mg, 0.02 mmol), tris(trimethylsilyl)silane (0.62 ml, 2 mmol), sodium carbonate (423 mg, 4.00 mmol), nickel chloride dimethoxyethane adduct (2 mg, 0.01 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (2.68 mg, 0.01 mmol), and 2-bromopyridine (0.19 mL, 2.00 mmol). The mixture was stirred for 12h under blue LED.The reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The organic phase was back washed with water and dried with anhydrous sodium sulfate, and the organic layers were combined. The organic phase was mixed with silica gel. The organic layer was concentrated under vacuum and purified by flash chromatography with petroleum ether / ethyl acetate (0-50%) to afford the title compound (150 mg, 30.2% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 249.1.

[0301] Step b: (S)-2-(Azetidin-2-ylmethyl)pyridine

[0302] To a mixture of tert-butyl (2S)-2-(2-pyridylmethyl)azetidine-1 -carboxylate (150 mg, 0.60 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (0.3 mL), and the mixture was stirred for 2h at 25 °C. The solvent was concentrated under vacuum to afford the crude product (70 mg, 78.6% yield) as a brown oil. The crude product was used for the next step without further purification. LCMS (ESI, m / z): [M+H]+= 149.1.

[0303] Step c: 6-((R)-6-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-(pyridin-2-ylmethyl)azetidin-1-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0304] Step c proceeded as in Step c of Route A to provide the title compound (32.6 mg, 43.6% yield) as a white solid. LCMS (ESI, m / z): [M+H]+= 660.2.

[0305] Untethered 6-Azas

[0306] Intermediate I

[0307] Intermediate I: 1-((1-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 H)-one

[0308] Step a: terf-Butyl 2-((2-oxopyridin-1(2H)-yl)methyl)azetidine-1-carboxylate

[0309] A solution of tert-butyl 2-(bromomethyl)azetidine-1 -carboxylate (11.7 g, 46.8 mmol), pyridin-2(1H)-one (3.0 g, 31.2 mmol) and potassium carbonate (13 g, 93.7 mmol) in A / , A / -dimethylacetamide (5 mL) was stirred at 100 °C for 4h. After completion, the reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 1) to afford the title compound (1 g, 11.1% yield) as a yellow solid. LCMS: (ESI, m / z): 264.1 [M+H]+.

[0310] Step b: 1-(Azetidin-2-ylmethyl)pyridin-2(1H)-one

[0311] A solution of tert-butyl 2-((2-oxopyridin-1(2H)-yl)methyl)azetidine-1-carboxylate (850 mg, 3.22 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was stirred at 25 °C for 1 h. After completion, the reaction mixture was concentrated under vacuum to afford the title compound (850 mg crude) as a yellow oil. LCMS: (ESI, m / z): 164.1 [M+H]+.

[0312] Step c: 1-((1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 H)-one

[0313] To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (300 mg, 1.19 mmol) in dichloromethane (10 mL) was added A / , / V-diisopropylethylamine (0.98 mL, 5.63 mmol) and 1-(Azetidin-2-ylmethyl)pyridin-2(1H)-one (660 mg, 1.13 mmol) at -40 °C. The resulting solution was stirred for 1h at -40 °C. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (3%) to afford the title compound (320 mg, 67.3% yield) as a yellow solid. LCMS: (ESI, m / z): 380.2 [M+H]+.

[0314] Step d: 1-((1-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0315] Under nitrogen, to a solution of ((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol (163 mg, 1.03 mmol) in tetrahydrofuran (50 mL) was added 1M sodium bis(trimethylsilyl)amide in THF (2.06 ml_, 2.06 mmol) at 0 °C. The resulting solution was stirred for 20 min at 0 °C. Then 1-((1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (260 mg, 0.68 mmol) was added and stirred at 25 °C for 1 h. After completion, the reaction mixture was adjusted to pH 7 with saturated ammonium chloride, extracted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum dichloromethane / methanol (10 / 1) to afford the title compound (95 mg, 18.5% yield) as a yellow solid. LCMS: (ESI, m / z): 503.4 [M+H]+.

[0316] Intermediate II

[0317] Intermediate II: 1-(((S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin- 2-yl)methyl)pyridin-2(1 H)-one

[0318] Step a: terf-Butyl (2S)-2-(bromomethyl)azetidine-1 -carboxylate

[0319] A solution of tert-butyl (2S)-2-(hydroxymethyl)azetidine-1 -carboxylate (5 g, 26.7 mmol) and carbon tetrabromide (18 g, 54.3 mmol), triphenylphosphine (14 g, 53.4 mmol) in dichloromethane (60 mL) was stirred at room temperature for 1h. The resulting solution was quenched with water and extracted with dichloromethane, and the organic layers were combined. The residue was purified by flash chromatography on silica gel eluting with PE / EA (70:30) to afford the title compound (5 g, 74.9% yield) as a colorless oil. LCMS (ESI, m / z): [M+H]+=250.0.

[0320] Step b: tert-Butyl (2S)-2-((2-oxo-1-pyridyl)methyl)azetidine-1 -carboxylate

[0321] A solution of 1H-pyridin-2-one (3 g, 31.6 mmol), tert-butyl (2S)-2-(bromomethyl)azetidine-1 -carboxylate (5 g, 19.99 mmol), and potassium carbonate (8.29 g, 59.97 mmol) in A / , A / -dimethylformamide (30 mL) was stirred at 100 °C for 1h. The resulting solution was quenched with water and extracted with ethyl acetate, and the organic layers were combined. The solvent was concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile 20-30% / 10 mmol ammonium bicarbonate in water) to afford the title compound (2.8 g, 53% yield) as a colorless oil. LCMS (ESI, m / z): [M+H]+=265.1.

[0322] Step c: 1-(((2S)-Azetidin-2-yl)methyl)pyridin-2-one

[0323] A solution of tert-butyl (2S)-2-((2-oxo-1-pyridyl)methyl)azetidine-1-carboxylate (2.5 g, 9.46 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (5 mL) was stirred at room temperature for 1h. LCMS showed the product formed and SM was consumed. The solvent was concentrated under vacuum. The crude product was directly used in the next step without purification. LCMS (ESI, m / z): [M+H]+=165.0.

[0324] Step d: 1-(((2S)-1-(2,7-Dichloro-8-fluoro-pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one

[0325] A solution of 2,4,7-trichloro-8-fluoro-pyrido(4,3-d)pyrimidine (12.8 g, 50.5 mmol) and N, N-diisopropylethylamine (4640 mg, 35.9 mmol) in dichloromethane (100 mL) was stirred at -40 °C for 5 min. Then 1 -(((2S)-azetidin-2-yl)methyl)pyridin-2-one (2.9 g, 7.06 mmol) was added and stirred at -40 °C for 1h. The solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile 30-40% / 10mmol / L ammonium bicarbonate in water) to afford the title compound (1.7 g, 63.3% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+=380.0.

[0326] Step e: 1-(((2S)-1-(7-Chloro-8-fluoro-2-(((2R,8S)-2-fluoro-1, 2, 3, 5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one

[0327] A solution of ((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methanol (400 mg, 2.51 mmol) and sodium hydride (300 mg, 7.5 mmol) in tetrahydrofuran (15 mL) was stirred at 0 °C for 10 min. Then 1-(((2S)-1-(2,7-dichloro-8-fluoro-pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one (1.0 g, 2.63 mmol) was added and stirred at 0 °C for 1h. LCMS showed the product formed and SM was consumed. The reaction mixture was quenched with saturated ammonium chloride. The organic layer was concentrated under vacuum. The resulting residue was purified byreverse phase chromatography (acetonitrile 30-40% / 10mmol / L ammonium bicarbonate in water) to afford the title compound (900 mg, 68% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+=503.2.

[0328] Intermediates III, IV, VIntermediate IV Intermediate V

[0329] Intermediate III: 4-(Benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0330] Intermediate IV: 4-(Benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidine

[0331] Intermediate V: 7-(8-Ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol

[0332] Step a: 4-(Benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine

[0333] To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1100 mg, 4.3 mmol) in 1,4-dioxane (50 mL) was added A / , A / -diisopropylethylamine (2.09 ml_, 11.99 mmol) and benzyl alcohol (0.49 ml_, 4.76 mmol) at 0 °C. The resulting solution was stirred for 12h at 60 °C under nitrogen. The reaction mixture was quenched with water, extracted with ethyl acetate and the organic layers were combined. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexanes (10%) to afford the title compound (450 mg, 31.5% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 324.0.

[0334] Step b: 4-(Benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate III)

[0335] Under nitrogen, a mixture of 4-benzyloxy-2,7-dichloro-8-fluoro-pyrido[4, 3-d]pyrimidine (1.5 g, 4.63 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.03 g, 6.47 mmol) and cesium carbonate (3.94 g, 12.1 mmol) in 1,4-dioxane (15 mL) was stirred at 80 °C for 1h. The reaction mixture was quenched with brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in DMF and purified by reverse-phase chromatography directly to afford the title compound (600 mg, 29% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 447.1.

[0336] Step c: 4-(Benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1 -yl)pyrido[4,3-d]pyrimidine (Intermediate IV)

[0337] Under nitrogen, to 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 (500 mg, 1.12 mmol) in tetrahydrofuran (8 mL) and water (2 mL) was added potassium phosphate tribasic (710 mg, 3.36 mmol), cataCXium A Pd G3 (163 mg, 0.22 mmol) and triisopropyl-(2-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl)ethynyl)silane (609 mg, 1.23 mmol) at room temperature. The resulting solution was stirred for 2h at 80 °C under nitrogen. The reaction mixture was quenched with water, extracted with ethyl acetate and the organic layers were combined. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (50%) to afford the title compound (800 mg, 82.6% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 779.4.

[0338] Step d: 7-(8-Ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol

[0339] To a solution of 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidine (300 mg, 0.39 mmol) in dimethyl sulfoxide (1 mL) was added the solution of sodium hydroxide (63 mg, 1.54 mmol) in water (0.2 mL) at room temperature. The resulting solution was stirred for 16h at room temperature. The resulting residue was purified by reverse phasechromatography (acetonitrile 0-40% / 0.1% NH4HCO3in water) to afford the title compound (180 mg, 79% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 533.2.

[0340] Intermediate VI, VIIstep a step bIntermediate III Intermediate VI Intermediate VII

[0341] Intermediate VI: 4-(Benzyloxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0342] Intermediate VII: 7-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol

[0343] Step a: 4-(Benzyloxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0344] Under nitrogen, 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 (500 mg, 1.12 mmol), 2-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl)ethynyl-triisopropyl-silane (600 mg, 1.17 mmol), potassium phosphate tribasic (700 mg, 3.3 mmol) and CataCXium A Pd G3 (100 mg, 0.14 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred for 2h at 80 °C. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (50%) to afford the title compound (670 mg, 75.1% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 797.4.

[0345] Step b: 7-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol

[0346] To a mixture of 4-(benzyloxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (1500 mg, 1.88 mmol) in dimethylsulfoxide (20mL) was added the solution of sodium hydroxide (225 mg, 5.65 mmol) in water (0.2 mL). The mixture was stirred for 12h at 25°C. The resulting residue was purified by reverse phase chromatography (acetonitrile 0-80% / 0.1% ammonium bicarbonate in water) to afford the title compound (600 mg, 57.9% yield) as a white solid. LCMS (ESI, m / z): [M+H]+= 551.2.

[0347] Intermediate VIIIIntermediate VI Intermediate VIII

[0348] Step a: 4-Benzyloxy-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidine

[0349] A solution of 2-(8-(4-benzyloxy-8-fluoro-2-(((2R,8S)-2-fluoro-1, 2, 3, 5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)-1-naphthyl)ethynyl-triisopropyl-silane (320 mg, 0.40 mmol) and caesium fluoride (320 mg, 2.11 mmol) in A / , A / -dimethylformamide (5 mL) was stirred at room temperature for 1h. The resulting residue was purified by reverse phase chromatography (acetonitrile 80-90% / 10mmol / L ammonium bicarbonate in water) to afford the title compound (240 mg, 93.3% yield) as a yellow solid. LCMS (ESI, m / z):[M+H]+=641.3

[0350] Step b: 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl) methoxy)pyrido(4,3-d)pyrimidin-4-ol

[0351] To a solution of 4-benzyloxy-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl) methoxy)pyrido(4,3-d)pyrimidine (230 mg, 0.36 mmol) in ethyl acetate (20 mL) was added Pd / C (75 mg, 0.71 mmol) at room temperature under nitrogen. The mixture was stirred overnight at room temperature under hydrogen. After filtration, the filtrate was concentrated under reduced pressure. The crude product was directly used in the next step without purification. This resulted in the title compound (180 mg, 90.4% yield) as a yellow solid. LCMS (ESI, m / z): [M+H] + =555.4.

[0352] Synthetic Route to Final Compounds

[0353] Route A

[0354] Example 9. 6-(((S)-1-(7-(8-Ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Compound 54)

[0355] Step a: tert-Butyl (S)-2-((1-benzyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)methyl)azetidine-1 -carboxylate

[0356] A solution of 1-benzyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (300 mg, 1.40 mmol), fert-butyl (S)-2-(bromomethyl)azetidine-1 -carboxylate (350 mg, 1.40 mmol) and potassium carbonate (580 mg, 4.20 mmol) in A / , A / -dimethylformamide (5 mL) was stirred at 100 °C for 2h. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (300 mg, 54.5% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 394.2.

[0357] Step b: tert-Butyl (S)-2-((7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)methyl)azetidine-1 -carboxylate

[0358] Under oxygen, a solution of tert-butyl (S)-2-((1-benzyl-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)methyl)azetidine-1 -carboxylate (300 mg, 0.76 mmol) and potassium tert-butoxide (598 mg, 5.34 mmol) in dimethyl sulfoxide (5 mL) was stirred at 60 °C for 12h. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (80 mg, 51.6% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 304.1.

[0359] Step c: (S)-6-(Azetidin-2-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one

[0360] A solution of fert-butyl (S)-2-((7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)methyl)azetidine-1 -carboxylate (80 mg, 0.26 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was stirred for 2h at room temperature. The solvent was removed under vacuum to afford the title compound (160 mg crude) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 204.1.

[0361] Step d: 6-(((S)-1-(7-(8-Ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0362] A solution of (S)-6-(azetidin-2-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (15 mg, 0.08 mmol), 7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (40 mg, 0.08 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (46 mg, 0.09 mmol) and A / , A / -diisopropylethylamine (0.2 mL) in dichloromethane (3 mL) was stirred at room temperature for 2h. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (30 mg, 55.6% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 718.3.

[0363] Step e: 6-(((S)-1-(7-(8-Ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0364] A solution of 6-(((S)-1-(7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (30 mg, 0.04 mmol) in dichloromethane (1 mL) and 4 M hydrogen chloride solution in 1,4-dioxane (0.5 mL) was stirred at room temperature for 1h. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) and Prep-HPLC to afford the title compound (7.7 mg, 24.9% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 674.2.

[0365] Route B

[0366] Example 10. 1-(((S)-1-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)-4,5-dimethylpyridin-2(1H)-one (Compound 62)

[0367] Step a: 4,5-Dimethylpyridin-2(1H)-one

[0368] A solution of tert-Butyl nitrite (2.4 mL, 20.5 mmol) in N, N-dimethylformamide (2 mL) was added dropwise to a stirred solution of 4,5-dimethylpyridin-2-amine (500 mg, 4.09 mmol) in A / , A / -dimethylformamide (2 mL). The resulting mixture was stirred for 1 h at 60 °C, cooled to room temperature, quenched with ice water and stirred for 0.5h. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (250 mg, 49.6% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 124.1.

[0369] Step b: tert-Butyl (S)-2-((4,5-dimethyl-2-oxopyridin-1(2H)-yl)methyl)azetidine-1 -carboxylate

[0370] A solution of 4,5-dimethylpyridin-2(1H)-one (250 mg, 2.03 mmol), fert-butyl (S)-2-(bromomethyl)azetidine-1 -carboxylate (507 mg, 2.03 mmol) and cesium carbonate (1.31 g, 4.06 mmol) in A / , A / -dimethylformamide (5 mL) was stirred at 90 °C for 2h. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (200 mg, 33.7% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 293.2.

[0371] Step c: (S)-1-(Azetidin-2-ylmethyl)-4,5-dimethylpyridin-2(1H)-one

[0372] To a solution of tert-butyl (S)-2-((4,5-dimethyl-2-oxopyridin-1(2H)-yl)methyl)azetidine-1 -carboxylate (200 mg, 0.68 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 1h.The solvent was concentrated under vacuum to afford the title compound (130 mg, 98.8% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 193.1.

[0373] Steps d and e were performed as described for steps d and e in Route A.

[0374] Route C

[0375] Example 11. 1-(((S)-1-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 / 7)-one (Compound 65)

[0376] Step a: 1-(((2S)-1-(8-Fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one

[0377] A solution of 1-(((2S)-1-(7-chloro-8-fluoro-2-(((2R,8S)-2-fluoro-1,2, 3,5,6, 7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one (100 mg, 0.20 mmol) and 2-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl)ethynyl-triisopropyl-silane (153 mg, 0.30 mmol), cataCXium A Pd G3(23 mg, 0.03 mmol), potassium phosphate tribasic (130 mg, 0.61 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 80 °C for 1h. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (82:18) to afford the title compound (140 mg, 82.5% yield) as a yellow solid. LCMS (ESI, m / z):[M+H]+=853.4.

[0378] Step b: 1-(((2S)-1-(7-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one

[0379] A solution of 1-(((2S)-1-(8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1 -naphthyl)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one (140 mg, 0.16 mmol) and caesium fluoride (126 mg, 0.83 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 1h. The resulting residue was purified by reverse phase chromatography (acetonitrile 70-80% / 10mmol / L ammonium bicarbonate in water) to afford the title compound (110 mg, 96.2% yield) as a yellow solid. LCMS (ESI): [M+H]+=697.3.

[0380] Step c: 1-(((2S)-1-(7-(8-Ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one

[0381] A solution of 1-(((2S)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one (100 mg, 0.14 mmol) and 4 M HCI / dioxane (0.5 mL) in dichloromethane (2 mL) was stirred at room temperature for 1h. The solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile 40-50% / 10 mmol / L ammonium bicarbonate in water) to afford the title compound. The crude product was purified by Prep-HPLC to afford the title compound (45.7 mg, 48.8% yield) as a yellow solid. LCMS (ESI): [M+H]+=653.2.

[0382] Route D

[0383] Example 12. 1-(((S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 / 7)-one (Compound 73)

[0384] Step a: 1-(((S)-1-(7-(8-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)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0385] Under hydrogen, a solution of 1-(((S)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 H)-one (180 mg, 0.26 mmol) and 10% Palladium on Carbon (210 mg, 1.98 mmol) in ethyl acetate (5 mL) was stirred at room temperature for 0.5h. The solids were filtered out and the solvent was concentrated under vacuum to afford the title compound (110 mg, 60.8%yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+=701.3.

[0386] Step b: 1-(((S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0387] A solution of 1-(((S)-1-(7-(8-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)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (100 mg, 0.14 mmol) and 4.0 M hydrogen chloride solution in 1,4-dioxane (0.5 mL) in dichloromethane (2 mL) was stirred at room temperature for 2h. The solvent was concentrated under vacuum. The crude product was purified by Prep-HPLC to afford the title compound (9.8 mg, 10.5% yield) as a white solid. LCMS (ESI, m / z): [M+H]+= 657.4.

[0388] Route E

[0389] Example 13. 1-(((2S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-(((2 / ?,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl) methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)-4-methyl-pyridin-2-one (Compound 74)

[0390] Step a: 1-(((2S)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl) methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)-4-methyl-pyridin-2-one

[0391] A solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-ol (60 mg, 0.11 mmol), 1-(((2S)-azetidin-2-yl)methyl)-4-methyl-pyridin-2-one (58 mg, 0.33 mmol), A / , A / -diisopropylethylamine (42 mg, 0.32 mmol) and benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (84 mg, 0.16 mmol) in dichloromethane (3 mL) was stirred at room temperature for 1h. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (87:13) to afford the title compound (70 mg, 90.5% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+=715.4.

[0392] Step b: 1-(((2S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)-4-methyl-pyridin-2-one

[0393] A solution of 1-(((2S)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)-4-methyl-pyridin-2-one (70 mg, 0.10 mmol) and 4 M HCI / dioxane (0.2 mL) in dichloromethane (2 mL) was stirred at room temperature for 1h. The solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile 60-70% / 10 mmol / Lammonium bicarbonate in water) to afford the title compound. The crude product was purified by Prep-HPLC to afford the title compound (18.4 mg, 28% yield) as a white solid. LCMS (ESI, m / z): [M+H]+=671.3.

[0394] Route F

[0395] Example 14. 1-(((S)-1-(7-(3-Amino-8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2 / ?,7aS) -2 -fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (Compound 83)

[0396] Step a: 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)me thoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-ol

[0397] A mixture of 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidine (700 mg, 0.90 mmol) and 10% Pd / C (100 mg) in ethanol (10 mL) was stirred for 1 h at room temperature under hydrogen. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (600 mg, 87.2% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+=689.05.

[0398] Step b: 1-(((S)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0399] To a solution of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-ol (200 mg, 0.29 mmol) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (187 mg, 1.45 mmol), 1-(((2S)-azetidin-2-yl)methyl) pyridin-2-one (289 mg, 0.58 mmol), and benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (302 mg, 0.58 mmol) at room temperature. The resulting solution was stirred for 1h at room temperature. The reaction mixture was quenched with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (6%) to afford the title compound (250 mg, 92.8% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 835.1.

[0400] Step c: 1-(((S)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)-7-(3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0401] To a solution of 1-(((S)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (250 mg, 0.30 mmol) in dichloromethane (3 mL) was added 4 M HCl / dioxane (0.5 mL) at room temperature. The resulting solution was stirred for 30 min at room temperature. The organic layer was concentrated under vacuum to afford the title compound (300 mg crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 791.1.

[0402] Step d: 4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-4-((S)-2-((2-oxopyridin-1 (2H)-yl)methyl)azetidin-1 -yl)pyrido[4, 3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl trifluoromethanesulfonate

[0403] To a solution of 1-(((S)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (300 mg, 0.38 mmol) and triethylamine (192 mg, 1.9 mmol) in 1,2-dichloroethane (5 mL) was added N-phenyl-bis(trifluoromethanesulfonimide) (271 mg, 0.76 mmol) at room temperature. The resulting solution was stirred for 1 h at room temperature. The reaction mixture was quenched with water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexanes (50%) to afford the title compound (280 mg, 72% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 923.1.

[0404] Step e: terf-Butyl (4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-((S)-2-((2-oxopyridin-1 (2H)-yl)methyl)azetidin-1 -yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate

[0405] To a solution of 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-((2-oxopyridin-1(2H)-yl)methyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl trifluoromethanesulfonate (100 mg, 0.11 mmol) and fert-butyl carbamate (20 mg, 0.17 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (107 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg, 0.02 mmol) at room temperature. The resulting solution was stirred for 1h at 100 °C under nitrogen. The reaction mixture was quenched with water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (5%) to afford the title compound (70 mg, 65.3% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 890.2.

[0406] Step f. terf-Butyl (5-ethynyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-((2-oxopyridin-1 (2H)-yl)methyl)azetidin-1 -yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)carbamate

[0407] To a solution of tert-butyl (4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-((2-oxopyridin-1(2H)-yl)methyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (70 mg, 0.08 mmol) in N,N-dimethylformamide (2 mL) was added cesium fluoride (48 mg, 0.32 mmol) at room temperature. The resulting solution was stirred for 1h at room temperature. The reaction mixture was quenched with water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (5%) to afford the title compound (50 mg, 78% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 734.3.

[0408] Step g: 1-(((S)-1-(7-(3-Amino-8-ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0409] A solution of tert-butyl (5-ethynyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((S)-2-((2-oxopyridin-1(2H)-yl)methyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)carbamate (40 mg, 0.05 mmol) in dichloromethane (1 mL) was added 4 M HCl / dioxane (0.5 mL) at room temperature. The resulting solution was stirred for 30 min at room temperature. The organic layer was concentrated under vacuum. The crude product was purified by Prep-HPLC to afford the title compound (6.3 mg, 17.6% yield) as a brown solid. LCMS (ESI, m / z): [M+H]+= 634.3.

[0410] Route Gstep b step a

[0411] Example 15. 1 -(((S)-1 -(7-(5-Amino-4-fluoro-3-methyl-2- (trifluoromethyl)phenyl)-8-fluoro-2 -(((2 / ?, 7aS)-2 -fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 H)-one (Compound 85)

[0412] Step a: 1-(((S)-1-(7-(5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0413] A mixture of (5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (200 mg, 0.42 mmol), 1-(((S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (170 mg, 0.34 mmol), RuPhos Pd G3 (56 mg, 0.07 mmol), RuPhos (28 mg, 0.06 mmol), and potassium carbonate (90 mg, 0.65 mmol) in 1,4-dioxane (2 mL) and water (0.40 mL) was stirred for 2h at 90 °C under nitrogen. The reaction mixture was concentrated under vacuum and purified by flash chromatography on silica gel eluting with dichloromethane / methanol (8%) to affordthe title compound (150 mg, 49.3% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 900.3.

[0414] Step b: 1-(((S)-1-(7-(5-Amino-4-fluoro-3-methyl-2- (trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 H)-one

[0415] A mixture of 1-(((S)-1-(7-(5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (150 mg, 0.17 mmol) in trifluoroacetic acid (2 mL) was stirred for 2h at 60 °C. The reaction mixture was concentrated under vacuum and purified by Prep-HPLC to afford the title compound (26 mg, 23.6% yield) as a white solid. LCMS (ESI, m / z): [M+H]+=660.2.

[0416] Route H

[0417] Example 16. 1-(((S)-1-(7-(8-Chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2 / ?,7aS) -2 -fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (Compound 86)

[0418] Step a: 2,4-Dibromo-5-chloronaphthalen-1-amine

[0419] To a solution of 5-chloronaphthalen-1 -amine (3000 mg, 16.9 mmol) in acetic acid (30 mL) was added the solution of bromine (5920 mg, 37.1 mmol) in acetic acid (30 mL) at 0 °C slowly, portion-wise. The resulting solution was stirred for 30 min at 10 °C. After filtration, the solids were collected and washed with acetic acid. Then the solids were triturated in the solution of 15% sodium hydride for 10 min. After filtration, the solids were collected and washed with water. The crude product was dried undervacuum to afford the title compound (5500 mg, 97.1% yield) as a purple solid. LCMS (ESI, m / z): [M+H]+=335.7.

[0420] Step b: 5-Bromo-6-chloronaphtho[1,2-d][1,2,3]oxadiazole

[0421] To a solution of 2,4-dibromo-5-chloronaphthalen-1-amine (5.5 g, 16.4 mmol) and propionic acid (12.2 g, 164.0 mmol) in acetic acid (50 mL) was added sodium nitrite (1.72 g, 24.6 mmol) at 10 °C. The resulting solution was stirred for 1h at room temperature. The organic layer was poured into ice water resulting in the appearance of a large number of solids. After filtration, the solids were collected and washed with water. The mixture was dried under vacuum to afford the title compound (4100 mg, 88.2% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 282.8.

[0422] Step c: 4-Bromo-5-chloronaphthalen-2-ol

[0423] To a solution of 5-bromo-6-chloronaphtho[1,2-d][1,2,3]oxadiazole (500 mg, 1.76 mmol) in ethanol (6 mL), and tetrahydrofuran (3 mL) was added sodium borohydride (133 mg, 3.52 mmol) at 0 °C. The resulting solution was stirred for 1h at room temperature. The reaction mixture was quenched with ice water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexanes (20%) to afford the title compound (250 mg, 38.5% yield) as a brown solid. LCMS (ESI, m / z): [M+H]+= 255.1.

[0424] Step d: 1-Bromo-8-chloro-3-(methoxymethoxy)naphthalene

[0425] To a solution of 4-bromo-5-chloronaphthalen-2-ol (100 mg, 0.39 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (150 mg, 1.16mmol), and bromomethyl methyl ether (75 mg, 0.60 mmol) at 0 °C. The resulting solution was stirred for 30 min at room temperature. The reaction mixture was quenched with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexanes (5%) to afford the title compound (110 mg, 65.8% yield) as a brown solid.

[0426] Step e: 2-(8-Chloro-3-(methoxymethoxy)naphthalen-1-yl)-4, 4,5,5-tetramethyl -1,3,2-dioxaborolane

[0427] To a solution of 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (230 mg, 0.76 mmol), and bis(pinacolato)diboron (388 mg, 1.53 mmol) in 1,4-dioxane (5 mL)was added potassium acetate (379 mg, 3.86mmol), and 1, T-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (64 mg, 0.08 mmol) at room temperature. The mixture was stirred at 80 °C for 1h under nitrogen. The reaction mixture was quenched with water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexanes (5%) to afford the title compound (160 mg, 57.2% yield) as a yellow oil.

[0428] Step f: 1-(((S)-1-(7-(8-Chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0429] To a solution of 1-(((S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (84 mg, 0.17 mmol) and 2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 0.2 mmol) in tetrahydrofuran (2.5 mL) and water (0.5 mL) was added potassium phosphate tribasic (127 mg, 0.6 mmol) and cataCXium A Pd G3 (29 mg, 0.04 mmol) at room temperature. The resulting solution was stirred for 2h at 80 °C under nitrogen. The reaction mixture was quenched with water, extracted with ethyl acetate and the organic layers were combined. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (10%) to afford the title compound (100 mg, 50.6% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 689.2.

[0430] Step g: 1-(((S)-1-(7-(8-Chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0431] To a solution of 1-(((S)-1-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (80 mg, 0.12 mmol) in dichloromethane (2 mL) was added 4M HCl in 1,4-dioxane (0.5 mL) at room temperature. The resulting solution was stirred for 10 min at room temperature. The solvent was concentrated under vacuum. The crude product was purified by Prep-HPLC to afford the title compound (20.8 mg, 27.2% yield) as a white solid. LCMS (ESI, m / z): [M+H]+= 645.3.

[0432] Route I

[0433] Example 17. 1-(((S)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2 -(((2 / ?,7aS)-2 -fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 / 7)-one (Compound 88)

[0434] Step a: 1-Bromo-8-fluoro-3-(methoxymethoxy)naphthalene

[0435] Sodium hydride (398 mg, 9.96 mmol) was added into the solution of 4-bromo-5-fluoro-naphthalen-2-ol (600 mg, 2.49 mmol) in A / , A / -dimethylformamide (6 mL) and stirred at 0 °C for 0.05 h. Then bromomethyl methyl ether (0.51 ml_, 6.22 mmol) was added and stirred at 0 °C for 0.5h. After completion, the reaction mixture was adjusted to pH 7 with saturated ammonium chloride, extracted with ethyl acetate, washed with water (30 mL) and the reaction mixture was combined. The reaction mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 1) to afford the title compound (300.0 mg, 42.3% yield) as a black solid. LCMS: (ESI, m / z): [M+H]+= 284.0.

[0436] Step b: 2-(8-Fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4, 4,5,5-tetramethyl-1,3,2-dioxaborolane

[0437] A solution of 1-bromo-8-fluoro-3-(methoxymethoxy)naphthalene (300 mg, 1.05 mmol), bis(pinacolato)diboron (400 mg, 1.58 mmol), potassium acetate (300 mg, 3.16 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (78.0 mg, 0.11 mmol) in 1,4-dioxane (1 mL) was stirred at 100 °C for 1.5h. After completion, the reaction mixture was concentrated under vacuum, diluted with dichloromethane(200 mL), washed with water (30 mL) and the reaction mixture was combined. The reaction mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 1) to afford the title compound (155.0 mg, 44.3% yield) as a black solid. LCMS (ESI, m / z): [M+H]+= 332.2.

[0438] Step c: 1-((1-(8-Fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0439] Under nitrogen, a solution of 1-((1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (100 mg, 0.2 mmol), 2-(8-fluoro-3-(methoxymethoxy)-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (99 mg, 0.3 mmol), cesium carbonate (194 mg, 0.6 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 95 °C for 1h. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to afford the title compound (62 mg, 46.4% yield) as a yellow solid. LCMS: (ESI, m / z):[M+H]+= 673.4.

[0440] Step d: 1-(((S)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one

[0441] A solution of 1-((1-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (80 mg, 0.12 mmol) in 4M HCI in 1,4-dioxane (1 mL) and dichloromethane (3 mL) was stirred at 25 °C for 0.5h. After completion, the reaction mixture was concentrated under vacuum, the residue was purified by reverse phase chromatography (acetonitrile 40 / 0.1% ammonium bicarbonate in water) and Prep-HPLC. The isomers were further isolated by Prep-CHIRAL-HPLC with the following conditions: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: hex: dichloromethane=3: 1(0.5% 2M NH3- methanol)-HPLC, Mobile Phase B: ethanol- HPLC; Flow rate: 20 mL / min; Gradient: 50% B to 50% B in 22 min; 220 / 254 nm; RT1: 14.84 min. 1-(((S)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1H)-one (3.2 mg, 4.2% yield) as a white solid. LCMS: (ESI, m / z):[M+H]+= 629.3. tR = 2.37 min (CHIRALPAK IE-3, 4.6*50 mm, 3 urn, (Hex: Dichloromethane=3:1)(0.1%DEA): EtOH=50:50, 1.0 mL / min).

[0442] Route J

[0443] Example 18. 1-(((S)-1-(7-(8-Ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2(1 / 7)-one (Compound 89)

[0444] Step a: 1-(((2S)-1-(7-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one

[0445] A solution of 1-(((2S)-1-(8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)-7-(3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one (250 mg, 0.30 mmol) and caesium fluoride (150 mg, 0.99 mmol) in A / , A / -dimethylformamide (2 mL) was stirred at room temperature for 1h. The resulting residue was purified by reverse phase chromatography (acetonitrile 30-40% / 10mmol / L ammonium bicarbonate in water) to afford the title compound (180 mg, 86.3% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+=679.3.

[0446] Step b: 1-(((2S)-1-(7-(8-Ethynyl-3-hydroxy-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one

[0447] A solution of 1-(((2S)-1-(7-(8-ethynyl-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)pyridin-2-one (160 mg, 0.24 mmol) and 4M HCI / dioxane (0.5 mL) in dichloromethane (2 mL) was stirred at room temperature for 1h. The solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile 40-50% / 10 mmol / L ammonium bicarbonatein water) to afford the title compound. The crude product was purified by Prep-HPLC to afford the title compound (87.5 mg, 58.5% yield) as a yellow solid. LCMS (ESI, m / z):[M+H]+=635.3.

[0448] Route K

[0449] Example 19. 2-(3-((( / ?)-1-(7-(8-Ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)-5-fluoropyridin-4-yl)acetonitrile (Compound 97)

[0450] Step a: (3-Bromo-5-fluoropyridin-4-yl)methanol

[0451] A solution of 3-bromo-5-fluoro-pyridine-4-carbaldehyde (1.00 g, 4.90 mmol) and sodium borohydride (556 mg, 14.7 mmol) in methyl alcohol (10 mL) was stirred at room temperature for 2h. The reaction mixture was quenched with water. The reaction mixture was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. Then the organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (0-100%), to afford the title compound (880 mg, 87.1% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+=206.0.

[0452] Step b: 3-Bromo-4-(chloromethyl)-5-fluoropyridine

[0453] A solution of (3-bromo-5-fluoropyridin-4-yl)methanol (870 mg, 4.22 mmol), thionyl chloride (0.5 mL) and A / , A / -dimethylformamide (0.2 mL) in dichloromethane (10 mL) was stirred at room temperature for 2h. The reaction mixture was quenched with water (5 mL). The reaction mixture was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate. Thenthe organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (0-100%), to afford the title compound (700 mg, 73.8% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 223.9.

[0454] Step c: 2-(3-Bromo-5-fluoropyridin-4-yl)acetonitrile

[0455] A solution of 3-bromo-4-(chloromethyl)-5-fluoropyridine (690 mg, 3.07 mmol) in acetonitrile (10 mL) was stirred at 0 °C. Then lithium hydroxide (74 mg,3.09 mmol) and trimethylsilanecarbonitrile (0.5 mL, 3.69 mmol) was added and stirred at 0 °C for 4 h. The reaction mixture was quenched with water. The reaction mixture was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. Then the organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (0-100%), to afford the title compound (190 mg, 28.7% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+=215.0.

[0456] Step d: tert-Butyl (R)-2-((4-(cyanomethyl)-5-fluoropyridin-3-yl)methyl)azetidine-1 -carboxylate

[0457] A solution of 2-(3-bromo-5-fluoropyridin-4-yl)acetonitrile (180 mg, 0.84 mmol), tert-butyl (S)-2-(bromomethyl)azetidine-1 -carboxylate (210 mg, 0.84 mmol), hexafluorophosphate (5 mg, 0.01 mmol), bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridinyl)phenyl)ruthenium hexafluorophosphate-4,4'-bis(2-methyl-2-propanyl)-2,2'-bipyridine (200 mg, 0.18 mmol), sodium carbonate (177 mg, 1.67 mmol), nickel(II) chloride dimethoxyethane adduct (5 mg, 0.0 1mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (2 mg, 0.01 mmol) in 1,2-dimethoxyethane (2 mL) was stirred at Blue LEDs and room temperature for 8h. The solvent was removed. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (0-100%), to afford the title compound (96 mg, 25.8% yield) as a yellow oil. LCMS (ESI, m / z): [M+H]+=306.2.

[0458] Step e: (R)-2-(3-(Azetidin-2-ylmethyl)-5-fluoropyridin-4-yl)acetonitrile

[0459] A solution of tert-butyl (R)-2-((4-(cyanomethyl)-5-fluoropyridin-3-yl)methyl)azetidine-1 -carboxylate (96 mg, 0.31 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (2 mL) was stirred at room temperature for 1h. The solvent was concentrated under vacuum. The crude product was directly used in the next step without purification. LCMS (ESI, m / z): [M+H]+=206.1.

[0460] Step f: 2-(3-(((R)-1 -(7-(8-Ethynyl-3-(methoxymethoxy)naphthalen-1 -y I )-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)-5-fluoropyridin-4-yl)acetonitrile

[0461] A solution of (R)-2-(3-(azetidin-2-ylmethyl)-5-fluoropyridin-4-yl)acetonitrile (96 mg, 0.47 mmol), 7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido(4,3-d)pyrimidin-4-ol (100 mg, 0.18 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (170 mg, 0.32 mmol) and A / , A / -diisopropylethylamine (0.5 mL) in dichloromethane (3 mL) was stirred at room temperature for 1h. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 10mmol / L ammonium bicarbonate in water) to afford the title compound (60 mg, 17.8% yield) as a yellow solid. LCMS (ESI, m / z): [M+H]+=720.3.

[0462] Step g: 2-(3-(((R)-1-(7-(8-Ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)-5-fluoropyridin-4-yl)acetonitrile

[0463] A solution of 2-(3-(((R)-1-(7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido(4,3-d)pyrimidin-4-yl)azetidin-2-yl)methyl)-5-fluoropyridin-4-yl)acetonitrile (65 mg, 0.09 mmol) and 4.0 M hydrogen chloride solution in 1,4-dioxane (0.5 mL) in dichloromethane (3 mL) was stirred at room temperature for 1h. The solvent was concentrated under vacuum. The crude product was purified by Prep-HPLC to afford the title compound (7.7 mg, 12.6% yield) as a yellow solid. LCMS (ESI, m / z):[M+H]+= 676.3.

[0464] Tethered Quinazolines

[0465] Intermediates l-IV

[0466] Step a: methyl 2-amino-4-bromo-3,6-difluorobenzoate

[0467] To a stirred solution of 2-amino-4-bromo-3,6-difluorobenzoic acid (300 g, 1190 mmol) in EtOAc (1.5L) and MeOH (1.5L) was added TMSCHN2(1490 mL, 2976 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 20 min at room temperature. The reaction mixture was quenched with the addition of HOAc (150 mL) at room temperature. The resulting mixture was concentrated under vacuum. The residue was adjusted to pH = 8 with saturated NaHCO3(aq.). The resulting mixture was triturated with water (1.5L). The precipitated solids were collected by filtration and washed with water. The resulting solid was dried to afford methyl 2-amino-4-bromo-3,6-difluorobenzoate (290 g, 91.6%) as a grey solid. LCMS (ESI): [M+H]+=266.0.

[0468] Step b: methyl 2-amino-3,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0469] To a solution of methyl 2-amino-4-bromo-3,6-difluorobenzoate (235 g, 883 mmol) and 2-(4,5-dimethyl-1,3,2-dioxaborolan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (299 g, 1325 mmol) in dioxane (2.5L) were added KOAc (260 g, 2650 mmol) and Pd(dppf)Cl2CH2Cl2(54 g, 66.25 mmol). After stirring overnight at 100 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM. The resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentratedunder reduced pressure to afford methyl 2-amino-3,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (350 g) as a crude red oil, which was used for the next step directly. LCMS (ESI): [M+H]+=314.10.

[0470] Step c: methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3,6-difluorobenzoate

[0471] To a solution of methyl 2-amino-3,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (350 g, crude), 6-bromo-N, N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (350 g, 706.6 mmol) in ACN (2L) and H2O (500 mL) were added KF (104 g, 1790 mmol) and Pd(PPh3)2Cl2(24.8 g, 35.3 mmol). After stirring for 1h at 80 °C under a nitrogen atmosphere, the mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with acetonitrile. The residue was purified by trituration with water (3L). The solids were collected by filtration and washed with water. The resulting solid was dried under infrared light. The resulting solid was dissolved in EtOAc at 70 °C. Then silica thiol (50g) and active carbon (50g) was added at 70 °C. After 30 min, the resulting mixture was filtered immediately, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. This resulted in methyl 2-amino-4-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3,6-difluorobenzoate (311 g, 73.17%) as a light yellow solid. LCMS (ESI): [M+H]+=602.15.

[0472] Step d: 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-3,6-difluorobenzoic acid

[0473] A solution / mixture of methyl 2-amino-4-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3,6-difluorobenzoate (311 g, 517 mmol) and NaOH (414 g, 10340 mmol) in THF (1L), MeOH (1L) and H2O (1L) was stirredat 50 °C. The resulting mixture was concentrated under reduced pressure until water was left. The residue was acidified to pH 6 with concentrated HCI. The aqueous layer was extracted with EtOAc (3x1000mL), and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. This resulted in the title compound (290 g, 95.47%) as a light yellow solid. LCMS (ESI): [M+H]+= 588.25.

[0474] Step e: 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-5-chloro-3,6-difluorobenzoic acid

[0475] To a solution of 2-amino-4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-3,6-difluoro-benzoic acid (20 g, 34 mmol) in 1-methyl-2-pyrrolidinone (100 mL) was added A / -chlorosuccinimide (9.1 g, 68.1 mmol). The mixture was stirred at 30 °C for 6h. After completion, the reaction mixture was quenched with saturated sodium thiosulfate solution. The reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layers were washed with water again. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product 2-amino-4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3- (trifluoromethyl)-2-pyridyl]-5-chloro-3,6-difluoro-benzoic acid (20 g, crude) was used in the next step directly without further purification. LC-MS: (ESI, m / z): 622.1 [M+H]+.

[0476] Step f: 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-5-chloro-3,6-difluorobenzamide

[0477] A solution of 2-amino-4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-5-chloro-3,6-difluoro-benzoic acid (120 g, crude), ammonium chloride (20.6 g, 385.9 mmol), A / , A / -diisopropylethylamine (49.9 g, 386 mmol) and HATU (47.7 g, 125.4 mmol) in A / , A / -dimethylformamide (500 mL) was stirred at 25 °C for 2h. After completion, the reaction mixture was quenched with saturated sodium thiosulfate solution. The reaction mixture was diluted with water (300 mL). The resulting solution was extracted with ethyl acetate (3 x 800 mL) and the organic layers were combined. The organic layers were washed with water (3 x 200 mL) again. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:8) to afford the title compound (60 g, 96.6 mmol, 50.1% yield)) as a brown solid. LC-MS: (ESI, m / z): 621.1 [M+H]+.

[0478] Step g: 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one (Intermediate I)

[0479] To a solution of 2-amino-4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-5-chloro-3,6-difluoro-benzamide (37 g, 59.5 mmol) in 1,4-dioxane (370 mL) was added thiophosgene (11.4 mL, 149 mmol) and the mixture was stirred at 105 °C for 20 minutes. After completion, the filtrate was concentrated under reduced pressure. To the residue was added methanol and the mixture wasstirred at 25 °C for 10 min. After filtration, the filter cake afforded 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-2,6-dichloro-5,8-difluoro-3H-quinazolin-4-one (36 g, 54.1 mmol, 90.8% yield) as a white solid. LC-MS: (ESI, m / z): 664.9 [M+H]+.

[0480] Step h: (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one

[0481] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one (100 g, 0.15 mol) was purified by Prep-Chiral-SFC with the following condition to afford the title compounds. Column: CHIRALPAK OX, 5*25cm, 10pm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 180 mL / min; Gradient (B%): isocratic 50% B; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 5.; Sample Solvent: MeOH: DCM=1: 1(0.1% 2M NH3-MeOH); Injection Volume: 7 mL. (R)-7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one (30 g, 30% yield) as a light yellow solid. LCMS (ESI, m / z) [M+H]+= 665.1. tR = 2.07 min (SFC, CHIRALCEL OX-33.0*100mm, 3pm, MeOH (0.1% DEA), 10% to 50% in 2.0 min, hold 1.0 min at 50% 2 ml / min, 220 nm). (S)-7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one (33 g, 30% yield) as a light yellow solid. LCMS (ESI, m / z) [M+H]+= 665.1. tR = 2.28 min (SFC, CHIRALCEL OX-33.0*100mm, 3pm, MeOH (0.1% DEA), 10% to 50% in 2.0 min, hold 1.0 min at 50% 2 ml / min, 220 nm).

[0482] Step i: (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0483] Under nitrogen, to a solution of (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one (1.0 g, 1.5 mmol), TBAI (56.4 mg, 0.15 mmol) and Cs2CO3 (982.81 mg, 3.01- mmol) in tetrahydrofuran (10 mL) was added SEMCI (376 mg, 2.26 mmol) and the mixture was stirred for 1h at room temperature. The reaction mixture was quenched with water and extracted with EA. The solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3:1) to afford the title compound (918 mg, 76.8% yield) as a yellow oil. LC-MS: (ESI, m / z): 795 [M+H]+.

[0484] Step j: (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (Intermediate III)

[0485] Under nitrogen, to a solution of ((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol (159 mg, 1.00 mmol) in toluene (10 mL) was added t-BuONa (193 mg, 2.00 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 minutes. Then (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (800 mg, 1.0 mmol) was added at 0 °C and stirred for 1h at room temperature. The reaction mixture was quenched with aqueous ammonium chloride solution. The reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (0-50%) to afford the title compound (400 mg, 43.6% yield) as a white solid. LC-MS: (ESI, m / z): 918 [M+H]+.

[0486] Step k: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (Intermediate IV)

[0487] A solution of (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (1.7 g, 1.85 mmol) in TFA (17 mL) was stirred at 60 °C for 3h. The solvent was removed. The resulting residue was purified by reverse phase chromatography to afford the title compound (600 mg, 59.2% yield) as a white solid. LC-MS: (ESI, m / z): 548 [M+H]+.

[0488] Intermediate VIntermediate V

[0489] Intermediate V: 1-(((2S,8R,11aS)-8-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5,9-dichloro-7-fluoro-1,2,11,11a-tetrahydroazeto[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)methyl)pyridin-2(1 H)-one

[0490] Step a: 1-(((2S,4S)-1-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4-yl)-4-(hydroxymethyl)azetidin-2-yl)methyl)pyridin-2(1 H)-one

[0491] A solution of 1-(((2S,4S)-4-(hydroxymethyl)azetidin-2-yl)methyl)pyridin-2(1H)-one (0.44 g, 2.25 mmol), (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one (1.0 g, 1.5 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.76 g, 3.01 mmol) and N, N-diisopropylethylamine (0.79 ml_, 4.51 mmol) in chloroform (10 mL) was stirred at 70 °C for 2h. The solvent was concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (80%) to afford the title compound (800 mg, 63.3% yield) as a yellow oil. LCMS (ESI, m / z) [M+H]+= 841.2.

[0492] Step b: 1-(((2S,11aS)-8-((R)-6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5,9-dichloro-7-fluoro-1,2, 11, 11 a-tetrahydroazeto[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)methyl)pyridin-2(1H)-one

[0493] To a solution of 1-(((2S,4S)-1-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4-yl)-4-(hydroxymethyl)azetidin-2-yl)methyl)pyridin-2(1H)-one (800 mg, 0.95 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (190 mg, 4.75 mmol) and the mixture was stirred at 0 °C for 0.5h. Then the solution was stirred at room temperature for 1h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution. The residue was purified by reverse phase chromatography (acetonitrile 0-40 / 0.1% ammonium bicarbonate in water) to afford the title compound (500 mg, 64% yield) as a yellow solid. LCMS (ESI, m / z) [M+H]+= 821.2.

[0494] Intermediate VIstep a step b / TrtO NIBoc

[0495] Intermediate VI: ((2S,4R)-4-methylazetidin-2-yl)methanol

[0496] Step a: tert-Butyl (2R,4S)-2-Methyl-4-((trityloxy)methyl)azetidine-1-carboxylate

[0497] A solution of fert-butyl (2S,4S)-2-(methylsulfonyloxymethyl)-4-(trityloxymethyl)azetidine-1-carboxylate (500 mg, 0.93 mmol) in THF (5 mL) was stirred at 0 °C. Then 1M lithium triethylborohydride in THF (4.65 ml_, 4.65 mmol) was added and stirred at 25 °C for 16h. After completion, the reaction mixture was quenched with water. The resulting solution was extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (10:7) to afford the title compound (380 mg, 92.1% yield) as a transparent oil. LC-MS: (ESI, m / z): 444.3 [M+H]+.

[0498] Step b: ((2S,4R)-4-Methylazetidin-2-yl)methanol

[0499] A solution of tert-butyl (2R,4S)-2-methyl-4-((trityloxy)methyl)azetidine-1-carboxylate (370 mg, 0.83 mmol) and trifluoroacetic acid (0.75 ml_, 9.73 mmol) in dichloromethane (4 mL) was stirred at room temperature for 1h. After completion, the organic layer was concentrated in vacuum. Then the crude product was purified by solid phase extraction column chromatography to afford the title compound (66 mg, 78.2% yield) as a transparent oil. LC-MS: (ESI, m / z): 102.2 [M+H]+.

[0500] Synthetic Routes to Final Compounds

[0501] Route A

[0502] Examples 20a and 20b. 1-(((11S,13S)-3-(6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((2 / ?,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)-15-oxa-6,8,10-triazatetracyclo(7.6.1.05,16.010,13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methyl)pyridin-2-one;formic acid (Compound 221a) & 1-(((11 / ?,13 / ?)-3-(6- Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((2 / ?,8S)-2-fluoro-1, 2, 3,5,6, 7-hexahydropyrrolizin-8-yl)methoxy)-15-oxa-6, 8,10-triazatetracyclo(7.6.1.05,16.010,13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methyl)pyridin-2-one;formic acid (Compound 221b)

[0503] Step a: trans-terf-Butyl (2S,4S)-2-(hydroxymethyl)-4-((2-oxopyridin-1 (2H)-yl)methyl)azetidine-1 -carboxylate

[0504] To a mixture of trans-tert-butyl (2S,4S)-2,4-bis(hydroxymethyl)azetidine-1 -carboxylate (300 mg, 1.38 mmol) in THF (3 mL) was added 1H-pyridin-2-one (105 mg, 1.1 mmol), triphenylphosphine (720 mg, 2.75 mmol) and the mixture was stirred for 5 min. Then diisopropyl azodicarboxylate (550 mg, 2.72 mmol) in THF (1 mL) was added and stirred for 1h at 0 °C. The reaction mixture was purified by reverse phase chromatography (acetonitrile 30-40 / 1 Ommol / L NH4HCO3in water) to afford the title compound (400 mg, 98.4% yield) as a white solid. LCMS (ESI): [M+H] + =295.3.

[0505] Step b: trans-1-(((2S,4S)-4-(Hydroxymethyl)azetidin-2-yl)methyl)pyridin- 2-one

[0506] A solution of trans-terf-butyl (2S,4S)-2-(hydroxymethyl)-4-((2-oxo-1-pyridyl)methyl)azetidine-1 -carboxylate (400 mg, 1.36 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (2 mL) was stirred at room temperature for 1 h. The solvent was concentrated under vacuum. The crude product was purified by solid-phase extraction to afford the title compound (90 mg, 34.1% yield) as a yellow oil. LCMS (ESI): [M+H]+=194.9.

[0507] Step c: trans-1-(((2S,4S)-1-(7-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2,6-dichloro-5,8-difluoro-quinazolin-4-yl)-4-(hydroxymethyl)azetidin-2-yl)methyl)pyridin-2-one

[0508] A solution of trans-7-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl- 3-(trifluoromethyl)-2-pyridyl)-2,6-dichloro-5,8-difluoro-3H-quinazolin-4-one (270 mg, 0.41 mmol) and 1-(((2S,4S)-4-(hydroxymethyl)azetidin-2-yl)methyl)pyridin-2-one (80 mg, 0.41 mmol), A / , A / -diisopropylethylamine (1 mL), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (155 mg, 0.61 mmol) in chloroform (3 mL) was stirred at 70 °C for 1h. The solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile 70-80 / 10 mmol / L NHUHCOs in water) to afford the title compound (300 mg, 87.8% yield) as a yellow solid. LCMS (ESI): [M+H]+=841.3.

[0509] Step d: trans-1-(((11S,13S)-3-(6-(bis((4-methoxyphenyl)methyl)amino)- 4-methyl-3-(trifluoromethyl)-2-pyridyl)-2,7-dichloro-4-fluoro-15-oxa-6,8, 10-triazatetracyclo(7.6.1.05, 16.010,13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methyl)pyridin-2-one

[0510] To a solution of trans-1-(((2S,4S)-1-(7-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2,6-dichloro-5,8-difluoro-quinazolin-4-yl)-4-(hydroxymethyl)azetidin-2-yl)methyl)pyridin-2-one (290 mg, 0.34 mmol) in THF (5 mL) was added sodium hydride (25 mg, 1.04 mmol) at 0 °C and the mixture was stirred for 1h at room temperature. The reaction mixture was quenched with saturated ammonium chloride aqueous solution The resulting solution was extracted with ethyl acetate and the organic layers were combined. The resulting residue was purified by reverse phase chromatography (acetonitrile 50-60 / 1 Ommol / L NH4HCO3in water) to afford the title compound (190 mg, 67.1% yield) as a yellow solid. LCMS (ESI): [M+H]+=821.3.

[0511] Step e: trans-1-(((11S,13S)-3-(6-(Bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((2R,8S)-2-fluoro-1, 2, 3,5,6, 7-hexahydropyrrolizin-8-yl)methoxy)-15-oxa-6, 8,10-triazatetracyclo(7.6.1.05, 16.010,13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methyl)pyridin-2-one

[0512] To a solution of ((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methanol (35 mg, 0.22 mmol) in THF (5 mL) was added sodium hydride (27 mg, 0.68 mmol) at 0 °C and the mixture was stirred for 10 min. Then trans-1-(((11S,13S)-3-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2,7-dichloro-4-fluoro-15-oxa-6,8, 10-triazatetracyclo(7.6.1.05, 16.010,13)hexadeca-1(16),2,4,6,8-pentaen-11-yl)methyl)pyridin-2-one (180 mg, 0.22 mmol) was added and stirred at room temperature for 1h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The resulting residue was purified by reverse phase chromatography (acetonitrile 60-70 / 1 Ommol / L NH4HCO3in water) to afford the title compound (100 mg, 48.3% yield) as a yellow solid. LCMS (ESI): [M+H]+=944.5.

[0513] Step f: 1-(((11S,13S)-3-(6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)-15-oxa-6,8, 10-triazatetracyclo(7.6.1.05, 16.010, 13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methyl)pyridin-2-one formic acid & 1-(((11R,13R)-3-(6-Amino-4-methyl-3- (trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((2R,8S)-2-fluoro-1, 2, 3, 5,6,7-hexahydropyrrolizin-8-yl)methoxy)-15-oxa-6,8, 10-triazatetracyclo(7.6.1.05, 16.010,13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methyl)pyridin-2-one formic acid

[0514] A solution of trans-1-(((11S,13S)-3-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)-15-oxa-6,8, 10-triazatetracyclo(7.6.1.05, 16.010,13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methyl)pyridin-2-one (90 mg, 0.10 mmol) in trifluoroacetic acid (3 mL) was stirred at 60 °C for 2h. The solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile 60-70 / 10 mmol / L NH4HCO3in water) to afford the title compound. The crude product was purified by Prep-HPLC with the following conditions: Column: X select CSH C18 OBD Column 30*150mm 5pm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 35% B in 10 min; Wave Length: 254 / 220 nm; RT1(min). Thestereochemistry of the isomers was arbitrarily assigned. 1-(((11S,13S)-3-(6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((2R,8S)-2-fluoro-1, 2, 3, 5,6,7-hexahydropyrrolizin-8-yl)methoxy)-15-oxa-6,8, 10-triazatetracyclo(7.6.1.05, 16.010,13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methyl)pyridin-2-one;formic acid (9.9 mg, 14.8% yield) as a white solid, LCMS (ESI):[M+H]+=704.2. 1-(((11R,13R)-3-(6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)-15-oxa-6,8,10-triazatetracyclo(7.6.1.05,16.010,13)hexadeca-1(16),2,4,6,8-pentaen-11-yl)methyl)pyridin-2-one;formic acid (10.2 mg, 14.3% yield) as a white solid, LCMS (ESI):[M+H]+=704.2.

[0515] Route B

[0516] Example 21. A / -(1-(((2S,8 / ?,11aS)-8-(6-Amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11 a-tetrahydroazeto[2', T:3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)-N-methylacetamide (Compound 100)

[0517] Step a: A / -(2-(Benzyloxy)pyridin-3-yl)acetamide

[0518] Under nitrogen, to a solution of 2-benzyloxy-3-bromo-pyridine (5.0 g, 18.9 mmol) in 1,4-dioxane (50 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (547 mg, 0.95 mmol). Then tris(dibenzylideneacetone)dipalladium (884 mg, 0.97 mmol), cesium carbonate (7.4 g, 22.7 mmol), and acetamide (1.1 g, 18.9 mmol) was added at room temperature. The resulting solution was stirred for 2h at 100 °C under nitrogen. After completion, the solvent was removed under vacuum. Theresidue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (5:1) to afford the title compound (4.6 g, 75.8% yield) as a red solid. LCMS (ESI): [M+H]+= 243.1.

[0519] Step b: A / -(2-(Benzyloxy)pyridin-3-yl)-A / -methylacetamide

[0520] To a solution of / V-(2-(benzyloxy)pyridin-3-yl)acetamide (2.0 g, 8.26 mmol) in THF (20 mL) was added sodium hydride (1.6 g, 41.3 mmol) and the mixture was stirred at 0 °C for 10 min. Then iodomethane (2.3 g, 16.5 mmol) was added and stirred at room temperature for 1h. After completion, the reaction mixture was quenched with saturated ammonium chloride solution. The resulting solution was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (5:1) to afford the title compound (1.8 g, 80.8% yield) as a red oil. LCMS (ESI): [M+H]+= 257.1.

[0521] Step c: A / -(2-Hydroxy-3-pyridyl)-A / -methyl-acetamide

[0522] Under hydrogen, a mixture of A / -(2-benzyloxy-3-pyridyl)-A / -methyl-acetamide (600 mg, 2.34 mmol) and 10% Pd / C (876 mg, 2.34 mmol) in MeOH (10 mL) was stirred for 0.5h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile 0-15% / 10 mmol / L ammonium bicarbonate in water) to afford the title compound (310 mg, 76.5% yield) as a yellow solid. LCMS (ESI): [M+H]+= 167.1.

[0523] Step d: tert-Butyl (2S,4S)-2-(hydroxymethyl)-4-((3-(A / -methylacetamido)-2-oxopyridin-1 (2H)-yl)methyl)azetidine-1 -carboxylate

[0524] Under nitrogen, to a solution of A / -(2-hydroxy-3-pyridyl)-A / -methyl-acetamide (181 mg, 1.09 mmol), tert-butyl (2S,4S)-2-(hydroxymethyl)-4-(trityloxymethyl)azetidine-1-carboxylate (500 mg, 1.09 mmol) and triphenylphosphine (452 mg, 1.73 mmol) in dichloromethane (5 mL) was added diisopropyl azodicarboxylate (362 mg, 1.79 mmol) at 0 °C. The resulting solution was stirred for 1h at room temperature. The reaction mixture was quenched with methanol and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (0-10%) to afford the title compound (500 mg, 83.5% yield) as a yellow oil. LCMS (ESI): [M+Na]+=388.1.

[0525] Step e: A / -(1-(((2S,4S)-4-(Hydroxymethyl)azetidin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)-A / -methylacetamide

[0526] To a solution of tert-butyl (2S,4S)-2-(hydroxymethyl)-4-((3-(A / -methylacetamido)-2-oxopyridin-1(2H)-yl)methyl)azetidine-1 -carboxylate (500 mg, 0.82 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3 mL) and the mixture was stirred at 25 °C for 1h. The solvent was concentrated under vacuum. The residue was purified by solid-phase extraction to afford the title compound (200 mg, 88% yield) as a yellow oil. LCMS (ESI): [M+H]+= 266.1.

[0527] Step f: A / -(1-(((2S,4S)-1-((R)-7-(6-Amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-4-(hydroxymethyl)azetidin-2-yl)methyl)-2-oxo-1, 2-dihydropyridin-3-yl)-A / -methylacetamide

[0528] To a solution of 7-(6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5,8-difluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)quinazolin-4-ol (110 mg, 0.20mmol) and A / -(1-(( (2S,4S)-4- (hydroxymethyl)azetidin-2-yl)methyl)-2-oxo-3-pyridyl)-A / -methyl-acetamide (66 mg, 0.25 mmol) in dichloromethane (2 mL) was added A / , A / -diisopropylethylamine (110 mg, 0.85 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (198 mg, 0.38 mmol) and the mixture was stirred at 25 °C for 1h. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile 0-57% / 10 mmol / L ammonium bicarbonate in water) to afford the title compound (140 mg, 87.7% yield) as a light yellow solid. LCMS (ESI):[M+H]+= 795.1.

[0529] Step g: A / -(1-(((2S,8R,11aS)-8-(6-Amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11a-tetrahydroazeto[2',1':3,4][1,4]oxazepino[5,6,7-cte]quinazolin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)-N-methylacetamide

[0530] To a solution of A / -(1-(((2S,4S)-1-(7-(6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl)-6-chloro-5,8-difluoro-2-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)quinazolin-4-yl)-4-(hydroxymethyl)azetidin-2-yl)methyl)-2-oxo-3-pyridyl)-A / -methyl-acetamide (135 mg, 0.17 mmol) in THF (2 mL)was added sodium hydride (45 mg, 1.13 mmol), and the mixture was stirred at 0 °C for 1h.The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine and dried with anhydrous sodium sulfate. The reaction mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile 0-80% / 10 mmol / L ammonium bicarbonate in water) and Prep-HPLC to afford the title compound (42.2 mg, 31.5% yield) as a white solid, LCMS (ESI): [M+H]+= 775.4.

[0531] Route C

[0532] Example 22. 1-(((2S,8R,11aS)-8-(6-Amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((3R)-3-fluoro-1-azabicyclo(3.2.0)heptan-5-yl)methoxy)-1,2,11,11a-tetrahydroazeto(2', T:3,4)(1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)pyridin-2(1H)-one (Compound 166)

[0533] Step a: 1-(((2S,8R,11aS)-8-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((3S)-3-((4-methoxybenzyl)oxy)-1-azabicyclo(3.2.0)heptan-5-yl)methoxy)-1,2, 11, 11 a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)pyridin-2(1 H)-one

[0534] To a solution of ((3S)-3-((4-Methoxyphenyl)methoxy)-1-azabicyclo(3.2.0)heptan-5-yl)methanol (300 mg, 1.14 mmol) in THF (10 mL) was added sodium hydride (260 mg, 6.50 mmol) at 0 °C and the mixture was stirred for 10 min at the same temperature. Then 1-(((11S,13S)-3-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2,7-dichloro-4-fluoro-15-oxa-6,8, 10-triazatetracyclo(7.6.1.05,16.010,13)hexadeca-1,3,5(16),6,8-pentaen-11-yl)methyl)pyridin-2-one (468 mg, 0.57 mmol) was added and stirred for 5 h at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate, and the organic layers were combined. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (20 %) to afford the title compound (150 mg, 25.1% yield) as a yellow solid. LCMS (ESI): [M+H]+= 1048.3.

[0535] Step b: 1-(((2S,8R,11aS)-8-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((3S)-3-hydroxy-1-azabicyclo(3.2.0)heptan-5-yl)methoxy)-1,2, 11, 11 a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)pyridin-2(1 H)-one

[0536] A solution of 1-(((11S,13S)-3-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((3S)-3-((4-methoxyphenyl)methoxy)-1-azabicyclo(3.2.0)heptan-5-yl)methoxy)-15-oxa-6,8,10-triazatetracyclo(7.6.1.05,16.010,13)hexadeca-1,3,5(16),6,8-pentaen-11-yl)methyl)pyridin-2-one (150 mg, 0.14 mmol) and trifluoroacetic acid (0.4 mL) in dichloromethane (2 mL) was stirred for 20 min at room temperature. The reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM Ammonium bicarbonate in water / acetonitrile) to afford the title compound (75 mg, 56.5% yield) as a white solid. LCMS (ESI): [M+H]+= 928.7.

[0537] Step c: 1-(((2S,8R,11aS)-8-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((3R)-3-fluoro-1-azabicyclo(3.2.0)heptan-5-yl)methoxy)-1,2, 11, 11 a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)pyridin-2(1 H)-one

[0538] To a solution of 1-(((11S,13S)-3-(6-(Bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((3S)-3-hydroxy-1 -azabicyclo(3.2.0)heptan-5-yl)methoxy)-15-oxa-6,8, 10-triazatetracyclo(7.6.1.05,16.010,13)hexadeca-1,3,5(16),6,8-pentaen-11-yl)methyl)pyridin-2-one (70 mg, 0.08 mmol) in dichloromethane (5 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (70 mg, 0.32 mmol) and the mixture was stirred for 1h at room temperature. The reaction mixture was quenched with saturated aqueous sodium bicarbonate. The reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (50 mg, 71.3 % yield) as a yellow solid. LCMS (ESI): [M+H]+= 930.2.

[0539] Step d: 1-(((2S,8R,11aS)-8-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((3R)-3-fluoro-1-azabicyclo(3.2.0)heptan-5-yl)methoxy)-1,2,11,11 a-tetrahydroazeto(2', 1 ': 3, 4)( 1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)pyridin-2(1 H)-one

[0540] A solution of 1-(((11S,13S)-3-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((3R)-3-fluoro-1-azabicyclo(3.2.0)heptan-5-yl)methoxy)-15-oxa-6,8,10-triazatetracyclo(7.6.1.05,16.010,13)hexadeca-1,3,5(16),6,8-pentaen-11-yl)methyl)pyridin-2-one (45 mg, 0.05 mmol) in trifluoroacetic acid (2 mL) was stirred at 60 °C for 2h. The organic layer was concentrated under vacuum. The crude product was purified by Prep-HPLC to afford the title compound (9 mg, 27.0 % yield) as a white solid. LCMS (ESI): [M+H]+= 690.3.

[0541] Route D

[0542] Example 23. ((2S,8 / ?,11aS)-8-(6-amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro- 1 H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11 a-tetrahydroazeto(2', T:3,4)(1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methanol (Compound 200)

[0543] Step a: (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-2,6-dichloro-8-fluoro-5-(((2S,4S)-4-(hydroxymethyl)azetidin-2-yl)methoxy)quinazolin-4(3H)-one

[0544] To a mixture of 7-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2,6-dichloro-5,8-difluoro-quinazolin-4-ol (400 mg, 0.60 mmol) in dimethyl sulfoxide (5.0 mL) was added sodium bis(trimethylsilyl)amide (220 mg, 1.20 mmol), and ((2R,4R)-4-(hydroxymethyl)azetidin-2-yl)methanol (140 mg, 1.20 mmol). The mixture was stirred for 2h at room temperature. The reaction mixture was quenched with water. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (150 mg, 50.1 % yield) as a white solid. LCMS (ESI): [M+H]+= 762.2.

[0545] Step b: ((2S,8R,11aS)-8-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5,9-dichloro-7-fluoro-1,2, 11, 11 a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methanol

[0546] To a mixture of 7-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2,6-dichloro-8-fluoro-5-(((2R,4R)-4-(hydroxymethyl)azetidin-2-yl)methoxy)-3H-quinazolin-4-one (150 mg, 0.20 mmol) in dichloromethane (3.0 mL) was added A / , A / -diisopropylethylamine (0.17 ml_, 0.98 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (100 mg, 0.39 mmol). The mixture was stirred for 2h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine and dried with anhydrous sodium sulfate. The organic phase was concentrated under vacuum to afford the crude product. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (130 mg, 88.8% yield) as a white solid. LCMS (ESI): [M+H]+= 744.2.

[0547] Step c: ((2S,8R,11aS)-8-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5,9-dichloro-7-fluoro-1,2, 11, 11 a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl acetate

[0548] To a mixture of ((11S,13S)-3-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2,7-dichloro-4-fluoro-15-oxa-6,8,10-triazatetracyclo(7.6.1.05, 16.010,13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methanol(170 mg, 0.23 mmol) in dichloromethane (3.0 mL) was added triethylamine (0.06 ml_, 0.46 mmol) and acetic anhydride (50 mg, 0.46 mmol). The mixture was stirred for 2h at room temperature. The reaction solution was quenched with MeOH. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (120 mg, 66.8% yield) as a white solid. LCMS (ESI): [M+H]+= 786.2.

[0549] Step d: ((2S,8R,11aS)-8-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methanol

[0550] To a mixture of ((11S,13S)-3-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2,7-dichloro-4-fluoro-15-oxa-6,8,10-triazatetracyclo(7.6.1.05, 16.010,13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methyl acetate (100 mg, 0.13 mmol) in toluene (3 mL) was added sodium tert-butoxide (24 mg, 0.25 mmol), and ((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methanol (20 mg, 0.13 mmol). The mixture was stirred for 2h at room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (30 mg, 26% yield) as a white solid. LCMS (ESI): [M+H]+= 867.3.

[0551] Step e: ((2S,8R,11aS)-8-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11a-tetrahydroazeto(2',1':3,4)(1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methanol

[0552] A mixture of ((11S,13S)-3-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-2-chloro-4-fluoro-7-(((2R,8S)-2-fluoro-1, 2, 3, 5,6,7-hexahydropyrrolizin-8-yl)methoxy)-15-oxa-6,8, 10-triazatetracyclo(7.6.1.05, 16.010,13)hexadeca-1 (16),2,4,6,8-pentaen-11 -yl)methanol (30 mg, 0.03 mmol) in trifluoroacetic acid (3 mL) was stirred for 2h at 60 °C. The solvent was removed. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the crude product. The crude product was purified by Prep-HPLC to afford the title compound (12.7 mg, 58.6% yield) as an off-white solid. LCMS (ESI): [M+H]+= 627.2.

[0553] Route E

[0554] Example 24. 3-(((2S,11aS)-8-(6-amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2 / ?,3 / ?)-3-fluoro-1-methylazetidin-2-yl)methoxy)-1,2,11,11a-tetrahydroazeto[2', T:3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one (Compound 98)

[0555] Step a: 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3- (trifluoromethyl)-2-pyridyl]-6-chloro-5,8-difluoro-2-[[(2R,3R)-3-fluoro-1-methyl-azetidin-2-yl]methoxy]-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one

[0556] To a dry 50 ml_ round-bottom flask equipped with a stirbar was added sodium tert-butoxide (121 mg, 1.26 mmol) and [(2R,3R)-3-fluoro-1-methyl-azetidin-2-yl]methanol (76.6 mg, 0.64 mmol). The vial was cooled to 0 °C and then dissolved in toluene (2.5 mL) and the mixture was allowed to stir at 0 °C for 0.5h. After this time, 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-2,6-dichloro-5,8-difluoro-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (400 mg, 0.503 mmol) was added to the reaction mixture as a solution in toluene (2.5 mL) via rapid cannula transfer and then the reaction mixture was allowed to stir at 0 °C for 40 min. After this time, the reaction mixture was diluted with water (50 mL) and DCM (50 mL). The aqueous layer was separated from the organics and washed with DCM (2 x 20 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash silica gel chromatography (gradient 0-100% IPrOAc in heptane) afforded 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5,8-difluoro-2-[[(2R,3R)-3-fluoro-1-methyl-azetidin-2-yl]methoxy]-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (204 mg, 0.233 mmol, 46.3% yield ) as a white foam. LC-MS: (ESI, m / z): [M+H]+= 878.20.

[0557] Step b: 7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5,8-difluoro-2-[[(2R,3R)-3-fluoro-1-methyl-azetidin-2-yl]methoxy]-3H-quinazolin-4-one

[0558] To a 20 ml_ vial equipped with a stirbar was added 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5,8-difluoro-2-[[(2R,3R)-3-fluoro-1-methyl-azetidin-2-yl]methoxy]-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (154 mg, 0.175 mmol) and treated with trifluoroacetic acid (3 mL). The mixture was heated to 60 °C with stirring for 3.5h. After this time, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. Purification by flash silica gel chromatography (gradient 0-70% MeOH in DCM) afforded 7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5,8-d ifl u oro-2-[[(2R, 3R)-3-f I uoro- 1 -methyl-azetidin-2-yl]methoxy]-3H-quinazolin-4-one (127 mg, 0.175 mmol, 70 mass%, 100% yield) as a yellow / orange solid. LC-MS: (ESI, m / z):[M+H]+= 508.05.

[0559] Step c: 3-[[(2S,4S)-1-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5,8-difluoro-2-[[(2R,3R)-3-fluoro-1-methyl-azetidin-2-yl]methoxy]quinazolin-4-yl]-4-(hydroxymethyl)azetidin-2-yl]methyl]-6-cyclopropyl-pyrimidin-4-one

[0560] To a 2-dram vial equipped with a stirbar was added 6-cyclopropyl-3-[[(2S,4S)-4-(hydroxymethyl)azetidin-2-yl]methyl]pyrimidin-4-one (25.2 mg, 0.107 mmol) and 7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5,8-difluoro-2-[[(2R,3R)-3-fluoro-1-methyl-azetidin-2-yl]methoxy]-3H-quinazolin-4-one (61.7 mg, 0.0851 mmol, 70 mass%) and then the mixture was dissolved in DCM (1 mL). To this solution was added PyAOP (64.7 mg, 0.119 mmol) and DIEA (76 μL, 0.436 mmol) and then the reaction mixture was allowed to stir at 30 °C for 4h. After this time, the reaction mixture was concentrated under reduced pressure. Purification by flash silica gel chromatography (gradient 0-50% MeOH in DCM) afforded 3-[[(2S,4S)-1-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5,8-difluoro-2-[[(2R,3R)-3-fluoro-1 -methyl-azetidin-2-yl]methoxy]quinazolin-4-yl]-4-(hydroxymethyl)azetidin-2-yl]methyl]-6-cyclopropyl-pyrimidin-4-one (55.5 mg, 0.0765 mmol, 90.0% yield) as a pale yellow solid. LC-MS: (ESI, m / z): [M+H]+= 725.15.

[0561] Step d: 3-[[(11S,13S)-3-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-2-chloro-4-fluoro-7-[[(2R,3R)-3-fluoro-1-methylazetidin-2-yl]methoxy]-15-oxa-6,8,10-triazatetracyclo[7.6.1.05, 16.010, 13]hexadeca-1 (16),2,4,6,8-pentaen-11 -y I] methy l]-6-cyclopropyl-pyrimidin-4-one

[0562] To a dry 2-dram vial equipped with a stirbar was added 3-[[(2S,4S)-1-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5,8-difluoro-2-[[(2R,3R)-3-fluoro-1-methyl-azetidin-2-yl]methoxy]quinazolin-4-yl]-4-(hydroxymethyl)azetidin-2-yl]methyl]-6-cyclopropyl-pyrimidin-4-one (47.9 mg, 0.0661 mmol) and THF (2 mL) and the mixture was then cooled to 0 °C. To this suspension was added sodium hydride (52.8 mg, 1.32 mmol, 60 mass% in mineral oil) and then the reaction mixture was allowed to stir at 0 °C for 10 min, and then allowed to warm to room temperature and stir for 2h. After this time, the reaction mixture was quenched with water (1 mL) at 0 °C and then further diluted with water (10 mL), brine (10 mL) and DCM (10 mL). The aqueous layer was separated from the organic layers and washed with DCM (2 x 10 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. This material was purified by prep HPLC (Column: XSelect CSH Prep C18, 50 x 30 mm 5 pm; Mobile Phase A: 0.1% ammonium hydroxide in water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 60% B in 10 min; 254 nm) to afford 3-(((2S,11aS)-8-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,3R)-3-fluoro-1-methylazetidin-2-yl)methoxy)-1,2,11,11a-tetrahydroazeto[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one (11.8 mg, 0.0167 mmol, 25.3% yield) as a white solid. LC-MS: (ESI, m / z): [M+H]+= 705.15.

[0563] Route F

[0564] Example 25. (2S,8 / ?,11aS)-8-(6-Amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11 a-tetrahydroazeto(2', T:3,4)(1,4)oxazepino(5,6,7-de)quinazoline-2-carbonitrile (Compound 238)

[0565] Step a: (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one

[0566] A solution of 7-((R)-6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (600 mg, 0.65 mmol) in dichloromethane (6 mL) and trifluoroacetic acid (1.2 mL) was stirred at room temperature for 1.5h. The reaction mixture was quenched with sodium bicarbonate aqueous solution. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile 0-58 / 0.1% ammonium bicarbonate in water) to afford the title compound (280 mg, 54.4% yield) as a light yellow solid. LCMS (ESI, m / z) [M+H]+= 788.2.

[0567] Step b: (2S,4S)-1-((R)-7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-4-(hydroxymethyl)azetidine-2-carboxamide

[0568] A solution of (2S,4S)-4-(Hydroxymethyl)azetidine-2-carboxamide (49 mg, 0.38 mmol), (R)-7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4(3H)-one (200 mg, 0.25 mmol), (3-hydroxy-3H-1,2,3-triazolo(4,5-b)pyridinato-O)tri-1 -pyrrolidinylphosphonium hexafluorophosphate (158 mg, 0.30 mmol) and A / , A / -diisopropylethylamine (0.13 ml_, 0.76 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1h. The reaction mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (180 mg, 78.8% yield) as a yellow solid. LCMS (ESI): [M+H]+= 900.3.

[0569] Step c: (2S,8R,11aS)-8-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazoline-2-carboxamide

[0570] To a solution of (2S,4S)-1-((R)-7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-4-(hydroxymethyl)azetidine-2-carboxamide (180 mg, 0.27 mmol) in THF (5 mL) was added sodium hydride (109 mg, 2.73 mmol) at 0 °C and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate, and the organic layers were combined and concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (150 mg, 85.9% yield) as a yellow solid. LCMS (ESI): [M+H]+= 880.3.

[0571] Step d: (2S,8R,11aS)-8-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazoline-2-carbonitrile

[0572] Under nitrogen, a solution of (2S,8R,11aS)-8-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-1,2, 11,11a-tetrahydroazeto(2',1':3,4)(1,4)oxazepino(5,6,7-de)quinazoline-2-carboxamide (140 mg, 0.16 mmol) and Burgess reagent (113 mg, 0.48 mmol) in THF (5 mL) was stirred at 70°C for 3h. The reaction mixture was quenched with water and extracted with ethyl acetate, the organic layers were combined and concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (70 mg, 51% yield) as a yellow solid. LCMS (ESI): [M+H]+= 862.3.

[0573] Step e: (2S,8R,11aS)-8-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11a-tetrahydroazeto(2',1':3,4)(1,4)oxazepino(5,6,7-de)quinazoline-2-carbonitrile

[0574] A solution of (2S,8R,11aS)-8-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11a-tetrahydroazeto(2',1':3,4)(1,4)oxazepino(5,6,7-de)quinazoline-2-carbonitrile (60 mg,0.07 mmol) in trifluoroacetic acid (3 mL) was stirred at 70 °C for 1h. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (16.9 mg, 38.3% yield) as a white solid, LCMS (ESI): [M+H]+= 622.2.

[0575] Route G

[0576] Example 26. 2-(((2S,8R,11 aS)-8-(6-Amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro- 1 H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11a-tetrahydroazeto[2', T:3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)methyl)pyridine 1 -oxide (Compound 115)

[0577] Step a: 1 -(tert-Butyl) 2-ethyl (2S,4S)-4-(bromomethyl)azetidine-1,2-di carboxyl ate

[0578] To a solution of 1 -(tert-butyl) 2-ethyl (2S,4S)-4-(hydroxymethyl)azetidine-1,2-dicarboxylate (4.00 g, 15.4 mmol) and triphenylphosphine (6.07 g, 23.1 mmol) indichloromethane (50 mL) was added carbon tetrabromide (7.67 g, 23.1 mmol) at 0 °C. The mixture was stirred at room temperature for 1h. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layers were combined and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (0-50%), to afford the title compound (4 g, 80.5% yield) as a yellow oil. LCMS (ESI): [M+H]+= 322.2.

[0579] Step b: 1 -(tert-Butyl) 2-ethyl (2S,4S)-4-(pyridin-2-ylmethyl)azetidine-1,2-di carboxyl ate

[0580] Under nitrogen and blue light, a mixture of 1 -(tert-Butyl) 2-ethyl (2S,4S)-4-(bromomethyl)azetidine-1,2-dicarboxylate (1.00 g, 3.10 mmol), 2-bromopyridine (0.44 ml_, 4.66 mmol), 4,4-Bis(tert-butyl)-2,2-bipyridine)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridinyl)phenyl)iridium(iii)hexafluorophosphate (0.03 g, 0.03 mmol), nickel(ii) chloride dimethoxyethane adduct (0.01 g, 0.03 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.01 g, 0.03 mmol), tris(trimethylsilyl)silane (0.96 ml_, 3.1 mmol) and sodium carbonate (0.66 g, 6.21 mmol) in 1,2-dimethoxyethane (10 mL) was stirred at room temperature for 12h. The reaction mixture was quenched with water and extracted with ethyl acetate, and the organic layers were combined and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (0-50%) to afford the title compound (400 mg, 40.2% yield) as a yellow oil. LCMS (ESI): [M+H]+= 321.2.

[0581] Step c: tert-Butyl (2S,4S)-2-(hydroxymethyl)-4-(pyridin-2-yl methyl )azetidine-1 -carboxylate

[0582] To a solution of 1 -(tert-butyl) 2-ethyl (2S,4S)-4-(pyridin-2-yl methyl )azetidine-1,2-dicarboxylate (400 mg, 1.25 mmol) in THF (5 mL) was added lithium aluminum hydride (2.5 M in THF) (0.74 mL, 1.87 mmol) at 0 °C and the mixture was stirred at room temperature for 2h. The reaction mixture was quenched with sodium sulfate decahydrate. The solids were filtered out and the solvent was concentrated under vacuum to afford the title compound (340 mg, 97.8% yield) as a yellow oil and as a crude product. LCMS (ESI): [M+H]+= 279.2.

[0583] Step d: ((2S,4S)-4-(Pyridin-2-ylmethyl)azetidin-2-yl)methanol

[0584] To a solution of tert-butyl (2S,4S)-2-(hydroxymethyl)-4-(pyridin-2-yl methyl )azetidine-1 -carboxylate (340 mg, 1.22 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) and the mixture was stirred at room temperature for 2h. The solvent was concentrated under vacuum. The residue was purified by solid phase extraction to afford the title compound (200 mg, 92% yield) as a yellow oil. LCMS (ESI):[M+H]+= 179.1.

[0585] Step e: ((2S,4S)-1-((R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-4-(pyridin-2-ylmethyl)azetidin-2-yl)methanol

[0586] A solution of ((2S,4S)-4-(pyridin-2-ylmethyl)azetidin-2-yl)methanol (146 mg, 0.82 mmol), (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol (150 mg, 0.27 mmol), (3-Hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (171 mg, 0.33 mmol) and N, N-diisopropylethylamine (0.14 ml_, 0.82 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2h. The reaction mixture was quenched with water and extracted with ethyl acetate, and the organic layers were combined and concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (150 mg, 75.7% yield) as a yellow solid. LCMS (ESI): [M+H]+= 708.2.

[0587] Step f: 6-((2S,8R,11aS)-9-Chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-2-(pyridin-2-ylmethyl)-1,2, 11, 11 a-tetrahydroazeto[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-8-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0588] To a solution of ((2S,4S)-1-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-4-(pyridin-2-ylmethyl)azetidin-2-yl)methanol (150 mg, 0.21 mmol) in THF (5 mL) was added sodium hydride (85 mg, 2.12mmol) at 0 °C and the mixture was stirred at room temperature for 2h. The reaction mixture was quenched with water and extracted with ethyl acetate, and the organic layers were combined and concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (140 mg, 96% yield) as a white solid. LCMS (ESI): [M+H]+= 688.2.

[0589] Step g: terf-Butyl (tert-butoxycarbonyl)(6-((2S,8R,11aS)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-2-(pyridin-2-ylmethyl)-1,2, 11,11 a-tetrahydroazeto[2', 1 ': 3, 4] [1,4]oxazepino[5,6,7-de]quinazolin-8-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-yl)carbamate

[0590] A solution of 6-((2S,8R,11aS)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(pyridin-2-ylmethyl)-1,2,11,11a-tetrahydroazeto[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-8-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (140 mg, 0.20mmol), di-tert-butyl dicarbonate (133 mg, 0.61 mmol) and 4-dimethylaminopyridine (24 mg, 0.20 mmol) in THF (5 mL) was stirred at 60 °C for 1h. The reaction mixture was quenched with water and extracted with ethyl acetate, and the organic layers were combined and concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (130 mg, 72% yield) as a yellow solid. LCMS (ESI): [M+H]+= 888.3.

[0591] Step h: (2R,7aS)-7a-((((2S,8R,11aS)-8-(6-(Bis(tert-butoxycarbonyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-2-((1-oxidopyridin-2-yl)methyl)-1,2,11,11 a-tetrahydroazeto[2', 1 ': 3, 4] [1,4]oxazepino[5,6,7-de]quinazolin-5-yl)oxy)methyl)-2-fluorohexahydropyrrolizine 4(1 H)-oxide

[0592] To a solution of fert-butyl (tert-butoxycarbonyl)(6-((2S,8R,11aS)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-2-(pyridin-2-ylmethyl)-1,2, 11,11 a-tetrahydroazeto[2', 1 ': 3, 4] [1,4]oxazepino[5,6,7-de]quinazolin-8-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-yl)carbamate (130 mg, 0.15 mmol) in dichloromethane (5 mL) was added 3-chloroperoxybenzoic acid (50 mg, 0.29mmol) at 0 °C and the mixture was stirred at room temperature for 2h. The reaction mixture was quenched with saturated aqueous sodium sulfite and extracted with dichloromethane. The organic layers were combined and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (0-30%) to afford the title compound (100 mg, 74% yield) as a yellow oil. LCMS (ESI):[M+H]+= 920.3.

[0593] Step i: 2-(((2S,8R,11aS)-8-(6-(Bis(terf-butoxycarbonyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11a-tetrahydroazeto[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)methyl)pyridine 1-oxide

[0594] To a solution of (2R,7aS)-7a-((((2S,8R,11aS)-8-(6-(bis(ferf-butoxycarbonyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-2-((1-oxidopyridin-2-yl)methyl)-1,2,11,11 a-tetrahydroazeto[2', 1 ': 3, 4] [1,4]oxazepino[5,6,7-de]quinazolin-5-yl)oxy)methyl)-2-fluorohexahydropyrrolizine 4(1H)-oxide (100 mg, 0.11 mmol) in acetonitrile (3 mL) was added bis(pinacolato)diboron (27 mg, 0.11 mmol) and the mixture was stirred at room temperature for 10 min. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) to afford the title compound (80 mg, 81.4% yield) as a yellow solid. LCMS (ESI): [M+H]+= 904.3.

[0595] Step j: 2-(((2S,8R,11aS)-8-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11a-tetrahydroazeto[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)methyl)pyridine 1 -oxide

[0596] A solution of 2-(((2S,8R,11aS)-8-(6-(bis(terf-butoxycarbonyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-1,2, 11, 11 a-tetrahydroazeto[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)methyl)pyridine 1-oxide (80 mg, 0.09 mmol) in trifluoroacetic acid (3 mL) was stirred at 50 °C for 1h. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography (10 mM ammonium bicarbonate in water / acetonitrile) and Prep-HPLC to afford the title compound (30.9 mg, 49% yield) as a white solid. LCMS (ESI): [M+H]+= 704.1.

[0597] Route H

[0598] Example 27. 6-((2R,8 / ?,11aS)-9-Chloro-7-fluoro-2-methyl-1,2,11,11a-tetrahydroazeto(2', T:3,4)(1,4)oxazepino(5,6,7-c / e)quinazolin-8-yl)-4-methyl-5-(trifluoromethyl)pyridin-2 -amine (Compound 255)

[0599] Step a: 2-Amino-4-bromo-5-chloro-3,6-difluoro-benzoic acid

[0600] To a solution of 2-amino-4-bromo-3,6-difluoro-benzoic acid (130 g, 516 mmol) in A / , A / -dimethylformamide (1.3L) was added A / -chlorosuccinimide (78 g, 584 mmol) and the mixture was stirred at 90 °C for 1h. The reaction mixture was added into ice water. After filtration, the solids were collected and dried to afford the title compound (139 g, 94.2% yield). LCMS (ESI, m / z) [M-H]+= 285.9.

[0601] Step b: 2-Amino-4-bromo-5-chloro-3,6-difluoro-benzamide

[0602] A mixture of 2-amino-4-bromo-5-chloro-3,6-difluoro-benzoic acid (125 g, 436 mmol), ammonium chloride (92.5 g, 1745 mmol), A / , A / -diisopropylethylamine (303 ml_, 1741 mmol) and HATU (338 g, 888 mmol) in A / , A / -dimethylformamide (1.3L) was stirred at room temperature for 2h. The reaction mixture was added into ice water. After filtration, the solid was concentrated and dried to afford the title compound (123 g, 98.7% yield) as a brown solid. LCMS (ESI, m / z) [M+H]+= 284.9.

[0603] Step c: 7-Bromo-6-chloro-5,8-difluoro-3H-quinazolin-4-one

[0604] A mixture of 2-amino-4-bromo-5-chloro-3,6-difluoro-benzamide (120 g, 420 mmol) and triethyl orthoformate (144 ml_, 857 mmol) in acetic acid (1200 mL) was stirred at 80 °C for 2h. The reaction mixture was added into ice water. After filtration, the solids were collected and washed with water (1.5L). The solid was dried to afford the title compound (114 g, 91.8% yield) as a yellow solid. LCMS (ESI, m / z) [M+H]+= 294.9.

[0605] Step d: Bromo-6-chloro-5,8-difluoro-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one

[0606] To a mixture of 7-bromo-6-chloro-5,8-difluoro-3H-quinazolin-4-one (114 g, 385.8 mmol), cesium carbonate (251 g, 769 mmol) and tetrabutylammonium iodide (13.7 g, 37.1 mmol) in N, N-dimethylformamide (2600 mL) was slowly added 2-(trimethylsilyl)ethoxymethyl chloride (95 ml_, 767 mmol) and the mixture was stirred at 0 °C for 1.5h. The reaction mixture was diluted with ethyl acetate (15L). The resulting solution was washed with water (15L) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether to afford the title compound (133 g, 80.7% yield) as an orange solid. LCMS (ESI, m / z) [M+H]+= 425.0.

[0607] Step e: 7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0608] Under nitrogen, a mixture of 7-bromo-6-chloro-5,8-difluoro-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (100 g, 235 mmol), 6-bromo-N, N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (176 g, 355 mmol), tris(dibenzylideneacetone)dipalladium (66 g, 72.2 mmol) and copper (76 g, 1200 mmol) in dimethyl sulfoxide (1000 mL) was stirred at 100 °C overnight. The reaction mixture was diluted with ethyl acetate (150L). The resulting solution was washed with water (3 x 15L) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether to afford the title compound(100 g, 55.9% yield) as a yellow oil. LCMS (ESI, m / z) [M+H]+= 761.2.

[0609] Step f: (S)-7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one & (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

[0610] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (100 g, 131 mmol) was subjected to separation by Chiral-SFC with the following conditions to afford the title compounds. Column: CHIRALPAK IG, 7*25cm, 10 pm; Mobile Phase A: CO₂, Mobile Phase B: IPA(0.5% 2M NH₃-MeOH); Flow rate: 250 mL / min; Gradient: isocratic 40% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 254 nm; RT 1 (min): 5.99; Injection Volume: 19 mL; Number Of Runs: 42. (S)-7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (isomer 1): (36.2 g, 36.2%); LCMS (ESI) [M+H]+= 761.2; tR = 1.235 min (SFC, CHIRALPAK IG-33.0*50 mm, 3 pm, SFC IPA (0.1%DEA) 10% to 50% in 2.0 min, hold 1.0 min at 50%), 2 ml / min, 220 nm). (R)-7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (isomer 2): (34.0 g, 34.0%); LCMS (ESI) [M+H]+= 761.2; tR = 1.462 min (SFC, CHIRALPAK IG-3 3.0*50 mm, 3 μm, IPA (0.1%DEA) 10% to 50% in 2.0 min, hold 1.0 min at 50%), 2 ml / min, 220 nm).

[0611] Step g: (R)-7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoroquinazolin-4(3H)-one

[0612] A solution of (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (34 g, 44.7 mmol) and 1M TBAF in tetrahydrofuran (340 mL, 340 mmol) was stirred at 50 °C overnight. The reaction mixture was diluted with ethyl acetate (1500 mL). The resulting solution was washed with water (3 x 1500 mL) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (5-20%) to afford the title compound (22.2 g, 78.8% yield) as a yellow solid. LCMS (ESI) [M+H]+= 631.1.

[0613] Step h: (R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoroquinazolin-4(3H)-one

[0614] A solution of 7-(6-(bis((4-methoxyphenyl)methyl)amino)-4-methyl-3-(trifluoromethyl)-2-pyridyl)-6-chloro-5,8-difluoro-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (2.00 g, 2.63 mmol) in trifluoroacetic acid (20 mL) was stirred at 70 °C for 3h. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography to afford the title compound (1 g, 97.4% yield) as a yellow solid. LC-MS: (ESI, m / z): 391.7 [M+H]+.

[0615] Step i: ((2S,4R)-1-(7-((R)-6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoroquinazolin-4-yl)-4-methylazetidin-2-yl)methanol((2S,4R)-1-(7-((R)-6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoroquinazolin-4-yl)-4-methylazetidin-2-yl)methanol

[0616] A solution of (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoroquinazolin-4(3H)-one (100 mg, 0.26 mmol), ((2S,4R)-4-methylazetidin-2-yl)methanol (31 mg, 0.31 mmol), (3-hydroxy-3H-1,2,3-triazolo(4,5-b)pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (267 mg, 0.51 mmol) and A / , A / -diisopropylethylamine (0.04 ml_, 0.26 mmol) in dichloromethane (3 mL) was stirred at room temperature for 1h. The resulting solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 10 mmol / L ammonium bicarbonate in water) to afford the title compound (100 mg, 82.7% yield) as a pink oil. LC-MS: (ESI, m / z): 474.0 [M+H]+.

[0617] Step j: 6-((2R,8R,11aS)-9-Chloro-7-fluoro-2-methyl-1,2,11,11a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazolin-8-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0618] A solution of ((2S,4R)-1-(7-((R)-6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoroquinazolin-4-yl)-4-methylazetidin-2-yl)methanol((2S,4R)-1-(7-((R)-6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoroquinazolin-4-yl)-4-methylazetidin-2-yl)methanol (100 mg, 0.21 mmol) and sodium hydride (41 mg, 1.01 mmol) in THF (3 mL) was stirred at room temperature for 1h. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC to afford the title compound (17.1 mg, 17.7% yield) as a white solid. LC-MS: (ESI, m / z): 454.2 [M+H]+.

[0619] Route I

[0620] Examples 28a and 28b. 3-(((2S,8 / ?,11S,11aS)-8-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-11 -methyl-1,2,11,11 a-tetrahydroazeto(2', T:3,4)(1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one (Compound 185a) & 3-(((2S,8 / ?,11S,11aS)-8-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-11 -methyl-1,2,11,11 a-tetrahydroazeto(2', T:3,4)(1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one (Compound 185b)

[0621] Step a: 1 -(terf-Butyl) 2-ethyl (2S,4S)-4-((4-cyclopropyl-6-oxopyrimidin-1 (6H)-yl)methyl)azetidine-1,2-dicarboxylate

[0622] To a solution of 1 -(tert-butyl) 2-ethyl (2S,4S)-4-(hydroxymethyl)azetidine-1,2-dicarboxylate (3.81 g, 14.7 mmol), 6-cyclopropylpyrimidin-4(3H)-one (2.00 g, 14.69 mmol) and triphenylphosphine (5.78 g, 22.0 mmol) in dichloromethane (40 mL) was added diisopropyl azodicarboxylate (4.34 ml_, 22.0 mmol) at 0 °C and the mixture was stirred at room temperature for 1h under nitrogen. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol and reverse phase chromatography (acetonitrile / 10 mMammonium bicarbonate in water) to afford the title compound (3.00 g, 54.1% yield) as a white solid. LCMS (ESI): [M+H]+=378.2.

[0623] Step b: (2S,4S)-1-(terf-Butoxycarbonyl)-4-((4-cyclopropyl-6-oxopyrimidin-1 (6H)-yl)methyl)azetidine-2-carboxylic acid

[0624] A solution of 1 -(tert-butyl) 2-ethyl (2S,4S)-4-((4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl)azetidine-1,2-dicarboxylate (3.00 g, 7.95 mmol) in MeOH (20 mL) was stirred at 0 °C. Then potassium hydroxide (892 mg, 15.9 mmol) in water (5 mL) was added and stirred at room temperature for 1h. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% formic acid in water) to afford the title compound (2.50 g, 90% yield) as a white solid. LCMS (ESI): [M+H]+=350.2.

[0625] Step c: tert-Butyl (2S,4S)-2-((4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl)-4-(methoxy(methyl)carbamoyl)azetidine-1 -carboxylate

[0626] A solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-((4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl)azetidine-2-carboxylic acid (2.49 g, 7.13 mmol), N-methoxymethanamine (1.31 g, 21.38 mmol), 2-(7-Azabenzotriazol-1-yl)-A / , A / , A / ', A / '-tetramethyluronium hexafluorophosphate (2.71 g, 7.13 mmol) and N, N-Diisopropylethylamine (1.24 mL, 7.13 mmol) in Dichloromethane (30 mL) was stirred at rt for 1 h. The solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 10 mM Ammonium bicarbonate in water) to afford the title compound (1.50 g, 53.6% yield) as a white solid. LCMS (ESI):[M+H]+=393.2.

[0627] Step d: tert-Butyl (2S,4S)-2-acetyl-4-((4-cyclopropyl-6-oxopyrimidin-1 (6H)-yl)methyl)azetidine-1 -carboxylate

[0628] Under nitrogen, to a solution of tert-butyl (2S,4S)-2-((4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl)-4-(methoxy(methyl)carbamoyl)azetidine-1 -carboxylate (500 mg, 1.28 mmol) in THF (5 mL) was added 1M methylmagnesium bromide in THF (1.53 mL, 1.53 mmol) at 0 °C and the mixture was stirred at room temperature for 20 min. The reaction mixture was quenched with water at 0 °C. The reaction mixture was extracted with ethyl acetate and the organic layers were combined and concentrated under vacuum. The solvent was concentrated under vacuum to afford the title compound (350 mg, 79.1% yield) as a yellow oil. LCMS (ESI): [M+H]+=348.2.

[0629] Step e: terf-Butyl (2S,4S)-2-((4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl)-4-((S)-1 -hydroxyethyl)azetidine-1 -carboxylate

[0630] To a solution of fert-butyl (2S,4S)-2-acetyl-4-((4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl)azetidine-1 -carboxylate (340 mg, 0.98 mmol) in THF (5 mL) was added sodium borohydride (56 mg, 1.5 mmol) and the mixture was stirred at room temperature for 1h. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layers were combined. The solvent was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol, to afford the title compound (340 mg, 99.4% yield) as a yellow oil. LCMS (ESI): [M+H]+=350.2.

[0631] Step f: 6-Cyclopropyl-3-(((2S,4S)-4-((S)-1-hydroxyethyl)azetidin-2-yl)methyl)pyrimidin-4(3H)-one

[0632] To a solution of tert-butyl (2S,4S)-2-((4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl)-4-((S)-1-hydroxyethyl)azetidine-1-carboxylate (330 mg, 0.94 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) and the mixture was stirred at room temperature for 1h. The solvent was concentrated under vacuum. The crude product was purified by solid-phase extraction to afford the title compound (230 mg, 97.7% yield) as a yellow solid. LCMS (ESI): [M+H]+=250.1.

[0633] Step g: 3-(((2S,4S)-1-((R)-7-(6-Amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-4-((R)-1-hydroxyethyl)azetidin-2-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one

[0634] A solution of 6-cyclopropyl-3-(((2S,4S)-4-((S)-1-hydroxyethyl)azetidin-2-yl)methyl)pyrimidin-4(3H)-one (220 mg, 0.88 mmol), (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol (200 mg, 0.37 mmol), N, N-diisopropylethylamine (0.15 mL, 0.88 mmol) and (3-hydroxy-3H-1,2,3-triazolo(4,5-b)pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (460 mg, 0.88 mmol) in dichloromethane (4 mL) was stirred at room temperature for 0.5h. The solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 10 mM ammonium bicarbonate in water) to afford the title compound (240 mg, 34.9% yield) as a yellow solid. LCMS (ESI): [M+H]+=779.3.

[0635] Step h: 3-(((2S,8R,11S,11aS)-8-(6-Amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11 -methyl-1,2,11,11a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one & 3-(((2S,8R,11S,11aS)-8-(6-amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11 -methyl-1,2,11,11a-tetrahydroazeto(2', 1 ': 3,4 )( 1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one

[0636] To a solution of 3-(((2S,4S)-1-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-4-((R)-1-hydroxyethyl)azetidin-2-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one (230 mg, 0.30 mmol) in THF (3 mL) was added sodium hydride (59 mg, 1.5 mmol) at 0 °C and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water at 0 °C and extracted with dichloromethane. The organic layers were combined. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 10 mM ammonium bicarbonate in water) and the solvent was concentrated under vacuum. The crude product was purified by Prep-CHIRAL-HPLC to afford the title compound. The stereochemistry of the isomers was arbitrarily assigned. 3-(((2S,8R, 11 S, 11 aS)-8-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11-methyl-1,2,11,11 a-tetrahydroazeto(2', 1 ': 3, 4)( 1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one (31.8 mg, 14.2% yield) as an off-white solid. tR = 3.60 min (CHIRALCellulose SB, 4.6*50 mm, 3 pm, Hex(0.1%DEA): EtOH=60:40, 1.0 mL / min), LCMS (ESI): [M+H]+=759.4 and 3-(((2S,8R,11S,11aS)-8-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-11 -methyl-1,2,11,11a-tetrahydroazeto(2',1':3,4)(1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)-6-cyclopropylpyrimidin-4(3H)-one (23.8 mg, 10.3% yield) as an off-white solid. tR = 4.26 min (CHIRALCellulose SB, 4.6*50 mm, 3 pm, Hex(0.1%DEA): EtOH=60:40, 1.0 mL / min), LCMS (ESI): [M+H]+=759.2.

[0637] Route J

[0638] Example 29. 5-(((2R,8R,11aS)-8-(6-amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-9-chloro-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,11,11 a-tetrahydroazeto(2', T:3,4)(1,4)oxazepino(5,6,7-de)quinazolin-2-yl)methyl)-2-cyclopropyl-3-methylpyrimidin-4(3H)-one (Compound 186)

[0639] Step a: 2-Cyclopropyl-3-methyl-pyrimidin-4-one

[0640] To a mixture of 2-cyclopropyl-1H-pyrimidin-6-one (2.00 g, 14.7 mmol) and potassium carbonate (4.05 g, 29.4 mmol) in A / , A / -dimethylformamide (10 mL) was added iodomethane (3.12 g, 22.0 mmol), and the mixture was stirred for 1h at 25 °C. The resulting residue was purified by reverse phase chromatography (acetonitrile 0-40% / 10 mmol / L NH4HCO3in water) to afford the title compound (1.00 g, 45.3% yield) as a yellow solid. LCMS (ESI): [M+H]+= 151.1.

[0641] Step b: 5-bromo-2-cyclopropyl-3-methyl-pyrimidin-4-one

[0642] A solution of 2-cyclopropyl-3-methyl-pyrimidin-4-one (1.00 g, 6.66 mmol) and A / -bromosuccinimide (1.42 g, 7.99 mmol) in A / , A / -dimethylformamide (5 mL) was stirred at 25 °C for 1h. The reaction mixture was diluted with water and extracted with ethyl acetate and the organic layers were combined. The organic layer was concentrated under vacuum and purified by flash chromatography with petroleumether / ethyl acetate (6:4) to afford the title compound (930 mg, 61% yield) as a yellow solid. LCMS (ESI): [M+H]+= 229.0.

[0643] Step c: 1 -(tert-butyl) 2-ethyl (2S,4R)-4-((2-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)azetidine-1,2-dicarboxylate

[0644] To a mixture of 5-bromo-2-cyclopropyl-3-methyl-pyrimidin-4-one (900 mg, 3.93 mmol) in A / , A / -dimethylacetamide (5 mL) was added 1 -(tert-butyl) 2-ethyl (2S,4S)-4-(bromomethyl)azetidine-1,2-dicarboxylate (1.26 g, 3.93 mmol), tris(trimethylsilyl)silane (977 mg, 3.93 mmol), sodium carbonate (833 mg, 7.86 mmol), 4-methoxy-2-(4-methoxypyridin-2-yl)pyridine (85 mg, 0.39 mmol), nickel(ll) bromide 2-methoxyethyl ether complex (138 mg, 0.39 mmol) and Ir(dF(CF3)ppy)2(dtbbpy)PF6(440 mg, 0.39 mmol) under nitrogen atmosphere, and the mixture was stirred for 18h at 25 °C under blue LEDs. The reaction mixture was diluted with water and extracted with ethyl acetate, and the organic layers were combined. The organic layer was concentrated under vacuum and purified by flash chromatography with petroleum ether / ethyl acetate (1:1) to afford the title compound (400 mg, 26% yield) as a yellow solid. LCMS (ESI): [M+H]+= 392.2.

[0645] Step d: tert-Butyl (2R,4S)-2-((2-cyclopropyl-1-methyl-6-oxo-pyrimidin-5-yl)methyl)-4-(hydroxymethyl)azetidine-1 -carboxylate

[0646] To a mixture of 1 -(tert-Butyl) 2-ethyl (2S,4R)-4-((2-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)azetidine-1,2-dicarboxylate (400 mg, 1.02 mmol) in THF (5 mL) was added lithium aluminum hydride (78 mg, 2.04 mmol) at 0 °C, and the mixture was stirred for 2h at 25 °C. The reaction mixture was quenched with water, 15% NaOH (aq.) and water. The solids were filtered out. The filtrate was concentrated to afford the title compound (320 mg, 89.6% yield) as a yellow oil. LCMS (ESI): [M+H]+= 350.2.

[0647] Step e: 2-Cyclopropyl-5-(((2R,4S)-4-(hydroxymethyl)azetidin-2-yl)methyl)-3-methyl-pyrimidin-4-one

[0648] A solution of tert-butyl (2R,4S)-2-((2-cyclopropyl-1-methyl-6-oxo-pyrimidin-5-yl)methyl)-4-(hydroxymethyl)azetidine-1 -carboxylate (320 mg, 0.92 mmol) and trifluoro...

Claims

1. What is claimed is:

1. A compound of Formula (I),or a pharmaceutically acceptable salt thereof, wherein:R1is halogen, cyclopropyl, halocyclopropyl, C1-3haloalkyl, or C1-3alkyl;R2is hydrogen and R3is hydrogen, methyl, or halomethyl; or R2and R3come together to form -OCHR4-;R4is H, methyl, or halomethyl;X1is N or CR°, wherein R° is H, halogen, C1-3alkyl, Ci-shaloalkyl, cyclopropyl, or halocyclopropyl;Q1is a carbocycle or heterocycle;m is an integer from 0 to 7;each R8is independently selected from the group consisting of halogen, Ci-ealkyl, Cs-ecycloalkyl, C2-ealkynyl, -CN, -OH, amino, and C-i-shaloalkyl; and two R8on adjacent carbon atoms may come together to form a cycloalkyl or heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from Ci-ealkyl, halo, and haloalkyl;Z is H, -OCRZ2-Q2, or Q2; wherein each Rzis independently H or halo;Q2is a heterocycle or carbocycle; wherein Q2is unsubstituted or substituted with 1 to 6 R9groups;each R9is independently selected from the group consisting of halogen, alkyl, amino, and C2-C4alkenyl, wherein each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, amino, -OH, alkoxy, haloalkoxy, and heterocycloalkyl;R10is cyano, alkyl, haloalkyl, hydroxyalkyl, heteroaryl, alkyl-R11, alkyl-R12, or alkyl-O-R12, wherein the heteroaryl is unsubstituted or substituted with arylalkyl;R11is selected from the group consisting of -N(R14)S(=O)2R15, -N(R14)S(=O)2N(R15)2, -N(R14)C(=O)R15, -N(R14)C(=O)N(R15)2, -N=S(=O)(R14)(R16), and NR14-S(=O)(=NH)R15; R14is H, alkyl, or cycloalkyl; each R15is independently H, alkyl, or cycloalkyl, or two R15attached to the same nitrogen form a cycle; and R16is H, alkyl, cycloalkyl, or heteroaryl;R12is a heterocyclyl group unsubstituted or substituted with one or more R13; andeach R13is independently oxo, cyano, cyano-alkyl, halo, alkyl, haloalkyl, alkoxy, alkoxy-alkyl, -S(O)2R13b, cycloalkyl, halocycloalkyl, heterocycloalkyl, or -N(R13a)C(=O)R13b, wherein the heterocycloalkyl is unsubstituted or substituted with oxo or hydroxyalkyl.

2. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:R1is halogen, cyclopropyl, halocyclopropyl, C-i-shaloalkyl, or C1-3alkyl;R4is H, methyl, or halomethyl;X1is N or CR°, wherein R° is H, halogen, C1-3alkyl, Ci-shaloalkyl, cyclopropyl, or halocyclopropyl;Q1is a carbocycle or heterocycle;m is an integer from 0 to 7;each R8is independently selected from the group consisting of halogen, Ci-ealkyl, Cs-ecycloalkyl, C2-6alkynyl, -CN, -OH, amino, and C-i-shaloalkyl; and two R8on adjacent carbon atoms may come together to form a cycloalkyl or heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from Ci-ealkyl, halo, and haloalkyl;Z is H, -OCRZ2-Q2, or Q2; wherein each Rzis independently H or halo; Q2is a heterocycle or carbocycle; wherein Q2is unsubstituted or substituted with 1 to 6 R9groups;each R9is independently selected from the group consisting of halogen, alkyl, amino, and C2-C4alkenyl, wherein each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, amino, -OH, alkoxy, haloalkoxy, and heterocycloalkyl;R10is cyano, alkyl, haloalkyl, hydroxyalkyl, heteroaryl, alkyl-R11, alkyl-R12, or alkyl-O-R12, wherein the heteroaryl is unsubstituted or substituted with arylalkyl;R11is selected from the group consisting of -N(R14)S(=O)2R15, -N(R14)S(=O)2N(R15)2, -N(R14)C(=O)R15, -N(R14)C(=O)N(R15)2, -N=S(=O)(R14)(R16), and NR14-S(=O)(=NH)R15; R14is H, alkyl, or cycloalkyl; each R15is independently H, alkyl, or cycloalkyl, or two R15attached to the same nitrogen form a cycle; and R16is H, alkyl, cycloalkyl, or heteroaryl;R12is a heterocyclyl group unsubstituted or substituted with one or more R13; andeach R13is independently oxo, cyano, cyano-alkyl, halo, alkyl, haloalkyl, alkoxy, alkoxy-alkyl, -S(O)2R13b, cycloalkyl, halocycloalkyl, heterocycloalkyl, or -N(R13a)C(=O)R13b, wherein the heterocycloalkyl is unsubstituted or substituted with oxo or hydroxyalkyl.

3. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein:R1is halogen, cyclopropyl, halocyclopropyl, C1-3haloalkyl, or C1-3alkyl;R3is hydrogen, methyl, or halo methyl;X1is N or CR°, wherein R° is H, halogen, C1-3alkyl, Ci-shaloalkyl, cyclopropyl, or halocyclopropyl;Q1is a carbocycle or heterocycle;m is an integer from 0 to 7;each R8is independently selected from the group consisting of halogen, Ci-ealkyl, Cs-ecycloalkyl, C2-ealkynyl, -CN, -OH, amino, and C-i-shaloalkyl; and two R8on adjacent carbon atoms may come together to form a cycloalkyl or heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from Ci-ealkyl, halo, and haloalkyl;Z is H, -OCRZ2-Q2, or Q2; wherein each Rzis independently H or halo;Q2is a heterocycle or carbocycle; wherein Q2is unsubstituted or substituted with 1 to 6 R9groups;each R9is independently selected from the group consisting of halogen, alkyl, amino, and C2-C4alkenyl, wherein each alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, amino, -OH, alkoxy, haloalkoxy, and heterocycloalkyl;R10is cyano, alkyl, haloalkyl, hydroxyalkyl, heteroaryl, alkyl-R11, alkyl-R12, or alkyl-O-R12, wherein the heteroaryl is unsubstituted or substituted with arylalkyl;R11is selected from the group consisting of -N(R14)S(=O)2R15, -N(R14)S(=O)2N(R15)2, -N(R14)C(=O)R15, -N(R14)C(=O)N(R15)2, -N=S(=O)(R14)(R16), and NR14-S(=O)(=NH)R15; R14is H, alkyl, or cycloalkyl; each R15is independently H, alkyl, or cycloalkyl, or two R15attached to the same nitrogen form a cycle; and R16is H, alkyl, cycloalkyl, or heteroaryl;R12is a heterocyclyl group unsubstituted or substituted with one or more R13; andeach R13is independently oxo, cyano, cyano-alkyl, halo, alkyl, haloalkyl, alkoxy, alkoxy-alkyl, -S(O)2R13b, cycloalkyl, halocycloalkyl, heterocycloalkyl, or-N(R13a)C(=O)R13b, wherein the heterocycloalkyl is unsubstituted or substituted with oxo or hydroxyalkyl.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:Q1is an aryl or heteroaryl; andZ is H, -OCH2-Q2, or Q2.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:R1is halogen;X1is N or CR°, wherein R° is H or halogen; andQ1is a C6-C10aryl or 5-10-membered heteroaryl comprising at least one annular N.

6. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:R1is fluoro;X1is N or CR°, wherein R° is chloro; andQ1is phenyl, naphthyl, pyridine, isoquinoline, or pyrazole.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein:m is an integer from 0 to 4; andeach R8is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, , C3-6cycloalkyl, -C≡CH, -CN, -OH, -NH2, -NHCH3, and CF3; and, independently, two R8on adjacent carbon atoms may come together to form a 6-membered ring unsubstituted or substituted with one or two methyl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X1is N.

9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X1is CR°.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R8-substituted Q1is:

11. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R8-substituted Q1is:

12. The compound any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Z is -O-CH2Q2and Q2is:

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is Q2and Q2is:

14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt thereof, wherein Q2is substituted by one or more R9selected from halogen, alkyl, hydroxyalkyl, haloalkyl, and dialkylaminoalkyl.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein:R10is -CH2-R11;R11is -N(R14)S(=O)2R15, -N(R14)S(=O)2N(R15)2, -N(R14)C(=O)R15, -N(R14)C(=O)N(R15)2, and -N=S(=O)(R14)(R16), or -NR14-S(=O)(=NH)R15;R14is H, methyl, or cyclopropyl;each R15is independently H, methyl, or cyclopropyl, or two R15attached to the same nitrogen come together to form a 5-6 membered heterocycloalkyl; andR16is 6-membered heteroaryl.

16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R10is cyano, methyl, ethyl, halomethyl, hydroxymethyl, or 5-membered heteroaryl substituted with phenyl-methyl.

17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein:R10is CH2-R12, or CH2-O-R12,R12is a 5-10-membered heteroaryl or 5-10-membered heterocycloalkyl, wherein the heteroaryl or heterocycloalkyl comprises 1-3 annular heteroatoms independently selected from N, O, S, SO2, and -N+O_and is substituted with one to five R13;each R13is independently oxo, cyano, cyano-CH2-, halo, C1-C3alkyl, C1-C3haloalkyl, -O-C1-C3alkyl, -CH2-O-CH3, -S(O)2R13b, cyclopropyl, halocyclopropyl, 4-5 membered heterocycloalkyl, -N(R13a)C(=O)R13b, or S(O)2R13b; wherein R13aand R13bare independently C-i-Csalkyl; and wherein the heterocycloalkyl is unsubstituted or substituted with oxo or hydroxyC1-C3alkyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R10is -CH2-R12.

19. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R10is -CH2-R12and R12, unsubstituted or substituted with one oxo, is:wherein the R12may be further substituted by one or more R13groups.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein the R12is not further substituted or is further substituted by 1 to 5 additional R13groups, wherein each R13is independently selected from oxo, cyano, cyano-CH2-, halo, Ci-C3alkyl, Ci-C3haloalkyl, -O-Ci-C3alkyl, -CH2-O-CH3, -S(O)2R13b, cyclopropyl, halocyclopropyl, 4-5 membered heterocycloalkyl, -N(R13a)C(=O)R13b, and S(O)2R13b; wherein R13aand R13bare independently Ci-C3alkyl; and wherein the heterocycloalkyl is unsubstituted or substituted with oxo or hydroxyCi-C3alkyl.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound selected from Table 1, or is a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition, comprising the compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. A method of treating a cancer in a human subject in need thereof, the method comprising administering to the subject an effective amount of a compound 1 to 21, or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein the cancer comprises a KRas-G12V mutation.

25. The method of claim 24, further comprising evaluating a tissue sample from the human subject for the absence or presence of a KRas-G12V mutation prior to administering the compound or pharmaceutically acceptable salt thereof.

26. The method of claim 25, wherein a KRas-G12V mutation is identified in the tissue sample from the human subject prior to administering the compound or pharmaceutically acceptable salt thereof.

27. The method of any one of claims 23 to 26, wherein the cancer is tissue agnostic.

28. The method of any one of any one of claims 23 to 27, further comprising administering at least one additional therapeutic agent to the human subject.

29. The method of claim 28, wherein the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, a SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular-signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an anti-metabolite agent, or an alkylating agent.

30. A method for inhibiting tumor metastasis in a human subject in need thereof, comprising administering to the human subject a therapeutically effectiveamount of a compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof.

31. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein the cell population is a human cell population.

33. A method for regulating activity of a KRas-G12V mutant protein, the method comprising reacting the mutant protein with a compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof.

34. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

35. The use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for the therapeutic treatment of cancer.

36. The use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of cancer.

37. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment of cancer.

38. The use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use in the method of any one of claims 24 to 33.

39. The use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in the method of any one of claims 24 to 33.

40. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use in the method of any one of claims 24 to 33.

41. A process for synthesizing a compound as set forth herein.

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