Small molecule inhibitors of kras g12c mutant

Description

FIELD OF THE INVENTION

[0001] The present disclosure relates to certain heteroaryl compounds and pharmaceutically acceptable salts thereof that inhibit the G12C mutant of Kirsten rat sarcoma (KRAS) protein and are expected to have utility as therapeutic agents, for example, for treatment of cancer. The present application also relates to pharmaceutical compounds containing such compounds as well as the compounds for use in treating cancer.BACKGROUND OF THE INVENTION

[0002] RAS proteins are membrane-associated guanine nucleotide-binding proteins which function as molecular switches. RAS proteins function as components of signalling pathways transmitting signals from cell-surface receptors to regulate cellular proliferation, survival and differentiation. RAS proteins cycle between an inactive GDP-bound state and an active GTP-bound state.

[0003] The most notable members of the RAS subfamily are HRAS, KRAS and NRAS, mainly being implicated in many types of cancer. However, there are many other members including DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; KIRAS1; KIRAS2; NRAS; RALA; RALB; RAPIA; RAPID; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS and RRAS2.

[0004] Mutations in any one of the three main isoforms of RAS (HRAS, NRAS, or KRAS) genes are among the most common events in human tumorigenesis. KRAS mutations are detected in 25-30% of tumors. By comparison, the rates of oncogenic mutation occurring in the NRAS and HRAS family members are much lower (8% and 3% respectively).

[0005] Exchange of a glycine for a cysteine at residue 12 of RAS (the G12C mutation) results from a mutation commonly found in RAS genes. Large-scale cancer sequencing studies indicate that the G12C mutation appeared most frequently in lung, colorectal and pancreatic cancers. Histological analysis of seven cancer types indicated non-small cell lung cancer contributed the most, 70-75%, to cancer cases having the KRAS G12C mutation. See Lindsay, C.R., et al., Br J Cancer 121, 197-198 (2019).

[0006] Accordingly, while progress has been made in this field, there remains a need in the art for improved compounds and methods for treatment of cancer, for example, by inhibition of a mutant KRAS, HRAS or NRAS protein (e.g., KRAS G12C). Embodiments of the present disclosure fulfill this need and provide further related advantages. Various KRAS G12C inhibitors are known from WO2020 / 050890, WO2018 / 119183 and WO2018 / 217651.SUMMARY OF THE DISCLOSURE

[0007] The technical information set out below may in some respects go beyond the scope of the present invention, which is defined by the appended claims. The additional technical information is provided to place the present invention in a broader technical context and to illustrate possible related technical developments.

[0008] The present disclosure provides compounds which modulate mutant KRAS, HRAS, and / or NRAS proteins and may be valuable pharmaceutically active compounds for the treatment of cancer. In some embodiments the disclosed compounds selectively inhibit the KRAS (G12C) protein. The compounds of Formula (I) and their pharmaceutically acceptable salts, can modulate the activity of KRAS, HRAS and / or NRAS activity and thereby effect the signaling pathway which regulates cell growth, differentiation, and proliferation associated with oncological disorders. In certain embodiments, the compounds of Formula (I) can inhibit the KRAS (G12C) protein. The disclosure furthermore provides processes for preparing compounds of Formula (I), and such compounds for use in treating oncological disorders, and pharmaceutical compositions which comprise compounds of Formula (I).DETAILED DESCRIPTION OF THE INVENTION

[0009] According to a first aspect defined in claim 1, the present invention relates to a compound, wherein the compound is selected from the group consisting of: 2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-18,21-difluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one; (5aSa,17aRa)-20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-dihydro-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one; (5aSa,17aRa)-20-Chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-di[(2H)hydro](11,12-2H2)-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one; (5aRa,18aRa)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18,21-tetrafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one; (5aRa,18aRa)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,17,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one; (5aRa,18aRa)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,15,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one; (5aRa,18aRa)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,16,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one; (5aSa,17aRa)-20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-16,17-difluoro-6-(propan-2-yl)-11,12-di[(2H)hydro](11,12-2H2)-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one; 2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,17,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)dipyrimido[4,5-f:1',6'-h][1,8,10]benzoxadiazacyclotridecin-4-one; 21-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18-trifluoro-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,5,8,10]benzodioxadiazacyclotridecin-4-one; 20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-17-fluoro-6-(propan-2-yl)-11,12-dihydro-4H,10H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,7,9]benzoxadiazacyclododecin-4-one; or a pharmaceutically acceptable salt thereof.

[0010] In a second aspect defined in claim 12, the present invention relates to a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of the first aspect.

[0011] In a third aspect defined in claim 13, the present invention relates to the compound or the pharmaceutically acceptable salt thereof of the first aspect for use in therapy.

[0012] In a fourth aspect defined in claim 14, the present invention relates to the compound or the pharmaceutically acceptable salt thereof of the first aspect, or a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof, for use in treating cancer.

[0013] In a fifth aspect defined in claim 15, the present invention relates to the compound or the pharmaceutically acceptable salt thereof of the first aspect, and an additional anti-cancer agent, or a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of the first aspect, and an additional anti-cancer agent, for use in the treatment of cancer.

[0014] In some embodiments, the present disclosure provides compounds which have low predicted oral human doses (e.g., < 500 mg, preferably < 200 mg once daily oral administration) which result from high cellular potencies (e.g., IC50 < 100 nM at 2 h incubation time in the phospho-ERK assay), and superior preclinical pharmacokinetic and stability properties (e.g., as measured in the compounds' concentration in rat and dog plasma and in plasma clearance studies).

[0015] The present disclosure includes the pharmaceutically acceptable salts of the compounds defined herein, including the pharmaceutically acceptable salts of all structural formulas, embodiments and classes defined herein. Reference to the compounds of structural Formula (I) includes the compounds of other generic structural Formulas, such as Formulae (IA) and (IB), and embodiments that fall within the scope of Formula (I).Definitions

[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0017] As used throughout this disclosure, "a compound of Formula (I)" is to be understood to include "a compound of Formula (I) or a pharmaceutically acceptable salt thereof". And "a compound of Formula (I)" is to be understood as to include "a compound of Formula (IA)" and "a compound of Formula (IB)" (and pharmaceutically acceptable salts of the compound of Formula (IA) and Formula (IB)).

[0018] "Alkyl", as well as other groups having the prefix "alk", such as alkoxy, means carbon chains which may be linear or branched, or combinations thereof, containing the indicated number of carbon atoms. In particular embodiments, linear alkyl groups have 1-6 carbon atoms and branched alkyl groups have 3-7 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, and nonyl.

[0019] "Alkylene" refers to optionally substituted alkylene radicals. A numerical range, which refers to the chain length in total, may be given. For example, C 3 -C 4 alkylene has a chain length of 3 or 4 atoms. Unless otherwise stated in the specification, alkylene groups may be substituted at carbon atoms in the radicals with one or more substituents which independently are oxo, fluoro, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, amino, hydroxy or two geminal or vicinal or hominal substitutions can combine with the carbon atoms to which they are substituted to form a C 3 -C 6 cycloalkyl.

[0020] "Alkoxy" and "alkyl-O-" are used interchangeably and refer to an alkyl group linked to oxygen.

[0021] "Alkylphenyl" refers to a C 1 -C 4 alkyl substituted with a phenyl group. The phenyl group may be anywhere on the carbon chain, e.g., at the end of the carbon chain.

[0022] "Bicyclo- ring system" refers to two joined rings. The rings may be fused, i.e., share two adjacent atoms, or "spirocyclic", i.e., share only a single atom.

[0023] "Cyanoalkyl" refers to an alkyl group substituted with a cyano group.

[0024] "Cycloalkyl" means a saturated cyclic hydrocarbon radical. In particular embodiments, the cycloalkyl group has 3-12 carbon atoms, forming 1-3 carbocyclic rings that are fused. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

[0025] "Fluoroalkyl" include mono-substituted as well as multiple fluoro-substituted alkyl groups, up to perfluoro substituted alkyl. For example, fluoromethyl, 1,1-difluoroethyl, trifluoromethyl or 1,1,1,2,2-pentafluorobutyl are included.

[0026] "Geminally substituted" refers to substitutions (e.g., functional groups) that are attached to the same atom in a molecule. For instance, 1,1-dichloroethane is an ethane molecule which is geminally substituted with two chlorine atoms.

[0027] The term "heteroalkylene" refers to optionally substituted alkylene radicals , which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, or sulfur, thereof. A numerical range, which refers to the chain length in total, may be given. For example, C 1 -C 7 heteroalkylene has a chain length of 1 to 7 atoms. For example, a - OCH 2 CH 2 CH 2 O- radical is referred to as a "C 5 heteroalkylene", which includes two heteroatoms in the atom chain length description. Connections to the rest of the molecule are through terminal carbon, nitrogen, oxygen or sulfur atoms in the heteroalkylene chain (e.g., to ring atoms of C y< and C z< ). The heteroalkylene groups may be substituted. Unless otherwise stated in the specification, heteroalkylene groups may be substituted at carbon atoms in the radicals with one or more substituents which independently are oxo, fluoro, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, amino, hydroxy or two geminal or vicinal or hominal substitutions can combine with the carbon atoms to which they are substituted to form a C 3 -C 6 cycloalkyl. In some embodiments, the heteroalkylene groups have 1-2 heteroatoms selected from nitrogen and oxygen atoms in the atom chain. In some embodiments, the heteroalkylene groups have 1 heteroatom selected from nitrogen and oxygen atoms in the atom chain.

[0028] "Heteroaryl" refers to aromatic monocyclic and bicyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S, or N atoms. Examples of heteroaromatic groups include pyridinyl, pyrimidinyl, pyrrolyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl.

[0029] "Halogen" or "halo" unless otherwise indicated, includes fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In one embodiment, halo is fluoro (-F) or chloro (-Cl).

[0030] "Hominally substituted" refers to substitutions or groups that are attached on a molecule in a 1,3-relationship. For instance, 1,3-dichloropropane ClCH 2 CH 2 CH 2 Cl is a propane molecule which is hominally substituted with two chlorine atoms.

[0031] "Hydroxyalkyl" includes mono-substituted as well as multiple hydroxy-substituted alkyl groups.

[0032] When any variable (e.g., R 3< , RY, etc.) occurs more than one time in any constituent or in Formula (I) or other generic formulas herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the various substituents, i.e., R 3< , R y< , etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaryl ring, or a saturated heterocycloalkyl ring) provided such ring substitution is chemically allowed and results in a stable compound. A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0033] The term "substituted" shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0034] "Vicinally substituted" refers to substitutions or groups that are attached to the adjacent atoms in a molecule. For instance, 1,2-dichloroethane is an ethane molecule which is vicinally substituted with two chlorine atoms.

[0035] Unless expressly depicted or described otherwise, variables depicted in a structural formula with a "floating" bond, such as R 3< or RY in Formula (I), are permitted on any available carbon atom in the ring to which the variable is attached. When a moiety is noted as being "optionally substituted" in Formula (I) or any embodiment thereof, it means that Formula (I) or the embodiment thereof encompasses compounds that contain the noted substituent (or substituents) on the moiety and also compounds that do not contain the noted substituent (or substituents) on the moiety.

[0036] The wavy line , as used herein, indicates a point of attachment to the rest of the compound.

[0037] Compounds of Formula (I) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereoisomeric mixtures and individual diastereoisomers. Centers of asymmetry that are present in the compounds of Formula (I) can all independently of one another have S configuration or R configuration. The compounds of this disclosure include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example, mixtures of enantiomers and / or diastereomers, in all ratios. Thus, enantiomers are a subject of the disclosure in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism, the disclosure includes both the cis form and the trans form as well as mixtures of these forms in all ratios. The present disclosure is meant to comprehend all such stereoisomeric forms of the compounds of Formula (I). Where a structural formula or chemical name specifies a particular configuration at a stereocenter, the enantiomer or stereoisomer of the compound resulting from that specified stereocenter is intended. Where a structural formula of the compounds of Formula (I) indicates a straight line at a chiral center, the structural formula includes both the S and R stereoisomers associated with the chiral center and mixtures thereof.

[0038] Compounds of Formula (I) may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Vibrational circular dichroism (VCD) may also be used to determine the absolute stereochemistry. Alternatively, any stereoisomer or isomers of a compound of Formula (I) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.

[0039] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereoisomeric mixture, followed by separation of the individual diastereoisomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0040] For compounds of Formula (I) described herein which contain olefinic double bonds, unless specified otherwise, they are meant to include both E and Z geometric isomers.

[0041] Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I of the present disclosure.

[0042] Some of the compounds described herein may exist as atropisomers when the rotational energy barrier around a single bond is sufficiently high to prevent free rotation at a given temperature, thus allowing isolation of individual conformers with distinct properties. A typical example of stable atropisomers are exemplified by intermediates Int-4d-1 and Int-4d-2 (described below), which can be resolved by supercritical fluid chromatography separation. The individual atropisomers as well as mixtures thereof are encompassed with compounds of Formula I of the present disclosure. When resolved, individual atropisomers can be designated by established conventions such as those specified by the International Union of Pure Applied Chemistry (IUPAC) 2013 Recommendations.

[0043] In the compounds of Formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of Formula (I) and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium ( 1< H) and deuterium ( 2< H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of Formula (I), can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0044] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present disclosure is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, and zinc salts. Preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts prepared from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines derived from both naturally occurring and synthetic sources. Pharmaceutically acceptable organic non-toxic bases from which salts can be formed include, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0045] When the compound of the present disclosure is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acid. Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. If the compounds of Formula (I) simultaneously contain acidic and basic groups in the molecule, the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula (I) by customary methods which are known to the person skilled in the art, for example, by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts. The present disclosure also includes all salts of the compounds of Formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0046] Furthermore, compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula (I), including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds of the instant disclosure may form solvates with water (i.e., a hydrate) or common organic solvents such as but not limited to ethyl acetate. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this disclosure, along with un-solvated and anhydrous forms.

[0047] Any pharmaceutically acceptable pro-drug modification of a compound of this disclosure which results in conversion in vivo to a compound within the scope of this disclosure is also within the scope of this disclosure.

[0048] The present disclosure also relates to processes for the preparation of the compounds of Formula (I) which are described in the following and by which the compounds of the disclosure are obtainable.

[0049] The terms "therapeutically effective (or efficacious ) amount" and similar descriptions such as "an amount efficacious for treatment" are intended to mean that amount of a compound of Formula (I) that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In a preferred embodiment, the term "therapeutically effective amount" means an amount of a compound of Formula (I) that alleviates at least one clinical symptom in a human patient. The terms "prophylactically effective (or efficacious) amount" and similar descriptions such as "an amount efficacious for prevention" are intended to mean that amount of a compound of Formula (I) that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.Dosages of the Compounds of Formula (I)

[0050] The dosage regimen utilizing a compound of the instant disclosure is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of an oncological condition, and a prophylactically effective amount, e.g., for prevention of an oncological condition.

[0051] While individual needs vary, determination of optimal ranges of effective amounts of the compound of the disclosure is within the skill of the art. For administration to a human in the curative or prophylactic treatment of the conditions and disorders identified herein, for example, typical dosages of the compounds of the present disclosure can be about 0.05 mg / kg / day to about 50 mg / kg / day, for example at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, or at least 0.5 mg / kg, and preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, or 10 mg / kg or less, which can be about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg), for example. For example, dosages of the compounds can be about 0.1 mg / kg / day to about 50 mg / kg / day, about 0.05 mg / kg / day to about 10 mg / kg / day, about 0.05 mg / kg / day to about 5 mg / kg / day, about 0.05 mg / kg / day to about 3 mg / kg / day, about 0.07 mg / kg / day to about 3 mg / kg / day, about 0.09 mg / kg / day to about 3 mg / kg / day, about 0.05 mg / kg / day to about 0.1 mg / kg / day, about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / day to about 500 mg / day, about 5 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. Such doses may be administered in a single dose or may be divided into multiple doses.Pharmaceutical Compositions

[0052] The compounds of Formula (I) and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical compositions. The term "subject" or "patient" includes animals, preferably mammals and especially humans, who use the instant active agents for the prevention or treatment of a medical condition. Administering of the drug to the subject includes both self-administration and administration to the patient by another person. The subject may be in need of, or desire, treatment for an existing disease or medical condition, or may be in need of or desire prophylactic treatment to prevent or reduce the risk of occurrence of said disease or medical condition. As used herein, a subject "in need" of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0053] The present disclosure therefore also provides the compounds of Formula (I) and their pharmaceutically acceptable salts for use as pharmaceuticals, their use for modulating the activity of mutant KRAS, HRAS and / or NRAS proteins and in particular their use in the therapy and prophylaxis of the below-mentioned diseases or disorders as well as their use for preparing medicaments for these purposes. In certain embodiments, the compounds of Formula (I) and their pharmaceutically acceptable salts inhibit the KRAS G12C protein.

[0054] Furthermore, the present disclosure provides pharmaceutical compositions which comprise as active component an effective dose of at least one compound of Formula (I) and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives.

[0055] Thus, the present disclosure provides, for example, said compound and its pharmaceutically acceptable salts for use as pharmaceutical compositions which comprise as active component an effective dose of the compound of Formula (I) and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, and the uses of said compound and / or a pharmaceutically acceptable salt thereof in the therapy or prophylaxis of the below-mentioned diseases or disorders, e.g., cancer, as well as their use for preparing medicaments for these purposes.

[0056] The pharmaceutical compositions according to the disclosure can be administered orally, for example, in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously in the form of solutions for injection or infusion.

[0057] Other suitable administration forms are, for example, percutaneous or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and on its severity.

[0058] The amount of active compound of Formula (I) and / or its pharmaceutically acceptable salts in the pharmaceutical composition normally is from 0.01 to 200 mg, such as from 0.1 to 200 mg, preferably from 1 to 200 mg, per dose, but depending on the type of the pharmaceutical composition, it can also be higher. In some embodiments, the amount of active compound of Formula (I) and / or its pharmaceutically acceptable salts in the pharmaceutical composition is from 0.01 to 10 mg per dose. The pharmaceutical compositions usually comprise 0.5 to 90 percent by weight of the compound of Formula (I) and / or their pharmaceutically acceptable salts. The preparation of the pharmaceutical compositions can be carried out in a manner known per se. For this purpose, one or more compounds of Formula (I) and / or their pharmaceutically acceptable salts, together with one or more solid or liquid pharmaceutical carrier substances and / or additives (or auxiliary substances) and, if desired, in combination with other pharmaceutically active compounds having therapeutic or prophylactic action, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human or veterinary medicine.

[0059] For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, starch, for example, maize starch, or starch derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the preparation of solutions, for example, of solutions for injection, or of emulsions or syrups are, for example, water, physiologically acceptable sodium chloride solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of Formula (I) and their pharmaceutically acceptable salts and to use the resulting lyophilisates, for example, for preparing preparations for injection or infusion. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.

[0060] Besides the active compounds and carriers, the pharmaceutical compositions can also contain customary additives, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.Methods of Using the Compounds of Formula (I)

[0061] The present application provides a method of inhibiting RAS-mediated cell signaling comprising contacting a cell with a compound of Formula (I) or a pharmaceutically acceptable salt 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) 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, pERK, or pAKT levels; 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.

[0062] The present application also provides compounds of Formula (I) (or their pharmaceutically acceptable salts) or pharmaceutical compositions containing such compounds for use in treating disease conditions, including but not limited to, conditions implicated by mutant KRAS, HRAS and / or NRAS proteins (e.g., cancer), and in some embodiments the KRAS G12C mutant.

[0063] In some embodiments, a compound or pharmaceutical composition for use in a method of treatment of cancer is provided, the method comprising administering a therapeutically effective amount a compound of Formula (I) (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment. In some embodiments, the cancer is mediated by a KRAS, HRAS or NRAS mutation, e.g., the KRAS G12C mutation. In various embodiments, the cancer is pancreatic cancer, colorectal cancer or lung cancer. In some embodiments, the cancer is gall bladder cancer, thyroid cancer, or bile duct cancer.

[0064] In some embodiments the present disclosure provides a compound or pharmaceutical composition for use in a method of treating a disorder in a subject in need thereof, wherein said method comprises determining if the subject has a KRAS, HRAS or NRAS mutation (e.g., KRAS G12C mutation) and if the subject is determined to have the KRAS, HRAS or NRAS mutation, then administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0065] The disclosed compounds inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, another embodiment of the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount a compound disclosed herein.

[0066] KRAS, HRAS or NRAS 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 the compounds of Formula (I) (e.g., in the form of a pharmaceutical composition) to a subject 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 are useful for treatment of lymphomas such as Hodgkins lymphoma or non-Hodgkins lymphoma. In various embodiments, the compounds are useful for treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom's macroglubunemia.

[0067] Determining whether a tumor or cancer comprises a KRAS, HRAS or NRAS mutation (e.g., the KRAS G12C mutation) can be undertaken by assessing the nucleotide sequence encoding the KRAS, HRAS or NRAS protein, by assessing the amino acid sequence of the KRAS, HRAS or NRAS protein, or by assessing the characteristics of a putative KRAS, HRAS or NRAS mutant protein. The sequences of wild-type human KRAS, HRAS or NRAS are known in the art.

[0068] Methods for detecting a mutation in a KRAS, HRAS or NRAS nucleotide sequence are also 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, HRAS or NRAS mutations (e.g., the KRAS G12C mutation) by real-time PCR. In real-time PCR, fluorescent probes specific for the KRAS, HRAS or NRAS G12C mutation are used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRAS, HRAS or NRAS mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and / or exon 3) in the KRAS, HRAS or NRAS gene.

[0069] Methods for detecting a mutation in a KRAS, HRAS or NRAS protein (e.g., the KRAS G12C mutation) are known by those of skill in the art. These methods include, but are not limited to, detection of a KRAS, HRAS or NRAS mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0070] A number of tissue samples can be assessed for determining whether a tumor or cancer comprises a KRAS, HRAS or NRAS mutation (e.g., the KRAS G12C mutation). In some embodiments, the sample 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 a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA.

[0071] The present application also provides a compound or pharmaceutical composition for use in a method of treating a hyperproliferative disorder comprising administering a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, said method relates to the treatment of a subject who suffers from a cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS- related cancers (e.g., Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, 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 lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver 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, myelodysplasia 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 lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, 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, stomach (gastric) 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. In some embodiments, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

[0072] In some embodiments, the methods for treatment are directed to treating lung cancers, and the methods comprise administering a therapeutically effective amount of the compounds of the disclosure (or pharmaceutical composition comprising such compounds) to a subject in need thereof. In certain embodiments, the lung cancer is a non-small cell lung carcinoma (NSCLC), for example, adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung carcinoma. Other lung cancers which the compounds of Formula (I) may provide therapeutic benefit for include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.

[0073] The present disclosure also provides methods of modulating a mutant KRAS, HRAS or NRAS protein activity (e.g., activity resulting from the KRAS G12C mutation) by contacting the protein with an effective amount of a compound of Formula (I). Modulation can be inhibiting or activating protein activity. In some embodiments, the present disclosure provides methods of inhibiting protein activity by contacting the mutant KRAS, HRAS or NRAS protein (e.g., KRAS G12C mutany) with an effective amount of a compound of Formula (I) in solution. In some embodiments, the present disclosure provides methods of inhibiting the mutant KRAS, HRAS or NRAS protein activity by contacting a cell, tissue, or organ that expresses the protein of interest. In some embodiments, the disclosure provides methods of inhibiting protein activity in subjects including, but not limited to, rodents and mammals (e.g., humans) by administering into the subjects an effective amount of a compound of Formula (I).Combination Therapies

[0074] One or more additional pharmacologically active agents may be administered in combination with a compound of Formula (I) (or a pharmaceutically acceptable salt thereof). An additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which are different from the compound of Formula (I). The additional active agents also include free-acid, free-base and pharmaceutically acceptable salts of said additional active agents. Generally, any suitable additional active agent or agents, including chemotherapeutic agents or therapeutic antibodies, may be used in any combination with the compound of Formula (I) in a single dosage formulation (e.g., a fixed dose drug combination), or in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents) to subjects. In addition, the compounds of Formula (I) (or pharmaceutically acceptable salts thereof) can be administered in combination with radiation therapy, hormone therapy, surgery or immunotherapy.

[0075] The present application also provides methods for combination therapies in which the additional active agent is known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes which are used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, such therapy includes, but is not limited to, the combination of one or more compounds of Formula (I) with chemotherapeutic agents, immunotherapeutic agents, hormonal and anti-hormonal agents, targeted therapy agents, and anti-angiogenesis agents, to provide a synergistic or additive therapeutic effect. In another embodiment, such therapy includes radiation treatment to provide a synergistic or additive therapeutic effect.

[0076] Examples of additional active agents (i.e., additional anti-cancer agents) include chemotherapeutic agents (e.g., cytotoxic agents), immunotherapeutic agents, hormonal and anti-hormonal agents, targeted therapy agents, and anti-angiogenesis agents. Many anti-cancer agents can be classified within one or more of these groups. While certain anti-cancer agents have been categorized within a specific group(s) or subgroup(s) herein, many of these agents can also be listed within one or more other group(s) or subgroup(s), as would be presently understood in the art. It is to be understood that the classification herein of a particular agent into a particular group is not intended to be limiting. Many anti-cancer agents are presently known in the art and can be used in combination with the compounds of the present disclosure.

[0077] Further, an agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition). For example, suitable for use are one or more agents (e.g., antibodies, antigen binding regions, or soluble receptors) that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as Scatter Factor), and antibodies or antigen binding regions that specifically bind its receptor "c-met".

[0078] In an embodiment, the additional anti-cancer agent is a chemotherapeutic agent, an immunotherapeutic agent, a hormonal agent, an anti-hormonal agent, a targeted therapy agent, or an anti-angiogenesis agent (or angiogenesis inhibitor). In an embodiment, the additional anti-cancer agent is selected from the group consisting of a chemotherapeutic agent, a mitotic inhibitor, a plant alkaloid, an alkylating agent, an anti-metabolite, a platinum analog, an enzyme, a topoisomerase inhibitor, a retinoid, an aziridine, an antibiotic, a hormonal agent, an anti-hormonal agent, an anti-estrogen, an anti-androgen, an anti-adrenal, an androgen, a targeted therapy agent, an immunotherapeutic agent, a biological response modifier, a cytokine inhibitor, a tumor vaccine, a monoclonal antibody, an immune checkpoint inhibitor, an anti-PD-1 agent, an anti-PD-L1 agent, a colony-stimulating factor, an immunomodulator, an immunomodulatory imide (IMiD), an anti-CTLA4 agent, an anti-LAGl agent, an anti-OX40 agent, a GITR agonist, a CAR-T cell, a BiTE, a signal transduction inhibitor, a growth factor inhibitor, a tyrosine kinase inhibitor, an EGFR inhibitor, a histone deacetylase (HDAC) inhibitor, a proteasome inhibitor, a cell-cycle inhibitor, an anti-angiogenesis agent, a matrix-metalloproteinase (MMP) inhibitor, a hepatocyte growth factor inhibitor, a TOR inhibitor, a KDR inhibitor, a VEGF inhibitor, a HIF-1α inhibitor a HIF-2α inhibitor, a fibroblast growth factor (FGF) inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, an AKT inhibitor, an MCL-1 inhibitor, a BCL-2 inhibitor, an SHP2 inhibitor, a HER-2 inhibitor, a BRAF-inhibitor, a gene expression modulator, an autophagy inhibitor, an apoptosis inducer, an antiproliferative agent, and a glycolysis inhibitor.

[0079] In one embodiment, the additional anti-cancer agent(s) is a chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents include mitotic inhibitors and plant alkaloids, alkylating agents, anti-metabolites, platinum analogs, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.

[0080] Non-limiting examples of mitotic inhibitors and plant alkaloids include taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel; demecolcine; epothilone; eribulin; etoposide (VP- 16); etoposide phosphate; navelbine; noscapine; teniposide; thaliblastine; vinblastine; vincristine; vindesine; vinflunine; and vinorelbine.

[0081] Non-limiting examples of alkylating agents include nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, cytophosphane, estramustine, ifosfamide, mannomustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, tris(2-chloroethyl)amine, trofosfamide, and uracil mustard; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, streptozotocin, and TA-07; ethylenimines and methylamelamines such as altretamine, thiotepa, triethylenemelamine, triethylenethiophosphaoramide, trietylenephosphoramide, and trimethylolomelamine; ambamustine; bendamustine; dacarbazine; etoglucid; irofulven; mafosfamide; mitobronitol; mitolactol; pipobroman; procarbazine; temozolomide; treosulfan; and triaziquone.

[0082] Non-limiting examples of anti-metabolites include folic acid analogues such as aminopterin, denopterin, edatrexate, methotrexate, pteropterin, raltitrexed, and trimetrexate; purine analogs such as 6-mercaptopurine, 6-thioguanine, fludarabine, forodesine, thiamiprine, and thioguanine; pyrimidine analogs such as 5-fluorouracil (5-FU), 6-azauridine, ancitabine, azacytidine, capecitabine, carmofur, cytarabine, decitabine, dideoxyuridine, doxifluridine, doxifluridine, enocitabine, floxuridine, galocitabine, gemcitabine, and sapacitabine; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; broxuridine; cladribine; cyclophosphamide; cytarabine; emitefur; hydroxyurea; mercaptopurine; nelarabine; pemetrexed; pentostatin; tegafur; and troxacitabine.

[0083] Non-limiting examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.

[0084] Non-limiting examples of enzymes include asparaginase and pegaspargase.

[0085] Non-limiting examples of topoisomerase inhibitors include acridine carboxamide, amonafide, amsacrine, belotecan, elliptinium acetate, exatecan, indolocarbazole, irinotecan, lurtotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.

[0086] Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin.

[0087] Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa.

[0088] Non-limiting examples of antibiotics include intercalating antibiotics; anthracenediones; anthracycline antibiotics such as aclarubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, nogalamycin, pirarubicin, and valrubicin; 6-diazo-5-oxo- L-norleucine; aclacinomysins; actinomycin; authramycin; azaserine; bleomycins; cactinomycin; calicheamicin; carabicin; carminomycin; carzinophilin; chromomycins; dactinomycin; detorubicin; esorubicin; esperamicins; geldanamycin; marcellomycin; mitomycins; mitomycin C; mycophenolic acid; olivomycins; novantrone; peplomycin; porfiromycin; potfiromycin; puromycin; quelamycin; rebeccamycin; rodorubicin; streptonigrin; streptozocin; tanespimycin; tubercidin; ubenimex; zinostatin; zinostatin stimalamer; and zorubicin.

[0089] In one embodiment, the additional anti-cancer agent(s) is a hormonal and / or anti-hormonal agent (i.e., hormone therapy). Non-limiting examples of hormonal and anti-hormonal agents include anti-androgens such as abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, goserelin, leuprolide, and nilutamide; anti-estrogens such as 4- hydroxy tamoxifen, aromatase inhibiting 4(5)-imidazoles, EM-800, fosfestrol, fulvestrant, keoxifene, LY 117018, onapristone, raloxifene, tamoxifen, toremifene, and trioxifene; anti-adrenals such as aminoglutethimide, dexaminoglutethimide, mitotane, and trilostane; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; abarelix; anastrozole; cetrorelix; deslorelin; exemestane; fadrozole; finasteride; formestane; histrelin (RL 0903); human chorionic gonadotropin; lanreotide; LDI 200 (Milkhaus); letrozole; leuprorelin; mifepristone; nafarelin; nafoxidine; osaterone; prednisone; thyrotropin alfa; and triptorelin.

[0090] In one embodiment, the additional anti-cancer agent(s) is an immunotherapeutic agent (i.e., immunotherapy). Non-limiting examples of immunotherapeutic agents include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony-stimulating factors, and immunomodulators.

[0091] Non-limiting examples of biological response modifiers, including cytokine inhibitors (cytokines) such as interferons and interleukins, include interferon alfa / interferon alpha such as interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon alfacon-1, peginterferon alfa-2a, peginterferon alfa-2b, and leukocyte alpha interferon; interferon beta such as interferon beta-1a, and interferon beta-1b; interferon gamma such as natural interferon gamma-1a, and interferon gamma-1b; aldesleukin; interleukin-1 beta; interleukin-2; oprelvekin; sonermin; tasonermin; and virulizin.

[0092] Non-limiting examples of tumor vaccines include APC 8015, AVICINE, bladder cancer vaccine, cancer vaccine (Biomira), gastrin 17 immunogen, Maruyama vaccine, melanoma lysate vaccine, melanoma oncolysate vaccine (New York Medical College), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), TICE ®< BCG (Bacillus Calmette-Guerin), and viral melanoma cell lysates vaccine (Royal Newcastle Hospital). Non-limiting examples of monoclonal antibodies include abagovomab, adecatumumab, aflibercept, alemtuzumab, blinatumomab, brentuximab vedotin, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), daclizumab, daratumumab, denosumab, edrecolomab, gemtuzumab zogamicin, HER- 2 and Fc MAb (Medarex), ibritumomab tiuxetan, idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), ipilimumab, lintuzumab, LYM-1 -iodine 131 MAb (Techni clone), mitumomab, moxetumomab, ofatumumab, polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), ranibizumab, rituximab, and trastuzumab.

[0093] Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 agents or antibodies such as cemiplimab, nivolumab, and pembrolizumab; anti-PD-L1 agents or antibodies such as atezolizumab, avelumab, and durvalumab; anti-CTLA-4 agents or antibodies such as ipilumumab; anti-LAG1 agents; and anti-OX40 agents.

[0094] Non-limiting examples of colony-stimulating factors include darbepoetin alfa, epoetin alfa, epoetin beta, filgrastim, granulocyte macrophage colony stimulating factor, lenograstim, leridistim, mirimostim, molgramostim, nartograstim, pegfilgrastim, and sargramostim.

[0095] Non-limiting examples of additional immunotherapeutic agents include BiTEs, CAR-T cells, GITR agonists, imiquimod, immunomodulatory imides (IMiDs), mismatched double stranded RNA (Ampligen), resiquimod, SRL 172, and thymalfasin.

[0096] In one embodiment, the additional anti-cancer agent(s) is a targeted therapy agent (i.e., targeted therapy). Targeted therapy agents include, for example, monoclonal antibodies and small molecule drugs. Non-limiting examples of targeted therapy agents include signal transduction inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell-cycle inhibitors, angiogenesis inhibitors, matrix-metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factors (FGF) inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, HER-2 inhibitors, BRAF-inhibitors, gene expression modulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.

[0097] Non-limiting examples of signal transduction inhibitors include tyrosine kinase inhibitors, multiple-kinase inhibitors, anlotinib, avapritinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, lonidamine, nilotinib, nintedanib, pazopanib, pegvisomant, ponatinib, vandetanib, and EGFR inhibitory agents.

[0098] Non-limiting examples of EGFR inhibitory agents include small molecule antagonists of EGFR such as afatinib, brigatinib, erlotinib, gefitinib, lapatinib, and osimertinib; and antibody-based EGFR inhibitors, including any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Antibody-based EGFR inhibitory agents may include, for example, those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al, 1995, Clin. Cancer Res. 1 : 1311-1318; Huang, S. M., et al., 1999, Cancer Res. 15:59(8): 1935-40; and Yang, X., et al., 1999, Cancer Res. 59: 1236-1243; monoclonal antibody Mab E7.6.3 (Yang, 1999 supra); Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof; specific antisense nucleotide or siRNA; afatinib, cetuximab; matuzumab; necitumumab; nimotuzumab; panitumumab; and zalutumumab.

[0099] Non-limiting examples of histone deacetylase (HDAC) inhibitors include belinostat, panobinostat, romidepsin, and vorinostat.

[0100] Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib.

[0101] Non-limiting examples of cell-cycle inhibitors, including CDK inhibitors, include abemaciclib, alvocidib, palbociclib, and ribociclib.

[0102] In one embodiment, the additional anti-cancer agent(s) is an anti-angiogenic agent (or angiogenesis inhibitor) including, but not limited to, matrix-metalloproteinase (MMP) inhibitors; VEGF inhibitors; EGFR inhibitors; TOR inhibitors such as everolimus and temsirolimus; PDGFR kinase inhibitory agents such as crenolanib; HIF-1α inhibitors such as PX 478; HIF-2α inhibitors such as belzutifan and the HIF-2α inhibitors described in WO 2015 / 035223; fibroblast growth factor (FGF) or FGFR inhibitory agents such as B-FGF and RG 13577; hepatocyte growth factor inhibitors; KDR inhibitors; anti-Ang1 and anti-Ang2 agents; anti-Tie2 kinase inhibitory agents; Tek antagonists (US 2003 / 0162712; US 6,413,932); anti-TWEAK agents (US 6,727,225); ADAM distintegrin domain to antagonize the binding of integrin to its ligands (US 2002 / 0042368); anti-eph receptor and / or anti-ephrin antibodies or antigen binding regions (US 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; and 6,057,124); and anti-PDGF-BB antagonists as well as antibodies or antigen binding regions specifically binding to PDGF-BB ligands.

[0103] Non-limiting examples of matrix-metalloproteinase (MMP) inhibitors include MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, prinomastat, RO 32-3555, and RS 13-0830. Examples of useful matrix metalloproteinase inhibitors are described, for example, in WO 96 / 33172, WO 96 / 27583, EP 1004578 , WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 0606046, EP 0931788, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667, WO 1999 / 007675 , EP 1786785, EP 1181017, US 2009 / 0012085 , US 5,863,949, US 5,861,510, and EP 0780386. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and / or MMP-9 relative to the other matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP- 8, MMP-10, MMP-11, MMP-12, and MMP-13).

[0104] Non-limiting examples of VEGF and VEGFR inhibitory agents include bevacizumab, cediranib, CEP 7055, CP 547632, KRN 633, orantinib, pazopanib, pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAP ™< .

[0105] The additional anti-cancer agent(s) may also be another anti-angiogenic agent including, but not limited to, 2-methoxyestradiol, AE 941, alemtuzumab, alpha-D148 Mab (Amgen, US), alphastatin, anecortave acetate, angiocidin, angiogenesis inhibitors, (SUGEN, US), angiostatin, anti-Vn Mab (Crucell, Netherlands), atiprimod, axitinib, AZD 9935, BAY RES 2690 (Bayer, Germany, BC 1 (Genoa Institute of Cancer Research, Italy), beloranib, benefin (Lane Labs, US), cabozantinib, CDP 791 (Celltech Group, UK), chondroitinase AC, cilengitide, combretastatin A4 prodrug, CP 564959 (OSI, US), CV247, CYC 381 (Harvard University, US), E 7820, EHT 0101, endostatin, enzastaurin hydrochloride, ER-68203-00 (IVAX, US), fibrinogen-E fragment, Flk-1 (ImClone Systems, US), forms of FLT 1 (VEGFR 1), FR-111142, GCS-100, GW 2286 (GlaxoSmithKline, UK), IL-8, ilomastat, IM-862, irsogladine, KM-2550 (Kyowa Hakko, Japan), lenalidomide, lenvatinib, MAb alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, US), MAb VEGF (Xenova, UK), marimastat, maspin (Sosei, Japan), metastatin, motuporamine C, M-PGA, ombrabulin, OXI4503, PI 88, platelet factor 4, PPI 2458, ramucirumab, rBPI 21 and BPI-derived antiangiogenic (XOMA, US), regorafenib, SC-236, SD-7784 (Pfizer, US), SDX 103 (University of California at San Diego, US), SG 292 (Telios, US), SU-0879 (Pfizer, US), TAN-1120, TBC-1635, tesevatinib, tetrathiomolybdate, thalidomide, thrombospondin 1 inhibitor, Tie-2 ligands (Regeneron, US), tissue factor pathway inhibitors (EntreMed, US), tumor necrosis factor-alpha inhibitors, tumstatin, TZ 93, urokinase plasminogen activator inhibitors, vadimezan, vandetanib, vasostatin, vatalanib, VE-cadherin-2 antagonists, xanthorrhizol, XL 784 (Exelixis, US), ziv-aflibercept, and ZD 6126.

[0106] In embodiments, the additional anti-cancer agent(s) is an additional active agent that disrupts or inhibits RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways or is a PD-1 and / or PD-L1 antagonist. In embodiments, the additional anti-cancer agent(s) is a RAF inhibitor, EGFR inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, AKT inhibitor, TOR inhibitor, MCL-1 inhibitor, BCL-2 inhibitor, SHP2 inhibitor, proteasome inhibitor, or immune therapy, including monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAGl, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs. Non-limiting examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib.

[0107] Non-limiting examples of MEK inhibitors include binimetinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and trametinib.

[0108] Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, ravoxertinib, ulixertinib, and an ERKi as described in WO 2017 / 068412.

[0109] Non-limiting examples of PI3K inhibitors include 17-hydroxywortmannin analogs (e.g., WO 06 / 044453); AEZS-136; alpelisib; AS-252424; buparlisib; CAL263; copanlisib; CUDC-907; dactolisib (WO 06 / 122806); demethoxyviridin; duvelisib; GNE-477; GSK1059615; IC87114; idelalisib; INK1117; LY294002; Palomid 529; paxalisib; perifosine; PI-103; PI-103 hydrochloride; pictilisib (e.g., WO 09 / 036,082; WO 09 / 055,730); PIK 90; PWT33597; SF1126; sonolisib; TGI 00-115; TGX-221; XL147; XL-765; wortmannin; and ZSTK474.

[0110] Non-limiting examples of AKT inhibitors include Akt-1-1 (inhibits Aktl) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (Barnett et al. (2005) Biochem. J. 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700); indole-3-carbinol and derivatives thereof (e.g., U.S. Patent No. 6,656,963; Sarkar and Li (2004) J Nutr. 134(12 Suppl), 3493S-3498S); perifosine, Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); triciribine (Yang et al. (2004) Cancer Res. 64, 4394-9); imidazooxazone compounds including trans-3-amino-1-methyl-3-[4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl]-cyclobutanol hydrochloride (WO 2012 / 137870) ; afuresertib;; capivasertib; MK2206; and patasertib.

[0111] Non-limiting examples of TOR inhibitors include deforolimus; ATP-competitive TORC1 / TORC2 inhibitors, including PI-103, PP242, PP30, and Torin 1; TOR inhibitors in FKBP12 enhancer, rapamycins and derivatives thereof, including temsirolimus, everolimus, WO 9409010; rapalogs, e.g. as disclosed in WO 98 / 02441 and WO 01 / 14387, e.g. AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin ; 40-epi-(tetrazolyl)-rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin, and other derivatives disclosed in WO 05 / 005434; derivatives disclosed in US 5,258,389, WO 94 / 090101, WO 92 / 05179, US 5,118,677, US 5,118,678, US 5,100,883, US 5,151,413, US 5,120,842, WO 93 / 111130, WO 94 / 02136, WO 94 / 02485, WO 95 / 14023, WO 94 / 02136, WO 95 / 16691, WO 96 / 41807, WO 96 / 41807 and US 5,256,790; and phosphorus-containing rapamycin derivatives (e.g., WO 05 / 016252).

[0112] Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845.

[0113] Non-limiting examples of SHP2 inhibitors include SHP2 inhibitors described in WO 2019 / 167000 and WO 2020 / 022323.

[0114] Additional non-limiting examples of anti-cancer agents that are suitable for use include 2-ethylhydrazide, 2,2',2"-trichlorotriethylamine, ABVD, aceglatone, acemannan, aldophosphamide glycoside, alpharadin, amifostine, aminolevulinic acid, anagrelide, ANCER, ancestim, anti-CD22 immunotoxins, antitumorigenic herbs, apaziquone, arglabin, arsenic trioxide, azathioprine, BAM 002 (Novelos), bcl-2 (Genta), bestrabucil, biricodar, bisantrene, bromocriptine, brostallicin, bryostatin, buthionine sulfoximine, calyculin, cell-cycle nonspecific antineoplastic agents, celmoleukin, clodronate, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), defofamine, denileukin diftitox, dexrazoxane, diaziquone, dichloroacetic acid, dilazep, discodermolide, docosanol, doxercalciferol, edelfosine, eflornithine, EL532 (Elan), elfomithine, elsamitrucin, eniluracil, etanidazole, exisulind, ferruginol, folic acid replenisher such as frolinic acid, gacytosine, gallium nitrate, gimeracil / oteracil / tegafur combination (S-1), glycopine, histamine dihydrochloride, HIT diclofenac, HLA-B7 gene therapy (Vical), human fetal alpha fetoprotein, ibandronate, ibandronic acid, ICE chemotherapy regimen, imexon, iobenguane, IT-101 (CRLX101), laniquidar, LC 9018 (Yakult), leflunomide, lentinan, levamisole + fluorouracil, lovastatin, lucanthone, masoprocol, melarsoprol, metoclopramide, miltefosine, miproxifene, mitoguazone, mitozolomide, mopidamol, motexafin gadolinium, MX6 (Galderma), naloxone + pentazocine, nitracrine, nolatrexed, NSC 631570 octreotide (Ukrain), olaparib, P-30 protein, PAC-1, palifermin, pamidronate, pamidronic acid, pentosan polysulfate sodium, phenamet, picibanil, pixantrone, platinum, podophyllinic acid, porfimer sodium, PSK (Polysaccharide-K), rabbit antithymocyte polyclonal antibody, rasburiembodiment, retinoic acid, rhenium Re 186 etidronate, romurtide, samarium (153 Sm) lexidronam, sizofiran, sodium phenylacetate, sparfosic acid, spirogermanium, strontium-89 chloride, suramin, swainsonine, talaporfin, tariquidar, tazarotene, tegafur-uracil, temoporfin, tenuazonic acid, tetrachlorodecaoxide, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, TLC ELL-12, tositumomab-iodine 131, trifluridine and tipiracil combination, troponin I (Harvard University, US), urethan, valspodar, verteporfin, zoledronic acid, and zosuquidar.

[0115] The present disclosure further provides a method for using the compounds of Formula (I) or pharmaceutical compositions provided herein, in combination with radiation therapy to treat cancer. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of Formula (I) in this combination therapy can be determined as described herein.

[0116] Radiation therapy can be administered through one of several methods, or a combination of methods, including, without limitation, external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachy therapy. The term "brachytherapy," as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, I-131, I -125, Y-90, Re-186, Re-188, Sm- 153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present disclosure include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as I-125, I -131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive microspheres.

[0117] The present disclosure also provides a compound or pharmaceutical composition for use in methods for combination therapies in which the additional active agent is known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes which are used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, such therapy includes, but is not limited to, the combination of one or more compounds of Formula (I) with chemotherapeutic agents, immunotherapeutic agents, hormonal therapy agents, therapeutic antibodies, targeted therapy agents, and radiation treatment, to provide a synergistic or additive therapeutic effect.

[0118] The compounds of the disclosure can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the one or more compounds of the disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound of Formula (I) and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of Formula (I) and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of Formula (I) can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of Formula (I) and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

[0119] As one aspect of the present disclosure contemplates the treatment of the disease / conditions with a combination of pharmaceutically active compounds that may be administered separately, the disclosure further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula (I), and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit comprises directions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.

[0120] The present disclosure also provides for the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for use in therapy, or use of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, in therapy. The present disclosure also provides for the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for use in treating cancer, or use of a compound of Formula (I), or the pharmaceutically acceptable salt thereof, for treating cancer. The present disclosure also provides for the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer, or use of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer. The present disclosure also provides for the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for use in the treatment of cancer, or use of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent for treating cancer. The disclosure also provides the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for the preparation of a medicament for the treatment of cancer, or use of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for the preparation of a medicament for the treatment of cancer. The present disclosure also provides for a pharmaceutical composition comprising the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for use in the treatment of cancer, or use of the pharmaceutical composition comprising the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for treating cancer. The present disclosure also provides for a pharmaceutical composition comprising the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for use in the treatment of cancer, or use of the pharmaceutical composition comprising the compound of Formula (I), or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for treating cancer.Methods of Preparing the Compounds of the Disclosure

[0121] Several methods for preparing the compounds of this disclosure are described in the following Examples. Starting materials and intermediates are purchased, made from known procedures, or as otherwise illustrated.

[0122] Throughout the synthetic schemes and examples, abbreviations and acronyms may be used with the following meanings unless otherwise indicated: anhydr. = Anhydrous; aq. = aqueous; atm = atmosphere; Bodipy-GDP = mixture of ((2R,3 S,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-(((2-(3-(5,5-difluoro-7,9-dimethyl-5H-4l4,5l4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-3-yl)propanamido)ethyl)carbamoyl)oxy)-4-hydroxytetrahydrofuran-2-yl)methyl hydrogen diphosphate and ((2R,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-(((2-(3-(5,5-difluoro-7,9-dimethyl-5H-4l4,5l4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-3-yl)propanamido)ethyl)carbamoyl)oxy)-3-hydroxytetrahydrofuran-2-yl)methyl hydrogen diphosphate (Invitrogen ™< catalog number G22360); br s = broad singlet; Bu = butyl; t-Bu = tert-butyl; cataCxium ®< C = trans-Di(µ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II), C= CDCl 3 = deuterated chloroform; CDI = 1,1'-carbonyldiimidazole, CELITE = diatomaceous earth; CF 3 = trifluoromethyl; cGMP = cyclic guanosine monophosphate; CH 3 NO 2 = nitromethane; DCM = dichloromethane; DETA-NO = Diethylenetriamine / nitric oxide adduct; DIAD = Diisopropyl azodicarboxylate; DIEA / DIPEA = N,N-Diisopropylethylamine; DME = dimethoxyethane, DMEA = N,N-Dimethylethanamine, DMF = N,N-dimethylformamide; DMP = Dess-Martin periodinane; DMS = dimethyl sulfide; DMSO = dimethylsulfoxide; DPPF or dppf = 1,1'-bis(diphenylphosphino)ferrocene; DTT = dithiothreitol; EDTA = ethylenediaminetetraacetic acid; equiv, eq. = equivalent(s); Et = ethyl; Et 3 N = triethylamine; EtOAc = ethyl acetate; EtOH = ethanol; Grubbs Catalyst = (1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium; GTP = guanosine triphosphate; h = hour; HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HMDS = hexamethydisilazane; HPLC = High pressure liquid chromatography; Int. = intermediate; iPr = isopropyl; IP = inflection points; i-PrOH = Isopropanol; KHMDS = Potassium bis(trimethylsilyl)amide; LCMS, LC / MS = liquid chromatography-mass spectrometry; min, min. = minute; LDA = lithium diisopropylamide; M = Molar; Me = methyl; MeCN, ACN = acetonitrile; MeOH = methanol; mp, m.p. = melting point; mpk = milligrams per kilogram; MsCl = Methanesulfonyl chloride; MPLC = medium pressure liquid chromatography; N = Normal; NaOMe = sodium methoxide; NMR = nuclear magnetic resonance; N.D. = not determined; PDA = photodiode array; Pet. ether = petroleum ether; Pd-C = palladium on carbon; Pd 2 (dba) 3 = tris(dibenzylideneacetone)dipalladium (0); Ph = phenyl; Pr = propyl; psi = pounds per square inch gauge; POCl 3 = phosphorus(V) oxide chloride; PTLC, prep TLC = preparative thin layer chromatography; rac = racemic; RT = retention time; RP-HPLC = reverse phase HPLC; rt = room temperature; sat. = saturated; SFC = supercritical fluid chromatography; SOS = Son of Sevenless; Sphos Pd G3 = (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; TBAF = tetra-n-butylammonium fluoride; TBSCl = tert-butyldimethylsilyl chloride; TFA = trifluoroacetic acid; TLC = thin layer chromatography; THF = tetrahydrofuran; TMS = trimethylsilyl; TWEEN = polyoxyethylene (20) sorbitan monolaurate; VCD = vibrational circular dichroism; v, v / v = volume, volume to volume; w, w / w = weight, weight to weight, XPhos-Pd-G3 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; µm = micrometer.EXAMPLES

[0123] The compounds described herein can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the disclosure. The examples further illustrate details for the preparation of the compounds of the present disclosure. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. These examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosure. Any intermediates described below may be referred to herein by their number preceded by "Int-."

[0124] Concentration refers to the removal of the volatile components at reduced pressure (e.g., by rotary evaporation) unless otherwise noted. All temperatures are in degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI) in positive ion detection mode and m / z refers to the [M+H] +< ion unless otherwise noted. 1< H NMR spectra were recorded at 400-500 MHz at ambient temperature unless otherwise noted. Protons reported as 0.5 H are due to rotameric signals. RP-HPLC refers to reverse-phase HPLC on C18-functionalized preparative or semi-preparative columns with gradient elution using acetonitrile and water modified with trifluoroacetic acid or ammonium hydroxide as eluents and fractions were lyophilized or concentrated by rotary evaporation unless otherwise noted. Purification by column chromatography on silica gel was accomplished using a flash chromatography system (e.g., ISCO ®< or Biotage ®< ) and commercial pre-packed silica gel columns with elution using the stated solvent systems. Compounds described herein were synthesized as the racemates unless otherwise noted in the experimental procedures and compound tables. Certain products / intermediates in the examples include indication of "Peak 1" and / or "Peak 2", which refer to the order of elution of the indicated product / intermediate from the chromatography column (e.g., an SFC column) used to isolate the compound under the specified conditions. Thus, for example, Peak 1 refers to the first eluting compound, e.g., first eluting stereoisomer (e.g., a first eluting atropisomer), under the specified conditions. The starting materials 2,5-dichloro-3-nitropyridine and (E)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane were purchased from Sigma Aldrich.

[0125] SFC Columns used in the chiral resolution of stereoisomers are summarized in the following Table: SFC ColumnSFC Column AbbreviationAD-H, 21 mm × 250 mmColumn AAD-H, 30 mm × 250 mmColumn BAD-H, 50 mm × 250 mmColumn CAD, 30 mm × 250 mmColumn DAS, 30 mm × 250 mmColumn EOD-H, 30 mm × 250 mmColumn FOD-H, 21 mm ×250 mmColumn GOD, 30 mm × 250 mmColumn HIA, 21 mm × 250 mmColumn IIC, 30 mm × 250 mmColumn JIF, 21 mm × 250 mmColumn KIG, 30 mm × 250 mmColumn LIG, 50 mm × 250 mmColumn MPhenomenex-Cellulose-2, 50 mm × 250 mmColumn NPhenomenex Lux Cellulose-4 , 30 mm x 250 mmColumn OPhenomenex-Cellulose-2, 30 mm × 250 mmColumn PLux-2, 21 mm × 250 mmColumn QLux-2, 30 mm × 250 mmColumn ROJ-H, 21 mm × 250 mmColumn S(R,R)-Whelk-O1, 21 mm × 250 mmColumn TChromegaChiral SFC CCO, 21 mm × 250 mmColumn UAD, 50 mm × 250 mmColumn V

[0126] In the following, Examples 8, 50, 51-1, 52, 54, 55, 56, 57, 58, 59 and 63 are according to the present invention. Examples 1a, 2a, 3a, 3b, 4a, 4b, 5, 6, 7, 9, 10a, 10b, 11a, 12a, 13a, 13b, 14a, 15a, 16a, 16b, 17a, 17b, 18a, 19a, 19b, 20a, 20b, 60, 61, 62, and 64 to 121 are reference examples.Example 1a: 18,21-Difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,5,8,10]benzodioxadiazacyclotridecin-4-one

[0127] Step A: 4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-2-chloro-3-nitropyridine (Int-1a)

[0128] 3-((tert-Butyldimethylsilyl)oxy)propan-1-ol (7.60 g, 39.9 mmol) was dissolved in tetrahydrofuran (121 mL), cooled to 0 °C and charged with sodium hydride (1.60 g, 39.9 mmol) and allowed to stir at that temperature for 30 minutes. The reaction was charged with 2,4-dichloro-3-nitropyridine (7.00 g, 36.3 mmol) portionwise, and allowed to slowly warm to rt over 2 h. The reaction was quenched with saturated aq. ammonium chloride, diluted with EtOAc, separated, washed with brine, dried over sodium sulfate, filtered, concentrated, and purified on silica gel 0-25% EtOAC / hexanes to provide 4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-chloro-3-nitropyridine (Int-1a ). MS (ESI) [M+H] +< m / z 347.Step B: 4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-1b)

[0129] 4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-2-chloro-3-nitropyridine (5.00 g, 14.4 mmol) and cesium carbonate (14.1 g, 43.2 mmol) were added to a 200 mL round-bottomed flask equipped with magnetic stir bar, evacuated under nitrogen, and charged with DME (38.4 mL) / water (9.6 mL) and isopropenyl boronic acid pinacol ester (3.25 mL, 17.3 mmol), degassed under nitrogen three times and charged with bis(triphenylphosphine) palladium(II) dichloride (1.01 g, 1.44 mmol). The reaction was degassed under nitrogen, affixed with a reflux condenser and heated to 100 °C overnight. The reaction was cooled to room temperature, quenched with 50 mL saturated aq. ammonium chloride extracted 2 × 100 mL EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated and purified on silica gel 10-50% EtOAc / hexanes to provide 4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-1b ). MS (ESI) m / z 353.Step C: 4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-amine (Int-1c )

[0130] 4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (4.20 g, 11.9 mmol) was dissolved in ethanol (100 mL), degassed under nitrogen, charged with Pd-C (10% w / w, wetted) (840 mg) degassed under nitrogen, evacuated under hydrogen balloon and allowed to stir for 24 h at room temperature under hydrogen atmosphere. The reaction was filtered through CELITE and concentrated in vacuo to provide 4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-amine (Int-1c ), which was used without further purification. MS (ESI) [M+H] +< : m / z 325.Step D: N-((4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-1d )

[0131] To a stirred solution of 2,6-dichloro-5-fluoronicotinamide (1.15 g, 5.48 mmol) in THF (25 mL) was added a 2 M solution of oxalyl chloride in DCM (2.60 mL, 5.20 mmol) and the reaction was heated to 75 °C with a reflux condenser attached for 1 h. The reaction was cooled to 0 °C and a solution of 4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-amine (1.87 g, 5.75 mmol) in THF (5 mL) was added dropwise. The reaction was allowed to stir for 1 h. The reaction was quenched with 10 mL saturated sodium ammonium chloride, extracted 2 × 50 mL EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified on silica gel 0-100% hexanes / 3:1 EtOAc / EtOH to provide N-((4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-1d ). MS (ESI) [M+H] +< : m / z 559 / 561.Step E: 1-(4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-1e )

[0132] N-((4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (1.72 g, 3.07 mmol) was dissolved in THF (20 mL), cooled to 0 °C, charged with a 1 M solution of KHMDS in THF (6.46 mL, 6.46 mmol) and allowed to warm to rt over 1 h. The reaction was quenched with 10 mL saturated ammonium chloride, extracted 2 × 50 mL EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide 1-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-1e ), which was used without further purification. MS (ESI) [M+H] +< : m / z 523.Step F: 1-(4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d])yrimidin-2(1H)-one (Int-1f )

[0133] 1-(4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.57 g, 3.00 mmol) was dissolved in CH 3 CN (20 mL), charged with DIEA (1.05 mL, 6.00 mmol) and POCl 3 (0.336 mL, 3.60 mmol) and heated to 80 °C for 1 h. The reaction was evaporated on the rotovap and dried under high vacuum for 10 minutes to provide 1-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (Int-1f ), and used without further purification MS (ESI) [M+H] +< : m / z 540.8 / 542.9.Step G: tert-butyl (S)-4-(1-(4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-1g )

[0134] 1-(4-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (1.63 g, 3.00 mmol) was dissolved in acetonitrile (20 mL), cooled to 0 °C, charged with DIEA (2.01 mL, 12.0 mmol) then tert-butyl (S)-3-methylpiperazine-1-carboxylate (0.721 g, 3.60 mmol) and allowed to stir for 30 minutes. The reaction was quenched with 1:1 saturated sodium bicarbonate / water, allowed to stir for 5 minutes, and the organics were separated. The aqueous layer was extracted with 2 × 25 mL EtOAc, combined, washed with brine, dried over sodium sulfate, filtered, concentrated and purified on silica gel 0-100% 3:1 EtOAc / EtOH / hexanes to provide tert-butyl (S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-1g ) MS (ESI) [M+H] +< m / z:705.Step H: tert-Butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-(3-hydroxypropoxy)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-1h )

[0135] tert-Butyl (S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.500 g, 0.709 mmol), potassium 3-fluoro-2-(trifluoro-λ 4< -boraneyl)phenolate (0.200 g, 0.922 mmol), potassium acetate (0.278 g, 2.84 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride were added to a 20 mL scintillation vial equipped with magnetic stir bar, degassed under nitrogen, charged with dioxane (3.0 mL) / water (0.50 mL), degassed 3 times under nitrogen and heated to 90 °C for 1 h. The reaction was cooled to room temperature, quenched with 10 mL 1:1 water / saturated sodium bicarbonate, extracted 2 × 25 mL EtOAc, washed with brine and concentrated in vacuo. The crude residue was taken up in 10 mL THF, charged with a 1 M solution of TBAF in THF (1.77 mL, 1.77 mmol) and allowed to stir for 1.5 h at room temperature. The reaction was quenched with saturated NH 4 Cl, extracted once EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified on silica gel 0-100% 3:1 EtOAc / EtOH / hexanes to provide tert-butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-(3-hydroxypropoxy)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-1h ). MS (ESI) [M+H] +< m / z:667.Step I: (Int-1i)

[0136] tert-Butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-(3-hydroxypropoxy)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (61 mg, 0.091 mmol) and triphenylphosphine (60.0 mg, 0.229 mmol) were charged with THF (4.7 mL), degassed under nitrogen, charged with diisopropyl azodicarboxylate (36.0 µl, 0.183 mmol) and sonicated for 10 minutes. The solvents were removed in vacuo and the residue was purified on silica gel 0-100% hexanes / 3:1 EtOAc / EtOH to provide Int-1i. MS (ESI) [M+H] +< m / z:647.Step J: Int-li

[0137] Int-1i (137 mg, 0.211 mmol) was dissolved in DCM (4 mL) charged with TFA (0.814 mL, 10.6 mmol) and allowed to stir at rt for 1 h. The reaction was evaporated in vacuo to provide crude Int-1j +3TFA, and used without further purification. MS (ESI) [M+H] +< m / z: 549.Step K: Ex. 1a: 18,21-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,5,8,10]benzodioxadiazacyclotridecin-4-one

[0138] Int-1j +3TFA (200 mg, 0.225 mmol) was dissolved in DCM (2.25 mL), cooled to 0 °C, charged with DIEA (157 µL, 0.898 mmol), acryloyl chloride (20 µL, 0.25 mmol) and allowed to stir for 1 h. The reaction was quenched by addition of 2 mL saturated sodium bicarbonate, extracted 2 × 10 mL EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo, purified on silica gel, 0-100% 3:1 EtOAc / EtOH. The racemic material was resolved by SFC Column A, Condition: MeOH w / 0.1% NH 4 OH to provide 18,21-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,5,8,10]benzodioxadiazacyclotridecin-4-one (Ex. 1a , peak 1) as a single atropisomer.

[0139] MS (ESI) [M+H] +< m / z: 603 1< H NMR (500 MHz, DMSO-d6) δ 8.38 (d, J = 5.7 Hz, 1H), 8.17 (m, 1H), 7.52 - 7.45 (m, 1H), 7.06 (d, J = 5.9 Hz, 1H), 6.98 - 6.90 (m, 2H), 6.90 - 6.79 (m, 1H), 6.26 - 6.16 (m, 1H), 5.77 (d, J = 10.4 Hz, 1H), 4.73 (m, 1H), 4.45 (m, 2H), 4.32 (m, 1H), 4.19 - 4.06 (m, 2H), 3.99 (m, 2H), 3.67 - 3.47 (m, 2H), 3.19 (m,1H), 2.87 (m, 1H), 1.96 (m, 1H), 1.90 - 1.76 (m, 1H), 1.41 (m, 3H), 1.13 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H).

[0140] Example 2a was prepared as described in Example 1 using Int-1g with (2-hydroxypyridin-3-yl)boronic acid). Ex. No. Structure Compound Name [M+H] + Found SFC Conditions 2a 21-fluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,19-(ethanediylidene)dipyri do[4,3-b:3',2'-h]pyrimido[1,6-d][1,10,4,6]dioxadiazac yclotridecin-4-one (Peak 1)586Column S MeOH w / 0.1% NH 4 OH 20% CO 2 Peak 1 Example 3a / 3b: 22-fluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,20-ethenopyrido[4',3':2,3]pyrimido[1',6':4,5][1,4,6,10]oxatriazacyclotridecino[8,9,10-hi]indazol-4-one

[0141] Step A: tert-butyl (S)-4-(6-fluoro-1-(4-(3-hydroxypropoxy)-2-isopropylpyridin-3-yl)-7-(1H-indazol-7-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-3a )

[0142] tert-Butyl (S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-1g ) (71.4 mg, 0.101 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.037 g, 0.152 mmol), potassium acetate (0.040 g, 0.405 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (8.3 mg, 10.1 µmol) were added to a 20 mL scintillation vial equipped with magnetic stir bar, degassed under nitrogen, charged with dioxane (0.87 mL) / water (0.15 mL), degassed three times under nitrogen and heated to 90 °C for 30 min. The reaction was cooled to room temperature, quenched with 2 mL 1:1 water / saturated ammonium chloride, extracted 1 × 25 mL EtOAc, washed with brine and concentrated in vacuo. The crude residue was taken up in 5 mL THF, charged with 1.0 M solution of TBAF in THF (0.506 mL, 0.506 mmol) and allowed to stir for 1.5 h at room temperature. The reaction was quenched with saturated NH 4 Cl, extracted 1 × 15 mL EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified on silica gel 0-100% 3:1 EtOAc / EtOH / DCM to provide tert-butyl (S)-4-(6-fluoro-1-(4-(3-hydroxypropoxy)-2-isopropylpyridin-3-yl)-7-(1H-indazol-7-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. Int-3a MS (ESI) [M+H] +< m / z 673.Step B: Int-3b

[0143] tert-Butyl (S)-4-(6-fluoro-1-(4-(3-hydroxypropoxy)-2-isopropylpyridin-3-yl)-7-(1H-indazol-7-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (58 mg, 0.086 mmol) was dissolved in dioxane (4.3 mL), charged with cyanomethylenetributylphosphorane (45.2 µl, 0.172 mmol), degassed under nitrogen and heated to 120 °C overnight. The reaction was concentrated in vacuo, purified on silica gel, 0-100% 3:1 (EtOAc / EtOH) / DCM to provide Int 3b with impurities. The resin was triturated with hexanes, sonicated, filtered, washed 1 × hexanes to provide Int-3b MS (ESI) [M+H] +< m / z 655.Step C: Int-3c

[0144] Int-3b (68 mg, 0.104 mmol) was dissolved in DCM (2.0 mL), charged with TFA (800 µl, 10.4 mmol) and allowed to stir for 1 h at rt. The reaction was concentrated in vacuo to provide Int-3c +3TFA as a crude residue used without further purification. MS (ESI) [M+H] +< m / z 555.Step D: Ex. 3a / 3b 22-fluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,20-ethenopyrido[4',3':2,3]pyrimido[1',6':4,5][1,4,6,10]oxatriazacyclotridecino[8,9,10-hi]indazol-4-one

[0145] Int-3c (90 mg, 0.146 mmol) was dissolved in 4 mL DCM, charged with DIEA (153 µl, 0.876 mmol), cooled to 0 °C, charged with acryloyl chloride (14.0 µl, 0.175 mmol) and allowed to stir at that temperature for 1 h. The reaction was quenched with 2 mL of 1:1 saturated sodium bicarbonate / water, filtered through a 4 mL phase separator, extracted once with 5 mL DCM, concentrated in vacuo and purified on silica gel, 0-100% 3:1 EtOAc / EtOH / DCM to provide racemic product. The product was resolved via SFC chromatography, using Column T, Condition: MeOH w / 0.25% DMEA, 50% CO 2 to provide 22-fluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12, 13-dihydro-4H,11H-1,20-ethenopyrido[4',3':2,3]pyrimido[1',6':4,5][1,4,6,10]oxatriazacyclotridecino[8,9,10-hi]indazol-4-one (Ex. 3a , peak 1) as a single atropisomer.

[0146] MS (ESI) [M+H] +< m / z 609. 1< H NMR (600 MHz, DMSO-d 6 ) δ 8.52 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 5.7 Hz, 1H), 8.28 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 6.7 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 5.7 Hz, 1H), 6.88 (dd, J = 16.9, 10.4 Hz, 1H), 6.22 (dd, J = 16.8, 8.6 Hz, 1H), 5.78 (dd, J = 10.4, 2.4 Hz, 1H), 5.11 (m, 1H), 4.45 (d, J = 13.6 Hz, 0.5H), 4.34 (d, J = 13.4 Hz, 0.5H), 4.18 (m, 2.5H), 4.08 (d, J = 13.9 Hz, 0.5.H), 4.00 - 3.77 (m, 3H), 3.72 (d, J = 13.5 Hz, 0.5H), 3.53 (dt, J = 14.0, 7.6 Hz, 1H), 3.37 (m, ov. 1H) 3.00 (t, J = 11.8 Hz, 0.5H), 2.91 (m, 1H), 2.41 - 2.24 (m, 1H), 2.16 (s, 1H), 1.37 - 1.23 (m, 3H), 1.15 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H).

[0147] Ex. 3b , Peak 2 - 22-fluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,20-ethenopyrido[4',3':2,3]pyrimido[1',6':4,5][1,4,6,10]oxatriazacyclotridecino[8,9,10-hi]indazol-4-one (Ex. 3b ). MS (ESI) [M+H] +< m / z 609. 1< H NMR (600 MHz, DMSO-d6) δ 8.35 (d, J = 8.6 Hz, 1H), 8.31 (d, J = 5.6 Hz, 1H), 8.29 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 7.0 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 5.7 Hz, 1H), 6.88 (td, J = 17.5, 11.1 Hz, 1H), 6.22 (t, J = 14.1 Hz, 1H), 5.78 (d, J = 10.7 Hz, 1H), 4.80 (m, 0.5H), 4.77 (m, 0.5H), 4.48 (d, J = 13.7 Hz, 1H), 4.42 (d, J = 13.3 Hz, 0.5H), 4.27 (d, J = 13.4 Hz, 0.5H), 4.17 (m, 1.5zH), 4.03 (d, J = 13.8 Hz, 0.5H), 3.93 - 3.75 (m, 2H), 3.74 - 3.54 (m, 2H), 3.50 (dt, J = 13.8, 7.4 Hz, 1H), 3.29 (m, ov. 0.5H), 3.23 (d, J = 13.3 Hz, 0.5H), 2.91 (p, J = 6.7 Hz, 1H), 2.36 - 2.25 (m, 1H), 2.14 (m, 1H), 1.47 - 1.39 (m, 3H), 1.15 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H).Example 4: 18,21-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one

[0148] Step A: (E)-4-(4-((tert-butyldimethylsilyl)oxy)but-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine. (Int-4a )

[0149] 2,4-Dichloro-3-nitropyridine (Int-1a ) (10.7 g, 55.5 mmol), cesium carbonate (63.3 g, 194 mmol), bis(triphenylphosphite) palladium(II) dichloride (3.90 g, 5.55 mmol) were added to a 250 mL round-bottomed flask equipped with magnetic stir bar, degassed under nitrogen, charged with DME (90 mL) / water (22.5 mL), degassed two times under nitrogen, charged with isopropenylboronic acid pinacol ester (11.0 mL, 58.3 mmol). The flask was fitted with a reflux condenser and allowed to stir for 5 h at 85 °C . The reaction was cooled to room temperature in an ice bath and over a funnel of argon, charged with (E)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (22.7 mL, 63.8 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (4.53 g, 5.55 mmol). The reaction was degassed 3 times under nitrogen and heated to reflux at 110 °C for 16 h. The reaction was diluted with 300 mL EtOAc and 200 mL saturated ammonium chloride. The aqueous and organic layers were filtered through a pad of CELITE and the organic layer was separated. The aqeous layer was extracted with 250 mL EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified on silica gel 0-40% EtOAc / hexanes, followed by slow gradient 0-15% EtOAc / hexanes to provide (E)-4-(4-((tert-butyldimethylsilyl)oxy)but-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-4a ). MS (ESI) [M+H] +< m / z:349.Step B: 4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-amine (Int-4b )

[0150] 4-(4-((tert-Butyldimethylsilyl)oxy)butyl)-3-nitro-2-(prop-1-en-2-yl)pyridine (1.67 g, 4.76 mmol) was dissolved in EtOH (24.0 mL), degassed under nitrogen, charged with Pd-C (0.101 g, 0.953 mmol), degassed under nitrogen, and allowed to stir under hydrogen atmosphere overnight. The reaction was filtered through a pad of CELITE and concentrated in vacuo. The residue was dissolved in 5 mL DCM and filtered through 0.2 uM filter to remove trace residual palladium on carbon to provide 4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-amine. (Int-4b ) MS (ESI) [M+H] +< m / z:323. 1< H NMR (500 MHz, CDCl 3 ) δ 8.00 (d, J = 4.8 Hz, 1H), 6.86 (d, J = 4.8 Hz, 1H), 3.70 (m, 4H), 3.07 (hept, J = 6.7 Hz, 1H), 2.55 - 2.50 (m, 2H), 1.73 (m, 2H), 1.68 - 1.62 (m, 2H), 1.33 (m, 6H), 0.92 (s, 9H), 0.08 (s, 6H).Step C: N-((4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-4c)

[0151] To a stirred solution of 2,6-dichloro-5-fluoronicotinamide (4.42 g, 21.2 mmol) in THF (20 mL) at 75 °C was added a 2 M solution of oxalyl chloride in DCM (12.5 mL, 25.0 mmol) and the reaction was heated to 75 °C with reflux condenser attached for 1 h. The reaction was evaporated in vacuo and dried under high vacuum for 30 minutes. The residue was charged with 20 mL THF, cooled to 0 °C and a solution of 4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-amine (6.20 g, 19.2 mmol) in THF (10 mL) was added dropwise. The reaction was allowed to stir for 1 h at 0 °C then was quenched at 0 °C with saturated ammonium chloride, and diluted with 100 mL EtOAc. The reaction was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification on silica gel, 0-50% 3:1 EtOAc-EtOH / DCM gave N-((4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-4c ). MS (ESI) [M+H] +< m / z 557 / 559.Step D: 1-(4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Peak 1 SFC) (Int-4d-1 )

[0152] N-((4-(4-((tert-Butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (5.10 g, 9.15 mmol) was dissolved in THF (15.2 mL), cooled to 0 °C, charged with KHMDS (19.2 mL, 19.2 mmol) and allowed to warm to rt for 1h. The reaction was cooled to 0 °C, quenched with 100 mL saturated ammonium chloride, extracted 2 × 150 mL EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel, 0-100% 3:1 EtOAc / EtOH / DCM to provide 1-(4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (mixture of atropisomers). The product was resolved by SFC, Column Q, Condition: 100% MeOH, 15% modifier in CO 2 , to provide: Peak 1 - Int-4d-1 - 1-(4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. MS (ESI) [M+H] +< m / z 521; and Peak 2 - Int-4d-2 - 1-(4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. MS (ESI) [M+H] +< m / z 521. Steps E and F: tert-Butyl (S)-4-(1-(4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-4f-1 )

[0153] 1-(4-(4-((tert-Butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Peak 1 SFC) (Int-4d-1 ) (1.80 g, 3.45 mmol) was charged with acetonitrile (17.3 mL), DIEA (1.81 mL, 10.36 mmol), POCl 3 (0.386 mL, 4.15 mmol) degassed under nitrogen and heated to 80 °C for 30 minutes. The reaction mixture containing 1-(4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (Int-4e-1 ) was cooled to 0 °C, charged with DIEA (1.81 mL, 10.4 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (0.830 g, 4.15 mmol) and allowed to stir at that temperature for 20 minutes. The reaction was quenched with 10 mL water, extracted 2 × 25 mL EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated and purified on silica gel, 0-100% 3:1 EtOAc / EtOH / hexanes to provide tert-butyl (S)-4-(1-(4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-4f-1 ). MS (ESI) [M+H] +< m / z 703.Step G: tert-Butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-(4-hydroxybutyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-4g-1 )

[0154] tert-Butyl (S)-4-(1-(4-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.50 g, 2.13 mmol), 3-fluoro-2-(trifluoro-λ 4< -boraneyl)phenolate (602 mg, 2.77 mmol), potassium acetate (837 mg, 8.53 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (174 mg, 0.213 mmol) were added to a 20 mL scintillation vial equipped with magnetic stir bar, degassed under nitrogen, charged with dioxane (9 mL) / water (1.5 mL), degassed 3 times under nitrogen and heated to 90 °C for 1 h. The reaction was cooled to room temperature, quenched with 10 mL 1:1 water / saturated sodium bicarbonate, extracted 2 × 25 mL EtOAc, washed with brine and concentrated in vacuo. The crude residue was taken up in 10 mL THF, charged with a 1 M solution of TBAF in THF (6.40 mL, 6.40 mmol) and allowed to stir for 1.5 h at room temperature. The reaction was quenched with 50 mL saturated NH 4 Cl / 100 mL EtOAc and allowed to stir for 5 minutes with vigorous stirring. The organic layer was separated, washed 1 × 25 mL saturated ammonium chloride, 25 mL brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified on silica gel 0-100% 3:1 EtOAC / EtOH / hexanes to provide tert-butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-(4-hydroxybutyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-4g-1 ). MS (ESI) [M+H] +< m / z 665.Step H: (Int-4h-1 ).

[0155] tert-Butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-(4-hydroxybutyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.10 g, 1.66 mmol) and triphenylphosphine (1.09 g, 4.14 mmol) were charged with THF (66 mL), degassed under nitrogen, sonicated and charged with diisopropyl azodicarboxylate (652 µL, 3.31 mmol) dropwise. The reaction was sonicated for 30 minutes, the solvents were removed under vacuum, and the residue was purified on silica gel 0-100% 3:1 EtOAc / EtOH / hexanes to provide Int-4h-1. MS (ESI) [M+H] +< m / z 647.Step I: Int-4i-1

[0156] Int-4i-1 (370 mg, 0.572 mmol) was dissolved in DCM (3.8 mL), charged with TFA (1.1 mL, 14.3 mmol) and allowed to stir for 20 minutes at rt. The solvents were removed in vacuo, and the residue was azeotroped 1 × toluene / 1 × pentane to provide Int-4i-1 as a tris-TFA salt. MS (ESI) [M+H] +< m / z 547.Step J: 18,21-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-ethenopyrido[4.3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one (Example 4a )

[0157] Int-4i-1 +3TFA (385 mg, 0.433 mmol) was dissolved in DCM (5.8 mL), cooled to 0 °C, charged with DIEA (378 µl, 2.17 mmol) followed by acryloyl chloride (38.7 µl, 0.48 mmol). The reaction was allowed to stir for 15 minutes and quenched with 2 mL saturated sodium bicarbonate, poured through phase separator, washed 1 × 6 mL DCM, evaporated in vacuo and purified on silica gel 0-100% hexanes (3:1 EtOAc / ethanol) to provide 18,21-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one (Example 4a ). MS (ESI) [M+H] +< m / z 601. 1< H NMR (500 MHz, DMSO-d6) δ 8.39 (d, J = 4.9 Hz, 1H), 8.36-8.27 (m, 1H), 7.46 (q, J = 8.3 Hz, 1H), 7.16 (d, J = 4.9 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.97 (t, J = 8.7 Hz, 1H), 6.94 - 6.78 (m, 1H), 6.25-6.17 (m, 1H), 5.81-5.74 (m, 1H), 4.90 (br s, 1H), 4.46-4.36 (m, 2H), 4.31-4.11 (m, 1H), 4.06-3.98 (m, 2H), 3.91-3.83 (m, 1H), 3.72-3.6 (m, 1H), 3.61-3.52 (m, 1H), 3.29 - 3.11 (m, 1H), 2.73 - 2.56 (m, 2H), 2.45-2.35 (m, 1H), 1.36-1.29 (overlapped m, 4H), 1.30 - 1.11 (m, 1H), 1.05 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H).18,21-Difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,12.13-tetrahydro-4H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one (Example 4b )

[0158] Example 4b was prepared using the steps described above for Example 4a from the second eluting isomer from SFC, Int-4d-2.

[0159] Example 4b: MS (ESI) [M+H] +< m / z 601. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.45 - 8.32 (m, 2H), 7.46 (q, J = 8.3 Hz, 1H), 7.16 (d, J = 4.9 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.96 (t, J = 8.7 Hz, 1H), 6.94 - 6.79 (m, 1H), 6.25-6.17 (m, 1H), 5.8-5.74 (m, 1H), 5.02 (brs, 1H), 4.45-4.37 (m, 1H), 4.35-4,25 (m, 1H), 4.18-4.12 (m, 1H), 4.08-4.0 (m, 2H), 3.9-3.83 (m, 1H), 3.82-3.73 (m, 1H), 3.7-3.64 (m, 1H), 3.16-3.06 (m, 1H), 2.68-2.58 (m, 2H), 2.46-2.35 (m, 1H), 1.39-1.2 (overlapped m, 5H), 1.05 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H).

[0160] Examples 5 and 6 were prepared in a similar manner to Example 4a, with Int-4f-1 substituting (1H-pyrazol-5-yl)boronic or 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole acid for Step G. Ex. No. Structure Compound Name [M+H] + Found 5 20-fluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,18-(ethanediylidene)pyrazolo[5,1-e]pyrido[4,3-k]pyrimido[1,6-a][1,3,6]triazacyclododecin-4-one557.36 22-fluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,20-(ethanediylidene)pyrido[4',3':12,13]pyrimid o[1',6':1,2][1,3,7]triazacyclotridecino[5,6,7-hi]indazol-4-one607.3 Example 7: 2-[(3R,5S)-3,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-18,21-difluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one

[0161] Step A: Int-7a

[0162] Int-4h-1 (330 mg, 0.510 mmol) was dissolved in MeOH (2.55 mL), charged with KOH (1 M in methanol) (1.53 mL, 1.53 mmol) and heated to 40 °C for 2 hrs, then allowed to cool to room temperature overnight. The reaction was diluted with 20 mL EtOAc, poured into 50 mL saturated ammonium chloride, stirred, and the organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified on silica gel, 0-100% 3:1 EtOAc / EtOH / hexanes to provide Int-7a . MS (ESI) [M+H] +< m / z 465.Step B: Int-7b

[0163] Int-7a (16.5 mg, 0.036 mmol) was dissolved in acetonitrile (710 µL), charged with DIEA (18.6 µL, 0.107 mmol), POCl 3 (3.97 µL, 0.043 mmol) and heated to 80 °C for 30 minutes. The reaction was cooled to 0 °C, charged with additional portion of DIEA (18.61 µL, 0.107 mmol) and tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (9.5 mg, 0.044 mmol) and allowed to warm to room temperature over 2 hrs. The reaction was concentrated in vacuo, purified on silica gel, 0-100% 3:1 EtOAc / EtOH / hexanes to provide Int-7b . MS (ESI) [M+H] +< m / z 661.Step C-D: Example 7

[0164] Int-7b (10 mg, 0.015 mmol) was dissolved in CH 2 Cl 2 , charged with TFA (58.3 µl, 0.757 mmol), allowed to stir at room temperature for 20 minutes, concentrated in vacuo, dissolved in CH 2 Cl 2 , charged with DIEA (13.2 µl, 0.076 mmol), cooled to 0 °C, and charged with acryloyl chloride (1.2 µl, 0.015 mmol) and allowed to stir for 30 minutes. The reaction was quenched with 1 mL saturated sodium bicarbonate, poured through a phase separator, washed 1 × 3 mL CH 2 Cl 2 , concentrated and purified on silica gel, 0-100% 3:1 EtOAc / EtOH / hexanes to provide 2-[(3R,5S)-3,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-18,21-difluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one (Ex. 7 ). MS (ESI) [M+H] +< m / z 615.

[0165] Example 8 was prepared in a similar manner to Example 7 , with Int-7a substituting tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate acid for the piperazine component in Step B. Ex. No. Structure Compound Name [M+H] Found 8 2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-18,21-difluoro-6-(propan-2-yl)-10, 11, 12, 13-tetrahydro-4H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one615.3 Example 9: 19-Chloro-16-fluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-10,11-dihydro-4H-1,17-ethenodibenzo[b,h]pyrimido[6,1-f][1,5,7]oxadiazacycloundecin-4-one

[0166] Step A: 2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)aniline (Int-9a )

[0167] To a stirred solution of 2-(2-aminophenyl)ethanol (2.00 g, 14.6 mmol) in DCM (30 mL) was added TBSCl (2.86 g, 19.0 mmol) and imidazole (2.98 g, 43.7 mmol), and the mixture was stirred at 20 °C for 16 h under N 2 atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel, 0-10% EtOAc / Pet. ether to give 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline (Int-9a ). 1< H NMR (400 MHz, CDCl 3 ) δ 6.96-7.09 (m, 2H), 6.62-6.80 (m, 2H), 3.98 (br s, 2H), 3.87 (t, J=6.24 Hz, 2H), 2.78 (t, J=6.11 Hz, 2H), 0.87 (d, J=1.71 Hz, 9H), -0.01 (s, 6H).Step B: 2,5,6-Trichloronicotinamide (Int-9b )

[0168] To a stirred solution of 2,5,6-trichloronicotinic acid (8.70 g, 38.4 mmol) in THF (90 mL) was added CDI (6.85 g, 42.3 mmol), and the reaction mixture was stirred at 50 °C for 1 h under N 2 atmosphere. Then toluene (20 mL) and ammonium hydroxide (concentrated, 10.7 mL, 77.0 mmol) was added at 0 °C, and the resulting mixture was stirred at 20 °C for 10 min. The reaction mixture was quenched with water (30 mL), and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified on silica gel, 0-100% EtOAc / Pet. ether to give 2,5,6-trichloronicotinamide (Int-9b ). MS (ESI): m / z (M+MeCN+H) + 266.1, 268.1.Step C: N-((2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)phenyl)carbamoyl)-2,5,6-trichloronicotinamide (Int-9c )

[0169] To a stirred solution of 2,5,6-trichloronicotinamide (Int-9b ) (2.50 g, 11.1 mmol) in THF (50 mL) was added oxalyl chloride (0.932 mL, 10.6 mmol) at 20 °C, and the mixture was stirred at 65 °C for 30 min under N 2 atmosphere. Then it was cooled to 20 °C and 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline (Int-9a ) (2.93 g, 11.6 mmol) was added. The resulting mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with brine (40 mL), and extracted with ethyl acetate (2 × 60 mL). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified on silica gel, 0-30% EtOAc / Pet. ether to give N-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)carbamoyl)-2,5,6-trichloronicotinamide (Int-9c ). MS (ESI): [M+H] +< m / z 502.3 / 504.3Step D: 1-(2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)phenyl)-6,7-dichloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-9d )

[0170] To a stirred solution ofN-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)carbamoyl)-2,5,6-trichloronicotinamide (3.00 g, 5.97 mmol) in THF (50 mL) was added a 1 M solution of potassium bis(trimethylsilyl)amide in THF (11.9 mL, 11.9 mmol) at 0 °C, and the mixture was stirred at 20 °C for 30 min under N 2 atmosphere. The reaction mixture was quenched with aqueous ammonium chloride (saturated, 35 mL), and extracted with ethyl acetate (2 × 80 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure to provide 1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-6,7-dichloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-9d). The crude product was used in the next step without further purification. MS (ESI): [M+H] +< m / z 466.2 / 468.1Step E: 1-(2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)phenyl)-4,6,7-trichloropyrido[2,3-d]pyrimidin-2(1H)-one (Int-9e)

[0171] To a stirred solution of 1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-6,7-dichloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.30 g, 4.93 mmol) in acetonitrile (50 mL) was added DIEA (2.15 mL, 12.3 mmol) and POCl 3 (0.689 mL, 7.40 mmol) at 25 °C, and the mixture was stirred at 80 °C for 1 h under N 2 atmosphere. The reaction mixture was concentrated to afford 1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-4,6,7-trichloropyrido[2,3-d]pyrimidin-2(1H)-one (Int-9e), which was used in next step without further purification. MS (ESI): m / z (M+H) +< 484.0 / 486.0.Step F: tert-Butyl (S)-4-(1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-6,7-dichloro-2-oxo-12-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-9f)

[0172] To a stirred solution of 1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-4,6,7-trichloropyrido[2,3-d]pyrimidin-2(1H)-one (2.39 g, 4.93 mmol) in DMF (40 mL) was added DIEA (2.15 mL, 12.3 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (1.23 g, 6.16 mmol) at 20 °C, and the mixture was stirred at 20 °C for 16 h under N 2 atmosphere. The reaction mixture was concentrated, and the residue was purified on silica gel, 0-40% EtOAc / Pet. ether to give (S)-tert-butyl 4-(1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-6,7-dichloro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-9f). MS (ESI): [M+H] +< m / z 648.2 / 650.2.Step G: tert-Butyl (3S)-4-(1-(2-(2-((tert-bulyldimethylsilyl)oxy)ethyl)i)henyl)-6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-12-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-9g )

[0173] To a stirred solution of (S)-tert-butyl 4-(1-(2-(2-((tertbutyldimethylsilyl)oxy)ethyl)phenyl)-6,7-dichloro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.00 g, 1.54 mmol), potassium acetate (0.756 g, 7.71 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.063 g, 0.077 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added 3-fluoro-2-(trifluoro-λ 4< -boraneyl)phenol, potassium salt (0.538 g, 2.47 mmol) in 1,4-dioxane (3 mL) at 90 °C under N 2 atmosphere, and the mixture was stirred at 20 °C for 2 h under N 2 atmosphere. The reaction mixture was quenched with brine (20 mL), and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified on silica gel, 0-50% EtOAc / Pet. ether to give (3S)-tert-butyl 4-(1-(2-(2-((tertbutyldimethylsilyl)oxy)ethyl)phenyl)-6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-9g). MS (ESI): [M+H] +< m / z 724.4.Step H: tert-Butyl (3S)-4-(6-chloro-7-(2-fluoro-6-hydroxyl)henyl)-1-(2-(2-hydroxyethyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-9h)

[0174] To a stirred solution of (3S)-tert-butyl 4-(1-(2-(2-((tertbutyldimethylsilyl)oxy)ethyl)phenyl)-6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.00 g, 1.38 mmol) in THF (10 mL) was added a 1 M solution of TBAF in THF (4.14 mL, 4.14 mmol), and the mixture was stirred at 20 °C for 16 h under N 2 atmosphere. The reaction mixture was concentrated in vacuo, and the residue was purified on silica gel, 0-8% MeOH / DCM to give (3S)-tert-butyl 4-(6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-hydroxyethyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-9h) MS (ESI): [M+H] +< m / z 610.4Step I: Int-9i

[0175] To a stirred solution of (3S)-tert-butyl 4-(6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-hydroxyethyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (300 mg, 0.492 mmol) in THF (30 mL) was added triphenylphosphine (871 mg, 1.23 mmol) (37% load on resin), and then DIAD (0.096 mL, 0.492 mmol) was added at 70 °C. The mixture was stirred at 70 °C for 1 h under N 2 atmosphere. The mixture was filtered and the filter cake was washed with dichloromethane (30 mL). The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC water (10 mM NH 4 HCO 3 ) / MeCN to provide Int-9i. MS (ESI): [M+H] +< m / z 592.2Step J: Int-9j

[0176] To a stirred solution of Int-9i (20 mg, 0.034 mmol) in DCM (2 mL) was added TFA (0.5 mL), and the mixture was stirred at 20 °C for 30 min under N 2 atmosphere. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC water (10 mM NH 4 HCO 3 ) / MeCN to provide Int-9j. MS (ESI): [M+H] +< m / z 492.2Step K: 19-Chloro-16-fluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-10,11-dihydro-4H-1,17-ethenodibenzo[b,h]pyrimido[6,1-f][1,5,7]oxadiazacycloundecin-4-one (Ex. 9)

[0177] To a stirred solution of Int-9j +TFA (20.5 mg, 0.034 mmol) in DCM (1.0 mL) was added DIEA (0.024 mL, 0.135 mmol) and acryloyl chloride (3.67 mg, 0.041 mmol), and the mixture was stirred at 20 °C for 30 min under N 2 atmosphere. It was concentrated and The residue was purified by preparative HPLC, water (10 mM NH 4 HCO 3 ) / MeCN to provide 19-chloro-16-fluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-10,11-dihydro-4H-1,17-ethenodibenzo[b,h]pyrimido[6,1-f][1,5,7]oxadiazacycloundecin-4-one (Ex. 9) as a mixture of atropisomers. MS (ESI): [M+H] +< m / z 546.2 (400 MHz, methanol-d 4 ) δ 8.43-8.30 (m, 1H), 7.47-7.38 (m, 1H), 7.37-7.27 (m, 3H), 7.20 (br d, J=8.07 Hz, 1H), 6.97 (d, J=8.31 Hz, 1H), 6.91-6.75 (m, 2H), 6.31 (br d, J =16.14 Hz, 1H), 5.84 (dd, J =1.83, 10.64 Hz, 1H), 5.32 (br s, 1H), 4.96 (br d, J=9.54 Hz, 1H), 4.81 (br s, 1H), 4.74-4.59 (m, 1H), 4.57-4.35 (m, 1H), 4.27-3.96 (m, 2H), 3.78- 3.40 (m, 2H), 2.95 (br dd, J=7.70, 13.57 Hz, 1H), 2.36 (br dd, J=6.36, 15.41 Hz, 1H), 1.57-1.36 (m, 3H).Examples 10-15 Preparation of 4-(3-((tert-Butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-amine (Int-10c)

[0178] Step A: 4-Chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10a)

[0179] A stirred solution of 2,4-dichloro-3-nitropyridine (11.0 g, 57.0 mmol) in DME (150 mL) and water (30 mL) was added Cs 2 CO 3 (55.7 g, 171 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (9.58 g, 57.0 mmol) and bis(triphenylphosphine)palladium(II) dichloride (4.00 g, 5.70 mmol), and the resulting mixture was stirred at 85 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with EtOAc (200 mL × 3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified on silica gel, Pet. ether / EtOAc= 10 / 1 to give 4-chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10a). MS (ESI): [M+H] +< m / z 198.8.Step B: (E)-4-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10b )

[0180] A stirred solution of 4-chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (10.0 g, 50.4 mmol) in DME (100 mL) and water (20 mL) was added Cs 2 CO 3 (49.2 g, 151 mmol), (E)-tert-butyldimethyl((3-(4, 4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (16.52 g, 55.4 mmol) and bis(triphenylphosphine)palladium(II) dichloride (3.53 g, 5.04 mmol), and the resulting mixture was stirred at 90 °C for 16 h. The reaction was cooled to room temperature and extracted with EtOAc (200 mL × 3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified on silica gel, eluting with Pet. ether / EtOAc= 5 / 1, to give (E)-4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine MS (ESI): [M+H] +< m / z 335.1.Step C: 4-(3-((tert-Bulyldimethylsilyl)oxy))propyl)-2-isopropylpyridin-3-amine (Int-10c )

[0181] To a mixture of (E)-4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (9.2 g, 27.5 mmol) in MeOH (300 mL) was added dry Pd-C (2.93 g, 27.5 mmol, 10% w / w) under argon atmosphere, and the mixture was degassed and purged with H 2 for three times and stirred at 25 °C for 15 h under H 2 atmosphere (40 psi). The reaction mixture was filtered and concentrated in vacuo to give crude product. The crude product was purified on silica gel, 0-30% EtOAc / Pet. ether to give 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-amine (Int-10c). MS (ESI): [M+H] +< m / z 309.3. 1< H NMR (400MHz, CDCl 3 ) δ: 7.87 (d, J=4.9 Hz, 1H), 6.74 (d, J=4.9 Hz, 1H), 3.79 (br s, 2H), 3.57 (t, J=5.7 Hz, 2H), 2.97 (spt, J=6.7 Hz, 1H), 2.52 (t, J=7.5 Hz, 2H), 1.79 - 1.68 (m, 2H), 1.23 (d, J=6.6 Hz, 6H), 0.85 - 0.83 (m, 9H), 0.00 (s, 6H).Preparation of 4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-amine (Int-10f )

[0182] Step A: 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-chloro-3-nitropyridine (Int-10d )

[0183] 2-((tert-Butyldimethylsilyl)oxy)ethan-1-ol (9.05 g, 51.3 mmol) was dissolved in tetrahydrofuran (155 mL), cooled to 0 °C and charged with sodium hydride (2.05 g, 51.3 mmol) and allowed to stir at that temperature for 30 minutes. The reaction was charged with 2,4-dichloro-3-nitropyridine (9.00 g, 46.6 mmol) portion wise, and allowed to slowly warm to rt over 2 h. The reaction was quenched with ammonium chloride, diluted with EtOAc, separated, washed with brine, dried over sodium sulfate, filtered, concentrated, and purified on silica gel eluting with 0-25% EtOAc / hexanes to provide 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-chloro-3-nitropyridine (Int-10d). MS (ESI) [M+H] +< m / z 333.Step B: 4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10e)

[0184] 4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-2-chloro-3-nitropyridine (12.0 g, 36.1 mmol), cesium carbonate (35.2 g, 108 mmol), bis(triphenylphosphine)palladium(II) dichloride (2.53 g, 3.61 mmol) were added to a 250 mL round-bottomed flask equipped with magnetic stir bar, degassed under nitrogen, charged with DME (72 mL) and water (18 mL), degassed two times under nitrogen, charged with isopropenylboronic acid pinacol ester (7.45 mL, 39.7 mmol) and allowed to stir for 3 h at 85 °C. The reaction was cooled to rt, diluted with 100 mL EtOAc, washed with 50 mL saturated ammonium chloride, brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification on silica gel 0-20% EtOAc / hexanes gave 4-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10e). MS (ESI) [M+H] +< m / z 339.Step C: 4-(2-((tert-buiyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-amine (Int-10f)

[0185] 4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (10.0 g, 29.5 mmol) was dissolved in EtOH (148 mL), degassed under nitrogen, charged with Pd-C (0.629 g, 5.91 mmol, 10% w / w), degassed under nitrogen, and allowed to stir under a hydrogen atmosphere for 24 h. The product mixture was thoroughly purged with nitrogen. The purged product mixture was filtered through a pad of CELITE. The filtrate was concentrated to dryness to afford 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-amine (Int-10f). 1< H NMR (500 MHz, DMSO-d 6 ) δ 7.73 (d, J = 5.3 Hz, 1H), 6.73 (d, J = 5.3 Hz, 1H), 4.45 (s, 2H), 4.09 (d, J =4.5 Hz, 2H), 3.95 (dd, J = 5.4, 4.1 Hz, 2H), 3.16 (p, J = 6.7 Hz, 1H), 1.14 (d, J = 6.7 Hz, 6H), 0.88 (s, 9H), 0.07 (s, 6H).Preparation of 4-(3-((tert-Butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-2-isopropylpyridin-3-amine (Int-10i)

[0186] Step A: 4-(3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-2-chloro-3-nitropyridine (Int-10g )

[0187] 3-((tert-Butyldimethylsilyl)oxy)-2,2-difluoropropan-1-ol (6.45 g, 28.5 mmol) was dissolved in tetrahydrofuran (86 mL), cooled to 0 °C and charged with sodium hydride (1.14 g, 28.5 mmol) and allowed to stir at that temperature for 30 minutes. The reaction was charged with 2,4-dichloro-3-nitropyridine (5.00 g, 25.9 mmol) portion wise, and allowed to slowly warm to rt over 2 h. The reaction was quenched with ammonium chloride , diluted with EtOAc, separated, washed with brine, dried over sodium sulfate, filtered, concentrated, and purified on silica gel, eluting with 0-25% EtOAc / hexanes, to provide 4-(3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-2-chloro-3-nitropyridine (Int-10g). MS (ESI) [M+H] +< m / z 383.Step B: 4-(3-((tert-Butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10h)

[0188] 4-(3-((tert-Butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-2-chloro-3-nitropyridine (7.00 g, 18.3 mmol), cesium carbonate (17.9 g, 54.8 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.28 g, 1.83 mmol) were added to a 250 mL round-bottomed flask equipped with magnetic stirbar, degassed under nitrogen, charged with DME (36 mL) and water (9.1 mL), degassed two times under nitrogen, charged with isopropenylboronic acid pinacol ester (3.78 mL, 20.1 mmol) and allowed to stir for 3 h at 85 °C . The reaction was cooled to rt, diluted with 100 mL EtOAc, washed with 50 mL saturated ammonium chloride, brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification on silica gel 0-20% EtOAc / hexanes gave 4-(3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-3-nitro-2-(prop-1-en-2-yl) (Int-10h). MS (ESI) [M+H] +< m / z 389.Step C: 4-(3-((tert-Butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-2-isopropylpyridin-3-amine (Int-10i)

[0189] 4-(3-((tert-Butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (6.60 g, 17.0 mmol) was dissolved in EtOH (85 mL), degassed under nitrogen, charged with Pd-C (0.362 g, 3.40 mmol, 10% w / w), degassed under nitrogen, and allowed to stir under hydrogen atmosphere for 24 h. The product mixture was thoroughly purged with nitrogen. The purged product mixture was filtered through a pad of CELITE. The filtrate was concentrated to afford 4-(3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-2-isopropylpyridin-3-amine (Int-10i). MS (ESI) [M+H] +< m / z 361.

[0190] Examples 10-15 were prepared in a similar method to Example 1, using Int-10c, Int-10f, and Int-10i in step D, and substituting a substituted, protected piperazine for step G. Example 11 utilized benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate as the substituted, protected piperazine in step G and, substituted palladium hydroxide / H 2 in MeOH for step J. Examples designated as "No. ## a" correspond to the first eluting peak on SFC. Examples designated as "No. ##b" correspond to the second eluting peak on SFC. Example 15 utilized (S)-2-(piperazin-2-yl)acetonitrile bis(hydrochloride) for step G. Ex. No. Structure Compound Name [M+H] + Found SFC Conditions 10a 17,20-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-11,12-dihydro-4H,10H-1,18-ethenopyrido[4,3-e]pyrimido[1,6-g][1,7,9]benzoxadiazacyclodo decin-4-one587Column F EtOH w / 0.1% NH 4 OH, Peak 110b 17,20-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-11,12-dihydro-4H,10H-1,18-ethenopyrido[4,3-e]pyrimido[1,6-g][1,7,9]benzoxadiazacyclodo decin-4-one587Column F EtOH w / 0.1% NH 4 OH, Peak 211a [(2S)-4-[17,20-difluoro-4-oxo-6-(propan-2-yl)-11,12-dihydro-4H,10H-1,18-ethenopyrido[4,3-e]pyrimido[1,6-g][1,7,9]benzoxadiazacyclodo decin-2-yl]-1-(prop-2-enoyl)piperazin-2-yl]acetonitrile612Column B EtOH w / 0.1 NH 4 OH, Peak 112a 17,20-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-11,12-dihydro-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacy clododecin-4-one589Column G MeOH w / 0.25% DMEA 60 %CO 2 Peak 113a 2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18,21-tetrafluoro-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,5,8,10]benzodioxadiazac yclotridecin-4-one653.5Column G MeOH w / 0.25% DMEA 75% CO 2 Peak 113b 2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18,21-tetrafluoro-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,5,8,10]benzodioxadiazac yclotridecin-4-one653.5Column G MeOH w / 0.25% DMEA 75% CO 2 Peak 214a [(2S)-4-[17,20-difluoro-4-oxo-6-(propan-2-yl)-11,12-dihydro-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacy clododecin-2-yl]-1-(prop-2-enoyl)piperazin-2-yl]acetonitrile614.2Column G MeOH w / 0.25% DMEA 60% CO 2 Peak 115a 2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-17,20-difluoro-6-(propan-2-yl)-11,12-dihydro-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacy clododecin-4-one603.3Column G MeOH w / 0.25% DMEA 60% CO 2 Peak 1 Example 16a / b: 19,22-Difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-7-propan-2-yl)-11,12,13,14-tetrahydro-4H-1,20-(ethanediylidene)-6,10-(metheno)pyrimido[1,6-k][1,8,11,13]benzoxatriazacyclohexadecin-4-one

[0191] Step A: 5-Chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-16a)

[0192] 2-Bromo-5-chloro-3-nitropyridine (Int-16) (5.00 g, 21.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.48 g, 2.11 mmol), and cesium carbonate (13.7 g, 42.1 mmol) were added in a 250 mL round-bottomed flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. DME (56 mL) and water (14 mL) were added into the reaction vessel and the resulting mixture was evacuated and backfilled with a balloon of nitrogen three times. 4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (4.16 mL, 22.1 mmol) was added into the reaction vessel and the resulting mixture was heated to 85 °C for 4 h. The product mixture was diluted with ethyl acetate (100 mL). The diluted product mixture was washed three times with saturated sodium bicarbonate aqueous solution (3 × 10 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with silica gel, eluting with hexanes initially, grading to 20% ethyl acetate-hexanes, linear gradient to afford 5-chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-16a). 1< H NMR (500 MHz, CDCl 3 ) δ 8.74 (d, J= 2.2 Hz, 1H), 8.09 (d, J= 2.2 Hz, 1H), 5.38 (dd, J= 1.7, 0.7 Hz, 1H), 5.17 (t, J= 1.0 Hz, 1H), 2.22 (t, J = 1.2 Hz, 3H).Step B: (E)-5-(4-((tert-Butyldimethylsilyl)oxy)but-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-16b )

[0193] 5-Chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (3.80 g, 19.1 mmol), cesium carbonate (12.t g, 38.3 mmol), and XPhos-Pd-G3 (0.810 g, 0.957 mmol) were added into a 250 mL round-bottomed flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen. Dioxane (51 mL) and water (13 mL) were added into the reaction vessel and the resulting mixture was degassed by bubbling nitrogen for 30 seconds. (E)-tert-Butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (7.17 g, 23.0 mmol) was added into the reaction vessel and the resulting mixture was heated at 90 °C for 2 h. The product mixture was cooled down to room temperature. The cooled product mixture was transferred to a separatory funnel. The organic layer was isolated and the isolated organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with silica gel, eluting with hexanes initially, grading to 20% ethyl acetate-hexanes, linear gradient, to afford (E)-5-(4-((tertbutyldimethylsilyl)oxy)but-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-16b). 1< H NMR (500 MHz, CDCl 3 ) δ 8.67 (d, J = 2.0 Hz, 1H), 8.00 (d, J= 2.0 Hz, 1H), 6.46 (t, J = 1.8 Hz, 2H), 5.34 (d, J= 1.2 Hz, 1H), 5.19 - 5.04 (m, 1H), 3.76 (t, J = 6.4 Hz, 2H), 2.49 (q, J = 6.2 Hz, 2H), 2.20 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H).Step C: 5-(4-((tert-Butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-amine (Int-16c)

[0194] (E)-5-(4-((tert-Butyldimethylsilyl)oxy)but-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (6.42 g, 18.4 mmol) was dissolved in EtOH (92 mL), degassed under nitrogen, charged with Pd-C (0.392 g, 3.68 mmol, 10% w / w), degassed under nitrogen, and allowed to stir under hydrogen atmosphere for 24 h. The product mixture was thoroughly purged with nitrogen. The purged product mixture was filtered through a pad of CELITE. The filtrate was concentrated to provide 5-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-amine (Int-16c ). MS (ESI): [M+H] +< m / z 323.Step D: N-((5-(4-((tert-Bulyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-16d)

[0195] 2,6-di-chloro-5-fluoronicotinamide (2.00 g, 9.57 mmol) was added in a 40 mL vial. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. THF (9.57 mL) was added into the reaction vessel to dissolve the starting material. A 2 M solution of oxalyl dichloride (5.74 mL, 11.5 mmol) was added dropwise into the reaction vessel and the resulting mixture was heated at 75 °C for 1 h. The intermediate solution was allowed to cool to room temperature. The cooled intermediate solution was concentrated to half of its volume. THF (5 mL) was added into the reaction vessel and the resulting mixture was cooled to 0 °C. In a separate 4 mL vial, 5-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-amine (Int-16c, 3.09 g, 9.57 mmol) was dissolved in THF (5 mL). The amine solution was added dropwise into the reaction vessel and the resulting mixture was stirred for 1h at 0 °C. The product mixture was warmed up to room temperature. The warmed product mixture was quenched with 2 mL of 1:1 mixture of saturated sodium chloride aqueous solution and ammonium chloride aqueous solution. The quenched product mixture was extracted three times with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness. The residue obtained was purified by flash column chromatography on silica gel, eluting with 5% (ethyl acetate:ethanol = 3:1 v / v)-dichloromethane, initially, grading to 100% (ethyl acetate:ethanol = 3:1 v / v), linear gradient, to afford N-((5-(4-((tertbutyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-16d). MS (ESI) [M+H] +< m / z: 557 / 559.Step E: 1-(5-(4-((tert-Butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-16e)

[0196] N-((5-(4-((tert-Butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (2.90 g, 5.20 mmol) was added in a 30 mL vial. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. THF (10.4 mL) was added into the reaction vessel and the resulting mixture was cooled to 0 °C. A 1 M solution of potassium bis(trimethylsilyl)amide (10.4 mL, 10.4 mmol) was added into the reaction vessel and the resulting mixture was stirred for 1 h at 0 °C. The product mixture was quenched with saturated ammonium chloride aqueous solution (3 mL). The quenched product mixture was extracted three times with ethyl acetate (3 × 20 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by silica gel flash column chromatography 0-100 EtOAc / hexanes, to provide 1-(5-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-16e). MS (ESI) [M+H] +< m / z: 521.Step F: tert-Butyl (S)-4-(1-(5-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-12-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-16f)

[0197] 1-(5-(4-((tert-Butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (500 mg, 0.959 mmol) was added in a 20 mL vial. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. Acetonitrile (1.9 mL), N,N-diisopropylethylamine (256 µL, 1.44 mmol), and phosphoryl trichloride (116 µL, 1.25 mmol) were added into the reaction vessel and the resulting mixture was heated to 80 °C for 1 h. The product mixture was concentrated to dryness. The residue was dissolved in acetonitrile (1.9 mL). N,N-Diisopropylethylamine (512 µl, 2.88 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (288 mg, 1.44 mmol) were added sequentially into the reaction vessel. The resulting mixture was stirred for 1 h at 24 °C. The product mixture was diluted with ethyl acetate (100 mL). The diluted product mixture was washed three times with saturated sodium bicarbonate aqueous solution (3 × 10 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with silica gel, eluting with hexanes initially, grading to 66% (ethyl acetate-ethanol = 3:1 v / v)-hexanes, linear gradient, to provide tert-butyl (S)-4-(1-(5-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-16f). MS (ESI) [M+H] +< m / z: 703.Step G: tert-Butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(5-(4-hydroxybutyl)-2-isopropylpyridin-3-yl)-2-oxo-12-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-16g)

[0198] tert-Butyl (S)-4-(1-(5-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (535 mg, 0.761 mmol), potassium 3-fluoro-2-(trifluoro-λ 4< -boraneyl)phenolate (215 mg, 0.989 mmol), potassium acetate (299 mg, 3.04 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (62.1 mg, 0.076 mmol) were added to a 20 mL scintillation vial equipped with magnetic stir bar, degassed under nitrogen, charged with dioxane (3.3 mL) and water (543 µl), degassed 3x under nitrogen and heated to 90 °C for 1 h. The reaction was cooled to rt, quenched with 10 mL 1:1 water / saturated sodium bicarbonate, extracted 2 × 25 mL EtOAc, washed with brine and concentrated in vacuo. The crude residue was taken up in 10 mL THF, charged with a 1 M solution of TBAF in THF (1.90 mL, 1.90 mmol) and allowed to stir for 1.5 h at rt. The reaction was quenched with saturated ammonium chloride, extracted 1 × EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified on silica gel 0-100% EtOAc:EtOH, 3:1 / hexanes to provide tert-butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(5-(4-hydroxybutyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-16g). MS (ESI) [M+H] +< m / z: 665.Step H: (Int-16h )

[0199] tert-Butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(5-(4-hydroxybutyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.150 mmol) and triphenylphosphine (99 mg, 0.376 mmol) were dissolved in THF (7.5 mL) in a 100 mL round-bottomed flask under nitrogen. Upon sonication, diisopropyl diazene-1,2-dicarboxylate (59.2 µl, 0.301 mmol) was added dropwise. The reaction mixture was sonicated for 15 min. The product mixture was concentrated to dryness. The residue obtained was purified by flash column chromatography with silica gel, eluting with hexanes initially, grading to 100% (ethyl acetate-ethanol = 3:1 v / v), linear gradient, to provide (Int-16h). MS (ESI) [M+H] +< m / z: 647.Step I: Int-16i

[0200] Int-16h (130 mg, 0.201 mmol) was added in a 20 mL vial. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. DCM (2.0 mL) was added into the reaction vessel. Trifluoroacetic acid (769 µL, 10.1 mmol) was added dropwise into the reaction vessel and the resulting mixture was stirred for 1h at 24 °C. The product mixture was concentrated to provide Int-16i. MS (ESI) [M+H] +< m / z: 547.Step J: 19,22-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-7-(propan-2-yl)-11,12,13,14-tetrahydro-4H-1,20-(ethanediylidene)-6,10-(metheno)pyrimido[1,6-k][1,8,11,13]benzoxatriazacyclohexadecin-4-one (Ex. 16a)

[0201] Int-16i +3-TFA (160 mg, 0.180 mmol) was added in a 20 mL vial. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. DCM (1.8 mL) was added into the reaction vessel and the resulting solution was cooled down to 0 °C. N,N-Diisopropylethylamine (160 µL, 0.900 mmol) and acryloyl chloride (21.4 µL, 0.270 mmol) were added into the reaction vessel and the resulting mixture was stirred for 1 h at 0 °C. The product mixture was diluted with ethyl acetate (50 mL). The diluted product mixture was washed three times with saturated sodium bicarbonate aqueous solution (3 × 10 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with silica gel, eluting with hexanes initially, grading to 100% (ethyl acetate:ethanol = 3:1). The racemic material was resolved by SFC Column U, Condtion: 35% modifier: MeOH w / 0.25% N,N-dimethylethylamine to provide the separated atropisomers: Peak 1 - Ex. 16a - MS (ESI) [M+H] +< m / z: 601. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.38 (d, J= 2.0 Hz, 1H), 8.22 (dd, J = 18.8, 9.2 Hz, 1H), 7.57 - 7.34 (m, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.01 - 6.78 (m, 2H), 6.21 (dd, J = 16.8, 9.3 Hz, 1H), 5.90 - 5.71 (m, 1H), 4.80 (s, 1H), 4.55 - 3.91 (m, 3H), 3.82 (td, J = 9.7, 4.7 Hz, 1H), 3.67 - 3.47 (m, 3H), 3.19 (d, J = 21.4 Hz, 1H), 2.96 (p, J = 6.8 Hz, 1H), 2.86 - 2.70 (m, 1H), 2.57 (d, J = 4.2 Hz, 1H), 1.85 (td, J = 10.8, 10.2, 5.7 Hz, 1H), 1.72 (t, J= 18.1 Hz, 1H), 1.54 - 1.42 (m, 1H), 1.40 (d, J= 6.5 Hz, 3H), 1.28 (d, J= 6.3 Hz, 1H), 1.17 (d, J= 6.7 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H); and Peak 2 - Ex. 16b - 19,22-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-7-(propan-2-yl)-11,12,13,14-tetrahydro-4H-1,20-(ethanediylidene)-6,10-(metheno)pyrimido[1,6-k][1,8,11,13]benzoxatriazacyclohexadecin-4-one. MS (ESI) [M+H] +< m / z: 601. Example 17: 18,21-Difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,13,14-tetrahydro-4H-1,19-ethenopyrido[3,4-e]pyrimido[6,1-c][9,2,4]benzoxadiazacyclotridecin-4-one

[0202] Step A: 2-(2-chloro-3-nitropyridin-4-yl)ethanol (Int-17a)

[0203] To a stirred solution of 2-chloro-4-methyl-3-nitropyridine (50.0 g, 290 mmol) in DMSO (150 mL) were added paraformaldehyde (6.96 g, 232 mmol) and benzyltrimethylammonium hydroxide (5.3 mL, ~0.02 eq, 40% in methanol) at 20 °C, and the mixture was stirred at 90 °C for 4 h under N 2 atmosphere. The reaction mixture was quenched with water (100 mL), and extracted with ethyl acetate (2 × 400 mL). The combined organic layers were washed with brine (4 × 60 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluent of 0~60% EtOAc / Pet. Ether to provide 2-(2-chloro-3-nitropyridin-4-yl)ethanol (Int-17a). MS (ESI): [M+H] +< m / z: 202.Step B: 2-(3-nitro-2-(prop-1-en-2-yl)pyridin-4-yl)ethanol (Int-17b)

[0204] To a stirred solution of 2-(2-chloro-3-nitropyridin-4-yl)ethanol (10 g, 49.4 mmol) in DME (100 mL) and water (20 mL) was added Cs 2 CO 3 (48.2 g, 148 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (9.95 g, 59.2 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.73 g, 2.47 mmol), and the resulting mixture was stirred at 85 °C for 16 h. The reaction was extracted with EtOAc (200 mL × 3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography Pet. ether / EtOAc=10 / 1, to provide 2-(3-nitro-2-(prop-1-en-2-yl)pyridin-4-yl)ethanol (Int-17b). MS (ESI): [M+H] +< m / z:208.Step C: 4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-17c)

[0205] To a stirred solution of 2-(3-nitro-2-(prop-1-en-2-yl)pyridin-4-yl)ethanol (9.1 g, 43.7 mmol) in DCM (120 mL) was added TBSCl (8.56 g, 56.8 mmol) and imidazole (8.93 g, 131 mmol), and the mixture was stirred at 20 °C for 16 h under N 2 atmosphere. The reaction mixture was quenched with water (60 mL), and extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (80 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure, which was purified by flash silica gel chromatography eluent of 0~8% EtOAc / Pet. ether gradient to provide 4-(2-((tertbutyldimethylsilyl)oxy)ethyl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-17c). MS (ESI): [M+H] +< m / z:323.Step D: 4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-amine (Int-17d)

[0206] To a stirred solution 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-nitro-2-(prop-1-en-2-yl)pyridine (13 g, 40.3 mmol) in MeOH (100 mL) was added PdC (2.15 g, 2.02 mmol, 10% w / w) under N 2 atmosphere, and the mixture was degassed and purged with hydrogen for three times. The resulting mixture was stirred at 20 °C for 16 h under hydrogen balloon (pressure: 15 psi). The mixture was filtered and the filtered cake was washed with methanol (100 mL). The filtrate was concentrated in vacuo to give 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-amine (Int-17d) which was used in next step without further purification. MS (ESI): [M+H] +< mz:295.Step E: N-((4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro -5-fluoronicotinamide (Int-17e)

[0207] To a stirred solution of 2,6-dichloro-5-fluoronicotinamide (3.00 g, 14.4 mmol) in THF (40 mL) was added oxalyl dichloride (1.19 mL, 13.6 mmol) at 20 °C, and the mixture was stirred at 65 °C for 30 min under N 2 atmosphere. The mixture was cooled to 20 °C, and added to a mixture of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-amine (Int-17d, 4.65 g, 15.8 mmol) in DCM (40 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. The reaction mixture was quenched with aqueous sodium hydrogen carbonate (saturated, 30 mL), and extracted with dichloromethane (2 × 60 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluent of 0~40% EtOAc / Pet. ether to give N-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-17e). MS (ESI): [M+H] +< m / z:529.Step F: 1-(4-(2-((tert-Bulyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido [2,3-d]pyrimidine-2,4(1H,3H-dione (Int-17f)

[0208] To a stirred solution of N-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (4.00 g, 7.55 mmol) in THF (60 mL) was added potassium bis(trimethylsilyl)amide (15.1 mL, 15.1 mmol) at 0 °C, and the mixture was stirred at 20 °C for 30 min under N 2 atmosphere. The reaction mixture was quenched with aqueous ammonium chloride (saturated, 20 mL), and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure to give the crude product 1-(4-(2-((tertbutyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-17f), which was used in next step without further purification. MS (ESI): [M+H] +< mz:493.Step G: 1-(4-(2-((tert-Bulyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (Int-17g)

[0209] To a stirred solution of 1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.72 g, 7.54 mmol) in acetonitrile (50 mL) was added DIEA (3.29 mL, 18.9 mmol) and POCl 3 (1.06 mL, 11.3 mmol) at 25 °C, and the mixture was stirred at 80 °C for 1 h under N 2 atmosphere. The reaction mixture was concentrated in vacuo to afford the crude product 1-(4-(2-((tertbutyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (Int-17g), which was used in next step without further purification. MS (ESI): [M-Cl+MeOH] +< m / z: 507.Step H: tert-Butyl (S)-4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-17h)

[0210] To a stirred solution of 1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (3.86 g, 7.55 mmol) in DMF (40 mL) was added DIPEA (3.30 mL, 18.9 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (1.89 g, 9.43 mmol) at 25 °C, and the mixture was stirred at 20 °C for 30 min under N 2 atmosphere. The reaction was concentrated in vacuo, and the residue was purified by flash silica gel chromatography, eluent of 0~40% EtOAc / Pet. ether to give (S)-tert-butyl 4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-17h). MS (ESI): [M+H] +< m / z:675.Step I: (3S)-tert-Butyl 4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-7-(2-chloro-6-fluorophenyl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-17i)

[0211] To a stirred solution of tert-butyl (S)-4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (300 mg, 0.444 mmol), potassium acetate (218 mg, 2.22 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (18 mg, 0.022 mmol) in 1,4-dioxane (10 mL), water (2 mL) was added (2-chloro-6-fluorophenyl)boronic acid (116 mg, 0.666 mmol), and the resulting mixture was stirred at 90 °C for 2 h under N 2 atmosphere. The reaction mixture was quenched with brine (10 mL), and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluent of 0~50% EtOAc / Pet. ether gradient to give (3S)-tert-butyl 4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-7-(2-chloro-6-fluorophenyl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-17i). MS (ESI): [M+H] +< m / z: 769.Step J: (3S)-tert-Butyl 4-(7-(2-chloro-6-fluorophenyl)-6-fluoro-1-(4-(2-hydroxyethyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-17j )

[0212] To a stirred solution of (3S)-tert-butyl 4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-7-(2-chloro-6-fluorophenyl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (240 mg, 0.312 mmol) in THF (5 mL) was added a 1 M solution of TBAF in THF (0.936 mL, 0.936 mmol), and the mixture was stirred at 20 °C for 1 h under N 2 atmosphere. The reaction mixture was concentrated in vacuo, and the residue was purified by flash silica gel chromatography eluent of 0-8% MeOH / DCM to give (3S)-tert-butyl 4-(7-(2-chloro-6-fluorophenyl)-6-fluoro-1-(4-(2-hydroxyethyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-17j). MS (ESI): [M+H] +< m / z: 655.Step K: (3S)-tert-Butyl 4-(7-(2-chloro-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-(2-(vinyloxy)ethyl)pyridin -3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-17k)

[0213] To a stirred solution of (3S)-tert-butyl 4-(7-(2-chloro-6-fluorophenyl)-6-fluoro-1-(4-(2-hydroxyethyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg, 0.763 mmol) in toluene (10 mL) was added chloro(1,5-cyclooctadiene)iridium(I) dimer (103 mg, 0.153 mmol), Na 2 CO 3 (162 mg, 1.53 mmol) and vinyl acetate (131 mg, 1.53 mmol), and the mixture was stirred at 100 °C for 3 h under N 2 atmosphere. The reaction mixture was concentrated in vacuo, and the residue was purified by flash silica gel chromatography eluent of 0~40% EtOAc / Pet. ether to provide (3S)-tert-butyl 4-(7-(2-chloro-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-(2-(vinyloxy)ethyl)pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-17k). MS (ESI): [M+H] +< m / z:681.Step L: Int-17I

[0214] To a stirred solution of (3S)-tert-butyl 4-(7-(2-chloro-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-(2-(vinyloxy)ethyl)pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (150 mg, 0.220 mmol) in DMF (15 mL) was added N,N-dicyclohexylmethylamine (688 mg, 3.52 mmol), tri-tert-butylphosphonium tetrafluoroborate (128 mg, 0.440 mmol) and cataCxium ®< C (206 mg, 0.220 mmol), and the mixture was stirred at 160 °C for 1 h under N 2 atmosphere in the microwave. The reaction mixture was concentrated in vacuum, and the residue was purified by Al 2 O 3 chromatography (eluent of 0~10% MeOH / DCM) to give Int-17I. MS (ESI): [M+H] +< m / z:645.Step M: Int-17m

[0215] To a stirred mixture of Int-17I (90 mg, 0.070 mmol) in MeOH (10 mL) was added Pd-C (22 mg, 0.021 mmol, 10 % w / w), and the mixture was degassed and purged with hydrogen three times. The resulting mixture was stirred at 20 °C for 16 h under hydrogen (pressure: 15 psi). The mixture was filtered and the filter cake was washed with methanol (20 mL). The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC chromatography, water (0.1% TFA)-MeCN to give Int-17m. MS (ESI): [M+H] +< m / z:647.Step N: 18,21-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,13,14-tetrahydro-4H-1,19-ethenopyrido[3,4-e]pyrimido[6,1-c][9,2,4]benzoxadiazacyclotridecin-4-one (Ex. 17a and 17b)

[0216] To a stirred solution of Int-17m (30 mg, 0.046 mmol) in DCM (2 mL) was added TFA (0.5 mL), and the mixture was stirred at 20 °C for 10 min. The reaction mixture was concentrated in vacuum, and the residue was dissolved in DCM (2 mL), and then DIEA (0.041 mL, 0.23 mmol) and acryloyl chloride (6.3 mg, 0.070 mmol) was added. The resulting mixture was stirred at 20 °C for 5 min. The reaction mixture was concentrated in vacuum, and the residue was purified by preparative TLC plate eluting with 10% MeOH / DCM. The racemic material was resolved by SFC Column B, Condition: water (0.1% NH 4 OH)-MeOH 35% to provide the separated atropisomers: Peak 1 - Ex. 17a - 18,21-difluoro-2-[(2S)-2-m ethyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,13,14-tetrahydro-4H-1,19-ethenopyrido[3,4-e]pyrimido[6,1-c][9,2,4]benzoxadiazacyclotridecin-4-one. MS (ESI): [M+H] +< m / z:601; 1< H NMR (500MHz, methanol-d 4 ) δ 8.42 (d, J=5.0 Hz, 1H), 8.33 - 8.21 (m, 1H), 7.37 (dt, J=5.9, 8.0 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.01 (t, J=8.9 Hz, 1H), 6.93 - 6.76 (m, 1H), 6.32 (br d, J=16.0 Hz, 1H), 5.84 (dd, J=1.8, 10.6 Hz, 1H), 5.02 (br s, 1H), 4.67 - 4.50 (m, 2H), 4.43 - 4.26 (m, 1H), 4.02 - 3.71 (m, 2H), 3.61 - 3.53 (m, 1H), 3.47 (br s, 1H), 3.42 - 3.32 (m, 3H), 2.86 (br d, J=7.9 Hz, 1H), 2.73 - 2.63 (m, 2H), 2.49 - 2.33 (m, 2H), 1.55 (br t, J=6.7 Hz, 3H), 1.20 (d, J=6.9 Hz, 3H), 0.99 (br d, J=6.1 Hz, 3H); and Peak 2 - Ex. 17b - 18,21-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,13,14-tetrahydro-4H-1,19-ethenopyrido[3,4-e]pyrimido[6,1-c][9,2,4]benzoxadiazacyclotridecin-4-one. MS (ESI) m / z (M+H) +< : 601; 1< H NMR (400MHz, methanol-d 4 ) δ \8.42 (d, J=5.5 Hz, 1H), 8.33 (br t, J=8.2 Hz, 1H), 7.45 - 7.35 (m, 1H), 7.31 (d, J=5.1 Hz, 1H), 7.08 (d, J=7.4 Hz, 1H), 7.02 (t, J=8.6 Hz, 1H), 6.93 - 6.76 (m, 1H), 6.33 (br d, J=17.2 Hz, 1H), 5.84 (dd, J=2.0, 10.6 Hz, 1H), 5.23 (br s, 1H), 4.60 (br s, 2H), 4.46 (br d, J=13.7 Hz, 1H), 4.26 - 4.09 (m, 1H), 3.97 (br s, 1H), 3.78 - 3.40 (m, 3H), 3.37- 3.15 (m, 2H), 2.84 (br d, J=6.7 Hz, 1H), 2.68 (br dd, J=5.5, 13.3 Hz, 2H), 2.47 (br s, 1H), 2.35 (td, J=6.8, 12.9 Hz, 1H), 1.46 (d, J=7.0 Hz, 3H), 1.19 (d, J=7.0 Hz, 3H), 0.99 (br d, J=6.3 Hz, 3H). Example 18a: 17,20-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11-dihydro-1,18-ethenopyrido[3,4-e]pyrimido[6,1-c][9,2,4]benzoxadiazacyclododecin-4(13H)-one

[0217] Step A: (S)-tert-Butyl 4-(7-chloro-6-fluoro-1-(4-(2-hydroxyethyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-18a)

[0218] To a stirred solution of 1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (Int-17g, 3.20 g, 6.26 mmol) in DMF (50 mL) was added DIEA (2.73 mL, 15.6 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (1.57 g, 7.82 mmol) at 25 °C, and the mixture was stirred at 20 °C for 30 min under N 2 atmosphere. The reaction was concentrated in vacuum, and the residue was purified by flash silica gel chromatography with an eluent of 0~100% EtOAc / Pet. ether gradient to give (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(4-(2-hydroxyethyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-18a). MS (ESI): [M+H] +< m / z:561.Step B: Int-18b

[0219] To a stirred solution of (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(4-(2-hydroxyethyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (300 mg, 0.535 mmol), potassium acetate (262 mg, 2.67 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (43.7 mg, 0.053 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added (2-fluoro-6-formylphenyl)boronic acid (180 mg, 1.07 mmol), and the mixture was stirred at 90 °C for 30 min under N 2 atmosphere. The reaction mixture was separated and the organic layer was dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography with an eluent of 0~5% MeOH / DCM gradient, followed by reverse-phase MPLC 0%~100% MeCN (0.5TFA) / H 2 O to give Int-18b MS (ESI): [M+H] +< m / z: 649.Step C: Int-18c

[0220] To a stirred solution of Int-18b (60 mg, 0.092 mmol) in CH 3 NO 2 (6 mL) were added triethylsilane (0.120 mL, 0.751 mmol) and TfOH (0.0500 mL, 0.563 mmol), and the mixture was stirred at 20 °C for 30 min under a N 2 atmosphere. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC eluting with water (0.04% NH 3 H 2 O+10 mM NH 4 HCO 3 )-MeCN 10- 100% B to provide Int-18c. MS (ESI): [M+H] +< m / z:533.Step D: 17,20-Difluoro-2-[(2S)-2-methyl-4-prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11-dihydro-1,18-ethenopyrido[3,4-e]pyrimido[6,1-c][9,2,4]benzoxadiazacyclododecin-4(13H)-one (Ex. 18a)

[0221] To a stirred solution of Int-18c (99.0 mg, 0.186 mmol) in DCM (2.0 mL) were added DIEA (0.0970 mL, 0.558 mmol) and acryloyl chloride (20.2 mg, 0.223 mmol), and the mixture was stirred at 20 °C for 10 min under N 2 atmosphere. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, eluting with water (0.04% NH 3 H 2 O+10 mM NH 4 HCO 3 )-MeCN. The racemic material was resolved by preparative SFC Column L, Condition: 0.1% NH 4 OH EtOH, 55%, to provide the separated atropisomers: Peak 1 - Ex 18a - 17,20-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11-dihydro-1,18-ethenopyrido[3,4-e]pyrimido[6,1-c][9,2,4]benzoxadiazacyclododecin-4(13H)-one. MS (ESI) m / z (M+H) +< : 587; 1< H NMR (400 MHz, methanol-d 4 ) δ 8.50 (d, J =5.1 Hz, 1H), 8.19 (br t, J=10.8 Hz, 1H), 7.56 (d, J =5.1 Hz, 1H), 7.46 (dt, J =5.5, 8.0 Hz, 1H), 7.24 - 7.15 (m, 2H), 6.96 - 6.76 (m, 1H), 6.32 (br d, J=17.2 Hz, 1H), 5.84 (br d, J =11.0 Hz, 1H), 4.97 - 4.91 (m, 1H), 4.70 (br t, J=15.1 Hz, 1H), 4.59 - 4.37 (m, 2H), 4.22 - 4.05 (m, 2H), 4.00 (d, J=9.4 Hz, 1H), 3.86 - 3.63 (m, 3H), 3.44 - 3.32 (m, 1H), 3.07 (quin, J=6.7 Hz, 1H), 2.59 - 2.47 (m, 1H), 2.44 - 2.29 (m, 1H), 1.58 (br t, J=7.2 Hz, 3H), 1.27 (d, J=6.7 Hz, 3H), 1.01 (d, J=7.0 Hz, 3H).Example 19: 18,21-Difluoro-2-[(2S)-2-methyl-4-prop-2-enoyl)piperazin-1-yl]-6-propan-2-yl)-10,11,12,13-tetrahydro-1,19-ethenopyrido[3,4-e]pyrimido[6,1-c][2,4,10]benzotriazacyclotridecine-4,14-dione

[0222] Step A: N-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-19a)

[0223] Under a nitrogen atmosphere, a flask was charged with 2,6-dichloro-5-fluoronicotinamide (2.0 g, 9.6 mmol), THF (40 mL) and oxalyl chloride (2.0 M in DCM, 4.8 mL, 9.6 mmol). The mixture was heated to 65 °C for 30 minutes. After 30 minutes, the mixture was cooled to room temperature and then a mixture of 4-(3-((tertbutyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-amine (Int-10c, 3.25 g, 10.5 mmol) in THF (20 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. After 1 hour, the mixture was concentrated under reduced pressure. To the resulting mixutre was added pyridine (50 mL) and the mixture was then cooled to 0 °C. Tert-butyldimethylchlorosilane (1.6 g, 10 mmol) was added. The mixture was allowed to warm to room temperature and was allowed to stir at room temperature for one hour. After one hour, the mixture was concentrated under reduced pressure and then purified by silica column chromatography (0-60% ethyl acetate gradient in hexanes) to afford an impure mixture. The mixture was re-purified (0-70% methyl tert-butyl ether gradient in hexanes) to afford N-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-19a). MS (ESI) m / z 543 [M+H] +< Step B: 1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyridor[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-19b)

[0224] To a mixture of N-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-19a, 6.3 g, 12 mmol) in THF (60 mL) at 0 °C under a nitrogen atmosphere was added potassium bis(trimethylsilyl)amide (1.0 M in THF, 23 mL, 23 mmol). The mixture was then allowed to warm to room temperature and was then stirred for 30 minutes as room temperature. After 30 minutes, the mixture was quenched with saturated aqueous ammonium chloride (15 mL) and then extracted with ethyl acetate (2 X 200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude 1-(4-(3-((tertbutyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-19b) that was used without further purification or characterization. MS (ESI) m / z 507 [M+H] +< Step C: 1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (Int-19c)

[0225] To a flask containing crude 1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-19b) in acetonitrile (100 mL) under a nitrogen atmosphere was added DIEA (11 mL, 62 mmol) and phosphorous oxychloride (1.7 mL, 18 mmol) at room temperature. The mixture was then heated to 80 °C for 2 hours. After 2 hours, the mixture was allowed to cool to room temperature and was then concentrated under reduced pressure to afford 1-(4-(3-((tertbutyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (Int-19c) that was used without further purification or characterization. MS (ESI) m / z 526 [M+H] +< Step D: (S)-tert-Butyl 4-(7-chloro-6-fluoro-1-(4-(3-hydroxypropyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-19d)

[0226] To a stirred solution of 1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-4,7-dichloro-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (Int-19c, 6.22 g, 11.8 mmol) in acetonitrile (60 mL) was added DIPEA (4.13 mL, 23.7 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (3.56 g, 17.8 mmol) at 30 °C and the mixture was stirred at 30 °C for 1 h under N 2 atmosphere. The residue was purified by flash silica gel chromatography eluent of 0~100% EtOAc / Pet. to provide (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(4-(3-hydroxypropyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-19d). MS (ESI): [M+H] +< m / z:575.Step E: (3S)-tert-Butyl 4-(7-(2-carbamoyl-6-fluorophenyl)-6-fluoro-1-(4-(3-hydroxypropyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-19E)

[0227] To a stirred solution of 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (387 mg, 1.56 mmol), (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(4-(3-hydroxypropyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-19d, 600 mg, 1.04 mmol) and potassium acetate (512 mg, 5.22 mmol) in 1,4-dioxane (7 mL) and water (2 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (85.0 mg, 0.104 mmol) at 20 °C under N 2 atmosphere, and the mixture was stirred at 90 °C for 15 h under N 2 atmosphere. The reaction mixture was quenched with brine (10 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluent of 0~10% DCM / MeOH gradient to provide (3S)-tert-butyl 4-(7-(2-carbamoyl-6-fluorophenyl)-6-fluoro-1-(4-(3-hydroxypropyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-19e). MS (ESI): [M+H] +< m / z:678.Step F: (3S)-tert-Butyl 4-(7-(2-carbamoyl-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-(3-((methylsul fonyl)oxy)propyl)pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-19f)

[0228] To a stirred solution of (3S)-tert-butyl 4-(7-(2-carbamoyl-6-fluorophenyl)-6-fluoro-1-(4-(3-hydroxypropyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-19e, 600 mg, 0.885 mmol) in DCM (10 mL) was added Et 3 N (0.370 mL, 2.66 mmol) and MsCl (0.207 mL, 2.66 mmol) at 0 °C, and the mixture was stirred at 30 °C for 15 h under N 2 atmosphere. The reaction mixture quenched with water (10 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography, 0-100% Pet. ether / EtOAc, to give (3S)-tert-butyl 4-(7-(2-carbamoyl-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-(3-((methylsulfonyl)oxy)propyl)pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-19f). MS (ESI): [M+H] +< mz:756.Step G: Int-19g

[0229] To a stirred solution of tert-butyl (3S)-4-(7-(2-carbamoyl-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-(3-((methylsulfonyl)oxy)propyl)pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-19f, 371 mg, 0.491 mmol) in DMF (5 mL) was added NaH (39.3 mg, 0.982 mmol) (60% in mineral oil) at 0 °C, and the mixture was stirred at 30 °C for 15 h under N 2 atmosphere. The reaction mixture was quenched with aqueous ammonium chloride (saturated, 15 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by prep-TLC (pure EtOAc) to give Int-19g. MS (ESI): [M+H] +< m / z:660.Step H: Int-19h

[0230] To a stirred solution of Int-19g (220 mg, 0.333 mmol) in CH 2 Cl 2 (3 mL) was added TFA (1.5 mL) at 30 °C, and the mixture was stirred at 30 °C for 1 h. The reaction mixture was concentrated in vacuo to afford Int-19h. MS (ESI): [M+H] +< m / z:560.Step I: 18,21-Difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,12,13-tetrahydro-1,19-ethenopyrido[3,4-e]pyrimido[6,1-c][2,4,10]benzotriazacyclotridecine-4,14-dione (Ex. 19a and 19b)

[0231] To a stirred solution of crude Int-19h +TFA (91.0 mg, 0.163 mmol) in DCM (2 mL) were added DIEA (0.0280 mL, 0.163 mmol) and acryloyl chloride (14.7 mg, 0.163 mmol) at 0 °C, and the mixture was stirred at 0 °C for 10 min. The residue was purified by prep-TLC (DCM:MeOH=10:1). The racemic material was separated by preparative SFC Column H, Condition: 0.1% NH 4 OH EtOH 35% to provide: Peak 1 - Ex. 19a - 18,21-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,12,13-tetrahydro-1,19-ethenopyrido[3,4-e]pyrimido[6,1-c][2,4,10]benzotriazacyclotridecine-4,14-dione. MS (ESI): [M+H] +< mz:614 ; (500 HMz, methanol-d 4 ) δ: 8.48 (d, J=5.0 Hz, 1H), 8.33 (br dd, J=9.1, 14.1 Hz, 1H), 7.54 (dt, J=5.3, 8.0 Hz, 1H), 7.42 (d, J=5.2 Hz, 1H), 7.32 (t, J=8.7 Hz, 1H), 7.26 (d, J=7.5 Hz, 1H), 6.98 - 6.78 (m, 1H), 6.34 (br dd, J=4.7, 16.8 Hz, 1H), 5.86 (dd, J=1.8, 10.5 Hz, 1H), 5.19 - 5.07 (m, 1H), 4.55 - 4.46 (m, 2H), 4.24 - 4.12 (m, 1H), 3.90 (br d, J=9.9 Hz, 1H), 3.83 - 3.60 (m, 2H), 3.40 -3.30 (br s, 1H), 3.19 - 3.06 (m, 1H), 2.78 - 2.65 (m, 1H), 2.64 - 2.47 (m, 2H), 2.21 - 2.08 (m, 1H), 1.99 - 1.82 (m, 1H), 1.52 (br t, J=5.5 Hz, 3H), 1.16 (d, J=6.9 Hz, 3H), 0.82 (br d, J=6.6 Hz, 3H); and Peak 2 - Ex. 19b -18,21-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-10,11,12,13-tetrahydro-1,19-ethenopyrido[3,4-e]pyrimido[6,1-c][2,4,10]benzotriazacyclotridecine-4,14-dione. MS (ESI): [M+H] +< m / z: 614; 1< H NMR (500 HMz,methanol-d 4 ) δ: 8.36 (d, J=5.2 Hz, 1H), 8.21 (br t, J=9.1 Hz, 1H), 7.41 (dt, J=5.3, 8.0 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 7.19 (t, J=8.7 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 6.82 - 6.68 (m, 1H), 6.22 (br dd, J=4.0, 16.8 Hz, 1H), 5.74 (br d, J=10.7 Hz, 1H), 5.09 - 4.97 (m, 1H), 4.48 - 4.29 (m, 2H), 4.13 - 4.00 (m, 1H), 3.79 (br s, 1H), 3.70 - 3.46 (m, 2H), 3.34 - 3.13 (m, 1H), 2.99 (td, J=4.5, 14.0 Hz, 1H), 2.65 - 2.51 (m, 1H), 2.50 - 2.38 (m, 2H), 2.08 - 1.96 (m, 1H), 1.88 - 1.75 (m, 1H), 1.38 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 0.68 (br d, J=6.6 Hz, 3H). Examples 20a and 20b: 17,20-Difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-1,18-ethenopyrido[3,4-e]pyrimido[6,1-c][7,2,4]benzoxadiazacyclododecin-4(11H)-one

[0232] Step A: 4-Methoxy-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-20a)

[0233] To a stirred solution of 4-chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10a, 8.00 g, 40.3 mmol) in MeOH (80 mL) was added sodium methoxide (5.44 g, 101 mmol). The resulting mixture was stirred at 75 °C for 16 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (40 mL) and EtOAc (100 mL × 3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, Pet. ether / EtOAc =3 / 1, to give 4-methoxy-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-20a). MS (ESI): [M+H] +< mz:195.Step B: 2-Isopropyl-4-methoxypyridin-3-amine (Int-20b)

[0234] To a solution of 4-methoxy-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-20a, 13.0 g, 66.9 mmol) in MeOH (300 mL) was added Pd-C (1.59 g, 0.67 mmol, 5% w / w) under argon atmosphere at 25 °C. The mixture was stirred at 25 °C under H 2 atmosphere (15 psi) for 15 h. After 15 h, another batch Pd-C (4.76 g, 2.01 mmol, 5% w / w) was added, and the mixture was stirred at 25 °C under H 2 atmosphere (30 psi) for 15 h. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography with an eluent of 0~30% ethyl acetate / petroleum ether gradient to give 2-isopropyl-4-methoxypyridin-3-amine (Int-20b). MS (ESI): [M+H] +< m / z:167.Step C: 2,6-Dichloro-5-fluoro-N-((2-isopropyl-4-methoxypyridin-3-yl)carbamoyl)nicotinamide (Int-20c)

[0235] To a solution of 2,6-dichloro-5-fluoronicotinamide (8.70 g, 41.6 mmol) in THF (82 mL) was added oxalyl chloride (3.52 mL, 41.6 mmol) at 25 °C under N 2 atmosphere, and the mixture was stirred at 65 °C for 30 min. Then the reaction was cooled to room temperature, 2-isopropyl-4-methoxypyridin-3-amine (Int-20b, 6.92 g, 41.6 mmol) in THF (65 mL) was added, and the mixture was stirred at 25 °C for 1 h. The mixture was evaporated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography eluent of 0~10% MeOH / DCM gradient to give 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methoxypyridin-3-yl)carbamoyl)nicotinamide (Int-20c ). MS (ESI): [M+H] +< mz:401.Step D: 7-chloro-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)- dione (Int-20d)

[0236] To a solution of 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methoxypyridin-3-yl)carbamoyl)nicotinamide (Int-20c, 11.5 g, 28.7 mmol) in THF (220 mL) was added KHMDS (71.7 mL, 71.7 mmol) (1.0 M in THF) at 0 °C under N 2 atmosphere. The mixture was stirred at 25 °C for 30 min. The mixture was evaporated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography with an eluent of 0~10% MeOH / DCM gradient to give 7-chloro-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-20d). MS (ESI): [M+H] +< mz:365.Step E: 4,7-Dichloro-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)pyrido[23-d]pyrimidin-2(1H)-one (Int-20e)

[0237] To a stirred solution of 7-chloro-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-20d, 3.64 g, 9.98 mmol) in MeCN (40 mL) was added DIEA (4.36 mL, 25.0 mmol) and POCl 3 (2.33 mL, 25.0 mmol) at 25 °C. The mixture was stirred at 80 °C for 30 min. The reaction mixture was concentrated in vacuo to give 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, which was used in the next step without further purification (Int-20e). MS (ESI): [M+H] +< m / z:383.Step F: tert-Butyl (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20f)

[0238] To a stirred solution of 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (Int-20e, 3.80 g, 9.92 mmol) in MeCN (40 mL) was added DIEA (5.20 mL, 29.7 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (3.97 g, 19.8 mmol) at 25 °C, and the mixture was stirred at 80 °C for 30 min. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel with an eluent of Pet. ether / EtOAc=1 / 1, to give (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20f). MS (ESI): [M+H] +< m / z:548.Step G: tert-Butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20g)

[0239] To a stirred solution of (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20f, 1.14 g, 2.08 mmol), potassium acetate (1.02 g, 10.4 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.170 g, 0.208 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate (0.909 g, 4.17 mmol) dissolved in 1,4-dioxane (0.5 mL) at 90 °C under N 2 atmosphere. The mixture was stirred at 90 °C for 0.5 h under N 2 atmosphere. The reaction mixture was quenched with brine (10 mL), and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluent of 0~50% DCM / MeOH gradient to give (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20g). MS (ESI): [M+H] +< m / z:624.Step H: tert-Butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20h)

[0240] To a stirred solution of (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20g, 500 mg, 0.803 mmol) in DCM (8 mL) was added pyridine (191 mg, 2.41 mmol), followed by Tf 2 O (0.407 mL, 2.41 mmol) at 0 °C under a N 2 atmosphere. The mixture was stirred at 20 °C for 2 h under the N 2 atmosphere. The reaction mixture was quenched with brine (10 mL), and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography using an eluent of 0~10% DCM / MeOH gradient to give (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20h). MS (ESI): [M+H] +< mz:755.Step I: tert-Butyl (3S)-4-(7-(2-((E)-3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20i)

[0241] To a stirred solution of (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20h, 350 mg, 0.464 mmol) in toluene (6 mL) was added (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (208 mg, 0.696 mmol), potassium phosphate (1.39 mL, 1.39 mmol) (1M in water) and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (33.4 mg, 0.046 mmol) at 25 °C under N 2 atmosphere, and the mixture was stirred at 60 °C for 12 h under N 2 atmosphere. The reaction was quenched with water (10 mL) and extracted with EtOAc (50 mL × 3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluting with Pet. ether / EtOAc=1 / 2, to give (3S)-tert-butyl 4-(7-(2-((E)-3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate Int-20i. MS (ESI): [M+H] +< m / z:777.Step J: tert-Butyl (3S)-4-(7-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20j)

[0242] To a stirred solution of (3S)-tert-butyl 4-(7-(2-((E)-3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20i, 200 mg, 0.257 mmol) in MeOH (5 mL) was added Pd-C (27.4 mg, 0.257 mmol, 10% w / w) at 25 °C under N 2 atmosphere. The mixture was degassed and purged with hydrogen three times and stirred at 25 °C for 12 h under H 2 balloon (15 psi). The mixture was filtered and the filtrate was concentrated in vacuo to give (3S)-tert-butyl 4-(7-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20j). MS (ESI): [M+H] +< m / z:779.Step K: 6-fluoro-7-(2-fluoro-6-(3-hydroxypropyl)phenyl)-1-(4-hydroxy-2-isopropylpyridin-3-yl)-4-((S)-2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (Int-20k)

[0243] To a stirred solution of (3S)-tert-butyl 4-(7-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20j, 110 mg, 0.141 mmol) in MeCN (1.5 mL) were added KI (23.4 mg, 0.141 mmol) and chlorotrimethylsilane (15.3 mg, 0.141 mmol), and the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was used directly in the next step without further purification. (Int-20k). MS (ESI): [M+H] +< m / z:551.Step L: tert-Butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-(3-hydroxypropyl)phenyl)-1-(4-hydroxy-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20l)

[0244] To a stirred solution of 6-fluoro-7-(2-fluoro-6-(3-hydroxypropyl)phenyl)-1-(4-hydroxy-2-isopropylpyridin-3-yl)-4-((S)-2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (Int-20k, 110 mg, 0.100 mmol) in MeCN (1 mL) were added sodium bicarbonate (8.4 mg, 0.10 mmol) in water (0.2 mL) and Boc 2 O (0.035 mL, 0.15 mmol) at 0 °C under N 2 atmosphere. The mixture was stirred at 25 °C for 1 h under N 2 atmosphere. The mixture was extracted with EtOAc (10 mL x 3), and the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC plate (SiO 2 , DCM / MeOH=10 / 1) to give tert-butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-(3-hydroxypropyl)phenyl)-1-(4-hydroxy-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20l ). MS (ESI): [M+H] +< mz:651.Step M: Int-20m

[0245] To a stirred solution of (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-(3-hydroxypropyl)phenyl)-1-(4-hydroxy-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-20l, 35.0 mg, 0.0550 mmol) in THF (3.0 mL) was added triphenylphosphine (36.0 mg, 0.137 mmol). The mixture was stirred at 65 °C under N 2 atmosphere, and then (E)-di-tert-butyl diazene-1,2-dicarboxylate (25.3 mg, 0.110 mmol) was added. The reaction was stirred at 65 °C for 3 h. The mixture was cooled to rt and was directly purified by preparative TLC plate (SiO 2 , DCM / MeOH=10 / 1) to provide Int-20m. MS (ESI): [M+H] +< mz:633.Step N: Int-20n

[0246] A solution of Int-20m (22 mg, 0.035 mmol) in DCM (0.5 mL) and TFA (0.1 mL) was stirred at 25 °C for 10 min. The mixture was concentrated in vacuo to give Int-20n, which was used in the next step with further purification. MS (ESI): [M+H] +< m / z:533.Step O: 17,20-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-1,18-ethenopyrido[3,4-e]pyrimido[6,1-c][7,2,4]benzoxadiazacyclododecin-4(11H)-one (Ex. 20a and 20b)

[0247] To a stirred solution of Int-20n (18.5 mg, 0.0350 mmol) in DCM (0.5 mL) were added DIEA (0.0180 mL, 0.104 mmol) and acryloyl chloride (6.3 mg, 0.070 mmol). The resulting mixture was stirred at 0 °C for 10 min. The mixture was purified by preparative TLC plate directly (SiO 2 , DCM / MeOH=10 / 1). The racemic material was separated by preparative SFC Column N,; Condition: 0.1% NH 4 OH MeOH, 55%, to afford resolved atropisomers: Peak 1 - Ex. 20a -17,20-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-1,18-ethenopyrido[3,4-e]pyrimido[6,1-c][7,2,4]benzoxadiazacyclododecin-4(11H)-one. MS (ESI): [M+H] +< m / z:587; 1< H NMR (400MHz, methanol-d 4 ) δ: 8.40 (d, J=5.9 Hz, 1H), 8.17 (br d, J=8.2 Hz, 1H), 7.49 - 7.32 (m, 1H), 7.18 - 7.09 (m, 2H), 7.05 (t, J=9.0 Hz, 1H), 6.95 - 6.74 (m, 1H), 6.31 (br d, J=16.4 Hz, 1H), 5.84 (br d, J=10.2 Hz, 1H), 4.77 - 4.62 (m, 2H), 4.59 (br s, 1H), 4.51 - 4.15 (m, 1H), 4.03 - 3.94 (m, 1H), 3.70 (br d, J=13.7 Hz, 2H), 3.43 - 3.31 (m, 1H), 3.07 - 2.93 (m, 1H), 2.85 (br, 1H), 2.18 - 2.06 (m, 1H), 1.94 (br, 1H), 1.81 - 1.65 (m, 2H), 1.57 (br t, J=7.4 Hz, 3H), 1.28 (d, J=6.7 Hz, 3H), 0.99 (d, J=6.7 Hz, 3H); and Peak 2 - Ex. 20b -17,20-difluoro-2-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-6-(propan-2-yl)-12,13-dihydro-1,18-ethenopyrido[3,4-e]pyrimido[6,1-c][7,2,4]benzoxadiazacyclododecin-4(11H)-one. MS (ESI): [M+H] +< mz:587; 1< H NMR (400MHz, methanol-d 4 ) δ: 8.40 (d, J=5.9 Hz, 1H), 8.32 (br d, J=8.6 Hz, 1H), 7.46-7.37 (m, 1H), 7.13 (dd, J=12.5, 7.0 Hz, 2H), 7.04 (t, J=9.0 Hz, 1H), 6.84 (br dd, J=16.4, 9.8 Hz, 1H), 6.32 (br d, J=16.8 Hz, 1H), 5.84 (dd, J=10.6, 2.0 Hz, 1H), 5.33 (br s, 1H), 4.72 (br d, J=11.7 Hz, 1H), 4.59 (br, 1H), 4.46-4.22 (m, 2H), 4.12-3.78 (m, 3H), 3.46 (br s, 1H), 3.00 (br d, J=6.7 Hz, 1H), 2.83 (br s, 1H), 2.11 (br t, J=10.6 Hz, 1H), 1.93 (br s, 1H), 1.79-1.64 (m, 1H), 1.37 (br s, 3H), 1.28 (d, J=7.0 Hz, 3H), 0.99 (d, J=6.7 Hz, 3H). Preparation of 2-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)nicotinonitrile (Int-21)

[0248]

[0249] 2,6-dichloro-5-fluoronicotinonitrile (2.86 g, 15 mmol), potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate (3.60 g, 16.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.549 g, 0.750 mmol) and potassium acetate (2.94 g, 30.0 mmol) were combined in a 500 mL round bottom flask. The flask was purged with nitrogen 3 times. Dioxane (150 mL) and water (15 mL) (10:1) were added. The reaction mixture was stirred at 60 °C for 16 h. The mixture was diluted with water and extracted with ethyl acetate 3-4 times and dried with anhydrous Na 2 SO 4 , then the solvent was evaporated under vacuum and purified by silica gel column chromatography using 10%-30% EtOAc / Hexane to give 2-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)nicotinonitrile (Int-21). 1< H NMR (400 MHz, CDCl 3 ) δ: 8.91 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.39 (q, J = 1.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.79-6.75 (m, 1H).Preparation of 2-(3-amino-2-isopropylpyridin-4-yl)ethanol (Int-22)

[0250]

[0251] To a stirred solution of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-isopropylpyridin-3-amine (Int-7c, 1 g, 3.4 mmol) in THF (10 mL) was added TBAF (8.49 mL, 8.49 mmol) (1 M in THF) at 20 °C, and the mixture was stirred at 20 °C for 4 h under nitrogen atmosphere. The reaction was concentrated and the residue was purified by flash silica gel chromatography using an eluent of 0~100% EtOAc / Pet. ether to give 2-(3-amino-2-isopropylpyridin-4-yl)ethanol (Int-22). 1< H NMR (400 MHz, CDCl 3 ) δ: 7.99 (d, J=4.7 Hz, 1H), 6.84 (d, J=4.7 Hz, 1H), 3.97 (t, J=6.1 Hz, 4H), 3.16 - 2.95 (m, 1H), 2.80 (t, J=6.1 Hz, 2H), 1.31 (d, J=6.7 Hz, 6H).Preparation of potassium (3,6-difluoro-2-hydroxyphenyl)trifluoroborate (Int-23c )

[0252] Step A: (3,6-difluoro-2-methoxyphenyl)boronic acid (Int-23a)

[0253] 1,4-Difluoro-2-methoxybenzene (2.40 mL, 20.8 mmol) was dissolved in THF (20.8 mL) under nitrogen. The resulting solution was cooled down to 0 °C. A 1 M solution of lithium diisopropylamide (25.0 mL, 25.0 mmol) in THF-hexanes was added dropwise into the reaction mixture at 0 °C. The resulting mixture was stirred for 15 min at 0 °C and then trimethyl borate (2.79 mL, 25.0 mmol) was added dropwise into the reaction vessel. The resulting mixture was stirred for 30 min at 0 °C. An ice-cold 2 M aqueous solution of sulfuric acid (52.0 mL, 104 mmol) was added dropwise into the reaction mixture and the resulting mixture was stirred for 2 h at 0 °C. The product mixture was extracted three times with chloroform (3 × 100 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained containing (3,6-difluoro-2-methoxyphenyl)boronic acid (Int-23a) was used directly in the next step without purification.Step B: (3,6-difluoro-2-hydroxyphenyl)boronic acid (Int-23b)

[0254] (3,6-Difluoro-2-methoxyphenyl)boronic acid (2.8 g, 14.9 mmol) was dissolved in DCM (49.7 mL) under nitrogen. The resulting solution was cooled down to 0 °C. Neat tribromoborane (4.31 mL, 44.7 mmol) was added dropwise into the reaction vessel carefully. The reaction mixture was stirred for 15 min at 0 °C when TLC showed full conversion of the starting material. The product mixture was carefully quenched by dropwise addition of ice-cold water (5 mL). The product mixture was extracted three times with chloroform (3 × 100 mL). The organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained containing (3,6-difluoro-2-hydroxyphenyl)boronic acid (Int-23b) was used directly into the next step without purification.Step C: potassium (3,6-difluoro-2-hydroxyphenyl)trifluoroborate (Int-23c)

[0255] (3,6-Difluoro-2-hydroxyphenyl)boronic acid (2.59 g, 14.9 mmol) was added into a 250 mL round bottom flask. The reaction vessel was evacuated and backfilled with nitrogen three times. Methanol (18.6 mL) was added into the reaction vessel to dissolve the starting material. In a separate 40 mL vial was added potassium bifluoride (4.65 g, 59.6 mmol) and water (18.6 mL). The resulting fluoride solution was added streamwise into the reaction vessel. The resulting mixture was stirred for 16 h at 24 °C. The product mixture was diluted with acetone (50 mL). The diluted product mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (100 mL). The diluted mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (3 mL) and then the solution was triturated with hexanes (200 mL). The product was collected by filtration to afford potassium (3,6-difluoro-2-hydroxyphenyl)trifluoroborate (Int-23c). 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.14 (q, J = 14.7 Hz, 1H), 6.86 (ddd, J = 10.8, 8.8, 5.2 Hz, 1H), 6.32 (td, J= 8.3, 3.2 Hz, 1H).Preparation of potassium (3,6-difluoro-2-hydroxyphenyl)trifluoroborate (Int-24)

[0256]

[0257] (2,3-Difluoro-6-hydroxyphenyl)boronic acid (0.500 g, 2.88 mmol) was added into a 250 mL round bottomed flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. Methanol (3.59 mL) was added into the reaction vessel to dissolve the starting material. In a separate 40 mL vial was added potassium bifluoride (0.898 g, 11.5 mmol) and water (3.59 mL). The resulting fluoride solution was added streamwise into the reaction vessel. The resulting mixture was stirred for 16h at 24 °C. The product mixture was diluted with acetone (20 mL). The diluted product mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (40 mL). The diluted mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (3 mL) and then the solution was triturated with hexanes (200 mL). The product was collected by filtration to afford potassium (3,6-difluoro-2-hydroxyphenyl)trifluoroborate (Int-24). 1< H NMR (500 MHz, DMSO-d 6 ) δ 7.84 (q, J = 13.3 Hz, 1H), 6.91 (q, J = 8.3 Hz, 1H), 6.32 (dd, J = 10.0, 5.0 Hz, 1H).Preparation of potassium trifluoro(2-hydroxy-3-(trifluoromethyl)phenyl)borate (Int-25)

[0258]

[0259] To 2-hydroxy-3-(trifluoromethyl)phenylboronic acid (500 mg, 2.43 mmol) in methanol (3.04 mL) / water (3.04 mL) was added potassium bifluoride (759 mg, 9.71 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with acetone (20 mL) and filtered. The filtrate was concentrated in vacuo and redissolved exclusively in acetone. Hexane was added (~4 mL) and the mixture was again filtered. The organics were concentrated again to give potassium trifluoro(2-hydroxy-3-(trifluoromethyl)phenyl)borate (Int-25). MS (ESI) m / z 229 [M-K] -< .Preparation of potassium trifluoro(2-hydroxy-5-(trifluoromethyl)phenyl)borate (Int-26)

[0260]

[0261] (2-Hydroxy-5-(trifluoromethyl)phenyl)boronic acid (0.500 g, 2.43 mmol) was added into a 250 mL round bottomed flask. The reaction vessel was evacuated and backfilled with nitrogen three times. Methanol (3.04 mL) was added into the reaction vessel to dissolve the starting material. In a separate 40 mL vial was added potassium bifluoride (0.759 g, 9.71 mmol) and water (3.04 mL). The resulting fluoride solution was added streamwise into the reaction vessel. The resulting mixture was stirred for 16h at 24 °C. The product mixture was diluted with acetone (25 mL). The diluted product mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (50 mL). The diluted mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (3 mL) and then the solution was triturated with hexanes (50 mL). The product was collected by filtration to afford potassium trifluoro(2-hydroxy-5-(trifluoromethyl)phenyl)borate (Int-26). 1< H NMR (500 MHz, DMSO-d 6 ) δ 7.91 (q, J = 9.7 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.28 (dd, J = 8.4, 2.5 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H).Preparation of potassium trifluoro(3-fluoro-2-hydroxyphenyl)borate (Int-27 )

[0262]

[0263] (3-Fluoro-2-hydroxyphenyl)boronic acid (1.15 g, 7.38 mmol) was added into a 50 mL round-bottomed flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. Methanol (14.8 mL) was added into the reaction vessel to dissolve the starting material. In a separate 40 mL vial was added potassium bifluoride (2.30 g, 29.5 mmol) and water (14.8 mL). The resulting fluoride solution was added streamwise into the reaction vessel. The resulting mixture was stirred for 16h at 24 °C. The product mixture was diluted with acetone (50 mL). The diluted product mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (100 mL). The diluted mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (3 mL) and then the solution was triturated with hexanes (200 mL). The product was collected by filtration to afford potassium trifluoro(3-fluoro-2-hydroxyphenyl)borate (Int-27). 1< H NMR (500 MHz, DMSO-d 6 ) δ 7.43 (d, J = 9.6 Hz, 1H), 6.92 (dd, J = 7.2, 1.6 Hz, 1H), 6.83 (ddd, J= 11.8, 7.9, 1.7 Hz, 1H), 6.60 (td, J = 7.6, 4.3 Hz, 1H).Preparation of potassium (4,5-difluoro-2-hydroxyphenyl)trifluoroborate (Int-28)

[0264]

[0265] (4,5-Difluoro-2-hydroxyphenyl)boronic acid (0.500 g, 2.88 mmol) was added into a 250 mL round-bottomed flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. Methanol (3.59 mL) was added into the reaction vessel to dissolve the starting material. In a separate 40 mL vial was added potassium bifluoride (0.898 g, 11.5 mmol) and water (3.59 mL). The resulting fluoride solution was added streamwise into the reaction vessel. The resulting mixture was stirred for 16 h at 24 °C. The product mixture was diluted with acetone (25 mL). The diluted product mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (40 mL). The diluted mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (3 mL) and then the solution was triturated with hexanes (~20 mL). The product was collected by filtration to afford potassium (4,5-difluoro-2-hydroxyphenyl)trifluoroborate (Int-28). 1< H NMR (500 MHz, DMSO-d 6 ) δ 7.52 (qd, J = 9.7, 1.4 Hz, 1H), 6.92 (t, J = 10.9 Hz, 1H), 6.51 (dd, J = 12.8, 6.5 Hz, 1H).Preparation of potassium (2-chloro-6-hydroxyphenyl)trifluoroborate (Int-29)

[0266]

[0267] (2-Chloro-6-hydroxyphenyl)boronic acid (0.500 g, 2.90 mmol) was added into a 250 mL round bottomed flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. Methanol (3.63 mL) was added into the reaction vessel to dissolve the starting material. In a separate 40 mL vial was added potassium bifluoride (0.906 g, 11.6 mmol) and water (3.63 mL). The resulting fluoride solution was added streamwise into the reaction vessel. The resulting mixture was stirred for 16 h at 24 °C. The product mixture was diluted with acetone (50 mL). The diluted product mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (100 mL). The diluted mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (3 mL) and then the solution was triturated with hexanes (200 mL). The product was collected by filtration to afford potassium (2-chloro-6-hydroxyphenyl)trifluoroborate (Int-29). 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.45 (q, J = 16.7 Hz, 1H), 6.92 (t, J= 7.9 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H).Preparation of potassium trifluoro(2-hydroxy-6-(trifluoromethyl)phenyl)borate(Int-30 )

[0268]

[0269] (2-Hydroxy-6-(trifluoromethyl)phenyl)boronic acid (0.500 g, 2.43 mmol) was added into a 250 mL round bottomed flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. Methanol (3.04 mL) was added into the reaction vessel to dissolve the starting material. In a separate 40 mL vial was added potassium bifluoride (0.759 g, 9.71 mmol) and water (3.04 mL). The resulting fluoride solution was added streamwise into the reaction vessel. The resulting mixture was stirred for 16 h at 24 °C. The product mixture was diluted with acetone (25 mL). The diluted product mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (40 mL). The diluted mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was diluted with acetone (3 mL) and then the solution was triturated with hexanes (~20 mL). The product was collected by filtration to afford potassium trifluoro(2-hydroxy-6-(trifluoromethyl)phenyl)borate (Int-30). 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.60 (q, J= 16.7 Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H).Preparation of 2-chloro-6-(3,6-difluoro-2-hydroxyphenyl)-5-fluoronicotinonitrile (Int-31)

[0270]

[0271] 2,6-Dichloro-5-fluoronicotinonitrile (0.382 g, 2.00 mmol), potassium (3,6-difluoro-2-hydroxyphenyl)trifluoroborate (0.472 g, 2.00 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.146 g, 0.200 mmol) and potassium acetate (0.393 g, 4.00 mmol) were combined in a 50 mL round bottom flask. The flask was purged with nitrogen 3 times. Dioxane (15.3 mL) and water (0.955 mL) (15:1) were added. The reaction mixture was stirred at 60 °C overnight. The reaction mixture was filtered and the crude product was purified by column chromatography using ethyl acetate-hexane 10%-20% to afford 2-chloro-6-(3,6-difluoro-2-hydroxyphenyl)-5-fluoronicotinonitrile (Int-31). 1< H NMR (600 MHz, CDCl 3 ) δ 7.94 (d, J = 7.8 Hz, 1H), 7.83 (d, J= 2.0 Hz, 1H), 7.26 (td, J = 9.5, 5.0 Hz, 1H), 6.75 (td, J= 9.2, 3.7 Hz, 1H).Preparation of 3-(3-amino-2-isopropylpyridin-4-yl)propan-1-ol (Int-32)

[0272]

[0273] To a flask containing 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-amine (Int-10c, 2.00 g, 6.48 mmol) was added THF (13 mL) and then TBAF (19.5 mL, 19.5 mmol, 1M in THF). The mixture was heated to 50 °C for one hour. Upon cooling to room temperature, the mixture was concentrated under reduced pressure and then the crude product was purified by column chromatography using 0-30% ethyl acetate in hexanes to afford 3-(3-amino-2-isopropylpyridin-4-yl)propan-1-ol (Int-32). MS (ESI) m / z 195 [M+H] +< .Preparation of (R)-3-(3-amino-2-isopropylpyridin-4-yl)propan-1-ol (Int-33b)

[0274] Step A: (R)-4-((1-(benzyloxy)propan-2-yl)oxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-33a)

[0275] (R)-1-(Benzyloxy)propan-2-ol (0.178 mL, 1.10 mmol) was dissolved in THF (2.98 mL) and cooled to 0°C. Next, sodium hydride (0.044 g, 1.1 mmol, 60 wt% in mineral oil) was added slowly and the reaction was stirred at 0 °C for 30 min. After that, 4-chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10a, 0.199 g, 1.00 mmol) was added dropwise and the reaction mixture was stirred at this temperature for 2 h until the starting material was consumed. Then it was quenched with saturated ammonium chloride and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated. The crude was purified by column chromatography to afford (R)-4-((1-(benzyloxy)propan-2-yl)oxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-33a). 1< H NMR (600 MHz, CDCl 3 ) δ 8.47 (d, J= 5.8 Hz, 1H), 7.40 - 7.29 (m, 5H), 6.98 (d, J = 5.8 Hz, 1H), 5.36 (dq, J = 2.1, 1.3 Hz, 1H), 5.30 - 5.22 (m, 1H), 4.78 (pd, J = 6.5, 3.9 Hz, 1H), 4.62 - 4.50 (m, 2H), 3.66 (dd, J = 10.6, 6.8 Hz, 1H), 3.62 (dd, J = 10.6, 3.9 Hz, 1H), 2.19 (t, J = 1.2 Hz, 3H), 1.38 (d, J = 6.3 Hz, 3H).Step B: (R)-2-((3-amino-2-isopropylpyridin-4-yl)oxy)propan-1-ol (Int-33b)

[0276] The mixture of (R)-4-((1-(benzyloxy)propan-2-yl)oxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (4 g, 12 mmol), AcOH (4 mL) and Pd / C (2 g) in EtOH (40 mL) was stirred overnight at 30°C under H 2 . The reaction mixture was filtered and concentrated to afford (R)-2-((3-amino-2-isopropylpyridin-4-yl)oxy)propan-1-ol (Int-33b). 1< H NMR (400MHz, methanol-d 4 ) δ 7.78 (d, J=5.6 Hz, 1H), 6.80 (d, J=5.6 Hz, 1H), 4.64 - 4.56 (m, 1H), 3.78 - 3.68 (m, 2H), 3.19 (s, 1H), 1.33 (d, J=6.4 Hz, 3H), 1.25 (dd, J =1.2, 6.6 Hz, 6H).Preparation of (S)-3-(3-amino-2-isopropylpyridin-4-yl)propan-1-ol (Int-34c )

[0277] Step A: (S)-4-((1-(benzyloxy)propan-2-yl)oxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-34a)

[0278] To a mixture of (S)-1-(benzyloxy)propan-2-ol (4.20 g, 25.3 mmol) in THF (40 mL) was added NaH (2.50 g, 63.3 mmol, 60 wt%) at 0 °C. The mixture was stirred for 1 h at room temperature and then 4-chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10a, 5.00 g, 25.3 mmol) in THF (10 mL) was added. The reaction mixture was stirred at room temperature overnight. The above solution was poured into NH 4 Cl solution. The solution was extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The crude was purified by column chromatography on silica gel (Pet. ether / EtOAc=50:1) to give (S)-4-((1-(benzyloxy)propan-2-yl)oxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-34a). 1< H NMR (400MHz, CDCl 3 ) δ 8.47 (d, J = 5.6 Hz, 1H), 7.40 - 7.28 (m, 5H), 6.97 (d, J = 6.0 Hz, 1H), 5.36 - 5.24 (m, 2H), 4.81 - 4.75 (m, 1H), 4.61 - 4.52 (m, 2H), 3.69 - 3.57 (m, 2H), 2.19 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H).Step B: (S)-2-((3-amino-2-isopropylpyridin-4-yl)oxy)propan-1-ol (Int-34b)

[0279] The mixture of (S)-4-((1-(benzyloxy)propan-2-yl)oxy)-3-nitro-2-(prop-1-en-2-yl)pyridine (4.0 g, 12 mmol), AcOH (4mL) and Pd / C (2.0 g, 10 wt%) in EtOH (40 mL) was stirred overnight at 30°C under H 2 . The reaction mixture was filtered and concentrated to give (S)-2-((3-amino-2-isopropylpyridin-4-yl)oxy)propan-1-ol (Int-34b) without further purification.Step C: (S)-3-(3-amino-2-isopropylpyridin-4-yl)propan-1-ol (Int-34c )

[0280] To a mixture of (S)-2-((3-amino-2-isopropylpyridin-4-yl)oxy)propan-1-ol (10.0 g, 47.6 mmol) and imidazole (6.50 g, 95.2 mmol) in DCM (100 mL) was added tert-butylchlorodimethylsilane (10.7 g, 71.4 mol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (20 mL) and concentrated. The crude was purified by column chromatography on silica gel (DCM / MeOH=100:1) to give (S)-3-(3-amino-2-isopropylpyridin-4-yl)propan-1-ol (Int-34c). MS (ESI) m / z 325 [M+H] +< .Preparation of 4-(2-((tert-bulyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isoproylpyridin-3-amine (Int-35c )

[0281] Step A: 2-((tert-butyldimethylsilyl)oxy)ethan-1,1,2,2-d 4 -1-ol (Int-35a)

[0282] Ethane-d 4 -1,2-diol (5.0 g, 76 mmol) was added in a 500 mL round bottomed flask. The reaction vessel was evacuated and backfilled with nitrogen three times. THF (100 mL) was added into the reaction vessel. Sodium hydride (3.0 g, 76 mmol 60% suspension in mineral oil) was added into the reaction vessel in six equal portions over 15 min at 24 °C. The resulting mixture was stirred for 1 h at 24 °C. In a 200 mL pointed flask, tert-butylchlorodimethylsilane (11.4 g, 76.0 mmol) was dissolved in 30 mL of THF under nitrogen. The resulting mixture was added dropwise into the reaction vessel via cannula. THF (2 × 10 mL) was added into the vessel containing the silyl chloride and the rinses were added dropwise into the reaction vessel. The resulting mixture was stirred for 1h at 24 °C. The product mixture was quenched with saturated ammonium chloride aqueous solution (20 mL). The quenched product mixture was extracted three times with ether (3 × 50 mL). The combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography, eluting with 0 to 30% ethyl acetate-hexanes to afford 2-((tert-butyldimethylsilyl)oxy)ethan-1,1,2,2-d 4 -1-ol (Int-35a). 1< H NMR (500 MHz, CDCl 3 ) δ 0.93 (s, 9H), 0.11 (s, 6H).Step B: 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-35b)

[0283] 2-((tert-Butyldimethylsilyl)oxy)ethan-1,1,2,2-d 4 -1-ol (4.82 g, 26.7 mmol) was added into a 500 mL round bottomed flask. The reaction vessel was evacuated and backfilled with nitrogen three times. THF (50 mL) was added into the reaction vessel. The resulting mixture was cooled down to 0 °C. Sodium hydride (1.12 g, 28.0 mmol 60% suspension in mineral oil) was added in five equal portions in 15 min. The resulting mixture was stirred for 30 min at 0 °C. In a pointed 100 mL flask, 4-chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10a, 5.05 g, 25.4 mmol) was dissolved in THF (25 mL) under nitrogen. The resulting solution was transferred to the reaction mixture dropwise via cannula at 0 °C. The resulting mixture was stirred for 2 h at 0 °C. The product mixture was quenched with saturated ammonium chloride aqueous solution (10 mL). The quenched product mixture was extracted three times with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography eluting with 0 to 40% ethyl acetate-hexanes to afford 4-(2-((tertbutyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-35b). 1< H NMR (500 MHz, Acetonitrile-d 3 ) δ 8.49 (d, J= 5.8 Hz, 1H), 7.13 (d, J = 5.8 Hz, 1H), 5.45 - 5.26 (m, 1H), 5.21 - 4.97 (m, 1H), 2.11 (s, 3H), 0.85 (s, 9H), 0.04 (s, 6H).Step C: 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-amine (Int-35c )

[0284] 4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-3-nitro-2-(prop-1-en-2-yl)pyridine (4.82 g, 14.1 mmol) was dissolved in EtOH (70 mL), degassed under nitrogen, charged with Pd-C (10 wt%, 0.300 g, 2.81 mmol), degassed under nitrogen, and allowed to stir under hydrogen atmosphere for 24h. The product mixture was thoroughly purged with nitrogen. The purged reaction mixture was filtered through a pad of CELITE. The filtrate was concentrated to dryness. The residue obtained was diluted with ethyl acetate (20 mL) and the diluted product mixture was filtered through a syringe filter to further remove the residue catalyst / activated carbon. The filtrate was concentrated to dryness to afford 4-(2-((tertbutyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-amine (Int-35c). 1< H NMR (500 MHz, Acetonitrile-d 3 ) δ 7.84 (d, J= 5.5 Hz, 1H), 6.73 (d, J = 5.5 Hz, 1H), 4.03 (s, 2H), 3.11 (p, J = 6.7 Hz, 1H), 1.23 (d, J = 6.7 Hz, 6H), 0.92 (s, 9H), 0.11 (s, 6H).Preparation of 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-isopropylpyrimidin-5-amine (Int-36c )

[0285] Step A: 4-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-6-chloropyrimidin-5-amine (Int-36a )

[0286] Into a 5000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DME (2000 mL), H 2 O (400 mL), Na 2 CO 3 (248 g, 2343 mmol, 3.00 equiv), tert-butyldimethyl[[(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]silane (233 g, 781 mmol, 1.00 equiv), 4,6-dichloropyrimidin-5-amine (128 g, 781 mmol, 1.00 equiv), Pd(PPh 3 ) 2 Cl 2 (47 g, 67 mmol, 0.10 equiv). The resulting solution was stirred for 3 h at 80°C in an oil bath. The resulting solution was cooled to room temperature, extracted with 2 × 500 mL of ethyl acetate and the organic layers were combined and concentrated under vacuum. The residue was purified by column chromatography using ethyl acetate / petroleum ether (1:1) to afford 4-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-6-chloropyrimidin-5-amine (Int-36a). MS (ESI) m / z 300 [M+H] +< .Step B: 4-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-6-(prop-1-en-2-yl)pyrimidin-5-amine (Int-36b)

[0287] Into a 5000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DME (2000 mL), H 2 O (400 mL), Cs 2 CO 3 (531 g, 1630 mmol, 3 equiv), 4-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-6-chloropyrimidin-5-amine (163 g, 543 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane (91 g, 544 mmol, 1.00 equiv), Pd(PPh 3 ) 2 Cl 2 (38 g, 54 mmol, 0.1 equiv). The resulting solution was stirred for 12 h at 100°C in an oil bath. The resulting solution was cooled to room temperature, and extracted with 2 × 500 mL of ethyl acetate. The organic layers were combined and concentrated under vacuum. The residue was purified by column chromatography with ethyl acetate / petroleum ether (1:1) to afford 4-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-6-(prop-1-en-2-yl)pyrimidin-5-amine (Int-36b). MS (ESI) m / z 306 [M+H] +< .Step C: 4-[3-[(tert-butyldimethylsilyl)oxy]propyl]-6-isopropylpyrimidin-5-amine (Int-36c )

[0288] Into a 3000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed ethanol (1500 mL), 4-[(1E)-3-[(tertbutyldimethylsilyl)oxy]prop-1-en-1-yl]-6-(prop-1-en-2-yl)pyrimidin-5-amine (107 g, 350 mmol, 1.00 equiv), andPd / C (3.73 g, 35.0 mmol, 0.1 equiv). H 2 (gas) was introduced into the mixture. The resulting solution was stirred for 12 h at 25°C. The solids were filtered out. The resulting mixture was concentrated. The residue was purified by column chromatography (EtOAc:Pet. ether=1:1) to afford 4-[3-[(tert-butyldimethylsilyl)oxy]propyl]-6-isopropylpyrimidin-5-amine (Int-36c). 1< H-NMR (300 MHz, DMSO-d 6 ): δ 8.28 (s, 1H), 5.00 (s, 2H), 3.66 (t, J = 6.5 Hz, 2H), 3.29-3.12 (m, 1H), 2.63 (t, J = 7.4 Hz, 2H), 1.93-1.77 (m, 2H), 1.14 (d, J = 6.6 Hz, 6H), 0.86 (s, 9H), 0.02 (s, 6H).Preparation of 4-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-2-isopropylpyridin-3-amine (Int-37d-1 and Int-37d-2)

[0289] Step A: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-ol (Int-37a)

[0290] A microwave vial containing a magnetic stir bar was charged with Pd(Ph 3 P) 4 (4.01 g, 3.47 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (26.4 g, 104 mmol). The vial was evacuated and backfilled with nitrogen three times. Toluene (24 mL) was added, followed by but-3-yn-1-ol (6.08 g, 87 mmol) and acetic acid (4.4 mL). The reaction mixture was prestirred for 5 min before heating to 80 °C for 30 min in the microwave. After allowing to cool to room temperature, the mixture was concentrated in vacuo, and the residue purified by column chromatography on silica gel (Pet. ether:EtOAc=50:1 to 20:1) to give 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-ol (Int-37a). The reaction was set up in four batches (1.52 g each). 1< H NMR (500MHz, CDCl 3 ) δ 5.89 (d, J=3.0 Hz, 1H), 5.70 (s, 1H), 3.67 (t, J=6.0 Hz, 2H), 2.42 (t, J=6.0 Hz, 2H), 1.26 (s, 12H).Step B: tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (Int-37b)

[0291] To a stirred solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-ol (15 g, 76 mmol) in DCM (260 mL) was added tert-butylchlorodimethylsilane (17.1 g, 114 mmol) and imidazole (10.3 g, 151 mmol), and the mixture was stirred at 20 °C for 16 h under a N 2 atmosphere. The reaction mixture was quenched with water (200 mL), and extracted with dichloromethane (250 mL × 3). The combined organic layers were washed with brine (180 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 60 : 1 to 30:1) to give tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (Int-37b). 1< H NMR (400MHz, CDCl 3 ) δ 5.78 (d, J=3.2 Hz, 1H), 5.62 (s, 1H), 3.61 (t, J=7.2 Hz, 2H), 2.33 (t, J=7.2 Hz, 2H), 1.21 (s, 12H), 0.84 (s, 9H), 0.00 (s, 6H).Step C: 4-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-37c)

[0292] A stirred solution of 4-chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10a, 4.00 g, 20.1 mmol) in DME (175 mL) and water (25 mL) was added cesium carbonate (13.1 g, 40.3 mmol), tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (9.44 g, 30.2 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.707 g, 1.01 mmol), and the resulting mixture was stirred at 70 °C for 16 h under a N 2 balloon. The mixture was cooled, diluted with water (200 mL), extracted with EtOAc (2 × 300 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by chromatographed on silica gel (EtOAc / Pet. ether, 1:10 to 1: 5) to give 4-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-37c ). MS (ESI) m / z 349 [M+H] +< . 1< H NMR (400MHz, CDCl 3 ) δ 8.58 (d, J=5.2 Hz, 1H), 7.18 (d, J=5.2 Hz, 1H), 5.31 (d, J=4.4 Hz, 2H), 5.15 (d, J=11.2 Hz, 2H), 3.69 (t, J=6.4 Hz, 2H), 2.57 (t, J=6.4 Hz, 2H), 2.18 (s, 3H), 0.86 (s, 9H), 0.00 (s, 6H).Step D: 4-(4-((tert-bulyldimethylsilyl)oxy)butan-2-yl)-2-isopropylpyridin-3-amine (Int-37d-1 and Int-37d-2)

[0293] To a stirred solution 4-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (4.00 g, 11.5 mmol) in MeOH (50 mL) was added Pd-C (1.22 g, 1.15 mmol) (10 wt%) under nitrogen atmosphere, and the mixture was degassed and purged with hydrogen for three times. The resulting mixture was stirred at 20 °C for 4 h under (Pressure: 15 psi) hydrogen balloon. The mixture was filtered and the filtered cake was washed with methanol (100 mL). The filtrate was concentrated in vacuum to give 4-(4-((tertbutyldimethylsilyl)oxy)butan-2-yl)-2-isopropylpyridin-3-amine. The racemic material was separated by preparative SFC Column M, Condition: 0.1% NH 3 H 2 O IPA to give 4-(4-((tertbutyldimethylsilyl)oxy)butan-2-yl)-2-isopropylpyridin-3-amine (Int-37d-1) as peak 1. MS (ESI) m / z 323 [M+H] +< . And 4-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-2-isopropylpyridin-3-amine (Int-37d-2) as peak 2. MS (ESI) m / z 323 [M+H] +< .Preparation of 4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-2-isopropylpyridin-3-amine (Int-38g)

[0294] Step A: 2-(((tert-butyldimethylsilyl)oxy)methyl)prop-2-en-1-ol (Int-38a)

[0295] NaH (60%) (8.85 g, 221 mmol) was added to a solution of 2-methylenepropane-1,3-diol (15.0 g, 170 mmol) in THF (800 mL) at 0 °C. After stirring at 0 °C for 0.5 h, tert-butylchlorodimethylsilane (26.9 g, 179 mmol) was added to the mixture at 0 °C to give a white mixture. The resulting mixture was stirred at 20 °C for another 2 h. The reaction was then slowly poured into 200 mL of ice-water. The resulting solution was extracted with ethyl acetate (2 × 300 mL), and the organic layers combined. The organic layers were washed with brine (500 mL), dried over Na 2 SO 4 , filtered and concentrated to give the crude product as an oil. The oil was purified by flash silica gel chromatography (0~3% EtOAc / Pet. ether) to give 2-(((tertbutyldimethylsilyl)oxy)methyl)prop-2-en-1-ol (Int-38a). 1< H NMR (500MHz, CDCl 3 ) δ 5.09 (dd, J=0.8, 9.0 Hz, 2H), 4.25 (s, 2H), 4.17 (d, J=5.8 Hz, 2H), 0.91 (s, 9H), 0.09 (s, 6H).Step B: ((2-(bromomethyl)allyl)oxy)(tert-butyl)dimethylsilane (Int-38b)

[0296] To a stirred solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)prop-2-en-1-ol (33.0 g, 163 mmol) in CH 2 Cl 2 (500 mL) at 0° C was added triphenylphosphine (51.3 g, 196 mmol) followed by perbromomethane (64.9 g, 196 mmol). The solution was stirred at 15 °C for 17 h. The solution was filtered and the filtrate was concentrated under vacuum. The residue was chromatographed on silica gel (EtOAc / Pet. ether, grading from 0:100 to 5:95) to give ((2-(bromomethyl)allyl)oxy)(tert-butyl)dimethylsilane (Int-38b). 1< H NMR (500MHz, CDCl 3 ) δ 5.27 - 5.21 (m, 2H), 4.27 (s, 2H), 4.01 (s, 2H), 0.92 (s, 9H), 0.10 (s, 6H).Step C: tert-butyldimethyl((2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)allyl)oxy)silane (Int-38c)

[0297] A two necked round-bottom flask equipped with a magnetic stir bar and condenser was charged with magnesium (3.30 g, 136 mmol) and fitted with a rubber septum. The flask was purged with argon and charged with dry THF (500 mL) followed by 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.5 g, 113 mmol). To the reaction mixture was added ((2-(bromomethyl)allyl)oxy)(tert-butyl)dimethylsilane (30.0 g, 113 mmol) dropwise with constant stirring at 25 °C. After 90 min of stirring at 25 °C, the reaction was then diluted with hexanes (200 mL) and quenched with saturated NH 4 Cl (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give tert-butyldimethyl((2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)allyl)oxy)silane (Int-38c). 1< H NMR (500MHz, CDCl 3 ) δ 5.00 (d, J=1.8 Hz, 1H), 4.81 (d, J=1.7 Hz, 1H), 4.07 (s, 2H), 1.67 (s, 2H), 1.24 (s, 12H), 0.91 (s, 9H), 0.06 (s, 6H).Step D: 4-chloro-2-isopropyl-3-nitropyridine (Int-38d)

[0298] To a stirred solution 4-chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10a, 6.00 g, 30.2 mmol) in ethanol (100 mL) and toluene (20 mL) was added tris(triphenylphosphine)rhodium(I) chloride (2.80 g, 3.02 mmol) under nitrogen atmosphere, and the mixture was degassed and purged with hydrogen for three times. The resulting mixture was stirred at 50 °C for 6 h under (Pressure: 50 psi) hydrogen. The reaction mixture was concentrated in vacuum, and the residue was purified by flash silica gel chromatography (eluent of 0~8% EtOAc / Pet. ether gradient) to give 4-chloro-2-isopropyl-3-nitropyridine (Int-38d). 1< H NMR (400MHz, CDCl 3 ) δ 8.59 (d, J=5.1 Hz, 1H), 7.33 (d, J=5.1 Hz, 1H), 3.12 - 3.01 (m, 1H), 1.31 (d, J=6.7 Hz, 6H).Step E: 4-(2-(((tert-butyldimethylsilyl)oxy)methyl)allyl)-2-isopropyl-3-nitropyridine (Int-38e)

[0299] To a stirred solution of 4-chloro-2-isopropyl-3-nitropyridine (4.90 g, 24.4 mmol) in dioxane (100 mL) was added tert-butyldimethyl((2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)allyl)oxy)silane (22.9 g, 73.3 mmol), Cs 2 CO 3 (16.3 mL, 48.8 mmol) (aq. 3 M) and RuPhos Pd G3 (1.90 g, 2.44 mmol) at 25 °C under N 2 atmosphere, and the mixture was stirred at 80 °C for 3 h under N 2 atmosphere. The reaction mixture was quenched with water (30 mL), and extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0~2% EtOAc / Pet. ether) to give 4-(2-(((tert-butyldimethylsilyl)oxy)methyl)allyl)-2-isopropyl-3-nitropyridine (Int-38e). 1< H NMR (500MHz, CDCl 3 ) δ 8.59 (d, J=4.9 Hz, 1H), 7.19 - 7.12 (m, 1H), 5.23 (s, 1H), 4.83 (d, J=1.2 Hz, 1H), 4.08 - 3.99 (m, 2H), 3.40 - 3.31 (m, 2H), 3.11 - 2.99 (m, 1H), 1.31 (d, J=6.7 Hz, 6H), 0.88 (s, 9H), 0.05 - 0.02 (m, 6H).Step F: 4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-2-isopropyl-3-nitropyridine (Int-38f)

[0300] To a stirred solution of 4-(2-(((tert-butyldimethylsilyl)oxy)methyl)allyl)-2-isopropyl-3-nitropyridine (6.00 g, 17.1 mmol) and Pd(OAc) 2 (0.192 g, 0.856 mmol) in DCM (200 mL) was added dropwise diazomethane (1.03 L, 514 mmol) (~0.5 M Et 2 O solution) at -20 °C to -10 °C in 3 h. The mixture was filtered and the filtered cake was washed with dichloromethane (50 mL). The filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent of 0~10% EtOAc / Pet. ether) to give 4-((1-(((tertbutyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-2-isopropyl-3-nitropyridine (Int-38f). 1< H NMR (400MHz, CDCl 3 ) δ 8.57 (d, J=5.1 Hz, 1H), 7.36 (d, J=5.1 Hz, 1H), 3.39 - 3.29 (m, 2H), 3.02 (td, J=6.7, 13.4 Hz, 1H), 2.77 - 2.67 (m, 2H), 1.30 (d, J=6.6 Hz, 6H), 0.86 (s, 9H), 0.55 - 0.49 (m, 2H), 0.48 - 0.43 (m, 2H), 0.00 - -0.05 (m, 6H).Step G: 4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-2-isopropylpyridin-3-amine (Int-38g)

[0301] To a stirred solution of 4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-2-isopropyl-3-nitropyridine (2.60 g, 7.13 mmol) in THF (30 mL) were added zinc powder (3.73 g, 57.1 mmol) and ammonium chloride (6.10 mL, saturated aqueous solution) in water (5 mL) at 0 °C, and the mixture was stirred at 20 °C for 2 h. The mixture was filtered and the filtered cake was washed with EtOAc (100 mL). The oganic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent of 0~20% EtOAc / Pet. ether) to give 4-((1-(((tertbutyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-2-isopropylpyridin-3-amine (Int-38g). 1< H NMR (400MHz, CDCl 3 ) δ 7.92 (d, J=4.9 Hz, 1H), 6.75 (d, J=4.9 Hz, 1H), 4.23 - 4.08 (s, 2H), 3.37 (s, 2H), 3.06 (spt, J=6.7 Hz, 1H), 2.71 (s, 2H), 0.97 (s, 9H), 0.91 - 0.82 (m, 6H), 0.38 (br d, J=3.4 Hz, 4H), 0.03 (s, 6H).Step H: (1-((3-amino-2-chloropyridin-4-yl)ethynyl)cyclopropyl)methanol (Int-38h)

[0302] To a flask containing 4-bromo-2-chloropyridin-3-amine (0.45 g, 2.2 mmol) in TEA (5.4 mL, 39 mmol) was added (1-ethynylcyclopropyl)methanol (0.25 g, 2.6 mmol), copper(I) iodide (21 mg, 0.11 mmol) and bis(triphenylphosphine)palladium(II) dichloride (29 mg, 0.043 mmol). The flask was purged with nitrogen and then heated to 75°C for three hours. After 3 hours, the mixture was allowed to cool to room temperature and then more (1-ethynylcyclopropyl)methanol (98 mg, 1.02 mmol) was added. The mixture was then heated to 75°C for 1 hour. After 1 hour, the mixture was allowed to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and brine were added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes and a 3:1 mixture of ethyl acetate:ethanol) to afford (1-((3-amino-2-chloropyridin-4-yl)ethynyl)cyclopropyl)methanol (Int-38h). MS (ESI) m / z 223 [M+H] +< Step I: 4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)ethynyl)-2-chloropyridin-3-amine (Int-38i)

[0303] A flask containg (1-((3-amino-2-chloropyridin-4-yl)ethynyl)cyclopropyl)methanol (Int-38h, 0.38g, 1.7 mmol) in DCM (5.0 mL) and DMF (0.50 mL) was cooled to 0°C. Tert-butylchlorodimethylsilane (0.34 g, 2.2 mmol) and imidazole (0.35 g, 5.2 mmol) were added, the mixture was allowed to warm to room temperature and was then stirred for 3 hours. After 3 hours, the mixture was concentrated under reduced pressure. Ethyl acetate and brine were added. The organic layer was separated, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate gradient in hexanes) to afford 4-((1-(((tertbutyldimethylsilyl)oxy)methyl)cyclopropyl)ethynyl)-2-chloropyridin-3-amine (Int-38i). MS (ESI) m / z 337 [M+H] +< Step J: 4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)ethynyl)-2-(prop-1-en-2-yl)pyridin-3-amine (Int-38j)

[0304] To a vial containing 4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)ethynyl)-2-chloropyridin-3-amine (Int-38i, 0.32 g, 0.96 mmol), potassium isopropenyltrifluoroborate (0.17 g, 1.1 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (78 mg, 0.096 mmol) and potassium carbonate (0.26 g, 1.9 mmol) was added dioxane (1.0 mL) and water (0.15 mL). The vial was purged with nitrogen and then heated to 90°C for 3 hours. After 3 hours, the mixture was allowed to cool to room temperature. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes and a 3:1 mixture of ethyl acetate:ethanol) to afford 4-((1-(((tertbutyldimethylsilyl)oxy)methyl)cyclopropyl)ethynyl)-2-(prop-1-en-2-yl)pyridin-3-amine (Int-38j). MS (ESI) m / z 343 [M+H] +< Step K: 4-(2-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)ethyl)-2-isopropylpyridin-3-amine (Int-38k)

[0305] A flask containing 4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)ethynyl)-2-(prop-1-en-2-yl)pyridin-3-amine (Int-38j, 0.32 g, 0.94 mmmol) in methanol (10 mL) was purged with nitrogen. Palladium on carbon (10% catalyst loading, 32 mg, 0.030 mmol) was added. The flask was then evaculated and purged with hydrogen. The mixture was then stirred at room temperature for one hour. After one hour, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and was the resulting residue was purified by silica gel column chromatography (hexanes and a 3:1 mixture of ethyl acetate:ethanol) to afford 4-(2-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)ethyl)-2-isopropylpyridin-3-amine (Int-38k). MS (ESI) m / z 349 [M+H] +< Preparation of tert-butyl (2R,5S)-4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-39c)

[0306] Step A: N-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-39a)

[0307] 2,6-Dichloro-5-fluoronicotinamide (500 mg, 2.39 mmol) was added in a 8 mL vial. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. THF (2.4 mL) was added into the reaction vessel to dissolve the starting material. A 2 M solution of oxalyl dichloride (1.44 mL, 2.87 mmol) was added dropwise into the reaction vessel and the resulting mixture was heated at 75 °C for 1 h. The intermediate solution was allowed to cool down to room temperature. The cooled intermediate solution was concentrated to half of its volume. THF (200 µL) was added into the reaction vessel and the resulting mixture was cooled down to 0 °C. In a separate 4 mL vial, 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-amine (Int-10f, 743 mg, 2.39 mmol) was dissolved in THF (200 µL). The amine solution was added dropwise into the reaction vessel and the resulting mixture was stirred for 1h at 0°C. The product mixture was warmed up to room temperature. The reaction mixture was quenched with 2 mL of 1:1 mixture of saturated sodium chloride aqueous solution and ammonium chloride aqueous solution. The mixture was extracted three times with ethyl acetate (3 × 20 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography eluting with 5% (ethyl acetate:ethanol, 3:1, v / v)-dichloromethane to 50% (ethyl acetate:ethanol, 3:1, v / v)-dichloromethane to afford N-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-39a). MS (ESI) m / z 545 [M+H] +< Step B: 1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-39b-1)

[0308] N-((4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (830 mg, 1.52 mmol) was added into a 20 mL vial. The reaction vessel was evacuated and backfilled with nitrogen three times. THF (3.0 mL) was added into the reaction vessel. The resulting mixture was cooled down to 0 °C. Potassium bis(trimethylsilyl)amide (3.04 mL, 3.04 mmol, 1 M in THF) was added dropwise into the reaction vessel. The resulting mixture was stirred for 1 h at 0 °C. The product mixture was quenched with saturated ammonium bicarbonate aqueous solution (2 mL). The resulting mixture was extracted three times with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography eluting with hexanes to to 66% (ethyl acetate-ethanol = 3:1 v / v)-hexanes. The racemic material was resolved by SFC Column C , Condition: MeOH w / 0.05% diethylamine to provide Peak 1 1-(4-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-39b-1) . MS (ESI) m / z: 509 [M+H] +< .Step C: tert-butyl (2R,5S)-4-(1-(4-(2-((tert-bulyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-39c-1)

[0309] 1-(4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-39b-1, 630 mg, 1.24 mmol) was added into a 20 mL vial. The reaction vessel was evacuated and backfilled with nitrogen three times. Acetonitrile (2.5 mL), N-ethyl-N-isopropylpropan-2-amine (330 µL, 1.86 mmol) and phosphoryl trichloride (150 µL, 1.601 mmol) were added into the reaction vessel and the resulting mixture was heated at 80 °C for 1 h. The mixture was concentrated to dryness. The residue obtained was dissolved in acetonitrile (1.3 mL) in a 20 mL vial. N-Ethyl-N-isopropylpropan-2-amine (341 µL, 1.91 mmol) and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (205 mg, 0.956 mmol) were added into the reaction vessel. The resulting mixture was stirred for 1 h at 24 °C. The product mixture was diluted with ethyl acetate (100 mL). The mixture was washed three times with saturated sodium bicarbonate aqueous solution (3 × 10 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography eluting with hexanes to 66% (ethyl acetate-ethanol = 3:1 v / v)-hexanes to afford tert-butyl (2R,5S)-4-(1-(4-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-39c-1). MS (ESI) m / z 706 [M+H] +< .

[0310] Intermediates Int-40-1 to Int-48 were prepared in a similar manner to Intermediate Int-39c-1, using the appropriate starting materials. Intermedi ate No. Structure Compound Name [M+H] +< Found SFC Conditions and Peak Fraction Isolated Int-40-1 tert-Butyl (2R,5S)-4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)et hoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate709Column I MeOH w / 0.1% NH 4 OH 80% CO 2 Peak 1Int-41-1 tert-Butyl (2R,5S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-2-isopropylpyridin-3-yl)-6,7-dichloro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate771Column I MeOH w / 0.1% NH 4 OH 90% CO 2 Peak 1Int-42-1 tert-Butyl (2R,5S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)pr opyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate703Column N MeOH w / 0.1% NH 4 OH 70% CO 2 Peak 1Int-43-1 tert-Butyl (S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)pr opyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate689Column N MeOH w / 0.1% NH 4 OH 70% CO 2 Peak 1Int-44 tert-Butyl (2R,5S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)pr opyl)-6-isopropylpyrimidin-5-yl)-6,7-dichloro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate722This intermediate was not resolved.Int-45 tert-butyl (2R,5S)-4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)et hyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate689This intermediate was not resolved.Int-46 tert-butyl (2R,5S)-4-(1-(4-(4-((tert-butyldimethylsilyl)oxy)b utan-2-yl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate718Atropisomers were not resolved. *Int-47 tert-butyl (2R,5S)-4-(1-(4-(4-((tert-butyldimethylsilyl)oxy)b utan-2-yl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2, 5-dimethylpiperazine-1-carboxylate718Atropisomers were not resolved. *Int-48 tert-butyl (2R,5S)-4-(1-(4-((1-(((tert-butyldimethylsilyl)oxy)m ethyl)cyclopropyl)methyl )-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2, 5-dimethylpiperazine-1-carboxylate730This intermediate was not resolved.*Int-46 and Int-47 resulted from the resolution of the starting substituted aminopyridine and carrying forth of the resolved enantiomers through Steps A-C. Preparation of 17,20-difluoro-6-(propan-2-yl)-11,12-dihydro-2H,10H-1,18-ethenopyrido[4,3-e]pyrimido[1,6-g][1,7,9]benzoxadiazacyclododecine-2,4(3H)-dione (Int-49d)

[0311] Step A: (3S)-tert-butyl 4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-dlpyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-49a-1)

[0312] To a stirred solution of (S)-tert-butyl 4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-43-1, 10.5 g, 15.2 mmol), potassium acetate (7.47 g, 76.0 mmol) and 1,1'-bis(diphenyl phosphino ferrocene-palladium(II)dichloride dichloromethane complex (0.62 g, 0.76 mmol) in 1,4-dioxane (100 mL) and water (20 mL) were added 3-fluoro-2-(trifluoro-14-boraneyl)phenol, potassium salt (4.98 g, 22.8 mmol) in 1,4-dioxane (0.2 mL) / water (0.1 mL) at 90 °C under a N 2 atmosphere, and the mixture was stirred at 90 °C for 2 h under a N 2 atmosphere. The reaction mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluent of 0~50% EtOAc / Pet. ether to give (3S)-tert-butyl 4-(1-(4-(3-((tertbutyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-49a-1). MS (ESI) m / z 765 [M+H] +< .Step B: (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-(3-hydroxypropyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-49b-1)

[0313] To a stirred solution of (3S)-tert-butyl 4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3methylpiperazine-1-carboxylate (Int-49a-1, 8.90 g, 11.6 mmol) in THF (100 mL) was added TBAF (34.9 mL, 34.9 mmol) (1 M in THF), and the mixture was stirred at 20 °C for 16 h under a N 2 atmosphere. The residue was purified by flash silica gel chromatography using an eluent of 0~8% MeOH / DCM to give (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-(3-hydroxypropyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-49b-1). MS (ESI) m / z 651 [M+H] +< .Step C: Int-49c-1

[0314] To a stirred solution of (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-(3-hydroxypropyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-49b-1, 7.10 g, 10.9 mmol) in THF (350 mL) was added triphenylphosphine (7.15 g, 27.3 mmol), and the mixture was stirred at 65 °C under N 2 atmosphere, and then DIAD (4.24 mL, 21.8 mmol) was added. The reaction was stirred at 65 °C for 10 min. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography eluent of 0~10% CH 2 Cl 2 / MeOH to give Int-49c-1. MS (ESI) m / z 633 [M+H] +< .Step D: 17,20-difluoro-6-(propan-2-yl)-11,12-dihydro-2H,10H-1,18-ethenopyrido[4,3-e]pyrimido[1,6-g][1,7,9]benzoxadiazacyclododecine-2,4(3H)-dione (Int-49d-1)

[0315] Int-49c-1 (3.50 g, 5.53 mmol) was dissolved in MeOH (50 mL). Then KOH (0.93 g, 16.6 mmol) was added to the mixture and heated to 40 °C. The reaction mixture was stirred at 40 °C for 15 h. The mixture was cooled to room temperature, quenched with 100 mL of saturated ammonium chloride, diluted with 150 mL of EtOAc, the combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography eluent of 0~60% EtOAc / Pet. ether to give 17,20-difluoro-6-(propan-2-yl)-11,12-dihydro-2H,10H-1,18-ethenopyrido[4,3-e]pyrimido[1,6-g][1,7,9]benzoxadiazacyclododecine-2,4(3H)-dione (Int-49d-1). MS (ESI) m / z 451 [M+H] +< .Example 50: (5aS a ,17aR a )-20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-dihydro-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one

[0316] Step A: N-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)carbamoyl)-2,5,6-trichloronicotinamide (Int-50a)

[0317] 2,5,6-Trichloronicotinamide (1.09 g, 4.83 mmol) was added in a 100 mL round-bottomed flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. THF (4.83 mL) was added into the reaction vessel to dissolve the starting material. A 2 M solution of oxalyl dichloride (2.90 mL, 5.80 mmol) was added dropwise into the reaction vessel, and the resulting mixture was heated at 75 °C for 1 h. The intermediate solution was allowed to cool down to room temnerature The cooled intermediate solution was concentrated to dryness. The residue obtained was dried under vacuum for 1 h. The reaction vessel was backfilled with a balloon of nitrogen, and THF (10 mL) was added into the reaction vessel. The resulting mixture was cooled down to 0 °C. In a separate 25 mL flask, 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-amine (Int-10f, 1.50 g, 4.83 mmol) was dissolved in THF (9.3 mL). The amine solution was added dropwise into the reaction vessel, and the resulting mixture was stirred for 1 h at 0°C. The product mixture was carefully quenched by addition of pH 7 buffer (10 mL). The quenched product mixture was extracted three times with ethyl acetate (3 × 20 mL). The organic layers were combined, and the combined organic layers were dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with a silica gel column, eluting with 5% (ethyl acetate:ethanol, 3:1, v / v)-dichloromethane, initially, grading to 50% (ethyl acetate:ethanol, 3:1, v / v)-dichloromethane, linear gradient, to afford N-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)carbamoyl)-2,5,6-trichloronicotinamide (Int-50a). MS (ESI) m / z 563 [M+H] +< .Step B: 5aS a -1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-6,7-dichloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-50b-1)

[0318] N-((4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)carbamoyl)-2,5,6-trichloronicotinamide (Int-50a, 2.00 g, 3.56 mmol) was added into a 100 mL flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. THF (7.1 mL) was added into the reaction vessel. The resulting mixture was cooled down to 0 °C. A 1 M THF solution of potassium bis(trimethylsilyl)amide (7.12 mL, 7.12 mmol) was added dropwise into the reaction vessel. The resulting mixture was stirred for 30 min at 0 °C. The product mixture was quenched with saturated ammonium bicarbonate aqueous solution (25 mL). The resulting mixture was extracted three times with ethyl acetate (3 × 100 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with a silica gel column, eluting with hexanes initially, grading to 66% (ethyl acetate-ethanol = 3:1 v / v)-hexanes, linear gradient, to afford 1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-6,7-dichloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The racemic material was resolved by SFC Column K, condition: MeOH w / 0.1% NH 4 OH to provide Peak 1 5aS a -1-(4-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-6,7-dichloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-50b-1) as a single atropisomer. 1< H-NMR (400 MHz, CDCl 3 ) δ: 8.62 (d, J = 5.6 Hz, 1H), 8.50 (s, 1 H), 6.87 (d, J = 6.0 Hz, 1H), 4.06-4.09 (m, 2H), 3.75-3.79 (m, 2H), 2.74-2.81 (m, 1H), 1.23 (d, J = 5.2 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 0.76 (s, 9H), 0.07 (s, 3H), 0.11 (s, 3H).Step C: tert-butyl (2R,5S)-4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-6,7-dichloro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-50c-1)

[0319] 5aS a -1-(4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-6,7-dichloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-50b-1, 800 mg, 1.52 mmol) was added in a 20 mL vial. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. Acetonitrile (3.0 mL), N-ethyl-N-isopropylpropan-2-amine (407 µL, 2.28 mmol), and phosphoryl trichloride (184 µL, 1.97 mmol) were added into the reaction vessel, and the resulting mixture was heated to 80 °C for 1 h. The product mixture was cooled down to room temperature. The cooled product mixture was concentrated to dryness. The residue was dissolved in acetonitrile (3.04 mL) in a 20 mL vial. N-ethyl-N-isopropylpropan-2-amine (812 µL, 4.56 mmol) and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (489 mg, 2.28 mmol) were added into the reaction vessel. The resulting mixture was stirred for 1h at 24 °C. The product mixture was diluted with ethyl acetate (100 mL). The diluted product mixture was washed three times with saturated sodium bicarbonate aqueous solution (3 × 10 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with a silica gel column, eluting with hexanes initially, grading to 66% (ethyl acetate-ethanol = 3:1 v / v)-hexanes, linear gradient, to afford tert-butyl (2R,5S)-4-(1-(4-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-6,7-dichloro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-50c-1). 1< H-NMR (400 MHz, DMSO-d 6 ) δ: 8.48 (s, 1H), 8.43 (s, 1 H), 7.07 (d, J = 5.6 Hz, 1H), 4.75 (s, 1H), 4.34 (s, 1H), 4.00-4.04 (m, 3H), 3.95 (s, 1H), 3.64-3.67 (m, 3H), 2.63-2.69 (m, 1H), 1.44 (s, 9H), 1.29 (d, J =6.4 Hz, 3H), 1.13 (d, J = 4.4 Hz, 3H), 1.07 (d, J =6.8 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H), 0.68 (s, 9H), 0.17 (s, 6H).Step D: (2R,5S)-tert-butyl 4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-6-chloro-7-(3,6-difluoro-2-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-50d-1)

[0320] To a stirred solution of tert-butyl (2R,5S)-4-(1-(4-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-6,7-dichloro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-50c-1, 12.0 g, 16.6 mmol) in dioxane (200 mL) and water (20 mL) was added potassium acetate (6.53 g, 66.5mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.35 g, 1.66 mmol) at 25 °C, and the mixture was stirred at 90 °C for 5 min under a N 2 atmosphere. Then potassium (3,6-difluoro-2-hydroxyphenyl)trifluoroborate (Int-23c, 6.50 g, 27.5 mmol) in 1,4-dioxane (20 mL) and water (20 mL) was added to the above mixture, and the mixture was stirred at 90 °C for 30 min. The reaction mixture was quenched with brine (50 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluent of 0~100% EtOAc / Pet. ether to give (2R,5S)-tert-butyl 4-(1-(4-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-6-chloro-7-(3,6-difluoro-2-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-50d-1). 1< H NMR (400MHz, Methanol-d 4 ) δ 8.44 - 8.32 (m, 2H), 7.10 (dt, J=5.3, 9.7 Hz, 1H), 6.99 (d, J=5.9 Hz, 1H), 6.55 (dt, J=3.4, 8.8 Hz, 1H), 4.92 - 4.86 (m, 1H), 4.59 - 4.38 (m, 2H), 4.09 - 4.04 (m, 1H), 4.00 - 3.93 (m, 1H), 3.91 - 3.79 (m, 2H), 3.77 - 3.69 (m, 1H), 3.68 - 3.61 (m, 1H), 3.59 - 3.39 (m, 1H), 2.93 (td, J=6.5, 13.3 Hz, 1H), 1.57 - 1.49 (m, 12H), 1.36 (d, J=6.8 Hz, 3H), 1.23 - 1.20 (m, 3H), 1.07 (d, J=6.6 Hz, 3H), 0.78 (s, 9H), -0.11 (d, J=5.6 Hz, 6H).Step E: (2R,5S)-tert-butyl 4-(6-chloro-7-(3,6-difluoro-2-hydroxyphenyl)-1-(4-(2-hydroxyethoxy)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-50e-1)

[0321] To a stirred solution of (2R,5S)-tert-butyl 4-(1-(4-(2-((tertbutyldimethylsilyl)oxy)ethoxy)-2-isopropylpyridin-3-yl)-6-chloro-7-(3,6-difluoro-2-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-50d-1, 17.0 g, 20.9 mmol) in DCM (200 mL) was added triethylamine trihydrofluoride (10.2 mL, 62.5 mmol) at 20 °C, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with 300 mL of DCM, quenched with aqueous sodium hydrogen carbonate (saturated, 200 mL), and extracted with dichloromethane (200 mL). The combined organic layers were washed with brine (200 mL), dried over Na 2 SO 4 , and filtered, and the solvent was evaporated under reduced pressure to give (2R,5S)-tert-butyl 4-(6-chloro-7-(3,6-difluoro-2-hydroxyphenyl)-1-(4-(2-hydroxyethoxy)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-50e-1). 1< H NMR (400MHz, Methanol-d 4 ) δ 8.45 - 8.33 (m, 2H), 7.06 (dt, J=5.4, 9.7 Hz, 1H), 7.00 (d, J=5.9 Hz, 1H), 6.58 - 6.39 (m, 1H), 4.97 - 4.88 (m, 1H), 4.55 - 4.31 (m, 2H), 4.17 - 4.08 (m, 1H), 3.98 (td, J=4.9, 10.1 Hz, 1H), 3.94 - 3.79 (m, 2H), 3.66 - 3.46 (m, 3H), 2.98 - 2.84 (m, 1H), 1.51 (s, 12H), 1.31 (br d, J=6.4 Hz, 3H), 1.23 - 1.18 (m, 3H), 1.07 (d, J=6.8 Hz, 3H).Step F: Int-50f-1

[0322] To a stirred solution of (2R,5S)-tert-butyl 4-(6-chloro-7-(3,6-difluoro-2-hydroxyphenyl)-1-(4-(2-hydroxyethoxy)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-50e-1, 14.0 g, 20.0 mmol) and triphenylphosphine (10.5 g, 39.9 mmol) in DCM (750 mL) was added dropwise DIAD (8.07 g, 39.9 mmol) at 40 °C. The resulting mixture was stirred at 40 °C for 30 min under nitrogen atmosphere. The reaction mixture was concentrated in vacuo, and the residue was purified by flash silica gel chromatography eluent of 0~0.5% MeOH / DCM to give Int-50f-1. 1< H NMR (400MHz, Methanol-d 4 ) δ 8.41 (d, J=5.9 Hz, 1H), 8.33 (s, 1H), 7.30 (ddd, J=5.1, 9.4, 11.0 Hz, 1H), 7.05 (d, J=5.9 Hz, 1H), 6.95 (dt, J=3.5, 8.8 Hz, 1H), 4.83 - 4.60 (m, 4H), 4.59 - 4.45 (m, 1H), 4.39 - 4.28 (m, 1H), 4.17 - 4.08 (m, 1H), 3.87 (d, J=13.7 Hz, 1H), 3.70 - 3.61 (m, 1H), 3.51 - 3.33 (m, 1H), 3.10 (td, J=6.9, 13.5 Hz, 1H), 1.60 (br d, J=5.9 Hz, 3H), 1.52 (br d, J=5.5 Hz, 9H), 1.40 (br d, J=6.3 Hz, 3H), 1.29 (d, J=7.0 Hz, 3H), 1.05 (d, J=7.0 Hz, 3H).Step G: Int-50g-1

[0323] To a solution of Int-50f- 1 (11.0 g, 16.1 mmol) in CH 2 Cl 2 (100 mL) was added TFA (50 mL), and the mixture was stirred at 20 °C for 30 min. The reaction mixture was concentrated in vacuo to afford Int-50g-1. MS (ESI) m / z 583 [M+H] +< .Step H: (5aS a ,17aR a )-20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-dihydro-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one (Ex. 50)

[0324] To a stirred solution of (Int-50g-1, 16.4 g, 20.5 mmol) and DIEA (35.9 mL, 205 mmol) in CH 2 Cl 2 (200 mL) was added dropwise acryloyl chloride (2.42 g, 26.7 mmol), and the mixture was stirred at 20 °C for 30 min. The reaction mixture was washed with water (50 mL), and the aqueous layer was extracted with DCM (100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography using an eluent of 0~10% MeOH / DCM, followed by preparative HPLC (Column: YMC Triart C18 250 mm * 50 mm, 7 µm; water (0.04% NH 3 H 2 O+10 mM NH 4 HCO 3 )-MeOH Begin B 25, End B 60; Gradient Time (min): 20; 100% B Hold Time (min): 3; FlowRate (mL / min) 110 . The product was further purified by preparative SFC Column E, Condition: 0.1% NH 3· H 2 O MeOH, Begin B 25%, End B 25%; FlowRate (mL / min): 200; Injections: 210") to give (5aS a ,17aR a )-20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-dihydro-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one (Ex. 50) as a single atropisomer. MS (ESI) m / z 637 [M+H] +< . 1< H NMR (500MHz, Methanol-d 4 ) δ 8.41 (d, J=5.8 Hz, 1H), 8.33 (d, J=17.9 Hz, 1H), 7.30 (ddd, J=5.1, 9.4, 10.8 Hz, 1H), 7.05 (d, J=6.0 Hz, 1H), 6.95 (dt, J=3.4, 8.8 Hz, 1H), 6.92 - 6.74 (m, 1H), 6.34 - 6.25 (m, 1H), 5.86 - 5.79 (m, 1H), 5.06 - 4.88 (m, 1H), 4.83 (br d, J=10.8 Hz, 1H), 4.78 - 4.27 (m, 5H), 4.18 - 4.09 (m, 1H), 3.95 - 3.72 (m, 1H), 3.66 (br d, J=14.0 Hz, 1H), 3.10 (qd, J=6.8, 10.5 Hz, 1H), 1.59 (br dd, J=7.0, 9.2 Hz, 3H), 1.47 (dd, J=6.7, 19.2 Hz, 3H), 1.29 (d, J=6.7 Hz, 3H), 1.05 (dd, J=3.4, 6.8 Hz, 3H).Example 51-1: (5aS a ,17aR a )-20-Chloro-2-r(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-di[ 2< H)hydro](11,12- 2< H 2 )-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one

[0325] Step A: N-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)carbamoyl)-2,5,6-trichloronicotinamide (Int-51a)

[0326] 2,5,6-Trichloronicotinamide (1.72 g, 7.63 mmol) was added into a 100 mL round-bottomed flask equipped with a reflux condensor. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. THF (7.6 mL) was added into the reaction vessel to dissolve the starting material. A 2 M solution of oxalyl dichloride (4.58 mL, 9.16 mmol) was added dropwise into the reaction vessel and the resulting mixture was heated at 75 °C for 1 h. The intermediate solution was allowed to cool down to room temperature. The cooled intermediate solution was concentrated to half of its volume. THF (3.8 mL) was added into the reaction vessel and the resulting mixture was cooled down to 0 °C. In a separate 20 mL vial, 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-amine (Int-35c, 2.40 g, 7.63 mmol) was dissolved in THF (3.8 mL). The amine solution was added dropwise into the reaction vessel and the resulting mixture was stirred for 1 h at 0°C. The product mixture was warmed up to room temperature. The warmed product mixture was quenched with 20 mL of pH 7 solution. The quenched product mixture was extracted three times with ethyl acetate (3 × 20 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with a silica gel column, eluting with 5% (ethyl acetate:ethanol, 3:1, v / v)-dichloromethane , initially, grading to 50% (ethyl acetate:ethanol, 3:1, v / v)-dichloromethane, linear gradient, to afford N-((4-(2-((tertbutyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)carbamoyl)-2,5,6-trichloronicotinamide (Int-51a). MS (ESI) m / z 567 [M+H] +< .Step B: 1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)-6,7-dichloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-51b)

[0327] N-((4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)carbamoyl)-2,5,6-trichloronicotinamide (3.35 g, 5.92 mmol) was added into a 100 mL flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. THF (11.8 mL) was added into the reaction vessel. The resulting mixture was cooled down to 0 °C. A 1 M THF solution of potassium bis(trimethylsilyl)amide (11.8 mL, 11.8 mmol) was added dropwise into the reaction vessel. The resulting mixture was stirred for 30 min at 0 °C . The product mixture was quenched with saturated ammonium bicarbonate aqueous solution (25 mL). The resulting mixture was extracted three times with ethyl acetate (3 × 100 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with a silica gel column, eluting with hexanes initially, grading to 66% (ethyl acetate-ethanol = 3:1 v / v)-hexanes, linear gradient, to afford 1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)-6,7-dichloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-51b). MS (ESI) m / z 529 [M+H] +< .Step C: tert-butyl (2R,5S)-4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)-6,7-dichloro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-51c)

[0328] 1-(4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)-6,7-dichloropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.95 g, 5.57 mmol) was added into a 20 mL vial. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. Acetonitrile (11.1 mL), N-ethyl-N-isopropylpropan-2-amine (1.49 mL, 8.36 mmol), and phosphoryl trichloride (0.67 mL, 7.2 mmol) were added into the reaction vessel and the resulting mixture was heated to 80 °C for 1 h. The resulting mixture was cooled down to 0 °C. N-Ethyl-N-isopropylpropan-2-amine (2.98 mL, 16.7 mmol) and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (1.79 g, 8.36 mmol) were added into the reaction mixture and the resulting mixture was stirred for 30 min at 0 °C. The product mixture was diluted with ethyl acetate (200 mL). The diluted product mixture was washed three times with saturated sodium bicarbonate aqueous solution (3 × 50 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with 80-g silica gel column, eluting with DCM initially, grading to 50% ethyl acetate:ethanol = 3:1 - DCM, linear gradient, to afford tert-butyl (2R,5S)-4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)-6,7-dichloro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-51c). MS (ESI) m / z 725 [M+H] +< .Step D: tert-butyl (2R,5S)-4-(6-chloro-7-(3,6-difluoro-2-hydroxyphenyl)-1-(4-(2-hydroxyethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-51d)

[0329] tert-Butyl (2R,5S)-4-(1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)-6,7-dichloro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.00 g, 1.38 mmol), potassium (3,6-difluoro-2-hydroxyphenyl)trifluoroborate (Int-23c, 0.421 g, 1.79 mmol), potassium acetate (0.540 g, 5.51 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.113 g, 0.138 mmol) were added to a 20 mL scintillation vial equipped with magnetic stir bar, degassed under nitrogen, charged with dioxane (5.9 mL) / water (0.98 mL), degassed three times under nitrogen and heated to 90 °C for 1h. The reaction was cooled to 24 °C, quenched with 10 mL 1:1 water / saturated sodium bicarbonate, extracted 2 × 25 mL EtOAc, washed with brine and concentrated in vacuo. The crude residue was taken up in 10 mL THF, charged with 1 M TBAF solution in THF (3.44 mL, 3.44 mmol) and allowed to stir for 1.5 h at 24 °C. The reaction was quenched with saturated NH 4 Cl, extracted once with EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified on silica gel 0-100% 3:1 EtOAc / EtOH / hexanes to provide tert-butyl (2R,5S)-4-(6-chloro-7-(3,6-difluoro-2-hydroxyphenyl)-1-(4-(2-hydroxyethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-51d). MS (ESI) m / z 705 [M+H] +< .Step E: Int-51e

[0330] tert-Butyl (2R,5S)-4-(6-chloro-7-(3,6-difluoro-2-hydroxyphenyl)-1-(4-(2-hydroxyethoxy-1,1,2,2-d 4 )-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (802 mg, 1.14 mmol) was added in a 100 mL flask equipped with a reflux condensor. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. Toluene (45.5 mL) and cyanomethylenetributylphosphorane (1.0 M in toluene, 2.3 mL, 2.3 mmol) were added into the reaction vessel. The resulting mixture was heated to 60 °C for 24 h. The product mixture was concentrated to dryness. The residue obtained was purified by flash column chromatography with a silica gel column, eluting with hexanes, initially, grading to 100% ethyl acetate:ethanol 3:1, linear gradient to afford Int-51e. MS (ESI) m / z 687 [M+H] +< .Step F: Int-51f

[0331] Int-51e (2.21 g, 0.322 mmol) was dissolved in DCM (3.2 mL) under nitrogen. Trifluoroacetic acid (1.23 mL, 16.1 mmol) was added into the reaction vessel. The resulting mixture was stirred for 1 h and the product mixture was concentrated to dryness. The residue obtained containing Int-51f was used directly in the next step without purification.Step G: (5aS a ,17aR a )-20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-di[( 2< H)hydro](11,12- 2< H 2 )-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one (Ex. 51-1)

[0332] Int-51f (299 mg, 322 µmol) was added into a 20 mL vial. The resulting mixture was dissolved with DCM (1.6 mL). The solution obtained was cooled down to 0 °C. N-Ethyl-N-isopropylpropan-2-amine (287 µL, 1.61 mmol) and acryloyl chloride (39 µL, 0.48 mmol) were added into the reaction vessel. The reaction mixture was stirred for 1 h at 0 °C. The product mixture was quenched with saturated ammonium bicarbonate aqueous solution (2 mL). The resulting mixture was extracted three times with ethyl acetate (3 × 20 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The racemic material was resolved by SFC Column G, Condition: MeOH w / 0.25% DMEA to provide Peak 1 (5aS a ,17aR a )-20-Chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-di[( 2< H)hydro](11,12- 2< H 2 )-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one (Ex. 51-1) as a single atropisomer. MS (ESI) m / z 641 [M+H] +< . 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.41 (d, J = 5.7 Hz, 1H), 8.23 (d, J = 19.9 Hz, 1H), 7.50 (ddd, J = 11.1, 9.3, 5.2 Hz, 1H), 7.34 - 7.09 (m, 2H), 6.84 (ddd, J = 50.1, 16.7, 10.5 Hz, 1H), 6.19 (ddd, J = 16.8, 8.1, 2.4 Hz, 1H), 5.76 (ddd, J = 10.4, 4.9, 2.3 Hz, 1H), 4.88 (s, 0.5H), 4.74 (s, 0.5H), 4.69 - 4.49 (m, 2H), 4.21 (d, J = 13.8 Hz, 0.5H), 3.85 (d, J = 14.1 Hz, 0.5H), 3.77 - 3.58 (m, 0.5H), 3.52 (t, J = 15.8 Hz, 1H), 3.25 (dd, J = 13.9, 3.9 Hz, 0.5), 3.05 (q, J = 6.4 Hz, 1H), 1.46 (t, J = 7.8 Hz, 3H), 1.40 - 1.32 (m, 3H), 1.17 (dd, J = 6.8, 2.0 Hz, 3H), 0.98 (dd, J = 6.7, 4.1 Hz, 3H).Example 52: (5aR a ,18aR a )-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18,21-tetrafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one

[0333] Step A: 1-(benzyloxy)but-3-yn-2-ol (Int-52a)

[0334] 2-(Benzyloxy)acetaldehyde (6.20 g, 41.3 mmol) was added into a 250 mL round-bottomed flask. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. THF (103 mL) was added into the reaction vessel. The resulting mixture was cooled down to 0 °C. Ethynylmagnesium bromide (0.50 M in THF, 100 mL, 49.5 mmol) was added dropwise and stirred for 2 h at 0 °C. The product mixture was quenched with saturated ammonium chloride aqueous solution (30 mL). The quenched product mixture was extracted three times with ethyl acetate (3 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with a silica gel column, eluting with hexanes initially, grading to 30% ethyl acetate-hexanes, linear gradient, to afford 1-(benzyloxy)but-3-yn-2-ol. (Int-52a). 1< H NMR (500 MHz, CDCl 3 ): δ 7.41 - 7.28 (m, 5H), 4.69 - 4.58 (m, 2H), 3.67 (dd, J = 9.8, 3.6 Hz, 1H), 3.59 (dd, J = 9.8, 7.1 Hz, 1H), 2.46 (d, J = 2.2 Hz, 1H).Step B: 1-(benzyloxy)but-3-yn-2-one (Int-52b)

[0335] 1-(Benzyloxy)but-3-yn-2-ol (Int-52a, 7.10 g, 40.3 mmol) was dissolved in DCM (water saturated) (101 mL) in a 250 mL round bottomed flask. Dess-Martin periodinane (20.5 g, 48.4 mmol) was added in 5 equal portions into the reaction vessel. The resulting mixture was stirred for 30 min. The product mixture was diluted with ether (100 mL). The diluted product mixture was quenched with saturated sodium bicarbonate aqueous solution (50 mL) and saturated sodium thiosulfate aqueous solution (50 mL). The quenched mixture was extracted three times with ether (3 × 100 mL). The organic layers were, dried over sodium sulfate. The dried solution was, filtered, and the filtrate was concentrated to dryness. The residue obtained was purified twice by flash column chromatography with a silica gel column, eluting with hexanes initially, grading to 25% ethyl acetate-hexanes, linear gradient to afford 1-(benzyloxy)but-3-yn-2-one (Int-52b). 1< H NMR (500 MHz, CDCl 3 ): δ 7.54 - 7.30 (m, 5H), 4.67 (s, 2H), 4.27 (s, 2H), 3.34 (s, 1H).Step C: 2,2-difluorobut-3-yn-1-yl)oxy)methyl)benzene (Int-52c)

[0336] Diethylamino(difluoro)sulfanium tetrafluoroborate (13.0 g, 56.8 mmol) was added into a 100 mL plastic tube. Triethylamine trihydrofluoride (12.3 mL, 76.0 mmol) was added into the reaction vessel. The resulting mixture was stirred for 5 min. In a separate vial, 1-(benzyloxy)but-3-yn-2-one (Int-52b, 6.60 g, 37.9 mmol) was dissolved in DCM (30 mL). The starting material solution was added dropwise into the reaction mixture via a plastic pipette. The starting material vessel was rinsed twice with DCM (2 × 4 mL). The rinses were added into the reaction vessel. The resulting mixture was stirred for 16 h at 24 °C. The product mixture was cooled down to 0 °C. Saturated sodium bicarbonate aqueous solution (10 mL) was added into the reaction vessel. The resulting biphasic mixture was further quenched by dropwise transfer into a chilled (0 °C) supersaturated sodium bicarbonate solution (100 mL + 20 g solid). The resulting mixture was stirred for 30 min. The resulting mixture was extracted three times with ether (3 × 200 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography twice with a silica gel column, eluting with hexanes initially, grading to 20% ethyl acetate-hexanes, linear gradient to afford (((2,2-difluorobut-3-yn-1-yl)oxy)methyl)benzene (Int-52c). 1< H NMR (500 MHz, CDCl 3 ): δ 7.52 - 7.30 (m, 5H), 4.74 (s, 2H), 3.81 (t, J = 12.1 Hz, 2H), 2.85 (t, J = 5.1 Hz, 1H).Step D: potassium (E)-(4-(benzyloxy)-3,3-difluorobut-1-en-1-yl)trifluoroborate (Int-52d)

[0337] 2,5-Dimethylhexa-2,4-diene (26.0 mL, 182 mmol) was added into a 500 mL round-bottomed flask under nitrogen. THF (14.3 mL) was added into the reaction vessel and the resulting solution was cooled down to 0 °C. A 1 M solution of borane-THF adduct (83.0 mL, 83.0 mmol) in THF was added dropwise into the reaction vessel over 15 min to maintain reaction temperature below 5 °C. The resulting mixture was stirred for 3 h at 0 °C. In a separate vessel, (((2,2-difluorobut-3-yn-1- yl)oxy)methyl)benzene (Int-52c, 6.50 g, 33.1 mmol) was dissolved in THF (25 mL) under nitrogen. The starting material solution was added dropwise into the reaction vessel over 25 min to maintain reaction temperature below 5 °C. The vessel containing the starting material was rinsed with THF (2 × 5 mL) and the rinses were added dropwise into the reaction vessel. The cooling bath was removed, and the reaction was allowed to warm up to rt over 30 min. The resulting mixture was stirred for 3 h at rt. The resulting mixture was cooled back down to 0 °C and water (11.9 mL) was added dropwise into the reaction vessel maintaining the reaction temperature below 5 °C. The resulting mixture was allowed to warm up to rt over 30 min and the resulting mixture was stirred for 2 h at 24 °C. A 37% w / w aqueous solution of formaldehyde (29.6 mL, 398 mmol) was added dropwise into the reaction mixture. A slight exothermic event was observed. The resulting mixture was cooled with a water bath and stirred at 24 °C for 12 h. The resulting mixture was quenched with saturated sodium chloride aqueous solution (30 mL) The resulting mixture was transferred to a separatory funnel. The aqueous layer was extracted three times with ethyl acetate (3 × 50 mL). The organic layers were combined, and the combined organic layers were dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to dryness. The residue obtained was diluted with acetonitrile (143 mL). In a separate vessel, potassium fluoride (7.70 g, 133 mmol) was dissolved in water (11.0 mL). The potassium fluoride solution was added streamwise into the reaction vessel and the resulting mixture was stirred for 15 min, when no cloudiness was observed. In a separate vessel, L-(+)-tartaric acid (9.94 g, 66.3 mmol) was dissolved in tetrahydrofuran (51.0 mL). The resulting solution was transferred to an addition funnel. The tartaric acid solution was added dropwise into the reaction mixture over 20 min at 24 °C. The resulting mixture was stirred for 30 min at 24 °C. The resulting mixture was filtered, and the filter cake was washed thoroughly with acetonitrile (3 × 50 mL). The residue obtained was azeotroped three times with ether (3 × 200 mL). The residue obtained was diluted with ether (100 mL). The mixture was stirred vigorously and cooled down to 0 °C. Ether (200 mL) and hexanes (200 mL) were added into the mixture and the resulting mixture was stirred for 1 h at 0 °C. The precipitation was collected and the solid obtained was washed with 20% ether-hexanes (10 × 50 mL). The product was potassium (E)-(4-(benzyloxy)-3,3-difluorobut-1-en-1-yl)trifluoroborate. (Int-52d). 1< H NMR (500 MHz, DMSO-d 6 ): δ 7.40 - 7.26 (m, 5H), 5.97 (dq, J = 18.2, 3.1 Hz, 1H), 5.75 - 5.46 (m, 1H), 4.57 (s, 2H), 3.66 (t, J = 13.7 Hz, 2H).Step E: (E)-4-(4-(benzyloxy)-3,3-difluorobut-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-52e)

[0338] 4-Chloro-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-10a, 2.10 g, 10.6 mmol), potassium (E)-(4-(benzyloxy)-3,3-difluorobut-1-en-1-yl)trifluoroborate (Int-52d, 3.54 g, 11.6 mmol), and catacxium ®< A-Pd-G3 (0.385 g, 0.529 mmol) were added into a 3-neck 250 mL round-bottomed flask fitted with two septa and one reflux condenser. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. THF (35 mL) and a 1 M aqueous solution of potassium phosphate tribasic (21.2 mL, 21.2 mmol) was added into the reaction vessel. The resulting mixture was degassed twice and heated at 60 °C for 16 h. TLC analysis showed full conversion. The product mixture was cooled, diluted with ether (100 mL), and washed with saturated sodium chloride aqueous solution (50 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with a silica gel column, eluting with hexanes initially, grading to 20% ethyl acetate-hexanes, linear gradient to afford the desired product (E)-4-(4-(benzyloxy)-3,3-difluorobut-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-52e). 1< H NMR (500 MHz, Acetonitrile-d 3 ): δ 8.72 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 5.2 Hz, 1H), 7.44 - 7.26 (m, 5H), 6.89 (dt, J = 16.0, 2.6 Hz, 1H), 6.71 (dt, J = 16.1, 10.9 Hz, 1H), 5.50 - 5.30 (m, 1H), 5.17 (d, J = 1.0 Hz, 1H), 4.65 (s, 2H), 3.88 (t, J = 12.8 Hz, 2H), 2.19 (t, J = 1.2 Hz, 3H).Step F: 4-(4-(benzyloxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-amine (Int-52f)

[0339] (E)-4-(4-(Benzyloxy)-3,3-difluorobut-1-en-1-yl)-3-nitro-2-(prop-1-en-2-yl)pyridine (Int-52e, 3.13 g, 8.69 mmol) was added into a 500 mL Parr shaker vessel. Methanol (87 mL) was added into the reaction vessel. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. Palladium on carbon (0.924 g, 0.869 mmol, 10 wt% Pd) was added into the reaction vessel. The resulting mixture was charged with 50 psi of hydrogen and reacted for 16 h. The product mixture was filtered and the filtrate was concentrated to dryness to provide 4-(4-(benzyloxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-amine (Int-52f). MS (ESI): m / z 335 [M+H] +< .Step G: 4-(4-((tert-butyldimethylsilyl)oxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-amine (Int-52g)

[0340] 4-(4-(Benzyloxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-amine (Int-52f, 3.00 g, 8.97 mmol) was added into a 500 mL Parr shaker vessel. Methanol (45 mL) was added into the reaction vessel. The reaction vessel was evacuated and backfilled with a balloon of nitrogen three times. A 1.25 M solution of hydrochloric acid (28.7 mL, 35.9 mmol) in methanol was added into the reaction vessel followed by palladium on carbon (0.955 g, 0.897 mmol), the reaction vessel was charged with 50 psi of hydrogen in a Parr shaker and reacted for 16 h. The resulting mixture was purged with nitrogen and the mixture was filtered and the filtrate was concentrated to dryness. The residue obtained was dissolved in DMF (20 mL). Triethylamine (25.0 mL, 179 mmol) and tert-butylchlorodimethylsilane (13.5 g, 90.0 mmol) were added into the reaction vessel and the resulting mixture was heated to 45 °C for 6 h. The product mixture was diluted with ethyl acetate (400 mL) The diluted product mixture was washed once with saturated sodium bicarbonate aqueous solution (100 mL) and five times with saturated sodium chloride aqueous solution (5 × 30 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to dryness. The residue obtained was purified with 220-g silica gel column, eluting with hexanes initially, grading to 100% ethyl acetate:ethano = 3:1, linear gradient, to afford 4-(4-((tert-butyldimethylsilyl)oxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-amine (Int-52g). 1< H NMR (500 MHz, Acetonitrile-d 3 ): δ 7.84 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 4.08 (q, J = 5.4, 3.8 Hz, 2H), 3.88 (t, J = 12.9 Hz, 2H), 3.13 (hept, J = 6.6 Hz, 1H), 2.81 - 2.52 (m, 2H), 2.31 - 2.19 (m, 2H), 1.23 (d, J = 6.7 Hz, 6H), 0.93 (s, 9H), 0.13 (s, 6H).Step H: N-((4-(4-((tert-butyldimethylsilyl)oxy)-2,2-difluorobutyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-52h)

[0341] To a stirred solution of 2,6-dichloro-5-fluoronicotinamide (1.34 g, 6.41 mmol) in THF (6.4 mL) at 75 °C was added oxalyl chloride (3.85 mL, 7.70 mmol, 2 M in dichloromethane) and the reaction was heated to 75 °C with reflux condenser for 1 h. The reaction mixture was evaporated to dryness and dried in vacuo for 30 minutes. The residue was then charged with THF (6.4 mL), cooled to 0 °C and a solution of 4-(4-((tert-butyldimethylsilyl)oxy)-2,2-difluorobutyl)-2-isopropylpyridin-3-amine (Int-52g, 2.3 g, 6.41 mmol) in THF (6.4 mL) was added dropwise. The reaction was allowed to stir for 1 h at 0 °C and quenched at 0 °C with 130 mL 1:1 pH 7 buffer / brine. This mixture was then diluted with 100 mL EtOAc, extracted a second time with 100 mL EtOAc, dried over sodium sulfate, filtered and concentrated in vacuo. Purification on silica gel, 0-50% 3:1 EtOAc / EtOH / hexanes gave N-((4-(4-((tertbutyldimethylsilyl)oxy)-2,2-difluorobutyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-52h). MS (ESI): m / z 593 [M+H] +< .Step I: 1-(4-(4-((tert-butyldimethylsilyl)oxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-52i-1)

[0342] N-((4-(4-((tert-Butyldimethylsilyl)oxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide (Int-52h, 3.35 g, 5.64 mmol) was dissolved in THF (9.4 mL), cooled to 0 °C, charged with KHMDS (11.8 mL, 11.8 mmol, 1M in THF) and allowed to stir for 5 minutes. The reaction was complete by LC / MS. It was then cooled to 0 °C, quenched with 100 mL saturated ammonium chloride and extracted with 2 × 150 mL EtOAc. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a silica gel column, 10-100% hexanes / 3:1 EtOAc / EtOH. The racemic material was resolved by SFC Column R, Condition: 15% CO 2 / MeOH to provide: to provide Peak 1 as 1-(4-(4-((tert-butyldimethylsilyl)oxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-52i-1) as a single atropisomer MS (ESI): m / z 557 [M+H] +< .Step J: (2R,5S)-4-(1-(4-(4-((tert-butyldimethylsilyl)oxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-52j-1)

[0343] 1-(4-(4-((tert-Butyldimethylsilyl)oxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Int-52i-1,

[0344] 658 mg, 1.18 mmol) was charged with acetonitrile (4725 µL), DIEA (619 µL, 3.54 mmol), POCl 3 (132 µL, 1.42 mmol), degassed under nitrogen and heated to 80 °C for 30 minutes. The reaction was cooled to 0 °C, a second portion of DIEA (619 µl, 3.54 mmol) was added, followed by solid tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (304 mg, 1.42 mmol) and the reaction was allowed to stir for 20 minutes at the same temperature. The reaction was evaporated in vacuo and purified on silica gel, 0-60% 3:1 EtOAc / EtOH / hexanes to provide tert-butyl (2R,5S)-4-(1-(4-(4-((tert-butyldimethylsilyl)oxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-52j-1). MS (ESI): m / z 753 [M+H] +< .Step K: tert-butyl (2R,5S)-4-(1-(4-(3,3-difluoro-4-hydroxybutyl)-2-isopropylpyridin-3-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-52k-1)

[0345] tert-Butyl (2R,5S)-4-(1-(4-(4-((tert-butyldimethylsilyl)oxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (200 mg, 0.265 mmol), potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate (75 mg, 0.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (22 mg, 0.027 mmol), potassium acetate (104 mg, 1.06 mmol), were added to a 20 mL scintillation vial, degased under nitrogen, charged with dioxane (1.1 mL) / water (190 µL), degassed three times under nitrogen and heated to 90 °C for 30 minutes. The reaction was cooled to 24 °C, quenched with 3 mL saturaed aq. ammonium chloride and with diluted with 10 mL EtOAc. The organics were seperated, washed once brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 4 mL THF, charged with 1 M THF solution of TBAF (1.06 mL, 1.06 mmol) and allowed to stir at 24 °C for 3 h. The reaction was quenched with 5 mL saturated ammonium chloride, diluted 5 mL EtOAc, the layers were separated, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The orange residue was purified on silica gel 0-80% 3:1 EtOAc / EtOH / hexanes to provide tert-butyl (2R,5S)-4-(1-(4-(3,3-difluoro-4-hydroxybutyl)-2-isopropylpyridin-3-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-52k-1). MS (ESI): m / z 715 [M+H] +< .Step L: Int-521-1

[0346] tert-Butyl (2R,5S)-4-(1-(4-(3,3-difluoro-4-hydroxybutyl)-2-isopropylpyridin-3-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (100 mg, 0.140 mmol) was added in a 20 mL vial. The reaction vessel was evacuated and back filled with a balloon of nitrogen three times. Toluene (7.0 mL) and CMBP (67.5 mg, 0.280 mmol) were added into the reaction vessel. The reaction mixture was heated at 120 °C for 16 h. The product mixtures was cooled down to room temperature. The cooled product mixture was concentrated to dryness. The residue obtained was purified by flash column chromatography with a silica gel column, eluting with hexanes initially, grading to 100% ethyl acetate:ethanol = 3:1, linear gradient, to afford Int-52l-1. MS (ESI): m / z 697 [M+H] +< .Step M: Int-52m-1

[0347] Int-52l-1 (67.9 mg, 0.097 mmol) was added into a 20 mL vial. The reaction vessel was evacuated and backfilled with a balloon of nitrogen. DCM (975 µL) was added into the reaction vessel followed by dropwise addition of trifluoroacetic acid (373 µL, 4.87 mmol). The reaction mixture was stirred for 1 h at 24 °C. The product mixture was concentrated to dryness. The residue obtained was azeotroped once with toluene (5 mL). The residue obtained containing Int-52m-1 was used directly in the next step without purification.Step N: (5aR a ,18aR a )-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18,21-tetrafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one (Ex. 52)

[0348] Int-52m-1 was added into a 20 mL vial. The resulting mixture was dissolved with DCM (485 µL). The solution obtained was cooled down to 0 °C. N-Ethyl-N-isopropylpropan-2-amine (86 µL, 0.49 mmol) and acryloyl chloride (12 µL, 0.15 mmol) were added into the reaction vessel. The reaction mixture was stirred for 1 h at 0 °C. The product mixture was quenched with saturated ammonium bicarbonate aqueous solution (2 mL). The resulting mixture was extracted three times with ethyl acetate (3 × 20 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by flash column chromatography with a silica gel column, eluting with hexanes initially, grading to 100% ethyl acetate-ethanol = 3:1 v / v, linear gradient, to afford (5aR a ,18aR a )-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18,21-tetrafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one (Ex. 52). MS (ESI): m / z 651 [M+H] +< . 1< H NMR (500 MHz, Acetonitrile-d 3 ): δ 8.48 (d, J = 5.0 Hz, 1H), 8.11 (dd, J = 8.9, 6.7 Hz, 1H), 7.50 (td, J = 8.5, 6.8 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 8.8 Hz, 1H), 6.76 (ddd, J = 47.1, 16.8, 10.5 Hz, 1H), 6.37 - 6.19 (m, 1H), 5.84 - 5.65 (m, 1H), 4.52 - 4.85 (m, 1.5H), 4.58 - 4.25 (m, 2H), 4.15 (q, J = 10.1 Hz, 1H), 3.96 - 3.65 (m, 3H), 3.40 (dd, J = 13.9, 4.0 Hz, 0.5H), 2.83 (h, J = 6.9 Hz, 1H), 2.75 (dd, J = 8.0, 5.9 Hz, 2H), 2.25 - 2.18 (m, 2H), 1.49 (dd, J = 6.8, 2.7 Hz, 3H), 1.32 (d, J = 7.1 Hz, 3H), 1.12 (d, J = 6.7 Hz, 3H), 0.92 - 0.87 (m, 3H).Step O: tert-butyl (2R,5S)-4-(1-(4-(4-((tert-butyldimethylsilyl)oxy)-3,3-difluorobutyl)-6-isopropylpyrimidin-5-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-52o)

[0349] Int-52o was prepared in a similar fashion to Int-52k-1 using Int-69d following steps h-k. MS (ESI): m / z 754 [M+H] +< .Step P: tert-butyl (2R,5S)-4-(1-(4-(2-(1-(((tertbutyldimethylsilyl)oxy)methyl)cyclopropyl)ethyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-y1)-2,5-dimethylpiperazine-1-carboxylate (Int-52p)

[0350] Int-52p was prepared in a similar fashion to Int-52k-1 using Int-38k following steps h-k. MS (ESI): m / z 743 [M+H] +< .Preparation of potassium (2,4-difluoro-6-hydroxyphenyl)trifluoroborate (Int-53d)

[0351] Step A: 2-bromo-1,5-difluoro-3-(methoxymethoxy)benzene (Int-53a)

[0352] To a solution of 2-bromo-3,5-difluorophenol (4.00 g, 19.1 mmol) and DIPEA (4.01 mL, 23.0 mmol) in DCM (40 mL) was added chloro(methoxy)methane (1.75 mL, 23.0 mmol) dropwise at 0 °C. The mixture was stirred for 2 h at room temperture under N 2 atmosphere. The solvent of the reaction was evaporated under reduced pressure to yield a crude product. The crude product was purified by flash silica gel chromatography Pet. Ether / EtOAc = 1 / 1 to give 2-bromo-1,5-difluoro-3-(methoxymethoxy)benzene (Int-53a). 1< H NMR (400 MHz, CDCl 3 ): δ 6.75 (dt, J=10.39, 2.26 Hz, 1 H), 6.58 (td, J=8.56, 2.69 Hz, 1 H), 5.23 (s, 2 H), 3.50 (s, 3 H).Step B: 2-(2,4-difluoro-6-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Int-53b)

[0353] To a stirred solution of 2-bromo-1,5-difluoro-3-(methoxymethoxy)benzene (2.50 g, 9.88 mmol), 4,4,4',4',5,5,5'-heptamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.11 g, 29.6 mmol) and potassium acetate (3.88 g, 39.5 mmol) in toluene (25 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.807 g, 0.988 mmol) under N 2 atmosphere. The mixture was stirred at 100 °C for 16 h under a N 2 atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash silica gel chromatography Pet. ether / EtOAc = 1 / 1, to give 2-(2,4-difluoro-6-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Int-53b). 1< H NMR (400MHz, CDCl 3 ): δ 6.59 - 6.51 (m, 1H), 6.44 - 6.34 (m, 1H), 5.11 (s, 2H), 3.44 (s, 3H), 1.34 (s, 12H).Step C: (2,4-difluoro-6-hydroxyphenyl)boronic acid (Int-53c)

[0354] To a stirred solution of 2-(2,4-difluoro-6-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.00 mmol) in dry DCM (3 mL) was added BBr 3 (0.473 mL, 5.00 mmol) dropwise at 0 °C under N 2 atmosphere. After stirring for 20 min, the reaction mixture was poured into ice water, basified to pH ~ 10 by 3 N NaOH and the organic layer was separated. The separated aqueous layer was adjusted to pH ~ 3 with 1 N HCI and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to yield (2,4-difluoro-6-hydroxyphenyl)boronic acid (Int-53c). 1< H NMR (400MHz, Methanol-d 4 ): δ 6.44 - 6.23 (m, 2H).Step D: potassium (2,4-difluoro-6-hydroxyphenyl)trifluoroborate (Int-53d)

[0355] To a stirred solution of (2,4-difluoro-6-hydroxyphenyl)boronic acid (170 mg, 0.978 mmol) in MeCN (3 mL) was added potassium fluoride (227 mg, 3.91 mmol) dissolved in water (0.5 mL), and the mixture was stirred at 20 °C for 10 min. A solution of L-(+)-tartaric acid (367 mg, 2.44 mmol) in THF (2 mL) was added to the above solution dropwise and the resulting mixture was stirred at 20 °C for 15 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford the crude product. Acetonitrile (3.0 mL) was added and the mixture was then filtered. The resulting solids were collected to afford potassium (2,4-difluoro-6-hydroxyphenyl)trifluoroborate (Int-53d). 1< H NMR (400 MHz, Methanol-d 4 ): δ 6.44 - 5.94 (m, 2H).Example 54: (5aRa,18aRa)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,17,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one

[0356] Step A: tert-butyl (2R,5S)-4-(1-(4-(3,3-difluoro-4-hydroxybutyl)-2-isopropylpyridin-3-yl)-7-(2,3-difluoro-6-hydroxyphenyl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-54a-1)

[0357] tert-Butyl (2R,5S)-4-(1-(4-(4-((tert-butyldimethylsilyl)oxy)-3,3-difluorobutyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-52j-1, 150 mg, 0.199 mmol), potassium 3,4-difluoro-2-(trifluoro-14-boraneyl)phenolate (Int-24, 61 mg, 0.26 mmol), potassium acetate (78 mg, 0.80 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (16 mg, 0.020 mmol) were added to a 20 mL scintillation vial equipped with magnetic stir bar, degassed under nitrogen. charged with dioxane (853 µL) / water (142 µL), degassed three times under nitrogen and heated to 90 °C for 1 h. The reaction was cooled to 24 °C, quenched with 10 mL 1:1 water / saturated sodium bicarbonate, extracted twice with 25 mL EtOAc, washed with brine and concentrated in vacuo. The crude residue was taken up in 10 mL THF, charged with a 1 M THF solution of TBAF (498 µL, 0.498 mmol) and allowed to stir for 1.5 h at 24 °C. The reaction was quenched with saturated NH 4 Cl, extracted once with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on silica gel 0-100% 3:1 EtOAc / EtOH / hexanes to provide tert-butyl (2R,5S)-4-(1-(4-(3,3-difluoro-4-hydroxybutyl)-2-isopropylpyridin-3-yl)-7-(2,3-difluoro-6-hydroxyphenyl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-54a-1). MS (ESI): m / z 733 [M+H] +< .Step B: Int-54b-1

[0358] tert-Butyl (2R,5S)-4-(1-(4-(3,3-difluoro-4-hydroxybutyl)-2-isopropylpyridin-3-yl)-7-(2,3-difluoro-6-hydroxyphenyl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Int-54a-1, 125 mg, 0.171 mmol) was added into a 20 mL vial. The rea...

Claims

1. A compound, wherein the compound is selected from the group consisting of: 2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-18,21-difluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-ethenopyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one; (5aSa,17aRa)-20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-dihydro-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one; (5aSa,17aRa)-20-Chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-l-yl]-14, 17-difluoro-6-(propan-2-yl)-11,12-di[(2H)hydro](11,12-2H2)-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one; (5aRa,18aRa)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18,21-tetrafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one; (5aRa,18aRa)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,17,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one; (5aRa,18aRa)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,15,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one; (5aRa,18aRa)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,16,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one; (5aSa,17aRa)-20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-l-yl]-16,17-difluoro-6-(propan-2-yl)-11,12-di[(2H)hydro](11,12-2H2)-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one; 2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,17,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)dipyrimido[4,5-f:1',6'-h][1,8,10]benzoxadiazacyclotridecin-4-one; 21-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18-trifluoro-6-(propan-2-yl)-12,13-dihydro-4H,11H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,5,8,10]benzodioxadiazacyclotridecin-4-one; 20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-17-fluoro-6-(propan-2-yl)-11,12-dihydro-4H,10H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,7,9]benzoxadiazacyclododecin-4-one; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound has the formula: or the pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound has the formula:

4. The compound according to claim 1, wherein the compound has the formula: or the pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound has the formula:

6. The compound according to claim 1, wherein the compound has the formula: or the pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein the compound has the formula:

8. The compound according to claim 1, wherein the compound has the formula: or the pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein the compound has the formula:

10. The compound according to claim 1, wherein the compound has the formula: or the pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, wherein the compound has the formula:

12. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-11, and a pharmaceutically acceptable carrier.

13. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1-11, for use in therapy.

14. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1-11, or a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-11, for use in treating cancer.

15. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1-11, and an additional anti-cancer agent, or a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-11, and an additional anti-cancer agent, for use in the treatment of cancer.

16. The compound or the pharmaceutically acceptable salt thereof for use, or the pharmaceutical composition or the pharmaceutically acceptable salt thereof for use, according to claim 15 wherein the additional anti-cancer agent is selected from an EGFR inhibitor, an anti-PD-1 agent, a SHP2 inhibitor, and an ERK inhibitor.