Tetracyclic derivatives, their compositions and methods

Abstract

This invention provides novel tetracyclic compounds and their derivatives, as well as pharmaceutical compositions thereof, and methods for treating various types of diseases and disorders, including cancer.

Description

[Technical Field]

[0001] Priority claim and related applications This application claims priority to U.S. Provisional Application No. 63 / 534,797 filed on 25 August 2023 and U.S. Provisional Application No. 63 / 627,442 filed on 31 January 2024, the entire contents of which are incorporated herein by reference for all purposes.

[0002] Technical field of the present invention The present invention generally relates to novel compounds and their therapeutic uses. More specifically, the present invention provides novel tetracyclic compounds and derivatives thereof that have been shown to be potent and selective inhibitors of KRas, particularly KRas(G12D). The present invention also provides pharmaceutical compositions comprising the compounds of the present invention, as well as methods for treating diseases and disorders associated with or related to KRas activity, such as various types of cancer. [Background technology]

[0003] KRAS (Kirsten rat sarcoma virus) is a gene that instructs the production of a protein called KRas, which is part of the RAS / MAPK pathway. This protein transmits extracellular signals to the cell nucleus, instructing cells to grow and divide (proliferate) or to mature and acquire specialized functions (differentiation). KRas functions as a molecular switch that circulates between an inactive form (GDP-bound) and an active form (GTP-bound), and controls a wide variety of processes, such as cell proliferation, by transmitting upstream cellular signals received from multiple tyrosine kinases to downstream effectors. The role of activated KRas in malignant tumors was first identified more than 30 years ago (Santos et al. 1984 Science 223:661-664; Alamgeer et al. 2013 Current Opin Pharmcol.13:394-401).

[0004] KRas mutations are found in nearly 30% of human cancers. For example, KRas mutations are observed in pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Mutations most often occur at the glycine residue at position 12 of KRas, with KRas(G12D) being the most frequent and carcinogenic variant. KRas(G12D) mutations have been shown to be found in approximately 25% of all pancreatic ductal adenocarcinoma patients, approximately 13% of all colorectal cancer patients, approximately 10% of all rectal cancer patients, approximately 4% of all non-small cell lung cancer patients, and approximately 1.7% of all small cell lung cancer patients (The AACR Project GENIE Consortium, 2017 Cancer Discovery 7(8):818-831, Dataset EnsempVersion 4).

[0005] Despite considerable effort over the past 30 years to develop KRas inhibitors for cancer treatment, no KRas(G12D) inhibitor has been clinically demonstrated to be sufficiently safe and / or effective to obtain regulatory approval (McCormick 2015 Clin Cancer Res. 21 (8):1797-1801; Sun et al. 2012 Agnew Chem Int Ed Engl. 51(25):6140-6143; Ostrem et al. 2013 Nature 503:548-551; Fell et al. 2018 ACS Med. Chem. Lett. 9:1230-1234; Cox, et al. 2014 Nature Rev Drug Discov. 13 (11), 828-51; Patricelli et al. 2016 Cancer Discov. 6(3), 316-29; Hunter). et al. 2015 Mol Cancer Res. 13(9), 1325-35.).

[0006] There still remains an urgent need for safe and effective, potent and selective KRas inhibitors, particularly inhibitors of KRas mutants, especially inhibitors of KRas (G12D), for use in the treatment of diseases and conditions associated with abnormal expression of KRAS, such as various types of cancer (e.g., ductal adenocarcinoma, colorectal cancer, rectal cancer, non-small cell lung cancer). Summary of the Invention

[0007] The present invention provides novel quinazoline derivatives, which have been shown to exhibit advantageous potency and selectivity profiles over known KRas inhibitors, as KRas inhibitors, particularly KRas (G12D) inhibitors. These novel compounds selectively target, bind to, inhibit, and / or modulate the activity of KRas. The compounds of the present invention have pharmacokinetic profiles suitable for development into orally administrable therapeutic agents for treating various diseases and disorders associated with or related to KRas activity, such as various types of cancer, and are also orally available.

[0008] In one aspect, the present invention generally provides a compound of the following structural formula (I): Chemical Formula wherein n is 1 or 2; X is CR x1 R x2 , wherein R x1 and R x2 are each independently selected from H, halo, and unsubstituted or substituted C 1-3 alkyl; Y is NH, NR y , CH2NH, CH2NR y , NHCH2, or NR y CH2, wherein R y is unsubstituted or substituted C 1-4 alkyl, P(O)(OCH3)2, C(O)OR w , C(O)R w , wherein R w is H or unsubstituted or substituted C 1-6 alkyl; R 2 (CH2) i R 2’ Here, i is an integer selected from 1 to 6, and (CH2) i This may be substituted as appropriate, R 2’ This includes H, halogen, CN, OH, C(O)NRR', unsubstituted or substituted C 1-6 Selected from the group consisting of alkyl, unsubstituted or substituted 3- to 6-membered carbon rings, unsubstituted or substituted 4- to 6-membered heterocyclic rings, and unsubstituted or substituted aryl 7- to 9-membered bicyclic heterocyclic rings; R 6 This includes H, halogen, CN, OR, unsubstituted or substituted C 1-4 Alkyl, unsubstituted, or substituted C 1-4 Selected from the group consisting of alkoxys, C(O)NRR', NRR', S(O)2CH3, unsubstituted or substituted 3-6 membered carbon-cyclic or heterocyclic rings, and unsubstituted or substituted 5-6 membered heteroaryls; R 7 It is an unsubstituted or substituted 6-10 member unsaturated monocyclic or bicyclic ring containing 0-5 heteroatoms selected from N, O, and S; R 8 This is H, halo, unsubstituted or substituted C. 1-4 It is alkyl, OR, or NRR'; R a , R b , and R c teeth, Each is independent of H, halo, unsubstituted or substituted C. 1-3 Selected from alkyl and OR; or One R a and one R b , or one R a and one R c Together with Y and the carbon atoms to which they are bonded, they form a 4- to 7-membered heterocyclic ring; R 10 These are H, Halo, or C, respectively, independently. 1-4 Alkyl; or R 10 ', together with the carbon atoms to which they are bonded, form a cyclopropyl or cyclobutyl group; R and R' are, independently, H, unsubstituted, or substituted C. 1-4 Selected from alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic rings, or R and R' are bonded to the same N atom, together forming an unsubstituted or substituted 4- to 6-membered heterocyclic ring. This relates to a compound represented by [the given formula], or to a pharmaceutically acceptable form thereof, or to an isotope derivative thereof.

[0009] In another aspect, the present invention generally relates to pharmaceutical compositions comprising the compounds of the present disclosure and pharmaceutically acceptable excipients, carriers, or diluents.

[0010] In yet another aspect, the present invention generally relates to unit dosage forms comprising the pharmaceutical compositions of the present disclosure.

[0011] In yet another aspect, the present invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting cells with an effective amount of the compound of the present disclosure.

[0012] In yet another aspect, the present invention generally relates to a method for regulating (e.g., inhibiting or reducing) KRas(G12D) activity in cells, comprising contacting the cells with a compound of the present disclosure.

[0013] In yet another aspect, the present invention generally relates to a method for treating a disease or disorder mediated by a Ras mutant protein, characterized by administering a therapeutically effective amount of the compound of the present disclosure to a subject in need of treatment.

[0014] In yet another aspect, the present invention generally relates to a method for treating or alleviating cancer or related diseases or disorders, characterized by administering a therapeutically effective amount of the compound of the present disclosure to a subject in need of treatment.

[0015] In yet another aspect, the present invention generally relates to a method for treating or alleviating cancer or related diseases or disorders, characterized by administering a therapeutically effective amount of the compound of the present disclosure to a subject in need of treatment.

[0016] In yet another aspect, the present invention generally relates to the use of the compounds of the present disclosure and pharmaceutically acceptable excipients, carriers, or diluents in the preparation of pharmaceuticals for the treatment of diseases or disorders. [Brief explanation of the drawing]

[0017] [Figure 1] Figure 1 shows a racemic mixture of intermediates 3 and 4. [Figure 2] Figure 2 shows that the trace of intermediate 3, prepared from intermediate 1, coincides with peak 1. [Figure 3] Figure 3 shows that the trace of intermediate 3, prepared from the known chiral starting material tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, also matches peak 1. [Figure 4] The spike experiment further confirms that the stereochemistry of intermediate 3 obtained from both reactions is the same. [Modes for carrying out the invention]

[0018] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which this invention pertains. General principles of organic chemistry, as well as specific functional parts and reactivity, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 2006.

[0019] As used herein, “at least” a particular value is understood to mean that value and all values ​​exceeding that value.

[0020] The term "contains," when used to define compositions and methods, is intended to mean that the composition and method include the enumerated elements but does not exclude other elements. The term "essentially consists of," when used to define compositions and methods, shall mean that the composition and method include the enumerated elements but exclude any other elements that are essentially important to the composition and method. For example, "essentially consists of" refers to the administration of pharmacologically active agents that are explicitly enumerated and excludes pharmacologically active agents that are not explicitly enumerated. The term "essentially consists of" does not exclude pharmacologically inactive or inactive agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "consists of," when used to define compositions and methods, shall mean the exclusion of trace elements of other components and substantial method steps. Embodiments defined by each of these transitional terms are within the scope of the present invention.

[0021] Unless otherwise specified or evident from the context, the term “about” as used herein is understood to mean within the normal tolerances in the art, e.g., within two standard deviations of the mean. “About” can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise evident from the context, all numerical values ​​provided herein may be modified by the term “about.”

[0022] As used herein, the terms “administer” or “administer” any of the disclosed compounds include delivery of any of the compounds described herein, or their prodrugs or other pharmaceutically acceptable forms, to a subject using any suitable formulation or route of administration as described herein.

[0023] As used herein, the term “simultaneous administration” means that two pharmacological agents are present simultaneously in the body of the subject (e.g., in the blood). The two pharmacological agents may be administered simultaneously or sequentially.

[0024] Unless otherwise specified, the terms “disease,” “disorder,” and “condition” are used interchangeably.

[0025] As used herein, the terms “effective dose” or “therapeutic dose” mean an amount of the compound or pharmaceutical composition described herein that is sufficient to achieve an intended use, including but not limited to the treatment of a disease, as described below.

[0026] In some embodiments, the amount is sufficient to negatively modulate or inhibit the activity of KRas(G12D). In some embodiments, the amount is effective for reducing or improving symptoms, or for stopping or reversing the progression of a disease or disorder such as cancer. In some embodiments, the amount is effective for a detectable reduction or inhibition of cancer cell growth or spread; tumor size or number; or other measures of cancer level, stage, progression, or severity.

[0027] The therapeutically effective dose may vary depending on the intended use or the target and condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the method of administration, and the patient's weight and age, and can be readily determined by those skilled in the art. Such a dose may be administered as a single dose or according to a regimen. This term also applies to doses that induce a specific response in target cells, e.g., a reduction in cell migration. The specific dose will vary, for example, depending on the particular compound selected, the species of the target and their age / current health status or health risk, the administration regimen followed, the severity of the disease, whether it is administered in combination with other drugs, the timing of administration, the tissue to which it is administered, and the physical delivery system through which it is carried.

[0028] As used herein, the terms “KRas(G12D)” or “KRas G12D” are used interchangeably and refer to a variant of the mammalian KRas protein in which the amino acid glycine at position 12 is substituted with aspartic acid. The amino acid codon and residue assignments of human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp.

[0029] As used herein, “KRas(G12D)” or “KRas G12D” “inhibitor” refers to a compound of the present invention that can negatively modulate or inhibit all or part of the enzymatic activity of KRas G12D.

[0030] As used herein, “KRas G12D-related” disease or disorder means a disease or disorder that is associated with, mediated by, or has a KRas G12D mutation. Examples of KRas G12D-related diseases or disorders include various types of KRas G12D-related cancers.

[0031] As used herein, the term “contact” refers to bringing together the indicated portions in vitro or in vivo. For example, “contact” KRas G12D with the compound of the Disclosure includes administering the compound to a subject having KRas G12D, as well as introducing the compound into a sample containing, for example, cells or a purified preparation containing KRas G12D. In some embodiments, cells in which inhibition of KRas G12D activity is desired are contacted with an effective amount of the compound of the Disclosure or a pharmaceutically acceptable form thereof to negatively modulate the activity of KRas G12D. By negatively modulating the activity of KRas G12D, the methods of the Disclosure are designed to inhibit undesirable cell proliferation resulting from enhanced intracellular KRas G12D activity. Desired negative modulation of KRas G12D can be achieved by contacting cells in single or multiple doses according to a specific therapeutic regimen. The ability of a compound to bind to KRas G12D can be monitored in vitro using methods known in the Art. The inhibitory activity of exemplary compounds in cells can be monitored, for example, by measuring the inhibition of KRas G12D activity using methods known in the art.

[0032] As used herein, the terms “unsubstituted or substituted” and “may be substituted as appropriate” are used interchangeably and refer to a situation in which a given chemical moiety (e.g., an alkyl group) can (but is not required to) bond to other substituents (e.g., a heteroatom). For example, a may-substituted alkyl group may be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same may-substituted alkyl group may have substituents other than hydrogen. For example, it may bond to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term “may be substituted as appropriate” means that a given chemical moiety may contain other functional groups, but is not necessarily required to have any further functional groups. Suitable substituents for optional substitution of the listed groups include, but are not limited to, halogens, oxo, CN, -COOH, -CH2CN, -O-C1-C6 alkyl, C1-C6 alkyl, -OC1-C6 alkenyl, -OC1-C6 alkynyl, -C1-C6 alkenyl, -C1-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -S(O)2-C1-C6 alkyl, -S(O)NHC1-C6 alkyl, and S(O)N(C1-C6 alkyl)2.

[0033] As used herein, “pharmaceutically acceptable forms” of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In one embodiment, “pharmaceutically acceptable forms” include, but are not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In some embodiments, “pharmaceutically acceptable forms” include, but are not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0034] In certain embodiments, a pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” refers to salts that, within the bounds of sound medical judgment, are suitable for use in contact with the target tissue without causing excessive toxicity, irritation, allergic reactions, etc., and that have a reasonable risk-benefit ratio. pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. pharmaceutically acceptable salts of the compounds provided herein include those derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed by using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or by using organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfons, besilates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptons, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, and 2-hydroxyethansulfates. Examples include honate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0035] Salts may be prepared in situ during the isolation and purification of the disclosed compound, or separately by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 This includes alkyl) 4 salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0036] In certain embodiments, a pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term “pharmaceutically acceptable ester” refers to an ester that hydrolyzes in vivo and includes those that readily decompose in the human body, leaving the parent compound or a salt thereof. Such esters can act as prodrugs as defined herein. pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including but not limited to carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids, and boronic acids. Examples of esters include formate esters, acetate esters, propionic acid esters, butyrate esters, acrylic acid esters, and ethyl succinate esters. Esters may be formed using a hydroxy or carboxylic acid group of the parent compound.

[0037] In certain embodiments, the pharmaceutically acceptable form is a “solvate” (e.g., a hydrate). As used herein, the term “solvate” refers to a compound further comprising stoichiometric or non-stoichiometric amounts of solvent bonded by non-covalent intermolecular forces. The solvate may be that of the disclosed compound or a pharmaceutically acceptable salt thereof. If the solvent is water, the solvate is a “hydrate.” Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. As used herein, the term “compound” will be understood to encompass compounds and solvates of compounds, as well as mixtures thereof.

[0038] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” (or “pro-drug”) refers to the disclosed compound or a compound that is converted in vivo to produce a pharmaceutically acceptable form of the compound. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in the blood). In certain cases, the prodrug has improved physical and / or delivery properties compared to the parent compound. When administered to a subject, the prodrug may increase the bioavailability of the compound compared to the parent compound (e.g., by enabling enhanced absorption into the blood after oral administration) or enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system). Exemplary prodrugs include derivatives of the disclosed compound that have enhanced water solubility or active transport across the intestinal membrane compared to the parent compound.

[0039] Prodrug compounds often offer advantages in mammalian organisms such as solubility, histocompatibility, or delayed release (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14 and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are fully incorporated herein by reference. Exemplary advantages of prodrugs include, but are not limited to, their physical properties, such as enhanced solubility for parenteral administration at physiological pH compared to the parent compound, or their ability to enhance absorption from the gastrointestinal tract, or their ability to enhance drug stability for long-term storage.

[0040] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic compatible substances employed in pharmaceutical preparations. Wetting agents, emulsifiers, lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, colorants, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0041] As used herein, the term "subject" refers to any animal (e.g., a mammal), including but not limited to humans, non-human primates, rodents, etc., that is the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein with reference to human subjects.

[0042] In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder that is treated with a compound of the present disclosure and / or in accordance with a method of the present disclosure. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRas G12D mutation. In some embodiments, the subject has a cancer that is positive for the KRas G12D mutation. In some embodiments, the subject is suspected of having a KRas G12D gene-associated cancer.

[0043] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the subject has the KRas G12D mutation using a sample from the subject (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample)). A variety of techniques can be used, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).

[0044] As used herein, the term “treatment” or “treating” a disease or disorder means a method of reducing, delaying, or improving such a condition before it occurs or after it has occurred. Treatment may target one or more effects or symptoms of a disease and / or underlying pathology. Treatment aims to obtain beneficial or desired outcomes, including, but not limited to, therapeutic and / or preventive benefits. Therapeutic benefit means the elimination or improvement of the underlying disorder being treated. Therapeutic benefit is also achieved by the elimination or improvement of one or more physiological symptoms associated with the underlying disorder, such that improvement is observed in the patient, even though the patient may still be suffering from the underlying disorder. With respect to preventive benefits, pharmaceutical compounds and / or compositions may be administered to patients at risk of developing a particular disease, or to patients reporting one or more physiological symptoms of the disease, even if they may not have been diagnosed with the disease. Treatment may be any reduction, or it may be the complete disappearance of the disease or its symptoms. Compared to an equivalent untreated control, such reduction or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%, as measured by any standard technique.

[0045] As used herein, the term “therapeutic effect” means the therapeutic and / or preventive benefits described herein. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0046] The compounds of the present invention, after their preparation, are preferably isolated and purified to obtain a composition containing 95% or more by weight ("substantially pure"), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention have a purity of more than 99%.

[0047] Solvates and polymorphs of the compounds of the present invention are also intended herein. Examples of solvates of the compounds of the present invention include hydrates.

[0048] As used herein, the terms “isolated” or “substantially isolated” molecules (e.g., polypeptides or polynucleotides) are those that have been manipulated to exist at a higher concentration than in nature or have been removed from their natural environment. For example, a target antibody is isolated, purified, substantially isolated, or substantially purified if at least 10%, 20%, 40%, 50%, 70%, or 90% of the non-target antibody material that accompanies it in nature has been removed. For example, a polynucleotide or polypeptide that exists naturally in a living animal is not “isolated,” but the same polynucleotide or polypeptide separated from its naturally occurring coexisting material is “isolated.” Furthermore, recombinant DNA molecules contained in a vector are considered isolated for the purposes of this invention. Isolated RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Isolated nucleic acid molecules further include molecules produced by synthesis. Furthermore, vector molecules contained in recombinant host cells are also isolated. Therefore, not all “isolated” molecules need to be “purified.”

[0049] As used herein, the term “purified,” when used in reference to a molecule, means that the concentration of the molecule being purified is increased relative to the molecules associated with it in its natural environment or in the environment in which it was produced, found, or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids, and sugars, but generally do not include water, buffers, and reagents added to maintain the integrity of the molecule being purified or to facilitate its purification. According to this definition, a substance may be 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100% pure relative to its impurities.

[0050] Definitions of specific functional groups and chemical terms are described in more detail below. When ranges of values ​​are listed, it is intended that each value and subrange within that range be included. For example, "C 1-4 "Alkyl" refers to C1, C2, C3, C4, C 1-3 , C 1-2 , C 2-4 , C 3-4 , and C 2-3 It is intended to include alkyl groups.

[0051] As used herein, the term "alkyl" means a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturation, and having 1 to 10 carbon atoms (e.g., C 1-10 This refers to alkyl. Whenever a numerical range such as "1 to 10" appears herein, it refers to each integer within a given range, for example, "1 to 10 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on, up to 10 carbon atoms. However, this definition also includes the existence of the term "alkyl" for which no numerical range is specified. In some embodiments, "alkyl" means C 1-6It may also be an alkyl group. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Typical saturated linear alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Saturated branched alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, etc. The alkyl group is bonded to the parent molecule by a single bond. Unless otherwise specified herein, alkyl groups include acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R x )3, -OR x , -SR x -OC(O)-R x , -N(R x )2, -C(O)R x , -C(O)OR x ,-OC(O)N(R x )2, -C(O)N(R x )2, -N(R x )C(O)OR x , -N(R x )C(O)R x , -N(R x )C(O)N(R x )2, -N(R x )C(NR x )N(R x)2, -N(R x )S(O) t N(R x )2 (where t is 1 or 2), -P(=O)(R x )(R x ), or -OP(=O)(OR x )2 may be appropriately substituted by one or more substituents independently comprising R x Each of these is independently hydrogen, alkyl, haloalkyl, carbocykyl, carbocykylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these parts may be appropriately substituted as defined herein. In non-limiting embodiments, the substituted alkyl may be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0052] Unless otherwise specifically defined, the terms “aromatic” or “aryl” refer to cyclic aromatic hydrocarbon groups having one or two aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. If two aromatic rings are present (e.g., bicyclic), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be appropriately substituted at any bonding point with one or more substituents, e.g., one to five substituents. Examples of substituents include, but are not limited to, H, halogen, -O-C1-C6 alkyl, C1-C6 alkyl, -C1-C6 alkenyl, -OC1-C6 alkynyl, -C1-C6 alkenyl, -C1-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(O)2-C1-C6 alkyl, -S(O)NHC1-C6 alkyl, and S(O)N(C1-C6 alkyl)2. Substituents may be substituted themselves as appropriate. Furthermore, if two fused rings are present, the aryl group as defined herein may have an unsaturated or partially saturated ring fused with a fully unsaturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoanurenyl.

[0053] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0054] As used herein, the terms “heteroaryl” or “hetero-aromatic” refer to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 p electrons shared in the cyclic array, and having, in addition to carbon atoms, 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S.Examples of heteroaryl groups include acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carborinyl, chromanil, clomenil, sinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanil, flazanil, imidazolinyl, imidazolyl, 1 H-indazolyl, indolenyl, indolinyl, indolidine, indolyl, 3H-indolyl, isobenzofuranil, isochromanil, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthilidinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxa Zolidinyl, pyrimidinyl, phenanthrolinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrrolyl, quinazolidinyl, quinolinyl, 4H-quinolidinyl, quinoxalidinyl, quinuclidinyl Examples include tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiadinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl."Heteroaryl" also refers to a bicyclic ring system that, in addition to carbon atoms, has 1 to 3 heteroatoms selected from the group consisting of N, O, and S per ring, and one of the ring systems may be saturated or partially saturated.

[0055] The heteroaryl group may be substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZ1Z2)carbonyl. The term "NZ1Z2," as used herein, refers to two groups Z1 and Z2 attached to the parent molecule via a nitrogen atom. Z1 and Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Typical examples of NZ1Z2 include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

[0056] As used herein, the term "alkoxy" refers to an -O-alkyl group.

[0057] As used herein, the terms “cycloalkyl” and “carbocyclyl” refer to monocyclic or polycyclic groups containing only carbon and hydrogen, which may be saturated or partially unsaturated. Unless otherwise specified herein, these terms are intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups may be called “cycloalkenyl” if the carbocyclic ring contains at least one double bond, or “cycloalkynyl” if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C 3-13(Cycloalkyl). Numerical ranges such as "3 to 10" refer to each integer within a given range whenever they appear herein; for example, "3 to 13 carbon atoms" means that the cycloalkyl group may consist of up to 13 carbon atoms, such as 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-polycyclic (i.e., rings sharing adjacent ring atom pairs) groups. Polycyclic aryl groups include dicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" means C 3-8 It may be a cycloalkyl group. In some embodiments, "cycloalkyl group" is C 3-5 It may also be a cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, the following: C 3-6 The carbocyclyl group includes, but is not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-7 An example of a carbocyclyl group is norbornyl (C7). 3-8 Examples of carbocyclyl groups include the aforementioned C 3-7 Examples include the carbocyclyl group, as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl. 3-13 Examples of carbocyclyl groups include the aforementioned C 3-8carbocyclyl groups, octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless otherwise specified herein, a cycloalkyl group is selected from acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azido, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )₃, -OR a , -SR a , -OC(O)-R a , -N(R a )₂, -C(O)R a , -C(O)OR a , -OC(O)N(R a )₂, -C(O)N(R a )₂, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )₂, -N(R a )C(NR a )N(R a )₂, -N(R a )S(O) t N(R a )₂ (wherein t is 1 or 2), -P(=O)(R a )(R a ), or -O-P(=O)(OR a )₂, and may be optionally substituted with one or more substituents independently selected from the above, R aEach of these is independently hydrogen, alkyl, haloalkyl, carbocyryl, carbocyrylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of these parts may be substituted as appropriate as defined herein. The terms “cycloalkenyl” and “cycloalkynyl” reflect the above description of “cycloalkyl,” with the prefix “alk” replaced by “alken” or “alkyn,” respectively, and the parent terms “alkenyl” or “alkynyl” are as described herein. For example, a cycloalkenyl group may have 3 to 13 ring atoms, for example, 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group may have 5 to 13 ring atoms.

[0058] As used herein, the term “heterocycloalkyl” refers to a cycloalkyl group having one or more skeletal chain atoms selected from atoms other than carbon, e.g., O, N, S, P, or combinations thereof. Unless otherwise specified herein, this term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Examples of heterocycloalkyl groups include 2-hydroxyaziridine-1-yl, 3-oxo-1-oxacyclobutan-2-yl, 2,2-dimethyltetrahydrofuran-3-yl, 3-carboxymorpholine-4-yl, 1-cyclopropyl-4-methylpiperazine-2-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, and 3,4-dihydro-2H-[1,4]oxazine.

[0059] As used herein, the terms “heterocyclic,” “heterocyclic,” or “heterocyclo” refer to fully saturated or partially unsaturated cyclic groups having at least one heteroatom (selected from the group consisting of N, O, and S) in at least one ring, such as 3- to 7-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 15-membered spirocyclic or tricyclic ring systems, where 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. Each ring of a heterocyclic group containing heteroatoms may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may be oxidized as appropriate, and the nitrogen heteroatom may be quaternized as appropriate. The heterocyclic group may be bonded at any heteroatom or carbon atom of the ring or ring system. The heterocyclic group may be substituted as appropriate. Examples of heterocyclic groups include epoxy, azetidinyl, azilidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 Dioxide, morpholinyl, azepanil, oxazepanil, azabicyclohexanil, azabicycloheptanil, azabicyclooctanil, azabicyclononanil (e.g., octahydroindolidine), azaspiroheptanil, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine], hexahydro-1H-pyrrolidinil, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinil, octahydroindolidine, oxazaspirononanil, oxazaspirooctanil, diazaspirononanil, oxaazabiocycloheptanil, hexahydropyrrolidinil Examples include, but are not limited to, 4(1H)-oxide, tetrahydro-2H-thiopyranyl 1-oxide, and tetrahydro-2H-thiopyranyl 1,1-dioxide.

[0060] Detailed description of the present invention The present invention is based, in part, on the discovery of KRas inhibitors, particularly KRas(G12D) inhibitors, that selectively target, bind to, inhibit or modulate the activity of KRas. Such novel compounds exhibit favorable potency and selectivity, as well as pharmacokinetic profiles suitable for development into orally administered therapeutic agents for treating diseases and disorders associated with or related to KRas activity, including various types of cancer.

[0061] In one aspect, the present invention generally provides a compound of the following structural formula (I):

Chemical Formula

[0062] In a particular embodiment of (I), n is 1, and equation (II): [ka] It has the structure of [the object].

[0063] In a particular embodiment of (I), one R a and one R b Y and the carbon atoms to which they are bonded form a 5-membered heterocyclic ring, and formula (I A ): [ka] It has the structure of [the object].

[0064] In a particular embodiment of (II), one R a and one R b Y and the carbon atoms to which they are bonded form a 5-membered heterocyclic ring, and formula (II A ): [ka] It has the structure of [the object].

[0065] (I A ) or (II A In a particular embodiment of ), R a and R b One of them is CH3, and the other is H.

[0066] (I A ) or (II A In a particular embodiment of ), R a and R b These are H, respectively.

[0067] (I)-(II A In a particular embodiment of ), R x1 and Rx2 Each of these is independently selected from H, F, and Cl.

[0068] (I)-(II A In a particular embodiment of ), R x1 and R x2 These are H, respectively.

[0069] (I)-(II A In a particular embodiment of ), R x1 and R x2 One of them is H, and the other is F or Cl.

[0070] (I)-(II A In a particular embodiment of ), R x1 and R x2 These are either F or Cl, respectively.

[0071] (I)-(II A In a particular embodiment of ), R x1 and R x2 At least one of them is either non-substitutive or substituted C 1-3 It is alkyl.

[0072] (I)-(II A In a particular embodiment of ), Y is NH.

[0073] (I)-(II A In a particular embodiment of ), Y is NR y That is the case.

[0074] In a particular embodiment, R y It is P(O)(OCH3)2.

[0075] In a particular embodiment, R y C(O)OR, where R is either non-substituted or substituted C. 1-4 It is alkyl.

[0076] In a particular embodiment, R y but, [ka] The formula includes, where R and R' are H or substituted or unsubstituted C, respectively. 1-6 Selected from alkyl or substituted or unsubstituted 3- to 6-membered carbon rings.

[0077] In a particular embodiment, R y teeth, [ka] Includes.

[0078] (I)-(II A In a particular embodiment of ), R 6 H is H.

[0079] (I)-(II A In a particular embodiment of ), R 6 It is F.

[0080] (I)-(II A In a particular embodiment of ), R 6 It is Cl.

[0081] (I)-(II A In a particular embodiment of ), R 6 C 1-3 Alkyl or C 3-4 It is a cycloalkyl group.

[0082] (I)-(II A In a particular embodiment of ), R 6 These are CH2F, CHF2, or CF3.

[0083] (I)-(II A In a particular embodiment of ), R 6 These are CN, S(O)2R, NRR', OR, or C(O)NRR'.

[0084] (I)-(II A In a particular embodiment of ), Rc These are H, respectively.

[0085] (I)-(II A In a particular embodiment of ), i is 1.

[0086] (I)-(II A In a particular embodiment of ), R 2’ This is 0 to 5 R 2A C is replaced by 3-6 It is a carbocyclic or heterocyclic ring, where R 2A These are D, Haro, and OC, each operating independently. 1-3 Alkyl, or C 1-3 Selected from alkyl, the C 1-3 The alkyl group may be appropriately substituted with one or more of the following: halo, OH, NRR', CN, and CONRR'.

[0087] (I)-(II A In a particular embodiment of ), R 2’ This is 0 to 5 R 2A C is replaced by 3-5 It is a carbocyclic ring.

[0088] R 2 Non-restrictive examples include: [ka] These are some examples.

[0089] (I)-(II A In a particular embodiment of ), R 2’ This is 0 to 5 R 2A C is replaced by 3-5 It is a heterocyclic ring.

[0090] R 2 Non-restrictive examples include: [ka] This can also be mentioned.

[0091] (I)-(II AIn a particular embodiment of ), R 2’ This is a biring non-substituted or substituted C. 6-10 It is a heterocyclic ring.

[0092] R 2 Non-restrictive examples include: [ka] This can also be mentioned.

[0093] R 2 Non-restrictive examples include: [ka] Further examples include:

[0094] (I)-(II A In a particular embodiment of ), R 7 This is an unsubstituted or substituted 6-membered aryl or heteroaryl ring containing 0 to 5 heteroatoms selected from N, O, and S.

[0095] In a particular embodiment, R 7 The structural formula is as follows: [ka] [In the formula, Z is N or CR 7E and; W is N or CR 7C and; R 7A This is H, halo, or substituted or unsubstituted C. 1-3 It is alkyl; R 7B This is H, halo, or substituted or unsubstituted C. 1-3 It is alkyl; R 7C is H or halo; R 7D is H, NRR', halo, or OR; R 7E [is H or halo] It is represented as follows.

[0096] In a particular embodiment, W is N and R 7 The structural formula is as follows: [ka] It is represented as follows.

[0097] In a particular embodiment, W is CR 7C And R 7 The structural formula is as follows: [ka] It is represented as follows.

[0098] In a particular embodiment, Z is N.

[0099] In a particular embodiment, Z is CH.

[0100] In a particular embodiment, Z is CF.

[0101] In a particular embodiment, R 7D It is NH2.

[0102] In a particular embodiment, R 7D It is OH.

[0103] In a particular embodiment, R 7A This is CF3.

[0104] In a particular embodiment, R 7A It is cyclopropyl.

[0105] In a particular embodiment, R 7B It is either CH3 or Cl.

[0106] In a particular embodiment, R 7C It is either F or H.

[0107] R7 Non-restrictive examples include: [ka] These are some examples.

[0108] R 7 Non-restrictive examples include: [ka] This can also be mentioned.

[0109] (I)-(II A In a particular embodiment of ), R 7 This is an unsubstituted or substituted 9 or 10-membered bicyclic aryl or heteroaryl ring containing 0 to 5 heteroatoms selected from N, O, and S.

[0110] In a particular embodiment, R 7 The structure is as follows: [ka] [In the formula, Ring A is a 6-membered aryl or heteroaryl ring having 0 to 2 N atoms; Ring B is a 5 or 6-membered carboncyclic, heterocyclic, aryl, or heteroaryl ring having 0 to 3 heteroatoms selected from N, O, and S; R 7F and R 7G These are, independently, halogen, OH, CN, NRR', unsubstituted or substituted C. 1-6 Alkyl and unsubstituted or substituted C 1-6 Alkoxy, (CH2) k NRR', (CH2) k C(=O)NRR', (CH2) k OC(=O)R, (CH2) k Selected from the group consisting of OC(=O)OR; p and q are independently 0, 1, 2, or 3; k is independently 0, 1, or 2. It holds.

[0111] In a particular embodiment, ring A is a six-membered aryl ring.

[0112] In a particular embodiment, ring A is a six-membered heteroaryl ring.

[0113] In a particular embodiment, ring B is a five-membered heterocyclic ring.

[0114] In a particular embodiment, ring B is a six-membered heterocyclic ring.

[0115] In a particular embodiment, ring B is a five-membered heteroaryl ring.

[0116] In a particular embodiment, ring B is a six-membered heteroaryl ring.

[0117] In a particular embodiment, ring B is a six-membered aryl ring.

[0118] R 7 Non-restrictive examples include: [ka] These are some examples.

[0119] R 7 Non-restrictive examples include: [ka] These are some examples.

[0120] R 7 Non-restrictive examples include: [ka] This can also be mentioned.

[0121] R 7 Non-restrictive examples include: [ka] Further examples include:

[0122] (I)-(II A In a particular embodiment of ), R 10 H is H.

[0123] (I)-(II A In a particular embodiment of ), R 10 This is CH3.

[0124] (I)-(II A In a particular embodiment of ), R 8 It is F.

[0125] (I)-(II A In certain embodiments of ), the compound has the following structural formula (III A ): [ka] It is represented as follows.

[0126] (I)-(II A In certain embodiments of ), the compound has the following structural formula (III B ): [ka] It is represented as follows.

[0127] (I)-(II A In certain embodiments of ), the compound has the following structural formula (III C ): [ka] It is represented as follows.

[0128] (I)-(II A In certain embodiments of ), the compound has the following structural formula (III D ): [ka] It is represented as follows.

[0129] (III A )-(III D In a particular embodiment of ), R 6 It is F.

[0130] (III A )-(III D In a particular embodiment of ), R 6 It is Cl.

[0131] (III A )-(III D In a particular embodiment of ), R y H is H.

[0132] (III A )-(III D In a particular embodiment of ), R y teeth, [ka] The formula includes, where R and R' are H or substituted or unsubstituted C, respectively. 1-6 Selected from alkyl or substituted or unsubstituted 3- to 6-membered carbon rings.

[0133] (III A )-(III D In a particular embodiment of ), R x2 H is H.

[0134] (III A )-(III D In a particular embodiment of ), R x1 H is H.

[0135] (III A )-(III D In a particular embodiment of ), R x1 and R x2 One of them is F.

[0136] Non-limiting examples of the compounds of the present invention include the compounds listed in Table 1. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0137] In certain embodiments, the compounds of the present invention are selected from Table 2.

[0138] In certain embodiments, the compounds of the present invention have one or more deuterium atoms instead of hydrogen atoms.

[0139] In certain embodiments, the compound of the present invention has one deuterium atom instead of a hydrogen atom.

[0140] In another aspect, the present invention generally relates to pharmaceutical compositions comprising the compounds of the present disclosure and pharmaceutically acceptable excipients, carriers, or diluents.

[0141] In certain embodiments, the pharmaceutical composition of the present invention is suitable for oral administration.

[0142] In yet another aspect, the present invention generally relates to a unit dosage form comprising a pharmaceutical composition containing the compounds of the present disclosure.

[0143] In certain embodiments, the unit dosage form is in the form of a tablet or a capsule.

[0144] In yet another aspect, the present invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting cells with an effective amount of the compound of the present disclosure.

[0145] In yet another aspect, the present invention generally relates to a method for regulating (e.g., inhibiting or reducing) KRas(G12D) activity in cells, comprising contacting the cells with a compound of the present disclosure.

[0146] In yet another aspect, the present invention generally relates to a method for treating a disease or disorder mediated by a Ras mutant protein, characterized by administering a therapeutically effective amount of the compound of the present disclosure to a subject in need of treatment.

[0147] In yet another aspect, the present invention generally relates to a method for treating or alleviating cancer or related diseases or disorders, characterized by administering a therapeutically effective amount of the compound of the present disclosure to a subject in need of treatment.

[0148] In yet another aspect, the present invention generally relates to the use of the compounds of the present disclosure and pharmaceutically acceptable excipients, carriers, or diluents in the preparation of pharmaceuticals for the treatment of diseases or disorders.

[0149] Examples of diseases or disorders that can be treated or alleviated by the compositions or methods of the present invention include, but are not limited to, tumors, cancer, autoimmune diseases, and macroglobulinemia.

[0150] In certain embodiments, cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0151] Examples of cancers targeted in the present invention include, but are not limited to, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer and rectal cancer), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), urinary tract cancer (e.g., kidney cancer, bladder cancer, prostate cancer, and testicular tumors), hematopoietic malignancies (e.g., leukemia, lymphoma, malignant lymphoma, and multiple myeloma), sarcomas (e.g., osteosarcoma and soft tissue sarcoma), skin cancer, brain tumors, carcinomas, squamous cell carcinoma, adenocarcinoma, neuroma, and melanoma. Examples include lung cancer, pancreatic cancer, rectal cancer, colon cancer, colorectal cancer, and uterine cancer. In certain embodiments, squamous cell carcinoma is cancer of the cervix, tarsal, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, or esophagus. In one embodiment, adenocarcinoma is cancer of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, or ovary. In certain embodiments, tumor is cancer of the rectum, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, leukemia, or uterine cancer.

[0152] In certain embodiments, cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendiceal cancer, cholangiocarcinoma, urothelial carcinoma of the bladder, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, and hematological malignancies.

[0153] In a particular embodiment, a subject suffering from any of the diseases selected above does not need to have the KRAS G12D mutant protein. In a particular embodiment, a subject suffering from any of the diseases selected above does have the KRAS G12D mutant protein.

[0154] In certain embodiments, the subject has mutations in KRAS, HRAS, and / or NRAS.

[0155] The amount of active compound administered depends on the target being treated, the severity of the disorder or condition, the route of administration, the distribution of the compound, and the discretion of the prescribing physician. In some cases, dose levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, even higher doses may be used without causing adverse side effects, and such higher doses are typically divided into several smaller doses for administration throughout the day.

[0156] Any suitable route of administration may be used, such as oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalation, oral, intraperitoneal, rectal, intrathoracic, and intrathecal administration. The most appropriate means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the treatment used and the nature of the active compound.

[0157] In certain preferred embodiments, the compound is administered orally. Pharmaceutical compositions of the present invention suitable for oral administration may be provided as individual units such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions; or packed in liposomes; and as boluses, etc. Soft gelatin capsules may be useful for containing such suspensions, which can beneficially increase the absorption rate of the compound.

[0158] Tablets can be prepared by compressing or molding with one or more adjuncts as optional. Compressed tablets can be prepared by compressing a fluid form of the active ingredient, such as a powder or granules, in a suitable machine, mixed with an optional binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent in a suitable machine. Tablets may be coated or scored as appropriate, and may be formulated to achieve slow or controlled release of the active ingredient therein. Methods for formulating such slow or controlled-release compositions of pharmaceutically active ingredients, such as those specified herein and other compounds known in the art, are known in the art and are described in several issued U.S. patents, some of which include, but are not limited to, U.S. Patents 4,369,172 and 4,842,866, and the references cited herein. The coating can be used for the delivery of the compound to the intestine (see, for example, U.S. Patents 6,638,534, 5,217,720, 6,569,457, 6,461,631, 6,528,080, 6,800,663, and the references cited herein). A useful formulation of the compound of the present invention is in the form of an enteric pellet in which the enteric layer contains hydroxypropyl methylcellulose acetate succinate.

[0159] For tablets intended for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners and / or flavorings and / or colorings may be added if necessary.

[0160] Suitable compositions for topical administration include lozenges containing flavoring agents, usually sucrose and gum arabic or tragacanth; and pastels containing active ingredients in an inert base such as gelatin and glycerin, or sucrose and gum arabic.

[0161] Suitable compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient; as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. The formulations may be supplied in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0162] Such injectable formulations may, for example, be in the form of sterile aqueous or oily suspensions for injection. These suspensions can be formulated according to techniques known in the art using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents. The sterile injectable formulations may also be sterile injectable formulations or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils have been conventionally used as solvents or suspending agents. For this purpose, any non-irritating non-volatile oil, including synthetic mono or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable formulations, as are naturally pharmaceutically acceptable oils such as olive oil or castor oil, particularly their polyoxyethylated forms. These oily formulations or suspensions may also contain long-chain alcohol diluents or dispersants.

[0163] The compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayers or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipids capable of forming liposomes may be used. The composition in liposomal form may contain stabilizers, preservatives, excipients, etc., in addition to the compounds of the present invention. Preferred lipids are both natural and synthetic phospholipids and phosphatidylcholine (lecithin). Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0164] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0165] The pharmaceutical compositions of the present invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulations and may be prepared as liquids in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, carbon fluoride, and / or other solubilizers or dispersants known in the art.

[0166] Topical administration of the pharmaceutical compositions of the present invention is particularly useful when the desired treatment involves an area or organ that is easily reachable by topical application. For topical application to the skin, the pharmaceutical compositions should be formulated as a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention may also be applied topically to the lower intestinal tract by rectal suppository formulations or by suitable enema formulations. Topical transdermal patch and iontophoresis administration are also included in the present invention.

[0167] The therapeutic methods disclosed herein may be used in combination with or in addition to other therapeutic methods. In certain embodiments, the subject to be treated may further undergo one or more of the following: chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormone therapy.

[0168] Exemplary additional therapeutic agents include, but are not limited to, drug compounds, organic small molecules such as those approved by the U.S. Food and Drug Administration (FDA) as listed in the Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, protein-linked small molecules, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0169] In certain embodiments, the compounds of the present invention may be administered in combination with endocrine therapies, such as drugs including letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[0170] In some embodiments, the compounds of the present invention may be administered in combination with chemotherapeutic agents, such as docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, or vinorelbine. In other embodiments, the compounds of the present invention may be administered in combination with anti-HER2 agents, such as trastuzumab or pertuzumab.

[0171] In certain embodiments, the methods of the present disclosure are combined with one or more of the following: immune checkpoint blockade, T cell co-signaling, and tumor-targeting antibody therapy.

[0172] In certain embodiments, the method further includes administering a chemotherapeutic agent to a target.

[0173] In certain embodiments, the method further includes being carried out for radiotherapy. In certain embodiments, the method further includes being carried out for targeted therapy. In certain embodiments, the method further includes being carried out for immunotherapy. In certain embodiments, the method further includes being carried out for hormone therapy.

[0174] As used herein, the term “chemotherapeutic agent” refers to a compound useful in the treatment of cancer. Examples of chemotherapy agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), sutent (SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), and ronafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs), and gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU Alkylating agents such as 5271; Sugen), thiotepa, and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan, and biposulfan; aziridines such as benzodopa, carbocone, meturedopa, and uredopa; ethyleneimines and methylamelamines such as altoretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine; acetogenins (especially bratacin and bratacinone); camptothecin (including its synthetic analog topotecan); bryostatin; calistatin; CC-1065 (including its synthetic analogs adzeresin, karzeresin, and bizeresin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); drastatin;Duocalmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictiin; spongstatin; chlorambucil, chlornafadin, chlorophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembitin, fenestrine, prednimustine, trophosphamide, nitrogen mustards such as uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; engine antibiotics (e.g., calicheamicin, especially calicheamicin gamma II and calicheamicin omega II) (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); Dynemicin containing dynemicin A; Bisphosphonates such as clodronate; Esperamicin; and neocartinostatin chromophore and related pigment proteins (antibiotic chromophores), aclasinomycin, actinomycin, autramycin, azaserin, bleomycin, kakutinomycin, carabicin, kaminomycin, cardinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine Antibiotics such as ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, and zolubicin;Antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folate analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamniprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; androgens such as carsterone, drostanolone propionate, epithiostanol, mepitiostane, and testolactone; adrenal inhibitors such as aminoglutethimide, mitotane, and trilostane; frolinic acid Folic acid supplements such as acid; acegraton; aldofamide glycoside; aminolevulinic acid; enyluracil; amsacrin; bestrabusil; bisanthren; edatraxate; defofamine; demecolsin; diazicon; elformithine; eriptinium acetate; epotilon; etogluside; gallium nitrate; hydroxyurea; lentinan; lonidainine; mayansinoids such as mayansin and anthamitocin; mitogluazone; mitoxantrone; mopidammol; nitraerine; pentostatin; fenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural, Eugene, Oregon) Products); Lazoxane; Rhizoxin; Sizofuran; Spirogermanium; Tenuazonic Acid; Triadicone; 2,2',2”-Trichlorotriethylamine; Trichothecenes (especially T-2 toxin, verracurin A, loridine A, and anguidin); Urethanes; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxoids, e.g., TAXOL (registered trademark) (Paclitaxel;ABRAXANE® (cremofol-free), an albumin-treated nanoparticle formulation of paclitaxel (Bristol-Myers Squibb Oncology, Princeton, New Jersey), (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (doxetaxel); (Antony, Rhone-Poulenc, France) Examples include Rorer; chlorambucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; and any pharmaceutically acceptable salts, acids, and derivatives of the above.

[0175] Examples of second (or further) drugs or treatments include immunotherapies, e.g., PD-1 inhibitors (pembrolizumab, nivolumab, cemiprimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonists, cell signaling inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab, etc.), and mitotic inhibitors (e.g., paclitaxel, vinca). Examples of anticancer agents include, but are not limited to, ristine, vinblastine, alkylating agents (e.g., cisplatin, cyclophosphamide, chlorambucil, carmustine, etc.), antimetabolites (e.g., methotrexate, 5-FU, etc.), intercalating anticancer agents (e.g., actinomycin, anthracyclines, bleomycin, mitomycin-C, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide, etc.), immunotherapeutic agents (e.g., interleukin, interferon, etc.), and antihormone agents (e.g., tamoxifen, raloxifene, etc.).

[0176] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention intends to include all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, within the scope of the invention. Additional chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers, and mixtures thereof, are intended to be included in the present invention.

[0177] Isomer mixtures having any of the various isomer ratios may be used in accordance with the present invention. For example, when only two isomers are combined, mixtures having isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are intended by the present invention. Those skilled in the art will readily understand that similar ratios are intended for more complex isomer mixtures.

[0178] For example, if a specific enantiomer of the compound of the present invention is desired, it may be prepared by asymmetric synthesis or by induction using a chiral auxiliary group, in which case the resulting diastereomer mixture is separated and the auxiliary group is cleaved to obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, the diastereomer salt is formed using a suitable optically active acid or base, and the diastereomer thus formed is subsequently separated by fractional crystallization or chromatography, which are well known in the art, and then the pure enantiomer is recovered.

[0179] Isotope-labeled compounds are also within the scope of this disclosure. As used herein, “isotope-labeled compound” refers to a compound of this disclosure, including its pharmaceutically acceptable salts and prodrugs, in which one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl is one example.

[0180] By isotope labeling the compounds of this disclosure, the compounds may be useful in drug and / or substrate tissue distribution assays. Tritiation ( 3 H) and carbon-14 ( 14 C) Labeled compounds are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium ( 2 Substitution with heavier isotopes, such as H), can result in certain therapeutic benefits due to superior metabolic stability, such as an increased in vivo half-life or a reduced dose, and may therefore be preferable in some situations. The isotope-labeled compounds of this disclosure, including their pharmaceutically acceptable salts, esters, and prodrugs, may be prepared by any means known in the art.

[0181] Furthermore, hydrogen is usually abundant 1 By substituting H) with a heavier isotope such as deuterium, certain therapeutic benefits can be obtained, for example, due to improved absorption, distribution, metabolism, and / or excretion (ADME) properties, and drugs with improved efficacy, safety, and / or tolerability can be created. 12 C 13 Benefits can also be gained by substituting with C. (See WO2007 / 005643, WO2007 / 005644, WO2007 / 016361, and WO2007 / 016431.)

[0182] Stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds disclosed herein, as well as racemates, diastereomers, and other mixtures of such isomers, are within the scope of this disclosure.

[0183] The compounds of the present invention, after their preparation, are preferably isolated and purified to obtain a composition containing 95% or more by weight ("substantially pure"), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention have a purity of more than 99%.

[0184] Solvates and polymorphs of the compounds of the present invention are also intended herein. Examples of solvates of the compounds of the present invention include hydrates.

[0185] Any suitable route of administration may be used, such as parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracavernosal, intraperitoneal, rectal, or oral administration. The most appropriate means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the treatment used and the nature of the active compound.

[0186] Compositions for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injection solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose, and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injection organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0187] These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as paragen, chlorobutanol, and phenolsorbic acid. The inclusion of isotonic agents such as sugars and sodium chloride may also be desirable. Sustained absorption of the pharmaceutical form for injection may be achieved by including absorption-delaying agents such as aluminum monostearate and gelatin.

[0188] The compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayers or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipids capable of forming liposomes may be used. The composition in liposomal form may contain stabilizers, preservatives, excipients, etc., in addition to the compounds of the present invention. Preferred lipids are both natural and synthetic phospholipids and phosphatidylcholine (lecithin). Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0189] The total daily dose of the composition of the present invention administered to a human or other mammalian host in a single or divided dose may be, for example, 0.0001 to 300 mg / kg body weight per day, more typically 1 to 300 mg / kg body weight. A dose of 0.0001 to 300 mg / kg body weight may be given twice a day.

[0190] The materials, compositions, and components disclosed herein are those that can be used for, in conjunction with, or in preparation thereof, or are products thereof, for the methods and compositions disclosed herein. Where combinations, subsets, interactions, groups, etc., of these materials are disclosed, specific references to various individual and collective combinations, as well as permutations, of each of these compounds may not be expressly disclosed, but it is understood that each is specifically contemplated and described herein. For example, where a method is disclosed and discussed, and several modifications that can be made to some molecules included in the method are discussed, all possible combinations and permutations of the method and possible modifications are specifically contemplated unless otherwise indicated. Similarly, any subsets or combinations thereof are also specifically contemplated and disclosed. This idea applies to all aspects of this disclosure, including, but not limited to, steps in methods using the compositions disclosed herein. Thus, where there are various additional steps that can be performed, each of these additional steps may be performed using any particular method step or combination of method steps of the disclosed method, and it is understood that each such combination or subset of combinations should be considered specifically contemplated and disclosed. [Examples]

[0191] The following examples are provided for illustrative purposes only and are not intended to limit the scope or spirit of the present invention.

[0192] The compounds of the present invention, including those specifically disclosed above and below in this specification, can be prepared as described in the following scheme. Although the present invention has been described in detail using preferred embodiments, those skilled in the art should understand that modifications, alterations, and equivalent substitutions made to the present invention within the scope of the present invention are protected by the present invention.

[0193] [Table 13] Table 14 Table 15 Table 16

[0194] Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28

[0195] General synthesis scheme [ka]

[0196] Scheme 1 illustrates one general procedure for preparing the disclosed compound using a metal-catalyzed reaction. A 2-chloro-4-amine-substituted quinazoline alkene intermediate is obtained by substituting the 4-chloro group of a 1,3-disubstituted quinazoline with a protected α-allyl-bridged piperazine or amine. Subsequently, an ether-substituted quinazoline intermediate is obtained by substituting the 2-chloro group with a suitable alcohol. This intermediate undergoes an intramolecular Heck reaction between an aryl bromide and an alkene to form a quinazoline condensed 7- or 8-membered ring with an exo-alkene group. After deprotonation and zincate formation, the desired aryl-aryl coupling product is obtained by Pd-catalyzed Negishi coupling with a suitable aryl halide. After removal of all protecting groups, the product is purified and subjected to SFC separation to obtain the desired diastereomer.

[0197] [ka]

[0198] Scheme 2 shows an alternative procedure for preparing the disclosed compound. The 4-chloro group of 1,3-disubstituted quinazoline was substituted with a protected α-allyl-bridged piperazine or amine, and then converted to 2-F by reacting 2-Cl with CsF. The 2-F quinazoline alkene forms a 2-F-7-arylquinazoline condensed 7- or 8-membered ring with an exo-alkene group via intramolecular Heck reaction and Negishi coupling with a suitable aryl halide. If necessary, the amine protecting group may be converted to another group. SNAr substitution of 2-F with a suitable alcohol yields an ether-substituted quinazoline intermediate. Removal of all protecting groups yields a diastereomer mixture, which can be separated by SFC to obtain the desired single diastereomer.

[0199] Synthesis of intermediates Intermediate 1 (1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane [ka]

[0200] Step 1: Synthesis of tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] In 245 mL of DMF, a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (15.0 g, 70.8 mmol, 1.0 eq) was added to K2CO3 (19.6 g, 141.5 mmol, 2.0 eq). The reaction mixture was then cooled to 0°C, and BnBr (18.1 g, 106.1 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 2 hours. HPLC and TLC indicated that the reaction was complete. The solution was diluted with water (750 mL) and extracted with RINKAN (150 mL x 3). The organic layer was separated, washed with water (50 mL) and saturated brine (50 mL), and dried over Na2SO4. After vacuum filtration and concentration, the crude product was purified by silica gel column chromatography (petroleum ether: dimethyl = 10:1) to obtain tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (15.0 g, 70.2%) as a yellow oil. LCMS: m / z 303.1 (M+H + )

[0201] Step 2: Synthesis of tert-butyl (1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] In 400 mL of THF, sec-butyllithium (264.8 mL, 264.8 mmol, 2.0 eq) was added dropwise to a solution of tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (40.0 g, 132.0 mmol, 1.0 eq) and N,N,N',N'-tetramethylethylenediamine (30.7 g, 264.8 mmol, 2.0 eq) under N2 conditions at -78°C. After stirring at -78°C for 40 minutes, 3-bromoprop-1-ene (79.2 g, 661.6 mmol, 5.0 eq) was added dropwise to 80 mL of THF. The reaction mixture was warmed to room temperature and stirred overnight. Then, saturated aqueous NaHCO3 (300 mL) was added to quench the reaction. The aqueous layer was separated and extracted with SiO2 (500 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over Na2SO4, concentrated, and the residue was obtained. The residue was purified by silica gel chromatography (eluting with petroleum ether:SiO2 = 30:1) to obtain four diastereomers as two separable spots. Each of these spots contained two enantiomers (spot 1 contained compounds C and D with lower molar concentrations, and spot 2 contained compounds A and B with greater polarity). The spot with greater polarity (spot 2, compounds A and B) was the desired racemic mixture, which was recovered as yellow oil (9.6 g, 21.2%). The stereochemistry of A and B was later confirmed using intermediates 1 and 2. A portion of this oil (5g, 14.6 mmol) was further separated by SFC, and two pure enantiomers: tert-butyl (1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (compound A; peak 1 in SFC, 1.2g, 5.1%) were obtained as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.45-7.15 (m, 5H), 5.88-5.58 (m, 1H), 5.10-4.90 (m, 2H), 3.67-3.47 (m, 3H), 3.40 (dd, J = 12.1, 1.8 Hz, 1H), 3.28 (dd, J = 12.1, 3.8 Hz, 1H), 3.20-3.15 (m, 3H), 2.20-2.06 (m, 1H), 2.07 -1.90 (m, 2H), 1.88-1.69 (m, 1H), 1.65-1.55 (m, 1H), 1.45 (s, 9H).LCMS: m / z 343.1 (M+H + )); and tert-butyl (1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (compound B, peak 2 in SFC, 1.1g, 4.7%) as yellow oil ( 1 H NMR (400 MHz, CDCl3) δ 7.45-7.15 (m, 5H), 5.88-5.58 (m, 1H), 5.10-4.90 (m, 2H), 3.67-3.47 (m, 3H), 3.40 (dd, J = 12.1, 1.8 Hz, 1H), 3.28 (dd, J = 12.1, 3.8 Hz, 1H), 3.20-3.15 (m, 3H), 2.20-2.06 (m, 1H), 2.07 -1.90 (m, 2H), 1.88-1.69 (m, 1H), 1.65-1.55 (m, 1H), 1.45 (s, 9H).LCMS: m / z 343.1 (M+H + I obtained it.

[0202] Step 3: Synthesis of (1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane [ka] In 8 mL of DCM, a solution of tert-butyl (1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (compound A, 3.0 g, 8.8 mmol, 1.0 eq) was added to TFA (15 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, (1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane TFA salt, as a yellow oil, which was used as is. LCMS: m / z 243.1 (M+H + )

[0203] Intermediate 2 (1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane [ka]

[0204] Step 1: Synthesis of (1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane [ka] In 5 mL of DCM, a solution of tert-butyl (1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (compound B obtained in step 2 of synthesis of intermediate 1, 540 mg, 1.58 mmol, 1.0 eq) was added to TFA (2.5 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain (1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane TFA salt as a yellow oil, which was used as is. LCMS: m / z 243.1 (M+H + )

[0205] Determination of the stereochemistry of intermediates 1 and 2 The stereochemistry of intermediates 1 and 2 was determined by chiral HPLC after derivatization to match intermediate 3, (1S,2R,5R)-2-allyl-8-benzyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, a common product prepared from the known chiral starting material. The results showed that the derivative derived from intermediate 1 was identical to that of intermediate 3.

[0206] Intermediate 3 (1S,2R,5R)-2-allyl-8-benzyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane (prepared from commercially available enantiomerically pure starting material, tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, as a chiral standard) [ka] Synthesis scheme [ka]

[0207] Step 1: Synthesis of tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] In 240 mL of DCM, a solution of known tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.0 g, 16.5 mmol, 1.0 eq) was mixed with TEA (3.3 g, 33.1 mmol, 2.0 eq) and 4-methoxybenzaldehyde (2.4 g, 17.3 mmol, 1.05 eq) at room temperature. After stirring at room temperature for 30 minutes, acetic acid (1.19 g, 19.8 mmol, 1.2 eq) and NaBH(OAc)3 (10.5 g, 49.6 mmol, 3.0 eq) were added. The mixture was stirred overnight and cooled to 0°C. A solution of KHCO3 (28 g in 100 mL of water) was added. The two layers were separated, and the aqueous layer was extracted with DCM (50 x 2 mL). The combined organic layers were washed with 5% NaHCO3 aqueous solution (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether: siRNA = 50:1) to obtain tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.2 g, 53.5%) as a white solid. LCMS: m / z 363.0 (M+H + )

[0208] Step 2: Synthesis of tert-butyl (1S,2S,5R)-3-(4-methoxybenzyl)-2-(((methylsulfonyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] In 7 mL of THF, a solution of tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was added to a solution of TEA (587 mg, 5.8 mmol, 3.0 eq) at room temperature. The mixture was cooled to 0°C, and Ms2O (505 mg, 2.9 mmol, 1.5 eq) was added. The solution was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. LC-MS: m / z 441.0 (M+H + ) NaI (5.1 g, 34.2 mmol, 18.0 eq) was added to the above solution at room temperature. The solution was heated overnight at 50°C and cooled to room temperature. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel chromatography (petroleum ether: siRNA = 3:1) to obtain tert-butyl (1S,2S,5R)-2-(iodomethyl)-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (613 mg, 67.2%) in two steps as a yellow oil. LCMS: m / z 472.9 (M+H + )

[0209] Step 3: Synthesis of tert-butyl (1S,2R,5R)-2-allyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] In 6.7 mL of THF, magnesium vinyl bromide (1 M, 18.06 mL, 18.06 mmol, 6.0 eq) was added to a solution of CuI (1.83 g, 9.63 mmol, 3.2 eq) under a N2 atmosphere at -40°C. The reaction mixture was stirred at the same temperature for 30 minutes. Next, tert-butyl (1S,2S,5R)-2-(iodomethyl)-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.42 g, 3.01 mmol, 1.0 eq) was added to 10 mL of THF. The reaction mixture was stirred at 10°C for 2 hours and diluted with toluene (35 mL), saturated ammonium chloride solution (35 mL), and ammonium hydroxide (7 mL). The mixture was extracted with toluene (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether: siRNA = 5:1) to obtain tert-butyl (1S,2R,5R)-2-allyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (305 mg, 27.2%) as a yellow oil. LCMS: m / z 373.0 ([M+H] + )

[0210] Step 4: Synthesis of (1S,2R,5R)-2-allyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane [ka] In a solution of tert-butyl (1S,2R,5R)-2-allyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (215 mg, 0.58 mmol, 1.0 eq) in DCM (5.8 mL), TFA (1.45 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain crude TFA salt (240 mg) as a yellow oil, which was used directly in the next step without further purification. LCMS: m / z 273.1 (M+H + )

[0211] Step 5: Synthesis of (1S,2R,5R)-2-allyl-8-benzyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane [ka] In 7.25 mL of DMF, a solution of (1S,2R,5R)-2-allyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane (240 mg, crude product) and K2CO3 (321 mg, 2.32 mmol, 4.0 eq) was added to BnBr (149 mg, 0.87 mmol, 1.5 eq) under an N2 atmosphere at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours and then diluted with H2O (5 mL). The mixture was extracted with ELISA (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (DCM:MeOH=15:1) to obtain (1S,2R,5R)-2-allyl-8-benzyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane (68 mg, 32.3%) in two steps as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.45 - 7.15 (m, 7H), 6.83 (d, J = 8.4 Hz, 2H), 5.59-6.56 (m, 1H), 5.10-4.90 (m, 2H), 4.04 (d, J = 12 Hz, 1H), 3.79 (s, 3H), 3.65-3.35 (m, 2H), 3.25-2.85 (m, 3H), 2.70-2.30 (m, 3H), 2.25 - 2.15 (m, 1H), 2.10-1.60 (m, 5H). LCMS: m / z 363.1 (M+H + )

[0212] Intermediate 3 is prepared from intermediate 1 to confirm its stereochemistry. [ka] In 1.0 mL of DMF, a solution of intermediate 1, (1S,2R,5R)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane (30 mg, 0.12 mmol, 1.0 eq), was prepared by adding K2CO3 (34 mg, 0.25 mmol, 2.0 eq) and PMBCl (25 mg, 0.16 mmol, 1.3 eq). The mixture was stirred at room temperature for 2 hours and quenched with water (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with H2O (10 mL) and saturated brine (10 mL x 2), dried over Na2SO4, and evaporated to dryness. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate l=3:1) to obtain the intermediate 3, (1S,2R,5R)-2-allyl-8-benzyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane (26 mg, 57.8%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.45 - 7.15 (m, 7H), 6.83 (d, J = 8.6 Hz, 2H), 5.59-6.56 (m, 1H), 5.10-4.90 (m, 2H), 4.04 (d, J = 13.5 Hz, 1H), 3.79 (s, 3H), 3.65-3.35 (m, 2H), 3.25-2.85 (m, 3H), 2.70-2.30 (m, 3H), 2.25 - 2.15 (m, 1H), 2.10-1.60 (m, 5H). LCMS: 363.2 (M+H) + )

[0213] Intermediate 4 (Enantiomer of Intermediate 3) From intermediate 2, (1R,2R,5S)-2-allyl-8-benzyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane [ka] In 1.0 mL of DMF, a solution of intermediate 2, (1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane (25 mg, 0.10 mmol, 1.0 eq), was prepared by adding K2CO3 (29 mg, 0.21 mmol, 2.0 eq) and PMBCl (21 mg, 0.13 mmol, 1.3 eq). The mixture was stirred at room temperature for 2 hours and quenched with water (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with H2O (10 mL) and saturated brine (10 mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate l=3:1) to obtain the intermediate 4, (1R,2R,5S)-2-allyl-8-benzyl-3-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane (17 mg, 45.9%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.45 - 7.15 (m, 7H), 6.83 (d, J = 8.4 Hz, 2H), 5.59-6.56 (m, 1H), 5.10-4.90 (m, 2H), 4.04 (d, J = 13.6 Hz, 1H), 3.79 (s, 3H), 3.65-3.35 (m, 2H), 3.25-2.85 (m, 3H), 2.70-2.30 (m, 3H), 2.25 - 2.15 (m, 1H), 2.10-1.60 (m, 5H). LCMS: 363.2 (M+H) + )

[0214] Determination of stereochemistry Using chiral HPLC, the racemic mixtures of intermediates 3 and 4, prepared from intermediates 1 and 2 respectively, were characterized. Peak 1 is consistent between intermediate 3 synthesized from the known chiral starting material, tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, and intermediate 3 synthesized from intermediate 1. Therefore, the stereochemistry of intermediates 1 and 2 was assigned accordingly. (Chiral HPLC conditions: Mobile phase: A is 0.1% TFA in H2O, B is 0.1% TFA in ACN. Gradient: A 60%. Column: OD-3R. Flow rate: 0.5 mL / min.)

[0215] Intermediate 5 4-((1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2-chloro-6,8-difluoroquinazoline [ka] Synthesis scheme: [ka]

[0216] Step 1: Synthesis of 3-bromo-4,6-difluoro-2-iodoaniline [ka] In 200 mL of EtOH, a solution of 5-bromo-2,4-difluoroaniline (10.0 g, 48.07 mmol, 1.0 eq) was prepared by adding iodine (13.42 g, 52.88 mmol, 1.1 eq) and silver sulfate (14.99 g, 48.07 mmol, 1.0 eq). The mixture was stirred at 25°C for 1 hour. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether) to obtain 3-bromo-4,6-difluoro-2-iodoaniline (7.5 g, 46.5%) as a red solid. 1 H NMR (300 MHz, DMSO-d6): δ 7.45 (dd, J = 11.1, 8.7 Hz, 1H), 5.33 (s, 2H)

[0217] Step 2: Synthesis of methyl 2-amino-6-bromo-3,5-difluorobenzoate [ka] In 148 mL of MeOH, a solution of 3-bromo-4,6-difluoro-2-iodoaniline (30.0 g, 89.8 mmol, 1.0 eq) was mixed with 209 mL of DMF, 27.3 g, 269.5 mmol, 3.0 eq, Pd(OAc)2 (1 g, 4.5 mmol, 0.05 eq), and dppf (1.25 g, 2.3 mmol, 0.025 eq). The mixture was stirred at 75°C for 15 hours under 0.4 MPa CO2. The mixture was concentrated to obtain the crude product. The mixture was diluted with 50 mL of water and extracted with ELISA (50 mL x 3). The organic layer was washed with water (100 mL x 2) and saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether: siRNA = 40:1) to obtain methyl 2-amino-6-bromo-3,5-difluorobenzoate (20.0 g, 83.7%) as a red liquid. 1 H NMR (400 MHz, DMSO-d6): δ 7.45 (dd, J = 11.2, 8.8 Hz, 1H), 5.55 (s, 2H), 3.87 (s, 3H)

[0218] Step 3: Synthesis of 2-amino-6-bromo-3,5-difluorobenzoic acid [ka] To a solution of 2-amino-6-bromo-3,5-difluorobenzoate (10 g, 37.6 mmol, 1.0 eq) in MeOH (185 mL), NaOH (3.0 g, 75.18 mmol, 2.0 eq) was added in water (185 mL). The mixture was stirred at 30°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain an intermediate. The pH of the solution was adjusted to 1 with 1 M HCl. The mixture was then filtered to obtain 2-amino-6-bromo-3,5-difluorobenzoic acid (5.1 g, 53.8%) as a yellow solid, which was used directly in the next step.

[0219] Step 4: Synthesis of 5-bromo-6,8-difluoroquinazoline-2,4-diol [ka] In 100 mL of DCM, a solution of 2-amino-6-bromo-3,5-difluorobenzoic acid (10 g, 39.7 mmol, 1.0 eq) was added to chlorosulfonyl isocyanate (12.9 g, 91.3 mmol, 2.3 eq) under a nitrogen atmosphere at 0°C. The mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and 300 mL of 6N HCl was added. The mixture was stirred at 100°C for 2 hours. The mixture was cooled to room temperature, filtered, and dried to obtain 5-bromo-6,8-difluoroquinazoline-2,4-diol (8.8 g, 80.1%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.43 (d, J = 66.4 Hz, 2H), 7.91 (s, 1H)

[0220] Step 5: Synthesis of 5-bromo-2,4-dichloro-6,8-difluoroquinazoline [ka] In POCl3 (20 mL), a solution of 5-bromo-6,8-difluoroquinazoline-2,4-diol (2.0 g, 7.25 mmol, 1.0 eq) was added to DIEA (2.0 mL). The mixture was stirred at 110 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude product, 5-bromo-2,4-dichloro-6,8-difluoroquinazoline, as a yellow oil (2.26 g), which was used as is.

[0221] Intermediate 6 [ka]

[0222] Synthesis of 4-((1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2-chloro-6,8-difluoroquinazoline [ka] In a 20 mL solution of 5-bromo-2,4-dichloro-6,8-difluoroquinazoline (intermediate 5, 2.26 g, 7.26 mmol, 1.0 eq), DIEA (8.2 g, 63.2 mmol, 8.7 eq) and tert-butyl (1R,2R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (intermediate 1, 2.1 g, 8.7 mmol, 1.2 eq) were added at -40°C under a nitrogen atmosphere. The mixture was stirred at -40°C for 2 hours, and water (30 mL) was added. The solution was extracted with 3 x 20 mL of DCM. The combined organic layers were washed with water (20 mL) and saturated brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether: siRNA = 30:1) to obtain 4-((1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2-chloro-6,8-difluoroquinazoline (2.6 g, 69.1%) as a yellow solid. LCMS: m / z 518.8, 520.8 (M+H + )

[0223] Intermediate 7 (1S,4R,14aR)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline [ka] Synthesis scheme: [ka]

[0224] Step 1: Synthesis of 4-((1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline [ka] To a solution of 4-((1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2-chloro-6,8-difluoroquinazoline (intermediate 6, 900 mg, 1.74 mmol, 1.0 eq), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (2.2 g, 13.9 mmol, 8.0 eq) and KF (205 mg, 3.53 mmol, 2.03 eq) were added. The mixture was stirred overnight at 100°C and diluted with H2O (55 mL). The solution was extracted with ELISA (20 mL x 3). The combined organic layers were washed with saturated saline (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether: siRNA = 3:1) to obtain 4-((1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline (700 mg, 62.7%) as a yellow solid. LCMS: m / z 641.9, 643.9 (M+H + )

[0225] Step 2: Synthesis of (1S,4R,14aR)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline [ka] In DMAc (24 mL), a solution of 4-((1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline (790 mg, 1.23 mmol, 1.0 eq) was added to KOAc (363 mg, 3.69 mmol, 3.0 eq), Pd(OAc)2 (28 mg, 0.12 mmol, 0.12 eq), and PPh3 (65 mg, 0.25 mmol, 0.2 eq) under a nitrogen atmosphere at room temperature. The mixture was stirred at 130 °C for 5 hours, and HPLC indicated that the reaction was complete. The reaction mixture was diluted with H2O (70 mL) and extracted with ELISA (20 mL x 3). The combined organic layer was washed with saturated saline (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (DCM:MeOH=60:1) to obtain (1S,4R,14aR)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline (280 mg, 40.6%) as a yellow solid. LCMS: m / z 562.0 (M+H + )

[0226] Intermediate 8 (1S,4R,14aR)-15-benzyl-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline [ka]

[0227] Step 1: 4-((1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2,6,8-trifluoroquinazoline [ka] In DMSO (8 mL), a solution of 4-(1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2-chloro-6,8-difluoroquinazoline (intermediate 6, 800 mg, 1.5 mmol, 1.0 eq) was added, to which KF (179 mg, 3.1 mmol, 2.0 eq) was added. The reaction mixture was then stirred under N2 at 90°C for 3 hours. HPLC and TLC indicated that the reaction was complete. The mixture was diluted with water (15 mL) and extracted with RINKAN (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography (eluting with petroleum ether:siRNA = 20:1) to obtain 4-((1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2,6,8-trifluoroquinazoline (620 mg, 80.1%) as a yellow oil. LCMS: m / z 503.1 (M+H + )

[0228] Step 2: (1S,4R,14aR)-15-benzyl-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline [ka] In DMAc (9 mL), a solution of 4-((1R,2R,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2,6,8-trifluoroquinazoline (310 mg, 0.62 mmol, 1.0 eq) was added, to which KOAc (181 mg, 1.85 mmol, 3.0 eq), PPh3 (32 mg, 0.12 mmol, 0.2 eq), and Pd(OAc)2 (14 mg, 0.06 mmol, 0.1 eq) were added. The reaction mixture was then stirred under N2 at 130 °C for 3 hours. The mixture was filtered, and the filtrate was diluted with water (15 mL) and extracted with ELISA (15 mL x 3). The combined organic layers were washed with saturated saline solution (20 mL), dried over Na2SO4, and the residue was purified by silica gel chromatography (eluting with petroleum ether:dimethyl 10:1) to obtain (1S,4R,14aR)-15-benzyl-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline (125 mg, 48.1%) as a yellow solid. LCMS: m / z 423.2 (M+H + )

[0229] Intermediate 9 6-((1S,4R,14aR)-15-benzyl-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Synthesis scheme: [ka]

[0230] Step 1: 6-((1S,4R,14aR)-15-benzyl-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] To a solution of (1S,4R,14aR)-15-benzyl-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline (intermediate 8, 210 mg, 0.50 mmol, 1.0 eq), (TMP)2Zn·2MgCl2·2LiCl was added to THF (0.4 M, 10 mL, 4 mmol, 8.0 eq) under N2 conditions. The mixture was stirred at 50°C for 1 hour. Quenching aliquots of the solution with D2O indicated that Zn-proton exchange was complete by LC-MS. Next, 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (295 mg, 0.60 mmol, 1.2 eq) and CPhos Pd G3 (40 mg, 0.05 mmol, 0.1 eq) were added to 1,4-dioxane (5 mL) in a solution. After heating the reaction mixture at 70°C for 3 hours, the solution was quenched with H2O (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated saline (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by silica gel chromatography (eluting with petroleum ether:HCl = 10:1) to obtain 6-((1S,4R,14aR)-15-benzyl-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (300 mg, 63.1%, including another 40 mg batch) as a yellow solid. LCMS: m / z 837.3 (M+H + )

[0231] Step 2: tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 5 mL of MeOH, a solution of 6-((1S,4R,14aR)-15-benzyl-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (50 mg, 0.06 mmol, 1.0 eq) was added to Pd / C (10 mol%, 30 mg) and (Boc)2O (20 mg, 0.09 mmol, 1.5 eq), and the mixture was hydrogenated in a hydrogen balloon at room temperature for 12 hours. The mixture was filtered, the filtrate was concentrated to obtain the crude product, which was purified by preparative TLC (PE:HCl=3:1) to obtain tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (50 mg, crude product) as a yellow solid. LCMS: m / z 847.3 (M+H + )

[0232] Intermediate 10 5-Bromo-2,4,6-trichloro-8-fluoroquinazoline [ka] Synthesis scheme: [ka]

[0233] Step 1: Synthesis of 3-bromo-4-chloro-6-fluoro-2-iodoaniline [ka] In 490 mL of EtOH, a solution of 5-bromo-4-chloro-2-fluoroaniline (24.5 g, 109.15 mmol, 1.0 eq) was mixed with iodine (30.47 g, 120.07 mmol, 1.1 eq) and silver sulfate (30.03 g, 109.15 mmol, 1.0 eq). The mixture was stirred at 25°C for 2 hours. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether) to obtain 3-bromo-4-chloro-6-fluoro-2-iodoaniline (33 g, 86.3%) as a red solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.54 (d, J = 10.8 Hz, 1H), 5.66 (s, 2H)

[0234] Step 2: Synthesis of methyl 2-amino-6-bromo-5-chloro-3-fluorobenzoate [ka] In 90 mL of MeOH, a solution of 3-bromo-4-chloro-6-fluoro-2-iodoaniline (20.0 g, 57.09 mmol, 1.0 eq) was mixed with 135 mL of DMF, 17.33 g, 171.26 mmol, 3.0 eq, Pd(OAc)2 (641 mg, 2.85 mmol, 0.05 eq), and dppf (791 mg, 1.43 mmol, 0.025 eq). The mixture was stirred at 75°C for 15 hours under 0.4 MPa CO2. The mixture was concentrated, diluted with water (50 mL), and extracted with RINKAN (50 mL x 3). The organic layer was washed with water (100 mL x 2) and saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether: siRNA = 80:1) to obtain methyl 2-amino-6-bromo-5-chloro-3-fluorobenzoate (9.0 g, 55.8%) as a red liquid. 1 H NMR (300 MHz, DMSO-d6): δ 7.52 (d, J = 11.1 Hz, 1H), 5.80 (s, 2H), 3.86 (s, 3H)

[0235] Step 3: Synthesis of 2-amino-6-bromo-5-chloro-3-fluorobenzoic acid [ka] In 160 mL of MeOH, a solution of methyl 2-amino-6-bromo-5-chloro-3-fluorobenzoate (8.95 g, 31.68 mmol, 1.0 eq) was added to 160 mL of water with NaOH (3.8 g, 95.05 mmol, 3.0 eq). The mixture was stirred at 45°C for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the MeOH. The resulting mixture was adjusted to approximately 1 pH with aqueous HCl. The mixture was then filtered and dried to obtain 2-amino-6-bromo-5-chloro-3-fluorobenzoic acid (7.6 g, 89.4%) as a white solid. LCMS: 265.8 (MH) - )

[0236] Step 4: Synthesis of 5-bromo-6-chloro-8-fluoroquinazoline-2,4-diol [ka] In 10 mL of DCM, a solution of 2-amino-6-bromo-5-chloro-3-fluorobenzoic acid (2 g, 7.45 mmol, 1.0 eq) was added to chlorosulfonyl isocyanate (2.64 g, 18.63 mmol, 2.5 eq) under N2 at 0°C. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and 600 mL of 6N HCl was added, and the mixture was stirred at 100°C for 2 hours. The mixture was then slowly cooled to room temperature to precipitate the solid, and the mixture was filtered and dried to obtain 5-bromo-6-chloro-8-fluoroquinazoline-2,4-diol (1.56 g, 71.4%) as a yellow solid. LCMS: 290.8 (MH) - )

[0237] Step 5: Synthesis of 5-bromo-2,4,6-trichloro-8-fluoroquinazoline [ka] In POCl3 (30 mL), a solution of 5-bromo-6-chloro-8-fluoroquinazoline-2,4-diol (3.0 g, 10.22 mmol, 1.0 eq) was added to DIEA (3.0 mL). The mixture was stirred at 110 °C for 5 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain 5-bromo-2,4,6-trichloro-8-fluoroquinazoline (4.2 g, crude product) as a brown oil.

[0238] Intermediate 11 4-((1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6-chloro-2,8-difluoroquinazoline [ka] Synthesis scheme: [ka]

[0239] Step 1: Synthesis of 4-((1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2,6-dichloro-8-fluoroquinazoline [ka] In a solution of 5-bromo-2,4,6-trichloro-8-fluoroquinazoline (3.39 g, 10.27 mmol, 1.0 eq) in DCM (40 mL), DIEA (11.55 g, 89.38 mmol, 8.7 eq) and (1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane (3.36 g, 12.33 mmol, 1.2 eq) were added at -40°C under a nitrogen atmosphere. The mixture was stirred at -40°C for 2 hours, diluted with water (30 mL), and extracted with DCM (20 mL x 3). The organic layer was washed with water (20 mL) and saturated saline (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel column chromatography (petroleum ether: siRNA = 15:1) to obtain 4-((1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2,6-dichloro-8-fluoroquinazoline (4.45 g, 76.5% in two steps) as a yellow solid. LCMS: 564.8 (M+H+ )

[0240] Step 2: 4-((1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6-chloro-2,8-difluoroquinazoline [ka] In DMSO (20 mL), a solution of 4-((1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2,6-dichloro-8-fluoroquinazoline (2.2 g, 3.89 mmol, 1.0 eq) was added, to which KF (903 mg, 15.54 mmol, 4.0 eq) was added. The reaction mixture was then stirred under N2 at 100 °C for 3 hours. HPLC and TLC indicated that the reaction was complete. The mixture was diluted with water (20 mL) and extracted with Âr (20 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography (eluting with petroleum ether:HCl = 10:1) to obtain 4-((1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6-chloro-2,8-difluoroquinazoline (1.8 g, 84.3%) as a yellow solid. LCMS: 548.8 (M+H + )

[0241] Intermediate 12 (1S,4R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline [ka] Synthesis scheme: [ka]

[0242] Step 1: 4-((1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline [ka] In 6 mL of THF, a solution of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (132 mg, 0.83 mmol, 1.2 eq) was added to NaH (in oil, 60%, 83 mg, 2.07 mmol, 3.0 eq), and the mixture was subsequently stirred under N2 for 0.5 hours. In 2 mL of THF, a solution of 4-((1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6-chloro-2,8-difluoroquinazoline (380 mg, 0.69 mmol, 1.0 eq) was added to the mixture, and the mixture was stirred at 25°C for 3 hours. HPLC and TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with siRNA (10 mL x 3). The combined organic layer was concentrated to obtain the crude product. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to obtain 4-((1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline (400 mg, 84.1%) as a yellow solid. LCMS: 687.8 (M+H + )

[0243] Step 2: (1S,4R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline [ka] In 4.8 mL of DMF, a solution of 4-((1S,2R,5R)-2-allyl-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline (400 mg, 0.58 mmol, 1.0 eq) was added to Cs2CO3 (227 mg, 0.70 mmol, 1.2 eq), Pd(OAc)2 (13 mg, 0.06 mmol, 0.1 eq), and PPh3 (38 mg, 0.15 mmol, 0.25 eq) under a nitrogen atmosphere at room temperature. The mixture was stirred under N2 at 80°C for 7 hours. HPLC showed that the reaction was complete. Next, H2O (15 mL) was added to the reaction mixture and extracted with siRNA (15 mL x 3). The combined organic layer was washed with saturated brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (DCM:MeOH=80:1) to obtain (1S,4R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline (273 mg, 77.3%) as a yellow solid. LCMS: 608.0 (M+H + )

[0244] Intermediate 13 4-Chloro-N,N-bis(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Synthesis scheme: [ka]

[0245] Step 1: Synthesis of 4-chloro-5-iodo-6-methylpyridine-2-amine [ka] In 60 mL of DMF, a solution of 4-chloro-6-methylpyridine-2-amine (6.0 g, 42.2 mmol, 1.0 eq) was mixed with NIS (10.0 mg, 44.4 mmol, 1.05 eq). The reaction mixture was stirred at 70°C for 3 hours under an N2 atmosphere. The reaction mixture was quenched with sodium thiosulfate (100 mL) and extracted with toluene (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:toluene = 4:1) to obtain 4-chloro-5-iodo-6-methylpyridine-2-amine (6.9 g, 60.9%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6): δ 6.47 (s, 1H), 6.30 (brs, 2H), 2.52 - 2.48 (m, 3H). LCMS: m / z 268.9 (M+H + ) Step 2: Synthesis of 4-chloro-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridine-2-amine [ka]

[0246] In 128 mL of DMF, a solution of 4-chloro-5-iodo-6-methylpyridine-2-amine (8.5 g, 31.7 mmol, 1.0 eq) was added to NaH (60%, 3.8 g, 95.2 mmol, 3.0 eq) at 0°C. The reaction mixture was stirred at 0°C for 1 hour under an N2 atmosphere. PMBCl (9.9 g, 63.4 mmol, 2.0 eq) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 1 hour. The reaction product was quenched with H2O (637 mL). The mixture was filtered and washed with water (200 mL). The filtered cake was diluted with methanol (50 mL) and filtered. The filtered cake was evaporated to dryness to obtain 4-chloro-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridine-2-amine (14.7 g, 91.2%) as a brown solid. 1H NMR (300 MHz, CDCl3): δ 7.18 - 7.08 (m, 4H), 6.89 - 6.79 (m, 4H), 6.42 (s, 1H), 4.64 (s, 4H), 3.79 (s, 6H), 2.70 (s, 3H). LCMS: m / z 509.1 (M+H + )

[0247] Step 3: Synthesis of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] In 340 mL of DMF, a solution of 4-chloro-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridine-2-amine (34 g, 66.9 mmol, 1.0 eq) was added to methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (32.1 g, 167.3 mmol, 2.5 eq) and CuI (38.2 g, 200.8 mmol, 3.0 eq). The reaction mixture was stirred at 100 °C for 15 hours under an N2 atmosphere. The reaction mixture was quenched with H2O (150 mL). The mixture was filtered, washed with RINKAN (200 mL), and separated. The aqueous layer was extracted with RINKAN (200 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, filtered, concentrated, and a crude product was obtained. The crude product was purified by silica gel column chromatography (petroleum ether: dimethyl = 1:1) to obtain 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine (18.8 g, 62.4%) as a brown solid. 1 H NMR (300 MHz, CDCl3): δ 7.20 - 7.08 (m, 4H), 6.93 - 6.79 (m, 4H), 6.39 (s, 1H), 4.68 (s, 4H), 3.80 (s, 6H), 2.64 - 2.54 (m, 3H). LCMS: m / z 451.1 (M+H + )

[0248] Intermediate 14 tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate [ka] Synthesis scheme: [ka]

[0249] Step 1: Synthesis of 4-chloro-5-fluoronicotinaldehyde [ka] To a solution of DIPA (120.0 g, 1.2 mol, 1.2 eq) in THF (1.3 L), 2.5 M n-BuLi was added in THF (474.4 mL, 1.2 mol, 1.2 eq) at -30°C. The reaction mixture was stirred at the same temperature for 30 minutes. To the solution, 4-chloro-3-fluoropyridine (130.0 g, 988.3 mmol, 1.0 eq) was added in THF (260 mL) at -78°C. The reaction mixture was stirred at -78°C for 8 hours. DMF (86.7 g, 1.2 mol, 1.2 eq) was added to the mixture. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was quenched with saturated NH4Cl aqueous solution (1 L) at 0°C. The resulting mixture was extracted with RINKAN (1 L x 2). The combined organic phases were washed with H2O (1 L x 2) and saturated brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-chloro-5-fluoronicotinaldehyde (180.0 g, crude product) as a yellow solid. 1 H NMR (300 MHz, CDCl3): δ 10.47 (s, 1H), 8.88 (s, 1H), 8.70 (s, 1H)

[0250] Step 2: Synthesis of (4-chloro-5-fluoropyridine-3-yl)methanol [ka] In 600 mL of MeOH, a solution of 60.0 g, 376.2 mmol, 1.0 eq of 4-chloro-5-fluoronicotinaldehyde was added to a solution of 17.1 g, 451.4 mmol, 1.2 eq of NaBH4 at 0°C. The mixture was stirred at the same temperature for 1 hour. The reaction product was quenched with 500 mL of saturated NaHCO3 aqueous solution. The resulting mixture was extracted with HCl (500 mL x 3). The combined organic phase was washed with 500 mL of saturated brine, dried over Na2SO4, filtered, concentrated, and the residue was obtained. The reaction was repeated three times with a total of 180.0 g of 4-chloro-5-fluoronicotinaldehyde. The residue was purified by silica gel column chromatography (petroleum ether:HCl = 3:1) to obtain (4-chloro-5-fluoropyridine-3-yl)methanol (70.0 g, 43.8%) as a yellow solid in two steps. 1 H NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 8.45 (s, 1H), 4.86 (d, J = 3.3 Hz, 1H). LCMS: 162.1 (M+H + )

[0251] Step 3: Synthesis of 4-chloro-3-(chloromethyl)-5-fluoropyridine [ka] In 200 mL of DCM, a solution of (4-chloro-5-fluoropyridine-3-yl)methanol (20.0 g, 123.8 mmol, 1.0 eq) was added dropwise to SOCl2 (17.7 g, 14.9 mmol, 1.2 eq) under an N2 atmosphere at 0°C. The reaction mixture was stirred at room temperature for 18 hours. The reaction was carried out twice with a total of 54.0 g of (4-chloro-5-fluoropyridine-3-yl)methanol. The mixture was quenched with H2O (300 mL) and separated. The resulting mixture was extracted with RINKAN (300 mL x 3). The combined organic phase was washed with saturated brine (300 mL), dried over Na2SO4, filtered, and concentrated to obtain 4-chloro-3-(chloromethyl)-5-fluoropyridine (65.0 g, crude product) as a yellow solid. LCMS: 180.0 (M+H + )

[0252] Step 4: Synthesis of 2-(4-chloro-5-fluoropyridine-3-yl)acetonitrile [ka] In 650 mL of ACN, a solution of 4-chloro-3-(chloromethyl)-5-fluoropyridine (65.0 g, 361.1 mmol, 1.0 eq) and TMSCN (179.1 g, 1.8 mol, 5.0 eq) was added to 650 mL of THF (472.1 g, 1.8 mol, 5.0 eq) at 0°C. The reaction mixture was stirred at room temperature for 1 hour under an N2 atmosphere. The reaction mixture was diluted with toluene (1 L), washed with H2O (1 L x 3) and saturated brine (1 L), dried over Na2SO4, filtered, concentrated, and the residue was obtained. The residue was purified by silica gel column chromatography (petroleum ether:toluene = 3:1) to obtain 2-(4-chloro-5-fluoropyridine-3-yl)acetonitrile (31.0 g, 50.2%) as a yellow solid. LCMS: 171.0 (M+H + )

[0253] Step 5: Synthesis of ethyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate [ka] In 150 mL of DMF, a solution of 2-(4-chloro-5-fluoropyridine-3-yl)acetonitrile (15.0 g, 87.9 mmol, 1.0 eq) was mixed with NaH (60%, 4.2 g, 105.5 mmol, 1.2 eq) at 0°C. The mixture was stirred at the same temperature for 0.5 hours. The compound ethoxycarbonyl isothiocyanate (23.1 g, 175.8 mmol, 2.0 eq) was added to the mixture. The mixture was stirred at 100°C for 1 hour. The reaction mixture was quenched with H2O (100 mL). The pH of the mixture was adjusted to approximately 6 with 300 mL of 5% citric acid aqueous solution. The formed precipitate was filtered, washed with H2O (500 mL), and vacuum-dried to obtain ethyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (17.0 g, crude product) as a yellow solid. LCMS: 266.0 (M+H + )

[0254] Step 6: Synthesis of 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitride [ka] A solution of ethyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (17.0 g, 64.1 mmol, 1.0 eq) was added to 5 M NaOH aqueous solution (340 mL, 1.7 mol, 26.5 eq) in DMSO (170 mL). The mixture was stirred at 105 °C for 1.5 hours and then cooled to room temperature. The reaction mixture was poured into an ice / water mixture (700 mL), stirred until all the ice had melted, filtered, and washed with H2O (300 mL). The solid was vacuum-dried to obtain crude 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitride. The aqueous layer was extracted with RINKAN (800 mL x 3). The combined organic layers were washed with saturated brine (800 mL), dried over Na2SO4, and evaporated to dryness to obtain compound 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (17.0 g, crude product) as a yellow solid. LCMS: 194.1 (M+H + )

[0255] Step 7: Synthesis of tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate [ka] A mixture of crude 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (17.0 g, 88.0 mmol, 1.0 eq), DCM (170 mL), DMF (170 mL), and DIEA (39.1 g, 264.0 mmol, 3.0 eq) was cooled to 0°C. DMAP (1.1 g, 8.8 mmol, 0.1 eq) and (Boc)2O (23.0 g, 105.6 mmol, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction product was diluted with DCM (400 mL) and 5% citric acid aqueous solution (250 mL). The aqueous phase was washed with DCM (400 mL x 2). The combined organic phases were washed with H2O (300 mL x 3), saturated NaHCO3 aqueous solution (300 mL), and saturated brine (300 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: siRNA = 3:1) to obtain tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (7.0 g, 27.1%) as a yellow solid in 3 steps. 1 H NMR (300 MHz, CDCl3): δ 8.83 (s, 1H), 8.36 (s, 1H), 8.00 (brs, 1H), 1.60 (s, 9H). LCMS: 294.2 (M+H + )

[0256] Step 8: Synthesis of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide [ka] 3-Chloroperbenzoic acid (883 mg, 5.1 mmol, 1.5 eq) was added to a solution of tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (1.0 g, 3.4 mmol, 1.0 eq) in DCM (20 mL). The reaction mixture was stirred overnight at room temperature. The solid was collected by filtration and vacuum-dried. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH=30:1) to obtain 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (850 mg, 81.0%) as a grayish-white solid. LCMS: 310.2 (M+H + )

[0257] Step 9: Synthesis of tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate [ka] A suspension of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (850 mg, 2.7 mmol, 1.0 eq) was cooled to 0°C in 1,2-dichloroethane (5 mL). A solution of phosphoryl chloride (8.4 g, 55.0 mmol, 20.0 eq) was added dropwise to 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 30 minutes and then at 45°C for 2 hours, and then cooled to room temperature. The reaction mixture was concentrated to obtain a crude product. The crude product was dissolved in THF (10 mL). DIEA (1.1 g, 8.2 mmol, 3.0 eq), DMAP (34 mg, 0.27 mmol, 0.1 eq), and (Boc)2O (719 mg, 3.3 mmol, 1.2 eq) were added to the mixture at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 5% citric acid aqueous solution (10 mL) and extracted with toluene (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:toluene = 3:1) to obtain tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (414 mg, 46.0%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 12.24 (brs, 1H), 8.34 (s, 1H), 1.54 (s, 9H). LCMS: 328.3 (M+H + )

[0258] Intermediate 15 (2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methane-d2-ol [ka] Synthesis scheme [ka]

[0259] Step 1: (2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methane-d 2 - All synthesis To a suspension of iAlD4 (155 mg, 3.4 mmol, 1.5 eq) in LTHF (5 mL), methyl 2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (500 mg, 2.3 mmol, 1.0 eq) was added in THF (5 mL) at 0°C. The reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was sequentially quenched with H2O (0.15 mL), 15% NaOH aqueous solution (0.15 mL), and H2O (0.45 mL). The mixture was dried over Na2SO4, filtered, concentrated, and a crude product was obtained. The crude product was purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain (2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methane-d2-ol (330 mg, 75.0%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 3.65 (d, J = 14.8 Hz, 1H), 3.35 (d, J = 14.4 Hz, 1H), 3.26 - 3.14 (m, 1H), 2.95 (brs, 1H), 2.72 - 2.62 (m, 1H), 2.52 - 2.30 (m, 2H), 2.08 - 1.72 (m, 4H)

[0260] Intermediate 16 6-Chloro-5-(difluoromethyl)-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine [ka] Synthesis scheme [ka]

[0261] Step 1: Synthesis of 6-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-5-vinylpyridine-2-amine [ka] In 50.0 mL of THF, a solution of 6-chloro-5-iodo-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine (5.0 g, 9.8 mmol, 1.0 eq) was added to tributyl(vinyl) stannane (4.7 g, 14.8 mmol, 1.5 eq) and XPhos Pd G3 (833 mg, 0.98 mmol, 0.1 eq) at room temperature. The reaction mixture was stirred at 50°C for 15 hours under N2. The mixture was partitioned with RINKAN (100 mL) and HCl (100 mL). Liquid-liquid extraction was performed. The aqueous layer was extracted with RINKAN (100 mL x 2). The combined organic layers were washed with H2O (40 mL) and saturated brine (100 mL x 2), dried over Na2SO4, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether:DCM=2:1) ​​to obtain 6-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-5-vinylpyridine-2-amine (6.0 g, crude product) as a yellow solid. LCMS: 409.3 (M+H + )

[0262] Step 2: Synthesis of 6-(bis(4-methoxybenzyl)amino)-2-chloro-4-methylnicotinaldehyde [ka] In 180 mL of THF and 18 mL of H2O, a solution of 6-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-5-vinylpyridine-2-amine (6.0 g, 14.7 mmol, 1.0 eq) was added to NaIO4 (19.0 g, 88.2 mmol, 6.0 eq) and K2OsO4·2H2O (458 mg, 1.5 mmol, 0.1 eq). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 15 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether:DCM = 1:1) to obtain 6-(bis(4-methoxybenzyl)amino)-2-chloro-4-methylnicotinaldehyde (1.6 g, 26.5%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 10.39 (s, 1H), 7.14 (d, J = 8.4 Hz, 4H), 6.92 - 6.80 (m, 4H), 6.19 (s, 1H), 4.71 (s, 4H), 3.80 (s, 6H), 2.49 (s, 3H). LCMS: 411.4 (M+H + )

[0263] Step 3: Synthesis of 6-chloro-5-(difluoromethyl)-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine [ka] In 12.0 mL of DCE, a solution of 6-(bis(4-methoxybenzyl)amino)-2-chloro-4-methylnicotinaldehyde (1.2 g, 2.9 mmol, 1.0 eq) was mixed with DAST (943 mg, 5.9 mmol, 2.0 eq). The reaction mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (40 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with H2O (20 mL) and saturated brine (20 mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether:DCM = 2:1) to obtain 6-chloro-5-(difluoromethyl)-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine (533 mg, 42.2%) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 7.25 - 6.94 (m, 5H), 6.90 - 6.81 (m, 4H), 6.21 (s, 1H), 4.66 (s, 4H), 3.80 (s, 6H), 2.36 (s, 3H)

[0264] Intermediate 17 tert-butyl (4-bromo-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)(tert-butoxycarbonyl)carbamate [ka] Synthesis scheme [ka]

[0265] Step 1: Synthesis of 4-chloro-5-fluoronicotinaldehyde [ka] A solution of diisopropylamine (232.7 g, 2.3 mol, 1.2 eq) in THF (2.5 L) was cooled to -30°C, and 2.5 M n-BuLi was added to n-hexane (0.92 L, 2.3 mol, 1.2 eq), and the mixture was stirred at -30°C for 20 minutes. Next, 4-chloro-3-fluoropyridine (250.0 g, 1.9 mol, 1.0 eq) was added to the mixture cooled to -78°C, and the mixture was stirred at -78°C for 9 hours. Next, DMF (168.1 g, 2.3 mol, 1.2 eq) was added to the reaction product, and the mixture was stirred at room temperature for 15 minutes. The mixture was quenched with saturated ammonium chloride aqueous solution (2.0 L) and extracted with RINKAN (2.0 L x 3). The combined organic layers were washed with saturated brine (1.0 L), dried over Na2SO4, filtered, and concentrated to obtain crude 4-chloro-5-fluoronicotinaldehyde (360.0 g, crude product) as a yellow oil. 1 H NMR (300 MHz, CDCl3): δ 10.45 (s, 1H), 8.87 (s, 1H), 8.69 (s, 1H)

[0266] Step 2: Synthesis of (4-chloro-5-fluoropyridine-3-yl)methanol [ka] In 3.6 L of MeOH cooled to 0°C, a solution of 4-chloro-5-fluoronicotinaldehyde (360.0 g, 2.3 mol, 1.0 eq) was added to NaBH4 (94.6 g, 2.5 mmol, 1.1 eq). The reaction mixture was stirred at 0°C for 1 hour. The mixture was quenched with saturated sodium bicarbonate aqueous solution (2.0 L) and extracted with Depositphotos (2.0 L x 3). The combined organic layers were washed with saturated brine (2.0 L), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / Depositphotos = 20:1) to obtain (4-chloro-5-fluoropyridine-3-yl)methanol (130.0 g, 52.3%) as a white solid in two steps. 1 H NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 8.45 (s, 1H), 4.86 (d, J = 3.6 Hz, 1H)

[0267] Step 3: Synthesis of 4-chloro-3-(chloromethyl)-5-fluoropyridine [ka] In 1.3 L of DCM cooled to 0°C, a solution of (4-chloro-5-fluoropyridine-3-yl)methanol (130.0 g, 0.8 mol, 1.0 eq) was mixed with SOCl2 (119.0 g, 1.0 mol, 1.2 eq). The reaction mixture was stirred at room temperature for 24 hours. The mixture was quenched with water (1.0 L) and extracted with DCM (1.0 L x 3). The combined organic layers were washed with saturated brine (1.0 L), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / Âi = 5:1) to obtain 4-chloro-3-(chloromethyl)-5-fluoropyridine (120.0 g, 82.9%) as a yellow solid. LCMS: m / z 180.1 ([M+H] + )

[0268] Step 4: Synthesis of 2-(4-chloro-5-fluoropyridine-3-yl)acetonitrile [ka] To a solution of 4-chloro-3-(chloromethyl)-5-fluoropyridine (120.0 g, 0.67 mol, 1.0 eq) and TMSCN (332.3 g, 3.35 mol, 5.0 eq) in ACN (2.4 L), TBAF (875.9 g, 3.35 mol, 5.0 eq) was added in THF (2.4 L) at 0°C. The reaction mixture was stirred at room temperature for 15 hours. The mixture was quenched with water (500 mL) and extracted with RINKAN (1.0 L x 2). The combined organic layer was washed with saturated brine (1.0 L), dried over Na2SO4, filtered, concentrated, and a crude product was obtained. The crude product was purified by silica gel column chromatography (petroleum ether / RINKAN = 5:1) to obtain 2-(4-chloro-5-fluoropyridine-3-yl)acetonitrile (85.0 g, 74.7%) as a yellow solid. 1 H NMR (300 MHz, CD3Cl3): δ 8.69 - 8.50 (m, 2H), 3.85 (s, 2H)

[0269] Step 5: Synthesis of ethyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate [ka] In 850 mL of DMF cooled to 0°C, a solution of 2-(4-chloro-5-fluoropyridine-3-yl)acetonitrile (85.0 g, 0.50 mol, 1.0 eq) was added to NaH (24.0 g, 0.60 mol, 1.2 eq), and the reaction mixture was stirred at 0°C for 0.5 hours. Next, O-ethyl carbon isothiocyanate (65.6 g, 0.60 mol, 1.2 eq) was added to the mixture, and the reaction mixture was stirred at 100°C for 2 hours. The mixture was quenched with water (1.0 L), filtered, and ethyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (100.0 g, crude product) was obtained as a yellow solid. LCMS: m / z 266.0 ([M+H] + )

[0270] Step 6: Synthesis of 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitride [ka] A solution of ethyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (100.0 g, 0.38 mol, 1.0 eq) was added to DMSO (1.0 L) with 4 M NaOH aqueous solution (2.0 L). The reaction mixture was stirred at 105°C for 2 hours. The mixture was poured into ice water (2.0 L), filtered, and 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (60.0 g, crude product) was obtained as a yellow solid. LCMS: m / z 194.0 ([M+H] + )

[0271] Step 7: Synthesis of tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate [ka] In 600 mL of DCM cooled to 0°C, a solution of 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (60.0 g, 0.31 mol, 1.0 eq) and DIEA (120.0 g, 0.93 mol, 3.0 eq) was prepared by adding Boc2O (81 g, 0.37 mol, 1.2 eq) and DMAP (1.9 g, 15.5 mmol, 0.05 eq). The reaction mixture was stirred at room temperature for 12 hours. The mixture was quenched with 400 mL of 5% aqueous citric acid solution and extracted with RINKAN (400 mL x 3). The combined organic layers were washed with saturated brine (400 mL), dried over Na2SO4, filtered, concentrated, and the crude product was obtained. The crude product was purified by silica gel column chromatography (petroleum ether / dimethyl = 1:1) to obtain tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (36.0 g, 41.0%) as a white solid in 3 steps. LCMS: m / z 294.1 ([M+H] + )

[0272] Step 8: Synthesis of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-5-oxide [ka] In 360 mL of DCM, m-CPBA (24.2 g, 0.14 mmol, 1.2 eq) was added to a solution of tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate. The reaction mixture was stirred at room temperature for 15 hours. The mixture was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 30:1) to obtain 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (29.0 g, 76.4%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 8.71 (brs, 1H), 8.47 (s, 1H), 8.12 (d, J = 4.4 Hz, 1H), 1.59 (s, 9H)

[0273] Step 9: Synthesis of tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate [ka] In 10 mL of DCE, POBr3 (1.4 g, 4.85 mmol, 1.5 eq) and PhNMe2 (1.2 g, 9.69 mmol, 3.0 eq) were added at 0°C to a solution of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (1.0 g, 3.23 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to obtain the crude product. The crude product was purified by flash (DCM / MeOH = 30:1) to obtain tert-butyl (4-bromo-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (0.5 g, 41.7%) as a white solid. LCMS: m / z 371.9, 374.0 ([M+H] + )

[0274] Intermediate 18 (1S,4R,14aR)-8,10-difluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-12-carbonitrile [ka] Synthesis scheme [ka]

[0275] In 5 mL of NMP, a solution of (1S,4R,14aR)-12-chloro-8,10-difluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline (300.0 mg, 0.64 mmol, 1.0 eq) was added to Zn(CN)2 (75.0 mg, 5.12 mmol, 8.0 eq) and Pd(t-Bu3P)2 (164.0 mg, 0.32 mmol, 0.5 eq) at room temperature under N2 conditions. The sealed vial was irradiated with microwaves at 140°C for 30 minutes. The reaction mixture was diluted with water (15 mL) and extracted with ELISA (20 mL x 3). The organic layer was washed with water (10 mL) and saturated saline (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to obtain the residue, which was purified by silica gel column chromatography (petroleum ether / dimethyl = 6:1) to obtain (1S,4R,14aR)-8,10-difluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-12-carbonitrile (60.0 mg, 20.3%) as a yellow solid. LCMS: 460.2 (M+H + )

[0276] Intermediate 19 tert-butyl (1S,4R,14aR)-11-bromo-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-12-(trifluoromethyl)-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] Synthesis scheme [ka]

[0277] Step 1: Synthesis of 2-amino-6-bromo-3-fluoro-5-iodobenzoic acid [ka] In 100 mL of DMF, a solution of 2-amino-6-bromo-3-fluorobenzoic acid (11 g, 47.0 mmol) was mixed with N-iodosulfirimine (8.94 g, 51.7 mmol). The reaction mixture was stirred at 80°C under N2 for 2 hours. The cooled reaction mixture was quenched with water, extracted with toluene (30 mL x 3), washed with water and saturated brine, dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (in DCM, MeOH = 0-10%) to obtain 2-amino-6-bromo-3-fluoro-5-iodobenzoic acid (11.5 g, 31.9 mmol, 67%) as an orange solid. LC / MS (ESI) m / z: 360.1 [M+H] +

[0278] Step 2: Synthesis of 5-bromo-8-fluoro-6-iodoquinazoline-2,4(1H,3H)-dione [ka] In 45 mL of DCM, chlorosulfonyl isocyanate (10.4 g, 73.4 mmol) was added dropwise to a solution of 2-amino-6-bromo-3-fluoro-5-iodobenzoic acid (11.5 g, 31.9 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. Next, HCl (200 mL, 6 mol) was added and the mixture was stirred at 100°C for 2 hours. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with water and dried under reduced pressure to obtain 5-bromo-8-fluoro-6-iodo-1,2,3,4-tetrahydroquinazoline-2,4-dione (11.5 g, 29.8 mmol, 93%) as a gray solid. LCMS: ESI m / z 385.1 [M + H] +

[0279] Step 3: 5-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline [ka] In a solution of 5-bromo-6,8-difluoroquinazoline-2,4-diol (10 g, 36.1 mmol) in ACN (100 mL) and POCl3 (27.8 g, 181 mmol), DIEA (11.7 g, 90.9 mmol) was added, and the mixture was stirred overnight at 110 °C. The cooled mixture was concentrated under vacuum to obtain the crude product, which was poured into saturated NaHCO3 and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (in PE, EA = 0-10%) to obtain 5-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (6.5 g, 15.409 mmol, 84%) as a yellow solid. LC / MS (ESI) m / z: 423.1 [M+H] +

[0280] Step 4: Synthesis of tert-butyl (1S,2R,5R)-2-allyl-3-(5-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] In a 5 mL solution of 5-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (7 g, 16.6 mmol), 2-methylpropan-2-yl(1S,2R,5R)-2-(prop-2-enyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.03 g, 19.9 mmol) and DIEA (6.43 g, 49.7 mmol) were added. The reaction mixture was stirred at -50°C under N2 for 2 hours. The cooled reaction mixture was quenched with water, extracted with 3 x 100 mL of DCM, washed with water and saturated saline, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE, EA = 0-20%) to obtain 2-methylpropan-2-yl(1S,2R,5R)-3-(5-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2-(prop-2-enyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.5 g, 10.2 mmol, 61%) as a yellow solid. LC / MS (ESI) m / z: 639.1 [M+H] +

[0281] Step 5: Synthesis of tert-butyl (1S,2R,5R)-2-allyl-3-(5-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] In DMA (90 mL), a solution of 2-methylpropan-2-yl(1S,2R,5R)-3-(5-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2-(prop-2-enyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.5 g, 10.193 mmol) was added to CuI (3.88 g, 20.4 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (11.75 g, 61.2 mmol). The reaction mixture was stirred at 100 °C under N2 for 3 hours. The cooled reaction mixture was quenched with water, extracted with EA (30 mL x 3), washed with water and saturated saline, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE, EA = 0-20%) to obtain 2-methylpropan-2-yl(1S,2R,5R)-3-[5-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl]-2-(prop-2-enyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.8 g, 6.55 mmol, 64%) as a yellow solid. LC / MS (ESI) m / z: 581.1 [M+H] +

[0282] Step 6: Synthesis of tert-butyl (1S,2R,5R)-2-allyl-3-(5-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of 2-methylpropan-2-yl(1S,2R,5R)-3-[5-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl]-2-(prop-2-enyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.8 g, 6.554 mmol), [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyrrolidine-7a-yl]methanol (8.35 g, 52.4 mmol) and Cs2CO3 (6.41 g, 19.6 mmol) were added. The reaction mixture was stirred over and over at 80°C under N2. The cooled reaction mixture was quenched with water, extracted with ethylethanol (20 mL x 3), washed with water and saturated brine, dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (in DCM, MeOH = 0-10%) to obtain 2-methylpropan-2-yl(1S,2R,5R)-3-[5-bromo-8-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyrrolidine-7a-yl]methyl}oxy)-6-(trifluoromethyl)quinazolin-4-yl]-2-(prop-2-enyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.6 g, 2.277 mmol, 34%) as a yellow solid. LC / MS (ESI) m / z: 704.1 [M+H] +

[0283] Step 7: Synthesis of tert-butyl (1S,4R,14aR)-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-12-(trifluoromethyl)-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In DMA (5 mL), a solution of 2-methylpropan-2-yl(1S,2R,5R)-3-[5-bromo-8-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyrrolidine-7a-yl]methyl}oxy)-6-(trifluoromethyl)quinazolin-4-yl]-2-(prop-2-enyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.6 g, 2.277 mmol) was mixed with PPh3 (0.12 g, 0.455 mmol), PPh3 (0.12 g, 0.455 mmol), and Pd(OAc)2 (0.05 g, 0.228 mmol). The reaction mixture was stirred at 100 °C under N2 for 2 hours. The cooled reaction mixture was quenched with water, extracted with toluene (10 mL x 3), washed with water and saturated brine, dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (in PE, EA = 0-10%) and obtained 2-methylpropan-2-yl(4R,7S,8R)-14-fluoro-17-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyrrolidine-7a-yl]methyl}oxy)-10-methylidene-12-(trifluoromethyl)-2,16,18,20-tetraazapentacyclo[13.3.1.1 4,7 .0 11,19 .0 2,8 Icosa-1(19),11(12),13,15(16),17-pentaene-20-carboxylate (1.1 g, 1.77 mmol, 77%) was obtained as an orange solid. LC / MS (ESI) m / z: 622.1 [M+H] +

[0284] Step 8: tert-butyl (1S,4R,14aR)-11-bromo-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-12-(trifluoromethyl)-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In THF (2 mL), 2-methylpropan-2-yl(4R,7S,8R)-14-fluoro-17-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyrrolidine-7a-yl]methyl}oxy)-10-methylidene-12-(trifluoromethyl)-2,16,18,20-tetraazapentacyclo[13.3.1.1 4,7 .0 11,19 .0 2,8 A solution of eicosa-1(19),11(12),13,15(16),17-pentaene-20-carboxylate (700 mg, 1.17 mmol) was mixed with LDA (180 mg, 1.689 mmol) at -65°C. The reaction mixture was heated to -15°C for 10 minutes under N2, then cooled to -60°C, and then 1,2-dibromo-1,1,2,2-tetrachloroethane (550 mg, 1.689 mmol) was added at -60°C. The reaction mixture was slowly heated to room temperature. The reaction mixture was quenched with ice water, and the mixture was extracted with dimethylammonium ammonium compounds (100 mL x 3). The organic layer was washed with saturated brine, dried over Na2SO4, and concentrated. The residue was tritulated with (DCM / MeOH=10 / 1), filtered, and 2-methylpropan-2-yl(4R,7S,8R)-13-bromo-14-fluoro-17-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyrrolidine-7a-yl]methyl}oxy)-10-methylidene-12-(trifluoromethyl)-2,16,18,20-tetraazapentacyclo[13.3.1.1 4,7 .0 11,19 .0 2,8 Icosa-1(19),11(12),13,15(16),17-pentaene-20-carboxylate (300 mg, 0.428 mmol, 38%) was obtained as a yellow solid. LCMS: ESI m / z 700.1 [M + H] +

[0285] Intermediate 20 (4-(difluoromethylene)-1,2-dimethylpyrrolidine-2-yl)methanol [ka] Synthesis scheme [ka]

[0286] Step 1: 1-(tert-butyl) 2-methyl 4-(difluoromethylene)-2-methylpyrrolidine-1,2-dicarboxylate [ka] In 50 mL of THF, a solution of 1-(tert-butyl) 2-methyl (S)-4-(difluoromethylene)pyrrolidine-1,2-dicarboxylate (10.0 g, 36.1 mmol, 1.0 eq) was added to 54.1 mL of LiHMDS (1 M in THF) at -15°C. The mixture was stirred under a nitrogen atmosphere at -15°C for 1.5 hours. Then, MeI (10.2 g, 72.2 mmol, 2.0 eq) was added to the mixture. The mixture was stirred under a nitrogen atmosphere at -15°C for 2.5 hours. HPLC showed that the reaction was complete. Water (100 mL) was added to the mixture and extracted with ELISA (200 mL x 3). The organic layer was washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether: siRNA = 10:1) to obtain 1-(tert-butyl) 2-methyl 4-(difluoromethylene)-2-methylpyrrolidine-1,2-dicarboxylate (8.3 g, yield: 79.0%) as a yellow liquid. LCMS: 192.2 (M-Boc + H + )

[0287] Step 2: Synthesis of methyl 4-(difluoromethylene)-2-methylpyrrolidine-2-carboxylate hydrochloride [ka] In 25 mL of DCM, a solution of 1-(tert-butyl) 2-methyl 4-(difluoromethylene)-2-methylpyrrolidine-1,2-dicarboxylate (5.0 g, 17.1 mmol, 1.0 eq) was added to 25 mL of HCl / dioxane (4 M). The mixture was stirred at 25 °C for 12 hours. HPLC indicated that the reaction was complete. 50 mL of saturated sodium carbonate was added to the mixture, and it was extracted with DCM:MeOH = (10:1) (3 mL x 50). The organic layer was washed with saturated brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain methyl 4-(difluoromethylene)-2-methylpyrrolidine-2-carboxylate hydrochloride (2.8 g, crude product) as a white solid. LCMS: 192.2 (M+H + )

[0288] Step 3: Synthesis of methyl 4-(difluoromethylene)-1,2-dimethylpyrrolidine-2-carboxylate [ka] In 30 mL of MeOH, a solution of methyl 4-(difluoromethylene)-2-methylpyrrolidine-2-carboxylate hydrochloride (2.8 g, 14.7 mmol, 1.0 eq) was added to formaldehyde (37% in H2O) (3.6 g, 44.1 mmol, 3.0 eq), and the mixture was stirred at 25°C for 0.5 hours. Then, sodium cyanoborohydride (1.1 g, 17.6 mmol, 1.2 eq) was added to the mixture, and the mixture was stirred at 25°C for 2 hours. HPLC showed that the reaction was complete. The mixture was then concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether: siRNA=15:1 and 0.3% ammonium hydroxide) to obtain methyl 4-(difluoromethylene)-1,2-dimethylpyrrolidine-2-carboxylate (1.2 g in two steps, yield: 34.0%) as a yellow liquid. LCMS: 206.2 (M+H + )

[0289] Step 4: Synthesis of (4-(difluoromethylene)-1,2-dimethylpyrrolidine-2-yl)methanol [ka] To a solution of methyl 4-(difluoromethylene)-1,2-dimethylpyrrolidine-2-carboxylate (1.2 g, 5.8 mmol, 1.0 eq) in THF (12 mL), LiBH4.THF (2 M) (4.7 mL, 9.4 mmol, 1.6 eq) was added at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred at 60 °C for 2 hours under N2. HPLC showed that the reaction was complete. The reaction mixture was quenched by adding 10H2O.Na2SO4 (3.8 g). The mixture was filtered, and the filtrate was concentrated to obtain (4-(difluoromethylene)-1,2-dimethylpyrrolidine-2-yl)methanol (1.1 g, crude product) as a yellow liquid. LCMS: 178.1 (M+H + )

[0290] Intermediate 21 tert-butyl (1S,4R,14aR)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] Synthesis scheme [ka]

[0291] Step 1: Synthesis of tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 100 mL of THF, a solution of tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (10.0 g, 22.3 mmol, 1.0 eq) was added dropwise to LDA (2.0 M, 33.4 mL, 3.0 eq in THF) under N2 conditions at -78°C. The mixture was stirred at -78°C for 1 hour, and then I2 (14.1 g, 55.7 mmol, 2.5 eq) was added dropwise to 10.0 mL of THF under N2 conditions at -78°C, and the mixture was stirred at -78°C for 1 hour. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic layer was washed with water (200 mL) and saturated brine (200 mL), and then dried over Na2SO4. 、 The mixture was filtered and concentrated to obtain the residue. The crude product was purified by silica gel chromatography (eluting with petroleum ether:dimethyl 10:1) to obtain tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (12.0 g, purity: 95.0%, yield: 93.6%). LCMS: 575.0 (M+H + )

[0292] Step 2: Synthesis of tert-butyl (1S,4R,14aR)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] t-BuONa (167.1 mg, 1.74 mmol, 2.0 eq) was added at 25°C to a solution of tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (500.0 mg, 0.87 mmol, 1.0 eq) and (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (197.0 mg, 1.04 mmol, 1.2 eq) in THF (5 mL). Next, DMF (1 mL) was added and the mixture was stirred under N2 at 25°C for 3 hours. The mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (10 mL x 3). The organic layer was washed with water (20 mL x 3) and saturated brine (20 mL), and then dried over Na2SO4. 、 The mixture was filtered and concentrated to obtain the residue. The crude product was purified by silica gel chromatography (eluting with petroleum ether:dimethyl 3:1) to obtain tert-butyl (1S,4R,14aR)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (1.2g, purity: 89%, yield: 77.3%) as a yellow solid. LCMS: 744.1 (M+H + )

[0293] Intermediate 22 tert-butyl (1S,4R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka]

[0294] Step 1: Synthesis of tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 30 mL of THF, a solution of tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (3.0 g, 6.7 mmol, 1.0 eq) was added dropwise to LDA (2 M, 20 mL, 20.1 mmol, 3.0 eq) under N2 conditions at -78°C. The mixture was stirred under N2 conditions at -78°C for 1 hour, and then a solution of I2 (4.26 g, 16.8 mmol, 2.5 eq) in 20 mL of THF was added under N2 conditions at -78°C, and the mixture was stirred under N2 conditions at -78°C for 3 hours. After the reaction was complete, the reaction mixture was poured into water (30 mL), extracted with toluene (50 mL x 3), washed with saturated brine (30 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / toluene = 10:1) to obtain tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (3.0 g, 77.6%) as a yellow solid. LCMS: 575.1 (M+H + )

[0295] Step 2: Synthesis of tert-butyl (1S,4R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 1.5 mL of THF, a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (124.1 mg, 0.78 mmol, 1.5 eq) was added, to which NaH (60%) (62.4 mg, 1.56 mmol, 3.0 eq) was added at 0°C. The mixture was then stirred for 0.5 hours at room temperature under N2, and tert-butyl was added to 3 mL of THF. A solution of (1S,4R,14aR)-12-chloro-8,10-difluoro-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (300.0 mg, 0.52 mmol, 1.0 eq) was added and the mixture was stirred at 25°C for 1.5 hours. HPLC and TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) and extracted with ELISA (20 mL x 3). The mixture was concentrated to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / dimethyl = 1:1) to obtain tert-butyl (1S,4R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-11-iodo-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (250.0 mg, 67.3%) as a yellow solid. LCMS: 714.1 (M+H + )

[0296] Intermediate 23 tert-butyl (1S,4R,14aR)-12-cyano-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka]

[0297] Step 1: Synthesis of tert-butyl (1S,4R,14aR)-12-cyano-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 10 mL of NMP, a solution of tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (1.0 g, 2.23 mol, 1.0 eq) was added to Zn(CN)2 (2.09 g, 17.84 mmol, 8.0 eq) and Pd(t-Bu3P)2 (574.6 mg, 1.12 mmol, 0.5 eq) at room temperature under N2 conditions. The sealed vial was irradiated with microwaves at 140°C for 30 minutes. The reaction mixture was diluted with water (40 mL) and then extracted with ELISA (20 mL x 3). The organic layer was washed with water (10 mL) and saturated saline (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to obtain the crude product. The residue was purified by silica gel column chromatography (eluting with petroleum ether:dimethyl 6:1) to obtain tert-butyl (1S,4R,14aR)-12-cyano-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (230 mg, 23.3%) as a yellow solid. LCMS: m / z 440.2 (M+H + )

[0298] Intermediate 24 3-Bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-5-methylaniline [ka] Synthesis scheme [ka]

[0299] Step 1: Synthesis of 3-bromo-2-fluoro-5-methylbenzoic acid [ka] In 1.5 L of anhydrous THF, a solution of 2-bromo-1-fluoro-4-methylbenzene (75.0 g, 396.8 mmol, 1.0 eq) and diisopropylamine (44.2 g, 436.4 mmol, 1.1 eq) was added dropwise to hexane (2.5 M, 190.4 mL, 476.1 mmol, 1.2 eq) under N2 at -78°C. The mixture was stirred at -78°C for 1 hour, solid CO2 (dry ice) was added, and the mixture was stirred at -78°C for 3 hours. After the reaction was complete, the mixture was diluted with water (1.0 L), the pH was adjusted to 2-3 with concentrated HCl (37%, 50 mL), and the mixture was extracted with RINKAN (1.0 L x 2). The organic layer was washed with saturated brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 3-bromo-2-fluoro-5-methylbenzoic acid (30.0 g, purity: 94.3%, yield: 30.6%) as a white solid, which was used in the next step without further purification. LCMS: 233.0, 230.8 (MH) - )

[0300] Step 2: Synthesis of tert-butyl (3-bromo-2-fluoro-5-methylphenyl)carbamate [ka] In a solution of 3-bromo-2-fluoro-5-methylbenzoic acid (30.0 g, 128.7 mmol, 1.0 eq) in toluene / t-BuOH (374 mL / 187 mL), DPPA (44.3 g, 160.9 mmol, 1.25 eq) and DIEA (20.0 g, 154.5 mmol, 1.2 eq) were added. The reaction mixture was stirred under reflux for 15 hours. The mixture was cooled, diluted with HCl (400 mL) and water (100 mL), and subsequently extracted with HCl (100 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / siRNA = 20:1) to obtain tert-butyl (3-bromo-2-fluoro-5-methylphenyl)carbamate (24.0 g, purity: 92.0%, yield: 56.4%) as a yellow solid. LCMS: 248.0, 250.0 (M-56+H + )

[0301] Step 3: Synthesis of 3-bromo-2-fluoro-5-methylaniline [ka] In 240 mL of iPrOH, a solution of tert-butyl (3-bromo-2-fluoro-5-methylphenyl)carbamate (24.1 g, 79.2 mmol, 1.0 eq) was added to concentrated HCl (37%, 67 mL). The reaction mixture was stirred at 60°C for 2 hours. The reaction system was concentrated, H₂O (600 mL) was added, and the pH was adjusted to 7-8 with aqueous NaOH solution (250 mL, 1 M). HCl (300 mL) and water (100 mL) were added to the mixture. The aqueous layer was extracted with HCl (100 mL x 3). The combined organic layers were washed with saturated brine (500 mL), dried over Na₂SO₄, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / acetate = 5:1) to obtain 3-bromo-2-fluoro-5-methylaniline (16.1 g, purity: 86.0%, yield: 85.6%) as a white solid. LCMS: 204.0, 206.1 (M+H + )

[0302] Step 4: Synthesis of 3-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-5-methylaniline [ka] In 90 mL of DMF, a solution of 6.0 g, 29.4 mmol, 1.0 eq of 3-bromo-2-fluoro-5-methylaniline was added to NaH (3.5 g, 60%, 87.5 mmol, 3.0 eq) under N2 at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then 11.5 g, 73.5 mmol, 2.5 eq of 4-methoxybenzyl chloride was added at 0°C, and the mixture was stirred at room temperature for 18 hours. After the reaction was complete, the mixture was quenched with saturated NH4Cl aqueous solution (200 mL) and extracted with siRNA (200 mL x 2). The combined organic layers were washed with water (100 mL x 2) and saturated brine (100 mL x 2), dried over Na2SO4, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / siRNA = 50:1) to obtain 3-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-5-methylaniline (12.0 g, purity: 83.8%, yield: 91.8%) as a yellow solid. LCMS: 444.0 446.0 (M+H + )

[0303] Intermediate 25 3-Bromo-2,6-difluoro-N,N-bis(4-methoxybenzyl)-5-methylaniline [ka] Synthesis scheme [ka]

[0304] Step 1: Synthesis of 3-bromo-2,6-difluoro-5-methylbenzoic acid [ka] In 50 mL of THF, a solution of 1-bromo-2,4-difluoro-5-methylbenzene (5.0 g, 24.1 mmol, 1.0 eq) was added to LDA (15.7 mL, 31.4 mmol, 1.3 eq) at -78°C. The reaction mixture was stirred at the same temperature for 2 hours. A large amount of dry ice was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated NH4Cl aqueous solution (50 mL), and the pH of the mixture was adjusted to approximately 1 with 1N HCl (40 mL). The mixture was extracted with RINKAN (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain 3-bromo-2,6-difluoro-5-methylbenzoic acid (3.0 g, 49.5%) as a white solid. LCMS: m / z 249 / 251 ([MH] - )

[0305] Step 2: Synthesis of tert-butyl (3-bromo-2,6-difluoro-5-methylphenyl)carbamate [ka] In t-BuOH (10 mL), solutions of 3-bromo-2,6-difluoro-5-methylbenzoic acid (1.0 g, 4.0 mmol, 1.0 eq), TEA (1.2 g, 12.0 mmol, 3.0 eq), and DPPA (2.2 g, 8.0 mmol, 2.0 eq) were stirred under reflux temperature for 2 hours. The mixture was quenched with H2O (10 mL) and extracted with RINKAN (10 mL x 3). The combined organic layer was washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / RINKAN 5 / 1) to obtain tert-butyl (3-bromo-2,6-difluoro-5-methylphenyl)carbamate (0.8 g, 80.2%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 7.26 - 7.21 (m, 1H), 5.95 (brs, 1H), 2.24 (s, 3H), 1.50 (s, 9H). LCMS: m / z 266 / 268 ([M-56+H] + )

[0306] Step 3: Synthesis of 3-bromo-2,6-difluoro-5-methylaniline [ka] A solution of tert-butyl (3-bromo-2,6-difluoro-5-methylphenyl)carbamate (800 mg, 2.5 mmol, 1.0 eq) in 4M HCl was stirred at 40°C for 2 hours in dioxane (8 mL). The formed precipitate was collected by filtration, washed with DCM (5 mL), and dried under reduced pressure to obtain 3-bromo-2,6-difluoro-5-methylaniline (0.3 g, 54.4%) as a white solid. LCMS: m / z 222.1 / 224.0 ([M+H] + )

[0307] Step 4: Synthesis of 3-bromo-2,6-difluoro-N,N-bis(4-methoxybenzyl)-5-methylaniline [ka] To a solution of 3-bromo-2,6-difluoro-5-methylaniline (300 mg, 1.4 mmol, 1.0 eq) in DMF (3 mL), t-BuOK (846 mg, 5.4 mmol, 4.0 eq) and PMBCl (622 mg, 4.1 mmol, 3.0 eq) were added at 0°C. The reaction mixture was stirred at the same temperature for 2 hours. The mixture was quenched with H2O (10 mL) and extracted with Âr (10 mL x 3). The combined organic layer was washed with saturated brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / Âr 10 / 1) to obtain tert-butyl (3-bromo-2,6-difluoro-5-methylphenyl)carbamate (400 mg, 64.0%) as a yellow solid. LCMS: m / z 462.0 / 464.0 ([M+H] + )

[0308] Intermediate 26 (4-(difluoromethyl)-1,3-dimethylpiperidine-3-yl)methanol [ka] Synthesis scheme [ka]

[0309] Step 1: Synthesis of 1-(tert-butyl)3-methyl3-methyl-4-oxopiperidine-1,3-dicarboxylate [ka] In acetonitrile (450 mL), a solution of 1-(tert-butyl) 3-methyl 4-oxopiperidine-1,3-dicarboxylate (30.0 g, 116.60 mmol, 1.0 eq) was added under N2 conditions to K2CO3 (56.1 g, 405.78 mmol, 3.5 eq) and MeI (30.0 g, 211.05 mmol, 1.8 eq). The mixture was stirred under N2 conditions at 40°C for 8 hours. HPLC and TLC indicated that the reaction was complete. The mixture was filtered through a Celite pad, and then water (100 mL) was added to the filtrate and extracted with DCM (200 mL x 3). The organic layer was washed with saturated saline (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(tert-butyl)3-methyl3-methyl-4-oxopiperidine-1,3-dicarboxylate (30.0 g, purity: 90%, yield: 94.8%) as a yellow liquid. LCMS: 172.2 (M-100+H + )

[0310] Step 2: Synthesis of 1-(tert-butyl)3-methyl4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate [ka] In 100 mL of DMF, a solution of 1-(tert-butyl) 3-methyl 3-methyl-4-oxopiperidine-1,3-dicarboxylate (10.0 g, 36.86 mmol, 1.0 eq) was added to 2-((difluoromethyl)sulfonyl)pyridine (10.7 g, 55.29 mmol, 1.5 eq) at 0°C under N2. Then, t-BuOK (in THF, 1 M) (66.3 mL, 66.34 mmol, 1.8 eq) was added to the mixture at 0°C, stirred for 2 hours at 0°C, and stirred for 3 hours at 25°C under N2. HPLC and TLC indicated that the reaction was complete. Water (100 mL) was added to the mixture, and it was extracted with DCM / MeOH (10:1, 200 mL x 3). The organic layer was washed with water (50 mL x 3) and saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether / Depositphotos = 30:1) to obtain 1-(tert-butyl) 3-methyl 4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (5.0 g, purity: 93%, yield: 44.4%) as a yellow liquid. LCMS: 250.1 (M-56+H + )

[0311] Step 3: Synthesis of 1-(tert-butyl)3-methyl4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylate [ka] In 80 mL of MeOH, a solution of 1-(tert-butyl) 3-methyl 4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (5.0 g, 16.38 mmol, 1.0 eq) was added to Pd / C (2.9 g) under H2. The mixture was stirred under H2 at 30°C for 12 hours. HPLC and TLC indicated that the reaction was complete. The mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain 1-(tert-butyl) 3-methyl 4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylate (3.7 g, crude product, yield: 73.5%) as a yellow liquid. LCMS: 252.0 (M-56+H + )

[0312] Step 4: Synthesis of methyl 4-(difluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride [ka] A solution of 1-(tert-butyl)3-methyl4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylate (3.7 g, 12.05 mmol, 1.0 eq) was stirred in HCl / dioxane (40.0 mL, 4N) at 25°C for 4 hours. HPLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to obtain methyl4-(difluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (3.7 g, crude product) as a white solid. LCMS: 208.3 (M+H + )

[0313] Step 5: Synthesis of methyl 4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate [ka] In 40 mL of MeOH, a solution of methyl 4-(difluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (3.7 g, 15.18 mmol, 1.0 eq) was prepared, to which formaldehyde (37% in H2O) (4.3 g, 52.98 mmol, 3.5 eq) was added. The mixture was stirred at 25°C for 0.5 hours, then sodium borohydride cyanohydride (1.3 g, 21.44 mmol, 1.4 eq) was added, and the mixture was stirred at 25°C for 2 hours. HPLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / siRNA = 15:1, 0.3% ammonium hydroxide) to obtain methyl 4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate (1.6 g in two steps, yield: 60.8%) as a yellow liquid. LCMS: 222.1 (M+H + )

[0314] Step 6: Synthesis of (4-(difluoromethyl)-1,3-dimethylpiperidine-3-yl)methanol [ka] In 16 mL of THF, a solution of methyl 4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate (1.6 g, 7.23 mmol, 1.0 eq) was added to LiAlH4·THF (11.6 mL, 1 M, 11.65 mmol, 1.6 eq) at room temperature under N2. The reaction mixture was then stirred at 0°C for 1 hour under N2. HPLC indicated that the reaction was complete. The reaction mixture was quenched with Na2SO4·10H2O (4.6 g), filtered, and the filtrate was concentrated to obtain (4-(difluoromethyl)-1,3-dimethylpiperidine-3-yl)methanol (1.6 g, crude product) as a yellow liquid. LCMS: 194.2 (M+H + )

[0315] Intermediate 27 (4-(difluoromethylene)-1,3-dimethylpiperidine-3-yl)methanol [ka] Synthesis scheme [ka]

[0316] Step 1: Synthesis of methyl 4-(difluoromethylene)-3-methylpiperidine-3-carboxylate hydrochloride [ka] A solution of 1-(tert-butyl)3-methyl4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (4.0 g, 13.11 mmol, 1.0 eq) was stirred in HCl / dioxane (40.0 mL, 4N) at 25°C for 4 hours. HPLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to obtain methyl4-(difluoromethylene)-3-methylpiperidine-3-carboxylate hydrochloride (4.0 g, crude product) as a white solid. LCMS: 206.2 (M+H + )

[0317] Step 2: Synthesis of methyl 4-(difluoromethylene)-1,3-dimethylpiperidine-3-carboxylate [ka] In 40 mL of MeOH, a solution of methyl 4-(difluoromethylene)-3-methylpiperidine-3-carboxylate hydrochloride (4.0 g, 13.11 mmol, 1.0 eq) was prepared, to which formaldehyde (37% in H2O) (4.6 g, 56.73 mmol, 4.3 eq) was added. The mixture was stirred at 25°C for 0.5 hours, then sodium borohydride cyanohydride (1.4 g, 23.18 mmol, 1.8 eq) was added, and the mixture was stirred at 25°C for 2 hours. HPLC indicated that the reaction was complete. The mixture was then concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / siRNA = 15:1, 0.3% ammonium hydroxide) to obtain methyl 4-(difluoromethylene)-1,3-dimethylpiperidine-3-carboxylate (1.7 g in two steps, purity: 92%, yield: 59.2%) as a yellow liquid. LCMS: 220.2 (M+H + )

[0318] Step 3: Synthesis of (4-(difluoromethylene)-1,3-dimethylpiperidine-3-yl)methanol [ka] To a solution of methyl 4-(difluoromethylene)-1,3-dimethylpiperidine-3-carboxylate (1.7 g, 8.25 mmol, 1.0 eq) in THF (17 mL), LiBH4 was added in THF (6.2 mL, 2 M, 12.38 mmol, 1.5 eq) at room temperature under N2. The reaction mixture was then stirred at 50 °C for 1 hour under N2. HPLC showed completion of the reaction. The reaction mixture was quenched by adding 10H2O·Na2SO4 (4.8 g). The mixture was filtered, and the filtrate was concentrated to obtain (4-(difluoromethylene)-1,3-dimethylpiperidine-3-yl)methanol (1.7 g, crude product) as a yellow liquid. LCMS: 192.0 (M+H + )

[0319] Intermediate 28 (4-(difluoromethyl)-1,2-dimethylpyrrolidine-2-yl)methanol [ka] Synthesis scheme [ka]

[0320] Step 1: Synthesis of methyl 4-(difluoromethyl)-1,2-dimethylpyrrolidine-2-carboxylate [ka] In 50 mL of MeOH, a solution of methyl 4-(difluoromethylene)-1,2-dimethylpyrrolidine-2-carboxylate (2.0 g, 9.75 mmol, 1.0 eq) was added to Pd / C (1.7 g) under H2. The mixture was stirred under H2 at 30°C for 12 hours. HPLC and TLC indicated that the reaction was complete. The mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain methyl 4-(difluoromethyl)-1,2-dimethylpyrrolidine-2-carboxylate (1.2 g, crude product) as a yellow liquid. LCMS: 208.2 (M+H + )

[0321] Step 2: Synthesis of (4-(difluoromethyl)-1,2-dimethylpyrrolidine-2-yl)methanol [ka] In 12 mL of THF, a solution of methyl 4-(difluoromethyl)-1,2-dimethylpyrrolidine-2-carboxylate (1.2 g, 6.32 mmol, 1.0 eq) was added to LiAlH4·THF (9.5 mL, 1 M, 9.48 mmol, 1.5 eq) at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred at 60 °C for 2 hours under N2. HPLC showed that the reaction was complete. The reaction mixture was quenched by adding 10H2O·Na2SO4 (3.8 g). The mixture was filtered, and the filtrate was concentrated to obtain (4-(difluoromethyl)-1,2-dimethylpyrrolidine-2-yl)methanol (1.1 g, crude product) as a yellow liquid. LCMS: 180.2 (M+3H + )

[0322] Intermediate 29 tert-butyl (1S,4R,14aR)-11-bromo-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-12-(trifluoromethyl)-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] Synthesis scheme [ka]

[0323] Step 1: Synthesis of tert-butyl (1S,2R,5R)-2-allyl-3-(5-bromo-2-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] In 30 mL of dioxane, a solution of 2-methylpropan-2-yl(1S,2R,5R)-3-[5-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl]-2-(prop-2-enyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.2 g, 5.52 mmol) was mixed with [(7aS)-2-(difluoromethylidene)-2,3,5,6,7,7a-hexahydro-1H-pyrrolidine-7a-yl]methanol (3.13 g, 16.6 mmol) and Cs2CO3 (5.39 g, 16.6 mmol). The mixture was stirred at 85°C under N2. The cooled reaction mixture was diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography in petroleum ether with ethyl acetate (gradient: 0-30%), yielding a yellow solid (2.1 g, 2.87 mmol, 52%). LCMS: ESI m / z 734.4 [M + H] +

[0324] Step 2: Synthesis of tert-butyl (1S,4R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-12-(trifluoromethyl)-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In DMA (20 mL), a solution of 2-methylpropan-2-yl(1S,2R,5R)-3-[2-({[(7aS)-2-(difluoromethylidene)-2,3,5,6,7,7a-hexahydro-1H-pyrrolidine-7a-yl]methyl}oxy)-5-bromo-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl]-2-(prop-2-enyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2 g, 2.73 mmol) was prepared by adding Pd(OAc)2 (0.07 g, 0.328 mmol), PPh3 (0.14 g, 0.546 mmol), and KOAc (0.54 g, 5.46 mmol). The mixture was stirred at 130 °C under N2 for 2 hours. The reaction mixture was diluted with water and extracted with EA. The organic phase was washed with saturated saline solution, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using methanol (gradient: 0-10%) in dichloromethane to obtain tert-butyl (1S,4R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-12-(trifluoromethyl)-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (1g, 1.54 mmol, 56%) as a yellow solid. LCMS: ESI m / z 652.4 [M + H] +

[0325] Step 3: Synthesis of tert-butyl (1S,4R,14aR)-11-bromo-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-12-(trifluoromethyl)-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In a solution of di(prop-2-yl)amine (0.398 mL, 2.824 mmol) in THF (5 mL), N-BULI (1.13 mL, 2.82 mmol) was added at -78°C for 15 minutes. Then, 2-methylpropan-2-yl(4R,7S,8R)-17-({[(7aS)-2-(difluoromethylidene)-2,3,5,6,7,7a-hexahydro-1H-pyrrolidine-7a-yl]methyl}oxy)-14-fluoro-10-methylidene-12-(trifluoromethyl)-2,16,18,20-tetraazapentacyclo[13.3.1.1 4,7 .0 11,19 .0 2,8 Icosa-1(19),11(12),13,15(16),17-pentaene-20-carboxylate (920 mg, 1.41 mmol) was added. The reaction mixture was stirred at -15°C for 15 minutes, then cooled to -78°C. 1,2-dibromo-1,1,2,2-tetrachloroethane (690 mg, 2.12 mmol) was added. The reaction mixture was stirred at -15°C for 15 minutes. The reaction mixture was diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography eluted with methanol (gradient: 0-10%) in dichloromethane, and 2-methylpropan-2-yl(4R,7S,8R)-17-({[(7aS)-2-(difluoromethylidene)-2,3,5,6,7,7a-hexahydro-1H-pyrrolidine-7a-yl]methyl}oxy)-13-bromo-14-fluoro-10-methylidene-12-(trifluoromethyl)-2,16,18,20-tetraazapentacyclo[13.3.1.1 4,7 .0 11,19 .0 2,8 Icosa-1(19),11(12),13,15(16),17-pentaene-20-carboxylate (250 mg, 0.342 mmol, 24%) was obtained as a yellow solid. LCMS: ESI m / z 732.3 [M + H] +

[0326] Intermediate 30 tert-butyl (1R,2R,5S)-2-allyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Synthesis scheme [ka]

[0327] Step 1: Synthesis of tert-butyl (3aS,4R,7S)-hexahydro-3H-4,7-epimino[1,2,3]oxathiazolo[3,4-a]azepine-10-carboxylate 1-oxide [ka] Imidazole (6.32 g, 92.9 mmol, 4.5 eq) and DCM (50 mL) were added to the reactor under N2 conditions. The solution was cooled to -10 to 0°C, SOCl2 (2.25 mL, 31 mmol, 1.5 eq) was added dropwise, and the mixture was stirred for 1 hour while maintaining the temperature at -10 to 0°C. Subsequently, a solution of tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 g, 20.65 mmol, 1.00 eq) was added in DCM (10 mL), and the mixture was warmed to room temperature and stirred for 12 hours. TLC indicated that the reaction was complete. The reactants were quenched with saturated NH4Cl (20 mL), separated, and the aqueous phase was extracted with DCM (10 mL). The organic phase was concentrated to obtain a crude product (5.95 g, 100% crude yield), which was then used directly in the next step.

[0328] Step 2: Synthesis of tert-butyl (3aS,4R,7S)-hexahydro-3H-4,7-epimino[1,2,3]oxathiazolo[3,4-a]azepine-10-carboxylate 1,1-dioxide [ka] A mixture of tert-butyl (3aS,4R,7S)-hexahydro-3H-4,7-epimino[1,2,3]oxathiazolo[3,4-a]azepine-10-carboxylate 1-oxide (5.95 g, 20.65 mmol, 1.00 eq), RuCl3·H2O (54.9 mg, 0.21 mmol, 0.01 eq), ACN (32 mL), and H2O (10 mL) was cooled to 0-10°C. NaIO4 (5.3 g, 24.8 mmol, 1.20 eq) was added in several portions, and the mixture was then warmed to room temperature and stirred for 4 hours. LC indicated that the reaction was complete. A solution of Na2SO3 (7.82 g, 3.00 eq) was added dropwise to H2O (20 mL) while controlling the temperature at 0-10°C. The mixture was extracted with ₹ (10 mL x 2), the combined organic layer was washed with saturated Na₂SO₃ solution, and then concentrated to obtain the crude product, which was triturated with n-heptane (10 mL) at 25°C for 1 hour. The solid was filtered, and the filtered cake was dried at 50°C to obtain the target product (3.5 g, 11.5 mmol, 55.7% yield).

[0329] Step 3: Synthesis of tert-butyl (1R,2R,5S)-2-allyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A solution of tert-butyl (3aS,4R,7S)-hexahydro-3H-4,7-epimino[1,2,3]oxatiazolo[3,4-a]azepine-10-carboxylate 1,1-dioxide (0.5 g, 1.64 mmol, 1 eq) and CuI (32 mg, 0.10 eq) was cooled to -45 to -35°C under N2, and vinyl Grignard solution (3.3 mmol, 2.00 eq) was added dropwise at -50 to -40°C. The solution was slowly warmed to room temperature and stirred for 16 hours, then slowly quenched at 0 to 10°C with 2N HCl (1.65 mL, 3.3 mmol, 2.00 eq). The reaction mixture was stirred at 25°C for 4 hours, and the pH was adjusted to 9-10 with 25% NH3.H2O (5 mmol, 3.00 eq). The solution was extracted with 2-Me-THF (10 mL x 2), the organic phase was concentrated, and the crude product was obtained. This was purified by silica gel chromatography to obtain the target product, tert-butyl (1R,2R,5S)-2-allyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.15 g, 0.6 mmol, 36.2% yield).

[0330] Intermediate 31 tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] Synthesis scheme [ka]

[0331] Step 1: Synthesis of tert-butyl (1S,2R,5R)-2-allyl-3-(5-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] In a solution of 5-bromo-2,4,6-trichloro-8-fluoroquinazoline (73.0 g, 221.21 mmol, 1.0 eq) in DCM (730 mL), tert-butyl (1S,2R,5R)-2-allyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (61.4 g, 243.33 mmol, 1.1 eq) was added at -40°C under N2, followed by the addition of DIEA (228.7 g, 1769.68 mmol, 8.0 eq) under N2. The mixture was stirred at -40°C for 2 hours. LC-MS then indicated that the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted with DCM (500 mL x 3). The organic layer was washed with saturated brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel column chromatography (petroleum ether / siRNA = 20:1) to obtain tert-butyl (1S,2R,5R)-2-allyl-3-(5-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (87 g, purity: 93%, yield: 72.2%) as a yellow solid. LCMS: 545.0 (M+H + )

[0332] Step 2: Synthesis of tert-butyl (1S,2R,5R)-2-allyl-3-(5-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] In DMSO (870 mL), a solution of tert-butyl (1S,2R,5R)-2-allyl-3-(5-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (87.0 g, 158.50 mmol, 1.0 eq) was added under N2 conditions. The mixture was stirred at 90°C for 3 hours. LC-MS then indicated that the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted with siRNA (500 mL x 3). The organic layer was washed with water (200 mL x 3) and saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel column chromatography (petroleum ether / siRNA = 20:1) to obtain tert-butyl (1S,2R,5R)-2-allyl-3-(5-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 g, purity: 93%, yield: 83.6%) as a yellow solid. LCMS: 529.0 (M+H + )

[0333] Step 3: Synthesis of tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 700 mL of 1,4-dioxane, a solution of tert-butyl (1S,2R,5R)-2-allyl-3-(5-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 g, 132.51 mmol, 1.0 eq) was mixed with PPh3 (10.4 g, 39.75 mmol, 0.3 eq), Pd(OAc)2 (4.5 g, 19.88 mmol, 0.15 eq), and DIEA (51.7 g, 397.53 mmol, 3.0 eq) under N2 conditions. The mixture was stirred at 110°C for 3 hours. LC-MS then indicated that the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted with ELISA (500 mL x 3). The organic layer was washed with saturated brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel column chromatography (petroleum ether / dimethyl = 20:1) to obtain tert-butyl (1S,4R,14aR)-12-chloro-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (51.5 g, purity: 89%, yield: 86.6%) as a yellow solid. LCMS: 449.1 (M+H + )

[0334] Intermediate 32 ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol [ka] Synthesis scheme [ka]

[0335] Step 1: Synthesis of ethyl (1S,7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (presumably) and ethyl (1R,7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate [ka] In 4.5 mL of THF, a solution of ethyl (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (900 mg, 4.30 mmol, 1.0 eq) was added to a sealed tube containing TMSCF3 (2.1 g, 15.05 mmol, 3.5 eq) at room temperature. The mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether / Depositphotos = 3:2) to obtain ethyl (1S,7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (estimated) (210 mg, fast spot, yield: 19.1%) as a yellow oil. Further purification by silica gel column chromatography (petroleum ether / Depositphotos = 1:5) was obtained to obtain ethyl (1R,7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (estimated) (200 mg, slow spot, yield: 18.2%) as a yellow oil. LCMS: 260.2 (M+H + )

[0336] Step 2: Synthesis of ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol [ka] In 3 mL of THF, LiAlH4 was added dropwise to a solution of ethyl (1S,7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (270 mg, 1.04 mmol, 1.0 eq) in 3.6 mL of THF (1 M, 3.65 mmol, 3.5 eq) at room temperature. The mixture was stirred at 65°C for 1 hour. HPLC and TLC indicated that the reaction was complete. The mixture was cooled, quenched with Na2SO4·10H2O (1.4g), filtered, and the filtrate was concentrated under reduced pressure to obtain ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (200mg, crude product) as a colorless oil. LCMS: 204.2 (M+H + )

[0337] Intermediate 33 ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol [ka] Synthesis scheme [ka]

[0338] Step 1: Synthesis of ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol In 3 mL of THF, LiAlH4 was added dropwise to a solution of ethyl (1R,7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (250 mg, 0.96 mmol, 1.0 eq) in 3.4 mL of THF (1 M, 3.40 mmol, 3.5 eq) at room temperature. The mixture was stirred at 65 °C for 1 hour. HPLC and TLC indicated that the reaction was complete. The mixture was cooled, then quenched with Na2SO4·10H2O (1.3g), filtered, and the filtrate was concentrated under reduced pressure to obtain ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (190mg, crude product) as a colorless oil. LCMS: 204.2 (M+H + )

[0339] Examples 1 & 2 6-((1S,4R,11S,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Example 1) [ka] 6-((1S,4R,11R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Example 2) [ka] Synthesis scheme [ka]

[0340] Step 1: Synthesis of 6-((1S,4R,14aR)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] (TMP)2Zn·2MgCl2·2LiCl (0.4M, 7.2mL, 2.9 mmol, 6.0eq) was added to a solution of (1S,4R,14aR)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline (intermediate 7, 270 mg, 0.48 mmol, 1.0 eq) under N2 conditions. The mixture was stirred at 50°C for 2 hours. Quenching with D2O indicated that deprotonation was complete, as measured by LC-MS. A mixture of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (285 mg, 0.58 mmol, 1.2 eq) and CPhos Pd G3 (40 mg, 0.05 mmol, 0.1 eq) was added to 1,4-dioxane (3 mL) in the mixture. The solution was stirred at 70°C for 3 hours. The reaction mixture was quenched with H2O (15 mL) and extracted with ELISA (15 mL x 3). The combined organic layers were washed with saturated saline (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by preparative TLC (DCM:MeOH = 10:1) to obtain 6-((1S,4R,14aR)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (280 mg, 59.8%) as a yellow solid. LCMS: m / z 975.9 (M+H + )

[0341] Step 2: Synthesis of 6-((1S,4R,14aR)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] A solution of 6-((1S,4R,14aR)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (280 mg, 0.29 mmol, 1.0 eq) was stirred at 40°C for 3 hours in TFA (15 mL). The mixture was concentrated to obtain 6-((1S,4R,14aR)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (crude) as a brown solid, which was used in the next step without further purification. LCMS: m / z 735.9 (M+H + )

[0342] Step 3: 6-((1S,4R,11S,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Example 1) Synthesis of 6-((1S,4R,11R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Example 2) [ka] A mixture of 6-((1S,4R,14aR)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (387 mg crude product, 0.29 mmol) and Pd / C (30%, 116 mg) was hydrogenated in an H2 balloon at room temperature for 1.5 hours. LC-MS indicated that the reaction was complete. The mixture was filtered and concentrated to obtain the crude product, which was then purified by preparative HPLC and subsequently subjected to SFC separation to obtain two single diastereomers:

[0343] 6-((1S,4R,11S,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (14.5 mg, 7.7% in two steps) was obtained as a white solid (SFC peak 1, Example 1),

[0344] 1H NMR (400 MHz, CD3CN): δ 6.57 (s, 1H), 5.66 (s, 1H), 5.48 (s, 2H), 5.44 (d, J = 4.0 Hz, 1H), 5.29 (d, J = 53.6 Hz, 1H), 5.10 (d, J = 11.6 Hz, 1H), 4.22 (d, J = 10.8 Hz, 1H), 4.12 (d, J = 10.8 Hz, 1H), 3.99 (dd, J = 11.8, 4.4 Hz, 1H), 3.65 (s, 1H), 3.48 (s, 1H), 3.24 - 3.20 (m, 2H), 3.15 - 3.12 (m, LCMS: m / z 645.9 (M+H + ); and

[0345] 6-((1S,4R,11R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (16.2 mg, 8.6% in two steps) was obtained as a white solid (SFC peak 2, Example 2),

[0346] 1H NMR (400 MHz, CD3CN): δ 6.56 (s, 1H), 5.65 (s, 1H), 5.46 (s, 2H), 5.40 (d, J = 4.0 Hz, 1H), 5.26 (d, J = 53.2 Hz, 1H), 5.14 (d, J = 12.4 Hz, 1H), 4.11 (dd, J = 22.8, 10.4 Hz, 2H), 3.89 (dd, J = 12.0, 4.0 Hz, 1H), 3.56 (s, 1H), 3.38 (s, 1H), 3.25-3.12 (m, 3H), 3.09 (s, 1H), 3.01 (d, J = 12.8 Hz, 1H), 2.94 - 2.88 (m, 1H), 2.79 (dd, J = 13.2, 4.0 Hz, 1H), 2.46-2.40 (m, 4H), 2.14 - 2.05 (m, 4H), 1.90 - 1.81 (m, 2H), 1.61 - 1.52 (m, 3H). LCMS: m / z 645.9 (M+H + ) Got it.

[0347] SFC separation conditions: Analysis method: Apparatus: Waters UPC2 analyzer for SFC (SFC-H). Camera: Chiralcel OX, 150 × 4.6 mm ID, 3 μm Mobile phase: AはCO2, Bはエタノール (0.05%DEA). Blend: B 40%. Flow rate: 2.5mL / min. Back pressure: 100bar. Cooling temperature: 35℃. Wavelength: 220nm.

[0348] Preparative method: Device: WATERS 150 points SFC (SFC-26). Color: Chiralcel OX, 250×30mm ID, 10μm. Mobile phase: AはCO2, Bはエタノール (0.1%NH3H2O). Mixing: B 45%. Flow rate: 150mL / min. Back pressure: 100bar. Curing temperature: 38℃. Wavelength: 220nm. Curing time: about 9.5 minutes.

[0349] Examples 3 & 4 6-((1R,4S,11S,14aS)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Example 3) [ka] 6-((1R,4S,11R,14aS)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Example 4) [ka] Synthesis scheme [ka]

[0350] Step 1: Synthesis of 4-((1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2-chloro-6,8-difluoroquinazoline [ka] In a solution of 5-bromo-2,4-dichloro-6,8-difluoroquinazoline (intermediate 5, 587 mg, 1.44 mmol, 1.0 eq) in DCM (10 mL), DIEA (1.6 g, 12.53 mmol, 8.7 eq) and (1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octane (intermediate 2, 419 mg, 1.73 mmol, 1.2 eq) were added at -40°C under a nitrogen atmosphere. The mixture was stirred at -40°C for 2 hours, and water (20 mL) was added. The mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with water (20 mL) and saturated brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether: Â1 = 30:1) to obtain 4-((1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2-chloro-6,8-difluoroquinazoline (0.35 g, 46.8%) as a yellow solid in two steps. LCMS: m / z 518.8, 520.8 (M+H + )

[0351] Step 2: 4-((1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline [ka] In DMSO (3 mL), a solution of 4-((1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-2-chloro-6,8-difluoroquinazoline (290 mg, 0.56 mmol, 1.0 eq) was added to ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (711 mg, 4.46 mmol, 8.0 eq) and KF (66 mg, 1.13 mmol, 2.03 eq). The solution was heated overnight at 100 °C. The reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (20 mL x 3). The combined organic layers were washed with saturated saline (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether: siRNA = 3:1) to obtain 4-((1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline (260 mg, 77.9%) as a yellow solid. LCMS: m / z 641.9, 643.9 (M+H + )

[0352] Step 3: (1R,4S,14aS)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline [ka] In DMAc (12 mL), a solution of 4-((1R,2S,5S)-2-allyl-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline (400 mg, 0.62 mmol, 1.0 eq) was added to KOAc (183 mg, 1.87 mmol, 3.0 eq), Pd(OAc)2 (14 mg, 0.06 mmol, 0.1 eq), and PPh3 (33 mg, 0.13 mmol, 0.2 eq) under a nitrogen atmosphere at room temperature. The mixture was heated at 130 °C for 5 hours, and HPLC indicated that the reaction was complete. The reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (30 mL x 3). The combined organic layer was washed with saturated saline (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (DCM:MeOH=60:1) to obtain (1R,4S,14aS)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline (123 mg, 35.2%) as a yellow solid. LCMS: m / z 562.0 (M+H + )

[0353] Step 4: 6-((1R,4S,14aS)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] (TMP)2Zn·2MgCl2·2LiCl (0.4M, 3.75mL, 1.5 mmol, 6.0 eq) was added to a solution of (1R,4S,14aS)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline (140 mg, 0.25 mmol, 1.0 eq) under N2 conditions. The mixture was stirred at 50°C for 2 hours. Quenching with D2O (0.1 mL) indicated that the reaction was complete, and LC-MS showed this. Next, a mixture of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (148 mg, 0.3 mmol, 1.2 eq) and CPhos Pd G3 (20 mg, 0.03 mmol, 0.1 eq) was added to 1,4-dioxane (6 mL). The mixture was heated at 70 °C for 3 hours and cooled to RT. H2O (15 mL) was added, and the mixture was extracted with RINKAN (15 mL x 3). The combined organic layers were washed with saturated saline (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by preparative TLC (DCM:MeOH = 10:1) to obtain 6-((1R,4S,14aS)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (87 mg, 35.7%) as a yellow solid. LCMS: m / z 975.9 (M+H + )

[0354] Step 5: 6-((1R,4S,14aS)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] A solution of 6-((1R,4S,14aS)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (85 mg, 0.09 mmol, 1.0 eq) in TFA (5 mL) at 50°C The mixture was stirred for 3 hours, concentrated, and the crude product, 6-((1R,4S,14aS)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (102 mg), was obtained as a brown solid and used in the next step without further purification. LCMS: m / z 735.9 (M+H + )

[0355] Step 6: 6-((1R,4S,11S,14aS)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Example 3) and Synthesis of 6-((1R,4S,11R,14aS)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Example 4) [ka] A mixture of 6-((1R,4S,14aS)-15-benzyl-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (130 mg crude product, 0.18 mmol) and Pd / C (30%, 35 mg) was hydrogenated in a hydrogen balloon at room temperature for 1.5 hours. HPLC indicated that the reaction was complete. The mixture was filtered and concentrated to obtain the crude product, which was then purified by preparative HPLC (in water, acetonitrile containing 0.1% FA, 25-40%), followed by SFC, to obtain two diastereomers:

[0356] 6-((1R,4S,11S,14aS)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (4.2 mg in 2 steps, ee>95%, 7.4%) was obtained as a white solid (SFC peak 1, Example 3), 1H NMR (400 MHz, CD3CN): δ 6.58 (s, 1H), 5.67 (s, 1H), 5.48 (s, 2H), 5.42 (d, J = 4.0 Hz, 1H), 5.40-5.10 (m, 2H), 4.18 (d, J = 10.4 Hz, 1H), 4.06 (d, J = 10.4 Hz, 1H), 3.91 (dd, J = 12.2, 4.4 Hz, 1H), 3.57 (s, 1H), 3.39 (d, J = 5.6 Hz, 1H), 3.25-2.75 (m, 6H), 2.50-2.40 (m, 4H), 2.15-2.05 (m, 4H), 1.95-1.80 (m, 2H), 1.67-1.53 ​​(m, 3H). LCMS: m / z 645.9 (M+H + ); and

[0357] 6-((1R,4S,11R,14aS)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (4.16 mg in two steps, ee>95%, 7.4%, including another 20 mg batch) as a white solid (SFC peak 2, Example 4), 1H NMR (400 MHz, CD3CN): δ 6.58 (s, 1H), 5.68 (s, 1H), 5.49 (s, 2H), 5.46 (d, J = 4.0 Hz, 1H), 5.30 (d, J = 53.2 Hz, 1H), 5.15 -5.02 (m, 1H), 4.25- 4.12 (m, 2H), 3.97 (dd, J = 11.6, 4.4 Hz, 1H), 3.64 (s, 1H), 3.46 (d, J = 5.2 Hz, 1H), 3.30-3.05 (m, 4H), 3.02-2.90 (m, 1H), 2.88-2.78 (m, 1H), 2.50-2.40 (m, 4H), 2.18 - 2.12 (m, 4H), 1.90-1.80 (m, 2H), 1.75-1.60 (m, 3H). LCMS: m / z 645.9 (M+H + ) Got it.

[0358] SFC conditions: Analytical separation method: Device: Waters UPC2 analysis SFC (SFC-H). Color: Chiralpak IC, 150×4.6mm ID, 3μm. Mobile phase: AはCO2, Bはエタノール (0.05%DEA). Blend: B 50%. Flow rate: 2.5mL / min. Back pressure: 100bar. Calorium temperature: 35℃. Wavelength: 220nm

[0359] Preparative separation method Device: WATERS 150-minute SFC (SFC-26). カラム: Chiralpak IC, 250×30mm ID, 10μm. Mobile phase: AはCO2, Bはエタノール (0.1%NH3H2O). Mixing: B 40%. Flow rate: 150mL / min. Back pressure: 100bar. Curing temperature: 38℃. Wavelength: 220nm. Curing time: about 13 minutes.

[0360] Example 5 1-(isobutyryloxy)ethyl (1S,4R,11S,14aR)-11-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate

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[0361] Synthesis of 1-(isobutyryloxy)ethyl (1S,4R,11S,14aR)-11-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 1 mL of DCM, DIEA (5.8 mg, 0.045 mmol, 3.0 eq) was added to a solution of 6-((1S,4R,11S,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (10 mg, 0.015 mmol, 1.0 eq), followed by 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl Isobutyrate (5.5 mg, 0.018 mmol, 1.2 eq) was added. The reaction mixture was stirred under N2 at room temperature for 36 hours. HPLC and TLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (DCM:MeOH = 10:1) to obtain 1-(isobutyryloxy)ethyl (1S,4R,11S,14aR)-11-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (6.23 mg, 50.1% yield) as a white solid. 1H NMR (400 MHz, CH3CN): δ 6.90-6.70 (m, 1H), 6.60 (s, 1H), 5.72 (s, 1H), 5.60-5.30 (m, 4H), 5.20 (d, J = 13.2 Hz, 1H), 4.53 (s, 2H), 4.42 (s, 1H), 4.23 (s, 1H), 410-3.90 (m, 1H), 3.80-3.40 (m, 3H), 3.25-3.05 (m, 2H), 3.00-2.85 (m, 1H), 2.60-2.50 (m, 1H), 2.48-2.38 (m, 4H), 1.88-1.75 (m, 2H), 1.55-1.25 (m, 11H), 1.15 (s, 6H). LCMS: m / z 803.9 (M+H + )

[0362] Examples 6 & 7 6-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Example 6)

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[0363] Step 1: tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate

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[0364] Step 2: 6-((1S,4R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] A mixture of tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (60 mg, 0.06 mmol) in TFA (3 mL) was stirred at 50°C for 3 hours. HPLC showed that the reaction was complete. The mixture was concentrated to obtain the residue, which was dissolved in DCM / MeOH(10 / 1) and washed with saturated NaHCO3 aqueous solution (10 mL) and saturated brine (10 mL). The organic layer was dried over Na2SO4, concentrated to obtain the residue, which was purified by preparative TLC(DCM / MeOH~10 / 1) to obtain a product having two diastereomers. LCMS: m / z 676.2 (M+H + )

[0365] The product was further separated by SFC and purified by HPLC to obtain the following: 6-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (SFC peak 1, Example 6, free base), 1H NMR (400 MHz, CD3CN): δ 6.56 (s, 1H), 5.65 (s, 1H), 5.48 (s, 2H), 5.43 (d, J = 4.0 Hz, 1H), 5.15-5.00 (m, 1H), 4.20-4.10 (m, 2H), 3.95-3.85 (m, 1H), 3.75-3.62 (m, 1H), 3.61-3.53 (br, 1H), 3.45-3.30 (m, 2H), 3.10-3.00 (m, 2H), 2.85-2.55 (m, 3H), 2.45-2.35 (m, 4H), 2.12-2.00 (m, 3H), 1.90-1.75 (m, 4H), 1.70-1.50 (m, 3H). LCMS: m / z 675.9 (M+H + );

[0366] 6-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine formate (0.4FA salt), 1 H NMR (400 MHz, CD3CN): δ 6.56 (s, 1H), 5.65 (s, 1H), 5.48 (s, 2H), 5.45-5.38 (br, 1H), 5.20-5.05 (m, 1H), 4.20-4.10 (m, 2H), 4.00-3.87 (m, 1H), 3.75-3.65 (m, 1H), 3.64-3.53 (br, 1H), 3.45-3.30 (m, 2H), 3.15-3.00 (m, 2H), 2.87-2.52 (m, 3H), 2.46-2.33 (m, 4H), 2.12-2.02 (m, 3H), 1.90-1.70 (m, 4H), 1.70-1.50 (m, 3H). LCMS: m / z 675.9 (M+H + ); and

[0367] 6-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (SFC peak 2, Example 7, free base), 1 H NMR (400 MHz, CD3CN): δ 8.14 (s, 0.6 H), 6.56 (s, 1H), 5.65 (s, 1H), 5.48 (s, 2H), 5.45-5.38 (br, 1H), 5.20-5.05 (m, 1H), 4.20-4.10 (m, 2H), 4.00-3.87 (m, 1H), 3.75-3.65 (m, 1H), 3.64-3.53 (br, 1H), 3.45-3.30 (m, 2H), 3.15-3.00 (m, 2H), 2.87-2.52 (m, 3H), 2.46-2.33 (m, 5H), 2.20-2.02 (m, 2H), 1.90-1.70 (m, 4H), 1.70-1.50 (m, 3H). LCMS: m / z 675.9 (M+H + );

[0368] 6-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine formate (0.6FA), 1H NMR (400 MHz, CD3CN): δ 8.14 (s, 0.6 H), 6.56 (s, 1H), 5.65 (s, 1H), 5.48 (s, 2H), 5.45-5.38 (br, 1H), 5.20-5.05 (m, 1H), 4.20-4.10 (m, 2H), 4.00-3.87 (m, 1H), 3.75-3.65 (m, 1H), 3.64-3.53 (br, 1H), 3.45-3.30 (m, 2H), 3.15-3.00 (m, 2H), 2.87-2.52 (m, 3H), 2.46-2.33 (m, 5H), 2.20-2.02 (m, 2H), 1.90-1.70 (m, 4H), 1.70-1.50 (m, 3H). LCMS: m / z 675.9 (M+H + ).

[0369] SFC separation conditions: Analysis method: Apparatus: Waters UPC2 analyzer for SFC (SFC-H). Camera: Chiralcel OX, 150 × 4.6 mm ID, 3 μm

[0370] Mobile phase: AはCO2, Bはエタノール (0.05%DEA). Blend: B 40%. Flow rate: 2.5mL / min. Back pressure: 100bar. Cooling temperature: 35℃. Wavelength: 220nm.

[0371] Preparative method: Device: WATERS 150 points SFC (SFC-26). Color: Chiralcel OX, 250×30mm ID, 10μm. Mobile phase: AはCO2, Bはエタノール (0.1%NH3H2O). Mixing: B 45%. Flow rate: 150mL / min. Back pressure: 100bar. Curing temperature: 38℃. Wavelength: 220nm. Curing time: about 7 minutes.

[0372] Example 8 1-(isobutyryloxy)ethyl (1S,4R,11R,14aR)-11-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate

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[0373] In 1 mL of DCM, a solution of 3-((1S,4R,11R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-5-methyl-4-(trifluoromethyl)aniline (10 mg, 0.016 mmol, 1.0 eq) is prepared, along with DIEA (6.2 mg, 0.048 mmol, 3.0 eq) and 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl Isobutyrate (5.6 mg, 0.019 mmol, 1.2 eq) was added. The reaction mixture was then stirred under N2 at room temperature for 36 hours. HPLC and TLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (DCM:MeOH = 10:1) to obtain 1-(isobutyryloxy)ethyl (1S,4R,11R,14aR)-11-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (8 mg, 64.2%) as a white solid. LCMS: m / z 803.2 (M+H + ). 1H NMR (300 MHz, DMSO-d6) δ 6.77 - 6.71 (m, 1H), 6.62 (s, 1H), 6.30 (s, 1H), 5.92 (brs, 2H), 5.73 (s, 1H), 5.45 (d, J = 3.0 Hz, 1H), 5.30 (d, J = 54.0, 1H), 5.05 - 4.85 (m, 1H), 4.38 (s, 1H), 4.00 - 4.25 (m, 3H), 3.92 - 3.70 (m, 1H), 3.19 - 2.72 (m, 8H), 2.36 (d, J = 2.1 Hz, 3H), 2.14 - 2.01 (m, 4H), 1.85-1.75 (m, 3H), 1.48 (d, J = 5.4 Hz, 3H), 1.41 - 1.24 (m, 3H), 1.09 - 1.05 (m, 6H). LCMS: m / z 803.2 (M+H + )

[0374] Examples 9 & 10 Example 9: 3-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-5-methyl-4-(trifluoromethyl)aniline

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[0375] Step 1: Synthesis of 3-((1S,4R,14aR)-15-benzyl-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline

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[0376] Step 2: Synthesis of tert-butyl (1S,4R,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 30 mL of MeOH, a solution of 3-((1S,4R,14aR)-15-benzyl-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline (500 mg, 0.6 mmol, 1.0 eq) was added, along with Pd / C (30%, 150 mg) and Boc2O (196 mg, 0.9 mmol, 1.5 eq). The mixture was hydrogenated at room temperature for 12 hours. HPLC indicated that the reaction was complete. The mixture was filtered and concentrated to obtain the crude product. The residue was purified by preparative TLC (DCM) to obtain tert-butyl (1S,4R,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (225 mg, 45%) as a yellow solid. LCMS: m / z 846.3 (M+H + )

[0377] Step 3: tert-butyl (1S,4R,11R,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate and tert-butyl Synthesis of (1S,4R,11S,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] The compound tert-butyl (1S,4R,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (550 mg, 0.65 mmol) was separated twice by SFC to obtain tert-butyl. (1S,4R,11R,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (P1, retention time = 1.862, 110 mg, 20.0%) and tert-butyl (1S,4R,11S,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (P2, retention time = 2.195, 140 mg, 25.5%) was obtained.

[0378] First SFC requirement: Analytical separation method: Instrument: Waters UPC2 analytical SFC (SFC-H). Column: Chiralpak IG, 150 × 4.6 mm ID, 3 μm. Mobile phase: A = CO2, B = Ethanol (0.05% DEA). Gradient: B 40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35°C. Wavelength: 220 nm

[0379] Preparative separation method Apparatus: WATERS 150-minute SFC (SFC-26). Column: Chiralpak IG, 250 x 30 mm ID, 10 μm. Mobile phase: A = CO2, B = Ethanol. Gradient: B 30%. Flow rate: 150 mL / min. Back pressure: 100 bar. Column temperature: 38°C. Wavelength: 220 nm. Cycle time: Approximately 6 minutes.

[0380] Second SFC requirement: Analytical separation method: Instrument: Waters UPC2 analytical SFC (SFC-H). Column: Cellulose-2, 150 × 4.6 mm ID, 3 μm

[0381] Mobile phase: A is CO2, B is methanol (0.05% DEA). Gradient: B 5-40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35°C. Wavelength: 220 nm.

[0382] Preparative separation method Apparatus: WATERS 150-portion SFC (SFC-26). Column: Cellulose-2, 250 x 30 mm ID, 10 μm. Mobile phase: A = CO2, B = methanol. Gradient: B 45%. Flow rate: 130 mL / min. Back pressure: 100 bar. Column temperature: 38°C. Wavelength: 220 nm. Cycle time: Approximately 6 minutes.

[0383] Step 4: tert-butyl (1S,4R,11R,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate and tert-butyl Synthesis of (1S,4R,11S,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 0.5 mL of THF, a solution of (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (38.7 mg, 0.20 mmol, 1.5 eq) was added to 60% NaH (16.0 mg, 0.39 mmol, 3.0 eq) at 0°C, and the mixture was subsequently stirred for 0.5 hours at room temperature under N2. A solution of tert-butyl (1S,4R,11R,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (110 mg, 0.13 mmol, 1.0 eq) was added to THF (1.5 mL) and the mixture was stirred at 25°C for 1.5 hours. HPLC and TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ELISA (10 mL x 3). The organic layer was concentrated to obtain the crude product. The residue was purified by preparative TLC (DCM:MeOH=10:1) to obtain tert-butyl (1S,4R,11R,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (70 mg, 51.7%) as a yellow solid. LCMS: 1015.2 (M+H + )

[0384] [ka] In 1 mL of THF, a solution of (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (47.2 mg, 0.25 mmol, 1.5 eq) was added to 60% NaH (20.0 mg, 0.50 mmol, 3.0 eq) at 0°C, and the mixture was subsequently stirred for 0.5 hours at room temperature under N2. A solution of tert-butyl (1S,4R,11S,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (140 mg, 0.17 mmol, 1.0 eq) was added to THF (2 mL) and the reaction mixture was stirred at 25°C for 1.5 hours. HPLC and TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ELISA (10 mL x 3). The organic layer was concentrated to obtain the crude product. The residue was purified by preparative TLC (DCM:MeOH=10:1) to obtain tert-butyl (1S,4R,11S,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (100 mg, 65.7%) as a yellow solid. LCMS: 1015.2 (M+H + )

[0385] Step 5: 3-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-5-methyl-4-(trifluoromethyl)aniline Synthesis of 3-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-5-methyl-4-(trifluoromethyl)aniline [ka] A mixture of tert-butyl (1S,4R,11R,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (70 mg, 0.069 mL) in TFA (1.5 mL) was stirred under N2 at 50°C for 3 hours. The mixture was concentrated to obtain the crude product. Next, saturated sodium bicarbonate aqueous solution (10 mL) was added to the crude product to adjust the pH to (7-8), and it was extracted with DCM / MeOH = 10 / 1 (10 mL x 3). The combined organic layers were washed with saturated saline solution (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (in water, acetonitrile containing 0.1% FA, 5%-50%) to obtain 3-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-5-methyl-4-(trifluoromethyl)aniline (8 mg, 17.4%) as a white solid. LCMS: m / z 675.3 (M+H + ). 11H NMR (300 MHz, CDCl3) δ 6.64 (s, 1H), 6.38 (s, 1H), 5.72 (s, 1H), 5.58 (d, J = 3.3 Hz, 1H), 5.34-5.29 (m, 1H), 4.57-4.52 (m, 3H), 4.29-4.23 (m, 2H), 4.00-3.96 (m, 3H), 3.75-3.60 (m, 3H), 3.03-2.98 (m, 1H), 2.94-2.82 (m, 2H), 2.64-2.55 (m, 1H), 2.50-2.47 (m, 4H), 2.40-2.33 (m, 2H), 2.25-2.12 (m, 4H), 2.04-1.97 (m, 3H)

[0386] [Chemical Formula] A mixture of tert-butyl (1S,4R,11S,14aR)-11-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (100 mg, 0.099 mmol) in TFA (2 mL) was stirred at 50°C for 3 hours under N2. The mixture was concentrated to obtain the crude product. Next, saturated sodium bicarbonate aqueous solution (10 mL) was added to the crude product to adjust the pH to (7-8), and it was extracted with DCM / MeOH = 10 / 1 (10 mL x 3). The combined organic layers were washed with saturated saline solution (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (in water, acetonitrile containing 0.1% FA, 5%-50%) to obtain 3-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-5-methyl-4-(trifluoromethyl)aniline (20.9 mg, 31.3%) as a white solid. LCMS: m / z 675.2 (M+H + )

[0387] 1H NMR (400 MHz, DMSO-d6) δ 6.61 (s, 1H), 6.28 (s, 1H), 5.91 (brs, 2H), 5.67 (s, 1H), 5.34 (s, 1H), 5.00 (d, J = 12.0 Hz, 1H), 4.12-4.05 (m, 2H), 3.87 (d, J = 12.0 Hz, 1H), 3.64 (d, J = 14.8 Hz, 1H), 3.54 (s, 1H), 3.86 (m, 1H), 3.32-3.29 (m, 1H), 3.05 - 2.98 (m, 2H), 2.84-2.81 (m, 1H), 2.65-2.55 (m, 3H), 2.42-2.36 (m, 5H), 2.01-1.92 (m, 2H), 1.85-1.73 (m, 3H), 1.57-1.55 (m, 3H)

[0388] Examples 11 & 12 Example 11: 6-((1S,4R,11R,14aR)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine

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[0389] Step 1: Synthesis of (1S,4R,14aR)-12-chloro-8,10-difluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline

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[0390] Step 2: Synthesis of 6-((1S,4R,14aR)-12-chloro-8,10-difluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] In 9 mL of THF, (1S,4R,14aR)-12-chloro-8,10-difluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline (850 mg, 1.8 mmol, 1.0 eq) was mixed with (TMP)2Zn·2MgCl2·2LiCl (0.4 M, 27.2 mL, 10.9 mmol, 6.0 eq) under N2 conditions. The mixture was stirred at 50°C for 2 hours. Subsequently, LC-MS indicated that the reaction was complete after quenching with D2O. To the mixture, a mixture of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (1.1 g, 2.2 mmol, 1.2 eq) and CPhos Pd G3 (145 mg, 0.18 mmol, 0.1 eq) was added to 1,4-dioxane (9 mL). The mixture was stirred at 70°C for 3 hours. The reaction mixture was quenched with H2O (15 mL) and extracted with ELISA (20 mL x 3). The organic layer was washed with saturated brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: dimethyl = 6:1) to obtain 6-((1S,4R,14aR)-12-chloro-8,10-difluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (1.0 g, 61.1%) as a yellow solid. LCMS: m / z 882.8 (M+H + )

[0391] Step 3: Synthesis of tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] A solution of 6-((1S,4R,14aR)-12-chloro-8,10-difluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (1.0 g, 1.1 mmol, 1.0 eq) and Lindlar catalyst (Pd / BaSO4) (50%, 500 mg) was hydrogenated in THF (15 mL) at 65°C for 20 hours using a hydrogen balloon. HPLC indicated that the reaction was complete. The mixture was filtered and concentrated to obtain the crude product. The residue was purified by preparative TLC (petroleum ether: dimethyl = 3:1) to obtain tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-8,10-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (510 mg, 53.5%) as a yellow solid. LCMS: m / z 863.2 (M+H + )

[0392] Step 4: tert-butyl (1S,4R,11R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate and tert-butyl Synthesis of (1S,4R,11S,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 1.5 mL of THF, a solution of (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (118 mg, 0.63 mmol, 1.5 eq) was added to 60% NaH (50.4 mg, 1.26 mmol, 3.0 eq) at 0°C, and the mixture was subsequently stirred for 0.5 hours at room temperature under N2. A solution of tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (360 mg, 0.42 mmol, 1.0 eq) was added to THF (4 mL) and the mixture was stirred at 25°C for 1.5 hours. HPLC and TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with toluene (10 mL x 3). The mixture was concentrated to obtain the crude product. The residue was purified by preparative TLC (DCM:MeOH=10:1) to obtain tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (300 mg, 69.0%) as a yellow solid. LCMS: 1032.4 (M+H + )

[0393] Diastereomers were separated by SFC to obtain tert-butyl (1S,4R,11R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (P1, retention time = 1.518 min, 150 mg, including another batch of approximately 200 mg) and tert-butyl (1S,4R,11S,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (P2, retention time = 2.164 mins, 87 mg, including another batch of approximately 200 mg).

[0394] SFC conditions: Analytical separation method: Equipment: Waters UPC2 analysis SFC (SFC-H). Column: Chiralpak IG, 150 x 4.6mm ID, 3μm.

[0395] Mobile phase: A is CO2, B is ethanol (0.05% DEA). Gradient: B 50%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35°C. Wavelength: 220 nm.

[0396] Preparative separation method Apparatus: WATERS 150-portion SFC (SFC-26). Column: Chiralpak IG, 250 x 30 mm ID, 10 μm. Mobile phase: A = CO2, B = Ethanol (0.1% NH3H2O). Gradient: B 45%. Flow rate: 120 mL / min. Back pressure: 100 bar. Column temperature: 38°C. Wavelength: 254 nm. Cycle time: Approximately 4 minutes.

[0397] Step 5: 6-((1S,4R,11R,14aR)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine Synthesis of 6-((1S,4R,11S,14aR)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2- [ka] A mixture of tert-butyl (1S,4R,11R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (150 mg, 0.15 mmol) in TFA (3 mL) was stirred at 50°C for 3 hours under N2 conditions. The mixture was concentrated to obtain a crude product, saturated sodium bicarbonate aqueous solution (15 mL) was added to adjust the pH to (7-8), and the product was extracted with DCM / MeOH = 10 / 1 (15 mL x 3). The combined organic layers were washed with saturated saline solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by preparative HPLC (in water, acetonitrile containing 0.1% FA, 20%-46%) to obtain 6-((1S,4R,11R,14aR)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (25 mg, containing 0.4 FA, 24%) as a white solid. LCMS: m / z 691.9 (M+H + )

[0398] 1 H NMR (300 MHz, DMSO-d6) δ 6.86 (brs, 2H), 6.47 (s, 1H), 5.75 (s, 1H), 5.30 (s, 1H), 5.02 (d, J = 11.7 Hz, 1H), 4.14 - 4.03 (m, 2H), 4.00-3.85 (m, 1H), 3.66-3.60 (m, 3H), 3.45-3.05 (m, 3H), 3.02-2.85 (m, 2H), 2.75-2.51 (m, 2H), 2.45-2.39 (m, 1H), 2.36 (d, J = 1.2, 3H), 2.29-2.21 (m, 1H), 2.00-1.71 (m, 5H), 1.61-1.55 (m, 3H)

[0399] [Chemical] A mixture of tert-butyl (1S,4R,11S,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (87 mg, 0.08 mL) in TFA (2.0 mL) was stirred at 50°C for 3 hours under N2 conditions. The mixture was concentrated to obtain a crude product, saturated sodium bicarbonate aqueous solution (15 mL) was added to adjust the pH to (7-8), and the product was extracted with DCM / MeOH = 10 / 1 (10 mL x 3). The combined organic layers were washed with saturated saline solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by preparative HPLC (in water, acetonitrile containing 0.1% FA, 10% to 65%) to obtain 6-((1S,4R,11S,14aR)-12-chloro-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10-fluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (13 mg, containing 0.8 FA, 23.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.82 (brs, 2H), 6.47 (s, 1H), 5.76 (s, 1H), 5.33 (s, 1H), 5.09 (d, J = 12.0 Hz, 1H), 4.15-4.01 (m, 2H), 4.00-3.90 (m, 1H), 3.69-3.55 (m, 2H), 3.50-3.05 (m, 3H), 3.02-2.89 (m, 2H), 2.70-2.60 (m, 1H), 2.42-2.21 (m, 7H), 1.96-1.77(m, 5H), 1.60-1.54 (m, 3H); LCMS: m / z 691.9 (M+H + )

[0400] Examples 13 & 14 Example 13: 6-((1S,4R,11R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine

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[0401] Step 1: 6-((1S,4R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine

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[0402] Step 2: tert-butyl (1S,4R,11R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate and tert-butyl (1S,4R,11S,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] A solution of 6-((1S,4R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (100 mg, 0.09 mmol, 1.0 eq) and Pd / C (30%, 33 mg) was hydrogenated in MeOH (7 mL) at 55°C for 40 hours using a hydrogen balloon. HPLC indicated that the reaction was complete. The mixture was filtered, concentrated, and the crude residue was obtained, which was purified by preparative TLC (DCM:MeOH = 10:1) to obtain tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (66 mg, 67.3%, diastereomer) as a yellow solid. LCMS: 1002.2 (M+H + )

[0403] The diastereomer was separated by SFC, and tert-butyl (1S,4R,11R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (P1, retention time = 1.910 min, 75 mg, including another batch of approximately 150 mg) was obtained as a yellow solid, and tert-butyl (1S,4R,11S,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (P2, retention time = 3.024 min, 55 mg, including another batch of approximately 150 mg) was obtained as a yellow solid.

[0404] SFC conditions: Analytical separation method: Equipment: Waters UPC2 analysis SFC (SFC-H). Column: Chiralpak IG, 150 x 4.6mm ID, 3μm.

[0405] Mobile phase: A is CO2, B is isopropanol (0.05% DEA). Gradient: B 40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35°C. Wavelength: 220 nm.

[0406] Preparative separation method Apparatus: WATERS 150-portion SFC (SFC-26). Column: Chiralpak IG, 250 x 30 mm ID, 10 μm. Mobile phase: A = CO2, B = Isopropanol (0.1% NH3H2O). Gradient: B 40%. Flow rate: 120 mL / min. Back pressure: 100 bar. Column temperature: 38°C. Wavelength: 220 nm. Cycle time: Approximately 4 minutes.

[0407] Step 3: 6-((1S,4R,11R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine 6-((1S,4R,11S,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] A mixture of tert-butyl (1S,4R,11R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (75 mg, 0.07 mmol) in TFA (2.5 mL) was stirred at 50°C for 3 hours. The mixture was concentrated to obtain the residue, and saturated NaHCO3 solution (15 mL) was added to adjust the pH to (7-8). The mixture was then extracted with DCM:MeOH = 10:1 (10 mL x 3). The combined organic layers were washed with saturated saline solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by preparative HPLC (in water, acetonitrile containing 0.1% FA, 10% to 65%) to obtain 6-((1S,4R,11R,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (18 mg, containing 0.87 FA, 35%) as a white solid.

[0408] 1 ¹H NMR (300 MHz, DMSO-d₆): δ 6.85 (s, 2H), 6.47 (s, 1H), 5.75 (s, 1H), 5.30 (s, 1H), 5.27 (d, J = 54.3 Hz, 1H), 5.03 (d, J = 12.0 Hz, 1H), 4.03 (dd, J = 35.1 Hz, 10.2 Hz, 2H), 3.95-3.88 (m, 1H), 3.59 (s, 2H), 3.42 (s, 2H), 3.15-3.08 (m, 3H), 2.99-2.90 (m, 2H), 2.86-2.71 (m, 1H), 2.36 (d, J = 1.5 Hz, 3H), 2.29-2.25 (m, 1H), 2.20 -2.12 (m, 1H), 2.05-1.92 (m, 3H), 1.85-1.75 (m, 3H), 1.54 (s, 2H). LCMS: m / z 661.9 (M+H⁺)

[0409] [Chemical Formula] A mixture of tert-butyl (1S,4R,11S,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (55 mg, 0.05 mL) in TFA (2.0 mL) was stirred at 50°C for 3 hours. The mixture was concentrated to obtain the residue, and saturated NaHCO3 solution (15 mL) was added to adjust the pH to (7-8). The mixture was then extracted with DCM:MeOH = 10:1 (10 mL x 3). The combined organic layers were washed with saturated saline solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by preparative HPLC (in water, acetonitrile containing 0.1% FA, 10% to 65%) to obtain 6-((1S,4R,11S,14aR)-12-chloro-10-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (21 mg, containing 0.6 FA, 57%) as a white solid.

[0410] 1H NMR (300 MHz, DMSO-d6): δ 6.82 (s, 2H), 6.47 (s, 1H), 5.76 (s, 1H), 5.31 (s, 1H), 5.27 (d, J = 54.3 Hz, 1H), 5.08 (d, J = 12.0 Hz, 1H), 4.11-3.89 (m, 3H), 3.59 (s, 2H), 3.41 (s, 2H), 3.13-3.08 (m, 3H), 2.99-2.89 (m, 2H), 2.86-2.71 (m, 1H), 2.36 (d, J = 1.2 Hz, 3H), 2.28-2.23 (m, 1H), 2.19-2.01 (m, 2H), 2.00-1.94 (m, 2H), 1.85-1.75 (m, 3H), 1.51-1.50 (m, 2H). LCMS: m / z 661.9 (M+H + )

[0411] Examples 15 & 16 Example 15: 4-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine 2,2,2-trifluoroacetate

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[0412] Step 1: Synthesis of N,N-bis(4-methoxybenzyl)-6-methyl-4-((1S,4R,14aR)-8,10,12-trifluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-5-(trifluoromethyl)pyridine-2-amine

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[0413] Step 2: Synthesis of tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridine-4-yl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] A solution of N,N-bis(4-methoxybenzyl)-6-methyl-4-((1S,4R,14aR)-8,10,12-trifluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-5-(trifluoromethyl)pyridine-2-amine (4.0 g, 4.6 mmol, 1.0 eq), Boc2O (1.5 g, 6.9 mmol, 1.5 eq), and Pd / BaSO4 (2.0 g, 50% w / w) was stirred at 65°C for 20 hours in THF (40 mL). The mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: dimethyl = 1:1) to obtain tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridine-4-yl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (3.0 g, 75.4%) as a yellow solid. LCMS: m / z 847.5 (M+H + )

[0414] Step 3: Synthesis of tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridine-4-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 6 mL of THF, a solution of compound (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (168 mg, 0.89 mmol, 1.5 eq) was mixed with NaH (60%, 71 mg, 1.77 mmol, 3.0 eq). The mixture was stirred at room temperature for 0.5 hours. The compound tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridine-4-yl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (500 mg, 0.59 mmol, 1.0 eq) was added. The mixture was stirred at 40°C for 1 hour. The reaction mixture was quenched with water (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with H2O (20 mL) and saturated brine (20 mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to obtain the compound tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridine-4-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (400 mg, 66.7%) as a yellow solid. LCMS: m / z 509.0 (M / 2+H + )

[0415] Step 4: Synthesis of 4-((1S,4R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] A solution of tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridine-4-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (400 mg, 0.39 mmol, 1.0 eq) was stirred at 50°C for 4 hours. The mixture was concentrated to obtain the residue. The residue was purified by preparative TLC (dichloromethane:methanol = 5:1, in MeOH, acetonitrile containing 0.1% NH4OH) to obtain compound 4-((1S,4R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine (108 mg, 40.6%) as a yellow solid.

[0416] Step 5: 4-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine 2,2,2-trifluoroacetate Synthesis of formate (1:0.2:0.6) and 4-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine formate (1:0.5) [ka] Compound 4-((1S,4R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine (130 mg) was subjected to chiral HPLC (column: CHIRALPAK IE, 2cm x 25cm, 5μm, mobile phase: A is hexane (0.5% 2mM)). Purified by NH3-MeOH, B is EtOH, flow rate: 20 mL / min, column temperature: 25°C, to 4-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine 2,2,2-trifluoroacetate Formate (1:0.2:0.6) (32 mg, 24.6%) and 4-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine formate (1:0.5) (24 mg, 18.5%) were obtained.

[0417] P1:4-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine 2,2,2-trifluoroacetate formate (1:0.2:0.6): Chiral purity: 98.55% de, retention time: 6.523 min; Chiral HPLC method: Column: CHIRALPAK IB N-3, 4.6 x 100 mm, 3 μm, Mobile phase: A is Hex, B is EtOH (0.1% TFA), Gradient: B 10%, Flow rate: 0.8 mL / min, Column temperature: 25°C. 1 H NMR (300 MHz, CD3OD): δ 8.49 (brs, 1H), 6.33 (s, 1H), 5.77 (s, 1H), 5.56 (d, J = 3.9 Hz, 1H), 5.30 (dd, J = 14.4, 2.8 Hz, 1H), 4.41 - 4.25 (m, 2H), 4.12 (dd, J = 11.4, 4.5 Hz, 1H), 4.03 (s, 1H), 3.94 - 3.79 (m, 2H), 3.52 (d, J = 14.1 Hz, 1H), 3.37 - 3.32 (m, 1H), 3.27 - 3.18 (m, 1H), 2.99 - 2.74 (m, 3H), 2.63 - 2.38 (m, 6H), 2.22 - 1.83 (m, 7H). LCMS: m / z 676.5 (M+H + )

[0418] P2:4-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine formate (1:0.5): Chiral purity: 97.57%de, retention time: 5.447 min; Chiral HPLC method: Column: CHIRALPAK IB N-3, 4.6 x 100 mm, 3 μm, Mobile phase: A is Hex, B is EtOH (0.1% TFA), Gradient: B 10%, Flow rate: 0.8 mL / min, Column temperature: 25°C. 1 H NMR (300 MHz, CD3OD): δ 8.49 (brs, 1H), 6.30 (s, 1H), 5.76 (s, 1H), 5.52 (d, J = 3.9 Hz, 1H), 5.32 (d, J = 13.5 Hz, 1H), 4.42 - 4.27 (m, 2H), 4.16 - 4.04 (m, 1H), 4.02 - 3.77 (m, 3H), 3.56 - 3.43 (m, 1H), 3.28 - 3.13 (m, 2H), 2.97 - 2.71 (m, 3H), 2.65 - 2.32 (m, 6H), 2.23 - 1.79 (m, 7H). LCMS: m / z 676.4 (M+H + )

[0419] Examples 17 & 18 Example 17: 4-((1S,4R,11R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Example 18: 4-((1S,4R,11S,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Synthesis scheme [ka]

[0420] Step 1: Synthesis of tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridine-4-yl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 6 mL of THF, a solution of the compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (113 mg, 0.71 mmol, 1.5 eq) was mixed with NaH (60%, 57 mg, 1.42 mmol, 3.0 eq). The mixture was stirred at room temperature for 0.5 hours. The compound tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridine-4-yl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (400 mg, 0.47 mmol, 1.0 eq) was added. The mixture was stirred at 40°C for 1 hour. The reaction mixture was quenched with water (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with H2O (20 mL) and saturated brine (20 mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to obtain the compound tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridine-4-yl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (300 mg, 64.4%) as a yellow solid. LCMS: m / z 986.5 (M+H + )

[0421] Step 2: Synthesis of 4-((1S,4R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] A solution of tert-butyl (1S,4R,14aR)-11-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridine-4-yl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (400 mg, 0.41 mmol, 1.0 eq) was stirred at 50°C for 4 hours. The mixture was concentrated to obtain the residue. The residue was purified by preparative TLC (dichloromethane:methanol = 5:1, in MeOH, acetonitrile containing 0.1% NH4OH) to obtain compound 4-((1S,4R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine (120 mg, 45.8%) as a yellow solid. LCMS: m / z 646.4 (M+H+)

[0422] Step 3: 4-((1S,4R,11R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine Synthesis of formate (1:1) and 4-((1S,4R,11S,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine formate (1:0.9) [ka] Compound 4-((1S,4R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine (150 mg) was subjected to chiral HPLC (column: CHIRALPAK IE, 2cm x 25cm, 5μm, mobile phase: A is hexane (0.5% 2mM)). The solution was purified by NH3-MeOH (where B is EtOH), flow rate: 20 mL / min, column temperature: 25°C, and then 4-((1S,4R,11R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine Formate (1:1) (53 mg, 35.3%) and 4-((1S,4R,11S,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine formate (1:0.9) (24 mg, 16.0%) were obtained.

[0423] P1:4-((1S,4R,11R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine formate (1:1): Chiral purity: 97.45%ee; Retention time: 7.337 mins; Chiral HPLC method: Column: CHIRALPAK IB N-3, 4.6 x 100 mm, 3 μm, Mobile phase: A is Hex, B is EtOH (0.1% TFA), Gradient: B 10%, Flow rate: 0.8 mL / min, Column temperature: 25°C. 1 H NMR (300 MHz, CD3OD): δ 8.49 (brs, 1H), 6.32 (s, 1H), 5.77 (s, 1H), 5.60 - 5.24 (m, 3H), 4.51 - 4.35 (m, 2H), 4.20 - 4.07 (m, 1H), 3.98 (s, 1H), 3.91 - 3.77 (m, 1H), 3.74 - 3.47 (m, 3H), 3.25 - 3.18 (m, 1H), 3.01 - 2.86 (m, 1H), 2.65 - 2.49 (m, 5H), 2.49 - 2.09 (m, 6H), 2.08 - 1.79 (m, 4H). LCMS: m / z 646.4 (M+H + )

[0424] P2:4-((1S,4R,11S,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine formate (1:0.9): Chiral purity: 98.24%ee; Retention time: 6.063 min; Chiral HPLC method: Column: CHIRALPAK IB N-3, 4.6 x 100 mm, 3 μm, Mobile phase: A is Hex, B is EtOH (0.1% TFA), Gradient: B 10%, Flow rate: 0.8 mL / min, Column temperature: 25°C. 1 H NMR (400 MHz, CD3OD): δ 8.51 (brs, 1H), 6.30 (s, 1H), 5.76 (s, 1H), 5.58 - 5.25 (m, 3H), 4.49 - 4.30 (m, 2H), 4.11 (dd, J = 11.6, 4.4 Hz, 1H), 3.92 (s, 1H), 3.77 (s, 1H), 3.66 - 3.41 (m, 3H), 3.28 - 3.12 (m, 2H), 2.92 (dd, J = 13.6, 4.4 Hz, 1H), 2.61 - 2.47 (m, 4H), 2.45 - 2.08 (m, 6H), 2.06 - 1.79 (m, 4H). LCMS: m / z 646.3 (M+H + )

[0425] Examples 19 & 20 Example 19: 2-Amino-4-((1S,4R,11S,14aR)-10,12-Difluoro-8-(((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-Methylene-1,2,3,4,5,13,14,14a-Octahydro-1,4-Epiminoazepino[1',2':1,7]azepino[2,3,4-de]Quinazolin-11-yl)-7-Fluorothieno[3,2-c]pyridine-3-Carbonitrile [ka] Example 20: 2-Amino-4-((1S,4R,11R,14aR)-10,12-Difluoro-8-(((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-Methylene-1,2,3,4,5,13,14,14a-Octahydro-1,4-Epiminoazepino[1',2':1,7]azepino[2,3,4-de]Quinazolin-11-yl)-7-Fluorothieno[3,2-c]pyridine-3-Carbonitrile [ka] Synthesis scheme [ka]

[0426] Step 1: Synthesis of tert-butyl (3-cyano-7-fluoro-4-((1S,4R,14aR)-8,10,12-trifluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)thieno[3,2-c]pyridine-2-yl)carbamate [ka] To a solution of (1S,4R,14aR)-8,10,12-trifluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline (400 mg, 0.88 mmol, 1.0 eq) in THF (13.3 mL, 5.3 mmol, 6.0 eq), 0.4 M (TMP) 2Zn·MgCl2·LiCl was added dropwise using a double-ended needle. The reaction mixture was stirred at 50°C for 2 hours under N2. To the reaction mixture, a solution of tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (319 mg, 0.97 mmol, 1.1 eq) and CPhos Pd G3 (71 mg, 0.09 mmol, 0.1 eq) was added in dioxane (4 mL). The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched with H2O (5 mL). The mixture was filtered, washed with RINKAN (200 mL), and separated. The aqueous layer was extracted with RINKAN (10 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, filtered, concentrated, and the crude product was obtained. The crude product was purified by silica gel column chromatography (petroleum ether: HCl = 2:1) to obtain tert-butyl (3-cyano-7-fluoro-4-((1S,4R,14aR)-8,10,12-trifluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)thieno[3,2-c]pyridine-2-yl)carbamate (400 mg, 60.9%) as a brown solid. LCMS: m / z 744.4 (M+H + )

[0427] Step 2: Synthesis of tert-butyl (1S,4R,14aR)-11-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] A solution of tert-butyl (3-cyano-7-fluoro-4-((1S,4R,14aR)-8,10,12-trifluoro-15-(4-methoxybenzyl)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)thieno[3,2-c]pyridine-2-yl)carbamate (140 mg, 0.19 mmol, 1.0 eq), Boc2O (123 mg, 0.57 mmol, 3.0 eq), and Pd / BaSO4 (70 mg, 50% w / w) was stirred at 65°C for 20 hours in THF (3 mL). The mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: dimethyl = 3:1) to obtain tert-butyl (1S,4R,14aR)-11-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (100 mg, 73.5%) as a yellow solid. LCMS: m / z 724.8 (M+H + )

[0428] Step 3: Synthesis of tert-butyl (1S,4R,14aR)-11-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 2 mL of THF, a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (66 mg, 0.41 mmol, 1.5 eq) was mixed with NaH (60%, 33 mg, 0.83 mmol, 3.0 eq). The mixture was stirred at room temperature for 0.5 hours. The compound tert-butyl (1S,4R,14aR)-11-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (200 mg, 0.28 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (5 mL). The aqueous layer was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine (5 mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified by preparative TLC (dichloromethane:methanol = 15:1) to obtain the compound tert-butyl (1S,4R,14aR)-11-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (200 mg, 83.9%) as a yellow solid. LCMS: 863.3 (M+H + )

[0429] Step 4: Synthesis of 2-amino-4-((1S,4R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:1) [ka] TFA (1.0 mL) was added to a solution of tert-butyl (1S,4R,14aR)-11-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (200 mg, 0.23 mmol, 1.0 eq). The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated to obtain the residue. The residue was purified by preparative HPLC (in water, acetonitrile containing 0.1% TFA, 15%-50%) to obtain compound 2-amino-4-((1S,4R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:1) (110 mg, 62.4%) as a yellow solid. 1 H NMR (400 MHz, CD3OD): δ 8.35 (s, 1H), 5.83 (d, J = 5.6 Hz, 1H), 5.74 - 5.38 (m, 3H), 4.80 - 4.59 (m, 2H), 4.39 - 4.21 (m, 2H), 4.18 - 4.12 (m, 1H), 4.09 - 3.89 (m, 3H), 3.53 - 3.42 (m, 2H), 3.08 - 2.95 (m, 1H), 2.76 - 2.30 (m, 7H), 2.20 - 2.00 (m, 4H). LCMS: 663.3 (M-TFA+H + )

[0430] Step 5: 2-Amino-4-((1S,4R,11S,14aR)-10,12-Difluoro-8-(((2R,7aS)-2-Fluorotetrahydro-1H-Pyrrolidine-7a(5H)-yl)methoxy)-13-Methylene-1,2,3,4,5,13,14,14a-Octahydro-1,4-Epiminoazepino[1',2':1,7]azepino[2,3,4-de]Quinazolin-11-yl)-7-Fluorothieno[3,2-c]Pyridine-3-Carbonitrile Synthesis of 2,2,2-trifluoroacetate (1:0.54) and 2-amino-4-((1S,4R,11R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:0.05) [ka] Compound 2-amino-4-((1S,4R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (140 mg) was subjected to chiral HPLC (column: CHIRALPAK IK, 2cm x 25cm, 5μm, mobile phase: A is MTBE (0.5% 2mM)). The solution was purified by 2-amino-4-((1S,4R,11S,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:0.54) (38 mg, 27.1%) was obtained as a white solid, and 2-amino-4-((1S,4R,11R,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:0.05) (50 mg, 35.7%) was obtained as a white solid.

[0431] P1:2-Amino-4-((1S,4R,11S,14aR)-10,12-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:0.54): Chiral purity: 98.08%ee; Retention time: 1.521 min; Chiral SFC method: Column: CHIRALPAK IK-3, 4.6x50mm, 3μm, Mobile phase: A is MTBE (0.1% DEA), B is EtOH:DCM=1:1, Gradient: B 20%, Flow rate: 1.0 mL / min, Back pressure: 100 bar, Column temperature: 25℃. 1 H NMR (400 MHz, CD3OD): δ 8.32 (s, 1H), 5.73 (s, 1H), 5.56 - 5.31 (m, 3H), 4.51 - 4.30 (m, 2H), 4.18 - 4.06 (m, 1H), 3.92 - 3.82 (m, LCMS: 663.2 (M-0.54TFA+H + )

[0432] P2:2-Amino-4-((1S,4R,11R,14aR)-10,12-Difluoro-8-(((2R,7aS)-2-Fluorotetrahydro-1H-Pyrrolidine-7a(5H)-yl)methoxy)-13-Methylene-1,2,3,4,5,13,14,14a-Octahydro-1,4-Epiminoazepino[1',2':1,7]azepino[2,3,4-de]Quinazolin-11-yl)-7-Fluorothieno[3,2-c]Pyridine-3-Carbonitrile 2,2,2-Trifluoroacetate (1:0.05): Chiral purity: 98.88%ee; Retention time: 1.521 min; Chiral SFC method: Column: CHIRALPAK IK-3, 4.6x50mm, 3μm, Mobile phase: A is MTBE (0.1% DEA), B is EtOH:DCM=1:1, Gradient: B 20%, Flow rate: 1.0 mL / min, Back pressure: 100 bar, Column temperature: 25℃. 1 H NMR (400 MHz, CD3OD): δ 8.31 (s, 1H), 5.71 (s, 1H), 5.57 (d, J = 3.6 Hz, 1H), 5.35 - 5.21 (m, 2H), 4.38 - 4.18 (m, 2H), 4.10 - 3.95 (m, LCMS: 663.2 (M-0.05TFA+H + )

[0433] Examples 21 & 22 Example 21: 2-Amino-4-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile [ka] Example 22: 2-Amino-4-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile [ka] Synthesis scheme [ka]

[0434] Step 1: Synthesis of tert-butyl (1S,4R,14aR)-11-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] In 2 mL of THF, a solution of (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (71 mg, 0.37 mmol, 1.5 eq) was mixed with NaH (60%, 30 mg, 0.75 mmol, 3.0 eq). The mixture was stirred at room temperature for 0.5 hours. The compound tert-butyl (1S,4R,14aR)-11-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-8,10,12-trifluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (180 mg, 0.25 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (5 mL). The aqueous layer was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine (5 mL), dried over Na2SO4, and evaporated to dryness. The crude product was purified by preparative TLC (dichloromethane:methanol = 15:1) to obtain the compound tert-butyl (1S,4R,14aR)-11-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (100 mg, 45.0%) as a yellow solid. LCMS: 893.2 (M+H + )

[0435] Step 2: Synthesis of 2-amino-4-((1S,4R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:1) [ka] TFA (1.0 mL) was added to a solution of tert-butyl (1S,4R,14aR)-11-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate (100 mg, 0.11 mmol, 1.0 eq). The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated to obtain the residue. The residue was purified by preparative HPLC (in water, acetonitrile containing 0.1% TFA, 15%-50%) to obtain compound 2-amino-4-((1S,4R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:1) (74 mg, 83.6%) as a yellow solid. 1 H NMR (400 MHz, CD3OD): δ 8.35 (s, 1H), 5.91 - 5.33 (m, 3H), 4.80 - 4.66 (m, 2H), 4.56 - 4.41 (m, 1H), 4.32 - 4.08 (m, 4H), 3.87 - 3.74 (m, 1H), 3.49 - 3.35 (m, 2H), 3.12 - 2.85 (m, 3H), 2.74 - 1.92 (m, 10H). LCMS: 693.3 (M-TFA+H + )

[0436] Step 3: 2-Amino-4-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile Synthesis of 2,2,2-trifluoroacetate (1:0.36) and 2-amino-4-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:0.44) [ka] Compound 2-amino-4-((1S,4R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:1) (74 mg) was prepared using chiral HPLC (column: CHIRALPAK IF, 2cm x 25cm, 5μm, mobile phase: A is MTBE (0.5% 2mM)). Separation was performed using NH3-MeOH, B is MeOH:DCM, gradient: B 20%, flow rate: 20 mL / min, column temperature: 25°C) and 2-amino-4-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-Trifluoroacetate (1:0.36) (13.6 mg, 18.4%) is presented as a white solid, and 2-amino-4-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:0.44) (14.2 mg, 19.2%) was obtained as a white solid.

[0437] P1:2-Amino-4-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:0.36): Chiral purity: 97%de; Retention time: 7.777 mins; UPCC method: Column: CHIRALPAK OD-3 4.6mm*250mm, 3μm, Mobile phase: A CO2;B 0.1% DEA in MeOH, flow rate: 2.0 mL / min, 210 nm, column temperature: 35 °C. 1 H NMR (300 MHz, CD3OD): δ 8.32 (s, 1H), 5.75 (s, 1H), 5.56 (d, J = 3.9 Hz, 1H), 5.37 (dd, J = 13.8, 2.7 Hz, 1H), 4.46 - 4.31 (m, 2H), 4.20 - 4.09 (m, 1H), 4.08 - 3.99 (m, 1H), 3.98 - 3.80 (m, 2H), 3.60 - 3.50 (m, 1H), 3.31 - 3.21 (m, 2H), 2.98 - 2.80 (m, 3H), 2.60 - 2.42 (m, 3H), 2.21 - 1.89 (m, 7H). LCMS: 693.4 (M-0.36TFA+H + )

[0438] P2:2-Amino-4-((1S,4R,11R,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2,2,2-trifluoroacetate (1:0.44): Chiral purity: 97.8% de; Retention time: 11.217 mins; UPCC method: Column: CHIRALPAK OD-3 4.6mm*250mm, 3μm, mobile phase: A CO2;B 0.1% DEA in MeOH, flow rate: 2.0mL / min, 210nm, column temperature: 35℃. 1 H NMR (400 MHz, CD3OD): δ 8.32 (s, 1H), 5.76 (s, 1H), 5.63 (d, J = 3.6 Hz, 1H), 5.32 (dd, J = 14.0, 3.2 Hz, 1H), 4.42 - 4.29 (m, 2H), 4.20 - 4.09 (m, 1H), 4.00 - 3.82 (m, 3H), 3.59 - 3.48 (m, 1H), 3.31 - 3.16 (m, 2H), 2.99 - 2.68 (m, 3H), 2.65 - 2.39 (m, 3H), 2.21 - 1.89 (m, 7H).LCMS: 693.4 (M-0.44TFA+H + )

[0439] Example 23 1-(isobutyryloxy)ethyl (1S,4R,11S,14aR)-11-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate [ka] Synthesis scheme [ka]

[0440] Step 1: Synthesis of 1-(isobutyryloxy)ethyl (1S,4R,11S,14aR)-11-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazoline-15-carboxylate In 3 mL of DCM, a solution of 6-((1S,4R,11S,14aR)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[1',2':1,7]azepino[2,3,4-de]quinazolin-11-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (27 mg, 0.04 mmol, 1.0 eq) is mixed with DIEA (16 mg, 0.12 mmol, 3.0 eq) and 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl Isobutyrate (15 mg, 0.05 mmol, 1.3 eq) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (DCM:MeOH = 10:1) to obtain the impure crude product, which was further purified by preparative HPLC (in water, acetonitrile) to obtain 1-(isobutyryloxy)ethyl (1S,4R,11S,14aR)-11-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-8-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-10,12-difluoro-13-methylene-1,2,3,4,5,13,14,14a-octahydro-1,4-epiminoazepino[...

Claims

1. The following structural formula (I): 【Chemistry 1】 [In the formula, n is either 1 or 2; X is CR ｘ１ R ｘ２ And here, R ｘ１ and R ｘ２ These are, independently, H, halo, and unsubstituted or substituted C. １－３ Selected from alkyl groups; Y is NH, NR ｙ , CH ２ NH, CH ２ NR ｙ , NHCH ２ , or NR ｙ CH ２ ; wherein R ｙ is unsubstituted or substituted C １－４ alkyl, P(O)(OCH ３ ) ２ , C(O)OR ｗ , C(O)R ｗ ; wherein R ｗ is H, or unsubstituted or substituted C １－６ alkyl; R ２ (CH ２ ) ｉ R ２’ Here, i is an integer selected from 1 to 6, (CH ２ ) ｉ R may be substituted as appropriate. ２’ This includes H, halogen, CN, OH, C(O)NRR', unsubstituted or substituted C １－６ Selected from the group consisting of alkyl, unsubstituted or substituted 3- to 6-membered carbocyclic rings, unsubstituted or substituted 4- to 6-membered heterocyclic rings, and unsubstituted or substituted aryl 7- to 9-membered bicyclic heterocyclic rings; R ６ This includes H, halogen, CN, OR, unsubstituted or substituted C １－４ Alkyl, unsubstituted, or substituted C １－４ Alkoxy, C(O)NRR', NRR', S(O) ２ CH ３ Selected from the group consisting of unsubstituted or substituted 3- to 6-membered carboncyclic or heterocyclic rings, and unsubstituted or substituted 5- to 6-membered heteroaryl rings; R ７ It is an unsubstituted or substituted 6-10 member unsaturated monocyclic or bicyclic ring containing 0-5 heteroatoms selected from N, O, and S; R ８ This is H, halo, unsubstituted or substituted C. １－４ It is alkyl, OR, or NRR'; R ａ , R ｂ , and R ｃ teeth, Each is independent of H, halo, unsubstituted or substituted C. １－３ Selected from alkyl and OR; or One R ａ and one R ｂ , or one R ａ and one R ｃ Together with Y and the carbon atoms to which they are bonded, they form a 4- to 7-membered heterocyclic ring; R １０ These are H, Halo, or C, respectively, independently. １－４ Alkyl; or R １０ ', together with the carbon atoms to which they are bonded, form a cyclopropyl or cyclobutyl group; R and R' are, independently, H, unsubstituted, or substituted C. １－４ Selected from alkyl groups, or unsubstituted or substituted 3- to 6-membered carbocyclic rings, or R and R' are bonded to the same N atom, together forming an unsubstituted or substituted 4- to 6-membered heterocyclic ring. A compound represented by , or a pharmaceutically acceptable form thereof, or an isotope derivative thereof.

2. n is 1, and equation (II): 【Chemistry 2】 The compound according to claim 1, having the structure.

3. One R ａ and one R ｂ However, together with Y and the carbon atoms to which they are bonded, they form a five-membered heterocyclic ring, and formula (I Ａ ): 【Transformation 3】 The compound according to claim 1, having the structure.

4. One R ａ and one R ｂ However, together with Y and the carbon atoms to which they are bonded, they form a five-membered heterocyclic ring, and formula (II Ａ ): 【Chemistry 4】 The compound according to claim 2, having the structure.

5. R ａ and R ｂ One of them is CH ３ The compound according to claim 3 or 4, wherein the other is H.

6. R ａ and R ｂ The compound according to claim 3 or 4, wherein each of the atoms is H.

7. R ｘ１ and R ｘ２ The compound according to any one of claims 1 to 6, wherein each is independently selected from H, F, and Cl.

8. R ｘ１ and R ｘ２ The compound according to claim 7, wherein each of them is H.

9. R ｘ１ and R ｘ２ The compound according to claim 7, wherein one of the atoms is H and the other is F or Cl.

10. R ｘ１ and R ｘ２ The compound according to claim 7, wherein each of the compounds is F or Cl.

11. R ｘ１ and R ｘ２ At least one of them is non-substitutive or substituted C １－３ A compound according to any one of claims 1 to 6, wherein it is alkyl.

12. The compound according to any one of claims 1 to 11, wherein Y is NH.

13. Y is NR ｙ The compound according to any one of claims 1 to 11.

14. Y is CH ２ NH or NHCH ２ The compound according to any one of claims 1 to 11.

15. Y is CH ２ NR ｙ or NR ｙ CH ２ The compound according to any one of claims 1 to 11.

16. R ｙ is P(O)(OCH ３ ) ２ The compound according to claim 15.

17. R ｙ However, C(O)OR, where R is either non-substituted or substituted C. １－４ The compound according to claim 15, wherein it is alkyl.

18. R ｙ but, 【Transformation 5】 The formula includes, where R and R' are H or substituted or unsubstituted C, respectively. １－６ The compound according to claim 17, selected from alkyl or substituted or unsubstituted 3- to 6-membered carbon rings.

19. R ｙ but, 【Transformation 6】 The compound according to claim 18, comprising:

20. R ６ The compound according to any one of claims 1 to 19, wherein H is present.

21. R ６ The compound according to any one of claims 1 to 19, wherein F is present.

22. R ６ The compound according to any one of claims 1 to 19, wherein the compound is Cl.

23. R ６ is C １－３ alkyl or C ３－４ cycloalkyl, the compound according to any one of claims 1 to 19.

24. R ６ However, CH ２ F, CHF ２ , or CF ３ The compound according to any one of claims 1 to 19.

25. R ６ is CN, S(O) ２ R, NRR', OR, or C(O)NRR', the compound according to any one of claims 1 to 19.

26. R ｃ The compound according to any one of claims 1 to 25, wherein each of the atoms is H.

27. The compound according to any one of claims 1 to 25, wherein i is 1.

28. R ２’ However, there are 0 to 5 R ２Ａ C is replaced by ３－６ It is a carbocyclic or heterocyclic ring, where R ２Ａ These are D, Halo, and OC, respectively, and are independent of each other. １－３ Alkyl, or C １－３ Selected from alkyl, the C １－３ The compound according to any one of claims 1 to 27, wherein the alkyl group may be appropriately substituted with one or more of halo, OH, NRR', CN, and CONRR'.

29. R ２’ However, there are 0 to 5 R ２Ａ C is replaced by ３－５ The compound according to claim 28, wherein it is a carbocyclic ring.

30. R ２ but, 【Transformation 7】 A compound according to claim 29, selected from the above.

31. R ２’ However, there are 0 to 5 R ２Ａ C is replaced by ３－５ The compound according to claim 28, which is a heterocyclic ring.

32. R ２ but, 【Transformation 8】 A compound according to claim 31, selected from the above.

33. R ２’ However, biring non-substituted or substituted C ６－１０ A compound according to any one of claims 1 to 27, wherein the compound is a heterocyclic ring.

34. R ２ but, 【Chemistry 9】 A compound according to claim 33, selected from the above.

35. R ２ but, 【Chemistry 10】 A compound according to claim 33, selected from the above.

36. R ７ The compound according to any one of claims 1 to 35, wherein the compound is an unsubstituted or substituted six-membered aryl or heteroaryl ring containing 0 to 5 heteroatoms selected from N, O, and S.

37. R ７ However, the following structural formula: 【Chemistry 11】 [In the formula, Z is N or CR ７Ｅ And; W is N or CR ７Ｃ And; R ７Ａ This is H, halo, or substituted or unsubstituted C. １－３ It is alkyl; R ７Ｂ This is H, halo, or substituted or unsubstituted C. １－３ It is alkyl; R ７Ｃ is H or halo; R ７Ｄ is H, NRR', halo, or OR; R ７Ｅ [This is H or halo] The compound according to claim 36, represented by [the formula].

38. W is N, and R ７ However, the following structural formula: 【Chemistry 12】 The compound according to claim 37, represented by [the specified symbol].

39. W is CR ７Ｃ And R ７ However, the following structural formula: 【Chemistry 13】 The compound according to claim 37, represented by [the specified symbol].

40. The compound according to any one of claims 37 to 39, wherein Z is N.

41. The compound according to any one of claims 37 to 39, wherein Z is CH.

42. The compound according to any one of claims 37 to 39, wherein Z is CF.

43. R ７Ｄ However, NH ２ The compound according to any one of claims 37 to 42.

44. R ７Ｄ The compound according to any one of claims 37 to 42, wherein the compound is an OH group.

45. R ７Ａ However, CF ３ The compound according to any one of claims 37 to 44.

46. R ７Ａ The compound according to any one of claims 37 to 44, wherein the compound is cyclopropyl.

47. R ７Ｂ However, CH ３ The compound according to any one of claims 37 to 46, or Cl.

48. R ７Ｃ The compound according to any one of claims 37 to 47, wherein if present, it is F.

49. R ７Ｃ The compound according to any one of claims 37 to 47, wherein if present, it is H.

50. R ７ but, 【Chemistry 14】 A compound according to claim 37, selected from the above.

51. R ７ but, 【Chemistry 15】 A compound according to claim 37, selected from the above.

52. R ７ The compound according to any one of claims 1 to 35, wherein the compound is an unsubstituted or substituted 9 or 10-membered bicyclic aryl or heteroaryl ring containing 0 to 5 heteroatoms selected from N, O, and S.

53. R ７ However, the structure is as follows: 【Chemistry 16】 [In the formula, Ring A is a six-membered aryl or heteroaryl ring having 0 to 2 N atoms; Ring B is a 5 or 6-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring having 0 to 3 heteroatoms selected from N, O, and S; R ７Ｆ and R ７Ｇ These are, independently, halogen, OH, CN, NRR', unsubstituted or substituted C. １－６ Alkyl and unsubstituted or substituted C １－６ Alkoxy, (CH ２ ) ｋ NRR', (CH ２ ) ｋ C(=O)NRR', (CH ２ ) ｋ OC(=O)R, (CH ２ ) ｋ Selected from the group consisting of OC (=O)OR; p and q are independently 0, 1, 2, or 3; k is independently 0, 1, or 2. The compound according to claim 52, having the following characteristics.

54. The compound according to claim 53, wherein ring A is a six-membered aryl ring.

55. The compound according to claim 53, wherein ring A is a six-membered heteroaryl ring.

56. The compound according to claim 54 or 55, wherein ring B is a five-membered heterocyclic ring.

57. The compound according to claim 54 or 55, wherein ring B is a six-membered heterocyclic ring.

58. The compound according to claim 54 or 55, wherein ring B is a five-membered heteroaryl ring.

59. The compound according to claim 54 or 55, wherein ring B is a six-membered heteroaryl ring.

60. The compound according to claim 54 or 55, wherein ring B is a six-membered aryl ring.

61. R ７ but, 【Chemistry 17】 A compound according to claim 53, selected from the above.

62. R ７ but, [Chemistry 18] A compound according to claim 53, selected from the above.

63. R ７ but, 【Chemistry 19】 A compound according to claim 53, selected from the above.

64. R ７ However, the structure is as follows: 【Chemistry 20】 The compound according to claim 53, having the following characteristics.

65. R １０ The compound according to any one of claims 1 to 64, wherein H is present.

66. R １０ However, CH ３ The compound according to any one of claims 1 to 64.

67. R ８ The compound according to any one of claims 1 to 66, wherein F.

68. The following structural formula (III) Ａ ): 【Chemistry 21】 The compound according to claim 1, represented by [the specified compound].

69. The following structural formula (III) Ｂ ): 【Chemistry 22】 The compound according to claim 1, represented by [the specified compound].

70. The following structural formula (III) Ｃ ): 【Chemistry 23】 The compound according to claim 1, represented by [the specified compound].

71. The following structural formula (III) Ｄ ): 【Chemistry 24】 The compound according to claim 1, represented by [the specified compound].

72. R ６ The compound according to any one of claims 68 to 71, wherein F is present.

73. R ６ The compound according to any one of claims 68 to 71, wherein the compound is Cl.

74. R ｙ The compound according to any one of claims 68 to 73, wherein H is present.

75. R ｙ but, 【Chemistry 25】 The formula includes, where R and R' are H or substituted or unsubstituted C, respectively. １－６ A compound according to any one of claims 68 to 73, selected from alkyl or substituted or unsubstituted 3 to 6-membered carbon rings.

76. R ｘ２ The compound according to any one of claims 68 to 75, wherein H is present.

77. R ｘ１ The compound according to any one of claims 68 to 76, wherein H is present.

78. R ｘ１ and R ｘ２ The compound according to any one of claims 68 to 75, wherein one of them is F.

79. A compound according to claim 1, selected from Table 1.

80. A compound according to claim 1, selected from Table 2.

81. A compound according to any one of claims 1 to 80, having one or more deuterium atoms instead of hydrogen.

82. The compound according to any one of claims 1 to 80, having one deuterium atom instead of a hydrogen atom.

83. A pharmaceutical composition comprising a compound according to any one of claims 1 to 82 and a pharmaceutically acceptable excipient, carrier, or diluent.

84. A pharmaceutical composition according to claim 83, suitable for oral administration.

85. A unit dosage form comprising the pharmaceutical composition according to claim 83 or 84.

86. The unit dosage form according to claim 85, which is in the form of a tablet or capsule.

87. A method for inhibiting cell proliferation in vitro or in vivo, comprising contacting cells with an effective amount of a compound according to any one of claims 1 to 82.

88. A method for regulating KRas(G12D) activity in cells, comprising contacting the cells with a compound according to any one of claims 1 to 82.

89. A method for treating a disease or disorder mediated by a Ras mutant protein, characterized by administering a therapeutically effective amount of the compound described in any one of claims 1 to 82 to a subject in need of treatment.

90. A method for treating or alleviating cancer or related diseases or disorders, characterized by administering a therapeutically effective amount of a compound described in any one of claims 1 to 82 to a subject in need of treatment.

91. The method according to claim 90, wherein the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

92. The method according to claim 90 or 91, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendiceal cancer, cholangiocarcinoma, urothelial carcinoma of the bladder, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, and hematological malignancies.

93. The method according to any one of claims 87 to 92, wherein the subject has mutations in KRAS, HRAS, and / or NRAS.

94. The method according to any one of claims 87 to 93, wherein the subject to be treated is further subjected to one or more of the following: chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormone therapy.

95. The use of a compound according to any one of claims 1 to 82, and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a pharmaceutical for the treatment of a disease or disorder.

96. The use according to claim 95, wherein the disease or disorder is cancer.

97. The use according to claim 96, wherein the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

98. The use according to claim 97, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendiceal cancer, cholangiocarcinoma, urothelial carcinoma of the bladder, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, and hematological malignancies.

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