AXL inhibitor compounds

Abstract

Provided herein are compounds of formula I that inhibit AXL: [Formula 1] Described herein are compounds of JPEG2024521712000112.jpg44170, compositions comprising the compound(s), and methods of synthesizing the compounds. Also described are uses of the compounds and compositions for the treatment of a wide variety of a number of diseases, disorders, and conditions, including cancer and immune-related disorders, that are mediated, at least in part, by AXL.

Description

[Technical Field] 【0001】 Cross-reference of related applications This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 191,636, filed on 21 May 2021, and its entire contents are incorporated herein by reference for all purposes. [Background technology] 【0002】 AXL is a receptor tyrosine kinase (RTK) belonging to the TAM family. AXL regulates important processes such as cell proliferation, migration, aggregation, and apoptosis. AXL can be activated by various mechanisms, including ligand-dependent and ligand-independent mechanisms. Once activated, AXL is involved in various signaling pathways, including the RAS-RAF-MEK-ERK pathway, which leads to cancer cell proliferation, and the PI3K / AKT pathway, which is involved in several pro-survival proteins. 【0003】 AXL has been shown to be overexpressed in various malignancies. In the cancer environment, AXL overexpression is associated with lower patient survival rates and resistance mechanisms (both targeted and non-targeted). 【0004】 Given the research linking AXL inhibition to diseases such as cancer, there is a strong demand for novel AXL inhibitors in this field. This disclosure addresses this need by offering advantages not found in conventional AXL inhibitors. [Overview of the project] 【0005】 Summary of the Invention This disclosure relates to a compound that inhibits the activity of AXL. The compound is of formula (I): [ka] A compound represented by , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, where R 1 , R2 , subscript n, condensed rings A and B, and vertex G 1 , G 2 , G 3 , G 4 , and G 5 In this specification, the terms have the meanings defined below. 【0006】 In relevant embodiments, this specification provides methods for treating AXL-mediated diseases or disorders in a subject (e.g., a human), comprising administering to the subject an effective dose of at least one AXL inhibitor described herein. AXL-mediated diseases and disorders include cancer, inflammation, autoimmune disorders, and metabolic disorders, as described below. Other diseases, disorders, and conditions that can be treated or prevented, whole or partially, by modulating AXL activity are candidate indications for the AXL inhibitor compounds provided herein. 【0007】 This specification also provides the use of the AXL inhibitors described herein in combination with one or more additional active agents, as described later. [Modes for carrying out the invention] 【0008】 Detailed explanation of disclosure Before further describing this disclosure, please understand that this disclosure is not limited to the specific embodiments described herein, and that the terms used herein are for the sole purpose of describing specific embodiments and are not intended to limit them. 【0009】 When a numerical range is provided, unless otherwise specified, each intermediate value that lies between the upper and lower limits of the range and is in units of up to one tenth of the lower limit, as well as any other numerical value or intermediate value within the numerical range, is included in this disclosure. Further, the upper and lower limits of these smaller ranges can be independently included in their respective smaller ranges according to any limiting values specifically excluded in the described range, and are also included in this disclosure. If the described range includes one or both of the limiting values, the range excluding one or both of the included limiting values is also included in this disclosure. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the technical field to which this disclosure belongs. 【0010】 As used in this specification, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should further be noted that the claims can be drafted to exclude any optional element. Thus, this description is intended to serve as a basis for the use of exclusive terms such as "solely", "only", etc. in relation to the recitation of elements in the claims or the use of "negative" limitations. 【0011】 The publications described in this specification are provided for the purpose of disclosure prior to the filing date of this application. Further, the provided publication date may differ from the actual publication date, which needs to be individually verified. 【0012】 Definitions Unless otherwise noted, the following terms are intended to have the meanings shown below. Other terms are defined elsewhere throughout this specification. 【0013】 The term "alkyl", by itself or as part of another substituent, unless otherwise specified, means a saturated straight-chain or branched hydrocarbon group having the specified number of carbon atoms (i.e., C1-8 means 1 to 8 carbons). Alkyl can be C1-2, C1-3, C 1-4 、C1-5、C1-6、C 1-7, C1-8, C1-9, C1- 10 , C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C 3-6 Alkyl groups can contain any number of carbon atoms, including C4-5, C4-6, and C5-6. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. 【0014】 The term "hydroxyalkyl" refers to an alkyl group that has the specified number of carbon atoms (e.g., C1-6 or C1-8) and is substituted with one or two hydroxy(OH) groups. 【0015】 The term "halohydroxyalkyl" refers to an alkyl group having the specified number of carbon atoms (e.g., C1-6 or C1-8), and substituted with one or two hydroxy(OH) groups and one to six halogen atoms (e.g., F, Cl). 【0016】 The term "alkylene" refers to a linear or branched saturated aliphatic radical, i.e., a divalent hydrocarbon radical, having the specified number of carbon atoms and bonding at least two other groups. The two parts bonded to the alkylene can be bonded to the same or different atoms of the alkylene group. For example, a linear alkylene is -(CH2) n It can be a divalent group, where n is 1, 2, 3, 4, 5, or 6. Typical alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. In some embodiments, the alkylene group may be substituted or unsubstituted. When a group containing an alkylene group is optionally substituted, it should be understood that any substitution may occur in the alkylene portion of that part. 【0017】 The term "cycloalkyl" refers to monocyclic, bicyclic, or polycyclic non-aromatic hydrocarbon ring systems having the indicated number of ring atoms (e.g., C3-6 ring carbon atoms). 3-6 This refers to cycloalkyl groups. Cycloalkyl groups can be saturated or partially unsaturated; that is, cycloalkyl groups can be characterized by one or more unsaturated points, as long as the unsaturation points do not lead to an aromatic system. Examples of monocyclic cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. Also, "cycloalkyl" refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane. In some embodiments, the cycloalkyl compounds of this disclosure are monocyclic C 3-6 This is the cycloalkyl portion. 【0018】 The term "heterocycloalkyl" refers to monocyclic, bicyclic, or polycyclic cycloalkyl rings having the indicated number of ring vertices (or members) (e.g., 3-14 members, or 4-10 members, or 4-8 members, or 4-6 members) and containing 1-5 heteroatoms selected from N, O, and S in a chemically stable configuration, substituting 1-5 of the carbon vertices, where the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Heterocycloalkyl groups can be saturated or partially unsaturated; that is, heterocycloalkyl groups can be characterized by one or more unsaturated sites, provided that the unsaturated sites do not lead to an aromatic system. The rings of bicyclic and polycyclic heterocycloalkyl groups can be condensed, bridged, or spirocyclic. Non-exclusive examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, oxa-6-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, piperazine, pyran, pyridone, oxetane, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, azetidine, and quinuclidine. Heterocycloalkyl groups are bonded to the remainder of the molecule via a ring carbon atom. If a heterocycloalkyl group is substituted, the substituent is bonded to the heterocycloalkyl group via a ring carbon atom or ring heteroatom, provided it is chemically acceptable. 【0019】 When used in this specification, the wavy lines intersect single, double, or triple bonds in any chemical structure described herein. [ka] The ∫ represents a single, double, or triple bond to the rest of the molecule. In addition, bonds extending from a substituent to the center of a ring (e.g., a phenyl ring) indicate a substituent bonded to the ring at any of the available ring vertices, meaning that the substituent's bond to the ring leads to a chemically stable configuration. 【0020】 As described herein, divalent components include both directions of the component (forward or reverse). For example, the group "-C(O)NH-" includes bonds in either direction, i.e., -C(O)NH- or -NHC(O)-, and similarly, "-O-CH2CH2-" is intended to include both -O-CH2CH2- and -CH2CH2-O-. 【0021】 The terms "halo" or "halogen" mean, alone or as part of another substituent, a fluorine, chlorine, bromine, or iodine atom unless otherwise specified. In addition, terms such as "haloalkyl" include monohaloalkyl and polyhaloalkyl. For example, "C 1-4 The term "haloalkyl" refers to compounds such as trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl. 【0022】 The term "aryl" means monocyclic, bicyclic, or tricyclic aromatic hydrocarbon groups unless otherwise specified. Bicyclic and tricyclic ring systems are fused or covalently bonded to each other. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and biphenyl. The term also means fusion cycloalkylphenyl and heterocycloalkylphenyl ring systems, such as indan, tetrahydronaphthalene, chroman, and isochroman rings. As substituents, the bonding sites to the remainder of the molecule can be via any carbon atom of the aromatic moiety, a carbon atom of the cycloalkyl moiety, or an atom of the heterocycloalkyl moiety for fusion ring systems. 【0023】 The term "heteroaryl" refers to a monocyclic or fused bicyclic aromatic group (or ring) containing one to five heteroatoms selected from N, O, and S in a chemically stable configuration, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Heteroaryl groups can be bonded to the remainder of the molecule via heteroatoms or carbon atoms. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazolyl, isobenzofuryl, isoindolyl, indolidinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranil, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, and thienyl. When a heteroaryl ring is substituted, the substituent is attached to the heteroaryl ring via a ring carbon atom or ring heteroatom, provided it is chemically acceptable. Substituents relating to the heteroaryl ring can be selected from the group of acceptable substituents listed below. 【0024】 As used herein, the term “heteroatom” means including oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). In some embodiments, the heteroatom is N, O, or S. 【0025】 The term “pharmaceutically acceptable salt” is intended to include salts of active compounds, which are prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. If the compounds of this disclosure contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, using either a pure base of the desired base or a suitable inert solvent containing the desired base. Examples of pharmaceutically acceptable salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc. Examples of pharmaceutically acceptable salts derived from organic bases include salts of primary, secondary, and tertiary amines, such as substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine. When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either using a pure desired acid or a suitable inert solvent containing the desired acid. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid.This also includes salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM, et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds in this disclosure contain both base and acidic functional groups that allow the compound to be converted into either a base-addition salt or an acid-addition salt. 【0026】 The neutral form of a compound can be regenerated by contacting the salt with a base or acid using conventional methods to isolate the parent compound. The parent form of a compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise, in this disclosure, the salt is equivalent to the parent form of the compound. 【0027】 In addition to salt forms, this disclosure provides compounds in prodrug forms. Prodrugs of the compounds described herein are compounds that readily undergo chemical transformation under physiological conditions to provide the compounds of this disclosure. In addition, prodrugs can be converted into the compounds of this disclosure by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be gradually converted into the compounds of this disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. 【0028】 Certain compounds in this disclosure may exist in non-solvated and solvated forms, including hydrated forms. Certain compounds in this disclosure may exist in multiple crystalline or amorphous forms. 【0029】 Certain compounds in this disclosure have a chiral carbon atom (optical center) or a double bond. Racemic mixtures, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separated enantiomers) are all intended to be within the scope of this disclosure. When describing stereochemistry, it means that the described isomer is present and substantially no other isomers. "Substantially no other isomers" means that the ratio of the described isomer to other isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or higher. In some embodiments, one of the isomers is present in an amount of at least 99%. 【0030】 The compounds of this disclosure may contain atomic isotopes in an unnatural proportion in one or more of the atoms constituting the compound. An unnatural proportion of isotopes can be defined as ranging from amounts found in nature to amounts that constitute 100% of the atom in question. For example, the compound may contain, for example, tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H), or carbon-13 ( 13 Non-radioactive isotopes such as C) may be incorporated. Such isotopic variations may provide further utility to those described elsewhere in this application. For example, isotopic variants of the compounds disclosed may find further applications as diagnostic and / or imaging reagents or as cytotoxic / radiotoxic therapeutic agents, but are not limited to these. In addition, isotopic variants of the compounds disclosed may have altered pharmacokinetic and pharmacodynamic properties. All isotopic variants of the compounds disclosed, whether radioactive or not, are intended to be included within the scope of this disclosure. 【0031】 The terms "patient" or "subject" are used interchangeably to refer to human or non-human animals (e.g., mammals). 【0032】 The terms “treat,” “treating,” and “treatment” refer to actions initiated after a disease, disorder, or condition, or its symptoms, have been diagnosed, recognized, etc., to eliminate, reduce, suppress, alleviate or improve, temporarily or permanently, at least one of the essential causes of the disease, disorder, or condition affecting the subject, or at least one of the symptoms associated with the disease, disorder, or condition affecting the subject. Therefore, treatment includes inhibiting active disease (e.g., preventing the onset or further onset of the disease, disorder, or condition, or the clinical symptoms associated therewith). 【0033】 As used herein, the term “requiring treatment” refers to the determination by a physician or other caregiver that a person requires treatment or would benefit from treatment. This determination is based on various factors within the scope of the physician's or caregiver's expertise. 【0034】 The terms "prevent," "preventing," and "prevention" refer to initiating a series of actions (e.g., administration of an AXL inhibitor or a pharmaceutical composition containing such an inhibitor) to temporarily or permanently prevent, suppress, inhibit, or reduce (e.g., by the absence of clinical symptoms) the risk of a subject developing a disease, disorder, or condition, or, more generally, delaying its onset in a subject predisposed to a particular disease, disorder, or condition. In certain cases, these terms may also refer to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to an adverse or undesirable condition. 【0035】 As used herein, the term “requiring prevention” refers to a judgment made by a physician or other caregiver that a person requires or would benefit from preventive care. This judgment is based on various factors within the scope of the physician's or caregiver's expertise. 【0036】 The term "therapeutic dose" refers to the amount of an active substance (e.g., the compound according to this disclosure) administered to a subject, either alone or as part of a pharmaceutical composition, and in a single dose or a series of doses, that produces any detectable positive effect on any symptom, condition, or characteristic of a disease, disorder, or pathological state at the time of administration. The therapeutic dose can be confirmed by measuring the relevant physiological effects and may be adjusted in relation to the administration regimen and the diagnostic analysis of the subject's pathological state. For example, measuring serum levels of the AXL inhibitor (or, for example, its metabolites) at a specific time after administration may be an indicator of whether a therapeutic dose has been used. In addition, the effective dose of the AXL inhibitor according to this disclosure may be the amount administered to a subject one or more times that produces the desired result compared to a healthy subject. For example, in a subject with a specific disorder, the effective dose may be a dose that improves the diagnostic parameters, measured values, markers, etc. of the disorder by at least approximately 5%, at least approximately 10%, at least approximately 20%, at least approximately 25%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, at least approximately 80%, at least approximately 90%, or a dose that shows improvement of more than 90%, where 100% is defined as the diagnostic parameters, measured values, markers, etc. shown by a normal subject. 【0037】 The phrase "enough to produce a change" means that there is a detectable difference between the level of a particular indicator measured before administration of that therapy (e.g., baseline level) and the level measured after administration. The indicator can be an objective parameter (e.g., serum concentration) or a subjective parameter (e.g., the subject's perceived health). 【0038】 The terms “inhibitor” and “antagonist,” or “activator” and “agonist,” refer, respectively, to inhibitory or activating molecules related to the activation of ligands, receptors, cofactors, genes, cells, tissues, or organs. An inhibitor is a molecule that reduces, blocks, prevents, delays, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that suppresses, blocks, or inactivates constitutive activity. An activator is a molecule that increases, activates, promotes, enhances, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell. An “agonist” is a molecule that interacts with a target to increase or promote its activation. An “antagonist” is a molecule that prevents the action of an agonist. Antagonists interfere with, suppress, inhibit, or neutralize the activity of agonists, and antagonists can also interfere with, inhibit, or suppress the constitutive activity of a target, such as a target receptor, even in the absence of an identified agonist. 【0039】 The terms "modulate" and "regulate" refer to the ability of a molecule (e.g., an activator or inhibitor) to directly or indirectly enhance or inhibit the function or activity of a specific target, such as AXL. Modulators may act alone or may use cofactors, such as proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds (e.g., the compounds described herein) and other bioorganic molecules. 【0040】 The “activity” of a molecule may describe or refer to the binding of the molecule to a ligand or receptor; catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation or maturation; antigenic activity; the regulation of the activity of other molecules; etc. The term “proliferative activity” includes normal cell division, as well as activity that promotes, requires, or is particularly associated with, cancer, tumor, dysplasia, cell transformation, metastasis, and angiogenesis. 【0041】 As used herein, “comparable,” “equivalent activity,” “equivalent activity,” “equivalent effect,” and “equivalent effect” are relative terms that can be recognized quantitatively and / or qualitatively. The meaning of these terms often depends on the context in which they are used. For example, two receptor-activating agents may be recognized as having comparable effects from a qualitative standpoint, but if, as determined by an assay accepted in the art (e.g., a dose-response assay) or an animal model accepted in the art, one agent achieves only 20% of the activity of the other agent, then the two agents are not considered to have comparable effects from a quantitative standpoint. When comparing one result to another (e.g., comparing one result to a reference standard), “comparable” often (but not always) means that one result deviates from the reference standard by less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%. In certain embodiments, if one result deviates from a reference standard by less than 15%, less than 10%, or less than 5%, that result is considered comparable to the reference standard. For example, activity or effect may refer to, but is not limited to, efficacy, stability, solubility, or immunogenicity. 【0042】 "Substantially pure" means that the component (e.g., the compound according to this disclosure) makes up more than about 50% of the total composition, and generally more than about 60% of the total composition. More generally, "substantially pure" means a composition in which the component of interest makes up at least 75%, at least 85%, at least 90%, or more of the total composition. In some cases, the component of interest makes up more than about 90%, or more than about 95%, of the total composition. 【0043】 The term "response", e.g., the response of a cell, tissue, organ, or organism, includes a change in biochemical or physiological behavior, e.g., a change in concentration, density, adhesion, or migration within a biological compartment, the rate of gene expression, or the state of differentiation, and the change correlates with an internal mechanism such as activation, stimulation, or treatment, or gene programming. In certain situations, terms such as "activation", "stimulation", etc. refer to cell activation regulated by an internal mechanism and an external or environmental factor; while terms such as "inhibition", "down-regulation", etc. refer to the opposite effect. 【0044】 A compound that is selective may be particularly useful in the treatment of a particular disorder or may suppress the likelihood of undesirable side effects. In certain embodiments, the compounds of the present disclosure are more selective than other receptor tyrosine kinases (e.g., MER and / or TYRO3). Selectivity can be determined, for example, by comparing the inhibition of a compound described herein for AXL with the inhibition of the compound for another receptor tyrosine kinase (e.g., MER and / or TYRO3). In certain embodiments, the selective inhibitory property of AXL is at least 1000-fold, 500-fold, 100-fold, 50-fold, 40-fold, 30-fold, or 20-fold greater than the inhibition of other receptor tyrosine kinases. 【0045】 The compounds of the present disclosure In a particular aspect, herein, formula (I) 【Chemical formula】 A compound having, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: In the formula: G 1 is N or CR G1 ; G 2 is CR [[ID=3I]] G2 or N; G 3 is CR G3 or N; G 4 is CRG4 or N; G 5 CR G5 or N; R G1 Select from the group consisting of H, C1-3 alkyl, halogen, C1-3 haloalkyl, and CN; R G2 , R G3 , R G4 , and R G5 Each of these is independently H, Haro, CN, C 1-7 Alkyl, C 3-7 Cycloalkyl, C1-3 haloalkyl, -O-C1-3 alkyl, -O-C1-3 haloalkyl, -NR a R b , and selected from the group consisting of 4-8 membered heterocycloalkyls having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the cycloalkyl group and heterocycloalkyl group are independently halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Substitute with 0 to 3 groups selected from alkyl and OH groups; R 1 H, C 1-4 Select from the group consisting of alkyl and NH2; A is a fused ring selected from the group consisting of azepane, piperidine, cycloheptane, cyclohexane, cyclopentane, 1,4-oxazepane, oxepane, tetrahydropyran, 1,4-diazepane, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which is either unsubstituted or has 1 to 4 R groups. 2 Substitution occurs, followed by further substitution with zero or one oxo (=O) adjacent to the nitrogen atom; B is a fused ring selected from the group consisting of 1,4-oxazepane, cycloheptane, tetrahydropyran, isothiazolidine 1,1-dioxide, oxepan, 1,4,5-oxathiazepane 4,4-dioxide, cyclohexane, cyclopentane, azepan, pyrrolidine, piperidine, piperazine, morpholine, diazepane, and 1,3-dioxolane, each of which is either unsubstituted or has 1 to 4 R 4 Substitution occurs, followed by further substitution with zero or one oxo (=O) adjacent to the nitrogen atom; Each R 2 These are independently: Halo, OH, C 1-7 Alkyl, C 3-7 Alkenil, C 3-7 Alkinyl, C 3-7 Cycloalkyl, -C(O)-C 1-7 Alkyl, -C(O)-C 3-7 Cycloalkyl, -C(O)-C 1-7 Alkylene-OH,-Y 1 -OC 1-7 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -NR a R b -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -C(O)NR a R b , 4-8 member heterocycloalkyl, and -NR a -Selected from the group consisting of (4-8 member heterocycloalkyl groups), each 4-8 member heterocycloalkyl group has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and heterocycloalkyl group are independently halo, CN, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Substituted with 0 to 3 groups selected from alkyl and OH groups; The subscript n is 0, 1, 2, or 3; Each R 3 These are, independently, halogen, CN, and C1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 3-7 Cycloalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 halohydroxyalkyl, -O-C 1-7 Alkyl, -O-C 3-7 Cycloalkyl, -O-C1-6 haloalkyl, -X 1 -CN, -X 1 -O-C 1-7 Alkyl, -O-Y 1 -O-C 1-7 Alkyl, -NR a R b 、-X 1 -NR a R b 、-O-Y 1 -NR a R b 、-C(O)-NR a R b 、-S(O)2-NR a R b 、-S(O)(NH)-C 1-7 Alkyl, -S(O)2-C 1-7 Alkyl, -S(O)2-C 1-7 Haloalkyl, -S(O)2-C 3-7 Cycloalkyl, -S(O)2-Y 1 -O-C1-3 alkyl, -S(O)2-C4-7 heterocycloalkyl, -C(O)NH-(4-8 membered heterocycloalkyl), 4-8 membered heterocycloalkyl, and -O-X 1 Selected from the group consisting of -(4-8 membered heterocycloalkyl), wherein the 4-8 membered heterocycloalkyl has 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and the heterocycloalkyl group are independently substituted with 0-3 groups selected from halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -O-C 1-4 Alkyl, and OH; Each R 4 Is independently H, halogen, hydroxy, CN, C 1-7Alkyl, C 2-7 Alkenil, C 3-7 Alkinyl, C 3-7 Cycloalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 halohydroxyalkyl, -OC 1-7 Alkyl, -OC 3-7 Cycloalkyl, -O-C1-6 haloalkyl, -X 1 -CN, -X 1 -OC 1-7 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -C(O)NR a R b , -NR a R b , -NR a -C(O)-C 1-7 Alkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a -S(O)2-C 1-7 Alkyl and -NR a -S(O)2-C 3-7 Selected from the group consisting of cycloalkyls, -NR a R b , -NR a -C(O)-C 1-7 Alkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a -S(O)2-C 1-7 Alkyl and -NR a -S(O)2-C 3-7 Cycloalkyl groups do not bond directly to the vertices of the nitrogen ring and do not form NN bonds; Alternatively, two R atoms bonded to a common carbon 4 However, when combined, C 3-6 A spirocycloalkyl group is formed, which is either unsubstituted or substituted with 1 to 3 elements independently selected from F, Cl, OH, and CH3; Each X 1 C 1-7 Alkylene or C 3-7 It is a cycloalkylene; Each Y 1 C 2-7 Alkylene or C 3-7 It is a cycloalkylene, where the two bonded heteroatoms are not bonded to a common carbon atom; R a and R b Each of these is independently H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl and C 3-7 Select from the group consisting of cycloalkyl groups; or R a and R b Together with the nitrogen atoms to which they are bonded, they form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatomic ring vertices selected from the group consisting of O, N, and S, and halogens, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 The present invention provides compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, that are substituted with 0 to 3 groups independently selected from alkyl, oxo, and OH groups. 【0046】 In some selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 1 The compound is N. In other selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 1 It is a compound in which CH is the main component. 【0047】 In some selected embodiments, including any selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 2 It is a compound in which CH or CF is present. 【0048】 In some selected embodiments, including the selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 3 However, it is a compound selected from the group consisting of CH, CF, C(CH3), and N. 【0049】 In some selected embodiments, including any selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 4 However, it is a compound that is CH, CCl, or N. 【0050】 In some selected embodiments, including any selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 5 However, it is a compound that is either CH or N. 【0051】 In some selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 1 If N and G 2 The compound is CH. In a further selected embodiment, G 1 N is G 2 CH is and G 3 CH is. In further selected embodiments, G 1 N is G 2 CH is G 3 CH is G 4 In yet another selected embodiment, G 1 N is G 2 CH is G 3 CH is G 4 CH is G 5 CH is. 【0052】 Referring to ring A, ring A is G 3 , G 4 and G 5It is understood that it is fused to the aromatic ring containing and that the presence of ring A does not disrupt the aromaticity of the aromatic ring. Specifically, the ring vertex that fuses the two rings is sp 2 These are hybrid carbon atoms. Therefore, each of these ring vertices has a p orbital that is involved in the conjugated pi system of the aromatic ring. Thus, it is understood that all ring A portions have an unsaturation point at the fusion point with respect to the rest of the molecule. For example, cyclopentane in ring A refers to cyclopentene, where the double bond lies between the two carbon atoms that fuse with the rest of the compound. 【0053】 Similar to ring A, ring B fuses to the aromatic phenyl ring, and the presence of ring B does not disrupt the aromaticity of the phenyl ring. Therefore, it can be considered that all ring B portions have an unsaturation point at the fusion point with respect to the molecular residue. For example, cycloheptane in ring B refers to cycloheptene, and in the formula, there is a double bond between the two carbon atoms that fuse to the residue of the compound. 【0054】 In some selected embodiments, including any selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, has a condensed ring A, [ka] The formula is selected from the group consisting of, and each is either unsubstituted or has 1 to 4 R 2 It is a compound substituted with: In some further selected embodiments, the fused ring A is of formula: [ka] It holds. 【0055】 In some further selected embodiments, including any selected embodiments described above, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is one R 2 However, -NR a R bis a compound. In still further selected embodiments, R a and R b together with the nitrogen to which each is attached form a 4- to 6-membered heterocycloalkyl ring having from 0 to 2 additional heteroatom ring vertices selected from O, N, and S, and are substituted with from 0 to 3 groups independently selected from halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -O-C 1-4 alkyl, oxo, and OH. In a further embodiment, R a and R b together with the nitrogen to which each is attached form a pyrrolidinyl ring, which is unsubstituted or substituted with from 1 to 3 groups independently selected from halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -O-C 1-4 alkyl, oxo, and OH. 【0056】 In some selected embodiments including any of the above selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, has a fused ring A that is of a formula selected from the group consisting of 【Chemical formula】 each of which is optionally substituted with an additional 1 to 2 R 2 groups. In still further selected embodiments, the fused ring A is of the formula: 【Chemical formula】 having. 【0057】 In further selected embodiments including any of the above selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, has R 2 being C 1-7 alkyl, C 3-7Cycloalkyl, -C(O)-C 1-7 Alkyl, -C(O)-C 3-7 Cycloalkyl, -C(O)-C 1-7 Alkylene-OH,-Y 1 -OC 1-7 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -C(O)NR a R b A compound selected from the group consisting of , and 4-8 membered heterocycloalkyl groups, wherein the 4-8 membered heterocycloalkyl group has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and heterocycloalkyl group are independently halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Substitution is made with 0 to 3 groups selected from alkyl and OH groups. 【0058】 In some selected embodiments, including any selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, the condensed ring B is selected from the group consisting of 1,4-oxazepane, tetrahydropyran, isothiazolidine 1,1-dioxide, 1,4,5-oxathiazepane 4,4-dioxide, azepane, and pyrrolidine, each of which is unsubstituted or has 1 to 3 R 4 The compounds are substituted with; and further substituted with zero or one oxo (=O) adjacent to the nitrogen atom. In further selected embodiments, each R 4 These are, independently, halogen, C 1-4 Alkyl, C 1-4 Selected from the group consisting of haloalkyl and OH, or two R groups bonded to a common carbon. 4 These combine to form C 3-6It forms a spirocycloalkyl group, which is either unsubstituted or substituted with 1 to 3 elements independently selected from F, Cl, OH, and CH3. 【0059】 In some selected embodiments, including any selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, has a condensed ring B, [ka] A compound having a formula selected from the group consisting of the following, each of which is either unsubstituted or has 1-2 R 4 It is replaced by. In some further selected embodiments, the fused ring B is not replaced. In other selected embodiments, the fused ring B is, [ka] That is the case. 【0060】 In some selected embodiments, including any selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, has a condensed ring B, [ka] A compound having a formula selected from the group consisting of the following, each of which is either unsubstituted or has 1 to 4 R 4 It is replaced by. In some further selected embodiments, the condensed ring B has 1 to 4 R 4 These are substituted with halogen, C 1-4 Alkyl, C 1-4 Select independently from the group consisting of haloalkyl and OH. 【0061】 In other selected embodiments, including any selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, has a condensed ring B, [ka] A compound having a formula selected from the group consisting of the following, each of which is either unsubstituted or has 1 to 3 R 4 It is replaced by. In some further selected embodiments, each R 4 C 1-4 Alkyl and C 1-4 Select independently from the group consisting of haloalkyls. 【0062】 In some selected embodiments, one of the compounds in Table 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided. 【0063】 Synthesis method A general method for preparing the claimed compound A useful method for constructing the compounds according to this disclosure consists of four components, which can be performed in any order: the joining of fragments a and b, the joining of fragments b and c, the joining of fragments c and d, or the modification of functional groups present in all of these fragments. A general retrosynthetic cleavage of the compounds into fragments a-d, which is useful for constructing the compounds according to this disclosure, is shown below: [ka] 【0064】 Several methods for preparing the claimed compounds are illustrated (Equations 1-6). Equation (1) shows one method for forming a bond between fragments a and b via reductive amination. The formation of the bond between fragments a and b may occur before or after the formation of the bond between fragments b and c. In the case of Equation (1), the desired amine is bonded to the desired ketone via the use of a hydride source and acetic acid, or any other known conditions relating to reductive amination. [ka] 【0065】 The relative positions of the amine and ketone can also be reversed, as illustrated in formula (2). Those skilled in the art will recognize other possible conditions that may result in the desired bonding properties and products. [ka] 【0066】 Equation (3) illustrates another method for forming an ab fragment by the initial condensation and amino formation of the two partners, followed by the addition of a Grignard reagent. This process results in additional alkyl substituents on carbon atoms adjacent to the amine nitrogen atom. [ka] 【0067】 The formation of the bond between fragments b and c may occur before or after the formation of the bond between fragments a and b or between fragments c and d. Equation (4) demonstrates one method of linking fragments b and c by cross-coupling. Y can be selected from suitable groups such as B(OH)2, B(OR)2, ZnCl, MgBr, and SnR3. Z can be selected from suitable groups such as Cl, Br, I, and OTf. The coupling is mediated by a transition metal catalyst, preferably palladium and a suitable ligand. This coupling can be assisted by an organic or inorganic base. The use of protecting groups such as SEM, Boc, THP, PMB, MOM, MEM, and TIPS on the bicyclic moiety generally improves the yield and purity of the desired product. [ka] 【0068】 Relative functionalization of bonding partners can also be carried out in the reverse direction, as shown in equation (5). Those skilled in the art will recognize other possible combinations and conditions that yield the desired product. [ka] 【0069】 The formation of the bond between fragments c and d may occur before or after the formation of the bond between fragments b and c. Equation (6) shows one method of linking fragments c and d by cross-coupling. Y can be selected from suitable groups such as B(OH)2, B(OR)2, ZnCl, MgBr, and SnR3. Z can be selected from suitable groups such as Cl, Br, I, and OTf. The coupling is mediated by a transition metal catalyst, preferably palladium and a suitable ligand. The coupling may be assisted by an organic or inorganic base. The use of protecting groups such as SEM, Boc, THP, PMB, MOM, MEM, and TIPS on the bicyclic moiety generally improves the yield and purity of the desired product. [ka] 【0070】 For the most efficient preparation of any particular compound of this disclosure, the timing and order of fragment bonding, as well as the modification of the functionalities present in any of the fragments, may vary and depend on the functionalities present. The various methods described above have been used to prepare the compounds of this disclosure and are illustrated below. The deuterated compounds of the following examples can be synthesized using a suitable deuterated intermediate. 【0071】 Therapeutic and prophylactic use This disclosure intends to use the AXL inhibitors described herein in the treatment or prevention of various diseases, disorders and / or conditions and / or symptoms thereof. Specific uses are described below, but it should be understood that this disclosure is not limited to them. Furthermore, general categories of specific diseases, disorders and conditions are described below, but some diseases, disorders and conditions may belong to two or more categories, and others may not belong to any of the disclosed categories. 【0072】 In some embodiments, the AXL inhibitors described herein are administered in amounts effective to reverse, halt, or delay the progression of AXL-mediated dysregulation. 【0073】 Tumor-related disorders. The AXL inhibitors described herein can be used to treat or prevent proliferative conditions or disorders such as cancers of the uterus, cervix, breast, prostate, testes, gastrointestinal tract (e.g., esophagus, cervix, oropharynx, stomach, small or large intestine, colon or rectum), kidney, renal cells, bladder, bone, bone marrow, skin, head and neck, liver, gallbladder, heart, lung, pancreas, salivary glands, adrenal glands, thyroid, brain (e.g., glioma), ganglia, central nervous system (CNS) and peripheral nervous system (PNS), and hematopoietic and immune system (e.g., spleen or thymus), and myelodysplastic syndromes. This disclosure also provides methods for treating or preventing other cancer-related diseases, disorders, or conditions, such as immunogenic tumors, non-immunogenic tumors, quiescent tumors, virus-induced cancers (e.g., epithelial cell carcinoma, endothelial cell carcinoma, squamous cell carcinoma, and papillomavirus), adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically induced cancers, metastases, and angiogenesis. In certain embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, bladder cancer (e.g., urothelial carcinoma), esophageal cancer, kidney cancer (e.g., clear cell renal cell carcinoma), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), melanoma, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer), head and neck cancer (e.g., head and neck squamous cell carcinoma), glioblastoma, leukemia (e.g., acute myeloid leukemia, and chronic lymphocytic leukemia), or myelodysplastic syndromes. In some embodiments, cancer is leukemia (e.g., acute myeloid leukemia), lung cancer (e.g., non-small cell lung cancer), or kidney cancer (e.g., clear cell renal cell carcinoma). The use of the term(s) cancer-related diseases, disorders and conditions means a broad range of conditions that are directly or indirectly related to cancer, including, for example, precancerous conditions such as angiogenesis and dysplasia. 【0074】 In some embodiments, the compounds according to this disclosure are useful in the treatment of renal cancer. In further embodiments, the renal cancer is renal cell carcinoma. In even further embodiments, the renal cell carcinoma is clear cell renal carcinoma (ccRCC). 【0075】 In some embodiments, the compounds according to this disclosure are useful in the treatment of lung cancer. In further embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In even further embodiments, the NSCLC is squamous cell carcinoma or adenocarcinoma of the lung. In some embodiments, the NSCLC is EGFR variant NSCLC. 【0076】 In some embodiments, the compounds of this disclosure are useful in the treatment of leukemia. In further embodiments, the leukemia is acute myeloid leukemia (AML). In even further embodiments, the AML is relapsed AML. 【0077】 In some embodiments, the compounds according to this disclosure are useful in the treatment of breast cancer. In further embodiments, breast cancer is hormone receptor-positive (e.g., ERα-positive breast cancer, PR-positive breast cancer, ERα-positive and PR-positive breast cancer), HER2-positive breast cancer, HER2-overexpressing breast cancer, or any combination thereof. In yet another embodiment, breast cancer is triple-negative breast cancer. 【0078】 In some embodiments, the compounds according to this disclosure are useful in the treatment of pancreatic cancer. In further embodiments, pancreatic cancer is a pancreatic neuroendocrine tumor or pancreatic adenocarcinoma (i.e., pancreatic ductal adenocarcinoma (PDAC)). 【0079】 In certain embodiments, cancer is metastatic, or may be at risk of becoming metastatic, or may be present in diffuse tissue, and includes cancers of the blood or bone marrow (e.g., leukemia or myelodysplastic syndrome). 【0080】 Hypoxic conditions in the tumor microenvironment have been shown to upregulate AXL expression. Therefore, in some embodiments, AXL inhibitors according to this disclosure may be useful in the treatment of hypoxic tumors. 【0081】 In one or more embodiments, the cancer is an oncogene-toxic cancer. Oncogene-toxic cancers depend on oncogenes that are dominant in terms of growth and survival, such as ALK, ABL, AURORA, AKT, PDGFR, KIT, EGFR, VEGF, FGFR3, FLT-3, MYC, RET, BRAF, PI3K, NF-κB, JAK, STAT, BCL-2, MCL-1, KRAS, HRAS, MEK, ERK, HER-2, HER-3, or MET. 【0082】 In some embodiments, the Disclosure provides methods for treating proliferative conditions, cancers, tumors, or precancerous conditions using an AXL inhibitor and at least one further therapeutic or diagnostic agent, examples of which are described elsewhere in this Spec. 【0083】 Immune and Inflammatory Disorders. Immune and inflammation-related diseases, disorders, and conditions that can be treated or prevented with the compounds and compositions of this disclosure include, but are not limited to, arthritis (e.g., rheumatoid arthritis), renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., cases in which inflammatory cytokines impede healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), chronic obstructive pulmonary disease (COPD), atherosclerosis, allergic contact dermatitis, and other eczema, systemic sclerosis, transplantation, and multiple sclerosis. 【0084】 In certain embodiments of this disclosure, AXL inhibitors are used to provide adjuvant activity to increase or enhance the immune response to an antigen. In certain embodiments, at least one antigen or vaccine is administered to a subject in combination with at least one AXL inhibitor of this disclosure to prolong the immune response to the antigen or vaccine. We also provide therapeutic compositions comprising at least one antigen or vaccine component in combination with at least one AXL inhibitor of this disclosure, such antigen or vaccine components include, but are not limited to, viruses, bacteria, and fungi or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines. 【0085】 In some embodiments, the AXL inhibitors described herein, when combined with immunosuppressants, can reduce the number of immune effector cells. 【0086】 Other disorders. Embodiments of this disclosure intend to administer the AXL inhibitors described herein to a subject for the treatment or prevention of any other disorders that may benefit from at least a certain level of AXL inhibition. Such diseases, disorders, and conditions include, for example, cardiovascular disorders (e.g., cardiac ischemia) and metabolic disorders (e.g., diabetes, insulin resistance, obesity). 【0087】 Patient selection In some embodiments, the patient evaluates and selects AXL expression (e.g., soluble AXL (sAXL), cell surface AXL, or total AXL) in the relevant tissue or sample. In some embodiments, the patient further evaluates and selects GAS6 expression in the relevant tissue or sample. In some embodiments, the disclosure provides a method for treating cancer in patients with high AXL expression with the compounds described herein. In some embodiments, the disclosure provides a method for treating cancer in patients with high cell surface AXL expression with the compounds described herein. In other embodiments, the disclosure provides a method for treating cancer in patients with high sAXL expression with the compounds described herein. In yet another embodiment, the disclosure provides a method for treating cancer in patients with a high ratio of sAXL expression to GAS6 expression with the compounds described herein. In some embodiments, the disclosure provides a method for administering a therapeutically effective dose of an AXL inhibitor to an individual for cancer treatment based on the determination of the relative amount of AXL expression. In other embodiments, the disclosure provides a method for administering a therapeutically effective dose of an AXL inhibitor to an individual for cancer treatment based on the determination of the relative amount of cell surface AXL expression. In another embodiment, the disclosure provides a method for administering a therapeutically effective dose of an AXL inhibitor to an individual for cancer treatment based on the determination of the relative amount of sAXL expression. In yet another embodiment, the disclosure provides a method for administering a therapeutically effective dose of an AXL inhibitor to an individual for cancer treatment based on the determination of the relative ratio of sAXL expression to GAS6 expression. 【0088】 Pharmaceutical composition The AXL inhibitors of this disclosure may be in the form of a composition suitable for administration to a subject. Generally, such a composition is a “pharmaceutical composition” comprising the AXL inhibitor(s) described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the AXL inhibitor is present in an effective yield. The pharmaceutical composition may be used in the manner of this disclosure. 【0089】 The pharmaceutical compositions of this disclosure can be formulated to suit an intended method or route of administration. Exemplary routes of administration are described herein. Furthermore, the pharmaceutical compositions may be used in combination with other therapeutically active substances or compounds described herein to treat or prevent the diseases, disorders, and conditions intended in this disclosure. 【0090】 Pharmaceutical compositions containing an active ingredient (e.g., an AXL inhibitor) may be in forms suitable for oral use, such as tablets, capsules, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral use may be prepared with one or more excipients, such as sweeteners, flavorings, colorants, and preservatives, to provide a pharmaceutically superior and palatable formulation. Tablets, capsules, etc., contain the active ingredient as a mixture with pharmaceutically acceptable and non-toxic excipients suitable for manufacture. These excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as gelatin or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. 【0091】 Formulations for oral use may also be provided as rigid gelatin capsules obtained by mixing the active ingredient with an inert solid diluent, such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or as soft gelatin capsules obtained by mixing the active ingredient with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. 【0092】 The aqueous suspension contains the active material as a mixture with excipients suitable for the preparation of the suspension. Such excipients may be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersants or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), or condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives. 【0093】 The oily suspension can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspension may contain a thickener, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings as described above can be added to provide an oral formulation with a pleasant mouthfeel. 【0094】 By adding water to dispersible powders and granules suitable for preparing aqueous suspensions, the active ingredient is provided as a mixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified herein. 【0095】 The pharmaceutical compositions of this disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, e.g., olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, e.g., acacia gum or tragacanth gum; naturally occurring phosphatides, e.g., soybean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, e.g., sorbitan monooleate; and condensation products of partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monooleate. 【0096】 A pharmaceutical composition typically comprises a therapeutically effective amount of the AXL inhibitor intended in this disclosure and one or more pharmaceutically acceptable and physiologically acceptable formulation components. Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers, or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethyl or n-propyl, p-hydroxybenzoate), emulsifiers, suspending agents, dispersants, solvents, fillers, bulking agents, surfactants, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be saline or citrate-buffered saline, which may be supplemented with other materials common in parenteral pharmaceutical compositions. Neutral-buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize the various buffers that can be used in the pharmaceutical compositions and dosage forms intended herein. Common buffering agents that can be incorporated into pharmaceutical compositions include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, buffering components may be water-soluble substances such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Examples of acceptable buffering agents include Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonate sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS). 【0097】 After formulation, pharmaceutical compositions may be stored in sterile vials as solutions, suspensions, gels, emulsions, solids, or dehydrated or lyophilized powders. Such formulations may be stored in any of the following forms: ready-to-use, lyophilized, requiring reconstitution before use, liquid, or other acceptable forms. In some embodiments, pharmaceutical compositions are provided in single-use containers (e.g., single-use vials, ampoules, syringes, or auto-injectors), while in other embodiments, they are provided in multi-use containers (e.g., multi-use vials). 【0098】 Pharmaceutical compositions may be in the form of aqueous or oily suspensions for sterile injection. These suspensions may be formulated using excipients such as appropriate dispersants, wetting agents, and / or suspending agents. Sterile injection formulations may also be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents as excipients, for example, a solution in 1,3-butanediol. Acceptable diluents, solvents, and dispersions that can be used as excipients include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL® (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile fixatives may be used as solvents or suspensions. For this purpose, any non-irritating fixative, such as synthetic monoglycerides or diglycerides, may be used. Furthermore, fatty acids such as oleic acid find applications in the preparation of injections. By including substances that slow down absorption (e.g., aluminum monostearate or gelatin), sustained absorption of certain injectable formulations can be achieved. 【0099】 The AXL inhibitors envisioned in this disclosure may be in the form of any other suitable pharmaceutical composition currently known or to be developed in the future (e.g., a spray used intranasally or inhaled). 【0100】 Route of administration This disclosure intends to provide AXL inhibitors and compositions thereof in any suitable mode of administration. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracapsular, intra-articular, intracerebral (intraparenchymal) and intraventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., perdermal), buccal, and inhalation. Generally, depot injections administered subcutaneously or intramuscularly can also be used to release the AXL inhibitors disclosed herein over a predetermined period of time. 【0101】 Certain embodiments of this disclosure are intended for oral administration. 【0102】 Combination therapy This disclosure envisions the use of AXL inhibitors alone or in combination with one or more active therapeutic agents. Further active therapeutic agents may be small chemical molecules; macromolecules such as proteins, antibodies, peptide bodies, peptides, DNA, RNA, or fragments of such macromolecules; or cell therapies or gene therapies. Combination therapies target different but complementary mechanisms of action, thereby producing synergistic therapeutic or preventive effects against the underlying disease, disorder, or condition. In addition, or alternatively, combination therapies may allow for dose reduction of one or more drugs, thereby mitigating, suppressing, or eliminating side effects associated with one or more drugs. 【0103】 The active therapeutic agents in such combination therapies may be formulated as a single composition or as separate compositions. When administered separately, each therapeutic agent in the combination may be administered simultaneously, nearly simultaneously, or at different times. Furthermore, even if the therapeutic agents have different forms of administration (e.g., oral capsules and intravenous), they may be administered in a “combination,” administered at different dosing intervals, one therapeutic agent may be administered regularly according to a dosing plan while the other is gradually increased, decreased, or discontinued, or each therapeutic agent in the combination may be independently increased, decreased, increased or decreased in dosage, or discontinued and / or resumed during the patient’s treatment course. When the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit. 【0104】 In some embodiments, the AXL inhibitors according to this disclosure are combined with at least one further therapeutic agent. In some embodiments, the at least one further therapeutic agent is independently an inhibitor of the CD47-SIRPα pathway (e.g., an anti-CD47 antibody), an inhibitor of HIF (e.g., a HIF-2α inhibitor), an immune checkpoint inhibitor, an agent that targets the extracellular production of adenosine (e.g., a CD73 inhibitor, a CD39 inhibitor, and / or an adenosine receptor inhibitor (e.g., A) 2A R and / or A 2B The treatment includes one or more agents selected from the group consisting of R inhibitors, radiotherapy, and chemotherapeutic agents. Each of these additional therapeutic agents is described in further detail below. 【0105】 In some embodiments, one or more additional therapeutic agents are immunomodulators. Suitable immunomodulators intended in this disclosure include activated monoclonal antibodies (mAbs) against stimulating receptors such as CD40L, B7, and B7RP1; anti-CD40, anti-CD38, anti-ICOS, and 4-1BB ligands; dendritic cell antigen loading (in vitro or in vivo); anti-cancer vaccines such as dendritic cell carcinoma vaccines; cytokines / chemokines such as IL1, IL2, IL12, IL18, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / β, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharide (LPS); indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors; and immunostimulatory oligonucleotides. 【0106】 In certain embodiments, the Disclosure provides a method for tumor suppression of tumor growth, which includes administering an AXL inhibitor described herein in combination with a signaling inhibitor (STI) to achieve additive or synergistic suppression of tumor growth. As used herein, the term “signaling inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway.The signal transduction inhibitors (STIs) intended in this disclosure include: (i) BCR-ABL kinase inhibitors (e.g., GLEEVEC®), (ii) Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), e.g., small molecule inhibitors (e.g., gefitinib, erlotinib, afatinib, and osimertinib), and anti-EGFR antibodies, (iii) Inhibitors of the human epidermal growth factor (HER) family of transmembrane tyrosine kinases, e.g., HER-2 / neu receptor inhibitors (e.g., HERCEPTIN®), and HER-3 receptor inhibitors, (iv) Vascular endothelial growth factor receptor (VEGFR) inhibitors, e.g., small molecule inhibitors (e.g., axitinib, sunitinib, and soraf). (v) Inhibitors of AKT family kinases or the AKT pathway (e.g., rapamycin), (vi) Inhibitors of serine / threonine protein kinase B-Raf (BRAF), e.g., vemurafenib, dabrafenib, and encorafenib, (vii) Inhibitors of relocation during transfection (RET), e.g., serpercatinib and pralcetinib, (viii) Tyrosine protein kinase Met(ME) (T) inhibitors (e.g., tepotinib, tivantinib, cabozantinib, pazopanib, tivozanib, XL-092, and crizotinib), (ix) anaplastic lymphoma kinase (ALK) inhibitors (e.g., ensartinib, ceritinib, lorlatinib, crizotinib, and brigatinib), (x) inhibitors of the RAS signaling pathway as described elsewhere herein (e.g., inhibitors of KRAS, HRAS, RAF, MEK, and ERK), (xi) FLT-3 inhibitors (e.g., gilteritinib) (x) (xii) Trop-2 inhibitors, (xiii) JAK / STAT pathway inhibitors, such as JAK inhibitors like tofacitinib and ruxolitinib, or STAT inhibitors like napabucasin, (xiv) NF-κB inhibitors, (xv) cell cycle kinase inhibitors (e.g., flavopyridol), (xvi) phosphatidylinositol kinase (PI3K) inhibitors, and (xvii) protein kinase B (AKT) inhibitors (e.g., capivacertib, mirancertib).The immunomodulatory agents may also be used in combination with the AXL inhibitors described herein to suppress tumor growth in cancer patients. In one or more embodiments, further therapeutic agents include inhibitors of EGFR, VEGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-κB, PI3K, AKT, BC1-2, MCL-1, CD47, or any combination thereof. 【0107】 In some embodiments, one or more further therapeutic agents include chemotherapeutic agents. Examples of chemotherapeutic agents include alkylating agents, e.g., thiotepa and cyclophosphamide; alkyl sulfonates, e.g., busulfan, improsulfan and piposulfan; aziridines, e.g., benzodopa, carbocone, metredopa and uredopa; ethyleneimines and methylameamines, e.g., altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; nitrogen mustards, e.g., chlorambucil, chloro Lunafadin, cyclophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembitin, fenestrine, prednimustine, troposphamide, uracil mustard; nitrosourea, e.g., carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, e.g., acrasinomycin, actinomycin, autoramycin, azaserin, bleomycin, kacchinomycin, calycephalone Aminocin, Carabicin, Kaminocycline, Cardinophilin, Chromomycin, Dactinomycin, Daunorubicin, Detorubicin, 6-Diazo-5-Oxo-L-Norleucine, Doxorubicin, Epirubicin, Esolubicin, Idarubicin, Marcelomycin, Mitomycin, Mycophenolic Acid, Nogaramycin, Olibomycin, Pomalidomide, Peplomycin, Potofilomycin, Puromycin, Keramycin, Rhodolubicin, Streptonigrin, Streptozocin, Tubercidine, Ube Antimetabolites such as Nimex, Zinostatin, Zolubicin; Methotrexate, and 5-Fluorouracil (5-FU); Folic acid analogs such as Denopterin, Methotrexate, Pteropterin, and Trimethrexate; Purine analogs such as Fludarabine, 6-Mercaptopurine, Thiamipurine, and Thioguanine; Pyrimidine analogs, e.g., Ancitabine, Azacitidine, 6-Azauridine, Carmofur, Cytarabine, Dideoxyuridine, Doxyfluridine, Enocitabine, Phloxuridine, and 5-FU;Androgens, such as carsterone, dromostanolone propionate, epithiostanol, metipithiostan, and testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; acegraton; aldofsphamide glycoside; aminolevulinic acid; amsacrin; bestrabusil; bisanthren; edatraxate; defofamine; demecolsin; diazicone; elformitin; elliptinic acid acetate Um; etoglucide; gallium nitrate; hydroxyurea; lentinan; ronidamin; mitoglucon; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; razoxane; schizophyllan; spirogermanium; tenuazonic acid; triadiquan; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacitosine; Arabinoside (Ara-C); Cyclophosphamide; Thiotepa; Taxoids, e.g., paclitaxel, nab-paclitaxel, and docetaxel; Chlorambucil; Gemcitabine; 6-thioguanine; Mercaptopurine; Methotrexate; Platinum and platinum-coordinated complexes, e.g., cisplatin, carboplatin, and oxaliplatin; Vinblastine; Etoposide (VP-16); Ifo Sphamide; Mitomycin C; Mitoxantrone; Vincristine; Vinorelbine; Navelbine; Novantrone; Teniposide; Daunomycin; Aminopterin; Xeloda; Ibandronate; CPT11; Topoisomerase inhibitors; Difluoromethylornithine (DMFO); Retinoic acid; Esperamicin; Capecitabine; Anthracyclines; and any of the above-mentioned pharmaceutically acceptable salts, acids, or derivatives, but not limited to these. In some embodiments, the chemotherapeutic agent is a platinum-based, anthracycline-based, or taxoid-based chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, or paclitaxel. 【0108】 As chemotherapeutic agents, anti-hormonal agents that act to modulate or inhibit hormonal action against tumors, such as anti-estrogens such as tamoxifen, raloxifen, aromatase inhibitory 4(5)-imidazole, 4-hydroxytamoxifen, trioxoxifen, kexifen, onapristone, and toremifene; and anti-androgen agents such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and also pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy comprises a chemotherapy regimen comprising one or more chemotherapeutic agents. In certain embodiments, the combination therapy comprises the administration of a hormone, or a related hormonal agent. 【0109】 The combination of AXL inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors described in this disclosure is also intended. Exemplary PARP inhibitors intended in this disclosure include olaparib, niraparib, and lucaparib. 【0110】 Further therapies that may be used in combination with AXL inhibitors include radiotherapy, monoclonal antibodies against tumor antigens, monoclonal antibody-toxin conjugates, T cell adjuvants, bone marrow transplantation, or antigen-presenting cells (e.g., dendritic cell therapy), including TLR agonists used to stimulate such antigen-presenting cells. 【0111】 In certain embodiments, this disclosure intends to use the compounds described herein in combination with adoptive cell therapy, a novel and promising form of personalized immunotherapy that involves administering immune cells with antitumor activity to cancer patients. Adoptive cell therapy has been studied using tumor-infiltrating lymphocytes (TILs) and T cells genetically engineered to express, for example, chimeric antigen receptors (CARs) or T cell receptors (TCRs). Typically, in adoptive cell therapy, T cells are harvested from an individual, genetically engineered to target specific antigens or enhance antitumor effects, amplified to a sufficient number, and then injected into cancer patients. T cells can be harvested from patients (e.g., autologously) to later reinject the proliferated cells, or from donor patients (e.g., allogeneically). 【0112】 In certain embodiments, this disclosure intends to use the compounds described herein in combination with RNA interference-based therapies for silencing gene expression. RNAi begins with cleaving longer double-stranded RNA into small interfering RNA (siRNA). One strand of the siRNA is incorporated into a ribonucleoprotein complex known as the RNA-induced silencing complex (RISC), which is then used to identify an mRNA molecule that is at least partially complementary to the incorporated siRNA strand. The RISC can either bind to the mRNA or cleave it, both of which inhibit translation. 【0113】 In certain embodiments, this disclosure envisions the use of the compounds described herein in combination with agents that target the extracellular production of adenosine. Such therapeutic agents may act on ectonucleotidases that catalyze the conversion of ATP to adenosine, such as ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​also known as CD39 or differentiation antigen group 39), which hydrolyzes ATP to ADP and ADP to AMP, and ecto-5'-nucleotidase (NT5E or 5NT, also known as CD73 or differentiation antigen group 73), which converts AMP to adenosine. The enzymatic activity of CD39 and CD73 plays a strategic role in modulating the duration, magnitude, and chemistry of purinergic signals delivered to various cells (e.g., immune cells). Alterations in the activity of these enzymes can alter or determine the course of several pathophysiological events, including cancer, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury, suggesting that these exenzymes represent novel therapeutic targets for addressing a variety of disorders. Exemplary anti-CD39 and anti-CD73 antibodies include ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, oleculumab (MEDI9447), NZV930, IPH5301, uriredlimab (TJD5, TJ004309), and BMS-986179. In one or more embodiments, the disclosure intends to use CD73 in combination with inhibitors described in, for example, WO 2017 / 120508, WO 2018 / 094148, WO 2018 / 067424, and WO 2020 / 046813. In one embodiment, the CD73 inhibitor is chemrecrustat (AB680). 【0114】 Another approach that targets the extracellular production of adenosine is adenosine A 2A and / or A 2B The goal is to target receptors. Therefore, in some embodiments, the present disclosure involves the compounds according to the present disclosure and A 2A and / or A 2BThe intention is to combine it with an agent that targets the receptor. Such a therapeutic agent targets the adenosine 2 receptor (A2R) (for example, A 2A and / or A 2B ) can act as an antagonist. Adenosine can act as an antagonist to four different G protein-coupled receptors, namely A1R, A 2A R_A 2B It can bind to and activate R and A3R. A is expressed in bone marrow cells such as T cells, natural killer cells, and dendritic cells. 2A The binding of adenosine to the R receptor increases intracellular levels of cyclic AMP, impairing the maturation and / or activation of such cells. This process significantly impairs the activation of the immune system against cancer cells. In addition, A 2A R is thought to be involved in the selective enhancement of anti-inflammatory cytokines, the promotion of PD-1 and CTLA-4 upregulation, the promotion of LAG-3 and Foxp3+ regulatory T cell generation, and the mediation of regulatory T cell inhibition. PD-1, CTLA-4, and other immune checkpoints are further described herein. The combinations of A2R antagonists described herein may provide at least an additive effect, considering their different mechanisms of action. In some embodiments, the therapeutic agent may be an adenosine receptor antagonist described in WO / 2018 / 136700, WO 2018 / 204661, or WO 2020 / 023846. In some embodiments, the adenosine receptor antagonist is AB928 (i.e., etrmadenant). 【0115】 In certain embodiments, this disclosure intends to use inhibitors of phosphatidylinositol 3-kinase (PI3K), particularly PI3Kγ isoforms, in combination with the compounds described herein. PI3Kγ inhibitors can modulate myeloid cells to stimulate an anti-cancer immune response, for example, by inhibiting suppressive myeloid cells, attenuating immunosuppressive tumor-infiltrating macrophages, or stimulating macrophages and dendritic cells to produce cytokines that contribute to an effective T-cell response, thereby suppressing cancer development and spread. Examples of PI3Kγ inhibitors are described in WO 2020 / 0247496A1. 【0116】 In certain embodiments, this disclosure intends to use in combination with the compounds described herein an arginase inhibitor that is the cause of, or involved in, pro-inflammatory immune dysfunction, tumor immune evasion, immunosuppression of infections, and immunopathology. Exemplary arginase compounds can be found, for example, in PCT / US2019 / 020507 and WO2020 / 102646. 【0117】 In certain embodiments, the present invention envisions the use of the AXL inhibitor according to this disclosure in combination with an inhibitor of HIF-2α, which plays an essential role in the cellular response to hypoxia availability. Under hypoxic conditions, hypoxia-inducible factor (HIF) transcription factors can activate the expression of genes that regulate metabolism, angiogenesis, cell proliferation, and survival, immune evasion, and inflammatory responses. Overexpression of HIF-2α is associated with suboptimal clinical outcomes in various cancer patients; hypoxia is also prevalent in numerous acute and chronic inflammatory diseases, such as inflammatory bowel disease and rheumatoid arthritis. Examples of HIF-2α inhibitors include berztifan, ARO-HIF2, PT-2385, AB521, and those described in WO 2021113436 and WO 2021188769. In some embodiments, the AXL inhibitor according to this disclosure is combined with AB521. 【0118】 Furthermore, this disclosure envisions combinations of the AXL inhibitors described herein with one or more RAS signaling inhibitors. Oncogenic mutations in RAS family genes, such as HRAS, KRAS, and NRAS, are associated with various cancers. For example, in the KRAS family genes, mutations in G12C, G12D, G12V, G12A, G13D, Q61H, G13C, and G12S have been observed in multiple tumor types. Direct and indirect methods of inhibiting mutant RAS signaling have been studied. Indirect inhibitors target non-RAS effectors in the RAS signaling pathway, and these inhibitors include, but are not limited to, inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g., SOS1), mTOR (e.g., mTORC1), SHP2 (PTPN11), and AKT. Examples of indirect inhibitors under development include, but are not limited to, RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, and BI1701963. Direct inhibitors of RAS variants are also being investigated, generally targeting the KRAS-GTP or KRAS-GDP complex. Exemplary direct RAS inhibitors under development include, but are not limited to, sotracib (AMG510), MRTX849, mRNA-5671, and ARS1620. In some embodiments, one or more RAS signaling inhibitors are selected from the group consisting of RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, SOS1 inhibitors, mTOR inhibitors, SHP2 inhibitors, and AKT inhibitors. In other embodiments, one or more RAS signaling inhibitors directly inhibit RAS variants. 【0119】 In some embodiments, one or more additional therapeutic agents are (i) agents that inhibit the enzyme poly(ADP-ribose) polymerase (e.g., olaparib, niraparib, and rucaparib); (ii) inhibitors of Bc1-2 family proteins (e.g., venetoclax, navitoclax, etc.); (iii) inhibitors of MCL-1; (iv) inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies); (v) isocitrate dehydrogenase (IDH) inhibitors, e.g., IDH-1 or IDH-2 inhibitors (e.g., ivosidenib, enasidenib, etc.). 【0120】 Immune checkpoint inhibitors. This disclosure intends to use the AXL inhibitors described herein in combination with immune checkpoint inhibitors. 【0121】 The vast number of genetic and epigenetic alterations characteristic of all cancers provide a diverse range of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the final amplitude of the response initiated by antigen recognition by the T cell receptor (TCR) (e.g., the level of cytokine production or proliferation), and the quality of the response (e.g., the type of immune response produced, such as the pattern of cytokine production), are regulated by a balance between co-stimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are crucial for preventing autoimmunity (i.e., maintaining self-tolerance) when the immune system is responding to pathogen infection, and also for protecting against tissue damage. The expression of immune checkpoint proteins can be dysregulated by tumors, which act as important immune resistance mechanisms. 【0122】 Most efforts are directed towards the therapeutic manipulation of endogenous antitumor immunity due to T cells' ability to: i) selectively recognize protein-derived peptides in all cellular compartments; ii) directly recognize and kill antigen-expressing cells (by CD8+ effector T cells; also known as cytotoxic T lymphocytes (CTLs)); and iii) modulate the diverse immune responses performed by CD4+ helper T cells, which integrate adaptive and innate effector mechanisms. 【0123】 In clinical practice, blocking immune checkpoints that amplify antigen-specific T cell responses has been shown to be a promising approach in the treatment of human cancer. 【0124】 T cell-mediated immunity involves multiple sequential steps, each step optimizing the response by canceling and modulating stimulating and inhibitory signals. Almost all inhibitory signals in the immune response ultimately modulate intracellular signaling pathways, many of which are initiated via membrane receptors, and their ligands are either membrane-bound or soluble (cytokines). Costimulatory and inhibitory receptors and ligands that modulate T cell activation are less likely to be overexpressed in cancer compared to normal tissue, while inhibitory ligands and receptors that modulate T cell effector function in tissue are commonly overexpressed in tumor cells or non-transformed cells associated with the tumor microenvironment. The function of soluble, membrane-bound receptor-ligand immune checkpoints can be modulated, for example, using agonist antibodies (for the copstimulatory pathway) or antagonist antibodies (for the inhibitory pathway). Therefore, in contrast to most antibodies currently approved for cancer treatment, antibodies that block immune checkpoints do not directly target tumor cells, but rather target lymphocyte receptors or their ligands to enhance endogenous antitumor activity [see Pardoll, (April 2012) Nature Rev. Cancer 12:252-64]. 【0125】 Examples of immune checkpoints (ligands and receptors) that are selectively upregulated in various types of tumor cells that are candidates for blockade include PD-1 (programmed cell death protein 1), PD-L1 (PD-1 ligand), BTLA (B and T lymphocyte attenuator), CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), TIM-3 (T cell membrane protein 3), LAG-3 (lymphocyte activation gene 3), TIGIT (T cell immune receptor with Ig and ITIM domains), and killer inhibitor receptors. These killer inhibitor receptors can be divided into two classes based on their structural characteristics: i) killer cell immunoglobulin-like receptors (KIRs), and ii) type C lectin receptors (components of the type II transmembrane receptor family). Other immune checkpoints whose definitions are not clearly established are described in the literature, including both receptors (e.g., the 2B4 (also known as the CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)) [see Pardoll, (April 2012) Nature Rev. Cancer 12:252-64]. 【0126】 This disclosure intends to use the AXL inhibitors described herein in combination with the immune checkpoint receptor and ligand inhibitors described above, as well as immune checkpoint receptors and ligands not yet described. Certain modulators of immune checkpoints are currently approved, and many others are under development. In 2011, the fully humanized CTLA-4 monoclonal antibody ipilimumab (YERVOY®, Bristo1-Myers Squibb) became the first immune checkpoint inhibitor to receive regulatory approval in the United States when it was approved for the treatment of melanoma. Fusion proteins containing CTLA-4 and the antibody (CTLA4-Ig, abatacept (ORENCIA®, Bristo1-Myers Squibb)) are used to treat rheumatoid arthritis, and other fusion proteins have been shown to be effective in kidney transplant patients sensitized to Epstein-Barr virus. The next class of immune checkpoint inhibitors to receive regulatory approval was against PD-1 and its ligands, PD-L1 and PD-L2. Approved anti-PD-1 antibodies include nivolumab (OPDIVO®, Bristo1-Myers Squibb) and pembrolizumab (KEYTRUDA®, Merck), which are used against various cancers such as squamous cell carcinoma, classical Hodgkin lymphoma, and urothelial carcinoma. Approved anti-PD-L1 antibodies include avelumab (BAVENCIO®, EMD Serono & Pfizer), atezolizumab (TECENTRIQ®, Roche / Genentech), and durvalumab (IMFINZI®, AstraZeneca), which are used against certain cancers, including urothelial carcinoma. Another approach targeting the PD-1 receptor is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.While no therapies targeting TIGIT or its ligands CD155 and CD112 have been approved, several are under development, including BMS-986207 (Bristo1-Myers Squibb), tiragolumab (Roche / Genentech), OMP-31M32 (OncoMed), etigirimab, osperirumab, vivostrimab, AB308, and AB154 (domvanarimab). 【0127】 In some embodiments, one or more additional therapeutic agents are cancer immunotherapy agents (e.g., immune checkpoint inhibitors). In some embodiments, the cancer immunotherapy agent is a PD-1 antagonist, e.g., an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO® (nivolumab), KEYTRUDA® (pembrolizumab), MEDI-0680 (AMP-514; WO2012 / 145493), valstilimab, buzigalimab, camrelizumab, semiprimab, dostallimab, emiprimab, ezabenlimab, pimivalimab, retifanlimab, sasamlimab, spartalizumab, scintillumab, tislerizumab, tripalimab, or zinberelimab. While pidilizumab (CT-011) is another potential cancer immunotherapy drug, its specificity for PD-1 binding is questionable. 【0128】 In some embodiments, the cancer immunotherapy agent targets PD-L1 and is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ® (atezolizumab, MPDL3280A, WO2010 / 077634), IMFINZI® (durvalumab, MEDI4736), BMS-936559 (WO2007 / 005874), cosivelimab, emvafolimab, and avelumab (MSB0010718C, WO2013 / 79174). 【0129】 In some combinations provided herein, the compounds disclosed herein are combined with one or more immune checkpoint inhibitors selected from MEDI-0608, nivolumab, pidilizumab, pembrolizumab, avelumab, atezolizumab, durvalumab, semiprimab, centimib, tislerizumab, AB308, domvanarimab, and zimbererimab. 【0130】 In certain aspects of this disclosure, the claimed AXL inhibitor is combined with an immunotherapy agent, which is (i) an agonist of a stimulating (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including coinhibitory) signal with respect to T cells, both of which amplify the antigen-specific T cell response. Certain stimulating and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), B7-H6, and B7-H7 (HHLA2). Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to members of the congeneral TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137(4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TR AILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT13R, LIGHT, Dc R3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin a / TNF13, TNFR2, TNFa, LT13R, lymphotoxin a 1132, FAS, FASL, RELT, DR6, TROY, NGFR. 【0131】 In another embodiment, cancer immunotherapy agents are cytokines that inhibit T cell activation (e.g., IL-6, IL-10, TGF-B, VEGF, and other immunosuppressive cytokines), or cytokines that stimulate T cell activation and thereby stimulate an immune response. 【0132】 In some embodiments, the T cell response can be stimulated by combining the disclosed AXL inhibitor with (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and / or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2. Other agents that can be combined with the AXL inhibitors of this disclosure for cancer treatment include antagonists of inhibitory receptors in NK cells or agonists of activating receptors in NK cells. For example, the compounds of this specification can be combined with KIR antagonists, such as lirilumab. 【0133】 Other agents for combination therapy include those that inhibit or deplete macrophages or monocytes, such as CSF-1R antagonists, e.g., RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044), or CSF-1R antagonist antibodies such as FPA-008 (WO11 / 140249, WO13169264, WO14 / 036357), but are not limited to these. 【0134】 In another embodiment, the disclosed AXL inhibitor can be used in conjunction with one or more agonists that bind positive costimulatory receptors, blocking agents that attenuate signaling via inhibitory receptors, antagonists, and one or more activators that systemically increase the frequency of antitumor T cells, activators that eliminate distinct immunosuppressive pathways in the tumor microenvironment (e.g., blocking the involvement of inhibitory receptors (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or ex vivo, by anti-CD25 bead depletion), or reversing / preventing T cell anergy or complete depletion), and activators that activate innate immunity and / or induce inflammation at the tumor site. 【0135】 In some embodiments, cancer immunotherapy agents are CTLA-4 antagonists, such as antagonistic CTLA-4 antibodies. Suitable CTLA-4 antibodies include, for example, YERVOY® (ipilimumab) or tremelimumab. 【0136】 In another embodiment, the cancer immunotherapy agent is a PD-1 antagonist as described elsewhere in this specification. 【0137】 In another embodiment, the cancer immunotherapy agent is a PD-L1 antagonist as described elsewhere in this specification. 【0138】 In another embodiment, the cancer immunotherapy agent is a TIGIT antagonist as described elsewhere in this specification. 【0139】 In another embodiment, the cancer immunotherapy agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG-3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273). 【0140】 In another embodiment, the cancer immunotherapy agent is a CD137(4-1BB) agonist, such as an activating CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566(W012 / 32433). 【0141】 In another embodiment, cancer immunotherapy agents include GITR agonists, such as activating GITR antibodies. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683). 【0142】 In another embodiment, the cancer immunotherapy agent is an OX40 agonist, such as an activating OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. 【0143】 In another embodiment, the cancer immunotherapy agent is an OX40L antagonist, such as an antagonistic OX40 antibody. A suitable OX40L antagonist is, for example, RG-7888 (WO06 / 029879). 【0144】 In another embodiment, the cancer immunotherapy agent is a CD40 agonist, for example, an agonistic CD40 antibody. In yet another embodiment, the cancer immunotherapy agent is a CD40 antagonist, for example, an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab. 【0145】 In another embodiment, the cancer immunotherapy drug is a CD27 agonist, such as an agonistic CD27 antibody. A suitable CD27 antibody is, for example, varylumab. 【0146】 In another embodiment, the cancer immunotherapy drug is MGA271 (WO11 / 109400) (against B7H3). 【0147】 Examples of therapeutic agents useful in combination therapy for the treatment of cardiovascular and / or metabolic diseases, disorders and conditions include statins that inhibit the enzymatic synthesis of cholesterol (e.g., CRESTOR®, LESCOL®, LIPITOR®, MEVACOR®, PRAVACOL®, and ZOCOR®), bile acid resins that sequester cholesterol and prevent its absorption (e.g., COLESTID, LO-CHOLEST, PREVALITE®, QUESTRAN®, and WELCHOL®), and cholesterol These include ezetimibe (ZETIA®), which blocks cholesterol absorption; fibrinic acid (e.g., TRICOR®), which can reduce triglycerides and moderately increase HDL; niacin (e.g., NIACOR®), which moderately reduces LDL cholesterol and triglycerides; and / or combinations of the above (e.g., VYTORIN (symvastatin and ezetimibe)). Various adjuvants and herbs (e.g., garlic, policosanol, and guggul) are candidates for alternative cholesterol treatments to be used in combination with the AXL inhibitors described herein. 【0148】 Examples of therapeutic agents useful in combination therapy for the treatment of diseases, disorders, or conditions related to immunity and inflammation include nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and other propionic acid derivatives (aluminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and thioxaprofen), and acetate derivatives (indomethacin, acemetacin, alclofenac, cridanac, diclofenac, fenclofenac) These include, but are not limited to, fenac, fenclodic acid, fentiazac, firofenac, ibufenac, isoxepac, oxpinac, sulindac, thiopinac, tolmetine, didomethacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, diflumic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicam (isooxicam, pyrooxicam, sudooxicam, and tenooxicam), salicylates (acetylsalicylic acid, sulfasalazine), and pyrazolone (apazon, bezpiperilone, feprazon, mofebutazone, oxyfenbutazone, and phenylbutazone). In addition, cyclooxygenase-2 (COX-2) inhibitors may be used in combination. 【0149】 Other active agents that can be used in combination include steroids, such as prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone, or hydrocortisone. Such combinations can be particularly advantageous because they can suppress or eliminate one or more adverse effects of steroids by gradually reducing the required dose of the steroid. 【0150】 For example, further examples of activators that may be used in combination with the treatment of rheumatoid arthritis include cytokine-suppressing anti-inflammatory drugs (CSAIDs); antibodies or antagonists against other human cytokines or growth factors, such as TNF, LT, IL-10, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, or PDGF. 【0151】 Certain combinations of activators can interfere at various points in the autoimmune and subsequent inflammatory cascade, and include TNF antagonists, e.g., chimeric, humanized or human TNF antibodies, REMICADE®, HUMIRA®, anti-TNF antibody fragments (e.g., CDP870), and soluble p55 or p75 TNF receptors, their derivatives, p75TNFRIgG (ENBREL®) or p55TNFR1gG (LENERCEPT), soluble IL-13 receptor (sIL-13), and TNFα-converting enzyme (TACE) inhibitors. Similarly, IL-1 inhibitors (e.g., interleukin-1-converting enzyme inhibitors) may also be effective. Other combinations include interleukin-11, anti-P7, and P-selectin glycoprotein ligands (PSGLs). Other examples of active ingredients useful in combination with the AXL inhibitors described herein include interferon-131a (AVONEX®), interferon-131b (BETASERON®); copaxone; hyperbaric oxygen; intravenous immunoglobulin; clavulivine; and antibodies against other human cytokines or growth factors or their antagonists (e.g., antibodies against CD40 ligand and CD80). 【0152】 In one or more embodiments, combinations of the AXL inhibitors described herein with DNA methyltransferase (DNMT) inhibitors or hypomethylating agents are also intended. Exemplary DNMT inhibitors include decitabine, zebralin, and azacitadine. 【0153】 In one or more embodiments, a combination of the AXL inhibitor described herein with a histone deacetylase (HDAC) inhibitor is also intended. Exemplary HDAC inhibitors include vorinostat, zivinostat, avexinostat, panobinostat, bellinostat, and trichostatin A. 【0154】 In some embodiments, the AXL inhibitor according to this disclosure is combined with a menin-MLL inhibitor. 【0155】 In some embodiments, combinations of the AXL inhibitors described herein with isocitrate dehydrogenase (IDH) inhibitors, such as IDH-1 or IDH-2, are also intended. An exemplary IDH-1 inhibitor is ivosidenib. An exemplary IDH-2 inhibitor is enasidenib. 【0156】 This disclosure includes any of the pharmaceutically acceptable salts, acids, or derivatives described above. 【0157】 The selection of further treatment(s) can be determined by the current standard of care for the specific cancer, and / or the mutational status of the cancer in question, and / or the stage of the disease. Detailed standard of care guidelines are published, for example, by the National Comprehensive Cancer Network (NCCN). For example, NCCN Acute Myeloid Leukemia v1.2022, NCCN Acute Lymphoblastic Leukemia v1.2022, NCCN Multiple Myeloma v5.2022, NCCN Non-Small Cell Lung Cancer v3.2022, NCCN Kidney Cancer v4.2022, NCCN Colon Cancer v1.2022, NCCN Rectal Cancer v1.2022, NCCN Hepatobiliary Cancer v1.2022, NCCN Pancreatic Adenocarcinoma v1.2022, NCCN Esophageal and Esophagogastric Junction Cancers v2.2022, NCCN Prostate Cancer v3.2022, NCCN Gastric Cancer v2.2022, Cervical Cancer v1.2022, Ovarian Cancer / Fallopian Tube Cancer / Primary Peritoneal Cancer v1.2022,NCCN Breast Cancer Please refer to v2.2022. 【0158】 dosage The AXL inhibitors of this disclosure may be administered to a subject in a dose determined, for example, by the administration goal (e.g., desired level of achievement), the age, weight, sex, and health and physical condition of the subject to whom the formulation is administered, the route of administration, and the nature of the disease, disorder, pathology, or symptom. The administration regimen may also take into account the presence, nature, and extent of any adverse effects associated with the administered active substance(s) and prior or combination therapy. Effective doses and administration regimens can be readily determined, for example, from safety and dose escalation studies and in vivo studies (e.g., animal models). 【0159】 Generally, drug administration parameters indicate that the dosage is below the maximum tolerated dose (MTD), which is irreversibly toxic to the subject, and above the amount necessary to produce a measurable effect on the subject. Such a dosage is determined, for example, by pharmacokinetic and pharmacodynamic parameters related to ADME, taking into account the route of administration and other factors. 【0160】 Generally, the disclosed methods involve administering a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a composition thereof, to a target subject in an effective amount. “Effective amount” with respect to AXL inhibitors in this disclosure means an amount of the compound sufficient to engage with the target (by inhibiting, acting on, or antagonizing the target) at a level demonstrating the compound’s efficacy. In the case of AXL, target engagement can be determined by one or more biochemical or cellular assays that yield similar values, such as EC50, ED50, EC90, IC50, or other values ​​that can be used as one assessment of the compound’s efficacy. Assays for determining target engagement include, but are not limited to, those described in the examples. An effective amount may be administered as a single amount or as multiple amounts in smaller quantities (e.g., one tablet of “x” amount, two tablets of “x / 2” amount, etc.). 【0161】 In certain embodiments, the AXL inhibitor intended in this disclosure can be administered at a dose level of approximately 0.01 mg / kg to approximately 50 mg / kg, or approximately 1 mg / kg to approximately 25 mg / kg, once or more times per day (e.g., orally or parenterally), in units of body weight / day, to obtain the desired therapeutic effect. 【0162】 For oral administration, the composition can be provided in the form of tablets, capsules, etc., containing 1 to 1000 mg of the active ingredient (i.e., the compound of formula (I), particularly 1, 3, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient). 【0163】 In certain embodiments, the desired dose of the AXL inhibitor is contained in a “unit dosage form.” The phrase “unit dosage form” refers to a physically distinct unit each containing a predetermined amount of the AXL inhibitor, either alone or in combination with one or more additional active agents, sufficient to produce the desired effect. It should be understood that the parameters of a unit dosage form depend on the specific active agent and the effect to be achieved. For intravenous administration, a unit dosage form may contain 1 to 1000 milligrams of the active ingredient (i.e., the compound of formula (I), in particular 1, 10, 25, 50, 100, 200, 300, or 500 milligrams). 【0164】 kit This disclosure also intends to include kits comprising the compounds described herein and their pharmaceutical compositions. Generally, the kits take the form of physical structures containing various components, as described below, and can be used, for example, in carrying out the methods described above. 【0165】 A kit may contain one or more of the compounds disclosed herein (e.g., in sterile containers) and may be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein may be provided in a ready-to-use form (e.g., tablets or capsules) or in a form that requires reconstitution or dilution before administration (e.g., powder). If the compounds described herein are in a form that requires reconstitution or dilution by the user, the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, etc., packaged together with or separately from the compounds described herein. Where combination therapy is intended, the kit may contain several active ingredients separately or they may be pre-packaged in the kit. Each component of the kit may be sealed in an individual container, and all of these containers may be housed in a single container. The kits of this disclosure may be designed to meet the conditions necessary for properly maintaining the components contained in the kit (e.g., refrigeration or freezing). 【0166】 The kit may include a label or accompanying document containing identification information for the components it contains, and instructions for their use (e.g., dosing parameters for the active ingredient(s), clinical pharmacology, e.g., mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or accompanying document may include manufacturer information such as lot number or expiration date. The label or accompanying document may, for example, be integrated into the physical structure containing the components, housed individually within the physical structure, or affixed to the components of the kit (e.g., ampoules, tubes, or vials). 【0167】 Labels or accompanying documents may further include or incorporate computer-readable media. In some embodiments, the actual instructions are not included in the kit, and means are provided for obtaining the instructions from a remote source, for example, via the Internet. 【0168】 experiment The following examples are provided to those skilled in the art to provide a complete disclosure and explanation of how to prepare and use this disclosure, and are not intended to limit the scope of the inventions that the inventors consider to be their own. While efforts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., quantities, temperatures, etc.), some degree of experimental error and deviation should be taken into consideration. 【0169】 Unless otherwise specified, temperature is in degrees Celsius (°C), and pressure is atmospheric pressure or close to it. Standard abbreviations are used, including: rt or rt = room temperature, min = seconds, h or hr = hours, ng = nanograms, μg = micrograms, mg = milligrams, g = grams, kg = kilograms, μl or μL = microliters, ml or mL = milliliters, l or L = liters, μM = micromolar concentration, mM = millimolar concentration, M = molar concentration, mol = mole, mmol = millimoles, aq. = aqueous solution, calcd = calculated value, DCM = dichloromethane, DCE = 1,2-dichloroethane, MTBE = methyl tert-butyl ether, THF = tetrahydrofuran, Depositphotos = ethyl acetate, ACN = acetonitrile, NMP = N-methyl-2-pyrrolidone, DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, IPA = isopropanol, EtOH = ethanol, MeOH = methanol H2 = hydrogen gas, N2 = nitrogen gas, DIPEA = N,N-diisopropylethylamine, DMEDA = N,N-dimethylethane-1,2-diamine, HATU = N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methylmethaneaminonium hexafluorophosphate N-oxide, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbody Imide, HOBt = hydroxybenzotriazole, NBS = N-bromosuccinimide, KOAc = potassium acetate, TFA = trifluoroacetic acid, (dppf)PdCl2 = [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, B2pin2 = bis(pinacolate)diborone, DMAP = 4-dimethylaminopyridine, MHz = megahertz, Hz = hertz, ppm = parts per million, ESI MS = electrospray ionization mass spectrometry, NMR = nuclear magnetic resonance. 【0170】 Materials and methods The following general materials and methods were used, or may be used, in the following examples, where explicitly stated. 【0171】 1¹H NMR spectra were recorded using a Varian 400 MHz NMR spectrometer equipped with an Oxford AS400 magnet. Chemical shifts (δ) are reported in parts per million (ppm) relative to the internal reference, which is a non-deuterated residual solvent. [Examples] 【0172】 Example 1: 8-{5-[7-(pyrroridine-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] Step a: To a mixture of methyl 4-bromo-2-hydroxybenzoate (4.62 g, 20.0 mmol), K2CO3 (5.53 g, 40.0 mmol), and DMF (40 mL), tert-butyl (2-bromoethyl) carbamate (4.71 g, 21.0 mmol) was added at room temperature. This reaction mixture was stirred at 65 °C for 3 hours, cooled to room temperature, diluted with SiO2 (200 mL), washed with 9:1 water:brine (4 × 200 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (120 g silica gel, hexane:SiO2) with a 0% to 50% gradient (25 minutes) to obtain the desired product as a pale yellow oil (7.02 g; 94%). 【0173】 Step b: The product from step a (7.02 g, 18.8 mmol) and a mixture of dioxane containing 4 M HCl (38 mL) were stirred at room temperature for 30 minutes and diluted with MTBE (300 mL). The precipitated solid was collected by filtration, washed with MTBE, and dried to obtain the desired product as a white solid (5.07 g; 87%). 【0174】 Step c: The mixture of the product from step b (5.07 g, 16.3 mmol) and MeOH (41 mL) was added at room temperature to NaOMe (7.47 mL, 32.6 mmol, containing 25 wt% MeOH). This reaction mixture was stirred at 65°C for 1 hour, cooled to room temperature, and saturated with MH4Cl (水溶液) The reaction was stopped at (7.5 mL) and diluted with siRNA (150 mL). The organic phase was washed with water (1 × 100 mL), dried over Na₂SO₄, and concentrated. The crude product was purified by column chromatography (80 g silica gel, CH₂Cl₂:MeOH) from 0% to 10% gradient (30 minutes) to obtain the desired product as a white solid (3.82 g; 97%). 【0175】 Step d: A mixture of the product from step c (1.21 g, 5.00 mmol), B2pin2 (1.27 g, 5.00 mmol), (dppf)PdCl2 (183 mg, 0.250 mmol), and KOAc (981 mg, 10.0 mmol) was placed under nitrogen. Degassed dioxane (25 mL) was added, and the reaction mixture was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature, concentrated, diluted with SiO2 (250 mL), filtered through Celite to remove solids, and concentrated again to obtain the desired product, which was used crudely in the next step. 【0176】 Step e: To a suspension of 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (40.3 g, 124 mmol) in DMF (5 mL), solid NaOt-Bu (14.6 g, 130 mmol) was added in three portions over approximately 20 minutes at 0°C, and the mixture was then stirred for a further 10 minutes. (2-(chloromethoxy)ethyl)trimethylsilane (23.0 mL, 130 mmol) was added over 30 minutes, and the reaction mixture was stirred for 15 hours, while warming it to room temperature once the condenser was finished. The mixture was cooled to 0°C and diluted with H2O (500 mL). The precipitated solid was collected by filtration, washed with H2O, and vacuum-dried to obtain the desired product as a pale yellow solid (51.2 g; 91%). 【0177】 Step f: To a mixture of the product from step e (4.76 g, 10.5 mmol), K₂CO₃ (2.90 g, 21.0 mmol), and (dppf)PdCl₂ (766 mg, 1.05 mmol), a solution of degassed dioxane (5 mL) containing the crude product from step d (10.5 mmol) was added under N₂, followed by the addition of degassed H₂O (12 mL). The reaction mixture was stirred at 85 °C for 20 hours, cooled to room temperature, and poured into H₂O (100 mL). The resulting solution was extracted with siRNA (3 ×), and the combined organic phase was washed with water and brine, dried over anhydrous Na₂CO₃, and concentrated. The crude residue was purified by silica gel chromatography (100% hexane to 100% siRNA) to obtain the desired product as a light brown solid (3.39 g; 66%). 【0178】 Step g: To a mixture of DCE (21.5 mL) containing 2-bromo-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-one (1.03 g, 4.31 mmol) and pyrrolidine (0.43 mL, 5.17 mmol), AcOH (0.25 mL, 4.31 mmol) was added, followed by NaBH(OAc)3 (1.19 g, 5.60 mmol). The reaction mixture was stirred at room temperature for 16 hours, and the reaction was carefully stopped with H2O and then saturated NaHCO3 aqueous solution. These layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 containing 10% MeOH from 100% CH2Cl2, 0.5% NET3), yielding the desired product as a viscous orange oil (978 mg; 77%). 【0179】 Step h: Dioxane (6.5 mL) was added to a mixture of the product from step g (191 mg, 0.649 mmol), B2pin2 (214 mg, 0.844 mmol), and KOAc (83 mg, 0.844 mmol), and this suspension was degassed with N2 for 10 minutes. (dppf)PdCl2 (24 mg, 0.0325 mmol) was added, and the reaction mixture was stirred at 90°C for 3 hours. As soon as it cooled, SiO2 (20 mL) was added, and this mixture was filtered by Celite. The filtrate was concentrated to obtain a viscous brown oily crude product. 【0180】 Step i: Dioxane (5.3 mL) and H2O (0.60 mL) were added to a mixture of the product from step f (144 mg, 0.295 mmol), the crude product from step h (0.325 mmol), and Na2CO3 (63 mg, 0.590 mmol). The suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (11 mg, 0.0148 mmol) was added, and the reaction mixture was stirred at 80°C for 14 hours. As soon as it cooled, CH2Cl2 (15 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 containing 10% MeOH from 100% CH2Cl2, 1% NH3) to obtain the desired product as a brown solid (127 mg; 69%). 【0181】 Step j: To a solution of CH2Cl2 (1.1 mL) containing the product from step i (129 mg, 0.207 mmol), TFA (1.1 mL) was added. This reaction was stirred at room temperature for 2 hours and then concentrated. MeOH (7N solution, 2.1 mL) containing NH3 was added to the residue, and this reaction was stirred at room temperature for 14 hours. After cooling, this reaction was concentrated. Following purification by C18 reverse-phase chromatography (100% H2O to 100% ACN, 0.1% TFA) and reverse-phase HPLC (H2O containing 10-70% ACN, 0.1% TFA), the product was freeze-dried to obtain the marked compound as a pale yellow solid (5 mg, 4%). 1H NMR (400MHz, methanol-d4) δ 8.79 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.83 (dd, J = 8.2, 1.8 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.51 (dd, J= 7.7, 2.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 4.46 (dd, J = 5.3, 4.3 Hz, 2H), 3.65 - 3.53 (m, 3H), 3.51 (dd, J = 5.2, 4.4 Hz, 2H), 3.29 - 3.17 (m, 2H), 3.11 - 2.86 (m, 4H), 2.53 - 2.42 (m, 2H), 2.22- 2.05 (m, 2H), 2.03 - 1.95 (m, 2H), 1.57 (p, J = 11.6, 11.2 Hz, 2H). ESI MS [M+H] + C 30 H 32 Calculated value for N5O2: 494.3, Measured value: 494.2. 【0182】 Example 2: 8-{5-[6-(pyrroridine-1-yl)-5,6,7,8-tetrahydronaphthalene-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0183】 The indicated compound was prepared in the same manner as in Example 1. 1H NMR (400 MHz, methanol-d4) δ 8.75 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 2.1 Hz, 1H), 7.99 (dd, J = 8.2, 0.4 Hz, 1H), 7.81 (dd, J = 8.2, 1.7 Hz, 1H), 7.67 (d, J = 1.3 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.27 (d, J = 7.9 Hz, 1H), 4.46 (dd, J = 5.5, 4.0 Hz, 2H), 3.86 - 3.73 (m, 2H), 3.66 - 3.55 (m, 1H), 3.51 (dd, J = 5.6, 4.1 Hz, 2H), 3.41 - 3.34 (m, 1H), 3.30 - 3.23 (m, 2H), 3.17 - 2.94 (m, 3H), 2.51 - 2.39 (m, 1H), 2.30 - 2.16 (m, 2H), 2.14 - 2.01 (m, 2H), 1.94 (ddt, J = 17.2, 11.8, 5.7 Hz, 1H). ESI MS [M+H] + C 29 H 30 Calculated value for N5O2: 480.2, Measured value: 480.2. 【0184】 Example 3: 8-{5-[7-(pyrroridine-1-yl)-5,6,7,8-tetrahydronaphthalene-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0185】 The indicated compound was prepared in the same manner as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.41 (t, J = 5.4 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.89 (dd, J = 8.2, 1.7 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.63 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.38 (dd, J = 5.3, 4.1 Hz, 2H), 3.72 - 3.58 (m, 3H), 3.47 - 3.30 (m, 3H), 3.30 - 3.12 (m, 2H), 3.08 - 2.96 (m, 2H), 2.95 - 2.83 (m, 1H), 2.40 - 2.29 (m, 1H), 2.14 - 2.00 (m, 2H), 1.98 - 1.76 (m, 3H). ESI MS [M+H] + C 29 H 30 Calculated value for N5O2: 480.2, Measured value: 480.2. 【0186】 Example 4: 8-[5-(6-{[(3S)-oxolan-3-yl]amino}-5,6,7,8-tetrahydronaphthalene-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0187】 The indicated compound was prepared using the same method as in Example 1. 1H NMR (400 MHz, methanol-d4) δ 9.17 (d, J = 1.9 Hz, 1H), 9.11 (d, J = 1.9 Hz, 1H), 8.06 (dd, J = 8.2, 0.4 Hz, 1H), 7.85 (dd, J = 8.2, 1.7 Hz, 1H), 7.72 (dd, J = 1.7, 0.4 Hz, 1H), 7.67 -7.58 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 4.51 -4.46 (m, 2H), 4.28 -4.20 (m, 1H), 4.14 -4.01 (m, 2H), 3.93 (dt, J = 10.9, 5.7 Hz, 1H), 3.79 (ddd, J = 8.9, 8.2, 7.3 Hz, 1H), 3.75 -3.65 (m, 1H), 3.53 (dd, J = 5.5, 4.1 Hz, 2H), 3.43 (dd, J = 16.2, 5.4 Hz, ESI MS [M+H] + C 29 H 30 Calculated value for N5O3: 496.2, Measured value: 496.2. 【0188】 Example 5: 8-[5-(6-{[(3R)-oxolan-3-yl]amino}-5,6,7,8-tetrahydronaphthalene-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0189】 The indicated compound was prepared in the same manner as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.31 -8.95 (m, 2H), 8.87 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1Hz, 1H), 8.41 (t, J = 5.3 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.89 (dd, J = 8.2, 1.7 Hz, 1H), 7.68 (dd, J= 1.7, 0.3 Hz, 1H), 7.67 -7.62 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 4.38 (dd, J = 5.4, 4.1Hz, 2H), 4.17 -4.07 (m, 1H), 4.00 -3.83 (m, 3H), 3.70 (q, J = 7.7 Hz, 1H), 3.65 -3.47 (m, 2H), 3.37 -3.26 (m, 2H), 3.09 -2.86 (m, 3H), 2.38 -2.24 (m, 2H), 2.14 -2.01 (m, 1H), 1.90 -1.76 (m, 1H). ESI MS [M+H] + C 29 H 30 Calculated value for N5O3: 496.2, Measured value: 496.2. 【0190】 Example 6: 6-Fluoro-8-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0191】 The indicated compound was prepared in the same manner as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.55 (t, J = 6.1 Hz, 1H), 7.80 (dd, J = 10.8, 1.5 Hz, 1H), 7.65 -7.61 (m, 2H), 7.57 (dd, J = 7.6, 2.0 Hz, 1H), 7.27 (dd, J = 7.8, 1.3 Hz, 1H), 4.27 (t, J = 5.5 Hz, 2H), 3.33 -3.29 (m, 2H), 3.01 -2.77 (m, 5H), 2.77 -2.65 (m, 2H), 2.44 (q, J = 8.3 Hz, 1H), 2.07 -1.94 (m, 2H), 1.88 -1.75 (m, 1H), 1.68 -1.49 (m, 2H), 1.49 -1.37 (m, 1H), 1.34 -1.21 (m, 2H), 1.02 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 31 H 33 Calculated value for FN5O2: 526.3, Measured value: 526.3. 【0192】 Example 7: 8-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0193】 Step a: To a mixture of DCE (5.2 mL) containing 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (272 mg, 1.04 mmol) and cyclopentanone (0.11 mL, 1.29 mmol), AcOH (60 μL, 1.04 mmol) was added, followed by NaBH(OAc)3 (331 mg, 1.56 mmol). The reaction mixture was stirred at room temperature for 17 hours, and then the reaction was carefully stopped with saturated NaHCO3 aqueous solution. These layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous MgSO4, and concentrated to obtain the desired product as a colorless oil (293 mg, 96%). 【0194】 Step b: Dioxane (3.8 mL) was added to a mixture of the product from step a (111 mg, 0.377 mmol), B2pin2 (129 mg, 0.490 mmol), and KOAc (48 mg, 0.490 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (14 mg, 0.0189 mmol) was added, and the reaction mixture was stirred at 90°C for 3 hours. As soon as it cooled, SiO2 (15 mL) was added, and the mixture was filtered by Celite. The filtrate was concentrated to obtain the crude product as a viscous brown oily substance. 【0195】 Step c: Dioxane (6.2 mL) and H2O (0.70 mL) were added to a mixture of the product from Example 1 and Step f (168 mg, 0.343 mmol), the crude product from Step b (0.377 mmol), and Na2CO3 (73 mg, 0.685 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (130 mg, 0.0148 mmol) was added, and the reaction mixture was stirred at 80°C for 14 hours. As soon as it cooled, CH2Cl2 (15 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 containing 10% MeOH from 100% CH2Cl2, 1% NH3) to obtain the desired product as a brown solid (144 mg; 67%). 【0196】 Step d: To a solution of CH2Cl2 (1.1 mL) containing the product from step c (144 mg, 0.231 mmol), TFA (1.1 mL) was added. This reaction mixture was stirred at room temperature for 1.5 hours and then concentrated. To the residue, MeOH (7N solution, 2.3 mL) containing NH3 was added, and this reaction mixture was stirred at room temperature for 14 hours. As soon as it cooled, this reaction mixture was concentrated. Purification was performed by C18 reverse-phase chromatography (100% H2O to 100% ACN, 0.1% TFA) and reverse-phase HPLC (H2O containing 10-90% ACN, 0.1% TFA), and then lyophilized to obtain the marked compound as a pale yellow solid (44 mg, 31%). 1 H NMR (400 MHz, methanol-d4) δ 8.81 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.01 (dd, J = 8.2, 0.4 Hz, 1H), 7.85 (dd, J = 8.2, 1.7 Hz, 1H), 7.71 (dd, J = 1.7, 0.4 Hz, 1H), 7.60 -7.43 (m, 2H), 7.28 (d, J= 7.6Hz, 1H), 4.46 (dd, J = 5.5, 4.0 Hz, 2H), 3.51 (dd, J = 5.4, 4.2 Hz, 2H), 3.12 -3.02 (m, 5H), 3.00 -2.71 (m, 4H), 2.06 -1.93 (m, 2H), 1.84 -1.69 (m, 2H), 1.69 -1.46 (m, 4H). ESI MS [M+H] + C 30 H 32 Calculated value for N5O2: 494.3, Measured value: 494.2. 【0197】 Example 8: 8-[5-(8-chloro-2-cyclopentyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0198】 The indicated compound was prepared in the same manner as in Example 7. 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (brs, 1H), 8.96 (d, J = 2.1 Hz, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.42 (t, J = 5.3 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.92 (dd, J = 8.2, 1.7 Hz, 1H), 7.86 (d, J = 1.4 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 4.57 (d, J = 16.9 Hz, 1H), 4.45 -4.35 (m, 3H), 3.87 -3.76 (m, 2H), 3.43 -3.34 (m, 3H), 3.30 -3.21 (m, 2H), 2.23 -2.09 (m, 2H), 1.96 -1.69 (m, 4H), 1.69 -1.52 (m, 2H). ESI MS [M+H] + C 29 H 29 Calculated value for ClN5O2: 514.2, Measured value: 514.2. 【0199】 Example 9: 8-(5-(2-cyclopentyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0200】 The indicated compound was prepared in the same manner as in Example 7. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 2.1 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.36 (t, J = 5.4 Hz, 1H), 7.95 -7.82 (m, 2H), 7.65 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.8 Hz, 1H), 4.34 (dd, J = 5.3, 4.1 Hz, 2H), 3.63 (s, 2H), 3.40 -3.33 (m, 2H), 2.87 (t, J = 5.9Hz, 2H), 2.73 -2.58 (m, 3H), 1.87 (d, J = 6.3 Hz, 2H), 1.62 (d, J = 7.3 Hz, 2H), 1.57 -1.34 (m, 4H). ESI MS [M+H] + C 29 H 30 Calculated value for N5O2: 480.2, Measured value: 480.2. 【0201】 Example 10: 8-(5-(2-cyclopentyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0202】 The indicated compound was prepared in the same manner as in Example 7. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.35 (t, J = 5.4 Hz, 1H), 7.95 -7.82 (m, 2H), 7.64 (dd, J = 1.7, 0.5 Hz, 1H), 7.59 -7.48 (m, 2H), 7.20 (d, J = 7.9 Hz, 1H), 4.34 (dd, J = 5.4, 4.1 Hz, 2H), 3.68 (s, 2H), 3.35 (q, J = 5.0 Hz, 2H), 2.85 -2.78 (m, 2H), 2.73 -2.58 (m, 3H), 1.88 (d, J = 5.7 Hz, 2H), 1.62 (d, J = 7.3 Hz, 2H), 1.58 -1.35 (m, 4H). ESI MS [M+H] + C 29 H 30 Calculated value for N5O2: 480.2, Measured value: 480.2. 【0203】 Example 11: 8-(5-(3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0204】 The indicated compound was prepared in the same manner as in Example 7. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.96 -7.89 (m, 1H), 7.85 (dd, J = 8.2, 1.7 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.72 -7.61 (m, 2H), 7.37 (d, J = 7.9 Hz, 1H), 4.83 (t, J = 7.1 Hz, 2H), 4.72 (t, J = 7.5 Hz, 2H), 4.44 (s, 1H), 4.38 -4.31 (m, 2H), 3.36 (q, J = 5.0 Hz, 2H), 3.29 -2.94 (m, 6H), 2.91 (s, 2H). ESI MS [M+H] + C 28 H 28 Calculated value for N5O3: 482.2, Measured value: 482.2. 【0205】 Example 12: 8-(5-(2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0206】 The indicated compound was prepared in the same manner as in Example 7. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.93 (dd, J = 8.2, 0.4 Hz, 1H), 7.87 (dd, J = 8.2, 1.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 2H), 7.65 (dd, J = 1.7, 0.5 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 4.81 (d, J = 6.5 Hz, 4H), 4.56 (d, J = ESI MS [M+H] + C 27 H 26 Calculated value for N5O3: 468.2, Measured value: 468.2. 【0207】 Example 13: 8-(5-(2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0208】 The indicated compound was prepared in the same manner as in Example 7. 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.93 (dd, J = 8.2, 0.4 Hz, 1H), 7.87 (dd, J = 8.2, 1.7 Hz, 1H), 7.79 -7.72 (m, 2H), 7.65 (dd, J = 1.7, 0.5 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.58 (d, J = 15.5 Hz, 1H), 4.44 -4.31 (m, 3H), 3.84 -3.69 (m, 3H), 3.53 -3.33 (m, 7H), 3.26 -3.07 (m, 3H). ESI MS [M+H] + C 27 H 28 Calculated value for N5O3: 470.2, Measured value: 470.2. 【0209】 Example 14: 3-Cyclopentyl-7-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine [ka] 【0210】 The indicated compound was prepared in the same manner as in Example 7. 1H NMR (400 MHz, DMSO-d6) δ 13.98 (s, 1H), 9.67 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 1.7, 0.4 Hz, 1H), 7.93 (dd, J = 8.4, 1.7 Hz, 1H), 7.77 -7.66 (m, 2H), 7.55 (dd, J = 8.4, 0.4 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 3.67 (s, 2H), 3.15 (qd, J = 28.3, 27.2, 14.3 Hz, 7H), 2.02 (d, J = 9.7 Hz, 2H), 1.72 (d, J = 14.7 Hz, 4H), 1.54 (s, 2H). ESI MS [M+H] + C 27 H 27 Calculated value for F2N4O2: 489.2, Measured value: 489.2. 【0211】 Example 15: 8-(5-(3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0212】 The indicated compound was prepared in the same manner as in Example 7. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.93 (dd, J = 8.1, 0.4 Hz, 1H), 7.85 (dd, J = 8.2, 1.7 Hz, 1H), 7.74 -7.61 (m, 3H), 7.34 (d, J = 7.8 Hz, 1H), 4.38 -4.31 (m, 2H), 3.73 -3.65 (m, 3H), 3.31 (s, 9H), 3.11 (td, J = 17.0, 16.1, 8.0 Hz, 4H). ESI MS [M+H] + C 28 H 30 Calculated value for N5O3: 484.2, Measured value: 484.2. 【0213】 Example 16: 8-{5-[3-(2-methylpropanoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0214】 Step a: To a suspension of CH2Cl2 (3.4 mL) containing 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (84 mg, 3.2 mmol), NET3 (0.13 mL, 0.960 mmol) was added, followed by 2-methylpropanoyl chloride (40 μL, 0.384 mmol). The reaction mixture was stirred at room temperature for 17 hours, and then the reaction was carefully stopped with saturated NH4Cl aqueous solution. These layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The combined organic layers were washed with brine, dried on anhydrous MgSO4, and concentrated. The crude residue was dissolved in CH2Cl2 (5 mL), washed with saturated NaHCO3 aqueous solution, and then the aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The combined organic layers were washed with brine, dried on anhydrous MgSO4, and concentrated to obtain the desired product as a pale pink, viscous oil (94 mg, 99%). 【0215】 Step b: Dioxane (9.8 mL) was added to a mixture of the product from Example 1 and Step f (481 mg, 0.983 mmol), B2pin2 (300 mg, 1.18 mmol), and KOAc (125 mg, 1.28 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (36 mg, 0.0492 mmol) was added, and the reaction mixture was stirred at 80°C for 4 hours. As soon as it cooled, SiO2 (30 mL) was added, and the mixture was filtered by Celite. The filtrate was concentrated to obtain a crude product of a viscous brown oily substance. 【0216】 Step c: Dioxane (4.4 mL) and H2O (0.50 mL) were added to a mixture of the product from step a (94 mg, 0.320 mmol), the crude product from step b (0.246 mmol), and Na2CO3 (74 mg, 0.492 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (9 mg, 0.0123 mmol) was added, and the reaction mixture was stirred at 100°C for 4 hours. As soon as it cooled, CH2Cl2 (15 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (100% hexane to 100% siRNA to 10% MeOH-containing siRNA) to obtain the desired product as a light brown solid (105 mg; 68%). 【0217】 Step d: To a solution of CH2Cl2 (1.7 mL) containing the product from step c (105 mg, 0.168 mmol), TFA (1.7 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. To the residue, MeOH (7N solution, 3.4 mL) containing NH3 was added, and the reaction mixture was stirred at 40°C for 2 hours. As soon as it cooled, the reaction mixture was concentrated and purified by silica gel chromatography (CH2Cl2 containing 10% MeOH from 100% CH2Cl2), and dried under vacuum to obtain the marked compound as an off-white solid (29 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.40 (t, J = 5.4 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 8.2, 1.7 Hz, 1H), 7.69 -7.65 (m, 2H), 7.62 (dd, J = 7.8, 1.9 Hz, 1H), 7.31 (dd, J = 7.7, 3.6 Hz, 1H), 4.38 (dd, J = 5.3, 4.1 Hz, 2H), 3.65 (dt, J = 17.6, 8.3 Hz, 4H), 3.43 -3.34 (m, 2H), 3.10 -2.83 (m, 5H), 1.03 (dd, J = 6.7, 2.9 Hz, 6H). + C 29 H 30 Calculated value for N5O3: 496.2, Measured value: 496.2. 【0218】 Example 17: 8-[5-(3-cyclopropanecarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0219】 The indicated compound was prepared in the same manner as in Example 16. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.69 (s, 1H), 8.40 (t, J = 5.3 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.90 (dd, J = 8.2, 1.7 Hz, 1H), 7.74 -7.65 (m, 2H), 7.62 (dd, J = 7.7, 2.0 Hz, 1H), 7.32 (t, J = 8.5 Hz, 1H), 4.38 (dd, J = 5.4, 4.0 Hz, 2H), 3.85 (t, J = 8.0 Hz, 2H), 3.64 (t, J = 8.5 Hz, 2H), 3.43 -3.38 (m, 2H), 3.12 -2.98 (m, 2H), 2.98 -2.85 (m, 2H), 2.21 -1.92 (m, 1H), 0.89 -0.55 (m, 4H). ESI MS [M+H] + C 29 H 28 Calculated value for N5O3: 494.2, Measured value: 494.2. 【0220】 Example 18: 8-[5-(3-methanesulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0221】 The indicated compound was prepared in the same manner as in Example 16. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.40 (t, J = 5.3 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 8.2, 1.7 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.65 (dd, J = 7.7, 2.0 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 4.38 (dd, J = 5.4, 4.1Hz, 2H), 3.43 3.35 (m, 6H), 3.17 -2.98 (m, 4H), 2.89 (s, 3H). ESI MS [M+H] + C 26 H 26 Calculated value for N5O4S: 504.2, Measured value: 504.2. 【0222】 Example 19: 8-(5-(3-(2-hydroxy-2-methylpropanoyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0223】 The indicated compound was prepared in the same manner as in Example 16. 1H NMR (400 MHz, DMSO-d6) δ 8.89 -8.82 (m, 1H), 8.70 -8.62 (m, 1H), 8.37 (t, J = 5.3 Hz, 1H), 7.96 -7.82 (m, 2H), 7.70 -7.60 (m, 2H), 7.57 (dd, J = 7.7, 2.0 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 4.34 (dd, J = 5.4, 4.1 Hz, 2H), 3.57 (s, 2H), 3.36 (q, J = 5.1 Hz, 2H), 2.95 (s, 2H), 1.67 -1.55 (m, 1H), 1.33 (s, 6H). ESI MS [M+H] + C 29 H 30 Calculated value for N5O4: 512.2, Measured value: 512.2. 【0224】 Example 20: 8-(5-(3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0225】 Step a: To a mixture of 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (100 mg, 0.38 mmol), (1-ethoxycyclopropoxy)trimethylsilane (264.9 mg, 1.5 mmol), and THF / MeOH (1:1, 1.5 mmol), AcOH (217.5 mL, 3.8 mmol) and NaBH3CN (107.4 mg, 1.7 mmol) were added and heated at 50°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered to remove all insoluble substances, concentrated, and purified by column chromatography (SiO2, CH2Cl2 / MeOH / 7N methanolNH3 (90:10:1) containing CH2Cl2 from 0 to 100%) to obtain the desired product as a light brown oily substance (62 mg, 61%). 【0226】 Step b: A mixture of the product from step a (62 mg, 0.23 mmol), B2pin2 (60 mg, 0.23 mmol), KOAc (46 mg, 0.47 mmol), and (dppf)PdCl2 (9 mg, 0.01 mmol) was placed under a nitrogen atmosphere. Degassed dioxane (1.5 mL) was added to this mixture and heated at 100°C for 6 hours. After cooling to room temperature, the reaction mixture was filtered to remove all insoluble substances, concentrated, and used directly in the next step. 【0227】 Step c: A mixture of the crude product obtained from step b (estimated value of 0.23 mmol), the product from Example 1 and step f (114 mg, 0.23 mmol), K2CO3 (65 mg, 0.47 mmol), and (dppf)PdCl2 (9 mg, 0.01 mmol) was placed under a nitrogen atmosphere. To this mixture, degassed dioxane (1.5 mL) and H2O (0.5 mL) were added, and the mixture was heated at 100 °C for 14 hours. After cooling to room temperature, siRNA (20 mL) was added. The phases were separated, and the aqueous phase was extracted with siRNA (2 × 20 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (SiO2, CH2Cl2 / MeOH / 7N methanol NH3 (90:10:1) containing CH2Cl2 from 0 to 100%) to obtain the desired product as a yellowish-brown solid (63 mg, 45%). 【0228】 Step d: To a solution of CH2Cl2 (1.0 mL) containing the product from step c (63 mg, 0.11 mmol), TFA (1.0 mL) was added. This reaction mixture was stirred at room temperature for 4 hours. The solvent was removed, and the crude product was resuspended in MeOH (1.0 mL). DMEDA (0.5 mL) was added to this mixture, and the mixture was stirred at 60°C for 1 hour. As soon as it cooled to room temperature, the solvent was removed, and the crude product was purified by reverse-phase HPLC with H2O + 0.1% TFA and CH3CN + 0.1% TFA as mobile phases, yielding the desired product as a yellow solid (15 mg; 26%). 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.93 (dd, J = 8.2, 0.4 Hz, 1H), 7.90 -7.82 (m, 1H), 7.81 -7.62 (m, 3H), 7.37 (d, J = 7.9 Hz, 1H), 4.38 -4.30 (m, 2H), 3.77 (s, 2H), 3.36 (q, J = 5.0 Hz, 2H), 3.16 (dtd, J = 29.8, 16.7, 15.5, 8.0 Hz, 6H), 2.94 (s, 1H), 1.04 (s, 2H), 0.87 (d, J = 7.1 Hz, 2H). ESI MS [M+H] + C 28 H 28 Calculated value for N5O2: 466.2, Measured value: 466.2. 【0229】 Example 21: 8-(5-(2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0230】 The indicated compound was prepared in the same manner as in Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.93 (dd, J = 8.2, 0.4 Hz, 1H), 7.86 (dd, J = 8.2, 1.7 Hz, 1H), 7.77 (d, J = 5.0 Hz, 2H), 7.65 (dd, J = 1.7, 0.5 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 4.66 (d, J = 16.3 Hz, 1H), 4.55 (s, 1H), 4.35 (dd, J = 5.4, 4.1 Hz, 2H), 3.79 (s, 2H), 3.56 (s, 2H), 3.36 (q, J = 5.0 Hz, 2H), 3.02 (s, 1H), 1.02 (d, J = 11.8 Hz, 2H), 0.90 (d, J = 7.3 Hz, 2H). ESI MS [M+H] + C 27 H 26 Calculated value for N5O: 452.2, Measured value: 452.2. 【0231】 Example 22: 8-{5-[7-methyl-7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0232】 Step a: Dioxane (4.3 mL) was added to a mixture of 2-bromo-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-one (205 mg, 0.857 mmol), B2pin2 (218 mg, 0.857 mmol), and KOAc (93 mg, 0.943 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (31 mg, 0.0429 mmol) was added, and the reaction mixture was stirred at 80°C for 3 hours. As soon as it cooled, SiO2 (15 mL) was added, and the mixture was filtered through Celite. The filtrate was concentrated to obtain the crude product as a viscous brown oily substance. 【0233】 Step b: Dioxane (7.7 mL) and H2O (0.90 mL) were added to a mixture of the product from Example 1 and Step f (445 mg, 0.909 mmol), the crude product from Step a (0.857 mmol), and Na2CO3 (182 mg, 1.71 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (31 mg, 0.0429 mmol) was added, and the reaction mixture was stirred at 90°C for 15 hours. As soon as it cooled, CH2Cl2 (20 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (100% hexane to 100% siRNA) to obtain the desired product as a brown solid (438 mg; 90%). 【0234】 Step c: To a mixture of the product from step b (115 mg, 0.202 mmol) and pyrrolidine (19 μL, 0.222 mmol) in toluene (50 mL), 1H-1,2,3-triazole (14 μL, 0.242 mmol) was added, and the reaction mixture was stirred at 100°C for 24 hours. Additional pyrrolidine (2.0 mL, 23.9 mmol) was added, and the reaction mixture was stirred under reflux for 17 hours, collecting water through a Dean-Stark trap. As cooling began, the toluene solution was added over 30 minutes to a cooled mixture (0°C) of MeMgBr solution (Et2O containing 3 M, 2.33 mL, 6.99 mmol) and THF (10 mL). The reaction mixture was stirred at 0°C for 1 hour, then heated to room temperature and stirred for 1 hour. The reaction mixture was cooled again to 0°C, and saturated NH4Cl aqueous solution was carefully added, followed by H2O. This aqueous layer was extracted with SiO(3 × 20 mL), and the combined organic layer was then washed with NaOH solution (H2O containing 2N, 2 × 30 mL) and brine, dried on anhydrous MgSO4, and concentrated to obtain a mixture of the starting material and the desired intermediate (approximately 1:1). To a solution of CH2Cl2(1.0 mL) containing the crude product, TFA(1.0 ​​mL) was added. This reaction mixture was stirred at room temperature for 2 hours and then concentrated. To a solution of EtOH(1.0 mL) and dioxane(0.5 mL) containing the residue, NaOH solution (H2O containing 2N, 1.0 mL) was added, and this reaction mixture was stirred at room temperature for 1 hour. Saturated NaHCO3 aqueous solution was added, and this mixture was extracted with CH2Cl2(3 × 10 mL) containing 10% MeOH, and then the combined organic layer was concentrated. The indicated compound was obtained as a pale yellow solid (19 mg, 15%, approximately 1:1 dr) by reverse-phase HPLC (H2O containing 10-70% ACN, 0.1% TFA) and lyophilization. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (p, J = 5.8 Hz, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.41 (t, J = 5.4 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.89 (dd, J = 8.2, 1.7 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.63 (dd, J = 7.7, 2.0 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 4.38 (dd, J = 5.4, 4.1 Hz, 2H), 3.39 (q, J = 5.0 Hz, 2H), 3.35 -3.25 (m, 4H), 3.02 -2.76 (m, 4H), 2.15 -2.04 (m, 2H), 1.99 -1.77 (m, 4H), 1.74 (d, J = 12.5 Hz, 1H), 1.67 (d, J = 12.8 Hz, 1H), 1.52 (s, 3H). ESI MS [M+H] + C 31 H 34 Calculated value for N5O2: 508.3, Measured value: 508.2. 【0235】 Example 23: 8-(5-{7-methyl-7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0236】 The indicated compound was prepared according to the same method as in Example 22. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (dd, J = 2.1, 0.8 Hz, 1H), 8.70 -8.53 (m, 2H), 8.38 (t, J = 5.4 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.86 (ddd, J = 8.2, 1.7, 0.5 Hz, 1H), 7.67 (s, 1H), 7.64 (d, J= 1.7 Hz, 1H), 7.60 (dd, J = 7.7, 2.0 Hz, 1H), 7.30 (dd, J = 8.0, 1.4 Hz, 1H), 4.34 (dd, J = 5.4, 4.1 Hz, 2H), 4.18 -4.01 (m, 1H), 3.36 (q, J = 5.1 Hz, 2H), 3.33 -3.21 (m, 2H), 3.01 -2.72 (m, 4H), 2.27 -2.11 (m, 1H), 2.10 -1.98 (m, 1H), 1.97 -1.55 (m, 6H), 1.51 (s, 3H), 1.25 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for N5O2: 522.3, Measured value: 522.2. 【0237】 Example 24: 8-(5-{7-methyl-7-[(2S)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0238】 The indicated compound was prepared according to the same method as in Example 22. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (dd, J = 2.1, 0.8 Hz, 1H), 8.69 -8.61 (m, 2H), 8.38 (t, J = 5.3 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 8.1, 1.4 Hz, 1H), 7.67 (s, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 7.8, 2.0 Hz, 1H), 7.30 (dd, J = 7.7, 1.4 Hz, 1H), 4.34 (dd, J = 5.4, ​​4.1Hz, 2H), 4.13 -4.06 (m, 1H), 3.39 -.22 (m, 4H), 2.97 -2.75 (m, 4H), 2.26 -2.10 (m, 1H), 2.10 -1.97 (m, 1H), 1.97 -1.78 (m, 3H), 1.77 -1.56 (m, 3H), 1.51 (s, 3H), 1.25 (d, J = 6.7 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for N5O2: 522.3, Measured value: 522.2. 【0239】 Example 25: 8-(5-{7-[(2R)-2-ethylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0240】 The indicated compound was prepared according to the same method as in Example 22. 1H NMR (400 MHz, chloroform-d) δ 11.90 (br. s, 1H), 8.88 (dd, J = 2.0, 0.9 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.85 -7.77 (m, 1H), 7.70 (td, J = 1.1, 0.5 Hz, 1H), 7.44 -7.38 (m, 2H), 7.30 -7.24 (m, 1H), 6.69 (t, J = 5.4 Hz, 1H), 4.58 -4.40 (m, 2H), 3.60 (q, J = 5.1 Hz, 2H), 3.03 -2.82 (m, 5H), 2.82 -2.73 (m, 1H), 2.73 -2.64 (m, 1H), 2.51 (q, J = 8.4 Hz, 1H), 2.25 -2.07 (m, 2H), 1.83 (dt, J = 11.8, 7.6 Hz, 1H), 1.80 -1.51 (m, 4H), 1.47 (td, J = 10.5, 9.0, 6.0 Hz, 1H), 1.43 -1.35 (m, 1H), 1.24 (dq, J = 15.4, 7.6 Hz, 1H), 0.91 (t, J = 7.4 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for N5O2: 522.3, Measured value: 522.2. 【0241】 Example 26: 7-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-4-methyl-3,4-dihydro-2H-1-benzopyran-4-ol [ka] 【0242】 Step a: A solution of THF (9.8 mL) containing 7-bromochromanone (1.00 g, 1.440 mmol) was added to a solution of THF (4.9 mL) containing methylmagnesium bromide (Et2O containing 3.0 M) (3.1 mL, 9.3 mmol) at room temperature over 40 minutes using a syringe pump. Immediately after the addition was complete, the mixture was stirred at room temperature for a further 1 hour. Then, the mixture was cooled with ice / saturated NH4Cl (水溶液) The mixture was poured into (50 mL). The product was extracted with alkyl hydroxide (3 × 50 mL), and the combined organic phase was washed with brine (50 mL) and dried (MgSO4). The material was used directly in the next step. 【0243】 Step b: The mixture of the product from step a (4.30 mmol), B2pin2 (1.09 g, 4.30 mmol), KOAc (0.844 g, 8.60 mmol), and dioxane (21.5 mL) was sparged with nitrogen for 10 minutes, then (dppf)PdCl2 (0.157 g, 0.215 mmol) was added, and sparging was continued for 5 minutes. This mixture was heated at 100°C for 2 hours, then cooled to room temperature and diluted with SiO2 (100 mL). This mixture was filtered through a Celite pad, the filtrate was concentrated, and the crude product was used in the next step. 【0244】 Step c: A 9:1 dioxane:H2O (29 mL) solution containing the product from Example 1 and Step e (1.33 g, 2.90 mmol), the product from Step b (3.23 mmol), and sodium carbonate (0.615 g, 5.80 mmol) was sparged with nitrogen for 10 minutes. (dppf)PdCl2 (0.424 g, 0.580 mmol) was added, and sparging was continued for a further 5 minutes. This mixture was stirred overnight at 100°C and then cooled to room temperature. CH2Cl2 (60 mL) was added, and the solution was dried over MgSO4, concentrated, and purified by flash chromatography (hexane containing SiO2, 0-50% siRNA) to obtain a beige solid (0.741 g; 52%). 【0245】 Step d: The desired substance was prepared (136 mg; 54%) using the same method as in step c. 【0246】 Step e: The mixture of the product from step d (63.8 mg, 0.102 mmol) and THF (1.0 mL) containing 1 M TBAF was heated overnight at 70°C. This mixture was concentrated and then saturated NaHCO3 3(水溶液) The solution was diluted with (5 mL). The product was extracted in CHCl3:IPA 9:1 (3 × 5 mL). The combined organic phases were dried with (Na2SO4) and concentrated. The residue was incorporated into MeOH (1.0 mL) and treated with DMEDA (0.08 mL, 0.77 mmol). The mixture was stirred at 45°C for 30 minutes and then concentrated. The residue was subjected to flash chromatography (10:1 of 1 to 10% MeOH / NH₃). 3(水溶液) When purified with CH2Cl2 (containing ), the labeled compound was obtained as an off-white solid (24.7 mg, 49%). 1 H NMR (400 MHz, DMSO-d6) δ 13.85 (br. s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 1.1 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 7.7, 2.0 Hz, 1H), 7.39 (t, J = 1.0 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 5.26 (s, 1H), 4.32 (ddd, J = 11.3, 7.7, 3.7 Hz, 1H), 4.24 (ddd, J = 10.9, 6.9, 3.7 Hz, 1H), 2.99 -2.97 (m, 2H), 2.94 -2.90 (m, 2H), 2.87 (p, J = 7.8 Hz, 1H), 2.72 -2.60 (m, 4H), 2.09 -1.94 (m, 2H), 1.87 -1.75 (m, 2H), 1.69 -1.56 (m, 2H), 1.55 -1.50 (m, 2H), 1.55 (s, 3H), 1.46 -1.33 (m, 2H). ESI MS [M+H]+ C 31 H 35 Calculated value for N4O2: 495.3, Measured value: 495.2. 【0247】 Example 27: 2-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-5-ol [ka] 【0248】 The indicated compound was prepared in the same manner as in Example 26. 1 H NMR (400 MHz, DMSO-d6) δ 13.81 (br. s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 8.2, 1.9 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 7.6, 2.0 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 5.04 (s, 1H), 3.10 (dd, J = 14.2, 7.0 Hz, 1H), 3.02 -2.90 (m, 5H), 2.87 (p, J = 8.0 Hz, 1H), 2.73 -2.58 (m, 4H), 2.00 -1.73 (m, 7H), 1.70 -1.56 (m, 2H), 1.55 -1.36 (m, 5H), 1.52 (s, 3H). ESI MS [M+H] + C 33 H 39 Calculated value for N4O: 507.3, Measured value: 507.2. 【0249】 Example 28: (8-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-methyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ol) [ka] 【0250】 The indicated compound was prepared in the same manner as in Example 26. 1 H NMR (400 MHz, chloroform-d) δ 11.49 (br. s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.1, 1.7 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.39 -7.37 (m, 1H), 7.26 -7.23 (m, 1H), 4.24 (ddd, J = 12.0, 6.0, 3.6 Hz, 1H), 3.96 (ddd, J = 11.7, 8.5, 2.9 Hz, 1H), 3.04 (ddd, J = 13.7, 5.7, 4.0 Hz, 4H), 2.90 (p, J = 8.0 Hz, 1H), 2.81 - 2.72 (m, 4H), 2.48 (s, 1H), 2.24 -1.96 (m, 4H), 1.95 -1.83 (m, 2H), 1.69 (s, 3H), 1.66 -1.41 (m, 6H). ESI MS [M+H] + C 32 H 37 Calculated value for N4O2: 509.3, Measured value: 509.2. 【0251】 Example 29: 4-methyl-7-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydro-2H-1-benzopyran-4-ol [ka] 【0252】 The indicated compound was prepared in the same manner as in Example 26. 1 H NMR (400 MHz, chloroform-d) δ 11.03 (br. s, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.60 (dd, J = 8.1, 1.7 Hz, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.43 -7.35 (m, 2H), 7.30 -7.22 (m, 1H), 4.42 -4.27 (m, 2H), 3.03 -2.82 (m, 6H), 2.82 -2.69 (m, 1H), 2.50 (q, J = 8.4 Hz, 2H), 2.23 -2.07 (m, 4H), 1.97 (s, 1H), 1.88 (ddt, J = 12.4, 9.0, 6.6 Hz, 1H), 1.71 (s, 3H), 1.66 -1.54 (m, 2H), 1.48 -1.32 (m, 2H), 1.11 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 32 H 37 Calculated value for N4O2: 509.3, Measured value: 509.2. 【0253】 Example 30: 1-Methyl-5-{5-[(7S)-7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3-dihydro-1H-inden-1-ol [ka] 【0254】 Step a: The desired product was prepared in the same manner as in Step a of Example 26 (2.01 g; 93%). 【0255】 Step b: The desired product was prepared in the same manner as in Step b of Example 26. 【0256】 Step c: The desired product was prepared in the same manner as in Example 26, Step c (107 mg; 23%). 【0257】 Step d: To a solution of the product from step c (107 mg, 0.310 mmol), triethylamine (0.09 mL, 0.62 mmol), DMAP (3.9 mg, 0.031 mmol), and CH2Cl2 (1.6 mL), anhydrous Boc (71.1 mg, 0.326 mmol) was added at room temperature. This mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The residue was purified by flash chromatography and hexane containing Â, 0-50%, to obtain the desired product (97 mg; 70%). 【0258】 Step e: To a mixture of (7S)-6,7,8,9-tetrahydro-7-(1-pyrrolidinyl)-5H-benzocyclohepten-2-amine (2.3 g, 10 mmol), AcOH (33.3 mL), and concentrated HBr (2.3 mL, 20 mmol), tBuNO2 (1.3 mL, 11 mmol) was added at room temperature. This mixture was stirred at room temperature for 30 minutes. CuBr (2.9 g, 20 mmol) dissolved in AcOH (20 mL) was added dropwise to this reaction mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with H2O (100 mL), followed by 28 wt% NH4. 3(水溶液)The solution was slowly added to adjust the pH to approximately 10 to 11. The crude product was then extracted with CH2Cl2 (2 × 100 mL). The combined organic phase was dried over Na2SO4, concentrated, and purified by column chromatography (SiO2, CH2Cl2 containing 0 to 100% CH2Cl2 / MeOH / 7N methanol NH3 (90:10:1)) to obtain the desired product as a light brown oily substance (2.2 g, 75%). 【0259】 Step f: The desired product was prepared in the same manner as in Example 26, Step b. 【0260】 Step g: The desired product was prepared (26 mg, 24%) in the same manner as in Example 26 and Step c. 1 H NMR (400 MHz, methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 7.87 -7.83 (m, 1H), 7.83 -7.81 (m, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 7.6, 2.0 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 3.11 (dt, J = 16.1, 6.7 Hz, 1H), 3.01 -2.76 (m, 6H), 2.73 (d, J = 6.5 Hz, 4H), 2.59 (t, J = 10.7 Hz, 1H), 2.34 -2.26 (m, 2H), 2.22 (t, J = 7.0 Hz, 2H), 1.81 (p, J = 3.1 Hz, 4H), 1.56 (s, 3H), 1.40 (p, J = 11.4 Hz, 2H). ESI MS [M+H] + C 31 H 35 Calculated value for N4O: 479.3, Measured value: 479.2. 【0261】 Example 31: 4-methyl-7-{5-[(7S)-7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-3,4-dihydro-2H-1-benzopyran-4-ol [ka] 【0262】 The indicated compound was prepared in the same manner as in Example 30. 1 H NMR (400 MHz, DMSO-d6) δ 13.85 (br. s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 1.1 Hz, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.7, 2.0 Hz, 1H), 7.40 (t, J = 1.1 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 5.26 (s, 1H), 4.32 (ddd, J = 11.3, 7.7, 3.6 Hz, 1H), 4.24 (ddd, J = 10.9, 6.8, 3.7 Hz, 1H), 3.20 -2.99 (m, 2H), 2.76 -2.59 (m, 2H), 2.60 -2.53 (m, 4H), 2.01 (qdt, J = 11.4, 7.6, 3.4 Hz, 2H), 1.95 -1.82 (m, 3H), 1.75 -1.69 (m, 4H), 1.66 -1.58 (m, 2H), 1.55 (s, 3H). ESI MS [M+H] + C 31 H 35 Calculated value for N4O2: 495.3, Measured value: 495.2. 【0263】 Example 32: 3,3-dimethyl-6-{5-[7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3-dihydro-1λ6 ,2-benzothiazole-1,1-dione [ka] 【0264】 Step a: Benzyl mercaptan (2.35 mL, 20.0 mmol) was added dropwise to a mixture of THF (40 mL) containing NaH (800 g, 20.0 mmol, 60 wt%) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and 4-bromo-2-fluoromethylbenzoic acid (4.66 g, 20.0 mmol) was added all at once at room temperature. The mixture was stirred at room temperature for 16 hours, concentrated on silica gel, and purified by column chromatography (120 g silica gel, hexane: siRNA) with a 0% to 25% gradient (25 minutes) to obtain the desired product as a white solid (5.86 g; 87%). 【0265】 Step b: To the product from step a (5.86 g, 17.4 mmol) and a mixture of 19:1 AcOH:water (87 mL), NCS (6.96 g, 52.1 mmol) was added all at once at room temperature. This reaction mixture was stirred at room temperature for 1 hour, concentrated, diluted with SiO2 (125 mL), and diluted with 1:1 saturated NHCO3. 3(水溶液) The mixture was washed with water (2 × 100 mL), dried on Na₂SO₄, and concentrated to obtain the desired product, which was then used directly in the next step. 【0266】 Step c: To a mixture of the product from step b (estimated 17.4 mmol), Et3N (12.1 mL, 87.0 mmol), and CH2Cl2 (87 mL), t-BuNH2 (5.49 mL, 52.2 mmol) was added at room temperature. This reaction mixture was stirred at room temperature for 3 hours, concentrated on silica gel, and purified by column chromatography (120 g silica gel, hexane:SiO) with a 0% to 50% gradient (20 minutes) to obtain the desired product as a white solid (5.39 g; 89%; 2 steps). 【0267】 Step d: To a mixture of THF (71 mL) containing the product from step c (4.96 g, 14.2 mmol), MeMgBr (18.9 mL, 56.6 mmol, Et2O containing 3 M) was added dropwise at 0°C. This reaction mixture was stirred at 0°C for 45 minutes, then stirred at room temperature for 14 hours, and saturated with NH4Cl (水溶液) The reaction was stopped, diluted with SiO(142 mL), dried over Na2SO4, and concentrated to obtain the desired product, which was used directly in the next step. 【0268】 Step e: To the mixture of the product from step d (estimated value of 14.2 mmol), NaI (4.09 g, 27.3 mmol), and ACN (68 mL), chlorotrimethylsilane (3.47 mL, 27.3 mmol) was added at room temperature. This reaction mixture was stirred at 67 °C for 2 hours, cooled to room temperature, and then mixed with 10% by weight of HaHSO₄. 3(水溶液) The reaction was stopped at (142 mL) and diluted with SiO (284 mL). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (40 g silica gel, hexane:SiO) with a 0% to 100% gradient (25 minutes) to obtain the desired product as a white solid (2.11 g; 54%; 2 steps). 【0269】 Step f: The desired product was prepared in the same manner as in Example 1 and Step d. 【0270】 Step g: To a mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (19.8 g, 100 mmol), camphor sulfonic acid (2.32 g, 10 mmol), and THF (250 mL), 3,4-dihydro-2H-pyran (18.3 mL, 200 mmol) was added at room temperature. This reaction mixture was stirred at 65 °C for 4 hours, cooled to room temperature, and 28% by weight of NH4 was added. 3(水溶液)The reaction was stopped at (10 mL). This mixture was concentrated on silica gel and purified by column chromatography (330 g silica gel, hexane:ethyl HCl) with a gradient from 0% to 50% (20 minutes) to obtain the desired product as a red oil (26.7 g, 95%). 【0271】 Step h: A mixture of 2-bromo-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-one (17.9 g, 75.0 mmol), B2pin2 (19.1 g, 75.0 mmol), (dppf)PdCl2 (2.74 g, 3.75 mmol), and KOAc (14.7 g, 150 mmol) was placed under nitrogen. Degassed dioxane (224 mL) was added, and the reaction mixture was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature and concentrated. MTBE (375 mL) was added, and the mixture was filtered through Celite, washed with MTBE, and concentrated to obtain the desired product, which was used directly in the next step. 【0272】 Step i: The mixture of the product from step g (21.2 g, 75 mmol), the product from step h (estimated value of 75.0 mmol), and (dppf)PdCl2 (5.49 g, 7.50 mmol) was placed under nitrogen, and degassed dioxane (375 mL) and degassed 2 M Na2CO2 were added. 3(水溶液) (75 mL) was added, and the reaction mixture was stirred at 95°C for 14 hours (or until complete). The mixture was cooled to room temperature, concentrated to almost dryness, dissolved in ethyl HCl (375 mL), dried over Na2SO4, and concentrated again. MeOH (400 mL) containing 3 M HCl was added, and the reaction mixture was stirred at room temperature for 2 hours and diluted with MTBE (4.00 L). The precipitated solid was collected by filtration, washed with MTBE, and dried under vacuum to obtain the desired product as a brown solid (19.4 g, 82%; 2 steps). 【0273】 Step j: The mixture of the product from step i (19.4 g, 61.8 mmol) and ethylene glycol (17.2 mL, 309 mmol) is stirred at 70°C for 24 hours to obtain 28% by weight of NH4.3(水溶液) The reaction was stopped at (20 mL) and the mixture was concentrated. HCl (500 mL) and water (250 mL) were added, the solid was filtered and recovered, and washed with HCl / water. The organic phase was washed with water (2 × 250 mL), dried on Na₂SO₄, concentrated, and combined with the previously recovered solid. The crude product was purified by column chromatography (330 g silica gel, CH₂Cl₂:MeOH) with a gradient from 0% to 3% (20 minutes) and then from 3% to 5% (10 minutes) to obtain the desired product as an orange solid (14.8 g, 75%). 【0274】 Step k: To a mixture of Step j (14.8 g, 46.1 mmol) and 2:1 CH2Cl2:AcOH (138 mL), NBS (8.62 g, 48.5 mmol) was added at room temperature. This reaction mixture was stirred at room temperature for 14 hours, concentrated on silica gel, and purified by column chromatography (330 g silica gel, CH2Cl2:MeOH) with a gradient from 0% to 5% (15 minutes) and then from 5% to 7.5% (5 minutes) to obtain the desired product as a brown solid (21.4 g, 74.5 wt%; residual succinimide). The pure product yielded 15.9 g (86% yield). 【0275】 Step l: To a mixture of the product from step k (21.4 g, 39.7 mmol, 74.5 wt%), DMAP (486 mg, 3.97 mmol), Et3N (26.4 mL, 189 mmol), and CH2Cl2 (199 mL), di-tert-butyl dicarbonate (21.7 g, 99.4 mmol) was added all at once at room temperature. This reaction mixture was stirred at room temperature for 1 hour, concentrated on silica gel, and purified by column chromatography (330 g silica gel, hexane:SiO2) with a gradient from 0% to 50% (25 minutes) to obtain the desired product as a white solid (18.2 g, 77.4 wt%); the remainder being N-Boc-succinimide). The pure product yielded 14.1 g (71% yield). 【0276】 Step m: The desired product was prepared (110 mg; 53%) in the same manner as in Example 7 and Step c. 【0277】 Step n: The mixture of the product from step m (110 mg, 0.213 mmol), HCl (426 μL, 0.426 mmol, 1 M water), and THF (1.1 mL) was stirred at 70°C for 1 hour. This mixture was cooled to room temperature and saturated with NaHCO₃⁻. 3(水溶液) The mixture was neutralized, washed with brine (1.1 mL), concentrated, diluted with CH2Cl2 (10 mL), dried over Na2SO4, and concentrated again. Pyrrolidine (21 μL, 0.26 mmol), AcOH (12 μL, 0.21 mmol), and DCE (1.1 mL) were added, followed by NaBH(OAc)3 (67 mg, 0.32 mmol). The reaction mixture was stirred at room temperature for 4 hours and then mixed with 1:1 saturated NaHCO3. 3(水溶液) The reaction was stopped with water (8.0 mL), and extracted with 4:1 CH2Cl2:IPA (1 × 25 mL). This organic phase was dried over Na2SO4 and concentrated. The crude product was purified by HPLC ((H2O / ACN) + 0.1% TFA) 5% to 95% gradient (30 minutes) to obtain the desired product as a pale yellow solid (106 mg; 79%). 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.44 (dd, J = 8.2, 1.6 Hz, 1H), 8.32 (dd, J = 1.6, 0.6 Hz, 1H), 8.04 (s, 1H), 7.85 (dd, J = 8.2, 0.6 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 7.7, 2.0 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 3.19 -2.96 (m, 2H), 2.76 -2.61 (m, 2H), 2.61 -2.43 (m, 5H), 2.03 -1.80 (m, 2H), 1.80 -1.66 (m, 4H), 1.60 (s, 8H). ESI MS [M+H] + C 30 H 34Calculated value for N5O2S: 528.2, Measured value: 528.3. 【0278】 Example 33: 3,3-dimethyl-6-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3-dihydro-1λ 6 ,2-benzothiazole-1,1-dione [ka] 【0279】 The indicated compound was prepared in the same manner as in Example 32. 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (dd, J = 2.0, 0.8 Hz, 1H), 8.71 (d, J = 0.6 Hz, 1H), 8.44 (ddd, J = 8.2, 1.6, 0.6 Hz, 1H), 8.32 (dt, J = 1.5, 0.7 Hz, 1H), 8.04 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 2.6 Hz, 1H), 7.56 (dd, J = 7.7, 2.0 Hz, 1H), 7.27 (dd, J = 7.7, 1.3 Hz, 1H), 3.01 -2.77 (m, 5H), 2.77 -2.65 (m, 2H), 2.44 (q, J = 8.2 Hz, 1H), 2.06 -1.95 (m, 2H), 1.87 -1.77 (m, 1H), 1.67 -1.50 (m, 8H), 1.44 (t, J = 12.3 Hz, 1H), 1.34 -1.21 (m, 2H), 1.02 (d, J = 6.0 Hz, 3H).ESI MS [M+H] + C 31 H 36 Calculated value for N5O2S: 542.3, Measured value: 542.2. 【0280】 Example 34: 6-(5-{7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,3-dimethyl-2,3-dihydro-1λ 6 ,2-benzothiazole-1,1-dione [ka] 【0281】 The indicated compound was prepared in the same manner as in Example 32. 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 1.9 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.44 (dd, J = 8.1, 1.6 Hz, 1H), 8.32 (dt, J = 1.5, 0.7 Hz, 1H), 8.04 (s, 1H), 7.85 (dd, J = 8.1, 0.7 Hz, 1H), 7.64 -7.60 (m, 1H), 7.56 (dd, J = 7.7, 2.0 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 3.38 -3.34 (m, 1H), 3.16 -3.09 (m, 1H), 2.99 -2.81 (m, 4H), 2.80 -2.65 (m, 3H), 2.54 -2.51 (m, 1H), 2.12 -2.02 (m, 2H), 1.72 -1.53 ​​(m, 10H), 1.46 -1.25 (m, 2H).ESI MS [M+H] + C 31 H 36 Calculated value for N5O3S: 558.3, Measured value: 558.2. 【0282】 Example 35: 3,3-dimethyl-8-{5-[7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0283】 Step a: To a mixture of 4-bromo-2-fluorobenzonitrile (2.00 g, 10.0 mmol), 2-amino-2-methyl-1-propanol (954 μL, 10.0 mmol), and THF (20 mL), NaH (400 g, 10.0 mmol, 60 wt% oil) was added all at once at 0°C. This reaction mixture was stirred at 0°C for 1 hour, then stirred at room temperature for 14 hours, concentrated on silica gel, and purified by column chromatography (80 g silica gel, CH2Cl2:MeOH) with a 0% to 20% gradient (30 minutes) to obtain the desired product as a yellow solid (1.82 g; 68%). 【0284】 Step b: The mixture of the product from step a (1.82 g, 6.76 mmol), NaOH (848 mg, 21.2 mmol), and 4:1 EtOH:water (14 mL) was stirred at 90°C for 14 hours, cooled to room temperature, and concentrated to remove the EtOH. 2 M HCl was added to the resulting mixture. (水溶液) (Approximately 2.5 equivalents) was added to adjust the pH to approximately 4. The formed solid was filtered and collected, washed with water, and dried to obtain the desired product as a light brown solid (1.93 g; 99%). 【0285】 Step c: To a mixture of the product from step b (1.93 g, 6.70 mmol), HOBt hydrate (1.13 g, 7.37 mmol), Et3N (3.73 mL, 26.8 mmol), and DMF (33 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.93 g, 10.1 mmol) was added all at once at room temperature. This reaction mixture was stirred at 40 °C for 3 days, diluted with SiO2 (125 mL), washed with 9:1 water:brine (4 × 100 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (40 g silica gel, hexane:SiO2) from 0% to 100% gradient (25 minutes) to obtain the desired product as a yellow solid (1.24 g; 69%). 【0286】 Step d: The desired product was prepared in the same manner as in Example 1 and Step d. 【0287】 Step e: The desired product was prepared (103 mg; 50%) in the same manner as in Example 7 and Step c. 【0288】 Step f: The desired product was prepared (37 mg; 37%) in the same manner as in Example 32 and Step n. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 7.86 (dd, J = 8.5, 1.8 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 7.6, 2.0 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 4.18 (s, 2H), 3.18 -2.98 (m, 2H), 2.77 -2.61 (m, 2H), 2.61 -2.45 (m, 5H), 2.01 -1.79 (m, 2H), 1.79 -1.65 (m, 4H), 1.65 -1.49 (m, 2H), 1.27 (s, 6H). ESI MS [M+H] + C 32 H 36 Calculated value for N5O2: 522.3, Measured value: 522.3. 【0289】 Example 36: 8-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-4,5-dihydro-2H-spiro[1,4-benzoxazepine-3,1'-cyclopropane]-5-one [ka] 【0290】 The indicated compound was prepared in the same manner as in Example 35. 1H NMR (400 MHz, DMSO-d6) δ 14.04 (s, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 8.2, 1.5, 0.6 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.62 (t, J = 2.3 Hz, 1H), 7.55 (dd, J = 7.7, 2.0 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 4.27 (s, 2H), 3.01 -2.76 (m, 5H), 2.76 -2.67 (m, 2H), 2.44 (q, J = 8.3 Hz, 1H), 2.06 -1.94 (m, 2H), 1.88 -1.76 (m, 1H), 1.68 -1.49 (m, 2H), 1.49 -1.37 (m, 1H), 1.35 -1.20 (m, 2H), 1.02 (d, J = 5.9 Hz, 3H), 0.79 (d, J = 7.1 Hz, 4H). ESI MS [M+H] + C 33 H 36 Calculated value for N5O2: 534.3, Measured value: 534.3. 【0291】 Example 37: 8-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-4,5-dihydro-2H-spiro[1,4-benzoxazepine-3,1'-cyclobutan]-5-one [ka] 【0292】 The indicated compound was prepared in the same manner as in Example 35. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.85 (ddd, J = 8.4, 1.8, 0.5 Hz, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.62 (t, J = 2.3 Hz, 1H), 7.55 (dd, J = 7.7, 2.0 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 4.40 (s, 2H), 3.02 -2.77 (m, 5H), 2.77 -2.65 (m, 2H), 2.44 (q, J = 8.2 Hz, 1H), 2.25 -2.14 (m, 2H), 2.13 -2.05 (m, 2H), 2.05 -1.95 (m, 2H), 1.87 -1.73 (m, 3H), 1.68 -1.49 (m, 2H), 1.49 -1.39 (m, 1H), 1.34 -1.21 (m, 2H), 1.03 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 34 H 38 Calculated value for N5O2: 548.3, Measured value: 548.3. 【0293】 Example 38: 3,3-dimethyl-6-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3-dihydro-1H-isoindole-1-one [ka] 【0294】 The indicated compound was prepared in the same manner as in Example 35. 1H NMR (400 MHz, DMSO-d6) δ 13.96 (s, 1H), 8.86 (d, J = 1.5 Hz, 1H), 8.78 (s, 1H), 8.63 (dd, J = 2.1, 1.0 Hz, 1H), 8.33 (dd, J = 7.9, 1.6 Hz, 1H), 8.18 (dd, J = 1.6, 0.7 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 2.4 Hz, 1H), 7.54 (dd, J = 7.7, 2.0 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 3.02 -2.76 (m, 5H), 2.76 2.63 (m, 2H), 2.44 (q, J = 8.2 Hz, 1H), 2.07 -1.93 (m, 2H), 1.88 -1.76 (m, 1H), 1.69 -1.37 (m, 9H), 1.35 -1.19 (m, 2H), 1.02 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for N5O: 506.3, Measured value: 506.3. 【0295】 Example 39: 3,3-dimethyl-8-(5-{2-[(2S)-2-methylpyrrolidine-1-yl]-2,3-dihydro-1H-inden-5-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0296】 The indicated compound was prepared in the same manner as in Example 35. 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.65 (dd, J = 2.2, 0.6 Hz, 1H), 8.32 (dt, J = 8.5, 0.5 Hz, 1H), 8.21 (s, 1H), 7.82 (ddd, J = 8.5, 1.8, 0.6 Hz, 1H), 7.77 -7.72 (m, 1H), 7.71 -7.64 (m, 2H), 7.40 (dd, J = 7.9, 5.9 Hz, 1H), 4.30 (dt, J = 11.6, 7.9Hz, 1H), 3.93 -3.25 (m, 6H), 3.18 (td, J = 14.9, 6.2 Hz, 3H), 2.23 (dq, J = 14.1, 7.3 Hz, 1H), 1.94 (ddq, J = 28.1, 13.9, 7.2, 6.7 Hz, 2H), 1.64 (dq, J = 14.1, 7.3 Hz, 1H), 1.39 (d, J = 6.6 Hz, 3H), 1.23 (s, 6H). ESI MS [M+H] + C 31 H 34 Calculated value for N5O2: 508.3, Measured value: 508.2. 【0297】 Example 40: 7-methyl-8-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0298】 The indicated compound was prepared in the same manner as in Example 35. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.1 Hz, 1H), 8.39 (t, J = 5.4 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.54 (s, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.25 -7.19 (m, 2H), 4.32 (dd, J = 5.3, 4.2 Hz, 2H), 3.41 -3.35 (m, 2H), 2.97 -2.75 (m, 4H), 2.75 -2.63 (m, 2H), 2.42 (d, J = 8.5 Hz, 1H), 2.39 (d, J = 0.7 Hz, 3H), 2.34 -2.31 (m, 1H), 2.03 -1.91 (m, 2H), 1.88 -1.74 (m, 1H), 1.68 -1.49 (m, 2H), 1.46 -1.35 (m, 1H), 1.33 -1.18 (m, 2H), 1.01 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for N5O2: 522.3, Measured value: 522.3. 【0299】 Example 41: 9-methyl-8-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0300】 The indicated compound was prepared in the same manner as in Example 35. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 2.1 Hz, 1H), 8.37 (t, J = 5.5 Hz, 1H), 8.23 ​​(d, J = 2.1 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.47 (dd, J = 7.7, 2.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 4.33 (d, J = 5.3 Hz, 2H), 3.55 -3.23 (m, 2H), 2.96 -2.62 (m, 7H), 2.42 (q, J = 8.3 Hz, 1H), 2.33 (s, 3H), 2.03 -1.93 (d, J = 13.1 Hz, 2H), 1.86 -1.74 (m, 1H), 1.68 -1.50 (m, 2H), 1.46 -1.36 (m, 1H), 1.32 -1.20 (m, 2H), 1.01 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for N5O2: 522.3, Measured value: 522.3. 【0301】 Example 42: 8-{5-[7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0302】 Step a: To a solution of CH2Cl2 (2.8 mL) containing the product from Step b of Example 22 (635 mg, 1.12 mmol), TFA (2.8 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. To a suspension of EtOH (5.6 mL) containing the residue, NaOH solution (H2O containing 2N, 5.6 mL) was added. Dioxane (10 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2 (3 × 15 mL) containing 10% MeOH. The combined organic layer was then concentrated to obtain the product as a yellow solid (230 mg; 47%). 【0303】 Step b: To a mixture of the product from step a (58 mg, 0.132 mmol) and cyclopentylamine (14 μL, 0.139 mmol) in 1,2-dichloroethane (1.4 mL), AcOH (7 μL, 0.132 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, then NaBH(OAc)3 (63 mg, 0.296 mmol) was added. This reaction mixture was stirred at room temperature for 15 hours, then the reaction was carefully stopped with H2O, followed by saturated NaHCO3. This mixture was extracted with CH2Cl2 (3 × 10 mL) containing 10% MeOH, and the combined organic layer was concentrated. Purification by reverse-phase HPLC (H2O containing 10-70% ACN, 0.1% TFA) and lyophilization yielded the marked compound as a white solid (16 mg, 19%). 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 8.2Hz, 1H), 7.86 (dd, J= 8.2, 1.7 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 7.7, 2.0 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 4.46 (dd, J = 5.1, 4.4 Hz, 2H), 3.80 (p, J = 7.4Hz, 1H), 3.56 -3.46 (m, 3H), 3.11 -3.04 (m, 1H), 3.04 -2.93 (m, 3H), 2.53 -2.40 (m, 2H), 2.25 -2.08 (m, 2H), 1.92 -1.78 (m, 2H), 1.78 -1.56 (m, 4H), 1.56 -1.38 (m, 2H). ESI MS [M+H] + C 31 H 34 Calculated value for N5O2: 508.3, Measured value: 508.2. 【0304】 Example 43: 8-(5-{7-[(2S)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0305】 The indicated compound was prepared in the same manner as in Example 42. 1H NMR (400 MHz, methanol-d4) δ 8.73 (dd, J = 2.1, 1.0 Hz, 1H), 8.49 (dd, J = 2.1, 1.1 Hz, 1H), 7.97 (dd, J = 8.2, 0.4 Hz, 1H), 7.77 (dd, J = 8.2, 1.7 Hz, 1H), 7.63 (dd, J = 1.6, 0.4 Hz, 1H), 7.48 (t, J= 2.2 Hz, 1H), 7.44 (ddd, J = 7.7, 2.1, 0.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 4.49 -4.37 (m, 2H), 3.85 -3.63 (m, 2H), 3.54 -3.48 (m, 2H), 3.48 -3.38 (m, 1H), 3.30 -3.18 (m, 1H), 3.11 -2.82 (m, 4H), 2.43 -2.33 (m, 2H), 2.29 (dq, J = ESI MS [M+H] + C 31 H 34 Calculated value for N5O2: 508.3, Measured value: 508.2. 【0306】 Example 44: 8-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0307】 The indicated compound was prepared in the same manner as in Example 42. 1H NMR (400 MHz, methanol-d4) δ 8.73 (dd, J = 2.1, 1.0 Hz, 1H), 8.49 (dd, J = 2.1, 1.1 Hz, 1H), 7.97 (dd, J = 8.2, 0.3 Hz, 1H), 7.77 (dd, J = 8.2, 1.7 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.48 (t, J = 2.2Hz, 1H), 7.44 (dd, J = 7.7, 1.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 4.44 (dd, J = 5.5, 4.1 Hz, 2H), 3.85 -3.63 (m, 2H), 3.52 -3.48 (m, 2H), 3.48 -3.40 (m, 1H), 3.28 -3.19 (m, 1H), 3.09 -2.85 (m, 4H), 2.43 -2.33 (m, 2H), 2.29 (dq, J = 13.6, ESI MS [M+H] + C 31 H 34 Calculated value for N5O2: 508.3, Measured value: 508.2. 【0308】 Example 45: 8-[5-(7-{[(3S)-oxolan-3-yl]amino}-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0309】 The indicated compound was prepared in the same manner as in Example 42. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.64 -8.46 (m, 2H), 8.41 (t, J = 5.4 Hz, 1H), 7.96 (dd, J = 8.2, 0.4 Hz, 1H), 7.90 (dd, J = 8.2, 1.7 Hz, 1H), 7.71 -7.66 (m, 2H), 7.63 (dd, J = 7.7, 1.9 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 4.38 (dd, J = 5.4, 4.1Hz, 2H), 4.16 -4.00 (m, 1H), 3.95 (td, J = 8.3, 5.4 Hz, 1H), 3.85 (d, J = 4.9 Hz, 2H), 3.71 -3.64 (m, 1H), 3.58 -3.43 (m, 1H), 3.39 (q, J = 5.0 Hz, ESI MS [M+H] + C 30 H 32 Calculated value for N5O3: 510.2, Measured value: 510.2. 【0310】 Example 46: 8-[5-(7-{[(3R)-oxolan-3-yl]amino}-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0311】 The indicated compound was prepared in the same manner as in Example 42. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.65 -8.49 (m, 2H), 8.41 (t, J = 5.4 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 8.2, 1.7 Hz, 1H), 7.68 (d, J = 1.5 Hz, 2H), 7.63 (dd, J = 7.8, 2.0 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 4.38 (dd, J = 5.3, 4.1Hz, 2H), 4.15 -4.03 (m, 1H), 3.95 (td, J = 8.4, 5.3 Hz, 1H), 3.85 (d, J = 5.0 Hz, 2H), 3.68 (ddd, J = 8.7, 7.8, 7.1 Hz, 1H), 3.55 -3.43 (m, 1H), 3.39 (q, J = 5.0 Hz, 2H), 3.04 -2.82 (m, 4H), 2.42 -2.24 (m, 3H), 2.03 -1.91 (m, 1H), 1.36 (p, J = 12.1 Hz, 2H). ESI MS [M+H] + C 30 H 32 Calculated value for N5O3: 510.2, Measured value: 510.2. 【0312】 Example 47: 8-{5-[7-(morpholine-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0313】 The indicated compound was prepared in the same manner as in Example 42. 1H NMR (400 MHz, methanol-d4) δ 8.78 (d, J = 2.0 Hz, 1H), 8.56 (dd, J = 2.1, 0.9 Hz, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.82 (ddd, J = 8.2, 1.7, 0.6 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.53 (s, 1H), 7.49 (dd, J = 7.7, 1.8 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 4.45 (dd, J = 5.6, 4.4 Hz, 2H), 4.13 -4.03 (m, 2H), 3.81 (ddd, J = 13.4, 10.0, 3.9 Hz, 2H), 3.61 (tt, J = 15.2, 4.0 Hz, 1H), 3.51 (dd, J = 5.4, 4.2Hz, 2H), 3.36 -3.34 (m, 4H), 3.15 -2.83 (m, 4H), 2.45 (t, J = 10.1 Hz, 2H), 1.64 (p, J = 12.0 Hz, 2H). ESI MS [M+H] + C 30 H 32 Calculated value for N5O3: 510.2, Measured value: 510.2. 【0314】 Example 48: 8-{5-[7-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0315】 The indicated compound was prepared in the same manner as in Example 42. 1H NMR (400 MHz, methanol-d4) δ 8.78 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 8.2Hz, 1H), 7.82 (dd, J = 8.2, 1.7 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 7.7, 2.0 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 4.46 (dd, J = 5.3, 4.2 Hz, 2H), 3.73 (tt, J = 11.9, 2.5 Hz, ESI MS [M+H] + C 30 H 33 Calculated value for N6O2: 509.3, Measured value: 509.2. 【0316】 Example 49: 8-(5-{7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0317】 The indicated compound was prepared in the same manner as in Example 42. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 2.0 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.36 (t, J = 5.4 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 8.2, 1.6 Hz, 1H), 7.65 (dd, J = 1.7, 0.5 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7.6, 2.0 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 4.34 (dd, J = 5.4, 4.1 Hz, ESI MS [M+H] + C 31 H 34 Calculated value for N5O3: 524.3, Measured value: 524.2. 【0318】 Example 50: 8-(5-{7-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0319】 The indicated compound was prepared in the same manner as in Example 42. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 2.1 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.37 (t, J = 5.4 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 8.2, 1.7 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 7.7, 2.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.34 (dd, J = 5.4, 4.1 Hz, 2H), 3.40 -3.34 (m, 4H), 3.10 (dd, J = 10.5, 7.7 Hz, 1H), 2.97 -2.58 (m, 8H), 2.03 (s, 2H), 1.68 -1.14 (m, 7H). ESI MS [M+H] + C 31 H 34 Calculated value for N5O3: 524.3, Measured value: 524.2. 【0320】 Example 51: 8-(5-(7-((R)-3-hydroxypyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0321】 The indicated compound was prepared in the same manner as in Example 42. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 2.1 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.37 (t, J = 5.4 Hz, 1H), 7.95 -7.82 (m, 2H), 7.65 (dd, J = 1.7, 0.5 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.34 (dd, J = 5.4, 4.1 Hz, 2H), 4.19 (s, 1H), 3.35 (d, J = 4.6 Hz, 2H), 3.02 (s, 4H), 2.86 (s, 1H), 2.69 (s, 4H), 1.96 (d, J = 13.4 Hz, 2H), 1.53 (s, 4H). ESI MS [M+H] + C 30 H 32 Calculated value for N5O3: 510.2, Measured value: 510.2. 【0322】 Example 52: 8-(5-(7-(azetidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0323】 The indicated compound was prepared in the same manner as in Example 42. 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.37 (t, J = 5.4 Hz, 1H), 7.96 -7.82 (m, 2H), 7.67 -7.55 (m, 3H), 7.28 (d, J = 7.8 Hz, 1H), 4.34 (dd, J = 5.4, 4.1 Hz, 2H), 4.17 (p, J = 9.5 Hz, 2H), 4.01 (d, J = 9.6 Hz, 2H), 3.46 -3.31 (m, 4H), 2.97 (dd, J = ESI MS [M+H] + C 29 H 30 Calculated value for N5O2: 480.2, Measured value: 480.2. 【0324】 Example 53: 8-(5-(2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0325】 Step a: Boc2O (176 mg, 0.76 mmol) was added to a mixture of 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (200 mg, 0.76 mmol), Et3N (0.3 mL, 0.22 mmol), DMAP (10 mg, 0.8 mmol), and CH2Cl2 (5 mL), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered to remove all insoluble matter, concentrated, and purified by column chromatography (SiO2, hexane containing 0-90% siRNA) to obtain the desired product as a white solid (219 mg; 88%). 【0326】 Step b: The desired product was prepared in the same manner as in Step b of Example 20. 【0327】 Step c: The desired product was prepared in the same manner as in Example 20, Step c (351 mg; quantitative value). 【0328】 Step d: The desired product was prepared (45 mg; 59%) in the same manner as in Example 20, Step d. 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.1 Hz, 2H), 8.65 (d, J = 2.1 Hz, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.93 (dd, J = 8.2, 0.4 Hz, 1H), 7.85 (dd, J = 8.2, 1.7 Hz, 1H), 7.74 -7.61 (m, 3H), 7.34 (d, J = 7.8 Hz, 1H), 4.34 (dd, J = 5.4, 4.1 Hz, 2H), 3.36 (q, J = 5.0 Hz, 2H), 3.29 -3.05 (m, 8H). ESI MS [M+H] + C 25 H 24 Calculated value for N5O2: 426.2, Measured value: 426.2. 【0329】 Example 54: 8-(5-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0330】 The indicated compound was prepared in the same manner as in Example 53. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.93 (dd, J = 8.2, 0.4 Hz, 1H), 7.86 (dd, J = 8.2, 1.7 Hz, 1H), 7.73 (d, J = 7.1 Hz, 2H), 7.65 (dd, J = 1.6, 0.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.43 -4.27 (m, 4H), 3.40 -3.29 (m, 4H), 3.08 (t, J = 6.3 Hz, 2H). ESI MS [M+H] + C 24 H 22 Calculated value for N5O2: 412.2, Measured value: 412.2. 【0331】 Example 55: 8-(5-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one [ka] 【0332】 The indicated compound was prepared in the same manner as in Example 53. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.93 (dd, J = 8.2, 0.4 Hz, 1H), 7.85 (dd, J = 8.2, 1.7 Hz, 1H), 7.80 -7.70 (m, 2H), 7.65 (dd, J = 1.7, 0.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 4.38 -4.31 (m, 4H), 3.37 (tt, J = 13.6, 7.5 Hz, 4H), 3.03 (t, J = 6.2 Hz, 2H). ESI MS [M+H] + C 24 H 22 Calculated value for N5O2: 412.2, Measured value: 412.2. 【0333】 Example 56: 8-{5-[(7R)-7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one 【0334】 Example 57: 8-{5-[(7S)-7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0335】 Step a: The racemic material from Example 1 was separated using a semi-preparative chiral AD-H column (20 × 250 mm; hexane containing 30% EtOH + 0.1% Et2NH). Optical isomer 1 (analytical retention time = 18.7 mins): white powder, 8 mg, >98:2 er was conveniently designated as Example 56. Subsequently, optical isomer 2 (analytical retention time = 24.5 mins): white powder, 12 mg, 88:12 er was designated as Example 57. 【0336】 Example 58: 8-(5-{3-fluoro-7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0337】 Step a: Mixture of 1-bromo-2-fluoro-4,5-dimethylbenzene (1.03 g, 5.07 mmol), KMnO4 (3.21 g, 20.3 mmol), and water (41 mL) is stirred at 100°C for 14 hours, and 10% by weight of NaHSO4 is added. 3(水溶液) Stop the reaction with (20 mL) and 2M NaOH (水溶液) The pH was then adjusted to approximately 12. Solid matter was filtered out and the mixture was washed with water. The filtrate was treated with 4M HCl. (水溶液) The pH was acidified to approximately 2, and the mixture was extracted with 4:1 CH2Cl2 / IPA (1 × 250 mL). After drying on Na2SO4 and concentrating, the desired product was obtained as a white solid (418 mg, 31%). 【0338】 Step b: To a mixture of the product from step a (418 g, 1.59 mmol) and THF (7.9 mL), boranedimethyl sulfide (452 ​​μL, 4.77 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then heated and stirred at 55°C for 14 hours. The mixture was cooled to room temperature and mixed with 2 M NaOH.(水溶液) (7.2 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. 12M HCl (水溶液) (0.10 mL) was added dropwise, the resulting organic phase was concentrated, and diluted with SiO(10 mL). The resulting aqueous phase was extracted with SiO(1 × 10 mL), and the combined organic phase was washed with 1:5 water:brine(10 mL), dried on Na2SO4, and concentrated to obtain the desired product, which was used directly in the next step. 【0339】 Step c: The product from step b and a mixture of HBr (1.6 mL, containing 48 wt% H2O) were stirred at 90°C for 2 hours. The mixture was cooled to room temperature, extracted with CH2Cl2 (3 × 10 mL), dried over Na2SO4, and concentrated to obtain the desired product as a brown oily substance (534 mg; 93%; 2 steps). 【0340】 Step d: The mixture of the product from step c (534 mg, 1.48 mmol), dimethyl-1,3-acetone dicarboxylate (309 mg, 1.78 mmol), tetrabutylammonium bromide (239 mg, 0.740 mmol), NaHCO3 (622 mg, 7.40 mmol), CH2Cl2 (3.0 mL), and water (7.4 mL) was vigorously stirred at 40°C for 3 days. The organic phase was separated, concentrated, diluted with SiO2 (10 mL), washed with 9:1 water:brine (4 × 10 mL), dried over Na2SO4, and concentrated. The residue was dissolved in EtOH (11 mL) and 2M NaOH (水溶液) (7.4 mL) was added. The reaction mixture was stirred at 90°C for 2 hours. The mixture was cooled to room temperature and 12M HCl was added. (水溶液) The pH was adjusted to approximately 7 by adding [the appropriate compound]. EtOH was removed under reduced pressure, and the resulting aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The organic phase was dried over Na2SO4 and concentrated. This crude product was purified by column chromatography (24 g silica gel, hexane: SiO2) with a gradient from 0% to 20% (20 minutes); then from 20% to 35% (10 minutes), yielding the desired product as an orange oily substance (141 mg; 37%). 【0341】 Step e: The desired product was prepared in the same manner as in Example 1 and Step d. 【0342】 Step f: The desired product was prepared (26.8 g; 85%) in the same manner as in Example 1 and Step g. 【0343】 Step g: The desired product was prepared (341 mg; 77%) in the same manner as in Example 7 and Step c. 【0344】 Step h: The desired product was prepared (199 mg; 67%) in the same manner as in Example 7 and Step c. 【0345】 Step i: To a mixture of the product from step h (199 mg, 0.368 mmol), (R)-2-methylpyrrolidine (38 mg, 0.44 mmol), AcOH (21 μL, 0.37 mmol), and DCE (1.8 mL), NaBH(OAc)3 (117 mg, 0.552 mmol) was added at room temperature. This reaction mixture was stirred at 40°C for 14 hours to obtain a saturated NaHCO₃ 3(水溶液) The reaction was stopped at (10 mL) and extracted with CH2Cl2 (10 mL). The organic phase was dried over Na2SO4 and concentrated to obtain the desired product, which was used directly in the next step. 【0346】 Step j: The mixture containing the product from step i (estimated value of 0.368 mmol) and MeOH containing 3M HCl (3.7 mL) was stirred at room temperature for 5 hours and diluted with MTBE (30 mL). The precipitated solid was collected by filtration and washed with MTBE. This crude product was purified by column chromatography (43 g C18, (H2O / ACN) + 0.1% TFA) with a 5% to 50% gradient (25 minutes) to obtain the desired product as a white solid (50 mg; 26%). 1H NMR (400 MHz, DMSO-d6) δ 8.72 (t, J = 2.0 Hz, 1H), 8.64 (d, J = 1.2 Hz, 1H), 8.40 (t, J = 5.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.85 (dd, J = 8.2, 1.7 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.48 (dd, J = 8.2, 2.4 Hz, 1H), 7.17 (dd, J = 11.4, 2.5 Hz, 1H), 4.37 (dd, J = 5.4, 4.1 Hz, 2H), 3.38 (q, J = 5.1 Hz, 2H), 2.99 -2.78 (m, 4H), 2.78 -2.62 (m, 3H), 2.44 (q, J = 8.3 Hz, 1H), 2.05 -1.91 (m, 2H), 1.87 -1.75 (m, 1H), 1.68 -1.51 (m, 2H), 1.45 (q, J = 12.1 Hz, 1H), 1.34 -1.21 (m, 2H), 1.02 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 31 H 33 Calculated value for FN5O2: 526.3, Measured value: 526.2. 【0347】 Example 59: (2R)-2-methyl-8-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0348】 Step a: Diisopropyl azodicarboxylate (2.07 mL, 10.5 mmol) was added dropwise to a mixture of methyl 4-bromo-2-hydroxybenzoate (2.31 g, 10.0 mmol), tert-butyl((S)-2-hydroxypropyl)carbamate (1.75 g, 10.0 mmol), PPh3 (2.75 g, 10.5 mmol), and THF (25 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then stirred at room temperature for 14 hours, concentrated on silica gel, and purified by column chromatography (80 g silica gel, hexane: SiO) with a 0% to 35% gradient (25 minutes) to obtain the desired product as a colorless oil (3.44 g; 89%). 【0349】 Step b: The desired product was prepared in the same manner as in Example 1, Step b (2.79 g; 97%). 【0350】 Step c: The desired product was prepared in the same manner as in Example 1, Step c (2.08 g; 94%). 【0351】 Step d: The desired product was prepared in the same manner as in Example 1 and Step d. 【0352】 Step e: The desired product was prepared in the same manner as in Example 7 and Step c (113 mg; 57%). 【0353】 Step f: Mix the product from step e (113 mg, 0.228 mmol), HCl (455 μL, 0.455 mmol, 1 M water), and THF (1.1 mL), stir at 70°C for 1 hour, cool to room temperature, and then add saturated NaHCO₃⁻. 3(水溶液)The mixture was neutralized with (1.0 mL), diluted with water (20 mL), filtered, and the precipitated solid was collected. These solids were washed with water and dried. To this mixture of solids, (R)-2-methylpyrrolidine (31 mg, 0.37 mmol), AcOH (21 μL, 0.37 mmol), and DMF (0.90 mL), NaBH(OAc)3 (97 mg, 0.46 mmol) was added at room temperature. The reaction mixture was stirred at 40 °C for 3 hours and diluted with SiO2 (18 mL), water (18 mL), and brine (3.0 mL). The aqueous phase was diluted with 2 M NaOH (水溶液) Then, the pH was adjusted to approximately 12. The organic phase was composed of water:2M NaOH. (水溶液) The solution was washed with brine (8:1:1) (1 × 10 mL), dried over Na₂SO₄, and concentrated. The crude product was purified by column chromatography (43 g C₁₄, (H₂O / ACN) + 0.1% TFA) with a 5% to 50% gradient (25 minutes) to obtain the desired product as an off-white solid (87 mg; 77%). 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 1.8 Hz, 1H), 8.40 (t, J = 5.7 Hz, 1H), 7.95 (dd, J = 8.1, 1.7 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.61 (t, J = 2.3 Hz, 1H), 7.55 (dd, J = 7.7, 1.9 Hz, 1H), 7.27 (dd, J = 7.9, 1.3 Hz, 1H), 4.59 (td, J = 6.4, 3.6 Hz, 1H), 3.33 -3.29 (m, 1H), 3.10 -3.00 (m, 1H), 3.00 -2.76 (m, 5H), 2.76 -2.65 (m, 2H), 2.44 (q, J = 8.2 Hz, 1H), 2.06 -1.94 (m, 2H), 1.87 -1.76 (m, 1H), 1.69 -1.49 (m, 2H), 1.49 -1.39 (m, 1H), 1.35 -1.22 (m, 5H), 1.02 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for N5O2: 522.3, Measured value: 522.3. 【0354】 Example 60: 9-Fluoro-8-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0355】 The indicated compound was prepared in the same manner as in Example 59. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.0 Hz, 1H), 8.54 (t, J = 5.4 Hz, 1H), 8.41 (s, 1H), 7.71 (dd, J = 8.4, 1.3 Hz, 1H), 7.63 (dd, J = 8.4, 6.2 Hz, 1H), 7.55 (s, 1H), 7.49 (dd, J = 7.8, 2.0 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 4.53 -4.41 (m, 2H), 3.44 (q, J = 5.1 Hz, 2H), 2.99 -2.75 (m, 5H), 2.74 -2.63 (m, 2H), 2.47 -2.40 (m, 1H), 2.34 -2.30 (m, 1H), 2.05 -1.94 (m, 2H), 1.87 -1.74 (m, 1H), 1.68 -1.50 (m, 2H), 1.48 -1.38 (m, 1H), 1.34 -1.21 (m, 3H), 1.02 (d, J = 5.9 Hz, 3H). ESI MS [M+H] + C 31 H 33 Calculated value for FN5O2: 526.3, Measured value: 526.2. 【0356】 Example 61: 7-Fluoro-8-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0357】 The indicated compound was prepared in the same manner as in Example 59. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 2.1 Hz, 1H), 8.56 (d, J = 5.4 Hz, 1H), 8.41 (t, J = 2.6 Hz, 1H), 7.71 (d, J = 11.2 Hz, 1H), 7.56 -7.50 (m, 2H), 7.50 -7.46 (m, 1H), 7.25 (d, J = 7.7 Hz, 1H), 4.39 -4.30 (m, 2H), 3.42 -3.37 (m, 2H), 2.97 -2.75 (m, 4H), 2.75 -2.65 (m, 2H), 2.47 -2.38 (m, 1H), 2.34 -2.30 (m, 1H), 2.04 -1.93 (m, 2H), 1.86 -1.76 (m, 2H), 1.65 -1.52 (m, 1H), 1.49 -1.37 (m, 1H), 1.35 -1.20 (m, 1H), 1.02 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 31 H 33 Calculated value for FN5O2: 526.3, Measured value: 526.2. 【0358】 Example 62: (2S)-2-methyl-8-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0359】 The indicated compound was prepared in the same manner as in Example 59. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.40 (t, J = 5.7 Hz, 1H), 7.95 (ddd, J = 8.1, 1.7, 0.8 Hz, 1H), 7.79 (dd, J = 8.2, 0.6 Hz, 1H), 7.65 (d, J = 1.3 Hz, 1H), 7.64 -7.58 (m, 1H), 7.55 (dd, J = 7.9, 1.8 Hz, 1H), 7.27 (d, J = 6.7 Hz, 1H), 4.59 (td, J = 6.4, 3.6 Hz, 1H), 3.33 -3.28 (m, 1H), 3.05 (dt, J = 15.3, 6.0 Hz, 1H), 3.00 -2.76 (m, 5H), 2.76 -2.67 (m, 2H), 2.44 (q, J = 8.2 Hz, 1H), 2.07 -1.95 (m, 2H), 1.87 -1.76 (m, 1H), 1.69 -1.50 (m, 2H), 1.49 -1.39 (m, 1H), 1.34 -1.22 (m, 5H), 1.02 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for N5O2: 522.3, Measured value: 522.3. 【0360】 Example 63: 8-{5-[7-(pyrroridine-1-yl)-5H,6H,7H,8H,9H-cyclohepta[b]pyridine-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0361】 Step a: Lithium borohydride (THF containing a 2.0 M solution) (13.6 mL, 27.2 mmol) was added dropwise at 0°C to a 38:1 THF:MeOH solution (34.5 mL) containing dimethyl 6-chloropyridine-2,3-dicarboxylate (2.50 g, 10.9 mmol). The condenser was removed and the mixture was stirred at room temperature for 2.5 hours. This mixture was then dissolved in saturated NaHCO₃⁻. 3(水溶液) The mixture was poured into (100 mL) and the product was extracted with ethyl acetate (5 × 100 mL). The combined organic phase was dried with (Na₂SO₄), concentrated, and used directly in the next step. 【0362】 Step b: Phosphorus tribromide (1.33 mL, 9.28 mmol) was added dropwise at 0°C to a suspension of THF (54 mL) containing the crude product from Step a (10.9 mmol). The condenser was removed, and the mixture was stirred at room temperature for 5 hours. The mixture was then cooled to 0°C and NaHCO₃ 3(水溶液) The mixture was carefully neutralized with (150 mL). These layers were separated, and any additional products were extracted in CH2Cl2 (2 × 150 mL). The combined organic phases were dried with (Na2SO4), concentrated, and used directly in the next step. 【0363】 Step c: A mixture of the crude product from step b (10.9 mmol), 1,5-dimethyl-3-oxopentanedioic acid (1.42 mL, 9.82 mmol), TBAB (1.32 g, 4.09 mmol), sodium bicarbonate (3.44 g, 40.9 mmol), CH2Cl2 (16.4 mL), and H2O (40.9 mL) was heated overnight at 40°C. CH2Cl2 was removed under vacuum, and the residue was dissolved in SiO2 (40 mL). This solution was washed with 9:1 H2O:brine (4 × 40 mL), dried (Na2SO4), concentrated, and used directly in the next step. 【0364】 Step d: Dissolve the crude product from step c in EtOH (63 mL) and 2N NaOH (水溶液)( 42 mL was added. This mixture was heated at 90°C for 2 hours. EtOH was removed under vacuum, and the solution was treated with 12N HCl. (水溶液)The pH was acidified to 6. The product was extracted in CH2Cl2 (2 × 30 mL), the combined solution was dried (Na2SO4), and concentrated. This crude product was purified by flash chromatography (hexane containing 0 to 100% siRNA) to obtain the desired product as a white solid (355 mg; 22%). 【0365】 Step e: Add sodium triacetoxyborohydride (288 mg, 1.36 mmol) and acetic acid (0.05 mL, 0.906 mmol) to a solution of DCE (4.5 mL) containing the product from step d (177 mg, 0.906 mmol) and pyrrolidine (0.09 mL, 1.09 mmol). Stir this mixture overnight at room temperature. The reaction product was then converted to saturated NaHCO₃⁻. 3(水溶液) The reaction was stopped at (10 mL), and the product was extracted with CH2Cl2 (3 × 10 mL). The combined organic phase was washed with brine (10 mL), dried, concentrated, and the crude product was used directly in the next step. 【0366】 Step f: The desired product was prepared in the same manner as in Example 1 and Step d. 【0367】 Step g: The desired product was prepared (60.3 mg; 33%) in the same manner as in Example 26 and Step c. 【0368】 Step h: MeOH (2.1 mL) containing 3N HCl was added to the product from step g (60.3 mg, 0.104 mmol), and the mixture was stirred overnight at room temperature. The reaction was concentrated, and the crude product was successively ground with MTBE and ACN to obtain the desired product (26.6 mg; 42%). 1H NMR (400 MHz, DMSO-d6) δ 11.22 (br. s, 1H), 9.21 (d, J = 24.7 Hz, 2H), 8.49 -8.41 (m, 1H), 8.21 (d, J = 7.5 Hz, 1H), 8.15 (br. s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 4.44 -4.37 (m, 2H), 3.67 -3.55 (m, 2H), 3.54 3.38 (m, 4H), 3.25 -3.08 (m, 2H), 2.92 (t, J = 13.3 Hz, 1H), 2.52 - 2.41 (m, 4H), 2.04 -1.84 (m, 4H), 1.85 -1.75 (m, 1H), 1.73 -1.61 (m, 1H). ESI MS [M+H] + C 29 H 31 Calculated value for N6O2: 495.3, Measured value: 495.2. 【0369】 Example 64: 8-(5-{3-methyl-7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0370】 Step a: To a mixture of 4-methylphthalic acid (18.0 g, 100 mmol), NaOH (12.0 g, 300 mmol), and water (100 mL), Br2 (5.12 mL, 100 mmol) was added dropwise at 0°C. Upon completion, the reaction mixture was heated and stirred at 80°C for 1.5 hours. The mixture was cooled to room temperature, water (100 mL) was added, followed by 2 M HCl (水溶液)(150 mL) was added. This solid was filtered and recovered, washed with water, and dried to obtain the desired product as a white solid (5.58 g, 22%). 【0371】 Step b: To the mixture of the product from step a (5.70 g, 22.0 mmol) and THF (110 mL), boranedimethyl sulfide (6.26 mL, 66.0 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then heated and stirred at 55°C for 14 hours. The mixture was cooled to room temperature and mixed with 2 M NaOH. (水溶液) (100 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. 12M HCl (水溶液) (17 mL) was added dropwise, the resulting organic phase was concentrated, and diluted with SiO(50 mL). The resulting aqueous phase was extracted with SiO(1 × 50 mL), and the combined organic phase was washed with 1:5 water:brine (60 mL), dried on Na2SO4, and concentrated to obtain the desired product as a white solid (4.57 g, 90%). 【0372】 Step c: The mixture of the product from step b and HBr (20 mL, containing 48 wt% H2O) was stirred at 90°C for 2 hours. The mixture was cooled to room temperature, the solid was collected by filtration, and washed with water to obtain the desired product, which was used directly in the next step. 【0373】 Step d: The mixture of the product from step c (estimated 19.8 mmol), dimethyl-1,3-acetone dicarboxylate (4.14 g, 23.6 mmol), tetrabutylammonium bromide (3.19 g, 9.90 mmol), NaHCO3 (8.32 g, 99.0 mmol), CH2Cl2 (40 mL), and water (99 mL) was vigorously stirred at 40°C for 4 days. The organic phase was separated, concentrated, diluted with SiO2 (100 mL), washed with 9:1 water:brine (4 × 100 mL), dried over Na2SO4, and concentrated. The residue was dissolved in EtOH (152 mL) and 2M NaOH (水溶液)(99 mL) was added. The reaction mixture was stirred at 90°C for 2 hours. The mixture was cooled to room temperature and 12M HCl was added. (水溶液) (15 mL) was added to adjust the pH to approximately 7. EtOH was removed under reduced pressure, and the resulting aqueous phase was extracted with CH2Cl2 (150 L). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (80 g silica gel, hexane: SiO) with a gradient from 0% to 20% (20 minutes) and a gradient from 20% to 35% (10 minutes) to obtain the desired product as a pale yellow solid (2.35 g, 47%; 2 steps). 【0374】 Step e: The desired product was prepared (138 mg; 85%) in the same manner as in Example 7, Step c. 【0375】 Step f: To a mixture of the product from step e (138 mg, 0.257 mmol), (R)-2-methylpyrrolidine (44 mg, 0.51 mmol), AcOH (30 μL, 0.51 mmol), and THF (1.3 mL), NaBH(OAc)3 (136 mg, 0.643 mmol) was added at room temperature. This reaction mixture was stirred at 40°C for 3 hours and diluted with SiO (15 mL), water (15 mL), and brine (2.0 mL). The aqueous phase was 2 M NaOH (水溶液) Then, the pH was adjusted to approximately 12. The organic phase was composed of water:2M NaOH. (水溶液) The mixture was washed with brine (8:1:1) (1 × 20 mL), dried over Na₂SO₄, and concentrated. MeOH (1.3 mL) containing 3 M HCl was added. The reaction mixture was stirred at room temperature for 2 hours and diluted with MTBE (20 mL). The precipitated solid was collected by filtration and washed with MTBE. The crude product was purified by column chromatography (43 g C18, (H₂O / ACN) + 0.1% TFA) with a 5% to 50% gradient (25 minutes) to obtain the desired product as a white solid (43 mg; 32%). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 2.0, 0.4 Hz, 1H), 8.47 (dd, J = 2.0, 0.9 Hz, 1H), 8.39 (t, J = 5.4 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.85 (dd, J = 8.2, 1.7 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.12 (s, 1H), 7.11 (s, 1H), 4.35 (dd, J = 5.4, 4.1 Hz, 2H), 3.37 (q, J = 5.1 Hz, 2H), 2.95 -2.59 (m, 7H), 2.43 (q, J = 8.2 Hz, 1H), 2.20 (s, 3H), 2.06 -1.90 (m, 2H), 1.86 -1.76 (m, 1H), 1.68 -1.49 (m, 2H), 1.43 (q, J = 11.8 Hz, 1H), 1.34 -1.20 (m, 2H), 1.02 (d, J = 5.1 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for N5O2: 522.3, Measured value: 522.3. 【0376】 Example 65: 8-(5-{4-chloro-7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-one [ka] 【0377】 Step a: A mixture of 5-bromo-1,2-dimethyl-3-nitrobenzene (4.60 g, 20.0 mmol), iron powder (5.59 g, 100 mmol), NH4Cl (5.35 g, 100 mmol), and 2:1 EtOH:water (80 mL) was stirred at 75°C for 90 minutes, cooled to room temperature, and filtered by Celite to remove solids (washed with siRNA (200 mL)). The organic phase was dried over Na2SO4, concentrated, diluted with siRNA (2 mL), dried again over Na2SO4, and concentrated again to obtain the desired product as an orange oil (4.02 g; >100%). 【0378】 Step b: Add 12M HCl to the mixture of EtOH (20 mL) containing the product from step a (4.02 g, 20.0 mmol) at room temperature. (水溶液) (8.0 mL) was added dropwise. This mixture was cooled to 0°C, and a solution of water (8.0 mL) containing NaNO2 (1.79 g, 26.0 mmol) was added dropwise. This reaction mixture was stirred at 0°C for 1 hour, and solid CuCl (3.96 g, 40.0 mmol) and 12 M HCl were added. (水溶液) (8.0 mL) was carefully added, stirred at 80°C for 1 hour, cooled to room temperature, and extracted with hexane (2 × 20 mL). The combined organic phase was dried over Na₂SO₄ and concentrated to obtain the desired product as an orange oil (4.06 g; 92%; 2 steps). 【0379】 Step c: The desired product was prepared in the same manner as in Example 58, Step a (1.46 g; 28%). 【0380】 Step d: The desired product was prepared (1.04 g; 80%) in the same manner as in Example 58, Step b. 【0381】 Step e: The desired product was prepared in the same manner as in Example 64, Step c (4.15 mmol; estimated value at 100% yield). 【0382】 Step f: The desired product was prepared (165 mg; 15%) in the same manner as in Example 64 and Step d. 【0383】 Step g: The desired product was prepared (235 mg; 70%) in the same manner as in Example 7 and Step c. 【0384】 Step h: The desired product was prepared (18 mg; 8%) in the same manner as in Example 64 and Step f. 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.40 (t, J = 5.4 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.91 (dd, J = 8.3, 1.7 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.66 -7.62 (m, 1H), 4.38 (dd, J = 5.4, 4.1 Hz, 2H), 3.43 -3.35 (m, 2H), 3.08 -2.90 (m, 2H), 2.90 -2.78 (m, 2H), 2.77 -2.67 (m, 2H), 2.67 -2.56 (m, 1H), 2.48 -2.39 (m, 1H), 2.08 -1.95 (m, 2H), 1.88 -1.76 (m, 1H), 1.67 -1.50 (m, 2H), 1.50 -1.35 (m, 1H), 1.36 -1.15 (m, 2H), 1.02 (d, J = 5.9 Hz, 3H). ESI MS [M+H] + C 31 H 33 Calculated value for ClN5O2: 542.2, Measured value: 542.2. 【0385】 Example 66: 7-(5-{7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)-3,4-dihydro-2H-5,1λ 6 ,2-Benzoxathiazepine-1,1-dione [ka] 【0386】 Step a: To a mixture of THF (8.2 mL) and H2O (4.1 mL) containing 4-bromo-2-fluorobenzenesulfonyl chloride (1.02 g, 3.73 mmol), K2CO3 (515 mg, 3.73 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. 2-aminoethanol (0.22 mL, 3.73 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 16 hours. RINKAN (15 mL) and H2O (15 mL) were added, and these layers were separated. The aqueous layer was extracted with RINKAN (2 × 15 mL), and the combined organic layers were then washed with brine, dried over MgSO4, and concentrated to obtain a light brown solid as the product (986 mg; 89%). 【0387】 Step b: To a solution of DMSO (6.6 mL) containing the product from step a (986 mg, 3.31 mmol), KOt-Bu (928 mg, 8.27 mmol) was added at room temperature, and the reaction mixture was stirred at 80°C for 24 hours. As soon as it cooled, H2O (10 mL) was added, followed by saturated NH4Cl aqueous solution (10 mL), and the mixture was extracted with ₹ (3 × 15 mL). The combined organic layers were washed with brine, dried on anhydrous MgSO4, concentrated, and purified by silica gel chromatography (CH2Cl2 containing 10% MeOH from CH2Cl2 containing 10% ₹ from CH2Cl2 containing 100% CH2Cl2 to CH2Cl2 containing 10% MeOH) to obtain the desired product as a white solid (544 mg; 59%). 【0388】 Step c: Dioxane (8.8 mL) was added to a mixture of the product from step b (245 mg, 0.881 mmol), B2pin2 (268 mg, 1.06 mmol), and KOAc (112 mg, 1.15 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (32 mg, 0.0441 mmol) was added, and the reaction mixture was stirred at 90°C for 2.5 hours. As soon as it cooled, SiO2 (20 mL) was added, and the mixture was filtered through Celite. The filtrate was concentrated to obtain a viscous brown oily crude product. 【0389】 Step d: Dioxane (7.2 mL) and H2O (0.80 mL) were added to a mixture of the product from Example 1 and Step e (364 mg, 0.800 mmol), the crude product from Step c (0.881 mmol), and Na2CO3 (170 mg, 1.60 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (29 mg, 0.0400 mmol) was added, and the reaction mixture was stirred at 90°C for 13 hours. As soon as it cooled, CH2Cl2 (20 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (MeOH containing 10% CH2Cl2 to 10% CH2Cl2) to obtain the desired product as an orange solid (378 mg; 90%). 【0390】 Step e: Dioxane (6.5 mL) and H2O (0.70 mL) were added to a mixture of the product from step d (378 mg, 0.719 mmol), the product from Example 32, step h (1.34 mmol), and Na2CO3 (152 mg, 1.44 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (26 mg, 0.0360 mmol) was added, and the reaction mixture was stirred at 90°C for 15 hours. As soon as it cooled, CH2Cl2 (20 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (MeOH containing 10% CH2Cl2 to 10% CH2Cl2) to obtain the desired product as an orange solid (244 mg; 56%). 【0391】 Step f: To a mixture of the product from step e (78 mg, 0.129 mmol) and DMF (2.7 mL) containing (2R)-2-methylpyrrolidine (30 μL, 0.296 mmol), AcOH (15 μL, 0.270 mmol) was added. This mixture was stirred at room temperature for 30 minutes, and then NaBH(OAc)3 (63 mg, 0.296 mmol) was added. This reaction mixture was stirred at room temperature for 14 hours, and the reaction was carefully stopped with H2O followed by saturated NaHCO3 aqueous solution. This mixture was extracted with siRNA (3 × 10 mL), and then the combined organic layers were washed with brine, dried on anhydrous MgSO4, and concentrated. Purification by silica gel chromatography (CH2Cl2 containing 10% MeOH from 100% CH2Cl2, 1% NH3) yielded the desired product as an orange solid (67 mg; 37%, approximately 1:1 dr). 【0392】 Step g: To a solution of CH2Cl2 (1.4 mL) containing the product from step f (67 mg, 0.0994 mmol), TFA (0.70 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. To a solution of MeOH (2.0 mL) containing the residue, DMEDA (80 μL, 0.746 mmol) was added, and the mixture was stirred at 45°C for 1 hour. As soon as it cooled, the reaction mixture was diluted with H2O (5 mL) and CH2Cl2 (5 mL), and these layers were separated. The aqueous layer was extracted with CH2Cl2 (2 × 10 mL) containing 10% MeOH, and then the combined organic layers were concentrated. The marked compound was obtained as an off-white solid (4 mg, 6%) by reverse-phase HPLC (H2O containing 10-70% ACN, 0.1% TFA) and lyophilization. 1 H NMR (400 MHz, methanol-d4) δ 8.82 (d, J = 2.1 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 7.99 -7.96 (m, 2H), 7.88 (dd, J = 1.1, 0.7 Hz, 1H), 7.59 (d, J = 2.0Hz, 1H), 7.55 (dd, J = 7.7, 1.9 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 4.28 -4.21 (m, 2H), 3.86 -3.69 (m, 2H), 3.60 (dd, J = 4.9, 3.8 Hz, 2H), 3.47 -3.39 (m, 1H), 3.29 -3.23 (m, 1H), 3.11 -2.90 (m, 4H), 2.45 -2.34 (m, 2H), 2.30 (dq, J = 13.8, 7.1 Hz, 1H), 2.11 -1.95 (m, 2H), 1.81 -1.68 (m, 1H), 1.68 -1.53 ​​(m, 2H), 1.47 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 30 H 34 Calculated value for N5O3S: 544.2, Measured value: 544.2. 【0393】 Biological examples Measurement of intracellular binding of Axl inhibitors The Axl NanoBRET® intracellular kinase assay (Promega, N2540) was performed according to the manufacturer's instructions. Briefly, HEK-293 cells were transiently transfected with the Axl-NanoLuc fusion vector (Promega, NV1071) using Fugene HD transfection reagent (Promega, E2311) the day before the experiment, according to the manufacturer's instructions. 【0394】 On the day of the assay, cells were harvested and resuspended in Opti-MEM medium (ThermoFisher, 31985070) at a concentration of 2 e5 cells / mL. The test compound was serially diluted and dispensed at 200 nL into a white 384-well polystyrene plate containing 100% DMSO. Next, 40 μL of resuspended cells were added to each well to bring the final condition to 8000 cells / well in 0.5% DMSO. After pre-incubation of the compound at 37°C and 5% CO2 for 1 hour, the cells were further incubated at 37°C and 5% CO2 for 2 hours using a 0.35 μM K-5 NanoBRET tracer. Following the kit instructions, 20 ml of 3X substrate and inhibitor solution was prepared and added to the cells, followed by a 30-second pulsed centrifugation spin. The plate was then immediately read using an Envision (Perkin Elmer) plate reader. The BRET signal is measured by obtaining the ratio of radiated readings at 610 nm and 450 nm. Compound binding is based on the decrease in the BRET signal due to the displacement of the K-5 tracer. The activity obtained by treatment with DMSO was used as a neutral control and normalized to 100% activity, and 20 μM of the CEP-40783 control compound, which reached 100% inhibition, was used as a positive control and normalized to 0% activity. IC of these compounds 50 The values ​​were determined by a four-parameter nonlinear regression fitting of the activity percentage using GraphPad Prism software. The numerical values ​​are reported in Table 1 (Cell Binding). 【0395】 Measurement of the biochemical efficacy of Axl inhibitors Purified recombinant human AXL, TYRO3, and MER proteins were purchased from Invitrogen®. 10 nM AXL, 2 nM TYRO3, or MER were incubated for 1 hour at room temperature in a 384-well microplate (Corning® #3640) containing 20 μl total volume of 50 mM HEPES, pH 7.4, 10 mM MgCl2, 0.01% BSA, 1 mM DTT, and 2% DMSO, each containing varying concentrations of the compound. The enzymatic reactions of AXL, TYRO3, and MER are initiated by transferring 10 μl of enzyme and compound mixture to 10 μl of 1.6 μM TK substrate-biotin (HTRF® KinEASE-TK kit, Cisbio), and 1400 μM ATP to a 384-well microplate (Corning® #3640) containing 50 mM HEPES, pH 7.4, 10 mM MgCl2, 0.01% BSA, 1 mM DTT, and 1 mM DTT, which are pre-incubated at room temperature to provide the following final reaction conditions: 5 nM AXL, 1 nM TYRO3, or MER containing various concentrations of the compound, 800 nM TK substrate-biotin, and 700 μM ATP in 50 mM HEPES, pH 7.4, 10 mM MgCl2, 0.01% BSA, 1 mM DTT, and 1% DMSO. After incubation at room temperature for 2 hours, the enzymatic reactions of AXL, TYRO3, and MER were stopped by transferring 10 μl of the reaction mixture to a white 384-well microplate (Perkin Elmer, OptiPlate 384) containing 10 μl of detection mix (400 nM Streptavidin-XL665, 200-fold diluted TK antibody-cryptate, and detection buffer, HTRF® KinEASE-TK kit, Cisbio). After incubation at room temperature for 1 hour, the plate was placed in a plate reader (Evision) and the 665 / 620 nm (acceptor / donor) values ​​for HTRF were read. The DMSO blank values ​​(MIN inhibition = 100% activity) were used as the negative control. The positive control was established by adding 5 μl of enzyme-DMSO mixture to 10 μl of detection mix, followed by 5 μl of TK substrate-biotin and ATP mixture (MAX inhibition = 0% activity).Equation 1 was used to calculate the percentage activity. (Ratio) 625 / 620 This is the value at a given compound concentration: 【number】 【0396】 Enzyme activity (IC) 50 The concentration of the compound that causes a 50% loss of ) was calculated using Equation 2 in GraphPad Prism, where N is the Hill coefficient: 【number】 The numerical values ​​are listed in Table 1 (Biochemical Efficacy). [Table 1-1] [Table 1-2] [Table 1-3] 【0397】 Specific embodiments of the present disclosure are described herein and include the best modes known to the inventors for carrying out the invention. Modifications to the disclosed embodiments will be obvious to those skilled in the art, and such modifications will be appropriately used by those skilled in the art. Therefore, it is intended that the present disclosure be carried out in any manner other than those specifically described herein, and that the present disclosure includes, to the extent permitted by applicable law, all modifications and equivalents of those described in the appended claims. Furthermore, unless otherwise specified herein, or unless clearly inconsistent with the context, any combination of the above elements with all possible modifications is included in the present disclosure. 【0398】 All publications, patent applications, accession numbers, and other references cited herein are incorporated by reference in the same way that each individual publication or patent application is incorporated by reference specifically and individually. The following are examples of the forms of this disclosure: [1] Equation (I) [ka] A compound represented by, or a pharmaceutically acceptable salt thereof, During the ceremony: G 1 is N or CR G1 is; G 2 CR G2 or N; G 3 CR G3 or N; G 4 CR G4 or N; G 5 CR G5 or N; R G1 Select from the group consisting of H, C1-3 alkyl, halogen, C1-3 haloalkyl, and CN; R G2 , R G3 , R G4 , and R G5 Each of these is independently H, Haro, CN, C 1-7 Alkyl, C 3-7 Cycloalkyl, C1-3 haloalkyl, -O-C1-3 alkyl, -O-C1-3 haloalkyl, -NR a R b The cycloalkyl group and heterocycloalkyl group are selected from the group consisting of O, N, and S, and a 4-8 membered heterocycloalkyl group having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and heterocycloalkyl group are independently halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4Substitute with 0 to 3 groups selected from alkyl and OH groups; R 1 H, C 1-4 Select from the group consisting of alkyl and NH2; A is a fused ring selected from the group consisting of azepane, piperidine, cycloheptane, cyclohexane, cyclopentane, 1,4-oxazepane, oxepane, tetrahydropyran, 1,4-diazepane, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which is either unsubstituted or has 1 to 4 R groups. 2 Substitution occurs, followed by further substitution with zero or one oxo (=O) adjacent to the nitrogen atom; B is 1,4-oxazepane, cycloheptane, tetrahydropyran, isothiazolidine. A fused ring selected from the group consisting of 1,1-dioxide, oxepan, 1,4,5-oxathiazepane, 4,4-dioxide, cyclohexane, cyclopentane, azepane, pyrrolidine, piperidine, piperazine, morpholine, diazepane, and 1,3-dioxolane, each of which is either unsubstituted or has 1 to 4 R groups. 4 Substitution occurs, followed by further substitution with zero or one oxo (=O) adjacent to the nitrogen atom; Each R 2 These are independently: Halo, OH, C 1-7 Alkyl, C 3-7 Alkenil, C 3-7 Alkinyl, C 3-7 Cycloalkyl, -C(O)-C 1-7 Alkyl, -C(O)-C 3-7 Cycloalkyl, -C(O)-C 1-7 Alkylene-OH,-Y 1 -OC 1-7 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -NR a R b -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7Cycloalkyl, -C(O)NR a R b , 4-8 member heterocycloalkyl, and -NR a -Selected from the group consisting of (4-8 member heterocycloalkyl groups), each 4-8 member heterocycloalkyl group has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and heterocycloalkyl group are independently halo, CN, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Substituted with 0 to 3 groups selected from alkyl and OH groups; The subscript n is 0, 1, 2, or 3; Each R 3 These are, independently, halogen, CN, and C 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Alkinyl, C 3-7 Cycloalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 halohydroxyalkyl, -OC 1-7 Alkyl, -OC 3-7 Cycloalkyl, -O-C1-6 haloalkyl, -X 1 -CN, -X 1 -OC 1-7 Alkyl, -OY 1 -OC 1-7 Alkyl, -NR a R b -X 1 -NR a R b ,-OY 1 -NR a R b -C(O)-NR a R b -S(O)2-NR a R b -S(O)(NH)-C 1-7 Alkyl, -S(O)2-C 1-7 Alkyl, -S(O)2-C 1-7 Haloalkyl, -S(O)2-C 3-7 Cycloalkyl, -S(O)2-Y 1-O-C1-3 alkyl, -S(O)2- (4-8 member heterocycloalkyl), -C(O)NH- (4-8 member heterocycloalkyl), 4-8 member heterocycloalkyl, and -OX 1 -Selected from the group consisting of (4-8 member heterocycloalkyl groups), the 4-8 member heterocycloalkyl group has 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and heterocycloalkyl group are independently halo, CN, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Substituted with 0 to 3 groups selected from alkyl and OH groups; Each R 4 These are independently H, halogen, hydroxyl, CN, and C 1-7 Alkyl, C 2-7 Alkenil, C 3-7 Alkinyl, C 3-7 Cycloalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 halohydroxyalkyl, -OC 1-7 Alkyl, -OC 3-7 Cycloalkyl, -O-C1-6 haloalkyl, -X 1 -CN, -X 1 -OC 1-7 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -C(O)NR a R b , -NR a R b , -NR a -C(O)-C 1-7 Alkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a -S(O)2-C 1-7 Alkyl and -NR a -S(O)2-C 3-7 Selected from the group consisting of cycloalkyls, -NR a R b , -NR a -C(O)-C 1-7Alkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a -S(O)2-C 1-7 Alkyl and -NR a -S(O)2-C 3-7 Cycloalkyl groups do not bond directly to the vertices of the nitrogen ring and do not form NN bonds; Alternatively, two R atoms bonded to a common carbon 4 However, when combined, C 3-6 A spirocycloalkyl group is formed, which is either unsubstituted or substituted with 1 to 3 elements independently selected from F, Cl, OH, and CH3; Each X 1 C 1-7 Alkylene or C 3-7 It is a cycloalkylene; Each Y 1 C 2-7 Alkylene or C 3-7 It is a cycloalkylene, where the two bonded heteroatoms are not bonded to a common carbon atom; R a and R b Each of these is independently H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl and C 3-7 Select from the group consisting of cycloalkyl groups; or R a and R b Together with the nitrogen atoms to which they are bonded, they form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatomic ring vertices selected from the group consisting of O, N, and S, and halogens, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 The compound, or a pharmaceutically acceptable salt thereof, is substituted with 0 to 3 groups independently selected from alkyl, oxo, and OH groups. [2] G 1The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein N is present. [3] G 1 However, the compound described in Embodiment 1, which is CH, or a pharmaceutically acceptable salt thereof. [4] G 2 The compound described in any one of embodiments 1 to 3, which is CH or CF, or a pharmaceutically acceptable salt thereof. [5] G 3 A compound according to any one of embodiments 1 to 4, wherein the compound is selected from the group consisting of CH, CF, C(CH3), and N, or a pharmaceutically acceptable salt thereof. [6] G 4 The compound described in any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is CH, CCl, or N. [7] G 5 A compound according to any one of embodiments 1 to 6, wherein the compound is CH or N, or a pharmaceutically acceptable salt thereof. [8] G 1 However, N is and G 2 A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein CH is present. [9] G 3 However, the compound described in Embodiment 8, or a pharmaceutically acceptable salt thereof, is CH.

[10] G 4 However, the compound described in embodiment 9, or a pharmaceutically acceptable salt thereof, is CH.

[11] G 5 However, the compound described in embodiment 10, or a pharmaceutically acceptable salt thereof, is CH.

[12] The condensed ring A is [ka] It has an expression for selecting from a group consisting of 1 to 4 R 2 A compound according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, substituted with [the compound].

[13] The fused ring A is given by formula: [ka] A compound according to embodiment 12, or a pharmaceutically acceptable salt thereof.

[14] One R 2 However, -NR a R b The compound described in embodiment 13, or a pharmaceutically acceptable salt thereof.

[15] One R 2 However, it is pyrrolidinyl, which is unsubstituted, or halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 The compound according to embodiment 14, or a pharmaceutically acceptable salt thereof, substituted with one to three substituents independently selected from the group consisting of alkyl, oxo, and OH.

[16] The condensed ring B is selected from the group consisting of 1,4-oxazepane, tetrahydropyran, isothiazolidine 1,1-dioxide, 1,4,5-oxathiazepane 4,4-dioxide, azepane, and pyrrolidine, each of which is unsubstituted or has 1 to 3 R 4 A compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, which is substituted with; and further substituted with zero or one oxo (=O) adjacent to the nitrogen atom.

[17] Each R 4 These are, independently, halogen, C 1-4 Alkyl, C 1-4 A group consisting of haloalkyl and OH, or R bonded to a common carbon. 4 However, when combined, C 3-6 A compound according to any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, which forms a spirocycloalkyl, which is unsubstituted or substituted with one to three elements independently selected from F, Cl, OH, and CH3.

[18] The condensed ring A is: [ka] The formula has to be selected from the group consisting of, and each of them can optionally have 1 to 2 R 2 A compound according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, substituted with [the compound].

[19] The condensed ring A is given by the above formula: [ka] A compound according to embodiment 18 having, or a pharmaceutically acceptable salt thereof.

[20] The aforementioned R 2 It is bonded to nitrogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, -C(O)-C 1-7 Alkyl, -C(O)C 3-7 Cycloalkyl, -C(O)C 1-7 Alkylene-OH,-Y 1 -OC 1-7 Alkyl, -Y 1 ― OC 3-7 Cycloalkyl, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3―7 Cycloalkyl, -C(O)NR a R b , and selected from the group consisting of 4-8 member heterocycloalkyl groups, wherein the 4-8 member heterocycloalkyl group has 1-3 heteroatomic ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and heterocycloalkyl group are independently halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 A compound according to embodiment 18 or 19, or a pharmaceutically acceptable salt thereof, substituted with 0 to 3 groups selected from alkyl and OH.

[21] The condensed ring B is [ka] The formula has a set of elements that are selected from a group consisting of, and each of them is either unsubstituted or has 1-2 R 4A compound according to any one of embodiments 1 to 11 or 18 to 20, or a pharmaceutically acceptable salt thereof, substituted with.

[22] The condensed ring B is an unsubstituted compound according to Embodiment 21, or a pharmaceutically acceptable salt thereof.

[23] The condensed ring B is [ka] The compound described in embodiment 21, or a pharmaceutically acceptable salt thereof.

[24] The condensed ring B is [ka] The formula has a set of elements that are selected from a group consisting of, each of which is either unsubstituted or has 1 to 4 R's. 4 A compound according to any one of embodiments 1 to 11 or 18 to 20, or a pharmaceutically acceptable salt thereof, substituted with.

[25] The condensed ring B has 1 to 4 R 4 They are substituted with, and each of them independently, halogen, C 1-4 Alkyl, C 1-4 A compound according to embodiment 24, selected from the group consisting of haloalkyl and OH, or a pharmaceutically acceptable salt thereof.

[26] The condensed ring B is [ka] The formula has a set of elements that are selected from a group consisting of, each of which is either unsubstituted or has 1 to 3 R's. 4 A compound according to any one of embodiments 1 to 11 or 18 to 20, or a pharmaceutically acceptable salt thereof, substituted with.

[27] Each R 4 C 1-4 Alkyl and C 1-4 A compound according to embodiment 26, selected from the group consisting of haloalkyls, or a pharmaceutically acceptable salt thereof.

[28] The following: [ka] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

[29] The following: [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] A compound according to Embodiment 1, selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[30] A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[31] A method for treating a disease, disorder or condition mediated by AXL, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 30.

[32] The method according to embodiment 31, wherein the compound is administered in an effective amount that reverses, delays, or halts the progression of AXL-mediated dysregulation.

[33] The method according to any one of embodiments 31 to 32, wherein the disease, disorder, or condition is cancer.

[34] The method according to embodiment 33, wherein the cancer is cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, uterus, brain, liver, bladder, ovaries, testes, head, neck, skin (such as melanoma and basal carcinoma), mesothelial endothelial, leukocyte (such as lymphoma and leukemia), esophagus, breast, muscle, connective tissue, intestine, lung (such as small cell lung cancer and non-small cell lung cancer), adrenal gland, thyroid, kidney, or bone; or glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma (such as Kaposi's sarcoma), choriocarcinoma, cutaneous basal cell carcinoma, or testicular seminoma.

[35] The method according to embodiment 33, wherein the cancer is selected from the group consisting of melanoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, Kaposi's sarcoma, renal cell carcinoma, head and neck cancer, esophageal cancer, and urothelial carcinoma.

[36] The method according to embodiment 31 or 32, wherein the disease, disorder, or condition is an immune-related disease, disorder, or condition.

[37] The method according to embodiment 36, wherein the immune-related disease, disorder, or condition is selected from the group consisting of rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergy, fibrosis, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis, and other eczema, systemic sclerosis, and multiple sclerosis.

[38] The method according to any one of embodiments 31 to 35, further comprising at least one further therapeutic agent.

[39] The method according to embodiment 38, wherein the at least one further therapeutic agent independently comprises one or more active agents selected from the group consisting of CD47-SIRPα pathway inhibitors (e.g., anti-CD47 antibodies), HIF inhibitors (e.g., HIF-2α inhibitors), immune checkpoint inhibitors, agents that target extracellular production of adenosine, radiotherapy agents, and chemotherapeutic agents.

[40] The method according to embodiment 38, wherein the at least one further therapeutic agent comprises an inhibitor of the CD47-SIRPα pathway.

[41] The method according to embodiment 38 or 40, wherein the at least one further therapeutic agent comprises one or more immune checkpoint inhibitors that block the activity of at least one of PD-1, PD-L1, BTLA, LAG-3, B7 family members, TIM-3, TIGIT, or CTLA-4.

[42] The method according to embodiment 41, wherein the one or more immune checkpoint inhibitors include immune checkpoint inhibitors that block the activity of PD-1 or PD-L1.

[43] The method according to embodiment 42, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is selected from the group consisting of avelumab, atezolizumab, valtilimab, buzigalimab, camrelizumab, cosivelimab, dostallimab, durvalumab, emiprimab, emvafolimab, ezabenlimab, nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, scintillumab, tislerizumab, tripalimab, and zinbererimab.

[44] The method according to aspect 42, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is zimberelimab.

[45] The method according to aspect 41, wherein the one or more immune checkpoint inhibitors include immune checkpoint inhibitors that block the activity of TIGIT.

[46] The method according to aspect 45, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is selected from AB308, domvanalimab, etigirimab, osiperlimab, triagolumab, or vivostrimab.

[47] The method according to aspect 45, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is AB308 or domvanalimab.

[48] ​​The at least one further therapeutic agent is A 2a R / A 2b The method according to any one of embodiments 38 to 47, comprising one or more agents that target extracellular production of adenosine, selected from the group consisting of R antagonists, CD73 inhibitors, and CD39 inhibitors.

[49] The method according to embodiment 48, wherein one or more active agents that target the extracellular production of adenosine are selected from the group consisting of etrumadenante, inupadenant, taminadenant, caffeine citrate, imaradenant, siphoradenante, and quemriculstat.

[50] The method according to embodiment 48, wherein one or more active agents that target the extracellular production of adenosine are eturmadenant and / or quemrecrustat.

[51] The method according to any one of embodiments 38 to 50, wherein the at least one further therapeutic agent comprises an inhibitor of HIF-2α selected from the group consisting of berzutifan, ARO-HIF2, PT-2385, and AB521.

[52] The method according to claim 51, wherein the HIF-2α inhibitor is AB521.

[53] The method according to any one of embodiments 38 to 52, wherein the at least one further therapeutic agent comprises a chemotherapeutic agent.

[54] The method according to any one of embodiments 38 to 53, wherein the at least one further therapeutic agent is radioactive.

[55] The method according to any one of embodiments 38 to 54, wherein the compound is administered in combination with the at least one further therapeutic agent.

[56] The method according to any one of embodiments 38 to 54, wherein the compound and the at least one further therapeutic agent are administered in succession.

[57] The method according to any one of embodiments 38 to 54, wherein the treatment periods for the administration of the compound and the at least one further therapeutic agent overlap.

[58] A combination comprising a compound according to any one of embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent.

[59] The combination according to embodiment 58, wherein the at least one further therapeutic agent independently comprises one or more agents selected from the group consisting of CD47-SIRPα pathway inhibitors (e.g., anti-CD47 antibodies), HIF inhibitors (e.g., HIF-2α inhibitors), immune checkpoint inhibitors, agents that target extracellular production of adenosine, radiotherapy, and chemotherapeutic agents.

[60] The combination according to embodiment 59, wherein the at least one further therapeutic agent comprises an inhibitor of the CD47-SIRPα pathway.

[61] The combination according to embodiment 59 or 60, wherein the at least one further therapeutic agent comprises one or more immune checkpoint inhibitors that block the activity of at least one of PD-1, PD-L1, BTLA, LAG-3, B7 family members, TIM-3, TIGIT, or CTLA-4.

[62] The combination according to embodiment 61, wherein the one or more immune checkpoint inhibitors include immune checkpoint inhibitors that block the activity of PD-1 or PD-L1.

[63] The combination according to embodiment 61, wherein the one or more immune checkpoint inhibitors include immune checkpoint inhibitors that block the activity of TIGIT.

[64] The combination of any one of the claims according to Embodiments 59 to 63, wherein the at least one further therapeutic agent comprises a platinum-based, anthracycline-based, or taxoid-based chemotherapeutic agent.

[65] The combination according to embodiment 64, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, and paclitaxel.

[66] A method for inhibiting the activity of AXL in a subject, comprising administering to the subject a compound according to any one of embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 30.

Claims

[Claim 1] Equation (I) 【Chemistry 1】 A compound represented by, or a pharmaceutically acceptable salt thereof, During the ceremony: G １ is N; G ２ CR Ｇ２ or N; G ３ CR Ｇ３ or N; G ４ CR Ｇ４ or N; G ５ is either CR Ｇ５ or N; R Ｇ２ , R Ｇ３ , R Ｇ４ , and R Ｇ５ Each of these is independently H, Halo, CN, C １－７ Alkyl, C ３－７ Cycloalkyl, C １ - ３ Haloalkyl, -O-C １ - ３ Alkyl, -O-C １ - ３ Haloalkyl, -NR ａ R ｂ The cycloalkyl group and the heterocycloalkyl group are selected from the group consisting of 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and the heterocycloalkyl group are independently halo, CN, and C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, -O-C １－４ Substitution with 0 to 3 groups selected from alkyl and OH groups; R １ H, C １－４ alkyl and NH ２ Choose from the group consisting of; A is a fused ring selected from the group consisting of azepane, piperidine, cycloheptane, cyclohexane, cyclopentane, 1,4-oxazepane, oxepane, tetrahydropyran, 1,4-diazepane, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which is either unsubstituted or has 1 to 4 R groups. ２ The substitution is performed by 0 or 1 oxo (=O) adjacent to the nitrogen atom; B is a fused ring selected from the group consisting of 1,4-oxazepane, cycloheptane, tetrahydropyran, isothiazolidine 1,1-dioxide, oxepan, 1,4,5-oxathiazepane 4,4-dioxide, cyclohexane, cyclopentane, azepan, pyrrolidine, piperidine, piperazine, morpholine, diazepane, and 1,3-dioxolane, each of which is either unsubstituted or has 1 to 4 R ４ The substitution is performed by 0 or 1 oxo (=O) adjacent to the nitrogen atom; Each R ２ These are independently: Halo, OH, C １－７ Alkyl, C ３－７ Alkenil, C ３－７ Alkinyl, C ３－７ Cycloalkyl, -C(O)-C １－７ Alkyl, -C(O)-C ３－７ Cycloalkyl, -C(O)-C １－７ Alkylene -OH, -Y １ -O-C １－７ Alkyl, -Y １ -O-C ３－７ Cycloalkyl, -NR ａ R ｂ , -S(O) ２ -C １－７ Alkyl, -S(O) ２ -C ３－７ Cycloalkyl, -C(O)NR ａ R ｂ , 4-8 member heterocycloalkyl, and -NR ａ - Selected from the group consisting of (4-8 membered heterocycloalkyls), each 4-8 membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and heterocycloalkyl group independently constitute a halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, -O-C １－４ Substituted with 0 to 3 groups selected from alkyl and OH groups; The subscript n is 0, 1, 2, or 3; Each R ３ is, independently, halogen, CN, C １－７ alkyl, C ２－７ alkenyl, C ３－７ alkynyl, C ３－７ cycloalkyl, C １ - ６ haloalkyl, C １ - ６ hydroxyalkyl, C １ - ６ halohydroxyalkyl, -O-C １－７ alkyl, -O-C ３－７ cycloalkyl, -O-C １ - ６ haloalkyl, -X １ -CN, -X １ -O-C １－７ alkyl, -O-Y １ -O-C １－７ alkyl, -NR ａ R ｂ , -X １ -NR ａ R ｂ , -O-Y １ -NR ａ R ｂ , -C(O)-NR ａ R ｂ , -S(O) ２ -NR ａ R ｂ , -S(O)(NH)-C １－７ alkyl, -S(O) ２ -C １－７ alkyl, -S(O) ２ -C １－７ haloalkyl, -S(O) ２ -C ３－７ cycloalkyl, -S(O) ２ -Y １ -O-C １ - ３ alkyl, -S(O) ２ -(4- to 8-membered heterocycloalkyl), -C(O)NH-(4- to 8-membered heterocycloalkyl), 4- to 8-membered heterocycloalkyl, and -O-X １ - Selected from the group consisting of (4-8 member heterocycloalkyls), the 4-8 member heterocycloalkyl has 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl are independently halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, -O-C １－４ Substituted with 0 to 3 groups selected from alkyl and OH groups; Each R ４ These are independently H, halogen, hydroxyl, CN, and C. １－７ Alkyl, C ２－７ Alkenil, C ３－７ Alkinyl, C ３－７ Cycloalkyl, C １ - ６ Haloalkyl, C １ - ６ Hydroxyalkyl, C １ - ６ Halohydroxyalkyl, -O-C １－７ Alkyl, -O-C ３－７ Cycloalkyl, -O-C １ - ６ Haloalkyl, -X １ -CN, -X １ -O-C １－７ Alkyl, -S(O) ２ -C １－４ Alkyl, -S(O) ２ -C ３－７ Cycloalkyl, -C(O)NR ａ R ｂ , -NR ａ R ｂ , -NR ａ -C(O)-C １－７ Alkyl, -NR ａ -C(O)-C ３－７ Cycloalkyl, -NR ａ -S(O) ２ -C １－７ Alkyl and -NR ａ -S(O) ２ -C ３－７ Selected from the group consisting of cycloalkyls, -NR ａ R ｂ , -NR ａ -C(O)-C １－７ Alkyl, -NR ａ -C(O)-C ３－７ Cycloalkyl, -NR ａ -S(O) ２ -C １－７ Alkyl and -NR ａ -S(O) ２ -C ３－７ Cycloalkyl groups do not bond directly to the vertices of the nitrogen ring and do not form N-N bonds; Alternatively, two R atoms bonded to a common carbon atom ４ However, when combined, C ３－６ Spirocycloalkyl is formed, which is either unsubstituted or contains F, Cl, OH, and CH. ３ It is replaced by 1 to 3 elements that are selected independently; Each X １ C １－７ Alkylene or C ３－７ It is a cycloalkylene; Each Y １ C ２－７ Alkylene or C ３－７ It is a cycloalkylene, and the two bonded heteroatoms are not bonded to a common carbon atom; R ａ and R ｂ Each of these is independently H, C １－７ Alkyl, C １－７ Haloalkyl, C １－４ Alkoxy C １－４ Alkyl and C ３－７ Select from the group consisting of cycloalkyl groups; or R ａ and R ｂ Together with the nitrogen atoms to which they are bonded, they form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatomic ring vertices selected from the group consisting of O, N, and S, and include halogens, CN, and C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, -O-C １－４ The compound, or a pharmaceutically acceptable salt thereof, is substituted with 0 to 3 groups independently selected from alkyl, oxo, and OH groups. [Claim 2] G ２ However, it is CH or CF, and / or G ３ , CH, CF, C(CH ３ Select from the group consisting of ), and N, and / or G ４ but is CH, CCl, or N, and / or G ５ However, it is CH or N. The compound according to claim 1, or a pharmaceutically acceptable salt thereof. [Claim 3] G ２ CH is, G ３ However, CH may also be used. G ４ However, CH may also be used. G ５ However, CH may also be used. The compound according to claim 1, or a pharmaceutically acceptable salt thereof. [Claim 4] Condensed ring A, 【Chemistry 2】 It has an expression for selecting from a group consisting of 1 to 4 R ２ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, substituted with. [Claim 5] The condensed ring A is given by formula: 【Transformation 3】 It has, One R ２ However, -NR ａ R ｂ It is fine, The compound according to claim 4, or a pharmaceutically acceptable salt thereof. [Claim 6] One R ２ However, it is pyrrolidinyl, which is unsubstituted, or halogen, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, -O-C １－４ The compound according to claim 5, or a pharmaceutically acceptable salt thereof, substituted with one to three substituents independently selected from the group consisting of alkyl, oxo, and OH. [Claim 7] The condensed ring B is selected from the group consisting of 1,4-oxazepane, tetrahydropyran, isothiazolidine 1,1-dioxide, 1,4,5-oxathiazepane 4,4-dioxide, azepane, and pyrrolidine, each of which is either unsubstituted or has 1 to 3 R groups. ４ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted with; and further substituted with zero or one oxo (=O) adjacent to the nitrogen atom. [Claim 8] Each R ４ These are, independently, halogen, C １－４ Alkyl, C １－４ R selected from the group consisting of haloalkyl and OH, or bonded to a common carbon ４ However, when combined, C ３－６ Spirocycloalkyl is formed, which is either unsubstituted or contains F, Cl, OH, and CH. ３ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted with one to three elements independently selected from the above. [Claim 9] The condensed ring A is: 【Chemistry 4】 The formula has to be selected from the group consisting of, and each of them has to be one or two more R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which may be substituted with. [Claim 10] The condensed ring A is given by the above formula: 【Transformation 5】 A compound according to claim 9, or a pharmaceutically acceptable salt thereof. [Claim 11] The aforementioned R ２ It is bonded to nitrogen, C １－７ Alkyl, C ３－７ Cycloalkyl, -C(O)-C １－７ Alkyl, -C(O)C ３－７ Cycloalkyl, -C(O)C １－７ Alkylene -OH, -Y １ -O-C １－７ Alkyl, -Y １ ― O-C ３－７ Cycloalkyl, -S(O) ２ -C １－７ Alkyl, -S(O) ２ -C ３―７ Cycloalkyl, -C(O)NR ａ R ｂ , and selected from the group consisting of 4-8 member heterocycloalkyl groups, wherein the 4-8 member heterocycloalkyl group has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and heterocycloalkyl group are independently halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, -O-C １－４ The compound according to claim 9, or a pharmaceutically acceptable salt thereof, substituted with 0 to 3 groups selected from alkyl and OH. [Claim 12] Condensed ring B, 【Transformation 6】 The formula has a set of formulas that select from a group consisting of, and each of them is either unsubstituted or has one or two R ４ It has been replaced with, The fused ring B does not have to be substituted, or Condensed ring B is, 【Transformation 7】 It is fine, A compound according to any one of claims 1 to 3 or 9 to 11, or a pharmaceutically acceptable salt thereof. [Claim 13] Condensed ring B is, 【Transformation 8】 The formula has a set of elements that are selected from a group consisting of, each of which is either unsubstituted or has 1 to 4 R's. ４ It has been replaced with, Condensed ring B has 1 to 4 R ４ They may be substituted with, and each of them independently of halogen, C １－４ Alkyl, C １－４ Selected from the group consisting of haloalkyl and OH, A compound according to any one of claims 1 to 3 or 9 to 11, or a pharmaceutically acceptable salt thereof. [Claim 14] Condensed ring B is, 【Chemistry 9】 The formula has a set of elements that are selected from a group consisting of, each of which is either unsubstituted or has 1 to 3 R's. ４ It has been replaced with, Each R ４ C １－４ Alkyl and C １－４ You may select from the group consisting of haloalkyls. A compound according to any one of claims 1 to 3 or 9 to 11, or a pharmaceutically acceptable salt thereof. [Claim 15] below: 【Chemistry 10-1】 【Chemistry 10-2】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following. [Claim 16] below: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 A compound according to claim 1, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof. [Claim 17] A pharmaceutical composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [Claim 18] A pharmaceutical product comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17, for use in a method of treating a disease, disorder, or condition mediated at least in part by AXL. [Claim 19] The pharmaceutical product according to claim 18, wherein the disease, disorder, or condition is cancer. [Claim 20] The pharmaceutical agent according to claim 18, further comprising administering at least one further therapeutic agent in the method described above. [Claim 21] The pharmacopoeia according to claim 20, wherein the at least one further therapeutic agent independently comprises one or more active agents selected from the group consisting of CD47-SIRPα pathway inhibitors (e.g., anti-CD47 antibodies), HIF inhibitors (e.g., HIF-2α inhibitors), immune checkpoint inhibitors, agents that target extracellular production of adenosine, radiotherapy agents, and chemotherapeutic agents. [Claim 22] A combination comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent. [Claim 23] The combination according to claim 22, wherein the at least one further therapeutic agent independently comprises one or more agents selected from the group consisting of CD47-SIRPα pathway inhibitors (e.g., anti-CD47 antibodies), HIF inhibitors (e.g., HIF-2α inhibitors), immune checkpoint inhibitors, agents that target extracellular production of adenosine, radiotherapy, and chemotherapeutic agents.