AXL compounds

Abstract

Provided herein are compounds of formula I that inhibit AXL: [Formula 1] Described herein are compounds of JPEG2024521706000191.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 / 191,631, 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 Initiative]

[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 , R5 , ring A, 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 between the upper and lower limits of the range and each intermediate value 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, are included in the present disclosure. Furthermore, the upper and lower limits of these smaller ranges can be independently included in their respective smaller ranges according to any limit values specifically excluded in the described range, and are also included in the present disclosure. If the described range includes one or both of the limit values, the range excluding one or both of the included limit values is also included in the present disclosure. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains.

[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. Accordingly, 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 the present 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 indicated 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-chain hydrocarbon group having the specified number of carbon atoms (i.e., C 1-8 means 1 to 8 carbons). Alkyl is C 1-2 C 1-3 C1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 Alkyl groups can contain any number of carbon atoms. 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 the number of carbon atoms indicated (for example, C 1-6 or C 1-8 This refers to an alkyl group that has a hydroxyl group and is substituted with one or two hydroxyl (OH) groups.

[0015] The term "hydroxyhaloalkyl" refers to the number of carbon atoms indicated (for example, C 1-6 or C 1-8 This refers to an alkyl group that has ) and is 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) nIt 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 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 one or more embodiments, the heteroatom is O, N, 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 forms 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 a 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," for example, the response of a cell, tissue, organ, or organism, includes changes in biochemical or physiological behavior, such as changes in concentration, density, adhesion, or migration within a biological compartment, the rate of gene expression, or the state of differentiation, and such changes correlate with internal mechanisms such as activation, stimulation, or treatment, or genetic programming. In certain contexts, terms such as "activation" and "stimulation" refer to cellular activation regulated by internal mechanisms and external or environmental factors; on the other hand, terms such as "inhibition" and "downregulation" refer to the opposite effect.

[0044] A selective compound may be particularly useful in treating a particular disorder or may suppress the potential for undesirable side effects. In some embodiments, the compounds of this 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 against AXL with the inhibition of a compound against another receptor tyrosine kinase (e.g., MER, and / or TYRO3). In some embodiments, the selective inhibitory effect on 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] Compounds of the Disclosure In a particular embodiment, formula (I) [ka] A compound having, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, During the ceremony: G 1 is N or CR G1 is; G 2 CR G2 or N; G 3 CR G3 or N; G4 CR G4 or N; G 5 CR G5 or N; R G1 H, C 1-3 Alkyl, halogen, C 1-3 Select from the group consisting of 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, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 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, and the cycloalkyl and heterocycloalkyl 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; A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-oxazepane, 1,4-diazepane, oxepane, tetrahydropyran, piperidine, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which has 1 to 4 R 2 Substitute with and further substitute with 0 or 1 oxo (=O) adjacent to the nitrogen atom; where A is piperidine or 1,4-oxazepane, G 1 is N: R 1 teeth: i) A 5- or 6-membered heteroaryl having 1 to 3 heteroatom ring vertices selected from the group consisting of phenyl, or O, N, and S, wherein each phenyl and heteroaryl is substituted with 0 to 3 R 3 ; ii) A 4- to 8-membered heterocycloalkyl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, substituted with 0 to 3 R 4 substituents and further substituted with 0 or 1 oxo (=O) adjacent to a nitrogen atom; and iii) C 4 cycloalkyl substituted with 0 to 3 R 3-7 substituents; selected from the group consisting of: Each R 2 is independently C 1-7 alkyl, C 3-7 alkenyl, C 3-7 alkynyl, C 3-7 cycloalkyl, -Y 1 -O-C 1-7 alkyl, -Y 1 -O-C 3-7 cycloalkyl, -NR a R b , -C(O)-C 1-7 alkyl, -C(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 , 4- to 8-membered heterocycloalkyl, -NR a -(4- to 8-membered heterocycloalkyl), -C(O)-(4- to 8-membered heterocycloalkyl), -X 1 -(4- to 8-membered heterocycloalkyl), and -O-X 1 -(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has from 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 halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4Hydroxyalkyl, -OC 1-4 Substituted with 0 to 3 groups independently selected from alkyl and OH groups; 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, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halohydroxyalkyl, -OC 1-7 Alkyl, -OC 3-7 Cycloalkyl, -OC 1-6 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 -OC 1-3 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 heterocycloalkyls), the 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, and C 1-4 Alkyl, C1-4 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 halo, hydroxyl, CN, -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, -C(O)OC 1-7 Alkyl, -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 are R 1 It does not directly bond to the nitrogen atom ring member of a 4- to 8-membered heterocycloalkyl group, thus not forming an NN bond; R 5 H, C 1-4 Select from the group consisting of alkyl and -NH2; Each X 1 C 1-7 Alkylene or C 3-7 It is a cycloalkylene; Each Y 1 C 2-7 Alkylene or C 3-7It 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 halo, 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 the 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 N, CH, and C(CH3).

[0049] 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 4 However, it is a compound that is N or CH.

[0050] 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 5 However, it is a compound that is N or CH.

[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 5 It 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 2These 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] In some selected embodiments, including the selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, has a condensed ring A, [ka] It has an expression for selecting from a group consisting of 1 to 4 R 2 It is a compound in which each R is substituted. In some embodiments, each R 2 Independently, C 1-7 Alkyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -NR a R b , -C(O)-C 1-7 Alkyl, -C(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 , 4-8 member heterocycloalkyl, -NR a -(4-8 member heterocycloalkyl), -C(O)-(4-8 member heterocycloalkyl), -X 1 -(4-8 member heterocycloalkyl), and -OX 1-Selected from the group consisting of (4-8 member heterocycloalkyls), each heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl are independently halo, CN, and 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. In further selected embodiments, each R 2 C 1-7 Alkyl, -NR a R b , and -NR a -Selected from (4-8 member heterocycloalkyls), each heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, independently of halo, CN, and 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.

[0054] In some further selected embodiments, including the selected embodiments described above, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the condensed ring A is of formula: [ka] It is a compound that has [a certain characteristic].

[0055] In some further selected embodiments, including the 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 b It is a compound that is [this compound].

[0056] In some embodiments, including the selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is R2 but: [ka] It is a compound that is [this compound].

[0057] In some selected embodiments, including the 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 has to be selected from the group consisting of, and each of them optionally has one or two additional independently selected R 2 Substitute with a base. In further selected embodiments, the condensed ring A is of formula: [ka] It has.

[0058] In further selected embodiments, including the selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is R 2 However, C 1-7 Alkyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -C(O)-C 1-7 Alkyl, -C(O)-C 3-7 Cycloalkyl, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, 4-8 member heterocycloalkyl, -C(O)-(4-8 member heterocycloalkyl), -X 1 -A compound selected from the group consisting of (4-8 member heterocycloalkyl groups), where the 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 1-4Substitution is made with 0 to 3 groups selected from alkyl and OH groups.

[0059] In some embodiments, including the selected embodiments described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is one R 2 but: [ka] It is a compound that is [this compound].

[0060] In some selected embodiments, including those described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is R 1 However, it is phenyl, which has 1 to 3 R's. 3 These are compounds in which R is arbitrarily substituted. In further selected embodiments, each R 3 If present, halogen, CN, 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, -OC 1-7 Alkyl, -OC 3-7 Cycloalkyl, -OC 1-6 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 1-7Alkyl, -S(O)2-C 1-7 Alkyl, -S(O)2-C 1-7 Haloalkyl, -S(O)2-C 3-7 Cycloalkyl and -S(O)2-Y 1 -OC 1-3 Selected from the group consisting of alkyl groups, cycloalkyl groups are independently halo, CN, and 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. In further embodiments, each R 3 If present, halogen, CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halohydroxyalkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -OC 1-4 Haloalkyl, -X 1 -CN, -X 1 -OC 1-4 Alkyl, -OY 1 -OC 1-4 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 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 1-4 Haloalkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-Y 1 -OC 1-3Alkyl, -S(O)2-(4-6 member heterocycloalkyl), -C(O)NH-(4-6 member) heterocycloalkyl, 4-6 member heterocycloalkyl, and -OX 1 -Selected from the group consisting of (4-6 member heterocycloalkyls), each heterocycloalkyl having 1-2 heteroatom vertices selected from the group consisting of O, N, and S, and cycloalkyls and heterocycloalkyls independently consist of halo, CN, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Substitution with 0 to 3 groups selected from alkyl and OH. In some embodiments, R 3 These are, independently, halogen, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halohydroxyalkyl, -OC 1-6 Haloalkyl, -X 1 -CN, -OY 1 -OC 1-7 Alkyl, -X 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 -OC 1-3 Alkyl, -C(O)NH- (4-8 member heterocycloalkyl), 4-8 member heterocycloalkyl, and -OX 1 -Selected from the group consisting of (4-8 member heterocycloalkyls), each heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl are independently halo, C 1-4Alkyl, 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.

[0061] In one or more embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is of formula (Ia): [ka] It is a compound of [the compound].

[0062] one In one or more embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formula (Ia1): [ka] It is a compound of the following, where the subscript p in the formula is 0, 1 or 2, and each R 3 They can be the same or different.

[0063] In one or more embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is of formula (Ib): [ka] It is a compound in which the subscript m in the formula is 0 or 1, and n is 0, 1 or 2, and each R 2 They can be the same or different.

[0064] In one or more embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formula (Ib1): [ka] It is a compound in which the subscript m in the formula is 0 or 1, and p is 0, 1 or 2, and each R 2 and R3 They can be the same or different.

[0065] In one or more embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is of formula (Ic): [ka] It is a compound in which the subscript m in the formula is 0 or 1, and n is 0, 1 or 2, and each R 2 They can be the same or different, R 6 , Haro, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Select from the group consisting of alkyl, oxo, and OH.

[0066] In one or more embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is formula (Ic1): [ka] It is a compound in which the subscript m in the formula is 0 or 1, n is 0, 1 or 2, p is 0, 1 or 2, and each R 2 and R 3 They can be the same or different, R 6 , Haro, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Select from the group consisting of alkyl, oxo, and OH.

[0067] In one or more embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is of formula (Id): [ka] It is a compound of which, in the formula, R 6, Haro, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Select from the group consisting of alkyl, oxo, and OH.

[0068] In one or more embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is of formula (Ie): [ka] The compound is such that the subscript n in the formula is 0, 1 or 2, and each R 2 They can be the same or different.

[0069] In one or more embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is of formula (If): [ka] The compound is such that the subscript n in the formula is 0, 1 or 2, and each R 2 They can be the same or different.

[0070] In one or more embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is of formula (If1): [ka] It is a compound in which the subscript n in the formula is 0, 1 or 2, p is 0, 1 or 2, and each R 2 and R 3 They can be the same or different.

[0071] In some selected embodiments, compounds of formula (I), or pharmaceutically acceptable salts, hydrates, or solvates thereof, belong to the following group: [ka] Choose from the options.

[0072] In some embodiments, formula (I) [ka] A compound having, or a pharmaceutically acceptable salt, hydrate, or solvate 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 CR G5 or N; R G1 H, C 1-3 Alkyl, halogen, C 1-3 Select from the group consisting of 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, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 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, and the cycloalkyl and heterocycloalkyl 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; A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-oxazepane, 1,4-diazepane, oxepane, tetrahydropyran, piperidine, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which has 1 to 4 R 2 Substitute with , and then further substitute with 0 or 1 oxo (=O) adjacent to the nitrogen atom; R 1 teeth: i) A phenyl or a 5-6 member heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, where each phenyl and heteroaryl has 0-3 R 3 Replace with; ii) Having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and 0 to 3 R 4 4- to 8-membered heterocycloalkyls that are substituted with substituents and further substituted with 0 or 1 oxo (=O) adjacent to the nitrogen atom; and iii) 0 to 3 R 4 C substituted with substituents 3-7 Cycloalkyl; Choose from the group consisting of: Each R 2 Independently, C 1-7 Alkyl, C 3-7 Alkenil, C 3-7 Alkinyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -NR a R b , -C(O)-C 1-7 Alkyl, -C(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 , 4-8 member heterocycloalkyl, -NRa -(4-8 member heterocycloalkyl), -C(O)-(4-8 member heterocycloalkyl), -X 1 -(4-8 member heterocycloalkyl), and -OX 1 -Selected from the group consisting of (4-8 member heterocycloalkyls), the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl 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 3 These are, independently, halogen, 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, -OC 1-7 Alkyl, -OC 3-7 Cycloalkyl, -OC 1-6 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 3-7Cycloalkyl, -S(O)2-Y 1 -OC 1-3 Alkyl, -S(O)2-C 4-7 Heterocycloalkyl, -C(O)NH- (4-8 member heterocycloalkyl), 4-8 member heterocycloalkyl, and -OX 1 -Selected from the group consisting of (4-8 member heterocycloalkyls), the 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, 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 halo, hydroxyl, CN, -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, -C(O)OC 1-7 Alkyl, -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 are R 1It does not directly bond to the nitrogen atom ring member of a 4- to 8-membered heterocycloalkyl group, thus not forming an NN bond; R 5 H, C 1-4 Select from the group consisting of alkyl and -NH2; 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 halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -X 1 -OC 1-7 Alkyl, -OC 1-4 The present invention provides compounds or pharmaceutically acceptable salts, hydrates, or solvates thereof, substituted with 0 to 3 groups independently selected from alkyl, oxo, and OH groups.

[0073] In some embodiments, formula (I) [ka] A compound having, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, During the ceremony: G1 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 H, C 1-3 Alkyl, halogen, C 1-3 Select from the group consisting of 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, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 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, and the cycloalkyl and heterocycloalkyl 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; A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-diazepane, oxepane, tetrahydropyran, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which has 1 to 4 R 2 Substitute with , and then further substitute with 0 or 1 oxo (=O) adjacent to the nitrogen atom; R 1 teeth: i) A phenyl or a 5-6 member heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, where each phenyl and heteroaryl has 0-3 R 3 Replace with; ii) Having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and 0 to 3 R 4 4- to 8-membered heterocycloalkyls that are substituted with substituents and further substituted with 0 or 1 oxo (=O) adjacent to the nitrogen atom; and iii) 0 to 3 R 4 C substituted with substituents 3-7 Cycloalkyl; Choose from the group consisting of: Each R 2 Independently, C 1-7 Alkyl, C 3-7 Alkenil, C 3-7 Alkinyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -NR a R b , -C(O)-C 1-7 Alkyl, -C(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 , 4-8 member heterocycloalkyl, -NR a -(4-8 member heterocycloalkyl), -C(O)-(4-8 member heterocycloalkyl), -X 1 -(4-8 member heterocycloalkyl), and -OX 1 -Selected from the group consisting of (4-8 member heterocycloalkyls), the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl are independently halo, CN, and C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Substituted with 0 to 3 groups selected from alkyl and OH groups; 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, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halohydroxyalkyl, -OC 1-7 Alkyl, -OC 3-7 Cycloalkyl, -OC 1-6 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 -OC 1-3 Alkyl, -S(O)2-C 4-7 Heterocycloalkyl, -C(O)NH- (4-8 member heterocycloalkyl), 4-8 member heterocycloalkyl, and -OX 1-Selected from the group consisting of (4-8 member heterocycloalkyls), the 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, 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 halo, hydroxyl, CN, -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, -C(O)OC 1-7 Alkyl, -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 are R 1 It does not directly bond to the nitrogen atom ring member of a 4- to 8-membered heterocycloalkyl group, thus not forming an NN bond; R 5 H, C 1-4 Select from the group consisting of alkyl and -NH2; Each X 1 C 1-7 Alkylene or C3-7 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 halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -X 1 -OC 1-7 Alkyl, -OC 1-4 The present invention provides compounds or pharmaceutically acceptable salts, hydrates, or solvates thereof, substituted with 0 to 3 groups independently selected from alkyl, oxo, and OH groups.

[0074] In some selected embodiments, one of the compounds in Table 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided.

[0075] Synthesis method A general method for preparing the claimed compound Common method: 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]

[0076] Several methods for preparing the claimed compounds are illustrated (Equations 1-7). 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]

[0077] 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]

[0078] 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]

[0079] The relative positions of the amine and ketone can also be reversed, as illustrated in formula (4). Those skilled in the art will recognize other possible conditions that yield the desired bonding affinity and product. The formation of the ab fragment, as illustrated in formulas (l) to (4), can occur either before or after the formation of the bc fragment. [ka]

[0080] 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 (5) 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, or SnR3. Z can be selected from suitable groups such as Cl, Br, I, or 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]

[0081] Relative functionalization of bonding partners can also be carried out in the reverse direction, as shown in equation (6). Those skilled in the art will recognize other possible combinations and conditions that yield the desired product. [ka]

[0082] 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 (7) 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]

[0083] 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.

[0084] 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.

[0085] In some embodiments, the AXL inhibitors described herein are administered in amounts effective to reverse, halt, or delay the progression of AXL-mediated dysregulation.

[0086] 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.

[0087] In some embodiments, the compounds according to this disclosure are useful in the treatment of renal cancer. In further embodiments, renal cancer is renal cell carcinoma. In even further embodiments, renal cell carcinoma is clear cell renal carcinoma (ccRCC).

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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)).

[0092] 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).

[0093] 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.

[0094] 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.

[0095] In some embodiments, the Disclosure provides methods for treating proliferative conditions, cancers, tumors, or precancerous conditions using AXL inhibitors and at least one further therapeutic or diagnostic agent, examples of which are described elsewhere in this Spec.

[0096] 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.

[0097] 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.

[0098] In some embodiments, the AXL inhibitors described herein, when combined with immunosuppressants, can reduce the number of immune effector cells.

[0099] 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).

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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).

[0110] 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).

[0111] 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.

[0112] 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).

[0113] 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.

[0114] Certain embodiments of this disclosure are intended for oral administration.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] In certain embodiments, the Disclosure provides a method for suppressing 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.

[0120] In some embodiments, 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, chlornafadin, cyclophosphamide Estramustine, ifosphamide, 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, kakuchinomycin, calichemycin, carabicin, caminomycin, cardinophilin, chloro Momycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogaramycin, olibomycin, pomalidomide, peplomycin, potophyllomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zorubicin; methotrexate, and 5-fluorouracil (5-FU ) and other antimetabolites; folate analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and 5-FU; androgens, e.g., carsterone, dromostanolone propionate, epithiostanol, metipithiostanol, and testolactone;Anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; acegraton; aldofrosphamide glycoside; aminolevulinic acid; amsacrin; bestrabusil; bisanthren; edatraxate; defofamine; demecolsin; diazicone; elformitin; eriptinium acetate; etogluside; gallium nitrate; hydroxyurea; lentinan; ronidamine; mitogluzone ; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Lazoxane; 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); ifosphamide; 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 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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).

[0125] 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.

[0126] 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 some 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 some embodiments, the CD73 inhibitor is chemrecrustat (AB680).

[0127] 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).

[0128] 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.

[0129] In certain embodiments, this disclosure intends to use in combination with the compounds described herein an arginase inhibitor that exhibits any of the following characteristics: being the cause of, or being 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 WO / 2020 / 102646.

[0130] 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.

[0131] Furthermore, this disclosure envisions a combination 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, Q13C, 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.

[0132] 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.).

[0133] Immune checkpoint inhibitors. This disclosure intends to use the AXL inhibitors described herein in combination with immune checkpoint inhibitors.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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].

[0138] 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].

[0139] 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).

[0140] In one or more 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.

[0141] 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).

[0142] 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, cintilimab, tislerizumab, AB308, domvanarimab, and zimbererimab.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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, WO13 / 169264, WO14 / 036357), but are not limited to these.

[0147] 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.

[0148] 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.

[0149] In another embodiment, the cancer immunotherapy agent is a PD-1 antagonist as described elsewhere in this specification.

[0150] In another embodiment, the cancer immunotherapy agent is a PD-L1 antagonist as described elsewhere in this specification.

[0151] In another embodiment, the cancer immunotherapy agent is a TIGIT antagonist as described elsewhere in this specification.

[0152] 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).

[0153] 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).

[0154] 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).

[0155] 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.

[0156] 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).

[0157] 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.

[0158] 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.

[0159] In another embodiment, the cancer immunotherapy drug is MGA271 (WO11 / 109400) (against B7H3).

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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).

[0165] 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.

[0166] 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.

[0167] In some embodiments, the AXL inhibitor according to this disclosure is combined with a menin-MLL inhibitor.

[0168] 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.

[0169] This disclosure includes any of the pharmaceutically acceptable salts, acids, or derivatives described above.

[0170] 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.

[0171] 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 receiving the formulation, 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).

[0172] 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.

[0173] 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.).

[0174] 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), to obtain the desired therapeutic effect.

[0175] 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).

[0176] 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).

[0177] 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.

[0178] 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).

[0179] 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).

[0180] 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.

[0181] 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.

[0182] 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)carbodiimide, 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, MHz = megahertz, Hz = hertz, ppm = parts per million, ESI MS = Electrospray Ionization Mass Spectrometry, NMR = Nuclear Magnetic Resonance

[0183] Materials and methods The following general materials and methods were used, or may be used, in the following examples, where explicitly stated.

[0184] 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]

[0185] Example 1: 3-(4-(cyclopropylsulfonyl)phenyl)-5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0186] Step a: To a mixture of 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (25.0 g, 77.2 mmol), camphor sulfonic acid (1.79 g, 7.72 mmol), and THF (193 mL), 3,4-dihydro-2H-pyran (14.1 mL, 154 mmol) was added at room temperature. This mixture was stirred at 65°C for 3 hours, cooled to room temperature, and 28% by weight of NH4 was added. 3(水溶液) The reaction was stopped at (10 mL). The mixture was concentrated on silica gel and purified by column chromatography (hexane:SiO, 4:1) to obtain the desired product as a white solid (26.8 g, 85%).

[0187] Step b: A mixture of 1-bromo-4-(cyclopropylsulfonyl)benzene (12.9 g, 49.3 mmol), B2pin2 (12.5 g, 49.3 mmol), (dppf)PdCl2 (1.80 g, 2.46 mmol), and KOAc (9.67 g, 98.6 mmol) was placed under nitrogen. Degassed dioxane (246 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 directly in step c.

[0188] Step c: A mixture of the product from step a (20.1 g, 49.3 mmol), the product from step b (estimated value of 49.3 mmol), (dppf)PdCl2 (3.61 g, 4.93 mmol), and K2CO3 (13.6 g, 98.6 mmol) was placed under nitrogen. Degassed dioxane (197 mL) and degassed water (49 mL) were added, and the reaction mixture was stirred at 80°C for 4 hours. The mixture was cooled to room temperature, concentrated, diluted with CH2Cl2 (250 mL), dried over Na2SO4, and concentrated again. The crude product was purified by column chromatography (330 g silica gel, CH2Cl2: siRNA) with a gradient from 0% to 50% (25 minutes) to obtain the desired product as an off-white solid (20.7 g, 91%).

[0189] Step d: The desired product was prepared in the same manner as in Example 1, step b, and used directly in step f. CH2Cl2 was used instead of ammonium as the solvent in the filtration step.

[0190] Step e: To a mixture of toluene (100 mL) containing 2-bromo-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-one (5.05 g, 21.1 mmol) and (2R)-2-methylpyrrolidine (2.3 mL, 23.2 mmol), 1H-1,2,3-triazole (1.5 mL, 25.3 mmol) was added. This reaction mixture was stirred under reflux for 12 hours, with water being recovered via a Dean-Stark trap. Once cooled, the toluene solution was added over 30 minutes to a mixture of cooled (0°C) MeMgBr solution (Et2O containing 3 M, 127 mmol) and THF (84 mL). This 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. The aqueous layer was extracted with SiO2 (3 × 100 mL), and the combined organic layers were washed with 2N NaOH aqueous solution (2 × 30 mL) and brine, dried on anhydrous MgSO4, and concentrated. Purification by silica gel chromatography (CH2Cl2 containing 100% CH2Cl2 to 10% MeOH, 1% NH4OH) followed by repeated precipitation with MeOH yielded the desired product as a white powder (4.44 g, 65%; approximately 1:1 d.r.).

[0191] Step f: The reaction mixture was stirred at 95°C for 20 hours, and the crude product was purified by column chromatography (330g silica gel, CH2Cl2:(Â+1%Et3N)) with a gradient from 0% to 100% (20 minutes). The desired product was then prepared in the same manner as in Example 1, Step c, except that the reaction mixture was stirred at 95°C for 20 hours and the crude product was purified by column chromatography. At 100% (5 minutes), the desired product was obtained as a pale yellow solid (12.7g, 49%).

[0192] Step g: The product from step f (12.7 g, 20.3 mmol) was mixed with MeOH (101 mL) containing 3 M HCl and stirred at room temperature for 23 hours, then diluted with MTBE (750 mL). The precipitated solid was collected by filtration and washed with MTBE. The crude product was purified by column chromatography (4 × 130 g C18, (H2O / ACN) + 0.1% TFA) with a gradient from 5% to 50% (25 minutes), and the combined fraction was saturated with NaHCO3 3(水溶液) The mixture was neutralized with (50 mL). ACN was removed under vacuum. The precipitated solid was collected by filtration, washed with water, and dried to obtain the desired product as a white solid (8.00 g, 73%). 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.5 Hz, 2H), 8.00 (d, J = 8.5 Hz, 2H), 7.55 (t, J = 2.3 Hz, 1H), 7.50 (dt, J = 7.6, 2.1 Hz, 1H), 7.20 (dd, J = 7.8, 3.5 Hz, 1H), 3.45 - 3.26 (m, 1H), 3.25 - 3.05 (m, 2H), 2.94 - 2.86 (m, 1H), 2.80 (t, J = 7.6 Hz, 1H), 2.69 - 2.48 (m, 3H), 1.96 - 1.56 (m, 5H), 1.44 - 1.19 (m, 3H), 1.18 - 1.10 (m, 2H), 1.10 - 1.03 (m, 2H), 1.00 (d, J = 6.2 Hz, 3H), 0.89 (s, 3H). ESI MS [M+H] + C 32 H 37 Calculated value for N4O2S: 541.3, Measured value: 541.3.

[0193] Example 2: 4-(2-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)morpholine [ka]

[0194] The indicated compound was prepared in the same manner as in Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.1 Hz, 1H), 8.75 (d, J = 1.5 Hz, 1H), 8.40 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 7.7, 2.0 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 3.75 - 3.59 (m, 4H), 3.32 - 3.21 (m, 2H), 2.99 - 2.87 (m, 1H), 2.55 - 2.50 (m, 4H), 2.48 - 2.37 (m, 2H), 2.16 - 2.05 (m, 2H), 1.30 - 1.14 (m, 4H), 1.14 - 1.05 (m, 2H), 0.86 (s, 3H). ESI MS [M+H] + C 31 H 35 Calculated value for N4O3S: 543.2, Measured value: 543.2.

[0195] Example 3: [(2R)-1-(2-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)pyrrolidine-2-yl]methanol [ka]

[0196] The indicated compound was prepared in the same manner as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 1.5 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 8.7 Hz, 2H), 7.60 (dd, J = 5.2, 1.9 Hz, 1H), 7.54 (dt, J = 7.7, 2.4 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 4.43 (s, 1H), 3.34 - 3.18 (m, 2H), 3.16 - 2.98 (m, 3H), 2.97 - 2.88 (m, 1H), 2.83 - 2.72 (m, 1H), 2.72 - 2.46 (m, 3H), 1.95 - 1.75 (m, 3H), 1.75 - 1.63 (m, 2H), 1.57 - 1.26 (m, 3H), 1.21 - 1.14 (m, 2H), 1.14 - 1.05 (m, 2H), 0.97 (s, 3H). ESI MS [M+H] + C 32 H 37 Calculated value for N4O3S: 557.3, Measured value: 557.2.

[0197] Example 4: [(2S)-1-(2-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)pyrrolidine-2-yl]methanol [ka]

[0198] The indicated compound was prepared in the same manner as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 1.5 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 8.7 Hz, 2H), 7.60 (dd, J = 5.1, 2.0 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.24 (t, J = 7.7 Hz, 1H), 4.43 (s, 1H), 3.33 - 3.17 (m, 2H), 3.17 - 3.07 (m, 1H), 3.07 - 2.97 (m, 2H), 2.97 - 2.89 (m, 1H), 2.83 - 2.74 (m, 1H), 2.72 - 2.49 (m, 3H), 1.96 - 1.75 (m, 3H), 1.75 - 1.64 (m, 2H), 1.57 - 1.27 (m, 3H), 1.21 - 1.13 (m, 2H), 1.13 - 1.04 (m, 2H), 0.97 (s, 3H). ESI MS [M+H] + C 32 H 37 Calculated value for N4O3S: 557.3; Measured value: 557.2.

[0199] Example 5: (2S)-1-(2-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)-2-methylpyrrolidine [ka]

[0200] The indicated compound was prepared in the same manner as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (brs, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.74 (t, J = 1.9 Hz, 1H), 8.39 - 8.34 (m, 2H), 8.05 - 7.96 (m, 2H), 7.68 (d, J = 2.0 Hz, 1H), 7.61 (ddd, J = 7.7, 2.0, 0.9 Hz, 1H), 7.30 (dd, J = 7.9, 1.7 Hz, 1H), 4.18 - 3.97 (m, 1H), 3.40 - 3.18 (m, 2H), 3.01 - 2.69 (m, 5H), 2.28 - 2.12 (m, 1H), 2.12 - 1.97 (m, 1H), 1.97 - 1.75 (m, 4H), 1.75 - 1.56 (m, 2H), 1.52 (s, 3H), 1.30 (d, J = 6.6 Hz, 3H), 1.17 - 1.11 (m, 2H), 1.09 - 1.02 (m, 2H). ESI MS [M+H] + C 32 H 37 Calculated value for N4O2S: 541.3; Measured value: 541.2.

[0201] Example 6: (2R)-1-(2-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-7-ethyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)-2-methylpyrrolidine [ka]

[0202] The indicated compound was prepared in the same manner as in Example 1. 1H NMR (400 MHz, methanol-d4) δ 8.89 (d, J = 1.9 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.39 - 8.24 (m, 2H), 8.17 - 7.95 (m, 2H), 7.62 (t, J = 2.8, 2.1 Hz, 1H), 7.57 (dd, J = 7.7, 2.0 Hz, 1H), 7.35 (dd, J = 7.8, 3.2 Hz, 1H), 4.26 - 4.16 (m, 1H), 3.51 - 3.36 (m, 2H), 3.13 - 2.84 (m, 4H), 2.75 (tt, J = 8.0, 4.8 Hz, 1H), 2.41 - 1.99 (m, 7H), 1.99 - 1.74 (m, 3H), 1.44 (d, J = 6.7 Hz, 3H), 1.34 - 1.24 (m, 2H), 1.16 (t, J = 7.4 Hz, 3H), 1.14 - 1.07 (m, 2H). ESI MS [M+H] + C 33 H 39 Calculated value for N4O2S: 555.3; Measured value: 555.2.

[0203] Example 7: 1-(2-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)azetidine [ka]

[0204] The indicated compound was prepared in the same manner as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 10.96 - 10.58 (m, 1H), 8.91 (d, J = 2.1 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.54 - 8.32 (m, 2H), 8.12 - 7.93 (m, 2H), 7.70 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 7.7, 2.0 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 4.20 (p, J = 9.1 Hz, 2H), 3.91 - 3.55 (m, 2H), 3.01 - 2.83 (m, 5H), 2.43 - 2.26 (m, 1H), 2.18 - 2.04 (m, 1H), 1.97 - 1.85 (m, 2H), 1.64 - 1.51 (m, 2H), 1.50 (s, 3H), 1.22 - 1.12 (m, 2H), 1.13 - 1.05 (m, 2H). ESI MS [M+H] + C 30 H 33 Calculated value for N4O2S: 513.2; Measured value: 513.2.

[0205] Example 8: (2R)-2-methyl-1-{7-methyl-2-[3-(4-trifluoromethanesulfonylphenyl)-1H-pyrazolo[3,4-b]pyridine-5-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl}pyrrolidine [ka]

[0206] The indicated compound was prepared in the same manner as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (t, J = 2.6 Hz, 1H), 8.88 - 8.81 (m, 1H), 8.81 - 8.76 (m, 1H), 8.60 (d, J = 8.7 Hz, 2H), 8.26 (d, J = 8.7 Hz, 2H), 7.73 (s, 1H), 7.68 - 7.63 (m, 1H), 7.35 (d, J = 7.8 Hz, 1H), 4.13 (s, 1H), 3.33 (s, 2H), 3.02 - 2.75 (m, 4H), 2.23 (s, 1H), 2.08 (s, 1H), 1.92 (s, 3H), 1.78 - 1.61 (m, 3H), 1.56 (s, 3H), 1.29 (d, J = 6.9 Hz, 3H). ESI MS [M+H] + C 30 H 32 Calculated value for F3N4O2S: 569.2; Measured value: 569.2.

[0207] Example 9: 2-(5-{5-[7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}pyridine-2-yl)propan-2-ol [ka]

[0208] Step a: 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 being heated to room temperature after 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%).

[0209] Step b: The product from step a (5.5 g, 12.0 mmol), a mixture of 2-[1-methyl-1-[(trimethylsilyl)oxy]ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.0 g, 12.0 mmol), K2CO3 (3.3 g, 24.0 mmol), and (dppf)PdCl2 (885 mg, 1.2 mmol) was placed under nitrogen. Degassed dioxane (60 mL) and degassed H2O (15 mL) were added to this mixture. The reaction mixture was heated at 80°C for 14 hours, cooled to room temperature, and butyl (100 mL) was added. The phases were separated, and the aqueous phase was extracted with butyl (2 × 100 mL). The combined organic phase was dried and concentrated on Na2O4, and then purified by column chromatography (SiO2, hexane containing 0-30% siRNA) to obtain the desired product as a brown solid (3.5 g, 64%).

[0210] Step c: Dioxane (5.4 mL) was added to a mixture of the product from step b (577 mg, 1.08 mmol), B2pin2 (356 mg, 1.40 mmol), and KOAc (138 mg, 1.40 mmol), and the suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (40 mg, 0.0540 mmol) was added, and the reaction mixture was stirred at 80°C for 15 hours. As soon as it cooled, SiO (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.

[0211] Step d: To DCE (21.5 mL) containing a mixture of 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 then carefully stopped with H2O, followed by 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 100% CH2Cl2 to 10% MeOH, 0.5% NET3), yielding the desired product as viscous orange oil (978 mg, 77%).

[0212] Step e: Dioxane (3.3 mL) and H2O (0.40 mL) were added to a mixture of the crude product from step c (0.367 mmol), the product from step d (162 mg, 0.551 mmol), and Na2CO3 (78 mg, 0.734 mmol), and the suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (13 mg, 0.0184.80 mmol) was added, and this reaction mixture was stirred at 80°C for 16 hours. As soon as it cooled, CH2Cl2 (15 mL) was added, and this mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 containing 100% CH2Cl2 to 10% MeOH), and the desired product was obtained as a brown solid (152 mg, 62% from the product of step b).

[0213] Step f: To a solution of CH2Cl2 (1.2 mL) containing the product from step e (152 mg, 0.227 mmol), TFA (1.2 mL) was added. This reaction mixture was stirred at room temperature for 2 hours and then concentrated. To the residue, MeOH (7N solution, 2.3 mL) containing NH3 was added, and this reaction mixture was stirred at 40°C for 2 hours. As soon as it cooled, H2O (10 mL) was added, and the precipitated solid was collected by filtration and washed with H2O. It was purified by C18 reverse-phase chromatography (H2O containing 100% H2O to 60% ACN, 0.1% TFA) and lyophilized to obtain the labeled compound as a pale yellow solid (48 mg, 43%). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.23 (dd, J = 2.3, 0.8 Hz, 1H), 8.91 (d, J = 2.1 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.50 (dt, J = 8.2, 2.3 Hz, 1H), 7.86 (dd, J = 8.1, 1.3 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.66 (dd, J = 7.8, 1.9 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 3.65 - 3.41 (m, 3H), 3.27 - 3.10 (m, 2H), 3.03 (dd, J = 14.6, 7.4 Hz, 1H), 2.94 (dd, J = 14.8, 7.1 Hz, 1H), 2.89 - 2.77 (m, 2H), 2.42 - 2.28 (m, 2H), 2.06 - 1.92 (m, 2H), 1.92 - 1.77 (m, 2H), 1.52 (s, 6H), 1.51 - 1.39 (m, 2H). ESI MS [M+H] + C 29 H 34 Calculated value for N5O: 468.3; Measured value: 468.2.

[0214] Example 10: 2-{5-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyridine-2-yl}propan-2-ol [ka]

[0215] 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. The 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%).

[0216] Step b: Dioxane (3.8 mL) and H2O (0.40 mL) were added to a mixture of the crude product from Step c of Example 9 (0.384 mmol), the product from Step a (169 mg, 0.576 mmol), and Na2CO3 (81 mg, 0.768 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (14 mg, 0.0192 mmol) was added, and the reaction mixture was stirred at 80°C for 16 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 100% CH2Cl2 to 10% MeOH) to obtain the desired product as a brown solid (237 mg, 92; 2 steps).

[0217] Step c: To a solution of CH2Cl2 (1.8 mL) containing the product from step b (237 mg, 0.354 mmol), TFA (1.8 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. MeOH (7N solution, 3.5 mL) containing NH3 was added to the residue, and the reaction mixture was stirred at 40°C for 2 hours. As soon as it cooled, H2O (10 mL) was added, and the precipitated solid was collected by filtration and washed with H2O. After purification by C18 reverse-phase chromatography (H2O containing 100% H2O to 60% ACN, 0.1% TFA) and lyophilization, the labeled compound was obtained as a pale yellow solid (95 mg, 46%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.78 - 9.62 (m, 1H), 9.24 (dt, J = 2.3, 0.7 Hz, 1H), 8.92 (d, J = 2.1 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.50 (dd, J = 8.2, 2.3 Hz, 1H), 7.87 (dt, J = 8.3, 0.8 Hz, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 7.7, 1.9 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 3.88 - 3.66 (m, 3H), 3.35 - 2.98 (m, 6H), 2.17 - 1.96 (m, 2H), 1.84 - 1.66 (m, 4H), 1.65 - 1.54 (m, 2H), 1.52 (s, 6H). + C 29 H 34 Calculated value for N5O: 468.3; Measured value: 468.2.

[0218] Example 11: 2-(2-chloro-4-{5-[7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}phenyl)propan-2-ol [ka]

[0219] Step a: In Example 9, a 9:1 dioxane:H2O (32 mL) containing the product of Step a (1.47 g, 3.24 mmol), 1-[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-one (1.00 g, 3.56 mmol), and sodium carbonate (0.687 g, 6.48 mmol) was sparged with nitrogen for 10 minutes. (dppf)PdCl2 (0.474 g, 0.648 mmol) was added, and sparging was continued for a further 5 minutes. The mixture was stirred overnight at 100°C and then cooled to room temperature. CH2Cl2 (70 mL) was added, and the solution was dried over MgSO4 and concentrated. The solution was purified by flash chromatography (SiO2, hexane containing 0-50% siRNA) to obtain the product as a white solid (0.630 g; 40%).

[0220] Step b: A solution of THF (2.8 mL) containing the product from step a (0.618 g, 1.28 mmol) was added to THF (1.4 mL) containing a solution of methylmagnesium bromide (0.73 mL, 2.18 mmol, 3.0 M Et2O) at room temperature over 40 minutes via a syringe pump. After the addition was complete, the mixture was stirred at room temperature for a further 1 hour. The mixture was then cooled in ice / saturated NH4Cl (水溶液) The mixture was poured into (25 mL). This product was extracted with ethyl acetate (3 × 25 mL), and the combined organic phase was washed with brine (50 mL) and dried (MgSO4). The crude product was purified by flash chromatography (hexane containing 0-40% ethyl acetate) to obtain the desired product as a white solid (0.542 g, 85%).

[0221] Step c: Dioxane (16.6 mL) was added to a mixture of the product from Step d of Example 9 (978 mg, 3.32 mmol), B2pin2 (927 mg, 3.65 mmol), and KOAc (391 mg, 3.98 mmol), and the suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (121 mg, 0.166 mmol) was added, and the reaction mixture was stirred at 90°C for 4 hours. As soon as it cooled, SiO (20 mL) was added, and the mixture was filtered through Celite. The filtrate was concentrated to obtain a viscous brown oily crude product, which was used directly in the next step.

[0222] Step d: The desired compound was prepared in the same manner as in step a (73.7 mg, 39%).

[0223] Step e: A solution of the product from step d (72.3 mg, 0.115 mmol) and tetrabutylammonium fluoride hydrate (180 mg, 0.687 mmol) in DMF (0.15 mL) was stirred overnight at room temperature under high vacuum. This mixture was then mixed with saturated NaHCO₃⁻. 3(水溶液) The mixture was diluted with (5 mL) and the product was extracted in 9:1 CHCl3:IPA (3 × 5 mL). The combined organic phase was dried (Na2SO4) and concentrated. The residue was placed in MeOH (1.15 mL) and treated with DMEDA (0.10 mL, 0.92 mmol). This mixture was stirred at 45°C for 30 minutes and then concentrated. The residue was flash-chromatographed (1-10% MeOH / NH₃). 3(水溶液) The compound was purified twice with CH2Cl2 containing 10:1 to obtain the marked compound as an off-white solid (21 mg, 36%). 1H NMR (400 MHz, chloroform-d) δ 8.83 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.02 (t, J = 1.1 Hz, 1H), 7.85 (s, 2H), 7.38 (dq, J = 3.7, 2.0 Hz, 2H), 7.27-7.24 (m, 1H), 3.13 - 2.99 (m, 2H), 2.76 (q, J = 12.5, 11.9 Hz, 3H), 2.66 (t, J = 5.8 Hz, 6H), 2.62 - 2.51 (m, 1H), 2.20 - 2.08 (m, 2H), 1.80 (s, 6H), 1.69 - 1.53 (m, 6H). ). ESI MS [M+H] + C 30 H 34 Calculated value for ClN4O: 501.2; Measured value: 501.2.

[0224] Example 12: 2-{2-chloro-4-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]phenyl}propan-2-ol [ka]

[0225] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, chloroform-d) δ 11.79 (br. s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.90 (dd, J = 8.2, 1.7 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.39 - 7.38 (m, 2H), 7.24 (s, 1H), 3.10 - 2.99 (m, 4H), 2.90 (p, J = 8.1 Hz, 1H), 2.82 - 2.74 (m, 4H), 2.68 (s, 1H), 1.95 - 1.85 (m, 2H), 1.80 (s, 6H), 1.75 - 1.65 (m, 2H), 1.59 - 1.43 (m, 4H). ESI MS [M+H] + C 30 H 34 Calculated value for ClN4O: 501.2; Measured value: 501.2.

[0226] Example 13: 2-{4-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]phenyl}-1,1,1-trifluoropropane-2-ol [ka]

[0227] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, chloroform-d) δ 11.09 (br. s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.06 (dt, J = 8.7, 2.0 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.41 (dd, J = 7.5, 2.0 Hz, 1H), 7.41 - 7.39 (d, J = 1.6 Hz, 2H), 7.27 - 7.25 (m, 1H), 3.05 (dt, J = 13.5, 5.2 Hz, 4H), 2.92 (q, J = 8.1 Hz, 1H), 2.84 - 2.74 (m, 4H), 2.62 (s, 1H), 1.91 (d, J = 10.0 Hz, 2H), 1.88 (s, 3H), 1.77 - 1.66 (m, 3H), 1.58 - 1.46 (m, 1H). ESI MS [M+H] + C 30 H 31 Calculated value for F3N4O: 520.2; Measured value: 521.2.

[0228] Example 14: 2-{4-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2-(trifluoromethoxy)phenyl}propan-2-ol [ka]

[0229] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, chloroform-d) δ 11.39 (br. s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 7.96 - 7.93 (m, 1H), 7.88 (d, J = 1.0 Hz, 2H), 7.40 (d, J = 7.6, 2.1 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.27 - 7.22 (m, 1H), 3.04 (dt, J = 11.2, 4.5 Hz, 4H), 2.89 (p, J = 8.0, 7.5 Hz, 1H), 2.84 - 2.72 (m, 4H), 2.20 (s, 1H), 1.95 - 1.84 (m, 2H), 1.71 (s, 6H), 1.64 - 1.43 (m, 7H). ESI MS [M+H] + C 31 H 34 Calculated value for F3N4O2: 551.3; Measured value: 551.2.

[0230] Example 15: 2-{2-chloro-4-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-4-fluoro-1H-pyrazolo[3,4-b]pyridine-3-yl]phenyl}propan-2-ol [ka]

[0231] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, chloroform-d) δ 11.36 (br. s, 1H), 8.68 (d, J = 9.1 Hz, 1H), 8.03 (dd, J = 1.7, 0.8 Hz, 1H), 7.90 (dt, J = 8.3, 1.7 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.26 - 7.22 (m, 1H), 3.03 (d, J = 6.5 Hz, 5H), 2.96 - 2.84 (m, 1H), 2.80 - 2.74 (m, 4H), 2.67 (s, 1H), 1.96 - 1.84 (m, 3H), 1.79 (s, 6H), 1.75 - 1.65 (m, 2H), 1.59 (s, 2H). ESI MS [M+H] + C 30 H 33 Calculated value for ClFN4O: 519.2; Measured value: 519.2.

[0232] Example 16: 2-{4-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-2-(trifluoromethyl)phenyl}propan-2-ol [ka]

[0233] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, chloroform-d) δ 11.66 (br. s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 1.9 Hz, 1H), 8.13 (dd, J = 8.3, 1.9 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.39 - 7.37 (m, 1H), 7.27 - 7.24 (m, 1H), 3.05 (dt, J = 11.3, 5.1 Hz, 4H), 2.90 (p, J = 8.1 Hz, 1H), 2.84 - 2.69 (m, 4H), 2.14 (d, J = 1.3 Hz, 1H), 1.96 - 1.81 (m, 2H), 1.76 (s, 6H), 1.74 - 1.68 (m, 2H), 1.58 - 1.46 (m, 4H). ESI MS [M+H] + C 31 H 34 Calculated value for F3N4O: 535.3; Measured value: 535.2.

[0234] Example 17: 2-{4-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-3-fluorophenyl}propan-2-ol [ka]

[0235] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, chloroform-d) δ 11.64 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.40 (dd, J = 3.2, 2.1 Hz, 1H), 7.91 - 7.86 (m, 1H), 7.46 - 7.36 (m, 4H), 7.24 - 7.21 (m, 1H), 3.09 - 2.97 (m, 4H), 2.89 (p, J = 8.0, 7.6 Hz, 1H), 2.83 - 2.69 (m, 4H), 1.97 - 1.82 (m, 3H), 1.74 - 1.45 (m, 6H), 1.65 (s, 6H). ESI MS [M+H] + C 30 H 34 Calculated value for FN4O: 485.3; Measured value: 485.2.

[0236] Example 18: 2-{4-[5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]phenyl}propan-2-ol [ka]

[0237] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, DMSO-d6) δ 13.83 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.06 - 8.01 (m, 2H), 7.68 - 7.62 (m, 2H), 7.61 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 7.7, 2.0 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 5.12 (s, 1H), 3.00 - 2.96 (m, 2H), 2.95 - 2.90 (m, 2H), 2.87 (p, J = 7.9 Hz, ESI MS [M+H] + C 30 H 35 Calculated value for N4O: 467.3; Measured value: 467.2.

[0238] Example 19: 5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl)-3-(4-methanesulfonylphenyl)-1H-pyrazolo[3,4-b]pyridine-6-amine [ka]

[0239] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, DMSO-d6) δ 13.26 (br. s, 1H), 9.71 (br. s, 1H), 8.25 - 8.19 (m, 2H), 8.03 - 7.98 (m, 3H), 7.41 (s, 1H), 7.38 (d, J = 1.2 Hz, 2H), 6.12 (br. s, 2H), 3.80 - 3.70 (m, 4H), 3.25 - 2.95 (m, 5H), 2.56 (s, 3H), 2.11 - 2.03 (m, 2H), 1.82 - 1.71, (m, 4H), 1.64 - 1.54 (m, 2H). ESI MS [M+H] + C 28 H 32 Calculated value for N5O2S: 502.2; Measured value: 502.2.

[0240] Example 20: 2-[4-(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-(trifluoromethyl)phenyl]propan-2-ol [ka]

[0241] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, chloroform-d) δ 11.71 (br. s, 1H), 8.91 (dd, J = 2.0, 1.1 Hz, 1H), 8.48 (dd, J = 2.1, 1.0 Hz, 1H), 8.45 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.44 - 7.41 (m, 2H), 7.32 - 7.26 (m, 1H), 3.04 - 2.85 (m, 7H), 2.84 - 2.73 (m, 1H), 2.53 (q, J = 8.4 Hz, 1H), 2.26 - 2.06 (m, 3H), 1.90 (ddt, J = 12.5, 8.9, 6.3 Hz, 1H), 1.78 (s, 6H), 1.78 - 1.53 (m, 3H), 1.50 - 1.33 (m, 2H), 1.14 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for F3N4O: 549.3; Measured value: 549.2.

[0242] Example 21: 2-[2-chloro-4-(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)phenyl]propan-2-ol [ka]

[0243] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, chloroform-d) δ 8.87 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.90 (dd, J = 8.2, 1.7 Hz, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.41 (dt, J = 5.8, 1.6 Hz, 1H), 3.63 (dd, J = 10.4, 3.9 Hz, 1H), 3.36 (dd, J = 10.5, 2.6 Hz, 1H), 3.10 (dt, J = 7.7, 3.8 Hz, 1H), 2.88 (ddd, J = 25.7, 14.4, 10.0 Hz, 6H), 2.80 - 2.67 (m, 1H), 2.69 (s, 1H), 2.66 - 2.58 (m, 1H), 2.22 - 2.06 (m, 2H), 1.88 - 1.40 (m, 6H), 1.80 (s, 7H). ESI MS [M+H] + C 31 H 36 Calculated value for ClN4O2: 531.3; Measured value: 531.2.

[0244] Example 22: 2-[5-(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)pyridine-2-yl]propan-2-ol [ka]

[0245] The indicated compound was prepared in the same manner as in Example 11. 1H NMR (400 MHz, DMSO-d6) δ 14.00 (br. s, 1H), 9.24 (dd, J = 2.4, 0.8 Hz, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.73 (dd, J = 2.1, 0.8 Hz, 1H), 8.47 (dd, J = 8.3, 2.3 Hz, 1H), 7.84 (dd, J = 8.3, 0.9 Hz, 1H), 7.63 (t, J = 2.6 Hz, 1H), 7.56 (dt, J = 7.7, 2.0 Hz, 1H), 7.23 (dd, J = 7.8, 3.5 Hz, 1H), 5.34 (s, 1H), 3.28 - 3.11 (m, 4H), 2.84 (t, J = 7.4 Hz, 1H), 2.72 - 2.54 (m, 2H), 1.98 - 1.60 (m, 5H), 1.53 (s, 6H), 1.49 - 1.21 (m, 3H), 1.05 (d, J = 6.2 Hz, 3H), 0.94 (s, 3H). ESI MS [M+H] + C 31 H 38 Calculated value for N5O: 496.3; Measured value: 496.2.

[0246] Example 23: 1-Methanesulfonyl-4-{5-[7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}piperidine [ka]

[0247] Step a: To a dioxane solution (30 mL) containing 1-(tert-butoxycarbonyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (15.8 g, 51.1 mmol), HCl solution (Et2O containing 4 M, 102 mL) was added. This reaction mixture was stirred at room temperature for 3 hours, then slowly diluted with hexane and stirred for 30 minutes. The precipitated white solid (6.95 g, 33.2 mmol) was collected by filtration and then dissolved in CH2Cl2 (130 mL), and this solution was cooled to 0°C. NEt3 (11.5 mL, 83.0 mmol) was added, followed by methanesulfonyl chloride (2.8 mL, 36.5 mmol), and the reaction mixture was stirred for 16 hours while warming to room temperature after the condenser was finished. The reaction mixture was cooled to 0°C, and then the reaction was carefully stopped with a saturated aqueous solution of NaHCO3. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were washed with brine, dried on anhydrous Na2SO4, and concentrated to obtain the desired product as an off-white solid (7.95 g, 54%).

[0248] Step b: To a mixture of the product from Step a (1.01 g, 2.22 mmol), the product from Step a (702 mg, 2.45 mmol), and Na2CO3 (471 mg, 4.44 mmol), dioxane (9.9 mL) and H2O (1.2 mL) were added, and the suspension was degassed with N2 for 10 minutes. (dppf)PdCl2 (81 mg, 0.111 mmol) was added, and the reaction mixture was stirred at 80°C for 21 hours. As soon as it cooled, CH2Cl2 (30 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (hexane containing 100% hexane to 50% siRNA) to obtain the desired product as a light brown solid (754 mg, 70%).

[0249] Step c: Dioxane (7.0 mL) and H2O (0.80 mL) were added to a mixture of the product from step b (191 mg, 0.392 mmol), the crude product from Example 11, step c (0.509 mmol), and Na2CO3 (83 mg, 0.784 mmol). The suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (14 mg, 0.0196 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 100% CH2Cl2 to 10% MeOH, 0.5% NET3) to obtain the desired product as a brown solid (134 mg, 55%).

[0250] Step d: The solution of the product obtained from MeOH (4.3 mL) containing Step c (134 mg, 0.215 mmol) was degassed with N2 for 5 minutes, then NEt3 (1 drop) was added, followed by Pd / C (10% anhydrous base, 46 mg, 0.0215 mmol). H2 was passed through the solution for 5 minutes, and then the reaction mixture was stirred at room temperature for 14 hours using an H2 balloon. The reaction mixture was filtered through Celite, washed with MeOH, and then concentrated. The residue was subjected to the same conditions again and stirred for 22 hours, then filtered through Celite and concentrated. TFA (2.1 mL) was added to the CH2Cl2 (2.1 mL) solution containing the residue. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. To this residue, MeOH (7N solution, 4.3 mL) containing NH3 was added, and the reaction mixture was stirred at 40°C for 2 hours. Once cooled, the reaction mixture was concentrated. H2O (10 mL) was added, and the precipitated solid was collected by filtration and washed with H2O. It was purified by C18 reverse-phase chromatography (100% H2O ~ 100% ACN, 0.1% TFA), followed by reverse-phase HPLC (H2O containing 10-90% ACN, 0.1% TFA), and then freeze-dried to obtain the labeled compound as a pale yellow solid (14 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.59 - 9.38 (m, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.49 (d, J = 2.1 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 7.7, 2.0 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 3.69 (dt, J = 11.1, 2.9 Hz, 2H), 3.63 - 3.40 (m, 3H), 3.26 (tt, J = 11.7, 3.7 Hz, 1H), 3.22 - 3.11 (m, 2H), 3.05 - 2.93 (m, 3H), 2.93 (s, 3H), 2.92 - 2.76 (m, 3H), 2.40 - 2.32 (m, 2H), 2.15 (dd, J = 13.6, 3.5 Hz, 2H), 2.07 - 1.76 (m, 6H), 1.46 (p, J = 12.9, 11.9, 11.5 Hz, 2H). ESI MS [M+H] + C 27 H 36 Calculated value for N5O2S: 494.3; Measured value: 494.2.

[0251] Example 24: 3-(4-(cyclopropylsulfonyl)phenyl)-5-(7-((S)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0252] Step a: To a mixture of 2-bromo-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-one (300 mg, 1.3 mmol), 2-(S)-methylpyrrolidine hydrochloride (182 mg, 1.5 mmol), AcOH (80 mL, 1.5 mmol), and DCE (8 mL), NaBH(OAc)3 (320 mg, 1.5 mmol) was added at room temperature. This mixture was stirred at room temperature for 14 hours. Brine (10 mL) and CH2Cl2 (20 mL) were added. The phases were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 20 mL). The combined organic phase was dried and concentrated on Na2SO4 and purified by column chromatography (SiO2, 0-100% CH2Cl2 / MeOH / 7N methanolNH3 (90:10:1) containing CH2Cl2) to obtain the desired product 6 as a light brown oily substance (126 mg, 32%).

[0253] Step b: The indicated compound was prepared in the same manner as in step c of Example 11.

[0254] Step c: A mixture of the crude product from Example 1 and Step b, the product from Example 9 and Step a (870 mg, 1.9 mmol), K2CO3 (529 mg, 3.8 mmol), and (dppf)PdCl2 (140 mg, 0.2 mmol) was placed under a nitrogen atmosphere. To this mixture, degassed dioxane (12 mL) and H2O (3 mL) were added and heated at 80°C for 14 hours. After cooling to room temperature, siRNA (50 mL) was added. These phases were separated, and the aqueous phase was extracted with siRNA (2 × 50 mL). The combined organic phase was dried and concentrated on Na2SO4 and purified by column chromatography (SiO2, hexane containing 0-100% siRNA) to obtain the desired product as a light brown solid (546 mg, 57%).

[0255] Step d: A mixture of the crude product obtained from step b, the product from step c (131 mg, 0.3 mmol), K2CO3 (71 mg, 0.5 mmol), and (dppf)PdCl2 (20 mg, 0.03 mmol) was placed under a nitrogen atmosphere. Degassed dioxane (2 mL) and H2O (0.5 mL) were added to this mixture and heated at 100 °C for 14 hours. After cooling to room temperature,  (20 mL) and brine (5 mL) were added. These phases were separated, and the aqueous phase was extracted with  (2 × 10 mL). The combined organic phases were dried and concentrated over Na2SO4 and purified by column chromatography (SiO2, CH2Cl2 / MeOH / 7N methanolNH3 (90:10:1)) to obtain the desired product as a brown solid (107 mg, 65%).

[0256] Step e: To a solution of CH2Cl2 (1.5 mL) containing the product from step d (107 mg, 0.2 mmol), TFA (1.5 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 (1.5 mL). DMEDA (0.5 mL) was added to this mixture, and the mixture was stirred at 60°C for 1 hour. Once cooled to room temperature, the solvent was removed, and the crude product was purified by reverse-phase HPLC using H2O + 0.1% TFA and ACN + 0.1% TFA as mobile phases, yielding the desired product: a yellow solid (30 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.88 (dd, J = 2.1, 1.1 Hz, 1H), 8.74 (dd, J = 2.1, 1.1 Hz, 1H), 8.40 - 8.32 (m, 2H), 8.05 - 7.97 (m, 2H), 7.72 - 7.65 (m, 1H), 7.65 - 7.58 (m, 1H), 7.31 (dd, J = 7.8, 4.6 Hz, 1H), 3.69 (t, J = 10.8 Hz, 2H), 3.30 (dt, J = 12.2, 6.2 Hz, 1H), 3.15 (d, J = 10.1 Hz, 1H), 3.03 - 2.78 (m, 5H), 2.27 (s, 2H), 2.12 (dq, J = 13.2, 6.8 Hz, 1H), 1.85 (p, J = 7.2 Hz, 2H), 1.57 (dt, J = 12.8, 8.2 Hz, 1H), 1.52 - 1.38 (m, 2H), 1.34 (dd, J = 6.5, 1.2 Hz, 3H), 1.23 - 1.00 (m, 4H). ESI MS [M+H] + C 31 H 35 Calculated value for N4O2S: 527.3; Measured value: 527.3.

[0257] Example 25: (2R)-1-(2-{3-[4-(cyclopropanesulfonyl)-3-fluorophenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)-2-methylpyrrolidine [ka]

[0258] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 2.1 Hz, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.21 (t, J = 10.1 Hz, 2H), 7.96 (t, J = 7.7 Hz, 1H), 7.60 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.24 (dd, J = 7.9, 3.5 Hz, 1H), 4.03 (s, 1H), 3.44 - 2.98 (m, 6H), 2.83 (d, J = 7.1 Hz, 1H), 2.67 (s, 2H), 1.98 - 1.48 (m, 7H), 1.48 - 1.34 (m, 1H), 1.20 - 1.12 (m, 4H), 1.04 (d, J = 6.1 Hz, 3H), 0.93 (s, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for FN4O2S: 559.3; Measured value: 559.2.

[0259] Example 26: 7-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-3-(oxan-4-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine [ka]

[0260] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.41 - 8.30 (m, 2H), 8.07 - 7.92 (m, 2H), 7.75 (d, J = 1.9 Hz, 1H), 7.68 (dd, J = 7.8, 1.9 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 3.93 (dd, J = 11.4, 4.2 Hz, 2H), 3.63 (dt, J = 27.6, 14.4 Hz, 4H), 3.31 (t, J = 11.5 Hz, 2H), 3.15 - 2.98 (m, 5H), 2.91 (tt, J = 7.9, 4.8 Hz, 1H), 2.03 - 1.96 (m, 2H), 1.86 - 1.65 (m, 2H), 1.17 - 1.00 (m, 4H). ESI MS [M+H] + C 30 H 33 Calculated value for N4O3S: 529.2; Measured value: 529.2.

[0261] Example 27: 7-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-3-[(oxolan-3-yl)methyl]-2,3,4,5-tetrahydro-1H-3-benzazepine [ka]

[0262] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.42 - 8.28 (m, 2H), 8.06 - 7.96 (m, 2H), 7.74 (d, J = 1.9 Hz, 1H), 7.69 (dd, J = 7.8, 2.0 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 3.87 (dd, J = 8.7, 7.2 Hz, 1H), 3.80 - 3.46 (m, 4H), 3.43 (ddd, J = 8.7, 6.6, 1.0 Hz, 1H), 3.28 - 2.95 (m, 8H), 2.91 (tt, J = 7.9, 4.8 Hz, 1H), 2.71 (dt, J = 14.4, 7.2 Hz, 1H), 2.11 (dtd, J = 12.6, 7.7, 4.9 Hz, 1H), 1.66 (dq, J = 12.2, 7.5 Hz, 1H), 1.18 - 0.99 (m, 4H). ESI MS [M+H] + C 30 H 33 Calculated value for N4O3S: 529.2; Measured value: 529.2.

[0263] Example 28: 2-(2-chloro-4-(5-(2-cyclopentyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl)propan-2-ol [ka]

[0264] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.05 (dd, J = 8.3, 1.8 Hz, 1H), 8.01 - 7.94 (m, 2H), 7.81 - 7.74 (m, 2H), 7.40 - 7.33 (m, 1H), 4.62 (d, J = 15.7 Hz, 1H), 4.45 - 4.35 (m, 1H), 3.84 - 3.61 (m, 4H), 3.35 (d, J = 20.1 Hz, 1H), 3.14 (s, 2H), 2.13 (q, J = 11.6, 10.5 Hz, 2H), 1.76 (d, J = 11.6 Hz, 4H), 1.62 (s, 6H). ESI MS [M+H] + C 29 H 32 Calculated value for ClN4O: 487.2; Measured value: 487.2.

[0265] Example 29: 2-(2-chloro-4-(5-(2-cyclopentyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl)propan-2-ol [ka]

[0266] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.07 - 7.93 (m, 3H), 7.80 (dd, J = 8.0, 1.9 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 4.63 (d, J = 15.2 Hz, 1H), 4.41 (dd, J = 15.4, 8.2 Hz, 1H), 3.72 - 3.64 (m, 4H), 3.38 (s, 1H), 3.20 - 3.08 (m, 2H), 2.11 (d, J = 15.8 Hz, 2H), 1.75 (q, J = 7.8, 7.1 Hz, 4H), 1.62 (s, 6H). ESI MS [M+H] + C 29 H 32 Calculated value for ClN4O: 487.2; Measured value: 487.2.

[0267] Example 30: 3-Cyclopentyl-7-(3-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine [ka]

[0268] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.39 - 8.31 (m, 2H), 8.09 - 8.01 (m, 2H), 7.77 - 7.66 (m, 2H), 7.36 (d, J = 7.9 Hz, 1H), 3.69 (d, J = 14.0 Hz, 2H), 3.30 (s, 3H), 3.26 (s, 3H), 3.24 - 2.85 (m, 7H), 2.02 (d, J = 9.8 Hz, 2H), 1.76 (d, J = 7.4 Hz, 2H), 1.71 (s, 2H), 1.54 (s, 2H). ESI MS [M+H] + C 28 H 31 Calculated value for N4O2S: 487.2; Measured value: 487.2.

[0269] Example 31: 7-(3-(3-chloro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine [ka]

[0270] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.81 - 9.75 (m, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.39 - 8.29 (m, 2H), 8.16 (dd, J = 8.2, 0.3 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 3.75 - 3.68 (m, 2H), 3.42 (s, 3H), 3.31 - 2.93 (m, 7H), 2.06 - 1.98 (m, 2H), 1.73 (d, J = 16.4 Hz, 4H), 1.53 (d, J = 8.4 Hz, 2H). ESI MS [M+H] + C 29 H 30 Calculated value for ClN4O2S: 521.2; Measured value: 521.2.

[0271] Example 32: 3-Cyclopentyl-7-(3-(3-fluoro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine [ka]

[0272] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (d, J = 7.6 Hz, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.23 ​​- 8.12 (m, 2H), 7.98 (dd, J = 8.1, 7.6 Hz, 1H), 7.78 - 7.67 (m, 2H), 7.37 (d, J = 7.9 Hz, 1H), 3.75 - 3.68 (m, 2H), 3.31 - 3.12 (m, 4H), 3.12 - 2.95 (m, 3H), 2.06 - 1.98 (m, 2H), 1.73 (d, J = 16.4 Hz, 4H), 1.53 (d, J = 8.1 Hz, 2H). ESI MS [M+H] + C 28 H 30 Calculated value for FN4O2S: 505.2; Measured value: 505.2.

[0273] Example 33: 2-(4-(5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl)-2-methylpropanenitrile [ka]

[0274] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 13.94 (s, 1H), 9.73 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.18 - 8.08 (m, 2H), 7.74 (d, J = 2.0 Hz, 1H), 7.72 - 7.63 (m, 3H), 7.35 (d, J = 7.9 Hz, 1H), 3.69 (d, J = 13.5 Hz, 4H), 3.29 - 2.98 (m, 6H), 2.02 (q, J = 6.0 Hz, 2H), 1.72 (s, 9H), 1.54 (s, 2H). ESI MS [M+H] + C 31 H 34 Calculated value for N5: 476.3; Measured value: 476.3.

[0275] Example 34: 2-(2-chloro-4-(5-(3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl)propan-2-ol [ka]

[0276] The indicated compound was prepared in the same manner as in Example 24. 1 H NMR (400 MHz, DMSO-d6) δ 13.98 (s, 1H), 9.82 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.07 - 7.93 (m, 3H), 7.74 - 7.64 (m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 3.69 (d, J = 10.0 Hz, 4H), 3.38 (d, J = 4.9 Hz, 2H), 3.31 (s, 5H), 3.18 - 2.99 (m, 4H), 1.62 (s, 6H). ESI MS [M+H] + C 28 H32 Calculated value for ClN4O2: 491.2; Measured value: 491.2.

[0277] Example 35: 2-(2-chloro-4-(5-(7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl)propan-2-ol [ka]

[0278] The indicated compound was prepared in the same manner as in Example 24. 1 H NMR (400 MHz, DMSO-d6) δ 13.94 (s, 1H), 8.83 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.05 (dd, J = 8.3, 1.8 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.60 - 7.47 (m, 2H), 7.22 (dd, J = 7.8, 1.3 Hz, 1H), 5.36 (s, 1H), 2.78 (ddt, J = 48.4, 23.5, 9.9 Hz, 7H), 2.41 (s, 1H), 1.97 (s, 2H), 1.86 - 1.70 (m, ESI MS [M+H] + C 31 H 36 Calculated value for ClN4O: 515.3; Measured value: 515.3.

[0279] Example 36: 5-(7-((S)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-3-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0280] The indicated compound was prepared in the same manner as in Example 24. 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 7.0 Hz, 1H), 8.88 (dd, J = 2.0, 1.1 Hz, 1H), 8.73 (dd, J = 2.1, 1.1 Hz, 1H), 8.40 - 8.31 (m, 2H), 8.09 - 8.00 (m, 2H), 7.68 (dd, J = 6.2, 2.0 Hz, 1H), 7.61 (dd, J = 7.8, 2.0 Hz, 1H), 7.31 (dd, J = 7.8, 4.3 Hz, 1H), 3.69 (d, J = 22.4 Hz, 2H), 3.26 (s, 4H), 3.15 (t, J = 8.8 Hz, 1H), 2.99 (dd, J = 14.3, 6.9 Hz, 1H), 2.87 (dt, J = 23.7, 11.9 Hz, 3H), 2.28 (s, 2H), 2.12 (dq, J = 13.1, 6.8 Hz, 1H), 1.85 (p, J = 7.2 Hz, 2H), 1.63 - 1.38 (m, 3H), 1.34 (dd, J = 6.4, 1.2 Hz, 3H). ESI MS [M+H] + C 29 H 33 Calculated value for N4O2S: 501.2; Measured value: 501.2.

[0281] Example 37: 2-(2-chloro-4-[5-(7-((S)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl)propan-2-ol [ka]

[0282] The indicated compound was prepared in the same manner as in Example 24. 1 H NMR (400 MHz, DMSO-d6) δ 13.93 (s, 1H), 8.83 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.05 (dd, J = 8.1, 1.7 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.58 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 5.36 (s, 1H), 2.80 (dd, J = 51.7, 37.1 Hz, 7H), 1.95 (s, 2H), 1.77 (s, 2H), 1.61 (s, 6H), 1.57 - 1.34 (m, 3H), 1.22 (d, J = 16.5 Hz, 2H), 0.99 (s, 3H). ESI MS [M+H] + C 31 H 36 Calculated value for ClN4O: 515.2; Measured value: 515.2.

[0283] Example 38: 5-(7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-3-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0284] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J = 7.0 Hz, 1H), 8.88 (dd, J = 2.1, 1.1 Hz, 1H), 8.73 (dd, J = 2.1, 1.0 Hz, 1H), 8.40 - 8.31 (m, 2H), 8.09 - 8.00 (m, 2H), 7.68 (dd, J = 5.9, 2.0 Hz, 1H), 7.61 (dd, J = 7.7, 2.0 Hz, 1H), 7.31 (dd, J = 7.8, 4.1 Hz, 1H), 3.69 (dd, J = 13.7, 8.5 Hz, 2H), 3.26 (s, 4H), 3.15 (t, J = 9.0 Hz, 1H), 3.03 - 2.78 (m, 4H), 2.28 (s, 2H), 2.12 (dq, J = 13.0, 6.7 Hz, 1H), 1.85 (p, J = 7.3 Hz, 2H), 1.63 - 1.38 (m, 3H), 1.34 (dd, J = 6.5, 1.1 Hz, 3H). ESI MS [M+H] + C 29 H 33 Calculated value for N4O2S: 501.2; Measured value: 501.2.

[0285] Example 39: 3-(4-(cyclopropylsulfonyl)phenyl)-5-(7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0286] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.88 (dd, J = 2.1, 1.1 Hz, 1H), 8.74 (dd, J = 2.1, 1.0 Hz, 1H), 8.40 - 8.32 (m, 2H), 8.05 - 7.97 (m, 2H), 7.69 (dd, J = 6.2, 2.0 Hz, 1H), 7.61 (dd, J = 7.8, 2.0 Hz, 1H), 7.31 (dd, J = 7.8, 4.4 Hz, 1H), 3.69 (t, J = 11.1 Hz, 3H), 3.30 (dq, J = 12.7, 6.5 Hz, 1H), 3.16 (t, J = 9.0 Hz, 1H), 3.00 - 2.86 (m, 4H), 2.28 (s, 2H), 2.12 (dq, J = 13.1, 6.7 Hz, 1H), 1.85 (p, J = 7.2 Hz, 2H), 1.63 - 1.39 (m, 3H), 1.34 (dd, J = 6.4, 1.2 Hz, 3H), 1.18 - 1.00 (m, 4H). ESI MS [M+H] + C 31 H 35 Calculated value for N5O2S: 527.2; Measured value: 527.2.

[0287] Example 40: (S)-3-(4-(cyclopropylsulfonyl)phenyl)-5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0288] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.40 - 8.32 (m, 2H), 8.05 - 7.96 (m, 2H), 7.71 - 7.58 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H), 3.50 (d, J = 24.4 Hz, 3H), 3.14 (s, 1H), 3.04 - 2.73 (m, 6H), 2.33 (s, 2H), 1.95 (s, 2H), 1.82 (dd, J = 7.7, 5.0 Hz, 2H), 1.44 (p, J = 12.2 Hz, 2H), 1.19 - 1.10 (m, 2H), 1.10 - 1.00 (m, 2H). ESI MS [M+H] + C 30 H 32 Calculated value for N4O2S: 513.3; Measured value: 513.3.

[0289] Example 41: (S)-3-(4-(ethylsulfonyl)phenyl)-5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0290] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.42 - 8.33 (m, 2H), 8.05 - 7.95 (m, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.59 (dd, J = 7.7, 1.9 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 3.53 - 3.39 (m, 3H), 3.33 (q, J = 7.3 Hz, 2H), 3.09 (s, 2H), 2.95 (ddd, J = 30.3, ESI MS [M+H] + C 29 H 33 Calculated value for N4O2S: 501.2; Measured value: 501.2.

[0291] Example 42: (S)-3-(4-(isopropylsulfonyl)phenyl)-5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0292] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.78 - 8.72 (m, 1H), 8.42 - 8.34 (m, 2H), 8.00 - 7.92 (m, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 7.7, 2.0 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 3.45 (p, J = 6.7 Hz, 3H), 3.11 (s, 1H), 2.95 (ddd, J = 30.4, 14.8, 7.5 Hz, 3H), 2.83 - 2.72 (m, 2H), 2.35 (s, 1H), 1.94 (d, J = 9.3 Hz, 1H), 1.84 (q, J = 7.8, 5.6 Hz, 2H), 1.48 (p, J = 12.7 Hz, 2H), 1.18 (d, J = 6.8 Hz, 6H). ESI MS [M+H] + C 31 H 35 Calculated value for N4O2S: 515.3; Measured value: 515.3.

[0293] Example 43: 3-(4-(isopropylsulfonyl)phenyl)-5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0294] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.75 (t, J = 2.0 Hz, 1H), 8.42 - 8.34 (m, 2H), 8.00 - 7.92 (m, 2H), 7.67 (d, J = 1.9 Hz, 1H), 7.60 (dd, J = 7.8, 1.5 Hz, 1H), 7.30 (dd, J = 7.7, 1.7 Hz, 1H), 4.07 (s, 1H), 3.45 (p, J = 6.7 Hz, 1H), 3.33 (s, 1H), 3.26 - 3.20 (m, 1H), 2.87 (dd, J = 25.0, 10.5 Hz, 4H), 2.22 (s, 1H), 2.04 (s, 1H), 1.86 (q, J = 12.5, 12.0 Hz, 4H), 1.65 (dd, J = 35.2, 11.3 Hz, 2H), 1.52 (s, 3H), 1.35 - 1.28 (m, 3H), 1.18 (d, J = 6.8 Hz, 6H). ESI MS [M+H] + C 32 H 39 Calculated value for N4O2S: 543.3; Measured value: 543.3.

[0295] Example 44: 3-(4-(ethylsulfonyl)phenyl)-5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0296] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.74 (t, J = 1.9 Hz, 1H), 8.41 - 8.33 (m, 2H), 8.05 - 7.95 (m, 2H), 7.67 (d, J = 1.9 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.30 (dd, J = 7.9, 1.7 Hz, 1H), 4.08 (s, 1H), 3.33 (q, J = 7.3 Hz, 3H), 3.25 (s, 1H), 2.87 (q, J = 13.6, 12.2 Hz, 4H), 2.21 (s, 2H), 2.10 - 2.01 (m, 2H), 1.97 - 1.75 (m, 4H), 1.64 (dd, J = 27.8, 11.6 Hz, 2H), 1.52 (s, 3H), 1.34 - 1.27 (m, 3H), 1.12 (t, J = 7.3 Hz, 3H). ESI MS [M+H] + C 31 H 37 Calculated value for N4O2S: 529.3; Measured value: 529.3.

[0297] Example 45: 3-(4-(cyclopentylsulfonyl)phenyl)-5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0298] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.75 (t, J = 2.0 Hz, 1H), 8.41 - 8.33 (m, 2H), 8.05 - 7.95 (m, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.60 (ddd, J = 7.8, 2.0, 1.1 Hz, 1H), 7.30 (dd, J = 8.1, 1.8 Hz, 1H), 4.07 (s, 1H), 3.81 (tt, J = 8.8, 6.8 Hz, 1H), 3.28 (d, J = 41.9 Hz, ESI MS [M+H] + C 34 H 41 Calculated value for N4O2S: 569.3; Measured value: 569.3.

[0299] Example 46: 3-(4-(cyclobutylsulfonyl)phenyl)-5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0300] The indicated compound was prepared in the same manner as in Example 24. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.40 - 8.32 (m, 2H), 7.99 - 7.91 (m, 2H), 7.58 - 7.46 (m, 2H), 7.19 (dd, J = 7.8, 3.6 Hz, 1H), 4.14 (p, J = 8.2 Hz, 1H), 3.22 - 3.01 (m, 2H), 2.79 (t, J = 7.5 Hz, 1H), 2.67 - 2.49 (m, 2H), 2.35 (dtd, J = 12.7, 10.1, 8.4 Hz, 2H), 2.20 - 2.06 (m, 2H), 2.00 - 1.87 (m, 2H), 1.84 (dd, J = 10.2, 5.4 Hz, 2H), 1.68 (tdt, J = 27.2, 12.9, 6.2 Hz, 4H), 1.43 - 1.12 (m, 4H), 1.00 (d, J = 6.2 Hz, 3H), 0.89 (s, 3H). LC- ESI MS [M+H] + C 33 H 39 Calculated value for N4O2S: 555.3; Measured value: 555.3.

[0301] Example 47: 1-(2-methyl-4-{5-[7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}benzoyl)piperazine [ka]

[0302] Step a: To a solution of CH2Cl2 (11.4 mL) containing 4-carboxy-3-methylphenylboronic acid (514 mg, 2.86 mmol), 1-(tert-butoxycarbonyl)piperazine (585 mg, 3.14 mmol) and NEt3 (1.2 mL, 8.58 mmol) were added, followed by HATU (1.30 g, 3.43 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then H2O (10 mL) was added. The mixture was extracted with CH2Cl2 (3 × 10 mL), and the combined organic layer was washed with brine, dried on anhydrous MgSO4, and concentrated. The crude product was dissolved in CH2Cl2, washed with saturated NH4Cl aqueous solution, dried on anhydrous MgSO4, concentrated, and purified by silica gel chromatography (100% hexane to 100% Â) to obtain an off-white solid as the crude product.

[0303] Step b: A mixture of the product from Example 1 and Step a (659 mg, 1.6 mmol), the product from Step a (1.4 mmol), K2CO3 (441.6 mg, 3.2 mmol), and (dppf)PdCl2 (102.4 mg, 0.14 mmol) was placed under a nitrogen atmosphere. Degassed dioxane (4 mL) and H2O (1 mL) were added to this mixture and heated at 80°C for 45 minutes. After cooling to room temperature, brine (2 mL) and siRNA (20 mL) were added. The phases were separated, the organic phase was dried and concentrated over Na2SO4, and purified by column chromatography (hexane containing SiO2 and 0-70% siRNA) to obtain the desired product as an off-white solid (492 mg, 64%).

[0304] Step c: A mixture of the product from step b (160 mg, 0.3 mmol), Example 11, the product from step c (0.6 mmol), K2CO3 (82.2 mg, 0.6 mmol), and (dppf)PdCl2 (21.9 mg, 0.03 mmol) was placed under a nitrogen atmosphere. Degassed dioxane (2 mL) and degassed H2O (0.5 mL) were added to this mixture and heated at 100 °C for 8 hours. After cooling to room temperature, siRNA (10 mL) was added. The phases were separated and the aqueous phase was extracted with siRNA (2 × 10 mL). The combined organic phases were dried and concentrated on Na2SO4 and purified by CH2Cl2 column chromatography (SiO2, 0-100% CH2Cl2 / MeOH / 7N methanolNH3 (90:10:1)) to obtain the desired product as a light brown solid (117 mg, 58%).

[0305] Step d: 3M methanol-HCl (2.0 mL) was added to the product from step c (117 mg, 0.2 mmol). This reaction mixture was stirred at room temperature for 8 hours. After removing the solvent, the crude product was ground with CH2Cl2 (10 mL) to obtain the desired product as a yellow solid (35 mg, 36%). 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.27 (s, 2H), 8.83 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.01 - 7.91 (m, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 7.7, 2.0 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 4.00 - 2.86 (m, 15H), 2.79 (q, J = 12.5, 11.8 Hz, 2H), 3.40 - 2.33 (m, 5H), 1.98 - 1.77 (m, 4H), 1.51 (p, J = 12.5 Hz, 2H). ESI MS [M+H]+ C 33 H 39 Calculated value for N6O2: 535.3; Measured value: 535.3.

[0306] Example 48: 2-methyl-1-(7-{3-[3-methyl-4-(piperazine-1-carbonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-2,3,4,5-tetrahydro-1H-3-benzazepine-3-yl)propan-1-one [ka]

[0307] Step a: To a mixture of 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (510 mg, 2.0 mmol), DIPEA (0.85 mL, 5.0 mmol), and THF (4.0 mL), isobutyryl chloride (239 μL, 2.4 mmol) was added dropwise at 0°C. This mixture was stirred at room temperature for 1 hour. H2O (5 mL) and RINKAN (20 mL) were added to this reaction mixture. The phases were separated, and the aqueous phase was extracted with RINKAN (2 × 10 mL). The combined organic phases were dried and concentrated over Na2SO4, and purified by column chromatography (SiO2, hexane containing 0-100% RINKAN) to obtain the desired product as a colorless solid (590 mg, quantitative).

[0308] Step b: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0309] Step c: The desired product was prepared (120 mg, 59%) in the same manner as in Example 47, Step c.

[0310] Step d: The desired product was prepared in the same manner as in Example 47, Step d (40 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 2H), 8.84 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 7.96 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.61 - 7.53 (m, 1H), 7.44 - 7.36 (m, 1H), 7.28 (dd, J = 7.8, 3.5 Hz, 1H), 3.89 (s, 7H), 3.68 - 3.54 (m, 4H), 3.42 - 3.38 (m, 2H), 3.26 - 2.80 (m, 4H), 2.33 (s, 3H), 1.00 (d, J = 6.7 Hz, 6H). ESI MS [M+H] + C 32 H 37 Calculated value for N6O2: 537.3; Measured value: 537.3.

[0311] Example 49: 2,6-dimethyl-4-{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}benzamide [ka]

[0312] Step a: To a mixture of 4-bromo-2,6-dimethylbenzoic acid (3.44 g, 15 mmol), CH2Cl2 (32 mL), and DMF (2 drops), (COC1)2 (1.4 mL, 16.5 mmol) was added at room temperature. This reaction mixture was stirred at room temperature for 14 hours. The solvent was removed, and the residue was resuspended in dry THF. After cooling the mixture to 0°C, (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. Brine (20 mL) and SiO (100 mL) were added to this reaction mixture. The phases were separated, and the aqueous phase was extracted with SiO (2 × 50 mL). The combined organic phases were dried and concentrated over Na2SO4 to obtain the desired product as a yellowish-brown solid (3.4 g, quantitative).

[0313] Step b: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0314] Step c: The desired compound was prepared (1.0 g, 47%) in the same manner as in Example 47, Step b.

[0315] Step d: 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 stirred at room temperature for 3 hours. The reaction mixture was diluted with H2O (100 mL), and then carefully added 28 wt% NH4. 3(水溶液) The pH was adjusted to approximately 10-11 by adding [the appropriate compound]. The crude product was then extracted with CH2Cl2 (2 × 100). The combined organic phase was dried and concentrated on Na2SO4, and then purified by column chromatography using CH2Cl2 containing SiO2, 0-100% CH2Cl2 / MeOH / 7N methanolNH3 (90:10:1). The desired product was obtained as a light brown oily substance (2.2 g, 75%).

[0316] Step e: The desired compound was prepared in the same manner as in Step c of Example 11.

[0317] Step f: The desired compound was prepared in the same manner as in Step c of Example 47 (84 mg, 50%).

[0318] Step g: The desired product was prepared in the same manner as in Step d of Example 47 (30 mg, 65%). 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 2.2 Hz, 1H), 7.77 (s, 1H), 7.74 - 7.68 (m, 2H), 7.61 (s, 1H), 7.58 - 7.50 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 3.43 - 3.28 (m, 4H), 3.14 - 3.06 (m, 2H), 2.95 (ddd, J = 31.8, 14.7, 7.4 Hz, 2H), 2.79 (q, J = 12.5, 11.8 Hz, 2H), 2.41 - 2.31 (m, 6H), 1.97 - 1.76 (m, 5H), 1.47 (q, J = 12.5 Hz, 2H). ESI MS [M+H] + C 30 H 34 Calculated for C48H50N5O: 480.3; Found: 480.3.

[0319] Example 50: 2-Chloro-6-methyl-4-{5-[(7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}benzamide

Chemical formula

[0320] The title compound was prepared in the same manner as in Example 49. 11H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.70 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 7.7, 2.0 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 3.49 - 3.37 (m, 3H), 3.13 - 2.86 (m, 4H), 2.85 - 2.71 (m, 2H), 2.40 - 2.33 (m, 5H), 1.97 - 1.77 (m, 4H), 1.51 (p, J = 12.4 Hz, 2H). ESI MS [M+H] + C 29 H 31 Calculated for ClN5O: 500.2; found: 500.2.

[0321] Example 51: 2-(3-Chloro-4-{5-[(7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)propan-2-ol

Chemical Structure

[0322] The title compound was prepared in the same manner as in Example 49. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 1.8 Hz, 0H), 7.47 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 7.7, 2.0 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 5.26 (s, 1H), 3.09 - 2.92 (m, 2H), 2.66 - 2.37 (m, 9H), 1.88 - 1.51 (m, 6H), 1.46 (s, 6H). ESI MS [M+H] + C 30 H 34 Calculated value for ClN4O: 501.2; Measured value: 501.2.

[0323] Example 52: 2-Fluoro-4-(5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzamide [ka]

[0324] The indicated compound was prepared in the same manner as in Example 49. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (dd, J = 2.1, 0.8 Hz, 1H), 8.79 (s, 1H), 8.71 (t, J = 2.1 Hz, 1H), 8.01 (dd, J = 8.1, 1.6 Hz, 1H), 7.92 (dd, J = 11.7, 1.6 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.74 (d, J = 2.6 Hz, 1H), 7.68 (d, J = 2.1 Hz, 2H), 7.62 (dd, J = 7.7, 2.0 Hz, 1H), 7.30 (dd, J = 7.9, 1.6 Hz, 1H), 4.09 (s, 1H), 3.00 - 2.76 (m, 5H), 2.19 (d, J = 8.6 Hz, 1H), 2.10 - 2.00 (m, 1H), 1.88 (pt, J = 11.6, 5.8 Hz, 4H), 1.77 - 1.57 (m, 4H), 1.52 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 30 H 33 Calculated value for N5O: 498.2; Measured value: 498.2.

[0325] Example 53: 2-Methoxy-4-(5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzamide [ka]

[0326] The indicated compound was prepared in the same manner as in Example 49. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.50 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.64 (s, 1H), 7.51 - 7.40 (m, 3H), 7.16 (dd, J = 7.7, 3.5 Hz, 1H), 4.00 (s, 3H), 3.23 - 3.09 (m, 2H), 2.80 (t, J = 7.4 Hz, 1H), 2.69 - 2.53 (m, 2H), 2.05 (d, J = 3.8 Hz, 1H), 1.93 - 1.56 (m, 6H), 1.44 - 1.19 (m, 4H), 1.00 (d, J = 6.0 Hz, 3H), 0.89 (s, 2H). ESI MS [M+H] + C 31 H 36 Calculated value for N5O2: 510.9; Measured value: 510.9.

[0327] Example 54: 4-(5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzamide [ka]

[0328] The indicated compound was prepared in the same manner as in Example 49. 1 1H NMR (400 MHz, DMSO-d 6ss) δ 8.86 (dd, J = 2.1, 0.8 Hz, 1H), 8.76 - 8.66 (m, 2H), 8.20 - 8.11 (m, 2H), 8.08 - 7.94 (m, 3H), 7.68 (d, J = 1.7 Hz, 1H), 7.61 (dd, J = 7.8, 2.0 Hz, 1H), 7.42 (s, 1H), 7.30 (dd, J = 7.8, 1.5 Hz, 1H), 4.09 (s, 1H), 3.28 (q, J = 6.3 Hz, 2H), 2.90 (t, J = 11.2 Hz, 3H), 2.81 - 2.73 (m, 1H), 2.18 (s, 1H), 2.09 - 2.01 (m, 1H), 1.97 - 1.77 (m, 3H), 1.75 - 1.59 (m, 3H), 1.52 (s, 3H), 1.25 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 30 H 34 Calculated value for N5O: 480.3; Measured value: 480.3.

[0329] Example 55: 1-(2,6-dimethyl-4-{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}benzoyl)piperazine [ka]

[0330] Steps a-g: The indicated compound was prepared (60 mg, 72%) in the same manner as in Example 49. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.31 (s, 2H), 8.81 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.61 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 7.7, 2.0 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 3.90 (t, J = 5.4 Hz, 2H), 3.40 (dt, J = 23.8, 5.7 Hz, 6H), 3.23 - 3.14 (m, 2H), 3.14 - 2.87 (m, 6H), 2.78 (q, J = 12.5, 11.8 Hz, 2H), 2.37 (s, 2H), 2.27 (s, 6H), 1.97 - 1.79 (m, 4H), 1.51 (p, J = 12.3 Hz, 2H). ESI MS [M+H] + C 34 H 41 Calculated value for N6O: 549.3; Measured value: 549.3.

[0331] Example 56: 1-(2-chloro-6-methyl-4-{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}benzoyl)piperazine [ka]

[0332] The indicated compound was prepared in the same manner as in Example 55. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.42 (s, 2H), 8.83 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 7.98 (ddd, J = 3.0, 1.6, 0.7 Hz, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 7.7, 1.9 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 3.90 (ddt, J = 44.5, 14.1, 5.4 Hz, 2H), 3.49 - 3.36 (m, 5H), 3.22 - 2.86 (m, 8H), 2.79 (q, J = 12.6, 12.2 Hz, 2H), 2.42 - 2.28 (m, 5H), 1.97 - 1.77 (m, 4H), 1.51 (p, J = 12.4 Hz, 2H). ESI MS [M+H] + C 33 H 38 Calculated value for ClN6O: 569.3; Measured value: 569.3.

[0333] Example 57: 2-[2-chloro-4-(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)phenyl]propan-2-ol [ka]

[0334] Step a: Dioxane (4.8 mL) was added to a mixture of the product from Example 1 and Step e (310 mg, 0.962 mmol), B2pin2 (244 mg, 0.962 mmol), and KOAc (104 mg, 1.06 mmol), and the suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (70 mg, 0.0962 mmol) was added, and the reaction mixture was stirred at 90°C for 4 hours. As soon as it cooled, siRNA (20 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.

[0335] Step b: To a mixture of the product from Step b of Example 11 (228 mg, 0.459 mmol), the crude product from Step a (0.562 mmol), and Na2CO3 (97 mg, 0.918 mmol), dioxane (4.1 mL) and H2O (0.50 mL) were added, and the suspension was degassed with N2 for 10 minutes. (dppf)PdCl2 (17 mg, 0.0230 mmol) was added, and this reaction mixture was stirred at 90°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 100% CH2Cl2 to 10% MeOH, 0.5% NEt3, followed by CH2Cl2 containing 100% CH2Cl2 to 5% MeOH, 0.5% NEt3), yielding an intermediate containing impurities as a brown solid (373 mg). To a THF solution (4.6 mL) containing the residue, a TBAF solution (1 M THF, 4.6 mL, 4.59 mmol) was added, and the reaction mixture was stirred at 70°C for 14 hours. After cooling, the reaction product was concentrated, then dissolved in siRNA, and washed with H2O. The aqueous layer was extracted with CH2Cl2 containing 10% MeOH (2 × 20 ml), and the combined organic layer was concentrated. To the residue, MeOH (4.6 mL) was added, followed by DMEDA (0.37 mL, 3.44 mmol), and the mixture was stirred at 45°C for 1 hour. Once cooled, the reaction product was concentrated and then purified by silica gel chromatography (CH2Cl2 containing 100% CH2Cl2 to 10% MeOH, 1% NEt3, and  containing 100%  to 5% MeOH, 1% NH3) to obtain the indicated compound as a white powder (70 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 2.1 Hz, 1H), 8.64 (dd, J = 2.1, 0.8 Hz, 1H), 8.08 (dd, J = 8.3, 1.8 Hz, 1H), 8.04 - 7.96 (m, 2H), 7.56 (t, J = 2.3 Hz, 1H), 7.51 (dt, J = 7.7, 2.0 Hz, 1H), 7.22 (dd, J = 7.7, 3.4 Hz, 1H), 5.40 (s, 1H), 3.46 - 3.36 (m, 1H), 3.27 - 3.09 (m, 2H), 2.87 - 2.79 (m, 1H), 2.72 - 2.53 (m, 2H), 2.49 - 2.39 (m, 1H), 1.94 - 1.59 (m, 11H), 1.46 - 1.22 (m, 3H), 1.03 (d, J = 6.2 Hz, 3H), 0.92 (s, 3H). ESI MS [M+H] + C 32 H 38 Calculated value for ClN4O: 529.3; Measured value: 529.2.

[0336] Example 58: 2-[2-chloro-4-(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)phenyl]propan-2-ol [ka]

[0337] The indicated compound was prepared in the same manner as in Example 57. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (t, J = 2.2 Hz, 1H), 8.70 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.07 (dt, J = 9.3, 2.3 Hz, 1H), 8.04 - 7.96 (m, 2H), 7.70 (s, 1H), 7.65 - 7.60 (m, 1H), 7.33 (d, J = 7.8 Hz, 1H), 4.19 - 4.05 (m, 1H), 3.40 - 3.24 (m, 2H), 3.04 - 2.75 (m, 4H), 2.29 - 2.14 (m, 1H), 2.14 - 2.01 (m, 1H), 2.00 - 1.81 (m, 3H), 1.78 - 1.59 (m, 9H), 1.55 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 32 H 38 Calculated value for ClN4O: 529.3; Measured value: 529.2.

[0338] Example 59: 2-(2-chloro-4-{5-[7-(pyrroridine-1-yl)-5H,6H,7H,8H,9H-cyclohepta[c]pyridine-3-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}phenyl)propan-2-ol [ka]

[0339] Step a: Add LiBH4 (10.9 mL, 21.8 mmol, 2.0 M THF solution) dropwise to a 38:1 THF:MeOH (27.5 mL) solution containing 3,4-diethyl 6-chloropyridine-3,4-dicarboxylate (2.00 g, 7.76 mmol) at 0°C. Remove the cold water bath and stir the mixture at room temperature for 2.5 hours. This mixture is then mixed with saturated NaHCO₃⁻. 3(水溶液)The mixture was placed in a 75 mL container, and the product was extracted with ethyl acetate (5 × 75 mL). The combined organic phase was dried (Na₂SO₄) and concentrated, and the crude product was sent to the next step.

[0340] Step b: Phosphorus tribromide (0.87 mL, 9.28 mmol) was added dropwise to THF (35 mL) containing a suspension of the crude product from step a (7.76 mmol) at 0°C. The cold water bath 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 (120 mL). The layers were separated, and additional products were extracted in CH2Cl2 (2 × 120 mL). The combined organic phases were dried with (Na2SO4), concentrated, and the crude product was purified by flash chromatography (hexane containing 0-100% siRNA) to obtain the desired product as a white solid (0.491 g, 21%).

[0341] Step c: The product from step b (0.991 g, 3.31 mmol), a mixture of 1,5-dimethyl-3-oxopentanedioic acid (0.57 mL, 3.97 mmol), TBAB (0.534 g, 1.66 mmol), sodium bicarbonate (1.39 g, 16.6 mmol), CH2Cl2 (6.6 mL), and H2O (16.5 mL) was heated overnight at 40°C. CH2Cl2 was removed under vacuum, and the residue was dissolved in Depositphotos (16 mL). This solution was washed with 9:1 H2O:brine (4 × 16 mL), dried (Na2SO4), concentrated, and the crude product was used in the next step.

[0342] Step d: The crude product of step c is mixed with 6 N HCl. (水溶液) The mixture was suspended and heated at 95°C for 2 hours. Once cooled to room temperature, solid NaOH was gradually added to the mixture to make it basic. The product was extracted in ethyl acetate (3 × 50 mL), the combined organic phase was washed with brine (50 mL), dried (Na₂SO₄), and concentrated. The crude product was purified by flash chromatography (hexane containing 0-100% ethyl acetate) to obtain the desired product as a white solid (308 mg, 43%).

[0343] Step e: NaBH(OAc)3 (122 mg, 0.575 mmol) and acetic acid (0.02 mL, 0.383 mmol) were added to a solution of DCE (1.9 mL) containing the product from step d (74.9 mg, 0.383 mmol) and pyrrolidine (0.04 mL, 0.459 mmol). This mixture was stirred overnight at room temperature. The reaction product was then converted to saturated NaHCO₃⁻. 3(水溶液) The reaction was stopped at (5 mL), and the product was extracted to CH2Cl2 (3 × 5 mL). The combined organic phase was washed with brine (5 mL), dried, concentrated, and the crude product was sent to the next step.

[0344] Step f: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0345] Step g: The desired compound was prepared (135 mg, 57%) in the same manner as in Example 11, Step a.

[0346] Step h: The desired compound was prepared in the same manner as in Example 11, step e (39.1 mg, 22%). 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.32 (d, J = 2.0 Hz, 1H), 9.07 (d, J = 2.0 Hz, 1H), 8.54 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 1.4 Hz, 2H), 8.01 (dd, J = 1.3, 0.9 Hz, 1H), 3.68 - 3.55 (m, 1H), 3.58 - 3.46 (m, 2H), 3.28 - 3.13 (m, 2H), 3.05 (td, J = 16.3, 15.9, 7.3 Hz, 2H), 2.97 - 2.85 (m, ESI MS [M+H]+ C 29 H 33 Calculated value for ClN5O: 502.2; Measured value: 502.2.

[0347] Example 60: 2-(2-chloro-4-{5-[7-(pyrroridine-1-yl)-5H,6H,7H,8H,9H-cyclohepta[b]pyridine-2-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}phenyl)propan-2-ol [ka]

[0348] The indicated compound was prepared in the same manner as in Example 59. 1 H NMR (400 MHz, chloroform-d) δ 11.95 (br. s, 1H), 9.24 (d, J = 2.0 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.89 (dd, J = 8.2, 1.8 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 3.42 (dd, J = 14.3, 9.0 Hz, 1H), 3.05 (d, J = 11.2 Hz, 1H), 2.99 (dd, J = 14.3, 10.6 Hz, 1H), 2.83 (br. s, 1H), 2.76 - 2.62 (m, 5H), 2.57 (tt, J = 9.3, 3.0 Hz, 1H), 2.23 - 2.06 (m, 2H), 1.80 (s, 6H), 1.77 - 1.56 (m,6H). ESI MS [M+H] + C 29 H 33 Calculated value for ClN5O: 502.2; Measured value: 502.2.

[0349] Example 61: 2-[2-chloro-4-{5-[13-(pyrrolidine-1-yl)tricyclo[8.2.1.0 3 ,8 ]trideca-3,5,7-trien-5-yl]-1H-pyrazolo[3,4-b]pyridine-3-yl}phenyl)propan-2-ol [ka]

[0350] The indicated compound was prepared in the same manner as in Example 59. 1 H NMR (400 MHz, chloroform-d) δ 11.29 (br. s, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.03 (dd, J = 1.8, 0.4 Hz, 1H), 7.90 (dd, J = 8.2, 1.8 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.23 - 7.17 (m, 1H), 3.75 - 3.47 (m, 2H), 2.67 (s, 1H), 2.63 - 2.47 (m, 8H), 2.44 (p, J = ESI MS [M+H] + C 32 H 36 Calculated value for ClN4O: 527.3; Measured value: 527.2.

[0351] Example 62: 1-[2-chloro-4-(5-{7-[(2R)-1-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrazolo[3,4-b]pyridine-1-yl)phenyl]cyclobutan-1-ol [ka]

[0352] Step a: At -78°C, n-butyllithium (12.6 mL, 31.5 mmol, 2.5 M hexane) was added to a solution of tetrahydrofuran (30 mL) containing 4-bromo-2-chloro-1-iodobenzene (10 g, 31.5 mmol) at a rate that maintained the internal temperature below -65°C. After 30 minutes, cyclobutanone (1.93 mL, 26.3 mmol) was added dropwise over 40 minutes, maintaining the internal temperature below -65°C. After a further 60 minutes at -78°C, saturated NH4Cl (水溶液) (20 mL) was added, and the resulting mixture was extracted with SiO2 (2 × 60 mL). The combined organic phase was dried and concentrated on Na2SO4. The crude product was purified by column chromatography (120 g silica gel, hexane:SiO2) with a gradient from 0% to 10% (30 minutes) to obtain the desired product as a white solid (4.81 g, 70%).

[0353] Step b: A mixture of the product from step a (450 mg, 1.72 mmol), B2pin2 (437 mg, 1.72 mmol), (dppf)PdCl2 (126 mg, 0.172 mmol), and KOAc (338 mg, 3.44 mmol) was placed under nitrogen. Degassed dioxane (8.6 mL) was added, and the reaction mixture was stirred at 100 °C for 1 hour. This mixture was cooled to room temperature, concentrated, diluted with SiO2 (50 mL), filtered through Celite to remove solids, and concentrated again to obtain the desired product, which was used directly in step i.

[0354] Step c: 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%).

[0355] Step d: 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 then used directly in the next step.

[0356] Step e: Place the mixture of the product from step c (21.2 g, 75 mmol), the product from step d (75.0 mmol, estimated value), and (dppf)PdCl2 (5.49 g, 7.50 mmol) under nitrogen, and add degassed dioxane (375 mL) and degassed 2M Na2CO2. 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).

[0357] Step f: The mixture of the product from step e (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 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 min); and a gradient from 3% to 5% (10 min), yielding the desired product as an orange solid (14.8 g, 75%).

[0358] To a mixture of Step g: Step f (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 min) and a gradient from 5% to 7.5% (5 min) to obtain the desired product as a brown solid (21.4 g, 74.5 wt%; residual succinimide). The amount of pure product was 15.9 g (86% yield).

[0359] Step h: To a mixture of the product from step g (21.4 g, 39.7 mmol, 74.5 wt%), 4-dimethylaminopyridine (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).

[0360] Step i: A mixture of the product from step h (688 mg, 1.38 mmol), the product from step b (531 mg, 1.72 mmol), and (dppf)PdCl2 (126 mg, 0.172 mmol) was placed under nitrogen. Degassed dioxane (6.9 mL) and degassed 2M Na2CO2 were added. 3(水溶液) (1.72 mL) was added, and the reaction mixture was stirred at 100°C for 12 hours. The mixture was cooled to room temperature, diluted with CH2Cl2 (30 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (24 g silica gel, hexane: siRNA) from 0% to 100% gradient (30 minutes) to obtain the desired product as a yellow solid (528 mg, 76%; 2 steps).

[0361] Step j: Add 1M HCl to the mixture of THF (0.84 mL) containing the product from Step i (84 mg, 0.17 mmol). (水溶液) (0.34 mL) was added, and the reaction mixture was stirred at 70°C for 1 hour. The mixture was cooled to room temperature and saturated with NaHCO₃⁻. 3(水溶液) The mixture was neutralized with (2 mL) and extracted with SiO2 (3 × 20 mL). The combined organic phase was dried over Na2SO4 and concentrated to obtain the desired product as a yellow solid. (R)-2-methylpyrrolidine (34 μL, 0.34 mmol), acetic acid (19 μL, 0.34 mmol), and DMF (1.7 mL) were added, followed by NaBH(OAc)3 (142 mg, 0.67 mmol). The reaction mixture was stirred at 40°C for 2 hours. The mixture was diluted with SiO2 (15 mL) and water:2 M NaOH (水溶液) The solution was washed with brine (8:1:1) (3 × 15 mL), dried and concentrated over Na₂SO₄, and purified by HPLC ((H₂O / ACN) + 0.1% TFA) with a gradient from 20% to 80% (20 minutes) to obtain the desired product as a white solid (49 mg, 56%; 2 steps). 11H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 7.9, 1.9 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 7.6, 2.0 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 5.48 (s, 1H), 3.00 - 2.59 (m, 7H), 2.47 - 2.41 (m, 1H), 2.40 - 2.30 (m, 4H), 2.12 - 1.94 (m, 2H), 1.87 - 1.74 (m, 1H), 1.70 - 1.50 (m, 4H), 1.48 - 1.38 (m, 1H), 1.33 - 1.21 (m, 2H), 1.02 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated for C + H 32 ClN4O: 527.3; Found: 527.2.

[0362] Example 63: 3-[2-Chloro-4-(5-{7-[(2R)-2-Methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl]oxolan-3-ol

Chemical Structure

[0363] The title compound was prepared in the same manner as in Example 62. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 5.62 (s, 1H), 4.13 (d, J = 9.1 Hz, 1H), 4.05 - 3.97 (m, 3H), 2.98 - 2.57 (m, 7H), 2.46 - 2.40 (m, 1H), 2.36 - 2.30 (m, 1H), 2.24 - 2.18 (m, 1H), 2.06 - 1.94 (m, 2H), 1.86 - 1.75 (m, 1H), 1.70 - 1.50 (m, 2H), 1.50 - 1.37 (m, 1H), 1.33 - 1.21 (m, 2H), 1.02 (d, J = 5.9 Hz, 3H). ESI MS [M+H] + C 32 H 36 Calculated value for ClN4O2: 543.3; Measured value: 543.2.

[0364] Example 64: 3-[2-chloro-4-(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)phenyl]oxetan-3-ol [ka]

[0365] The indicated compound was prepared in the same manner as in Example 62. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 7.8 Hz, 1H), 6.36 (s, 1H), 5.12 (d, J = 7.1 Hz, 2H), 4.75 (d, J = 7.1 Hz, 2H), 2.99 - 2.65 (m, 7H), 2.46 - 2.38 (m, 1H), 2.35 - 2.31 (m, 1H), 2.05 - 1.95 (m, 2H), 1.86 - 1.74 (m, 1H), 1.67 - 1.49 (m, 2H), 1.49 - 1.35 (m, 1H), 1.34 - 1.21 (m, 2H), 1.02 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 31 H 34 Calculated value for ClN4O2: 529.2; Measured value: 529.2.

[0366] Example 65: 2-[3-chloro-5-(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)pyridine-2-yl]propan-2-ol [ka]

[0367] The indicated compound was prepared in the same manner as in Example 62. 1H NMR (400 MHz, DMSO-d6) δ 9.26 (dd, J = 1.9, 0.5 Hz, 1H), 9.11 (br. s, 1H), 8.94 (dd, J = 2.1, 1.1 Hz, 1H), 8.80 (dd, J = 2.1, 1.3 Hz, 1H), 8.48 (d, J = 1.9 Hz, 1H), 7.83 - 7.73 (m, 1H), 7.69 (dd, J = 7.7, 2.0 Hz, 1H), 7.35 (dd, J = 7.8, 4.5 Hz, 1H), 3.82 - 3.68 (m, 2H), 3.41 - 3.28 (m, 1H), 3.21 (p, J = 8.0 Hz, 1H), 3.04 (dd, J = 14.5, 6.9 Hz, 1H), 2.92 (p, J = 13.1, 12.7 Hz, 4H), 2.40 - 2.27 (m, 2H), 2.18 (dq, J = 12.9, 6.8 Hz, 1H), 1.90 (p, J = 7.1 Hz, 2H), 1.67 (s, 6H), 1.65 - 1.44 (m, 3H), 1.39 (d, J = 6.5 Hz, 3H). + C 30 H 35 Calculated value for ClN5O: 516.3; Measured value: 516.2

[0368] Example 66: (S)-(2-chloro-4-(5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl)(4-methoxypiperidine-1-yl)methanone [ka]

[0369] Step a: EDC-HCl (1.9 g, 10.2 mmol) was added to a mixture of 4-bromo-2-chlorobenzoic acid (2.0 g, 8.5 mmol), 4-methoxypiperidine (1.2 g, 10.2 mmol), Et3N (1.8 mL, 12.7 mmol), and CH2Cl2 (20 mL). This mixture was stirred at room temperature for 14 hours, and then H2O (5 mL) and CH2Cl2 (50 mL) were added. The phases were separated, the organic phase was dried and concentrated over Na2SO4, and purified by column chromatography (hexane containing SiO2 and 0-90% siRNA) to obtain the desired product (731 mg, 26%).

[0370] Step b: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0371] Step c: The desired product was prepared in the same manner as in Example 24, Step c (286 mg, 55%).

[0372] Step d: The desired product was prepared in the same manner as in Example 24, Step d (49 mg, 29%).

[0373] Step e: 3M methanol-HCl (1.0 mL) was added to the product from step d (49 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 3 hours. After removing the solvent, the crude product was purified by reverse-phase HPLC using H2O + 0.1% TFA and ACN + 0.1% TFA as the mobile phase, and the desired product was obtained as a yellow solid (40 mg, 93%). 1H NMR (400 MHz, DMSO-d6) δ 9.54 (d, J = 7.6 Hz, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.16 - 8.09 (m, 2H), 7.69 - 7.57 (m, 2H), 7.49 (t, J = 8.2 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 3.94 (s, 1H), 3.59 - 3.40 (m, 4H), 3.40 - 3.27 (m, 2H), 3.23 (s, 3H), 3.16 - 2.71 (m, 8H), 2.33 (s, 2H), 1.95 (s, 2H), 1.86 - 1.78 (m, 2H), 1.43 (p, J = 12.6 Hz, 4H). ESI MS [M+H] + C 34 H 39 Calculated value for ClN5O2: 584.3; Measured value: 584.3.

[0374] Example 67: 1-[2-chloro-4-(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)benzoyl]-4-methoxypiperidine [ka]

[0375] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.1 Hz, 1H), 8.69 (s, 1H), 8.16 (d, J = 7.8 Hz, 2H), 7.60 - 7.46 (m, 3H), 7.23 (s, 1H), 4.06 - 3.93 (m, 1H), 3.65 - 2.30 (m, 7H), 3.26 (s, 3H), 3.15 - 3.01 (m, 2H), 2.88 - 2.73 (m, 2H), 2.72 - 2.29 (m, 4H), 1.97 - 1.65 (m, 4H), 1.56 - 1.35 (m, 4H), 1.03 (s, 3H), 0.92 (s, 3H). ESI MS [M+H] + C 36 H 43 Calculated value for ClN5O2: 612.3; Measured value: 612.3.

[0376] Example 68: 2-Chloro-4-(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)benzamide [ka]

[0377] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 2.6 Hz, 1H), 8.63 (s, 1H), 8.17 - 8.05 (m, 2H), 7.93 (s, 1H), 7.63 (s, 1H), 7.59 - 7.51 (m, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 4.13 (s, 1H), 3.50 - 3.22 (m, 2H), 3.07 - 2.77 (m, 4H), 2.44 - 2.29 (m, 2H), 1.94 - 1.57 (m, 4H), 1.47 - 1.28 (m, 2H), 1.01 (d, J = 6.0 Hz, 3H), 0.89 (s, 3H). ESI MS [M+H] + C 30 H 33 Calculated value for ClN5O: 514.2; Measured value: 514.2.

[0378] Example 69: N-Cyclopropyl-4-(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)benzamide [ka]

[0379] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 8.89 - 8.83 (m, 1H), 8.71 - 8.63 (m, 1H), 8.53 (s, 1H), 8.18 (d, J = 11.1 Hz, 2H), 7.98 (d, J = 11.0 Hz, 2H), 7.60 - 7.45 (m, 2H), 7.22 (s, 1H), 4.09 - 3.92 (m, 1H), 3.64 - 3.08 (m, 6H), 2.96 - 2.74 (m, 1H), 2.70 - 2.56 (m, 2H), 1.99 (s, 1H), 1.89 (d, J = 12.8 Hz, ESI MS [M+H] + C 33 H 38 Calculated value for N5O: 520.3; Measured value: 520.2.

[0380] Example 70: 4-(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)-N-(propan-2-yl)benzamide [ka]

[0381] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 8.89 - 8.83 (m, 1H), 8.71 - 8.63 (m, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 8.2 Hz, 2H), 8.06 - 7.95 (m, 2H), 7.57 (t, J = 2.3 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.23 (dd, J = 7.8, 3.5 Hz, 1H), 4.19 - 4.08 (m, 1H), 3.31 - 3.28 (m, 4H), 3.27 - 3.08 (m, 2H), 2.83 (t, J = 7.4 Hz, 1H), 2.69 - 2.54 (m, 2H), 1.94 - 1.80 (m, 2H), 1.79 - 1.64 (m, 2H), 1.46 - 1.35 (m, 1H), 1.27 - 1.22 (d, J = 3.4 Hz, 1H), 1.19 (dd, J = 6.6, 0.8 Hz, 6H), 1.04 (d, J = 6.2 Hz, 3H), 0.93 (s, 3H). ESI MS [M+H] + C 33 H 40 Calculated value for N5O: 522.3; Measured value: 522.3.

[0382] Example 71: N-methyl-4-(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)benzamide [ka]

[0383] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.1 Hz, 1H), 8.70 (s, 1H), 8.54 (d, J = 5.0 Hz, 1H), 8.20 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 8.2 Hz, 2H), 7.57 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.29 - 7.15 (m, 1H), 4.07 - 3.97 (m, 1H), 3.64 - 3.08 (m, 6H), 2.82 (d, J = 4.5 Hz, 3H), 2.69 - 2.54 (m, 2H), 1.94 - 1.80 (m, 2H), 1.77 - 1.57 (m, 1H), 1.46 - 1.33 (m, 2H), 1.23 - 1.09 (m, 1H), 1.04 (d, J = 6.2 Hz, 3H), 0.93 (s, 3H). ESI MS [M+H] + C 31 H 36 Calculated value for N5O: 494.3; Measured value: 494.3.

[0384] Example 72: N-(2-methoxyethyl)-4-(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)benzamide [ka]

[0385] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 2.9 Hz, 1H), 8.70 (d, J = 4.0 Hz, 1H), 8.63 (d, J = 4.6 Hz, 1H), 8.20 (dd, J = 8.5, 3.8 Hz, 2H), 8.01 (dd, J = 8.3, 3.8 Hz, 2H), 7.58 (d, J = 3.7 Hz, 1H), 7.52 (s, 1H), 7.23 (dd, J = 7.7, 4.0 Hz, 1H), 4.07 - 3.97 (m, 1H), 3.52 - 3.41 (m, 6H), 3.28 (d, J = 4.4 Hz, 3H), 3.25 - 3.10 (m, 2H), 2.89 - 2.76 (m, 1H), 2.69 - 2.61 (s, 1H), 2.33 (s, 1H), 1.96 - 1.76 (m, 3H), 1.74 - 1.57 (m, 2H), 1.47 - 1.21 (m, 2H), 1.04 (d, J = 6.5 Hz, 3H), 0.92 (s, 3H). ESI MS [M+H] + C 33 H 40 Calculated value for N5O2: 538.3; Measured value: 538.3.

[0386] Example 73: 2-Chloro-4-(5-{7-ethyl-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)benzamide [ka]

[0387] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.0 Hz, 1H), 8.76 - 8.63 (m, 2H), 8.14 (dd, J = 7.9, 1.7 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.97 (s, 1H), 7.70 - 7.66 (m, 2H), 7.64 - 7.59 (m, 2H), 7.32 (dd, J = 7.9, 3.6 Hz, 1H), 4.22 - 4.07 (m, 1H), 3.46 - 3.33 (m, 1H), 3.34 - 3.21 (m, 1H), 3.11 - 2.77 (m, 4H), 2.31 - 2.10 (m, 2H), 2.08 - 1.58 (m, 8H), 1.37 (d, J = 6.6 Hz, 3H), 1.07 (t, J = 7.3 Hz, 3H). ESI MS [M+H] + C 31 H 35 Calculated value for ClN5O: 528.3; Measured value: 528.2.

[0388] Example 74: 2-Chloro-4-(5-{7-ethyl-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)benzamide [ka]

[0389] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.1 Hz, 1H), 8.78 (brs, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.15 (dd, J = 7.9, 1.6 Hz, 1H), 8.12 (d, J = 1.5 Hz, 1H), 7.97 (s, 1H), 7.68 (dd, J = 3.5, 2.0 Hz, 2H), 7.64 - 7.59 (m, 2H), 7.32 (dd, J = 8.0, 1.8 Hz, 1H), 4.03 - 3.93 (m, 1H), 3.66 - 3.51 (m, 2H), 3.50 - 3.39 (m, 1H), 3.39 - 3.28 (m, 1H), 2.99 - 2.78 (m, 4H), 2.25 - 2.11 (m, 2H), 2.09 - 1.97 (m, 2H), 1.96 - 1.63 (m, 6H), 1.09 (t, J = 7.3 Hz, 3H). ESI MS [M+H] + C 31 H 35 Calculated value for ClN5O2: 544.2; Measured value: 544.2.

[0390] Example 75: 2-Chloro-4-(5-{7-ethyl-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)benzamide [ka]

[0391] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.0 Hz, 1H), 8.72 - 8.57 (m, 2H), 8.14 (dd, J = 7.9, 1.6 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.97 (s, 1H), 7.74 - 7.66 (m, 2H), 7.66 - 7.58 (m, 2H), 7.32 (dd, J = 7.8, 2.0 Hz, 1H), 4.06 - 3.88 (m, 1H), 3.69 - 3.50 (m, 2H), 3.49 - 3.28 (m, 2H), 3.08 - 2.76 ESI MS [M+H] + C 31 H 35 Calculated value for ClN5O2: 544.2; Measured value: 544.2.

[0392] Example 76: (2R)-1-(2-{3-[4-(azetidine-1-carbonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)-2-methylpyrrolidine [ka]

[0393] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.58 (t, J = 2.3 Hz, 1H), 7.52 (dt, J = 7.7, 2.1 Hz, 1H), 7.22 (dd, J = 7.8, 3.6 Hz, 1H), 4.38 (t, J = 7.7 Hz, 2H), 4.08 (t, J = 7.8 Hz, 2H), 3.47 - 3.30 (m, 1H), 3.27 - 3.09 (m, 2H), 2.83 (t, J = 7.5 Hz, 1H), 2.70 - 2.45 (m, 3H), 2.29 (p, J = 7.8 Hz, 2H), 1.95 - 1.61 (m, 5H), 1.48 - 1.22 (m, 3H), 1.04 (d, J = 6.2 Hz, 3H), 0.93 (s, 3H). ESI MS [M+H] + C 33 H 38 Calculated value for N5O: 520.3; Measured value: 520.3.

[0394] Example 77: 2-Chloro-4-(5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzamide [ka]

[0395] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.17 - 8.06 (m, 2H), 7.94 (s, 1H), 7.69 - 7.51 (m, 4H), 7.30 (d, J = 7.8 Hz, 1H), 3.46 (d, J = 5.0 Hz, 3H), 3.13 (s, 2H), 3.04 - 2.75 (m, 4H), 2.33 (s, 2H), 1.95 (s, 2H), 1.82 (dd, J = 7.7, 4.9 Hz, 2H), 1.43 (p, J = 12.4 Hz, 2H). ESI MS [M+H] + C 28 H 29 Calculated value for ClN5O: 486.2; Measured value: 486.2.

[0396] Example 78: 4-(5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzamide [ka]

[0397] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 14.00 (s, 1H), 9.46 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.19 - 8.12 (m, 2H), 8.07 - 7.93 (m, 3H), 7.67 (d, J = 2.0 Hz, 1H), 7.61 (dd, J = 7.7, 2.0 Hz, 1H), 7.42 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 3.17 (d, J = 28.0 Hz, 3H), 2.99 (dd, J = 14.7, 7.4 Hz, 2H), 2.91 (dd, J = 14.7, 7.2 Hz, 2H), 2.86 - 2.73 (m, 2H), 2.33 (s, 2H), 1.95 (s, 2H), 1.81 (d, J = 5.3 Hz, 2H), 1.43 (p, J = 12.4 Hz, 2H). ESI MS [M+H] + C 28 H 30 Calculated value for N5O: 452.2; Measured value: 452.2.

[0398] Example 79: 2-Fluoro-6-methyl-4-(5-(7-(pyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzamide [ka]

[0399] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 11.04 (d, J = 7.8 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 1.5, 0.8 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.66 - 7.53 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 3.42 (dt, J = 11.3, 5.2 Hz, 3H), 3.12 - 2.87 (m, 4H), 2.78 (q, J = 11.8 Hz, 2H), 2.42 - 2.30 (m, 5H), 1.95 - 1.78 (m, 4H), 1.61 - 1.43 (m, 2H). + C 29 H 31 Calculated value for FN5O: 484.2; Measured value: 484.2.

[0400] Example 80: 4-(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-(trifluoromethyl)benzamide [ka]

[0401] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (d, J = 7.3 Hz, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.50 - 8.42 (m, 1H), 8.36 - 8.30 (m, 1H), 8.05 - 8.00 (m, 1H), 7.71 - 7.62 (m, 3H), 7.58 (dd, J = 7.8, 2.0 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 3.53 - 3.39 (m, 3H), 3.09 (s, 2H), 2.95 (ddd, J = ESI MS [M+H] + C 29 H 29 Calculated value for F3N5O: 520.2; Measured value: 520.2.

[0402] Example 81: 2-Fluoro-4-(5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzamide [ka]

[0403] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (d, J = 7.3 Hz, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.02 (dd, J = 8.1, 1.6 Hz, 1H), 7.93 (dd, J = 11.7, 1.6 Hz, 1H), 7.84 - 7.72 (m, 2H), 7.71 - 7.63 (m, 2H), 7.59 (dd, J = 7.7, 2.0 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 3.43 (dd, J = 10.9, 6.2 Hz, 3H), 3.08 (d, J = 4.3 Hz, 2H), 2.96 (ddd, J = 32.8, 15.2, 7.9 Hz, 2H), 2.79 (q, J = 12.1 Hz, 2H), 2.37 (s, 2H), 1.94 - 1.76 (m, 4H), 1.51 (p, J = 12.8 Hz, 2H). ESI MS [M+H] + C 28 H 29 Calculated value for FN5O: 470.2; Measured value: 470.2.

[0404] Example 82: (S)-(2-chloro-4-(5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl)(piperazine-1-yl)methanone [ka]

[0405] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 10.99 (d, J = 7.3 Hz, 1H), 9.46 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.21 - 8.13 (m, 2H), 7.67 - 7.54 (m, 3H), 7.29 (d, J = 7.8 Hz, 1H), 3.98 (d, J = 14.5 Hz, 1H), 3.80 (d, J = 8.4 Hz, 1H), 3.54 (s, 5H), 3.16 (d, J = 21.4 Hz, 2H), 3.13 - 2.86 (m, ESI MS [M+H] + C 32 H 36 Calculated value for ClN6O: 555.3; Measured value: 555.3.

[0406] Example 83: (S)-2-fluoro-6-methyl-4-(5-(7-(pyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzamide [ka]

[0407] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (d, J = 7.4 Hz, 1H), 8.83 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 7.98 (s, 1H), 7.78 (dd, J = 1.5, 0.8 Hz, 1H), 7.76 - 7.68 (m, 2H), 7.66 - 7.54 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 3.42 (d, J = 11.2 Hz, 3H), 3.11 - 2.87 (m, 4H), 2.79 (q, J = 11.8 Hz, 2H), 2.40 (d, J = 0.7 Hz, 5H), 1.96 - 1.77 (m, 4H), 1.60 - 1.43 (m, 2H). ESI MS [M+H] + C 29 H 31 Calculated value for FN5O: 484.2; Measured value: 484.2.

[0408] Example 84: (S)-2-chloro-4-(5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzamide [ka]

[0409] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (d, J = 8.1 Hz, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.15 - 8.06 (m, 2H), 7.94 (s, 1H), 7.68 - 7.54 (m, 4H), 7.30 (d, J = 7.8 Hz, 1H), 3.61 - 3.42 (m, 3H), 3.13 (s, 2H), 3.01 - 2.78 (m, 4H), 2.34 (s, 2H), 1.95 (s, 2H), 1.82 (dd, J = 7.7, 4.9 Hz, 2H), 1.44 (p, J = 12.5 Hz, 2H). ESI MS [M+H] + C 28 H 29 Calculated value for ClN5O: 486.2; Measured value: 486.2.

[0410] Example 85: (S)-(2-chloro-4-(5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl)(4-hydroxypiperidine-1-yl)methanone [ka]

[0411] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.17 - 8.10 (m, 2H), 7.65 (d, J = 2.0 Hz, 1H), 7.59 (dd, J = 7.8, 2.0 Hz, 1H), 7.52 - 7.43 (m, 1H), 7.29 (d, J = 7.8 Hz, 1H), 4.04 (d, J = 13.4 Hz, 2H), 3.76 - 3.67 (m, 1H), 3.54 - 3.41 (m, 3H), 3.35 - 3.19 (m, 2H), 3.12 - 2.97 (m, 4H), 2.97 - 2.82 (m, 2H), 2.82 - 2.72 (m, 2H), 2.36 (s, 2H), 1.92 (s, 1H), 1.86 (d, J = 9.7 Hz, 1H), 1.83 - 1.79 (m, 1H), 1.67 (s, 1H), 1.46 (dq, J = 33.0, 11.2, 9.8 Hz, 4H). + C 33 H 37 Calculated value for ClN5O2: 570.3; Measured value: 570.3.

[0412] Example 86: (S)-3-methyl-4-(5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzamide [ka]

[0413] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 13.94 (s, 1H), 9.56 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 8.02 (s, 1H), 7.90 (dt, J = 2.0, 0.6 Hz, 1H), 7.82 (ddd, J = 8.0, 1.9, 0.7 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.7, 2.0 Hz, 1H), 7.39 (s, 1H), 7.26 (d, J = 7.8 Hz, 1H), 3.14 (d, J = 9.3 Hz, 2H), 2.92 (ddd, J = 29.2, 14.7, 7.3 Hz, 2H), 2.83 - 2.71 (m, 2H), 2.45 (s, 3H), 2.31 (t, J = 10.0 ESI MS [M+H] + C 29 H 32 Calculated value for N5O: 466.2; Measured value: 466.2.

[0414] Example 87: 2-Methoxy-4-(5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzenesulfonamide [ka]

[0415] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO- d6) δ 8.78 (s, 1H), 8.61 (s, 1H), 7.86 - 7.80 (m, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.55 - 7.44 (m, 2H), 7.18 (dd, J = 7.8, 3.5 Hz, 1H), 7.09 (s, 2H), 4.00 (s, 3H), 3.26 - 3.11 (m, 2H), 2.80 (t, J = 7.4 Hz, 1H), 2.65 - 2.51 (m, 2H), 1.99 - 1.55 (m, 6H), 1.43 - 1.17 (m, 4H), 1.00 (d, J = 6.2 Hz, 3H), 0.89 (s, 3H). ESI MS [M+H] + C 30 H 36 Calculated value for N5O3S: 546.3; Measured value: 546.3.

[0416] Example 88: 4-(5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide [ka]

[0417] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.86 (dd, J = 2.1, 0.6 Hz, 1H), 8.67 (t, J = 2.2 Hz, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.20 - 8.12 (m, 2H), 8.05 - 7.96 (m, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.29 (dd, J = 7.8, 1.8 Hz, 1H), 4.07 - 3.93 (m, 2H), 3.86 (dd, J = 10.5, 4.2 Hz, 2H), 3.37 (td, J = 11.7, 2.1 Hz, 3H), 3.29 - 3.19 (m, 1H), 2.94 - 2.76 (m, 4H), 2.22 (s, 1H), 2.05 (s, 1H), 1.96 - 1.81 (m, 4H), 1.76 - 1.70 (m, 2H), 1.62 (dd, J = 11.7, 4.7 Hz, 3H), 1.57 (d, J = 4.0 Hz, 1H), 1.52 (s, 3H), 1.32 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 35 H 42 Calculated value for N5O2: 564.3; Measured value: 564.3.

[0418] Example 89: (4-Methoxypiperidine-1-yl)(4-(5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl)methanone [ka]

[0419] The indicated compound was prepared in the same manner as in Example 66. 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.69 (t, J = 2.1 Hz, 1H), 8.18 - 8.11 (m, 2H), 7.65 (d, J = 1.8 Hz, 1H), 7.63 - 7.54 (m, 1H), 7.54 - 7.48 (m, 2H), 7.28 (dd, J = 7.9, 1.8 Hz, 1H), 4.05 (s, 1H), 3.91 (s, 1H), 3.58 - 3.29 (m, 4H), 3.26 - 3.19 (m, 4H), 2.95 - 2.77 (m, 4H), 2.22 (s, 1H), 2.04 (s, 1H), 1.96 - 1.76 (m, 6H), 1.70 (d, J = 12.7 Hz, 1H), 1.60 (t, J = 7.1 Hz, 1H), 1.52 (s, 3H), 1.48 (s, 1H), 1.43 (s, 1H), 1.32 (d, J = 6.5 Hz, 3H). ESI MS [M+H] + C 36 H 44 Calculated value for N5O2: 578.3; Measured value: 578.3.

[0420] Example 90: 2-[2-chloro-4-(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)phenyl]propan-2-ol [ka]

[0421] 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%).

[0422] 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%).

[0423] 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 filtered and collected, and washed with water to obtain the desired product, which was used directly in the next step.

[0424] 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).

[0425] Step e: A mixture of the product from step d (101 mg, 0.400 mmol), Example 59, the product from step f (305 mg, 0.560 mmol), and (dppf)PdCl2 (29 mg, 0.040 mmol) was placed under nitrogen. Degassed dioxane (2.0 mL) and degassed 2M Na2CO2 were added. 3(水溶液) (0.40 mL) was added, and the reaction mixture was stirred at 80°C for 18 hours. The mixture was cooled to room temperature, diluted with CH2Cl2 (30 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (24 g silica gel, hexane: HCl) with a gradient from 0% to 100% (30 minutes) to obtain the desired product as a white solid (192 mg, 81%).

[0426] Step f: To a mixture of the product from step e (192 mg, 0.325 mmol), (R)-2-methylpyrrolidine (55 mg, 0.65 mmol), acetic acid (38 μL, 0.65 mmol), and THF (1.6 mL), NaBH(OAc)3 (172 mg, 0.813 mmol) was added. This reaction mixture was stirred at 40°C for 16 hours. This mixture was diluted with ¼ mL of toluene and water: 2 M NaOH (水溶液)The mixture was washed with brine (8:1:1) (3 × 15 mL), dried on Na₂SO₄, and concentrated to obtain a white solid (188 mg). TBAF (2.9 mL, 2.9 mmol, in a 1 M THF solution) was added, and the reaction mixture was stirred at 70°C for 16 hours. This mixture was cooled to room temperature, diluted with SiO₂ (125 mL), washed with 1:1 water:brine (4 × 100 mL), dried on Na₂SO₄, and concentrated. MeOH (3 mL) containing 7 M NH₃ was added, and the reaction mixture was stirred at 60°C for 2 hours. This mixture was concentrated and purified by column chromatography (43 g C₁₄, (H₂O / ACN) + 0.1% TFA) with a gradient from 5% to 50% (25 minutes) to obtain the desired product as a white solid (40 mg, 23%). 1 H NMR (400 MHz, DMSO-d6) δ 13.99 (s, 1H), 8.54 (dd, J = 2.0, 0.6 Hz, 1H), 8.46 (dd, J = 2.0, 0.7 Hz, 1H), 8.04 (dd, J = 8.3, 1.9 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 3.0 Hz, 2H), 5.38 (s, 1H), 2.94 - 2.59 (m, 7H), 2.48 - 2.38 (m, 1H), 2.21 (s, 3H), 2.06 - 1.90 (m, 2H), 1.88 - 1.76 (m, 1H), 1.63 (s, 6H), 1.62 - 1.51 (m, 2H), 1.43 (q, J = 11.3 Hz, 1H), 1.34 - 1.18 (m, 2H), 1.02 (d, J = 6.3 Hz, 3H). ESI MS [M+H] + C 32 H 38 Calculated value for ClN4O: 529.3; Measured value: 529.2.

[0427] Example 91: (S)-2-chloro-4-(5-(7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzenesulfonamide [ka]

[0428] Step a: The desired product was prepared (241 mg, 58%) in the same manner as in Example 24 and Step c.

[0429] Step b: The desired product was prepared (61 mg, 37%) in the same manner as in Example 24 and Step d.

[0430] Step c: The desired product was prepared (35 mg, 72%) in the same manner as in Example 24, Step e. 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (d, J = 7.2 Hz, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.30 - 8.20 (m, 2H), 8.13 - 8.06 (m, 1H), 7.67 (d, J = 6.9 Hz, 3H), 7.61 (dd, J = 7.7, 2.0 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 3.51 - 3.43 (m, 2H), 3.14 (t, J = 9.1 Hz, 2H), 2.95 (ddd, J = 30.0, 14.7, 7.4 Hz, 2H), 2.87 - 2.73 (m, 2H), 2.34 (s, 2H), 2.02 - 1.93 (m, 2H), 1.82 (dd, J = 7.6, 4.8 Hz, 2H), 1.44 (p, J = 12.4 Hz, 2H). ESI MS [M+H] + C 27 H 29 Calculated value for ClN5O2S: 522.2; Measured value: 522.2.

[0431] Example 92: 2-Chloro-4-(5-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzenesulfonamide [ka]

[0432] The indicated compound was prepared in the same manner as in Example 91. 1 H NMR (400 MHz, DMSO-d6) δ 9.79 - 9.72 (m, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.29 - 8.20 (m, 2H), 8.13 - 8.06 (m, 1H), 7.77 - 7.66 (m, 4H), 7.36 (d, J = 7.8 Hz, 1H), 3.71 (d, J = 7.8 Hz, 2H), 3.13 (ddd, J = 43.4, 23.2, 10.2 Hz, 7H), 2.12 - 1.96 (m, 2H), 1.74 (d, J = 24.0 Hz, 4H), 1.53 (d, J = 8.0 Hz, 2H). ESI MS [M+H] + C 27 H 29 Calculated value for ClN5O2S: 522.2; Measured value: 522.2.

[0433] Example 93: 2-Chloro-4-(5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzenesulfonamide [ka]

[0434] The indicated compound was prepared in the same manner as in Example 91. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.72 (t, J = 2.2 Hz, 1H), 8.31 - 8.20 (m, 2H), 8.10 (d, J = 8.2 Hz, 1H), 7.72 - 7.63 (m, 3H), 7.59 (dt, J = 7.8, 1.6 Hz, 1H), 7.29 (dd, J = 7.9, 2.0 Hz, 1H), 4.05 (s, 1H), 3.35 (s, 1H), 3.21 (s, 1H), 2.87 (d, J = 21.9 Hz, 4H), 2.23 (s, 1H), 2.04 (s, 1H), 1.97 - 1.78 (m, 4H), 1.71 (d, J = 11.5 Hz, 1H), 1.59 (d, J = 10.5 Hz, 1H), 1.52 (s, 3H), 1.33 (d, J = 6.5 Hz, 3H). ESI MS [M+H] + C 29 H 33 Calculated value for ClN5O2S: 550.2; Measured value: 550.2.

[0435] Example 94: 2-Chloro-4-(5-(7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzenesulfonamide [ka]

[0436] The indicated compound was prepared in the same manner as in Example 91. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.87 (dd, J = 2.1, 1.1 Hz, 1H), 8.77 - 8.69 (m, 1H), 8.31 - 8.20 (m, 2H), 8.13 - 8.05 (m, 1H), 7.71 - 7.61 (m, 3H), 7.59 (d, J = 1.9 Hz, 1H), 7.30 (dd, J = 7.8, 2.9 Hz, 1H), 3.65 (d, J = 9.7 Hz, 2H), 3.34 - 3.22 (m, 1H), 3.17 - 3.05 (m, 1H), 3.05 - 2.78 (m, 4H), 2.29 (s, 1H), 2.09 (tt, J = 11.2, 5.6 Hz, 1H), 1.83 (dq, J = 15.6, 7.8 Hz, 2H), 1.68 - 1.41 (m, 3H), 1.38 (d, J = 6.4 Hz, 3H). ESI MS [M+H] + C 28 H 31 Calculated value for ClN5O2S: 536.2; Measured value: 536.2.

[0437] Example 95: 4-(5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl)benzenesulfonamide [ka]

[0438] The indicated compound was prepared in the same manner as in Example 91. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (dd, J = 2.1, 0.6 Hz, 1H), 8.72 (t, J = 1.8 Hz, 2H), 8.31 - 8.24 (m, 2H), 7.99 - 7.91 (m, 2H), 7.71 - 7.58 (m, 2H), 7.44 (s, 2H), 7.30 (dd, J = 7.9, 1.5 Hz, 1H), 4.09 (s, 1H), 3.31 (s, 1H), 3.04 - 2.76 (m, 4H), 2.23 - 2.15 (m, 1H), 2.09 - 2.01 (m, 1H), 2.00 - 1.76 (m, 4H), 1.67 (dd, J = 31.4, 12.7 Hz, 4H), 1.52 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 30 H 34 Calculated value for N5O2S: 516.2; Measured value: 516.2.

[0439] Example 96: 2-[2-chloro-4-(5-{5,6,8,9-tetrahydrospiro[benzo[7]anulen-7,2'-pyrrolidine]-3-yl}-1H-pyrazolo[3,4-b]pyridine-3-yl)phenyl]propan-2-ol [ka]

[0440] Step a: A mixture of 2-bromo-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-one (523 mg, 2.19 mmol) and a MeOH solution (7N, 4.4 mL) containing NH3 was stirred for 30 minutes, then 4,4,5,5-tetramethyl-2-(2-propen-1-yl)-1,3,2-dioxaborolane (0.66 mL, 3.50 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and 1.5 mL of 1N aqueous HCl was carefully added, followed by CH2Cl2 (5 mL). The layers were separated, and the aqueous layer was washed with CH2Cl2 (5 mL). The aqueous layer was made basic with NaOH solution (to pH=10) and extracted with CH2Cl2 (3 × 15 mL) containing 10% MeOH. The combined organic layers were washed with brine, dried on MgSO4, and concentrated. To a cooled (0°C) mixture of the intermediate and CH2Cl2 (10.9 mL) containing NEt3 (0.46 mL, 3.28 mmol), anhydrous trifluoroacetic acid (0.36 mL, 2.62 mmol) was slowly added, and the reaction mixture was stirred for 17 hours while being heated to room temperature after the condenser was closed. A saturated aqueous NH4Cl solution was carefully added, and the mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine, dried on anhydrous MgSO4, concentrated, and purified by silica gel chromatography (hexane containing 100% hexane to 60% siRNA) to obtain the desired product as a colorless oil (737 mg, 90%).

[0441] Step b: To a suspension of THF (5.2 mL) containing NaBH4 (178 mg, 4.70 mmol), a solution of THF (8.9 mL) containing I2 (298 mg, 2.32 mmol) was added over 30 minutes, followed by the addition of a solution of THF (2.1 mL) containing the product from step a (737 mg, 1.96 mmol) over 30 minutes. The mixture was then stirred at room temperature for 1.5 hours. A NaOH solution (H2O containing 3 M, 3.2 mL, 9.80 mmol) was added over 2.5 hours, followed by the addition of an H2O2 solution (H2O containing 30%, 9.80 mmol) over 45 minutes. The mixture was then stirred at room temperature for 30 minutes. Brine was added, and the mixture was extracted with SiO2 (3 × 20 mL). The combined organic matter was then washed with brine, dried over MgSO4, and concentrated to provide a mixture of the starting material and the desired product. To a THF solution containing the residue (9.8 mL), a 9-borabicyclo[3.3.1]nonane solution (7.8 mL of THF containing 0.5 M, 3.92 mmol) was added over 30 minutes, and the reaction mixture was stirred at room temperature for 4.5 hours. This mixture was cooled to 0°C, and a NaOH solution (H2O containing 2 M, 2.0 mL, 3.92 mmol) was added over 15 minutes, followed by a H2O2 solution (H2O containing 30%, 2.0 mL) over 15 minutes. After the condenser was empty, the mixture was stirred for 15 hours while being heated to room temperature. This mixture was diluted with brine (20 mL) and RINKAN (20 mL), and the layers were separated. The aqueous layer was extracted with siRNA (2 × 20 mL), the combined organic layers were washed with brine, dried on MgSO4, concentrated, and purified by silica gel chromatography (100% hexane to 100% siRNA) to obtain the desired product as a white solid (276 mg, 36%).

[0442] Step c: To a solution of CH2Cl2 (3.5 mL) containing the product from step b (276 mg, 0.700 mmol), DIPEA (0.15 mL, 0.840 mmol) was added at 0°C, followed by methanesulfonyl chloride (0.55 μL, 0.721 mmol). After the condenser was finished, the reaction mixture was stirred for 17 hours while being heated to room temperature. A saturated aqueous NH4Cl solution was added, and the mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine, dried on anhydrous MgSO4, and concentrated. To a mixture of THF (4.7 mL) containing the crude intermediate, NaH (mineral oil containing a 60% dispersion, 42 mg, 1.05 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour, followed by stirring at 60°C for 17 hours. As soon as it cooled, NH4Cl was added, and the mixture was extracted with ₹ (3 × 5 mL). The combined organic layers were washed with brine, dried on anhydrous MgSO4, concentrated, and purified by silica gel chromatography (hexane containing 100% to 50% siRNA) to obtain the desired product as a yellow solid (164 mg, 62%).

[0443] Step d: Dioxane (4.4 mL) was added to a mixture of the product from step c (164 mg, 0.436 mmol), B2pin2 (111 mg, 0.436 mmol), and KOAc (51 mg, 523 mmol), and this suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (16 mg, 0.0218 mmol) was added, and the reaction mixture was stirred at 90°C for 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 the crude product as a viscous brown oily substance.

[0444] Step e: A mixture of the product from Step b of Example 11 (217 mg, 0.436 mmol), the crude product from Step d (0.436 mmol), and Na2CO3 (69 mg, 0.654 mmol) was mixed with dioxane (4.4 mL) and H2O (0.40 mL). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (16 mg, 0.0218 mmol) was added, and the reaction mixture was stirred at 90°C for 18 hours. As soon as it cooled, CH2Cl2 (15 mL) was added, and this mixture was then dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (100% hexane to 100% SiO) to obtain an intermediate containing impurities (254 mg). To a solution of THF (3.5 mL) containing this residue, a TBAF solution (1 M THF, 3.5 mL, 3.47 mmol) was added, and the reaction mixture was stirred at 70°C for 14 hours. Once cooled, the reaction product was concentrated and purified by silica gel chromatography (100% hexane ~ 100% SiO, followed by CH2Cl2 + 1% NH3 containing 10% MeOH) to obtain an intermediate containing impurities. To this residue, MeOH (4.6 mL) and pulverized NaOH (28 mg, 0.694 mmol) were added, and this mixture was stirred at room temperature for 14 hours and at 45°C for 3 hours. Further pulverized NaOH (28 mg, 0.694 mmol) was added, and the reaction product was stirred at 60°C for 2 hours. Once cooled, H2O (5 mL), saturated NaHCO3 aqueous solution (10 mL), and CH2Cl2 (15 mL) were added, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL) containing 10% MeOH, and the combined organic layer was concentrated. C18 reverse-phase chromatography (100% H2O ~ 100% ACN, 0.1% TFA) and freeze-drying were performed to obtain the labeled compound as a yellow solid (52 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.62 (t, J = 5.4 Hz, 2H), 8.08 (dd, J = 8.3, 1.8 Hz, 1H), 8.03 - 7.98 (m, 2H), 7.69 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 7.7, 2.0 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 5.40 (s, 1H), 3.40 - 3.19 (m, 2H), 3.01 - 2.74 (m, 4H), 2.11 - 1.91 (m, 6H), 1.91 - 1.71 (m, 2H), 1.65 (s, 6H). ESI MS [M+H] + C 29 H 32 Calculated value for ClN4O: 487.2; Measured value: 487.2.

[0445] Example 97: 2-[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)pyridine-3-yl]propan-2-ol [ka]

[0446] Step a: The product of Example 62, step h (1.04 g, 1.61 mmol) was suspended in 4:1 acetic acid:H2O (8.0 mL), and this mixture was heated at 65°C for 5 hours. This mixture was concentrated and saturated with NaHCO3 3(水溶液) The product, diluted with (50 mL), was extracted in 9:1 CHCl3:IPA (3 × 50 mL). The combined organic phase was washed with brine (50 mL), dried, and concentrated (MgSO4). The crude product was used in the next step.

[0447] Step b: A 1:1 suspension of the product from step a (1.61 mmol), 3,4-dihydro-2H-pyran (0.22 mL, 2.37 mmol), and p-toluenesulfonic acid monohydrate (31.0 mg, 0.158 mmol) in THF:CHCl3 (8.8 mL) was heated overnight at 60°C. This mixture was concentrated and purified by flash chromatography (hexane containing 0-50% siRNA) to obtain the desired product as an off-white solid (0.460 g, 65%).

[0448] Step c: The desired compound was prepared in the same manner as in Example 59, step e.

[0449] Step d: Degassed toluene (1.6 mL) was added to a vial containing the product from step c (115 mg, 0.227 mmol), hexamethylditine (96.6 mg, 0.295 mmol), and Pd(PPh3)4 (91.8 mg, 0.0795 mmol). This mixture was stirred at 110°C for 1 hour, then concentrated and flash-chromatographed (MeOH / NH₃). 3(水溶液) When purified using CH2Cl2 containing 10:1 (1-10%), the desired product was obtained as a yellow oily substance (48.7 mg, 36%).

[0450] Step e: The desired product was prepared in the same manner as in Example 11, Step b (0.928 g, 93%).

[0451] Step f: Degassed toluene (0.68 mL) was added to a vial containing the product from step d (48.7 mg, 0.0820 mmol), the product from step e (17.7 mg, 0.0820 mmol), and Pd(PPh3)4 (9.5 mg, 0.0082 mmol). This mixture was stirred overnight at 110°C, then concentrated and flash-chromatographed (MeOH / NH₃). 3(水溶液) When purified using CH2Cl2 containing 10:1 (1-10%), the desired product was obtained as a yellow oily substance (26.8 mg, 58%).

[0452] Step g: A solution of 3N methanol-HCl (1.0 mL) containing the product of step f (26.8 mg, 0.0474 mmol) was stirred overnight at room temperature. This mixture was concentrated and saturated with NaHCO₃ 3(水溶液) The solution (5 mL) was added. The product was extracted in 9:1 CHCl3:IPA (3 × 5 mL), and the combined organic phase was dried (Na2SO4), concentrated, and flash chromatographed (MeOH / NH). 3(水溶液) When purified using CH2Cl2 containing 10:1 (1-10%), the labeled compound was obtained as a beige solid (8.7 mg, 38%). 1 H NMR (400 MHz, chloroform-d) δ 11.65 (br. s, 1H), 9.16 (d, J = 2.1 Hz, 1H), 8.90 - 8.89 (m, 1H), 8.87 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.96 (dd, J = 8.3, 2.4 Hz, 1H), 7.49 - 7.47 (m, 1H), 7.46 - 7.44 (m, 1H), 7.28 - 7.24 (m, 1H), 3.03 - 2.83 (m, 7H), 2.78 (p, J = 12.3 Hz, 1H), 2.51 (q, J = 8.4 Hz, 1H), 2.23 - 2.06 (m, 2H), 1.95 - 1.81 (m, 2H), 1.81 - 1.70 (m, 1H), 1.68 (s, 6H), 1.68 - 1.52 (m, 3H), 1.12 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 30 H 36 Calculated value for N5O: 482.3; Measured value: 482.2.

[0453] Example 98: 2-[3-chloro-5-(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)pyridine-2-yl]propan-2-ol [ka]

[0454] Step a: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0455] Step b: The desired compound was prepared (161 mg, 30%) in the same manner as in Example 11, Step a.

[0456] Step c: The desired compound was prepared (94.7 mg, 57%) in the same manner as in Example 11, Step b.

[0457] Step d: The desired compound was prepared in the same manner as in Example 11, Step a (94.4 mg, 73%).

[0458] Step e: The desired compound was prepared in the same manner as in Example 97, Step g (49.0 mg, 60%). 1 H NMR (400 MHz, chloroform-d) δ 12.03 (br. s, 1H), 9.09 (dd, J = 1.8, 0.5 Hz, 1H), 8.93 (ddd, J = 2.0, 1.4, 0.5 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.39 (dd, J = 1.8, 0.5 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.28 - 7.20 (m, 1H), 6.12 (d, J = 1.2 Hz, 1H), 3.54 - 3.34 (m, 1H), 3.33 - 3.17 (m, 2H), 2.93 (t, J = 7.6 Hz, 1H), 2.75 - 2.63 (m, 1H), 2.63 - 2.49 (m, 2H), 2.00 - 1.81 (m, 3H), 1.76 (s, 6H), 1.73 - 1.51 (m, 3H), 1.52 - 1.40 (m, 2H), 1.09 (d, J = 6.2 Hz, 3H), 1.01 (s, 3H). ESI MS [M+H] +C 31 H 37 Calculated value for ClN5O: 530.3; Measured value: 530.2.

[0459] Example 99: 4-(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)-N-[(3R)-oxolan-3-yl]benzamide [ka]

[0460] The indicated compound was prepared in the same manner as in Example 98. 1 H NMR (400 MHz, DMSO-d6) δ 14.02 (br. s, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.70 (dd, J = 2.2, 0.9 Hz, 1H), 8.66 (d, J = 6.5 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.59 (t, J = 2.4 Hz, 1H), 7.54 (dt, J = 7.7, 2.0 Hz, 1H), 7.24 (dd, J = 7.8, 3.6 Hz, 1H), 4.51 (dddd, J = 10.9, 8.3, 6.4, 4.5 Hz, 1H), 3.95 - 3.84 (m, 2H), 3.75 (td, J = 8.1, 5.8 Hz, 1H), 3.63 (dd, J = 8.9, 4.4 Hz, 1H), 3.36 - 3.32 (m, 1H), 3.29 - 3.10 (m, 2H), 2.85 (t, J = 7.5 Hz, 1H), 2.72 - 2.53 (m, 4H), 2.24 - 2.14 (m, 1H), 2.04 - 1.62 (m, 6H), 1.50 - 1.23 (m, 3H), 1.05 (d, J = 6.2 Hz, 3H), 0.94 (s, 3H). ESI MS [M+H] + C 34 H40 Calculated value for N5O2: 550.3; Measured value: 550.2.

[0461] Example 100: Ethyl (imino)[4-(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)phenyl]-λ 6 -Sulfanone [ka]

[0462] Step a: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0463] Step b: The desired compound was prepared in the same manner as in Example 11, Step a (169 mg, 41%).

[0464] Step c: The desired compound was prepared (41.1 mg, 36%) in the same manner as in Example 11, Step a.

[0465] Step d: The desired compound was prepared (17.4 mg, 49%) in the same manner as in Example 97 and Step g. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 2.1 Hz, 1H), 8.75 (d, J = 1.9 Hz, 1H), 8.39 - 8.35 (m, 2H), 8.06 - 8.01 (m, 2H), 7.60 (t, J = 2.3 Hz, 1H), 7.55 (dt, J = 7.7, 2.1 Hz, 1H), 7.25 (dd, J = 7.8, 3.6 Hz, 1H), 4.28 (s, 1H), 3.27 - 3.17 (m, 2H), 3.20 (q, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 1H), 2.72 - 2.54 (m, 2H), 1.99 - 1.61 (m, 5H), 1.49 - 1.21 (m, 3H), 1.13 (t, J = 7.3 Hz, 3H), 1.05 (d, J = 6.2 Hz, 3H), 0.94 (s, 3H). ESI MS [M+H] + C 31 H 38 Calculated value for N5OS: 528.3; Measured value: 528.2.

[0466] Example 101: (2R)-1-(3-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-5H,6H,7H,8H,9H-cyclohepta[b]pyridine-7-yl)-2-methylpyrrolidine [ka]

[0467] The indicated compound was prepared in the same manner as in Example 100. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 2.0 Hz, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.46 - 8.41 (m, 2H), 8.07 - 8.02 (m, 3H), 3.16 - 3.08 (m, 1H), 3.07 - 2.92 (m, 5H), 2.88 (q, J = 6.4 Hz, 1H), 2.82 - 2.72 (m, 2H), 2.52 - 2.44 (m, 2H), 2.02 (d, J = 18.6Hz, 2H), 1.91 - 1.79 ESI MS [M+H] + C 30 H 34 Calculated value for N5O2S: 528.2; Measured value: 528.2.

[0468] Example 102: (2R)-1-[(7S)-3-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-5H,6H,7H,8H,9H-cyclohepta[b]pyridine-7-yl]-2-methylpyrrolidine [ka]

[0469] The indicated compound was prepared in the same manner as in Example 100. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 2.1 Hz, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.75 (d, J = 2.3 Hz, 1H), 8.46 - 8.41 (m, 2H), 8.08 - 8.02 (m, 3H), 3.12 (dd, J = 13.9, 7.7 Hz, 1H), 3.06 - 2.91 (m, 2H), 2.93 - 2.80 (m, 4H), 2.75 (td, J = 8.2, 3.4 Hz, 1H), 2.48 (q, J = 8.5 Hz, 1H), 2.10 - 1.97 (m, 2H), 1.92 - 1.78 (m, 1H), 1.72 - 1.46 (m, 4H), 1.41 - 1.24 (m, 2H), 1.22 - 1.16 (m, 2H), 1.15 - 1.07 (m, 2H), 1.05 (d, J = 6.0 Hz, 3H). ESI MS [M+H] + C 30 H 34 Calculated value for N5O2S: 528.2; Measured value: 528.2.

[0470] Example 103: 3-(4-((4-methoxypiperidine-1-yl)sulfonyl)phenyl)-5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0471] Step a: A mixture of 4-bromobenzenesulfonyl chloride (2.0 g, 7.8 mmol), 4-methoxypiperidine (947 mg, 8.2 mmol), and CH2Cl2 (35 mL) was mixed with DIPEA (3.4 mL, 19.6 mmol) and stirred at room temperature for 14 hours. H2O (50 mL) and CH2Cl2 (50 mL) were added to separate the phases, and the organic phase was dried and concentrated over Na2SO4 to obtain the desired product (2.4 g, 92%).

[0472] Step b: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0473] Step c: The desired compound was prepared (278 mg, 52%) in the same manner as in Example 24, Step c.

[0474] Step d: The desired product was prepared in the same manner as in Example 24, Step d (102 mg, 58%).

[0475] Step e: To the product from step d (102 mg, 0.15 mmol), 3.0 mL of MeOH containing 3 M HCl was added. This reaction mixture was stirred at room temperature for 14 hours. After removing the solvent, the crude product was ground with ACN (5 mL) to obtain the desired product as a yellow solid (85 mg, 94%). 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.75 (t, J = 1.9 Hz, 1H), 8.40 - 8.32 (m, 2H), 7.89 - 7.81 (m, 2H), 7.68 (d, J = 2.0 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.30 (dd, J = 7.9, 1.6 Hz, 1H), 4.08 (s, 1H), 3.31 (d, J = 8.3 Hz, 1H), 3.23 (dq, J = 6.9, 3.3, 2.9Hz, 2H), 3.12 (m, 5H), 2.88 (q, J = 12.8, 11.6 Hz, 6H), 2.21 (s, 1H), 2.04 (s, 1H), 1.96 - 1.73 (m, 6H), 1.72 - 1.41 (m, 7H), 1.30 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 35 H 44 Calculated value for N5O3S: 614.3; Measured value: 614.3.

[0476] Example 104: (2R)-1-[2-{3-[4-(azetidine-1-sulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)-2-methylpyrrolidine [ka]

[0477] The marked compound was prepared in the same manner as in Example 103, except that Boc was used as the azindazole protecting group. Acid-mediated ring-opening of azetidine was avoided by thermal deprotection (95°C, 18 hours). 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.23 (dd, J = 7.8, 3.6 Hz, 1H), 3.73 (t, J = 7.6 Hz, 4H), 3.46 - 3.34 (m, 1H), 3.27 - 3.10 (m, 2H), 2.83 (t, J = 7.5 Hz, 1H), 2.71 - 2.52 (m, 3H), 2.03 (p, J = 7.6 Hz, 2H), 1.97 - 1.62 (m, 5H), 1.49 - 1.21 (m, 3H), 1.04 (d, J = 6.2 Hz, 3H), 0.93 (s, 3H). ESI MS [M+H] + C 32 H 38 Calculated value for N5O2S: 556.3; Measured value: 556.3.

[0478] Example 105: (2R)-1-(2-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)-2-methylpyrrolidine [ka]

[0479] Step a: A mixture of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (10.8 g, 33.4 mmol), K2CO3 (5.07 g, 36.7 mmol), and DMF (67 mL) was cooled to 0°C, and 2-(trimethylsilyl)ethoxymethyl chloride (10.5 mL, 59.5 mmol) was added dropwise. This reaction mixture was heated to room temperature and stirred for 14 hours. Depositphotos (400 mL) was added, and the mixture was washed with 3:1 water; brine (4 × 400 mL). This organic phase was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (120 g silica gel, hexane: Depositphotos) with a gradient from 0% to 20% (20 minutes) to obtain the desired product as an orange solid (7.82 g, 52%).

[0480] Step b: The desired product was prepared (300 mg, 29%) in the same manner as in Example 90 and Step e.

[0481] Step c: A mixture of the product from step b (300 mg, 0.591 mmol), the product from Example 57, the product from step a (0.600 mmol), and (dppf)PdCl2 (43 mg, 0.059 mmol) was placed under nitrogen. Degassed dioxane (3.0 mL) and degassed 2M Na2CO2 were added. 3(水溶液)(0.59 mL) was added, and this reaction mixture was stirred at 95°C for 18 hours. This mixture was cooled to room temperature, diluted with CH2Cl2 (30 mL), dried on Na2SO4, and concentrated. The crude product was purified by column chromatography (24 g silica gel, CH2Cl2:((4:1 CH2Cl2;MeOH)+2%Et3N)) with a gradient from 0% to 50% (20 minutes) to obtain a dark brown solid (208 mg). TBAF (3.5 mL, 3.5 mmol, containing 1 M THF) was added, and this reaction mixture was stirred at 70°C for 15 hours. This mixture was cooled to room temperature, diluted with ₹ (100 mL), and water:2M NaOH (水溶液) The solution was washed with brine (8:1:1) (4 × 75 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (43 g C18, (H2O / ACN) + 0.1% TFA) with a gradient from 5% to 50% (25 minutes) to obtain the desired product as a white solid (56 mg, 18%). 1 H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.12 (s, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 2.5 Hz, 1H), 7.43 (dt, J = 7.7, 2.1 Hz, 1H), 7.16 (dd, J = 7.8, 3.6 Hz, 1H), 3.39 - 3.30 (m, 1H), 3.24 - 3.04 (m, 2H), 2.90 - 2.82 (m, 1H), 2.82 - 2.76 (m, 1H), 2.67 - 2.56 (m, 1H), 2.56 - 2.40 (m, 2H), 1.92 - 1.57 (m, 5H), 1.45 - 1.19 (m, 3H), 1.16 - 1.07 (m, 2H), 1.07 - 0.96 (m, 5H), 0.89 (s, 3H). ESI MS [M+H] + C 33 H 38Calculated value for N3O2S: 540.3; Measured value: 540.2.

[0482] Example 106: 2-(2-chloro-4-{5-[7-(pyrroridine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-yl}phenyl)propan-2-ol [ka]

[0483] The indicated compound was prepared in the same manner as in Example 105. 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (d, J = 2.6 Hz, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.76 (dd, J = 8.2, 1.9 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 7.7, 2.0 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 5.30 (s, 1H), 3.17 - 2.97 (m, 2H), 2.73 - 2.60 (m, 2H), 2.60 - 2.52 (m, 4H), 2.49 - 2.44 (m, 1H), 2.00 - 1.80 (m, 2H), 1.74 - 1.66 (m, 4H), 1.63 (s, 6H), 1.61 - 1.50 (m, 2H). ESI MS [M+H] + C 31 H 35 Calculated value for ClN3O: 500.2; Measured value: 500.2.

[0484] Example 107: 4-[4-(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)phenyl]morpholine [ka]

[0485] Step a: The desired product was prepared (337 mg, 61%) in the same manner as in Example 90 and Step e. rxn 4 hours. Column: (40g silica gel, hexane:SiO) 0% to 50% gradient (20 minutes).

[0486] Step b: A mixture of the product from step a (266 mg, 0.600 mmol), Example 57, step a (0.600 mmol), and (dppf)PdCl2 (44 mg, 0.060 mmol) was placed under nitrogen. Degassed dioxane (3.0 mL) and degassed 2M Na2CO2 were added. 3(水溶液) (0.60 mL) was added, and this reaction mixture was stirred at 95°C for 18 hours. This mixture was cooled to room temperature, diluted with CH2Cl2 (30 mL), dried on Na2SO4, and concentrated. The crude product was purified by column chromatography (24 g silica gel, CH2Cl2:((4:1 CH2Cl2:MeOH)+2%Et3N)) with a gradient from 0% to 50% (20 minutes) to obtain a brown solid. MeOH (3.0 mL) containing 3 M HCl was added, and this reaction mixture was stirred at room temperature for 20 hours. This mixture was diluted with MTBE (30 mL), and the precipitated solid was washed with MTBE. The crude product was purified by column chromatography (43 g C18, (H2O / ACN)+0.1%TFA) with a gradient from 5% to 50% (25 minutes) to obtain the desired product as a pale yellow solid (173 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 13.65 (s, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 1.3 Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.55 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.21 (dd, J = 7.8, 3.5 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 3.81 - 3.72 (m, 4H), 3.44 - 3.29 (m, 1H), 3.27 - 3.06 (m, 6H), 2.82 (t, J = 7.5 Hz, ESI MS [M+H] + C 33 H 40 Calculated value for N5O: 522.3; Measured value: 522.3.

[0487] Example 108: (2-Methoxyethyl)({[4-(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)phenyl]methyl})amine [ka]

[0488] Step a: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0489] Step b: The desired compound was prepared (204 mg, 39%) in the same manner as in Example 11, Step a.

[0490] Step c: The desired compound was prepared (190 mg, 74%) in the same manner as in Example 11, Step a.

[0491] Step d: 2:1 THF:2N HCl containing the product of step c (95.0 mg, 0.160 mmol) (水溶液) (1.1 mL) of the solution was stirred overnight at 65°C, and then THF was removed under vacuum. The mixture was saturated with NaHCO3 3(水溶液) The solution was made basic with (5 mL), and the product was extracted in 9:1 CHCl3:IPA (3 × 5 mL). The combined organic phase was dried (Na2SO4), concentrated, and the residue was flash-chromatographed (1-10% MeOH / NH₃). 3(水溶液) The intermediate was purified with a 10:1 CH2Cl2 solution containing 25.8 mg of NaBH(OAc)3 (17.7 mg, 0.0833 mmol) and added to a solution of the intermediate (25.8 mg, 0.0555 mmol) and 2-methoxyethylamine (6.3 mg, 0.083 mmol) in DCE (25.8 mL). The mixture was stirred at room temperature for 2 hours and then concentrated. This material was purified by reverse-phase preparative HPLC (water containing 5-100% acetonitrile) to obtain the desired product as a pale yellow solid (16.3 mg, 34%). 1 H NMR (400 MHz, methanol-d4) δ 8.82 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.19 - 8.12 (m, 2H), 7.72 - 7.65 (m, 2H), 7.58 (s, 1H), 7.54 (dd, J = 7.7, 2.0 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 4.32 (s, 2H), 4.20 - 4.13 (m, 1H), 3.70 - 3.67 (m, 2H), 3.43 (s, 3H), 3.41 - 3.36 (m, 1H), 3.29 - 3.25 (m, 2H), 3.11 - 2.87 (m, 4H), 2.38 - 2.26 (m, 1H), 2.24 - 2.15 (m, 1H), 2.16 - 1.96 (m, 3H), 1.92 - 1.72 (m, 3H), 1.66 (s, 3H), 1.40 (d, J = 6.7 Hz, 3H). ESI MS [M+H]+ C 33 H 42 Calculated value for N5O: 524.3; Measured value: 524.3.

[0492] Example 109: (2R)-1-(2-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)-2-methylpyrrolidine [ka]

[0493] Step a: To MeMgBr (16.0 mL, 48.0 mmol, 3M Et2O), a solution of Et2O (20 mL) containing 7-bromo-1-tetralone (9.00 g, 40.0 mmol) was added dropwise at 0°C. This reaction mixture was heated and stirred at room temperature for 30 minutes, at which point Et2O (15 mL) was added. This reaction mixture was stirred at room temperature for 16 hours and saturated with NH4Cl (水溶液) The reaction was stopped. This mixture was diluted with water (20 mL) and siRNA (150 mL). The organic phase was dried over Na4SO4 and concentrated. The crude product was purified by column chromatography (220 g silica gel, hexane:siRNA) with a gradient from 0% to 20% (20 min) and a gradient from 20% to 30% (5 min) to obtain the desired product as an off-white solid (8.70 g, 90%).

[0494] Step b: The product from step a (8.70 g, 36.1 mmol), p-toluenesulfonic acid monohydrate (343 mg, 1.80 mmol), and MeOH (72 mL) were mixed and stirred at 70°C for 3 hours. The mixture was cooled to room temperature, concentrated, diluted with 4:1 hexane:CH2Cl2 (150 mL), washed with water (2 × 100 mL), dried over Na2SO4, and concentrated. The crude product was purified by isocratic column chromatography (80 g silica gel, hexane) for 10 minutes to obtain the desired product as a colorless oil (5.97 g, 74%; containing approximately 20% extracyclic alkene isomers).

[0495] Step c: To a mixture of Step b (5.74 g, 25.7 mmol) and 3:3:4 CCl4:ACN:H2O (257 mL), NaIO4 (11.0 g, 51.4 mmol) and RuCl3 (534 mg, 2.57 mmol) were added at room temperature. This reaction mixture was stirred at room temperature for 2 hours, and an additional NaO4 (11.0 g, 51.4 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The mixture was filtered through Celite to remove solids and washed with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (80 g silica gel, CH2Cl2:(siRNA+1%AcOH)) with a gradient from 0% to 50% (30 minutes) to obtain the desired product as a white solid (4.25 g, 61%).

[0496] Step d: To a mixture of the product from step c (4.25 g, 15.7 mmol), oxalyl chloride (1.41 mL, 16.5 mmol), and CH2Cl2 (47 mL), DMF (12 μL) was added at room temperature. This reaction mixture was stirred at room temperature for 4 hours, and EtOH (9.15 mL, 157 mmol) was added dropwise. This reaction mixture was stirred at room temperature for 20 hours, and saturated NaHCO3 was added. 3(水溶液) The mixture was neutralized with (50 mL), dried on Na2SO4, and concentrated to obtain the desired composition, which was then used directly in the next step.

[0497] Step e: The mixture of the product from step d (15.7 mmol, estimated), KOt-Bu (3.88 g, 34.5 mmol), and t-BuOH (462 mL) was stirred at 80°C for 1 hour. This mixture was cooled to room temperature and then dissolved in 2 M HCl. (水溶液) The mixture was acidified with (17.5 mL), concentrated, and diluted with toluene (100 mL). This mixture was washed with water (50 mL), dried over Na₂SO₄, and concentrated. The crude product was purified by column chromatography (80 g silica gel, hexane:toluene) with a gradient from 0% to 100% (30 minutes) to obtain the desired product as an orange solid (3.52 g, 89%; 2 steps).

[0498] Step f: The mixture of the product from step e (3.40 g, 13.4 mmol), ethylene glycol (749 μL, 13.4 mmol), p-toluenesulfonic acid monohydrate (128 mg, 0.672 mmol), and toluene (54 mL) was stirred at 100°C for 90 minutes. This mixture was cooled to room temperature and saturated with NaHCO3. 3(水溶液) The solution was neutralized with (67 mL), diluted with HCl (335 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (120 g silica gel, hexane:HCl) with a gradient from 0% to 100% (25 minutes) to obtain the desired product as a brown solid (1.26 g, 89%; contaminated with some of the starting material).

[0499] Step g: To the mixture of the product from step f (1.04 g, 3.50 mmol) and Et2O (3.5 mL), MeMgBr (3.50 mL, 10.5 mmol, Et2O containing 3 M) was added at 0°C. This reaction mixture was stirred at room temperature for 1 hour and then added 2 M HCl. (水溶液) The pH was then acidified to approximately 1. This mixture was diluted with dimethyl glycol (70 mL), washed with water (70 mL), dried on Na2SO4, and concentrated to obtain the desired product, which was then used directly in the next step.

[0500] Step h: The mixture of the product from step g (3.50 mmol, estimated value), HCl (7 mL, 7.00 mL, 1 M water), and THF (18 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 solution was neutralized, diluted with HCl (100 mL), washed with brine (100 mL), dried on Na2SO4, and concentrated. The crude product was purified by column chromatography (40 g silica gel, hexane:HCl) with a gradient from 0% to 100% (25 minutes) to obtain the desired product as a brown solid (123 mg, 14%; 2 steps).

[0501] Step i: At room temperature, under nitrogen, n-BU2S (222 μL, 1.27 mmol) was added to CuI (140 mg, 0.735 mmol). This mixture was stirred at room temperature for 5 minutes, or until homogenized, at which point Et2O (1.2 mL) was added. The mixture was cooled to 0°C, and MeLi (918 μL, 1.47 mmol, Et2O containing 1.6 M) was added dropwise. This mixture was stirred at 0°C for 30 minutes, and a solution of the product from step h (123 mg, 0.490 mmol) in Et2O (0.60 mL) was added. This reaction mixture was heated to room temperature over 14 hours and mixed with 1:1 NH4Cl (水溶液) Stop the reaction with water (10 mL), dilute with toluene (20 mL), and add 28% by weight of NH4. 3(水溶液) The solution was washed with (3 × 10 mL), dried on Na₂SO₄, and concentrated. The crude product was purified by column chromatography (24 g silica gel, hexane: siRNA) with a gradient from 0% to 50% (25 minutes) to obtain the desired product as an off-white solid (82 mg, 63%).

[0502] Step j: A mixture of the product from Step i (82 mg, 0.31 mmol), Example 1, the product from Step d (0.31 mmol, estimated value), and (dppf)PdCl2 (22 mg, 0.031 mmol) was placed under nitrogen. Degassed dioxane (1.6 mL) and degassed 2M Na2CO2 were added. 3(水溶液)(0.31 mL) was added, and the reaction mixture was stirred at 95°C for 1 hour. The mixture was cooled to room temperature, diluted with HCl (16 mL), dried on Na2SO4, and concentrated. The crude product was purified by column chromatography (24 g silica gel, hexane:HCl) with a gradient from 0% to 100% (30 minutes) to obtain the desired product as a brown oil (174 mg, 99%).

[0503] Step k: To a mixture of the product from step j (174 mg, 0.305 mmol), (R)-2-methylpyrrolidine (52 mg, 0.61 mmol), acetic acid (35 μL, 0.61 mmol), and THF (1.5 mL), NaBH(OAc)3 (162 mg, 0.764 mmol) was added. This reaction mixture was stirred at 40°C for 15 hours. This mixture was diluted with SiO20 mL and 0.1 M NaOH (水溶液) The mixture was washed with (2 × 10 mL) and dried on Na₂SO₄ before concentration. 1.5 mL of MeOH containing 3 M HCl was added, and the reaction mixture was stirred at room temperature for 8 hours. The mixture was diluted with MTBE (15 mL), the precipitated solids were collected by filtration, and washed with MTBE. The crude product was purified by column chromatography (43 g C₁₄, (H₂O / ACN) + 0.1% TFA) with a gradient from 5% to 50% (25 minutes) to obtain the desired product as an off-white solid (26 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.39 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 7.7, 1.9 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 3.07 - 2.88 (m, 4H), 2.85 - 2.68 (m, 2H), 2.48 - 2.39 (m, 1H), 2.02 - 1.91 (m, 1H), 1.89 - 1.76 (m, 1H), 1.76 - 1.43 (m, 8H), 1.39 (s, 3H), 1.33 - 1.22 (m, 1H), 1.21 - 1.13 (m, 2H), 1.13 - 1.05 (m, 2H), 0.99 (d, J = 5.9 Hz, 3H). ESI MS [M+H] + C 33 H 39 Calculated value for N4O2S: 555.3; Measured value: 555.3.

[0504] Example 110: 3-(4-(2-methoxyethoxy)phenyl)-5-(7-methyl-7-((R)-2-methylpyrrolidine-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0505] Step a: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0506] Step b: The desired compound was prepared (212 mg, 49%) in the same manner as in Example 24 and Step c.

[0507] Step c: The desired compound was prepared (97 mg, 62%) in the same manner as in Example 24 and Step d.

[0508] Step d: The desired product was prepared (66 mg, 65%) in the same manner as in Example 66 and Step e. 1 H NMR (400 MHz, DMSO-d6) δ 13.72 (s, 1H), 8.82 (dd, J = 2.1, 0.8 Hz, 1H), 8.65 - 8.56 (m, 2H), 8.03 - 7.95 (m, 2H), 7.66 (s, 1H), 7.58 (dd, J = 7.7, 2.0 Hz, 1H), 7.29 (dd, J = 7.9, 1.4 Hz, 1H), 7.12 - 7.04 (m, 2H), 4.18 - 4.06 (m, 3H), 3.71 - 3.63 (m, 2H), 3.34 - 3.18 (m, 5H), 2.98 - 2.75 (m, ESI MS [M+H] + C 32 H 39 Calculated value for N4O2: 511.3; Measured value: 511.3.

[0509] Example 111: (2R)-1-(2-{3-[4-(2-methoxyethanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)-2-methylpyrrolidine [ka]

[0510] Step a: m-CPBA (2.96 g, 8.50 mmol) was added in small amounts to a solution of dichloromethane (9.7 mL) containing 1-bromo-4-[(2-methoxyethyl)thio]benzene (1.00 g, 4.05 mmol), and the mixture was stirred overnight at room temperature. 1N NaOH(水溶液) The reaction was stopped with a solution (25 mL), and the product was extracted in ethyl acetate (3 × 25 mL). The combined organic phase was then mixed with 1N NaOH. (水溶液) The sample was washed with solution (25 mL), dried (MgSO4), and the crude product was subjected to the next step.

[0511] Step b: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0512] Step c: The desired compound was prepared (115 mg, 27%) in the same manner as in Example 24, Step c.

[0513] Step d: The desired compound was prepared (87.1 mg, 57%) in the same manner as in Example 11, Step a.

[0514] Step e: The desired compound was prepared (48.0 mg, 64%) in the same manner as in Example 97 and Step g. 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.39 - 8.31 (m, 2H), 8.02 - 7.96 (m, 2H), 7.55 (t, J = 2.3 Hz, 1H), 7.50 (dt, J = 7.4, 2.1 Hz, 1H), 7.20 (dd, J = 7.8, 3.6 Hz, 1H), 3.63 (s, 4H), 3.20 (t, J = 7.0 Hz, 2H), 3.10 (s, 3H), 2.80 (t, J = 7.5 Hz, 1H), 2.68 - 2.50 (m, 4H), 1.94 - 1.55 (m, 5H), 1.46 - 1.16 (m, 4H), 1.00 (d, J = 6.2 Hz, 3H), 0.89 (m, 3H). ESI MS [M+H] + C 32 H 39 Calculated value for N4O3S: 559.3; Measured value: 559.2.

[0515] Example 112: 7-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-3-[(2S)-pyrrolidine-2-carbonyl]-2,3,4,5-tetrahydro-1H-3-benzazepine [ka]

[0516] Step a: Et3N (1.4 mL, 10.0 mmol) was added dropwise at room temperature to a mixture of 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (524.0 mg, 2.0 mmol), N-Boc-L-(-)-proline (516.5 mg, 2.4 mmol), HOBt (459.3 mg, 3.0 mmol), EDC-HCl (460.0 mg, 2.4 mmol), and NMP (10 mL). The mixture was stirred at 40°C for 14 hours. To this reaction mixture, H2O (5 mL) and siRNA (20 mL) were added. The phases were separated, and the aqueous phase was extracted with siRNA (2 × 10 mL). The combined organic phase was washed with H2O (3 × 20 mL), dried on Na2SO4, concentrated, and purified by column chromatography (SiO2, hexane containing 0-80% siRNA) to obtain the desired product as a colorless solid (802 mg, 95%).

[0517] Step b: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0518] Step c: The desired compound was prepared (170 mg, 78%) in the same manner as in Example 47, Step c.

[0519] Step d: The desired compound was prepared (130 mg, 98%) in the same manner as in Example 47, Step d. 1H NMR (400 MHz, DMSO-d6) δ 10.11 - 9.98 (m, 1H), 8.89 (dd, J = 4.0, 2.0 Hz, 1H), 8.76 (dd, J = 2.8, 2.1 Hz, 1H), 8.50 - 8.40 (m, 1H), 8.39 - 8.34 (m, 2H), 8.00 (d, J = 8.5 Hz, 2H), 7.69 (dd, J = 8.7, 2.1 Hz, 1H), 7.63 (dd, J = 7.7, 1.9 Hz, 1H), 7.31 (dd, J = 10.3, 7.9 Hz, 1H), 4.63 (d, J = 6.4 Hz, 1H), 3.78 - 3.53 (m, 4H), 3.31 - 2.84 (m, 7H), 2.45 - 2.35 (m, 1H), 2.00 - 1.84 (m, 2H), 1.83 - 1.70 (m, 1H), 1.18 - 1.10 (m, 2H), 1.07 - 1.00 (m, 2H). ESI MS [M+H] + C 30 H 32 Calculated value for N5O3S: 542.2; Measured value: 542.2.

[0520] Example 113: 7-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-3-[(2R)-pyrrolidine-2-carbonyl]-2,3,4,5-tetrahydro-1H-3-benzazepine [ka]

[0521] The indicated compound was prepared in the same manner as in Example 112. 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.89 (dd, J = 4.0, 2.1 Hz, 1H), 8.76 (t, J = 2.3 Hz, 1H), 8.45 (q, J = 6.0, 5.4 Hz, 1H), 8.40 - 8.30 (m, 2H), 8.04 - 7.96 (m, 2H), 7.69 (dd, J = 8.4, 2.0 Hz, 1H), 7.63 (dd, J = 7.8, 2.0 Hz, 1H), 7.32 (dd, J = 10.4, 7.9 Hz, 1H), 4.63 (d, J = 5.5 Hz, 1H), 3.77 - 3.52 (m, 4H), 3.31 - 2.83 (m, 7H), 2.45 - 2.36 (m, 1H), 1.91 (h, J = 6.5 Hz, 2H), 1.83 - 1.72 (m, 1H), 1.20 - 1.00 (m, 4H). [M+H] + C 30 H 32 Calculated value for N5O3S: 542.2; Measured value: 542.2.

[0522] Example 114: (2R)-1-{2-[3-(4-{[(2R-1,4-dioxan-2-yl]methoxy}-3-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-yl]-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl}-2-methylpyrrolidine [ka]

[0523] Step a: To a solution of CH2Cl2 (21.4 mL) containing (S)-2-(hydroxymethyl)-1,4-dioxane (506 mg, 4.28 mmol), NEt3 (0.89 mL, 6.42 mmol) was added at 0°C, followed by methanesulfonyl chloride (0.33 mL, 4.28 mmol). This reaction mixture was stirred for 22 hours, and after the condenser was finished, it was heated to room temperature. This reaction mixture was cooled to 0°C, and then the reaction was carefully stopped with saturated aqueous NH4Cl2. The 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 a mixture of the crude intermediate and DMF (8.6 mL) containing 4-bromo-2-methoxyphenol (869 mg, 4.28 mmol), K2CO3 (887 mg, 6.42 mmol) was added. The reaction mixture was stirred at 90°C for 4 hours, then cooled to room temperature, and H2O (30 ml) and siRNA (30 mL) were added. The layers were separated, and the organic layer was washed with H2O (2 × 15 mL), and the combined aqueous washes were extracted with siRNA (1 × 15 mL). The combined organic layer was washed with brine, dried on anhydrous MgSO4, concentrated, and purified by silica gel chromatography (100% hexane to 100% siRNA) to obtain the desired product as an off-white solid (876 mg, 67%).

[0524] Step b: Dioxane (5.0 mL) was added to a mixture of the product from step a (300 mg, 0.990 mmol), B2pin2 (251 mg, 0.990 mmol), and KOAc (107 mg, 1.09 mmol), and the suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (36 mg, 0.0495 mmol) was added, and the reaction mixture was stirred at 90°C for 2.5 hours. As soon as it cooled, siRNA (20 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.

[0525] Step c: Dioxane (6.0 mL) and H2O (0.60 mL) were added to a mixture of the product from Step a of Example 1 (404 mg, 0.990 mmol), the crude product from Step b (0.990 mmol), and Na2CO3 (157 mg, 1.49 mmol). The suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (36 mg, 0.0495 mmol) was added, and the reaction mixture was stirred at 80°C for 14 hours. As soon as it cooled, CH2Cl2 (20 mL) was added, and the mixture was then 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 viscous brown oil (261 mg, 52%).

[0526] Step d: Dioxane (7.0 mL) and H2O (0.80 mL) were added to a mixture of the product from step c (261 mg, 0.507 mmol), the product from Example 57, step a (0.403 mmol), and Na2CO3 (85 mg, 0.806 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (15 mg, 0.0202 mmol) was added, and the reaction mixture was stirred at 90°C for 17 hours. As soon as it cooled, CH2Cl2 (20 mL) was added, and the mixture was then dried over anhydrous MgSO4, filtered, and concentrated. Purification by silica gel chromatography (CH2Cl2 containing 100% CH2Cl2 to 10% MeOH, 1% NH4OH) yielded the desired product as a brown solid (138 mg, 51%).

[0527] Step e: To the product from step d (138 mg, 0.207 mmol), an HCl solution (MeOH containing 3 M, 3 mL) was added. The reaction mixture was stirred at room temperature for 15 hours and then concentrated. It was purified by reverse-phase HPLC (H2O containing 10-70% ACN, 0.1% TFA), lyophilized, then concentrated with MeOH (2×) containing HCl, and dried under vacuum to obtain the marked compound as an orange solid (82 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 9.61 (brs, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.62 (t, J = 2.0 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 8.0, 1.7 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.32 (dd, J = 7.7, 1.7 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.15 - 4.06 (m, 1H), 4.06 - 3.96 (m, 2H), 3.94 - 3.83 (m, 5H), 3.82 - 3.75 (m, 1H), 3.72 - 3.60 (m, 2H), 3.57 - 3.45 (m, 1H), 3.43 (dd, J = 11.2, 9.7 Hz, 1H), 3.39 - 3.33 (m, 1H), 3.33 - 3.20 (m, 1H), 3.05 - 2.76 (m, 4H), 2.31 - 2.18 (m, 1H), 2.14 - 2.03 (m, 1H), 2.01 - 1.80 (m, 4H), 1.77 - 1.60 (m, 2H), 1.56 (s, 3H), 1.34 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 35 H 43 Calculated value for N4O4: 583.3; Measured value: 583.2.

[0528] Example 115: (3S)-N-(2-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)oxolan-3-amine [ka]

[0529] Step a: A mixture of 2-bromo-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-one (2.39 g, 10.0 mmol), (S)-3-aminotetrahydrofuran (871 mg, 10.0 mmol), and toluene (10 mL) was heated under reflux for 4 hours with azeotropic removal of water (Dean-Stark apparatus). The mixture was cooled to room temperature, and the supernatant obtained was diluted with THF (100 mL). This mixture was cooled to -78 °C, and BF3·OEt2 (2.47 mL, 20.0 mmol) was added dropwise. This mixture was stirred at -78 °C for 1 hour, and MeLi (18.8 mL, 30.0 mmol, Et2O containing 1.6 M) was added dropwise. This reaction mixture was heated to room temperature over 14 hours, at which point 2 M NaOH was added. (水溶液) (30 mL), water (100 mL), brine (20 mL), and MTBE (200 mL) were added and mixed. The organic phase was separated and 2 M NaOH (水溶液) The crude product was washed with (30 mL), water (100 mL), and brine (20 mL), dried on Na2SO4, and concentrated. The crude product was purified by column chromatography (80 g silica gel, hexane: (siRNA + 1% Et3N)) with a gradient from 0% to 100% (20 minutes), then to 100% (5 minutes), to obtain the desired product as a yellow oily substance (902 mg, 28%).

[0530] Step b: The desired compound was prepared in the same manner as in Example 109, step j. rxn :14-hour column: (24g silica gel, hexane (SiO+1%Et3N)) 0% to 100% gradient (25 minutes); 100% (10 minutes).

[0531] Step c: To the product from step b, 3.0 mL of MeOH containing 3 M HCl was added. This reaction mixture was stirred at room temperature for 14 hours and diluted with MTBE (30 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 gradient from 5% to 50% (25 minutes) to obtain the desired product as a white solid (141 mg, 43%). 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 2.1 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 7.6, 2.0 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 3.84 (d, J = 6.8 Hz, 1H), 3.77 (td, J = 8.3, 5.1 Hz, 1H), 3.67 (q, J = 7.6 Hz, 1H), 3.48 - 3.38 (m, 1H), 3.23 (t, J = 7.5 Hz, 1H), 3.20 - 3.00 (m, 2H), 2.99 - 2.90 (m, 1H), 2.66 - 2.51 (m, 2H), 2.16 - 2.02 (m, 1H), 1.85 - 1.57 (m, 4H), 1.52 - 1.29 (m, 2H), 1.20 - 1.13 (m, 2H), 1.13 - 1.01 (m, 5H). ESI MS [M+H] + C 31 H 35 Calculated value for N4O3S: 543.2; Measured value: 543.3.

[0532] Example 116: 1-Methanesulfonyl-4-(5-{7-methyl-7-[(2R)-2-methylpyrrolidine-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl}-1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine [ka]

[0533] Step a: A mixture of the product from Step a (3.63 g, 8.00 mmol) from Example 105, the product from Step a (2.30 g, 8.00 mmol) from Example 23, (dppf)PdCl2 (293 mg, 0.400 mmol), and K2CO3 (2.21 g, 16.0 mmol) was placed under nitrogen. Degassed dioxane (22 mL) and degassed water (5.4 mL) were added, and the reaction mixture was stirred at 80°C for 1 hour. The mixture was cooled to room temperature, diluted with CH2Cl2 (270 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (120 g silica gel, hexane: siRNA) with a gradient from 0% to 100% (30 minutes) to obtain the desired product as a light brown solid (1.63 g, 42%).

[0534] Step b: To the product from step a (239 mg, 0.491 mmol), dioxane (4.3 mL) and H2O (0.50 mL) were added to a mixture of the product from Example 57, the product from step a (0.478 mmol), and Na2CO3 (76 mg, 0.717 mmol). This suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (17 mg, 0.0239 mmol) was added, and the reaction mixture was stirred at 90°C for 20 hours. As soon as it cooled, CH2Cl2 (15 mL) was added, and this mixture was then dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 containing 100% CH2Cl2 to 10% MeOH, 1% NH4OH) to obtain a brown solid containing impurities (92 mg). A solution of MeOH (2.8 mL) containing the intermediate was degassed with N2 for 5 minutes, then NEt3 (20 μL, 0.142 mmol) was added, followed by Pd / C (10% dry basis, 60 mg, 0.0284 mmol). H2 was passed through the solution for 5 minutes, and then the reaction mixture was stirred at room temperature for 15 hours under an H2 balloon. The reaction mixture was filtered through Celite, washed with MeOH, and then concentrated. The residue was subjected to the same conditions again, stirred for 4 hours, filtered through Celite, and concentrated. To a solution of CH2Cl2 (1.0 mL) containing the residue, TFA (1.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. MeOH (7N solution, 2.0 mL) containing NH3 was added to the residue, and this reaction mixture was stirred at 40°C for 5 hours. As soon as it cooled, this reaction mixture was concentrated. The compound was purified by reverse-phase HPLC (H2O containing 10-70% ACN, 0.1% TFA), then freeze-dried, followed by concentration with H2O (2×) containing HCl, and dried under vacuum to obtain the labeled compound as a pale yellow solid (13 mg, 5%). 1H NMR (400MHz, DMSO-d6) δ 11.63 (s, 1H), 9.23 (s, 1H), 8.51 (d, J = 1.7 Hz, 1H), 8.30 (s, 1H), 7.59 (s, 1H), 7.51 (dd, J = 7.8, 1.9 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 7.8, 1.6 Hz, 1H), 4.24 - 3.98 (m, 1H), 3.73 - 3.64 (m, 2H), 3.42 - 3.20 (m, 2H), 3.06 - 2.74 (m, 10H), 2.30 - 2.15 (m, 1H), 2.15 - 2.01 (m, 3H), 2.01 - 1.61 (m, 8H), 1.55 (s, 3H), 1.32 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 30 H 41 Calculated value for N4O2S: 521.3; Measured value: 521.2.

[0535] Example 117: 4-(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)-N-[(3S)-oxolan-3-yl]benzamide [ka]

[0536] Step a: The desired compound was prepared in the same manner as in Step a of Example 11 (0.541 g, 49%).

[0537] Step b: The desired compound was prepared in the same manner as in Example 11, Step a (0.129 g, 52%).

[0538] Step c: Dissolve the product from step b (126 mg, 0.189 mmol) in 1:1 TFA:CH2Cl2 (2.4 mL), and stir the reaction mixture at room temperature for 1 hour. Concentrate the mixture and azeotrope it with toluene (3×). Add the residue to THF (0.86 mL) and cool to 0°C. Add triethylamine (0.12 mL, 0.851 mmol) and PyBOP (118 mg, 0.227 mmol) and stir at 0°C for 30 minutes. Add (S)-3-aminotetrahydrofuran (16.5 mg, 0.189 mmol) and stir the mixture at room temperature for 1 hour. Saturated NaHCO3 3(水溶液) (5 mL) was added, and the product was extracted in 9:1 CHCl3:IPA (3 × 5 mL). The combined organic phase was dried (Na2SO4) and concentrated. The residue was dissolved in MeOH (1.9 mL) and DMEDA (0.1 mL, 0.945 mmol) was added. This mixture was stirred at 45°C for 30 minutes, then concentrated and flash-chromatographed (1-10% MeOH / NH₃). 3(水溶液) When purified with CH2Cl2 containing 10:1, the labeled compound was obtained as an off-white solid (15.5 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 13.95 (br. s, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.62 (dd, J = 2.1, 0.9 Hz, 1H), 8.58 (d, J = 6.5 Hz, 1H), 8.19 - 8.06 (m, 2H), 8.03 - 7.88 (m, 2H), 7.51 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.16 (dd, J = 7.8, 3.6 Hz, 1H), 4.47 - 4.39 (m, 1H), 3.88 - 3.76 (m, 2H), 3.67 (td, J = 8.1, 5.8 Hz, 1H), 3.55 (dd, J = 8.9, 4.4 Hz, 1H), 3.21 - 3.04 (m, 2H), 2.83 - 2.71 (m, 6H), 2.66 - 2.46 (m, 1H), 2.18 - 2.04 (m, 1H), 1.96 - 1.53 (m, 5H), 1.43 - 1.17 (m, 2H), 0.97 (d, J = 6.2 Hz, 3H), 0.86 (s, 3H). + C 34 H 40 Calculated value for N5O2: 550.3; Measured value: 550.2.

[0539] Example 118: (2R)-2-methyl-1-(7-methyl-2-{3-[4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}-6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)pyrrolidine [ka]

[0540] The indicated compound was prepared in the same manner as in Example 117. 1H NMR (400 MHz, chloroform-d) δ 11.26 (br. s, 1H), 8.84 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.42 - 7.31 (m, 2H), 7.25 - 7.16 (m, 1H), 3.68 (t, J = 6.9 Hz, 2H), 3.50 (t, J = 6.5 Hz, 2H), 4.18 - 3.4 (m, 4H), 2.99 - 2.84 (m, 2H), 2.73 - 2.65 (m, 1H), 2.61 - 2.44 (m, 4H), 2.04 - 1.82 (m, 6H), 1.77 - 1.66 (m, 1H), 1.49 - 1.43 (m, 1H), 1.08 (d, J = 6.1 Hz, 3H), 1.00 (s, 3H). ESI MS [M+H] + C 34 H 40 Calculated value for N5O: 534.3; Measured value: 534.3.

[0541] Example 119: 3-Cyclopropyl-7-{3-[3-methyl-4-(piperazine-1-carbonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-yl}2,3,4,5-tetrahydro-1H-3-benzazepine [ka]

[0542] Step a: To a mixture of 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (520 mg, 2.0 mmol), (1-ethoxycyclopropoxy)trimethylsilane (1.7 g, 10.0 mmol), and THF / MeOH (1:1, 4 mL), AcOH (1.2 mL, 20 mmol) and NaBH3CN (620 mg, 10 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, 0-100% CH2Cl2 / MeOH / 7N methanolNH3 (90:10:1) containing CH2Cl2) to obtain the desired product as a light brown oily substance (500 mg, 94%).

[0543] Step b: A mixture of the product from step a (159 mg, 0.6 mmol), B2pin2 (152.5 mg, 0.6 mmol), KOAc (117.8 mg, 1.2 mmol), and (dppf)PdCl2 (43.9 mg, 0.06 mmol) was placed under a nitrogen atmosphere. Degassed dioxane (2.0 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.

[0544] Step c: The desired product was prepared (60 mg, 30%) in the same manner as in Example 47, Step c.

[0545] Step d: The desired product was prepared (40 mg, 85%) in the same manner as in Example 47, Step d. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 8.86 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.01 - 7.88 (m, 2H), 7.73 (s, 1H), 7.68 (d, J ESI MS [M+H] + C 31 H 35 Calculated value for N6O: 507.3; Measured value: 507.3.

[0546] Example 120: 7-{3-[4-(cyclopropanesulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}3-(1-methylcyclopentyl)-2,3,4,5-tetrahydro-1H-3-benzazepine [ka]

[0547] Step a: A mixture of toluene (8 mL) containing 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (904 mg, 4.0 mmol), cyclopentanone (389.6 μL, 4.4 mmol), and 1,2,3-triazole (331.5.6 mg, 4.8 mmol) was heated under reflux for 24 hours using a Dean-Stark trap. After cooling to room temperature, THF (8 mL) was added and stirred to form a homogeneous mixture. To this reaction mixture, a solution of MeMgBr (8 mL, 24 mmol, 3.0 M THF solution) was added and stirred for 1 hour. 2.0 M aqueous NaOH was added dropwise until the pH was approximately 10. The phases were separated and extracted with RINKAN (2 × 50 mL). The combined organic phase was dried and concentrated on Na2SO4 and purified by column chromatography (SiO2, CH2Cl2 containing 0-100% CH2Cl2 / MeOH / 7N methanol NH3 (90:10:1)) to obtain the desired product 2 as a light brown oily substance (273 mg, 22%).

[0548] Step b: The desired compound was prepared in the same manner as in Example 11 and Step c.

[0549] Step c: The desired product was prepared (100 mg, 51%) in the same manner as in Example 47, Step c.

[0550] Step d: In Example 47, the desired product was prepared (72 mg, 80%) using the same method as in Step d. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.39 - 8.30 (m, 2H), 8.05 - 7.93 (m, 2H), 7.76 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 7.8, 2.0 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 3.70 (s, 3H), 3.39 - 3.00 (m, 7H), 2.91 (tt, J = 7.9, 4.9 Hz, 1H), 2.04 - 1.61 (m, 6H), 1.20 (s, 3H), 1.17 - 1.11 (m, 2H), 1.11 - 1.00 (m, 2H). ESI MS [M+H] + C 31 H 35 Calculated value for N4O2S: 527.2; Measured value: 527.2.

[0551] Example 121: 3-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl]-2H-pyrazolo[3,4-b]pyridine-3-yl}phenyl)-1,3-oxazolidine-2-one [ka]

[0552] Step a: In a 40 mL screw-top vial equipped with a magnetic star bar, 1-bromo-4-iodobenzene (566 mg, 2.00 mmol, 1 equivalent), oxazolidinone (191 mg, 2.20 mmol, 1.1 equivalent), CU(OAc)2 (36 mg, 0.20 mmol, 0.1 equivalent), 3,4,7,8-tetramethyl-1,10-phenanthroline (71 mg, 0.30 mmol, 0.15 equivalents), potassium tribase monohydrate phosphate (920 mg, 4.00 mmol, 2 equivalents), and DMSO (20 mL) were added. The resulting reaction mixture was stirred at 80°C for 4 hours. The reaction product was monitored by TLC / LC-MS and then cooled to room temperature. Water (10 mL) was added, and the resulting mixture was extracted in ethyl acetate (3 × 15 mL). The organic layer was washed with water, concentrated to dryness under vacuum, and purified by silica gel chromatography to obtain the desired product as a white solid (388 mg, 80%). 1 H NMR (400 MHz, CDCl3) δ 7.53-7.41 (m, 4H), 4.53-4.46 (m, 2H), 4.08-4.00 (m, 2H);ESI MS [M+H] + C 10 H 10 Calculated value for BrNO: 241.1; Measured value: 241.3.

[0553] Step b: A mixture of the product from step a (388 mg, 1.60 mmol), B2pin2 (488 mg, 1.92 mmol), PdCl2 (dppf) (59 mg, 0.080 mmol), and KOAc (250 mg, 2.56 mmol) was placed under nitrogen. Degassed dioxane (16 mL) was added, and the reaction mixture was stirred at 100 °C for 3 hours. The mixture was cooled to room temperature, concentrated, diluted with SiO2 (30 mL), filtered through Celite to remove solids, and then concentrated again to obtain the desired product, which was used without further purification.

[0554] Step c: The crude product from step b (463 mg, 1.60 mmol), 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (651 mg, 1.60 mmol), PdCl2 (dppf) (59 mg, 0.080 mmol), and K2CO3 (441 mg, 3.20 mmol) were placed under nitrogen. Degassed dioxane (8 mL) and degassed water (2 mL) were added, and the reaction mixture was stirred at 80°C for 4 hours. The mixture was cooled to room temperature, concentrated, diluted with siRNA (30 mL), dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography (40 g silica gel, hexane:siRNA) with a gradient from 0% to 70% (25 minutes) to obtain the desired product as an off-white solid (350 mg, 49%).

[0555] Step d: The product from step c (177 mg, 0.400 mmol), B2pin2 (123 mg, 0.480 mmol), PdCl2 (dppf) (15 mg, 0.020 mmol), and KOAc (63 mg, 0.64 mmol) were placed under nitrogen. Degassed dioxane (10 mL) was added, and the reaction mixture was stirred at 100 °C for 4 hours. This mixture was cooled to room temperature, concentrated, diluted with SiO2 (30 mL), filtered through Celite to remove solids, and concentrated again to obtain the desired product, which was used without further purification.

[0556] Step e: To a mixture of DCM (92 mL) containing 3-oxa-6-azabicyclo[3.1.1]heptane 4-methylbenzenesulfonate (5.00 g, 18.4 mmol), 2-bromo-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-one (4.63 g, 19.4 mmol) was added at room temperature, followed by the addition of NaBH(OAc)3 (4.69 g, 22.1 mmol). The reaction mixture was then stirred at room temperature. Further additions of NaBH(OAc)3 (4.69 g each) were added at t=4 hours and t=8 hours. After the final additions, the reaction mixture was stirred at room temperature for a further 4 hours. DCM (250 mL), water (250 mL), and 2M NaOH (水溶液) Add (100 mL, or until pH > 12), stir the mixture, and separate the organic phase. The organic phase was separated into a 4:1:1 water:brine:2M NaOH solution. (水溶液) The solution was washed with (300 mL), dried on Na2SO4, and concentrated. The crude product was purified by silica gel chromatography (hexane:(Â+1%Et3N); ...

Claims

1. Formula (Ib) or Formula (Ie) 【Chemistry 1】 【Chemistry 2】 A compound represented by, or a pharmaceutically acceptable salt thereof, During the ceremony: G ３ It is CRG3; G ４ This is CRG4; G ５ It is CRG5; R Ｇ２ 、 R Ｇ３ 、 R Ｇ４ 、 and R Ｇ５ each independently consists of a group selected from 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 and is selected from the group consisting of 4- to 8-membered heterocycloalkyl having 1 to 3 heteroatom rings selected from the group consisting of O, N, and S, and cycloalkyl and heterocycloalkyl are independently substituted with 0 to 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; R １ This is a six-membered heteroaryl having phenyl or 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and each phenyl and heteroaryl has 0 to 3 R ３ It is replaced by; The subscript m is 0 or 1; n is 0, 1 or 2; Each R ２ Independently, C １－７ Alkyl, C ３－７ Alkenil, C ３－７ Alkinyl, C ３－７ Cycloalkyl, -Y １ -O-C １－７ Alkyl, -Y １ -O-C ３－７ Cycloalkyl, -NR ａ R ｂ , -C(O)-C １－７ Alkyl, -C(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 , 4-8 member heterocycloalkyl, -NR ａ - (4- to 8-membered heterocycloalkyl), -C(O)- (4- to 8-membered heterocycloalkyl), -X １ - (4- to 8-membered heterocycloalkyl groups), and -O-X １ - Selected from the group consisting of (4-8 member heterocycloalkyls), the heterocycloalkyl has 1-3 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 ３ These are, independently, halogen, 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, -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 -C ４－７ Heterocycloalkyls, -C(O)NH- (4-8 membered heterocycloalkyls), 4-8 membered heterocycloalkyls, and -O-X １ - Selected from the group consisting of (4-8 membered heterocycloalkyls), the heterocycloalkyl has one or two 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 alkyl, and is substituted with 0 to 3 groups selected from OH; Each X １ C １－７ Alkylene or C ３－７ It is a cycloalkylene; Each Y １ is C ２－７ alkylene or C ３－７ 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 Selected 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 halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, -X １ -O-C １－７ Alkyl, -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.

2. G ３ However, CH and C(CH ３ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following:

3. G ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G5 is CH and / or G5 is CH.

4. G ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G is CH, optionally G 4 may be CH, and optionally G 5 may be CH.

5. The condensed cyclopentane ring in formula (Ib) is: 【Transformation 3】 It has, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein one R2 may optionally be -NR a R b.

6. R １ However, it is phenyl, which has 1 to 3 R's. ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, substituted with.

7. 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, 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 and -S(O) ２ -Y １ -O-C １－３ Selected from the group consisting of alkyl groups, the cycloalkyl group is independently 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, or Each R3 is independently a halogen, CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 halohydroxyalkyl, -O-C1-4 alkyl, -O-C3-6 cycloalkyl, -O-C1-4 haloalkyl, -X1-CN, -X1-O-C1-4 alkyl, -O-Y1-O-C1-4 alkyl, -NR a R b, -X1-NR a R b, -O-Y1-NR a R b, -C(O)-NR a R b, -S(O)2-NR a R b, -S(O)(NH)-C1-4 alkyl, -S(O)2 -C1-4 alkyl, -S(O)2 -C1-4 haloalkyl, -S(O)2 -C3-6 cycloalkyl, -S(O)2 -Y1 -O-C1-3 alkyl, -S(O)2 - (4-6 membered heterocycloalkyl), -C(O)NH- (4-6 membered heterocycloalkyl), 4-6 membered heterocycloalkyl, and -O-X1 - (4-6 membered heterocycloalkyl), wherein the heterocycloalkyl has 1-2 heteroatom vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl are independently substituted with 0-3 groups selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -O-C1-4 alkyl, and OH, or Each R3 is independently a halogen, C1-7 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 halohydroxyalkyl, -O-C1-6 haloalkyl, -X1-CN, -O-Y1-O-C1-7 alkyl, -X1-NR a R b, -C(O)-NR a R b, -S(O)2-NR a R b, -S(O)(NH)-C1-7 alkyl, -S(O)2-C1-7 alkyl, -S(O)2-C1-7 haloalkyl, -S(O)2-C3-7 cycloalkyl, -S(O)2-Y1-O-C1-3 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl, -C(O)NH- (4-8 membered heterocycloalkyl), 4-8 membered heterocycloalkyl, and -O-X1- (4-8 membered heterocycloalkyl), wherein the heterocycloalkyl has one or two heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl are independently substituted with 0 to 3 groups selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -O-C1-4 alkyl, and OH.

8. The condensed azepane ring in formula (Ie) is: 【Chemistry 4】 It has, Optionally, the R2 bonded to nitrogen may be selected from the group consisting of C1-7 alkyl, C3-6 cycloalkyl, -Y1-O-C1-4 alkyl, -Y1-O-C3-7 cycloalkyl, -C(O)-C1-7 alkyl, -C(O)-C3-7 cycloalkyl, C4-7 heterocycloalkyl, -C(O)-(4-8 membered heterocycloalkyl), and -X1-(4-8 membered heterocycloalkyl). The heterocycloalkyl has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S. The cycloalkyl and heterocycloalkyl groups are independently halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, and -O-C1-4 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, substituted with 0 to 3 groups selected from alkyl and OH.

9. Formula (Ic): 【Transformation 5】 It has, in the formula, R ６ Halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, -O-C １－４ Selected from the group consisting of alkyl, oxo, and OH, Optionally, the expression (Id): 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which may have the properties of the compound according to claim 1.

10. below: 【Transformation 7】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

11. 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 Table 1-10 Table 1-11 Table 1-12 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. A pharmaceutical or pharmaceutical composition according to claim 12, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease, disorder, or condition mediated at least in part by AXL.

14. The pharmaceutical or pharmaceutical composition according to claim 13, wherein the disease, disorder, or condition is cancer.

15. The pharmaceutical or pharmaceutical composition according to claim 13, wherein the method further comprises administering at least one further therapeutic agent.

16. The pharmaceutical or pharmaceutical composition according to claim 15, 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.

17. A combination comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent.

18. The combination according to claim 17, 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.

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