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 TO RELATED APPLICATIONS This application claims the benefit of priority under 35 USC § 119(e) to U.S. Provisional Application No. 63 / 191,631, filed May 21, 2021, the entire contents of which 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 participates in various signaling pathways, including the RAS-RAF-MEK-ERK pathway, which leads to cancer cell proliferation, and the PI3K / AKT pathway, which involves several pro-survival proteins.

[0003] AXL has been shown to be overexpressed in a variety of malignancies, and in the cancer setting, AXL overexpression is associated with poor patient survival and resistance mechanisms (both targeted and untargeted).

[0004] In light of research linking AXL inhibition to diseases such as cancer, there is a need in the art for novel AXL inhibitors. The present disclosure addresses this need by providing additional advantages not found in conventional AXL inhibitors. Summary of the Invention

[0005] Summary of the Invention The present disclosure relates to compounds that inhibit the activity of AXL. The compounds have the formula (I): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 , R5 , ring A, and vertex G 1 , G 2 , G 3 , G 4 , and G 5 has the meaning defined herein below.

[0006] In a related aspect, provided herein are methods for treating an AXL-mediated disease or disorder in a subject (e.g., a human), comprising administering to the subject an effective amount 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, in whole or in part, by modulating AXL activity are candidate indications for the AXL inhibitor compounds provided herein.

[0007] Also provided herein are uses of the AXL inhibitors described herein in combination with one or more additional agents described below. DETAILED DESCRIPTION OF THE INVENTION

[0008] Detailed Description of Disclosure Before the present disclosure is further described, it is to be understood that the disclosure is not limited to particular embodiments described herein, and that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0009] Where a range of values ​​is provided, unless otherwise specified, each intervening value between the upper and lower limits of that range, to the nearest tenth of the lower limit, and any other numerical or intervening value in that range, is encompassed within the disclosure. Furthermore, the upper and lower limits of these smaller ranges may independently be included in the smaller ranges, subject to any specifically excluded limit in the stated range, and are also encompassed within the disclosure. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also encompassed within the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0010] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to serve as a premise for the use of exclusive terminology, such as "solely," "solely," and the like, in connection with the recitation of elements or the use of a "negative" limitation in the claims.

[0011] The publications discussed herein are provided for their disclosure prior to the filing date of the present application. Further, the publication dates provided may be different from the actual publication dates, which may need to be independently confirmed.

[0012] definition Unless otherwise stated, the following terms are intended to have the meanings indicated below. Other terms are defined elsewhere throughout the specification.

[0013] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a saturated, straight- or branched-chain hydrocarbon radical 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 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0014] The term "hydroxyalkyl" refers to a group having the indicated number of carbon atoms (e.g., C 1-6 or C 1-8 ) and is substituted with one or two hydroxy (OH) groups.

[0015] The term "hydroxyhaloalkyl" refers to a group having the indicated number of carbon atoms (e.g., C 1-6 or C 1-8 ) 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 straight-chain or branched-chain saturated aliphatic radical, i.e., a divalent hydrocarbon radical, having the specified number of carbon atoms and linking at least two other groups. The two moieties linked to the alkylene can be attached to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) n-, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. In some embodiments, alkylene groups can be substituted or unsubstituted. When a group containing an alkylene group is optionally substituted, it is understood that the optional substitution can occur on the alkylene portion of the moiety.

[0017] The term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic non-aromatic hydrocarbon ring system having the indicated number of ring atoms (e.g., C 12 having 3 to 6 ring carbon atoms). 3-6 "Cycloalkyl" refers to a monocyclic cycloalkyl group. Cycloalkyl groups can be saturated or partially unsaturated; i.e., the cycloalkyl group can be characterized by one or more points of unsaturation, as long as the unsaturation does not result in an aromatic system. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, and the like. "Cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. In some embodiments, the cycloalkyl compounds of the present disclosure are monocyclic C 3-6 It is a cycloalkyl moiety.

[0018] The term "heterocycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring having the indicated number of ring vertices (or members) (e.g., 3 to 14, 4 to 10, 4 to 8, or 4 to 6 members) and one to five heteroatoms selected from N, O, and S in a chemically stable arrangement, replacing one to five of the carbon vertices; the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Heterocycloalkyl groups can be saturated or partially unsaturated; i.e., heterocycloalkyl groups can be characterized by one or more points of unsaturation, provided that the unsaturation does not result in an aromatic system. The rings of bicyclic and polycyclic heterocycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting 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, quinuclidine, and the like. Heterocycloalkyl groups are bonded to the remainder of the molecule through a ring carbon atom. When a heterocycloalkyl is substituted, the substituents, if chemically permissible, are bonded to the heterocycloalkyl through a ring carbon atom or ring heteroatom.

[0019] As used herein, a wavy line crossing a single, double, or triple bond in any chemical structure described herein [ka] represents the point of attachment of a single, double, or triple bond to the rest of the molecule. Additionally, a bond extending from a substituent to the center of a ring (e.g., a phenyl ring) is intended to indicate attachment of the substituent to the ring at any of the available ring vertices, i.e., such that attachment of the substituent to the ring results in a chemically stable configuration.

[0020] As described herein, a divalent moiety includes either orientation (forward or reverse) of that moiety. For example, the group "-C(O)NH-" includes either orientation of the bond, i.e., -C(O)NH-, or -NHC(O)-; similarly, "-O-CHCH-" is intended to include both -O-CHCH- and -CHCH-O-.

[0021] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, "C 1-4 The term "haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0022] The term "aryl," unless otherwise specified, refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group. Bicyclic and tricyclic ring systems are fused or covalently linked to each other. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and biphenyl. This term is also meant to include fused cycloalkylphenyl and heterocycloalkylphenyl ring systems, such as, for example, indane, tetrahydronaphthalene, chroman, and isochroman rings. As a substituent, the point of attachment to the rest of the molecule can be through any carbon atom of the aromatic portion, a carbon atom of the cycloalkyl portion, or an atom of the heterocycloalkyl portion for fused 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 arrangement, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom. 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, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. When a heteroaryl is substituted, the substituents are attached to the heteroaryl via a ring carbon atom or ring heteroatom, if chemically permissible. Substituents for the heteroaryl ring can be selected from the group of acceptable substituents described below.

[0024] As used herein, the term "heteroatom" is meant to include 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 salts" is intended to include salts of active compounds, which are prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either pure or in a suitable inert solvent containing the desired base. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, such as substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either pure, or with the desired acid in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as those 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, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present disclosure contain both basic and acid functional groups that allow the compounds to be converted into either base or acid addition salts.

[0026] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of this disclosure.

[0027] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that easily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be gradually converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0028] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms.

[0029] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds. All racemic mixtures, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separated enantiomers) are intended to be included within the scope of the present disclosure. When stereochemistry is described, it refers to a compound in which the described isomer is present and is substantially free of other isomer(s). "Substantially free" of other isomer(s) refers to a ratio of at least 80 / 20, more preferably 90 / 10, or 95 / 5 or greater, of the described isomer to the other isomer(s). In some embodiments, one of the isomers is present in an amount of at least 99%.

[0030] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as a range from the amount found in nature to the amount that constitutes 100% of the atom in question. For example, a 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 additional utilities to those described elsewhere in this application. For example, but not limited to, isotopic variants of the disclosed compounds may find additional uses as diagnostic and / or imaging reagents or cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of the disclosed compounds may have modified pharmacokinetic and pharmacodynamic properties. All isotopic variants of the disclosed compounds, whether radioactive or not, are intended to be included within the scope of this disclosure.

[0031] The terms "patient" and "subject" are used interchangeably to refer to a human or non-human animal (eg, a mammal).

[0032] The terms "treat," "treating," "treatment," and the like refer to an action initiated after a disease, disorder, or condition, or a symptom thereof, has been diagnosed, recognized, or the like (such as administering an inhibitor of AXL, or a pharmaceutical composition comprising same), which eliminates, reduces, suppresses, alleviates, or ameliorates, temporarily or permanently, at least one of the underlying causes of the disease, disorder, or condition afflicting the subject, or at least one of the symptoms associated with the disease, disorder, or condition afflicting the subject. Thus, treatment includes inhibiting active disease (e.g., preventing the onset or further development of the disease, disorder, or condition, or clinical symptoms associated therewith).

[0033] As used herein, the term "in need of treatment" refers to a determination by a physician or other caregiver that a subject is in need of or would benefit from treatment. This determination is made based on a variety of factors within the physician's or caregiver's expertise.

[0034] The terms "prevent," "preventing," "prevention," and the like refer to initiating a course of action (e.g., administering an AXL inhibitor or a pharmaceutical composition containing the inhibitor) (e.g., before a disease, disorder, condition, or symptoms thereof are observed) to temporarily or permanently prevent, suppress, inhibit, or reduce a subject's risk of developing a disease, disorder, condition, or the like (e.g., as determined by the absence of clinical symptoms), or, generally, to delay the onset of a particular disease, disorder, or condition in a subject predisposed to having it. In certain instances, these terms also refer to slowing the progression of a disease, disorder, or condition, or inhibiting progression to an adverse or unwanted condition.

[0035] As used herein, the term "in need of prevention" refers to a determination by a physician or other caregiver that a subject needs or would benefit from preventative care. This determination is made based on a variety of factors within the physician's or caregiver's expertise.

[0036] The phrase "therapeutically effective amount" refers to an amount of an agent (e.g., a compound according to the present disclosure) administered to a subject, either alone or as part of a pharmaceutical composition, and either in a single dose or a series of doses, that is capable of producing any detectable positive effect on any symptom, condition, or characteristic of a disease, disorder, or condition when administered to a subject. A therapeutically effective amount can be determined by measuring the relevant physiological effect and can be adjusted in conjunction with dosing regimens, diagnostic assays for the subject's condition, and the like. For example, measuring serum levels of an AXL inhibitor (or, for example, a metabolic product thereof) at a particular time after administration can indicate whether a therapeutically effective amount has been used. Additionally, an effective amount of an AXL inhibitor of the present disclosure can be an amount that, when administered one or more times to a subject, produces a desired result compared to healthy subjects. For example, in a subject having a particular disorder, an effective dose can be one that improves a diagnostic parameter, measurement, marker, etc. of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or a dose that shows greater than a 90% improvement, where 100% is defined as the diagnostic parameter, measurement, marker, etc., exhibited by a normal subject.

[0037] The phrase "in an amount sufficient to effect a change" means that there is a detectable difference between the level of the indicator measured before administration of a particular therapy (e.g., baseline level) and after administration, whether the indicator is an objective parameter (e.g., serum concentration) or a subjective parameter (e.g., a subject's sense of well-being).

[0038] The terms "inhibitor" and "antagonist" or "activator" and "agonist" refer to inhibitory or activating molecules, respectively, with respect to the activation of, for example, a ligand, receptor, cofactor, gene, cell, tissue, or organ. 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 can also be defined as a molecule that suppresses, blocks, or inactivates constitutive activity. An activator is a molecule that increases, activates, promotes, enhances activation, 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 the activation of the target. An "antagonist" is a molecule that prevents the action(s) of an agonist. An antagonist prevents, suppresses, inhibits, or neutralizes the activity of an agonist; an antagonist can also prevent, inhibit, or suppress the constitutive activity of a target, e.g., a target receptor, even in the absence of an identified agonist.

[0039] The terms "modulate," "modulation," and the like refer to the ability of a molecule (e.g., an activator or inhibitor) to enhance or suppress, either directly or indirectly, the function or activity of a particular target, e.g., AXL. Modulators can act alone or can use cofactors, e.g., proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds (e.g., compounds according to the present disclosure) 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; modulation of the activity of other molecules; etc. The term "proliferative activity" includes activity that promotes, requires, or is specifically associated with normal cell division, as well as cancer, tumors, metaplasia, cell transformation, metastasis, and angiogenesis.

[0041] As used herein, "comparable," "equivalent activity," "activity equivalent to," "equivalent effect," "equivalent effect to," and the like are relative terms that can be quantitatively and / or qualitatively recognized. The meaning of these terms often depends on the context in which they are used. As an example, two agents that activate a receptor may be recognized as having comparable effects from a qualitative standpoint, but if one agent achieves only 20% of the activity of the other agent as determined in an art-recognized assay (e.g., a dose-response assay) or in an art-recognized animal model, the two agents would not be recognized as having 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 the 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, a result is comparable to a reference standard if the result deviates from the reference standard by less than 15%, less than 10%, or less than 5%. By way of example, activity or effect can refer to, but is not limited to, efficacy, stability, solubility, or immunogenicity.

[0042] "Substantially pure" indicates that a component (e.g., a compound according to the present disclosure) is present in greater than about 50% of the total content of the composition, typically greater than about 60% of the total content. More generally, "substantially pure" refers to a composition in which the component of interest constitutes at least 75%, at least 85%, at least 90%, or more of the total composition. In some cases, the component of interest comprises greater than about 90%, or greater than about 95%, of the total content of the composition.

[0043] The term "response," e.g., of a cell, tissue, organ, or organism, includes changes in biochemical or physiological behavior, e.g., changes in concentration, density, adhesion, or migration within a biological compartment, rate of gene expression, or state of differentiation, which changes correlate with internal mechanisms such as activation, stimulation, or treatment, or genetic programming. In certain contexts, terms such as "activation," "stimulation," and the like refer to cellular activation regulated by internal mechanisms and external or environmental factors; whereas terms such as "inhibition," "downregulation," and the like refer to the opposite effect.

[0044] A compound that is selective may be particularly useful in treating certain disorders or may reduce the potential for undesirable side effects. In certain embodiments, the compounds of the present disclosure are selective over other receptor tyrosine kinases (e.g., MER and / or TYRO3). Selectivity may be determined, for example, by comparing the inhibition of AXL by a compound described herein to the inhibition of another receptor tyrosine kinase (e.g., MER and / or TYRO3). In certain embodiments, the selective inhibition of AXL is at least 1000-fold, 500-fold, 100-fold, 50-fold, 40-fold, 30-fold, or 20-fold greater than the inhibition of the other receptor tyrosine kinase.

[0045] Compounds of the Disclosure In one particular aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, During the ceremony: G 1 is N or CR G1 is; G 2 is CR G2 or N; G 3 is CR G3 or N; G4 is CR G4 or N; G 5 is CR G5 or N; R G1 A, H, C 1-3 Alkyl, halogen, C 1-3 selected from the group consisting of haloalkyl, and CN; R G2 , R G3 , R G4 , and R G5 Each of the is independently H, halo, 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 4-8 membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the cycloalkyl and heterocycloalkyl are independently selected from halo, CN, 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; 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 is selected from the group consisting of 1 to 4 R 2 and further substituted with 0 or 1 oxo (=O) adjacent to the nitrogen atom; 1 is N: R 1 teeth: i) phenyl or a 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein each phenyl and heteroaryl is selected from the group consisting of 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 a 4-8 membered heterocycloalkyl substituted with a substituent and further substituted with 0 or 1 oxo (=O) adjacent to the nitrogen atom; and iii) 0 to 3 R 4 C substituted with a substituent 3-7 cycloalkyl; Select from the group consisting of: Each R 2 independently, C 1-7 Alkyl, C 3-7 Alkenyl, C 3-7 Alkynyl, 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 membered heterocycloalkyl, -NR a -(4- to 8-membered heterocycloalkyl), -C(O)-(4- to 8-membered heterocycloalkyl), -X 1 -(4- to 8-membered heterocycloalkyl) and -OX 1 -(4-8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl groups are selected from the group consisting of 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; Each R 3 are independently halogen, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halohydroxyalkyl, -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- to 8-membered heterocycloalkyl), -C(O)NH-(4- to 8-membered heterocycloalkyl), 4- to 8-membered heterocycloalkyl, and -OX 1 -(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl groups are independently selected from halo, CN, 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; Each R 4 are independently halo, hydroxy, 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 cycloalkyl; —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 The cycloalkyl group is R 1 does not bond directly to the nitrogen atom ring member of a 4- to 8-membered heterocycloalkyl to form an N-N bond; R 5 is H, C 1-4 Selected from the group consisting of alkyl and -NH2; Each X 1 is C 1-7 Alkylene or C 3-7 is a cycloalkylene; Each Y 1 is C 2-7 Alkylene or C 3-7cycloalkylene, wherein the two bonded heteroatoms are not bonded to a common carbon atom; R a and R b Each of these independently represents H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, and C 3-7 cycloalkyl; or R a and R b together with the nitrogen to which they are attached form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, and is not limited to halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Provided is a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, substituted with 0 to 3 groups independently selected from alkyl, oxo, and OH.

[0046] In some selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is 1 In other selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein G 1 is a compound where

[0047] In some selected embodiments, including those described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 2 is CH or CF.

[0048] In some selected embodiments, including those described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 3 is a compound selected from the group consisting of N, CH, and C(CH3).

[0049] In some selected embodiments, including those described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 4 is N or CH.

[0050] In some selected embodiments, including those described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is G 5 is N or CH.

[0051] In some selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is 1 is N and G 2 In selected further embodiments, G 1 is N and G 2 is CH, and G 3 is CH. In still further selected embodiments, G 1 is N and G 2 is CH and G 3 is CH and G 4 is CH. In yet another selected embodiment, G 1 is N and G 2 is CH and G 3 is CH and G 4 is CH and G 5 is CH.

[0052] Referring to ring A, if ring A is G 3 , G 4 and G 5 It is understood that the ring A is fused to an aromatic ring containing the aromatic ring, and the presence of ring A does not disrupt the aromaticity of the aromatic ring. Specifically, the ring vertex fusing the two rings is sp 2The ring vertices are hybridized carbon atoms. Therefore, each of these ring vertices has a p orbital that participates in the conjugated pi system of the aromatic ring. Therefore, it is understood that all Ring A moieties have a point of unsaturation at the point of fusion to the rest of the molecule. For example, cyclopentane in Ring A refers to cyclopentene, where the double bond is between the two carbon atoms that are fused to the rest of the compound.

[0053] In some selected embodiments, including those described above, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein the fused ring A is: [ka] and each of which has a formula selected from the group consisting of 1 to 4 R 2 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 membered heterocycloalkyl, -NR a -(4- to 8-membered heterocycloalkyl), -C(O)-(4- to 8-membered heterocycloalkyl), -X 1 -(4- to 8-membered heterocycloalkyl), and -OX 1-(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl groups are independently selected from halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 In further selected embodiments, each R 2 is C 1-7 Alkyl, -NR a R b , and -NR a -(4- to 8-membered heterocycloalkyl), wherein heterocycloalkyl has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and independently selected from halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 It is substituted with 0 to 3 groups selected from alkyl and OH.

[0054] In some still further selected embodiments, including those described above, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is one in which the fused ring A is of the formula: [ka] It is a compound having the formula:

[0055] In some still further selected embodiments, including those described above, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises one R 2 But, -NR a R b It is a compound in which

[0056] In some embodiments, including select 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 in which

[0057] In some selected embodiments, including those described above, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is one in which the fused ring A is: [ka] and each of which optionally has a formula selected from the group consisting of an additional 1 to 2 independently selected R 2 In still further selected embodiments, fused ring A is substituted with a group of formula: [ka] It has.

[0058] In further selected embodiments, including those described above, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is R 2 But 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- to 8-membered heterocycloalkyl, —C(O)—(4- to 8-membered heterocycloalkyl), —X 1 -(4-8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl groups are independently selected from halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4It is substituted with 0 to 3 groups selected from alkyl and OH.

[0059] In some embodiments, including select embodiments described above, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises one R 2 but: [ka] It is a compound in which

[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 is phenyl, which has 1 to 3 R 3 In further selected embodiments, each R 3 If present, halogens, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halohydroxyalkyl, -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 alkyl, and cycloalkyl is independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 In yet another embodiment, each R 3 If present, halogens, 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- to 6-membered heterocycloalkyl), -C(O)NH-(4- to 6-membered)heterocycloalkyl, 4- to 6-membered heterocycloalkyl, and -OX 1 -(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 selected from halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 In some embodiments, R is substituted with 0 to 3 groups selected from alkyl, and OH. 3 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- to 8-membered heterocycloalkyl), 4- to 8-membered heterocycloalkyl, and -OX 1 -(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl groups are independently selected from halo, C 1-4Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 It is substituted with 0 to 3 groups selected from alkyl and OH.

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

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

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

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

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

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

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

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

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

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

[0071] In some selected embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is selected from the group consisting of: [ka] Choose from:

[0072] In some embodiments, the compounds of formula (I) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, During the ceremony: G 1 is N; G 2 is CR G2 or N; G 3 is CR G3 or N; G 4 is CR G4 or N; G 5 is CR G5 or N; R G1 A, H, C 1-3 Alkyl, halogen, C 1-3 selected from the group consisting of haloalkyl, and CN; R G2 , R G3 , R G4 , and R G5 Each of the is independently H, halo, 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 4-8 membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the cycloalkyl and heterocycloalkyl are independently selected from halo, CN, 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; 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 is selected from the group consisting of 1 to 4 R 2 and further substituted with 0 or 1 oxo (=O) adjacent to the nitrogen atom; R 1 teeth: i) phenyl or a 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein each phenyl and heteroaryl is selected from the group consisting of 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 a 4-8 membered heterocycloalkyl substituted with a substituent and further substituted with 0 or 1 oxo (=O) adjacent to the nitrogen atom; and iii) 0 to 3 R 4 C substituted with a substituent 3-7 cycloalkyl; Select from the group consisting of: Each R 2 independently, C 1-7 Alkyl, C 3-7 Alkenyl, C 3-7 Alkynyl, 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 membered heterocycloalkyl, -NRa -(4- to 8-membered heterocycloalkyl), -C(O)-(4- to 8-membered heterocycloalkyl), -X 1 -(4- to 8-membered heterocycloalkyl) and -OX 1 -(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl groups are independently selected from halo, CN, 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; Each R 3 are independently halogen, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halohydroxyalkyl, -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- to 8-membered heterocycloalkyl), 4- to 8-membered heterocycloalkyl, and —OX 1 -(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl groups are independently selected from halo, CN, 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; Each R 4 are independently halo, hydroxy, 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 cycloalkyl; —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 The cycloalkyl group is R 1does not bond directly to the nitrogen atom ring member of a 4- to 8-membered heterocycloalkyl to form an N-N bond; R 5 is H, C 1-4 Selected from the group consisting of alkyl and -NH2; Each X 1 is C 1-7 Alkylene or C 3-7 is a cycloalkylene; Each Y 1 is C 2-7 Alkylene or C 3-7 cycloalkylene, wherein the two bonded heteroatoms are not bonded to a common carbon atom; R a and R b Each of these independently represents H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, and C 3-7 cycloalkyl; or R a and R b together with the nitrogen to which they are attached form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, and is not limited to halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -X 1 -OC 1-7 Alkyl, -OC 1-4 Provided is a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, substituted with 0 to 3 groups independently selected from alkyl, oxo, and OH.

[0073] In some embodiments, the compounds of formula (I) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, During the ceremony: G1 is CR G1 is; G 2 is CR G2 or N; G 3 is CR G3 or N; G 4 is CR G4 or N; G 5 is CR G5 or N; R G1 A, H, C 1-3 Alkyl, halogen, C 1-3 selected from the group consisting of haloalkyl, and CN; R G2 , R G3 , R G4 , and R G5 Each of the is independently H, halo, 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 4-8 membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the cycloalkyl and heterocycloalkyl are independently selected from halo, CN, 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; 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 contains one to four R 2 and further substituted with 0 or 1 oxo (=O) adjacent to the nitrogen atom; R 1 teeth: i) phenyl or a 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein each phenyl and heteroaryl is selected from the group consisting of 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 a 4-8 membered heterocycloalkyl substituted with a substituent and further substituted with 0 or 1 oxo (=O) adjacent to the nitrogen atom; and iii) 0 to 3 R 4 C substituted with a substituent 3-7 cycloalkyl; Select from the group consisting of: Each R 2 independently, C 1-7 Alkyl, C 3-7 Alkenyl, C 3-7 Alkynyl, 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 membered heterocycloalkyl, -NR a -(4- to 8-membered heterocycloalkyl), -C(O)-(4- to 8-membered heterocycloalkyl), -X 1 -(4- to 8-membered heterocycloalkyl) and -OX 1 -(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl groups are independently selected from halo, CN, 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; Each R 3 are independently halogen, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halohydroxyalkyl, -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- to 8-membered heterocycloalkyl), 4- to 8-membered heterocycloalkyl, and —OX 1-(4- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl and heterocycloalkyl groups are independently selected from halo, CN, 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; Each R 4 are independently halo, hydroxy, 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 cycloalkyl; —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 The cycloalkyl group is R 1 does not bond directly to the nitrogen atom ring member of a 4- to 8-membered heterocycloalkyl to form an N-N bond; R 5 is H, C 1-4 Selected from the group consisting of alkyl and -NH2; Each X 1 is C 1-7 Alkylene or C3-7 is a cycloalkylene; Each Y 1 is C 2-7 Alkylene or C 3-7 cycloalkylene, wherein the two bonded heteroatoms are not bonded to a common carbon atom; R a and R b Each of these independently represents H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, and C 3-7 cycloalkyl; or R a and R b together with the nitrogen to which they are attached form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, and is not limited to halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -X 1 -OC 1-7 Alkyl, -OC 1-4 Provided is a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof, substituted with 0 to 3 groups independently selected from alkyl, oxo, and OH.

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

[0075] Synthesis method General Methods for Preparing the Claimed Compounds Common methods: Without limitation, useful methods for constructing compounds according to the present disclosure can consist of four components, which can be performed in any order: combining the a and b fragments, combining the b and c fragments, combining the c and d fragments, or modifying functional groups present on all of these fragments. A general retrosynthetic cleavage of the compounds into fragments a through d useful for constructing compounds of the present disclosure is shown below: [ka]

[0076] Several methods for preparing the claimed compounds are illustrated (Schemes 1-7). Scheme (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 can occur before or after the formation of the bond between fragments b and c. In the case of Scheme (1), the desired amine is coupled to the desired ketone via the use of a hydride source and acetic acid, or any other conditions known for reductive amination. [ka]

[0077] The relative positions of the amine and ketone can be reversed as well, as illustrated in equation (2). Those skilled in the art will recognize other possible conditions that will result in the desired connectivity and product. [ka]

[0078] Equation (3) shows another method for forming the ab fragment by first condensing the two partners and forming an amine, followed by the addition of a Grignard reagent. This sequence introduces an additional alkyl substituent at the carbon atom adjacent to the amine nitrogen atom. [ka]

[0079] The relative positions of the amine and ketone can be reversed as well, as exemplified in formula (4). One skilled in the art will recognize other possible conditions that will result in the desired connectivity and product. Formation of the ab fragment, as exemplified in formulas (1)-(4), can occur either before or after formation of the bc fragment. [ka]

[0080] The bond formation between fragments b and c can occur before or after the bond formation between fragments a and b or between fragments c and d. Equation (5) demonstrates one method for connecting fragments b and c via 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, and OTf. The coupling is mediated by a transition metal catalyst, preferably palladium, and a suitable ligand. The coupling can be assisted by an organic or inorganic base. The use of protecting groups for the bicyclic moiety, such as SEM, Boc, THP, PMB, MOM, MEM, or TIPS, generally improves the yield and purity of the desired product. [ka]

[0081] The relative functionalization of the binding partners can also be performed in the reverse direction, as shown in equation (6). Those skilled in the art will recognize other possible combinations and conditions that will result in the desired product. [ka]

[0082] The bond formation between fragments c and d can occur before or after the bond formation between fragments b and c. Equation (7) shows one method for connecting fragments c and d via 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 can be assisted by an organic or inorganic base. The use of protecting groups for the bicyclic moiety, such as SEM, Boc, THP, PMB, MOM, MEM, and TIPS, generally improves the yield and purity of the desired product. [ka]

[0083] For the most efficient preparation of any particular compound of the present disclosure, the timing and order of attachment of fragments, as well as the modification of functionality present on any of the fragments, may vary and depend on the functionality present. The various methods described above have been used to prepare compounds of the present disclosure and are exemplified below. The deuterated versions of the following examples can be synthesized using the appropriate deuterated intermediates.

[0084] Therapeutic and prophylactic uses The present disclosure contemplates the use of the AXL inhibitors described herein in the treatment or prevention of various diseases, disorders, and / or conditions, and / or their symptoms. Details regarding specific applications are provided below, but it should be understood that the present disclosure is not limited thereto. Additionally, while general categories of certain diseases, disorders, and conditions are described below, some diseases, disorders, and conditions may fall into more than one category, and others may not fall into any of the disclosed categories.

[0085] In some embodiments, the AXL inhibitors described herein are administered in an amount effective to reverse, stop, or slow 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, testis, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestine, colon or rectum), kidney, kidney cells, bladder, bone, bone marrow, skin, head and neck, liver, gallbladder, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., glioma), ganglion, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the hematopoietic and immune systems (e.g., spleen or thymus), and myelodysplastic syndromes. The present disclosure also provides methods of treating or preventing other cancer-related diseases, disorders, or conditions, such as, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virus-induced cancers (e.g., epithelial cell carcinoma, endothelial cell carcinoma, squamous cell carcinoma, and papillomavirus), adenocarcinoma, lymphoma, carcinoma, melanoma, leukemia, myeloma, sarcoma, teratocarcinoma, chemically induced cancer, metastasis, 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 syndrome. In some embodiments, the 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 is meant to refer broadly to conditions directly or indirectly related to cancer, including, for example, pre-cancerous conditions such as angiogenesis and dysplasia.

[0087] In some embodiments, the compounds according to the present disclosure are useful in treating kidney cancer. In further embodiments, the kidney cancer is renal cell carcinoma. In yet further embodiments, the renal cell carcinoma is clear cell renal carcinoma (ccRCC).

[0088] In some embodiments, the compounds according to the present disclosure are useful for treating lung cancer.In further embodiments, the lung cancer is non-small cell lung cancer (NSCLC).In yet further embodiments, the NSCLC is lung squamous cell carcinoma or lung adenocarcinoma.In some embodiments, the NSCLC is EGFR mutant NSCLC.

[0089] In some embodiments, the compounds according to the present disclosure are useful in treating leukemia. In further embodiments, the leukemia is acute myeloid leukemia (AML). In yet further embodiments, the AML is relapsed AML.

[0090] In some embodiments, the compounds according to the present disclosure are useful in treating breast cancer. In further embodiments, the breast cancer is hormone receptor-positive (e.g., ERa-positive breast cancer, PR-positive breast cancer, ERa-positive and PR-positive breast cancer), HER2-positive breast cancer, HER2-overexpressing breast cancer, or any combination thereof. In yet further embodiments, the breast cancer is triple-negative breast cancer.

[0091] In some embodiments, compounds according to the present disclosure are useful in the treatment of pancreatic cancer. In further embodiments, the pancreatic cancer is a pancreatic neuroendocrine tumor or pancreatic adenocarcinoma (i.e., pancreatic ductal adenocarcinoma (PDAC)).

[0092] In certain embodiments, the cancer may be metastatic or at risk of becoming metastatic, or may be present in diffuse tissues, including 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, and therefore, in some embodiments, AXL inhibitors according to the present disclosure are useful for treating hypoxic tumors.

[0094] In one or more embodiments, the cancer is an oncogene-addicted cancer, which is addicted to an oncogene that is dominant in proliferation and survival, such as, for example, 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 present disclosure provides methods of treating a proliferative condition, cancer, tumor, or precancerous condition using an AXL inhibitor and at least one additional therapeutic or diagnostic agent, examples of which are described elsewhere herein.

[0096] Immune and Inflammation-Related Disorders. Immune- and inflammation-related diseases, disorders, and conditions that can be treated or prevented with the compounds and compositions of the present 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 where inflammatory cytokines interfere with 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, infectious diseases, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), chronic obstructive pulmonary disease (COPD), atherosclerosis, allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation, and multiple sclerosis.

[0097] In certain embodiments of the present 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 the present disclosure to prolong the immune response to the antigen or vaccine. Therapeutic compositions comprising at least one antigenic agent or vaccine component, including, but not limited to, viruses, bacteria, and fungi, or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines, in combination with at least one AXL inhibitor of the present disclosure are also provided.

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

[0099] Other Disorders. Embodiments of the present disclosure contemplate administering an AXL inhibitor described herein to a subject for the treatment or prevention of any other disorder that may benefit from at least some level of AXL inhibition. Such diseases, disorders, and conditions include, for example, cardiovascular (e.g., cardiac ischemia) disorders and metabolic (e.g., diabetes, insulin resistance, obesity) disorders.

[0100] Patient selection In some embodiments, patients are selected by assessing AXL expression (e.g., soluble AXL (sAXL), cell surface AXL, or total AXL) in relevant tissues or samples. In some embodiments, patients are further selected by assessing GAS6 expression in relevant tissues or samples. In some embodiments, the disclosure provides methods of treating cancer in patients with high AXL expression with compounds described herein. In an embodiment, the disclosure provides methods of treating cancer in patients with high cell surface AXL expression with compounds described herein. In another embodiment, the disclosure provides methods of treating cancer in patients with high sAXL expression with compounds described herein. In yet another embodiment, the disclosure provides methods of treating cancer in patients with a high ratio of sAXL expression to GAS6 expression with compounds described herein. In some embodiments, the disclosure provides methods of administering a therapeutically effective amount of an AXL inhibitor to treat cancer to an individual based on determining the relative amount of AXL expression. In another embodiment, the disclosure provides methods of administering a therapeutically effective amount of an AXL inhibitor to treat cancer to an individual based on determining the relative amount of cell surface AXL expression. In another embodiment, the present disclosure provides a method of administering to an individual a therapeutically effective amount of an AXL inhibitor for treating cancer based on determining the relative amount of sAXL expression. In yet another embodiment, the present disclosure provides a method of administering to an individual a therapeutically effective amount of an AXL inhibitor for treating cancer based on determining the relative ratio of sAXL expression to GAS6 expression.

[0101] Pharmaceutical Composition The AXL inhibitor of the present 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 amount. The pharmaceutical composition may be used in the method of the present disclosure.

[0102] The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the 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 agents or compounds described herein to treat or prevent the diseases, disorders, and conditions contemplated by the present disclosure.

[0103] Pharmaceutical compositions containing an active ingredient (e.g., an inhibitor of AXL) may be in a form suitable for oral use, such as tablets, capsules, troches, 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 using one or more excipients, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically acceptable and palatable formulation. Tablets, capsules, and the like contain the active ingredient in a mixture with pharmaceutically acceptable, non-toxic excipients suitable for manufacturing. 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 presented as hard gelatin capsules made 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 made by mixing the active ingredient with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0105] Aqueous suspensions contain the active ingredient in admixture with excipients suitable for the manufacture of such suspensions. Such excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions can also contain one or more preservatives.

[0106] Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents, such as those mentioned above, may be added to provide a palatable oral preparation.

[0107] Dispersible powders and granules suitable for preparation of an aqueous suspension are provided by the addition of water to the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0108] The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum acacia or gum tragacanth; naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0109] Pharmaceutical compositions typically contain a therapeutically effective amount of an AXL inhibitor contemplated by the present disclosure and one or more pharmaceutically and physiologically acceptable formulation components. Suitable pharmaceutically 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, dispersing agents, solvents, fillers, extenders, surfactants, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be saline or citrate-buffered saline, supplemented with other materials commonly used in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize various buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Common buffers that can be incorporated into pharmaceutical compositions include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, buffer components can 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. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0110] After the pharmaceutical composition is formulated, it can be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations can be stored in a ready-to-use form, a lyophilized form that needs to be reconstituted before use, a liquid form that needs to be diluted before use, or any other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, an ampoule, a syringe, or an autoinjector), while in other embodiments, a multi-use container (e.g., a multi-use vial) is provided.

[0111] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated using suitable dispersing, wetting, and / or suspending agents and other excipients. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that may 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. Additionally, sterile fixed oils may be used as solvents or suspending media. For this purpose, any bland fixed oil, such as synthetic mono- or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, find use in the preparation of injectables. Prolonged absorption of certain injectable formulations can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0112] AXL inhibitors contemplated by this disclosure may be in the form of any other suitable pharmaceutical composition (e.g., a spray for nasal or inhaled use) now known or later developed.

[0113] Route of administration The present disclosure contemplates that AXL inhibitors and compositions thereof may be administered in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracapsular, intraarticular, intracerebral (intraparenchymal), and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation. Depot injections, typically administered subcutaneously or intramuscularly, may also be utilized to release the AXL inhibitors disclosed herein over a predetermined period of time.

[0114] Certain embodiments of the present disclosure contemplate oral administration.

[0115] Combination therapy The present disclosure contemplates the use of AXL inhibitors alone or in combination with one or more active therapeutic agents. The additional active therapeutic agent can be a small chemical molecule; a macromolecule such as a protein, antibody, peptibody, peptide, DNA, RNA, or a fragment of such a macromolecule; or a cell therapy or gene therapy. Combination therapy targets different but complementary mechanisms of action, thereby providing a synergistic therapeutic or preventative effect against the underlying disease, disorder, or condition. Additionally or alternatively, combination therapy allows for a reduced dosage of one or more drugs, thereby alleviating, suppressing, or eliminating side effects associated with one or more drugs.

[0116] The active therapeutic agents in such combination therapy can be formulated as a single composition or as separate compositions. When administered separately, each therapeutic agent in the combination can be administered simultaneously or nearly simultaneously, or at different times. Furthermore, even if the therapeutic agents are administered in different dosage forms (e.g., oral capsules and intravenous), they can be administered "in combination," they can be administered at different dosage intervals, one therapeutic agent can be administered periodically according to a dosing schedule while the other is titrated up, tapered, or discontinued, or each therapeutic agent in the combination can be independently titrated up, tapered, increased or decreased in dosage, or discontinued and / or resumed during the course of a patient's treatment. When the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0117] In some embodiments, an AXL inhibitor according to the present disclosure is combined with at least one additional therapeutic agent. In some embodiments, the at least one additional 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 targeting the extracellular production of adenosine (e.g., a CD73 inhibitor, a CD39 inhibitor, and / or an adenosine receptor inhibitor (e.g., an AXL inhibitor). 2A R and / or A 2B R inhibitors), radiation therapy, and chemotherapeutic agents. Each of the additional therapeutic agents is described in further detail below.

[0118] In some embodiments, the one or more additional therapeutic agents are immunomodulatory agents. Suitable immunomodulatory agents contemplated by the present disclosure include activating monoclonal antibodies (mAbs) against stimulatory receptors such as CD40L, B7, and B7RP1; anti-CD40, anti-CD38, anti-ICOS, and 4-1BB ligand; dendritic cell antigen loading (in vitro or in vivo); anti-cancer vaccines such as dendritic cell cancer vaccines; cytokines / chemokines such as IL1, IL2, IL12, IL18, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / b, 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 present disclosure provides methods for tumor inhibition of tumor growth, comprising administering an AXL inhibitor described herein in combination with a signal transduction inhibitor (STI) to achieve additive or synergistic inhibition of tumor growth. As used herein, the term "signal transduction inhibitor" refers to an agent that selectively inhibits one or more steps in a signal transduction pathway.Signal transduction inhibitors (STIs) contemplated in the present disclosure include: (i) BCR-ABL kinase inhibitors (e.g., GLEEVEC®), (ii) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), such as 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, such as HER-2 / neu receptor inhibitors (e.g., HERCEPTIN®), and HER-3 receptor inhibitors, and (iv) vascular endothelial growth factor receptor (VEGFR) inhibitors, such as small molecule inhibitors (e.g., axitinib, sunitinib, and sorafenib). (v) inhibitors of AKT family kinases or the AKT pathway (e.g., rapamycin); (vi) inhibitors of serine / threonine protein kinase B-Raf (BRAF), such as vemurafenib, dabrafenib, and encorafenib; (vii) inhibitors of rearrangement during transfection (RET), such as selpercatinib and pralsetinib; (viii) inhibitors of tyrosine-protein kinase Met (MET), such as cerebrospinal fluid (CF) kinase (CFT), and tyrosine-protein kinase Met (MET). (i) anaplastic lymphoma kinase (ALK) inhibitors (e.g., tepotinib, tivantinib, cabozantinib, pazopanib, tivozanib, XL-092, and crizotinib), (ii) anaplastic lymphoma kinase (ALK) inhibitors (e.g., ensartinib, ceritinib, lorlatinib, crizotinib, and brigatinib), (iii) inhibitors of the RAS signaling pathway (e.g., inhibitors of KRAS, HRAS, RAF, MEK, ERK) as described elsewhere herein, (iv) FLT-3 inhibitors (e.g., gilteritinib, (xii) inhibitors of Trop-2, (xiii) inhibitors of the JAK / STAT pathway, for example, JAK inhibitors such as tofacitinib and ruxolitinib, or STAT inhibitors such as napabucasin, (xiv) inhibitors of NF-κB, (xv) cell cycle kinase inhibitors (e.g., flavopiridol), (xvi) phosphatidylinositol kinase (PI3K) inhibitors, and (xvii) protein kinase B (AKT) inhibitors (e.g., capivasertib, milansertib).Agents involved in immune modulation can also be used in combination with the AXL inhibitors described herein to suppress tumor growth in cancer patients. In one or more embodiments, the additional therapeutic agent comprises an inhibitor 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, the additional therapeutic agent comprises a chemotherapeutic agent. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metoledopa, and uredopa; ethylenimines and methylameramines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, and cyclophosphamide. benzodiazepines, e.g., benzodiazepines ... Momycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, pomalidomide, peplomycin, potfilomycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; methotrexate, and 5-fluorouracil (5-FU) ); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calsterone, dromostanolone propionate, epithiostanol, methypitiostane, testolactone;Antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; Bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformitin; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone ;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin;Fenameth;Pirarubicin;Podophyllic acid;2-Ethylhydrazide;Procarbazine;Razoxane;Sizofiran;Spirogermanium;Tenuazonic acid;Triaziquone;2,2',2''-Trichlorotriethylamine;Urethane;Vindesine;Dacarbazine;Mannomustine;Mitobronitol;Mitolactol;Pipobroman;Gacytosine; Arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids such as paclitaxel, nab-paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; Examples of chemotherapeutic agents include, but are not limited to, mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine; anthracyclines; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. 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] Chemotherapeutic agents include antihormonal agents that regulate or inhibit hormone action on tumors, such as antiestrogens, such as tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxoxifene, ketoxifene, onapristone, and toremifene; and antiandrogens, such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy includes a chemotherapy regimen that includes one or more chemotherapy agents. In certain embodiments, the combination therapy includes the administration of hormones or related hormonal agents.

[0122] Combinations of AXL inhibitors according to the present disclosure with poly(ADP-ribose) polymerase (PARP) inhibitors are also contemplated. Exemplary PARP inhibitors contemplated by the present disclosure include olaparib, niraparib, and rucaparib.

[0123] Additional therapies that may be used in combination with AXL inhibitors include radiation therapy, monoclonal antibodies against tumor antigens, monoclonal antibody-toxin conjugates, T-cell adjuvants, bone marrow transplants, or antigen-presenting cells (e.g., dendritic cell therapy), including TLR agonists used to stimulate such antigen-presenting cells.

[0124] In certain embodiments, the present disclosure contemplates the use of the compounds described herein in combination with adoptive cell therapy, a novel and promising form of personalized immunotherapy in which immune cells with anti-tumor activity are administered 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). Generally, adoptive cell therapy involves collecting T cells from an individual, genetically modifying them to target specific antigens or enhance anti-tumor effects, expanding them to sufficient numbers, and then infusing the genetically engineered T cells into a cancer patient. T cells can be collected from the patient (e.g., autologous) for later reinfusion of the expanded cells, or they can be collected from a donor patient (e.g., allogeneic).

[0125] In certain embodiments, the present disclosure contemplates the use of the compounds described herein in combination with RNA interference-based therapy for silencing gene expression.RNAi begins by cleaving longer double-stranded RNA into small interfering RNA (siRNA).One strand of siRNA is incorporated into a ribonucleoprotein complex known as RNA-induced silencing complex (RISC), and then used to identify the mRNA molecule that is at least partially complementary to the incorporated siRNA strand.RISC can bind to mRNA or cleave it, both of which inhibit translation.

[0126] In certain embodiments, the present disclosure contemplates 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 cluster of differentiation 39), which hydrolyzes ATP to ADP and ADP to AMP, and ecto-5'-nucleotidase (NT5E or 5NT, also known as CD73 or cluster of differentiation 73), which converts AMP to adenosine. The enzymatic activities of CD39 and CD73 play strategic roles in modulating the duration, magnitude, and chemical nature of the purinergic signals delivered to various cells (e.g., immune cells). Alterations in the activity of these enzymes can alter the course or determine the outcome of several pathophysiological events, such as cancer, autoimmune diseases, infectious diseases, atherosclerosis, and ischemia-reperfusion injury, suggesting that these ectoenzymes 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, oleculab (MEDI9447), NZV930, IPH5301, uriledolimab (TJD5, TJ004309), and BMS-986179. In certain embodiments, the present disclosure contemplates combination with inhibitors of CD73, e.g., those described in WO 2017 / 120508, WO 2018 / 094148, WO 2018 / 067424, and WO 2020 / 046813. In certain embodiments, the CD73 inhibitor is chemlicustat (AB680).

[0127] Another approach to targeting extracellular production of adenosine is adenosine A 2A and / or A 2B Thus, in some embodiments, the present disclosure provides a method for treating a cancer cell line comprising administering to a patient a compound according to the present disclosure and a compound ... 2A and / or A 2BCombination with agents that target receptors is contemplated. Such therapeutic agents include those that target the adenosine 2 receptor (A2R) (e.g., A 2A and / or A 2B ) antagonists. Adenosine binds to four different G protein-coupled receptors: A1R, A2R, and A3R. 2a R.A. 2b It can bind to and activate A3R and A3R. A3R is expressed on myeloid cells such as T cells, natural killer cells, and dendritic cells. 2a The binding of adenosine to R receptors 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 A2R is implicated in selectively potentiating anti-inflammatory cytokines, promoting upregulation of PD-1 and CTLA-4, promoting the generation of LAG-3 and Foxp3+ regulatory T cells, and mediating the inhibition of regulatory T cells. PD-1, CTLA-4, and other immune checkpoints are further described herein. Combinations of A2R antagonists in the combinations described herein may provide at least additive effects, given their different mechanisms of action. In some embodiments, the therapeutic agent can 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., etormadenant).

[0128] In certain embodiments, the present disclosure contemplates the use of inhibitors of phosphatidylinositol 3-kinase (PI3K), particularly the PI3Kγ isoform, in combination with the compounds described herein. PI3Kγ inhibitors can modulate myeloid cells to stimulate anti-cancer immune responses, for example, by inhibiting suppressive myeloid cells, attenuating immunosuppressive tumor-infiltrating macrophages, or stimulating macrophages and dendritic cells to produce cytokines that contribute to effective T-cell responses, thereby suppressing the development and spread of cancer. PI3Kγ inhibitors include those described in WO 2020 / 0247496A1.

[0129] In certain embodiments, the present disclosure contemplates the use of compounds described herein in combination with inhibitors of arginase, which have been shown to cause or contribute to pro-inflammatory immune dysfunction, tumor immune evasion, immunosuppression and immunopathology of infectious diseases. Exemplary arginase compounds can be found, for example, in PCT / US2019 / 020507 and WO / 2020 / 102646.

[0130] In certain embodiments, the present invention contemplates the use of an AXL inhibitor according to the present disclosure in combination with an inhibitor of HIF-2α, which plays an essential role in the cellular response to low oxygen 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 poor clinical outcomes in patients with various cancers; 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 velzutifan, ARO-HIF2, PT-2385, AB521, and those described in WO 2021113436 and WO 2021188769. In some embodiments, an AXL inhibitor according to the present disclosure is combined with AB521.

[0131] The present disclosure also contemplates the combination of an AXL inhibitor 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 KRAS family genes, mutations G12C, G12D, G12V, G12A, G13D, Q61H, Q13C, and G12S, among others, have been observed in multiple tumor types. Direct and indirect inhibition approaches to inhibit mutant RAS signaling have been investigated. Indirect inhibitors target effectors other than RAS 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 mutants are also under investigation, generally targeting the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors under development include, but are not limited to, sotorasib (AMG510), MRTX849, mRNA-5671, and ARS1620. In some embodiments, the one or more RAS signaling inhibitors are selected from the group consisting of a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an SOS1 inhibitor, an mTOR inhibitor, a SHP2 inhibitor, and an AKT inhibitor. In other embodiments, the one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0132] In some embodiments, the one or more additional therapeutic agents are: (i) agents that inhibit the enzyme poly(ADP-ribose) polymerase (e.g., olaparib, niraparib, and rucaparib, etc.); (ii) inhibitors of the Bc1-2 family of 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 The present disclosure contemplates the use of inhibitors of AXL described herein in combination with immune checkpoint inhibitors.

[0134] The vast array of genetic and epigenetic alterations characteristic of all cancers provides a diverse array of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the ultimate amplitude (e.g., level of cytokine production or proliferation) and quality (e.g., type of immune response generated, including the pattern of cytokine production) of the response initiated by the T cell receptor (TCR) upon antigen recognition are regulated by the balance between costimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are important for preventing autoimmunity (i.e., maintaining self-tolerance) when the immune system is responding to pathogen infection and for protecting against tissue damage. The expression of immune checkpoint proteins can be dysregulated by tumors, serving as an important immune resistance mechanism.

[0135] T cells have focused much of their efforts on therapeutically manipulating endogenous antitumor immunity due to their i) ability to selectively recognize peptides derived from proteins in all cellular compartments, ii) ability to directly recognize and kill antigen-expressing cells (by CD8+ effector T cells; also known as cytotoxic T lymphocytes (CTLs)), and iii) ability to orchestrate diverse immune responses exerted by CD4+ helper T cells that integrate adaptive and innate effector mechanisms.

[0136] In clinical settings, blockade of immune checkpoints leading to the amplification of antigen-specific T cell responses has shown promise in the treatment of human cancers.

[0137] T cell-mediated immunity involves multiple sequential steps, each of which involves counteracting and modulating stimulatory and inhibitory signals to optimize the response. Nearly all inhibitory signals in an immune response ultimately regulate intracellular signaling pathways, many of which are initiated through membrane receptors, and their ligands are either membrane-bound or soluble (cytokine) in nature. Costimulatory and inhibitory receptors and ligands that regulate T cell activation are less frequently overexpressed in cancer compared with normal tissues, whereas inhibitory ligands and receptors that regulate T cell effector function in tissues are commonly overexpressed in tumor cells or in non-transformed cells associated with the tumor microenvironment. The function of soluble and membrane-bound receptor-ligand immune checkpoints can be modulated, for example, using agonistic antibodies (for costimulatory pathways) or antagonistic antibodies (for inhibitory pathways). Thus, in contrast to most antibodies currently approved for cancer therapy, immune checkpoint-blocking antibodies do not target tumor cells directly, but rather target lymphocyte receptors or their ligands to enhance intrinsic antitumor activity [see Pardoll, (April 2012) Nature Rev. Cancer 12:252-64].

[0138] Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of tumor cells, making them 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 immunoreceptor with Ig and ITIM domains), and killer inhibitory receptors, which can be divided into two classes based on structural features: i) killer cell immunoglobulin-like receptors (KIRs) and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints have been described in the literature, including both receptors (e.g., the 2B4 (also known as 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] The present disclosure contemplates the use of the AXL inhibitors described herein in combination with inhibitors of the immune checkpoint receptors and ligands described above, as well as immune checkpoint receptors and ligands yet to be described. Certain modulators of immune checkpoints are currently approved, and many others are in development. In 2011, the fully humanized CTLA-4 monoclonal antibody ipilimumab (YERVOY®, Bristol-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 antibodies (CTLA4-Ig, abatacept (ORENCIA®, Bristol-Myers Squibb)) have been used to treat rheumatoid arthritis, and other fusion proteins have shown efficacy in kidney transplant patients sensitized to Epstein-Barr virus. The next class of immune checkpoint inhibitors to receive regulatory approval were directed against PD-1 and its ligands, PD-L1 and PD-L2. Approved anti-PD-1 antibodies include nivolumab (OPDIVO®, Bristol-Myers Squibb) and pembrolizumab (KEYTRUDA®, Merck), which are used for a variety of cancers, including 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 for certain cancers, including urothelial carcinoma. Another approach to 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.Therapies targeting TIGIT or its ligands CD155 and CD112 are not approved but are in development, including BMS-986207 (Bristoll-Myers Squibb), tiragolumab (Roche / Genentech), OMP-31M32 (OncoMed), etigilimab, osipellimab, vibostolimab, AB308, and AB154 (domvanalimab).

[0140] In one or more embodiments, one or more of the additional therapeutic agents is a cancer immunotherapy (e.g., an immune checkpoint inhibitor). In some embodiments, the cancer immunotherapy 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), balstilimab, budigalimab, camrelizumab, cemiplimab, dostallimab, emiprimab, ezabenlimab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilumab, tislelizumab, toripalimab, or zimberelimab. Another potential cancer immunotherapy drug is pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned.

[0141] In some embodiments, the cancer immunotherapeutic agent targets PD-L1 and is a PD-L1 antagonist, e.g., an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ® (atezolizumab, MPDL3280A, WO2010 / 077634), IMFINZI® (durvalumab, MEDI4736), BMS-936559 (WO2007 / 005874), cosibelimab, embafolimab, and avelumab (MSB0010718C, WO2013 / 79174).

[0142] In some combinations provided herein, a compound according to the disclosure is combined with one or more immune checkpoint inhibitors selected from MEDI-0608, nivolumab, pidilizumab, pembrolizumab, avelumab, atezolizumab, durvalumab, cemiplimab, sintilimab, tislelizumab, AB308, domvanalimab, and zimberelimab.

[0143] In certain embodiments of the present disclosure, the claimed AXL inhibitors are combined with cancer immunotherapeutics that are (i) agonists of stimulatory (including costimulatory) receptors or (ii) antagonists of inhibitory (including coinhibitory) signals in T cells, both of which amplify antigen-specific T cell responses. Certain stimulatory 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 costimulatory or costimulatory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRILR1 / DR4, TR ...2 / DR5, TRILR3 / DR4, TRILR4 / DR5, TRILR5 / DR5, TRILR6 / DR5, TRILR7 / DR5, TRILR8 / DR5, TRILR9 / DR5, TRILR10 / DR4, TRILR11 / DR4, TRILR12 / DR5, TRILR13 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 aspect, the cancer immunotherapeutic is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-B, VEGF, and other immunosuppressive cytokines) or that stimulates T cell activation to stimulate an immune response.

[0145] In certain aspects, T cell responses can be stimulated by combining a disclosed AXL inhibitor with one or more of (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 the present disclosure for cancer treatment include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds herein can be combined with KIR antagonists, such as lirilumab.

[0146] Still other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, such as, but not limited to, 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).

[0147] In another aspect, the disclosed AXL inhibitors can be used in conjunction with one or more agonist agents that bind positive costimulatory receptors, blocking agents that attenuate signaling via inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that ablate distinct immunosuppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), agents that deplete or inhibit Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or ex vivo anti-CD25 bead depletion), or agents that reverse / prevent T cell anergy or complete exhaustion), and agents that cause innate immune activation and / or inflammation at the tumor site.

[0148] In some embodiments, the cancer immunotherapeutic is a CTLA-4 antagonist, e.g., an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY® (ipilimumab) or tremelimumab.

[0149] In another embodiment, the cancer immunotherapeutic is a PD-1 antagonist as described elsewhere herein.

[0150] In another embodiment, the cancer immunotherapeutic is a PD-L1 antagonist as described elsewhere herein.

[0151] In another embodiment, the cancer immunotherapeutic is a TIGIT antagonist as described elsewhere herein.

[0152] In another embodiment, the cancer immunotherapeutic agent is a LAG-3 antagonist, e.g., 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 immunotherapeutic is a CD137 (4-1BB) agonist, e.g., an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (W012 / 32433).

[0154] In another embodiment, the cancer immunotherapeutic is a GITR agonist, e.g., an agonistic GITR antibody. 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 immunotherapeutic is an OX40 agonist, e.g., an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0156] In another embodiment, the cancer immunotherapeutic is an OX40L antagonist, e.g., an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0157] In another aspect, the cancer immunotherapeutic agent is a CD40 agonist, e.g., an agonistic CD40 antibody. In yet another embodiment, the cancer immunotherapeutic agent is a CD40 antagonist, e.g., an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0158] In another embodiment, the cancer immunotherapeutic is a CD27 agonist, e.g., an agonistic CD27 antibody. A suitable CD27 antibody is, for example, varlilumab.

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

[0160] Examples of therapeutic agents useful in combination therapy for the treatment of cardiovascular and / or metabolic related diseases, disorders and conditions include statins, which inhibit the enzymatic synthesis of cholesterol (e.g., CRESTOR®, LESCOL®, LIPITOR®, MEVACOR®, PRAVACOL®, and ZOCOR®), bile acid resins, which sequester cholesterol and prevent its absorption (e.g., COLESTID, LO-CHOLEST, PREVALITE®, QUESTRAN®, and WELCHOL®), cholesterol-lowering agents, and steroids (e.g., ACE inhibitors ... These include ezetimibe (ZETIA®), which blocks cholesterol absorption; fibric acids (e.g., TRICOR®), which reduce triglycerides and may modestly increase HDL; niacin (e.g., NIACOR®), which modestly reduce LDL cholesterol and triglycerides; and / or combinations of the above (e.g., VYTORIN (simvastatin and ezetimibe)). Alternative cholesterol treatments that may be candidates for use in combination with the AXL inhibitors described herein include various adjuvants and herbs (e.g., garlic, policosanol, and guggul).

[0161] Examples of therapeutic agents useful in combination therapy for the treatment of immune and inflammation-related diseases, disorders, or conditions include nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and other propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fluprofen, fluprofen, fluprofenic acid, and tioxaprofen), These include, but are not limited to, flufenamic acid, meclofenamic acid, fentiazac, filofenac, ibufenac, isoxepak, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac, fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isooxicam, piroxicam, sudoxicam, and tenoxicam), salicylates (acetylsalicylic acid, sulfasalazine), and pyrazolones (apazone, bezupiperylone, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone). Others use cyclooxygenase-2 (COX-2) inhibitors in combination.

[0162] Other active agents used in combination include steroids such as prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone, or hydrocortisone. Such combinations can be particularly advantageous because they can reduce or eliminate one or more of the adverse effects of steroids by gradually reducing the required dose of steroids.

[0163] Further examples of active agents that may be used in combination, for example in the treatment of rheumatoid arthritis, include cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies or antagonists to 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] Specific combinations of active agents can interfere at various points in the autoimmune and subsequent inflammatory cascade, including TNF antagonists, such as 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 receptors (sIL-13), and TNFα-converting enzyme (TACE) inhibitors; IL-1 inhibitors (e.g., interleukin-1 converting enzyme inhibitors) may also be effective. Another combination is interleukin-11, anti-P7, and P-selectin glycoprotein ligand (PSGL). Other examples of agents useful in combination with the AXL inhibitors described herein include interferon-131a (AVONEX®), interferon-131b (BETASERON®); copaxone; hyperbaric oxygen; intravenous immunoglobulin; clavulivin; and antibodies to or antagonists of other human cytokines or growth factors (e.g., antibodies to CD40 ligand and CD80).

[0165] In one or more embodiments, a combination of an AXL inhibitor according to the present disclosure with a DNA methyltransferase (DNMT) inhibitor or hypomethylating agent is also contemplated. Exemplary DNMT inhibitors include decitabine, zebularine, and azacitadine.

[0166] In one or more embodiments, a combination of an AXL inhibitor according to the present disclosure with a histone deacetylase (HDAC) inhibitor is also contemplated. Exemplary HDAC inhibitors include vorinostat, divinostat, abexinostat, panobinostat, belinostat, and trichostatin A.

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

[0168] In some embodiments, the present disclosure also contemplates a combination of an AXL inhibitor with an isocitrate dehydrogenase (IDH) inhibitor, such as IDH-1 or IDH-2. An exemplary IDH-1 inhibitor is ivosidenib. An exemplary IDH-2 inhibitor is enasidenib.

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

[0170] The choice of additional therapeutic agent(s) may be informed by the current standard of care for the particular 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 the present disclosure may be administered to a subject in an amount determined, for example, by the goal of administration (e.g., desired degree of achievement), the age, weight, sex, and health and physical condition of the subject to whom the formulation is administered, the route of administration, and the nature of the disease, disorder, condition, or symptom. The dosing regimen may also take into account the presence, nature, and extent of any adverse effects associated with the administered agent(s) and previous or concomitant therapy. Effective dosages and administration regimens can be readily determined, for example, from safety and dose escalation studies, in vivo studies (e.g., animal models).

[0172] Generally, dosage parameters indicate that the dosage is below the amount that is irreversibly toxic to the subject (maximum tolerated dose (MTD)) and at least the amount necessary to have a measurable effect on the subject, determined, for example, by ADME-related pharmacokinetic and pharmacodynamic parameters, taking into account the route of administration and other factors.

[0173] Generally, the disclosed methods involve administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a composition thereof, to a subject in need thereof. An "effective amount," with respect to AXL inhibitors of the present disclosure, refers to an amount of compound sufficient to engage a target (by inhibiting, agonizing, or antagonizing the target) at a level indicative of the compound's efficacy. In the case of AXL, target engagement can be determined by one or more biochemical or cellular assays that yield an EC50, ED50, EC90, IC50, or similar value that can be used as an assessment of a compound's efficacy. Assays for determining target engagement include, but are not limited to, those described in the Examples. An effective amount can be administered as a single amount or in multiple smaller amounts (e.g., one tablet of "x" amount, two tablets each of "x / 2" amount, etc.).

[0174] In certain embodiments, AXL inhibitors contemplated by the present disclosure can be administered at a dosage level of about 0.01 mg / kg to about 50 mg / kg, or about 1 mg / kg to about 25 mg / kg of subject body weight / day, one or more times per day (e.g., orally, parenterally) to achieve the desired therapeutic effect.

[0175] For oral administration, the compositions can be provided in the form of tablets, capsules, etc., containing 1 to 1000 mg of the active ingredient (i.e., 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 of a compound of formula (I) in particular).

[0176] In certain embodiments, the desired dose of AXL inhibitor is contained in a "unit dosage form." The phrase "unit dosage form" refers to physically discrete units, each containing a predetermined amount of an AXL inhibitor, alone or in combination with one or more additional active agents, sufficient to provide a desired effect. It is understood that the parameters of the unit dosage form depend on the particular active agent and the effect to be achieved. For intravenous administration, a unit dosage form may contain 1 to 1000 milligrams of active ingredient (i.e., a compound of formula (I), particularly 1, 10, 25, 50, 100, 200, 300, or 500 milligrams).

[0177] kit The present disclosure also contemplates kits comprising the compounds described herein, and pharmaceutical compositions thereof. Generally, the kits are in the form of physical structures housing various components, as described below, and can be used, for example, in practicing the methods described above.

[0178] The kits can include one or more compounds disclosed herein (e.g., in a sterile container) and can be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein can be provided in a ready-to-use form (e.g., a tablet or capsule) or in a form that requires reconstitution or dilution, for example, before administration (e.g., a powder). If the compounds described herein are in a form that requires reconstitution or dilution by the user, the kit can also include a diluent (e.g., sterile water), buffer, pharmaceutically acceptable excipient, etc., packaged together with or separately from the compounds described herein. When combination therapy is contemplated, the kit can contain several agents separately or prepackaged in the kit. Each component of the kit can be enclosed in a separate container, or all of these containers can be contained in a single container. The kits of the present disclosure can be designed for conditions (e.g., refrigeration or freezing) necessary to properly maintain the components contained in the kit.

[0179] The kit may include a label or package insert that describes the identity of the components contained therein and instructions for their use (e.g., dosing parameters of the active ingredient(s), clinical pharmacology, e.g., mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or package insert may include manufacturer information, such as a lot number or expiration date. The label or package insert may, for example, be integral to the physical structure that contains the component, may be contained separately within the physical structure, or may be affixed to a component of the kit (e.g., an ampoule, tube, or vial).

[0180] The label or package insert may further comprise or be incorporated into a computer readable medium. In some embodiments, the actual instructions are not included in the kit, but rather a means is provided for obtaining the instructions from a remote source, for example, via the internet.

[0181] experiment The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0182] Unless otherwise specified, temperatures are in degrees Celsius (°C) and pressures are at or near atmospheric. Standard abbreviations are used, including: rt or rt = room temperature, min = second(s), h or hr = hour(s), ng = nanogram, μg = microgram, mg = milligram, g = gram, kg = kilogram, μl or μL = microliter, ml or mL = milliliter, l or L = liter, μM = micromolar, mM = millimolar, M = molar, mol = mole, mmol = millimole, aq. = aqueous, calcd = calculated, DCM = dichloromethane, DCE = 1,2-dichloroethane, MTBE = methyl tert-butyl ether, THF = tetrahydrofuran, EtOAc = 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]pyridin-1-ylmethylene]-N-methylmethanaminium 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(pinacolato)diboron, 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 where indicated or may be used in the examples below.

[0184] 1H NMR spectra were recorded on a Varian 400 MHz NMR spectrometer equipped with an Oxford AS400 magnet. Chemical shifts (δ) are reported in parts per million (ppm) relative to residual undeuterated solvent, which is an internal reference. [Example]

[0185] Example 1: 3-(4-(cyclopropylsulfonyl)phenyl)-5-(7-methyl-7-((R)-2-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-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), camphorsulfonic acid (1.79 g, 7.72 mmol), and THF (193 mL) was added 3,4-dihydro-2H-pyran (14.1 mL, 154 mmol) at room temperature. The mixture was stirred at 65° C. for 3 hours, cooled to room temperature, and 28% by weight of NH 3(水溶液) The reaction was quenched with 10 mL of HCl. The mixture was concentrated onto silica gel and purified by column chromatography (hexane:EtOAc, 4:1) to give 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 h. The mixture was cooled to room temperature, concentrated, diluted with EtOAc (250 mL), filtered through Celite to remove solids, and concentrated again to give 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 49.3 mmol), (dppf)PdCl (3.61 g, 4.93 mmol), and KCO (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 h. The mixture was cooled to room temperature, concentrated, diluted with CHCl (250 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (330 g silica gel, CHCl:EtOAc) using a 0% to 50% gradient (25 min) to give the desired product as an off-white solid (20.7 g, 91%).

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

[0190] Step e: To a mixture of 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) in toluene (100 mL) was added 1H-1,2,3-triazole (1.5 mL, 25.3 mmol). The reaction mixture was stirred at reflux for 12 h while collecting water via a Dean-Stark trap. Upon cooling, the toluene solution was added over 30 min to a cooled (0 °C) mixture of MeMgBr solution (3 M in EtO, 42 mL, 127 mmol) and THF (84 mL). The reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature and stirred for 1 h. The reaction mixture was cooled back to 0 °C, and saturated aqueous NH4Cl was carefully added, followed by H2O. The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined organic layers were then washed with 2 N aqueous NaOH (2 × 30 mL) and brine, dried over anhydrous MgSO4, and concentrated. Purification by silica gel chromatography (100% CHCl2 to 10% MeOH in CHCl2, 1% NH4OH), followed by repeated precipitation with MeOH, afforded the desired product as a white powder (4.44 g, 65%; ca. 1:1 d.r.).

[0191] Step f: The desired product was prepared in a similar manner to Example 1, step c, except that the reaction mixture was stirred at 95° C. for 20 h and the crude material was purified by column chromatography (330 g silica gel, CHCl:(EtOAc+1% EtN)) with a gradient of 0% to 100% (20 min) to give the desired product as a pale yellow solid (12.7 g, 49%) in 100% (5 min).

[0192] Step g: A mixture of the product of step f (12.7 g, 20.3 mmol) and 3 M HCl in MeOH (101 mL) was stirred at room temperature for 23 h and diluted with MTBE (750 mL). The precipitated solid was collected by filtration and washed with MTBE. The crude material was purified by column chromatography (4 x 130 g C18, (HO / ACN) + 0.1% TFA) with a 5% to 50% gradient (25 min), and the combined fractions were purified with saturated NaHCO 3(水溶液) (50 mL). The ACN was removed under vacuum. The precipitated solid was collected by filtration, washed with water, and dried to give 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]annulen-7-yl)morpholine [ka]

[0194] The title compound was prepared in a similar manner to 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]pyridin-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidin-2-yl]methanol [ka]

[0196] The title compound was prepared in a similar manner to 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]pyridin-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidin-2-yl]methanol [ka]

[0198] The title compound was prepared in a similar manner to 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]pyridin-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-2-methylpyrrolidine [ka]

[0200] The title compound was prepared in a similar manner to 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]pyridin-5-yl}-7-ethyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-2-methylpyrrolidine [ka]

[0202] The title compound was prepared in a similar manner to 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]annulen-7-yl)azetidine [ka]

[0204] The title compound was prepared in a similar manner to 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]pyridin-5-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl}pyrrolidine [ka]

[0206] The title compound was prepared in a similar manner to 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; Found: 569.2.

[0207] Example 9: 2-(5-{5-[7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyridin-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) at 0° C., solid NaOt-Bu (14.6 g, 130 mmol) was added in three portions over approximately 20 min, and the mixture was then stirred for an additional 10 min. (2-(chloromethoxy)ethyl)trimethylsilane (23.0 mL, 130 mmol) was added over 30 min, and the reaction was then stirred for 15 h while warming to room temperature after the cooling bath had expired. The mixture was cooled to 0° C. and diluted with HO (500 mL). The precipitated solid was collected by filtration, washed with HO, and dried under vacuum to give the desired product as a pale yellow solid (51.2 g, 91%).

[0209] Step b: A mixture of the product from step a (5.5 g, 12.0 mmol), 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. To this mixture was added degassed dioxane (60 mL) and degassed HO (15 mL). The reaction mixture was heated at 80 °C for 14 h, cooled to room temperature, and EtOAc (100 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic phases were dried over Na2O4, concentrated, and purified by column chromatography (SiO2, 0-30% EtOAc in hexanes) to give the desired product as a brown solid (3.5 g, 64%).

[0210] Step c: To a mixture of the product of step b (577 mg, 1.08 mmol), B2pin2 (356 mg, 1.40 mmol), and KOAc (138 mg, 1.40 mmol), dioxane (5.4 mL) was added, and the suspension was then degassed with N2 for 10 min. (dppf)PdCl2 (40 mg, 0.0540 mmol) was added, and the reaction mixture was stirred at 80 °C for 15 h. Upon cooling, EtOAc (15 mL) was added, and the mixture was filtered through Celite. The filtrate was concentrated to give the crude product as a viscous brown oil.

[0211] Step d: To 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) in DCE (21.5 mL) was added AcOH (0.25 mL, 4.31 mmol), followed by NaBH(OAc) (1.19 g, 5.60 mmol). The reaction was stirred at room temperature for 16 h and then carefully quenched with HO followed by saturated aqueous NaHCO. The layers were separated, and the aqueous layer was extracted with CHCl (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel chromatography (100% CH2Cl2 to 10% MeOH in CH2Cl2, 0.5% NEt3) to give the desired product as a viscous orange oil (978 mg, 77%).

[0212] Step e: 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), dioxane (3.3 mL) and HO (0.40 mL) were added, and the suspension was then degassed with N2 for 10 min. (dppf)PdCl2 (13 mg, 0.0184.80 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. Upon cooling, CHCl2 (15 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (100% CHCl2 to 10% MeOH in CHCl2) to give the desired product as a brown solid (152 mg, 62% from the product from step b).

[0213] Step f: To a solution of the product of step e (152 mg, 0.227 mmol) in CHCl (1.2 mL) was added TFA (1.2 mL). The reaction was stirred at room temperature for 2 h and then concentrated. To the residue was added NH in MeOH (7N solution, 2.3 mL), and the reaction mixture was stirred at 40 °C for 2 h. Upon cooling, H2O (10 mL) was added, and the precipitated solid was collected by filtration and washed with H2O. Purification by C18 reverse-phase chromatography (100% H2O to 60% ACN in H2O, 0.1% TFA) and lyophilization afforded the title 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-benzazepin-7-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyridin-2-yl}propan-2-ol [ka]

[0215] Step a: To a mixture of 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (272 mg, 1.04 mmol) and cyclopentanone (0.11 mL, 1.29 mmol) in DCE (5.2 mL) was added AcOH (60 μL, 1.04 mmol), followed by NaBH(OAc) (331 mg, 1.56 mmol). The reaction was stirred at room temperature for 17 h and then carefully quenched with saturated aqueous NaHCO. The layers were separated, and the aqueous layer was extracted with CHCl (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, and concentrated to give the desired product as a colorless oil (293 mg, 96%).

[0216] Step b: 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), dioxane (3.8 mL) and HO (0.40 mL) were added, and the suspension was then degassed with N2 for 10 min. (dppf)PdCl2 (14 mg, 0.0192 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. Upon cooling, CHCl2 (15 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (100% CHCl2 to 10% MeOH in CHCl2) to give the desired product as a brown solid (237 mg, 92; 2 steps).

[0217] Step c: To a solution of the product of step b (237 mg, 0.354 mmol) in CHCl (1.8 mL) was added TFA (1.8 mL). The reaction was stirred at room temperature for 2 h and then concentrated. To the residue was added NH in MeOH (7N solution, 3.5 mL), and the reaction mixture was stirred at 40 °C for 2 h. Upon cooling, H2O (10 mL) was added, and the precipitated solid was collected by filtration and washed with H2O. Purification by C18 reverse-phase chromatography (100% H2O to 60% ACN in H2O, 0.1% TFA) and lyophilization afforded the title compound as a pale yellow solid (95 mg, 46%). 1 H 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-(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 [ka]

[0219] Step a: A solution of the product from Example 9, Step a (1.47 g, 3.24 mmol), 1-[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-one (1.00 g, 3.56 mmol), and sodium carbonate (0.687 g, 6.48 mmol) in 9:1 dioxane:HO (32 mL) was sparged with nitrogen for 10 minutes. (dppf)PdCl (0.474 g, 0.648 mmol) was added, and sparging continued for an additional 5 minutes. The mixture was stirred at 100 °C overnight and then cooled to room temperature. CHCl (70 mL) was added, and the solution was dried over MgSO, concentrated, and purified by flash chromatography (SiO, 0–50% EtOAc in hexanes) to give the product as a white solid (0.630 g; 40%).

[0220] Step b: A solution of the product of step a (0.618 g, 1.28 mmol) in THF (2.8 mL) was added via syringe pump over 40 minutes to a solution of methylmagnesium bromide (0.73 mL, 2.18 mmol, 3.0 M in EtO) in THF (1.4 mL) at room temperature. After the addition was complete, the mixture was stirred for an additional hour at room temperature. The mixture was then cooled to room temperature with ice / saturated NH4Cl. (水溶液) (25 mL). The product was extracted into EtOAc (3 x 25 mL), and the combined organic phases were washed with brine (50 mL) and dried (MgSO). The crude material was purified by flash chromatography (0-40% EtOAc in hexanes) to give the desired product as a white solid (0.542 g, 85%).

[0221] Step c: To a mixture of the product of Step d, Example 9 (978 mg, 3.32 mmol), B2pin2 (927 mg, 3.65 mmol), and KOAc (391 mg, 3.98 mmol), dioxane (16.6 mL) was added, and the suspension was then degassed with N2 for 10 min. (dppf)PdCl2 (121 mg, 0.166 mmol) was added, and the reaction mixture was stirred at 90 °C for 4 h. Upon cooling, EtOAc (20 mL) was added, and the mixture was filtered through Celite. The filtrate was concentrated to give the crude product as a viscous brown oil, which was used directly in the next step.

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

[0223] Step e: A solution of the product of step d (72.3 mg, 0.115 mmol) and tetrabutylammonium fluoride hydrate (180 mg, 0.687 mmol) in DMF (0.15 mL) was stirred under high vacuum at room temperature overnight. 3(水溶液) (5 mL) and the product was extracted into 9:1 CHCl3:IPA (3 x 5 mL). The combined organic phases were dried (Na2SO4) and concentrated. The residue was taken up in MeOH (1.15 mL) and treated with DMEDA (0.10 mL, 0.92 mmol). The mixture was stirred at 45 °C for 30 min and then concentrated. The residue was purified by flash chromatography (1-10% MeOH / NH 3(水溶液) Purification twice with 10:1 CH2Cl2 gave the title 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 for ClNO: 501.2; Found: 501.2.

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

[0225] The title compound was prepared in a similar manner to 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 for ClNO: 501.2; Found: 501.2.

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

[0227] The title compound was prepared in a similar manner to 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-benzazepin-7-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-2-(trifluoromethoxy)phenyl}propan-2-ol [ka]

[0229] The title compound was prepared in a manner similar to that of 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; Found value: 551.2.

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

[0231] The title compound was prepared in a similar manner to 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 for ClFNO: 519.2; Found: 519.2.

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

[0233] The title compound was prepared in a manner similar to that of 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-benzazepin-7-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-3-fluorophenyl}propan-2-ol [ka]

[0235] The title compound was prepared in a similar manner to 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-benzazepin-7-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]phenyl}propan-2-ol [ka]

[0237] The title compound was prepared in a similar manner to 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-benzazepin-7-yl)-3-(4-methanesulfonylphenyl)-1H-pyrazolo[3,4-b]pyridin-6-amine [ka]

[0239] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(trifluoromethyl)phenyl]propan-2-ol [ka]

[0241] The title compound was prepared in a similar manner to 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)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 [ka]

[0243] The title compound was prepared in a similar manner to 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 for ClN4O2: 531.3; Found: 531.2.

[0244] Example 22: 2-[5-(5-{7-methyl-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)pyridin-2-yl]propan-2-ol [ka]

[0245] The title compound was prepared in a manner similar to that of 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}piperidine [ka]

[0247] Step a: To a solution of 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) in dioxane (30 mL) was added HCl solution (4 M in EtO, 102 mL). The reaction mixture was stirred at room temperature for 3 h, then slowly diluted with hexane and stirred for 30 min. The precipitated white solid (6.95 g, 33.2 mmol) was collected by filtration and dissolved in CHCl (130 mL), and the solution was cooled to 0 °C. NEt (11.5 mL, 83.0 mmol) was added, followed by methanesulfonyl chloride (2.8 mL, 36.5 mmol), and the reaction was stirred for 16 h, warming to room temperature after the cooling bath had expired. The reaction mixture was cooled to 0 °C and then carefully quenched with saturated aqueous NaHCO. The layers were separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to give the desired product as an off-white solid (7.95 g, 54%).

[0248] Step b: To a mixture of the product from Step a of Example 9 (1.01 g, 2.22 mmol), the product from Step a (702 mg, 2.45 mmol), and NaCO (471 mg, 4.44 mmol), dioxane (9.9 mL) and HO (1.2 mL) were added, and the suspension was degassed with N for 10 minutes. (dppf)PdCl (81 mg, 0.111 mmol) was added, and the reaction mixture was stirred at 80 °C for 21 hours. Upon cooling, CHCl (30 mL) was added, and the mixture was dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography (100% hexane to 50% EtOAc in hexane) to give the desired product as a light brown solid (754 mg, 70%).

[0249] Step c: 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), dioxane (7.0 mL) and HO (0.80 mL) were added, and the suspension was degassed with N2 for 10 min. (dppf)PdCl2 (14 mg, 0.0196 mmol) was added, and the reaction mixture was stirred at 80 °C for 14 h. Upon cooling, CHCl2 (15 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (100% CHCl2 to 10% MeOH in CHCl2, 0.5% NEt3) to give the desired product as a brown solid (134 mg, 55%).

[0250] Step d: A solution of the product from step c (134 mg, 0.215 mmol) in MeOH (4.3 mL) was degassed with N for 5 minutes, then NEt (1 drop) was added, followed by Pd / C (10% anhydrous, 46 mg, 0.0215 mmol). H was bubbled through the solution for 5 minutes, then the reaction was stirred at room temperature for 14 hours using a H balloon. The reaction was filtered through Celite, washed with MeOH, and concentrated. The residue was resubmitted to the same conditions and stirred for 22 hours, then filtered through Celite and concentrated. To a solution of the residue in CHCl (2.1 mL) was added TFA (2.1 mL). The reaction was stirred at room temperature for 3 hours and then concentrated. To the residue was added NH in MeOH (7N solution, 4.3 mL), and the reaction mixture was stirred at 40° C. for 2 hours. Upon cooling, the reaction mixture was concentrated. HO (10 mL) was added and the precipitated solid was collected by filtration and washed with HO. Purification by C18 reverse-phase chromatography (100% HO to 100% ACN, 0.1% TFA), followed by reverse-phase HPLC (10 to 90% ACN in HO, 0.1% TFA), and lyophilization afforded the title 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-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-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) was added NaBH(OAc) (320 mg, 1.5 mmol) at room temperature. The mixture was stirred at room temperature for 14 h. Brine (10 mL) and CHCl (20 mL) were added. The phases were separated, and the aqueous phase was extracted with CHCl (2 × 20 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (SiO2, 0–100% CH2Cl2 / MeOH / 7N methanolic NH3 (90:10:1) in CH2Cl2 to give the desired product 6 as a light brown oil (126 mg, 32%).

[0253] Step b: The title compound was prepared in a similar manner to Example 11, step c.

[0254] Step c: A mixture of the crude material from Example 1, Step b, the product of Example 9, 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 was added degassed dioxane (12 mL) and HO (3 mL) and heated at 80 °C for 14 h. After cooling to room temperature, EtOAc (50 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (SiO2, 0–100% EtOAc in hexanes) to give the desired product as a light brown solid (546 mg, 57%).

[0255] Step d: A mixture of the crude material from step b, the product of 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. To this mixture was added degassed dioxane (2 mL) and HO (0.5 mL) and heated at 100 °C for 14 h. After cooling to room temperature, EtOAc (20 mL) and brine (5 mL) were added. The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phase was dried over Na2SO4, concentrated, and purified by column chromatography (SiO2, 0–100% CHCl2 / MeOH / 7N methanolic NH3 (90:10:1) in CHCl2 to give the desired product as a brown solid (107 mg, 65%).

[0256] Step e: To a solution of the product of step d (107 mg, 0.2 mmol) in CHCl (1.5 mL) was added TFA (1.5 mL). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed, and the crude material was resuspended in MeOH (1.5 mL). DMEDA (0.5 mL) was added to the mixture, which was stirred at 60 °C for 1 h. Upon cooling to room temperature, the solvent was removed, and the crude material was purified by reverse-phase HPLC using HO + 0.1% TFA and ACN + 0.1% TFA as mobile phases to give the desired product as 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]pyridin-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-2-methylpyrrolidine [ka]

[0258] The title compound was prepared in a similar manner to 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 title compound was prepared in a similar manner to 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 title compound was prepared in a similar manner to 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-tetrahydroisoquinolin-6-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)propan-2-ol [ka]

[0264] The title compound was prepared in a similar manner to 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 for ClNO: 487.2; Found: 487.2.

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

[0266] The title compound was prepared in a similar manner to 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 for ClNO: 487.2; Found: 487.2.

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

[0268] The title compound was prepared in a similar manner to 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 title compound was prepared in a similar manner to 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 for ClN4O2S: 521.2; Found: 521.2.

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

[0272] The title compound was prepared in a similar manner to 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]azepin-7-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)-2-methylpropanenitrile [ka]

[0274] The title compound was prepared in a similar manner to 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]azepin-7-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)propan-2-ol [ka]

[0276] The title compound was prepared in a similar manner to 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 for ClN4O2: 491.2; Found: 491.2.

[0277] Example 35: 2-(2-chloro-4-(5-(7-((R)-2-methylpyrrolidin-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 [ka]

[0278] The title compound was prepared in a similar manner to 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 for ClNO: 515.3; Found: 515.3.

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

[0280] The title compound was prepared in a similar manner to 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-methylpyrrolidin-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 [ka]

[0282] The title compound was prepared in a similar manner to 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 for ClNO: 515.2; Found: 515.2.

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

[0284] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0286] The title compound was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0288] The title compound was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0290] The title compound was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0292] The title compound was prepared in a similar manner to 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, 7.5Hz, 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-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0294] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0296] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0298] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0300] The title compound was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}benzoyl)piperazine [ka]

[0302] Step a: To a solution of 4-carboxy-3-methylphenylboronic acid (514 mg, 2.86 mmol) in CHCl (11.4 mL) was added 1-(tert-butoxycarbonyl)piperazine (585 mg, 3.14 mmol) and NEt (1.2 mL, 8.58 mmol), followed by HATU (1.30 g, 3.43 mmol). The reaction mixture was stirred at room temperature for 16 h, and then HO (10 mL) was added. The mixture was extracted with CHCl (3 × 10 mL), and the combined organic layers were washed with brine, dried over anhydrous MgSO, and concentrated. The crude material was dissolved in CHCl, washed with saturated aqueous NHCl, dried over anhydrous MgSO, concentrated, and purified by silica gel chromatography (100% hexanes to 100% EtOAc) to give an off-white solid as the crude product.

[0303] Step b: A mixture of the product from Step a of Example 1 (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. To this mixture was added degassed dioxane (4 mL) and HO (1 mL) and heated at 80 °C for 45 min. After cooling to room temperature, brine (2 mL) and EtOAc (20 mL) were added. The phases were separated, and the organic phase was dried over Na2SO4, concentrated, and purified by column chromatography (SiO2, 0–70% EtOAc in hexanes) to give 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), the product from step c of Example 11 (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. To this mixture was added degassed dioxane (2 mL) and degassed HO (0.5 mL) and heated at 100 °C for 8 h. After cooling to room temperature, EtOAc (10 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (SiO2, 0–100% CHCl2 / MeOH / 7N methanolic NH3 (90:10:1)) in CHCl2 to give the desired product as a light brown solid (117 mg, 58%).

[0305] Step d: To the product of step c (117 mg, 0.2 mmol) was added 3 M methanolic HCl (2.0 mL). The reaction mixture was stirred at room temperature for 8 h. The solvent was removed, and the crude material was triturated with CHCl (10 mL) to give 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]pyridin-5-yl}-2,3,4,5-tetrahydro-1H-3-benzazepin-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) was added isobutyryl chloride (239 μL, 2.4 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. To the reaction mixture were added HO (5 mL) and EtOAc (20 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were dried over NaSO, concentrated, and purified by column chromatography (SiO, 0–100% EtOAc in hexane) to give the desired product as a colorless solid (590 mg, quantitative).

[0308] Step b: The desired compound was prepared in a similar manner to Example 11, step c.

[0309] Step c: In a similar manner to Example 47, step c, the desired product was prepared (120 mg, 59%).

[0310] Step d: The desired product was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}benzamide [ka]

[0312] Step a: To a mixture of 4-bromo-2,6-dimethylbenzoic acid (3.44 g, 15 mmol), CHCl (32 mL), and DMF (2 drops) was added (COCl) (1.4 mL, 16.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 14 h. The solvent was removed, and the residue was resuspended in dry THF. After the mixture was cooled to 0 °C, (5 mL) was added and stirred at room temperature for 1 h. To the reaction mixture were added brine (20 mL) and EtOAc (100 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phases were dried over NaSO and concentrated to give the desired product as a tan solid (3.4 g, quantitative).

[0313] Step b: The desired compound was prepared in a similar manner to Example 11, step c.

[0314] Step c: In a similar manner to Example 47, step b, the desired compound was prepared (1.0 g, 47%).

[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), tBuNO (1.3 mL, 11 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. CuBr (2.9 g, 20 mmol) dissolved in AcOH (20 mL) was added dropwise to the reaction mixture, which was stirred at room temperature for 3 hours. HO (100 mL) was added to dilute the reaction mixture, followed by careful addition of 28% by weight of NH 3(水溶液) The pH was adjusted to approximately 10-11 by the addition of HCl. The crude product was then extracted with CHCl (2 × 100). The combined organic phases were dried over NaSO, concentrated, and purified by column chromatography (SiO, 0-100% CHCl / MeOH / 7N methanolic NH (90:10:1) in CHCl to give the desired product as a light brown oil (2.2 g, 75%).

[0316] Step e: The desired compound was prepared in a similar manner to Example 11, step c.

[0317] Step f: In a similar manner to Example 47, step c, the desired compound was prepared (84 mg, 50%).

[0318] Step g: In a similar manner to Example 47, step d, the desired product was prepared (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 value for N5O: 480.3; Measured value: 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 [ka]

[0320] The title compound was prepared in a similar manner to Example 49. 1H 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 ClNO: 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 [ka]

[0322] The title compound was prepared in a similar manner to 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 for ClNO: 501.2; Found: 501.2.

[0323] Example 52: 2-fluoro-4-(5-(7-methyl-7-((R)-2-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0324] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0326] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0328] The title compound was prepared in a similar manner to Example 49. 1 H 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}benzoyl)piperazine [ka]

[0330] Steps ag: The title compound was prepared in a similar manner to Example 49 (60 mg, 72%). 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}benzoyl)piperazine [ka]

[0332] The title compound was prepared in a similar manner to 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 for ClNO: 569.3; Found: 569.3.

[0333] Example 57: 2-[2-chloro-4-(5-{7-methyl-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]propan-2-ol [ka]

[0334] Step a: To a mixture of the product of Example 1, Step e (310 mg, 0.962 mmol), B2pin2 (244 mg, 0.962 mmol), and KOAc (104 mg, 1.06 mmol) was added dioxane (4.8 mL), 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. Upon cooling, EtOAc (20 mL) was added, and the mixture was filtered through Celite. The filtrate was concentrated to give the crude product as a viscous brown oil.

[0335] Step b: To a mixture of the product of Step b of Example 11 (228 mg, 0.459 mmol), the crude product of Step a (0.562 mmol), and Na2CO3 (97 mg, 0.918 mmol), dioxane (4.1 mL) and HO (0.50 mL) were added, and the suspension was then degassed with N2 for 10 minutes. (dppf)PdCl2 (17 mg, 0.0230 mmol) was added, and the reaction mixture was stirred at 90 °C for 14 hours. Upon cooling, CHCl2 (15 mL) was added, and the mixture was then dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (100% CHCl to 10% MeOH in CHCl, 0.5% NEt, then 100% CHCl to 5% MeOH in CHCl, 0.5% NEt) to give the impure intermediate as a brown solid (373 mg). To a solution of the residue in THF (4.6 mL) was added a TBAF solution (1 M in THF, 4.6 mL, 4.59 mmol), and the reaction mixture was stirred at 70 °C for 14 h. Upon cooling, the reaction was concentrated, then dissolved in EtOAc and washed with H2O. The aqueous layer was extracted with 10% MeOH in CHCl (2 × 20 mL), and the combined organic layers were concentrated. To the residue was added MeOH (4.6 mL), followed by DMEDA (0.37 mL, 3.44 mmol), and the mixture was stirred at 45 °C for 1 h. Once cooled, the reaction was concentrated and then purified by silica gel chromatography (100% CH2Cl2 to 10% MeOH in CH2Cl2, 1% NEt3, and 100% EtOAc to 5% MeOH in EtOAc, 1% NH3) to give the title 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 for ClNO: 529.3; Found: 529.2.

[0336] Example 58: 2-[2-chloro-4-(5-{7-methyl-7-[(2S)-2-methylpyrrolidin-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 [ka]

[0337] The title compound was prepared in a similar manner to 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 for ClNO: 529.3; Found: 529.2.

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

[0339] Step a: LiBH4 (10.9 mL, 21.8 mmol, 2.0 M solution in THF) is added dropwise to a solution of 3,4-diethyl 6-chloropyridine-3,4-dicarboxylate (2.00 g, 7.76 mmol) in 38:1 THF:MeOH (27.5 mL) at 0 °C. The cold water bath is removed and the mixture is stirred at room temperature for 2.5 h. This mixture is added to saturated NaHCO 3(水溶液)(75 mL) and the product was extracted into EtOAc (5 x 75 mL). The combined organic phases were dried (Na2SO4) and concentrated and the crude product was carried on to the next step.

[0340] Step b: Phosphorus tribromide (0.87 mL, 9.28 mmol) was added dropwise to a suspension of the crude product of step a (7.76 mmol) in THF (35 mL) at 0° C. The cold water bath was removed and the mixture was stirred at room temperature for 5 h. The mixture was then cooled to 0° C. and NaHCO 3(水溶液) (120 mL). The layers were separated and additional product was extracted into CHCl (2×120 mL). The combined organic phases were dried (NaSO) and concentrated, and the crude material was purified by flash chromatography (0–100% EtOAc in hexanes) to give the desired product as a white solid (0.491 g, 21%).

[0341] Step c: A mixture of the product from step b (0.991 g, 3.31 mmol), 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), CHCl (6.6 mL), and HO (16.5 mL) was heated at 40 °C overnight. The CHCl was removed in vacuo, and the residue was dissolved in EtOAc (16 mL). This solution was washed with 9:1 HO:brine (4 × 16 mL), dried (NaSO), concentrated, and the crude product was used in the next step.

[0342] Step d: The crude product from step c was diluted with 6 N HCl (水溶液) The resulting mixture was suspended in hexane and heated at 95°C for 2 hours. Upon cooling to room temperature, the mixture was made basic by the portionwise addition of solid NaOH. The product was extracted into EtOAc (3 x 50 mL), and the combined organic phases were washed with brine (50 mL), dried (NaSO), and concentrated. The crude material was purified by flash chromatography (0-100% EtOAc in hexanes) to give 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 the product of step d (74.9 mg, 0.383 mmol) and pyrrolidine (0.04 mL, 0.459 mmol) in DCE (1.9 mL), and the mixture was stirred at room temperature overnight. The reaction was cooled to room temperature with saturated NaHCO 3(水溶液) The reaction was quenched with (5 mL) and the product was extracted into CH2Cl2 (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), concentrated and the crude product was carried on to the next step.

[0344] Step f: The desired compound was prepared in a similar manner to Example 11, step c.

[0345] Step g: In a similar manner to Example 11, step a, the desired compound was prepared (135 mg, 57%).

[0346] Step h: The desired compound was prepared in a similar manner to 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 for ClNO: 502.2; Found: 502.2.

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

[0348] The title compound was prepared in a similar manner to 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 for ClNO: 502.2; Found: 502.2.

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

[0350] The title compound was prepared in a similar manner to 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 for ClNO: 527.3; Found: 527.2.

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

[0352] Step a: To a solution of 4-bromo-2-chloro-1-iodobenzene (10 g, 31.5 mmol) in tetrahydrofuran (30 mL) at −78° C. was added n-butyllithium (12.6 mL, 31.5 mmol, 2.5 M hexane) at a rate to maintain the internal temperature below −65° C. After 30 min, cyclobutanone (1.93 mL, 26.3 mmol) was added dropwise over 40 min, maintaining the internal temperature below −65° C. After an additional 60 min at −78° C., saturated NH4Cl (水溶液) (20 mL) was added, and the resulting mixture was extracted with EtOAc (2 × 60 mL). The combined organic phases were dried over NaSO and concentrated. The crude material was purified by column chromatography (120 g silica gel, hexane:EtOAc) with a gradient of 0% to 10% (30 min) to give the desired product as a white solid (4.81 g, 70%).

[0353] Step b: A mixture of the product of 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 h. The mixture was cooled to room temperature, concentrated, diluted with EtOAc (50 mL), filtered through Celite to remove solids, and concentrated again to give 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), camphorsulfonic acid (2.32 g, 10 mmol), and THF (250 mL) was added 3,4-dihydro-2H-pyran (18.3 mL, 200 mmol) at room temperature. The reaction mixture was stirred at 65° C. for 4 hours, cooled to room temperature, and 28% by weight of NH 3(水溶液)The reaction was quenched with (10 mL) and the mixture was concentrated onto silica gel and purified by column chromatography (330 g silica gel, hexane:ethyl EtOAc) with a gradient of 0% to 50% (20 min) to give 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 h. 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 give the desired product, which was used directly in the next step.

[0356] Step e: A mixture of the product of step c (21.2 g, 75 mmol), the product of step d (75.0 mmol, estimated), and (dppf)PdCl (5.49 g, 7.50 mmol) was placed under nitrogen and diluted with degassed dioxane (375 mL) and degassed 2 M NaCO 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 near dryness, dissolved in ethyl acetate (375 mL), and dried over NaSO and concentrated again. 3 M HCl in MeOH (400 mL) 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 give the desired product as a brown solid (19.4 g, 82%; 2 steps).

[0357] Step f: A mixture of the product of step e (19.4 g, 61.8 mmol), ethylene glycol (17.2 mL, 309 mmol) was stirred at 70 °C for 24 h to give a 28 wt% NH3(水溶液) The reaction was quenched with 20 mL of HCl and concentrated. EtOAc (500 mL) and water (250 mL) were added, and the solid was collected by filtration and washed with EtOAc / water. The organic phase was washed with water (2 x 250 mL), dried over NaSO, concentrated, and combined with the previously collected solid. The crude material was purified by column chromatography (330 g silica gel, CHCl:MeOH) using a 0% to 3% gradient (20 min); a 3% to 5% gradient (10 min) to give the desired product as an orange solid (14.8 g, 75%).

[0358] Step g: To a mixture of step f (14.8 g, 46.1 mmol) and 2:1 CHCl:AcOH (138 mL) was added NBS (8.62 g, 48.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 14 h, concentrated onto silica gel, and purified by column chromatography (330 g silica gel, CHCl:MeOH) with a 0% to 5% gradient (15 min); a 5% to 7.5% gradient (5 min) to give the desired product as a brown solid (21.4 g, 74.5 wt %; residual succinimide). 15.9 g (86% yield) of pure product was obtained.

[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), EtN (26.4 mL, 189 mmol), and CHCl (199 mL) at room temperature, di-tert-butyl dicarbonate (21.7 g, 99.4 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 1 h, concentrated onto silica gel, and purified by column chromatography (330 g silica gel, hexanes:EtOAc) with a 0% to 50% gradient (25 min) to give the desired product as a white solid (18.2 g, 77.4 wt%; residual N-Boc-succinimide). 14.1 g (71% yield) of pure product was obtained.

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

[0361] Step j: To a mixture of the product of step i (84 mg, 0.17 mmol) in THF (0.84 mL) was added 1 M HCl (水溶液) (0.34 mL) was added and the reaction mixture was stirred at 70° C. for 1 h. The mixture was cooled to room temperature and saturated NaHCO 3(水溶液) The mixture was neutralized with (2 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated to give 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 h. The mixture was diluted with EtOAc (15 mL) and diluted with water:2 M NaOH. (水溶液) The residue was washed with 8:1:1 brine (3 × 15 mL), dried over NaSO, concentrated, and purified by HPLC ((HO / ACN) + 0.1% TFA) with a gradient of 20% to 80% (20 min) to give the desired product as a white solid (49 mg, 56%; 2 steps). 1H 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 ClNO: 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 [ka]

[0363] The title compound was prepared in a similar manner to 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 for ClN4O2: 543.3; Found: 543.2.

[0364] Example 64: 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]oxetan-3-ol [ka]

[0365] The title compound was prepared in a similar manner to 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 for ClN4O2: 529.2; Found: 529.2.

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

[0367] The title compound was prepared in a similar manner to 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 for ClNO: 516.3; Found: 516.2

[0368] Example 66: (S)-(2-chloro-4-(5-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)(4-methoxypiperidin-1-yl)methanone [ka]

[0369] Step a: To a mixture of 4-bromo-2-chlorobenzoic acid (2.0 g, 8.5 mmol), 4-methoxypiperidine (1.2 g, 10.2 mmol), EtN (1.8 mL, 12.7 mmol), and CHCl (20 mL) was added EDC-HCl (1.9 g, 10.2 mmol). The mixture was stirred at room temperature for 14 h, and then HO (5 mL) and CHCl (50 mL) were added. The phases were separated, and the organic phase was dried over NaSO, concentrated, and purified by column chromatography (SiO, 0–90% EtOAc in hexanes) to give the desired product (731 mg, 26%).

[0370] Step b: The desired compound was prepared in a similar manner to Example 11, step c.

[0371] Step c: In a similar manner to Example 24, step c, the desired product was prepared (286 mg, 55%).

[0372] Step d: The desired product was prepared in a similar manner to Example 24, step d (49 mg, 29%).

[0373] Step e: To the product of step d (49 mg, 0.07 mmol) was added 3 M methanolic HCl (1.0 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed, and the crude material was purified by reverse-phase HPLC using HO+0.1% TFA and ACN+0.1% TFA as mobile phases to give the desired product (40 mg, 93%) as a yellow solid. 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 for ClN5O2: 584.3; Found: 584.3.

[0374] Example 67: 1-[2-chloro-4-(5-{7-methyl-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)benzoyl]-4-methoxypiperidine [ka]

[0375] The title compound was prepared in a similar manner to 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 for ClN5O2: 612.3; Found: 612.3.

[0376] Example 68: 2-chloro-4-(5-{7-methyl-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)benzamide [ka]

[0377] The title compound was prepared in a similar manner to 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 for ClNO: 514.2; Found: 514.2.

[0378] Example 69: N-cyclopropyl-4-(5-{7-methyl-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)benzamide [ka]

[0379] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)-N-(propan-2-yl)benzamide [ka]

[0381] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0383] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0385] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0387] The title compound was prepared in a similar manner to 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 for ClNO: 528.3; Found: 528.2.

[0388] Example 74: 2-chloro-4-(5-{7-ethyl-7-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0389] The title compound was prepared in a similar manner to 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 for ClN5O2: 544.2; Found: 544.2.

[0390] Example 75: 2-chloro-4-(5-{7-ethyl-7-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0391] The title compound was prepared in a similar manner to 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 for ClN5O2: 544.2; Found: 544.2.

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

[0393] The title compound was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0395] The title compound was prepared in a similar manner to 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 for ClNO: 486.2; Found: 486.2.

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

[0397] The title compound was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0399] The title compound was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(trifluoromethyl)benzamide [ka]

[0401] The title compound was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0403] The title compound was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)(piperazin-1-yl)methanone [ka]

[0405] The title compound was prepared in a similar manner to 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 for ClNO: 555.3; Found: 555.3.

[0406] Example 83: (S)-2-Fluoro-6-methyl-4-(5-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0407] The title compound was prepared in a similar manner to 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide [ka]

[0409] The title compound was prepared in a similar manner to 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 for ClNO: 486.2; Found: 486.2.

[0410] Example 85: (S)-(2-chloro-4-(5-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)(4-hydroxypiperidin-1-yl)methanone [ka]

[0411] The title compound was prepared in a similar manner to 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). ESI MS [M+H] + C 33 H 37 Calculated for ClN5O2: 570.3; Found: 570.3.

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

[0413] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzenesulfonamide [ka]

[0415] The title compound was prepared in a similar manner to 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; Found: 546.3.

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

[0417] The title compound was prepared in a similar manner to 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-Methoxypiperidin-1-yl)(4-(5-(7-methyl-7-((R)-2-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)methanone [ka]

[0419] The title compound was prepared in a similar manner to 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-methylpyrrolidin-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 [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) was added Br2 (5.12 mL, 100 mmol) dropwise at 0 °C. Upon completion, the reaction mixture was warmed and stirred at 80 °C for 1.5 h. The mixture was cooled to room temperature and water (100 mL) was added, followed by 2 M HCl.(水溶液) (150 mL) was added, and the solid was collected by filtration, washed with water, and dried to give the desired product as a white solid (5.58 g, 22%).

[0422] Step b: To a mixture of the product of step a (5.70 g, 22.0 mmol) and THF (110 mL) was added borane dimethyl sulfide (6.26 mL, 66.0 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 10 min, then warmed and stirred at 55° C. for 14 h. The mixture was cooled to room temperature and diluted with 2 M NaOH. (水溶液) (100 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. (水溶液) (17 mL) was added dropwise, and the resulting organic phase was concentrated and diluted with EtOAc (50 mL). The resulting aqueous phase was extracted with EtOAc (1×50 mL), and the combined organic phase was washed with 1:5 water:brine (60 mL), dried over NaSO, and concentrated to give the desired product as a white solid (4.57 g, 90%).

[0423] Step c: A mixture of the product of step b and HBr (20 mL, 48 wt% in HO) was stirred for 2 h at 90° C. The mixture was cooled to room temperature, and the solid was collected by filtration and washed with water to give the desired product, which was used directly in the next step.

[0424] Step d: A mixture of the product of step c (estimated 19.8 mmol), dimethyl 1,3-acetonedicarboxylate (4.14 g, 23.6 mmol), tetrabutylammonium bromide (3.19 g, 9.90 mmol), NaHCO (8.32 g, 99.0 mmol), CHCl (40 mL), and water (99 mL) was vigorously stirred at 40 °C for 4 days. The organic phase was separated, concentrated, diluted with EtOAc (100 mL), washed with 9:1 water:brine (4 × 100 mL), dried over NaSO, and concentrated. The residue was dissolved in EtOH (152 mL) and diluted with 2 M 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 12 M HCl (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 CHCl (150 L). The organic phase was dried over NaSO and concentrated. The crude material was purified by column chromatography (80 g silica gel, hexanes:EtOAc) using a 0% to 20% gradient (20 min), followed by a 20% to 35% gradient (10 min) to give the desired product as a pale yellow solid (2.35 g, 47%; 2 steps).

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

[0426] Step f: To a mixture of the product of 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) was added NaBH(OAc) (172 mg, 0.813 mmol). The reaction mixture was stirred at 40° C. for 16 h. The mixture was diluted with EtOAc (15 mL) and diluted with water:2M NaOH. (水溶液)The mixture was washed with 1:1 water:brine (8:1:1) (3 × 15 mL), dried over NaSO, and concentrated to give a white solid (188 mg). TBAF (2.9 mL, 2.9 mmol, 1 M in THF) was added, and the reaction mixture was stirred at 70 °C for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (125 mL), washed with 1:1 water:brine (4 × 100 mL), dried over NaSO, and concentrated. 7 M NH in MeOH (3 mL) was added, and the reaction mixture was stirred at 60 °C for 2 h. The mixture was concentrated and purified by column chromatography (43 g C18, (HO / ACN) + 0.1% TFA) with a 5% to 50% gradient (25 min) to give 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 for ClNO: 529.3; Found: 529.2.

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

[0428] Step a: In a similar manner to Example 24, step c, the desired product was prepared (241 mg, 58%).

[0429] Step b: In a similar manner to Example 24, step d, the desired product was prepared (61 mg, 37%).

[0430] Step c: In a similar manner to Example 24, step e, the desired product was prepared (35 mg, 72%). 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 for ClN5O2S: 522.2; Found: 522.2.

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

[0432] The title compound was prepared in a similar manner to 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 for ClN5O2S: 522.2; Found: 522.2.

[0433] Example 93: 2-chloro-4-(5-(7-methyl-7-((R)-2-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzenesulfonamide [ka]

[0434] The title compound was prepared in a similar manner to 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 for ClN5O2S: 550.2; Found: 550.2.

[0435] Example 94: 2-chloro-4-(5-(7-((R)-2-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzenesulfonamide [ka]

[0436] The title compound was prepared in a similar manner to 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 for ClN5O2S: 536.2; Found: 536.2.

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

[0438] The title compound was prepared in a similar manner to 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]annulene-7,2'-pyrrolidin]-3-yl}-1H-pyrazolo[3,4-b]pyridin-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 NH in MeOH (7N, 4.4 mL) was stirred for 30 min, 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 h. The reaction mixture was concentrated, and 1 N aqueous HCl (1.5 mL) was carefully added, followed by CHCl (5 mL). The layers were separated, and the aqueous layer was washed with CHCl (5 mL). The aqueous layer was basified with NaOH (to pH = 10) and extracted with 10% MeOH in CHCl (3 × 15 mL). The combined organic layers were washed with brine, dried over MgSO, and concentrated. To a cooled (0 °C) mixture of the intermediate and NEt (0.46 mL, 3.28 mmol) in CHCl (10.9 mL) was slowly added trifluoroacetic anhydride (0.36 mL, 2.62 mmol), and the reaction was stirred over 17 h, warming to room temperature after the cooling bath had expired. Saturated aqueous NHCl was carefully added, and the mixture was extracted with CHCl (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, concentrated, and purified by silica gel chromatography (100% hexanes to 60% EtOAc in hexanes) to give the desired product as a colorless oil (737 mg, 90%).

[0441] Step b: To a suspension of NaBH (178 mg, 4.70 mmol) in THF (5.2 mL) was added a solution of I (298 mg, 2.32 mmol) in THF (8.9 mL) over 30 min, followed by a solution of the product of step a (737 mg, 1.96 mmol) in THF (2.1 mL) over 30 min, and the mixture was stirred at room temperature for 1.5 h. NaOH solution (3 M in HO, 3.2 mL, 9.80 mmol) was added over 2.5 h, followed by HO solution (30% in HO, 9.80 mmol) over 45 min, and the mixture was stirred at room temperature for 30 min. Brine was added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine, dried over MgSO, and concentrated to provide a mixture of starting material and desired product. To a solution of the residue in THF (9.8 mL), a solution of 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 7.8 mL, 3.92 mmol) was added over 30 min, and the reaction mixture was stirred at room temperature for 4.5 h. The mixture was cooled to 0 °C, and a solution of NaOH (2 M in HO, 2.0 mL, 3.92 mmol) was added over 15 min, followed by a solution of HO (30% in HO, 2.0 mL) over 15 min. After the cooling bath had expired, the mixture was stirred for 15 h while warming to room temperature. The mixture was diluted with brine (20 mL) and EtOAc (20 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layers were washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography (100% hexanes to 100% EtOAc) to give the desired product as a white solid (276 mg, 36%).

[0442] Step c: To a solution of the product of step b (276 mg, 0.700 mmol) in CHCl (3.5 mL) at 0 °C, DIPEA (0.15 mL, 0.840 mmol) was added, followed by methanesulfonyl chloride (0.55 μL, 0.721 mmol). The reaction mixture was stirred for 17 h while warming to room temperature after the cooling bath had expired. Saturated aqueous NHCl was added, and the mixture was extracted with CHCl (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, and concentrated. To a mixture of the crude intermediate in THF (4.7 mL), NaH (60% dispersion in mineral oil, 42 mg, 1.05 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h and then at 60 °C for 17 h. Upon cooling, NHCl was added, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, concentrated, and purified by silica gel chromatography (100% hexanes to 50% EtOAc in hexanes) to give the desired product as a yellow solid (164 mg, 62%).

[0443] Step d: To a mixture of the product of step c (164 mg, 0.436 mmol), B2pin2 (111 mg, 0.436 mmol), and KOAc (51 mg, 523 mmol), dioxane (4.4 mL) was added, and the suspension was then degassed with N2 for 10 min. (dppf)PdCl2 (16 mg, 0.0218 mmol) was added, and the reaction mixture was stirred at 90 °C for 5 h. Upon cooling, EtOAc (20 mL) was added, and the mixture was filtered through Celite. The filtrate was concentrated to give the crude product as a viscous brown oil.

[0444] Step e: To 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 NaCO (69 mg, 0.654 mmol), dioxane (4.4 mL) and HO (0.40 mL) were added, and the suspension was degassed with N for 10 min. (dppf)PdCl (16 mg, 0.0218 mmol) was added, and the reaction mixture was stirred at 90 °C for 18 h. Upon cooling, CHCl (15 mL) was added, and the mixture was dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography (100% hexanes to 100% EtOAc) to give the impure intermediate (254 mg). To a solution of this residue in THF (3.5 mL) was added a TBAF solution (1 M in THF, 3.5 mL, 3.47 mmol), and the reaction mixture was stirred at 70 °C for 14 h. Upon cooling, the reaction was concentrated and purified by silica gel chromatography (100% hexanes to 100% EtOAc, followed by 10% MeOH in CHCl + 1% NH) to give an impure intermediate. To the residue was added MeOH (4.6 mL) and crushed NaOH (28 mg, 0.694 mmol), and the mixture was stirred at room temperature for 14 h and at 45 °C for 3 h. An additional amount of crushed NaOH (28 mg, 0.694 mmol) was added, and the reaction was stirred at 60 °C for 2 h. Upon cooling, H0 (5 mL), saturated aqueous NaHCO (10 mL), and CHCl (15 mL) were added, and the layers were separated. The aqueous layer was extracted with 10% MeOH in CH2Cl2 (3 × 10 mL), and the combined organic layers were concentrated. After C18 reverse-phase chromatography (100% H2O to 100% ACN, 0.1% TFA) and lyophilization, the title compound was obtained 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 for ClNO: 487.2; Found: 487.2.

[0445] Example 97: 2-[6-(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)pyridin-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:HO (8.0 mL) and the mixture was heated at 65° C. for 5 h. The mixture was concentrated and saturated NaHCO 3(水溶液) The product was diluted with (50 mL), extracted into 9:1 CHCl:IPA (3 x 50 mL), and the combined organic phases were washed with brine (50 mL), dried (MgSO), and concentrated. The crude material was used in the next step.

[0447] Step b: A 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 1:1 THF:CHCl3 (8.8 mL) was heated overnight at 60° C. The mixture was concentrated and purified by flash chromatography (0 to 50% EtOAc in hexanes) to give the desired product as an off-white solid (0.460 g, 65%).

[0448] Step c: The desired compound was prepared in a similar manner to Example 59, step e.

[0449] Step d: To a vial containing the product of step c (115 mg, 0.227 mmol), hexamethylditin (96.6 mg, 0.295 mmol), and Pd(PPh3)4 (91.8 mg, 0.0795 mmol) was added degassed toluene (1.6 mL). The mixture was stirred at 110 °C for 1 h, then concentrated and purified by flash chromatography (MeOH / NH 3(水溶液) Purification using 10:1 HCl in CH2Cl2 (1-10%) gave the desired product as a yellow oil (48.7 mg, 36%).

[0450] Step e: In a similar manner to Example 11, step b, the desired product was prepared (0.928 g, 93%).

[0451] Step f: To a vial containing the product of step d (48.7 mg, 0.0820 mmol), the product of step e (17.7 mg, 0.0820 mmol), and Pd(PPh3)4 (9.5 mg, 0.0082 mmol) was added degassed toluene (0.68 mL). The mixture was stirred at 110 °C overnight, then concentrated and purified by flash chromatography (MeOH / NH 3(水溶液) Purification using 10:1 HCl in CH2Cl2 (1-10%) gave the desired product as a yellow oil (26.8 mg, 58%).

[0452] Step g: A solution of the product of step f (26.8 mg, 0.0474 mmol) in 3N methanolic HCl (1.0 mL) was stirred at room temperature overnight. The mixture was concentrated and saturated NaHCO 3(水溶液) Solution (5 mL) was added. The product was extracted into 9:1 CHCl:IPA (3 x 5 mL) and the combined organic phases were dried (NaSO), concentrated and purified by flash chromatography (MeOH / NH 3(水溶液) Purification using 10:1 HCl in CH 2 Cl 2 (1-10%) afforded the title compound 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-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-yl]propan-2-ol [ka]

[0454] Step a: The desired compound was prepared in a similar manner to Example 11, step c.

[0455] Step b: In a similar manner to Example 11, step a, the desired compound was prepared (161 mg, 30%).

[0456] Step c: In a similar manner to Example 11, step b, the desired compound was prepared (94.7 mg, 57%).

[0457] Step d: In a similar manner to Example 11, step a, the desired compound was prepared (94.4 mg, 73%).

[0458] Step e: The desired compound was prepared in a similar manner to 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 for ClNO: 530.3; Found: 530.2.

[0459] Example 99: 4-(5-{7-methyl-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)-N-[(3R)-oxolan-3-yl]benzamide [ka]

[0460] The title compound was prepared in a similar manner to 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-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl]-λ 6 -Sulfanone [ka]

[0462] Step a: The desired compound was prepared in a similar manner to Example 11, step c.

[0463] Step b: In a similar manner to Example 11, step a, the desired compound was prepared (169 mg, 41%).

[0464] Step c: In a similar manner to Example 11, step a, the desired compound was prepared (41.1 mg, 36%).

[0465] Step d: In a similar manner to Example 97, step g, the desired compound was prepared (17.4 mg, 49%). 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]pyridin-5-yl}-5H,6H,7H,8H,9H-cyclohepta[b]pyridin-7-yl)-2-methylpyrrolidine [ka]

[0467] The title compound was prepared in a manner similar to 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]pyridin-5-yl}-5H,6H,7H,8H,9H-cyclohepta[b]pyridin-7-yl]-2-methylpyrrolidine [ka]

[0469] The title compound was prepared in a manner similar to 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-methoxypiperidin-1-yl)sulfonyl)phenyl)-5-(7-methyl-7-((R)-2-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0471] Step a: To a mixture of 4-bromobenzenesulfonyl chloride (2.0 g, 7.8 mmol), 4-methoxypiperidine (947 mg, 8.2 mmol), and CHCl (35 mL), DIPEA (3.4 mL, 19.6 mmol) was added and stirred at room temperature for 14 h. HO (50 mL) and CHCl (50 mL) were added, the phases were separated, and the organic phase was dried over NaSO and concentrated to give the desired product (2.4 g, 92%).

[0472] Step b: The desired compound was prepared in a similar manner to Example 11, step c.

[0473] Step c: In a similar manner to Example 24, step c, the desired compound was prepared (278 mg, 52%).

[0474] Step d: In a similar manner to Example 24, step d, the desired product was prepared (102 mg, 58%).

[0475] Step e: To the product of step d (102 mg, 0.15 mmol) was added 3 M HCl in MeOH (3.0 mL). The reaction mixture was stirred at room temperature for 14 h. The solvent was removed and the crude was triturated with ACN (5 mL) to give 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]pyridin-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-2-methylpyrrolidine [ka]

[0477] The title compound was prepared in a similar manner to Example 103, except that Boc was used as the azaindazole protecting group. Thermal deprotection (95° C., 18 h) was used to avoid acid-mediated ring opening of the azetidine. 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]pyridin-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-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. The reaction mixture was allowed to warm to room temperature and stirred for 14 h. EtOAc (400 mL) was added, and the mixture was washed with 3:1 water:brine (4 × 400 mL). The organic phase was dried over Na2SO4 and concentrated. The crude material was purified by column chromatography (120 g silica gel, hexanes:EtOAc) using a 0% to 20% gradient (20 min) to give the desired product (7.82 g, 52%) as an orange solid.

[0480] Step b: In a similar manner to Example 90, step e, the desired product was prepared (300 mg, 29%).

[0481] Step c: A mixture of the product of step b (300 mg, 0.591 mmol), the product of Example 57, step a (0.600 mmol), and (dppf)PdCl (43 mg, 0.059 mmol) was placed under nitrogen in degassed dioxane (3.0 mL) and degassed 2M NaCO. 3(水溶液)(0.59 mL) was added and the reaction mixture was stirred at 95 °C for 18 h. The mixture was cooled to room temperature, diluted with CHCl (30 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (24 g silica gel, CHCl:((4:1 CHCl;MeOH) + 2% EtN)) gradient (20 min) from 0% to 50% to give a dark brown solid (208 mg). TBAF (3.5 mL, 3.5 mmol, 1 M in THF) was added and the reaction mixture was stirred at 70 °C for 15 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), and diluted with water:2 M NaOH. (水溶液) The crude material was washed with 8:1:1 HCl (4 × 75 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (43 g C18, (HO / ACN) + 0.1% TFA) with a 5% to 50% gradient (25 min) to give 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-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)propan-2-ol [ka]

[0483] The title compound was prepared in a similar manner to 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 for ClNO: 500.2; Found: 500.2.

[0484] Example 107: 4-[4-(5-{7-methyl-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]morpholine [ka]

[0485] Step a: In a manner similar to Example 90, step e, the desired product was prepared (337 mg, 61%). rxn Column: (40 g silica gel, hexane: EtOAc) 0% to 50% gradient (20 min).

[0486] Step b: A mixture of the product of step a (266 mg, 0.600 mmol), Example 57, step a (0.600 mmol), and (dppf)PdCl (44 mg, 0.060 mmol) was placed under nitrogen. Degassed dioxane (3.0 mL) and degassed 2M NaCO 3(水溶液) (0.60 mL) was added, and the reaction mixture was stirred at 95 °C for 18 h. The mixture was cooled to room temperature, diluted with CHCl (30 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (24 g silica gel, CHCl:((4:1 CHCl:MeOH) + 2% EtN)) with a 0% to 50% gradient (20 min) to give a brown solid. 3 M HCl in MeOH (3.0 mL) was added, and the reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with MTBE (30 mL), and the precipitated solid was washed with MTBE. The crude material was purified by column chromatography (43 g C18, (HO / ACN) + 0.1% TFA) with a 5% to 50% gradient (25 min) to give 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-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl]methyl})amine [ka]

[0488] Step a: The desired compound was prepared in a similar manner to Example 11, step c.

[0489] Step b: In a similar manner to Example 11, step a, the desired compound was prepared (204 mg, 39%).

[0490] Step c: Prepared in a similar manner as in Example 11, step a, the desired compound (190 mg, 74%).

[0491] Step d: The product of step c (95.0 mg, 0.160 mmol) in 2:1 THF:2N HCl (水溶液) (1.1 mL) was stirred at 65° C. overnight, then the THF was removed in vacuo. This mixture was added to saturated NaHCO 3(水溶液) (5 mL) and the product was extracted into 9:1 CHCl:IPA (3 x 5 mL). The combined organic phases were dried (NaSO) and concentrated, and the residue was purified by flash chromatography (1-10% MeOH / NH 3(水溶液) The intermediate was purified with 10:1 CHCl (containing 2-methoxyethylamine) to give the intermediate product as a yellow oil (25.8 mg). NaBH(OAc) (17.7 mg, 0.0833 mmol) was 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 h and then concentrated. This material was purified by reverse-phase preparative HPLC (5–100% acetonitrile in water) to give 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]pyridin-5-yl}-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-2-methylpyrrolidine [ka]

[0493] Step a: To MeMgBr (16.0 mL, 48.0 mmol, 3 M EtO) was added dropwise a solution of 7-bromo-1-tetralone (9.00 g, 40.0 mmol) in EtO (20 mL) at 0 °C. The reaction mixture was warmed and stirred at room temperature for 30 min, at which point EtO (15 mL) was added. The reaction mixture was stirred at room temperature for 16 h and saturated NH4Cl was added. (水溶液) The reaction was quenched with HCl. The mixture was diluted with water (20 mL) and EtOAc (150 mL). The organic phase was dried over NaSO and concentrated. The crude material was purified by column chromatography (220 g silica gel, hexane:EtOAc) using a 0% to 20% gradient (20 min); a 20% to 30% gradient (5 min) to give the desired product as an off-white solid (8.70 g, 90%).

[0494] Step b: A mixture of the product from step a (8.70 g, 36.1 mmol), p-toluenesulfonic acid monohydrate (343 mg, 1.80 mmol), and MeOH (72 mL) was stirred at 70 °C for 3 h. The mixture was cooled to room temperature, concentrated, diluted with 4:1 hexane:CHCl (150 mL), washed with water (2 × 100 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (80 g silica gel, hexane) isocratic (10 min) to give the desired product as a colorless oil (5.97 g, 74%; contains approximately 20% of the exocyclic alkene isomer).

[0495] Step c: To a mixture of step b (5.74 g, 25.7 mmol) and 3:3:4 CCl:ACN:HO (257 mL) at room temperature, NaIO (11.0 g, 51.4 mmol) and RuCl (534 mg, 2.57 mmol) were added. The reaction mixture was stirred at room temperature for 2 h, and additional NaIO (11.0 g, 51.4 mmol) was added and stirred at room temperature for 14 h. The mixture was filtered through Celite to remove solids and washed with CHCl. ​​The organic phase was dried over NaSO and concentrated. The crude material was purified by column chromatography (80 g silica gel, CHCl:(EtOAc + 1% AcOH)) using a 0% to 50% gradient (30 min) to give the desired product (4.25 g, 61%) as a white solid.

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

[0497] Step e: A mixture of the product of step d (15.7 mmol, estimated), K0t-Bu (3.88 g, 34.5 mmol), and t-BuOH (462 mL) was stirred at 80° C. for 1 h. The mixture was cooled to room temperature and diluted with 2 M HCl. (水溶液) The mixture was acidified with hexanes (17.5 mL), concentrated, and diluted with EtOAc (100 mL). The mixture was washed with water (50 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (80 g silica gel, hexanes:EtOAc) using a 0% to 100% gradient (30 min) to give the desired product as an orange solid (3.52 g, 89%; 2 steps).

[0498] Step f: A mixture of the product of 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 min. The mixture was cooled to room temperature and saturated NaHCO 3(水溶液) (67 mL), diluted with EtOAc (335 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (120 g silica gel, hexanes:EtOAc) with a 0% to 100% gradient (25 min) to give the desired product as a brown solid (1.26 g, 89%; contaminated with some starting material).

[0499] Step g: To a mixture of the product of step f (1.04 g, 3.50 mmol) and EtO (3.5 mL) was added MeMgBr (3.50 mL, 10.5 mmol, 3 M in EtO) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then diluted with 2 M HCl. (水溶液) The mixture was acidified to a pH of about 1. The mixture was diluted with EtOAc (70 mL), washed with water (70 mL), dried over Na2SO4 and concentrated to give the desired product, which was used as is in the next step.

[0500] Step h: A mixture of the product of step g (3.50 mmol, estimated), HCl (7 mL, 7.00 mL, 1 M in water), and THF (18 mL) was stirred at 70° C. for 1 h. The mixture was cooled to room temperature and added with saturated NaHCO 3(水溶液) The mixture was neutralized with hexanes, diluted with EtOAc (100 mL), washed with brine (100 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (40 g silica gel, hexanes:EtOAc) using a 0% to 100% gradient (25 min) to give the desired product as a brown solid (123 mg, 14%; 2 steps).

[0501] Step i: To CuI (140 mg, 0.735 mmol) under nitrogen at room temperature was added n-BU2S (222 μL, 1.27 mmol). The mixture was stirred at room temperature for 5 min or until homogeneous, at which point Et2O (1.2 mL) was added. The mixture was cooled to 0 °C, and MeLi (918 μL, 1.47 mmol, 1.6 M in Et2O) was added dropwise. The mixture was stirred at 0 °C for 30 min, and then a solution of the product of step h (123 mg, 0.490 mmol) in Et2O (0.60 mL) was added. The reaction mixture was allowed to warm to room temperature over 14 h and diluted with 1:1 NH4Cl. (水溶液) : The reaction was quenched with water (10 mL), diluted with EtOAc (20 mL), and 28 wt% NH 3(水溶液) (3×10 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (24 g silica gel, hexanes:EtOAc) with a 0% to 50% gradient (25 min) to give the desired product as an off-white solid (82 mg, 63%).

[0502] Step j: A mixture of the product of step i (82 mg, 0.31 mmol), the product of step d, Example 1 (0.31 mmol, estimated), and (dppf)PdCl (22 mg, 0.031 mmol) was placed under nitrogen in degassed dioxane (1.6 mL) and degassed 2M NaCO. 3(水溶液)(0.31 mL) was added and the reaction mixture was stirred at 95° C. for 1 h. The mixture was cooled to room temperature, diluted with EtOAc (16 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (24 g silica gel, hexane:EtOAc) with a gradient of 0% to 100% (30 min) to give the desired product as a brown oil (174 mg, 99%).

[0503] Step k: To a mixture of the product of 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) was added NaBH(OAc) (162 mg, 0.764 mmol). The reaction mixture was stirred at 40° C. for 15 h. The mixture was diluted with EtOAc (20 mL) and diluted with 0.1 M NaOH. (水溶液) The crude material was purified by column chromatography (43 g C18, (HO / ACN) + 0.1% TFA) with a 5% to 50% gradient (25 min) to give 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-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka]

[0505] Step a: The desired compound was prepared in a similar manner to Example 11, step c.

[0506] Step b: In a similar manner to Example 24, step c, the desired compound was prepared (212 mg, 49%).

[0507] Step c: In a similar manner to Example 24, step d, the desired compound was prepared (97 mg, 62%).

[0508] Step d: In a similar manner to Example 66, step e, the desired product was prepared (66 mg, 65%). 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]pyridin-5-yl}-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-2-methylpyrrolidine [ka]

[0510] Step a: m-CPBA (2.96 g, 8.50 mmol) was added portionwise to a solution of 1-bromo-4-[(2-methoxyethyl)thio]benzene (1.00 g, 4.05 mmol) in dichloromethane (9.7 mL), and the mixture was stirred at room temperature overnight.(水溶液) The reaction was quenched with 1N NaOH (25 mL) and the product was extracted into EtOAc (3 x 25 mL). The combined organic phase was washed with 1N NaOH. (水溶液) The solution was washed with water (25 mL), dried (MgSO4) and the crude was taken onto the next step.

[0511] Step b: The desired compound was prepared in a similar manner to Example 11, step c.

[0512] Step c: In a similar manner to Example 24, step c, the desired compound was prepared (115 mg, 27%).

[0513] Step d: In a similar manner to Example 11, step a, the desired compound was prepared (87.1 mg, 57%).

[0514] Step e: In a similar manner to Example 97, step g, the desired compound was prepared (48.0 mg, 64%). 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]pyridin-5-yl}-3-[(2S)-pyrrolidine-2-carbonyl]-2,3,4,5-tetrahydro-1H-3-benzazepine [ka]

[0516] Step a: 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) was added EtN (1.4 mL, 10.0 mmol) dropwise at room temperature. The mixture was stirred at 40 °C for 14 h. To the reaction mixture was added HO (5 mL) and EtOAc (20 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with HO (3 × 20 mL), dried over NaSO, concentrated, and purified by column chromatography (SiO, 0–80% EtOAc in hexanes) to give the desired product as a colorless solid (802 mg, 95%).

[0517] Step b: The desired compound was prepared in a similar manner to Example 11, step c.

[0518] Step c: In a similar manner to Example 47, step c, the desired compound was prepared (170 mg, 78%).

[0519] Step d: In a similar manner to Example 47, step d, the desired compound was prepared (130 mg, 98%). 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]pyridin-5-yl}-3-[(2R)-pyrrolidine-2-carbonyl]-2,3,4,5-tetrahydro-1H-3-benzazepine [ka]

[0521] The title compound was prepared in a similar manner to 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]pyridin-5-yl]-7-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl}-2-methylpyrrolidine [ka]

[0523] Step a: To a solution of (S)-2-(hydroxymethyl)-1,4-dioxane (506 mg, 4.28 mmol) in CHCl (21.4 mL) at 0 °C, NEt (0.89 mL, 6.42 mmol) was added, followed by methanesulfonyl chloride (0.33 mL, 4.28 mmol). The reaction mixture was stirred for 22 h and allowed to warm to room temperature after the cooling bath had expired. The reaction mixture was cooled to 0 °C and then carefully quenched with saturated aqueous NHCl. The layers were separated, and the aqueous layer was extracted with CHCl (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, and concentrated. To a mixture of the crude intermediate and 4-bromo-2-methoxyphenol (869 mg, 4.28 mmol) in DMF (8.6 mL) was added KCO (887 mg, 6.42 mmol). The reaction mixture was stirred at 90° C. for 4 h, then cooled to room temperature, and HO (30 mL) and EtOAc (30 mL) were added. The layers were separated, and the organic layer was washed with HO (2×15 mL), then the combined aqueous washes were extracted with EtOAc (1×15 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, concentrated, and purified by silica gel chromatography (100% hexanes to 100% EtOAc) to give the desired product as an off-white solid (876 mg, 67%).

[0524] Step b: To a mixture of the product of step a (300 mg, 0.990 mmol), B2pin2 (251 mg, 0.990 mmol), and KOAc (107 mg, 1.09 mmol), dioxane (5.0 mL) was added, and the suspension was then degassed with N2 for 10 min. (dppf)PdCl2 (36 mg, 0.0495 mmol) was added, and the reaction mixture was stirred at 90 °C for 2.5 h. Upon cooling, EtOAc (20 mL) was added, and the mixture was filtered through Celite. The filtrate was concentrated to give the crude product as a viscous brown oil.

[0525] Step c: 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), dioxane (6.0 mL) and HO (0.60 mL) were added, and the suspension was degassed with N2 for 10 min. (dppf)PdCl2 (36 mg, 0.0495 mmol) was added, and the reaction mixture was stirred at 80 °C for 14 h. Upon cooling, CHCl2 (20 mL) was added, and the mixture was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (100% hexanes to 100% EtOAc) to give the desired product as a viscous brown oil (261 mg, 52%).

[0526] Step d: To a mixture of the product from Step c (261 mg, 0.507 mmol), the product from Step a of Example 57 (0.403 mmol), and Na2CO3 (85 mg, 0.806 mmol), dioxane (7.0 mL) and HO (0.80 mL) were added. The suspension was then degassed with N2 for 10 min. (dppf)PdCl2 (15 mg, 0.0202 mmol) was added, and the reaction mixture was stirred at 90 °C for 17 h. Upon cooling, CHCl2 (20 mL) was added. The mixture was then dried over anhydrous MgSO4, filtered, and concentrated. Purification by silica gel chromatography (100% CHCl2 to 10% MeOH in CHCl2, 1% NH4OH) gave the desired product as a brown solid (138 mg, 51%).

[0527] Step e: To the product of step d (138 mg, 0.207 mmol) was added HCl solution (3 M in MeOH, 3 mL). The reaction mixture was stirred at room temperature for 15 h and then concentrated. Purification by reverse-phase HPLC (10–70% ACN in HO, 0.1% TFA) and lyophilization, followed by concentration with HCl in MeOH (2×) and drying in vacuo, afforded the title 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]annulen-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 h with azeotropic removal of water (Dean-Stark apparatus). The mixture was cooled to room temperature, and the resulting supernatant was diluted with THF (100 mL). The mixture was cooled to −78 °C, and BF₃·OEt₂ (2.47 mL, 20.0 mmol) was added dropwise. The mixture was stirred at −78 °C for 1 h, and MeLi (18.8 mL, 30.0 mmol, 1.6 M in Et₂O) was added dropwise. The reaction mixture was allowed to warm to room temperature over 14 h, 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 added with 2M NaOH. (水溶液) (30 mL), water (100 mL), and brine (20 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (80 g silica gel, hexane:(EtOAc+1% EtN)) with a gradient of 0% to 100% (20 min), then 100% (5 min) to give the desired product as a yellow oil (902 mg, 28%).

[0530] Step b: The desired compound was prepared in a similar manner to Example 109, step j. rxn : 14 h Column: (24 g silica gel, hexane (EtOAc + 1% Et3N)) gradient from 0% to 100% (25 min); 100% (10 min).

[0531] Step c: To the product of step b, 3 M HCl in MeOH (3.0 mL) was added. The reaction mixture was stirred at room temperature for 14 h and diluted with MTBE (30 mL). The precipitated solid was collected by filtration and washed with MTBE. The crude material was purified by column chromatography (43 g C18, (HO / ACN) + 0.1% TFA) with a 5% to 50% gradient (25 min) to give 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-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine [ka]

[0533] Step a: A mixture of the product from Step a, Example 105 (3.63 g, 8.00 mmol), the product from Step a, Example 23 (2.30 g, 8.00 mmol), (dppf)PdCl (293 mg, 0.400 mmol), and KCO (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 h. The mixture was cooled to room temperature, diluted with CHCl (270 mL), dried over NaSO, and concentrated. The crude material was purified by column chromatography (120 g silica gel, hexanes:EtOAc) using a 0% to 100% gradient (30 min) to give the desired product as a light brown solid (1.63 g, 42%).

[0534] Step b: To a mixture of the product from Step a (239 mg, 0.491 mmol), the product from Step a (Example 57) (0.478 mmol), and Na2CO3 (76 mg, 0.717 mmol), dioxane (4.3 mL) and HO (0.50 mL) were added. The suspension was then degassed with N2 for 10 min. (dppf)PdCl2 (17 mg, 0.0239 mmol) was added, and the reaction mixture was stirred at 90 °C for 20 h. Upon cooling, CHCl2 (15 mL) was added. The mixture was then dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (100% CHCl2 to 10% MeOH in CHCl2, 1% NH4OH) to give an impure brown solid (92 mg). A solution of the intermediate in MeOH (2.8 mL) was degassed with N for 5 minutes, then NEt (20 μL, 0.142 mmol) was added, followed by Pd / C (10% dry basis, 60 mg, 0.0284 mmol). H was bubbled through the solution for 5 minutes, then the reaction was stirred under a H balloon for 15 hours at room temperature. The reaction was filtered through Celite, washed with MeOH, and concentrated. The residue was resubmitted to the same conditions and stirred for 4 hours before being filtered through Celite and concentrated. To a solution of the residue in CHCl (1.0 mL) was added TFA (1.0 mL). The reaction was stirred at room temperature for 1 hour and then concentrated. To the residue was added NH in MeOH (7N solution, 2.0 mL), and the reaction mixture was stirred at 40° C. for 5 hours. Upon cooling, the reaction mixture was concentrated. Purification by reverse-phase HPLC (10-70% ACN in HO, 0.1% TFA) and lyophilization, followed by concentration with HCl in HO (2x) and drying in vacuo, afforded the title 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-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}-1H-pyrazolo[3,4-b]pyridin-3-yl)-N-[(3S)-oxolan-3-yl]benzamide [ka]

[0536] Step a: In a similar manner to Example 11, step a, the desired compound was prepared (0.541 g, 49%).

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

[0538] Step c: The product of step b (126 mg, 0.189 mmol) was dissolved in 1:1 TFA:CHCl (2.4 mL) and the reaction was stirred at room temperature for 1 h. The mixture was concentrated and azeotroped with toluene (3×). The residue was taken up in THF (0.86 mL) and cooled to 0° C. Triethylamine (0.12 mL, 0.851 mmol) and PyBOP (118 mg, 0.227 mmol) were added and stirred at 0° C. for 30 min. (S)-3-aminotetrahydrofuran (16.5 mg, 0.189 mmol) was added and the mixture was stirred at room temperature for 1 h. Saturated NaHCO 3(水溶液) (5 mL) was added and the product was extracted into 9:1 CHCl3:IPA (3 x 5 mL). The combined organic phases were dried (Na2SO4) and concentrated. The residue was dissolved in MeOH (1.9 mL) and DMEDA (0.1 mL, 0.945 mmol) was added. The mixture was stirred at 45 °C for 30 min, then concentrated and purified by flash chromatography (1-10% MeOH / NH 3(水溶液) Purification with 10:1 CH2Cl2 gave the title compound 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]pyridin-5-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidine [ka]

[0540] The title compound was prepared in a similar manner to 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]pyridin-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 NaBHCN (620 mg, 10 mmol) was added and heated at 50 °C for 24 h. After cooling to room temperature, the reaction mixture was filtered to remove any insoluble material, concentrated, and purified by column chromatography (SiO, 0–100% CHCl / MeOH / 7N methanolic NH (90:10:1) in CHCl to give the desired product (500 mg, 94%) as a light brown oil.

[0543] Step b: A mixture of the product of 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. To this mixture was added degassed dioxane (2.0 mL) and heated at 100 °C for 6 h. After cooling to room temperature, the reaction mixture was filtered to remove any insoluble material, concentrated, and used directly in the next step.

[0544] Step c: In a similar manner to Example 47, step c, the desired product was prepared (60 mg, 30%).

[0545] Step d: In a similar manner to Example 47, step d, the desired product was prepared (40 mg, 85%). 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 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) in toluene (8 mL) was heated to reflux for 24 h 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 was added a solution of MeMgBr (8 mL, 24 mmol, 3.0 M in THF) and stirred for 1 h. 2.0 M aqueous NaOH was added dropwise until the pH reached approximately 10. The phases were separated and extracted with EtOAc (2 × 50 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by column chromatography (SiO2, 0–100% CH2Cl2 / MeOH / CH2Cl2 with 7N methanolic NH3 (90:10:1)) to give the desired product 2 as a light brown oil (273 mg, 22%).

[0548] Step b: The desired compound was prepared in a similar manner to Example 11, step c.

[0549] Step c: In a similar manner to Example 47, step c, the desired product was prepared (100 mg, 51%).

[0550] Step d: In a similar manner to Example 47, step d, the desired product was prepared (72 mg, 80%). 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]annulen-2-yl]-2H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)-1,3-oxazolidin-2-one [ka]

[0552] Step a: A 40 mL screw-cap vial equipped with a magnetic stir bar was charged with 1-bromo-4-iodobenzene (566 mg, 2.00 mmol, 1 equiv.), oxazolidinone (191 mg, 2.20 mmol, 1.1 equiv.), CU(OAc)2 (36 mg, 0.20 mmol, 0.1 equiv.), 3,4,7,8-tetramethyl-1,10-phenanthroline (71 mg, 0.30 mmol, 0.15 equiv.), potassium phosphate tribasic monohydrate (920 mg, 4.00 mmol, 2 equiv.), and DMSO (20 mL). The reaction mixture was stirred at 80 °C for 4 h. The reaction was monitored by TLC / LCMS and then cooled to room temperature. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 × 15 mL). The organic layer was washed with water, concentrated to dryness in vacuo, and purified by silica gel chromatography to give 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 for BrNO: 241.1; Found: 241.3.

[0553] Step b: A mixture of the product of 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 h. The mixture was cooled to room temperature, concentrated, diluted with EtOAc (30 mL), filtered through Celite to remove solids, and concentrated again to give 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), PdCl(dppf) (59 mg, 0.080 mmol), and KCO (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 h. The mixture was cooled to room temperature, concentrated, diluted with EtOAc (30 mL), dried over MgSO, and concentrated. The crude material was purified by silica gel chromatography (40 g silica gel, hexanes:EtOAc) using a 0% to 70% gradient (25 min) to give the desired product as an off-white solid (350 mg, 49%).

[0555] Step d: The product of 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 h. The mixture was cooled to room temperature, concentrated, diluted with EtOAc (30 mL), filtered through Celite to remove solids, and concentrated again to give the desired product, which was used without further purification.

[0556] Step e: To a mixture of 3-oxa-6-azabicyclo[3.1.1]heptane 4-methylbenzenesulfonate (5.00 g, 18.4 mmol) in DCM (92 mL) at room temperature was added 2-bromo-5,6,8,9-tetrahydro-7H-benzocyclohepten-7-one (4.63 g, 19.4 mmol), followed by NaBH(OAc) (4.69 g, 22.1 mmol). The reaction mixture was then stirred at room temperature. Additional NaBH(OAc) (4.69 g each increment) was added at t = 4 h and t = 8 h. After the final addition, the reaction mixture was stirred at room temperature for an additional 4 h. DCM (250 mL), water (250 mL), and 2 M NaOH were added. (水溶液) (100 mL, or until the pH was >12), the mixture was stirred, and the organic phase was separated. The organic phase was diluted with 4:1:1 water:brine:2M NaOH (水溶液) (300 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography (hexane:(EtOAc+1% Et3N); 0-100%, 5 min; 100%, 20 min) to give the desired product as a white solid (5.13 g, 86%). The desired enantiomer was obtained using chiral column chromatography.

[0557] Step f: The product of step d (0.400 mmol), the product of step e (103 mg, 0.320 mmol), PdCl(dppf) (15 mg, 0.020 mmol), and KCO (110 mg, 0.800 mmol) were placed under nitrogen. Degassed dioxane (8 mL) and degassed water (2 mL) were added, and the reaction mixture was stirred at 100 °C for 1 h. The mixture was cooled to room temperature, concentrated, diluted with EtOAc (30 mL), dried over MgSO, and concentrated. The crude material was purified by silica gel chromatography (12 g silica gel, DCM:MeOH) with a 0% to 15% gradient (25 min) to give the desired product as an orange solid (110 mg, 52%).

[0558] Step g: The product of step f (110 mg, 0.18 mmol) was dissolved in methanol (5 mL) and 3 M HCl in methanol (5 mL) was added. The reaction mixture was stirred at room temperature for 23 h. The methanol was evaporated and the residue was saturated with NaHCO 3(水溶液) The reaction was quenched with 5 mL of HCl. The aqueous layer was extracted with 3×20 mL of EtOAc, and the combined organic layers were dried over MgSO and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g silica gel, DCM:MeOH) with a gradient of 0% to 15% (25 min) to give the desired product as an off-white solid (25 mg, 27%). 1 H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.13 - 8.10 (m, 2H), 7.72 - 7.70 (m, 2H), 7.58 - 7.57 (m, 1H), 7.52 - 7.50 (m, 1H), 7.23 - 7.20 (m, 1H), 4.48-4.43 (m, 2H), 4.14 - 4.09 (m, 3H), 3.57-3.50 (m, 3H), 3.14 (s, 1H), 3.02-2.88 (m, 4H), 2.81-2.71 (m, 1H), 2.32 (m, 1H), 1.82 (m, 1H), 1.65 (d, J = 7.9 Hz, 1H), 1.22-1.13 (m, 3H), 0.85-0.80 (m, 1H). ESI MS [M+H] + C 31 H 31 Calculated value for N5O3: 522.3; Measured value: 522.3.

[0559] Example 122: 1-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-2H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)pyrrolidin-2-one [ka]

[0560] The title compound was prepared in a similar manner to Example 121. 1 H NMR (400 MHz, CDCl3) δ 11.19 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.02 - 7.99 (m, 2H), 7.81 - 7.79 (m, 2H), 7.38-7.35 (m, 2H), 7.25-7.23 (m, 2H), 4.30 (d, J = 10.7 Hz, 2H), 3.93 (t, J = 7.0 Hz, 2H), 3.74-3.65 (m, 4H), 3.28-3.24 (m, 1H), 3.04-2.94 (m, 2H), 2.89-2.80 ESI MS [M+H] + C 32 H 33 Calculated value for N5O2: 520.3; Measured value: 520.3.

[0561] Example 123: 6-[(7S)-2-{3-[4-(2-methoxyethoxy)phenyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl]-3-oxa-6-azabicyclo[3.1.1]heptane [ka]

[0562] The title compound was prepared in a similar manner to Example 121. 1H NMR (400 MHz, DMSO-d6) δ 13.70 (s, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.59 (s, 1H), 8.01 - 7.99 (m, 2H), 7.56 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.09 - 7.06 (m, 1H), 4.15-4,.12 (m, 3H), 3.68-3.66 (m, 2H), 3.57 - 3.51 (m, 3H), 3.30 (s, 5H), 3.14 (d, J = 9.2 Hz, 1H), 3.07-2.71 (m, 4H), 2.33 (brs, 1H), 1.84 (brs, 2H), 1.65 (d, J = 8.0 Hz, 1H), 1.21-1.13 (m, 2H), 0.90 - 0.73 (m, 1H). ESI MS [M+H] + C 31 H 34 Calculated value for N4O3: 511.3; Measured value: 511.3.

[0563] Example 124: 6-[(7S)-2-{3-[4-(2-methylpropane-2-sulfonyl)phenyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl]-3-oxa-6-azabicyclo[3.1.1]heptane [ka]

[0564] The title compound was prepared in a similar manner to Example 121. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.41 - 8.38 (m, 2H), 7.94 - 7.91 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.7, 2.0 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 4.13 (d, J = 10.6 Hz, 2H), 3.58 - 3.51 (m, 3H), 3.30 (brs, 2H), 3.14-3.13 (m, 1H), 3.01-2.76 (m, 4H), 2.33 (brs, 1H), 1.87-1.84 (brs, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.26 (s, 9H), 1.16 - 1.10 (m, 2H). + C 32 H 36 Calculated value for N4O3S: 557.3; Measured value: 557.2.

[0565] Example 125: N,N-dimethyl-4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-2H-pyrazolo[3,4-b]pyridine-3 -yl}benzamide [ka]

[0566] The title compound was prepared in a similar manner to Example 121. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.2, 6.6 Hz, 3H), 7.22 (d, J = 7.8 Hz, 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.53 (dd, J = 18.6, 8.3 Hz, 4H), 3.19 - 3.09 (m, 1H), 3.04 - 2.85 (m, 8H), 2.76 (q, J = ESI MS [M+H] + C 31 H 34 Calculated value for N5O2: 508.3; Measured value: 508.3.

[0567] Example 126: (1R,4R)-5-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-2H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0568] The title compound was prepared in a similar manner to Example 121. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.55 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.1 Hz, 2H), 4.62 (d, J = 4.3 Hz, 2H), 4.13 (d, J = 10.7 Hz, 2H), 3.76 (d, J = 7.5 Hz, 1H), 3.68 (d, J = 7.4Hz, 1H), 3.62 - 3.45 (m, 5H), 3.20 - 3.09 (m, 1H), 3.05 - 2.86 (m, 3H), 2.76 (q, J = 13.9 Hz, 2H), 2.38 - 2.26 (m, 1H), 1.99 - 1.91 (m, 1H), 1.90 - 1.77 (m, 3H), 1.65 (d, J = 7.9 Hz, 1H), 1.25 - 1.02 (m, 2H). ESI MS [M+H] + C 33 H 36 Calculated value for N5O2: 534.3; Measured value: 534.2.

[0569] Example 127: 6-[(7S)-2-{3-[4-(3-fluoroazetidin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl]-3-oxa-6-azabicyclo[3.1.1]heptane [ka]

[0570] The title compound was prepared in a similar manner to Example 121. 1H NMR (400 MHz, DMSO-d6) δ 11.80 (d, J = 2...

Claims

1. A compound represented by formula (Ib) or formula (Ie), or a pharmaceutically acceptable salt thereof, wherein: 【Chemical 1】 [[Chemical 2]] In the formula: The subscript m is 0 or 1; n is 0, 1 or 2; G ３ is CRG3; G ４ is CRG4; G ５ 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 a group consisting of 4- to 8-membered heterocycloalkyl having 1 to 3 heteroatom vertices selected from the group consisting of O, N, and S, and cycloalkyl and heterocycloalkyl are each 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 is a phenyl or a 6-membered heteroaryl having 1 to 3 heteroatom rings selected from the group consisting of O, N, and S, and each phenyl and heteroaryl is substituted with 0 to 3 R ３ ; The subscript m is 0 or 1; n is 0, 1 or 2; 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), and is selected from the group consisting of, wherein the heterocycloalkyl has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and the heterocycloalkyl group are independently 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; Each R ３ is independently halogen, CN, C １－７ alkyl, C ２－７ alkenyl, C ３－７ alkynyl, C ３－７ cycloalkyl, C １－６ haloalkyl, C １－６ hydroxyalkyl, C １－６ halohydroxyalkyl, -O-C １－７ alkyl, -O-C ３－７ cycloalkyl, -O-C １－６ haloalkyl, -X １ -CN, -X １ -O-C １－７ alkyl, -O-Y １ -O-C １－７ alkyl, -NR ａ R ｂ , -X １ -NR ａ R ｂ , -O-Y １ -NR ａ R ｂ , -C(O)-NR ａ R ｂ , -S(O) ２ -NR ａ R ｂ , -S(O)(NH)-C １－７ alkyl, -S(O) ２ -C １－７ alkyl, -S(O) ２ -C １－７ haloalkyl, -S(O) ２ -C ３－７ cycloalkyl, -S(O) ２ -Y １ -O-C １－３ alkyl, -S(O) ２ -C ４－７ heterocycloalkyl, -C(O)NH-(4- to 8-membered heterocycloalkyl), 4- to 8-membered heterocycloalkyl, and -O-X １ - (4- to 8-membered heterocycloalkyl) selected from the group consisting of, said heterocycloalkyl having 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and the heterocycloalkyl group are independently halo, CN, 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 is C １－７ alkylene or C ３－７ 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 which is independently selected from the group consisting of H, C １－７ alkyl, C １－７ haloalkyl, C １－４ alkoxy C １－４ alkyl, and C ３－７ cycloalkyl; or R ａ and R ｂ together with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkyl ring having 0 to 2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, and are substituted with 0 to 3 groups independently selected from 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 alkyl, oxo, and OH, or a pharmaceutically acceptable salt thereof.

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

3. G ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G 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 G4 may be CH, and optionally G5 may be CH.

5. The fused cyclopentane ring in formula (Ib) has the formula: 【Chemical Formula 3】 And optionally, one of R2 may be -NRaRb. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6.

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

8. The fused azepane ring in formula (Ie) has the formula: 【Chemical 4】 having Optionally, said 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- to 8-membered heterocycloalkyl) and -X1-(4- to 8-membered heterocycloalkyl), said heterocycloalkyl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and the cycloalkyl group and the heterocycloalkyl group are independently substituted with 0 to 3 groups selected from halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -O-C1-4 alkyl, and OH. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. Formula (Ic): 【Chemical Formula 5】 having, wherein R ６ is halo, CN, C １－４ alkyl, C １－４ haloalkyl, C １－４ hydroxyalkyl, -O-C １－４ alkyl, oxo, and OH, and is selected from the group consisting of Optionally, formula (Id): 【Chemical Formula 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which may have.

10. The following: [Chemical Formula 7] A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

11. The following: 【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, or a pharmaceutically acceptable salt thereof.

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

13. A medicament 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, or the pharmaceutical composition according to claim 12.

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

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

16. The pharmaceutical or pharmaceutical composition according to claim 15, wherein the at least one additional therapeutic agent independently comprises one or more agents selected from the group consisting of an inhibitor of the CD47-SIRPα pathway (e.g., an anti-CD47 antibody), an inhibitor of HIF (e.g., an HIF-2α inhibitor), an immune checkpoint inhibitor, an agent targeting extracellular production of adenosine, a radiotherapy agent, and a chemotherapeutic agent.

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 additional therapeutic agent.

18. The combination according to claim 17, wherein the at least one additional therapeutic agent independently comprises one or more agents selected from the group consisting of an inhibitor of the CD47-SIRPα pathway (e.g., an anti-CD47 antibody), an inhibitor of HIF (e.g., an HIF-2α inhibitor), an immune checkpoint inhibitor, an agent targeting extracellular production of adenosine, radiotherapy, and a chemotherapeutic agent.

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