Compounds as AXL inhibitors

Abstract

Described herein are AXL-inhibiting compounds of Formula I, and compositions containing the compounds and methods for synthesizing the compounds. Also described are uses of such compounds and compositions for the treatment of a diverse range of diseases, disorders and conditions mediated, at least in part, by AXL, including cancer. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application Serial No. 63 / 356,421, filed on June 28, 2022, the disclosure of which is incorporated herein by reference in its entirety. Background Art

[0003] The following discussion is provided to assist the reader in understanding the present disclosure and is not admitted to describe or constitute prior art.

[0004] AXL is a receptor tyrosine kinase (RTK) belonging to the TAM family. AXL regulates important processes such as cell growth, migration, aggregation, and apoptosis. AXL can be activated by multiple mechanisms, including ligand-dependent and ligand-independent mechanisms. Once activated, AXL participates in multiple signaling pathways, including the RAS-RAF-MEK-ERK pathway, which leads to cancer cell proliferation, and the PI3K / AKT pathway, which is responsible for several pro-survival proteins.

[0005] AXL has been shown to be overexpressed in a variety of malignancies. In the cancer setting, AXL overexpression is associated with poor patient survival and drug resistance mechanisms (both targeted and non-targeted).

[0006] In light of research linking AXL inhibition to diseases such as cancer, there is a need in the art for new AXL inhibitors. The present disclosure addresses this need and provides additional advantages over previous AXL inhibitors. Summary of the Invention

[0007] In one aspect, the present disclosure relates to compounds that inhibit AXL activity. The compound is represented by formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] X is CR 5 or N;

[0011] G 1 Is N or CR G1 ;

[0012] G 2 It's CR G2 or N;

[0013] G 3 It's CR G3 or N;

[0014] G 4 It's CR G4or N;

[0015] G 5 It's CR G5 or N;

[0016] R G1 Selected from the group consisting of: H, C 1-3 Alkyl, halogen, C 1-3 Haloalkyl and CN;

[0017] Each R G2 、R G3 、R G4 and R G5 are independently selected from the group consisting of: H, halogen, CN, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 Halogenated alkyl, -NR a R b and 5-8 membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein the cycloalkyl and heterocycloalkyl are substituted with 0-3 groups independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and OH;

[0018] 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 replaced by 1 to 4 R 2 and further substituted with 0 or 1 oxo (=O) located on the carbon atom adjacent to the nitrogen atom;

[0019] R 1 is selected from the group consisting of phenyl and 5 to 6 membered heteroaryl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each phenyl and heteroaryl is separated by one R 1a and 0-3 Rs 3 replace;

[0020] R 1aselected from the group consisting of phenyl and 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the N atom when present is optionally oxidized, and wherein each phenyl and heteroaryl is substituted by 0-4 R 4 replace;

[0021] Each R 2 Independently selected from the group consisting of: 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 , 5- to 8-membered heterocycloalkyl, -NR a -(5- to 8-membered heterocycloalkyl), -C(O)-(5- to 8-membered heterocycloalkyl), -X 1 -5 to 8 membered heterocycloalkyl and -OX 1 -(5 to 8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each cycloalkyl and heterocycloalkyl is substituted with 0-3 groups independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and OH;

[0022] Each R 3 Independently selected from the group consisting of halogen, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated hydroxyalkyl, -OC 1-7 Alkyl, -OC 1-6 Halogenated alkyl, -NR a R b 、-C(O)-NR a R b 、-S(O)2-NRa R b 、-S(O)(NH)-C 1-7 Alkyl, -S(O)2-C 1-7 Alkyl and -S(O)2-C 1-7 alkyl halide;

[0023] Each R 4 Independently selected from the group consisting of: C 1-7 Alkyl, halogen, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene-CN, hydroxyl, C 1-7 Hydroxyalkyl, -C(O)NR a R b 、C 3-7 Cycloalkyl, -NR a -C(O)-C 1-7 Alkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -S(O)2-NR a R b 、-NR a -S(O)2-C 1-7 Alkyl and -NR a -S(O)2-C 3-7 Cycloalkyl, wherein each cycloalkyl and heterocycloalkyl is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl, halide, and hydroxyl groups;

[0024] Or, two R on the same ring vertex 4 The groups combine to form an oxo (=O); or

[0025] Two R on adjacent ring vertices 4 The groups are combined to form a 5- to 6-membered heterocycloalkyl group having 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5- to 6-membered heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl and halide groups;

[0026] R 5 Selected from the group consisting of: H, C 1-4 Alkyl and -NH2;

[0027] Each X 1 It is C 1-7 Alkylene or C 3-7 cycloalkylene;

[0028] Each Y 1 It is C 2-7 Alkylene or C 3-7 cycloalkylene;

[0029] Each R a and R b Independently selected from the group consisting of: H, C 1-7 Alkyl, C 1-7 Halogenated alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-7 Cycloalkyl, wherein the cycloalkyl is optionally substituted with -OC 1-3 Alkyl substitution; or

[0030] R a and R b Together with the nitrogen to which they are attached, they form a 4- to 8-membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the heterocycloalkyl ring is substituted with 0-3 groups, each group being independently selected from halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and X 1 -OC 1-3 Alkyl and OH; or two groups at the same ring vertex combine to form oxo (=O).

[0031] In another aspect, the present disclosure relates to pharmaceutical compositions comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0032] In another aspect, the present disclosure relates to a method of inhibiting AXL in a subject, comprising administering to the subject an effective amount of a compound described herein.

[0033] In another aspect, the present disclosure provides a method for treating a disease, condition, or disorder in a subject that is at least partially mediated by AXL, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Diseases, conditions, and disorders mediated by AXL include, for example, cancer, viral infections, and fibrosis. Certain aspects of the present disclosure further include the administration of one or more additional therapeutic agents, as described below. DETAILED DESCRIPTION

[0034] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to the particular embodiments set forth herein and that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0035] Where a range of values ​​is provided, unless the context clearly dictates otherwise, each intermediate value (to one tenth of the unit of the lower limit) between the upper and lower limits of this range and any other specified value or intermediate value within the sub-specified range are encompassed within the present disclosure. The upper and lower limits of these smaller ranges may be independently included within the smaller range and are also encompassed within the present disclosure, subject to any specific exclusive limitations within the specified range. Where the specified range includes one or both of the limits, the range excluding either or both of those included limits is also encompassed within the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs.

[0036] Unless otherwise defined, all technical terms, symbols, and other scientific terms or terminology used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0037] The term "about" as used herein has its ordinary meaning of approximation and is intended to provide literal support for the exact number preceding it and a number close to or approximately the number preceding the term. In general, the term "about" refers to the usual error range of the respective values ​​that are readily known to those skilled in the art. If the degree of approximation is not otherwise obvious from the context, "about" means within plus or minus 10% of the value provided, or rounded to the nearest significant figure, including the value provided in all cases. Where a range is provided, it includes the boundary values.

[0038] definition

[0039] Unless otherwise stated, the following terms are intended to have the meanings set forth below. Other terms are defined elsewhere throughout the specification.

[0040] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a saturated straight or branched chain hydrocarbon radical (i.e., C 1-8 represents one to eight carbons). Alkyl groups may include any number of carbons, such as C 1-2 、C 1-3 、C 1-4 、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 (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. In some embodiments, alkyl is C 1-4 an alkyl group (eg, methyl, ethyl, isopropyl, or tert-butyl).

[0041] The term "hydroxyalkyl" refers to a group having the specified number of carbon atoms (e.g., C 1-6 or C 1-8 ) and substituted with one or two hydroxy (OH) groups.

[0042] The term "alkylene" refers to a straight or branched chain saturated aliphatic group having a specified number of carbon atoms and linking at least two other groups, i.e., divalent hydrocarbon groups. The two moieties linked to the alkylene group may be linked to the same atom or to different atoms of the alkylene group. For example, a straight chain alkylene group may be -(CH2) n -divalent radical, wherein n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secondary butylene, pentylene and hexylene. In some embodiments, the alkylene group may be substituted or unsubstituted. When a group comprising an alkylene group is optionally substituted, it is understood that the optional substitution may be on the alkylene portion of the moiety. In some embodiments, the alkylene group is C 1-3 Alkylene (e.g., methylene, ethylene, propylene, or isopropylene).

[0043] The term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic non-aromatic hydrocarbon ring system (e.g., C 3-6Cycloalkyl groups have 3 to 6 ring carbon atoms). Cycloalkyl groups may be saturated or partially unsaturated, i.e., a cycloalkyl group may be characterized by one or more points of unsaturation, provided that 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 groups of the present disclosure are monocyclic C 3-5 A cycloalkyl moiety (eg, cyclopropyl, cyclobutyl, or cyclopentyl).

[0044] The term "heterocycloalkyl" refers to a non-aromatic monocyclic, bicyclic, or polycyclic cycloalkyl ring having, in some embodiments, 3 to 14 members (e.g., 3 to 14-membered heterocycle), or 3 to 10 members (e.g., 3 to 10-membered heterocycle), or 3 to 8 members (e.g., 3 to 8-membered heterocycle), or 3 to 6 members (e.g., 3 to 6-membered heterocycle), or 5 to 6 members (e.g., 5 to 6-membered heterocycle), and having one to five, one to four, one to three, one to two, or one heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S). In some embodiments, the nitrogen and sulfur atoms of the heterocycloalkyl are optionally oxidized (e.g., N-oxide (N-Oxide)). + -O -), sulfoxide (S=O) or sulfone (S(=O) 2)), and the nitrogen atom is optionally quaternized. Heterocycloalkyl is saturated or characterized by one or more points of unsaturation (e.g., one or more carbon-carbon double bonds, carbon-carbon triple bonds, carbon-nitrogen double bonds and / or nitrogen-nitrogen double bonds), provided that the unsaturation does not result in an aromatic system. The rings of bicyclic and polycyclic heterocycloalkyls can be fused, bridged or spirocyclic. Non-limiting examples of heterocycloalkyls include aziridine, oxirane, thiirane, pyrrolidine, imidazolidine, pyrazolidine, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, 3,4,5,6-tetrahydropyridazine, pyran, decahydroisoquinoline, 3-pyrrolidine, thiopyran, tetrahydrofuran, Tetrahydropyran, tetrahydrothiophene, quinuclidine, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 1-oxaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane, etc. When chemically permitted, the heterocycloalkyl group can be attached to the rest of the molecule through a ring carbon atom or a ring heteroatom. In some embodiments, the heterocycloalkyl groups of the present disclosure are monocyclic 5- to 8-membered heterocycloalkyl moieties having one or two heteroatoms or heteroatom groups selected from N and O (e.g., oxazolidine, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydropyran, dioxane, 3-oxa-6-azabicyclo[3.1.1]heptane, or 2-oxa-5-azabicyclo[2.2.1]heptane).

[0045] As used herein, a wavy line that intersects a single, double, or triple bond in any chemical structure depicted herein Indicates 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 benzene ring) is intended to indicate that the substituent is attached to the ring at any available ring vertex, i.e., such that attachment of the substituent to the ring results in a chemically stable arrangement.

[0046] Unless otherwise stated, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0047] The term "aryl" refers to a group containing one ring or two or three rings fused together and having, in some embodiments, six to fourteen carbon atoms (ie, C 6-14 aryl), or six to ten carbon atoms (i.e., C6-10 In some embodiments, the aryl group is a phenyl group.

[0048] The term "heteroaryl" refers to a monocyclic or fused bicyclic aromatic group (or ring) having, in some embodiments, 5 to 14 members (i.e., ring vertices) (i.e., 5- to 14-membered heteroaryl), or 5 to 10 members (i.e., 5- to 10-membered heteroaryl), or 5 to 6 members (i.e., 5- to 6-membered heteroaryl), and containing one to five, one to four, one to three, one to two, or one heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S). In some embodiments, the nitrogen and sulfur atoms are optionally oxidized (e.g., N-oxides (N-Oxides)). + -O - ), sulfoxide (S=O) or sulfone (S(=O)2)), and the nitrogen atom is optionally quaternized. When chemically permitted, the heteroaryl group can be attached to the rest of the molecule through a carbon atom or a heteroatom of the heteroaryl group. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thiarolyl, thiazolyl, furanyl, thienyl, and the like. When heteroaryl is substituted, the substituent is connected to the heteroaryl through a ring carbon atom or a ring heteroatom when chemically permitted. In some embodiments, the heteroaryl of the present disclosure is a monocyclic 5 to 6 membered heteroaryl moiety containing 1-3 heteroatoms independently selected from N, O and S, and wherein the N atom is optionally oxidized (e.g., pyridyl, pyridyl N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl or thiazolyl) when present.

[0049] The compounds of the present disclosure may exist in their neutral form, or as pharmaceutically acceptable salts, isomers, polymorphs or solvates thereof, and may exist in crystalline form, amorphous form or mixtures thereof.

[0050] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. 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, including 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, glucosamine, glucosamine, histidine, hydrazine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively nontoxic 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain basic and acidic functional groups that allow the compounds to be converted into base or acid addition salts.

[0051] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for purposes of this disclosure, the salts are equivalent to the parent form of the compound.

[0052] The present disclosure also encompasses isomers (e.g., stereoisomers and atropisomers) of the compounds described herein. For example, certain compounds of the present disclosure possess asymmetric carbon atoms (chiral centers) or hindered rotation about single bonds; their racemates, diastereomers, enantiomers, and atropisomers (e.g., R a 、S a , P and M isomers) are intended to be encompassed within the scope of this disclosure. Stereoisomeric forms may be defined in terms of absolute stereochemistry as (R) or (S), and / or depicted using dashes and / or wedges. When stereochemistry is described (e.g., using dashes), and / or wedge ) is shown in a chemical structure, or stereochemical assignment (e.g., using (R) and (S) symbols) is named in a chemical name, indicating that the depicted isomer is present and is substantially free of one or more other isomers (e.g., when present, enantiomers and diastereomers). "Substantially free" of other isomers means that the ratio of the specified isomer to the other isomers is at least 70 / 30, more preferably 80 / 20, 90 / 10 or 95 / 5 or higher. In some embodiments, the specified isomer will be present in an amount of at least 99%. Chemical bonds to asymmetric carbons depicted as solid lines (-) indicate that all possible stereoisomers (e.g., enantiomers, diastereomers, racemic mixtures, etc.) on the carbon atom are included. In such cases, the compound can exist as a racemic mixture, a non-racemic (scalemic) mixture, or a mixture of diastereomers.

[0053] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms comprising such compounds. An unnatural proportion of an isotope may be defined as the amount ranging from the amount found in nature to that consisting of 100% of the relevant atoms. For example, a compound may incorporate a radioactive isotope, such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C). Such isotopic variations may be those described elsewhere herein to provide additional utility. For example, isotopic variants of the disclosed compounds may find additional utility, including but not limited to as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of the disclosed compounds may have altered pharmacokinetic and pharmacodynamic characteristics, which may help enhance safety, tolerability, or efficacy during treatment. All isotopic variations of the disclosed compounds, whether radioactive or not, are intended to be encompassed within the scope of this disclosure. In some embodiments, the compounds according to the present disclosure are characterized by one or more deuterium atoms.

[0054] The terms "patient" or "subject" are used interchangeably to refer to a human or a non-human animal (eg, a mammal).

[0055] The terms "treat," "treating," "treatment," and the like refer to a course of action that temporarily or permanently eliminates, reduces, inhibits, lessens, ameliorates, or prevents worsening of the disease, disorder, or condition, or at least one symptom associated therewith, to which the term applies. Treatment includes alleviating symptoms, reducing the extent of the disease, inhibiting (e.g., arresting the development or further development of) active disease, delaying or slowing disease progression, improving quality of life, and / or prolonging a subject's survival as compared to expected survival if not receiving treatment or as compared to published standard of care treatment for the particular disease.

[0056] As used herein, the term "in need of treatment" refers to a judgment made by a physician or similar professional that a subject requires or will benefit from treatment. This judgment is based on a variety of factors within the physician's expertise, which may include a positive diagnosis of a disease, condition, or disorder.

[0057] The terms "prevent," "preventing," "prevention," "prophylaxis," and the like refer to a course of action initiated in some manner (e.g., before the onset of a disease, condition, illness, or its symptoms) to temporarily or permanently prevent, curb, inhibit, or reduce the risk of a subject developing a disease, condition, illness, or similar condition (e.g., as determined by the absence of clinical symptoms) or delaying its onset, typically in the case of a subject susceptible to a particular disease, condition, or illness. In some cases, the terms also refer to slowing the progression of a disease, condition, or illness or inhibiting its progression to a harmful or undesirable state. Preventing also refers to a course of action initiated in a subject after the subject has been treated for a disease, condition, illness, or related symptom to prevent the recurrence of the disease, condition, illness, or symptom.

[0058] As used herein, the term "in need of prevention" refers to a judgment made by a physician or other health care provider that a subject requires or will benefit from preventive care. This judgment is based on a variety of factors within the physician's or health care provider's expertise.

[0059] "Substantially pure" means that a component (e.g., a compound according to the present disclosure) comprises greater than about 50% of the total content of the composition, and typically comprises greater than about 60% of the total content. More typically, "substantially pure" refers to a composition in which at least 75%, at least 85%, at least 90%, or more of the total composition is the component of interest. In some cases, the component of interest will comprise greater than about 90% or greater than about 95% of the total content of the composition.

[0060] Compounds with selectivity may be particularly useful in treating certain conditions or may reduce the likelihood of undesirable side effects. In some embodiments, the compounds of the present disclosure are selective relative to other tyrosine kinases. Specific examples include TYRO3 and MER. Selectivity can be determined, for example, by comparing the inhibition of AXL by a compound described herein with the inhibition of another protein by a compound described herein. In one embodiment, the selective inhibition of AXL is at least 1000 times greater, 500 times greater, or 100 times greater, or 75 times greater, or 50 times greater, or 40 times greater, or 30 times greater, or 25 times greater, or 20 times greater than the inhibition of another kinase (e.g., TYRO3 and / or MER).

[0061] The compounds provided herein can have favorable pharmacokinetic characteristics, including, for example, inhibition of CYP, bioavailability, and / or inhibition of the human Ether-a-go-go related gene (hERG) potassium channel.

[0062] Compounds of the present disclosure

[0063] In some aspects, provided herein are compounds represented by formula (I)

[0064]

[0065] or a pharmaceutically acceptable salt thereof, wherein:

[0066] X is CR 5 or N;

[0067] G 1 Is N or CR G1 ;

[0068] G 2 It's CR G2 or N;

[0069] G 3 It's CR G3 or N;

[0070] G 4 It's CR G4 or N;

[0071] G 5 It's CR G5 or N;

[0072] R G1 Selected from the group consisting of: H, C 1-3 Alkyl, halogen, C 1-3 Haloalkyl and CN;

[0073] Each R G2 、R G3 、R G4 and RG5 are independently selected from the group consisting of: H, halogen, CN, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 Halogenated alkyl, -NR a R b and 5-8 membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein the cycloalkyl and heterocycloalkyl are substituted with 0-3 groups independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and OH;

[0074] 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 replaced by 1 to 4 R 2 and further substituted with 0 or 1 oxo (=O) located on the carbon atom adjacent to the nitrogen atom;

[0075] R 1 is selected from the group consisting of phenyl and 5 to 6 membered heteroaryl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each phenyl and heteroaryl is separated by one R 1a and 0-3 Rs 3 replace;

[0076] R 1a selected from the group consisting of phenyl and 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the N atom when present is optionally oxidized, and wherein each phenyl and heteroaryl is substituted by 0-4 R 4 replace;

[0077] Each R 2 Independently selected from the group consisting of: 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 Rb 、-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 , 5- to 8-membered heterocycloalkyl, -NR a -(5- to 8-membered heterocycloalkyl), -C(O)-(5- to 8-membered heterocycloalkyl), -X 1 -5 to 8 membered heterocycloalkyl and -OX 1 -(5 to 8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each cycloalkyl and heterocycloalkyl is substituted with 0-3 groups independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and OH;

[0078] Each R 3 Independently selected from the group consisting of halogen, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated hydroxyalkyl, -OC 1-7 Alkyl, -OC 1-6 Halogenated alkyl, -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 and -S(O)2-C 1-7 alkyl halide;

[0079] Each R 4 Independently selected from the group consisting of: C 1-7 Alkyl, halogen, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene-CN, hydroxyl, C 1-7 Hydroxyalkyl, -C(O)NR a Rb 、C 3-7 Cycloalkyl, -NR a -C(O)-C 1-7 Alkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -S(O)2-NR a R b 、-NR a -S(O)2-C 1-7 Alkyl and -NR a -S(O)2-C 3-7 Cycloalkyl, wherein each cycloalkyl and heterocycloalkyl is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl, halide, and hydroxyl groups;

[0080] Or, two R on the same ring vertex 4 The groups combine to form an oxo (=O); or

[0081] Two R on adjacent ring vertices 4 The groups are combined to form a 5- to 6-membered heterocycloalkyl group having 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5- to 6-membered heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl and halide groups;

[0082] R 5 Selected from the group consisting of: H, C 1-4 Alkyl and -NH2;

[0083] Each X 1 It is C 1-7 Alkylene or C 3-7 cycloalkylene;

[0084] Each Y 1 It is C 2-7 Alkylene or C 3-7 cycloalkylene;

[0085] Each R a and R b Independently selected from the group consisting of: H, C1-7 Alkyl, C 1-7 Halogenated alkyl, C 1-4 Alkoxy C 1-4 Alkyl and C 3-7 Cycloalkyl, wherein the cycloalkyl is optionally substituted with -OC 1-3 Alkyl substitution; or

[0086] R a and R b Together with the nitrogen to which they are attached, they form a 4- to 8-membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the heterocycloalkyl ring is substituted with 0-3 groups, each group being independently selected from halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and X 1 -OC 1-3 Alkyl and OH; or two groups at the same ring vertex combine to form oxo (=O).

[0087] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 1 Is N or CR G1 , where R G1 Is H. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 1 is N. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 1 It's CR G1 , where R G1 It’s H.

[0088] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 2 It's CR G2 , where R G2 is H or F. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 2 It's CR G2 , where R G2 Is H. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 2 It's N.

[0089] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 3 Is N or CR G3 , and R G3 It is H or CH3.

[0090] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 4 Is N or CR G4 , where R G4 It’s H.

[0091] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 5 Is N or CR G5 , where R G5 It’s H.

[0092] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 1 is N, and G 2 It's CR G2 , where R G2 It’s H.

[0093] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 3 It's CR G3 , where R G3 It’s H.

[0094] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 4 It's CR G4 , where R G4 It’s H.

[0095] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein G 5 It's CR G5 , where R G5 It’s H.

[0096] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein X is N or CR 5 , where R 5 Is H. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein X is CR5 , where R 5 It’s H.

[0097] As for A, it can be understood from the formula shown above that A and G 3 , G 4 and G 5 The aromatic rings are fused, and the presence of A does not destroy the 3 , G 4 and G 5 Specifically, the ring vertex fusing the two rings together is sp 2 hybridized carbon atoms. Thus, each of these ring vertices has a p orbital that participates in the conjugated π system of the aromatic ring. Thus, as will be understood from the formula shown above, moiety A has a point of unsaturation at the point of fusion with the rest of the molecule. For example, cyclopentane at A refers to cyclopentene, in which the double bond is between the two carbon atoms fused to the rest of the compound, as further exemplified and detailed throughout.

[0098] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein A has a formula selected from the group consisting of:

[0099]

[0100] Each of them is represented by 1 to 4 R 2 replace.

[0101] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein A has a formula selected from the group consisting of:

[0102]

[0103] Each of them is represented by 1 to 4 R 2 replace.

[0104] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein A has the formula

[0105]

[0106] It is composed of 1 to 4 R 2 replace.

[0107] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein A has the formula

[0108]

[0109] Where A is replaced by 1 to 4 R 2 replace.

[0110] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein A is replaced by at least one R selected from the group consisting of 2 Replaces: -C 2-7 Alkylene-OC 1-4 Alkyl and C 3-7 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein A is replaced by at least one R selected from the group consisting of 2 replace:

[0111] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein A has the formula:

[0112]

[0113] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein A has the formula:

[0114]

[0115] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein A has the formula:

[0116]

[0117] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R 2 Independently selected from the group consisting of: 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 3-7Cycloalkyl, -C(O)NR a R b , 5- to 8-membered heterocycloalkyl, -NR a -(5- to 8-membered heterocycloalkyl), -C(O)-(5- to 8-membered heterocycloalkyl), -X 1 -5 to 8 membered heterocycloalkyl and -OX 1 -(5- to 8-membered heterocycloalkyl), wherein said 5- to 8-membered heterocycloalkyl, -NR a -(5- to 8-membered heterocycloalkyl), -C(O)-(5- to 8-membered heterocycloalkyl), -X 1 -5 to 8 membered heterocycloalkyl and -OX 1 -(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein said C 3-7 Cycloalkyl, -Y 1 -OC 3-7 Cycloalkyl, -C(O)-C 3-7 Cycloalkyl, -S(O)2-C 3-7 Cycloalkyl, 5- to 8-membered heterocycloalkyl, -NR a -(5- to 8-membered heterocycloalkyl), -C(O)-(5- to 8-membered heterocycloalkyl), -X 1 -5 to 8 membered heterocycloalkyl and -OX 1 -(5 to 8 membered heterocycloalkyl) each substituted by 0-3 groups independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein one R 2 Yes-NR a R b .

[0118] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein one R 2 Selected from the group consisting of:

[0119]

[0120] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein one R 2 yes

[0121]

[0122] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl and pyrazolyl, wherein R 1 By an R 1a and 0-2 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 is selected from the group consisting of phenyl, pyridyl, pyridazinyl and pyrazolyl, wherein R 1 By an R 1a and 0-2 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 is selected from the group consisting of pyrimidinyl, pyrazinyl and oxadiazolyl, wherein R 1 By an R 1a and 0-2 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 is phenyl or pyridyl, where R 1 By an R 1a and 0-2 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 Is an R 1a and 0-2 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 Is an R 1a and 0-2 R 3 Substituted phenyl.

[0123] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 Selected from the group consisting of:

[0124]

[0125] where the subscript p is 0 or 1.

[0126] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1Selected from the group consisting of:

[0127]

[0128] where the subscript p is 0 or 1.

[0129] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 Selected from the group consisting of:

[0130]

[0131] where the subscript p is 0 or 1.

[0132] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 Selected from the group consisting of:

[0133]

[0134] where the subscript p is 0 or 1.

[0135] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 Selected from the group consisting of:

[0136]

[0137] where the subscript p is 0 or 1.

[0138] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 yes

[0139]

[0140] where the subscript p is 0 or 1.

[0141] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 yes

[0142]

[0143] where the subscript p is 0 or 1.

[0144] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 yes

[0145]

[0146] where the subscript p is 0 or 1.

[0147] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 0 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1 By 1 R 3 Group substitution.

[0148] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R 3 When present, independently selected from the group consisting of: halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated hydroxyalkyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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 and -S(O)2-C 1-4 Halogenated alkyl.

[0149] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R 3 When present, independently selected from the group consisting of: halogen, C 1-4 Alkyl and -OC 1-4 alkyl.

[0150] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R 3 When present are independently selected from the group consisting of chloro, fluoro, methyl and methoxy.

[0151] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R3 When present is independently selected from the group consisting of fluoro, methyl and methoxy.

[0152] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a is selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl N-oxide and phenyl, wherein R 1a 0-3 R 4 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a is selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and phenyl, wherein R 1a 0-3 R 4 replace.

[0153] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0154]

[0155] where subscript q is 0, 1, or 2.

[0156] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0157]

[0158] where subscript q is 0, 1, or 2.

[0159] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0160]

[0161] where subscript q is 0, 1, or 2.

[0162] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0163]

[0164] where subscript q is 0, 1, or 2.

[0165] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0166]

[0167] where subscript q is 0, 1, or 2.

[0168] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0169]

[0170] where subscript q is 0, 1, or 2.

[0171] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0172]

[0173] where subscript q is 0, 1, or 2.

[0174] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0175]

[0176] where subscript q is 0, 1, or 2.

[0177] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0178]

[0179] where subscript q is 0, 1, or 2.

[0180] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0181]

[0182] where subscript q is 0, 1, or 2.

[0183] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0184]

[0185] where q is either 0 or 1.

[0186] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0187]

[0188] Each of which is optionally replaced by an additional R 4 replace.

[0189] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Selected from the group consisting of:

[0190]

[0191] In some embodiments, R 1a The heteroaryl moiety in includes groups substituted by one or more oxo substituents according to Huckel's rule. Therefore, in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a The heteroaryl group includes two R groups bonded at the same ring vertex to form an oxo group (=O). 4 Group. Exemplary groups include, but are not limited to, pyridazinone and pyridinone. Thus, in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound wherein R 1a Two R groups bonded to the same ring vertex to form an oxo group (=O) 4 The groups together form a heteroaryl moiety selected from the group consisting of pyridazinone and pyridinone, wherein R 1a 0-2 additional R 4 Group substitution.

[0192] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 1a Include 2-4 R's 4 Part and selected from the group consisting of:

[0193]

[0194] where subscript q is 0, 1, or 2.

[0195] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 4 Independently selected from the group consisting of: C 1-7 Alkyl, halogen, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene-CN, hydroxyl, C 1-7 Hydroxyalkyl, -C(O)NR a R b 、C 3-7 Cycloalkyl, -NR a -C(O)-C 1-7 Alkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -S(O)2-NR a R b 、-NR a -S(O)2-C 1-7 Alkyl and -NR a -S(O)2-C 3-7 Cycloalkyl, wherein each C 3-7 Cycloalkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -S(O)2-C 3-7 Cycloalkyl, -NR a -S(O)2-C 3-7Cycloalkyl, -O-(5- to 8-membered heterocycloalkyl), and -5- to 8-membered heterocycloalkyl are substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl, halo and hydroxy.

[0196] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R 4 When present, independently selected from the group consisting of: C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, CN, -C 1-4 Alkylene -CN, C 1-4 Hydroxyalkyl, -C(O)NR a R b 、C 3-7 Cycloalkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 6-membered heterocycloalkyl) having 1-3 heteroatoms selected from the group consisting of O, N and S, -S(O)2-C 1-4 Alkyl and -S(O)2-NR a R b , wherein each cycloalkyl and heterocycloalkyl group is substituted with 0 to 2 groups selected from the group consisting of: C 1-4 Alkyl, halogen and hydroxyl; or, two R groups at the same ring vertex combined to form an oxo group (=O) 4 group.

[0197] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R 4 When present, independently selected from the group consisting of: C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, CN, -C 1-4 Alkylene -CN, C 1-4 Hydroxyalkyl, -C(O)NR a R b 、C 3-7 Cycloalkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a Rb 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 6-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O)2-C 1-4 Alkyl and -S(O)2-NR a R b , wherein each cycloalkyl and heterocycloalkyl group is substituted with 0 to 2 groups selected from the group consisting of: C 1-4 Alkyl, halogen and hydroxyl; or, two R groups at the same ring vertex combined to form an oxo group (=O) 4 group.

[0198] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R 4 When present, independently selected from the group consisting of: C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, CN, -C 1-4 Alkylene -CN, C 1-4 Hydroxyalkyl, -C(O)NR a R b 、C 3-7 Cycloalkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 6-membered heterocycloalkyl) having 1-3 heteroatoms selected from the group consisting of O, N and S, -S(O)2-C 1-4 Alkyl, -S(O)2-NR a R b , wherein each cycloalkyl and heterocycloalkyl group is substituted with 0 to 2 groups selected from the group consisting of: C 1-4 Alkyl, halo and hydroxy.

[0199] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R 4 When present, independently selected from the group consisting of: C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -OC1-4 Haloalkyl, CN, -C 1-4 Alkylene -CN, C 1-4 Hydroxyalkyl, -C(O)NR a R b 、C 3-7 Cycloalkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 6-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O)2-C 1-4 Alkyl, -S(O)2-NR a R b , wherein each cycloalkyl and heterocycloalkyl group is substituted with 0 to 2 groups selected from the group consisting of: C 1-4 Alkyl, halo and hydroxy.

[0200] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R 4 When present, independently selected from the group consisting of: methyl, ethyl, fluoro, chloro, difluoromethyl, trifluoromethyl, CN, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy,

[0201]

[0202] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein each R 4 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R 4 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R 4 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R 4 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R 4 When present, it is independently CN.

[0203] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein two R 4 The groups are combined to form a 5- to 6-membered heterocycloalkyl group having 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5- to 6-membered heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl and halide.

[0204] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein two R 4 The groups are combined to form a heterocycloalkyl group selected from the group consisting of:

[0205]

[0206] wherein the heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 In some embodiments, the heterocycloalkyl group is replaced by a C 1-4 Alkyl substitution.

[0207] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein A has a formula selected from the group consisting of:

[0208]

[0209] Each of which is further represented by 0 to 2 independently selected R 2 Group substitution.

[0210] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein A has the formula:

[0211]

[0212] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound wherein R 2 Selected from the group consisting of: C 1-7 Alkyl, C 3-6 Cycloalkyl, -Y 1 -OC 1-4 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -C(O)-C 1-7 Alkyl, -C(O)-C 3-7Cycloalkyl, 5- to 8-membered heterocycloalkyl, -C(O)-(5- to 8-membered heterocycloalkyl), and -X 1 -(5 to 8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein the cycloalkyl and heterocycloalkyl are substituted with 0-3 groups independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and OH.

[0213] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound having formula (Ia):

[0214]

[0215] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (Ia1):

[0216]

[0217] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (Ib):

[0218]

[0219] wherein subscript m is 0 or 1; and n is 0, 1, or 2, and each R 2 Can be the same or different.

[0220] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (Ib1):

[0221]

[0222] wherein subscript m is 0 or 1; and n is 0, 1, or 2, and each R 2 Can be the same or different.

[0223] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (Ic):

[0224]

[0225] where R 6 Selected from the group consisting of: halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C1-4 Hydroxyalkyl, -OC 1-4 Alkyl, oxo and OH.

[0226] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (Ic1):

[0227]

[0228] where R 6 Selected from the group consisting of: halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl, oxo and OH.

[0229] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (Id):

[0230]

[0231] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (Id1):

[0232]

[0233] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (Ie):

[0234]

[0235] where subscript n is 0, 1, or 2, and each R 2 Can be the same or different.

[0236] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (Ie1):

[0237]

[0238] where subscript n is 0, 1, or 2, and each R 2 Can be the same or different.

[0239] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound having formula (If):

[0240]

[0241] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (If1):

[0242]

[0243] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein m is 0.

[0244] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound wherein n is 0.

[0245] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound having formula (II):

[0246]

[0247] or a pharmaceutically acceptable salt thereof, wherein:

[0248] X is CH or N;

[0249] G 1 is N or CH;

[0250] A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, and azepane, each of which is surrounded by 1 to 4 R 2 replace;

[0251] R 1 is selected from the group consisting of phenyl and 5 to 6 membered heteroaryl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each phenyl and heteroaryl is separated by one R 1a and 0-3 Rs 3 replace;

[0252] R 1a selected from the group consisting of phenyl and 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the N atom when present is optionally oxidized, and wherein each phenyl and heteroaryl is substituted by 0-4 R 4 replace;

[0253] Each R 2 Independently selected from the group consisting of: C 1-7 Alkyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -NR a R b , 5- to 8-membered heterocycloalkyl and -NRa -(5- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each cycloalkyl and heterocycloalkyl is substituted with 0-3 groups independently selected from: C 1-4 Alkyl and -OC 1-4 alkyl;

[0254] Each R 3 Independently selected from the group consisting of: halogen, C 1-7 Alkyl and -OC 1-7 alkyl;

[0255] Each R 4 Independently selected from the group consisting of: C 1-7 Alkyl, halogen, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene -CN, C 1-7 Hydroxyalkyl, -C(O)NR a R b 、C 3-7 Cycloalkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -S(O)2-C 1-7 Alkyl and -S(O)2-NR a R b , wherein each cycloalkyl and heterocycloalkyl group is substituted by 0 to 2 groups independently selected from the following: C 1-4 Alkyl and hydroxyl groups;

[0256] Or, two R on adjacent ring vertices 4 The groups are combined to form a 5- to 6-membered heterocycloalkyl group having 1 to 2 heteroatoms selected from the group consisting of O, N, and S, wherein the 5- to 6-membered heterocycloalkyl group is surrounded by 0 to 2 C 1-4 Alkyl substitution;

[0257] Each X 1 It is C 1-7 alkylene;

[0258] Each Y 1 It is C 2-7 alkylene;

[0259] Each R a and R b Independently selected from the group consisting of: H, C 1-7 Alkyl, C 3-7 Cycloalkyl, wherein the cycloalkyl is optionally substituted with -OC 1-3 Alkyl substitution; or

[0260] R a and R b Together with the nitrogen to which they are attached, they form a 4- to 8-membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the heterocycloalkyl ring is substituted with 0-3 groups, each group being independently selected from C 1-4 Alkyl, -OC 1-4 Alkyl and X 1 -OC 1-3 or two groups at the same ring vertex combine to form an oxo (=O).

[0261] In some selected embodiments, any one of the compounds described in the Examples or a pharmaceutically acceptable salt, solvate or hydrate thereof is provided. In some embodiments, any one of the compounds described in the Examples or a pharmaceutically acceptable salt thereof is provided. In other embodiments, any one of the compounds described in the Examples is provided.

[0262] Methods for preparing compounds of the present disclosure

[0263] In some aspects, the disclosure relates to methods for preparing compounds that inhibit the activity of AXL.

[0264] In some embodiments, the present disclosure relates to a method comprising:

[0265] a) contacting a compound of formula (A) with a compound of formula (B) in the presence of a first palladium catalyst to form a compound of formula (C):

[0266] as well as

[0267] b) contacting the compound of formula (C) with a deprotecting agent to form a compound of formula (D):

[0268]

[0269] Among them, X, G 1 、R 1 、R 1a and R 2 As defined herein; Q is N, CH or CR 2; PG is a protecting group; and one of Y and Z is Cl, Br, I or OTf, and the other is a borate ester.

[0270] In another embodiment, the present disclosure relates to a method comprising:

[0271] a) contacting a compound of formula (E) with a compound of formula (B-2) in the presence of a first palladium catalyst to form a compound of formula (C):

[0272] as well as

[0273] b) contacting the compound of formula (C) with a deprotecting agent to form a compound of formula (D):

[0274]

[0275] Among them, X, G 1 、R 1 、R 1a and R 2 As defined herein; Q is N, CH or CR 2 ; PG is a protecting group; and one of Y' and Z' is Cl, Br, I or OTf, and the other is a borate ester.

[0276] Any suitable borate ester can be used. Exemplary borate esters include, but are not limited to, pinacol borane (Bpin), catechol borane, and N-methyliminodiacetic acid borate (MIDA borate). In some embodiments, the borate ester is a borate having the formula -B(OR x )2, where each R x is H or C1-C3 alkyl, or two -OR x The groups together with the boron atom to which they are attached form pinacol borane (Bpin). In one embodiment, the boronate ester is Bpin.

[0277] The term "protecting group" refers to a compound portion that masks or changes the properties of a functional moiety. The protecting group can be removed to restore the functional moiety to its original state. Chemical protecting groups and protection / deprotection strategies are well known in the art. See also Protective Groups in Organic Chemistry, Peter G.M. Wuts and Theodora W. Greene, 4th edition, 2006. Protecting groups are typically used to mask the reactivity of certain functional moieties to help improve the efficiency of a desired chemical reaction, for example, to form and break chemical bonds in an orderly and planned manner. For example, a nitrogen protecting group refers to a protecting group that can be used to mask a nitrogen atom, for example, to prevent an amine or nitrogen-containing heteroaromatic hydrocarbon from reacting during an intermediate step. Exemplary nitrogen protecting groups include, but are not limited to, allyloxycarbonyl (Alloc), benzoylcarbonyl (Cbz), benzyl (Bz), allyl (All), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), trityl (Tr), tetrahydropyranyl ether (THP), and sulfonyl (e.g., methylsulfonyl (Ms), p-toluenesulfonyl (Ts), nitrobenzenesulfonyl (Ns), trifluoromethanesulfonyl (Tf), and phenylsulfone (—S(O) 2Ph)) groups. In some embodiments, the protecting group is phenylsulfone (—S(O) 2Ph), p-toluenesulfonyl (Ts), trityl (Tr), 2-(trimethylsilyl)ethoxymethyl (SEM), or tetrahydropyranyl ether (THP).

[0278] A "deprotecting agent" is a chemical reactant that can affect the removal of a protecting group. The deprotecting agent used will depend on, for example, the characteristics of the protecting group to be removed, and the reactivity of other functional groups present on the molecule. Typical deprotecting agents include reducing agents, oxidizing agents, acids, Lewis acids, bases, fluoride reagents, and enzymes. In general, ether protecting groups can be removed under acidic conditions; alkyl protecting groups can be removed under reducing conditions or by treatment with a Lewis acid; trityl protecting groups can be removed under acidic conditions or by treatment with a Lewis acid; acyl protecting groups can be removed under reducing conditions, under alkaline conditions, or by treatment with an enzyme; and benzyl protecting groups can be removed under reducing conditions or by treatment with a Lewis acid. Exemplary reducing agents include, but are not limited to, hydrogen, metal hydrides (e.g., diisobutylaluminum hydride (DIBAL) and lithium aluminum hydride (LAH)), or borohydrides (e.g., sodium borohydride). Exemplary bases include, but are not limited to, ammonia, methylamine, sodium methoxide, metal hydroxides (e.g., LiOH, NaOH, and KOH), and the like. Exemplary acids include, but are not limited to, HCl, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, etc. Exemplary Lewis acids include, but are not limited to, ZnCl2, ZnBr2, TiCl4, BF3, trimethylsilyl iodide (TMSI), etc. Exemplary oxidizing agents include, but are not limited to, dicyanodichloroquinone (DDQ), triethylenediamine (DABCO), poly (4-vinylpyridinium tribromide), hydrogen peroxide, etc. Exemplary enzymes include, but are not limited to, ester hydrolases or lipases.

[0279] In some embodiments, the protecting group is -S(O)2Ph or p-toluenesulfonyl (Ts), and the deprotecting agent is a base (e.g., NaOH). In another embodiment, the protecting group is tetrahydropyranyl ether (THP), trityl (Tr) or 2-(trimethylsilyl)ethoxymethyl (SEM), and the deprotecting agent is an acid (e.g., trifluoroacetic acid). In some embodiments, the deprotecting agent further comprises a silane (e.g., triethylsilane or trimethylsilane) or an amine (e.g., NH3 or N,N-dimethylethylenediamine).

[0280] Any suitable palladium catalyst may be used in the preparation of the compound of formula (C). Exemplary palladium catalysts that may be used include, but are not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)), palladium(II) acetate (Pd(OAc)2), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), dichloro(1,5-cyclooctadiene)palladium(II) ((COD)PdCl2), bis[1,2-bis(diphenylphosphino)ethane]palladium(0) (Pd(dppe)2), bis(triphenylphosphine)dichloropalladium(II) ((PPh3)2PdCl2), (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonatepalladium(II) (SPhos Pd G3), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] methanesulfonate palladium (II) (XPhos Pd G3), tris (dibenzylideneacetone) dipalladium (0) (Pd2 (dba) 3), etc. In one embodiment, the palladium catalyst is PdCl2 (dppf).

[0281] In some embodiments, the method further comprises contacting a compound of formula (A) with a compound of formula (B) in the presence of a first palladium catalyst and a base. Any suitable base can be used. Exemplary bases include, but are not limited to, sodium carbonate, potassium carbonate, potassium acetate, sodium acetate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, and the like. In some embodiments, the base is sodium carbonate, potassium carbonate, or potassium acetate.

[0282] In one or more embodiments, the compound of formula (B) is formed by contacting a compound of formula (B-1) with a compound of formula (B-2) in the presence of a second palladium catalyst:

[0283]

[0284] wherein one of Y' and Z' is Cl, Br, I, or OTf, and the other is a boronate; and PG is a protecting group. The remaining variables have the above identifications.

[0285] In general, Y, Y', and Z' are selected such that Y' and Z' are better coupling partners than Y' and Y. For example, when Y' is a boronate, and Y and Z' are each Cl, Br, I, or OTf, Z' is preferably more reactive than Y. In some embodiments, Y' is a boronate; Z' is I or OTf; and Y is Cl or Br. In one embodiment, Y' is a boronate; Z' is I; and Y is Br.

[0286] In other embodiments, the compound of formula (E) is formed by contacting a compound of formula (A) with a compound of formula (B-1) in the presence of a second palladium catalyst:

[0287]

[0288] wherein one of Y and Z is Cl, Br, I, or OTf, and the other is a boronate; and PG is a protecting group. The remaining variables have the above identifications.

[0289] In general, Y, Z, and Z' are selected such that Y and Z are better coupling partners than Z and Z'. For example, when Z is a boronate, and Y and Z' are each Cl, Br, I, or OTf, Y is preferably more reactive than Z'. In some embodiments, Z is a boronate, Y is I or OTf, and Z' is Cl or Br. In one embodiment, Z is a boronate; Y is I; and Z' is Br.

[0290] In one or more embodiments, the borate ester is a ester having the formula -B(OR x )2, where each R x is H or -C1-C3 alkyl, or two -OR x The groups together with the boron atom to which they are attached form pinacol borane (Bpin). In one embodiment, the boronate ester is Bpin.

[0291] Any suitable palladium catalyst may be used in the preparation of the compound of formula (B). Exemplary palladium catalysts that may be used include, but are not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)), palladium(II) acetate (Pd(OAc)2), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), dichloro(1,5-cyclooctadiene)palladium(II) ((COD)PdCl2), bis[1,2-bis(diphenylphosphino)ethane]palladium(0) (Pd(dppe)2), bis(triphenylphosphine)dichloropalladium(II) ((PPh3)2PdCl2), (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonatepalladium(II) (SPhos Pd G3), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] methanesulfonate palladium (II) (XPhos Pd G3), tris (dibenzylideneacetone) dipalladium (0) (Pd2 (dba) 3), etc. In one embodiment, the palladium catalyst is PdCl2 (dppf).

[0292] In one or more embodiments, G 1is N. In certain such embodiments, a compound of formula (B) can be formed by contacting a compound of formula (B-3) with hydrazine or a hydrate thereof:

[0293]

[0294] where Z a is halo; and m is 0 or 1. In some embodiments, Z a is F. The remaining variables have identities as defined above.

[0295] In one or more embodiments, the compound of formula (B-3) is prepared by:

[0296] a) contacting a compound of formula (B-4) with a lithiating agent to form a compound of formula (B-5):

[0297] as well as

[0298] b) contacting the compound of formula (B-5) with the compound of formula (B-6):

[0299]

[0300] where R o is H or C1-C3 alkyl. The remaining variables have the same designations as defined above.

[0301] Any suitable lithiation agent can be used. Exemplary lithiation agents include, but are not limited to, lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidinium (LTMP), lithium dicyclohexylamide, lithium dimethylamide, lithium diethylamide, lithium amide, lithium bis(trimethylsilyl)amide, and the like. In some embodiments, the lithiation agent is LDA.

[0302] In other embodiments, the compound of formula (B-3) is prepared by:

[0303] The compound of formula (B-7) is contacted with the compound of formula (B-8):

[0304]

[0305] where Q 1 is halo, -CN, -C(O)OH, -C(O)O-(C1-C3 alkyl), -C(O)Cl, or -C(O)N(C1-C3 alkyl)-O-(C1-C3 alkyl); Q 2 is -Li, -Mg-halogen or -B(OR x )2; and each R x is H or C1-C3 alkyl, or two -OR xThe groups, together with the boron atom to which they are attached, form pinacol borane (Bpin). The remaining variables have the designations defined above.

[0306] In some embodiments, Q 1 is -Cl, -Br, -I, -CN, -C(O)OH, -C(O)OCH3, -C(O)Cl, or -C(O)N(CH3)OCH3. In some embodiments, Q 2 It is -Li, -MgCl, -MgBr, -B(OH)2 or -Bpin.

[0307] In other embodiments, Q 1 is -CN, -C(O)OH, -C(O)OCH3, -C(O)Cl or -C(O)N(CH3)O(CH3), and Q 2 Is -Li, -MgCl or -MgBr. In certain embodiments, Q 1 Yes-CN,Q 2 is -MgCl or -MgBr, and the method further comprises adding water.

[0308] In other embodiments, Q 1 is -C(O)Cl, Q 2 Yes-B(OR x )2 (e.g., B(OH)2 or -Bpin), and the method further comprises adding a palladium catalyst, such as those described elsewhere herein.

[0309] In yet other embodiments, Q 1 is a halogen group (eg, -Cl, -Br or -I), Q 2 is -Li, -MgCl, or -MgBr, and the method further comprises adding CO and a palladium catalyst, such as those described elsewhere herein.

[0310] In order to most efficiently prepare any particular compound of the present disclosure, the time and order of linking of the fragments and the modification of the functionality present in any fragment can vary and will depend on the functionality present. The above-mentioned various methods have been used to prepare compounds of the present disclosure and are illustrated in the following examples. The deuterated forms of the following examples can be synthesized using appropriate deuterated intermediates.

[0311] Therapeutic and preventive uses

[0312] The present disclosure provides methods for using the compounds described herein in the preparation of a medicament for inhibiting AXL. As used herein, the terms "inhibit," "inhibition," and the like refer to the ability of an antagonist to reduce the function or activity of a specific target, such as AXL. The reduction is preferably at least 50%, and can be, for example, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%. The present disclosure also encompasses the use of the compounds described herein in the preparation of a medicament for treating or preventing a disease, condition, and / or disorder that would benefit from inhibiting AXL. As an example, the present disclosure encompasses the use of the compounds described herein in the preparation of a medicament for treating cancer. In another embodiment, the present disclosure encompasses the use of the compounds described herein in the preparation of a medicament for treating a fibrotic disease. In another embodiment, the present disclosure encompasses the use of the compounds described herein in the preparation of a medicament for treating a viral infection. In some embodiments of the above methods, the compounds described herein are used in combination with at least one additional therapy, examples of which are described elsewhere herein.

[0313] AXL is expressed in cancer, selected immune cells, and stromal cells and has been implicated in the development of resistance / relapse to chemotherapy, radiotherapy, targeted therapies, and immunotherapy. AXL is activated by its ligand, growth arrest-specific protein 6 (GAS6), or by ligand-independent dimerization, thereby promoting AXL phosphorylation and initiating a signaling cascade that promotes cancer cell proliferation, survival, and an immunosuppressive microenvironment. Therefore, inhibiting AXL is a promising therapeutic strategy to overcome resistance to chemotherapy, radiotherapy, targeted therapies, and / or immunotherapy.

[0314] As demonstrated herein, compounds according to the present disclosure effectively inhibit AXL.Diseases, disorders and / or conditions that would benefit from AXL inhibition may include those characterized by overexpression of AXL.

[0315] Thus, in some embodiments, the compounds described herein are administered to a subject in need thereof in an amount effective to inhibit AXL. AXL inhibition can be assessed by measuring soluble AXL (sAXL) levels or AXL expression in plasma, or phospho-AXL (pAXL) levels in a peripheral blood sample or a tissue sample (e.g., a tumor sample) obtained from the subject. For example, activity can be determined by comparison with a previous sample obtained from the subject (i.e., before administration of the AXL inhibitor), or by comparison with a reference value for a control group (e.g., standard of care, placebo, etc.).

[0316] Alternatively or additionally, in some embodiments, the compounds described herein are administered to a subject in need thereof in an amount effective to inhibit AXL phosphorylation. Inhibition of AXL phosphorylation (pAXL) can be assessed by measuring pAXL expression in a peripheral blood sample or tissue sample (e.g., a tumor sample) obtained from the subject. For example, activity can be determined by comparison with a previous sample obtained from the subject (i.e., before administration of the disclosed compounds), or by comparison with a reference value for a control group (e.g., standard of care, placebo, etc.). Inhibition of pAXL can also be assessed by measuring the levels of sAXL, GAS6, or other factors in serum or plasma obtained from the subject.

[0317] Alternatively or additionally, in some embodiments, the compounds described herein are administered to a subject in need thereof to treat and / or prevent cancer or a cancer-related disease, disorder, or condition. In some embodiments, the compounds described herein are administered to a subject in need thereof to treat cancer, optionally in combination with at least one additional therapy, examples of which are described elsewhere herein.

[0318] Alternatively or additionally, in some embodiments, the compounds described herein are administered to a subject in need thereof to treat and / or prevent a viral infection, as described in further detail below.

[0319] Alternatively or additionally, in some embodiments, the compounds described herein are administered to a subject in need thereof to treat and / or prevent a fibrotic disease, disorder, or condition, as described in further detail below.

[0320] Alternatively or additionally, in some embodiments, the compounds described herein are administered to a subject in need thereof to treat and / or prevent pain, as described in further detail below.

[0321] Alternatively or additionally, in some embodiments, the compounds described herein are administered to a subject in need thereof to treat and / or prevent an immune-related disease, disorder, or condition.

[0322] In a specific embodiment of the present disclosure, the compound is used to increase or enhance the immune response to a tumor or viral infection. In a specific embodiment, at least one antigen or vaccine is administered to a subject in combination with at least one compound of the present disclosure to prolong the immune response to the antigen or vaccine. A therapeutic composition is also provided, comprising a combination of at least one antigenic agent or vaccine component (including but not limited to viruses, bacteria and fungi, or parts thereof, proteins, peptides, tumor-specific antigens and nucleic acid vaccines) and at least one compound of the present disclosure.

[0323] Oncology and oncology-related conditionsIn one or more embodiments, the compounds described herein can be used to treat and / or prevent cancer (e.g., carcinoma, sarcoma, leukemia, lymphoma, myeloma, etc.). In certain embodiments, the cancer may be locally advanced and / or unresectable, metastatic, or at risk of metastasis. Alternatively or additionally, the cancer may relapse or no longer respond to treatment, such as standard of care treatment known to those skilled in the art. Exemplary cancer types encompassed by the present disclosure include genitourinary tract cancer (e.g., bladder cancer, kidney cancer, renal cell carcinoma, penile cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, Von Hippel-Lindau disease, etc.), breast cancer, gastrointestinal cancer (e.g., esophageal cancer, oropharyngeal cancer, gastric cancer, small or large intestine cancer, colon cancer or rectal cancer), bone cancer, bone marrow cancer, skin cancer (e.g., melanoma, squamous cell carcinoma or basal cell carcinoma), head and neck cancer, liver cancer, gallbladder cancer, bile duct cancer, heart cancer, lung cancer, pancreatic cancer, salivary gland cancer, adrenal cancer, thyroid cancer, brain cancer (e.g., glioma), ganglion cancer, central nervous system (CNS) cancer, peripheral nervous system (PNS) cancer, hematopoietic system cancer (i.e., blood malignancies) and immune system cancer (e.g., spleen cancer or thymus cancer). In some embodiments, the patient with cancer is determined to have an STK11 mutation.

[0324] In some embodiments, the compounds according to the present disclosure can be used to treat and / or prevent hematological malignancies. Exemplary cancer types affecting the hematopoietic system include leukemias, lymphomas, and myelomas, including acute myeloid leukemia, adult T-cell leukemia, T-cell large granular lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute monocytic leukemia, Hodgkin's and non-Hodgkin's lymphomas, diffuse large B-cell lymphomas, and multiple myeloma. In some embodiments, the hematological malignancy is acute myeloid leukemia.

[0325] In another embodiment, the compounds according to the present disclosure can be used to treat and / or prevent solid tumors. Solid tumors can be, for example, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, breast cancer, lung cancer (small cell or non-small cell), colon cancer, prostate cancer, cervical cancer, bile duct cancer, pancreatic cancer, gastric cancer, esophageal cancer, liver cancer (hepatocellular carcinoma), kidney cancer (renal cell carcinoma), head and neck tumors, mesothelioma, melanoma, sarcoma, central nervous system (CNS) hemangioblastoma and brain tumors (e.g., gliomas, such as astrocytomas, oligodendrogliomas and glioblastomas).

[0326] In some embodiments, the compounds of the present disclosure can be used to treat lung cancer (e.g., non-small cell lung cancer (NSCLC)), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), ovarian cancer (e.g., epithelial ovarian cancer (EOC), high-grade serous ovarian cancer (HSOC), or platinum-resistant ovarian cancer (PROC)), breast cancer (e.g., triple-negative breast cancer (TNBC)), bladder cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC)), kidney cancer (e.g., clear cell renal cell carcinoma (ccRCC)), liver cancer, glioblastoma, mesothelioma, melanoma, or leukemia (e.g., acute myeloid leukemia (AML) or myelodysplastic syndrome). In some embodiments, the cancer is lung cancer, pancreatic cancer, ovarian cancer, breast cancer, head and neck cancer, kidney cancer, leukemia, or myelodysplastic syndrome. In one embodiment, the cancer is NSCLC, PDAC, ccRCC, or AML.

[0327] In some embodiments, the compounds according to the present disclosure can be used to treat kidney cancer. In other embodiments, the kidney cancer is renal cell carcinoma. In yet other embodiments, the renal cell carcinoma is clear cell renal carcinoma (ccRCC).

[0328] In some embodiments, the compounds according to the present disclosure can be used to treat lung cancer. In other embodiments, lung cancer is non-small cell lung cancer (NSCLC). In yet other embodiments, NSCLC is lung squamous cell carcinoma or lung adenocarcinoma. In some embodiments, NSCLC is EGFR mutant NSCLC. In some embodiments, NSCLC is STK11 mutant NSCLC. In some embodiments, NSCLC has recurred and requires treatment, including but not limited to anti-PD-L1 or other immunotherapy, targeted therapy or chemotherapy. In some embodiments, lung cancer is squamous cell carcinoma (SCC).

[0329] In some embodiments, the compounds according to the present disclosure can be used to treat head and neck cancer. In other embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, HNSCC is recurrent or resistant to radiation, chemotherapy or immunotherapy.

[0330] In some embodiments, compounds according to the present disclosure can be used to treat leukemia or myelodysplastic syndrome (MDS). In other embodiments, the leukemia is acute myeloid leukemia (AML). In yet other embodiments, AML or MDS is relapsed or refractory AML or MDS. In some embodiments, AML is FLT-3 mutant AML.

[0331] In some embodiments, the compounds according to the present disclosure can be used to treat breast cancer. In other embodiments, breast cancer is hormone receptor positive (e.g., ERα positive breast cancer, PR positive breast cancer, ERα positive and PR positive breast cancer), HER2 positive breast cancer, HER2 overexpression breast cancer or any combination thereof. In yet other embodiments, breast cancer is triple negative breast cancer (TNBC).

[0332] In some embodiments, compounds according to the present disclosure may be used to treat pancreatic cancer. In other embodiments, the pancreatic cancer is a pancreatic neuroendocrine tumor (PNET) or pancreatic cancer (ie, pancreatic ductal adenocarcinoma (PDAC)).

[0333] In some embodiments, the compounds of the present disclosure can be used to treat ovarian cancer. In other embodiments, the ovarian cancer is metastatic. In other embodiments, the ovarian cancer is epithelial ovarian cancer (EOC). In some embodiments, the ovarian cancer is high-grade serous ovarian cancer (HGSOC). In some embodiments, the ovarian cancer is characterized by a mesenchymal (MES) molecular subtype. In some embodiments, the ovarian cancer is resistant to therapy, including but not limited to platinum- or taxane-based therapies (e.g., platinum-resistant ovarian cancer (PROC)).

[0334] In one or more embodiments, the cancer is an oncogene-addicted cancer. Oncogene-addicted cancers are those that rely on dominant oncogenes for growth and survival, such as, for example, ALK, ABL, AURORA, AKT, PDGFR, KIT, EGFR, VEGFR, 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. In one embodiment, the oncogene is KRAS.

[0335] In the foregoing embodiments, the methods of the present disclosure can be practiced in an adjuvant setting or a neoadjuvant setting.The methods described herein can be indicated as first-line, second-line, third-line, or higher-line therapy.

[0336] In some embodiments, the methods of the present disclosure may be indicated as first-line therapy in subjects identified as having STK11 mutant cancer. In another embodiment, the methods of the present disclosure may be indicated as second-line therapy in subjects identified as having therapy-resistant cancer (e.g., resistance to chemotherapy, radiation, etc.). In one embodiment, standard therapy is ineffective, intolerable, or considered inappropriate for treating the patient's cancer.

[0337] The present disclosure also provides methods for treating or preventing other cancer-related diseases, conditions, or disorders. The use of the terms cancer-related diseases, conditions, and disorders broadly refers to conditions that are directly or indirectly related to cancer and non-cancerous proliferative diseases, and includes, for example, angiogenesis, precancerous conditions such as dysplasia, and non-cancerous proliferative disease conditions or disorders, such as benign proliferative breast disease and papilloma. For clarity, the terms cancer-related diseases, conditions, and disorders do not include cancer itself.

[0338] In general, the disclosed methods for treating or preventing cancer or a cancer-related disease, condition, or disorder in a subject in need thereof comprise administering to the subject a compound disclosed herein. In some embodiments, the disclosure provides methods for treating or preventing cancer or a cancer-related disease, condition, or disorder with a compound disclosed herein and at least one additional therapy, examples of which are described elsewhere herein.

[0339] Viral infection. AXL has been found to promote infection by a variety of enveloped viruses, including, for example, coronaviruses, poxviruses, retroviruses, flaviviruses, arenaviruses, filoviruses, and alphaviruses. In particular, enveloped viruses display phosphatidylserine. AXL's ligand, GAS6, connects envelope phosphatidylserine to the cell surface receptor AXL, thereby facilitating the entry of enveloped viruses into cells. Specifically for SARS-CoV-2, AXL is a co-receptor for ACE2, to which the viral spike protein attaches, allowing subsequent entry into host cells. Furthermore, AXL signaling inhibits the virus-induced type I interferon (IFN) response, leading to increased viral replication in infected cells and reduced antiviral defenses in neighboring cells. Therefore, inhibiting AXL is a useful strategy for treating viral infections.

[0340] In some embodiments, the compound according to the present disclosure can be used to treat viral infection. In some embodiments, viral infection is caused by enveloped viruses. Exemplary viral infection includes those caused by coronavirus, poxvirus, retrovirus, flavivirus, arenavirus, filovirus or alphavirus. In some embodiments, viral infection is caused by coronavirus (for example, MERS-CoV, SARS-CoV, SARS-CoV-2, 229E, NL63, OC43 or HKU1). In some embodiments, viral infection is caused by poxvirus (for example, orthopoxvirus, parapoxvirus, molluscumpoxvirus, yatapoxvirus, sheeppoxvirus, swinepoxvirus, rabbitpoxvirus, monkeypoxvirus or fowlpoxvirus). In some embodiments, viral infection is caused by retrovirus (for example, human immunodeficiency virus (HIV), human T-lymphotropic virus type 1 (HTLV-1) or human T-lymphotropic virus type 2 (HTLV-II)). In some embodiments, the viral infection is caused by a flavivirus (e.g., West Nile, dengue, tick-borne encephalitis, yellow fever, Zika, classical swine fever, hepatitis C, or Japanese encephalitis). In some embodiments, the viral infection is caused by an arenavirus (e.g., Chapare, Guanarito, Junin, Lassa, Machupo, Sabia, Whitewater Arroyo, or Lujo). In some embodiments, the viral infection is caused by a filovirus (e.g., Ebola, Marburg, Cueva, Dianlo, Stria, or Thamno).In some embodiments, the viral infection is caused by an alphavirus (e.g., Aura, Barmah Forest, Bebaru, Caaingua, Cabassou, Chikungunya, Eastern equine encephalitis, Eilat, Everglades, Fort Morgan, Getah, Highlands J, Madariaga, Mayaro, Middelburg, Mosso das Pedras, Mucambo, Ndumu, O'nyong'nyong, Pixuna, Rio Negro, Ross River, Salmon pancreas) disease, Semliki Forest virus, Sindbis virus, Southern elephant seal virus, Tonate virus, Trocara virus, Una virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus, or Waitaroa virus).

[0341] In some embodiments, the compounds according to the present disclosure can be used to treat infections caused by SARS-CoV-2, Ebola virus, monkeypox, or Zika virus. In some embodiments, the compounds according to the present disclosure can be used to treat infections caused by SARS-CoV-2, Ebola virus, or Zika virus. In one embodiment, the infection is caused by SARS-CoV-2.

[0342] Fibrosis. AXL is expressed on fibroblasts and is associated with myofibroblast activation. Activated myofibroblasts are key effector cells associated with fibrosis in multiple organ systems. Therefore, inhibition of AXL is a promising anti-fibrotic therapeutic approach.

[0343] In some embodiments, the compounds according to the present disclosure can be used to treat fibrosis. In some embodiments, fibrosis is renal fibrosis (e.g., chronic kidney disease), intestinal fibrosis (e.g., Crohn's disease), liver fibrosis, or pulmonary fibrosis (e.g., asthma or idiopathic pulmonary fibrosis (IPF)). In some embodiments, fibrosis is associated with cancer and tumor growth. In some embodiments, fibrosis is tumor-associated tissue fibrosis. In some embodiments, tumor-associated tissue fibrosis is associated with pancreatic cancer.

[0344] In one embodiment, the compound can be used to treat renal fibrosis. In some embodiments, renal fibrosis is associated with chronic kidney disease. In other embodiments, the compound can be used to treat renal fibrosis after unilateral ureteral obstruction (UUO). In one embodiment, renal fibrosis is associated with IgA nephropathy (i.e., Berger's disease).

[0345] In some embodiments, the compounds are useful for treating intestinal fibrosis. In one embodiment, the intestinal fibrosis is associated with Crohn's disease.

[0346] In some embodiments, the compounds can be used to treat liver fibrosis. In some embodiments, liver fibrosis is associated with chronic liver disease. In one embodiment, liver fibrosis is associated with non-alcoholic fatty liver disease (NAFLD).

[0347] In some embodiments, the compound can be used to treat pulmonary fibrosis. In some embodiments, pulmonary fibrosis is associated with chronic lung disease. In other embodiments, pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In another embodiment, pulmonary fibrosis is associated with asthma.

[0348] pain. AXL is upregulated in injured dorsal root ganglia and has been implicated in neuropathic pain. Therefore, inhibition of AXL is a promising strategy for pain treatment.

[0349] In one embodiment, the compounds according to the present disclosure are useful for treating pain. In some embodiments, the pain is neuropathic pain.

[0350] Oncology patient selection.In some cases, the methods according to the present disclosure may be provided in selected patients, such as subjects identified as having, for example, elevated AXL expression or AXL pathway activation in relevant tissues or samples, or having high microsatellite instability or high tumor mutation burden. 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 selected by assessing phospho-AXL levels. In some embodiments, patients are selected by assessing AXL gene signatures. In some embodiments, patients are selected by further assessing GAS6 expression in relevant tissues or samples. In some embodiments, the present disclosure provides a method for treating cancer in patients with elevated AXL expression, phospho-AXL levels, or AXL gene signatures using a compound as described herein. In one embodiment, the present disclosure provides a method for treating cancer in patients with elevated cell surface AXL expression using a compound as described herein. In another embodiment, the present disclosure provides a method for treating cancer in patients with elevated sAXL expression using a compound as described herein. In another embodiment, the present disclosure provides a method of treating cancer in a patient with elevated phospho-AXL levels using a compound as described herein. In another embodiment, the present disclosure provides a method of treating cancer in a patient with elevated AXL gene signature using a compound as described herein. In yet another embodiment, the present disclosure provides a method of treating cancer in a patient with elevated sAXL expression to GAS6 expression ratio using a compound as described herein. In some embodiments, the present disclosure provides a method of treating cancer by administering a therapeutically effective amount of an AXL inhibitor to a subject based on a determination of the relative amount of AXL expression. In another embodiment, the present disclosure provides a method of treating cancer by administering an effective amount of an AXL inhibitor to a subject based on a determination of the relative amount of cell surface AXL expression. In another embodiment, the present disclosure provides a method of treating cancer by administering an effective amount of an AXL inhibitor to a subject based on a determination of the relative amount of sAXL expression or by complex AXL (cAXL) levels. In another embodiment, the present disclosure provides a method of treating cancer by administering an effective amount of an AXL inhibitor to a subject based on a determination of the relative amount of phospho-AXL levels. In another embodiment, the present disclosure provides a method of treating cancer by administering an effective amount of an AXL inhibitor to a subject based on a determination of the relative strength of the AXL gene signature. In yet another embodiment, the present disclosure provides a method of administering an effective amount of an AXL inhibitor to a subject for treating cancer based on determination of the relative amount of sAXL expression to GAS6 expression ratio.In another embodiment, the present disclosure provides a method for administering an effective amount of an AXL inhibitor to a subject for treating cancer based on the presence of a STK11 mutation or deletion. In some such embodiments, such subjects can be identified by performing LKB1 protein detection assessment in a sample by sequencing such as next generation sequencing or by IHC in a suitable assay (e.g., Foundation I liquid CDx). In some cases, the subject is identified as having a cancer driven by an oncogene, wherein the cancer has at least one gene associated with cancer mutated or overexpressed, such as ALK, ABL, AURORA, AKT, PDGFR, KIT, EGFR, VEGFR, 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. In some embodiments, the subject is identified as having resistance to a previous line of treatment (e.g., chemotherapy, radiation, etc.).

[0351] Route of administration

[0352] In some embodiments, pharmaceutical compositions containing compounds according to the present disclosure may be in a form suitable for oral administration. Oral administration may involve swallowing the formulation, thereby allowing the compound to be absorbed into the bloodstream of the gastrointestinal tract. Alternatively, oral administration may involve buccal, lingual, or sublingual administration, thereby allowing the compound to be absorbed into the bloodstream through the oral mucosa.

[0353] In another embodiment, the pharmaceutical composition containing the compound according to the present disclosure can be in a form suitable for parenteral administration. The form of parenteral administration includes but is not limited to intravenous, intraarterial, intramuscular, intradermal, intraperitoneal, intrathecal, intracisternal, intracerebral, intraventricular, intraventricular and subcutaneous. Pharmaceutical compositions suitable for parenteral administration can be formulated using suitable aqueous or non-aqueous carriers. Depot injections, typically administered subcutaneously or intramuscularly, can also be used to release the compounds disclosed herein within a specified time period.

[0354] Other routes of administration are also contemplated by the present disclosure, including, but not limited to, nasal, vaginal, intraocular, rectal, topical (eg, transdermal), and inhalation.

[0355] Particular embodiments of the present disclosure contemplate oral or parenteral administration.

[0356] Combination therapy

[0357] The present disclosure contemplates the use of the AXL inhibitors described herein alone or in combination with one or more additional therapies. Each additional therapy can be a therapeutic agent or another treatment modality. In embodiments comprising one or more additional therapeutic agents, each agent can target different but complementary mechanisms of action. The compounds of the present disclosure, when used in combination with one or more additional therapies, can have a synergistic therapeutic or preventive effect on the underlying disease, condition, or disorder. Additionally or alternatively, combination therapy can allow for a reduction in the dosage of one or more therapies, thereby ameliorating, reducing, or eliminating adverse reactions associated with one or more agents.

[0358] In embodiments that include one or more additional therapeutic modalities, the AXL inhibitor can be administered before, after, or during treatment with the additional therapeutic modality. In embodiments that include one or more additional therapeutic agents, the therapeutic agents used in such combination therapy can be formulated as a single composition or as separate compositions. If administered separately, each therapeutic agent in the combination can be administered simultaneously, approximately simultaneously, or at different times. Furthermore, the therapeutic agents are administered "in combination" even if they have different administration forms (e.g., oral capsule and intravenous), and the therapeutic agents are administered at different dosing intervals during the course of the patient's treatment, one therapeutic agent is administered at a constant dosing regimen while the other therapeutic agent is titrated up, titrated down, or interrupted, or each therapeutic agent in the combination is independently titrated up, titrated down, increased or decreased in dose, or interrupted and / or resumed. If the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0359] cancer therapy

[0360] The present disclosure encompasses the use of the AXL inhibitors described herein in combination with one or more additional therapies useful in the treatment of cancer.

[0361] In some embodiments, the one or more additional therapies are additional treatment modalities.Exemplary treatment modalities include, but are not limited to, surgical resection of the tumor, bone marrow transplantation, radiation therapy, and photodynamic therapy.

[0362] In some embodiments, one or more additional therapies are therapeutic agents. Exemplary therapeutic agents include chemotherapeutics, radiopharmaceuticals, hormone therapy, epigenetic regulators, ATP-adenosine axis targeting agents, targeted therapies, signal transduction inhibitors, RAS signaling inhibitors, PI3K inhibitors, arginase inhibitors, HIF inhibitors, PAK4 inhibitors, immunotherapeutics, cell therapy, gene therapy, immune checkpoint inhibitors, and agonists that stimulate or costimulate immune checkpoints. In one or more embodiments, one or more additional therapies are selected from the group consisting of: inhibitors of CD47-SIRPα pathways, kinase inhibitors, inhibitors of HIF, inhibitors of PARP, RAS signaling inhibitors, immune checkpoint inhibitors, agents produced outside the cell targeting adenosine, radiotherapy, and chemotherapeutics.

[0363] In some embodiments, the one or more additional therapeutic agents are chemotherapeutic agents. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and trimethylmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorphosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;Antibiotics such as aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid acid), nogalamycin, olivomycin, pomalidomide, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, nimex), zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;Pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadreners such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycosides glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine;Mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; paclitaxel, such as paclitaxel, nab-paclitaxel, 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; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide eniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib; topoisomerase inhibitors such as irinotecan, topotecan, etoposide, mitoxantrone, and teniposide; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine;Anthracycline (anthracycline) and any of the above pharmaceutically acceptable salts, acids or derivatives. In certain embodiments, the combination therapy includes a chemotherapy regimen comprising one or more chemotherapeutic agents. In one embodiment, the combination therapy includes a chemotherapy regimen comprising one or more of the following: FOLFOX (folinic acid, fluorouracil and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil and irinotecan), paclitaxel (e.g., docetaxel, paclitaxel, albumin-bound paclitaxel, etc.), low-dose cytarabine (LDAC) and / or gemcitabine. In one embodiment, the combination therapy comprises a chemotherapy regimen comprising one or more of: FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), a paclitaxel (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), low-dose cytarabine (LDAC), gemcitabine, and / or a platinum-based therapy (e.g., cisplatin, carboplatin, and oxaliplatin).

[0364] In some embodiments, one or more additional therapeutic agents are radiopharmaceuticals. Radiopharmaceuticals are a form of internal radiation therapy in which a radioactive source (i.e., one or more radionuclides) is placed in the subject's body. The radioactive source can be in solid or liquid form. Non-limiting examples of radiopharmaceuticals include sodium iodide I-131, radium-223 dichloride, benzylguanidine iodine-131, radioiodinated vesicles (e.g., saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles), various forms of brachytherapy, and various forms of targeted radionuclides. Targeted radionuclides include radionuclides that are bound (e.g., by covalent or ionic interactions) to a molecule ("targeting agent") that specifically binds to a target on a cell, typically a cancer cell or an immune cell. Targeting agents can be small molecules, carbohydrates (including oligosaccharides and polysaccharides), antibodies, lipids, proteins, peptides, non-natural polymers, or aptamers. In some embodiments, the targeting agent is a carbohydrate (including oligosaccharides and polysaccharides), a lipid, a protein, or a peptide, and the target is a tumor-associated antigen (enriched but not specific for cancer cells), a tumor-specific antigen (rarely expressed to not expressed in normal tissues), or a neoantigen (a cancer cell genome-specific antigen generated by a non-synonymous mutation in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen (i.e., an antigen that is enriched but not specific for cancer cells), a tumor-specific antigen (i.e., an antigen that is rarely expressed to not expressed in normal tissues), or a neoantigen (i.e., a cancer cell genome-specific antigen generated by a non-synonymous mutation in the tumor cell genome). Non-limiting examples of targeting radionuclides include radionuclides attached to: somatostatin or its peptide analogs (e.g., 177Lu-Dotatate, etc.); prostate specific membrane antigen or its peptide analogs (e.g., 177Lu-PSMA-617, 225Ac-PSMA-617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); cognate ligands of receptors, peptides derived from said ligands, or variants thereof (e.g., 188Re-labeled VEGF 125-136 or variants thereof with higher affinity for VEGF receptors, etc.); antibodies targeting tumor antigens (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-omburtamab, etc.).

[0365] In some embodiments, the one or more additional therapeutic agents are hormone therapies. Hormone therapies are used to regulate or inhibit the effects of hormones on tumors. Examples of hormone therapies include, but are not limited to, selective estrogen receptor degraders such as fulvestrant, giredestrant, SAR439859, RG6171, AZD9833, rintodestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549; selective estrogen receptor modulators such as tamoxifen, raloxifene, 4-hydroxytamoxifen, tamoxifen, keoxifene, toremifene; aromatase inhibitors such as anastrozole, exemestane, letrozole and other inhibitors. 4 (5) -imidazoles of aromatase; gonadotropin-releasing hormone agonists such as nafarelin, triptorelin, goserelin; gonadotropin-releasing hormone antagonists such as degarelix; antiandrogens such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide, leuprolide; 5α-reductase inhibitors such as finasteride, dutasteride; etc. In certain embodiments, the combination therapy comprises the administration of hormones or related hormonal agents. In one embodiment, the combination therapy comprises the administration of enzalutamide.

[0366] In some embodiments, one or more additional therapeutic agents are epigenetic regulators. Epigenetic regulators change the epigenetic mechanism that controls gene expression, and can be, for example, inhibitors or activators of epigenetic enzymes. Non-limiting examples of epigenetic regulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HDAC) inhibitors. In one or more embodiments, AXL inhibitors according to the present disclosure are combined with DNA methyltransferase (DNMT) inhibitors or hypomethylating agents. Exemplary DNMT inhibitors include decitabine, zebularine, and azacitidine. In one or more embodiments, combinations of compounds according to the present disclosure with histone deacetylase (HDAC) inhibitors are also contemplated. Exemplary HDAC inhibitors include vorinostat, givinostat, abexinostat, panobinostat, belinostat, and trichostatin A.

[0367] In some embodiments, one or more additional therapeutic agents are ATP-adenosine axis targeting agents. ATP-adenosine axis targeting agents alter signaling mediated by adenosine nucleosides and nucleotides (e.g., adenosine, AMP, ADP, ATP), for example by regulating adenosine levels or targeting adenosine receptors. Adenosine and ATP, acting on different classes of receptors, generally have opposite effects on inflammation, cell proliferation, and cell death. For example, ATP and other adenine nucleotides have anti-tumor effects via activation of the PS2Y1 receptor subtype, while the accumulation of adenosine in the tumor microenvironment has been shown to inhibit the anti-tumor function of various immune cells and enhance the immunosuppressive activity of myeloid and regulatory T cells by binding to cell surface adenosine receptors. In certain embodiments, the ATP-adenosine axis targeting agent is an inhibitor of an ectonucleotidase involved in the conversion of ATP to adenosine or an antagonist of an adenosine receptor. Ectonucleotidases involved in the conversion of ATP to adenosine include ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​also known as CD39 or cluster of differentiation 39) and ecto-5'-nucleotidase (NT5E or 5NT, also known as CD73 or cluster of differentiation 73). Exemplary small molecule CD73 inhibitors include CB-708, ORIC-533, LY3475070, and quemliclustat (AB680). Exemplary anti-CD39 and anti-CD73 antibodies include ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, oleclumab (MEDI9447), NZV930, IPH5301, GS-1423, uliledlimab (TJD5, TJ004309), AB598, and BMS-986179. In one embodiment, the present disclosure contemplates combinations of the AXL inhibitors described herein with CD73 inhibitors, such as those described in WO 2017 / 120508, WO 2018 / 067424, WO 2018 / 094148, and WO 2020 / 046813. In other embodiments, the CD73 inhibitor is quinolistat. Adenosine can bind to and activate four different G protein-coupled receptors: A1R, A2R, and A3R. 2A R, A 2BR and A3R. A2R antagonists include etrumadenant, inupadenant, taminadenant, caffeine citrate, NUV-1182, TT-702, DZD-2269, INCB-106385, EVOEXS-21546, AZD-4635, imaradenant, RVU-330, ciforadenant, PBF-509, PBF-999, PBF-1129, and CS-3005. In some embodiments, the present disclosure contemplates the use of the AXL inhibitors described herein with A2R. A R antagonist, A2 B R antagonists or A2 A R and A2 B In some embodiments, the present disclosure contemplates combinations of compounds described herein with an adenosine receptor antagonist described in WO 2018 / 136700, WO 2018 / 204661, WO 2018 / 213377, or WO 2020 / 023846. In one embodiment, the adenosine receptor antagonist is elumetinib.

[0368] In some embodiments, one or more additional therapeutic agents are targeted therapies. In one aspect, targeted therapies may include chemotherapeutic agents, radionuclides, hormone therapy, or another small molecule drug connected to a targeting agent. The targeting agent may be a small molecule, a carbohydrate (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a carbohydrate (including oligosaccharides and polysaccharides), a lipid, a protein, or a peptide, and the target is a tumor-associated antigen (enriched but not specific for cancer cells), a tumor-specific antigen (rarely expressed to no expression in normal tissues), or a new antigen (cancer cell genome-specific antigen produced by non-synonymous mutations in tumor cell genomes). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen (enriched but not specific for cancer cells), a tumor-specific antigen (rarely expressed to no expression in normal tissues), or a new antigen (cancer cell genome-specific antigen produced by non-synonymous mutations in tumor cell genomes). Specific examples include, but are not limited to, patritumab deruxtecan and telisotuzumab vedotin. In other aspects, targeted therapies can inhibit or interfere with specific proteins that contribute to tumor growth and / or spread. Non-limiting examples of such targeted therapies include signal transduction inhibitors, RAS signaling inhibitors, oncogenic transcription factor inhibitors, oncogenic transcription factor repressor activators, angiogenesis inhibitors, immunotherapeutics, kinase inhibitors, ATP-adenosine axis targeting agents, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, HIF-2α inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists, and PD-1 antagonists. ATP-adenosine axis targeting agents are described above, while other agents are described in further detail below.

[0369] In some embodiments, the one or more additional therapeutic agents are signal transduction inhibitors. Signal transduction inhibitors are agents that selectively inhibit one or more steps in a signaling pathway. Signal transduction inhibitors (STIs) contemplated by the present disclosure include, but are not limited to: (i) BCR-ABL kinase inhibitors (e.g., imatinib); (ii) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), including small molecule inhibitors (e.g., CLN-081, gefitinib, erlotinib, afatinib, icotinib, 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., trastuzumab) and HER-3 receptor inhibitors; (iv) vascular endothelial growth factor receptor (VEGF) inhibitors. GFR) inhibitors, including small molecule inhibitors (e.g., axitinib, sunitinib, and sorafenib), VEGF kinase inhibitors (e.g., lenvatinib, cabozantinib, pazopanib, tivozanib, XL092, etc.), and anti-VEGF antibodies (e.g., bevacizumab); (v) inhibitors of AKT family kinases or AKT pathways (e.g., rapamycin, (vi) inhibitors of the serine / threonine protein kinase B-Raf (BRAF), such as, for example, vemurafenib, dabrafenib, and encorafenib; (vii) inhibitors of rearranged during transfection (RET), including, for example, selpercatinib and pralsetinib; (viii) inhibitors of the tyrosine protein kinase Met (c-MET) (e.g., tepotinib, tivatinib, (e.g., tivantinib, cabozantinib, and crizotinib); (ix) pleomorphic lymphoma kinase (ALK) inhibitors (e.g., ensartinib, ceritinib, lorlatinib, crizotinib, and brigatinib); (x) inhibitors of the RAS signaling pathway as described elsewhere herein (e.g., inhibitors of KRAS, HRAS, RAF, MEK, ERK);(xi) FLT-3 inhibitors (e.g., gilteritinib); (xii) inhibitors of Trop-2, such as, for example, the antibody drug conjugate sacituzumab govitecan-hziy; (xiii) inhibitors of the JAK / STAT pathway, such as JAK inhibitors (including 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; (xix) protein kinase B (AKT) inhibitors (e.g., capivasertib, miratibifenazolidinib, and miratibifenazolidinib); (xx) platelet-derived growth factor receptor (PDGFR) inhibitors (e.g., imatinib, sunitinib, regorafenib, avapritinib, lenvatinib, nintedanib, famitinib, ponatinib, axitinib, repretinib, etc.); and (xxi) insulin-like growth factor receptor (IGFR) inhibitors (e.g., erlotinib, afatinib, gefitinib, osimertinib, dacomitinib). In one or more embodiments, the additional therapeutic agent comprises an inhibitor of EGFR, VEGFR, PDGFR, IGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-κB, PI3K, and / or AKT, or any combination thereof. In one embodiment, the additional therapeutic agent comprises a kinase inhibitor that inhibits one or more of EGFR, VEGFR, HER-2, HER-3, BRAF, PDGFR, c-MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK, and / or FGFR. In some embodiments, the additional therapeutic agent comprises a kinase inhibitor that inhibits one or more of EGFR, VEGFR, and / or c-MET.

[0370] In some embodiments, one or more additional therapeutic agents are agents that prevent, inhibit or slow down autophagy. Autophagy increases in various tumor environments and drives the downregulation of major histocompatibility complex class I molecules (MHC-I) and related antigen presentation mechanisms. Downregulation of antigen presentation can reduce the sensitivity of cancer cells to T cell-mediated killing. One strategy for preventing, inhibiting or slowing down autophagy is to target Unc-51-like autophagy-activating kinases 1 / 2 (ULK1 and / or ULK2). Exemplary inhibitors of ULK1 and / or ULK2 include DC-3116, ERAS-5 and ENV-201. In some embodiments, one or more additional therapeutic agents are inhibitors of ULK1, ULK2 or both ULK1 and ULK2.

[0371] In some embodiments, one or more additional therapeutic agents are RAS signaling inhibitors. Oncogenic mutations in the RAS gene family (e.g., HRAS, KRAS, and NRAS) are associated with a variety of cancers. For example, mutations such as G12C, G12D, G12V, G12A, G13D, Q61H, G13C, and G12S in the KRAS gene family have been observed in a variety of tumor types. Direct and indirect inhibition strategies for suppressing mutant RAS signaling have been studied. Indirect inhibitors target effectors other than RAS in the RAS signaling pathway, including but not limited to inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g., SOS1), mTORC1, SHP2 (PTPN11), and AKT. Non-limiting examples of indirect inhibitors under development include RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, BI1701963, everolimus. Direct inhibitors of RAS mutants have also been explored, and KRAS-GTP complexes or KRAS-GDP complexes are generally targeted. Exemplary direct RAS inhibitors under development include but are not limited to sotorasib (AMG510), adagrasib (MRTX849), mRNA-5671 and ARS1620. In some embodiments, one or more RAS signaling inhibitors are selected from the group consisting of: RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, SOS1 inhibitors, mTORC1 inhibitors, SHP2 inhibitors and AKT inhibitors. In other embodiments, one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0372] In some embodiments, one or more additional therapeutic agents are inhibitors of phosphatidylinositol 3-kinases (PI3K), particularly inhibitors of PI3Kγ and / or PI3Kδ isoforms. PI3Kγ inhibitors can stimulate anti-cancer immune responses by regulating myeloid cells, such as by suppressing suppressive myeloid cells, suppressing immunosuppressive tumor-infiltrating macrophages, or by stimulating macrophages and dendritic cells to produce cytokines that contribute to effective T cell responses, thereby reducing the development and spread of cancer. Exemplary PI3Kγ inhibitors include copanlisib, duvelisib, AT-104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458, and pictilisib. In some embodiments, according to the AXL inhibitor of the present disclosure, one or more PI3Kγ inhibitors are combined with those described in WO 2020 / 0247496A1. In addition, PI3Kδ is expressed on malignant B cells and plays a role in promoting B cell activation, differentiation, proliferation and survival. Exemplary PI3Kδ inhibitors include duvixib, leniolisib, idelalisib, parsaclisib, cobancoxib, umbralisib, zandelisib, ilperlisib, pilaralisib and tenalisib,

[0373] In some embodiments, one or more additional therapeutic agents is an inhibitor of arginase. Arginase has been shown to be responsible for or involved in inflammation-induced immune dysfunction, tumor immune escape, immunosuppression, and the immunopathology of infectious diseases. Exemplary arginase compounds include CB-1158 and OAT-1746. In some embodiments, AXL inhibitors according to the present disclosure are combined with one or more arginase inhibitors described in WO / 2019 / 173188 and WO 2020 / 102646.

[0374] In some embodiments, one or more additional therapeutic agents are inhibitors of oncogenic transcription factors or activators of oncogenic transcription factor repressors. Suitable agents can act at the expression level (e.g., RNAi, siRNA, etc.), by physical degradation, at the protein / protein level, at the protein / DNA level, or by binding in the activation / inhibition pocket. Non-limiting examples include inhibitors of one or more subunits of the MLL complex (e.g., HDAC, DOT1L, BRD4, Menin, LEDGF, WDR5, KDM4C (JMJD2C), and PRMT1), inhibitors of hypoxia-inducible factor (HIF) transcription factors, and the like.

[0375] In some embodiments, one or more additional therapeutic agents are hypoxia-inducible factor (HIF) transcription factors, particularly inhibitors of HIF-2α. Exemplary HIF-2α inhibitors include belzutifan, ARO-HIF2, PT-2385, and those described in WO 2021113436 and WO 2021188769. In some embodiments, according to the compound of the present disclosure, one or more HIF-2α inhibitors are combined with those described in WO 2021188769. In one embodiment, the HIF-2α inhibitor is AB521.

[0376] In some embodiments, one or more additional therapeutic agents are inhibitors of p21-activated kinase 4 (PAK4). PAK4 overexpression has been confirmed in a variety of cancer types, including in particular cancers that are resistant to PD-1 therapy. Although no PAK4 inhibitors have yet been approved, some are under development and exhibit dual PAK4 / NAMPT inhibitor activity, such as ATG-019 and KPT-9274. In some embodiments, the compounds according to the present disclosure are combined with PAK4 selective inhibitors. In some embodiments, the compounds according to the present disclosure are combined with PAK4 / NAMPT dual inhibitors such as ATG-019 or KPT-9274.

[0377] In some embodiments, the one or more additional therapeutic agents are (i) an agent that inhibits the enzyme poly (ADP-ribose) polymerase (e.g., olaparib, niraparib, and rucaparib, etc.); (ii) an inhibitor of the Bcl-2 protein family (e.g., venetoclax, navitoclax, etc.); (iii) an inhibitor of MCL-1; (iv) an inhibitor of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies, magrolimab, etc.); (v) an isocitrate dehydrogenase (IDH) inhibitor, such as an IDH-1 or IDH-2 inhibitor (e.g., ivosidenib, enasidenib, etc.).

[0378] In some embodiments, one or more additional therapeutic agents are immunotherapeutics. Immunotherapeutics treat diseases by stimulating or suppressing the immune system. Immunotherapeutics that can be used to treat cancer typically trigger or enhance an immune response to cancer cells. Non-limiting examples of suitable immunotherapeutics include: immunomodulators; cellular immunotherapy; vaccines; gene therapy; ATP-adenosine axis targeting agents; immune checkpoint regulators; and certain signal transduction inhibitors. ATP-adenosine axis targeting agents and signal transduction inhibitors are described above. Immunomodulators, cellular immunotherapy, vaccines, gene therapy, and immune checkpoint regulators are further described below.

[0379] In some embodiments, the one or more additional therapeutic agents are immunotherapeutic agents, more specifically cytokines or chemokines, such as IL-1, IL-2, IL-12, IL-18, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, TNF, IL-15, MDC, IFNa / b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharide (LPS); organic or inorganic adjuvants that activate antigen-presenting cells and promote presentation of antigenic epitopes on major histocompatibility complex molecule agonists, including but not limited to Toll-like receptor (TLR) agonists, antagonists of the mevalonate pathway, agonists of STING; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and immunostimulatory oligonucleotides, as well as other T cell adjuvants.

[0380] In some embodiments, one or more additional therapeutic agents are immunotherapeutics, more specifically cell therapy. Cell therapy is a form of treatment in which living cells are administered to a subject. In certain embodiments, one or more additional therapeutic agents are cellular immunotherapies that activate or suppress the immune system. Cell immunotherapies that can be used to treat cancer typically trigger or enhance immune responses. Cells can be autologous or allogeneic immune cells (e.g., monocytes, macrophages, dendritic cells, NK cells, T cells, etc.) collected from one or more subjects. Alternatively, cells can be "(re)programmed" allogeneic immune cells produced by immune precursor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell precursor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells can be expanded cell subsets with different effector functions and / or maturation markers (e.g., adaptive memory NK cells, tumor-infiltrating lymphocytes, immature dendritic cells, monocyte-derived dendritic cells, plasmacytoid dendritic cells, conventional dendritic cells (sometimes referred to as classical dendritic cells), M1 macrophages, M2 macrophages, etc.), can be genetically modified to target cells to specific antigens and / or enhance the anti-tumor effects of cells (e.g., engineered T cell receptor (TCR) cell therapy, chimeric antigen receptor (CAR) cell therapy, lymph node homing of antigen-loaded dendritic cells, etc.), can be designed to express or increase the expression of tumor-associated antigens, or can be any combination thereof. Non-limiting types of cell therapy include CAR-T cell therapy, CAR-NK cell therapy, TCR therapy, and dendritic cell vaccines. Exemplary cellular immunotherapies include Sipuleucel-T, tisagenlecleucel, lisocabtagene maraleucel, idecabtagene vicleucel, brexucabtagene autoleucel, and axicabtagene ciloleucel, as well as CTX110, JCAR015, JCAR017, MB-CART19.1, MB-CART20.1, MB-CART2019.1, UniCAR02-T-CD123, BMCA-CAR-T, JNJ-68284528, BNT211, and NK-92 / 5.28.z.

[0381] In some embodiments, one or more additional therapeutic agents are immunotherapeutics, more specifically gene therapy. Gene therapy includes recombinant nucleic acids administered ex vivo to a subject or subject's cells to modify the expression of endogenous genes or result in heterologous expression of proteins (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, microRNA (miRNA) agents, viral or bacterial gene delivery, etc.), and gene editing therapies that may or may not include nucleic acid components (e.g., large-range nucleases, zinc finger nucleases, TAL nucleases, CRISPR / Cas nucleases, etc.), oncolytic viruses, etc. Non-limiting examples of gene therapies that can be used for cancer treatment include (rAd-p53), (rAD5-H101), talimogene laherparepvec, Mx-dnG1, ARO-HIF2 (Arrowhead), quaratusugeneozeplasmid (Immunogene), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics) and CTX130 (CRISPR Therapeutics).

[0382] In some embodiments, one or more additional therapeutic agents are immunotherapeutics, more specifically agents that regulate immune checkpoints. Immune checkpoints are a group of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells, etc.). When proteins on the surface of immune cells recognize and bind to their cognate ligands, immune checkpoints are involved. The present invention encompasses the use of AXL inhibitors described herein in combination with agonists of stimulatory or costimulatory pathways and / or antagonists of inhibitory pathways. Agonists of stimulatory or costimulatory pathways and antagonists of inhibitory pathways can be used as agents to overcome different immunosuppressive pathways in the tumor microenvironment, inhibit T regulatory cells, reverse / prevent T cell anergy or exhaustion, trigger innate immune activation and / or inflammation at the tumor site, or a combination thereof.

[0383] In some embodiments, one or more additional therapeutic agents is an immune checkpoint inhibitor. As used herein, the term "immune checkpoint inhibitor" refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. The terms "immune checkpoint inhibitor," "checkpoint inhibitor," and "CPI" are used interchangeably herein. Immune checkpoint inhibitors can antagonize inhibitory or co-inhibitory immune checkpoints by interfering with receptor-ligand binding and / or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of cancer cells and can be antagonized, include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T lymphocyte-associated antigen 4); TIM-3 (protein 3 containing T cell immunoglobulin and mucin domains); LAG-3 (lymphocyte activation gene 3); TIGIT (T with Ig and ITIM domains). Cell immune receptors); CD276 (B7-H3), PD-L2, galectin 9, CEACAM-1, CD69, galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1 and TIM-4, as well as killer inhibitory receptors, which can be divided into two categories based on their structural characteristics: i) killer cell immunoglobulin-like receptors (KIR), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints described in the literature are also considered, including receptors (e.g., 2B4 (also known as CD244) receptors) 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].

[0384] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 antagonist. In other embodiments, the CTLA-4 antagonist can be an antagonistic CTLA-4 antibody. Suitable antagonistic CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab or tremelimumab, and bispecific antibodies such as MEDI5752 and KN046.

[0385] In some embodiments, the immune checkpoint inhibitor is a PD-1 antagonist. In other embodiments, the PD-1 antagonist can be an antagonist PD-1 antibody, small molecule, or peptide. Suitable antagonist PD-1 antibodies include, for example, monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, cemiplimab, ezabenlimab (BI-754091), MEDI-0680 (AMP-514; WO2012 / 145493), nivolumab, pablo Pembrolizumab, pidilizumab (CT-011), pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilmab, tislelizumab, toripalimab and zimberelimab;And bispecific antibodies, such as LY3434172.In other embodiments, PD-1 antagonists can be recombinant proteins consisting of the extracellular domain (B7-DC) of PD-L2 fused to the Fc portion (AMP-224) of IgG1.In certain embodiments, the immune checkpoint inhibitor is sepalimonab.

[0386] In some embodiments, the immune checkpoint inhibitor is a PD-L1 antagonist. In other embodiments, the PD-L1 antagonist can be an antagonistic PD-L1 antibody. Suitable antagonistic PD-L1 antibodies include, for example, monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and envafolimab, and bispecific antibodies such as LY3434172 and KN046.

[0387] In some embodiments, the immune checkpoint inhibitor is a TIGIT antagonist. In other embodiments, the TIGIT antagonist can be an antagonist TIGIT antibody. Suitable antagonistic anti-TIGIT antibodies include monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS 986207, COM902, domvanalimab, EOS-448, etigilimab, IBI-929, JS006, M6223, ociperlimab, SEA-TGT, tiragolumab, vibostolimab; and bispecific antibodies such as AGEN1777 and AZD2936. In certain embodiments, the immune checkpoint inhibitor is an antagonist anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In certain embodiments, the immune checkpoint inhibitor is dofantazumab or AB308.

[0388] In some embodiments, the immune checkpoint inhibitor is a LAG-3 antagonist. In other embodiments, the LAG-3 antagonist can be an antagonistic LAG-3 antibody. Suitable antagonistic LAG-3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0389] In certain embodiments, the immune checkpoint inhibitor is a B7-H3 antagonist. In other embodiments, the B7-H3 antagonist is an antagonist B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, enoblituzumab (MGA271; WO11 / 109400), omburtumab, DS-7300a, ABBV-155, and SHR-A1811.

[0390] In some embodiments, one or more additional therapeutic agents activate stimulatory or costimulatory immune checkpoints.Examples of stimulatory or costimulatory immune checkpoints (ligands and receptors) include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2.

[0391] In some embodiments, the agent of activating stimulatory or costimulatory immune checkpoints is a CD137 (4-1BB) agonist. In other embodiments, a CD137 agonist can be an agonist CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and utomilumab (PF-05082566; WO12 / 32433). In some embodiments, the agent of activating stimulatory or costimulatory immune checkpoints is a GITR agonist. In other embodiments, a GITR agonist can be an agonist GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683). In some embodiments, the agent of activating stimulatory or costimulatory immune checkpoints is an OX40 agonist. In other embodiments, the OX40 agonist can be an agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383, MEDI-6469, MEDI-0562, PF-04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, the agent that activates stimulatory or costimulatory immune checkpoints is a CD40 agonist. In other embodiments, the CD40 agonist can be an agonist CD40 antibody. In some embodiments, the agent that activates stimulatory or costimulatory immune checkpoints is a CD27 agonist. In other embodiments, the CD27 agonist can be an agonist CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0392] In some embodiments, one or more additional therapeutic agents is an agent that inhibits or depletes immunosuppressive immune cells. For example, to inhibit or eliminate immunosuppressive macrophages or monocytes, the agent can be a CSF-1R antagonist, such as a CSF-1R antagonist antibody, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264). As another example, WO14 / 036357. Ex vivo anti-CD25 bead depletion of Tregs.

[0393] In some embodiments, each additional therapeutic agent can independently be a chemotherapeutic agent, a radiopharmaceutical, a hormone therapy, an epigenetic modulator, a targeted agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. For example, in one embodiment, the present disclosure encompasses the use of an AXL inhibitor described herein in combination with one or more chemotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeted agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure encompasses the use of an AXL inhibitor described herein in combination with one or more chemotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeted agent, an immunotherapeutic agent, or a cell therapy. In another embodiment, the present disclosure encompasses the use of an AXL inhibitor described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeted agent, a chemotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure encompasses the use of an AXL inhibitor described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, or a cell therapy. In another embodiment, the present disclosure encompasses the use of an AXL inhibitor as described herein in combination with one or more immune checkpoint inhibitors and / or one or more ATP-adenosine axis targeting agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeting agent, an immunotherapeutic agent, or a cell therapy. In other embodiments of the above, (a) the targeting agent can be a PI3K inhibitor, an arginase inhibitor, a HIF2α inhibitor, an inhibitor of the CD47-SIRPα pathway, a kinase inhibitor, a PARP inhibitor, or a PAK4 inhibitor; (b) the kinase inhibitor can inhibit one or more of the following: EGFR, VEGF, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK, and / or FGFR; (c) the kinase inhibitor can inhibit one or more of the following: EGFR, VEGFR, and / or c-MET; (d) the immunotherapeutic agent is an ATP-adenosine axis targeting agent or an immune checkpoint inhibitor; (e) the ATP-adenosine axis targeting agent is an A2 A R and / or A2 BR antagonist, CD73 inhibitor or CD39 inhibitor; (f) ATP-adenosine axis targeting agent is elumelin, quinolizumab or AB598; (g) immunotherapeutic agent is anti-PD-1 antagonist antibody or anti-TIGIT antagonist antibody; (h) immunotherapeutic agent is zimberelimab, dovanumab or AB308; or (i) any combination thereof. In other embodiments of the above, the present disclosure contemplates the use of a combination of an AXL inhibitor as described herein with dovanumab, elumelin, quinolizumab, sepalizumab, AB308, AB598, AB521 or any combination thereof.

[0394] In one or more embodiments, one or more additional therapies are selected from the group consisting of: inhibitors of the CD47-SIRPα pathway, kinase inhibitors, inhibitors of HIF, inhibitors of PARP, RAS signaling inhibitors, immune checkpoint inhibitors, agents targeting the extracellular production of adenosine, radiotherapy, and chemotherapeutic agents. In some embodiments, the inhibitor of the CD47-SIRPα pathway is an anti-CD47 antibody. In some embodiments, the kinase inhibitor inhibits one or more of the following: EGFR, VEGF, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK, and / or FGFR. In some embodiments, the kinase inhibitor is an inhibitor of EGFR, VEGF, and / or c-MET. In some embodiments, the kinase inhibitor is osimertinib, lenvatinib, axitinib, sunitinib, cabozantinib, XL092, or bevacizumab. In some embodiments, the inhibitor of HIF comprises an inhibitor of HIF-2α. In certain embodiments, the HIF-2α inhibitor is AB521. In some embodiments, the PARP inhibitor is olaparib, rucaparib, or niraparib. In some embodiments, the RAS signaling inhibitor is an inhibitor of KRAS. In some embodiments, the immune checkpoint inhibitor inhibits one or more of the following: PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, and / or TIGIT. In certain embodiments, the immune checkpoint inhibitor inhibits one or more of PD-1, PD-L1, or TIGIT. In some embodiments, the immune checkpoint inhibitor includes one or more of the following: sepalizumab, dofenac, and / or AB308. In some embodiments, agents targeting the extracellular production of adenosine include one or more of the following: CD73 inhibitors, CD39 inhibitors, A 2A R inhibitors, A 2B R inhibitors and / or A 2A R and A 2BInhibitors of R. In certain embodiments, the agent targeting the extracellular production of adenosine includes one or more of the following: elumetin, quinoliz and / or AB598. In some embodiments, the chemotherapeutic agent includes one or more of the following: platinum-based, paclitaxel-based, anthracycline-based chemotherapeutic agents, low-dose cytarabine (LDAC) or gemcitabine. In certain embodiments, the chemotherapeutic agent is selected from cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, paclitaxel, albumin-bound paclitaxel, low-dose cytarabine (LDAC) and gemcitabine. In another embodiment, the AXL inhibitor described herein is administered together with docetaxel. In yet another embodiment, the AXL inhibitor is administered together with a checkpoint inhibitor. In yet another embodiment, the AXL inhibitor is administered in combination with docetaxel and a checkpoint inhibitor such as sepalidomide.

[0395] The selection of additional therapeutic agents can be informed by the current standard of care for a particular cancer and / or the mutational status and / or disease stage of the subject's cancer. For example, the National Comprehensive Cancer Network (NCCN) has published detailed standard of care guidelines. See, for example, NCCN Acute Myeloid Leukemia v1.2022, NCCN Squamous Cell Skin Cancer v.2.2022, NCCN Head and Neck Cancer v.2.2022, NCCN Ovarian / Fallopian Tube / Primary Peritoneal Cancer v.1.2022, NCCN Pancreatic Cancer v.1.2022, NCCN Bladder Cancer v.1.2022, NCCN Malignant Peritoneal Mesothelioma v.1.2022, NCCN Malignant Pleural Mesothelioma v.1.2022, NCCN Melanoma: Skin v.2.2022, NCCN Melanoma: Uveal v2.2022, NCCN Non-Small Cell Lung Cancer v.3.2022, NCCN Kidney Cancer v.4.2022.

[0396] Pharmaceutical composition

[0397] The AXL inhibitors disclosed herein may be in the form of compositions suitable for administration to a subject. Typically, such compositions are pharmaceutical compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In certain embodiments, the AXL inhibitor may be present in an effective amount. Pharmaceutical compositions can be used in the methods disclosed herein; thus, for example, a pharmaceutical composition comprising a compound disclosed herein can be administered to a subject to practice the therapeutic and preventive methods and uses described herein.

[0398] In one or more embodiments, the pharmaceutical composition comprises an AXL inhibitor according to the present disclosure in an amount between about 10 mg and about 1,000 mg. In one or more embodiments, the pharmaceutical composition comprises an AXL inhibitor according to the present disclosure in an amount between about 10 mg and about 500 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount between about 10 mg and about 300 mg, such as, for example, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 510 mg, 510 mg, 510 mg, 510 mg, 510 mg 15mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 1 80mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 2 45mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg or 500 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount between about 10 mg and about 50 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount between about 25 mg and about 75 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount between about 25 mg and about 50 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount between about 50 mg and about 100 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount between about 100 mg to about 200 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount between about 100 mg to about 150 mg.In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of between about 150 mg and about 200 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of between about 200 mg and about 300 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of between about 200 mg and about 250 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of between about 250 mg and about 300 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of between about 300 mg and about 400 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of between about 300 mg and about 350 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of between about 350 mg and about 400 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of between about 400 mg and about 500 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of between about 400 mg and about 450 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount between about 450 mg to about 500 mg.

[0399] The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration. Routes of administration may include those known in the art. Exemplary routes of administration are oral and parenteral. In addition, the pharmaceutical compositions can be used in combination with one or more other therapies described herein to treat or prevent the diseases, conditions, and disorders encompassed by the present disclosure. In one embodiment, the one or more other therapeutic agents contemplated by the present disclosure are included in the same pharmaceutical composition comprising the AXL inhibitor according to the present disclosure. In another embodiment, the one or more other therapeutic agents are in a separate composition from the pharmaceutical composition comprising the AXL inhibitor according to the present disclosure.

[0400] In one aspect, the compounds described herein can be administered orally. Oral administration can be carried out, for example, via capsules or tablets. When preparing a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, the tablet or capsule typically comprises at least one pharmaceutically acceptable excipient. Non-limiting examples of pharmaceutically acceptable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, polyethylene glycol, cellulose, sterile water, syrup, and methylcellulose. Other pharmaceutically acceptable excipients include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate.

[0401] In another aspect, the compounds described herein can be administered parenterally, for example, by intravenous injection. Pharmaceutical compositions suitable for parenteral administration can be formulated as solutions for injection or can be reconstituted for injection in an appropriate system, such as a physiological solution. Such solutions can include sterile water for injection, salts, a buffer, and a tonicity excipient in amounts suitable to achieve isotonicity under appropriate physiological conditions.

[0402] The pharmaceutical compositions described herein can be stored in one or more suitable sterile containers. In some embodiments, the container is designed to maintain the stability of the pharmaceutical composition over a given period of time.

[0403] Application

[0404] In general, the disclosed methods comprise administering an effective amount of an AXL inhibitor described herein, or a composition thereof, to a subject in need thereof. An "effective amount" with respect to the AXL inhibitors of the present disclosure refers to an amount of the compound sufficient to engage the target (by inhibiting or antagonizing the target) at a level indicative of the compound's efficacy. For AXL, target engagement can be determined by one or more biochemical or cellular assays, thereby generating an EC50, ED50, EC90, IC50, or similar values ​​that can be used as an assessment of compound 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 as multiple, smaller amounts (e.g., as one tablet having an amount "x," as two tablets each having an amount "x / 2," etc.).

[0405] In some embodiments, the disclosed methods comprise administering a therapeutically effective amount of a compound described herein to a subject in need thereof. As used herein, the phrase "therapeutically effective amount" with respect to AXL refers to a dosage regimen (i.e., amount and interval) of a compound that provides a specific pharmacological effect, for which the compound is administered to a subject in need of such treatment. For prophylactic use, a therapeutically effective amount can be effective in eliminating or reducing the risk, lessening the severity, or delaying the onset of a disease, including biochemical, histological, and / or behavioral signs or symptoms of the disease. For treatment, a therapeutically effective amount can be effective in reducing, ameliorating, or eliminating one or more signs or symptoms associated with the disease, slowing disease progression, prolonging survival, reducing the dose of other drugs required to treat the disease, or a combination thereof. Specifically for cancer, a therapeutically effective amount can, for example, result in killing of cancer cells, a reduction in cancer cell count, a decrease in tumor burden, a reduction in tumor volume, elimination of a tumor or metastasis, or a reduction in metastatic spread. The therapeutically effective amount can vary based on, for example, one or more of the following: the age and weight of the subject, the subject's general health, the stage of the subject's disease, the route of administration, and prior or concomitant treatments.

[0406] Administration can include one or more (eg, one, two, or three or more) dosing cycles.

[0407] In certain embodiments, the AXL inhibitors encompassed by the present disclosure can be administered (e.g., orally, parenterally, etc.) at a dose of about 0.01 mg / kg to about 100 mg / kg, or about 0.1 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 25 mg / kg, or about 0.1 mg / kg to about 15 mg / kg, or about 0.1 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 5 mg / kg of the subject's body weight daily, weekly, or monthly, one or more times daily, weekly, or monthly, to achieve the desired effect. In some embodiments, the appropriate weight-based dose of the compounds contemplated by the present disclosure is used to determine the dose administered independently of the subject's body weight. In certain embodiments, the AXL inhibitors of the present disclosure are administered (e.g., orally, parenterally, etc.) at a fixed dose level of about 1 mg to about 1000 mg daily, weekly, or monthly, one or more times daily, weekly, or monthly, to achieve the desired effect. In some embodiments, the AXL inhibitors according to the present disclosure are administered at a fixed dose level of between about 10 mg and about 500 mg daily, weekly, or monthly, one or more times daily, weekly, or monthly, to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered at a dosage of between about 10 mg and about 300 mg, particularly 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, In some embodiments, the AXL inhibitors of the present invention are administered at a fixed dose level of 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg or 300 mg once or more daily, weekly or monthly to achieve the desired effect. In some embodiments, the AXL inhibitors of the present invention are administered at a fixed dose level of 10 mg to about 50 mg once or more daily, weekly or monthly to achieve the desired effect. In some embodiments, the AXL inhibitors of the present invention are administered at a fixed dose level of about 25 mg to about 75 mg once or more daily, weekly or monthly to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 50 mg and about 100 mg once or more daily, weekly, or monthly to achieve the desired effect.In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 100 mg and about 200 mg once or more per day, week, or month to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 100 mg and about 150 mg once or more per day, week, or month to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 200 mg and about 300 mg once or more per day, week, or month to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 250 mg and about 300 mg once or more per day, week, or month to achieve the desired effect.

[0408] In some embodiments, an AXL inhibitor according to the present disclosure is administered once or more daily, weekly, or monthly to achieve the desired effect. In some embodiments, the AXL inhibitor is administered once or twice daily. In one embodiment, the AXL inhibitor is administered twice daily. In another embodiment, the AXL inhibitor is administered once daily.

[0409] In certain embodiments, the AXL inhibitor is contained in a "unit dosage form." The phrase "unit dosage form" refers to physically discrete units, each unit containing a predetermined quantity of the AXL inhibitor sufficient to produce the desired effect, alone or in combination with one or more additional agents. It will be understood that the parameters of the unit dosage form will depend on the specific agent and the effect to be achieved.

[0410] Implementation Plan

[0411] Embodiment 1. A compound represented by formula (I)

[0412]

[0413] or a pharmaceutically acceptable salt thereof, wherein:

[0414] X is CR 5 or N;

[0415] G 1 Is N or CR G1 ;

[0416] G 2 It's CR G2 or N;

[0417] G 3 It's CR G3 or N;

[0418] G 4 It's CR G4 or N;

[0419] G5 It's CR G5 or N;

[0420] R G1 Selected from the group consisting of: H, C 1-3 Alkyl, halogen, C 1-3 Haloalkyl and CN;

[0421] Each R G2 、R G3 、R G4 and R G5 are independently selected from the group consisting of: H, halogen, CN, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 Halogenated alkyl, -NR a R b and 5-8 membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein the cycloalkyl and heterocycloalkyl are substituted with 0-3 groups independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and OH;

[0422] 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 replaced by 1 to 4 R 2 and further substituted with 0 or 1 oxo (=O) located on the carbon atom adjacent to the nitrogen atom;

[0423] R 1 is selected from the group consisting of phenyl and 5 to 6 membered heteroaryl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each phenyl and heteroaryl is separated by one R 1a and 0-3 Rs 3 replace;

[0424] R 1a selected from the group consisting of phenyl and 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the N atom, when present, is optionally oxidized, and wherein each phenyl and heteroaryl is substituted by 0-4 R 4 replace;

[0425] Each R 2 Independently selected from the group consisting of: 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 , 5- to 8-membered heterocycloalkyl, -NR a -(5- to 8-membered heterocycloalkyl), -C(O)-(5- to 8-membered heterocycloalkyl), -X 1 -5 to 8 membered heterocycloalkyl and -OX 1 -(5 to 8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each cycloalkyl and heterocycloalkyl is substituted with 0-3 groups independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and OH;

[0426] Each R 3 Independently selected from the group consisting of halogen, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated hydroxyalkyl, -OC 1-7 Alkyl, -OC 1-6 Halogenated alkyl, -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 and -S(O)2-C 1-7 alkyl halide;

[0427] Each R 4 Independently selected from the group consisting of: C 1-7 Alkyl, halogen, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene-CN, hydroxyl, C 1-7 Hydroxyalkyl, -C(O)NR a R b 、C 3-7 Cycloalkyl, -NR a -C(O)-C 1-7 Alkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -S(O)2-NR a R b 、-NR a -S(O)2-C 1-7 Alkyl and -NR a -S(O)2-C 3-7 Cycloalkyl, wherein each cycloalkyl and heterocycloalkyl is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl, halide, and hydroxyl groups;

[0428] Or, two R on the same ring vertex 4 The groups combine to form an oxo (=O); or

[0429] Two R on adjacent ring vertices 4 The groups are combined to form a 5- to 6-membered heterocycloalkyl group having 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5- to 6-membered heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl and halide groups;

[0430] R 5 Selected from the group consisting of: H, C 1-4 Alkyl and -NH2;

[0431] Each X1 It is C 1-7 Alkylene or C 3-7 cycloalkylene;

[0432] Each Y 1 It is C 2-7 Alkylene or C 3-7 cycloalkylene;

[0433] Each R a and R b Independently selected from the group consisting of: H, C 1-7 Alkyl, C 1-7 Halogenated alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-7 Cycloalkyl, wherein the cycloalkyl is optionally substituted with -OC 1-3 Alkyl substitution; or

[0434] R a and R b Together with the nitrogen to which they are attached, they form a 4- to 8-membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the heterocycloalkyl ring is substituted with 0-3 groups, each group being independently selected from halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and X 1 -OC 1-3 Alkyl and OH; or two groups at the same ring vertex combine to form oxo (=O).

[0435] Embodiment 2. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein:

[0436] G 3 It's CR G3 , and R G3 It is H;

[0437] G 4 It's CR G4 And R G4 is H; and

[0438] G 5 Each is CR G5 And R G5 It’s H.

[0439] Embodiment 3. The compound according to embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein G 1 Is N or CR G1 , where R G1 It’s H.

[0440] Embodiment 4. The compound of any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein G 2 It's CR G2 And R G2 It’s H.

[0441] Embodiment 5. A compound according to any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is CR 5 And R 5 It’s H.

[0442] Embodiment 6. The compound of any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A has a formula selected from the group consisting of:

[0443]

[0444] Each of them is represented by 1 to 4 R 2 replace.

[0445] Embodiment 7. The compound of embodiment 6 or a pharmaceutically acceptable salt thereof, wherein A has the formula:

[0446]

[0447] Embodiment 8. A compound according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein one R 2 Yes-NR a R b .

[0448] Embodiment 9. A compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein one R 2 Selected from the group consisting of:

[0449]

[0450] Embodiment 10. The compound or pharmaceutically acceptable salt of embodiment 9, wherein one R 2 yes

[0451]

[0452] Embodiment 11. A compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl and pyrazolyl, wherein R 1 By an R 1a and 0-2 R 3replace.

[0453] Embodiment 12. The compound according to embodiment 11 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

[0454]

[0455] where the subscript p is 0 or 1.

[0456] Embodiment 13. The compound according to embodiment 11 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

[0457]

[0458] where the subscript p is 0 or 1.

[0459] Embodiment 14. A compound according to any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein each R 3 When present, independently selected from the group consisting of: halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated hydroxyalkyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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 and -S(O)2-C 1-4 Halogenated alkyl.

[0460] Embodiment 15. The compound of embodiment 14 or a pharmaceutically acceptable salt thereof, wherein each R 3 When present, independently selected from the group consisting of: halogen, C 1-4 Alkyl and -OC 1-4 alkyl.

[0461] Embodiment 16. The compound of embodiment 14 or a pharmaceutically acceptable salt thereof, wherein each R 3 When present are independently selected from the group consisting of fluoro, chloro, methyl and methoxy.

[0462] Embodiment 17. A compound according to any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 1a is selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl N-oxide and phenyl, wherein R 1a 0-3 R 4 replace.

[0463] Embodiment 18. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R 1a Selected from the group consisting of:

[0464]

[0465] where subscript q is 0, 1, or 2.

[0466] Embodiment 19. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R 1a Selected from the group consisting of:

[0467]

[0468] where subscript q is 0, 1, or 2.

[0469] Embodiment 20. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R 1a Selected from the group consisting of:

[0470]

[0471] Embodiment 21. A compound as described in any one of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R 4 When present, independently selected from the group consisting of: C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, CN, -C 1-4 Alkylene -CN, C 1-4 Hydroxyalkyl, -C(O)NR a R b 、C 3-7 Cycloalkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4alkyl, -O-(5- to 6-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O)2-C 1-4 Alkyl and -S(O)2-NR a R b , wherein each cycloalkyl and heterocycloalkyl group is substituted with 0 to 2 groups selected from the group consisting of: C 1-4 Alkyl, halo and hydroxy.

[0472] Embodiment 22. The compound of embodiment 21 or a pharmaceutically acceptable salt thereof, wherein each R 4 When present, independently selected from the group consisting of: methyl, ethyl, fluoro, chloro, difluoromethyl, trifluoromethyl, CN, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy,

[0473]

[0474]

[0475] Embodiment 23. A compound as described in any one of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein two R 4 The groups are combined to form a 5- to 6-membered heterocycloalkyl group having 1 to 2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5- to 6-membered heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl and halide.

[0476] Embodiment 24. The compound of embodiment 23, wherein two R 4 The groups are combined to form a heterocycloalkyl group selected from the group consisting of:

[0477]

[0478] wherein the heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl and halide.

[0479] Embodiment 25. A compound according to any one of Embodiments 1 to 2 or 5 to 24, or a pharmaceutically acceptable salt thereof, having a structure selected from Formula (Ia) or Formula (Ia1):

[0480]

[0481] Embodiment 26. A compound according to any one of Embodiments 1 to 2, 5, or 8 to 24, or a pharmaceutically acceptable salt thereof, having a structure according to Formula (Ib) or Formula (Ib1):

[0482]

[0483] wherein for each of Formula (Ib) and Formula (Ib1), subscript m is 0 or 1; and n is 0, 1 or 2, and each R 2 Can be the same or different.

[0484] Embodiment 27. The compound according to Embodiment 26 or a pharmaceutically acceptable salt thereof, which has the structure of Formula (If) or Formula (If1):

[0485]

[0486] Embodiment 28. The compound of embodiment 26 or 27, wherein m is 0.

[0487] Embodiment 29. The compound of any one of embodiments 26 to 28, wherein n is 0.

[0488] Embodiment 30. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510] Embodiment 31. A compound represented by formula (II)

[0511]

[0512] or a pharmaceutically acceptable salt thereof, wherein:

[0513] X is CH or N;

[0514] G 1 is N or CH;

[0515] A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, and azepane, each of which is surrounded by 1 to 4 R 2 replace;

[0516] R 1 is selected from the group consisting of phenyl and 5 to 6 membered heteroaryl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each phenyl and heteroaryl is separated by one R 1a and 0-3 Rs 3 replace;

[0517] R 1a selected from the group consisting of phenyl and 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the N atom, when present, is optionally oxidized, and wherein each phenyl and heteroaryl is substituted by 0-4 R 4 replace;

[0518] Each R 2 Independently selected from the group consisting of: C 1-7 Alkyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -NRa R b , 5- to 8-membered heterocycloalkyl and -NR a -(5- to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each cycloalkyl and heterocycloalkyl is substituted with 0-3 groups independently selected from: C 1-4 Alkyl and -OC 1-4 alkyl;

[0519] Each R 3 independently selected from the group consisting of: halogen, C 1-7 Alkyl and -OC 1-7 alkyl;

[0520] Each R 4 Independently selected from the group consisting of: C 1-7 Alkyl, halogen, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene -CN, C 1-7 Hydroxyalkyl, -C(O)NR a R b 、C 3-7 Cycloalkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, -S(O)2-C 1-7 Alkyl and -S(O)2-NR a R b , wherein each cycloalkyl and heterocycloalkyl group is substituted by 0 to 2 groups independently selected from the following: C 1-4 Alkyl and hydroxyl groups;

[0521] Or, two R on adjacent ring vertices 4 The groups are combined to form a 5- to 6-membered heterocycloalkyl group having 1 to 2 heteroatoms selected from the group consisting of O, N, and S, wherein the 5- to 6-membered heterocycloalkyl group is surrounded by 0 to 2 C 1-4 Alkyl substitution;

[0522] Each X 1 It is C 1-7 alkylene;

[0523] Each Y 1 It is C 2-7 alkylene;

[0524] Each R a and R b Independently selected from the group consisting of: H, C 1-7 Alkyl, C 3-7 Cycloalkyl, wherein the cycloalkyl is optionally substituted with -OC 1-3 Alkyl substitution; or

[0525] R a and R b Together with the nitrogen to which they are attached, they form a 4- to 8-membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the heterocycloalkyl ring is substituted with 0-3 groups, each group being independently selected from C 1-4 Alkyl, -OC 1-4 Alkyl and X 1 -OC 1-3 or two groups at the same ring vertex combine to form an oxo (=O).

[0526] Embodiment 32. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 31 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0527] Embodiment 33. The pharmaceutical composition of embodiment 32, wherein the composition comprises 10 to 300 mg of the compound of any one of embodiments 1 to 31 or a pharmaceutically acceptable salt thereof.

[0528] Embodiment 34. A method of treating cancer, fibrosis, viral infection, or pain, comprising administering to a subject in need thereof a compound of any one of Embodiments 1 to 31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 32 or 33.

[0529] Embodiment 35. A method of treating a disease, condition, or disorder mediated at least in part by AXL, comprising administering to a subject in need thereof 10 to 300 mg once daily of a compound of any one of Embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 32 or 33.

[0530] Embodiment 36. The method of embodiment 34 or 35, wherein the disease, disorder or condition is cancer.

[0531] Embodiment 37. The method of embodiment 36, wherein the cancer is prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, stomach cancer, endometrial cancer, uterine cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal carcinoma), mesothelial lining cancer, white blood cell cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, intestinal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), adrenal cancer, thyroid cancer, kidney cancer, or bone cancer; or is glioblastoma, mesothelioma, renal cell carcinoma, stomach cancer, sarcoma (including Kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the skin, or testicular seminoma, or any combination thereof

[0532] Embodiment 38. The method of embodiment 36, wherein the cancer is selected from the group consisting of skin cancer (e.g., melanoma), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), breast cancer (e.g., triple-negative breast cancer), bladder cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer), leukemia (e.g., acute myeloid leukemia or myelodysplastic syndrome), brain tumor (e.g., glioblastoma), ovarian cancer (e.g., epithelial ovarian cancer (EOC), high-grade serous ovarian cancer (HGSOC), or platinum-resistant ovarian cancer (PROC)), kidney cancer (e.g., clear cell renal cell carcinoma), mesothelioma, and head and neck cancer (e.g., head and neck squamous cell carcinoma).

[0533] Embodiment 39. The method of embodiment 38, wherein the cancer is acute myeloid leukemia, myelodysplastic syndrome, non-small cell lung cancer, ovarian cancer, or clear cell renal cell carcinoma.

[0534] Embodiment 40. The method of any one of Embodiments 36 to 39, wherein the cancer is recurrent or resistant to radiation therapy, chemotherapy, or immunotherapy.

[0535] Embodiment 41. The method of embodiment 34 or 35, wherein the disease, disorder, or condition is a viral infection.

[0536] Embodiment 42. The method of embodiment 41, wherein the viral infection is caused by SARS-CoV-2, Ebola virus, monkeypox, or Zika virus.

[0537] Embodiment 43. The method of embodiment 34 or 35, wherein the disease, disorder or condition is fibrosis.

[0538] Embodiment 44. The method of embodiment 43, wherein the fibrosis is renal fibrosis (e.g., chronic kidney disease), intestinal fibrosis (e.g., Crohn's disease), liver fibrosis (e.g., chronic liver disease), or lung fibrosis (e.g., idiopathic pulmonary fibrosis).

[0539] Embodiment 45. The method of any one of embodiments 35 to 40, further comprising administering to the subject at least one additional therapeutic agent.

[0540] Embodiment 46. The method of embodiment 45, wherein the at least one additional therapeutic agent comprises one or more agents independently selected from the group consisting of inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies), kinase inhibitors, inhibitors of HIF (e.g., HIF-2α inhibitors), inhibitors of PARP, RAS signaling inhibitors, immune checkpoint inhibitors, agents targeting extracellular production of adenosine, radiation therapy, and chemotherapeutic agents.

[0541] Embodiment 47. The method of embodiment 46, wherein the at least one additional therapeutic agent comprises an inhibitor of the CD47-SIRPα pathway, wherein the inhibitor of the CD47-SIRPα pathway is an anti-CD47 antibody.

[0542] Embodiment 48. The method of embodiment 46 or 47, wherein the at least one additional therapeutic agent comprises one or more kinase inhibitors that inhibit one or more of: EGFR, VEGFR, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK and / or FGFR.

[0543] Embodiment 49. The method of any one of Embodiments 46 to 48, wherein the at least one additional therapeutic agent comprises one or more immune checkpoint inhibitors that block the activity of at least one of: PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT, or CTLA-4.

[0544] Embodiment 50. The method of embodiment 49, wherein the one or more immune checkpoint inhibitors include an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

[0545] Embodiment 51. The method of embodiment 50, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is selected from the group consisting of: avelumab, atezolizumab, batilizumab, bregmalizumab, camrelizumab, coxilimab, dotalimab, durvalumab, epilizumab, envolimab, ebenlimab, nivolumab, pembrolizumab, pidilizumab, pimivasamonab, rivalizumab, samralizumab, spartalizumab, sintilimab, tislelizumab, toripalimab, and sepalizumab.

[0546] Embodiment 52. The method of embodiment 50, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is sepalimumab.

[0547] Embodiment 53. The method of any one of Embodiments 46 to 52, wherein the one or more immune checkpoint inhibitors include an immune checkpoint inhibitor that blocks the activity of TIGIT.

[0548] Embodiment 54. The method of embodiment 53, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is selected from AB308, dofantuzumab, etilizumab, osperlimab, tisleliumab, or vembralizumab.

[0549] Embodiment 55. The method of embodiment 53, wherein the immune checkpoint inhibitor is dofantazumab or AB308.

[0550] Embodiment 56. The method of any one of embodiments 46 to 55, wherein the at least one additional therapeutic agent comprises one or more agents targeting the extracellular production of adenosine selected from the group consisting of: A 2a R / A 2b R antagonists, CD73 inhibitors and CD39 inhibitors.

[0551] Embodiment 57. The method of embodiment 56, wherein the one or more agents targeting the extracellular production of adenosine are selected from the group consisting of AB598, elumelin, elupalin, talminalin, caffeine citrate, elumalin, safralin, and quinolistat.

[0552] Embodiment 58. The method of embodiment 56, wherein the one or more agents targeting the extracellular production of adenosine are AB598, elumetinib and / or quinolistat.

[0553] Embodiment 59. The method of any one of embodiments 46 to 58, wherein the at least one additional therapeutic agent comprises an inhibitor of HIF-2α selected from the group consisting of benztifan, ARO-HIF2, PT-2385, and AB521.

[0554] Embodiment 60. The method of embodiment 59, wherein the inhibitor of HIF-2α is AB521.

[0555] Embodiment 61. The method of any one of Embodiments 46 to 60, wherein the at least one additional therapeutic agent comprises an inhibitor of PARP selected from the group consisting of olaparib, rucaparib, and niraparib.

[0556] Embodiment 62. The method of any one of Embodiments 46 to 61, wherein the at least one additional therapeutic agent comprises a chemotherapeutic agent.

[0557] Embodiment 63. The method of any one of Embodiments 46 to 62, wherein the at least one additional therapeutic agent comprises radiation therapy.

[0558] Embodiment 64. The method of any one of Embodiments 46 to 63, wherein the compound and the at least one additional therapeutic agent are administered in combination.

[0559] Embodiment 65. The method of any one of embodiments 46 to 64, wherein the compound and the at least one additional therapeutic agent are administered sequentially.

[0560] Embodiment 66. The method of any one of embodiments 46 to 64, wherein the treatment periods for administering the compound and the at least one additional therapeutic agent overlap.

[0561] Embodiment 67. A combination comprising a compound as described in any one of Embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

[0562] Embodiment 68. The combination of embodiment 67, wherein the at least one additional therapeutic agent comprises one or more agents independently selected from the group consisting of inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies), kinase inhibitors, inhibitors of HIF (e.g., HIF-2α inhibitors), inhibitors of PARP, RAS signaling inhibitors, immune checkpoint inhibitors, agents targeting the extracellular production of adenosine, radiation therapy, and chemotherapeutic agents.

[0563] Embodiment 69. The combination of embodiment 68, wherein the at least one additional therapeutic agent comprises an inhibitor of the CD47-SIRPα pathway, wherein the inhibitor of the CD47-SIRPα pathway is an anti-CD47 antibody.

[0564] Embodiment 70. The combination of embodiment 68 or 69, wherein the at least one additional therapeutic agent comprises one or more kinase inhibitors that inhibit one or more of: EGFR, VEGFR, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK and / or FGFR.

[0565] Embodiment 71. The combination of any one of Embodiments 68 to 70, wherein the at least one additional therapeutic agent comprises one or more immune checkpoint inhibitors that block the activity of at least one of: PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT, or CTLA-4.

[0566] Embodiment 72. The combination of embodiment 71, wherein the one or more immune checkpoint inhibitors include an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

[0567] Embodiment 73. The combination of embodiment 72, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is selected from the group consisting of: avelumab, atezolizumab, batilizumab, bregmalizumab, camrelizumab, coxilimab, dotalimab, durvalumab, epilizumab, envolimab, ebenlimab, nivolumab, pembrolizumab, pidilizumab, pimivasamonab, rivalizumab, samralizumab, spartalizumab, sintilimab, tislelizumab, toripalimab, and sepalizumab.

[0568] Embodiment 74. The combination of embodiment 73, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is sepalimumab.

[0569] Embodiment 75. The combination of any one of Embodiments 68 to 74, wherein the one or more immune checkpoint inhibitors include an immune checkpoint inhibitor that blocks the activity of TIGIT.

[0570] Embodiment 76. The combination of embodiment 75, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is AB308, dofantuzumab, etilizumab, osperlimab, tisleliumab, or vembryomab.

[0571] Embodiment 77. The combination of embodiment 76, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is AB308 or dofantuzumab.

[0572] Embodiment 78. The combination of any one of embodiments 68 to 77, wherein the at least one additional therapeutic agent comprises one or more agents targeting the extracellular production of adenosine selected from the group consisting of: A 2a R / A 2b R antagonists, CD73 inhibitors and CD39 inhibitors.

[0573] Embodiment 79. The combination of embodiment 78, wherein the one or more agents targeting the extracellular production of adenosine are selected from the group consisting of AB598, elumelin, elupalin, talminalin, caffeine citrate, elumalin, safralin, or quinolistat.

[0574] Embodiment 80. The combination of embodiment 79, wherein the one or more agents targeting the extracellular production of adenosine are elumetinib and / or quinolistat.

[0575] Embodiment 81. The combination of any one of embodiments 68 to 80, wherein the at least one additional therapeutic agent comprises an inhibitor of HIF-2α selected from the group consisting of benztifan, ARO-HIF2, PT-2385, and AB521.

[0576] Embodiment 82. The combination of embodiment 81, wherein the inhibitor of HIF-2α is AB521.

[0577] Embodiment 83. The combination of any one of embodiments 68 to 82, wherein the at least one additional therapeutic agent comprises an inhibitor of PARP selected from the group consisting of olaparib, rucaparib, and niraparib.

[0578] Embodiment 84. The combination of any one of embodiments 68 to 83, wherein the at least one additional therapeutic agent comprises a chemotherapeutic agent.

[0579] Embodiment 85. The combination of embodiment 84, wherein the chemotherapeutic agent comprises gemcitabine, cytarabine, a platinum-based, a paclitaxel-based, or an anthracycline-based chemotherapeutic agent.

[0580] Embodiment 86. The combination of embodiment 85, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, and paclitaxel.

[0581] Embodiment 87. The combination of any one of Embodiments 68 to 86, wherein the at least one additional therapeutic agent comprises radiation therapy.

[0582] experiment

[0583] The following examples are presented to provide a person of ordinary skill in the art with a complete disclosure and a description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors consider to be their invention. Other compounds within the scope of the present disclosure may be prepared using methods based on those illustrated in these examples or based on other methods known in the art. Efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be taken into account.

[0584] All reactions were carried out at specified temperatures using a magnetic stirring bar coated with polytetrafluoroethylene (Teflon) and, when specified, under an inert atmosphere. All chemicals were used as is. Reaction was monitored by TLC (silica gel 60 with fluorescent F254, visualized with a shortwave / longwave UV lamp) and / or LCMS (Agilent 1100 or 1200 series LCMS, wherein a binary solvent system [0.1% formic acid in MeCN / 0.1% formic acid in H2O] was used to detect UV at 254 or 220 nm, using one of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm id × 100 mm], Waters XSelect HSS C18 [3.5 μm, 2.1 mm id × 75 mm]). Flash chromatography was performed on silica gel using an automated system (CombiFlash RF+ manufactured by Teledyne ISCO) with detection wavelengths of 254 and 280 nm and optionally equipped with an evaporative light scattering detector. Reverse phase preparative HPLC was performed on an Agilent 1260 or 1290 Infinity series HPLC. A binary solvent system (MeCN / H2O with an acid modifier such as 0.1% TFA or 0.1% formic acid as needed) was used on a Gemini C18 The samples were eluted using a gradient elution on a column (21.2 mm id x x 250 mm) and variable wavelength detection was performed. The final compound obtained by preparative HPLC was concentrated by lyophilization. All reported yields are isolated yields. All compounds tested were purified to ≥ 95% purity, as determined by 1H NMR or LCMS (Agilent 1100 or 1200 series LCMS with UV detection at 254 or 220 nm using a binary solvent system [0.1% formic acid in MeCN / 0.1% formic acid in H2O] using one of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm i.d. × 100 mm], Waters XSelect HSS C18 [3.5 μm, 2.1 mm id × 75 mm]). 1 H NMR spectra were recorded on a Varian 400 MHz NMR spectrometer or a Bruker AVANCE NEO 400 MHz NMR spectrometer equipped with an Oxford AS400 magnet. Chemical shifts (δ) are reported as parts per million (ppm) relative to residual undeuterated solvent or tetramethylsilane as an internal reference. The abbreviations s, br s, d, t, q, dd, dt, ddd, dddt, and m represent singlet, broad singlet, doublet, triplet, quartet, doublet of a doublet, doublet of a triplet, doublet of a doublet of a doublet, and multiplet, respectively.

[0585] Unless otherwise indicated, temperatures are in degrees Celsius (° C.) and pressures are at or near atmospheric. Standard abbreviations are used, including the following: rt or rt = room temperature; min = minute; h or hr = hour; t = elapsed time; mg = milligram; g = gram; μl or μL = microliter; ml or mL = milliliter; l or L = liter; mM = millimolar; M = molar; mol = molar; mmol = millimolar; aq. = aqueous; calcd = calculated; sat. = saturated; DCM or CH2Cl2 = dichloromethane; DCE = 1,2-dichloroethane; MTBE = methyl tert-butyl ether; THF = tetrahydrofuran; Et2O = diethyl ether; EtOAc = ethyl acetate; ACN = acetonitrile; AcOH = acetic acid; TFA = trifluoroacetic acid; NMP = N-methyl-2-pyrrolidone; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; IPA = isopropanol; EtOH = ethanol; MeOH = methanol; m-CPBA = meta-chloroperbenzoic acid; H2 = hydrogen; N2 = nitrogen; NH3 = ammonia; Cs2CO3 = cesium carbonate; NaH = sodium hydride; NaBH(OAc)3 = sodium triacetoxyborohydride; Na OH = sodium hydroxide; Na2SO4 = sodium sulfate; MgSO4 = magnesium sulfate; Na2CO3 = sodium carbonate; NaHCO3 = sodium bicarbonate; Et3N = triethylamine; MeMgBr = methylmagnesium bromide; LDA = lithium diisopropylamide; DIPEA = N,N-diisopropylethylamine; DMEDA = N,N-dimethylethane-1,2-diamine; SEMCl = 2-(trimethylsilyl)ethoxymethyl chloride; HATU = N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5 -b]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N-oxide; EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HOBt = hydroxybenzotriazole; NBS = N-bromosuccinimide; KOAc = potassium acetate; K3PO4 = potassium phosphate; K2CO3 = potassium carbonate; TFA = trifluoroacetic acid; MeI = iodomethane; PdCl2(dppf) or (dppf)PdCl2 = [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; XPhos Pd G3 = (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II); Xantphos = (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine); Pd2dba3 = tris(dibenzylideneacetone)dipalladium(0); Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0); B2pin2 = bis(pinacol)diboron; MHz = megahertz; Hz = hertz; ppm = parts per million; ESI-MS = electrospray ionization-mass spectrometry; NMR = nuclear magnetic resonance.

[0586] Example

[0587] Example 1: 6-[(7S)-2-{3-[4-(3-methylpyridin-2-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

[0588]

[0589] Step a: To a mixture of 3-oxa-6-aza-bicyclo[3.1.1]heptane 4-toluenesulfonic acid (5.00 g, 18.4 mmol) in CHCl (92 mL) was added 2-bromo-5,6,8,9-tetrahydro-benzocycloheptene-7-one (4.63 g, 19.4 mmol) at room temperature, followed by NaBH(OAc) (4.69 g, 22.1 mmol). The reaction mixture was then stirred at room temperature for 4 hours. Additional NaBH(OAc) (4.69 g each) was added at t = 4 hours and t = 8 hours. After the last addition, the reaction mixture was stirred at room temperature for another 4 hours. The reaction mixture was washed with CHCl (250 mL), water (250 mL) and 2M NaOH. (aq) (100 mL, or until pH>12) and stirred. The organic phase was diluted with 4:1:1 water:brine:2M NaOH (aq) The mixture was washed with 4-nitropropene (300 mL), dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography (hexane: (EtOAc + 1% Et3N) 0 to 100% gradient) to give the racemic product (5.13 g, 86%) as a white solid. The racemic mixture was resolved using chiral HPLC (Daicel CHIRALPAK IA; MeOH / DEA 100 / 0.1 volume / volume; 1.0 mL / min; UV 230 nm; 5.3 minutes (desired isomer), 7.0 minutes (other isomers)).

[0590] Step b: To a mixture of 2-bromo-3-methylpyridine (2.0 g, 12 mmol), (4-chlorophenyl)boronic acid (1.82 g, 11.6 mmol) and Na2CO3 (2.46 g, 23.2 mmol) was added dioxane (64 mL) and water (14 mL). The suspension was degassed with nitrogen for 10 min and PdCl2(dppf) (425 mg, 0.581 mmol) was added. The reaction mixture was stirred at 95 ° C for 16 hours, cooled, diluted with EtOAc (15 mL), dried over MgSO4, filtered through celite and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 100% gradient) to give the desired product (2.0 g, 86%) as an off-white solid.

[0591] Step c: To a mixture of the product from step b (2.0 g, 9.8 mmol), B2pin2 (5 g, 20 mmol) and K3PO4 (5.22 g, 24.6 mmol) was added dioxane (100 mL). The suspension was degassed with nitrogen for 10 minutes and XPhosPd G3 (834 mg, 0.985 mmol) was added. The reaction mixture was stirred at 95° C. for 16 hours, cooled, diluted with EtOAc (15 mL), filtered through celite and concentrated to give the desired product, which was used as crude in step d.

[0592] Step d: To a mixture of the product of step c (4.9 mmol), 1- (benzenesulfonyl) -5- bromo -3- iodopyrrolo [2,3-b] pyridine (2.26 g, 4.88 mmol) and K CO (1.35 g, 9.77 mmol) was added dioxane (30 mL) and water (5 mL). The suspension was degassed with nitrogen for 10 minutes, and PdCl (dppf) (180 mg, 0.245 mmol) was added. The reaction mixture was stirred at 80 ° C for 4 hours, cooled, diluted with CH Cl (15 mL), dried over MgSO, filtered through celite and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 100% gradient) to give the desired product (1.8 g, 73% in two steps) as an off-white solid.

[0593] Step e: To a mixture of the product from step d (350 mg, 0.694 mmol), B2pin2 (353 mg, 1.39 mmol) and KOAc (136 mg, 1.39 mmol) was added dioxane (7 mL). The suspension was degassed with nitrogen for 10 minutes and PdCl2(dppf) (26 mg, 0.035 mmol) was added. The reaction mixture was stirred at 95°C for 16 hours, cooled, diluted with EtOAc, filtered through celite and concentrated to give the desired product, which was used as crude in step f.

[0594] Step f: To a mixture of the product of step e (0.694 mmol), 6-[(7S)-3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl]-3-oxa-6-azabicyclo[3.1.1]heptane (222 mg, 0.689 mmol) and K2CO3 (192 mg, 1.39 mmol) was added dioxane (5.8 mL) and water (1.2 mL). The suspension was degassed with nitrogen for 10 minutes and PdCl2(dppf) (26 mg, 0.035 mmol) was added. The reaction mixture was stirred at 95°C for 3 hours, cooled, diluted with CH2Cl2 (15 mL), dried over MgSO4, filtered through celite and concentrated. The product was purified by silica gel chromatography ((CH2Cl2:MeOH) + 1% NH 3(aq，28重量％) The crude material was purified (0 to 10% gradient) to afford the desired product (302 mg, 65% in two steps) as a white solid.

[0595] Step g: To a solution of the product from step f (280 mg, 0.420 mmol) in dioxane (4 mL) was added 6 M NaOH (aq) In the mixture was added 4-[ ... 1HNMR (400 MHz, chloroform-d) δ 10.78 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.55 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.79–7.71 (m, 2H), 7.67–7.55 (m, 4H), 7.39 (d, J = 6.5 Hz, 2H), 7.22–7.15 (m, 2H), 4.30 (d, J = 10.8 Hz,2H),3.74(d,J=10.8Hz,2H),3.70(d,J=6.0Hz,2H),3.27(dd,J=11.1,7.8Hz,1H),2.97(m,2H),2.83(q, J=12.9Hz,2H),2.65–2.56(m,1H),2.43(s,3H),1.93(d,J=8.1Hz,2H),1.85(d,J=8.4Hz,1H),1.37(m,2H). C 35 H 35 ESIMS of N4O[M+H] + , calculated value 527.3, measured value 527.3.

[0596] Example 2: 6-[(7S)-2-{3-[4-(3-methylpyridin-2-yl)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

[0597]

[0598] Steps a and b: The compound formed from step b was prepared in a manner similar to that described in Example 1, steps b and c.

[0599] Step c: To a mixture of the product from step b (4.9 mmol), 5-bromo-3-iodo-1-(oxane-2-yl)pyrazolo[3,4-b]pyridine (2.0 g, 4.9 mmol) and KCO (1.35 g, 9.8 mmol) was added dioxane (30 mL) and water (5 mL). The suspension was degassed with nitrogen for 10 minutes and PdCl(dppf) (180 mg, 0.245 mmol) was added. The reaction mixture was stirred at 80 ° C for 4 hours, cooled, diluted with CHCl (15 mL), dried over MgSO, filtered through celite and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 100% gradient) to give the desired product (1.5 g, 68% in two steps) as an off-white solid.

[0600] Step d: To a mixture of the product from step c (250 mg, 0.556 mmol), B2pin2 (283 mg, 1.11 mmol) and KOAc (110 mg, 1.11 mmol) was added dioxane (6 mL). The suspension was degassed with nitrogen for 10 minutes and PdCl2(dppf) (20 mg, 0.027 mmol) was added. The reaction mixture was stirred at 95°C for 16 hours, cooled, diluted with EtOAc (10 mL), filtered through celite and concentrated to give the desired product, which was used as a crude product in step c.

[0601] Step e: To a mixture of the product from step d (0.556 mmol), 6-[(7S)-3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl]-3-oxa-6-azabicyclo[3.1.1]heptane (177 mg, 0.549 mmol) and K2CO3 (153 mg, 1.11 mmol) was added dioxane (5 mL) and water (1 mL). The suspension was degassed with nitrogen for 10 minutes and PdCl2(dppf) (20 mg, 0.027 mmol) was added. The reaction mixture was stirred at 95°C for 3 hours, cooled, diluted with CH2Cl2 (15 mL), dried over MgSO4, filtered through celite and concentrated. The product was purified by silica gel chromatography ((CH2Cl2:MeOH) + 1% NH 3(aq，28％重量) The crude material was purified (0 to 10% gradient) to afford the desired product (218 mg, 65% over two steps) as a white solid.

[0602] Step f: To a solution of the product from step e (200 mg, 0.327 mmol) in CH Cl (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 16 hours and concentrated. The crude material was purified by C18 reverse phase chromatography ((water:ACN)+1% TFA 0 to 70% gradient), then partially concentrated and K CO was added. The mixture was extracted with CH Cl (3 x 50 mL). The combined organic phases were dried over MgSO and concentrated to obtain the desired product (152 mg, 88%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 12.87 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.55 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.12–8.04 (m, 2H), 7.74–7.66 (m, 2H), 7.60 (ddt, J = 7.7, 1.8, 0.8 Hz, 1H), 7.38 (d, J = 6.3 Hz, 2H), 7.24–7.17 (m, 2H), 4.31 (d,J=10.7Hz,2H),3.73(d,J=10.7Hz,2H),3.67(d,J=6.1Hz,2H),3.31–3.21(m,1H),3.04–2.91(m,2H),2.85(q,J=12 .2Hz, 2H), 2.56 (q, J = 6.7Hz, 1H), 2.42 (s, 3H), 1.96 (d, J = 12.2Hz, 2H), 1.84 (d, J = 8.3Hz, 1H), 1.37 (q, J = 11.3Hz, 2H). C 34 H 34 ESIMS of N5O[M+H] + , calculated value 528.3, measured value 528.2.

[0603] Example 3: 6-[(7S)-2-(3-{4-[3-(2-methoxyethoxy)pyridin-2-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

[0604]

[0605] Step a: To a solution of 2-bromopyridin-3-ol (2.0 g, 11 mmol) in DMF (25 mL) was added KCO (3.17 g, 22.9 mmol) and 1-bromo-2-methoxyethane (2.4 g, 17 mmol) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, cooled, diluted with MTBE, filtered through celite, washed twice with water, dried over MgSO and concentrated to give the desired product (assumed 11 mmol), which was used in the next step without any further purification.

[0606] Step bg: The title compound was prepared in a similar manner to Example 1 using step bg. 1H NMR (400 MHz, chloroform-d) δ 10.55 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.34 (dd, J = 4.6, 1.4 Hz, 1H), 8.15–8.07 (m, 2H), 7.79–7.70 (m, 2H), 7.61 (d, J = 2.4 Hz, 1H), 7.39 (dq, J = 3.4, 2.0 Hz, 2H), 7.32 (dd, J = 8.3, 1.4 Hz, 1H), 7.23–7.18 (m, 2 H),4.30(d,J=10.7Hz,2H),4.22–4.15(m,2H),3.81–3.68(m,4H),3.65(d,J=6.1Hz,2H),3.43(s,3H),3.24(d,J=9.8Hz,1H),2. 98(m,2H),2.84(q,J=13.1Hz,2H),2.56(q,J=6.8Hz,1H),1.98(d,J=5.0Hz,2H),1.83(d,J=8.3Hz,1H),1.34(p,J=10.0Hz,2H). C 37 H 39 ESIMS of N4O3[M+H] + , calculated value 587.3, measured value 587.3.

[0607] Example 4: 6-[(7S)-2-(3-{4-[3-(pyrrolidine-1-carbonyl)pyridin-2-yl]phenyl}-1H-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

[0608]

[0609] Step a: HATU (2.48 g, 6.52 mmol), diisopropylethylamine (1.3 mL, 7.5 mmol) and pyrrolidine (0.45 mL, 5.5 mmol) were added to a stirred solution of 2-bromopyridine-3-carboxylic acid (1.0 g, 5.0 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours, diluted with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 100% gradient) to obtain the desired product (755 mg, 60%) as a white solid.

[0610] Steps bg: The title compound was prepared in a similar manner to Example 2.1 H NMR (400 MHz, chloroform-d) δ 12.15 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.76 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.15–8.07 (m, 2H), 8.01–7.93 (m, 2H), 7.80 (dd, J = 7.7, 1.7 Hz, 1H), 7.43–7.30 (m, 3H), 7.24 (m, 1H), 4.34–4.26 (m, 2H) ,3.73(d,J=10.7Hz,2H),3.65(d,J=6.1Hz,2H),3.51(bs,1H),3.31–3.22(m,1H),3.07–2.73(m,5H),2.57(q,J=6. 7Hz, 1H), 1.96 (d, J = 11.6Hz, 2H), 1.84 (d, J = 8.3Hz, 1H), 1.79–1.63 (m, 5H), 1.54 (bs, 1H), 1.36 (d, J = 12.3Hz, 2H). C 38 H 39 ESI MS of N6O2[M+H] + , calculated value 611.3, measured value 611.3.

[0611] Example 5: 6-[(7S)-2-(3-{4-[3-(morpholin-4-yl)pyridin-2-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

[0612]

[0613] Step a: to the bromo-3-iodopyridine of 2- (2.0g, 7.0mmol), morpholine (668 μ L, 7.75mmol) and CsCO(2.52g, 7.75mmol) mixture, add toluene (20mL).Suspension is degassed with nitrogen 10 minutes, and add Xantphos (611mg, 1.06mmol) and Pddba(322mg, 0.352mmol).Reaction mixture is stirred at 90 ℃ for 16 hours, cooling, dilutes with EtOAc (10mL), is filtered through diatomite and concentrated.By silica gel chromatography (hexane:EtOAc 0 to 100% gradient) purification of crude material to obtain required product (342mg, 20%).

[0614] Step bg: The title compound was prepared in a similar manner to Example 1 using step bg. 1H NMR (400 MHz, chloroform-d) δ 11.37 (d, J = 2.4 Hz, 1H), 8.65–8.60 (m, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.38 (dd, J = 4.6, 1.4 Hz, 1H), 8.14–8.06 (m, 2H), 7.79–7.71 (m, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.39 (dq, J = 3.9, 2.0 Hz, 2H), 7.33 (dd, J = 8 .2,1.5Hz,1H),7.27–7.14(m,2H),4.30(d,J=10.7Hz,2H),3.76–3.67(m,6H),3.67–3.61(m,2H),3.29–3.19( m,1H),3.05–2.78(m,8H),2.54(q,J=6.7Hz,1H),1.93(bs,2H),1.83(d,J=8.2Hz,1H),1.33(p,J=10.0Hz,2H). C 38 H 40 ESIMS of N5O2[M+H] + , calculated value 598.3, measured value 598.3.

[0615] Example 6: N,N-dimethyl-2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridine-3-sulfonamide

[0616]

[0617] Step a: To a stirred solution of 2-bromopyridine-3-sulfonyl chloride (2.5 g, 9.7 mmol) in THF (50 mL) was added N,N-dimethylamine (5.89 mL, 11.8 mmol, 2 M in THF) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 70% gradient) to give the desired product (1.1 g, 35%) as an off-white solid.

[0618] Step bg: The title compound was prepared in a similar manner to Example 1 using step bg. 1H NMR (400 MHz, chloroform-d) δ 11.52 (s, 1H), 8.82 (dd, J = 4.8, 1.7 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.47–8.39 (m, 2H), 7.81–7.73 (m, 2H), 7.73–7.65 (m, 2H), 7.62 (d, J = 1.3 Hz, 1H), 7.48–7.35 (m, 3H), 7.24–7.17 (m,1H),4.30(d,J=10.7Hz,2H),3.78–3.65(m,4H),3.31–3.21(m,1H),3.05–2.76(m,4H),2.60(dd ,J=9.4,4.8Hz,1H),2.39(s,6H),1.99–1.91(m,2H),1.84(d,J=8.4Hz,1H),1.36(p,J=10.6Hz,2H). C 36 H 38 ESIMS of N5O3S[M+H] + , calculated value 620.3, measured value 620.3.

[0619] Example 7: 1-[2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridin-3-yl]pyrrolidin-2-one

[0620]

[0621] Step a: 2-pyrrolidone (3.62 g, 42.5 mmol) and NaH (1.5 g, 38 mmol, 60 wt % in oil) were added to a stirred solution of 2-bromo-3-fluoropyridine (5.0 g, 28 mmol) in DMF (60 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 minutes, at 85 ° C for 16 hours, cooled, carefully diluted with water (50 mL), and extracted with EtOAc (3x50 mL). The combined organic phases were dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 100% gradient) to obtain the desired product (3.8 g, 55%).

[0622] Step bg: The title compound was prepared in a similar manner to Example 1 using step bg. 1H NMR (400 MHz, chloroform-d) δ 11.17 (s, 1H), 8.64 (dd, J = 4.7, 1.6 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.77–7.66 (m, 5H), 7.62 (s, 1H), 7.39–7.30 (m, 2H), 7.22 –7.13(m,2H),4.34(d,J=11.8Hz,2H),4.12(s,2H),3.90(d,J=11.7Hz,2H),3.35(t ,J=7.0Hz,3H),3.01–2.70(m,5H),2.50(t,J=8.1Hz,2H),1.97(m,5H),1.52(s,2H). C 38 H 38 ESIMS of N5O2[M+H] + , calculated value 596.3, measured value 596.3.

[0623] Example 8: 2-[5-methyl-6-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridin-2-yl]propan-2-ol

[0624]

[0625] Step a: To a stirred solution of methyl 6-chloro-5-methylpyridine-2-carboxylate (1.0 g, 5.4 mmol) in THF (20 mL) was added methylmagnesium bromide (8.9 mL, 27 mmol, 3 M in diethyl ether) at -15°C. The reaction mixture was stirred at -15°C for 15 minutes, at room temperature for 16 hours, and washed with saturated NH4Cl. (aq) (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over MgSO4 and concentrated to give the desired product (assumed 5.4 mmol), which was used in the next step without any further purification.

[0626] Step bg: The title compound was prepared in a similar manner to Example 1 using step bg. 1H NMR (400 MHz, chloroform-d) δ10.88 (s, 1H), 8.58–8.53 (m, 1H), 8.46–8.40 (m, 1H), 7.79–7.63 (m, 4H), 7.63–7.54 (m, 2H), 7.42–7.32 (m, 2H), 7.27–7.14 (m, 2H), 5.66 (s, 1H), 4. 33(d,J=11.3Hz,2H),3.93(d,J=5.7Hz,2H),3.84(d,J=11.4Hz,2H),3.37–3.27(m, 1H),2.99–2.75(m,5H),2.43(s,3H),2.02–1.88(m,3H),1.56(s,6H),1.46(bs,2H). C 38 H 41 ESIMS of N4O2[M+H] + , calculated value 585.3, measured value 585.3.

[0627] Example 9: 3,6-dimethyl-6'-{5-[(7S)-7-[(1R)-3-oxa-6-azabicyclo[3.1.1]hept-6-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-2,3'-bipyridine

[0628]

[0629] Step a:To a solution of 3-bromo-5-chloro-1H-pyrazolo[3,4-b]pyridine (10 g, 43 mmol) in DMF (150 mL) was added KCO (17.88 g, 129.6 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes. Triphenylmethane (14.45 g, 51.84 mmol) was added to the above reaction mixture at 0 ° C. The mixture was stirred at rt for 16 hours and water (100 mL) was added. The aqueous phase was extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, concentrated, and purified by silica gel chromatography (hexane: EtOAc 0 to 20% gradient) to obtain the desired product (15.98 g, 78%) as a white solid.

[0630] Step b: A mixture of the product from step a (269 mg, 0.566 mmol), B2pin2 (144 mg, 0.566 mmol), PdCl2(dppf) (20.7 mg, 0.0283 mmol) and KOAc (111 mg, 1.13 mmol) was placed under nitrogen. Degassed dioxane (20 mL) was added and the reaction mixture was stirred at 100° C. for 4 hours. The mixture was cooled to rt, concentrated, diluted with CHCl (50 mL), filtered through celite to remove solids, and concentrated again to give the desired product, which was used as the crude product in step d.

[0631] Step c: To a mixture of 2-chloro-5-pyridineboronic acid (789 mg, 5.01 mmol), 2-chloro-3,6-dimethylpyridine (708 mg, 5.00 mmol), PdCl2(dppf) (183 mg, 0.250 mmol) and K2CO3 (1.38 g, 10.0 mmol) was added degassed dioxane (20 mL) and degassed water (5 mL) under nitrogen. The reaction mixture was stirred at 95 ° C for 16 hours, cooled, concentrated, diluted with CH2Cl2 (25 mL), dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 20% gradient) to give the desired product (547 mg, 50%) as a white solid.

[0632] Step d: To a mixture of the product from step b (assumed 0.566 mmol), the product from step c (103 mg, 0.471 mmol), PdCl2(dppf) (17.2 mg, 0.0236 mmol), and K2CO3 (130 mg, 0.942 mmol) was added degassed dioxane (2.4 mL) and degassed water (0.48 mL). The reaction mixture was stirred at 100°C for 16 hours, cooled, concentrated, diluted with CHCl (25 mL), dried over MgSO4, and concentrated. The crude material was purified by silica gel chromatography (hexanes:EtOAc 0 to 20% gradient) to give the desired product (81.2 mg, 30%) as a white solid.

[0633] Step e: The product from step d (81.2 mg, 0.140 mmol), B 2pA mixture of in2 (42.7 mg, 0.168 mmol), K3PO4 (59.4 mg, 0.280 mmol) and XPhos Pd G3 (5.9 mg, 0.0070 mmol) was placed under nitrogen. Degassed dioxane (0.7 mL) was added and the mixture was purged with nitrogen for 10 minutes. The reaction mixture was stirred at 100°C for 2 hours, cooled, concentrated, diluted with CH2Cl2 (10 mL), filtered through celite to remove solids, and concentrated again to give the desired product, which was used as a crude product in step f.

[0634] Step f: To a mixture of the product from step e (assumed 0.140 mmol), 6-[(7S)-3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl]-3-oxa-6-azabicyclo[3.1.1]heptane (45.1 mg, 0.140 mmol), PdCl(dppf) (5.1 mg, 0.0070 mmol) and KCO (38.7 mg, 0.280 mmol) was added degassed dioxane (0.7 mL) and degassed water (0.14 mL) under nitrogen. The reaction mixture was stirred at 95° C. for 16 hours, cooled, concentrated, diluted with CHCl (10 mL), dried over MgSO and concentrated. The crude material was purified by silica gel chromatography (CHCl:MeOH 0 to 15% gradient) to give the desired product (89 mg, 81%) as a grey solid.

[0635] Step g: To a mixture of the product from step f (89 mg, 0.11 mmol) and CHCl (10 mL) was added triethylsilane (66.3 mg, 0.570 mmol) at 0°C, followed by slow dropwise addition of TFA (65.0 mg, 0.570 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated. The crude material was purified by silica gel chromatography (CHCl: MeOH 0 to 15% gradient) to obtain the desired product (42.3 mg, 69% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.03(d,J=2.2Hz,1H),8.92(dd,J=2.3,0.9Hz,1H),8.85(d,J=2.2Hz,1H),8.26(dd,J=8.3,0. 9Hz,1H),8.09(dd,J=8.2,2.3Hz,1H),7.64(d,J=7.8Hz,1H),7.51(s,1H),7.48–7.43(m,1H),7.24(d,J=7.8Hz,1H),7. 20(d,J=7.8Hz,1H),4.13(d,J=10.7Hz,2H),3.53(dd,J=18.8,8.3Hz,4H),3.21–3.10(m,1H),3.04–2.85(m,2H),2.77 (q,J=14.4Hz,2H),2.48–2.45(m,3H),2.40–2.26(m,4H),1.91–1.75(m,2H),1.65(d,J=8.0Hz,1H),1.26–1.08(m,2H). C 34 H 35 ESIMS of N6O[M+H] + , calculated value 543.3, measured value 543.3.

[0636] Example 10: 2-[2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)pyridin-3-yl]propan-2-ol

[0637]

[0638] Step a: A mixture of methyl 2-bromonicotinate (1.71 g, 10.0 mmol), 4-chlorophenylboronic acid (1.56 g, 10.0 mmol), KCO (2.76 g, 20.0 mmol) and PdCl(dppf) (365 mg, 0.500 mmol) was placed under nitrogen. Degassed dioxane (25 mL) and degassed water (25 mL) were added and the reaction mixture was stirred at 95 ° C for 4 hours. The mixture was cooled to rt, concentrated, diluted with CHCl (25 mL), dried over MgSO and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 20% gradient) to give the desired product (2 g, 80%) as a colorless liquid.

[0639] Step b: To a solution of the product from step a (2 g, 8 mmol) in THF (20 mL) was added methylmagnesium bromide (8.0 mL, 24 mmol, 3 M in ether) dropwise at 0°C. The mixture was stirred at rt for 16 hours. Saturated NH4Cl was added (aq) (20 mL) and the mixture was extracted with EtOAc (2 x 20 mL).The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the desired product (1.6 g, 65%).

[0640] Step c: A mixture of the product from step b (1.3 g, 5.2 mmol), B2pin2 (2.66 g, 10.4 mmol), K3PO4 (2.77 g, 13.1 mmol), XPhosPdG3 (221 mg, 0.260 mmol) and dioxane (50 mL) was purged with nitrogen for 10 minutes. The reaction mixture was stirred at 100° C. for 16 hours, cooled to rt, concentrated, diluted with CH2Cl2 (50 mL), filtered through celite to remove solids, and concentrated again to give the desired product, which was used as a crude product in the next step.

[0641] Step dg: The title compound was prepared in a similar manner to Example 2. 1 H NMR (400MHz, chloroform-d) δ11.53(s,1H),8.83(d,J=2.0Hz,1H),8.55(dd,J=4.7,1.6Hz,1H),8.48(d,J=2.0Hz,1H),8.0 9–8.02(m,2H),7.59–7.52(m,2H),7.40–7.35(m,2H),7.32(dd,J=8.1,4.7Hz,1H),7.22(s,1H),4.30(d,J=10.7Hz ,2H),3.72(d,J=10.7Hz,2H),3.64(d,J=6.1Hz,2H),3.25(t,J=9.6Hz,1H),3.03-2.94(m,2H),2.85(q,J=13.1Hz, 2H), 2.56(q,J=6.8Hz,1H),1.94(brs,2H),1.85-1.83(m,2H),1.52(s,6H),1.41–1.23(m,2H),0.91–0.82(m,1H). C 36 H 38 ESIMS of N5O2[M+H] + , calculated value 572.3, measured value 572.3.

[0642] Example 11: 6-[(7S)-2-{3-[4-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl]-1H-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

[0643]

[0644] Step a: under rt, dimethylacetamide dimethyl acetal (1.2g, 10mmol) is added to the solution of acetohydrazide (740mg, 10.0mmol) and ACN (4mL).Reactant mixture is stirred at 50 DEG C for 30 minutes.Add a solution of 4-bromoaniline (1.72mg, 10.0mmol) in ACN (4mL), then add acetic acid (3mL).Then reactant mixture is stirred at 120 DEG C for 3 hours, cooling, concentrated, and by silica gel chromatography (100% EtOAc, then 95% EtOAc / 5%0.7M ammonia in methanol) purifying to obtain required product (832mg, 35%).

[0645] Step bf: The title compound was prepared in a manner analogous to Example 2, Step bf. 1 H NMR (400 MHz, chloroform-d) δ 12.17 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 8.24–8.12 (m, 2H), 7.52–7.40 (m, 2H), 7.37 (d, J = 7.2 Hz, 2H), 7.24 (s, 1H), 4.3 0(d,J=10.8Hz,2H),3.76-3.68(m,4H),3.28(t,J=9.9Hz,1H),3.04–2.75(m,4H),2.59 (q,J=6.8Hz,1H),2.49(s,3H),1.99(s,2H),1.86(d,J=8.4Hz,1H),1.43–1.25(m,2H). C 31 H 32 ESIMS of N7O [M+H] + , calculated value 518.3, measured value 518.3.

[0646] Example 12: N,N-dimethyl-4'-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-2H-pyrazolo[3,4-b]pyridin-3-yl}-[1,1'-biphenyl]-2-carboxamide

[0647]

[0648] Step a: To a mixture of methyl[2-(dimethylcarbamoyl)phenyl]boronic acid (1.25 g, 6.48 mmol), 1,4-dibromobenzene (1.52 g, 6.44 mmol), KCO (1.76 g, 12.8 mmol), and PdCl(dppf) (234 mg, 0.324 mmol) was added degassed dioxane (16 mL) and degassed water (16 mL) under nitrogen. The reaction mixture was stirred at 70 ° C for 4 hours, cooled to rt, concentrated, diluted with CH Cl (25 mL), dried over MgSO and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 20% gradient) to give the desired product (700 mg, 35%) as a colorless liquid.

[0649] Step bf: The title compound was prepared in a manner analogous to Example 2, Step bf. 1 H NMR (400MHz, chloroform-d) δ11.30(brs,1H),8.83(d,J=2.0Hz,1H),8.50(d,J=2.1Hz,1H),8.15–7.92(m,2H),7.70–7 .52(m,2H),7.50–7.45(m,1H),7.43(dd,J=2.8,1.5Hz,1H),7.41–7.35(m,1H),7.24(s,4H),4.30(d,J=10.7Hz ,2H),3.73(d,J=10.8Hz,2H),3.66(d,J=6.1Hz,2H),3.27(t,J=9.7Hz,1H),3.06-2.95(m,2H),2.89(s,3H),2. 48–2.47(s,3H),2.47(s,2H),2.03–1.88(m,2H),1.84(d,J=8.3Hz,1H),1.44–1.19(m,2H),0.89–0.75(m,1H). C 37 H 38 ESIMS of N5O2[M+H] + , calculated value 584.3, measured value 584.4.

[0650] Example 13: 6-[(7S)-2-{3-[4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl]-1H-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

[0651]

[0652] Step a: To a mixture of 1,4-dibromobenzene (944 mg, 4.00 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole (836 mg, 4.00 mmol), PdCl2(dppf) (293 mg, 0.400 mmol) and K2CO3 was added degassed dioxane (16 mL) and degassed water (4 mL) at room temperature under nitrogen. The reaction mixture was stirred at 90 ° C for 14 hours, cooled, diluted with CH2Cl2 (200 mL), dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 100% gradient) to give the desired product (390 mg, 41%) as a light yellow oil.

[0653] Step bf: The title compound was prepared in a manner analogous to Example 2, Step bf. 1 H NMR (400 MHz, DMSO-d6, citrate) δ 14.03 (s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 8.3 Hz, 2H), 8.02 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.69 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 7.8 Hz ,1H),4.40–4.19(m,3H),4.16(s,3H),4.01–3.79(m,2H),3.76–3.59(m,1H),3.51–3.16(m,3H),3.06 –2.83(m,4H),2.62(d,J=15.2Hz,2H),2.54(d,J=15.3Hz,2H),2.21–1.93(m,2H),1.27–1.13(m,2H). C 31 H 32 ESIMS of N7O [M+H] + , calculated value 518.3, measured value 518.3.

[0654] Example 14: 6-[(7S)-2-{3-[4-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)phenyl]-1H-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

[0655]

[0656] Step a: To a solution of 4-methylbenzenesulfonylhydrazide (16.4 g, 88.2 mmol) in MeOH (88 mL) was added 4′-bromopropiophenone (18.8 g, 88.2 mmol) in one portion at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and concentrated to give the desired product (33.5 g, 99%) as a white solid.

[0657] Step b: to a mixture of the product (7.63g, 20.0mmol), sodium azide (1.56g, 24.0mmol) and DMSO (100mL) from step a, iodine (5.08g, 20.0mmol) was added at room temperature. The mixture was stirred at room temperature for 5 minutes and methanesulfonic acid (1.30mL, 20.0mmol) was added. The reaction mixture was stirred at 100°C for 4 hours and cooled. KCO (13.8g, 100mmol) was added to the mixture, followed by iodomethane (2.49mL, 40.0mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with EtOAc (1.0L), washed with water (1x 1.0L), washed with 3:2 water: brine (2x 1.0L), dried over NaSO and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 100% gradient) to obtain the desired product (439mg, 9%) as a light yellow oil.

[0658] Step cg: The title compound was prepared in a manner analogous to Example 2, steps bf. 1 H NMR (400 MHz, DMSO-d6, citrate) δ 13.93 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.23 ​​(d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.68 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 4.29 (d, J = 12.1 Hz, 2H),4.23–4.07(m,1H),4.01(s,3H),3.97–3.79(m,2H),3.72–3.54(m,1H),3.49–3.20(m,3H),3.07–2.83( m,4H),2.61(d,J=15.2Hz,2H),2.53(s,3H),2.53(d,J=15.9Hz,2H),2.20–1.91(m,2H),1.28–1.11(m,2H). C 32 H 34 ESIMS of N7O [M+H] + , calculated value 532.3, measured value 532.4.

[0659] Example 15: 3-(2-methoxyethyl)-7-{3-[4-(3-methylpyridin-2-yl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-2,3,4,5-tetrahydro-1H-3-benzazepine

[0660]

[0661] Step a: Add 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine to the reaction mixture at room temperature. To a mixture of 2-bromoethyl methyl ether (565 mg, 2.50 mmol), K2CO3 (691 mg, 5.00 mmol) and DMF (13 mL) was added 2-bromoethyl methyl ether (235 μL, 2.50 mmol). The reaction mixture was stirred at 70°C for 3 hours and at 80°C for 12 hours, cooled, diluted with EtOAc (125 mL), and washed with 0.2 M NaOH. (aq) (4 x 100 mL), washed with water, dried over Na2SO4 and concentrated. The crude material was purified by C18 reverse phase chromatography ((water:ACN) + 1% TFA 5 to 35% gradient) followed by saturated NaHCO 3(aq) Neutralized and partially concentrated to remove ACN. The mixture was diluted with EtOAc (200 mL) and washed with 0.2 M NaOH. (aq) (2 x 200 mL), dried over Na 2 SO 4 and concentrated to give the desired product (342 mg, 48%) as a light yellow oil.

[0662] Steps bc: The title compound was prepared in a manner analogous to Example 2, steps e and f. 1 H NMR (400 MHz, DMSO-d6, citrate) δ 13.97 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.53 (dd, J = 4.8, 1.0 Hz, 1H), 8.21 (d, J = 8.4 Hz, 2H), 7.79–7.69 (m, 4H), 7.66 (dd, J = 7.7, 2.0 Hz, 1H),7.34(d,J=7.7Hz,1H),7.33(d,J=7.7Hz,1H),3.61(t,J=5.2Hz,2H),3.44–3.26(m,2H), 3.31(s,3H),3.20–3.00(m,8H),2.64(d,J=15.2Hz,2H),2.55(d,J=15.2Hz,2H),2.42(s,3H). C 31 H 32 ESIMS of N5O[M+H] +, calculated value 490.3, measured value 490.3.

[0663] Example 16: 3-Methyl-2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridin-1-ium-1-olate

[0664]

[0665] Step a: To a solution of the product from Example 1, Step d (504 mg, 1.00 mmol) in CHCl (5.0 mL) at room temperature was added m-CPBA (230 mg, 1.00 mmol, 75% by weight in water). The reaction mixture was stirred at room temperature for 14 hours and additional m-CPBA (115 mg, 0.500 mmol, 75% by weight in water) was added. The reaction mixture was stirred at room temperature for 5 hours and concentrated. The crude material was purified by silica gel chromatography (CHCl:MeOH 0 to 10% gradient) to give the desired product (350 mg, 67%) as a light brown solid.

[0666] Step b: To a mixture of the product from Example 1, step a (64 mg, 0.20 mmol), B2pin2 (51 mg, 0.20 mmol), PdCl2(dppf) (7 mg, 0.01 mmol) and KOAc (39 mg, 0.40 mmol) was added degassed dioxane (1.0 mL) at room temperature under nitrogen. The reaction mixture was stirred at 100° C. for 14 h, cooled, diluted with EtOAc (10 mL), filtered through celite and concentrated to give the desired product, which was used crude in step c.

[0667] Steps cd: The title compound was prepared in a manner analogous to Example 1, steps f and g. 1H NMR (400 MHz, DMSO-d6, citrate) δ 12.08 (d, J = 2.7 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.22 (t, J = 3.9 Hz, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.64–7.58 (m, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7. 34(d,J=3.9Hz,2H),7.31–7.24(m,1H),4.37–4.06(m,3H),4.00–3.77(m,2H),3.68–3.49(m,1H),3.46–3.24(m,3H),3 .05–2.80(m,4H),2.61(d,J=15.2Hz,2H),2.53(d,J=13.5Hz,2H),2.13(s,3H),2.11–1.88(m,2H),1.41–1.09(m,2H). C 35 H 35 ESIMS of N4O2[M+H] + , calculated value 543.3, measured value 543.3.

[0668] Example 17: 6-[(7S)-3-[3-[6-(3-methylpyridin-2-yl)pyridazin-3-yl]-1H-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

[0669]

[0670] Step a: To a mixture of 3-methyl-2-(tributyltinyl)pyridine (1.91 g, 5.00 mmol), 3,6-dibromopyridazine (1.19 g, 5.00 mmol), CuI (190 mg, 0.997 mmol) and Pd(PPh 3 ) 4 (578 mg, 0.501 mmol) was added dioxane (25 mL). The mixture was purged with nitrogen for 10 minutes, stirred at 100 ° C for 3.5 hours, cooled, diluted with EtOAc, filtered through celite and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 100% gradient) to obtain the desired product (590 mg, 47%).

[0671] Step be: The title compound was prepared in a manner analogous to Example 9, steps dg. 1H NMR (400 MHz, chloroform-d) δ 11.27 (s, 1H), 9.32 (d, J = 2.2 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.65–8.58 (m, 1H), 8.53 (d, J = 8.9 Hz, 1H), 8.23 ​​(d, J = 8.8 Hz, 1H), 7.76–7.68 (m, 1H), 7.51–7.43 (m, 2H), 7.37–7.20 (m,2H),4.33(d,J=10.7Hz,2H),3.76(m,2H),3.67(m,2H),3.28(m,1H),2.99(td,J=23.8,23.0,1 4.5Hz,2H),2.91–2.79(m,2H),2.73(s,3H),1.97(m,2H),1.88(m,1H),1.39(m,2H),1.26(m,1H). C 32 H 32 ESIMS of N7O [M+H] + , calculated value 530.3, measured value 530.3.

[0672] Example 18: 3-[(7S)-7-methyl-7-[(2R)-2-methylpyrrolidin-1-yl]-5,6,8,9-tetrahydrobenzo[7]annulene-3-yl]-5-[4-(3-methylpyridin-2-yl)phenyl]-7H-pyrrolo[2,3-c]pyridazine

[0673]

[0674] Step a: A flask containing 2-bromo-5,6,8,9-tetrahydro-benzocycloheptene-7-one (23.9 g, 100 mmol), (R)-2-methylpyrrolidine (9.06 mL, 105 mmol), 1,2,3-triazole (7.60 g, 110 mmol) and toluene (100 mL) was equipped with a Dean-Stark trap and heated to reflux for 18 hours with azeotropic removal of water. The mixture was cooled and added dropwise to a mixture of MeMgBr (133 mL, 400 mmol, 3 M in Et2O) and THF (400 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour, at room temperature for 2 hours and carefully quenched with water (7.2 mL). The mixture was washed with 1M HCl. (aq) (500 mL) and MTBE (250 mL) were diluted and stirred. The organic phase was washed with 1M HCl (aq) The acidic aqueous phases were combined and extracted with CH2Cl2 (2 x 500 mL). The combined organic phases were concentrated. Water (500 mL) was added and the mixture was stirred for 2 h by adding 2 M NaOH. (aq)(100 mL) to make the solution alkaline. Add MTBE (500 mL) and stir and separate the phases. The organic phase is washed with 2M NaOH. (aq) The mixture was washed with 4% paraformaldehyde (3 x 250 mL) and dried over Na 2 SO 4 to give the crude product as a light orange solid (21.2 g, 1:1 diastereomeric ratio by NMR).

[0675] The mixture of diastereomers is dissolved in isopropyl alcohol (424mL) when gradually heating. Once solid dissolves, solution is cooled. The mixture is allowed to stand for 24 hours and solid is collected by filtration (not washed) to obtain the product (5.12g, 24% recovery, diastereomeric ratio of 83:17 is obtained by NMR). The enriched material is dissolved in isopropyl alcohol (102mL) when gradually heating. Once solid dissolves, solution is cooled. The mixture is allowed to stand for 24 hours and solid is collected by filtration (not washed) to obtain the required product (3.60g, 70% recovery, diastereomeric ratio of >=95:5 is obtained by NMR) as a white solid.

[0676] The diastereomeric mixture could also be resolved using chiral HPLC (YMC Amylose-SA; MeOH / DEA 100 / 0.1 v / v; 0.5 mL / min; UV 227 nm; 10.7 min (desired isomer), 12.2 min (other isomer)).

[0677] Step b: at rt to a mixture of 3-chloro-5-iodo-7H-pyrrolo[2,3-c]pyridazine (1.40 g, 5.01 mmol), CsCO(3.26 g, 10.0 mmol) and DMF (7 mL) add SEMCl (1.33 mL, 7.51 mmol). The reaction mixture was stirred for 16 hours, diluted with EtOAc (70 mL), washed with water (3 x 70 mL), washed with brine (70 mL), dried over NaSO and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 50% gradient) to obtain the desired product (1.44 g, 70%).

[0678] Step c: The desired product was prepared in a manner similar to Example 1, step d.

[0679] Step de: The desired product was prepared in a similar manner to Example 16, steps bc.

[0680] Step f: to the product of step e (129 mg, 0.207 mmol) in CH Cl (1 mL) in a solution of TFA (1 mL) was added. The reaction mixture was stirred at rt for 2 hours and concentrated. To the residue was added NH (2 mL, a 7M solution in MeOH). The reaction mixture was stirred at rt for 16 hours and concentrated. The crude material was purified by C18 reverse phase chromatography ((water:ACN)+1% TFA 20 to 80% gradient) to obtain the desired product (10 mg, 9%) as a light yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 12.07 (s, 1H), 8.63–8.56 (m, 1H), 8.37 (s, 1H), 7.94 (s, 1H), 7.91–7.85 (m, 1H), 7.83–7.72 (m, 3H), 7.74–7.59 (m, 3H), 7.30–7.18 (m, 2H), 3.41 (br s,1H),3.29–3.22(m,2H),2.93(t,J=7.7Hz,1H),2.68(m,2H),2.55(m,1H),2.46( s,3H),1.90(m,3H),1.72(m,3H),1.47(m,2H),1.08(d,J=6.3Hz,3H),1.00(s,3H). C 35 H 38 N5 ESIMS [M+H] + , calculated value 528.3, measured value 528.3.

[0681] Example 19: 3-methyl-2-(4-{5-[6-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)pyridine

[0682]

[0683] Step a: To a mixture of 6-bromo-3,4-dihydro-2(1H)-naphthalenone (440 mg, 1.95 mmol), pyrrolidine (0.16 ml, 2.0 mmol) and DCE (9.8 ml) was added AcOH (0.11 ml, 2.0 mmol) followed by NabH(oac)3 (820 mg, 3.90 mmol). The reaction mixture was stirred at room temperature for 20 hours, carefully quenched with water, and then washed with saturated NaHCO 3(aq)The mixture was quenched. The phases were separated and the organic phase was extracted with CHCl (2 x 15 ml). The combined organic phases were washed with brine, dried over NaSO and concentrated. The crude material was purified by silica gel chromatography (CHCl:MeOH 0 to 10% gradient) to give the desired product (376 mg, 69%) as a brown oil.

[0684] Step b: To a mixture of the product from Example 2, step c (132 mg, 0.294 mmol), B2pin2 (97 mg, 0.83 mmol) and KOAc (37 mg, 0.83 mmol) was added dioxane (2.9 mL). The suspension was degassed with nitrogen for 5 minutes and PdCl2(dppf) (11 mg, 0.015 mmol) was added. The reaction mixture was stirred at 100°C for 16 hours, cooled, diluted with EtOAc (15 mL), filtered through celite and concentrated to give the desired product, which was used as the crude product in step c.

[0685] Step c: To a mixture of the product from step a (87 mg, 0.30 mmol), the product from step b (0.294 mmol) and NaCO (62 mg, 0.59 mmol) was added dioxane (2.7 mL) and water (0.30 mL). The suspension was degassed with nitrogen for 5 minutes and PdCl(dppf) (11 mg, 0.015 mmol) was added. The reaction mixture was stirred at 100° C. for 16 hours, cooled, diluted with CHCl (15 mL), dried over MgSO and concentrated. The product was purified by silica gel chromatography ((CHCl:MeOH) + 1% NH 3(aq，28％重量) The crude material was purified (0 to 10% gradient) to afford the desired product (64 mg, 38% over 2 steps) as a brown solid.

[0686] Step d: To the mixture of the product (64 mg, 0.11 mmol) and CH2Cl2 (1.2 mL) from step c, TFA (1.2 mL) was added. The reaction mixture was stirred at room temperature for 4 hours and concentrated. The crude material was purified by C18 reverse phase chromatography ((water:ACN)+1% TFA5 to 50% gradient), then partially concentrated and K2CO3 was added. The mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic phases were dried over MgSO4 and concentrated to obtain the desired product (17 mg, 31%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.86(d,J=2.0Hz,1H),8.72(d,J=2.1Hz,1H),8.53(dd,J =4.8,1.6Hz,1H),8.27–8.10(m,2H),7.85–7.69(m,3H),7.62–7.47(m,2H),7.33 (dd,J=7.7,4.7Hz,1H),7.22(d,J=7.8Hz,1H),3.10–2.89(m,2H),2.89–2.70(m, 2H),2.70–2.55(m,3H),2.48–2.34(m,5H),2.20–2.00(m,1H),1.81–1.51(m,5H). C 32 H 32 N5 ESIMS [M+H] + , calculated value 486.3, measured value 486.3.

[0687] Example 20: 2,5-dimethyl-6-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2,3-dihydropyridazin-3-one

[0688]

[0689] Step a:To the mixture of 6-chloro-5-methyl-3 (2H)-pyridazinone (952mg, 6.59mmol), KCO(1.18g, 8.57mmol) and DMF (13mL), MeI (0.45mL, 7.2mmol) is added.The reaction mixture is stirred at room temperature for 16 hours, diluted with water (30mL), and extracted with MTBE (3x 20mL) and EtOAc (1x 20mL).The organic phase merged is washed with water (20mL), washed with salt water (20mL), dried over MgSO and concentrated.The crude material is purified by silica gel chromatography (hexane:EtOAc 0 to 100% gradient) to obtain the required product (816mg, 78%) as a white solid.

[0690] Step b: To a mixture of the product from step a (816 mg, 5.15 mmol), (4-chlorophenyl)boronic acid (671 mg, 4.29 mmol) and Na2CO3 (1.19 g, 8.58 mmol) was added dioxane (17.2 mL) and water (4.3 mL). The suspension was degassed with nitrogen for 10 minutes and PdCl2(dppf) (157 mg, 0.215 mmol) was added. The reaction mixture was stirred at 80 ° C for 16 hours, cooled, and diluted with EtOAc (20 mL). The organic phase was dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 50% gradient) to give the desired product (1.09 g, 90%) as a light yellow solid.

[0691] Step cg: The title compound was prepared in a manner similar to Example 1, step cg. 1 H NMR (400MHz, chloroform-d) δ9.71(s,1H),8.62(s,1H),8.40(s,1H),7.78(dt,J=8.2,1.6Hz,2H),7.65–7.57(m,1H),7.53(dt,J =8.2,1.6Hz,2H),7.44–7.33(m,2H),7.23(d,J=8.1Hz,1H),6.86(d,J=1.4Hz,1H),4.31(d,J=10.7Hz,2H),3.85(s,3H), 3.74(d,J=10.7Hz,2H),3.65(d,J=6.1Hz,2H),3.26(t,J=9.8Hz,1H),2.99(td,J=15.1,8.5Hz,2H),2.86(q,J=13.2Hz,2 H), 2.56 (q, J = 8.1, 7.6Hz, 1H), 2.26 (d, J = 1.3Hz, 3H), 2.03–1.89 (m, 2H), 1.85 (d, J = 8.2Hz, 1H), 1.34 (p, J = 10.6Hz, 2H). C 35 H 36 ESIMS of N5O2[M+H] + , calculated value 558.3, measured value 558.3.

[0692] Example 21: 2-methyl-2-[2-[4-[5-[(7S)-7-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl]pyridin-3-yl]propionitrile

[0693]

[0694] Step a: 2-chloro-3-pyridineacetonitrile (5.0 g, 33 mmol), 4-chlorophenylboronic acid (7.7 g, 49 mmol), 2M Na2CO 3(aq) To a mixture of 4-[ ...

[0695] Step b: A mixture of the product from step a (1.14 g, 4.98 mmol), iodomethane (1.09 mL, 17.5 mmol) and THF (8.5 mL) was added dropwise to a refluxing mixture of sodium hydride (0.60 g, 15 mmol, 60% w / w in mineral oil) and THF (8.5 mL). The resulting mixture was heated at reflux for three hours. The reaction was cooled to room temperature and carefully washed with saturated NH4Cl (aq) The reaction was quenched. The reaction was extracted with EtOAc and the organics were dried over MgSO4 and then concentrated. The material was used directly in the next step without further purification.

[0696] Step cg: The title compound was prepared in a manner similar to Example 1, step cg. 1 H NMR (400MHz, chloroform-d) δ9.56(s,1H),8.64(dd,J=4.7,1.6Hz,1H),8.58(d,J=8.58Hz,1H),8.40(d,J=8.40Hz,1H), 8.01(dd,=8.1,1.6Hz,1H),7.76-7.73(m,2H),7.57(d,J=2.2Hz,1H),7.51-7.48(m,2H),7.39-7.34(m,3H),7.2 1-7.19(m,1H),4.29(d,J=10.7Hz,2H),3.72(d,J=10.7Hz,2H),3.64(d,J=6.1Hz,2H),3.26-3.21(m,1H),3.02 -2.77(m,4H),2.54(dd,J=13.4,7.1Hz,1H),1.93(s,2H),1.83(d,J=8.3Hz,1H)1.69(s,6H),1.34-1.25(m,2H). C 38 H 38 ESIMS of N5O[M+H] +, calculated value 580.3, measured value 580.3.

[0697] Example 22: 1-[2-[4-[5-[(7S)-7-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl]pyridin-3-yl]cyclobutan-1-ol

[0698]

[0699] Step a: A mixture of 2,3-dibromopyridine (11.8 g, 49.8 mmol), 4-chlorophenylboronic acid (8.21 g, 52.5 mmol), triphenylphosphine (1.31 g, 5.00 mmol), KCO (13.8 g, 100 mmol) and 2:1 ACN:water (375 mL) was purged with nitrogen for ten minutes, followed by the addition of Pd(OAc) (561 mg, 2.50 mmol). The reaction was heated to 50° C. for four hours, cooled, filtered through celite, concentrated, and purified by silica gel chromatography (CHCl:EtOAc 0 to 50% gradient) to give the desired product.

[0700] Step b: A mixture of the product from step a (999 mg, 3.72 mmol) and THF (11.2 mL) was cooled to -78°C. n-BuLi (1.63 mL, 4.08 mmol, 2.5 M in hexane) was added dropwise and the reaction was stirred at -78°C for 90 minutes. Cyclobutanone (822 μL, 11.2 mmol) was slowly added and the mixture was slowly warmed to room temperature over two hours. The reaction was washed with saturated NaHCO 3(aq) Quenched, extracted with EtOAc, and dried over Na 2 SO 4 The crude material was purified by silica gel chromatography (CH 2 Cl 2 :EtOAc 0 to 50% gradient) to give the desired product.

[0701] Step cg: The title compound was prepared in a manner similar to Example 1, step cg. 1H NMR (400 MHz, chloroform-d) δ9.97 (s, 1H), 8.62 (dd, J = 4.7, 1.7 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.75-7.66 (m, 5H), 7.50 (s, 1H), 7.36-7.33 (m, 2H), 7.28 (dd, J = 7.8, 4.7 Hz,1H),7.18-7.16(m,1H),4.36-4.29(m,2H),3.98-3.82(m,4H),3.37-3.30(m,1H),3.02 -2.77(m,6H),2.40-2.30(m,2H),2.12-2.09(m,3H),1.98-1.88(m,3H),1.66-1.57(m,3H). C 38 H 39 ESIMS of N4O2[M+H] + , calculated value 583.3, measured value 583.3.

[0702] Example 23: 6-[(7S)-2-{3-[4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)phenyl]-1H-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

[0703]

[0704] Step a: To a solution of 4-bromobenzoic acid (1.01 g, 5.02 mmol) in DMF (18 mL) was added acetamidine hydrochloride (709 mg, 7.50 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.61 mL, 15.0 mmol). The reaction mixture was stirred at room temperature for 2 hours, then methylhydrazine (0.40 mL, 7.5 mmol) and acetic acid (2.86 mL, 50.0 mmol) were added. The reaction mixture was stirred at 80 ° C for 3 hours, cooled to room temperature, diluted with EtOAc (200 mL), and washed with saturated NaHCO 3(aq) The crude material was purified by silica gel chromatography (hexanes:EtOAc 0 to 100% gradient) to give the desired product (895 mg, 71%) as a white solid.

[0705] Step b: The desired product was prepared in a manner similar to Example 1, step e.

[0706] Steps cf: The desired product was prepared in a similar manner to Example 2.1 H NMR (400MHz, DMSO-d6) δ13.99(s,1H),8.85(d,J=2.1Hz,1H),8.71(d,J=2.1Hz,1H),8.31–8.23(m,2H),7. 93–7.85(m,2H),7.59(d,J=2.0Hz,1H),7.53(dd,J=7.5,2.0Hz,1H),7.23(d,J=7.8Hz,1H),4.13(d,J=10.6 Hz,2H),3.93(s,3H),3.53(dd,J=18.8,8.3Hz,4H),3.20–3.09(m,1H),3.05–2.85(m,2H),2.77(q,J=14.7, 14.2Hz,2H),2.37–2.29(m,1H),2.26(s,3H),1.90–1.77(m,2H),1.65(d,J=7.8Hz,1H),1.25–1.04(m,2H). C 32 H 34 ESIMS of N7O [M+H] + , calculated value 532.3, measured value 532.3.

[0707] Example 24: 3-cyclopentyl-7-{3-[4-(3-methylpyridin-2-yl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-2,3,4,5-tetrahydro-1H-3-benzazepine

[0708]

[0709] Step a: To 7-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine To a mixture of hydrochloride (272 mg, 1.04 mmol), cyclopentanone (0.11 mL, 1.3 mmol) and DCE (5.2 mL) was added AcOH (60 μL, 1.0 mmol) followed by NaBH(OAc) 3 (331 mg, 1.56 mmol). The reaction mixture was stirred at room temperature for 17 hours and carefully washed with saturated NaHCO 3(aq) The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired product (293 mg, 96%) as a colorless oil.

[0710] Step b: To a mixture of the product from step a (111 mg, 0.377 mmol), B2pin2 (129 mg, 0.490 mmol) and KOAc (48 mg, 0.49 mmol) was added dioxane (3.8 mL). The suspension was degassed with nitrogen for 10 minutes and PdCl2(dppf) (14 mg, 0.019 mmol) was added. The reaction mixture was stirred at 90°C for 3 hours, cooled, diluted with EtOAc (15 mL), filtered through celite and concentrated to give the desired product, which was used as a crude product in step c.

[0711] Step cd: The desired product was prepared in a manner analogous to Example 2, Steps e and f, using the bromoazaindazole intermediate formed in Example 2, Step c. 1 H NMR (400MHz, DMSO-d6) δ13.94(s,1H),8.87(d,J=2.1Hz,1H),8.73(d,J=2.1Hz,1H),8.53(dd,J=5.0,1 .6Hz,1H),8.24–8.17(m,2H),7.80–7.70(m,3H),7.65–7.53(m,2H),7.33(dd,J=7.7,4.7Hz,1H),7.25 (d,J=7.7Hz,1H),3.03–2.94(m,2H),2.94–2.88(m,2H),2.88–2.80(m,1H),2.74–2.54(m,4H),2.42(s ,3H),1.88–1.70(m,2H),1.67–1.56(m,2H),1.56–1.44(m,2H),1.44–1.33(m,2H),1.31–1.21(m,1H). C 33 H 34 N5 ESIMS [M+H] + , calculated value 500.3, measured value 500.3.

[0712] Example 25: 6-[(7S)-2-{3-[5-(3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1H-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

[0713]

[0714] Step a: To a mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (1.21 g, 5.00 mmol) and MeOH (12.5 mL) was added sulfuric acid (0.5 mL, 98 wt %). The reaction mixture was stirred at 75 ° C for 18 hours, cooled, and concentrated to give the desired product, which was used as a crude product in step b.

[0715] Step b: To a mixture of the product from step a (5.00 mmol), camphorsulfonic acid (117 mg, 0.504 mmol) and THF (12.5 mL) was added 3,4-dihydro-2H-pyran (0.92 mL, 10 mmol) at room temperature. The reaction mixture was stirred at 65° C. for 4 h, cooled, and washed with NH 3(aq) (10 mL, 28 wt%) was quenched and concentrated. The crude material was purified by silica gel chromatography (hexanes:EtOAc 0 to 50% gradient) to give the desired product (1.20 g, 70% over two steps) as a white solid.

[0716] Step c: To a mixture of the product from step b (1.20 g, 3.52 mmol) in 1:1 THF / MeOH (10 mL) was added hydrazine monohydrate (0.86 mL, 18 mmol). The mixture was stirred at 75 ° C for 18 hours, cooled and concentrated. The crude material was purified by silica gel chromatography (hexane: EtOAc 0 to 50% gradient) to give the desired product (1.16 g, 97%) as a white solid.

[0717] Step d: To a mixture of the product from step c (579 mg, 1.70 mmol) and DMF (5.1 mL) was added 3-methylpyridine-2-carboxylic acid (280 mg, 2.04 mmol), HATU (2.09 g, 2.55 mmol) and triethylamine (0.47 mL, 3.4 mmol). The mixture was stirred at room temperature for 18 h, diluted with EtOAc (100 mL), and washed with saturated NaHCO 3(aq) The crude material was purified by silica gel chromatography (hexanes:EtOAc 0 to 100% gradient) to give the desired product (711 mg, 91%) as a colorless oil.

[0718] Step e: To a mixture of the product from step d (711 mg, 1.55 mmol) and CH2Cl2 (20 mL) was added triethylamine (1.08 mL, 7.75 mmol), triphenylphosphine (509 mg, 1.94 mmol) and carbon tetrachloride (0.19 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 4 h, diluted with EtOAc (100 mL) and washed with saturated NaHCO3. 3(aq)The crude material was purified by silica gel chromatography (hexanes:EtOAc 0 to 100% gradient) to give the desired product (499 mg, 73%) as a colorless oil.

[0719] Step fh: The desired product was prepared in a manner similar to Example 2, steps df. 1 HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.71–8.64(m,2H),7.94(dd,J=7.9,1.6Hz,1H ),7.58–7.54(m,2H),7.50(dd,J=7.7,2.0Hz,1H),7.26(d,J=7.8Hz,1H),4.13(d,J=1 0.6Hz,2H),3.59–3.49(m,4H),3.20–2.10(m,1H),3.06–2.86(m,2H),2.85–2.71(m, 5H),2.38–2.28(m,1H),1.91–1.78(m,2H),1.65(d,J=7.9Hz,1H),1.25–1.04(m,2H). C 30 H 30 ESIMS of N7O2[M+H] + , calculated value 520.3, measured value 520.3.

[0720] Example 26: 3-Methyl-6'-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-2,3'-bipyridine

[0721]

[0722] Step a: To a mixture of methyl 5-bromo-2-picolinate (648 mg, 3.00 mmol), Bpin (762 mg, 3.00 mmol), PdCl(dppf) (110 mg, 0.150 mmol) and KOAc (589 mg, 6.00 mmol) was added degassed dioxane (15 mL) at room temperature under nitrogen. The reaction mixture was stirred at 100° C. for 1 hour, cooled, diluted with EtOAc (30 mL), filtered through celite and concentrated to give the desired product, which was used as crude in step b.

[0723] Step b: To a mixture of the product from step a (assumed 3.00 mmol), 2-bromo-3-methylpyridine (774 mg, 4.50 mmol), PdCl2(dppf) (110 mg, 0.150 mmol) and Na2CO3 (636 mg, 6.00 mmol) was added degassed toluene (9.0 mL), ACN (6.0 mL) and water (3.0 mL) at room temperature under nitrogen. The reaction mixture was stirred at 70°C for 2 hours, cooled, diluted with EtOAc (30 mL), washed with water, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography (hexane:EtOAc 0 to 100% gradient) to give the desired product (524 mg, 76%) as a light brown solid.

[0724] Step c: To a solution of 2-fluoro-6-bromopyridine (823 μL, 8.00 mmol) in THF (16 mL) was added LDA (4.00 mL, 8.00 mmol, 2 M in ethylbenzene / THF / heptane) dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 minutes. To the mixture was added a solution of the product from step b (913 mg, 4.00 mL) in THF (4.0 mL) at -78°C. The reaction mixture was stirred at -78°C for 1 hour and washed with saturated NH4Cl at -78°C. (aq) Quenched, allowed to warm to room temperature, and diluted with EtOAc (20 mL).The organic phase was dried over Na2SO4, concentrated, and triturated with hexanes to give the desired product (872 mg, 59%) as a brown solid.

[0725] Step d: at room temperature to the product from step c (186 mg, 0.500 mmol) in 1: 1 i-PrOH: dioxane (2.5 mL) in a mixture of monohydrated hydrazine (24 μ L, 0.50 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. At room temperature, triethylamine (87 μ L, 0.60 mmol) and dioxane (2.5 mL) were added to the mixture. The reaction mixture was stirred at room temperature for 3 hours, stirred at 60 ° C for 1 hour, diluted with water (25 mL). The precipitated solid was collected by filtration, washed with water, dried (149 mg), and recrystallized with EtOAc (5 mL) to obtain the desired product (93 mg, 51%) as a pale solid.

[0726] Step e: To a mixture of the product (366 mg, 1.00 mmol) from step d and THF (5.0 mL) was added potassium tert-butoxide (106 mg, 1.10 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and 4-methylbenzenesulfonyl chloride (191 mg, 1.00 mmol) was added at a time. The reaction mixture was stirred at room temperature for 30 minutes, diluted with water (25 mL). The precipitated solid was collected by filtration, washed with water and dried to obtain the desired product (458 mg, 88%) as a brown solid.

[0727] Step fg: The title compound was prepared in a manner analogous to Example 16, steps c and d. 1 H NMR (400 MHz, chloroform-d) δ 11.66 (s, 1H), 9.17 (d, J = 2.1 Hz, 1H), 8.94 (dd, J = 2.3, 0.9 Hz, 1H), 8.85 (d, J = 2.2 Hz, 1H), 8.58 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 8.31 (dd, J = 8.2, 0.9 Hz, 1H), 8.02 (dd, J = 8.2, 2.3 Hz, 1H), 7.63 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.44 (dq, J = 3.8, 2.0 Hz, 2H),7.25(s,1H),7.23–7.20(m,1H),4.30(d,J=10.7Hz,2H),3.73(d,J=10.7Hz,2H),3.66(d,J=6.1Hz,1H),3.26(t,J=9.6Hz,1H) ,3.07–2.79(m,3H),2.57(q,J=6.8Hz,1H),2.46(s,3H),1.94(s,2H),1.84(d,J=8.3Hz,1H),1.41–1.20(m,3H),0.89–0.72(m,1H). C 33 H 33 ESIMS of N6O[M+H] + , calculated value 529.3, measured value 529.3.

[0728] Example 27: 6-[(7S)-2-{3-[1-(3-methylpyridin-2-yl)-1H-pyrazol-4-yl]-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

[0729]

[0730] Step a: A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.94 g, 10.0 mmol), 2-fluoro-3-methylpyridine (1.11 g, 10.0 mmol), CsCO (3.58 g, 11.0 mmol) and DMSO (10 mL) was stirred at 120 ° C for 15 hours, cooled, diluted with EtOAc (100 mL), washed with 9:1 water:brine (4 x 200 mL), dried over NaSO and concentrated. The crude material was purified by silica gel chromatography (hexane:EtOAc 0 to 50% gradient) to give the desired product (515 mg, 18%) as a white solid.

[0731] Step be: The title compound (citrate salt) was prepared in a manner analogous to Example 1, steps dg. 1 H NMR (400MHz, DMSO-d6) δ11.87(d,J=2.6Hz,1H),8.84(d,J=0.8Hz,1H),8.55(d,J=2.1Hz,1H),8.43(d,J=2.1Hz,1H),8.41(dd ,J=4.5,1.3Hz,1H),8.35(d,J=0.8Hz,1H),7.94(d,J=2.5Hz,1H),7.91(dd,J=7.5,0.9Hz,1H),7.63(s,1H),7.57(d,J=7.7Hz, 1H),7.40(dd,J=7.6,4.7Hz,1H),7.27(d,J=7.8Hz,1H),4.39–4.07(m,3H),4.01–3.79(m,2H),3.73–3.55(m,1H),3.50–3.17( m,3H),3.07–2.80(m,4H),2.61(d,J=15.2Hz,2H),2.54(s,3H),2.53(d,J=14.4Hz,2H),2.21–1.90(m,2H),1.30–1.11(m,2H). C 32 H 33 ESIMS of N6O[M+H] + , calculated value 517.3, measured value 517.3.

[0732] Example 28: 6-[(7S)-3-[3-[4-(5-fluoro-3-methylpyridin-2-yl)phenyl]-1H-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

[0733]

[0734] The title compound was prepared in a similar manner to Example 2 from appropriate starting materials. 1 HNMR (400 MHz, chloroform-d) δ 10.84 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.43 (dd, J = 2.8, 0.6 Hz, 1H), 8.13–8.05 (m, 2H), 7.72–7.64 (m, 2H), 7.43–7.33 (m, 3H), 7.30–7.21 (m, 1H), 4.31 (d, J = 10.7Hz,2H),3.74(d,J=10.9Hz,2H),3.66(m,2H),3.27(m,1H),3.04–2.93(m,2H),2.86(q,J=13.2 Hz,2H),2.57(m,1H),2.46(t,J=0.7Hz,3H),1.98(m,2H),1.85(d,J=8.2Hz,1H),1.37–1.22(m,2H). C 34 H 33 ESIMS of FN5O [M+H] + , calculated value 546.3, measured value 546.3.

[0735] Example 29: 6-[(7S)-3-[3-[4-(5-fluoro-3-methylpyridin-2-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

[0736]

[0737] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1 HNMR (400 MHz, chloroform-d) δ8.89 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.45–8.38 (m, 2H), 7.80–7.72 (m, 2H), 7.65–7.54 (m, 3H), 7.39 (s, 2H), 7.42–7.32 (m, 1H), 7.23–7.20 (m, 1H), 4.31 (d, J=10.7Hz,2H),3.73(d,J=10.7Hz,2H),3.64(d,J=6.0Hz,2H),3.25(m,1H),3.01–2.77( m,4H),2.56(m,1H),2.47(s,3H),1.94(m,2H),1.84(d,J=8.2Hz,1H),1.36–1.24(m,2H). C35 H 34 ESIMS of FN4O[M+H] + , calculated value 545.3, measured value 545.3.

[0738] Example 30: 6-[(7S)-3-[3-[2-methyl-4-(3-methylpyridin-2-yl)phenyl]-1H-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

[0739]

[0740] The title compound was prepared in a similar manner to Example 2 from appropriate starting materials. 1 HNMR (400 MHz, chloroform-d) δ 11.51 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.56 (ddd, J = 4.7, 1.8, 0.7 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.67–7.60 (m, 2H), 7.57 (dt, J = 1.8, 0.6 Hz, 1H), 7.50 (ddd, J = 7.8, 1.9, 0.7 Hz, 1H), 7.34 (d, J = 11.8 Hz, 2H), 7.21 (dd, J = 7.8, 4.8Hz,2H),4.31(d,J=10.8Hz,2H),3.73(dd,J=10.6,4.1Hz,2H),3.66(d,J=5.8Hz,2H),3.26(t,J=9.9Hz,1H),3.05–2. 80(m,4H),2.57(q,J=6.8Hz,1H),2.52(s,3H),2.44(s,3H),1.94(m,2H),1.84(dd,J=8.3,3.6Hz,1H),1.38–1.28(m,2H). C 35 H 36 ESIMS of N5O[M+H] + , calculated value 542.3, measured value 542.3.

[0741] Example 31: 1-[4-[5-[(7S)-7-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-3-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl]phenyl]pyridin-2-one

[0742]

[0743] The title compound was prepared in a similar manner to Example 2 from appropriate starting materials. 1 HNMR (400 MHz, chloroform-d) δ 11.51 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.16–8.08 (m, 2H), 7.62–7.54 (m, 2H), 7.48–7.36 (m, 4H), 7.30–7.21 (m, 1H), 6.71 (ddd, J = 9.2, 1.3, 0.9 Hz, 1H), 6.30 (td, J =6.7,1.3Hz,1H),4.33(d,J=10.9Hz,2H),3.78(m,3H),3.30(m,1H),3.01(td,J=15.5,7.9Hz,2H),2.8 6(q,J=13.4,13.0Hz,2H),2.64(m,1H),1.97(m,2H),1.88(d,J=8.4Hz,1H),1.42(m,2H),1.26(m,1H). C 33 H 32 ESIMS of N5O2[M+H] + , calculated value 530.3, measured value 530.2.

[0744] Example 32: (3S)-N-[(7S)-3-[3-(4-pyridin-2-ylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl]oxan-3-amine.

[0745]

[0746] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR(400MHz, chloroform-d)δ9.66(s,1H),8.76–8.69(m,1H),8.61(d,J=2.0Hz,1H),8.44(d,J=2.1Hz,1H),8.16–8.08(m,2H) ,7.84–7.76(m,4H),7.63(d,J=2.3Hz,1H),7.41(dq,J=3.5,2.0Hz,2H),7.29–7.19(m,2H),3.93(dd,J=11.0,3.3Hz,1H ),3.81(dt,J=11.2,4.1Hz,1H),3.48–3.37(m,1H),3.23–3.13(m,1H),3.01–2.86(m,3H),2.83(t,J=10.3Hz,2H),2.75 (d,J=13.8Hz,1H),2.11(t,J=12.8Hz,2H),2.01–1.93(m,1H),1.77–1.56(m,2H),1.35(dq,J=30.8,18.0,15.1Hz,4H). C 34 H 35 ESIMS of N4O[M+H] + , calculated value 515.3, measured value 515.3.

[0747] Example 33: (1S,4S)-5-[(7S)-3-[3-(4-pyridin-2-ylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl]-2-oxa-5-azabicyclo[2.2.1]heptane

[0748]

[0749] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR(400MHz, chloroform-d)δ9.43(s,1H),8.76–8.69(m,1H),8.61(d,J=2.0Hz,1H),8.43(d,J=2.0Hz,1H),8.16–8.08(m, 2H),7.84–7.77(m,4H),7.62(d,J=2.5Hz,1H),7.39(dq,J=3.5,2.0Hz,2H),7.29–7.18(m,2H),4.43(s,1H),4.09(d ,J=7.7Hz,1H),3.77(s,1H),3.68(dd,J=7.5,1.6Hz,1H),3.15(m,J=9.7Hz,3H),2.83(s,1H),2.72(m,2H),2.51(d, J=9.6Hz,1H),1.98(m,2H),1.90(d,J=9.9Hz,1H),1.78(d,J=9.8Hz,1H),1.27(m,J=7.7Hz,1H),0.92–0.81(m,1H). C 34 H 33 ESIMS of N4O[M+H] + , calculated value 513.3, measured value 513.3.

[0750] Example 34: 3-[4-(5-fluoro-3-methylpyridin-2-yl)phenyl]-5-[(7S)-7-methyl-7-[(2R)-2-methylpyrrolidin-1-yl]-5,6,8,9-tetrahydrobenzo[7]annulene-3-yl]-1H-pyrrolo[2,3-b]pyridine

[0751]

[0752] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1 HNMR (400 MHz, chloroform-d) δ9.81 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.46–8.39 (m, 2H), 7.81–7.73 (m, 2H), 7.65–7.57 (m, 3H), 7.42–7.32 (m, 3H), 7.21 (d, J = 8.2 Hz, 1H), 3.39 (br s,1H),3.29–3.20(m,2H),2.92(t,J=7.6Hz,1H),2.74–2.48(m,3H),2.47(s,3H),1.99– 1.83(m,3H),1.79–1.61(m,3H),1.51–1.41(m,2H),1.08(d,J=6.3Hz,3H),1.00(s,3H). C 36 H38 ESIMS of FN4 [M+H] + , calculated value 545.3, measured value 545.3.

[0753] Example 35: 6-[(7S)-3-[3-[5-(5-fluoro-3-methylpyridin-2-yl)pyridin-2-yl]-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

[0754]

[0755] The title compound was prepared in a similar manner to Example 9 from appropriate starting materials. 1 HNMR (400MHz, chloroform-d) δ10.93(s,1H),8.94(d,J=2.1Hz,1H),8.84(dd,J=2.3,0.8Hz,1H),8.63(d,J=2.1Hz,1H),8.44(dd,J=2.8,0.7Hz,1H ),8.02(d,J=1.9Hz,1H),7.91(dd,J=8.2,2.3Hz,1H),7.78(dd,J=8.2,0.9Hz,1H),7.44(dq,J=3.7,2.0Hz,2H),7.37(ddd,J=9.0,2.8,0.8 Hz,1H),7.23(d,J=8.2Hz,1H),4.32(d,J=10.7Hz,2H),3.71(dd,J=27.1,8.4Hz,4H),3.32–3.22(m,1H),2.99(td,J=19.7,17.0,7.8Hz,2 H), 2.86 (q, J = 13.7, 13.1Hz, 2H), 2.59 (q, J = 6.8Hz, 1H), 2.48 (d, J = 0.8Hz, 3H), 1.96 (m, 2H) 1.85 (d, J = 8.3Hz, 1H), 1.36 (p, J = 10.4Hz, 2H). C 34 H 33 ESIMS of FN5O [M+H] + , calculated value 546.3, measured value 546.3.

[0756] Example 36: 6-[(7S)-3-[5-[4-(3-methylpyridin-2-yl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl]-3-oxa-6-azabicyclo[3.1.1]heptane

[0757]

[0758] The title compound was prepared in a similar manner to Example 18 from appropriate starting materials. 1 H NMR (400 MHz, chloroform-d) δ 12.27 (s, 1H), 8.65–8.55 (m, 1H), 8.38 (s, 1H), 7.96–7.90 (m, 2H), 7.87–7.71 (m, 3H), 7.72–7.58 (m, 3H), 7.31–7.17 (m, 2H), 4.32 (d, J = 10.6 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.67 ( d,J=6.0Hz,2H),3.32–3.22(m,1H),3.06(dt,J=18.8,9.6Hz,1H),2.98(s,1H),2.90(p,J=13.9Hz,2 H), 2.57 (q, J = 6.8Hz, 1H), 2.45 (s, 3H), 1.96 (t, J = 10.7Hz, 2H), 1.85 (d, J = 8.2Hz, 1H), 1.34 (m, 2H). C 34 H 34 ESIMS of N5O[M+H] + , calculated value 528.3, measured value 528.3.

[0759] Example 37: 6-[(7S)-3-[3-[5-(3-methylpyridin-2-yl)pyrimidin-2-yl]-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

[0760]

[0761] The title compound was prepared in a similar manner to Example 9 from appropriate starting materials. 1HNMR (400 MHz, chloroform-d) δ 10.36 (s, 1H), 9.17 (d, J = 2.2 Hz, 1H), 8.99 (s, 2H), 8.65–8.57 (m, 2H), 8.40 (d, J = 2.5 Hz, 1H), 7.65 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.47 (dq, J = 3.4, 1.8 Hz, 2H), 7.30–7.20 (m, 2H), 4.32 (d, J = 10.7 Hz, 2H), 3.74 (d, J = 10.7Hz,2H),3.70–3.63(m,2H),3.33–3.23(m,1H),3.00(ddd,J=22.8,14.3,7.8Hz,2H),2.90(d,J=14.8Hz,1H),2.8 4(d,J=14.6Hz,1H),2.57(q,J=6.7Hz,1H),2.49(s,3H),1.96(s,2H),1.85(d,J=8.3Hz,1H),1.35(p,J=10.5Hz,2H). C 33 H 33 ESIMS of N6O[M+H] + , calculated value 529.3, measured value 529.3.

[0762] Example 38: 6-[(7S)-3-[3-[2-(3-methylpyridin-2-yl)pyrimidin-5-yl]-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

[0763]

[0764] The title compound was prepared in a similar manner to Example 17 from appropriate starting materials. 1H NMR (400 MHz, chloroform-d) δ10.55 (s, 1H), 9.25 (s, 2H), 8.72–8.63 (m, 2H), 8.42 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.68 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.40 (dq, J = 4.6, 2.1 Hz, 2H), 7.32 (dd, J = 7.7, 4.7 Hz, 1H), 7.24 (t, J = 8.4 Hz, 1H), 4.32 (dd, J = 10.6, 3.2 Hz, 2H). 4(d,J=10.9Hz,2H),3.66(d,J=6.0Hz,2H),3.26(t,J=9.7Hz,1H),3.00(td,J=18.5,16.6,7.9Hz,2H),2.89(d,J=13.4Hz,1H),2.83 (d,J=14.1Hz,1H),2.64(s,3H),2.56(q,J=6.8Hz,1H),1.96(d,J=11.2Hz,2H),1.85(d,J=8.2Hz,1H),1.36(q,J=11.2,10.6Hz,2H). C 33 H 33 ESIMS of N6O[M+H] + , calculated value 529.3, measured value 529.3.

[0765] Example 39: 1-methyl-6-[4-[5-[(7S)-7-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl]pyridin-2-one

[0766]

[0767] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400 MHz, chloroform-d) δ9.61 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.82–7.74 (m, 2H), 7.62 (d, J = 2.5 Hz, 1H), 7.49–7.41 (m, 2H), 7.43–7.33 (m, 3H), 7.29–7.19 (m, 1H), 6.63 (dd, J = 9.1, 1.4 Hz, 1H), 6.18 (dd, J = 6.8, 1.4 Hz, 1H ),4.31(d,J=10.7Hz,2H),3.74(d,J=10.7Hz,2H),3.66(d,J=6.0Hz,2H),3.48(s,3H),3.26(t,J=9.7Hz,1H),2.99(td ,J=14.9,7.8Hz,2H),2.86(q,J=13.5Hz,2H),2.56(q,J=6.8Hz,1H),1.95(m,2H),1.85(d,J=8.3Hz,1H),1.33(m,2H). C 35 H 35 ESIMS of N4O2[M+H] + , calculated value 543.3, measured value 543.3.

[0768] Example 40: 6-[(7S)-2-{3-[3-fluoro-4-(pyridin-2-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

[0769]

[0770] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, DMSO-d6) δ12.15(d,J=2.7Hz,1H),8.77–8.70(m,1H),8.59–8.53(m,1H),8.49(d,J=2.1Hz,1H),8.12(d,J=2.7 Hz,1H),8.06(t,J=8.4Hz,1H),7.92(td,J=7.7,1.8Hz,1H),7.89–7.78(m,2H),7.80–7.70(m,1H),7.58–7.52(m,1H),7.53–7 .46(m,1H),7.40(ddd,J=7.4,4.8,1.2Hz,1H),7.23(d,J=7.7Hz,1H),4.16(d,J=10.7Hz,2H),3.62–3.51(m,4H),3.22–3.12( m,1H),3.07–2.88(m,2H),2.87–2.71(m,2H),2.41–2.32(m,1H),1.93–1.79(m,2H),1.68(d,J=7.8Hz,1H),1.22–1.09(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-116.73–-116.85(m). C 34 H 32 ESIMS of FN4O[M+H] + , calculated value 531.3, measured value 531.3.

[0771] Example 41: 6-[(7S)-2-{3-[4-(pyridin-4-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

[0772]

[0773] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, chloroform-d) δ9.27(s,1H),8.73–8.63(m,2H),8.60(d,J=2.1Hz,1H),8.39(d,J=2.0Hz,1H),7.85–7.71(m ,4H),7.59(d,J=2.5Hz,1H),7.58–7.52(m,2H),7.41–7.34(m,2H),7.21(d,J=8.3Hz,1H),4.29(d,J=10.6Hz,2H), 3.71(d,J=10.6Hz,2H),3.62(d,J=6.1Hz,2H),3.31–3.20(m,1H),2.98(td,J=14.4,8.0Hz,2H),2.87(d,J=12.5Hz ,1H),2.80(d,J=13.2Hz,1H),2.54(q,J=6.7Hz,1H),2.01–1.88(m,2H),1.83(d,J=8.1Hz,1H),1.41–1.25(m,2H). C 34 H 33 ESIMS of N4O[M+H] + , calculated value 513.3, measured value 513.3.

[0774] Example 42: 6-[(7S)-2-{3-[4-(3-fluoropyridin-2-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

[0775]

[0776] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, chloroform-d) δ9.32(s,1H),8.62(d,J=2.1Hz,1H),8.55(dt,J=4.6,1.6Hz,1H),8.44(d,J=1.9Hz,1H),8.11(dq,J=8.4,1.9H z,2H),7.85–7.76(m,2H),7.62(d,J=2.6Hz,1H),7.52(ddd,J=11.2,8.2,1.4Hz,1H),7.44–7.36(m,2H),7.30–7.26(m,1H),7.22(d ,J=8.3Hz,1H),4.31(d,J=10.7Hz,2H),3.73(d,J=10.7Hz,2H),3.64(d,J=6.1Hz,2H),3.32–3.18(m,1H),3.09–2.92(m,2H),2.88( d,J=12.8Hz,1H),2.82(d,J=13.6Hz,1H),2.56(q,J=6.7Hz,1H),2.01–1.88(m,2H),1.84(d,J=8.2Hz,1H),1.34(p,J=10.5Hz,2H). 19 FNMR (376MHz, chloroform-d) δ-122.80–-122.88 (m). C 34 H 32 ESI MS of FN4O [M+H] + , calculated value 531.3, measured value 531.3.

[0777] Example 43: 6-[(7S)-2-{3-[4-(3-chloropyridin-2-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

[0778]

[0779] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, DMSO-d6) δ12.07(d,J=2.6Hz,1H),8.66(dd,J=4.6,1.5Hz,1H),8.56(d,J=2.1Hz,1H),8.48(d,J=2.1Hz,1H),8.07 (dd,J=8.1,1.5Hz,1H),8.03(d,J=2.6Hz,1H),7.96–7.87(m,2H),7.83–7.76(m,2H),7.54(d,J=1.9Hz,1H),7.49(dd,J=7.6,1.9H z,1H),7.44(dd,J=8.1,4.6Hz,1H),7.23(d,J=7.8Hz,1H),4.16(d,J=10.6Hz,2H),3.65–3.46(m,4H),3.22–3.11(m,1H),3.08–2. 87(m,2H),2.78(q,J=14.4,13.9Hz,2H),2.36(q,J=6.5,5.8Hz,1H),1.93–1.76(m,2H),1.68(d,J=7.8Hz,1H),1.22–1.08(m,2H). C 34 H 32 ESIMS of ClN4O[M+H] + , calculated value 547.2, measured value 547.2.

[0780] Example 44: 6-[(7S)-2-{3-[3-chloro-4-(pyridin-2-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

[0781]

[0782] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400 MHz, chloroform-d) δ9.79 (s, 1H), 8.76 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.63 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.82–7.67 (m, 5H), 7.62 (d, J = 2.5 Hz, 1H), 7.43–7.37 (m, 2H), 7.31 (ddd, J = 7.2, 4.9, 1.5 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 4.31 ( d,J=10.6Hz,2H),3.73(d,J=10.6Hz,2H),3.65(d,J=6.1Hz,2H),3.26(t,J=9.6Hz,1H),3.00(td,J=16.5,15.9,7.7 Hz,2H),2.86(q,J=13.3Hz,2H),2.56(q,J=6.8Hz,1H),2.03–1.88(m,2H),1.85(d,J=8.2Hz,1H),1.41–1.30(m,2H). C 34 H 32 ESIMS of ClN4O[M+H] + , calculated value 547.2, measured value 547.2.

[0783] Example 45: 6-[(7S)-2-{3-[1-(pyridin-4-yl)-1H-pyrazol-4-yl]-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

[0784]

[0785] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR(400MHz,DMSO-d6)δ11.91(d,J=2.6Hz,1H),9.16(s,1H),8.73–8.59(m,2H),8.59–8.47(m,2H),8 .40(s,1H),8.01–7.97(m,2H),7.96(d,J=2.6Hz,1H),7.59–7.53(m,1H),7.51(dd,J=7.6,1.7Hz,1H), 7.25(d,J=7.7Hz,1H),4.17(d,J=10.7Hz,2H),3.64–3.47(m,4H),3.24–3.12(m,1H),3.08–2.88(m,2H ),2.88–2.72(m,2H),2.42–2.29(m,1H),1.96–1.79(m,2H),1.69(d,J=7.9Hz,1H),1.25–1.10(m,2H). C 31 H 31 ESIMS of N6O[M+H] + , calculated value 503.3, measured value 503.2.

[0786] Example 46: 2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridine-3-carbonitrile

[0787]

[0788] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, DMSO-d6) δ12.14(s,1H),8.96(dd,J=4.8,1.7Hz,1H),8.57(d,J=2.0Hz,1H),8.51(d,J=2.0Hz,1H),8.45(dd, J=8.0,1.8Hz,1H),8.10(d,J=2.7Hz,1H),8.03(d,J=8.5Hz,2H),7.99(d,J=8.5Hz,2H),7.61(dd,J=7.9,4.8Hz,1H),7.56(d ,J=2.0Hz,1H),7.50(dd,J=7.7,1.7Hz,1H),7.23(d,J=7.7Hz,1H),4.16(d,J=10.6Hz,2H),3.65–3.48(m,4H),3.22–3.09(m ,1H),3.07–2.87(m,2H),2.87–2.70(m,2H),2.41–2.28(m,1H),1.96–1.78(m,2H),1.68(d,J=7.9Hz,1H),1.24–1.08(m,2H). C 35 H 32 ESIMS of N5O[M+H] + , calculated value 538.3, measured value 538.2.

[0789] Example 47: 6-[(7S)-2-{3-[4-(5-methylpyrimidin-4-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

[0790]

[0791] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, DMSO-d6) δ12.11(d,J=2.7Hz,1H),9.10(s,1H),8.74(s,1H),8.57(d,J=2.1Hz,1H),8.49(d,J=2.1Hz,1H),8.0 7(d,J=2.7Hz,1H),7.97(dt,J=8.5,1.9Hz,2H),7.82(dt,J=8.5,2.0Hz,2H),7.55(d,J=2.0Hz,1H),7.49(dd,J=7.6,2.0Hz,1H ),7.23(d,J=7.8Hz,1H),4.16(d,J=10.6Hz,2H),3.59(d,J=10.6Hz,2H),3.54(d,J=6.0Hz,2H),3.23–3.09(m,1H),3.09–2.86 (m,2H),2.79(q,J=14.3Hz,2H),2.45(s,3H),2.41–2.26(m,1H),1.95–1.75(m,2H),1.68(d,J=7.8Hz,1H),1.28–1.05(m,2H). C 34 H 34 ESIMS of N5O[M+H] + , calculated value 528.3, measured value 528.3.

[0792] Example 48: 6-[(7S)-2-{3-[4-(3-methylpyrazin-2-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

[0793]

[0794] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, DMSO-d6) δ12.09(d,J=2.7Hz,1H),8.59–8.57(m,1H),8.56(d,J=2.1Hz,1H),8.52(d,J=2.5Hz,1H),8.48(d,J=2 .1Hz,1H),8.04(d,J=2.7Hz,1H),7.99–7.91(m,2H),7.78–7.70(m,2H),7.54(d,J=1.9Hz,1H),7.48(dd,J=7.9,1.8Hz,1H),7.2 3(d,J=7.8Hz,1H),4.15(d,J=10.5Hz,2H),3.58(d,J=10.6Hz,2H),3.54(d,J=6.0Hz,2H),3.22–3.09(m,1H),3.09–2.85(m,2H) ,2.78(q,J=13.8Hz,2H),2.66(s,3H),2.36(q,J=7.2,6.7Hz,1H),1.94–1.73(m,2H),1.68(d,J=7.8Hz,1H),1.29–1.02(m,2H). C 34 H 34 ESIMS of N5O[M+H] + , calculated value 528.3, measured value 528.3.

[0795] Example 49: 6-[(7S)-2-{3-[4-(4-methylpyridazin-3-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

[0796]

[0797] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, DMSO-d6) δ12.09(d,J=2.8Hz,1H),9.08(d,J=5.2Hz,1H),8.57(d,J=2.0Hz,1H),8.49(d,J=2.1Hz,1H),8.0 5(d,J=2.6Hz,1H),8.00–7.90(m,2H),7.80–7.68(m,2H),7.66(dd,J=5.2,1.0Hz,1H),7.55(d,J=1.8Hz,1H),7.49(dd,J=7 .5,2.0Hz,1H),7.23(d,J=7.8Hz,1H),4.16(d,J=10.6Hz,2H),3.68–3.46(m,4H),3.24–3.07(m,1H),3.06–2.87(m,2H),2 .79(q,J=14.4,13.9Hz,2H),2.42(s,3H),2.41–2.28(m,1H),1.93–1.80(m,2H),1.68(d,J=7.9Hz,1H),1.26–1.00(m,2H). C 34 H 34 ESIMS of N5O[M+H] + , calculated value 528.3, measured value 528.3.

[0798] Example 50: 6-[(7S)-2-{3-[4-(3,5-dimethylpyrazin-2-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

[0799]

[0800] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, chloroform-d) δ10.21(s,1H),8.64(d,J=2.0Hz,1H),8.44(d,J=2.0Hz,1H),8.40(s,1H),7.87–7.75(m,2H),7 .75–7.66(m,2H),7.63(d,J=2.5Hz,1H),7.47–7.35(m,2H),7.23(d,J=8.3Hz,1H),4.31(d,J=10.6Hz,2H),3.73(d,J =10.7Hz,2H),3.65(d,J=6.1Hz,2H),3.32–3.17(m,1H),3.00(td,J=17.1,16.1,7.9Hz,2H),2.86(q,J=13.6Hz,2H) ,2.70(s,3H),2.60(s,3H),2.56(q,J=6.4Hz,1H),2.04–1.89(m,2H),1.85(d,J=8.2Hz,1H),1.34(p,J=10.1Hz,2H). C 35 H 36 ESIMS of N5O[M+H] + , calculated value 542.3, measured value 542.3.

[0801] Example 51: 4-methyl-3-(4-{5-[(7S)-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}phenyl)pyridazine

[0802]

[0803] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, DMSO-d6) δ12.08(s,1H),9.08(d,J=5.1Hz,1H),8.56(d,J=2.1Hz,1H),8.48(d,J=2.0H z,1H),8.05(d,J=2.7Hz,1H),8.00–7.84(m,2H),7.78–7.68(m,2H),7.66(dt,J=5.1,0.7Hz,1H),7.51 (s,1H),7.46(d,J=7.8Hz,1H),7.20(d,J=7.7Hz,1H),3.29–3.09(m,3H),2.83(t,J=7.6Hz,1H),2.71 –2.52(m,3H),2.42(s,3H),1.96–1.57(m,5H),1.46–1.20(m,3H),1.03(d,J=6.2Hz,3H),0.92(s,3H). C 35 H 38 N5 ESIMS [M+H] + , calculated value 528.3, measured value 528.3.

[0804] Example 52: 2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)pyridine-3-carbonitrile

[0805]

[0806] The title compound was prepared in a similar manner to Example 2 from appropriate starting materials. 1 HNMR (400MHz, DMSO-d6) δ9.03–8.93(m,1H),8.89(d,J=2.0Hz,1H),8.78(d,J=2.1Hz,1H),8.48(dd,J =7.9,1.7Hz,1H),8.42–8.26(m,2H),8.18–7.96(m,2H),7.70–7.59(m,2H),7.58(d,J=7.7Hz,1H),7. 26(d,J=7.7Hz,1H),4.16(d,J=11.0Hz,2H),3.71–3.44(m,4H),3.23–3.10(m,1H),3.10–2.89(m,2H) ,2.89–2.71(m,2H),2.42–2.28(m,1H),2.00–1.79(m,2H),1.68(d,J=7.7Hz,1H),1.24–1.09(m,2H). C 34 H31 ESIMS of N6O[M+H] + , calculated value 539.3, measured value 539.3.

[0807] Example 53: 6-[(7S)-2-{3-[4-(3,6-dimethylpyrazin-2-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

[0808]

[0809] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1 HNMR (400MHz, DMSO-d6) δ12.08(d,J=2.7Hz,1H),8.56(d,J=2.1Hz,1H),8.48(d,J=2.0Hz,1H),8.41(s,1H),8.03(d,J=2.7Hz,1 H),7.97–7.88(m,2H),7.77–7.65(m,2H),7.54(d,J=1.9Hz,1H),7.48(dd,J=7.7,2.0Hz,1H),7.23(d,J=7.8Hz,1H),4.15(d,J= 10.6Hz,2H),3.58(d,J=10.6Hz,2H),3.54(d,J=6.0Hz,2H),3.17(t,J=8.5Hz,1H),2.97(ddd,J=33.5,13.7,8.6Hz,2H),2.78(q ,J=13.8Hz,2H),2.60(s,3H),2.52(s,3H),2.36(q,J=6.9Hz,1H),1.94–1.76(m,2H),1.68(d,J=7.9Hz,1H),1.26–1.07(m,2H). C 35 H 36 ESIMS of N5O[M+H] + , calculated value 542.3, measured value 542.3.

[0810] Example 54: 6-[(7S)-2-{3-[5-(3-methylpyrazin-2-yl)pyridin-2-yl]-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

[0811]

[0812] The title compound was prepared in a similar manner to Example 9 from appropriate starting materials. 1 HNMR (400MHz, chloroform-d) δ10.75(d,J=13.3Hz,1H),8.97(d,J=1.7Hz,1H),8.95(dt,J=2.3,0.7Hz,1H),8.64(s,1H),8.55(dt,J=2.5,0. 7Hz,1H),8.50(d,J=2.4Hz,1H),8.05(s,1H),8.01(dd,J=8.2,2.5Hz,1H),7.83(dt,J=8.3,0.7Hz,1H),7.49–7.41(m,2H),7.24(d,J =8.2Hz,1H),4.32(d,J=10.7Hz,2H),3.75(d,J=10.7Hz,2H),3.68(d,J=6.1Hz,2H),3.27(t,J=9.7Hz,1H),3.00(ddd,J=20.7,14.4, 7.8Hz,2H),2.95–2.79(m,2H),2.76(s,3H),2.58(q,J=6.6Hz,1H),2.03–1.91(m,2H),1.86(d,J=8.3Hz,1H),1.36(p,J=9.8Hz,2H). C 33 H 33 ESIMS of N6O[M+H] + , calculated value 529.3, measured value 529.3.

[0813] Example 55: 6-[(7S)-2-{3-[5-(3-methylpyrazin-2-yl)pyridin-2-yl]-1H-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

[0814]

[0815] The title compound was prepared in a similar manner to Example 9 from appropriate starting materials. 1HNMR (400 MHz, chloroform-d) δ12.16 (s, 1H), 9.19 (s, 1H), 9.11–8.96 (m, 1H), 8.88 (s, 1H), 8.58–8.55 (m, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.38 (dt, J = 8.2, 0.9 Hz, 1H), 8.09 (ddd, J = 8.3, 2.3, 0.8 Hz, 1H), 7.51–7.36 (m, 2H), 7.26–7.2 2(m,1H),4.33(d,J=10.7Hz,2H),3.75(d,J=10.7Hz,2H),3.68(d,J=6.1Hz,2H),3.35–3.20(m,1H),3.08–2. 78(m,4H),2.76(s,3H),2.60(q,J=6.9Hz,1H),2.08–1.89(m,2H),1.87(d,J=8.2Hz,1H),1.46–1.28(m,2H). C 32 H 32 ESIMS of N7O [M+H] + , calculated value 530.3, measured value 530.3.

[0816] Example 56: 6-[(7S)-2-{3-[5-(4-methylpyridazin-3-yl)pyridin-2-yl]-1H-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

[0817]

[0818] The title compound was prepared in a similar manner to Example 9 from appropriate starting materials. 1HNMR(400MHz,DMSO-d6)δ9.15(d,J=5.2Hz,1H),9.07(d,J=2.2Hz,1H),9.06–9.03(m,1H),8.90(d,J=2.2Hz,1H),8.3 6(dd,J=8.2,0.8Hz,1H),8.25(dd,J=8.3,2.2Hz,1H),7.73(dt,J=5.1,0.7Hz,1H),7.54(s,1H),7.48(dd,J=7.7,1.9 Hz,1H),7.28(d,J=7.7Hz,1H),4.16(d,J=10.6Hz,2H),3.66–3.44(m,4H),3.25–3.09(m,1H),3.09–2.88(m,2H),2.8 0(q,J=13.9Hz,2H),2.46(s,3H),2.36(q,J=7.2Hz,1H),2.03–1.78(m,2H),1.68(d,J=7.9Hz,1H),1.29–0.97(m,2H). C 32 H 32 ESIMS of N7O [M+H] + , calculated value 530.3, measured value 530.3.

[0819] Example 57: 3,5-dimethyl-2-(4-{5-[(7S)-7-methyl-7-[(2R)-2-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyrazine

[0820]

[0821] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400 MHz, chloroform-d) δ9.27 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 1.8 Hz, 1H), 8.40 (s, 1H), 7.87–7.73 (m, 2H), 7.73–7.64 (m, 2H), 7.60 (d, J = 2.5 Hz, 1H), 7.42–7.34 (m, 2H), 7.21 (d, J = 8. 1Hz,1H),3.52–3.29(m,1H),3.24(p,J=6.5Hz,2H),2.92(t,J=7.6Hz,1H),2.77–2.44(m,9H), 2.01–1.78(m,3H),1.79–1.62(m,2H),1.55–1.37(m,3H),1.08(d,J=6.3Hz,3H),1.00(s,3H). C 36 H 40 N5 ESIMS [M+H] + , calculated value 542.3, measured value 542.3.

[0822] Example 58: 2,5-dimethyl-3-(4-{5-[(7S)-7-methyl-7-[(2R)-2-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyrazine

[0823]

[0824] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1 HNMR (400 MHz, chloroform-d) δ9.32 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.35 (s, 1H), 7.89–7.74 (m, 2H), 7.74–7.65 (m, 2H), 7.60 (d, J = 2.5 Hz, 1H), 7.42–7.33 (m, 2H), 7.21 (d, J = 8.2 Hz, 1H ),3.52–3.30(m,1H),3.30–3.17(m,2H),2.92(t,J=7.6Hz,1H),2.74–2.63(m,4H),2.64–2.45(m, 5H), 1.99–1.80 (m, 3H), 1.79–1.62 (m, 2H), 1.56–1.39 (m, 3H), 1.08 (d, J = 6.3Hz, 3H), 1.00 (s, 3H). C 36 H 40 N5 ESIMS [M+H] +, calculated value 542.3, measured value 542.3.

[0825] Example 59: 3,5-dimethyl-2-(4-{5-[(7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyrazine

[0826]

[0827] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1 HNMR (400MHz, chloroform-d) δ9.20 (s, 1H), 8.62 (s, 1H), 8.43 (d, J = 1.3Hz, 1H), 8.40 (s ,1H),7.83–7.75(m,2H),7.70(dt,J=8.3,0.7Hz,2H),7.60(d,J=2.3Hz,1H),7 .42–7.37(m,2H),7.23(d,J=7.8Hz,1H),3.15–2.95(m,2H),2.82–2.68(m,5H) ,2.69–2.50(m,8H),2.19–2.01(m,2H),1.87–1.73(m,4H),1.68–1.60(m,2H). C 34 H 36 N5 ESIMS [M+H] + , calculated value 514.3, measured value 514.3.

[0828] Example 60: 3,5-dimethyl-2-(6-{5-[(7S)-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-3-yl)pyrazine

[0829]

[0830] The title compound was prepared in a similar manner to Example 9 from appropriate starting materials. 1HNMR (400MHz, chloroform-d) δ11.62(s,1H),9.20(d,J=1.9Hz,1H),8.99(dd,J=2.3,0.9Hz,1H),8.90(s,1H), 8.44(s,1H),8.36(dd,J=8.2,0.9Hz,1H),8.07(dd,J=8.2,2.3Hz,1H),7.49–7.37(m,2H),7.23(d,J=8 .1Hz,1H),3.48–3.33(m,1H),3.33–3.17(m,2H),2.93(t,J=7.7Hz,1H),2.77–2.57(m,8H),2.58–2.45 (m,1H),2.02–1.79(m,3H),1.80–1.64(m,2H),1.56–1.39(m,3H),1.09(d,J=6.5Hz,3H),1.00(s,3H). C 34 H 38 N7 ESIMS [M+H] + , calculated value 544.3, measured value 544.3.

[0831] Example 61: 2,5-dimethyl-3-(6-{5-[(7S)-7-methyl-7-[(2R)-2-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyridin-3-yl)pyrazine

[0832]

[0833] The title compound was prepared in a similar manner to Example 9 from appropriate starting materials. 1 HNMR (400 MHz, chloroform-d) δ 11.68 (s, 1H), 9.20 (s, 1H), 9.00 (dt, J = 2.3, 0.7 Hz, 1H), 8.91 (s, 1H), 8.41 (s, 1H), 8.36 (dt, J = 8.3, 0.7 Hz, 1H), 8.08 (dd, J = 8.1, 2.1 Hz, 1H), 7.48–7.39 (m, 2H), 7.24 (d, J = 8.2 Hz ,1H),3.53–3.34(m,1H),3.34–3.16(m,2H),2.93(t,J=7.6Hz,1H),2.76–2.58(m,8H),2.59–2.44(m ,1H),2.03–1.80(m,3H),1.80–1.63(m,2H),1.58–1.37(m,3H),1.09(d,J=6.3Hz,3H),1.01(s,3H). C 34 H38 N7 ESIMS [M+H] + , calculated value 544.3, measured value 544.3.

[0834] Example 62: (1S,4S)-5-[(7S)-2-{3-[4-(3,6-dimethylpyrazin-2-yl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl]-2-oxa-5-azabicyclo[2.2.1]heptane

[0835]

[0836] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1 HNMR (400MHz, DMSO-d6) δ12.07(s,1H),8.56(d,J=2.1Hz,1H),8.47(d,J=2.1Hz,1H),8.41(s,1H),8.02(d,J=2.6Hz ,1H),7.97–7.86(m,2H),7.79–7.61(m,2H),7.54(s,1H),7.48(d,J=8.0Hz,1H),7.22(d,J=7.7Hz,1H),4.34(s,1H) ,3.91(d,J=7.5Hz,1H),3.71(s,1H),3.54(d,J=7.4Hz,1H),3.18–2.93(m,3H),2.80–2.61(m,3H),2.60(s,3H),2.5 2(s,3H),2.35(d,J=9.8Hz,1H),2.00–1.76(m,2H),1.73(d,J=9.3Hz,1H),1.62(d,J=9.3Hz,1H),1.58–1.30(m,2H). C 35 H 36 ESIMS of N5O[M+H] + , calculated value 542.3, measured value 542.3.

[0837] Example 63: 3-(4-{5-[(7S)-7-[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2,5-dimethylpyrazine

[0838]

[0839] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400 MHz, chloroform-d) δ9.29 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.35 (s, 1H), 7.83–7.74 (m, 2H), 7.73–7.65 (m, 2H), 7.60 (d, J = 2.5 Hz, 1H), 7.43–7.34 (m, 2H), 7.22 (d, J = 7.7 Hz, 1H), 3.35 ( s,3H),3.32(dd,J=7.0,4.0Hz,2H),3.21–3.00(m,2H),2.88–2.77(m,1H),2.77–2.62(m,7H),2.61(s ,3H),2.57–2.49(m,1H),2.49–2.36(m,2H),2.13–1.83(m,3H),1.75–1.61(m,2H),1.54–1.36(m,1H). C 36 H 40 ESIMS of N5O[M+H] + , calculated value 558.3, measured value 558.3.

[0840] Example 64: 2,5-dimethyl-3-(4-{5-[(7S)-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)pyrazine

[0841]

[0842] The title compound was prepared in a similar manner to Example 2 from appropriate starting materials. 1 HNMR (400 MHz, chloroform-d) δ 11.62 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.20–8.03 (m, 2H), 7.82–7.70 (m, 2H), 7.46–7.33 (m, 2H), 7.24 (d, J = 8.2 Hz, 1H) ,3.55–3.33(m,1H),3.33–3.16(m,2H),2.93(t,J=7.4Hz,1H),2.74–2.48(m,9H),2.02– 1.80(m,3H),1.80–1.63(m,2H),1.58–1.39(m,3H),1.09(d,J=6.3Hz,3H),1.00(s,3H). C 35 H 39 ESIMS of N6 [M+H] +, calculated value 543.3, measured value 543.3.

[0843] Example 65: 6-[(7S)-2-{3-[4-(3,6-dimethylpyrazin-2-yl)phenyl]-1H-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

[0844]

[0845] The title compound was prepared in a similar manner to Example 2 from appropriate starting materials. 1 HNMR (400MHz, DMSO-d6) δ13.97(s,1H),8.88(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.44(s,1H),8.2 5(d,J=8.3Hz,2H),7.81(d,J=8.2Hz,2H),7.63(s,1H),7.56(d,J=7.9Hz,1H),7.26(d,J=7.8Hz,1H),4. 16(d,J=10.6Hz,2H),3.66–3.42(m,4H),3.24–3.11(m,1H),3.11–2.87(m,2H),2.88–2.71(m,2H),2.6 1(s,3H),2.53(s,3H),2.41–2.30(m,1H),2.01–1.76(m,2H),1.69(d,J=8.1Hz,1H),1.26–0.98(m,2H). C 34 H 35 ESIMS of N6O[M+H] + , calculated value 543.3, measured value 543.3.

[0846] Example 66: 2-(4-{5-[(7S)-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)pyridine-3-carbonitrile

[0847]

[0848] The title compound was prepared in a similar manner to Example 2 from appropriate starting materials. 1HNMR (400 MHz, chloroform-d) δ 11.68 (s, 1H), 8.93 (dd, J = 4.8, 1.8 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.26–8.19 (m, 2H), 8.18–8.11 (m, 3H), 7.48–7.36 (m, 3H), 7.24 (d, J = 7.9 Hz,1H),3.49–3.34(m,1H),3.34–3.12(m,2H),2.93(t,J=7.7Hz,1H),2.77–2.43(m,3H),2. 02–1.80(m,3H),1.79–1.66(m,2H),1.58–1.41(m,3H),1.09(d,J=6.3Hz,3H),1.01(s,3H). C 35 H 35 ESIMS of N6 [M+H] + , calculated value 539.3, measured value 539.3.

[0849] Example 67: 3-methyl-2-(4-{5-[7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)pyridine

[0850]

[0851] The title compound was prepared in a similar manner to Example 19 from appropriate starting materials. 1 H NMR (400 MHz, chloroform-d) δ 11.28 (s, 1H), 8.86 (dd, J = 2.1, 1.0 Hz, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.54–8.43 (m, 1H), 8.19–8.01 (m, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.45–7.32 (m ,2H),7.25–7.20(m,2H),3.19(dd,J=16.4,4.4Hz,1H),3.05–2.82(m,3H),2.83–2.63(m,4H ),2.60–2.47(m,1H),2.45(s,3H),2.35–2.19(m,1H),1.99–1.81(m,4H),1.83–1.69(m,1H). C 32 H 32 N5 ESIMS [M+H] + , calculated value 486.3, measured value 486.3.

[0852] Example 68: 2,5-dimethyl-3-(6-{5-[(7S)-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}pyridin-3-yl)pyrazine

[0853]

[0854] The title compound was prepared in a similar manner to Example 9 from appropriate starting materials. 1 HNMR (400MHz, chloroform-d) δ10.09(s,1H),8.94(d,J=2.1Hz,1H),8.92(dd,J=2.4,0.8Hz,1H),8.64(d,J=2.1Hz,1H), 8.38(s,1H),8.02(d,J=2.6Hz,1H),7.99(dd,J=8.2,2.3Hz,1H),7.82(dd,J=8.2,0.9Hz,1H),7.47–7.37(m,2H) ,7.22(d,J=8.2Hz,1H),3.52–3.34(m,1H),3.25(p,J=7.0,6.5Hz,2H),2.98–2.88(m,1H),2.74–2.57(m,8H),2 .57–2.48(m,1H),2.02–1.80(m,3H),1.80–1.64(m,2H),1.59–1.39(m,3H),1.08(d,J=6.3Hz,3H),1.01(s,3H). C 35 H 39 ESIMS of N6 [M+H] + , calculated value 543.3, measured value 543.3.

[0855] Example 69: 6-[(7S)-2-{3-[5-(3,6-dimethylpyrazin-2-yl)pyridin-2-yl]-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

[0856]

[0857] The title compound was prepared in a similar manner to Example 9 from appropriate starting materials. 1HNMR (400 MHz, chloroform-d) δ 10.38 (s, 1H), 9.03–8.79 (m, 2H), 8.63 (s, 1H), 8.42–8.26 (m, 1H), 8.11–7.90 (m, 2H), 7.81 (dd, J = 8.2, 4.0 Hz, 1H), 7.48–7.30 (m, 2H), 7.25–7.20 (m, 1H), 4.32 (d, J = 9.8 Hz, 2H), 3.73(dd,J=11.3,3.7Hz,2H),3.66(d,J=5.9Hz,2H),3.33–3.17(m,1H),3.09–2.76(m,4H),2.70(s ,3H),2.62(s,3H),2.58–2.50(m,1H),2.06–1.88(m,2H),1.85(d,J=8.3Hz,1H),1.41–1.24(m,2H). C 34 H 35 ESIMS of N6O[M+H] + , calculated value 543.3, measured value 543.3.

[0858] Example 70: 6-methyl-2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)pyridine-3-carbonitrile

[0859]

[0860] The title compound was prepared in a similar manner to Example 2 from appropriate starting materials. 1 HNMR(400MHz,DMSO-d6)δ8.89(d,J=2.0Hz,1H),8.77(d,J=2.0Hz,1H),8.42–8.24(m,3H),8.05(d ,J=8.4Hz,2H),7.64(s,1H),7.58(d,J=7.7Hz,1H),7.51(d,J=8.1Hz,1H),7.26(d,J=7.7Hz,1H), 4.16(d,J=10.7Hz,2H),3.70–3.43(m,4H),3.25–3.08(m,1H),3.08–2.88(m,2H),2.88–2.68(m,2 H), 2.66 (s, 3H), 2.43–2.27 (m, 1H), 2.00–1.76 (m, 2H), 1.69 (d, J = 7.9Hz, 1H), 1.25–1.08 (m, 2H). C 35 H 33ESIMS of N6O[M+H] + , calculated value 553.3, measured value 553.3.

[0861] Example 71: 6-methyl-2-(4-{5-[(7S)-7-methyl-7-[(2R)-2-methylpyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)pyridine-3-carbonitrile

[0862]

[0863] The title compound was prepared in a similar manner to Example 2 from appropriate starting materials. 1 HNMR (400 MHz, chloroform-d) δ11.44 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.26–8.17 (m, 2H), 8.17–8.09 (m, 2H), 7.99 (d, J = 8.0 Hz, 1H), 7.43–7.34 (m, 2H), 7.29–7.26 (m, 1H), 7.24 (d, J = 8.2 Hz,1H),3.56–3.35(m,1H),3.32–3.16(m,2H),2.93(t,J=7.6Hz,1H),2.73(s,3H),2.72–2.45(m, 3H), 2.02–1.80 (m, 3H), 1.80–1.63 (m, 2H), 1.55–1.39 (m, 3H), 1.09 (d, J = 6.3Hz, 3H), 1.01 (s, 3H). C 36 H 37 ESIMS of N6 [M+H] + , calculated value 553.3, measured value 553.3.

[0864] Example 72: 6-methyl-2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridine-3-carbonitrile

[0865]

[0866] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, chloroform-d) δ10.27(s,1H),8.64(d,J=2.0Hz,1H),8.45(d,J=2.0Hz,1H),8.10–8.00(m,2H),7.97(d,J=8.0 Hz,1H),7.88–7.82(m,2H),7.66(d,J=2.5Hz,1H),7.45–7.35(m,2H),7.24(d,J=7.9Hz,2H),4.32(d,J=10.7Hz,2H), 3.74(d,J=10.7Hz,2H),3.66(d,J=6.1Hz,2H),3.27(t,J=9.6Hz,1H),3.01(ddd,J=22.5,14.4,8.0Hz,2H),2.86(q,J =14.1Hz,2H),2.72(s,3H),2.57(q,J=6.7Hz,1H),2.02–1.89(m,2H),1.85(d,J=8.2Hz,1H),1.35(p,J=10.6Hz,2H). C 36 H 34 ESIMS of N5O[M+H] + , calculated value 552.3, measured value 552.3.

[0867] Example 73: 6-[(7S)-2-{3-[4-(2,6-dimethylpyridin-3-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

[0868]

[0869] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400MHz, DMSO-d6) δ12.04(d,J=2.5Hz,1H),8.55(d,J=2.1Hz,1H),8.45(d,J=2.1Hz,1H),7.98(d,J=2.7Hz,1H),7.9 2–7.80(m,2H),7.60–7.52(m,2H),7.52–7.41(m,3H),7.22(d,J=7.8Hz,1H),7.17(d,J=7.8Hz,1H),4.15(d,J=10.6Hz,2H) ,3.58(d,J=10.6Hz,2H),3.54(d,J=6.0Hz,2H),3.17(t,J=10.2Hz,1H),2.96(ddd,J=33.1,14.0,8.5Hz,2H),2.78(q,J=1 4.4Hz,2H),2.48(s,3H),2.47(s,3H),2.36(q,J=6.9Hz,1H),1.93–1.79(m,2H),1.68(d,J=7.9Hz,1H),1.26–1.04(m,2H). C 36 H 37 ESIMS of N4O[M+H] + , calculated value 541.3, measured value 541.3.

[0870] Example 74: 6-[(7S)-2-{3-[4-(2-methylpyridin-3-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

[0871]

[0872] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400 MHz, chloroform-d) δ9.25 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.53 (dd, J = 5.0, 1.7 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.81–7.72 (m, 2H), 7.62–7.54 (m, 2H), 7.48–7.42 (m, 2H), 7.42–7.36 (m, 2H), 7.24–7.18 (m, 2H), 4.31 (d, J = 10.7 Hz, 2H),3.73(d,J=10.7Hz,2H),3.65(d,J=6.1Hz,2H),3.32–3.19(m,1H),2.99(td,J=15.8,15.3,9.5Hz,2H),2.85 (q,J=13.3Hz,2H),2.60(s,3H),2.59–2.51(m,1H),2.01–1.88(m,2H),1.85(d,J=8.3Hz,1H),1.39–1.26(m,2H). C 35 H 35 ESI MS of N4O[M+H] + , calculated value 527.3, measured value 527.2.

[0873] Example 75: 5-methyl-6-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridine-2-carbonitrile

[0874]

[0875] The title compound was prepared in a similar manner to Example 1 from appropriate starting materials. 1HNMR (400 MHz, chloroform-d) δ 10.30 (s, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.84–7.77 (m, 2H), 7.78–7.71 (m, 1H), 7.70–7.62 (m, 3H), 7.60 (d, J = 7.8 Hz, 1H), 7.45–7.37 (m, 2H), 7.23 (d, J = 8.2 Hz, 1H), 4.32 (d, J = 10.7 Hz, 2H), 3.7 4(d,J=10.7Hz,2H),3.66(d,J=6.1Hz,2H),3.27(t,J=9.7Hz,1H),3.00(td,J=18.6,16.5,7.8Hz,2H),2.86(q,J=13. 5Hz,2H),2.58(q,J=5.8,4.6Hz,1H),2.54(s,3H),2.03–1.89(m,2H),1.85(d,J=8.2Hz,1H),1.35(p,J=10.2Hz,2H). C 36 H 34 ESIMS of N5O[M+H] + , calculated value 552.3, measured value 552.3.

[0876] Example 76: 5-methyl-6-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]hept-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridine-2-carboxamide

[0877]

[0878] Step a: During the preparation of Example 75, the azaindole deprotection conditions (5 eq. of 6NNaOH in dioxane) were used. (aq) Stir at 70° C. for 1 hour) to provide the title compound (see Example 1, step g). 1H NMR (400MHz, chloroform-d) δ10.27(s,1H),8.63(d,J=2.0Hz,1H),8.45(d,J=2.0Hz,1H),8.12(d,J=7.8Hz,1H),7.96(d,J=4.6Hz,1H ),7.85–7.74(m,3H),7.70–7.66(m,2H),7.65(d,J=2.5Hz,1H),7.46–7.37(m,2H),7.23(d,J=8.2Hz,1H),5.82(d,J=4.6Hz,1 H),4.31(d,J=10.6Hz,2H),3.73(d,J=10.7Hz,2H),3.65(d,J=6.1Hz,2H),3.34–3.19(m,1H),2.99(td,J=15.1,7.8Hz,2H),2 .86(q,J=13.4Hz,2H),2.56(q,J=6.8Hz,1H),2.52(s,3H),2.03–1.88(m,2H),1.85(d,J=8.2Hz,1H),1.33(p,J=10.0Hz,2H). C 36 H 36 ESIMS of N5O2[M+H] + , calculated value 570.3, measured value 570.3.

[0879] Example 77: 6-[(7S)-2-{3-[4-(4,6-dimethylpyridazin-3-yl)phenyl]-1H-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

[0880]

[0881] The title compound (citrate salt) was prepared in a similar manner to Example 2 from appropriate starting materials. 1H NMR (400MHz, DMSO-d6) δ13.91(s,1H),8.90(d,J=2.0Hz,1H),8.77(d,J=2.1Hz,1H),8.27(d,J=8.3Hz, 2H),7.78(d,J=8.4Hz,2H),7.69(s,1H),7.63(d,J=7.7Hz,1H),7.56(s,1H),7.31(d,J=7.7Hz,1H),4.3 8–4.07(m,3H),4.00–3.78(m,2H),3.70–3.60(m,1H),3.49–3.18(m,3H),3.08–2.80(m,4H),2.64(s,3 H), 2.62 (d, J = 15.5Hz, 2H), 2.53 (d, J = 16.0Hz, 2H), 2.38 (s, 3H), 2.18–1.90 (m, 2H), 1.29–1.12 (m, 2H). C 34 H 35 ESIMS of N6O[M+H] + , calculated value 543.3, measured value 543.3.

[0882] Example 78: 4,6-dimethyl-3-(4-{5-[(7S)-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)pyridazine

[0883]

[0884] The title compound (citrate salt) was prepared in a similar manner to Example 2 from appropriate starting materials. 1H NMR (400MHz, DMSO-d6) δ14.00(s,1H),8.90(d,J=2.0Hz,1H),8.75(d,J=2.1Hz,1H),8.27(d,J=8.4Hz,2H),7.79 (d,J=8.4Hz,2H),7.72(s,1H),7.65(d,J=7.7Hz,1H),7.56(s,1H),7.33(d,J=7.8Hz,1H),3.34(s,4H),3.04–2. 75(m,4H),2.65(s,3H),2.57(d,J=15.2Hz,2H),2.49(d,J=14.9Hz,2H),2.38(s,3H),2.23–2.11(m,1H),2.11–1 .99(m,1H),1.99–1.83(m,3H),1.83–1.73(m,1H),1.73–1.59(m,2H),1.59–1.40(m,2H),1.26(d,J=6.5Hz,3H). C 35 H 39 ESIMS of N6 [M+H] + , calculated value 543.3, measured value 543.3.

[0885] Example 79: 6-[(7S)-2-{3-[1-(3-methylpyridin-2-yl)-1H-pyrazol-4-yl]-1H-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

[0886]

[0887] The title compound (citrate salt) was prepared in a similar manner to Example 27 from appropriate starting materials. 1H NMR (400MHz, DMSO-d6) δ13.73(s,1H),9.10(d,J=0.8Hz,1H),8.87(d,J=2.0Hz,1H),8.75(d,J=2.1Hz,1H),8.49(d,J=0. 8Hz,1H),8.44(dd,J=4.8,1.1Hz,1H),7.95(dd,J=7.5,1.0Hz,1H),7.69(s,1H),7.64(d,J=7.7Hz,1H),7.45(dd,J=7.6, 4.8Hz,1H),7.29(d,J=7.8Hz,1H),4.40–4.07(m,3H),3.99–3.79(m,2H),3.74–3.54(m,1H),3.50–3.20(m,3H),3.07–2. 81 (m, 4H), 2.62 (d, J = 15.2Hz, ...

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is CR 5 or N; G 1 Is N or CR G1 ; G 2 Yes CR G2 or N; G 3 Yes CR G3 or N; G 4 Yes CR G4 or N; G 5 Yes CR G5 or N; R G1 Selected from the group consisting of: H, C 1-3 Alkyl, halogen, C 1-3 Haloalkyl and CN; Each R G2 , R G3 , R G4 and R G5 are independently selected from the group consisting of: H, halogen, 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 5-8 membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein the cycloalkyl and heterocycloalkyl are substituted with 0-3 groups independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 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 fused with 1 to 4 R 2 and further substituted with 0 or 1 oxo (═O) on the carbon atom adjacent to the nitrogen atom; R 1 is selected from the group consisting of phenyl and a 5- to 6-membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each phenyl and heteroaryl is separated by one R 1a and 0-3 R 3 replace; R 1a selected from the group consisting of phenyl and 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the N atom when present is optionally oxidized, and wherein each phenyl and heteroaryl is substituted by 0-4 R 4 replace; Each R 2 Independently selected from the group consisting of: 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 , 5- to 8-membered heterocycloalkyl, -NR a -(5- to 8-membered heterocycloalkyl), -C(O)-(5- to 8-membered heterocycloalkyl), -X 1 -5 to 8 membered heterocycloalkyl and -OX 1 -(5 to 8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each cycloalkyl and heterocycloalkyl is substituted with 0-3 groups independently selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and OH; Each R 3 Independently selected from the group consisting of halogen, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated hydroxyalkyl, -OC 1-7 Alkyl, -OC 1-6 Haloalkyl, -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 and -S(O)2-C 1-7 Haloalkyl; Each R 4 Independently selected from the group consisting of: C 1-7 Alkyl, halogen, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene-CN, hydroxyl, C 1-7 Hydroxyalkyl, -C(O)NR a R b , C 3-7 Cycloalkyl, -NR a -C(O)-C 1-7 Alkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -S(O)2-NR a R b 、-NR a -S(O)2-C 1-7 Alkyl and -NR a -S(O)2-C 3-7 Cycloalkyl, wherein each cycloalkyl and heterocycloalkyl is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl, halide and hydroxyl groups; Or, two R on the same ring vertex 4 The groups combine to form an oxo group (=O); or Two R on adjacent ring vertices 4 The groups are combined to form a 5- to 6-membered heterocycloalkyl group having 1 to 2 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the 5- to 6-membered heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl and halide; R 5 Selected from the group consisting of: H, C 1-4 Alkyl and -NH2; Each X 1 It is C 1-7 Alkylene or C 3-7 Cycloalkylene; Each Y 1 It is C 2-7 Alkylene or C 3-7 Cycloalkylene; Each R a and R b Independently selected from the group consisting of: H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-7 Cycloalkyl, wherein the cycloalkyl is optionally substituted with -OC 1-3 Alkyl substitution; or R a and R b Together with the nitrogen to which they are attached, they form a 4- to 8-membered heterocycloalkyl ring with 0-2 additional heteroatom ring vertices selected from the group consisting of O, N and S, wherein the heterocycloalkyl ring is substituted with 0-3 groups, each group independently selected from halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 Alkyl and X 1 -OC 1-3 Alkyl and OH; or two groups at the same ring vertex combine to form oxo (=O).

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: G 3 Yes CR G3 , and R G3 It is H; G 4 Yes CR G4 And R G4 is H; and G 5 Each is CR G5 And R G5 It's H.

3. The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein G 1 Is N or CR G1 , where R G1 It's H.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein G 2 Yes CR G2 And R G2 It's H.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein X is CR 5 And R 5 It's H.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein A has a formula selected from the group consisting of: Each of them is represented by 1 to 4 R 2 replace.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein A has the formula:

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein one R 2 Yes - NR a R b .

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein one R 2 Selected from the group consisting of:

10. The compound or pharmaceutically acceptable salt of claim 9, wherein one R 2 yes 11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1 is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl and pyrazolyl, wherein R 1 By an R 1a and 0-2 R 3 replace.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: where the subscript p is 0 or 1.

13. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: where the subscript p is 0 or 1.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein each R 3 When present, independently selected from the group consisting of: halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated hydroxyalkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -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 and -S(O)2-C 1-4 Halogenated alkyl.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein each R 3 When present, independently selected from the group consisting of: halogen, C 1-4 Alkyl and -OC 1-4 alkyl.

16. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein each R 3 When present is independently selected from the group consisting of fluoro, chloro, methyl and methoxy.

17. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein R 1a is selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl N-oxide and phenyl, wherein R 1a 0-3 R 4 replace.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 1a Selected from the group consisting of: where subscript q is 0, 1, or 2.

19. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 1a Selected from the group consisting of: where subscript q is 0, 1, or 2.

20. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 1a Selected from the group consisting of:

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R 4 When present, independently selected from the group consisting of: C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, CN, -C 1-4 Alkylene -CN, C 1-4 Hydroxyalkyl, -C(O)NR a R b , C 3-7 Cycloalkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 6-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O)2-C 1-4 Alkyl and -S(O)2-NR a R b , wherein each cycloalkyl and heterocycloalkyl group is substituted with 0 to 2 groups selected from the group consisting of: C 1-4 Alkyl, halo and hydroxy.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein each R 4 When present, independently selected from the group consisting of: methyl, ethyl, fluoro, chloro, difluoromethyl, trifluoromethyl, CN, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 23. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 20, wherein two R on adjacent ring vertices are 4 The groups are combined to form a 5- to 6-membered heterocycloalkyl group having 1 to 2 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the 5- to 6-membered heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C 1-4 Alkyl and halide.

24. The compound of claim 23, wherein two R 4 The groups are combined to form a heterocycloalkyl group selected from: wherein the heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: 1-4 Alkyl and halide.

25. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 5 to 24, having a structure selected from Formula (Ia) or Formula (Ia1):

26. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 2, 5, or 8 to 24, having a structure according to Formula (Ib) or Formula (Ib1): wherein for each of Formula (Ib) and Formula (Ib1), subscript m is 0 or 1; and n is 0, 1 or 2, and each R 2 Can be the same or different.

27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, which has a structure of Formula (If) or Formula (If1):

28. The compound of claim 26 or 27, wherein m is 0.

29. The compound of any one of claims 26 to 28, wherein n is 0.

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

31. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; G 1 is N or CH; A is a fused ring selected from the group consisting of cycloheptane, cyclohexane and azepane, each of which is fused with 1 to 4 R 2 replace; R 1 is selected from the group consisting of phenyl and a 5- to 6-membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each phenyl and heteroaryl is separated by one R 1a and 0-3 R 3 replace; R 1a selected from the group consisting of phenyl and 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the N atom when present is optionally oxidized, and wherein each phenyl and heteroaryl is substituted by 0-4 R 4 replace; Each R 2 Independently selected from the group consisting of: C 1-7 Alkyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -NR a R b , 5- to 8-membered heterocycloalkyl and -NR a -(5 to 8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each cycloalkyl and heterocycloalkyl is substituted with 0-3 groups independently selected from: C 1-4 Alkyl and -OC 1-4 alkyl; Each R 3 Independently selected from the group consisting of halogen, C 1-7 Alkyl and -OC 1-7 alkyl; Each R 4 Independently selected from the group consisting of: C 1-7 Alkyl, halogen, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene -CN, C 1-7 Hydroxyalkyl, -C(O)NR a R b , C 3-7 Cycloalkyl, -NR a -C(O)-C 3-7 Cycloalkyl, -NR a R b 、-OC 1-4 Alkylene-OC 1-4 alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -5- to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O)2-C 1-7 Alkyl and -S(O)2-NR a R b , wherein each cycloalkyl and heterocycloalkyl is substituted by 0 to 2 groups independently selected from the following: 1-4 Alkyl and hydroxyl groups; Or, two R on adjacent ring vertices 4 The groups are combined to form a 5- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms selected from the group consisting of O, N and S, wherein the 5- to 6-membered heterocycloalkyl is surrounded by 0 to 2 C 1-4 Alkyl substitution; Each X 1 It is C 1-7 Alkylene; Each Y 1 It is C 2-7 Alkylene; Each R a and R b Independently selected from the group consisting of: H, C 1-7 Alkyl, C 3-7 Cycloalkyl, wherein the cycloalkyl is optionally substituted with -OC 1-3 Alkyl substitution; or R a and R b Together with the nitrogen to which they are attached, they form a 4- to 8-membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N and S, wherein the heterocycloalkyl ring is substituted with 0-3 groups, each group being independently selected from C 1-4 Alkyl, -OC 1-4 Alkyl and X 1 -OC 1-3 Alkyl; or two groups at the same ring vertex are combined to form oxo (=O).

32. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

33. The pharmaceutical composition of claim 32, wherein the composition comprises 10 to 300 mg of a compound as claimed in any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

34. A method of treating cancer, fibrosis, viral infection or pain, the method comprising administering to a subject in need thereof a compound as described in any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 32 or 33.

35. A method of treating a disease, condition or disorder mediated at least in part by AXL, the method comprising administering to a subject in need thereof once daily 10 to 300 mg of a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32 or 33.

36. The method of claim 34 or 35, wherein the disease, disorder or condition is cancer.

37. The method of claim 36, wherein the cancer is prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, stomach cancer, endometrial cancer, uterine cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal carcinoma), mesothelial lining cancer, white blood cell cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, intestinal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), adrenal cancer, thyroid cancer, kidney cancer or bone cancer; or is glioblastoma, mesothelioma, renal cell carcinoma, stomach cancer, sarcoma (including Kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the skin or testicular seminoma, or any combination thereof 38. The method of claim 36, wherein the cancer is selected from the group consisting of skin cancer (e.g., melanoma), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), breast cancer (e.g., triple-negative breast cancer), bladder cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer), leukemia (e.g., acute myeloid leukemia or myelodysplastic syndrome), brain tumor (e.g., glioblastoma), ovarian cancer (e.g., epithelial ovarian cancer (EOC), high-grade serous ovarian cancer (HGSOC), or platinum-resistant ovarian cancer (PROC)), kidney cancer (e.g., clear cell renal cell carcinoma), mesothelioma, and head and neck cancer (e.g., head and neck squamous cell carcinoma).

39. The method of claim 38, wherein the cancer is acute myeloid leukemia, myelodysplastic syndrome, non-small cell lung cancer, ovarian cancer, or clear cell renal cell carcinoma.

40. The method of any one of claims 36 to 39, wherein the cancer is recurrent or resistant to radiation therapy, chemotherapy, or immunotherapy.

41. The method of claim 34 or 35, wherein the disease, disorder or condition is a viral infection.

42. The method of claim 41, wherein the viral infection is caused by SARS-CoV-2, Ebola virus, monkeypox, or Zika virus.

43. The method of claim 34 or 35, wherein the disease, disorder or condition is fibrosis.

44. The method of claim 43, wherein the fibrosis is renal fibrosis (eg, chronic kidney disease), intestinal fibrosis (eg, Crohn's disease), liver fibrosis (eg, chronic liver disease), or pulmonary fibrosis (eg, idiopathic pulmonary fibrosis).

45. The method of any one of claims 35 to 40, further comprising administering to the subject at least one additional therapeutic agent.

46. ​​The method of claim 45, wherein the at least one additional therapeutic agent comprises one or more agents independently selected from the group consisting of inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies), kinase inhibitors, inhibitors of HIF (e.g., HIF-2α inhibitors), inhibitors of PARP, RAS signaling inhibitors, immune checkpoint inhibitors, agents targeting extracellular production of adenosine, radiation therapy, and chemotherapeutic agents.

47. The method of claim 46, wherein the at least one additional therapeutic agent comprises an inhibitor of the CD47-SIRPα pathway, wherein the inhibitor of the CD47-SIRPα pathway is an anti-CD47 antibody.

48. The method of claim 46 or 47, wherein the at least one additional therapeutic agent comprises one or more kinase inhibitors that inhibit one or more of: EGFR, VEGFR, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK and / or FGFR.

49. The method of any one of claims 46 to 48, wherein the at least one additional therapeutic agent comprises one or more immune checkpoint inhibitors that block the activity of at least one of: PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT, or CTLA-4.

50. The method of claim 49, wherein the one or more immune checkpoint inhibitors include an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

51. The method of claim 50, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is selected from the group consisting of avelumab, atezolizumab, batilizumab, brigalimab, camrelizumab, cocilimab, dotalimumab, durvalumab, epilizumab, envolimab, ebenalizumab, nivolumab, pembrolizumab, pidilizumab, pimivasamonab, rivulizumab, samralizumab, spartalizumab, sintilimab, tislelizumab, toripalizumab, and sepalizumab.

52. The method of claim 50, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is sepalizumab.

53. The method of any one of claims 46 to 52, wherein the one or more immune checkpoint inhibitors include an immune checkpoint inhibitor that blocks the activity of TIGIT.

54. The method of claim 53, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is selected from AB308, dovanumab, etilizumab, osperlimumab, tirilimumab, or vembrin.

55. The method of claim 53, wherein the immune checkpoint inhibitor is dofantazumab or AB308.

56. The method of any one of claims 46 to 55, wherein the at least one additional therapeutic agent comprises one or more agents targeting the extracellular production of adenosine selected from the group consisting of: A 2a R / A 2b R antagonists, CD73 inhibitors and CD39 inhibitors.

57. The method of claim 56, wherein the one or more agents targeting the extracellular production of adenosine are selected from the group consisting of AB598, elumelin, elupalem, tamiprofen, caffeine citrate, emaramel, safrinamel, and quinolistat.

58. The method of claim 56, wherein the one or more agents targeting the extracellular production of adenosine are AB598, elumelam and / or quinolistat.

59. The method of any one of claims 46 to 58, wherein the at least one additional therapeutic agent comprises an inhibitor of HIF-2α selected from the group consisting of beztifan, ARO-HIF2, PT-2385, and AB521.

60. The method of claim 59, wherein the inhibitor of HIF-2α is AB521.

61. The method of any one of claims 46 to 60, wherein the at least one additional therapeutic agent comprises an inhibitor of PARP selected from the group consisting of olaparib, rucaparib, and niraparib.

62. The method of any one of claims 46 to 61, wherein the at least one additional therapeutic agent comprises a chemotherapeutic agent.

63. The method of any one of claims 46 to 62, wherein the at least one additional therapeutic agent comprises radiation therapy.

64. The method of any one of claims 46 to 63, wherein the compound and the at least one additional therapeutic agent are administered in combination.

65. The method of any one of claims 46 to 64, wherein the compound and the at least one additional therapeutic agent are administered sequentially.

66. The method of any one of claims 46 to 64, wherein treatment periods for administration of the compound and the at least one additional therapeutic agent overlap.

67. A combination comprising a compound as claimed in any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

68. The combination of claim 67, wherein the at least one additional therapeutic agent comprises one or more agents independently selected from the group consisting of inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies), kinase inhibitors, inhibitors of HIF (e.g., HIF-2α inhibitors), inhibitors of PARP, RAS signaling inhibitors, immune checkpoint inhibitors, agents targeting extracellular production of adenosine, radiation therapy, and chemotherapeutic agents.

69. The combination of claim 68, wherein the at least one additional therapeutic agent comprises an inhibitor of the CD47-SIRPα pathway, wherein the inhibitor of the CD47-SIRPα pathway is an anti-CD47 antibody.

70. The combination of claims 68 or 69, wherein the at least one additional therapeutic agent comprises one or more kinase inhibitors that inhibit one or more of: EGFR, VEGFR, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK and / or FGFR.

71. The combination of any one of claims 68 to 70, wherein the at least one additional therapeutic agent comprises one or more immune checkpoint inhibitors that block the activity of at least one of: PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT, or CTLA-4.

72. The combination of claim 71, wherein the one or more immune checkpoint inhibitors include an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

73. The combination of claim 72, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is selected from the group consisting of avelumab, atezolizumab, batilizumab, brigalimab, camrelizumab, cocilimab, dotalimumab, durvalumab, epilizumab, envolimab, ebenalizumab, nivolumab, pembrolizumab, pidilizumab, pimivasamonab, rivulizumab, samralizumab, spartalizumab, sintilimab, tislelizumab, toripalizumab, and sepalizumab.

74. The combination of claim 73, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is sepalizumab.

75. The combination of any one of claims 68 to 74, wherein the one or more immune checkpoint inhibitors include an immune checkpoint inhibitor that blocks the activity of TIGIT.

76. The combination of claim 75, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is AB308, dovanumab, etilizumab, osperlimumab, tisleliumab, or vembrin.

77. The combination of claim 76, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is AB308 or dofenac.

78. The combination of any one of claims 68 to 77, wherein the at least one additional therapeutic agent comprises one or more agents targeting the extracellular production of adenosine selected from the group consisting of: A 2a R / A 2b R antagonists, CD73 inhibitors and CD39 inhibitors.

79. The combination of claim 78, wherein the one or more agents targeting the extracellular production of adenosine are selected from the group consisting of AB598, elumelin, elupalem, tamiprofen, caffeine citrate, emaramel, safiramel, or quinolistat.

80. The combination of claim 79, wherein the one or more agents targeting the extracellular production of adenosine are elumelam and / or quinolistat.

81. The combination of any one of claims 68 to 80, wherein the at least one additional therapeutic agent comprises an inhibitor of HIF-2α selected from the group consisting of beztifan, ARO-HIF2, PT-2385, and AB521.

82. The combination of claim 81, wherein the inhibitor of HIF-2α is AB521.

83. The combination of any one of claims 68 to 82, wherein the at least one additional therapeutic agent comprises an inhibitor of PARP selected from the group consisting of olaparib, rucaparib, and niraparib.

84. The combination of any one of claims 68 to 83, wherein the at least one additional therapeutic agent comprises a chemotherapeutic agent.

85. The combination of claim 84, wherein the chemotherapeutic agent comprises gemcitabine, cytarabine, a platinum-based, paclitaxel-based or anthracycline-based chemotherapeutic agent.

86. The combination of claim 85, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, and paclitaxel.

87. The combination of any one of claims 68 to 86, wherein the at least one additional therapeutic agent comprises radiation therapy.

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