Compounds as inhibitors of AXL

Abstract

Compounds that inhibit AXL for the treatment of various diseases, disorders, and conditions, including cancer, that are at least in part mediated by AXL, are provided. Described herein are compounds of Formula I that inhibit AXL, compositions containing the compound(s), and methods for synthesizing the compounds. Also described are uses of such compounds and compositions for the treatment of various diseases, disorders, and conditions, including cancer, that are mediated, at least in part, by AXL. TIFF2026041858000392.tif48165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 356,421, filed June 28, 2022, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] The following discussion is provided to aid the reader in understanding the present disclosure and is not admitted to describe or constitute prior art to the present disclosure.

[0003] 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 various mechanisms, including ligand-dependent and ligand-independent mechanisms. Once activated, AXL participates in various signaling pathways, such as the RAS-RAF-MEK-ERK pathway, which leads to cancer cell proliferation, and the PI3K / AKT pathway, which mediates the expression of several pro-survival proteins.

[0004] AXL has been shown to be overexpressed in a variety of malignancies, and in the cancer setting, AXL overexpression is associated with decreased patient survival and resistance mechanisms (both targeted and non-targeted).

[0005] In light of research linking AXL inhibition to diseases such as cancer, there is a need in the art for novel AXL inhibitors. The present disclosure addresses this need and offers additional advantages over previous AXL inhibitors. Summary of the Invention

[0006] In one aspect, the present disclosure relates to a compound that inhibits the activity of AXL. The compound has formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is CR 5 or N; G 1 is N or CR G1 and; G 2 is CR G2 or N; G 3 is CR G3 or N; G 4 is CR G4 or N; G 5 is CR G5 or N; R G1 is H, C 1-3 Alkyl, halogen, C 1-3 selected from the group consisting of haloalkyl, and CN; Each R G2 , R G3 , R G4 and R G5 are independently H, halo, CN, and 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, wherein cycloalkyl and heterocycloalkyl are selected from halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 substituted with 0-3 groups independently selected from alkyl, and OH; A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-oxazepane, 1,4-diazepane, oxepane, tetrahydropyran, piperidine, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which contains 1 to 4 R 2 and further substituted with zero or one oxo (=O) on the carbon atom adjacent to the nitrogen atom; R 1 is 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, and each phenyl and heteroaryl is selected from one R 1a and 0 to 3 R 3 is replaced by; R 1a is 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, where the N atom, if present, is optionally oxidized, and wherein each phenyl and heteroaryl is selected from the group consisting of 0-4 R 4 is replaced with; Each R 2 independently, C 1-7 Alkyl, C 3-7 Alkenyl, C 3-7 Alkynyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -NR a R b , -C(O)-C 1-7 Alkyl, -C(O)-C 3-7 Cycloalkyl, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -C(O)NR a R b , 5-8 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- (5-8 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 selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 substituted with 0-3 groups independently selected from alkyl, and OH; Each R 3 are independently halogen, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halohydroxyalkyl, -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, C 1-7 Alkyl, Halo, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene-CN, Hydroxy, C 1-7 Hydroxyalkyl, -C(O)NR a R b , C 3-7 Cycloalkyl, -NR a -C(O)-C1-7 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 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1 to 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 selected from the group consisting of C 1-4 substituted with 0 to 2 groups independently selected from the group consisting of alkyl, halo, and hydroxy; Or, two R on the same ring vertex 4 the groups combine to form an oxo (=O); or Two R on adjacent ring vertices 4 The groups combine to form a 5-6 membered heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5-6 membered heterocycloalkyl is 1-4 substituted with 0 to 2 groups independently selected from the group consisting of alkyl and halo; R 5 is H, C 1-4 selected from the group consisting of alkyl, and -NH; each X 1 is C 1-7 Alkylene or C 3-7 is cycloalkylene; Each Y 1 is C 2-7 Alkylene or C 3-7 is cycloalkylene; Each R a and R b are independently H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-7 cycloalkyl, wherein said cycloalkyl is optionally selected from the group consisting of -OC 1-3 substituted with alkyl; or R a and R b are taken together with the nitrogen to which they are attached to form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, where the heterocycloalkyl ring is substituted with 0-3 groups, each group being 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 on the same ring vertex combine to form oxo (=O).

[0007] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0008] In another aspect, the disclosure relates to a method of inhibiting AXL in a subject, comprising administering to the subject an effective amount of a compound described herein.

[0009] In yet another aspect, the present disclosure provides a method for treating a disease, disorder, or condition 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, disorders, and conditions mediated by AXL include, for example, cancer, viral infection, and fibrosis. Certain aspects of the present disclosure further comprise administering one or more additional therapeutic agents described herein below. DETAILED DESCRIPTION OF THE INVENTION

[0010] Before the present disclosure is further described, it is to be understood that the disclosure is not limited to particular embodiments described herein, and that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0011] Where a range is stated, it is understood that each intervening value between the upper and lower limits of that range, to the tenth of the unit of the lower limit, and any other stated or intervening value in that stated range, is encompassed within the invention, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specific excluded limits in the stated range. Where a stated range includes one or both limits, ranges excluding either or both of those included limits are also included within the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0012] Unless otherwise defined, all technical terms, notation, and other scientific or technical terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0013] The term "about" as used herein has the inherent meaning of approximately and literally supports the exact number preceded by the term and numbers that are near or approximate to the number preceded by the term. In general, the term "about" refers to the normal error range of each value, which is easily understood by those skilled in the art. If the degree of approximation is not clear from the context, "about" means within plus or minus 10% of the provided value, or rounded to the nearest significant figure, and in all cases includes the provided value. When ranges are provided, the boundaries of those ranges are included. definition

[0014] Unless otherwise stated, the following terms shall have the meanings set forth below: Other terms may be defined elsewhere throughout this specification.

[0015] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms stated (i.e., C1-8 means 1 to 8 carbons). 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, iso-propyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. In some embodiments, an alkyl group is C 1-4It is an alkyl group (eg, methyl, ethyl, isopropyl, or t-butyl).

[0016] The term "hydroxyalkyl" refers to an alkyl group, as defined herein, having the indicated number of carbon atoms (e.g., C 1-6 or C 1-8 ), refers to an alkyl group substituted with one or two hydroxy (OH) groups.

[0017] The term "alkylene" refers to a straight-chain or branched saturated aliphatic group, i.e., a divalent hydrocarbon group, having the indicated number of carbon atoms and linking at least two other groups. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) n -, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. Alkylene groups, in some embodiments, may be substituted or unsubstituted. When a group containing alkylene is optionally substituted, it is understood that any substitution may be on the alkylene portion of the moiety. In some embodiments, an alkylene group is a C 1-3 Alkylene groups (eg, methylene, ethylene, propylene, and isopropylene).

[0018] The term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic non-aromatic hydrocarbon ring system having the indicated number of ring atoms (e.g., C 3-6Cycloalkyl has 3 to 6 ring carbon atoms. Cycloalkyl groups can be saturated or partially unsaturated, i.e., they can feature one or more points of unsaturation, provided that the points of unsaturation do 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).

[0019] The term "heterocycloalkyl," in some embodiments, refers to a non-aromatic monocyclic, bicyclic, or polycyclic cycloalkyl ring having 3 to 14 members (e.g., a 3-14 membered heterocycle), or 3 to 10 members (e.g., a 3-10 membered heterocycle), or 3 to 8 members (e.g., a 3-8 membered heterocycle), or 3 to 6 members (e.g., a 3-6 membered heterocycle), or 5 to 6 members (e.g., a 5-6 membered heterocycle), and having 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S). In some embodiments, the nitrogen and sulfur atoms of a heterocycloalkyl group are optionally oxidized (e.g., N-oxide (N)). + -O -), sulfoxide (S=O), or sulfone (S(=O)2), and the nitrogen atom(s) are optionally quaternized. Heterocycloalkyl groups are 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 these points of unsaturation do not result in an aromatic system. The rings of bicyclic and polycyclic heterocycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting examples of heterocycloalkyl groups include 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-pyrroline, thiopyran, tetrahydroisoquinoline ... Examples include dihydrofuran, 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. Heterocycloalkyl groups can be attached to the remainder of the molecule through a ring carbon atom or a ring heteroatom, if chemically permissible. In some embodiments, 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).

[0020] As used herein, a wavy line crossing a single bond, double bond, or triple bond in any chemical structure shown herein [ka] represents the point of attachment of a single, double, or triple bond to the rest of the molecule. Additionally, a bond extending from a substituent to the center of a ring (e.g., a phenyl ring) is meant to indicate that the substituent may be attached to the ring at any available ring vertex, i.e., that the attachment of the substituent to the ring results in a chemically stable configuration.

[0021] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-4 haloalkyl" is meant to include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0022] The term "aryl" refers to a group containing one ring or two or three rings fused together, and in some embodiments, six to fourteen (i.e., C 6-14 aryl), or 6 to 10 (i.e., C 6-10 aryl), or 6 (i.e., C6 aryl) carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, and anthracenyl. In some embodiments, the aryl group is phenyl.

[0023] The term "heteroaryl," in some embodiments, refers to a monocyclic or fused bicyclic aromatic group (or ring) having 5 to 14 (i.e., 5-14 membered heteroaryl), or 5 to 10 (i.e., 5-10 membered heteroaryl), or 5 to 6 (i.e., 5-6 membered heteroaryl) members (i.e., ring vertices) and containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S). In some embodiments, the nitrogen and sulfur atoms are optionally oxidized (e.g., N-oxide (N + -O -), sulfoxide (S=O), or sulfone (S(=O)2), and the nitrogen atom(s) are optionally quaternized. Heteroaryl groups can be attached to the remainder of the molecule through a carbon atom or a heteroatom of the heteroaryl group, if chemically permissible. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. When a heteroaryl is substituted, the substituent is connected to the heteroaryl via a ring carbon atom or ring heteroatom, if chemically permissible. In some embodiments, the heteroaryl groups of the present disclosure are monocyclic 5- to 6-membered heteroaryl moieties having 1-3 heteroatoms independently selected from N, O, and S, where the N atom, if present, is optionally oxidized (e.g., pyridinyl, pyridyl N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, or thiazolyl).

[0024] The compounds of the present disclosure may exist in their neutral form or as its pharmaceutically acceptable salt, isomer, polymorph, or solvate, and may exist in crystalline form, amorphous form, or a mixture thereof.

[0025] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired base. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid.Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids, such as arginate, and salts of organic acids, such as glucuronic acid or galactunolonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

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

[0027] The present disclosure also contemplates isomers (e.g., stereoisomers and atropisomers) of the compounds described herein. For example, certain compounds of the present disclosure have asymmetric carbon atoms (chiral centers) or hindered rotation about a single bond; their racemates, diastereomers, enantiomers, and atropisomers (e.g., R a , S aStereoisomers (R, P and M isomers) are all intended to be encompassed within the scope of the present disclosure. Stereoisomers may be defined in terms of absolute stereochemistry as (R) or (S) and / or may be depicted using dashes and / or wedges. Stereochemical depictions (e.g., dashes, [ka] and / or wedge-shaped, [ka] When a stereochemical assignment (e.g., using (R) and (S) designations) is shown in a chemical structure, or when a stereochemical assignment (e.g., using (R) and (S) designations) is made in a chemical name, this is meant to indicate that the indicated stereoisomer is present and is substantially free of one or more other isomer(s) (e.g., enantiomers and diastereomers, if present). "Substantially free" of other isomer(s) indicates that the ratio of the indicated isomer to the other isomer(s) is at least 70 / 30, more preferably 80 / 20, 90 / 10, or 95 / 5 or greater. In some embodiments, the indicated isomer will be present in an amount of at least 99%. Solid line [ka] A chemical bond to an asymmetric carbon indicated by indicates that all possible stereoisomers at that carbon atom are included (e.g., enantiomers, diastereomers, racemic mixtures, etc.). In such cases, the compound may exist as a racemic mixture, a scalenemic mixture, or a mixture of diastereomers.

[0028] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. An unnatural proportion of an isotope can be defined as the range from the amount found in nature for that atom to the amount that constitutes 100%. For example, the compounds may contain radioactive isotopes, such as 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), etc. Such isotopic variations may provide additional utility to those described elsewhere herein. For example, isotopic variants of the disclosed compounds may find additional utility, including, but not limited to, as diagnostic and / or imaging reagents, or cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the disclosed compounds may have altered pharmacokinetic and pharmacodynamic properties that may contribute to improved 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 the present invention. In some embodiments, compounds according to the present disclosure are characterized by one or more deuterium atoms.

[0029] The terms "patient" or "subject" are used interchangeably and refer to a human or non-human animal (eg, a mammal).

[0030] The terms "treat," "treating," "treatment," and the like refer to a course of action that eliminates, alleviates, suppresses, relieves, improves, or prevents the worsening of the disease, disorder, or condition to which the term applies, or at least one symptom associated therewith, either temporarily or permanently. Treatment includes alleviating symptoms, reducing the extent of disease, inhibiting active disease (e.g., preventing the onset or further development of the disease, disorder, or condition, or clinical symptoms associated therewith), delaying or slowing the progression of disease, improving quality of life, and / or prolonging the survival of a subject when compared to expected survival if not receiving treatment or when compared to the published standard of care for the particular disease.

[0031] 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 would benefit from treatment. This judgment is made based on a variety of factors within the physician's area of ​​expertise and may include a positive diagnosis of a disease, disorder, or condition.

[0032] The terms "prevent," "preventing," "prevention," "prophylaxis," and the like, generally refer to a course of action initiated in some manner (e.g., prior to the onset of a disease, disorder, condition, or symptoms thereof) in the context of a subject who is prone to having a particular disease, disorder, or condition, in order to temporarily or permanently prevent, suppress, inhibit, or reduce the subject's risk of developing the disease, disorder, condition, or the like (e.g., as determined by the absence of clinical symptoms) or delay its onset. In certain instances, the term also refers to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or otherwise undesirable state. Prevention also refers to a course of action initiated in a subject after the subject has been treated for a disease, disorder, condition, or symptoms associated therewith, in order to prevent the recurrence of the disease, disorder, condition, or symptoms.

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

[0034] "Substantially pure" indicates that the component (e.g., a compound according to the present disclosure) constitutes more than about 50% of the total content of the composition, typically more than about 60% of the total content. More typically, "substantially pure" refers to a composition in which the component of interest constitutes at least 75%, at least 85%, at least 90% or more of the total composition. In some cases, the component of interest will constitute more than about 90%, or more than about 95% of the total content of the composition.

[0035] A compound that is selective may be particularly useful in treating a particular disorder or may reduce the potential for unwanted side effects. In some embodiments, the compounds of the present disclosure are selective over other tyrosine kinases. Specific examples include TYRO3 and MER. Selectivity may be determined, for example, by comparing the inhibition of a compound described herein against AXL with the inhibition of a compound described herein against another protein. In one embodiment, the selective inhibition of AXL is at least 1000-fold, 500-fold, 100-fold, 75-fold, 50-fold, 40-fold, 30-fold, 25-fold, or 20-fold greater than the inhibition of another kinase (e.g., TYRO3 and / or MER).

[0036] The compounds provided herein can have advantageous pharmacokinetic profiles, including, for example, inhibition of CYPs, bioavailability, and / or inhibition of the human rapidly activating delayed rectifier potassium channel gene (Ether-a-go-go Related Gene) (hERG) potassium channel. Compounds of the Disclosure

[0037] In some embodiments, compounds of formula (I) are provided herein. [ka] or a pharmaceutically acceptable salt thereof, wherein: X is CR 5 or N; G 1is N or CR G1 and; G 2 is CR G2 or N; G 3 is CR G3 or N; G 4 is CR G4 or N; G 5 is CR G5 or N; R G1 is H, C 1-3 Alkyl, halogen, C 1-3 selected from the group consisting of haloalkyl, and CN; Each R G2 , R G3 , R G4 and R G5 are independently H, halo, CN, and 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, wherein cycloalkyl and heterocycloalkyl are selected from halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 substituted with 0-3 groups independently selected from alkyl, and OH; A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-oxazepane, 1,4-diazepane, oxepane, tetrahydropyran, piperidine, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which contains 1 to 4 R 2and further substituted with zero or one oxo (=O) on the carbon atom adjacent to the nitrogen atom; R 1 is 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, and each phenyl and heteroaryl is selected from one R 1a and 0 to 3 R 3 is replaced by; R 1a is 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, where the N atom, if present, is optionally oxidized, and wherein each phenyl and heteroaryl is selected from the group consisting of 0-4 R 4 is replaced with; Each R 2 independently, C 1-7 Alkyl, C 3-7 Alkenyl, C 3-7 Alkynyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -NR a R b , -C(O)-C 1-7 Alkyl, -C(O)-C 3-7 Cycloalkyl, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -C(O)NR a R b , 5-8 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 -(5-8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and each cycloalkyl and heterocycloalkyl is selected from the group consisting of halo, CN, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 substituted with 0-3 groups independently selected from alkyl, and OH; Each R 3 are independently halogen, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halohydroxyalkyl, -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, C 1-7 Alkyl, Halo, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene-CN, Hydroxy, 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 1-4alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1 to 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 selected from the group consisting of C 1-4 substituted with 0 to 2 groups independently selected from the group consisting of alkyl, halo, and hydroxy; Or, two R on the same ring vertex 4 the groups combine to form an oxo (=O); or Two R on adjacent ring vertices 4 The groups combine to form a 5-6 membered heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5-6 membered heterocycloalkyl is 1-4 substituted with 0 to 2 groups independently selected from the group consisting of alkyl and halo; R 5 is H, C 1-4 selected from the group consisting of alkyl, and -NH; each X 1 But C 1-7 Alkylene or C 3-7 is cycloalkylene; Each Y 1 is C 2-7 Alkylene or C 3-7 is cycloalkylene; Each R a and R b are independently H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-4 Alkoxy C 1-4Alkyl, and C 3-7 cycloalkyl, wherein said cycloalkyl is optionally selected from the group consisting of -OC 1-3 substituted with alkyl; or R a and R b are taken together with the nitrogen to which they are attached to form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, where 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 The compound is provided wherein the two groups on the same ring vertex combine to form an oxo (=O).

[0038] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 is N or CR G1 (In the formula, R G1 is H. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound of formula (I) 1 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound of formula (I), wherein: 1 is CR G1 where R G1 is a compound where

[0039] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 2 is CR G2 where R G2is H or F. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is 2 is CR G2 and R G2 is H. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is 2 is a compound in which N

[0040] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 3 But N or CR G3 and R G3 is H, or CH3.

[0041] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 4 But N or CR G4 and R G4 is a compound where

[0042] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 5 But N or CR G5 where R G5 is a compound where

[0043] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 is N and G 2 But, CR G2 where R G2 is a compound where

[0044] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 3 But, CR G3 where RG3 is a compound where

[0045] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 4 But, CR G4 where R G4 is a compound where

[0046] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 5 But, CR G5 where R G5 is a compound where

[0047] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) wherein X is N, or CR 5 where R 5 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is a compound of formula (I) wherein X is CR 5 where R 5 is a compound where

[0048] With respect to A, A is G 3 , G 4 and G 5 The presence of A is fused to an aromatic ring containing G 3 , G 4 , and G 5 It is understood from the formula shown above that the aromatic rings containing the aromatic rings do not destroy the aromaticity of the aromatic rings. Specifically, the vertices of the rings that fuse two rings together are not sp 2The carbon atoms in the A ring are hybridized. Thus, each of the vertices of these rings has a p orbital that participates in the conjugated π system of the aromatic ring. Therefore, from the formula shown above, it is understood that the A moiety has a point of unsaturation at the point of fusion to the rest of the molecule. For example, cyclopentane in A refers to cyclopentene, where a double bond is between the two carbon atoms that are fused to the rest of the compound, as further exemplified and detailed.

[0049] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound wherein A is a compound having a formula selected from the group consisting of: [ka] Each of these has 1 to 4 R 2 is replaced with

[0050] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein A is [ka] having a formula selected from the group consisting of: Each of these has 1 to 4 R 2 is a compound substituted with

[0051] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein A is [ka] and this has 1 to 4 R 2 is a compound substituted with

[0052] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein A is [ka] wherein A is 1 to 4 R 2 is a compound substituted with

[0053] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein A is -C 2-7 Alkylene-OC 1-4 Alkyl and C 3-7 At least one R selected from cycloalkyl 2 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound wherein A is substituted with: [ka] At least one R selected from 2 is a compound substituted with

[0054] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein A is of the formula: [ka] It is a compound having the formula:

[0055] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein A is of the formula: [ka] It is a compound having the formula:

[0056] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein A is of the formula: [ka] It is a compound having the formula:

[0057] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises each R 2 independently, C 1-7 Alkyl, C 3-7 Alkenyl, C 3-7 Alkynyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -NR a R b , -C(O)-C 1-7 Alkyl, -C(O)-C 3-7 Cycloalkyl, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -C(O)NR a R b , 5-8 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) has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein each of said C 3-7 Cycloalkyl is -Y 1 -OC 3-7 Cycloalkyl, -C(O)-C 3-7 Cycloalkyl, -S(O)2-C 3-7 Cycloalkyl, 5-8 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-(5-8 membered heterocycloalkyl) is a 5- to 8-membered heterocycloalkyl group, including halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, 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 substituted with 0 to 3 groups independently selected from one R 2 Ga-NR a R b is a compound.

[0058] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises one R 2 but, [ka] is a compound selected from the group consisting of:

[0059] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises one R 2 but [ka] is a compound.

[0060] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, and pyrazolyl, wherein R 1 But one R 1a and 0 to 2 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound substituted with R 1 is selected from the group consisting of phenyl, pyridyl, pyridazinyl, and pyrazolyl, wherein R 1But one R 1a and 0 to 2 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) wherein R 1 is selected from the group consisting of pyrimidinyl, pyrazinyl, and oxadiazolyl, wherein R 1 But one R 1a and 0 to 2 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) wherein R 1 is phenyl or pyridyl, 1 But one R 1a and 0 to 2 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) wherein R 1 is one R 1a and 0 to 2 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound substituted with R 1 But R 1a and 0 to 2 R 3 is a phenyl substituted with

[0061] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 but, [ka] is a compound selected from the group consisting of where the subscript p is a compound that is 0 or 1.

[0062] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 but, [ka] is selected from the group consisting of where the subscript p is a compound that is 0 or 1.

[0063] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 but, [ka] is selected from the group consisting of where the subscript p is a compound that is 0 or 1.

[0064] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 but, [ka] is selected from the group consisting of where the subscript p is a compound that is 0 or 1.

[0065] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 but, [ka] is selected from the group consisting of where the subscript p is a compound that is 0 or 1.

[0066] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 but, [ka] and where the subscript p is a compound that is 0 or 1.

[0067] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 but, [ka] where the subscript p is 0 or 1.

[0068] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 but, [ka] where the subscript p is 0 or 1.

[0069] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1 But there are 0 R 3 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound substituted with a group, wherein R 1 But one R 3 It is a compound substituted with a group.

[0070] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises each R 3 When present, independently, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halohydroxyalkyl, -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 haloalkyl.

[0071] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises each R 3 When present, independently, halogen, C 1-4 Alkyl and -OC 1-4 alkyl.

[0072] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises each R 3 When present, is a compound independently selected from the group consisting of chloro, fluoro, methyl, and methoxy.

[0073] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises each R 3 When present, is a compound independently selected from the group consisting of fluoro, methyl, and methoxy.

[0074] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a is selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl N-oxide, and phenyl, wherein R 1a However, 0 to 3 R 4 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound substituted with R 1a is selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and phenyl, wherein R1a However, 0 to 3 R 4 It is a compound substituted with

[0075] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] is selected from the group consisting of wherein the subscript q is 0, 1, or 2.

[0076] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] is selected from the group consisting of wherein the subscript q is 0, 1, or 2.

[0077] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] is selected from the group consisting of wherein the subscript q is 0, 1, or 2.

[0078] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] is selected from the group consisting of wherein the subscript q is 0, 1, or 2.

[0079] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] is selected from the group consisting of wherein the subscript q is 0, 1, or 2.

[0080] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] is selected from the group consisting of wherein the subscript q is 0, 1, or 2.

[0081] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] is selected from the group consisting of wherein the subscript q is 0, 1, or 2.

[0082] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] is selected from the group consisting of wherein the subscript q is 0, 1, or 2.

[0083] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1abut, [ka] wherein the subscript q is 0, 1, or 2.

[0084] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] wherein the subscript q is 0, 1, or 2.

[0085] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] wherein q is 0 or 1.

[0086] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] each of which optionally contains one additional R 4 is a compound substituted with

[0087] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a but, [ka] is a compound selected from the group consisting of:

[0088] In some embodiments, R 1a The heteroaryl moiety in includes groups substituted with one or more oxo substituents according to Huckel's rule. Thus, in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is R 1a The heteroaryl group is attached to two R 4 groups, which are linked to form oxo (=O). Exemplary groups include, but are not limited to, pyridazinonyl and pyridinonyl. Thus, in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises R 1a are two R on the same ring vertex 4 together with the group form oxo (=O) to form a heteroaryl moiety selected from the group consisting of pyridazinonyl and pyridinonyl, wherein R 1a but 0 to 2 additional R 4 It is a compound substituted with a group.

[0089] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 1a However, 2 to 4 R 4 contains a part, and [ka] is selected from the group consisting of wherein the subscript q is 0, 1, or 2.

[0090] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is 4 But independently, C 1-7 Alkyl, Halo, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene-CN, Hydroxy, C 1-7Hydroxyalkyl, -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 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5 to 8-membered heterocycloalkyl having 1 to 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 3-7 Cycloalkyl, -O-(5- to 8-membered heterocycloalkyl), and -5- to 8-membered heterocycloalkyl are C 1-4 It is substituted with 0 to 2 groups independently selected from the group consisting of alkyl, halo, and hydroxy.

[0091] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises each R 4 If present, independently, C 1-4 Alkyl, Halo, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, CN, -C 1-4Alkylene-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 -O-(5- to 6-membered heterocycloalkyl) having 1 to 3 heteroatom ring vertices selected from the group consisting of alkyl, O, N, and S, -S(O)2-C 1-4 Alkyl, and -S(O)2-NR a R b wherein each cycloalkyl and heterocycloalkyl is selected from the group consisting of C 1-4 substituted with 0 to 2 groups selected from the group consisting of alkyl, halo, and hydroxy; or two R 4 A compound in which groups combine to form an oxo (=O).

[0092] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises each R 4 If present, independently, C 1-4 Alkyl, Halo, 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 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S; 5- to 8-membered heterocycloalkyl having 1 to 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 is selected from the group consisting of C 1-4 substituted with 0 to 2 groups selected from the group consisting of alkyl, halo, and hydroxy; or two R 4 A compound in which groups combine to form an oxo (=O).

[0093] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises each R 4 If present, independently, C 1-4 Alkyl, Halo, 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 -O-(5-6 membered heterocycloalkyl) having 1 to 3 heteroatom ring vertices selected from the group consisting of alkyl, O, N and S, -S(O)2-C 1-4 Alkyl, -S(O)2-NR a R b wherein each cycloalkyl and heterocycloalkyl is selected from the group consisting of C 1-4 It is a compound substituted with 0 to 2 groups selected from the group consisting of alkyl, halo, and hydroxy.

[0094] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises each R 4 If present, independently, C 1-4 Alkyl, Halo, 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 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S; 5- to 8-membered heterocycloalkyl having 1 to 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 is selected from the group consisting of C 1-4 It is a compound substituted with 0 to 2 groups selected from the group consisting of alkyl, halo, and hydroxy.

[0095] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises each R 4 If present, independently, methyl, ethyl, fluoro, chloro, difluoromethyl, trifluoromethyl, CN, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, [ka] is a compound selected from the group consisting of:

[0096] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof comprises 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, they are independently CN.

[0097] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has two R s on adjacent ring vertices. 4 groups join to form a 5-6 membered heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5-6 membered heterocycloalkyl is 1-4 substituted with 0 to 2 groups independently selected from the group consisting of alkyl and halo.

[0098] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has two R s on adjacent ring vertices. 4 The groups combine to form: [ka] A compound forming a heterocycloalkyl selected from The heterocycloalkyl is C 1-4In some embodiments, heterocycloalkyl is a compound substituted with 0 to 2 groups independently selected from the group consisting of alkyl and halo. 1-4 It is substituted with alkyl.

[0099] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) wherein A is: [ka] A compound having a formula selected from the group consisting of: Each of these is selected from 0 to 2 independently selected R 2 The compound is further substituted with a group.

[0100] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein A is of the formula: [ka] It is a compound having the formula:

[0101] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula: 2 But 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 3-7 Cycloalkyl, 5- to 8-membered heterocycloalkyl, —C(O)—(5- to 8-membered heterocycloalkyl), and —X 1 -(5-8 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 selected from the group consisting of halo, CN, C 1-4Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC- 1-4 It is a compound substituted with 0 to 3 groups independently selected from alkyl and OH.

[0102] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (Ia): [ka] It is a compound having the formula:

[0103] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (Ia1): [ka] It is a compound having the formula:

[0104] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (Ib): [ka] and The subscript m is 0 or 1; and n is 0, 1, or 2, and R 2 are compounds which may be the same or different.

[0105] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (Ib1): [ka] and The subscript m is 0 or 1; and n is 0, 1, or 2, and R 2 may be the same or different compounds.

[0106] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (Ic): [ka] and In the formula, R 6 But, Halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 A compound selected from the group consisting of alkyl, oxo, and OH.

[0107] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (Ic1): [ka] and In the formula, R 6 But, Halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 A compound selected from the group consisting of alkyl, oxo, and OH.

[0108] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (Id): [ka] It is a compound having the formula:

[0109] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (Id1): [ka] It is a compound having the formula:

[0110] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (Ie): [ka] and wherein the subscript n is 0, 1, or 2; and R 2 may be the same or different compounds.

[0111] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (Ie1): [ka] and wherein the subscript n is 0, 1, or 2; and R 2 may be the same or different compounds.

[0112] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (If): [ka] It is a compound having the formula:

[0113] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has the formula (If1): [ka] It is a compound having the formula:

[0114] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound wherein m is 0.

[0115] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a compound wherein n is 0.

[0116] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof has formula (II): [ka] 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 selected from 1 to 4 R 2 has been replaced with; R 1 is 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, and each phenyl and heteroaryl is selected from the group consisting of one R 1a and 0 to 3 R 3 is replaced by; R 1a is 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, where the N atom, if present, is optionally oxidized, and wherein each phenyl and heteroaryl is selected from the group consisting of 0-4 R 4 is replaced with; Each R 2 independently, 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-(5-8 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 selected from the group consisting of C 1-4 Alkyl and -OC 1-4 substituted with 0 to 3 groups independently selected from alkyl; Each R 3 Ha, Halo, C 1-7 alkyl, and -OC 1-7 independently selected from the group consisting of alkyl; Each R 4 independently, C 1-7 Alkyl, Halo, 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 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1 to 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 selected from the group consisting of C 1-4 substituted with 0 to 2 groups independently selected from the group consisting of alkyl, and hydroxy; Alternatively, two R on adjacent ring vertices 4The groups combine to form a 5-6 membered heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, where the 5-6 membered heterocycloalkyl has 0-2 C 1-4 substituted with alkyl; each X 1 But C 1-7 is alkylene; Each Y 1 But C 2-7 is alkylene; Each R a and R b However, independently, H, C 1-7 Alkyl, C 3-7 cycloalkyl, wherein said cycloalkyl is optionally selected from the group consisting of -OC 1-3 substituted with alkyl; or R a and R b are taken together with the nitrogen to which they are attached to form a 4-8 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 compounds where two groups on the same ring vertex combine to form oxo (=O).

[0117] 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 further embodiments, any one of the compounds described in the Examples is provided.

[0118] Processes for preparing compounds of the present disclosure In some aspects, the present disclosure relates to methods for preparing compounds that inhibit the activity of AXL.

[0119] In some embodiments, the present disclosure provides a method comprising: a) contacting a compound of Formula (A) with a compound of Formula (B) in the presence of a first palladium catalyst to produce a compound of Formula (C): [ka] and forming; b) contacting the compound of formula (C) with a deprotecting agent to produce a compound of formula (D): [ka] forming a In the formula, X, G 1 , R 1 , R 1a , and R 2 is as defined herein and 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 boronic ester.

[0120] In another embodiment, the present disclosure provides a method, comprising: a) contacting a compound of formula (E) with a compound of formula (B-2) in the presence of a first palladium catalyst to produce a compound of formula (C): [ka] and forming; b) contacting the compound of formula (C) with a deprotecting agent to produce a compound of formula (D): [ka] forming a In the formula, X, G 1 , R 1 , R 1a , and R 2 is as defined herein and Q is N, CH, or CR 2PG is a protecting group; and one of Y' and Z' is Cl, Br, I, or OTf, and the other is a boronic ester.

[0121] Any suitable boronic ester may be utilized. Exemplary boronic esters include, but are not limited to, pinacolborane (Bpin), catecholborane, and N-methyliminodiacetic acid boronate (MIDA boronate). In some embodiments, the boronic ester has the formula -B(OR x )2, wherein 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 pinacolborane (Bpin). In one embodiment, the boronic ester is Bpin.

[0122] The term "protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group. A protecting group may be removed to restore the functional group to its original state. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See also Protective Groups in Organic Chemistry, Peter G.M.Wuts and Theodora W. Greene, 4th Ed., 2006. Protecting groups are often utilized to mask the reactivity of particular functional moieties and aid in the efficiency of desired chemical reactions (e.g., creating and breaking chemical bonds in an orderly and deliberate manner). For example, a nitrogen protecting group refers to a protecting group useful for masking a nitrogen atom (e.g., to render an amine or nitrogen-containing heteroarenes unreactive 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., mesyl (Ms), tosyl (Ts), nosyl (Ns), triflyl (Tf), and phenylsulfone (-S(O))Ph) groups. In some embodiments, the protecting group is phenylsulfone (-S(O)Ph), tosyl (Ts), trityl (Tr), 2-(trimethylsilyl)ethoxymethyl (SEM), or tetrahydropyranyl ether (THP).

[0123] A "deprotecting agent" is a chemical reactant capable of effecting the removal of a protecting group. The deprotecting agent used depends, for example, on the identity of the protecting group to be removed and the reactivity of other functional groups present in the molecule. Typical deprotecting agents include reducing agents, oxidizing agents, acids, Lewis acids, bases, fluoride reagents, and enzymes. Generally, ether protecting groups can be removed under acidic conditions; alkyl protecting groups can be removed under reductive conditions or by treatment with Lewis acids; trityl protecting groups can be removed under acidic conditions or by treatment with Lewis acids; acyl protecting groups can be removed under reductive conditions, basic conditions, or by treatment with enzymes; and benzyl protecting groups can be removed under reductive conditions or by treatment with Lewis acids. Exemplary reducing agents include, but are not limited to, hydrogen, metal hydrides (e.g., diisobutylaluminum hydride (DIBAL) and lithium aluminum hydride (LAH)), or boron hydrides (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, and the like. Exemplary Lewis acids include, but are not limited to, ZnCl, ZnBr, TiCl, BF, trimethylsilyl iodide (TMSI), and the like. Exemplary oxidizing agents include, but are not limited to, dicyanodichloroquinone (DDQ), triethylenediamine (DABCO), poly(4-vinylpyridinium tribromide), hydrogen peroxide, and the like. Exemplary enzymes include, but are not limited to, ester hydrolases or lipases.

[0124] In some embodiments, the protecting group is -S(O)Ph or tosyl (Ts) and the deprotecting agent is a base (e.g., NaOH). In other embodiments, 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., NH or N,N-dimethylethylenediamine).

[0125] Any suitable palladium catalyst may be utilized 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(diphenylphosphine)ferrocene]palladium(II) dichloride (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)palladium(II) dichloride ((PPh3)2PdCl2), (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (SPhos Pd G3), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), and the like. In one embodiment, the palladium catalyst is PdCl2(dppf).

[0126] In some embodiments, the process further comprises contacting the compound of Formula (A) with a compound of Formula (B) in the presence of a first palladium catalyst and a base. Any suitable base may 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.

[0127] 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: [ka] wherein one of Y' and Z' is Cl, Br, I, or OTf, and the other is a boronic ester; and PG is a protecting group. The remaining variables have the same identity as above.

[0128] Generally, Y, Y', and Z' are selected such that Y' and Z' are better coupling partners than Y' and Y. For example, if Y' is a boronate ester and each of Y and Z' is Cl, Br, I, or OTf, then Z' is preferably more reactive than Y. In some embodiments, Y' is a boronate ester; Z' is I or OTf; and Y is Cl or Br. In one embodiment, Y' is a boronate ester; Z' is I; and Y is Br.

[0129] In other embodiments, a 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: [ka] wherein one of Y and Z is Cl, Br, I, or OTf, and the other is a boronic ester; and PG is a protecting group. The remaining variables have the same identity as above.

[0130] Generally, Y, Z, and Z' are selected such that Y and Z are better coupling partners than Z and Z'. For example, if Z is a boronate ester and each of Y and Z' is Cl, Br, I, or OTf, then Y is preferably more reactive than Z'. In some embodiments, Z is a boronic ester, Y is I or OTf, and Z' is Cl or Br. In one embodiment, Z is a boronic ester; Y is I; and Z' is Br.

[0131] In one or more embodiments, the boronic ester has the formula -B(OR x )2, wherein 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 pinacolborane (Bpin). In one embodiment, the boronic ester is Bpin.

[0132] Any suitable palladium catalyst may be utilized 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(diphenylphosphine)ferrocene]palladium(II) dichloride (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)palladium(II) dichloride ((PPh3)2PdCl2), (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (SPhos Pd G3), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), and the like. In one embodiment, the palladium catalyst is PdCl2(dppf).

[0133] In one or more embodiments, G 1 is N. In certain such embodiments, a compound of formula (B) may be formed by contacting a compound of formula (B-3) with hydrazine or a hydrate thereof: [ka] In the formula, Z a is halo; and m is 0 or 1. In some embodiments, Z a is F. The remaining variables have the identities defined above.

[0134] In one or more embodiments, the compound of formula (B-3) is: a) contacting a compound of formula (B-4) with a lithiation reagent to form a compound of formula (B-5): [ka] b) contacting a compound of formula (B-5) with a compound of formula (B-6): [ka] Prepared by; In the formula, R o is H or C1-C3 alkyl. The remaining variables have the same identity as above.

[0135] Any suitable lithiation reagent may be used. Exemplary lithiation reagents include, but are not limited to, lithium diisopropylamide (LDA), 2,2,6,6-tetramethylpiperidine lithium (LTMP), lithium dicyclohexylamide, lithium dimethylamide, lithium diethylamide, lithium amide, lithium bis(trimethylsilyl)amide, and the like. In some embodiments, the lithiation reagent is LDA.

[0136] In a further embodiment, the compound of formula (B-3) is: It is prepared by contacting a compound of formula (B-7) with a compound of formula (B-8): [ka] In the formula, Q 1 is halo, —CN, —C(O)OH, —C(O)O—(C-C alkyl), —C(O)Cl, or —C(O)N(C-C alkyl)-O—(C-C alkyl); Q 2 -Li, -Mg-halo, or -B(OR x )2; and 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 pinacolborane (Bpin). The remaining variables have the same identity as above.

[0137] 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 is -Li, -MgCl, -MgBr, -B(OH)2, or -Bpin.

[0138] In a further embodiment, 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 is -CN and Q 2 is -MgCl or -MgBr, and the process further includes the addition of water.

[0139] In a further embodiment, Q 1 is -C(O)Cl, and Q 2 is -B(OR x )2 (e.g., B(OH)2, or -Bpin), and the process further comprises the addition of a palladium catalyst such as those described elsewhere herein.

[0140] In yet a further embodiment, Q 1 is halo (e.g., -Cl, -Br, or -I), and Q 2 is —Li, —MgCl, or —MgBr, and the process further includes the addition of CO and includes a palladium catalyst, such as a catalyst described anywhere else herein.

[0141] For the most efficient preparation of any particular compound of the present disclosure, the timing and order of linking fragments, as well as the modification of functional groups present on any of the fragments, can vary and depend on the functional groups present. The various methods described above 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 the appropriate deuterated intermediates.

[0142] Therapeutic and prophylactic use The present disclosure provides methods for the use of compounds described herein in the preparation of a medicament for the inhibition of 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 particular target, e.g., AXL. This reduction is preferably at least 50%, and may 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 compounds described herein in the preparation of a medicament for the treatment or prevention of diseases, disorders, and / or conditions that would benefit from the inhibition of AXL. In another example, the present disclosure encompasses the use of compounds described herein in the preparation of a medicament for the treatment of cancer. In another embodiment, the present disclosure encompasses the use of compounds described herein in the preparation of a medicament for the treatment of a fibrotic disease. In another embodiment, the present disclosure encompasses the use of compounds described herein in the preparation of a medicament for the treatment of a viral infection. In some embodiments of the aforementioned methods, the compounds described herein are used in combination with at least one additional therapy, examples of which are described elsewhere herein.

[0143] AXL is expressed in cancer, select immune cells, and stromal cells and has been associated with the development of resistance / relapse to chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Activation of AXL by its ligand, growth arrest-specific protein 6 (GAS6), or by ligand-independent dimerization promotes AXL phosphorylation, initiating a signaling cascade that promotes cancer cell proliferation, survival, and an immunosuppressive microenvironment. Therefore, inhibition of AXL is a promising therapeutic strategy for overcoming resistance to chemotherapy, radiation therapy, targeted therapy, and / or immunotherapy.

[0144] As demonstrated herein, compounds according to the present disclosure potently inhibit AXL. Diseases, disorders, and / or conditions that would benefit from AXL inhibition may include those characterized by overexpression of AXL.

[0145] Therefore, in some embodiments, the compounds described herein are administered to a subject in need of AXL inhibition in an amount effective to inhibit AXL. AXL inhibition can be assessed by measuring soluble AXL (sAXL) levels in plasma, or AXL expression, or phospho-AXL (pAXL) levels in peripheral blood samples or tissue samples (e.g., tumor samples) obtained from the subject. Activity can be determined, for example, by comparing with a previous sample obtained from the subject (i.e., before administration of the AXL inhibitor) or by comparing with a reference value from a control group (e.g., standard treatment, placebo, etc.).

[0146] Alternatively, or in addition, 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. Activity can be determined, for example, by comparison with a prior sample obtained from the subject (i.e., before administration of a compound according to the present disclosure) or by comparison with a reference value from 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.

[0147] 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.

[0148] 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 more detail below.

[0149] 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 more detail below.

[0150] 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 more detail below.

[0151] 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.

[0152] In certain embodiments of the present disclosure, the compounds are used to increase or enhance the immune response to tumors or viral infections. In certain embodiments, 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. Therapeutic compositions are also provided that include at least one antigenic agent or vaccine component, including, but not limited to, viruses, bacteria, and fungi, or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines, in combination with at least one compound of the present disclosure.

[0153] Oncology and Oncology-Related Disorders. In one or more embodiments, the compounds described herein are useful for the treatment and / or prevention of 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 becoming metastatic. Alternatively or additionally, the cancer may recur or become unresponsive to treatment, such as standard treatments known to those skilled in the art. Examples of cancer types contemplated by the present disclosure include cancers of the genitourinary tract (e.g., bladder, kidney, renal cell, penis, prostate, testis, ovary, cervix, uterus, von Hippel-Lindau disease, etc.), breast, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestine, colon, or rectum), bone, bone marrow, skin (e.g., melanoma, squamous cell carcinoma, or basal cell carcinoma), head and neck, liver, gallbladder, bile duct, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., glioma), ganglia, central nervous system (CNS), peripheral nervous system (PNS), hematopoietic system (i.e., hematologic malignancies), and immune system (e.g., spleen or thymus). In some embodiments, a patient with cancer is determined to have an STK11 mutation.

[0154] In some embodiments, the compounds according to the present disclosure are useful for the treatment and / or prevention of hematological malignancies. Examples of cancer types that affect the hematopoietic system include leukemia, lymphoma, and myeloma, including acute myeloid leukemia, adult T-cell leukemia, T-cell large granular lymphocyte leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute monocytic leukemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, and multiple myeloma. In some embodiments, the hematological malignancy is acute myeloid leukemia.

[0155] In another embodiment, the compounds according to the present disclosure are useful for the treatment and / or prevention of solid tumors, which may 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, biliary tract 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, including astrocytoma, oligodendroglioma, and glioblastoma).

[0156] In some embodiments, compounds according to the present disclosure are useful for treating 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.

[0157] In some embodiments, the compounds according to the present disclosure are useful for treating kidney cancer. In further embodiments, the kidney cancer is renal cell carcinoma. In yet further embodiments, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC).

[0158] In some embodiments, the compounds according to the present disclosure are useful for treating lung cancer. In further embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In still further embodiments, the NSCLC is lung squamous cell carcinoma or lung adenocarcinoma. In some embodiments, the NSCLC is EGFR mutant NSCLC. In some embodiments, the NSCLC is STK11 mutant NSCLC. In some embodiments, the NSCLC has relapsed despite treatment, including but not limited to anti-PD-L1 or other immunotherapy, targeted therapy, or chemotherapy. In some embodiments, the lung cancer is squamous cell carcinoma (SCC).

[0159] In some embodiments, the compounds according to the present disclosure are useful for treating head and neck cancer. In further embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the HNSCC is recurrent or resistant to radiation, chemotherapy, or immunotherapy.

[0160] In some embodiments, the compounds according to the present disclosure are useful for treating leukemia or myelodysplastic syndrome (MDS). In further embodiments, the leukemia is acute myeloid leukemia (AML). In still further embodiments, the AML or MDS is relapsed or refractory AML or MDS. In some embodiments, the AML is FLT-3 mutated AML.

[0161] In some embodiments, compounds according to the present disclosure are useful for treating breast cancer. In further embodiments, the breast cancer is hormone receptor positive (e.g., ERa positive breast cancer, PR positive breast cancer, ERa positive and PR positive breast cancer), HER2 positive breast cancer, HER2 overexpressing breast cancer, or any combination thereof. In yet further embodiments, the breast cancer is triple-negative breast cancer (TNBC).

[0162] In some embodiments, compounds according to the present disclosure are useful for treating pancreatic cancer. In further embodiments, the pancreatic cancer is a pancreatic neuroendocrine tumor (PNET) or a pancreatic adenocarcinoma (i.e., pancreatic ductal adenocarcinoma (PDAC)).

[0163] In some embodiments, compounds according to the present disclosure are useful for treating ovarian cancer. In further embodiments, the ovarian cancer is metastatic. In further embodiments, the ovarian cancer is epithelial ovarian cancer (EDC). 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 treatment, including but not limited to, platinum-based or taxane-based therapy (e.g., platinum-resistant ovarian cancer (PROC)).

[0164] In one or more embodiments, the cancer is an oncogene-dependent cancer. An oncogene-dependent cancer is one that is dependent on a dominant oncogene for proliferation and survival, such as, for example, ALK, ABL, AURORA, AKT, PDGFR, KIT, EGFR, VEGFR, FGFR3, FLT-3, MYC, RET, BRAF, PI3K, NFκ-B, JAK, STAT, BCL-2, MCL-1, KRAS, HRAS, MEK, ERK, HER-2, HER-3, or MET. In one embodiment, the oncogene is KRAS.

[0165] In all described embodiments, the methods of the present disclosure can be performed in an adjuvant setting or a neoadjuvant setting. The methods described herein may be indicated as first-line, second-line, third-line, or higher-line treatments.

[0166] In some embodiments, the methods of the present disclosure may be indicated as first-line therapy in subjects identified as having an STK11 mutant cancer. In another embodiment, the methods of the present disclosure may be indicated as second-line therapy in subjects identified as having a cancer that is resistant to treatment (e.g., resistant to chemotherapy, radiation, etc.). In one embodiment, standard therapy is considered ineffective, intolerable, or inappropriate for treating the patient's cancer.

[0167] The present disclosure also provides methods of treating or preventing other cancer-related diseases, disorders, or conditions. The use of the term cancer-related diseases, disorders, and conditions is meant to refer broadly to conditions directly or indirectly related to cancer and non-cancerous proliferative diseases, including, for example, pre-cancerous conditions such as angiogenesis, dysplasia, and non-cancerous proliferative diseases, disorders, or conditions such as benign proliferative breast disease and papillomas. For clarity, the term cancer-related diseases, disorders, and conditions does not include cancer itself.

[0168] Generally, the disclosed methods for treating or preventing cancer, or a cancer-related disease, disorder, or condition, 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, disorder, or condition, using a compound disclosed herein and at least one additional therapy, examples of which are described elsewhere herein.

[0169] Viral Infection. AXL has been shown to promote infection by a wide range of enveloped viruses, including coronaviruses, poxviruses, retroviruses, flaviviruses, arenaviruses, filoviruses, and alphaviruses. In particular, enveloped viruses display phosphatidylserine. Crosslinking of the AXL ligand, GAS6, envelopes phosphatidylserine to the cell surface receptor AXL, thereby facilitating the entry of the enveloped virus into cells. Specifically for SARS-CoV-2, AXL is a co-receptor for ACE2, to which the viral spike protein binds, subsequently enabling entry into host cells. Furthermore, AXL signaling suppresses the virus-induced type I interferon (IFN) response, resulting in increased viral replication in infected cells and reduced antiviral defenses in neighboring cells. Therefore, inhibiting AXL is a useful strategy for treating viral infections.

[0170] In some embodiments, compounds according to the present disclosure are useful for treating viral infections. In some embodiments, the viral infection is caused by an enveloped virus. Exemplary viral infections include infections caused by coronaviruses, poxviruses, retroviruses, flaviviruses, arenaviruses, filoviruses, or alphaviruses. In some embodiments, the viral infection is caused by a coronavirus (e.g., MERS-CoV, SARS-CoV, SARS-CoV-2, 229E, NL63, OC43, or HKU1). In some embodiments, the viral infection is caused by a poxvirus (e.g., orthopox, parapox, molluscipox, yatapox, capripox, suipox, leporipox, monkeypox, or avipox). In some embodiments, the viral infection is caused by a retrovirus (e.g., 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, Diano, Sutoria, or Tamuno).In some embodiments, the viral infection is caused by an alphavirus (e.g., Aula, Bama Forest, Bebaru, Kaigua, Cabasu, Chikungunya, Eastern Equine Encephalitis, Eilat, Everglades, Fort Morgan, Getah, Highlands J, Madriaga, Mayaro, Middelburg, Mosso das Pedras, Mucambo, Ndumu, O'nyong-nyong, Pixuna, Rio Negro, Ross River, Salmon Pancreas Disease, Semliki Forest, Sindbis, Southern Elephant Seal, Tonato, Trocara, Una, Venezuelan Equine Encephalitis, Western Equine Encephalitis, or Wataroa).

[0171] In some embodiments, compounds according to the present disclosure are useful for treating an infection caused by SARS-CoV-2, Ebola virus, monkeypox, or Zika virus. In some embodiments, compounds according to the present disclosure are useful for treating an infection caused by SARS-CoV-2, Ebola virus, or Zika virus. In one embodiment, the infection is caused by SARS-CoV-2.

[0172] Fibrosis. AXL is expressed in fibroblasts and is involved in myofibroblast activation. Activated myofibroblasts are key effector cells involved in fibrosis in multiple organ systems. Therefore, inhibition of AXL is a promising approach for antifibrotic therapy.

[0173] In some embodiments, compounds according to the present disclosure are useful for treating fibrosis. In some embodiments, the 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, the fibrosis is associated with cancer and tumor growth. In some embodiments, the fibrosis is tumor-associated tissue fibrosis. In some embodiments, the tumor-associated tissue fibrosis is associated with pancreatic cancer.

[0174] In one embodiment, the compounds are useful for treating renal fibrosis. In some embodiments, the renal fibrosis is associated with chronic kidney disease. In a further embodiment, the compounds are useful for treating renal fibrosis following unilateral urethral obstruction (UUO). In one embodiment, the renal fibrosis is associated with IgA nephropathy (i.e., Berger's disease).

[0175] In some embodiments, the compounds are useful for treating intestinal fibrosis, hi one embodiment, the intestinal fibrosis is associated with Crohn's disease.

[0176] In one embodiment, the compound is useful for treating liver fibrosis. In some embodiments, the liver fibrosis is associated with chronic liver disease. In one embodiment, the liver fibrosis is associated with non-alcoholic fatty liver disease (NAFLD).

[0177] In some embodiments, the compounds are useful for treating liver fibrosis. In some embodiments, the liver fibrosis is associated with chronic lung disease. In further embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In another embodiment, the pulmonary fibrosis is associated with asthma.

[0178] Pain. AXL is upregulated in injured dorsal root ganglia and is associated with neuropathic pain. Therefore, inhibition of AXL is a promising strategy for the treatment of pain.

[0179] In one embodiment, compounds according to the present disclosure are useful for treating pain, which in some embodiments is neuropathic pain.

[0180] Selection of Cancer Patients. In some cases, methods according to the present disclosure may be provided for selected patients, for example, subjects identified as having elevated AXL expression, or activation of the AXL pathway, or high microsatellite instability or high tumor mutation burden in relevant tissues or samples. 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 an AXL gene signature. In some embodiments, patients are selected by further assessing GAS6 expression in relevant tissues or samples. In some embodiments, the present disclosure provides methods of treating cancer in patients with elevated AXL expression, phospho-AXL levels, or an AXL gene signature with a compound described herein. In one embodiment, the present disclosure provides a method of treating cancer in patients with elevated cell surface AXL expression using a compound described herein. In another embodiment, the present disclosure provides a method of treating cancer in a patient with elevated sAXL expression with a compound described herein. In another embodiment, the present disclosure provides a method of treating cancer in a patient with elevated phospho-AXL levels with a compound described herein. In another embodiment, the present disclosure provides a method of treating cancer in a patient with an elevated AXL gene signature with a compound described herein. In yet another embodiment, the present disclosure provides a method of treating cancer in a patient with an elevated ratio of sAXL expression to GAS6 expression with a compound described herein. In some embodiments, the present disclosure provides a method of administering a therapeutically effective amount of an AXL inhibitor to an individual for the treatment of cancer based on determining the relative amount of AXL expression. In another embodiment, the present disclosure provides a method of administering a therapeutically effective amount of an AXL inhibitor to an individual for the treatment of cancer based on determining the relative amount of cell surface AXL expression.In another embodiment, the present disclosure provides a method for administering an effective amount of an AXL inhibitor to an individual for the treatment of cancer based on determining the relative amount of sAXL expression or by composite AXL (cAXL) levels. In another embodiment, the present disclosure provides a method for administering an effective amount of an AXL inhibitor to an individual for the treatment of cancer based on determining the relative amount of phospho-AXL levels. In another embodiment, the present disclosure provides a method for administering an effective amount of an AXL inhibitor to an individual for the treatment of cancer based on determining the relative intensity of an AXL gene signature. In yet another embodiment, the present disclosure provides a method for administering an effective amount of an AXL inhibitor to an individual for the treatment of cancer based on determining the relative ratio of sAXL expression to GAS6 expression. In another embodiment, the present disclosure provides a method for administering an effective amount of an AXL inhibitor to a subject for the treatment of cancer based on determining the presence of a mutation or deletion in STK11. In certain such embodiments, such subjects can be identified by evaluating a suitable sample (e.g., blood or plasma) in an appropriate assay (e.g., Foundation I liquid CDx) by sequencing, such as next-generation sequencing, or by IHC for detecting LKB1 protein in the sample. In certain cases, the subject is identified as having an oncogene-driven cancer with mutation or overexpression in at least one gene associated with cancer, such as ALK, ABL, AURORA, AKT, PDGFR, KIT, EGFR, VEGFR, FGFR3, FLT-3, MYC, RET, BRAF, PI3K, NFκ-B, JAK, STAT, BCL-2, MCL-1, KRAS, HRAS, MEK, ERK, HER-2, HER-3, or MET. In some embodiments, the subject is identified as being resistant to a previous course of treatment (e.g., chemotherapy, radiation, etc.).

[0181] Route of administration In some embodiments, pharmaceutical compositions containing compounds according to the present disclosure may be in a form suitable for oral administration. Oral administration involves swallowing the formulation, thereby allowing the compound to be absorbed into the bloodstream from the gastrointestinal tract. Alternatively, oral administration may involve buccal, lingual, or sublingual administration, allowing the compound to be absorbed into the bloodstream through the oral mucosa.

[0182] In another embodiment, the pharmaceutical composition containing the compound according to the present disclosure may be in a form suitable for parenteral administration.Parenteral administration forms include, but are 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 a suitable aqueous or non-aqueous carrier.Depot injections, generally administered subcutaneously or intramuscularly, can also be used to release the compounds disclosed herein over a specified period of time.

[0183] Other routes of administration are also contemplated by the present disclosure, including, but not limited to, nasal, vaginal, ocular, rectal, topical (eg, transdermal), and inhalation.

[0184] Certain embodiments of the present disclosure contemplate oral or parenteral administration.

[0185] Combination therapy 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 may be a therapeutic agent or another treatment modality. In embodiments including one or more additional therapeutic agents, each agent may target a different but complementary mechanism of action. When the compounds of the present disclosure are used in combination with one or more additional therapies, they may have a synergistic therapeutic or preventive effect on the underlying disease, disorder, or condition. Additionally or alternatively, combination therapy may allow for a reduction in the dose of one or more therapies, thereby improving, alleviating, or eliminating adverse effects associated with one or more agents.

[0186] In embodiments including one or more additional treatment modalities, the AXL inhibitor may be administered before, after, or during treatment with the additional treatment modality. In embodiments including one or more additional therapeutic agents, the therapeutic agents used in such combination therapy may be formulated as a single composition or as separate compositions. When administered separately, each therapeutic agent in the combination may be given simultaneously, at or near the same time, or at different times. Furthermore, therapeutic agents can be "administered in combination" even in different dosage forms (e.g., oral capsules and intravenous), given at different dosing intervals, one therapeutic agent given on a fixed dosing regimen while another is titrated, tapered, or discontinued, or each therapeutic agent in the combination is independently titrated, tapered, increased or reduced in dosage, or discontinued and / or resumed during the course of a patient's treatment. When the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0187] Cancer therapy The present disclosure contemplates the use of the AXL inhibitors described herein in combination with one or more additional therapeutic agents useful in the treatment of cancer.

[0188] In some embodiments, one or more of the additional therapies is an additional treatment modality. Exemplary treatment modalities include, but are not limited to, surgical resection of the tumor, bone marrow transplant, radiation therapy, and photodynamic therapy.

[0189] In some embodiments, the one or more additional therapies are therapeutic agents. Exemplary therapeutic agents include chemotherapeutic agents, radiopharmaceuticals, hormone therapy, epigenetic modulators, ATP-adenosine axis targeting agents, targeted therapies, signal transduction inhibitors, RAS signaling inhibitors, PI3K inhibitors, arginase inhibitors, HIF inhibitors, PAK4 inhibitors, immunotherapeutic agents, cell therapy, gene therapy, immune checkpoint inhibitors, and agonists of stimulatory or costimulatory immune checkpoints. In one or more embodiments, one or more of the additional therapies is 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, radiation therapy, and chemotherapeutic agents.

[0190] In some embodiments, one or more of the additional therapeutic agents is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, mesuredopa, and uredopa; ethyleneimines and methylameramines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine. elamime); nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine antibiotics, such as aclacinomycins, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivivir; Bomycin, pomalidomide, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, 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 analogues, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens, such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal agents, such as aminoglutethimide, mitotane, trilostane; folic acid replenishers, such as folinic acid; aceglatone; aldophosphamide glycosides; amino Nolevulinic acid; Amsacrine; Bestravcil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquone; Elformithine; Elliptinium acetate; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triazoline Zicone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, such as paclitaxel, nab-paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, such as cisplatin, carboplatin, and oxaliplatin; vinblastine; ethanone riboside (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; proteasome inhibitors, e.g., bortezomib, carfilzomib, and ixazomib; topoisomerase inhibitors, e.g., irinotecan, topotecan, etoposide, mitoxantrone, teniposide; difluoromethylornithine (DMFO); retinoic acid; esperamycin; capecitabine;Examples of the combination therapy include anthracyclines and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy includes a chemotherapy regimen including one or more chemotherapeutic agents. In one embodiment, the combination therapy includes a chemotherapy regimen including one or more of FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), taxoids (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), low-dose cytarabine (LDAC), and / or gemcitabine. In one embodiment, the combination therapy comprises a chemotherapy regimen including one or more of FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), taxoids (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), low-dose cytarabine (LDAC), gemcitabine, and / or platinum-based therapies (e.g., cisplatin, carboplatin, and oxaliplatin);

[0191] In some embodiments, the 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 inside the subject's body. The radioactive source may be in solid or liquid form. Non-limiting examples of radiopharmaceuticals include sodium iodide I-131, radium-223 dichloride, lobenguane iodine-131, radioactive iodide vesicles (e.g., saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles), various forms of brachytherapy, and various forms of targeted radionuclides. Targeted radionuclides include radionuclides associated (e.g., by covalent or ionic interactions) with a molecule (a "targeting agent") that specifically binds to a target on a cell, typically a cancer cell or immune cell. The targeting agent may be a small molecule, a sugar (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 sugar (including oligosaccharides and polysaccharides), lipid, protein, or peptide, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neo-antigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations 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 enriched but not specific to cancer cells), a tumor-specific antigen (i.e., an antigen with minimal or no expression in normal tissues), or a neo-antigen (i.e., an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). Non-limiting examples of targeted radionuclides include radionuclides conjugated to: somatostatin or a peptide analogue thereof (e.g., 177Lu-Dotatate, etc.); prostate-specific membrane antigen or a peptide analogue thereof (e.g., 177Lu-PSMA-617, 225Ac-PSMA-617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); a receptor's cognate ligand, a peptide derived from that ligand, or a variant thereof (e.g., 188Re-labeled VEGF 125-136or variants thereof with higher affinity for the VEGF receptor; antibodies targeting tumor antigens (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-omburtamab, etc.).

[0192] In some embodiments, one or more additional therapeutic agents are hormone therapy.Hormonal therapy acts to regulate or inhibit hormone action on tumor.Examples of hormone therapy include, but are not limited to, selective estrogen receptor degraders, such as fulvestrant, giredestrant, SAR439859, RG6171, AZD9833, lindestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549; selective estrogen receptor modulators, such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, toremifene; aromatase inhibitors, such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, toremifene; Examples of aromatase inhibitors include anastrozole, exemestane, letrozole, and other 4(5)-imidazoles; gonadotropin-releasing hormone agonists, such as nafarelin, triptorelin, and goserelin; gonadotropin-releasing hormone antagonists, such as degarelix; antiandrogens, such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide, and leuprolide; and 5α-reductase inhibitors, such as finasteride and dutasteride. In certain embodiments, the combination therapy includes the administration of a hormone or related hormone agent. In one embodiment, the combination therapy includes the administration of enzalutamide.

[0193] In some embodiments, the one or more additional therapeutic agents are epigenetic modulators. Epigenetic modulators alter the epigenetic mechanisms that control gene expression and may be, for example, inhibitors or activators of epigenetic enzymes. Non-limiting examples of epigenetic modulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HDAC) inhibitors. In one or more embodiments, an AXL inhibitor according to the present disclosure is combined with a DNA methyltransferase (DNMT) inhibitor or hypomethylating agent. Exemplary DNMT inhibitors include decitabine, zebularine, and azacitadine. In one or more embodiments, a combination of a compound according to the present disclosure with a histone deacetylase (HDAC) inhibitor is also contemplated. Exemplary HDAC inhibitors include vorinostat, divinostat, abexinostat, panobinostat, belinostat, and trichostatin A.

[0194] In some embodiments, the one or more additional therapeutic agents are ATP-adenosine axis targeting agents. ATP-adenosine axis targeting agents alter signal transduction mediated by adenine nucleosides and nucleotides (e.g., adenosine, AMP, ADP, ATP), for example, by regulating adenosine levels or targeting adenosine receptors. Adenosine and ATP act on different classes of receptors and often have opposing effects on inflammation, cell proliferation, and cell death. For example, ATP and other adenine nucleotides exert antitumor effects through activation of the PS2Y1 receptor subtype, while the accumulation of adenosine in the tumor microenvironment has been shown to inhibit the antitumor 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 ectonucleotidase, which is involved in the conversion of ATP to adenosine, or an adenosine receptor antagonist. 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 quemlicustat (AB680). Examples of anti-CD39 and anti-CD73 antibodies include ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, oleculab (MEDI9447), NZV930, IPH5301, GS-1423, uriledolimab (TJD5, TJ004309), AB598, and BMS-986179. In one embodiment, the present disclosure contemplates the combination of an AXL inhibitor described herein with a CD73 inhibitor, such as those described in WO2017 / 120508, WO2018 / 067424, WO2018 / 094148, and WO2020 / 046813. In a further embodiment, the CD73 inhibitor is quemlicustat.Adenosine binds to four different G protein-coupled receptors: A1R, A2R, A3R, A4R, A5R, A6R, A7R, A8R, A9R, A10R, A11R, A12R, A13R, A14R, A15R, A16R, A17R, A18R, A19R, A20R, A21R, A22R, A23R, A24R 2A R.A. 2B A2R antagonists can bind to and activate A2R, A3R, and A3R. A2R antagonists include etormadenant, 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 provides a combination of an AXL inhibitor described herein and an A2R antagonist. A R antagonist, A2 B R antagonist, or A2 A R and A2 B In some embodiments, the present disclosure contemplates a combination of a compound described herein with an adenosine receptor antagonist described in WO2018 / 136700, WO2018 / 204661, WO2018 / 213377, or WO2020 / 023846. In one embodiment, the adenosine receptor antagonist is etremadenant.

[0195] In some embodiments, the one or more additional therapeutic agents are targeted therapies. In one aspect, the targeted therapy may include a chemotherapeutic agent, a radionuclide, a hormone therapy, or another small molecule drug conjugated to the targeting agent. The targeting agent may be a small molecule, a sugar (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 sugar (including oligosaccharides and polysaccharides), a lipid, a protein, or a peptide, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neoantigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neoantigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). Specific examples include, but are not limited to, patritumab deruxtecan and telisotuzumab vedotin. In other embodiments, targeted therapies may inhibit or interfere with specific proteins that aid in tumor growth and / or spread. Non-limiting examples of such targeted therapies include signal transduction inhibitors, RAS signaling inhibitors, inhibitors of oncogenic transcription factors, activators of oncogenic transcription factor repressors, angiogenesis inhibitors, immunotherapeutic agents, kinase inhibitors, ATP-adenosine axis targeting agents, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, HIF2α 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 more detail below.

[0196] 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 signal transduction 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 tyrosine kinase inhibitors), including small molecule inhibitors (e.g., CLN-081, gefitinib, erlotinib, afatinib, icotinib, and osimertinib). (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 (VEGFR) inhibitors, such as 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 the AKT family kinase or AKT pathway (e.g., rapamycin); (vi) inhibitors of the serine / threonine protein kinase B-Raf (BRAF), such as vemurafenib, dabrafenib, and encorafenib; (vii) inhibitors of the BRAF family of serine / threonine protein kinase, such as selpercatinib and prazolam; (viii) rearrangement in transfection (RET) inhibitors, including rusetinib; (viii) tyrosine protein kinase Met (c-MET) inhibitors (e.g., tepotinib, tivantinib, cabozantinib, and crizotinib); (ix) anaplastic lymphoma kinase (ALK) inhibitors (e.g., ensartinib, ceritinib, lorlatinib, crizotinib, and brigatinib); (x) inhibitors of the RAS signaling pathway (e.g., inhibitors of KRAS, HRAS, RAF, MEK, ERK) as described elsewhere herein; (xi) FLT-3 inhibitors (e.g., gilteritinib); (xii) inhibitors of Trop-2, such as 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) NF-κB inhibitors; (xv) cell cycle kinase inhibitors (e.g., flavopiridol); (xvi) phosphatidylinositol kinase (PI3K) inhibitors; (xix) protein kinase B (AKT) inhibitors (e.g., capivasertib, miransertib), (xx) platelet-derived growth factor receptor (PDGFR) inhibitors (e.g., imatinib, sunitinib, regorafenib, avapritinib, lenvatinib, nintedanib, famitinib, ponatinib, axitinib, ripretinib, 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.

[0197] In some embodiments, the one or more additional therapeutic agents are agents that prevent, inhibit, or delay autophagy. Autophagy is increased in various tumor conditions and drives downregulation of major histocompatibility complex class I molecules (MHC-I) and associated antigen presentation machinery. Downregulation of antigen presentation can reduce the susceptibility of cancer cells to T cell-mediated killing. One strategy to prevent, inhibit, or delay autophagy is to target Unc-51-like autophagy-activating kinase 1 / 2 (ULK1 and / or ULK2). Exemplary inhibitors of ULK1 and / or ULK2 include DC-3116, ERAS-5, and ENV-201. In some embodiments, the one or more additional therapeutic agents are inhibitors of ULK1, ULK2, or both ULK1 and ULK2.

[0198] In some embodiments, the one or more additional therapeutic agents are RAS signaling inhibitors. Oncogenic mutations in RAS family genes, such as HRAS, KRAS, and NRAS, are associated with various cancers. For example, among KRAS family genes, G12C, G12D, G12V, G12A, G13D, Q61H, G13C, and G12S mutations have been observed in multiple tumor types. Direct and indirect inhibitory strategies have been investigated to inhibit mutant RAS signaling. 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, and everolimus. Direct inhibitors of RAS mutants are also being investigated, generally targeting the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors under development include sotorasib (AMG510), adagrasib (MRTX849), mRNA-5671, and ARS1620. In some embodiments, the one or more RAS signaling inhibitors are selected from the group consisting of a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an SOS1 inhibitor, an mTORC1 inhibitor, an SHP2 inhibitor, and an AKT inhibitor. In other embodiments, the one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0199] In some embodiments, one or more of the additional therapeutic agents are inhibitors of phosphatidylinositol 3-kinase (PI3K), particularly inhibitors of the PI3Kγ and / or PI3Kδ isoforms. PI3Kγ inhibitors can stimulate anti-cancer immune responses through modulation of myeloid cells, for example by inhibiting suppressive myeloid cells, by attenuating immunosuppressive tumor-infiltrating macrophages, or by stimulating macrophages and dendritic cells to produce cytokines that contribute to effective T cells, thereby reducing the development and spread of cancer. Examples of PI3Kγ inhibitors include copanlisib, duvelisib, AT-104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458, and pictilisib. In some embodiments, an AXL inhibitor according to the present disclosure is combined with one or more PI3Kγ inhibitors described in WO2020 / 0247496A1. Furthermore, PI3Kδ is also expressed on malignant B cells and is involved in promoting B cell activation, differentiation, proliferation, and survival. Exemplary PI3Kδ inhibitors include duvelisib, leniolisib, idelalisib, parasaclisib, copanlisib, ambralisib, zandelisib, eganelisib, limpellisib, pilalalisib, and tenalisib.

[0200] In some embodiments, the one or more additional therapeutic agents are arginase inhibitors. Arginase has been shown to cause or contribute to inflammation-induced immune dysfunction, tumor immune evasion, immunosuppression and immunopathology of infectious diseases. Exemplary arginase compounds include CB-1158 and OAT-1746. In some embodiments, an AXL inhibitor according to the present disclosure is combined with one or more arginase inhibitors described in WO / 2019 / 173188 and WO2020 / 102646.

[0201] In some embodiments, the one or more additional therapeutic agents are inhibitors of oncogenic transcription factors or activators of oncogenic transcription factor repressors. Suitable agents may act at the expression level (e.g., RNAi, siRNA, etc.), through 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, etc.

[0202] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of hypoxia-inducible factor (HIF) transcription factors, particularly HIF-2α. Exemplary HIF-2α inhibitors include velzutifan, ARO-HIF2, PT-2385, and inhibitors described in WO2021113436 and WO2021188769. In some embodiments, a compound according to the present disclosure is combined with one or more HIF-2α inhibitors described in WO2021188769. In one embodiment, the HIF-2α inhibitor is AB521.

[0203] In some embodiments, the one or more additional therapeutic agents are inhibitors of p21-activated kinase 4 (PAK4). Overexpression of PAK4 has been demonstrated across a variety of cancer types, including cancers that are particularly resistant to PD-1 therapy. While no PAK4 inhibitors have yet been approved, they are in development, and some, such as ATG-019 and KPT-9274, demonstrate dual PAK4 / NAMPT inhibitor activity. In some embodiments, a compound according to the present disclosure is combined with a PAK4-selective inhibitor. In some embodiments, a compound according to the present disclosure is combined with a PAK4 / NAMPT dual inhibitor, e.g., ATG-019 or KPT-9274.

[0204] In some embodiments, one or more of the additional therapeutic agents is (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.); or (v) an isocitrate dehydrogenase (IDH) inhibitor, e.g., an IDH-1 inhibitor or an IDH-2 inhibitor (e.g., ivosidenib, enasidenib, etc.).

[0205] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent. Immunotherapeutic agents treat diseases by stimulating or suppressing the immune system. Immunotherapeutic agents useful for treating cancer typically induce or amplify an immune response against cancer cells. Non-limiting examples of suitable immunotherapeutic agents include immunomodulators; cellular immunotherapies; vaccines; gene therapies; ATP-adenosine axis targeting agents; immune checkpoint modulators; and specific signal transduction inhibitors. ATP-adenosine axis targeting agents and signal transduction inhibitors are described above. Immunomodulators, cellular immunotherapies, vaccines, gene therapies, and immune checkpoint modulators are further described below.

[0206] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically, a cytokine or chemokine, 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); an organic or inorganic adjuvant that activates antigen-presenting cells and promotes the presentation of antigen epitopes on major histocompatibility complex molecules, such as, but not limited to, Toll-like receptor (TLR) agonists, mevalonate pathway antagonists, and STING agonists; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, and immunostimulatory oligonucleotides, as well as other T cell adjuvants.

[0207] In some embodiments, the one or more additional therapeutic agents are immunotherapeutic agents, more specifically cell therapy. Cell therapy is a form of treatment in which viable cells are administered to a subject. In certain embodiments, the one or more additional therapeutic agents are cellular immunotherapies that activate or suppress the immune system. Cellular immunotherapies useful for cancer treatment typically induce or amplify an immune response. The 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, the cells can be "(re)programmed" allogeneic immune cells generated from immune progenitor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell progenitor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells may be expanded subsets of cells with distinct 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.), may be genetically modified to target the cells to specific antigens and / or to enhance the anti-tumor effect of the 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.), may be engineered to express or increase the expression of tumor-associated antigens, or 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, lysocabtagene maraleucel, idecbutagen biclucel, brexcabtagene 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.

[0208] In some embodiments, one or more additional therapeutic agents are immunotherapeutic agents, more particularly gene therapy.Gene therapy includes recombinant nucleic acids administered ex vivo to a subject or a subject's cells to modify the expression of endogenous genes and cause 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.), as well as gene editing therapy, which may or may not include nucleic acid components (e.g., meganucleases, zinc finger nucleases, TAL nucleases, CRISPR / Cas nucleases, etc.), oncolytic viruses, etc. Non-limiting examples of gene therapies that may be useful in cancer treatment include Gendicine® (rAd-p53), Oncorine® (rAD5-H101), talimogene laherparepvec, Mx-dnG1, ARO-HIF2 (Arrowhead), quaratusugene ozeplasmid (Immunogene), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics), and CTX130 (CRISPR Therapeutics).

[0209] In some embodiments, the one or more additional therapeutic agents are immunotherapeutic agents, more specifically, agents that modulate immune checkpoints. Immune checkpoints are a series of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells). Immune checkpoints function when proteins on the surface of immune cells recognize and bind to their cognate ligands. The present invention contemplates the use of the 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 may be useful as agents to overcome different immunosuppressive pathways within the tumor microenvironment, inhibit regulatory T cells, reverse / prevent T cell anergy or exhaustion, induce innate immune activation and / or inflammation at the tumor site, or a combination thereof.

[0210] In some embodiments, the one or more additional therapeutic agents are immune checkpoint inhibitors. 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" may be used interchangeably herein. Immune checkpoint inhibitors may antagonize inhibitory or co-inhibitory immune checkpoints by preventing receptor-ligand binding and / or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated and can be antagonized in various types of cancer cells, 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 (T-cell immunoglobulin and mucin domain-containing protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (Ig and ITI) These include T cell immunoreceptors with M domains; 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, and killer inhibitory receptors, which can be divided into two classes based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs) and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., specific B7 family inhibitory ligands such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)), are also contemplated. [See Pardoll, (April 2012) Nature Rev. Cancer 12:252-64].

[0211] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 antagonist. In further 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.

[0212] In some embodiments, the immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonistic PD-1 antibody, a small molecule, or a peptide. Suitable antagonistic PD-1 antibodies include, for example, monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab, dostallimab, cemiplimab, ezabenlimab (BI-754091), MEDI-0680 (AMP-514; WO2012 / 145493), nivolumab, pembrolizumab, pidilizumab (CT-011), pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimberelimab; and bispecific antibodies such as LY3434172. In yet a further embodiment, the PD-1 antagonist may be a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1 (AMP-224). In a specific embodiment, the immune checkpoint inhibitor is zimberelimab.

[0213] In some embodiments, the immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist may be an antagonistic PD-L1 antibody. Suitable antagonistic PD-L1 antibodies include, for example, monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and embafolimab, and bispecific antibodies such as LY3434172 and KN046.

[0214] In some embodiments, the immune checkpoint inhibitor is a TIGIT antagonist. In further embodiments, the TIGIT antagonist may be an antagonistic TIGIT antibody. Suitable antagonistic anti-TIGIT antibodies include monospecific antibodies, such as AGEN1327, AB308 (WO2021247591), BMS986207, COM902, domvanalimab, EOS-448, etigilimab, IBI-929, JS006, M6223, osipelimab, SEA-TGT, tiragolumab, and vibostolimab; and bispecific antibodies such as AGEN1777 and AZD2936. In certain embodiments, the immune checkpoint inhibitor is an antagonistic anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In certain embodiments, the immune checkpoint inhibitor is domvanalimab or AB308.

[0215] In some embodiments, the immune checkpoint inhibitor is a LAG-3 antagonist. In further 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).

[0216] In certain embodiments, the immune checkpoint inhibitor is a B7-H3 antagonist. In further embodiments, the B7-H3 antagonist is an antagonistic B7-H3 antibody. Suitable antagonistic B7-H3 antibodies include, for example, enoblituzumab (MGA271; WO11 / 109400), omburtumab, DS-7300a, ABBV-155, and SHR-A1811.

[0217] In some embodiments, the one or more additional therapeutic agents activate a stimulatory or costimulatory immune checkpoint. 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.

[0218] In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and utomilumab (PF-05082566; WO12 / 32433). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist can be an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is an OX40 agonist. In further embodiments, the OX40 agonist can be an agonistic 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 a stimulatory or costimulatory immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonistic CD40 antibody. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD27 agonist. In further embodiments, the CD27 agonist can be an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0219] In some embodiments, one or more of the additional therapeutic agents are agents that inhibit or deplete immunosuppressive immune cells.For example, to inhibit or deplete immunosuppressive macrophages or monocytes, the agent can be a CSF-1R antagonist, for example, 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).Another example is WO14 / 036357).Anti-CD25 bead depletion of Tregs ex vivo.

[0220] In some embodiments, each additional therapeutic agent can independently be a chemotherapeutic agent, a radiopharmaceutical, a hormone therapy, an epigenetic modulator, a targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. For example, in one embodiment, the present disclosure contemplates 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 targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure contemplates 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 targeting agent, an immunotherapeutic agent, or a cell therapy. In another embodiment, the present disclosure contemplates 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 targeting agent, a chemotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of an AXL inhibitor described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, where each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, or a cell therapy. In another embodiment, the present disclosure contemplates the use of an AXL inhibitor 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, where each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, an immunotherapeutic agent, or a cell therapy.In further embodiments, the (a) targeting agent may 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 may inhibit one or more of EGFR, VEGF, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK, and / or FGFR; (c) the kinase inhibitor may inhibit one or more of EGFR, VEGFR, and / or c-MET; (d) the immunotherapeutic agent is an ATP-adenosine axis targeting agent or an immune checkpoint inhibitor; and (e) the ATP-adenosine axis targeting agent is A2. A R and / or A2 B (f) the ATP-adenosine axis targeting agent is etormadenant, quemlicustat, or AB598; (e) the immunotherapeutic agent is an anti-PD-1 antagonist antibody or an anti-TIGIT antagonist antibody; (f) the immunotherapeutic agent is zimberelimab, domvanalimab, or AB308; or (i) any combination thereof. In still further embodiments of the above, the present disclosure contemplates the use of an AXL inhibitor described herein in combination with domvanalimab, etormadenant, quemlicustat, zimberelimab, AB308, AB598, AB521, or any combination thereof.

[0221] In one or more embodiments, one or more of the 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 extracellular production of adenosine, radiation therapy, 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 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 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 comprises one or more of zimbeliimab, donvanalimab, and / or AB308. In some embodiments, the agent targeting extracellular production of adenosine is a CD73 inhibitor, a CD39 inhibitor, an A inhibitor, or a steroid inhibitor. 2A R inhibitor, A 2B R inhibitors, and / or A 2A R and A 2BIn certain embodiments, the agent targeting the extracellular production of adenosine comprises one or more of etormadenant, quemlicustat, and / or AB598. In some embodiments, the chemotherapeutic agent comprises one or more of a platinum-based, taxoid-based, anthracycline-based chemotherapeutic agent, low-dose cytarabine (LDAC), or gemcitabine. In certain embodiments, the chemotherapeutic agent is selected from cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, paclitaxel, nab-paclitaxel, low-dose cytarabine (LDAC), and gemcitabine. In yet another embodiment, the AXL inhibitor described herein is administered with docetaxel. In yet another embodiment, the AXL inhibitor is administered with a checkpoint inhibitor. In yet another embodiment, the AXL inhibitor is administered in combination with docetaxel and a checkpoint inhibitor, such as dinbelimab.

[0222] The choice of additional therapeutic agent(s) may be informed by the current standard of care for the particular cancer and / or the mutational status and / or stage of the cancer of interest. Detailed standard of care guidelines are published, for example, by the National Comprehensive Cancer Network (NCCN). For example, NCCN acute myeloid leukemia v1.2022, NCCN squamous cell skin cancer v.2.2022, NCCN head and neck cancer v.2.2022, NCCN ovarian cancer / fallopian tube cancer / primary peritoneal cancer v.1.2022, NCCN pancreatic adenocarcinoma 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: Uvea v2.2022, NCCN Non-Small Cell Lung Cancer v.3.2022, NCCN Kidney Cancer v.4.2022.

[0223] Pharmaceutical Composition The AXL inhibitor of the present disclosure may be in the form of a composition suitable for administration to a subject. Generally, such a composition is a pharmaceutical composition comprising a compound according to the present disclosure or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In certain embodiments, the AXL inhibitor may be present in a therapeutically effective amount. Pharmaceutical compositions may be used in the methods of the present disclosure; thus, for example, pharmaceutical compositions comprising a compound according to the present disclosure can be administered to a subject to practice the therapeutic and prophylactic methods and uses described herein.

[0224] In one or more embodiments, the pharmaceutical composition comprises an AXL inhibitor according to the present disclosure in an amount of about 10 mg to about 1,000 mg. In one or more embodiments, the pharmaceutical composition comprises an AXL inhibitor according to the present disclosure in an amount of about 10 mg to about 500 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of about 10 mg to about 300 mg, e.g., 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, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 200 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 250 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 300 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 20mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 18 5mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250m g, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, or 300mg, 305mg, 310mg, 31 5mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380 In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 10 mg to about 50 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 25 mg to about 75 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 25 mg to about 50 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 50 mg to about 100 mg. In some embodiments, the AXL inhibitor according to the present disclosure is present in an amount of about 100 mg to about 200 mg.In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 100 mg to about 150 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 150 mg to about 200 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 200 mg to about 300 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 200 mg to about 250 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 250 mg to about 300 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 300 mg to about 400 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 300 mg to about 350 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 350 mg to about 400 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 400 mg to about 500 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 400 mg to about 450 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of about 450 mg to about 500 mg.

[0225] The pharmaceutical compositions of the present disclosure may be formulated to be compatible with the intended method or route of administration. Routes of administration include those known in the art. Exemplary routes of administration are oral and parenteral. Furthermore, the pharmaceutical compositions may be used in combination with one or more other therapies described herein to treat or prevent the diseases, disorders, and conditions contemplated by the present disclosure. In one embodiment, one or more other therapeutic agents contemplated by the present disclosure are included in the same pharmaceutical composition containing an AXL inhibitor according to the present disclosure. In another embodiment, the one or more other additional therapeutic agents are in a separate composition from the pharmaceutical composition containing an AXL inhibitor according to the present disclosure.

[0226] In one aspect, the compounds described herein may be orally administered. Oral administration may be, for example, via capsules or tablets. When preparing pharmaceutical compositions containing a compound of formula (I) or its pharmaceutically acceptable salt, tablets or capsules typically contain at least one pharmaceutically acceptable excipient. Non-limiting examples of pharmaceutically acceptable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, sterile water, syrup, and methylcellulose. Additional pharmaceutically acceptable excipients include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; and preservatives such as methyl and propylhydroxybenzoates.

[0227] In another embodiment, the compounds described herein can be administered parenterally, for example, by intravenous injection. Pharmaceutical compositions suitable for parenteral administration can be formulated in a solution for injection or reconstituted for injection in a suitable system, such as a physiological solution. Such a solution can contain an appropriate amount of sterile water for injection, salts, buffers, and isotonic excipients to achieve isotonicity at the appropriate physiological level.

[0228] The pharmaceutical compositions described herein may be stored in a suitable sterile container(s). In some embodiments, the container is designed to maintain the stability of the pharmaceutical composition for a given period of time.

[0229] Administration Generally, the disclosed methods include 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 disclosed AXL inhibitors, refers to an amount of compound sufficient to bind to a target (by inhibiting or antagonizing the target) at a level indicative of the compound's efficacy. For AXL, target binding can be determined by one or more biochemical or cellular assays, which can provide an EC50, ED50, EC90, IC50, or similar value that can be used as an assessment of the compound's efficacy. Assays for determining target binding include, but are not limited to, those described in the Examples. An effective amount can be administered as a single dose or as multiple smaller doses (e.g., as one tablet containing "x" amount, as two tablets each containing "x / 2" amount, etc.).

[0230] In some embodiments, the disclosed methods include 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 dosing regimen (i.e., amount and interval) of the compound that results in the specific pharmacological effect of administering the compound to a subject in need of such treatment. In the case of prophylactic use, a therapeutically effective amount may be effective to eliminate or reduce the risk, reduce the severity, or delay the onset of disease, including biochemical, histological, and / or behavioral signs or symptoms of the disease. In the case of treatment, a therapeutically effective amount may be effective to reduce, ameliorate, or eliminate one or more signs or symptoms associated with the disease, slow disease progression, prolong survival, reduce the dose of other pharmaceutical(s) required to treat the disease, or a combination thereof. With particular reference to cancer, a therapeutically effective amount may, for example, result in the death of cancer cells, reduce the number of cancer cells, reduce tumor burden, reduce tumor volume, eliminate tumors or metastases, or reduce metastatic spread. A therapeutically effective amount can vary based on, for example, one or more of the following: the subject's age and weight, the subject's overall health, the subject's stage of disease, the route of administration, and previous or concurrent treatments.

[0231] Administration can include one or more (eg, 1, 2, or 3 or more) dosing cycles.

[0232] In certain embodiments, AXL inhibitors contemplated by the present disclosure may be administered (e.g., orally, parenterally, etc.) at 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 subject body weight per day, once or more times daily, weekly, or monthly to achieve the desired effect. In some embodiments, a suitable weight-based dose of a compound contemplated by the present disclosure is used to determine the dose to be administered independently of the subject's body weight. In certain embodiments, AXL inhibitors of the present disclosure are administered (e.g., orally, parenterally, etc.) at a fixed dosage level of about 1 mg to about 1000 mg, once or more times daily, weekly, or monthly to achieve the desired effect. In some embodiments, AXL inhibitors according to the present disclosure are administered at a fixed dosage level of about 10 mg to about 500 mg, one or more times daily, weekly, or monthly, to achieve the desired effect. In some embodiments, AXL inhibitors according to the present disclosure are administered at a fixed dosage level of about 10 mg to 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, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 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, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 610 mg, 620 mg, 630 mg In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount of about 10 mg to about 50 mg, 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 in an amount of about 25 mg to about 75 mg, 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 in an amount of about 50 mg to about 100 mg, 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 in an amount of about 100 mg to about 200 mg, 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 in an amount of about 100 mg to about 150 mg, 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 in an amount of about 200 mg to about 300 mg, 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 in an amount of about 250 mg to about 300 mg, one or more times daily, weekly, or monthly to achieve the desired effect.

[0233] In some embodiments, the AXL inhibitor according to the present disclosure is administered one or more times 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.

[0234] In certain embodiments, the AXL inhibitor is contained in a "unit dosage form." The term "unit dosage form" refers to a physically separate unit, each unit containing a predetermined amount of the AXL inhibitor, alone or in combination with one or more additional drugs, sufficient to produce the desired effect. It will be understood that the parameters of the unit dosage form depend on the specific drug and the effect to be achieved.

[0235] Embodiment Embodiment 1. A compound represented by formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein: X is CR 5 or N; G 1 is N or CR G1 and; G 2 is CR G2 or N; G 3 is CR G3 or N; G 4 is CR G4 or N; G 5 is CR G5 or N; R G1 H, C1-3 Alkyl, halogen, C 1-3 selected from the group consisting of haloalkyl, and CN; Each R G2 , R G3 , R G4 and R G5 are independently H, halo, CN, and 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, wherein cycloalkyl and heterocycloalkyl are selected from halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 substituted with 0-3 groups independently selected from alkyl, and OH; A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-oxazepane, 1,4-diazepane, oxepane, tetrahydropyran, piperidine, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which contains 1 to 4 R 2 and further substituted with zero or one oxo (=O) on the carbon atom adjacent to the nitrogen atom; R 1 is 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, and each phenyl and heteroaryl is selected from one R 1a and 0 to 3 R 3 is replaced by; R 1a is 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, where the N atom, if present, is optionally oxidized, and wherein each phenyl and heteroaryl is selected from the group consisting of 0-4 R 4 is replaced with; Each R 2 independently, C 1-7 Alkyl, C 3-7 Alkenyl, C 3-7 Alkynyl, C 3-7 Cycloalkyl, -Y 1 -OC 1-7 Alkyl, -Y 1 -OC 3-7 Cycloalkyl, -NR a R b , -C(O)-C 1-7 Alkyl, -C(O)-C 3-7 Cycloalkyl, -S(O)2-C 1-7 Alkyl, -S(O)2-C 3-7 Cycloalkyl, -C(O)NR a R b , 5-8 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 -(5-8 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 selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -OC 1-4 substituted with 0-3 groups independently selected from alkyl, and OH; Each R 3 are independently halogen, CN, C 1-7 Alkyl, C 2-7 Alkenyl, C 3-7 Alkynyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halohydroxyalkyl, -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, C 1-7 Alkyl, Halo, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C 1-7 Alkylene-CN, Hydroxy, C 1-7 Hydroxyalkyl, -C(O)NR a R b , C 3-7 Cycloalkyl, -NR a -C(O)-C1-7 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 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1 to 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 selected from the group consisting of C 1-4 substituted with 0 to 2 groups independently selected from the group consisting of alkyl, halo, and hydroxy; Or, two R on the same ring vertex 4 the groups combine to form an oxo (=O); or Two R on adjacent ring vertices 4 groups combine to form a 5-6 membered heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5-6 membered heterocycloalkyl is 1-4 substituted with 0 to 2 groups independently selected from the group consisting of alkyl and halo; R 5 is H, C 1-4 selected from the group consisting of alkyl, and -NH; each X 1 is C 1-7 Alkylene or C 3-7 is cycloalkylene; Each Y 1 is C 2-7 Alkylene or C 3-7 is cycloalkylene; Each R a and R b are independently H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-7 cycloalkyl, wherein said cycloalkyl is optionally selected from the group consisting of -OC 1-3 substituted with alkyl; or R a and R b are taken together with the nitrogen to which they are attached to form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, where the heterocycloalkyl ring is substituted with 0-3 groups, each group being 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 on the same ring vertex combine to form oxo (=O), or a pharmaceutically acceptable salt thereof.

[0236] Embodiment 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein G 3 But, CR G3 and R G3 is H; G 4 But, CR G4 and R G4 is H; and G 5 are respectively, CR G5 and R G5 is H, or a pharmaceutically acceptable salt thereof.

[0237] Embodiment 3. wherein G 1 is N or CR G1 and R G1is H, or a pharmaceutically acceptable salt thereof.

[0238] Embodiment 4. wherein G 2 is CR G2 and R G2 The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein is H.

[0239] Embodiment 5. wherein X is CR 5 and R 5 The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein is H.

[0240] Embodiment 6. A compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein A is: [ka] having a formula selected from the group consisting of: Each of these has 1 to 4 R 2 or a pharmaceutically acceptable salt thereof, wherein

[0241] Embodiment 7. The compound of embodiment 6, or a pharmaceutically acceptable salt thereof, wherein A is of the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0242] Embodiment 8. wherein one R 2 But, -NR a R b 8. The compound of any one of embodiments 1-7, wherein:

[0243] Embodiment 9. A compound according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein one R 2 But the following: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0244] Embodiment 10. A compound of embodiment 9, or a pharmaceutically acceptable salt thereof, wherein two R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0245] Embodiment 11. wherein R 1 is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, and pyrazolyl, wherein R 1 But one R 1a and 0 to 2 R 3 11. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, substituted with:

[0246] Embodiment 12. A compound of embodiment 11, or a pharmaceutically acceptable salt thereof, wherein R 1 but: [ka] is selected from the group consisting of wherein the subscript p is 0 or 1, or a pharmaceutically acceptable salt thereof.

[0247] Embodiment 13. A compound of embodiment 11, or a pharmaceutically acceptable salt thereof, wherein R 1 but: [ka] is selected from the group consisting of wherein the subscript p is 0 or 1, or a pharmaceutically acceptable salt thereof.

[0248] Embodiment 14. A compound of any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein each R 3 When present, independently, halogen, CN, C 1-4 Alkyl, C 1-4 Harolkill, C 1-4 Hydroxyalkyl, C 1-4 Halohydroxyalkyl, -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 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0249] Embodiment 15. A compound of embodiment 14, or a pharmaceutically acceptable salt thereof, wherein each R 3 If present, halogen, C 1-4 Alkyl and -OC 1-4 or a pharmaceutically acceptable salt thereof, wherein the compound is independently selected from the group consisting of alkyl.

[0250] Embodiment 16. A compound of embodiment 14, or a pharmaceutically acceptable salt thereof, wherein each R 3 is, if present, independently selected from the group consisting of fluoro, chloro, methyl, and methoxy, or a pharmaceutically acceptable salt thereof.

[0251] Embodiment 17. A compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein R 1ais selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl N-oxide, and phenyl, wherein R 1a However, 0 to 3 R 4 or a pharmaceutically acceptable salt thereof, wherein

[0252] Embodiment 18. A compound of embodiment 17, or a pharmaceutically acceptable salt thereof, wherein R 1a is the following: [ka] wherein the subscript q is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0253] Embodiment 19. A compound of embodiment 17, or a pharmaceutically acceptable salt thereof, wherein R 1a But the following: [ka] wherein the subscript q is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0254] Embodiment 20. A compound of embodiment 17, or a pharmaceutically acceptable salt thereof, wherein R 1a But the following: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0255] Embodiment 21. A compound of any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R 4 If present, independently, C 1-4 Alkyl, Halo, 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 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S; 5- to 8-membered heterocycloalkyl having 1 to 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 is selected from the group consisting of C 1-4 The compound, or a pharmaceutically acceptable salt thereof, which is substituted with 0 to 2 groups selected from the group consisting of alkyl, halo, and hydroxy.

[0256] Embodiment 22. A compound of embodiment 21, or a pharmaceutically acceptable salt thereof, wherein each R 4 If present, independently, methyl, ethyl, fluoro, chloro, difluoromethyl, trifluoromethyl, CN, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0257] Embodiment 23. A compound according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein two R on adjacent ring vertices are 4groups join to form a 5-6 membered heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5-6 membered heterocycloalkyl is 1-4 The compound, or a pharmaceutically acceptable salt thereof, substituted with 0 to 2 groups independently selected from the group consisting of alkyl and halo.

[0258] Embodiment 24. A compound of embodiment 23, wherein two R on adjacent ring vertices 4 The groups combine to form: [ka] forming a heterocycloalkyl selected from The heterocycloalkyl may be C 1-4 The compound is substituted with 0 to 2 groups independently selected from the group consisting of alkyl and halo.

[0259] Embodiment 25. A compound of any one of embodiments 1-2 or 5-24, having a structure selected from Formula (Ia), or Formula (Ia1), or a pharmaceutically acceptable salt thereof: [ka]

[0260] Embodiment 26. A compound of any one of embodiments 1-2, 5, or 8-24, having a structure according to Formula (Ib), or Formula (Ib1), or a pharmaceutically acceptable salt thereof: [ka] wherein for each of Formula (Ib) and Formula (Ib1), the subscript m is 0 or 1; and n is 0, 1, or 2; and each R 2 may be the same or different, said compound, or a pharmaceutically acceptable salt thereof.

[0261] Embodiment 27. A compound of embodiment 26 having the structure of formula (If), or formula (If1), or a pharmaceutically acceptable salt thereof: [ka]

[0262] Embodiment 28. The compound of embodiment 26 or 27, wherein m is 0.

[0263] Embodiment 29. The compound of any one of embodiments 26-28, wherein n is 0.

[0264] Embodiment 30. A compound of embodiment 1, or a pharmaceutically acceptable salt thereof, comprising: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0265] Embodiment 31. A compound represented by formula (II) [ka] 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 selected from 1 to 4 R 2 has been replaced with; R 1 is 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, and each phenyl and heteroaryl is selected from the group consisting of one R 1a and 0 to 3 R 3 is replaced by; R 1a is 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, where the N atom, if present, is optionally oxidized, and wherein each phenyl and heteroaryl is selected from the group consisting of 0-4 R 4 is replaced with; Each R 2 independently, 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 -(5-8 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 selected from the group consisting of C 1-4 Alkyl and -OC 1-4 substituted with 0 to 3 groups independently selected from alkyl; Each R 3 But halogen, C 1-7 alkyl, and -OC 1-7 independently selected from the group consisting of alkyl; Each R 4 independently, C 1-7 Alkyl, Halo, C 1-7 Haloalkyl, -OC 1-7 Alkyl, -OC 1-7 Haloalkyl, CN, -C1-7 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 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1 to 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 selected from the group consisting of C 1-4 substituted with 0 to 2 groups independently selected from the group consisting of alkyl, and hydroxy; Alternatively, two R on adjacent ring vertices 4 The groups combine to form a 5-6 membered heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the 5-6 membered heterocycloalkyl has 0-2 C 1-4 substituted with alkyl; each X 1 But C 1-7 is alkylene; Each Y 1 But C 2-7 is alkylene; Each R a and R b However, independently, H, C 1-7 Alkyl, C 3-7 cycloalkyl, wherein said cycloalkyl is optionally selected from the group consisting of -OC 1-3 substituted with alkyl; or R a and R bare taken together with the nitrogen to which they are attached to form a 4-8 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 on the same ring vertex combine to form oxo (=O), or a pharmaceutically acceptable salt thereof.

[0266] 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.

[0267] Embodiment 33. The pharmaceutical composition of embodiment 32, comprising 10 to 300 mg of a compound of any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof.

[0268] Embodiment 34. A method for 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.

[0269] Embodiment 35. A method for treating a disease, disorder, or condition mediated at least in part by AXL, comprising administering to a subject in need thereof 10 to 300 mg 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, once daily.

[0270] Embodiment 36. The method of embodiment 34 or 35, wherein the disease, disorder, or condition is cancer.

[0271] Embodiment 37. The method of embodiment 36, wherein the cancer is cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, uterus, brain, liver, bladder, ovaries, fallopian tubes, peritoneum, testes, head, neck, skin (including melanoma and basal cell carcinoma), mesothelial lining, white blood cells (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, intestine, lung (including small cell lung cancer and non-small cell lung cancer), adrenal gland, thyroid, kidney, or bone; or glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma (including Kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the skin, or testicular seminoma, or any combination thereof.

[0272] 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 cancer (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).

[0273] 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.

[0274] Embodiment 40. The method of any one of embodiments 36-39, wherein the cancer is recurrent or resistant to radiation therapy, chemotherapy, or immunotherapy.

[0275] Embodiment 41. The method of embodiment 34 or 35, wherein the disease, disorder, or condition is a viral infection.

[0276] Embodiment 42. The method of embodiment 41, wherein the viral infection is caused by SARS-CoV-2, Ebola virus, monkeypox, or Zika virus.

[0277] Embodiment 43. The method of embodiment 34 or 35, wherein the disease, disorder, or condition is fibrosis.

[0278] 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), hepatic fibrosis (e.g., chronic liver disease), or pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis).

[0279] Embodiment 45. The method of any one of embodiments 35-40, further comprising administering to the subject at least one additional therapeutic agent.

[0280] 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 an inhibitor of the CD47-SIRPα pathway (e.g., an anti-CD47 antibody), a kinase inhibitor, an inhibitor of HIF (e.g., a HIF-2α inhibitor), an inhibitor of PARP, a RAS signaling inhibitor, an immune checkpoint inhibitor, an agent that targets the extracellular production of adenosine, radiation therapy, and a chemotherapeutic agent.

[0281] Embodiment 47. The method of embodiment 46, wherein the at least one additional therapeutic agent comprises an inhibitor of the CD47-SIRPα pathway, and the inhibitor of the CD47-SIRPα pathway is an anti-CD47 antibody.

[0282] 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.

[0283] Embodiment 49. The method of any one of embodiments 46-48, 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.

[0284] Embodiment 50. The method of embodiment 49, wherein the one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

[0285] 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, balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, durvalumab, emiprimab, emvafolimab ezabenlimab, nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimberelimab.

[0286] Embodiment 52. The method of embodiment 50, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is dimverelimab.

[0287] Embodiment 53. The method of any one of embodiments 46-52, wherein the one or more immune checkpoint inhibitors comprises an immune checkpoint inhibitor that blocks the activity of TIGIT.

[0288] Embodiment 54. The method of embodiment 53, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is chosen from AB308, donvanalimab, etigilimab, osipelimab, tiragolumab, or vibostolimab.

[0289] Embodiment 55. The method of embodiment 53, wherein the immune checkpoint inhibitor is domvanalimab or AB308.

[0290] Embodiment 56. The at least one additional therapeutic agent is A 2a R / A 2b 56. The method of any one of embodiments 46-55, comprising one or more agents targeting extracellular production of adenosine selected from the group consisting of R antagonists, CD73 inhibitors, and CD39 inhibitors.

[0291] Embodiment 57. The method of embodiment 56, wherein the one or more agents targeting extracellular production of adenosine are selected from the group consisting of AB598, etrumadenant, inupadenant, taminadenant, caffeine citrate, imaladenant, ciforadenant, and quemlicustat.

[0292] Embodiment 58. The method of embodiment 56, wherein the one or more agents targeting extracellular production of adenosine are AB598, etormadenant, and / or quemlicustat.

[0293] Embodiment 59. The method of any one of embodiments 46-58, wherein the at least one additional therapeutic agent comprises an inhibitor of HIF-2α selected from the group consisting of belzutifan, ARO-HIF2, PT-2385, and AB521.

[0294] Embodiment 60. The method of embodiment 59, wherein the inhibitor of HIF-2α is AB521.

[0295] Embodiment 61. The method of any one of embodiments 46-60, wherein the at least one additional therapeutic agent comprises an inhibitor of PARP selected from the group consisting of olaparib, rucaparib, and niraparib.

[0296] Embodiment 62. The method of any one of embodiments 46-61, wherein the at least one additional therapeutic agent comprises a chemotherapeutic agent.

[0297] Embodiment 63. The method of any one of embodiments 46-62, wherein the at least one additional therapeutic agent comprises radiation therapy.

[0298] Embodiment 64. The method of any one of embodiments 46-63, wherein the compound and the at least one additional therapeutic agent are administered in combination.

[0299] Embodiment 65. The method of any one of embodiments 46-64, wherein the compound and the at least one additional therapeutic agent are administered sequentially.

[0300] Embodiment 66. The method of any one of embodiments 46-64, wherein the treatment periods for said administration of said compound and said at least one additional therapeutic agent overlap.

[0301] Embodiment 67. A combination comprising a compound according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

[0302] 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 an inhibitor of the CD47-SIRPα pathway (e.g., an anti-CD47 antibody), a kinase inhibitor, an inhibitor of HIF (e.g., a HIF-2α inhibitor), an inhibitor of PARP, a RAS signaling inhibitor, an immune checkpoint inhibitor, an agent that targets the extracellular production of adenosine, radiation therapy, and a chemotherapeutic agent.

[0303] Embodiment 69. The combination of embodiment 68, wherein the at least one additional therapeutic agent comprises an inhibitor of the CD47-SIRPα pathway, and the inhibitor of the CD47-SIRPα pathway is an anti-CD47 antibody.

[0304] Embodiment 70. The combination of any one of embodiments 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.

[0305] Embodiment 71. The combination of any one of embodiments 68-70, 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.

[0306] Embodiment 72. The combination of embodiment 71, wherein the one or more immune checkpoint inhibitors comprises an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

[0307] 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, balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, durvalumab, emiprimab, emvafolimab ezabenlimab, nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimberelimab.

[0308] Embodiment 74. The combination of embodiment 73, wherein the immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1 is dimverelimab.

[0309] Embodiment 75. The combination of any one of embodiments 68 to 74, wherein the one or more immune checkpoint inhibitors comprises an immune checkpoint inhibitor that blocks the activity of TIGIT.

[0310] Embodiment 76. The combination of embodiment 75, wherein said immune checkpoint inhibitor that blocks the activity of TIGIT is AB308, donvanalimab, etigilimab, osipelimab, tiragolumab, or vibostolimab.

[0311] Embodiment 77. The combination of embodiment 76, wherein said immune checkpoint inhibitor that blocks the activity of TIGIT is AB308 or donvanalimab.

[0312] Embodiment 78. The at least one additional therapeutic agent is A 2a R / A 2b 78. The combination according to any one of embodiments 68 to 77, comprising one or more agents targeting the extracellular production of adenosine selected from the group consisting of R antagonists, CD73 inhibitors, and CD39 inhibitors.

[0313] Embodiment 79. The combination of embodiment 78, wherein the one or more agents targeting extracellular production of adenosine are selected from the group consisting of AB598, etrumadenant, inupadenant, taminadenant, caffeine citrate, imaladenant, ciforadenant, or quemlicustat.

[0314] Embodiment 80. The combination of embodiment 79, wherein the one or more agents targeting the extracellular production of adenosine are etremadenant and / or quemlicustat.

[0315] 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 belzutifan, ARO-HIF2, PT-2385, and AB521.

[0316] Embodiment 82. The combination of embodiment 81, wherein the inhibitor of HIF-2α is AB521.

[0317] 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.

[0318] Embodiment 84. The combination of any one of embodiments 68 to 83, wherein the at least one additional therapeutic agent comprises a chemotherapeutic agent.

[0319] Embodiment 85. The combination of embodiment 84, wherein the chemotherapeutic agent comprises gemcitabine, cytarabine, a platinum-based, taxoid-based, or anthracycline-based chemotherapeutic agent.

[0320] 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.

[0321] Embodiment 87. The combination of any one of embodiments 68 to 86, wherein the at least one additional therapeutic agent comprises radiation therapy.

[0322] experiment The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their invention. Additional compounds within the scope of the present disclosure can be made using methods based on the methods shown in these examples or other methods known in the art. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0323] All reactions were carried out at the indicated temperatures using Teflon-coated magnetic stir bars and, where noted, under an inert atmosphere. All chemicals were used as received. Reactions were monitored by TLC (silica gel 60 with fluorescent F254, visualized with a short-wave / long-wave UV lamp) and / or LCMS (Agilent 1100 or 1200 series LCMS with UV detection 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 XSelectHSS C18 [3.5 μm, 2.1 mm id] × 75 mm], using a binary solvent system [0.1% formic acid in MeCN / 0.1% formic acid in HO]). Flash chromatography was performed on silica gel using an automated system (Teledyne ISCO CombiFlash RF+) optionally equipped with an evaporative light scattering detector, at detection wavelengths of 254 and 280 nm. Reverse-phase preparative HPLC was performed on an Agilent 1260 or 1290 Infinity series HPLC. Samples were eluted with gradient elution on a Gemini C18 110 Å column (21.2 mm id x 250 mm) using a binary solvent system (MeCN / HO with an acid modifier as needed - e.g., 0.1% TFA or 0.1% formic acid) and detected at variable wavelengths. Final compounds obtained by preparative HPLC were concentrated by lyophilization. All reported yields are isolated yields. All assayed compounds were analyzed by 1Purification to ≥95% purity as determined by H NMR or LCMS (Agilent 1100 or 1200 series LCMS with UV detection 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 XSelectHSS C18 [3.5 μm, 2.1 mm id] × 75 mm], using a binary solvent system [0.1% formic acid in MeCN / 0.1% formic acid in HO]. H NMR spectra were recorded on a Varian 400 MHz NMR spectrometer equipped with an Oxford AS400 magnet or a Bruker AVANCE NEO 400 MHz NMR spectrometer. Chemical shifts (δ) are reported as parts per million (ppm) relative to residual non-deuterated solvent or tetramethylsilane as an internal standard. The abbreviations s, brs, d, t, q, dd, dt, ddd, dddt, and m stand for singlet, broad singlet, doublet, triplet, quartet, double doublet, double triplet, double double doublet, and multiplet, respectively.

[0324] Unless otherwise specified, temperatures are in degrees Celsius (°C) and pressure is at or near atmospheric. Standard abbreviations are used, including: rt or rt = room temperature; min = minute(s), h or hr = hour(s), t = elapsed time; mg = milligram; g = gram; μl or μL = microliter; ml or mL = milliliter; l or L = liter; mM = millimole, M = molar; mol = mole; mmol = millimole; aq. = aqueous; calcd = theoretical (calculated); sat. = saturated; DCM or CHCl = dichloromethane; DCE = 1,2-dichloroethane; MTBE = methyl tert-butyl ether -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-chloroperoxybenzoic acid; H2 = hydrogen gas; N2 = nitrogen gas; NH3 = ammonia; Cs2CO3 = cesium carbonate; Na H = sodium hydride; NaBH(OAc)3 = sodium triacetoxyborohydride; NaOH = 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) (methyl)ethoxymethyl chloride; HATU = N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HOBt = hydroxybenzotriazole; NBS = N-bromosuccinimide; KOAc = potassium acetate; 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)] palladium(II) methanesulfonate; Xantphos = (9,9-dimethyl-9H-xanthene-4,5-diyl) bis(diphenylphosphane); Pd2dba3 = tris(dibenzylideneacetone)dipalladium(0); Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0); B2pin2 = bis(pinacolato)diboron; MHz = megahertz, Hz = hertz; ppm = parts per million; ESI-MS = electrospray ionization mass spectrometry; NMR = nuclear magnetic resonance. [Example]

[0325] 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 [ka]

[0326] Step a: To a mixture of 3-oxa-6-aza-bicyclo[3.1.1]heptane 4-methylbenzenesulfonic acid (5.00 g, 18.4 mmol) in CHCl (92 mL) at room temperature was added 2-bromo-5,6,8,9-tetrahydro-benzocyclohepten-7-one (4.63 g, 19.4 mmol) followed by NaBH(OAc) (4.69 g, 22.1 mmol). The reaction mixture was then stirred at room temperature for 4 hours. Additional NaBH(OAc) (4.69 g each) was added at t = 4 hours and t = 8 hours. After the final addition, the reaction mixture was stirred at room temperature for an additional 4 hours. The reaction mixture was diluted with CHCl (250 mL), water (250 mL), and 2 M NaOH. (aq)(100 mL, or until pH > 12) and stirred. The organic phase was diluted with 4:1:1 water:brine:2M NaOH. (aq) (300 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography (hexane:(EtOAc + 1% Et3N) 0-100% gradient) to give the racemic product as a white solid (5.13 g, 86%). The racemic mixture was resolved using chiral HPLC (Daicel CHIRALPAK IA; MeOH / DEA 100 / 0.1 v / v; 1.0 mL / min; UV 230 nm; 5.3 min (desired isomer), 7.0 min (other isomer)).

[0327] 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 minutes, 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 (0 to 100% gradient of hexanes:EtOAc) to give the desired product as an off-white solid (2.0 g, 86%).

[0328] 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 min, and Xphos Pd G3 (834 mg, 0.985 mmol) was added. The reaction mixture was stirred at 95 °C for 16 h, cooled, diluted with EtOAc (15 mL), filtered through Celite, and concentrated to give the desired product, which was used crude in step d.

[0329] Step d: To a mixture of the product from step c (4.9 mmol), 1-(benzenesulfonyl)-5-bromo-3-iodopyrrolo[2,3-b]pyridine (2.26 g, 4.88 mmol), and K2CO3 (1.35 g, 9.77 mmol), dioxane (30 mL) and water (5 mL) were added. The suspension was degassed with nitrogen for 10 min, and PdCl2(dppf) (180 mg, 0.245 mmol) was added. The reaction mixture was stirred at 80 °C for 4 h, cooled, diluted with CHCl2 (15 mL), dried over MgSO4, filtered through Celite, and concentrated. The crude material was purified by silica gel chromatography (0–100% gradient of hexanes:EtOAc) to give the desired product as an off-white solid (1.8 g, 73%, 2 steps).

[0330] 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 min, and PdCl2(dppf) (26 mg, 0.035 mmol) was added. The reaction mixture was stirred at 95 °C for 16 h, cooled, diluted with EtOAc, filtered through Celite, and concentrated to give the desired product, which was used crude in step f.

[0331] 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]annulen-7-yl]-3-oxa-6-azabicyclo[3.1.1]heptane (222 mg, 0.689 mmol) and K2CO3 (192 mg, 1.39 mmol), dioxane (5.8 mL) and water (1.2 mL) were added. The suspension was degassed with nitrogen for 10 min, and PdCl2(dppf) (26 mg, 0.035 mmol) was added. The reaction mixture was stirred at 95 °C for 3 h, cooled, diluted with C2Cl2 (15 mL), dried over MgSO4, filtered through Celite, and concentrated. The crude material was purified by silica gel chromatography ((CH2Cl2:MeOH)+1% NH3 (aq, 28 wt%) 0-10% gradient) to give the desired product as a white solid (302 mg, 65%, 2 steps).

[0332] 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) (84 mg, 2.1 mmol) was added. The reaction mixture was stirred at 90 °C for 2 h, cooled, diluted with water, and extracted with CHCl (3 × 50 mL). The combined organic phases were dried over MgSO and concentrated. The crude material was purified by C reverse-phase chromatography ((water:ACN) + 1% TFA 0-70% gradient), followed by partial concentration and addition of KCO. The mixture was extracted with CHCl (3 × 50 mL). The combined organic phases were dried over MgSO and concentrated to give the desired product as a white solid (199 mg, 90%). 1H NMR (400MHz, chloroform-d) δ10.78(s,1H),8.61(d,J=2.0Hz,1H),8.55(ddd,J=4.7,1.7,0.7Hz,1H),8.43(d,J =2.0Hz,1H),7.79-7.71(m,2H),7.67-7.55(m,4H),7.39(d,J=6.5Hz,2H),7.22-7.15(m,2H),4.30(d,J=10. 8Hz,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). ESI MS[M+H] + is C 35 H 35 For N4O, the theoretical value was 527.3, and the measured value was 527.3.

[0333] 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 [ka]

[0334] Steps a and b: The compound formed from step b was prepared in a similar manner as described for steps b and c of Example 1.

[0335] Step c: To a mixture of the product from step b (4.9 mmol), 5-bromo-3-iodo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine (2.0 g, 4.9 mmol), and K2CO3 (1.35 g, 9.8 mmol), dioxane (30 mL) and water (5 mL) were added. The suspension was degassed with nitrogen for 10 min, and PdCl2(dppf) (180 mg, 0.245 mmol) was added. The reaction mixture was stirred at 80 °C for 4 h, cooled, diluted with CHCl2 (15 mL), dried over MgSO4, filtered through Celite, and concentrated. The crude material was purified by silica gel chromatography (0–100% gradient of hexanes:EtOAc) to give the desired product as an off-white solid (1.5 g, 68%, 2 steps).

[0336] 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 min, and PdCl2(dppf) (20 mg, 0.027 mmol) was added. The reaction mixture was stirred at 95 °C for 16 h, cooled, diluted with EtOAc (10 mL), filtered through Celite, and concentrated to give the desired product, which was used crude in step c. 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]annulen-7-yl]-3-oxa-6-azabicyclo[3.1.1]heptane (177 mg, 0.549 mmol), and K2CO3 (153 mg, 1.11 mmol), dioxane (5 mL) and water (1 mL) were added. 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 C2Cl2 (15 mL), dried over MgSO4, filtered through Celite, and concentrated. The crude material was purified by silica gel chromatography ((CH2Cl2:MeOH)+1% NH3 (aq, 28 wt%) 0-10% gradient) to give the desired product as a white solid (218 mg, 65%, 2 steps).

[0337] Step f: To a solution of the product from step e (200 mg, 0.327 mmol) in CHCl (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 16 h and concentrated. The crude material was purified by C reverse-phase chromatography (0-70% gradient of (water:ACN) + 1% TFA), followed by partial concentration and addition of KCO. The mixture was extracted with CHCl (3 × 50 mL). The combined organic phases were dried over MgSO and concentrated to give the desired product as a white solid (152 mg, 88%). 1H NMR(400MHz,chloroform-d)δ12.87(s,1H),8.85(d,J=2.1Hz,1H),8.55(ddd,J=4.8,1.7,0.7Hz,1H),8.51(d,J=2.1Hz,1H) ,8.12-8.04(m,2H),7.74-7.66(m,2H),7.60(ddt,J=7.7,1.8,0.8Hz,1H),7.38(d,J=6.3Hz,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=1 2.2Hz,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). ESI MS[M+H] + is C 34 H 34 For N5O, the theoretical value was 528.3 and the measured value was 528.2.

[0338] 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 [ka]

[0339] 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 h, cooled, diluted with MTBE, filtered through Celite, washed twice with water, dried over MgSO, and concentrated to give the desired product, which was used in the next step without further purification (assuming 11 mmol).

[0340] Step bg: The title compound was prepared in a manner similar to Example 1 using step bg. 1 H NMR(400MHz,chloroform-d)δ10.55(d,J=2.4Hz,1H),8.61(d,J=2.0Hz,1H),8.44(d,J=2.0Hz,1H),8.34(dd,J=4.6,1.4Hz,1H),8.1 5-8.07(m,2H),7.79-7.70(m,2H),7.61(d,J=2.4Hz,1H),7.39(dq,J=3.4,2.0Hz,2H),7.32(dd,J=8.3,1.4Hz,1H),7.23-7.18(m ,2H),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). ESI MS[M+H] + is C 37 H 39 For N4O3, the theoretical value was 587.3, and the measured value was 587.3.

[0341] 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 [ka]

[0342] Step a: To a stirred solution of 2-bromopyridine-3-carboxylic acid (1.0 g, 5.0 mmol) in DMF (10 mL) at room temperature, HATU (2.48 g, 6.52 mmol), diisopropylethylamine (1.3 mL, 7.5 mmol), and pyrrolidine (0.45 mL, 5.5 mmol) were added. The reaction mixture was stirred at room temperature for 16 h, diluted with water (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over MgSO and concentrated. The crude material was purified by silica gel chromatography (0–100% gradient of hexanes:EtOAc) to give the desired product as a white solid (755 mg, 60%).

[0343] Step bg: The title compound was prepared in a similar manner to Example 2. 1 H NMR(400MHz,chloroform-d)δ12.15(s,1H),8.85(d,J=2.0Hz,1H),8.76(dd,J=4.8,1.7Hz,1H),8.51(d,J=2.0Hz,1H), 8.15-8.07(m,2H),8.01-7.93(m,2H),7.80(dd,J=7.7,1.7Hz,1H),7.43-7.30(m,3H),7.24(m,1H),4.34-4.26(m,2 H),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). ESI MS[M+H] + is C 38 H 39 For N6O2, the theoretical value was 611.3, and the measured value was 611.3.

[0344] 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 [ka]

[0345] Step a: To a mixture of 2-bromo-3-iodopyridine (2.0 g, 7.0 mmol), morpholine (668 μL, 7.75 mmol), and CsCO (2.52 g, 7.75 mmol) was added toluene (20 mL). The suspension was degassed with nitrogen for 10 min, and Xantphos (611 mg, 1.06 mmol) and Pddba (322 mg, 0.352 mmol) were added. The reaction mixture was stirred at 90 °C for 16 h, cooled, diluted with EtOAc (10 mL), filtered through Celite, and concentrated. The crude material was purified by silica gel chromatography (0 to 100% gradient of hexane:EtOAc) to give the desired product (342 mg, 20%).

[0346] Step bg: The title compound was prepared in a manner similar to Example 1 using step bg. 1H NMR (400MHz, chloroform-d) δ11.37(d,J=2.4Hz,1H),8.65-8.60(m,1H),8.44(d,J=2.0Hz,1H),8.38(dd,J=4.6,1. 4Hz,1H),8.14-8.06(m,2H),7.79-7.71(m,2H),7.64(d,J=2.3Hz,1H),7.39(dq,J=3.9,2.0Hz,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). ESI MS[M+H] + is C 38 H 40 For N5O2, the theoretical value was 598.3, and the measured value was 598.3.

[0347] Example 6: N,N-Dimethyl-2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridine-3-sulfonamide [ka]

[0348] Step a: To a stirred solution of 2-bromopyridine-3-sulfonyl chloride (2.5 g, 9.7 mmol) in THF (50 mL) at 0 °C, N,N-dimethylamine (5.89 mL, 11.8 mmol, 2 M in THF) was added. The reaction mixture was stirred at room temperature for 16 h and concentrated. The crude material was purified by silica gel chromatography (0-70% gradient of hexanes:EtOAc) to give the desired product as an off-white solid (1.1 g, 35%).

[0349] Step bg: The title compound was prepared in a manner similar to Example 1 using step bg. 1 H NMR (400MHz, chloroform-d) δ11.52(s,1H),8.82(dd,J=4.8,1.7Hz,1H),8.61(d,J=2.1Hz,1H),8.47-8. 39(m,2H),7.81-7.73(m,2H),7.73-7.65(m,2H),7.62(d,J=1.3Hz,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(d d,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). ESI MS[M+H] + is C 36 H 38 For N5O3S, the theoretical value was 620.3, and the measured value was 620.3.

[0350] Example 7: 1-[2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridin-3-yl]pyrrolidin-2-one [ka]

[0351] Step a: To a stirred solution of 2-bromo-3-fluoropyridine (5.0 g, 28 mmol) in DMF (60 mL) at 0 °C, 2-pyrrolidone (3.62 g, 42.5 mmol) and NaH (1.5 g, 38 mmol, 60 wt % in oil) were added. The reaction mixture was stirred at 0 °C for 15 min, 85 °C for 16 h, cooled, carefully diluted with water (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over MgSO and concentrated. The crude material was purified by silica gel chromatography (0–100% gradient of hexanes:EtOAc) to give the desired product (3.8 g, 55%).

[0352] Step bg: The title compound was prepared in a manner similar to Example 1 using step bg. 1 H 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). ESI MS[M+H] + is C 38 H 38 For N5O2, the theoretical value was 596.3, and the measured value was 596.3. Example 8: 2-[5-methyl-6-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridin-2-yl]propan-2-ol [ka]

[0353] 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 for 15 min at −15° C. and 16 h at room temperature and then added 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, which was used in the next step without further purification (assuming 5.4 mmol).

[0354] Step bg: The title compound was prepared in a manner similar to Example 1 using step bg. 1 H NMR (400MHz, chloroform-d) δ 10.88 (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). ESI MS[M+H] + is C 38 H 41 For N4O2, the theoretical value was 585.3, and the measured value was 585.3.

[0355] Example 9: 3,6-Dimethyl-6'-{5-[(7S)-7-[(1R)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-2,3'-bipyridine [ka]

[0356] Step a: To a solution of 3-bromo-5-chloro-1H-pyrazolo[3,4-b]pyridine (10 g, 43 mmol) in DMF (150 mL) at 0 °C was added K2CO3 (17.88 g, 129.6 mmol). The mixture was stirred at 0 °C for 30 min. Triphenylchloromethane (14.45 g, 51.84 mmol) was added to the reaction mixture at 0 °C. The mixture was stirred at room temperature for 16 h, and water (100 mL) was added. The aqueous phase was extracted with EtOAc (3 × 60 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, concentrated, and purified by silica gel chromatography (hexane:EtOAc 0–20% gradient) to give the desired product as a white solid (15.98 g, 78%).

[0357] Step b: 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) were placed under nitrogen. Degassed dioxane (20 mL) was added, and the reaction mixture was stirred at 100 °C for 4 h. The mixture was cooled to rt, concentrated, diluted with CHCl2 (50 mL), filtered through Celite to remove solids, and concentrated again to give the desired product, which was used crude in step d.

[0358] 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), PdCl(dppf) (183 mg, 0.250 mmol), and KCO (1.38 g, 10.0 mmol) under nitrogen, degassed dioxane (20 mL) and degassed water (5 mL) were added. The reaction mixture was stirred at 95 °C for 16 h, cooled, concentrated, diluted with CHCl (25 mL), dried over MgSO, and concentrated. The crude material was purified by silica gel chromatography (hexane:EtOAc 0–20% gradient) to give the desired product as a white solid (547 mg, 50%).

[0359] 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), PdCl(dppf) (17.2 mg, 0.0236 mmol), and KCO (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 h, cooled, concentrated, diluted with CHCl (25 mL), dried over MgSO, and concentrated. The crude material was purified by silica gel chromatography (hexane:EtOAc 0–20% gradient) to give the desired product as a white solid (81.2 g, 30%).

[0360] Step e: Product from step d (81.2 mg, 0.140 mmol), B 2p A 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 min. The reaction mixture was stirred at 100 °C for 2 h, cooled, concentrated, diluted with CHCl2 (10 mL), filtered through Celite to remove solids, and concentrated again to give the desired product, which was used crude in Step f.

[0361] Step f: To a mixture of the product from step e (assumed to be 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) under nitrogen, degassed dioxane (0.7 mL) and degassed water (0.14 mL) were added. The reaction mixture was stirred at 95 °C for 16 h, cooled, concentrated, diluted with CHCl (10 mL), dried over MgSO, and concentrated. The crude material was purified by silica gel chromatography (0-15% gradient of CH2Cl2:MeOH) to give the desired product as a gray solid (89 mg, 81%).

[0362] Step g: To a mixture of the product from step f (89 mg, 0.11 mmol) and CHCl (10 mL) at 0 °C, triethylsilane (66.3 mg, 0.570 mmol) was added dropwise, followed by TFA (65.0 mg, 0.570 mmol). The reaction mixture was stirred at room temperature for 1 h and concentrated. The crude material was purified by silica gel chromatography (0-15% gradient of CHCl:MeOH) to give the desired product as a white solid (42.3 mg, 69% yield). 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). ESI MS[M+H] + is C 34 H 35 For N6O, the theoretical value was 543.3 and the measured value was 543.3.

[0363] Example 10: 2-[2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)pyridin-3-yl]propan-2-ol [ka]

[0364] Step a: A mixture of methyl 2-bromonicotinate (1.71 g, 10.0 mmol), 4-chlorophenylboronic acid (1.56 g, 10.0 mmol), K2CO3 (2.76 g, 20.0 mmol), and PdCl2(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 h. The mixture was cooled to rt, concentrated, diluted with CHCl2 (25 mL), dried over MgSO4, and concentrated. The crude material was purified by silica gel chromatography (hexane:EtOAc 0–20% gradient) to give the desired product as a colorless liquid (2 g, 80%).

[0365] Step b: To a solution of the product from step a (2 g, 8 mmol) in THF (20 mL) at 0 °C was added dropwise methylmagnesium bromide (8.0 mL, 24 mmol, 3 M in diethyl ether). The mixture was stirred at rt (room temperature) for 16 h. Saturated NH4Cl(aq) (20 mL) was added and the mixture was extracted with EtOAc (2 × 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%).

[0366] 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), XPhos Pd G3 (221 mg, 0.260 mmol), and dioxane (50 mL) was purged with nitrogen for 10 min. The reaction mixture was stirred at 100 °C for 16 h, cooled to rt, diluted with CHCl2 (50 mL), filtered through Celite to remove solids, and concentrated again to give the desired product, which was used crude in the next step.

[0367] Step dg: The title compound was prepared in a similar manner to Example 2. 1H 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), 8.09-8.02(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=10.7 Hz,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). ESI MS[M+H] + is C 36 H 38 For N5O2, the theoretical value was 572.3, and the measured value was 572.3.

[0368] 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 [ka]

[0369] Step a: To a solution of acetic acid hydrazide (740 mg, 10.0 mmol) and ACN (4 mL) at rt (room temperature) was added dimethylacetamide dimethyl acetal (1.2 g, 10 mmol). The reaction mixture was stirred at 50° C. for 30 min. To a solution of 4-bromoaniline (1.72 mg, 10.0 mmol) in ACN (4 mL) was added, followed by acetic acid (3 mL). The reaction mixture was then stirred at 120° C. for 3 h, cooled, concentrated, and purified by silica gel chromatography (100% EtOAc followed by 95% EtOAc / 5% 0.7 M ammonia in methanol) to give the desired product (832 mg, 35%).

[0370] Step bf: The title compound was prepared in a manner similar 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 .30(d,J=10.8Hz,2H),3.76-3.68(m,4H),3.28(t,J=9.9Hz,1H),3.04-2.75(m,4H),2.5 9(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). ESI MS[M+H] + is C 31 H 32 For N7O, the theoretical value was 518.3, and the measured value was 518.3.

[0371] Example 12: N,N-Dimethyl-4'-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-2H-pyrazolo[3,4-b]pyridin-3-yl}-[1,1'-biphenyl]-2-carboxamide [ka]

[0372] Step a: To a mixture of methyl[2-(dimethylcarbamoyl)phenyl]boronate (1.25 g, 6.48 mmol), 1,4-dibromobenzene (1.52 g, 6.44 mmol), K2CO3 (1.76 g, 12.8 mmol), and PdCl2(dppf) (234 mg, 0.324 mmol) under nitrogen, degassed dioxane (16 mL) and degassed water (16 mL) were added. The reaction mixture was stirred at 70 °C for 4 h, cooled to rt, concentrated, diluted with CHCl2 (25 mL), dried over MgSO4, and concentrated. The crude material was purified by silica gel chromatography (hexane:EtOAc 0–20% gradient) to give the desired product as a colorless liquid (700 mg, 35%).

[0373] Step bf: The title compound was prepared in a manner similar 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),7.7 0-7.52(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=10.7 Hz,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). ESI MS[M+H] + is C 37 H 38 For N5O2, the theoretical value was 584.3 and the measured value was 584.4.

[0374] 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 [ka]

[0375] 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), PdCl(dppf) (293 mg, 0.400 mmol), and KCO 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 h, cooled, diluted with CHCl (200 mL), dried over NaSO, and concentrated. The crude material was purified by silica gel chromatography (0–100% gradient of hexane:EtOAc) to give the desired product as a pale yellow oil (390 mg, 41%).

[0376] Step bf: The title compound was prepared in a manner similar to Example 2, step bf. 1H NMR (400MHz, DMSO-d6, citrate) δ14.03(s,1H),8.91(d,J=2.0Hz,1H),8.75(d,J=2.0Hz,1H),8.29(d,J =8.3Hz,2H),8.02(s,1H),7.80(d,J=8.3Hz,2H),7.69(s,1H),7.62(d,J=7.6Hz,1H),7.31(d,J=7.8H z,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),3.0 6-2.83(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). ESI MS[M+H] + is C 31 H 32 For N7O, the theoretical value was 518.3, and the measured value was 518.3.

[0377] 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. [ka]

[0378] Step a: To a solution of 4-methylbenzenesulfonyl hydrazide (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 as a white solid (33.5 g, 99%).

[0379] Step b: To a mixture of the product from step a (7.63 g, 20.0 mmol), sodium azide (1.56 g, 24.0 mmol), and DMSO (100 mL) at room temperature was added iodine (5.08 g, 20.0 mmol). The mixture was stirred at room temperature for 5 minutes, and methanesulfonic acid (1.30 mL, 20.0 mmol) was added. The reaction mixture was stirred at 100 °C for 4 hours and cooled. To the mixture was added K2CO3 (13.8 g, 100 mmol), followed by methyl iodide (2.49 mL, 40.0 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with EtOAc (1.0 L), washed with water (1 × 1.0 L), washed with 3:2 water-brine (2 × 1.0 L), dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography (0-100% gradient of hexanes: EtOAc) to give the desired product as a pale yellow oil (439 mg, 9%).

[0380] Step cg: The title compound was prepared in a manner similar to Example 2, step bf. 1 H NMR (400MHz, DMSO-d6, citrate) δ13.93(s,1H),8.89(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.23(d,J=8.3H) z,2H),7.88(d,J=8.3Hz,2H),7.68(s,1H),7.62(d,J=7.7Hz,1H),7.31(d,J=7.8Hz,1H),4.29(d,J=12.1Hz ,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). ESI MS[M+H] + is C 32 H 34 For N7O, the theoretical value was 532.3 and the measured value was 532.4.

[0381] 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 [ka]

[0382] Step a: To a mixture of 7-bromo-2,3,4,5-tetrahydro-1H-3-benzpine (565 mg, 2.50 mmol), KCO (691 mg, 5.00 mmol), and DMF (13 mL) was added 2-bromoethyl methyl ether (235 μL, 2.50 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 3 h, at 80 °C for 12 h, cooled, diluted with EtOAc (125 mL), and diluted with 0.2 M NaOH. (aq) (4x100 mL), dried over Na2SO4, and concentrated. The crude material was purified by C18 reverse phase chromatography (5-35% gradient of (water:ACN) + 1% TFA) followed by saturated NaHCO 3(aq) The mixture was neutralized with 0.2 M NaOH and partially concentrated to remove ACN. The mixture was diluted with EtOAc (200 mL) and diluted with 0.2 M NaOH. (aq) (2 x 200 mL), dried over Na2SO4 and concentrated to give the desired product as a pale yellow oil (342 mg, 48%).

[0383] Step bc: The title compound was prepared in a manner similar to Example 2, steps e and f. 1H NMR (400MHz, DMSO-d6, citrate) δ13.97(s,1H),8.89(d,J=2.0Hz,1H),8.74(d,J=2.1Hz,1H),8 .53(dd,J=4.8,1.0Hz,1H),8.21(d,J=8.4Hz,2H),7.79-7.69(m,4H),7.66(dd,J=7.7,2.0Hz, 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). ESI MS[M+H] + is C 31 H 32 For N5O, the theoretical value was 490.3 and the measured value was 490.3.

[0384] Example 16: 3-methyl-2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridin-1-ium-1-oleate [ka]

[0385] 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 wt % in water). The reaction mixture was stirred at room temperature for 14 hours, and additional m-CPBA (115 mg, 0.500 mmol, 75 wt % 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 (0-10% gradient of CHCl:MeOH) to give the desired product as a light brown solid (350 mg, 67%).

[0386] 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) under nitrogen at room temperature was added degassed dioxane (1.0 mL). The reaction mixture was stirred at 110 °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.

[0387] Step cd: The title compound was prepared in a manner similar to Example 1, steps f and g. 1 H NMR (400MHz, DMSO-d6, citrate) δ12.08(d,J=2.7Hz,1H),8.58(d,J=2.0Hz,1H),8.47(d,J=2.1Hz,1H),8.22(t,J=3.9Hz ,1H),8.02(d,J=2.6Hz,1H),7.91(d,J=8.3Hz,2H),7.64-7.58(m,1H),7.54(d,J=7.6Hz,1H),7.42(d,J=8.3Hz,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). ESI MS[M+H] + is C 35 H 35 For N4O2, the theoretical value was 543.3, and the measured value was 543.3.

[0388] 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 [ka]

[0389] Step a: To a mixture of 3-methyl-2-(tributylstannyl)pyridine (1.91 g, 5.00 mmol), 3,6-dibromopyridazine (1.19 g, 5.00 mmol), CuI (190 mg, 0.997 mmol), and Pd(PPh3)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 (0 to 100% gradient of hexanes:EtOAc) to give the desired product (590 mg, 47%).

[0390] Step be: The title compound was prepared in a manner similar to Example 9, step dg. 1 H 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), 7.37-7.78 (m, 1H). 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, 14.5Hz, 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). ESI MS[M+H] + is C 32 H 32 For N7O, the theoretical value was 530.3, and the measured value was 530.3.

[0391] Example 18: 3-[(7S)-7-methyl-7-[(2R)-2-methylpyrrolidin-1-yl]-5,6,8,9-tetrahydrobenzo[7]annulen-3-yl]-5-[4-(3-methylpyridin-2-yl)phenyl]-7H-pyrrolo[2,3-c]pyridazine [ka]

[0392] Step a: A flask containing 2-bromo-5,6,8,9-tetrahydro-benzocyclohepten-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 fitted with a Dean-Stark trap and heated to reflux for 18 h with azeotropic water removal. The mixture was cooled and added dropwise to a mixture of MeMgBr (133 mL, 400 mmol, 3 M in EtO) and THF (400 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, at room temperature for 2 h, and carefully quenched with water (7.2 mL). The mixture was diluted with 1 M HCl. (aq) (500 mL) and MTBE (250 mL) and stirred. The organic phase was diluted with 1 M HCl (aq) (500 mL). The acidic aqueous phases were combined and extracted once with CH2Cl2 (2 x 500 mL). The combined organic phases were concentrated. Water (500 mL) was added and the solution was diluted with 2M NaOH (aq) The mixture was basified by the addition of 2M NaOH (100 mL). MTBE (500 mL) was added and the phases were stirred and separated. The organic phase was diluted with 2M NaOH (100 mL). (aq) (3 x 250 mL) and dried over Na2SO4 to give the crude product as a pale orange solid (21.2 g, 1:1 by drNMR).

[0393] The mixture of diastereomers was dissolved in isopropanol (424 mL) with gentle heating. Once the solids had dissolved, the solution was allowed to cool. The mixture was allowed to stand for 24 hours, and the solid was collected by filtration (no washing) to give the diastereomerically enriched product (5.12 g, 24% recovery, dr NMR of 83:17). The concentrated material was dissolved in isopropanol (102 mL) with gentle heating. Once the solids had dissolved, the solution was allowed to cool. The mixture was allowed to stand for 24 hours, and the solid was collected by filtration (no washing) to give the desired product as a white solid (3.60 g, 70% recovery, dr NMR of ≥ 95:5).

[0394] The diastereomeric mixture may 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)).

[0395] Step b: 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) was added SEMCl (1.33 mL, 7.51 mmol) at room temperature. The reaction mixture was stirred for 16 h, diluted with EtOAc (70 mL), washed with water (3 × 70 mL), washed with brine (70 mL), dried over NaSO, and concentrated. The crude material was purified by silica gel chromatography (hexane:EtOAc 0–50% gradient) to give the desired product (1.44 g, 70%).

[0396] Step c: The desired product was prepared in a similar manner to Example 1, step d.

[0397] Step de: The desired product was prepared in a similar manner to Example 16, step bc.

[0398] Step f: To a solution of the product of step e (129 mg, 0.207 mmol) in CHCl (1 mL) was added TFA (1 mL). The reaction mixture was stirred at rt for 2 h and concentrated. To the residue was added NH (2 mL, 7 M in MeOH). The reaction mixture was stirred at rt for 16 h and concentrated. The crude material was purified by C reverse-phase chromatography (20-80% gradient of (water:ACN) + 1% TFA) to give the desired product as a pale yellow solid (10 mg, 9%). 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). ESI MS[M+H] + is C 35 H 38 For N5, the theoretical value was 528.3 and the measured value was 528.3.

[0399] 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 [ka]

[0400] 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 h and then diluted with water followed by saturated NaHCO. 3(aq) The mixture was carefully quenched with HCl. The phases were separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 15 mL). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated. The crude material was purified by silica gel chromatography (0-10% CH₂Cl₂:MeOH gradient) to give the desired product as a light brown solid (376 mg, 69%).

[0401] 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 h, cooled, diluted with EtOAc (15 mL), filtered through Celite, and concentrated to give the desired product, which was used crude in step c.

[0402] 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 Na2CO3 (62 mg, 0.59 mmol), dioxane (2.7 mL) and water (0.30 mL) were added. The suspension was degassed with nitrogen for 5 min, and PdCl2(dppf) (11 mg, 0.015 mmol) was added. The reaction mixture was stirred at 100 °C for 16 h, cooled, diluted with CHCl2 (15 mL), dried over MgSO4, and concentrated. The crude material was purified by silica gel chromatography ((CHCl2:MeOH) + 1% NH3 (aq, 28 wt%) 0–10% gradient) to give the desired product as a white solid (64 mg, 38%, 2 steps).

[0403] Step d: To a mixture of the product from step c (64 mg, 0.11 mmol) and CHCl (1.2 mL), 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 C reverse-phase chromatography ((water:ACN) + 1% TFA 5-50% gradient), followed by partial concentration and addition of KCO. The mixture was extracted with CHCl (3 × 10 mL). The combined organic phases were dried over MgSO and concentrated to give the desired product as a white solid (17 mg, 31%). 1 H 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). ESI MS [M+H] + is C 32 H 32 For N5, the theoretical value was 486.3 and the measured value was 486.3.

[0404] Example 20: 2,5-dimethyl-6-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2,3-dihydropyridazin-3-one [ka]

[0405] Step a: To a mixture of 6-chloro-5-methyl-3(2H)-pyridazinone (952 mg, 6.59 mmol), KCO (1.18 g, 8.57 mmol), and DMF (13 mL) was added MeI (0.45 mL, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with water (30 mL), and extracted with MTBE (3 × 20 mL) and EtOAc (1 × 20 mL). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over MgSO, and concentrated. The crude material was purified by silica gel chromatography (0–100% gradient of hexanes:EtOAc) to give the desired product as a white solid (816 mg, 78%).

[0406] 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), dioxane (17.2 mL) and water (4.3 mL) were added. 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 0–50% gradient) to give the desired product as a pale yellow solid (1.09 g, 90%).

[0407] Step cg: The title compound was prepared in a manner similar to Example 1, step cg. 1H 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(d t,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, 2H), 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). ESI MS[M+H] + is C 35 H 36 For N5O2, the theoretical value was 558.3, and the measured value was 558.3. Example 21: 2-methyl-2-[2-[4-[5-[(7S)-7-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl]pyridin-3-yl]propanenitrile [ka]

[0408] Step a: A mixture of 2-chloro-3-pyridineacetonitrile (5.0 g, 33 mmol), 4-chlorophenylboronic acid (7.7 g, 49 mmol), 2 M NaCO(aq) (49.2 mL, 98.3 mmol), and dioxane (164 mL) was purged with nitrogen for 10 minutes, after which PdCl(dppf) (2.4 g, 3.3 mmol) was added. The resulting solution was heated to 90 °C. The reaction mixture was stirred at 90 °C for 36 hours, cooled, filtered through Celite to remove solids, and concentrated. The crude material was purified by silica gel chromatography (0-100% gradient of hexanes:EtOAc) to give the desired product.

[0409] Step b: A mixture of the product from step a (1.14 g, 4.98 mmol), methyl iodide (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 to reflux for 3 h. The reaction was cooled to room temperature and diluted with saturated NH4Cl (aq) The reaction was carefully quenched with HCl. The reaction was extracted with EtOAc, and the organics were dried over MgSO4 and concentrated. This material was used directly in the next step without further purification.

[0410] Step cg: The title compound was prepared in a similar manner to Example 1, step c. 1H 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,1 H),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 .21-7.19(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),3.0 2-2.77(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). ESI MS[M+H] + is C 38 H 38 For N5O, the theoretical value was 580.3 and the measured value was 580.3.

[0411] Example 22: 1-[2-[4-[5-[(7S)-7-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl]pyridin-3-yl]cyclobutan-1-ol [ka]

[0412] 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), K2CO3 (13.8 mmol, 100 mmol), and 2:1 ACN:water (375 mL) was purged with nitrogen for 10 minutes, after which Pd(OAc)2 (561 mg, 2.50 mmol) was added. The reaction was heated to 50 °C for 4 hours, cooled, filtered through Celite, concentrated, and purified by silica gel chromatography (0 to 50% gradient of CHCl2:EtOAc) to give the desired product.

[0413] 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 hexanes) was added dropwise, and the reaction was stirred at −78 °C for 90 min. Cyclobutanone (822 μL, 11.2 mmol) was added slowly, and the mixture was allowed to warm slowly to room temperature over 2 h. The reaction was quenched with saturated NaHCO3(aq), extracted with EtOAc, and dried over Na2SO4. The crude material was purified by silica gel chromatography (CHCl:EtOAc 0–50% gradient) to give the desired product.

[0414] Step cg: The title compound was prepared in a manner similar to Example 1, step cg. 1H NMR(400MHz,chloroform-d)δ9.97(s,1H),8.62(dd,J=4.7,1.7Hz,1H),8.54(d,J=2.0Hz,1H),8 .35(d,J=2.0Hz,1H),7.75-7.66(m,5H),7.50(s,1H),7.36-7.33(m,2H),7.28(dd,J=7.8,4 .7Hz,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),3.0 2-2.77(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). ESI MS[M+H] + is C 38 H 39 For N4O2, the theoretical value was 583.3, and the measured value was 583.3.

[0415] 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 [ka]

[0416] 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 h, and 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 h, cooled to room temperature, diluted with EtOAc (200 mL), washed with saturated NaHCO (aq) (1 × 200 mL), dried over Na SO , and concentrated. The crude material was purified by silica gel chromatography (0–100% gradient of hexanes:EtOAc) to give the desired product as a white solid (895 mg, 71%).

[0417] Step b: The desired product was prepared in a similar manner to Example 1, step e.

[0418] Step 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). ESI MS[M+H] + is C 32 H 34 For N7O, the theoretical value was 532.3, and the measured value was 532.3.

[0419] 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 [ka]

[0420] Step a: To a mixture of 7-bromo-2,3,4,5-tetrahydro-1H-3-benzap- ine 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 h and saturated NaHCO3 3(aq) The mixture was carefully quenched with HCl. 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 as a colorless oil (293 mg, 96%).

[0421] 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 min, and PdCl2(dppf) (14 mg, 0.019 mmol) was added. The reaction mixture was stirred at 90 °C for 3 h, cooled, diluted with EtOAc (15 mL), filtered through Celite, and concentrated to give the desired product, which was used crude in step c.

[0422] Step cd: The desired product was prepared in a similar manner to Example 2, steps e and f, using the bromoazaindazole intermediate formed from Example 2, step c. 1H 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). ESI MS[M+H] + is C 33 H 34 For N5, the theoretical value is 500.3 and the measured value is 500.3.

[0423] 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 [ka]

[0424] 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 h, cooled, and concentrated to give the desired product, which was used crude in step b.

[0425] 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) at room temperature was added 3,4-dihydro-2H-pyran (0.92 mL, 10 mmol). The reaction mixture was stirred at 65° C. for 4 h, cooled, and purified with NH 3(aq) (10 mL, 28 wt%) and concentrated. The crude material was purified by silica gel chromatography (hexanes: EtOAc 0-50% gradient) to give the desired product as a white solid (1.20 g, 70%, 2 steps).

[0426] 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 h, cooled, and concentrated. The crude material was purified by silica gel chromatography (0-50% gradient of hexanes:EtOAc) to give the desired product as a white solid (1.16 g, 97%).

[0427] 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 saturated NaHCO 3(aq) (1×20 mL), dried over NaSO, and concentrated. The crude material was purified by silica gel chromatography (0-100% gradient of hexanes:EtOAc) to give the desired product as a colorless oil (711 mg, 91%).

[0428] Step e: To a mixture of the product from step d (711 mg, 1.55 mmol) and CHCl (20 mL), triethylamine (1.08 mL, 7.75 mmol), triphenylphosphine (509 mg, 1.94 mmol), and carbon tetrachloride (0.19 mL, 2.0 mmol) were added. The reaction mixture was stirred at room temperature for 4 h, diluted with EtOAc (100 mL), and saturated NaHCO 3(aq) (1×20 mL), dried over NaSO, and concentrated. The crude material was purified by silica gel chromatography (0-100% gradient of hexanes:EtOAc) to give the desired product as a colorless oil (499 mg, 73%).

[0429] Step fh: The desired product was prepared in a similar manner to Example 2, step df. 1 H NMR(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). ESI MS[M+H] + is C 30 H 30 For N7O2, the theoretical value was 520.3, and the measured value was 520.3.

[0430] Example 26: 3-methyl-6'-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-2,3'-bipyridine [ka]

[0431] Step a: To a mixture of methyl 5-bromo-2-pyridinecarboxylate (648 mg, 3.00 mmol), B2pin2 (762 mg, 3.00 mmol), PdCl2(dppf) (110 mg, 0.150 mmol), and KOAc (589 mg, 6.00 mmol) under nitrogen at room temperature was added degassed dioxane (15 mL). The reaction mixture was stirred at 100 °C for 1 h, cooled, diluted with EtOAc (30 mL), filtered through Celite, and concentrated to give the desired product, which was used crude in Step b.

[0432] Step b: To a mixture of the product from step a (assumed 3.00 mmol), 2-bromo-3-methylpyridine (774 mg, 4.50 mmol), PdCl(dppf) (110 mg, 0.150 mmol), and NaCO (636 mg, 6.00 mmol) at room temperature under nitrogen, degassed toluene (9.0 mL), ACN (6.0 mL), and water (3.0 mL) were added. The reaction mixture was stirred at 70 °C for 2 h, cooled, diluted with EtOAc (30 mL), washed with water, washed with brine, dried over NaSO, and concentrated. The crude material was purified by silica gel chromatography (0 to 100% gradient of hexane:EtOAc) to give the desired product as a light brown solid (524 mg, 76%).

[0433] Step c: To a solution of 2-fluoro-6-bromopyridine (823 μL, 8.00 mmol) in THF (16 mL) at −78° C., LDA (4.00 mL, 8.00 mmol, 2 M ethylbenzene / THF / heptane) was added dropwise. 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). The reaction mixture was stirred at −78° C. for 1 hour and then cooled to −78° C. with saturated NH4Cl. (aq) The mixture was quenched with HCl, 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 as a brown solid (872 mg, 59%).

[0434] Step d: To a mixture of the product from step c (186 mg, 0.500 mmol) in 1:1 i-PrOH:dioxane (2.5 mL) was added hydrazine monohydrate (24 μL, 0.50 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours. To this mixture was added triethylamine (87 μL, 0.60 mmol) and dioxane (2.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, stirred at 60° C. for 1 hour, and 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 give the desired product as an off-white solid (93 mg, 51%).

[0435] Step e: To a mixture of the product from step d (366 mg, 1.00 mmol) and THF (5.0 mL) at room temperature, sodium tert-butoxide (106 mg, 1.10 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 15 minutes, and 4-methylbenzenesulfonyl chloride (191 mg, 1.00 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 30 minutes and diluted with water (25 mL). The precipitated solid was collected by filtration, washed with water, and dried to give the desired product as a brown solid (458 mg, 88%).

[0436] Step fg: The title compound was prepared in a similar manner to Example 16, steps c and d. 1H 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, 1H) z,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). ESI MS[M+H] + is C 33 H 33 For N6O, the theoretical value is 529.3, and the measured value is 529.3.

[0437] 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 [ka]

[0438] 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 h, cooled, diluted with EtOAc (100 mL), washed with 9:1 water:brine (4 × 200 mL), dried over NaSO, and concentrated. The crude material was purified by silica gel chromatography (hexane:EtOAc 0–50% gradient) to give the desired product as a white solid (515 mg, 18%).

[0439] Step be: The title compound (citrate salt) was prepared in a similar manner to Example 1, step 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). ESI MS[M+H] + is C 32 H 33 For N6O, the theoretical value was 517.3, and the measured value was 517.3.

[0440] 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 [ka]

[0441] The title compound was prepared in a manner similar to Example 2 from the appropriate starting materials. 1 H NMR (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. 2Hz,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). ESI MS[M+H] + is C 34 H 33 For FN5O, the theoretical value was 546.3 and the measured value was 546.3. 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 [ka]

[0442] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials.1 H NMR (400 MHz, chloroform-d) δ 8.89 (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). ESI MS[M+H] + is C 35 H 34 For FN4O, the theoretical value was 545.3 and the measured value was 545.3.

[0443] 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 [ka]

[0444] The title compound was prepared in a manner similar to Example 2 from the appropriate starting materials. 1H NMR(400MHz,chloroform-d)δ11.51(s,1H),8.87(d,J=2.1Hz,1H),8.56(ddd,J=4.7,1.8,0.7Hz,1H),8.20(d,J=2.1Hz,1H),7 .67-7.60(m,2H),7.57(dt,J=1.8,0.6Hz,1H),7.50(ddd,J=7.8,1.9,0.7Hz,1H),7.34(d,J=11.8Hz,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). ESI MS[M+H] + is C 35 H 36 For N5O, the theoretical value was 542.3, and the measured value was 542.3. Example 31: 1-[4-[5-[(7S)-7-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl]phenyl]pyridin-2-one [ka]

[0445] The title compound was prepared from the appropriate starting materials in a manner similar to that of Example 2. 1H NMR(400MHz,chloroform-d)δ11.51(s,1H),8.86(d,J=2.1Hz,1H),8.50(d,J=2.1Hz,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=9.2,1.3,0.9Hz,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. 86(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). ESI MS[M+H] + is C 33 H 32 For N5O2, the theoretical value was 530.3 and the measured value was 530.2.

[0446] 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 [ka]

[0447] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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,2 H),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,1 H),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),2.7 5(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). ESI MS[M+H] + is C 34 H 35 For N4O, the theoretical value was 515.3, and the measured value was 515.3.

[0448] 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]annulen-7-yl]-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0449] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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). ESI MS[M+H] + is C 34 H 33 For N4O, the theoretical value was 513.3, and the measured value was 513.3.

[0450] 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]annulen-3-yl]-1H-pyrrolo[2,3-b]pyridine [ka]

[0451] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR (400 MHz, chloroform-d) δ 9.81 (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). ESI MS[M+H] + is C 36 H 38 For FN4, the theoretical value is 545.3 and the measured value is 545.3.

[0452] 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 [ka]

[0453] The title compound was prepared from the appropriate starting materials in a manner similar to Example 9. 1H NMR(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 .8Hz,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, 2H),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). ESI MS[M+H] + is C 34 H 33 For FN5O, the theoretical value was 546.3 and the measured value was 546.3.

[0454] 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 [ka]

[0455] The title compound was prepared from the appropriate starting materials in a manner similar to Example 18. 1H NMR (400MHz, chloroform-d) δ12.27(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=10.6Hz,2H),3.74(d,J=10.7Hz,2H),3.6 7(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, 2H), 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). ESI MS[M+H] + is C 34 H 34 For N5O, the theoretical value was 528.3, and the measured value was 528.3.

[0456] 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 [ka]

[0457] The title compound was prepared from the appropriate starting materials in a manner similar to Example 9. 1H NMR(400MHz,chloroform-d)δ10.36(s,1H),9.17(d,J=2.2Hz,1H),8.99(s,2H),8.65-8.57(m,2H),8.40(d,J=2.5Hz,1H) ,7.65(ddd,J=7.7,1.7,0.8Hz,1H),7.47(dq,J=3.4,1.8Hz,2H),7.30-7.20(m,2H),4.32(d,J=10.7Hz,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. 84(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). ESI MS[M+H] + is C 33 H 33 For N6O, the theoretical value is 529.3, and the measured value is 529.3.

[0458] 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 [ka]

[0459] The title compound was prepared in a manner similar to Example 17 from the appropriate starting materials. 1H NMR(400MHz,chloroform-d)δ10.55(s,1H),9.25(s,2H),8.72-8.63(m,2H),8.42(d,J=2.0Hz,1H),7.76(d,J=2.3Hz,1H),7.68(ddd,J=7 .7,1.7,0.8Hz,1H),7.40(dq,J=4.6,2.1Hz,2H),7.32(dd,J=7.7,4.7Hz,1H),7.24(t,J=8.4Hz,1H),4.32(dd,J=10.6,3.2Hz,2H),3 .74(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),2.8 3(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). ESI MS[M+H] + is C 33 H 33 For N6O, the theoretical value is 529.3, and the measured value is 529.3.

[0460] Example 39: 1-methyl-6-[4-[5-[(7S)-7-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl]pyridin-2-one [ka]

[0461] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(400MHz,chloroform-d)δ9.61(s,1H),8.62(d,J=2.1Hz,1H),8.40(d,J=2.0Hz,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=9.1,1.4Hz,1H),6.18(dd,J=6.8,1.4Hz, 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(t d,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). ESI MS[M+H] + is C 35 H 35 For N4O2, the theoretical value was 543.3, and the measured value was 543.3.

[0462] 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 [ka]

[0463] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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=2.7H) z,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). ESI MS[M+H] + is C 34 H 32 For FN4O, the theoretical value was 531.3, and the measured value was 531.3.

[0464] 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 [ka]

[0465] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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=12.5H z,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). ESI MS[M+H] + is C 34 H 33 For N4O, the theoretical value was 513.3, and the measured value was 513.3.

[0466] 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 [ka]

[0467] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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 .9Hz,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 F NMR (376 MHz, chloroform-d) δ -122.80--122.88 (m). ESI MS [M+H] + is C 34 H 32 For FN4O, the theoretical value was 531.3, and the measured value was 531.3.

[0468] 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 [ka]

[0469] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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=7.6,1.9Hz ,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). ESI MS[M+H] + is C 34 H 32 For ClNO, the theoretical value is 547.2, and the measured value is 547.2.

[0470] 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 [ka]

[0471] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR (400 MHz, chloroform-d): δ 9.79 (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). ESI MS[M+H] + is C 34 H 32 For ClNO, the theoretical value is 547.2, and the measured value is 547.2.

[0472] 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 [ka]

[0473] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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). ESI MS[M+H] + is C 31 H 31 For N6O, the theoretical value was 503.3 and the measured value was 503.2.

[0474] Example 46: 2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridine-3-carbonitrile [ka]

[0475] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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). ESI MS[M+H] + is C 35 H 32 For N5O, the theoretical value was 538.3 and the measured value was 538.2.

[0476] 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 [ka]

[0477] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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),8.07 (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). ESI MS[M+H] + is C 34 H 34 For N5O, the theoretical value was 528.3, and the measured value was 528.3.

[0478] 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 [ka]

[0479] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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),7.23 (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). ESI MS[M+H] + is C 34 H 34 For N5O, the theoretical value was 528.3, and the measured value was 528.3.

[0480] 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 [ka]

[0481] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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),8.05 (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). ESI MS[M+H] + is C 34 H 34 For N5O, the theoretical value was 528.3, and the measured value was 528.3.

[0482] 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 [ka]

[0483] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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). ESI MS[M+H] + is C 35 H 36 For N5O, the theoretical value was 542.3, and the measured value was 542.3.

[0484] 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 [ka]

[0485] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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=2.0Hz ,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). ESI MS[M+H] + is C 35 H 38 For N5, the theoretical value was 528.3 and the measured value was 528.3.

[0486] Example 52: 2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)pyridine-3-carbonitrile [ka]

[0487] The title compound was prepared in a manner similar to Example 2 from the appropriate starting materials. 1H NMR(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). ESI MS[M+H] + is C 34 H 31 For N6O, the theoretical value was 539.3, and the measured value was 539.3.

[0488] 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 [ka]

[0489] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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). ESI MS[M+H] + is C 35 H 36 For N5O, the theoretical value was 542.3, and the measured value was 542.3. 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 [ka]

[0490] The title compound was prepared from the appropriate starting materials in a manner similar to Example 9. 1H NMR(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). ESI MS[M+H] + is C 33 H 33 For N6O, the theoretical value is 529.3, and the measured value is 529.3.

[0491] 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 [ka]

[0492] The title compound was prepared from the appropriate starting materials in a manner similar to Example 9. 1H NMR (400 MHz, chloroform-d) δ 12.16 (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), 7.26-7.7 .22(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). ESI MS[M+H] + is C 32 H 32 For N7O, the theoretical value was 530.3, and the measured value was 530.3.

[0493] 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 [ka]

[0494] The title compound was prepared from the appropriate starting materials in a manner similar to Example 9. 1H NMR(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),8.36 (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=7.7,1.9H z,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),2.80 (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). ESI MS[M+H] + is C 32 H 32 For N7O, the theoretical value was 530.3, and the measured value was 530.3.

[0495] 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]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyrazine [ka]

[0496] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR (400MHz, chloroform-d) δ9.27(s,1H),8.62(d,J=2.0Hz,1H),8.42(d,J=1.8Hz,1H),8.40(s,1 H),7.87-7.73(m,2H),7.73-7.64(m,2H),7.60(d,J=2.5Hz,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). ESI MS[M+H] + is C 36 H 40 For N5, the theoretical value was 542.3 and the measured value was 542.3.

[0497] 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]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyrazine [ka]

[0498] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR (400 MHz, chloroform-d) δ 9.32 (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) H),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). ESI MS[M+H] + is C 36 H 40 For N5, the theoretical value was 542.3 and the measured value was 542.3.

[0499] Example 59: 3,5-dimethyl-2-(4-{5-[(7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyrazine [ka]

[0500] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1 H NMR (400MHz, chloroform-d) δ9.20(s,1H),8.62(s,1H),8.43(d,J=1.3Hz,1H),8.4 0(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). ESI MS [M+H] +is C 34 H 36 For N5, the theoretical value was 514.3 and the measured value was 514.3.

[0501] 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 [ka]

[0502] The title compound was prepared from the appropriate starting materials in a manner similar to Example 9. 1 H NMR (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),2.58-2.4 5(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). ESI MS[M+H] + is C 34 H 38 For N7, the theoretical value is 544.3 and the measured value is 544.3.

[0503] 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]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyridin-3-yl)pyrazine [ka]

[0504] The title compound was prepared from the appropriate starting materials in a manner similar to Example 9. 1 H NMR (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 = 8.2H) z,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). ESI MS[M+H] + is C 34 H 38 For N7, the theoretical value is 544.3 and the measured value is 544.3.

[0505] 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]annulen-7-yl]-2-oxa-5-azabicyclo[2.2.1]heptane [ka]

[0506] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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),2.52 (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). ESI MS[M+H] + is C 35 H 36 For N5O, the theoretical value was 542.3, and the measured value was 542.3.

[0507] Example 63: 3-(4-{5-[(7S)-7-[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-2,5-dimethylpyrazine [ka]

[0508] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR (400 MHz, chloroform-d) δ 9.29 (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), 3.3 5(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). ESI MS[M+H] + is C 36 H 40 For N5O, the theoretical value was 558.3, and the measured value was 558.3.

[0509] 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 [ka]

[0510] The title compound was prepared from the appropriate starting materials in a manner similar to that of Example 2. 1H NMR (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). ESI MS[M+H] + is C 35 H 39 For N6, the theoretical value was 543.3 and the measured value was 543.3.

[0511] 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 [ka]

[0512] The title compound was prepared from the appropriate starting materials in a manner similar to that of Example 2. 1H NMR(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),8.25 (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). ESI MS[M+H] + is C 34 H 35 For N6O, the theoretical value was 543.3 and the measured value was 543.3.

[0513] 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 [ka]

[0514] The title compound was prepared from the appropriate starting materials in a manner similar to that of Example 2. 1H NMR(400MHz,chloroform-d)δ11.68(s,1H),8.93(dd,J=4.8,1.8Hz,1H),8.91(d,J=2.0Hz,1H), 8.56(d,J=2.0Hz,1H),8.26-8.19(m,2H),8.18-8.11(m,3H),7.48-7.36(m,3H),7.24(d,J=7 .9Hz,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). ESI MS[M+H] + is C 35 H 35 For N6, the theoretical value was 539.3 and the measured value was 539.3.

[0515] 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 [ka]

[0516] The title compound was prepared from the appropriate starting materials in a manner similar to Example 19. 1 H NMR(400MHz,chloroform-d)δ11.28(s,1H),8.86(dd,J=2.1,1.0Hz,1H),8.58(d,J=4.8Hz,1H),8 .54-8.43(m,1H),8.19-8.01(m,2H),7.73(d,J=8.1Hz,2H),7.63(d,J=7.7Hz,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,4 H),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). ESI MS[M+H]+ is C 32 H 32 For N5, the theoretical value was 486.3 and the measured value was 486.3.

[0517] 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 [ka]

[0518] The title compound was prepared from the appropriate starting materials in a manner similar to Example 9. 1 H NMR (400 MHz, chloroform-d) δ 10.09 (s, 1H), 8.94 (d, J = 2.1 Hz, 1H), 8.92 (dd, J = 2.4, 0.8 Hz, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.38 (s, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.99 (dd, J = 8.2, 2.3 Hz, 1H), 7.82 (dd, J = 8.2, 0.9 Hz, 1H), 7.47-7.37 (m, 2 H),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). ESI MS[M+H] + is C 35 H 39 For N6, the theoretical value was 543.3 and the measured value was 543.3.

[0519] 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 [ka]

[0520] The title compound was prepared from the appropriate starting materials in a manner similar to Example 9. 1 H NMR (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). ESI MS[M+H] + is C 34 H 35 For N6O, the theoretical value was 543.3 and the measured value was 543.3.

[0521] Example 70: 6-methyl-2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrazolo[3,4-b]pyridin-3-yl}phenyl)pyridine-3-carbonitrile [ka]

[0522] The title compound was prepared in a manner similar to Example 2 from the appropriate starting materials. 1 H NMR(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). ESI MS[M+H] + is C 35 H 33 For N6O, the theoretical value is 553.3, and the measured value is 553.3.

[0523] Example 71: 6-methyl-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 [ka]

[0524] The title compound was prepared in a manner similar to Example 2 from the appropriate starting materials. 1H NMR (400MHz, chloroform-d) δ11.44(s,1H),8.89(d,J=2.0Hz,1H),8.55(d,J=2.0Hz,1H),8.26-8.17(m ,2H),8.17-8.09(m,2H),7.99(d,J=8.0Hz,1H),7.43-7.34(m,2H),7.29-7.26(m,1H),7.24(d,J=8 .2Hz,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). ESI MS[M+H] + is C 36 H 37 For N6, the theoretical value is 553.3 and the measured value is 553.3.

[0525] Example 72: 6-methyl-2-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridine-3-carbonitrile [ka]

[0526] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR (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 .0Hz,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). ESI MS[M+H] + is C 36 H 34 For N5O, the theoretical value was 552.3, and the measured value was 552.3.

[0527] 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 [ka]

[0528] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(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),7.92 -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). ESI MS[M+H] + is C 36 H 37 For N4O, the theoretical value was 541.3 and the measured value was 541.3.

[0529] 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 [ka]

[0530] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(400MHz,chloroform-d)δ9.25(s,1H),8.61(d,J=2.0Hz,1H),8.53(dd,J=5.0,1.7Hz,1H),8.43(d,J=2.0Hz,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=10.7H z,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),2.8 5(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). ESI MS[M+H] + is C 35 H 35 For N4O, the theoretical value was 527.3 and the measured value was 527.2.

[0531] Example 75: 5-methyl-6-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridine-2-carbonitrile [ka]

[0532] The title compound was prepared in a manner similar to Example 1 from the appropriate starting materials. 1H NMR(400MHz,chloroform-d)δ10.30(s,1H),8.64(d,J=2.0Hz,1H),8.44(d,J=2.0Hz,1H),7.84-7.77(m,2H),7.78-7.71( m,1H),7.70-7.62(m,3H),7.60(d,J=7.8Hz,1H),7.45-7.37(m,2H),7.23(d,J=8.2Hz,1H),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=9.7Hz,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). ESI MS[M+H] + is C 36 H 34 For N5O, the theoretical value was 552.3, and the measured value was 552.3.

[0533] Example 76: 5-methyl-6-(4-{5-[(7S)-7-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)pyridine-2-carboxamide [ka]

[0534] Step a: The title compound was prepared during the preparation of Example 75 using azaindole deprotection conditions (5 equivalents of 6N NaOH in dioxane stirred at 70° C. for 1 hour). (aq) ) (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 ,1H),4.31(d,J=10...

Claims

1. Compounds represented by formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: X is CR ５ or N; G １ is N or CR Ｇ１ and G ２ is CR Ｇ２ or N; G ３ is CR Ｇ３ or N; G ４ is CR Ｇ４ or N; G ５ is CR Ｇ５ or N; R Ｇ１ is H, C １－３ Alkyl, halogen, C １－３ selected from the group consisting of haloalkyl, and CN; Each R Ｇ２ , R Ｇ３ , R Ｇ４ and R Ｇ５ are independently H, halo, CN, C １－７ Alkyl, C ３－７ Cycloalkyl, C １－３ Haloalkyl, —O—C １－３ Alkyl, —O—C １－３ Haloalkyl, —NR ａ R ｂ and 5-8 membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein cycloalkyl and heterocycloalkyl are selected from the group consisting of halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, —O—C １－４ substituted with 0-3 groups independently selected from alkyl, and OH; A is a fused ring selected from the group consisting of cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-oxazepane, 1,4-diazepane, oxepane, tetrahydropyran, piperidine, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6]undecane, and cyclooctane, each of which contains 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 5-6 membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and each phenyl and heteroaryl is selected from one R １ａ and 0 to 3 R ３ is replaced by; R １ａ is 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, where the N atom, if present, is optionally oxidized, and wherein each phenyl and heteroaryl is selected from the group consisting of 0-4 R ４ is replaced with; Each R ２ are independently １－７ Alkyl, C ３－７ Alkenyl, C ３－７ Alkynyl, C ３－７ cycloalkyl, -Y １ -O-C １－７ Alkyl, -Y １ -O-C ３－７ Cycloalkyl, —NR ａ R ｂ , —C(O)—C １－７ Alkyl, —C(O)—C ３－７ Cycloalkyl, —S(O) ２ -C １－７ Alkyl, —S(O) ２ -C ３－７ cycloalkyl, —C(O)NR ａ R ｂ , 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 -O-X １ -(5- to 8-membered heterocycloalkyl), wherein said heterocycloalkyl has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each cycloalkyl and heterocycloalkyl is selected from the group consisting of halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, —O—C １－４ substituted with 0-3 groups independently selected from alkyl, and OH; Each R ３ are independently halogen, CN, C １－７ Alkyl, C ２－７ Alkenyl, C ３－７ Alkynyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Halohydroxyalkyl, —O—C １－７ Alkyl, —O—C 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 is independent, C １－７ Alkyl, halo, C １－７ Haloalkyl, —O—C １－７ Alkyl, —O—C １－７ Haloalkyl, CN, -C １－７ Alkylene-CN, Hydroxy, 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 , —O—C １－４ Alkylene -O-C １－４ alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S; -5- to 8-membered heterocycloalkyl having 1 to 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 selected from the group consisting of C １－４ substituted with 0 to 2 groups independently selected from the group consisting of alkyl, halo, and hydroxy; Alternatively, two R on the same ring vertex ４ the groups combine to form an oxo (=O); or Two R on adjacent ring vertices ４ The groups combine to form a 5-6 membered heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein said 5-6 membered heterocycloalkyl is C １－４ substituted with 0 to 2 groups independently selected from the group consisting of alkyl and halo; R ５ is H, C １－４ Alkyl, and —NH ２ selected from the group consisting of: Each X １ is C １－７ Alkylene or C ３－７ is cycloalkylene; Each Y １ is C ２－７ Alkylene or C ３－７ is cycloalkylene; Each R ａ and R ｂ are independently H, C １－７ Alkyl, C １－７ Haloalkyl, C １－４ Alkoxy C １－４ Alkyl, C ３－７ cycloalkyl, wherein said cycloalkyl is optionally selected from the group consisting of —O—C １－３ is substituted with alkyl; or R ａ and R ｂ are taken together with the nitrogen to which they are attached to form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, wherein said 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, —O—C １－４ Alkyl, and X １ -O-C １－３ alkyl, and OH; or two groups on the same ring vertex combine to form oxo (=O), or a pharmaceutically acceptable salt thereof.

2. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: G ３ But, CR Ｇ３ and R Ｇ３ is H; G ４ But, CR Ｇ４ and R Ｇ４ is H; and G ５ Each is CR Ｇ５ and R Ｇ５ is H, or a pharmaceutically acceptable salt thereof.

3. In the formula, G １ is N or CR Ｇ１ and R Ｇ１ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein:

4. In the formula, G ２ is CR Ｇ２ and R Ｇ２ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is H.

5. In the formula, X is CR ５ and R ５ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is H.

6. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is: 【Chemistry 2】 having a formula selected from the group consisting of: Each of these is 1 to 4 R ２ or a pharmaceutically acceptable salt thereof, wherein

7. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein A is of the formula: 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

8. wherein one R ２ But, -NR ａ R ｂ 8. The compound according to any one of claims 1 to 7, wherein:

9. 9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein one R ２ but the following: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

10. 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein one R ２ but, 【Transformation 5】 or a pharmaceutically acceptable salt thereof.

11. In the formula, R １ is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, and pyrazolyl, wherein R １ But one R １ａ and 0 to 2 R ３ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, substituted with:

12. 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R １ but the following: 【Transformation 6】 is selected from the group consisting of wherein the subscript p is 0 or 1, or a pharmaceutically acceptable salt thereof.

13. 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R １ but the following: 【Transformation 7】 is selected from the group consisting of wherein the subscript p is 0 or 1, or a pharmaceutically acceptable salt thereof.

14. 14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein each R ３ When present, independently, halogen, CN, C １－４ Alkyl, C １－４ Harolkill, C １－４ Hydroxyalkyl, C １－４ Halohydroxyalkyl, —O—C １－４ Alkyl, —O—C 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 haloalkyl, or a pharmaceutically acceptable salt thereof.

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

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

17. 17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R １ａ is selected from the group consisting of pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl N-oxide, and phenyl, wherein R １ａ But 0 to 3 R ４ or a pharmaceutically acceptable salt thereof, wherein

18. 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R １ａ but the following: 【Transformation 8】 wherein the subscript q is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

19. 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R １ａ but the following: 【Chemistry 9】 wherein the subscript q is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

20. 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R １ａ but the following: 【Chemistry 10】 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

21. 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R ４ If present, independently, C １－４ Alkyl, halo, C １－４ Haloalkyl, —O—C １－４ Alkyl, —O—C 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 , —O—C １－４ Alkylene -O-C １－４ alkyl, —O-(5- to 6-membered heterocycloalkyl) having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S; 5- to 8-membered heterocycloalkyl having 1 to 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 is selected from the group consisting of C １－４ The compound, or a pharmaceutically acceptable salt thereof, substituted with 0 to 2 groups selected from the group consisting of alkyl, halo, and hydroxy.

22. 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein each R ４ When present, independently, methyl, ethyl, fluoro, chloro, difluoromethyl, trifluoromethyl, CN, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

23. 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein two R on the vertices of adjacent rings are ４ groups join to form a 5-6 membered heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein said 5-6 membered heterocycloalkyl is １－４ The compound, or a pharmaceutically acceptable salt thereof, substituted with 0 to 2 groups independently selected from the group consisting of alkyl and halo.

24. 24. The compound of claim 23, wherein two R on adjacent ring vertices ４ The groups combine to form: 【Chemistry 12】 forming a heterocycloalkyl selected from The heterocycloalkyl is C １－４ The compound is substituted with 0 to 2 groups independently selected from the group consisting of alkyl and halo.

25. 25. The compound of any one of claims 1-2 or 5-24, having a structure selected from Formula (Ia), or Formula (Ia1), or a pharmaceutically acceptable salt thereof: 【Chemistry 13】

26. 25. The compound of any one of claims 1-2, 5, or 8-24, having a structure according to Formula (Ib), or Formula (Ib1), or a pharmaceutically acceptable salt thereof: 【Chemistry 14】 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 may be the same or different, said compound, or a pharmaceutically acceptable salt thereof.

27. 27. The compound of claim 26, having the structure of formula (If), or formula (If1), or a pharmaceutically acceptable salt thereof: 【Chemistry 15】

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

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

30. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 【Chemistry 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 【Chemistry 16-4】 【Chemistry 16-5】 【Chemistry 16-6】 【Chemistry 16-7】 【Chemistry 16-8】 【Chemistry 16-9】 【Chemistry 16-10】 【Chemistry 16-11】 【Chemistry 16-12】 [Chemistry 16-13] [Chemistry 16-14] 【Chemistry 16-15】 【Chemistry 16-16】 [Chemistry 16-17] [Chemistry 16-18] [Chemistry 16-19] 【Chemistry 16-20】 [Chemistry 16-21] [Chemistry 16-22] [Chemistry 16-23] [Chemistry 16-24] or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

31. Compounds represented by formula (II) 【Chemistry 17】 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 contains 1 to 4 R ２ is replaced with; R １ is 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, and each phenyl and heteroaryl is selected from one R １ａ and 0 to 3 R ３ is replaced by; R １ａ is 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, where the N atom, if present, is optionally oxidized, and wherein each phenyl and heteroaryl is selected from the group consisting of 0-4 R ４ is replaced with; Each R ２ became independent and C １－７ Alkyl, C ３－７ cycloalkyl, -Y １ -O-C １－７ Alkyl, —NR ａ R ｂ , 5- to 8-membered heterocycloalkyl, and —NR ａ -(5- to 8-membered heterocycloalkyl), wherein said heterocycloalkyl has 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each cycloalkyl and heterocycloalkyl is selected from the group consisting of C １－４ Alkyl, and —O—C １－４ substituted with 0 to 3 groups independently selected from alkyl; Each R ３ But halogen, C １－７ alkyl, and -O-C １－７ independently selected from the group consisting of alkyl; Each R ４ became independent and C １－７ Alkyl, halo, C １－７ Haloalkyl, —O—C １－７ Alkyl, —O—C 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 , —O—C １－４ Alkylene -O-C １－４ alkyl, -O-(5- to 8-membered heterocycloalkyl) having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, -5- to 8-membered heterocycloalkyl having 1 to 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 selected from the group consisting of C １－４ substituted with 0 to 2 groups independently selected from the group consisting of alkyl, and hydroxy; Alternatively, two R on the vertices of adjacent rings ４ The groups combine to form a 5-6 membered heterocycloalkyl having 1-2 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein said 5-6 membered heterocycloalkyl has 0-2 C １－４ substituted with alkyl; Each X １ But C １－７ alkylene; Each Y １ But C ２－７ alkylene; Each R ａ and R ｂ However, independently, H, C １－７ Alkyl, C ３－７ cycloalkyl, wherein said cycloalkyl is optionally selected from the group consisting of -O-C １－３ is substituted with alkyl; or R ａ and R ｂ together with the nitrogen to which they are attached form a 4-8 membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, wherein said heterocycloalkyl ring is substituted with 0-3 groups, each group independently selected from C １－４ Alkyl, —O—C １－４ Alkyl, and X １ -O-C １－３ alkyl; or two groups on the same ring vertex combine to form oxo (=O), or a pharmaceutically acceptable salt thereof.

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

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

34. 34. A method for treating cancer, fibrosis, viral infection, or pain, comprising administering to a subject in need thereof 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.

35. 34. A method of treating a disease, disorder, or condition mediated at least in part by AXL, comprising administering to a subject in need thereof 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, once daily.

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

37. 37. The method of claim 36, wherein the cancer is cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, uterus, brain, liver, bladder, ovaries, fallopian tubes, peritoneum, testes, head, neck, skin (including melanoma and basal cell carcinoma), mesothelial lining, white blood cells (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, intestine, lung (including small cell lung cancer and non-small cell lung cancer), adrenal gland, thyroid, kidney, or bone; or glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma (including Kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the skin, or testicular seminoma, or any combination thereof.

38. 37. 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. 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. 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. 36. The method of claim 34 or 35, wherein the disease, disorder, or condition is a viral infection.

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

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

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

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

46. 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 that target extracellular production of adenosine, radiation therapy, and chemotherapeutic agents.

47. 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. 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. 49. The method of any one of claims 46-48, 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. 50. The method of claim 49, wherein the one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

51. 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, balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, durvalumab, emiprimab, emvafolimab ezabenlimab, nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimberelimab.

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

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

54. 54. The method of claim 53, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is selected from AB308, donvanalimab, etigilimab, osipelimab, tiragolumab, or vibostolimab.

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

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

57. 57. The method of claim 56, wherein the one or more agents targeting the extracellular production of adenosine are selected from AB598, etrumadenant, inupadenant, taminadenant, caffeine citrate, imaladenant, ciforadenant, and quemlicustat.

58. 57. The method of claim 56, wherein the one or more agents that target the extracellular production of adenosine are AB598, etormadenant and / or quemlicustat.

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

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

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

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

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

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

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

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

68. 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., an anti-CD47 antibody), kinase inhibitors, inhibitors of HIF (e.g., a HIF-2α inhibitor), inhibitors of PARP, RAS signaling inhibitors, immune checkpoint inhibitors, agents that target extracellular production of adenosine, radiation therapy, and chemotherapeutic agents.

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

70. 70. The combination of claim 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. 71. The combination of any one of claims 68-70, 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. 72. The combination of claim 71, wherein said one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1.

73. 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, balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, durvalumab, emiprimab, emvafolimab ezabenlimab, nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimberelimab.

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

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

76. 76. The combination of claim 75, wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is AB308, donvanalimab, etigilimab, osipelimab, tiragolumab, or vibostolimab.

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

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

79. 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, etrumadenant, inupadenant, taminadenant, caffeine citrate, imaladenant, ciforadenant, or quemliculstat.

80. 80. The combination of claim 79, wherein the one or more agents that target the extracellular production of adenosine are etremadenant and / or quemlicustat.

81. 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 belzutifan, ARO-HIF2, PT-2385, and AB521.

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

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

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

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

86. 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. 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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