Indazole compounds as kinase inhibitors

Abstract

This invention provides effective and selective small molecule kinase inhibitors, and methods for using such compounds in the treatment of cancer. [Solution] An indazole compound represented by formula (I) and a method for treating diseases and / or conditions associated with FGFR inhibition are provided. JPEG2026048777000247.jpg55170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Patent Application No. 63 / 132,031, filed on 30 December 2020, and U.S. Provisional Patent Application No. 63 / 216,879, filed on 30 June 2021. Each of these applications is incorporated herein by reference in its entirety.

[0002] This disclosure relates to indazole compounds useful for treating cancer, pharmaceutical compositions comprising one or more such indazole compounds, and methods of using such indazole compounds in the treatment of cancer. [Background technology]

[0003] Kinase inhibitors have been used to treat cancer by blocking the activity of kinases, thereby inhibiting the mitotic process, for example. These kinase inhibitors are often small molecules that target kinases to block the development, growth, or spread of cancer.

[0004] However, despite the existence of various kinase inhibitors, there remains a need for selective inhibitors used to treat diseases, such as hyperproliferative disorders, that offer one or more advantages compared to current compounds. These advantages include: improved activity and / or efficacy; a beneficial kinase selectivity profile according to the respective therapeutic needs; improved side effect profiles, e.g., reduced undesirable side effects, reduced side effect intensity, or reduced (cyto)toxicity; improved targeting of mutant receptors in affected cells; improved physicochemical properties, e.g., improved solubility / stability in water, body fluids, and / or pharmaceutical formulations; improved pharmacokinetic properties, e.g., enabling dose reduction or simplification of drug delivery schemes; and simplified production of active pharmaceutical ingredients, e.g., shortened synthesis pathways or simplified purification. [Prior art documents] [Patent Documents]

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Rev. Cancer, 10(2): pp. 116-129, 2010 [Overview of the project] [Problems that the invention aims to solve]

[0007] The compounds disclosed herein provide effective and selective small molecule kinase inhibitors. [Means for solving the problem]

[0008] In some embodiments, the present disclosure relates to compounds of formula (I).

[0009] [ka]

[0010] or a pharmaceutically acceptable salt thereof [In the formula, n = 1, 2, or 3, m = 0, 1, 2, or 3, Each R 1 These are independently H, CN, or optionally substituted C1-C6 alkyl groups. Each R 2 These are independently H, CN, or optionally substituted C1-C6 alkyl groups. or two R atoms bonded to the same carbon atom 1 The groups, together with the carbon atoms to which both are bonded, optionally form a substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring. or two R atoms bonded to the same carbon atom 1 The group, together with its carbon atom, represents a carbonyl group (C=O), or two R atoms bonded to the same carbon atom 2 The groups, together with the carbon atoms to which both are bonded, optionally form a substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring. or two R atoms bonded to the same carbon atom 2 The group, together with its carbon atom, represents a carbonyl group (C=O), or two R atoms bonded to different carbon atoms 1The groups together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or two Rs attached to different carbon atoms 2 groups together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or R 1 groups and R 2 groups are attached to form a 6- to 9-membered bridged bicyclic ring, A = N or CH, Z = S(O)2; S(O); O, NR 3 or CR 4 R 4' where R 3 is H; optionally substituted C1-C6 alkyl, 3- to 5-membered cycloalkyl, 3- to 5-membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O)2R c ; or -S(O)2NR a R b or or R 3 is R 1 or R 2 together form an optionally substituted 3- to 7-membered heterocycloalkyl ring, R a is H or C1-C6 alkyl, or R b is H or C1-C6 alkyl, or or R a and R b together with the N atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring, R c is optionally substituted C1-C6 alkyl, or cycloalkyl, or R 4 is H, -F, or optionally substituted C1-C6 alkyl, or R 4'This is H, -F, -OH, -CN, -NH2, -NH(C1~C3 alkyl), -N(C1~C3 alkyl)2, -N(C1~C3 alkyl)-SO2(C1~C3 alkyl), -C1~C6 haloalkyl, optionally substituted C1~C6 alkyl, or optionally substituted C1~C6 alkoxyl. or R 4 and R 4' These, together with the C atom to which they are bonded, may form a substituted 3- to 7-membered heterocycloalkyl ring or a substituted 3- to 7-membered cycloalkyl ring, or R 4 and R 4' These two, together with the carbon atom to which they are bonded, either form an oxo group, or R 4' R 1 Or R 2 Together with it, it forms a optionally substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring, Y is a 5- or 6-membered heteroaryl ring, or a 6-membered aryl ring. Q 5 Q 6 Q 7 Q 8 , and Q 9 These are, independently, N or CR. 5 Q 5 Q 6 Q 7 Q 8 , and Q 9 One or two of them are N, and the rest are CR 5 And, R 5 These are H, halogen, C1-C3 alkyl; C1-C3 alkoxyl, or cycloalkyl. X = O, S, or NR, and R is H or C1-C3 alkyl. R 6 These are C1-C6 alkyl groups, R 7These are H, halogen, -C1~C6 alkyl; -C1~C6 alkoxyl, or -cycloalkyl, R 8 This includes H, halogens, -C1~C6 alkyl; -C1~C6 alkoxyl, or -cycloalkyl.

[0011] In some embodiments, the compound of formula (I) (In the formula, n=1, 2, or 3, m = 1, 2, or 3, Each R 1 These are independently H; or optionally substituted C1-C6 alkyl groups. Each R 2 These are independently H; or optionally substituted C1-C6 alkyl groups. or two R atoms bonded to the same carbon atom 1 The groups, together with the carbon atoms to which both are bonded, optionally form a substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring. or two R atoms bonded to the same carbon atom 1 The group, together with its carbon atom, represents a carbonyl group (C=O), or two R atoms bonded to the same carbon atom 2 The groups, together with the carbon atoms to which both are bonded, optionally form a substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring. or two R atoms bonded to the same carbon atom 2 The group, together with its carbon atom, represents a carbonyl group (C=O), or two R atoms bonded to different carbon atoms 1 The groups, together with the carbon atoms to which they are bonded, form a 3- to 7-membered cycloalkyl ring, or two R atoms bonded to different carbon atoms 2The groups, together with the carbon atoms to which they are bonded, form a 3- to 7-membered cycloalkyl ring, or R 1 Base and R 2 The bases combine to form a 6-9 membered bridged biring ring, A=N or CH Z=S(O)²;S(O);O, NR 3 or CR 4 R 4' And, R 3 H; optionally substituted C1-C6 alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O)2R c ; or -S(O)2NR a R b And, R a Is it H or C1-C6 alkyl? R b Is it H or C1-C6 alkyl? or R a and R b These, together with the N atom to which they are bonded, form a optionally substituted 3- to 7-membered heterocycloalkyl ring. R c Depending on the case, it may be a substituted C1-C6 alkyl or cycloalkyl group. R 4 is either H or a C1-C6 alkyl group which may be substituted. R 4' is H, -OH, or a C1-C6 alkyl group which may be substituted. or R 4 and R 4' These, together with the C atom to which they are bonded, form a optionally substituted 3- to 7-membered heterocycloalkyl ring. Y is a 5- or 6-membered heteroaryl ring, Q 5 Q 6 Q7 , Q 8 , and Q 9 are each independently N or CR 5 , Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 one or two of are N and the rest are CR 5 , R 5 is H, halogen, C1-C3 alkyl; C1-C3 alkoxyl, or cycloalkyl, X = O, S, or NR, where R is H or C1-C3 alkyl, R 6 is C1-C6 alkyl, R 7 is H, halogen, -C1-C6 alkyl; -C1-C6 alkoxyl, or -cycloalkyl, R 8 is a compound such as H, halogen, -C1-C6 alkyl; -C1-C6 alkoxyl, or -cycloalkyl).

[0012] Stereoisomers of the compounds of formula (I), as well as their pharmaceutical salts and solvates are also described. Methods of using the compounds of formula (I), as well as pharmaceutical compositions containing the compounds of formula (I) are described.

Mode for Carrying Out the Invention

[0013] The present disclosure may be more fully understood by reference to the following description, which includes the following definitions and examples. Certain features of the disclosed compositions and methods described herein in the context of separate aspects may also be provided in combination with a single aspect. Instead, for the sake of brevity, the various features of the disclosed compositions and methods described in the context of a single aspect may also be provided separately or in any sub-combination.

[0014] Where used herein, the terms “occasionally substituted” or “substituted” refer to substituents as defined herein, which are halo (i.e., -F, -Cl, -Br, -I), cyano, -OH, -C1-C6 alkyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, -C3-C6 spirocycloalkyl, 3-7 member spiroheterocycloalkyl, crosslinked cycloalkyl, crosslinked heterocycloalkyl, C2 ~C6 alkenyl, C2~C6 alkynyl, C1~C6 haloalkyl (e.g., -CF3;-CHF2, -CH2CF3, etc.), -C1~C6 alkoxy, -C1~C6 haloalkoxy (e.g., -OCF3;-OCHF2, -OCH2CF3, etc.), C1~C6 alkylthio (e.g., -SCH3;-SCH2CH3, etc.), C1~C6 alkylamino (e.g., -CH2NH2;-CH2CH2NH2, etc.), -NH2, -NH(C1~C6 alkyl), -N(C1~C -6 Alkyl)2,-NH(C1~C6 alkoxy),-C(O)NHC1~C6 alkyl,-C(O)N(C1~C6 alkyl)2,-COOH,-C1~C6 alkylCOOH 、- C3-C6 cycloalkyl COOH, -C(O)NH2, -C1-C6 alkyl CONH 2、-C3~C6 cycloalkyl CONH2, -C1~C6 alkyl CONHC1~C6 alkyl, -C1~C6 alkyl CON(C1~C6 alkyl)2, -C(O)C1~C6 alkyl, -C(O)OC1~C6 alkyl, -NHCO(C1~C6 alkyl), -N(C1~C6 alkyl)C(O)(C1~C6 alkyl), -S(O)C1~C6 alkyl, -S(O)2C1~C6 alkyl, oxo (i.e., =O), 6~12 membered aryl, or 5~12 membered heteroaryl groups may be substituted, but substitution is not necessarily required. In other embodiments, "optionally substituted" or "substituted" means that the substituent may be substituted with one or more of the following groups: -C(O)(C1-C6 haloalkyl), -NHSO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), or -P(O)(C1-C6 alkyl)2 (e.g., -P(O)(CH3)2), but is not necessarily substituted. In some embodiments, each of the above optional substituents is optionally substituted with one or two of these groups.

[0015] When a range of carbon atoms, such as C1 to C6, is used herein, it encompasses the entire range of carbon atoms, as well as individual numbers. For example, "C1 to C3" means C 1~ C3, C 1~ C2, C 2~ This includes C3, C1, C2, and C3. Therefore, for example, the "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms (e.g., 1, 2, 3, or 4), i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. The "C1-C6 alkyl" group refers to all alkyl groups having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6).

[0016] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl group may be branched or linear. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, and t-butyl. Examples of linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and n-heptyl. Alkyl groups may have 1 to 30 carbon atoms (wherever this appears herein, a numerical range is always specified; for example, "1 to 30" refers to each integer within the given range. For example, "1 to 30 carbon atoms" means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms. However, the definitions of this invention also cover instances of the term "alkyl" where no numerical range is specified). The "alkyl" group may also be an intermediate-sized alkyl having 1 to 12 carbon atoms. The "alkyl" group may also be a lower alkyl having 1 to 6 carbon atoms. Alkyl groups may be substituted or unsubstituted. Although merely illustrative, "C1-C5 alkyl" indicates that there are 1 to 5 carbon atoms in the alkyl chain, meaning the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and linear), etc. Typical alkyl groups, though by no means limited to these, include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. In some embodiments, "Me" is methyl (e.g., CH3).

[0017] As used herein, “alkenyl” refers to an alkyl group containing one or more double bonds in a linear or branched hydrocarbon chain. The alkenyl group may be unsubstituted or substituted.

[0018] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a linear or branched hydrocarbon chain. The alkynyl group may be unsubstituted or substituted.

[0019] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is completely saturated (without double or triple bonds). If it consists of two or more rings, the rings may be linked together in a condensed form. Cycloalkyl groups can contain between 3 and 12 carbon atoms. For example, C3-C6 cycloalkyl groups indicate that the ring contains between 3 and 6 carbon atoms, and this ring is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. Cycloalkyl groups may be unsubstituted or substituted.

[0020] As used herein, the term “spirocycloalkyl ring” refers to a cycloalkyl ring that shares one carbon atom with another cyclic ring. For example, a 3- to 7-membered spirocycloalkyl ring indicates the presence of 3, 4, 5, 6, or 7 carbon atoms within a cycloalkyl ring that shares a single carbon atom with another cyclic ring. Examples of exemplary 3- to 7-membered spirocycloalkyl groups bonded to a piperidine ring are shown below:

[0021] [ka]

[0022] As used herein, "aryl" refers to a carbocyclic (all-carbon), monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbocyclics share a chemical bond) having a completely delocalized pi-electron system throughout the entire ring. The number of carbon atoms in an aryl group can vary. For example, an aryl group may be C6-C6 14 Aryl group, C6~C 10The group can be an aryl group or a C6 aryl group. Examples of aryl groups, but not limited to these, include benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0023] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic ring system (a ring system having a completely delocalized pi-electron system) containing one or more heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group may contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term “heteroaryl” includes a fused ring system in which two rings, e.g., at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl rings may also contain a bridgehead nitrogen atom. Examples, but are not limited to, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, and pyrazolo[1,5-a]pyrimidine. The heteroaryl group may be substituted or unsubstituted.

[0024] As used herein, “heterocycloalkyl” refers to monocyclic, bicyclic, and tricyclic ring systems of up to 3, 4, 5, 6, 7, 8, 9, 10, and 18 members, in which carbon atoms together with heteroatoms from 1 to 5 carbon atoms to form the ring system. Heterocycloalkyls may optionally contain one or more unsaturated bonds located in this manner, however, a completely delocalized pi-electron system does not occur throughout the entire ring. Heteroatoms are, but are not limited to, elements other than carbon, including oxygen, sulfur, and nitrogen. Heterocycloalkyls may further contain one or more carbonyl or thiocarbonyl functional groups, thereby including oxo and thio systems, e.g., lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates, in the definition. If composed of two or more rings, the rings may be linked together in a fused form. Furthermore, any nitrogen in the heterocycloalkyl may be quaternized. Heterocycloalkyls may be unsubstituted or substituted.Examples of such "heterocycloalkyl" groups, but not limited to these, include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxatian, 1,4-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxatian, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoly Examples include imidazolidine, isoxazolidine, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidinone, morpholine, oxiran, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-condensed analogs (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).

[0025] As used herein, the term “spiroheterocycloalkyl ring” refers to a heterocycloalkyl ring that shares one carbon atom with another cyclic ring. For example, a 3- to 7-membered spiroheterocycloalkyl ring indicates that the heterocycloalkyl ring contains 3, 4, 5, 6, or 7 atoms, and that only one of the carbon atoms in that heterocycloalkyl ring is also a member of another cyclic ring. Exemplary 3- to 7-membered spiroheterocycloalkyl groups bonded to a piperidine ring are shown below as examples:

[0026] [ka]

[0027] As used herein, the term “bridged bicyclic ring” refers to a ring system comprising two linked cycloalkyl or heterocycloalkyl rings sharing at least three atoms, for example, a 6- to 9-membered bridged bicyclic ring indicates the presence of 6, 7, 8, or 9 atoms within the bridged bicyclic ring. Exemplary 6- to 9-membered bridged bicyclic rings are shown below as examples:

[0028] [ka]

[0029] As used herein, the term "amino" refers to the -NH2 group.

[0030] As used herein, the term "hydroxy" refers to the -OH group.

[0031] As used herein, the terms "halogen atom" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0032] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not invalidate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxyl or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting compounds with bases to form salts, such as ammonium salts, alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, salts of organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids, such as arginine and lysine.

[0033] Other pharmaceutically acceptable salts include trifluoroacetate.

[0034] Where absolute stereochemistry is not explicitly shown for any compound described herein having one or more chiral centers, it should be understood that each center may independently be in an R-configuration, an S-configuration, or a mixture thereof. Thus, the compounds provided herein may be pure as enantiomers, enantiomer-enriched, racemic mixtures, pure as diastereomers, diastereomer-enriched, or stereoisomeric mixtures. In addition, it should be understood that in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, each double bond may independently be E or Z or a mixture thereof. It is also understood that all possible diastereomers are assumed for any compound described herein having one or more chiral centers. It is also understood that all tautomers are assumed for any compound described herein. It is also understood that all isotopes of the atoms contained in any compound described herein are assumed. For example, any case of hydrogen may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium), or other isotopes. Any instance of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes. Any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes. Any instance of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes. Any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0035] As used herein, the term “kinase inhibitor” means any compound, molecule, or composition that inhibits or reduces the activity of a kinase. Inhibition can be achieved, for example, by blocking the phosphorylation of the kinase (e.g., by competing with adenosine triphosphate (ATP), the phosphorylating entity), by binding to a site outside the active site, by affecting its activity through a structural change, or by depriving the kinase of access to the chaperone systems of molecules on which it depends for cellular stability, resulting in their ubiquitination and degradation.

[0036] As used herein, “subject,” “host,” “patient,” and “individual” are used interchangeably and given their ordinary meanings, and also refer to organisms possessing FGFR proteins. This includes mammals, such as humans, non-human primates, ungulates, dogs, cats, horses, mice, rats, etc. The term “mammal” includes both humans and non-human mammals.

[0037] The terms “sample” or “biological sample” are to be used in their ordinary sense and encompass a wide variety of sample types obtained from living organisms and can be used in imaging assays, diagnostic assays, prognostic assays, or monitoring assays. This term includes blood and other liquid samples of biological origin, solid tissue samples, such as biopsy specimens or tissue cultures or cells derived therefrom and their offspring. This term includes samples that have been manipulated after acquisition by any method, such as treatment with reagents, solubilization, or enrichment with a particular component. The term encompasses clinical samples and also includes cells in cell cultures, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.

[0038] Terms such as “treatment,” “to treat,” and “to treat” are given their ordinary meanings and are included herein to generally refer to obtaining a desired pharmacological and / or physiological effect. The effect may be a prophylactic effect in that it completely or partially prevents a disease or its symptoms, and / or a therapeutic effect in that it partially or completely stabilizes or cures a disease and / or adverse effects caused by the disease. “Treatment,” as used herein, is given its ordinary meaning and also encompasses any treatment of a disease in mammals, especially humans, and includes: (a) preventing the development of a disease or symptoms in an object that may be susceptible to the disease or symptoms but has not yet been diagnosed with the disease or symptoms; (b) inhibiting the symptoms of a disease, e.g., stopping its onset; and / or (c) reducing the symptoms of a disease, e.g., causing regression of the disease or symptoms.

[0039] The terms “cancer,” “neoplasm,” and “tumor” are used herein interchangeably, with their common meanings attached, and refer to cells exhibiting relatively autonomous growth, and thus cells exhibiting an abnormal growth phenotype characterized by a significant loss of control over cell proliferation. Generally, cells targeted for detection or treatment in this application include precursor, precancerous (e.g., benign), malignant, premetastatic, metastatic, and nonmetastatic cells. As used herein, “FGFR-related cancer” refers to cancers involving increased activity in mutant FGFR kinases, such as sustained activation of FGFR.

[0040] The term “control” is given its ordinary meaning and also includes a sample or standard substance used for comparison with a sample that has been tested, treated, characterized, analyzed, etc. In some embodiments, the control is a sample obtained from a healthy patient or a non-tumor tissue sample obtained from a patient diagnosed with a tumor. In some embodiments, the control is a historical control or standard reference value or range of values. In some embodiments, the control is a comparison with a wild-type FGFR configuration or scenario.

[0041] Any substantially plural and / or singular use herein can be translated from plural to singular and / or singular to plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly described herein for clarity. The indefinite article "a" or "an" does not exclude plural. The mere fact that certain means are enumerated in different dependent claims does not imply that these means cannot be combined and used advantageously. No reference numeral in the claims shall be construed as limiting scope.

[0042] In some embodiments, the present disclosure relates to compounds of formula (I).

[0043] [ka]

[0044] Alternatively, the subject may be a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, n in the compound of formula (I) is 1, 2, or 3.

[0046] In some embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3.

[0047] In other embodiments, m of the compound of formula (I) is 0, 1, 2, or 3. In some embodiments, m of the compound of formula (I) is 0 or 1. In some embodiments, m of the compound of formula (I) is 0, 1, or 2. In some embodiments, m of the compound of formula (I) is 1 or 2. In some embodiments, m of the compound of formula (I) is 2 or 3.

[0048] In other embodiments, m in the compound of formula (I) is 1, 2, or 3.

[0049] In some embodiments, m is 1. In other embodiments, m is 2. In other embodiments, m is 3.

[0050] In some embodiments, m is 0.

[0051] In some embodiments, each R of the compound of formula (I) 1 These are independently H, CN, or optionally substituted C1-C6 alkyl groups.

[0052] In some embodiments, each R of the compound of formula (I) 1 These are independently H or optionally substituted C1-C6 alkyl groups.

[0053] In some embodiments, at least one R of the compound of formula (I) 1 is H. In other embodiments, each R of the compound of formula (I) 1 H is H.

[0054] In some embodiments, the R of the compound of formula (I) 1 These include optionally substituted C1-C6 alkyl groups, such as optionally substituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc.

[0055] In some embodiments, the R of the compound of formula (I) 1 These are unsubstituted C1-C6 alkyl groups, such as C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0056] In some embodiments, the R of the compound of formula (I) 1 It is -CH3.

[0057] In some embodiments of the compound of formula (I), one or more R 1 H is H, and one or more R 1 These are C1-C6 alkyl groups that may be substituted depending on the case.

[0058] In some embodiments of the compound of formula (I), one or more R 1 R is a substituted C1-C6 alkyl. In some embodiments of the compound of formula (I), one or more R 1 The substituted C1-C6 alkyl group is, for example, -CH2OH, -CH2N(CH3)2, or -CH2-CN, -CH2SO2CH3, or -CH2N(CH3)SO2CH3.

[0059] In some embodiments, each R of the compound of formula (I) 2 These are independently H, CN, or optionally substituted C1-C6 alkyl groups.

[0060] In some embodiments, each R of the compound of formula (I) 2 These are independently H or optionally substituted C1-C6 alkyl groups.

[0061] In some embodiments, at least one R of the compound of formula (I) 2 is H. In other embodiments, each R of the compound of formula (I) 2 H is H.

[0062] In some embodiments, the R of the compound of formula (I) 2 These include optionally substituted C1-C6 alkyl groups, such as optionally substituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc.

[0063] In some embodiments, the R of the compound of formula (I) 2 These include unsubstituted C1-C6 alkyl groups, for example, optionally substituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc.

[0064] In some embodiments, the R of the compound of formula (I) 2 It is -CH3.

[0065] In some embodiments of the compound of formula (I), one or more R 2 H is H, and one or more R 2 These are C1-C6 alkyl groups that may be substituted depending on the case.

[0066] In some embodiments of the compound of formula (I), one or more R 2 R is a substituted C1-C6 alkyl. In some embodiments of the compound of formula (I), one or more R 1 The substituted C1-C6 alkyl group is, for example, -CH2OH, -CH2N(CH3)2, or -CH2-CN, -CH2SO2CH3, or -CH2N(CH3)SO2CH3.

[0067] In some embodiments of the compound of formula (I), two R atoms bonded to the same carbon atom 1 The groups, together with the carbon atom to which both are bonded, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring.

[0068] In some embodiments of the compound of formula (I), two R atoms bonded to the same carbon atom 1The groups, together with the carbon atom to which both are bonded, form a optionally substituted 3- to 7-membered spirocycloalkyl ring. In some embodiments, two R groups 1 The 3- to 7-membered spirocycloalkyl rings formed by the group are optionally substituted 3-membered spirocycloalkyl rings, optionally substituted 4-membered spirocycloalkyl rings, optionally substituted 5-membered spirocycloalkyl rings, optionally substituted 6-membered spirocycloalkyl rings, optionally substituted 7-membered spirocycloalkyl rings, optionally substituted spirocyclopropyl rings, optionally substituted spirocyclobutyl rings, optionally substituted spirocyclopentyl rings, optionally substituted spirocyclohexyl rings, or optionally substituted spirocycloheptyl rings.

[0069] In some embodiments, two R 1 The ring formed by the group is a spirocyclopropyl ring.

[0070] In some embodiments, two R 1 The three rings formed by the group are spirocyclobutyl rings.

[0071] In some embodiments, two R 1 The ring formed by the group is a spirocyclopentyl ring.

[0072] In some embodiments, two R 1 The ring formed by the group is a spirocyclohexyl ring.

[0073] In some embodiments, two R 1 The ring formed by the group is a spirocycloheptyl ring.

[0074] In other embodiments of the compound of formula (I), two R atoms bonded to the same carbon atom 1 The groups, together with the carbon atom to which both are bonded, form a optionally substituted 3- to 7-membered spiroheterocycloalkyl ring. In some embodiments, two R groups1 The 3- to 7-membered spiroheterocycloalkyl rings formed by the group may include optionally substituted 3-membered spiroheterocycloalkyl rings, optionally substituted 4-membered spiroheterocycloalkyl rings, optionally substituted 5-membered spiroheterocycloalkyl rings, optionally substituted 6-membered spiroheterocycloalkyl rings, optionally substituted 7-membered spiroheterocycloalkyl rings, optionally substituted spiroazilidinyl rings, optionally substituted spiroazetidinyl rings, optionally substituted spiropyrrolidinyl rings, optionally substituted spiropiperidinyl rings, optionally substituted spiroazepanyl rings, optionally substituted spirooxyranyl rings, optionally substituted spirooxetanyl rings, optionally substituted spirotetrahydrofuranyl rings, optionally substituted spirotetrahydropyranyl rings, optionally substituted spirooxepanyl rings, etc.

[0075] In some embodiments of the compound of formula (I), two R atoms bonded to the same carbon atom 1 The group, together with its carbon atom, represents a carbonyl group (C=O).

[0076] In some embodiments of the compound of formula (I), two R atoms bonded to the same carbon atom 2 The groups, together with the carbon atom to which both are bonded, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring.

[0077] In some embodiments of the compound of formula (I), two R atoms bonded to the same carbon atom 2 The groups, together with the carbon atom to which both are bonded, form a optionally substituted 3- to 7-membered spirocycloalkyl ring. In some embodiments, two R groups 2The 3- to 7-membered spirocycloalkyl ring formed by the group is optionally a substituted 3-membered spirocycloalkyl ring, optionally a substituted 4-membered spirocycloalkyl ring, optionally a substituted 5-membered spirocycloalkyl ring, optionally a substituted 6-membered spirocycloalkyl ring, optionally a substituted 7-membered spirocycloalkyl ring, optionally a substituted spirocyclopropyl ring, optionally a substituted spirocyclobutyl ring, optionally a substituted spirocyclopentyl ring, optionally a substituted spirocyclohexyl ring, or optionally a substituted spirocycloheptyl ring.

[0078] In some embodiments, two R 2 The ring formed by the group is a spirocyclopropyl ring.

[0079] In some embodiments, two R 2 The ring formed by the group is a spirocyclobutyl ring.

[0080] In some embodiments, two R 2 The ring formed by the group is a spirocyclopentyl ring.

[0081] In some embodiments, two R 2 The ring formed by the group is a spirocyclohexyl ring.

[0082] In some embodiments, two R 2 The spirocycloalkyl ring formed by the group is a spirocycloheptyl ring.

[0083] In other embodiments of the compound of formula (I), two R atoms bonded to the same carbon atom 2 The groups, together with the carbon atom to which both are bonded, form a optionally substituted 3- to 7-membered spiroheterocycloalkyl ring. In some embodiments, two R groups 2The 3- to 7-membered spiroheterocycloalkyl rings formed by the group may include optionally substituted 3-membered spiroheterocycloalkyl rings, optionally substituted 4-membered spiroheterocycloalkyl rings, optionally substituted 5-membered spiroheterocycloalkyl rings, optionally substituted 6-membered spiroheterocycloalkyl rings, optionally substituted 7-membered spiroheterocycloalkyl rings, optionally substituted spiroazilidinyl rings, optionally substituted spiroazetidinyl rings, optionally substituted spiropyrrolidinyl rings, optionally substituted spiropiperidinyl rings, optionally substituted spiroazepanyl rings, optionally substituted spirooxyranyl rings, optionally substituted spirooxetanyl rings, optionally substituted spirotetrahydrofuranyl rings, optionally substituted spirotetrahydropyranyl rings, optionally substituted spirooxepanyl rings, etc.

[0084] In some embodiments of the compound of formula (I), two R atoms bonded to the same carbon atom 2 The group, together with its carbon atom, represents a carbonyl group (C=O).

[0085] In some embodiments of the compound of formula (I), two R atoms bonded to different carbon atoms 1The groups, together with the carbon atoms to which they are bonded, optionally form a substituted 3- to 7-membered cycloalkyl ring, for example, an optionally substituted 3- to 7-membered cycloalkyl ring, an optionally substituted 3- to 6-membered cycloalkyl ring, an optionally substituted 3- to 5-membered cycloalkyl ring, an optionally substituted 3- to 4-membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 7-membered cycloalkyl ring, an optionally substituted cyclopropyl ring, an optionally substituted cyclobutyl ring, an optionally substituted cyclopentyl ring, an optionally substituted cyclohexyl ring, or an optionally substituted cycloheptyl ring.

[0086] In some embodiments of the compound of formula (I), two R atoms bonded to different carbon atoms 2 The groups, together with the carbon atoms to which they are bonded, optionally form a substituted 3- to 7-membered cycloalkyl ring, for example, an optionally substituted 3- to 7-membered cycloalkyl ring, an optionally substituted 3- to 6-membered cycloalkyl ring, an optionally substituted 3- to 5-membered cycloalkyl ring, an optionally substituted 3- to 4-membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 7-membered cycloalkyl ring, an optionally substituted cyclopropyl ring, an optionally substituted cyclobutyl ring, an optionally substituted cyclopentyl ring, an optionally substituted cyclohexyl ring, or an optionally substituted cycloheptyl ring.

[0087] In some embodiments of the compound of formula (I), R 1 Base and R 2The groups combine to form 6- to 9-membered bridging bicyclic rings, such as 6- to 9-membered bridging bicyclic rings, 6- to 8-membered bridging bicyclic rings, 6- to 7-membered bridging bicyclic rings, 6-membered bridging bicyclic rings, 7-membered bridging bicyclic rings, 8-membered bridging rings, and 9-membered bridging bicyclic rings.

[0088] In some embodiments, A in the compound of formula (I) is N or CH.

[0089] In some embodiments of the compound of formula (I), A is N.

[0090] In some embodiments of the compound of formula (I), A is CH.

[0091] In some aspects of this disclosure, Z of the compound of formula (I) is S(O)2;S(O);O, NR 3 or CR 4 R 4' That is the case.

[0092] In some embodiments of the compound of formula (I), Z is S(O)2.

[0093] In some embodiments of the compound of formula (I), Z is S(O).

[0094] In some embodiments of the compound of formula (I), Z is O.

[0095] In some embodiments of the compound of formula (I), Z is NR 3 That is the case.

[0096] In some embodiments of the compound of formula (I), Z is CR 4 R 4' That is the case.

[0097] In certain aspects of this disclosure, the R of the compound of formula (I) 3 H is optionally substituted with C1-C6 alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c;-S(O)2R c ; or -S(O)2NR a R b is or R 3 R 1 Or R 2 Together with these, they form a substituted 3- to 7-membered heterocycloalkyl ring in some cases.

[0098] In certain aspects of this disclosure, the R of the compound of formula (I) 3 H; optionally substituted C1-C6 alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O)2R c ; or -S(O)2NR a R b That is the case.

[0099] In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 H is H.

[0100] In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 These include optionally substituted C1-C6 alkyl groups, such as optionally substituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc.

[0101] In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 The R of the compound of formula (I) is a 3-5 membered cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, etc. In some embodiments of the compound of formula (I), the R of the compound of formula (I) is 3These are 3- to 5-membered substituted cycloalkyl groups, such as substituted cyclopropyl, cyclobutyl, and cyclopentyl.

[0102] In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 It is a substituted cyclobutyl.

[0103] In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 is a 3-5 member heterocycloalkyl. In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 These are 3- to 5-membered substituted heterocycloalkyl groups.

[0104] In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 -C(O)NR a R b That is the case.

[0105] In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 is -C(O)OR c That is the case.

[0106] In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 -C(O)R c That is the case.

[0107] In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 -S(O)2R c That is the case.

[0108] In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 -S(O)2NR a R b That is the case.

[0109] In certain aspects of this disclosure, the R of the compound of formula (I) a It is H or C1-C6 alkyl.

[0110] In some embodiments of the compound of formula (I), the R of the compound of formula (I) a H is H.

[0111] In some embodiments of the compound of formula (I), the R of the compound of formula (I) a These include C1-C6 alkyl groups, such as C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0112] In certain aspects of this disclosure, the R of the compound of formula (I) b It is H or C1-C6 alkyl.

[0113] In some embodiments of the compound of formula (I), the R of the compound of formula (I) b H is H.

[0114] In some embodiments of the compound of formula (I), the R of the compound of formula (I) b These include C1-C6 alkyl groups, such as C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0115] In some aspects of this disclosure, R a and R bThese, together with the N atom to which they are bonded, optionally form a substituted 3- to 7-membered heterocycloalkyl ring, for example, an optionally substituted 3- to 7-membered heterocycloalkyl ring, an optionally substituted 3- to 6-membered heterocycloalkyl ring, an optionally substituted 3- to 5-membered heterocycloalkyl ring, an optionally substituted 3- to 4-membered heterocycloalkyl ring, an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, an optionally substituted 7-membered heterocycloalkyl ring, an optionally substituted azilidinyl ring, an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, or an optionally substituted azepanyl ring.

[0116] In certain aspects of this disclosure, the R of the compound of formula (I) c These are C1-C6 alkyl or cycloalkyl groups that may be substituted depending on the case.

[0117] In some embodiments of the compound of formula (I), R c These include optionally substituted C1-C6 alkyl groups, such as optionally substituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc.

[0118] In some embodiments, R c It is methyl.

[0119] In some embodiments, R c This is (dimethylamino)methyl, i.e., -CH2N(CH3)2.

[0120] In some embodiments, R c It is ethyl.

[0121] In some embodiments, R c This is (dimethylamino)ethyl, i.e., -CH2CH2N(CH3)2.

[0122] In other embodiments of the compound of formula (I), R c These are cycloalkyl compounds, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0123] In some embodiments of the compound of formula (I), the R of the compound of formula (I) 3 R 1 or R 2 Together with these, they form a substituted 3- to 7-membered heterocycloalkyl ring, such as aziridine, azetidine, pyrrolidine, pyrazine, imidazoline, etc. Therefore, in some embodiments of the compounds of formula (I), the underlying structure

[0124] [ka]

[0125] For example,

[0126] [ka]

[0127] That is

[0128] In certain aspects of this disclosure, the R of the compound of formula (I) 4 This is a C1-C6 alkyl group that is H, -F, or optionally substituted.

[0129] In certain aspects of this disclosure, the R of the compound of formula (I) 4 This is a C1-C6 alkyl group that is H or optionally substituted.

[0130] In some embodiments of the compound of formula (I), R 4 H is H.

[0131] In some embodiments of the compound of formula (I), R 4 These are C1-C6 alkyl groups that may be substituted, for example, C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc.

[0132] In some embodiments of the compound of formula (I), R 4 These are unsubstituted C1-C6 alkyl groups, such as C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc. In some embodiments of the compound of formula (I), R 4 It is methyl (i.e., -CH3).

[0133] In some embodiments of the compound of formula (I), R 4 is a substituted C1-C6 alkyl. In some embodiments of the compound of formula (I), R 4 It is -CH2OH.

[0134] In some embodiments of the compound of formula (I), R 4 is -F.

[0135] In certain aspects of this disclosure, the R of the compound of formula (I) 4'is H, -F, -OH, -CN, -NH2, -NH(C1~C3 alkyl), -N(C1~C3 alkyl)2, -N(C1~C3 alkyl)-SO2(C1~C3 alkyl), -C1~C6 haloalkyl, optionally substituted C1~C6 alkyl, optionally substituted C1~C6 alkoxyl, or R 4 and R 4' These, together with the C atom to which they are bonded, optionally form a substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring, or R 4 and R 4' These two together form an oxo group with the carbon atom to which they are bonded, or R 4' R 1 Or R 2 Together with it, it forms a optionally substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring.

[0136] In certain aspects of this disclosure, the R of the compound of formula (I) 4' is a C1-C6 alkyl group that is H, -OH, or optionally substituted.

[0137] In some embodiments of the compound of formula (I), R 4' H is H.

[0138] In some embodiments of the compound of formula (I), R 4' is -F.

[0139] In some embodiments of the compound of formula (I), R 4' It is -OH.

[0140] In some embodiments of the compound of formula (I), R 4' is -CN.

[0141] In some embodiments of the compound of formula (I), R 4' It is -NH2.

[0142] In some embodiments of the compound of formula (I), R 4' is -NH(C1~C3 alkyl), for example, -NH(C1 alkyl), -NH(C2 alkyl), -NH(C3 alkyl), -NH(CH3), -NH-CH(CH3)2, etc. In some embodiments of the compound of formula (I), R 4' is -NH(CH3). In some embodiments of the compound of formula (I), R 4' It is -NH-CH(CH3)2.

[0143] In some embodiments of the compound of formula (I), R 4' is -N(C1~C3 alkyl)2, for example, -N(C1 alkyl)2, -N(C2 alkyl)2, -N(C3 alkyl)2, -N(C1 alkyl)(C2 alkyl), -N(CH3)2, etc. In some embodiments of the compound of formula (I), R 4' It is -N(CH3)2.

[0144] In some embodiments of the compound of formula (I), R 4' These are -N(C1~C3alkyl)-SO2(C1~C3alkyl), for example, -N(C1alkyl)-SO2(C1~C3alkyl), -N(C2alkyl)-SO2(C1~C3alkyl), -N(C3alkyl)-SO2(C1~C3alkyl), -N(C1~C3alkyl)-SO2(C1alkyl), -N(C1~C3alkyl)-SO2(C2alkyl), -N(C1~C3alkyl)-SO2(C3alkyl), -NH-SO2(CH3), -N(CH3)-SO2(CH3), etc. In some embodiments of the compound of formula (I), R 4' It is -N(CH3)-SO2(CH3).

[0145] In some embodiments of the compound of formula (I), R 4' These include -C1~C6 haloalkyl groups, such as -C1 haloalkyl, -C2 haloalkyl, -C3 haloalkyl, -C4 haloalkyl, -C5 haloalkyl, -C6 haloalkyl, -CF3, -CH2CF3, -CHF2, -CH2CHF2, etc.

[0146] In some embodiments of the compound of formula (I), R 4' These include optionally substituted C1-C6 alkyl groups, such as optionally substituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc.

[0147] In some embodiments of the compound of formula (I), R 4' R is an unsubstituted C1-C6 alkyl, for example, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc. In some embodiments of the compound of formula (I), R 4' It is methyl (i.e., -CH3).

[0148] In some embodiments of the compound of formula (I), R 4' This is a substituted C1-C6 alkyl group, for example, -CH2OH, -CH2N(CH3)2, -C(CH3)2-OH, -CH2-CN, -CH2SO2CH3, or -CH2N(CH3)SO2CH3.

[0149] In some embodiments of the compound of formula (I), R 4' These include C1-C6 alkoxyls that are substituted in some cases, such as C1-C6 alkoxyls, C1-C5 alkoxyls, C1-C4 alkoxyls, C1-C3 alkoxyls, C1-C2 alkoxyls, C1 alkoxyls, C2 alkoxyls, C3 alkoxyls, C4 alkoxyls, C5 alkoxyls, C6 alkoxyls, methoxyls, ethoxyls, n-propoxyls, isopropoxyls, n-butoxyls, isobutoxyls, sec-butoxyls, etc.

[0150] In some embodiments of the compound of formula (I), R 4' These are unsubstituted C1-C6 alkoxyls, such as C1-C6 alkoxyls, C1-C5 alkoxyls, C1-C4 alkoxyls, C1-C3 alkoxyls, C1-C2 alkoxyls, C1 alkoxyls, C2 alkoxyls, C3 alkoxyls, C4 alkoxyls, C5 alkoxyls, C6 alkoxyls, methoxyls, ethoxyls, n-propoxyls, isopropoxyls, n-butoxyls, isobutoxyls, sec-butoxyls, etc. In some embodiments of the compound of formula (I), R 4' It is -OCH3.

[0151] In certain aspects of this disclosure, the R of the compound of formula (I) 4 and R 4'These, together with the carbon atom to which they are bonded, optionally substituted 3- to 7-membered heterocycloalkyl rings or optionally substituted 3- to 7-membered cycloalkyl rings, for example optionally substituted 3- to 7-membered heterocycloalkyl rings, optionally substituted 3- to 6-membered heterocycloalkyl rings, optionally substituted 3- to 5-membered heterocycloalkyl rings, optionally substituted 3- to 4-membered heterocycloalkyl rings, optionally substituted 3-membered heterocycloalkyl rings, optionally substituted 4-membered heterocycloalkyl rings, optionally substituted 5-membered heterocycloalkyl rings, optionally substituted 6-membered heterocycloalkyl rings, optionally substituted 7-membered heterocycloalkyl rings, optionally substituted azilidinyl rings, optionally substituted azetidinyl rings, optionally substituted pyrrolidinyl rings, optionally substituted piperidinyl rings, optionally substituted azepanyl rings, optionally substituted It forms an oxetanyl ring, optionally a substituted tetrahydrofuranyl ring, optionally a substituted tetrahydrothiophene 1,1-dioxide, optionally a substituted tetrahydro-2H-thiopyran 1,1-dioxide, optionally a substituted 3- to 7-membered cycloalkyl ring, optionally a substituted 3- to 6-membered cycloalkyl ring, optionally a substituted 3- to 5-membered cycloalkyl ring, optionally a substituted 3- to 4-membered cycloalkyl ring, optionally a substituted 3-membered cycloalkyl ring, optionally a substituted 4-membered cycloalkyl ring, optionally a substituted 5-membered cycloalkyl ring, optionally a substituted 6-membered cycloalkyl ring, optionally a substituted 7-membered cycloalkyl ring, optionally a substituted cyclopropanyl ring, optionally a substituted cyclobutanyl ring, optionally a substituted cyclopentanyl ring, optionally a substituted cyclohexanyl ring, or optionally a substituted cycloheptanyl ring.

[0152] In certain aspects of this disclosure, the R of the compound of formula (I) 4 and R 4'These, together with the carbon atom to which they are bonded, optionally form a substituted 3- to 7-membered heterocycloalkyl ring, for example, an optionally substituted 3- to 7-membered heterocycloalkyl ring, an optionally substituted 3- to 6-membered heterocycloalkyl ring, an optionally substituted 3- to 5-membered heterocycloalkyl ring, an optionally substituted 3- to 4-membered heterocycloalkyl ring, an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, an optionally substituted 7-membered heterocycloalkyl ring, an optionally substituted azilidinyl ring, an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, or an optionally substituted azepanyl ring.

[0153] In embodiments of this disclosure, the R of the compound of formula (I) 4 and R 4' These, together with the carbon atom to which they are bonded, optionally form a substituted 3- to 7-membered cycloalkyl ring, for example, an optionally substituted 3- to 7-membered cycloalkyl ring, an optionally substituted 3- to 6-membered cycloalkyl ring, an optionally substituted 3- to 5-membered cycloalkyl ring, an optionally substituted 3- to 4-membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 7-membered cycloalkyl ring, an optionally substituted cyclopropanyl ring, an optionally substituted cyclobutanyl ring, an optionally substituted cyclopentanyl ring, an optionally substituted cyclohexanyl ring, or an optionally substituted cycloheptanyl ring.

[0154] In some embodiments, the R of the compound of formula (I) 4 and R 4'These, together with the carbon atom to which they are bonded, form a optionally substituted four-membered cycloalkyl ring or an optionally substituted five-membered cycloalkyl ring.

[0155] In some embodiments, the R of the compound of formula (I) 4 and R 4' These, together with the carbon atom to which they are bonded, may form a substituted cyclobutanyl ring or, in some cases, a cyclopentanyl ring.

[0156] In some embodiments, the R of the compound of formula (I) 4 and R 4' These, together with the carbon atom to which they are bonded, form a hydroxysubstituted cyclopentanyl ring, for example,

[0157] [ka]

[0158] It forms.

[0159] In other embodiments, the R of the compound of formula (I) 4 and R 4' These, together with the carbon atom to which they are bonded, form a methoxy-substituted cyclobutanyl ring, for example,

[0160] [ka]

[0161] It forms.

[0162] In some embodiments of formula (I), R 4' R 1 or R 2 Together with these, they form a optionally substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring.

[0163] In some embodiments of formula (I), R 4' R 1 or R 2 Together with other elements, they form a 3- to 7-membered heterocycloalkyl ring, which may be substituted depending on the circumstances.

[0164] In other embodiments of formula (I), R 4' R 1 or R 2 Together with these, they form optionally substituted 3- to 7-membered cycloalkyl rings, such as optionally substituted 3-membered cycloalkyl rings, optionally substituted 4-membered cycloalkyl rings, optionally substituted 5-membered cycloalkyl rings, optionally substituted 6-membered cycloalkyl rings, optionally substituted condensed 7-membered cycloalkyl rings, cyclopropyl rings, and the like.

[0165] In some embodiments, R 4' is R 1 or R 2 Together with it, it forms a cyclopropyl ring which may be substituted. Thus, in some embodiments of the compound of formula (I), the lower structure

[0166] [ka]

[0167] For example,

[0168] [ka]

[0169] That is the case.

[0170] In certain aspects of this disclosure, the R of the compound of formula (I) 4 and R 4' These, together with the carbon atom to which they are bonded, form an oxo group, that is,

[0171] [ka]

[0172] It forms.

[0173] In some aspects of this disclosure, Y in the compound of formula (I) is a 5- or 6-membered heteroaryl ring or a 6-membered aryl ring.

[0174] In some aspects of this disclosure, Y in the compound of formula (I) is a 5- or 6-membered heteroaryl ring. In some aspects of this disclosure, Y in the compound of formula (I) is a substituted 5- or 6-membered heteroaryl ring.

[0175] In some embodiments, Y in the compound of formula (I) is a five-membered heteroaryl ring, such as furan, pyrrole, thiophene, isoxazole, oxazole, pyrazole, imidazole, isothiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,5-thiatriazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,3,5-oxatriazole, 2H-1,2,3-triazole, 1H-1,2,4-triazole, 1H-1,2,3-triazole, 4H-1,2,4-triazole, 2H-tetrazole, 1H-tetrazole, etc.

[0176] In some embodiments, Y in the compound of formula (I) is a substituted five-membered heteroaryl ring, such as a substituted furan, pyrrole, thiophene, isoxazole, oxazole, pyrazole, imidazole, isothiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,5-thiatriazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,3,5-oxatriazole, 2H-1,2,3-triazole, 1H-1,2,4-triazole, 1H-1,2,3-triazole, 4H-1,2,4-triazole, 2H-tetrazole, 1H-tetrazole, etc.

[0177] In some embodiments, Y in the compound of formula (I) is a six-membered heteroaryl ring, such as pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, etc. In some embodiments, Y in the compound of formula (I) is a substituted six-membered heteroaryl ring, such as a substituted pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, etc.

[0178] In some embodiments of the compound of formula (I), Y is a six-membered aryl ring. In some embodiments, Y is a substituted six-membered aryl ring. In some embodiments, Y is a phenyl ring. In some embodiments, Y is a substituted phenyl ring.

[0179] In some embodiments, Y is

[0180] [ka]

[0181] That is the case.

[0182] In some aspects of this disclosure, the Q of the compound of formula (I) 5 Q 6 Q 7 Q 8 , and Q 9 Each is independently N or CR 5 Q 5 Q 6 Q 7 Q 8 , and Q 9 One or two of them are N, and the rest are each independently CR 5 That is the case.

[0183] In some embodiments, Q 5 Q 6 Q 7 Q 8 , or Q 9 One of them is N, and the rest are each independently CR 5 That is the case.

[0184] In some embodiments, Q 5 is N and Q 6 Q 7 Q 8 , and Q 9 Each is independently CR 5 That is the case.

[0185] In some embodiments, Q 6 is N and Q 5 Q 7 Q 8 , and Q 9 Each is independently CR 5 That is the case.

[0186] In some embodiments, Q 7 is N and Q 5 Q 6 Q 8 , and Q 9 Each is independently CR 5 That is the case.

[0187] In some embodiments, Q8 is N and Q 5 Q 6 Q 7 , and Q 9 Each is independently CR 5 That is the case.

[0188] In some embodiments, Q 9 is N and Q 5 Q 6 Q 7 , and Q 8 Each is independently CR 5 That is the case.

[0189] In other embodiments, Q 5 Q 6 Q 7 Q 8 , or Q 9 Two of them are N, and the rest are CR, each independently. 5 That is the case.

[0190] In some embodiments, Q 5 and Q 6 is N and Q 7 Q 8 , and Q 9 Each is independently CR 5 That is the case.

[0191] In some embodiments, Q 5 and Q 7 is N and Q 6 Q 8 , and Q 9 Each is independently CR 5 That is the case.

[0192] In some embodiments, Q 5 and Q 8 is N and Q 6 Q 7 , and Q 9 Each is independently CR 5 That is the case.

[0193] In some embodiments, Q 5 and Q 9 is N and Q6 Q 7 , and Q 8 Each is independently CR 5 That is the case.

[0194] In some embodiments, Q 6 and Q 7 is N and Q 5 Q 8 , and Q 9 Each is independently CR 5 That is the case.

[0195] In some embodiments, Q 6 and Q 8 is N and Q 5 Q 7 , and Q 9 Each is independently CR 5 That is the case.

[0196] In some embodiments, Q 6 and Q 9 is N and Q 5 Q 7 , and Q 8 Each is independently CR 5 That is the case.

[0197] In some embodiments, Q 7 and Q 8 N and Q 5 Q 6 , and Q 9 Each is independently CR 5 That is the case.

[0198] In some embodiments, Q 7 and Q 9 is N and Q 5 Q 6 , and Q 8 Each is independently CR 5 That is the case.

[0199] In some embodiments, Q 8 and Q 9 is N and Q 5 Q 6 , and Q 7Each is independently CR 5 That is the case.

[0200] In certain aspects of this disclosure, each R of the compound of formula (I) 5 R is independently H, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or cycloalkyl. In some aspects of this disclosure, each R of the compound of formula (I) 5 These are independently H, halogen, substituted C1-C3 alkyl, substituted C1-C3 alkoxyl, or substituted cycloalkyl.

[0201] In some embodiments of the compound of formula (I), R 5 H is H.

[0202] In some embodiments of the compound of formula (I), R 5 is a halogen, for example, -F, -Cl, -Br, or -I.

[0203] In some embodiments, at least one R 5 It is -Cl.

[0204] In some embodiments of the compound of formula (I), R 5 These are C1-C3 alkyl groups, for example, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, -CH3 groups, -CH2CH3 groups, -propyl groups, etc. In some embodiments, R 5 It is -CH3.

[0205] In some embodiments of the compound of formula (I), R 5 These are C1-C3 alkoxyls, for example, C1-C3 alkoxyls, C1-C2 alkoxyls, C1 alkoxyls, C2 alkoxyls, C3 alkoxyls, -OCH3, -OCH2CH3, -propoxyls, etc. In some embodiments, R 5 It is -OCH3.

[0206] In some embodiments of the compound of formula (I), R 5These are cycloalkyl compounds, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0207] In some embodiments of the compound of formula (I), two R 5 is halogen, and the remaining R 5 H is H.

[0208] In other embodiments of the compound of formula (I), two R 5 is -Cl, and the remaining R 5 H is H.

[0209] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 and Q 8 Each is independently CR 5 And R 5 H is Q 7 It is N.

[0210] In some embodiments of the compound of formula (I), Q 5 Q 8 , and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 7 It is N.

[0211] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 and Q 8 Each is independently CR 5 And R 5 H is Q 7 It is N.

[0212] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 CR 5 And R 5 is -F and Q 7 It is N.

[0213] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 8 CR 5 And R 5 It is a C1-C3 alkyl group, Q 7 It is N.

[0214] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 CR 5 And R 5 is -CH3, Q 7 It is N.

[0215] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 8 is N and Q7 CR 5 And R 5 H is H.

[0216] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 CR 5 And R 5 H is H.

[0217] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 It is N.

[0218] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 It is N.

[0219] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 It is a C1-C3 alkyl group, Q 6 CR 5 And R 5 H is Q 8is N and Q 7 It is N.

[0220] In some embodiments of the compound of formula (I), Q 5 and Q 9 Each is independently CR 5 And each R 5 is -CH3, Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 It is N.

[0221] In some aspects of this disclosure, X in the compound of formula (I) is O, S, or NR, and R is H or a C1-C3 alkyl group.

[0222] In some embodiments of the compound of formula (I), X is O.

[0223] In some embodiments of the compound of formula (I), X is S.

[0224] In some embodiments of the compound of formula (I), X is NR and R is H or C1-C3 alkyl.

[0225] In some embodiments of the compound of formula (I), X is NR, R is H, and that is, X is NH.

[0226] In some embodiments of the compound of formula (I), X is NR, and R is C1-C3 alkyl, i.e., -N(C1-C3 alkyl)-, for example -N(C1-C3 alkyl)-, -N(C1-C2 alkyl)-, -N(C1 alkyl)-, -N(C2 alkyl)-, -N(C3 alkyl)-, -N(CH3)-, -N(CH2CH3)-, -N(CH2CH2CH3)-, etc.

[0227] In certain aspects of this disclosure, the R of the compound of formula (I) 6These include C1-C6 alkyl groups, such as C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0228] In some embodiments of the compounds disclosed herein, R 6 It is -CH3.

[0229] In some embodiments, the R of the compound of formula (I) 7 These are H, halogen, -C1~C6 alkyl, -C1~C6 alkoxyl, or -cycloalkyl.

[0230] In some embodiments, the R of the compound of formula (I) 7 H is H.

[0231] In some embodiments, the R of the compound of formula (I) 7 is a halogen, for example, -F, -Cl, -Br, or -I.

[0232] In some embodiments, the R of the compound of formula (I) 7 is -F.

[0233] In other embodiments, the R of the compound of formula (I) 7 It is -Cl.

[0234] In some embodiments, the R of the compound of formula (I) 7 These include C1-C6 alkyl groups, such as substituted or unsubstituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc. In some embodiments, R 7 It is -CH3.

[0235] In some embodiments, the R of the compound of formula (I) 7 These include -C1~C6 alkoxyls, for example, -C1~C6 alkoxyls, -C1~C5 alkoxyls, -C1~C4 alkoxyls, -C1~C3 alkoxyls, -C1~C2 alkoxyls, -C1 alkoxyls, -C2 alkoxyls, -C3 alkoxyls, -C4 alkoxyls, -C5 alkoxyls, -C6 alkoxyls, -OCH3, -OCH2CH3, -propoxyls, etc. In some embodiments, R 7 It is -OCH3.

[0236] In some embodiments, the R of the compound of formula (I) 7 These are cycloalkyl compounds, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0237] In some embodiments, R 8 The elements are H, halogen, -C1~C6 alkyl, -C1~C6 alkoxyl, or -cycloalkyl.

[0238] In some embodiments, the R of the compound of formula (I) 8 H is H.

[0239] In some embodiments, the R of the compound of formula (I) 8 is a halogen, for example, -F, -Cl, -Br, or -I.

[0240] In some embodiments, the R of the compound of formula (I) 8 C1-C6 alkyl groups, for example, substituted or unsubstituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc. In some embodiments, R 8 It is -CH3.

[0241] In some embodiments, the R of the compound of formula (I) 8 These are -C1~C6 alkoxyls, for example, -C1~C6 alkoxyls, -C1~C5 alkoxyls, -C1~C4 alkoxyls, -C1~C3 alkoxyls, -C1~C2 alkoxyls, -C1 alkoxyls, -C2 alkoxyls, -C3 alkoxyls, -C4 alkoxyls, -C5 alkoxyls, -C6 alkoxyls, -OCH3, -OCH2CH3, -propoxyls, etc. In some embodiments, R 8 It is -OCH3.

[0242] In some embodiments, the R of the compound of formula (I) 8 These are cycloalkyl compounds, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0243] In some embodiments of the compound of formula (I), R 7 is -F, and R 8 H is H.

[0244] In some embodiments of the compound of formula (I), R 7 is -Cl, and R 8 H is H.

[0245] In some embodiments of the compound of formula (I), R 7 is -CH3, R 8 H is H.

[0246] In some embodiments of the compound of formula (I), R 7 is -OCH3, and R 8 H is H.

[0247] In some embodiments of the compound of formula (I), R 7 is -H, and R 8 is -F.

[0248] In some embodiments of the compound of formula (I), R 7 is -H, and R 8 It is -Cl.

[0249] In some embodiments of the compound of formula (I), R 7 is -H, and R 8 It is -CH3.

[0250] In some embodiments of the compound of formula (I), R 7 is -H, and R 8 It is OCH3.

[0251] In certain aspects of this disclosure, a compound of formula (I) is a compound of formula (IA):

[0252] [ka]

[0253] [In the formula, Q 1 Q 2 Q 3 Q 4 One or two of them are N, and the rest are CR independently. 5a And each R 5a [The elements are independently H, halogen, -CN, -C1~C3 alkyl, -C1~C3 haloalkyl, -C1~C3 alkoxyl, -SO2C1~C3 alkyl, -CH2-OH, -CH2-N(C1~C3 alkyl)2, or -CH2-NH(C1~C3 alkyl), and the other variable elements are as described for formula (I)].

[0254] In some aspects of this disclosure, the compound of formula (I) is the compound of formula (IA) (wherein R 5a is -P(O)(C1~C6 alkyl)2, for example, -P(O)(CH3)2).

[0255] In certain aspects of this disclosure, the compound of formula (I) is the compound of formula (IA) (wherein each R 5a (These are independently H, halogen, -CN, or C1-C3 alkyl.)

[0256] In some embodiments, Q 1 Q 2 Q3 Q 4 One of them is N, and the rest are each independently CR 5a That is the case.

[0257] In some embodiments, Q 1 is N and Q 2 Q 3 , and Q 4 Each is independently CR 5a That is the case.

[0258] In some embodiments, Q 2 is N and Q 1 Q 3 , and Q 4 Each is independently CR 5a That is the case.

[0259] In some embodiments, Q 3 is N and Q 1 Q 2 , and Q 4 Each is independently CR 5a That is the case.

[0260] In some embodiments, Q 4 is N and Q 1 Q 2 , and Q 3 Each is independently CR 5a That is the case.

[0261] In other embodiments, Q 1 Q 2 Q 3 Q 4 Two of them are N, and the rest are CR, each independently. 5a That is the case.

[0262] In some embodiments, Q 1 and Q 2 is N and Q 3 , and Q 4 Each is independently CR 5a That is the case.

[0263] In some embodiments, Q 1 and Q3 is N and Q 2 and Q 4 Each is independently CR 5a That is the case.

[0264] In some embodiments, Q 1 and Q 4 is N and Q 2 and Q 3 Each is independently CR 5a That is the case.

[0265] In some embodiments, Q 2 and Q 3 is N and Q 1 and Q 4 Each is independently CR 5a That is the case.

[0266] In some embodiments, Q 2 and Q 4 is N and Q 1 and Q 3 Each is independently CR 5a That is the case.

[0267] In some embodiments, Q 3 and Q 4 is N and Q 1 and Q 2 Each is independently CR 5a That is the case.

[0268] In some embodiments of the compound of formula (IA), each R 5a These are independently H, halogen, -CN, or C1-C3 alkyl.

[0269] In other embodiments of the compound of formula (IA), each R 5a The elements are H, halogen, -CN, C1~C3 alkyl, -C1~C3 haloalkyl, -C1~C3 alkoxyl, -SO2C1~C3 alkyl, -CH2-N(C1~C3 alkyl)2, or -CH2-NH(C1~C3 alkyl).

[0270] In some embodiments of the compound of formula (IA), R 5aH is H.

[0271] In some embodiments of the compound of formula (IA), R 5a These are halogens, i.e., -F, -Cl, -Br, or -I.

[0272] In some embodiments of the compound of formula (IA), at least one R 5a is -F.

[0273] In some embodiments of the compound of formula (IA), R 5a is -CN.

[0274] In some embodiments of the compound of formula (IA), R 5a These are C1-C3 alkyl groups, for example, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, -CH3 groups, -CH2CH3 groups, -propyl groups, etc. In some embodiments, R 5a It is -CH3.

[0275] In some embodiments of the compound of formula (IA), R 5a These are C1-C3 haloalkyl groups, for example, C1-C3 haloalkyl groups, C1-C2 haloalkyl groups, C1 haloalkyl groups, C2 haloalkyl groups, C3 haloalkyl groups, -CF3 groups, -CH2CF3 groups, etc. In some embodiments, R 5a It is -CF3.

[0276] In some embodiments of the compound of formula (IA), R 5a is a -C1~C3 alkoxyl, for example, -C3 alkoxyl, -C2 alkoxyl, or -C1 alkoxyl, -OCH2CH3, -OCH3, etc. In some embodiments, R 5a It is -OCH3.

[0277] In some embodiments of the compound of formula (IA), R 5a is -SO2C1~C3 alkyl, for example, -SO2C1 alkyl, -SO2C2 alkyl, -SO2C3 alkyl, -SO2CH2CH3, -SO2CH3, etc. In some embodiments, R 5aIt is -SO2CH3.

[0278] In some embodiments of the compound of formula (IA), R 5a This is -CH2-N(C1~C3 alkyl)2, for example, -CH2-N(C3 alkyl)2, -CH2-N(C2 alkyl)2, -CH2-N(C1 alkyl)2, -CH2-N(C3 alkyl)(C1 alkyl), -CH2-N(C2 alkyl)(C1 alkyl), -CH2-N(C3 alkyl)(C2 alkyl), -CH2-N(CH3)2, etc. In some embodiments, R 5a It is -CH2-N(CH3)2.

[0279] In some embodiments of the compound of formula (IA), R 5a is -CH2-NH(C1~C3 alkyl), for example, -CH2-NH(C3 alkyl), -CH2-NH(C2 alkyl), -CH2-NH(C1 alkyl), -CH2-NH(CH3), etc. In some embodiments, R 5a It is -CH2-NH(CH3).

[0280] In some embodiments of the compound of formula (IA), X is O.

[0281] In some aspects of this disclosure, a compound of formula (IA) is a compound of formula (IA-1):

[0282] [ka]

[0283] [In the formula, the variable elements have the values ​​listed above for formulas (I) and (IA)].

[0284] In some embodiments of the compound of formula (IA-1), R 6 It is -CH3.

[0285] In some embodiments of the compound of formula (IA-1), Q 3 CR 5a That is the case.

[0286] In some embodiments of the compound of formula (IA-1), at least one R 5a It is a halogen.

[0287] In some embodiments of the compound of formula (IA-1), at least one R 5a is -F.

[0288] In some aspects of this disclosure, the compound of formula (IA) is the compound of formula (IA-2):

[0289] [ka]

[0290] [In the formula, the variable elements have the values ​​listed above for formulas (I) and (IA)].

[0291] In some embodiments of the compound of formula (IA-2), n is 2 and m is 2.

[0292] In some embodiments of the compound of formula (IA-2), n is 1 and m is 1.

[0293] In some embodiments of the compound of formula (IA-2), n is 1 and m is 2.

[0294] In some embodiments of the compound of formula (IA-2), n is 3 and m is 2.

[0295] In some aspects of this disclosure, the compound of formula (IA-2) is the compound of formula (IA-3):

[0296] [ka]

[0297] [In the formula, the variable elements have the values ​​listed above for formula (IA-2)].

[0298] In some embodiments of the compound of formula (IA-3), each R 1 and each R 2 These are independently H or optionally substituted C1-C6 alkyl groups.

[0299] In some embodiments of the compound of formula (IA-3), each R 1 and each R 2 H is H.

[0300] In some embodiments of the compound of formula (IA-3), each R 1 and each R 2 These are, independently, optionally substituted C1-C6 alkyl groups, such as optionally substituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc.

[0301] In some embodiments of the compound of formula (IA-3), at least one R 1 H is H and at least one R 2 These are C1-C6 alkyl groups that may be substituted depending on the case.

[0302] In some embodiments of the compound of formula (IA-3), at least one R 1 is a C1-C6 alkyl which may be substituted, and at least one R 2 H is H.

[0303] In some embodiments of the compound of formula (IA-3), each R 1 H is one R 2 These are C1-C6 alkyl groups that may be substituted depending on the case.

[0304] In some embodiments of the compound of formula (IA-3), one R 1 R is a C1-C6 alkyl which may be substituted depending on the case, and each R 2H is H.

[0305] In some embodiments of the compound of formula (IA-3), each R 1 It is H, and two Rs bonded to the same carbon atom. 2 The groups, together with the carbon atom to which they are bonded, form a 3- to 7-membered spirocycloalkyl ring, such as a 3-membered spirocycloalkyl ring, a 4-membered spirocycloalkyl ring, a 5-membered spirocycloalkyl ring, a 6-membered spirocycloalkyl ring, a 7-membered spirocycloalkyl ring, a spirocyclopropyl ring, a spirocyclobutyl ring, a spirocyclopentyl ring, a spirocyclohexyl ring, or a spirocycloheptyl ring.

[0306] In some embodiments of the compound of formula (IA-3), each R 1 It is H, and two Rs bonded to the same carbon atom. 2 The groups, together with the carbon atom to which they are bonded, form a three-membered spirocycloalkyl ring, such as a spirocyclopropyl ring.

[0307] In some embodiments of the compound of formula (IA-3), one R 1 Base and one of the R 2 The groups bond to form a 6-9 membered bridging bicyclic ring, and the other R 1 H is H, and the other R is R 2 is H. In such embodiments, the 6- to 9-membered bridging biring ring is a 6-membered bridging biring ring, a 7-membered bridging biring ring, an 8-membered bridging biring ring, or a 9-membered bridging biring ring. In some embodiments, the 6- to 9-membered bridging biring ring is a 7-membered bridging biring ring.

[0308] In some embodiments of the compound of formula (IA-3), each R 1 It is H, and two Rs bonded to the same carbon atom. 2 The group, together with its carbon atom, represents a carbonyl group (C=O).

[0309] In some aspects of this disclosure, the compound of formula (IA-2) is the compound of formula (IA-4):

[0310] [ka]

[0311] [In the formula, the variable elements have the values ​​listed above for formula (IA-2)].

[0312] In some embodiments of the compound of formula (IA-4), two R atoms bonded to the same carbon atom 2 The group, together with its carbon atom, represents a carbonyl group (C=O).

[0313] In some aspects of this disclosure, the compound of formula (IA-2) is the compound of formula (IA-5):

[0314] [ka]

[0315] [In the formula, the variable elements have the values ​​listed above for formula (IA-2)].

[0316] In some embodiments of the compound of formula (IA-5), each R 1 and each R 2 These are independently H or optionally substituted C1-C6 alkyl groups, such as optionally substituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc.

[0317] In some embodiments of the compound of formula (IA-5), each R 1 and each R 2 H is H.

[0318] In some embodiments of the compound of formula (IA-5), each R 1 It is H, and two Rs bonded to the same carbon atom.2 The groups, together with the carbon atom to which they are bonded, form a 3- to 7-membered spirocycloalkyl ring, such as a 3-membered spirocycloalkyl ring, a 4-membered spirocycloalkyl ring, a 5-membered spirocycloalkyl ring, a 6-membered spirocycloalkyl ring, a 7-membered spirocycloalkyl ring, a spirocyclopropyl ring, a spirocyclobutyl ring, a spirocyclopentyl ring, a spirocyclohexyl ring, or a spirocycloheptyl ring.

[0319] In some embodiments of the compound of formula (IA-5), the 3- to 7-membered spirocycloalkyl ring is a 3-membered spirocycloalkyl ring.

[0320] In some embodiments of the compound of formula (IA-5), one R 1 Base and one of the R 2 The groups combine to form a 6-9 membered bridged biring ring, and the other R 1 H is H, and the other R is R 2 is H. In such embodiments, the 6- to 9-membered bridging biring ring is a 6-membered bridging biring ring, a 7-membered bridging biring ring, an 8-membered bridging biring ring, or a 9-membered bridging biring ring. In some embodiments, the 6- to 9-membered bridging biring ring is a 7-membered bridging biring ring.

[0321] In certain aspects of this disclosure, the compound of formula (I) is the compound of formula (IA-8):

[0322] [ka]

[0323] [In the formula, R 9 [wherein the set is -C1~C6 alkyl, -C1~C6 haloalkyl, -C(O)C1~C6 haloalkyl, -C(O)OC1~C6 alkyl, -C(O)C1~C6 alkyl, -C(O)N(C1~C6 alkyl)2, or -SO2-C1~C6 alkyl, and the other variable elements have the values ​​listed above for formula (I)].

[0324] In some embodiments of the compound of formula (IA-8), R 9is -CH2CF3, -CH2CHF2, -C(O)CF3, -C(O)OCH3, -C(O)OCH2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -CH3, -CH(CH3)2, -C(O)N(CH3)2, or -SO2CH3.

[0325] In some embodiments of the compound of formula (IA-8), R 7 and R 8 These are H.

[0326] In some embodiments of the compound of formula (IA-8), each R 1 and each R 2 H is H.

[0327] In some embodiments of the compound of formula (IA-8), Q 1 Q 2 Q 3 Q 4 One of them is N, and the rest are each independently CR 5a That is the case.

[0328] In some embodiments of the compound of formula (IA-8), Q 4 is N and Q 1 Q 2 Q 3 Each is independently CR 5a That is the case.

[0329] In other embodiments of the compound of formula (IA-8), Q 1 Q 2 Q 3 Q 4 Two of them are N, and the rest are CR, each independently. 5a That is the case.

[0330] In other embodiments of the compound of formula (IA-8), Q 2 and Q 4 is N and Q 1 and Q 3 Each is independently CR 5a That is the case.

[0331] In some embodiments of the compound of formula (IA-8), Q 5 Q 6 Q 7 Q 8 , or Q 9 One of them is N, and the rest are each independently CR 5 That is the case.

[0332] In some embodiments of the compound of formula (IA-8), Q 7 is N and Q 5 Q 6 Q 8 , and Q 9 Each is independently CR 5 That is the case.

[0333] In some embodiments of the compound of formula (IA-8), Q 5 Q 6 Q 7 Q 8 , or Q 9 Two of them are N, and the rest are CR, each independently. 5 That is the case.

[0334] In some embodiments, Q 6 and Q 7 is N and Q 5 Q 8 , and Q 9 Each is independently CR 5 That is the case.

[0335] In some aspects of this disclosure, the compound of formula (IA-2) is the compound of formula (IA-6):

[0336] [ka]

[0337] [In the formula, the variable elements have the values ​​listed above for formula (IA-2)].

[0338] In some embodiments of the compound of formula (IA-6), two R atoms bonded to the same carbon atom 1The group, together with its carbon atom, represents a carbonyl group (C=O).

[0339] In some embodiments of the compound of formula (IA-6), two R atoms bonded to the same carbon atom 2 The groups, together with the carbon atom to which both are bonded, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring.

[0340] In some embodiments of the compound of formula (IA-6), two R atoms bonded to the same carbon atom 2 The groups, together with the carbon atom to which both are bonded, optionally form substituted 3- to 7-membered spiroheterocycloalkyl rings, such as optionally substituted 3-membered spiroheterocycloalkyl rings, optionally substituted 4-membered spiroheterocycloalkyl rings, optionally substituted 5-membered spiroheterocycloalkyl rings, optionally substituted 6-membered spiroheterocycloalkyl rings, optionally substituted 7-membered spiroheterocycloalkyl rings, optionally substituted spiroazilidinyl rings, optionally substituted spiroazetidinyl rings, optionally substituted spiropyrrolidinyl rings, optionally substituted spiropiperidinyl rings, optionally substituted spiroazepanyl rings, optionally substituted spirooxyranyl rings, optionally substituted spirooxetanyl rings, optionally substituted spirotetrahydrofuranyl rings, optionally substituted spirotetrahydropyranyl rings, optionally substituted spirooxepanyl rings, etc.

[0341] In some embodiments of the compounds of formula (IA-6), the optionally substituted 3- to 7-membered spiroheterocycloalkyl ring is optionally substituted spiroazetinyl ring, optionally substituted spiropyrrolidinyl ring, or optionally substituted spiropiperidinyl ring.

[0342] In some embodiments of the compounds of formula (IA-6), the optionally substituted 3- to 7-membered spiroheterocycloalkyl rings are spiroazethinyl rings, spiropyrrolidinyl rings, spiropiperidinyl rings, N-methylspiropiperidinyl rings, or N-(methylsulfonyl)spiropiperidinyl rings.

[0343] In some aspects of this disclosure, the compound of formula (IA-2) is the compound of formula (IA-7):

[0344] [ka]

[0345] [In the formula, the variable elements have the values ​​listed above for formula (IA-2)].

[0346] In some embodiments of the compound of formula (IA-7), each R 1 H is H.

[0347] In some embodiments of the compound of formula (IA-7), two R atoms bonded to the same carbon atom 1 The group, together with its carbon atom, represents a carbonyl group (C=O).

[0348] In some embodiments of the compound of formula (IA-7), each R 2 H is H.

[0349] In some embodiments of the compound of formula (IA-7), two R atoms bonded to the same carbon atom 2 The group, together with its carbon atom, represents a carbonyl group (C=O).

[0350] In certain aspects of this disclosure, compounds of formula (IA) (and subgroups IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7) are Q 2 It is a compound in which N is. In other aspects of this disclosure, the compound of formula (IA) (and subgroup IA-8) is Q 2 It is a compound in which N is present.

[0351] In certain aspects of this disclosure, compounds of formula (IA) (and subgroups IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7) are Q 4 It is a compound in which N is. In other aspects of this disclosure, the compound of formula (IA) (and subgroup IA-8) is Q 4 It is a compound in which N is present.

[0352] In certain aspects of this disclosure, the compound of formula (IA) is Q 2 and Q 4 This is a compound in which both atoms are nitrogen.

[0353] In certain aspects of this disclosure, the compound of formula (IA) is Q 4 CR 5a It is a compound that is [this compound].

[0354] Q 4 CR 5a In some embodiments, R 5a H is H.

[0355] Q 4 CR 5a In some embodiments, R 5a It is a halogen.

[0356] Q 4 CR 5a In some embodiments, R 5a is -F.

[0357] In some embodiments of the compound of formula (IA), Q 2 is N and Q 4 CR 5a And R 5a is -F.

[0358] In certain aspects of this disclosure, the compound of formula (I) is the compound of formula (IB):

[0359] [ka]

[0360] [In the formula, the variable elements have the values ​​listed above for formula (I)].

[0361] In some aspects of this disclosure, the compound of formula (IB) is the compound of formula (IB-1):

[0362] [ka]

[0363] [In the formula, the variable elements have the values ​​listed above for formula (I)].

[0364] In some aspects of this disclosure, the compound of formula (IB-1) is the compound of formula (IB-2):

[0365] [ka]

[0366] [In the formula, the variable elements have the values ​​listed above for formula (I)].

[0367] In some embodiments of the compounds of formulas (IB), (IB-1), and (IB-2), n=2 and m=2.

[0368] In other embodiments of the compounds of formulas (IB), (IB-1), and (IB-2), n=1 and m=1.

[0369] In some embodiments of the compounds of formulas (IB), (IB-1), and (IB-2), n=1 and m=2.

[0370] In other embodiments of the compounds of formulas (IB), (IB-1), and (IB-2), n=3 and m=2.

[0371] In some embodiments of the compounds of formulas (IB), (IB-1), and (IB-2), each R 1 H is H, and each R 2H is H.

[0372] In some embodiments, A in the compound of formula (I) is N or CH.

[0373] In some embodiments of the compound of formula (I), A is N.

[0374] In some embodiments of the compound of formula (I), A is CH.

[0375] In some embodiments, Z of the compound in formula (I) is S(O)2;S(O);O;NR 3 ; or CR 4 R 4' That is the case.

[0376] In some embodiments of the compound of formula (I), Z is S(O)2.

[0377] In some embodiments of the compound of formula (I), Z is S(O).

[0378] In some embodiments of the compound of formula (I), Z is O.

[0379] In some embodiments of the compound of formula (I), Z is NR 3 That is the case.

[0380] Z is NR 3 In some embodiments of the compound of formula (I), R 3 H is H.

[0381] Z is NR 3 In other embodiments of the compound of formula (I), R 3 -C(O)NR a R b That is the case.

[0382] Z is NR 3 In other embodiments of the compound of formula (I), R 3 -S(O)2NR a R b That is the case.

[0383] R 3 -C(O)NR a R b Or -S(O)2NR a R b In some embodiments of the compound of formula (I), R a H is R b H is H.

[0384] In some embodiments of the compound of formula (I), R 3 It is -C(O)NH2.

[0385] R 3 -C(O)NR a R b Or -S(O)2NR a R b In some embodiments of the compound of formula (I), R a H is R b These include C1-C6 alkyl groups, such as C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0386] R 3 -C(O)NR a R b Or -S(O)2NR a R b In some embodiments of the compound of formula (I), R a These include C1-C6 alkyl groups, for example, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc. bThese include C1-C6 alkyl groups, such as C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0387] In some embodiments of the compound of formula (I), R 3 It is -C(O)N(CH3)2.

[0388] R 3 -C(O)NR a R b Or -S(O)2NR a R b In some embodiments of the compound of formula (I), R a and R b These, together with the N atom to which they are bonded, optionally form a substituted 3- to 7-membered heterocycloalkyl ring, for example, an optionally substituted 3-membered heterocycloalkyl, an optionally substituted 4-membered heterocycloalkyl, an optionally substituted 5-membered heterocycloalkyl, an optionally substituted 6-membered heterocycloalkyl, or an optionally substituted 7-membered heterocycloalkyl.

[0389] In some embodiments of the compound of formula (I), the optionally substituted 3- to 7-membered heterocycloalkyl ring is optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted morpholinyl ring.

[0390] In some embodiments of the compound of formula (I), the optionally substituted 3- to 7-membered heterocycloalkyl ring is 4-methylpiperazine-1-yl or a morpholinyl ring.

[0391] R 3 -C(O)NR a R bIn some embodiments of the compound of formula (I), R 3 teeth

[0392] [ka]

[0393] That is the case.

[0394] R 3 -S(O)2NR a R b In some embodiments of the compound of formula (I), R 3 teeth,

[0395] [ka]

[0396] That is the case.

[0397] Z is NR 3 In some embodiments of the compound of formula (I), R 3 is -C(O)OR c That is the case.

[0398] Z is NR 3 In some embodiments of the compound of formula (I), R 3 -C(O)R c That is the case.

[0399] Z is NR 3 In some embodiments of the compound of formula (I), R 3 -S(O)2R c That is the case.

[0400] Z is NR 3 And R 3 ga-C(O)OR c , -C(O)R c , or -S(O)2R c In some embodiments of the compound of formula (I), R cThese are C1-C6 alkyl groups or 3-7 membered cycloalkyl groups, which may be substituted depending on the case.

[0401] In some embodiments of the compound of formula (I), R c These include optionally substituted C1-C6 alkyl groups, such as optionally substituted C1-C6 alkyl groups, C1-C5 alkyl groups, C1-C4 alkyl groups, C1-C3 alkyl groups, C1-C2 alkyl groups, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, pentanyl groups, hexanyl groups, etc.

[0402] In some embodiments of the compound of formula (I), R c It is methyl, i.e., -CH3.

[0403] In some embodiments of the compound of formula (I), R c This is (C1~C6 alkyl)2N-methyl, that is, -CH2N(C1~C6 alkyl)2.

[0404] In some embodiments of the compound of formula (I), R c This is (dimethylamino)methyl, i.e., -CH2N(CH3)2.

[0405] In some embodiments of the compound of formula (I), R c It is ethyl.

[0406] In some embodiments of the compound of formula (I), R c This is (C1~C6 alkyl)2N-ethyl, that is, -CH2CH2N(C1~C6 alkyl)2.

[0407] In some embodiments of the compound of formula (I), R c This is (dimethylamino)ethyl, i.e., -CH2CH2N(CH3)2.

[0408] Z is NR 3In some embodiments of the compound of formula (I), R 3 This is -C(O)OCH3, -C(O)CH3, or -S(O)2CH3.

[0409] Z is NR 3 In some embodiments of the compound of formula (I), R 3 It is -C(O)OCH3.

[0410] Z is NR 3 In some embodiments of the compound of formula (I), R 3 It is -C(O)CH3.

[0411] Z is NR 3 In some embodiments of the compound of formula (I), R 3 It is -C(O)CH2N(CH3)2.

[0412] Z is NR 3 In some embodiments of the compound of formula (I), R 3 The formula is -C(O)CH2CH2N(CH3)2.

[0413] Z is NR 3 In some embodiments of the compound of formula (I), R 3 It is -S(O)2CH3.

[0414] In other embodiments of the compound of formula (I), R c It is -CH2CH3.

[0415] Z is NR 3 In some embodiments of the compound of formula (I), R 3 This is -C(O)OCH2CH3, -C(O)CH2CH3, or -S(O)2CH2CH3.

[0416] Z is NR 3 In some embodiments of the compound of formula (I), R 3 The expression is -C(O)OCH2CH3.

[0417] Z is NR 3In some embodiments of the compound of formula (I), R 3 It is -C(O)CH2CH3.

[0418] Z is NR 3 In some embodiments of the compound of formula (I), R 3 The expression is -S(O)2CH2CH3.

[0419] In some embodiments of the compound of formula (I), R c These are 3- to 7-membered cycloalkyl groups, for example, 3-membered cycloalkyl groups, 4-membered cycloalkyl groups, 5-membered cycloalkyl groups, 6-membered cycloalkyl groups, or 7-membered cycloalkyl groups.

[0420] Z is NR 3 In some embodiments of the compound of formula (I), R 3 These are C1-C6 alkyl groups that may be substituted in some cases, such as C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0421] Z is NR 3 And R 3 In some embodiments of the compound of formula (I), where C1-C6 alkyl is optionally substituted, C1-C6 alkyl is -CH3.

[0422] Z is NR 3 And R 3 In some embodiments of the compound of formula (I), where C1-C6 alkyl is optionally substituted, C1-C6 alkyl is -CH2CH3.

[0423] Z is NR 3 And R 3 In other embodiments of the compound of formula (I), where the C1-C6 alkyl is optionally substituted, the C1-C6 alkyl is -CH(CH3)2.

[0424] Z is NR 3 And R 3 In other embodiments of the compound of formula (I), where the optionally substituted C1-C6 alkyl is 2-hydroxyethyl, i.e., -CH2CH2OH.

[0425] Z is NR 3 And R 3 In other embodiments of the compound of formula (I), where the optionally substituted C1-C6 alkyl is -CH2C(CH3)2OH.

[0426] Z is NR 3 In some embodiments of the compound of formula (I), R 3 These are 3- to 5-membered cycloalkyl groups, for example, 3-membered cycloalkyl groups, 4-membered cycloalkyl groups, or 5-membered cycloalkyl groups.

[0427] Z is NR 3 And R 3 In some embodiments of the compound of formula (I), where is a 3- to 5-membered cycloalkyl group, the 3- to 5-membered cycloalkyl group is cyclobutyl.

[0428] Z is NR 3 In some embodiments of the compound of formula (I), R 3 These are 3- to 5-membered heterocycloalkyl groups, for example, 3-membered heterocycloalkyl groups, 4-membered heterocycloalkyl groups, or 5-membered heterocycloalkyl groups.

[0429] Z is NR 3 And R 3 In some embodiments of the compound of formula (I), where is a 3-5 member heterocycloalkyl, the 3-5 member heterocycloalkyl is oxetanyl.

[0430] [ka]

[0431] is as follows.

[0432] In some embodiments of the compound of formula (I), Z is CR 4 R 4' is as follows.

[0433] In some embodiments of the compound of formula (I) where Z is CR 4 R 4' R 4 and R 4' are each H.

[0434] In some embodiments of the compound of formula (I) where Z is CR 4 R 4' R 4 and R 4' are each optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0435] In some embodiments of the compound of formula (I) where Z is CR 4 R 4' R 4 is H and R 4' is OH.

[0436] In some embodiments of the compound of formula (I) where Z is CR 4 R 4' R 4 and R 4'These, together with the carbon atom to which they are bonded, optionally form a substituted 3- to 7-membered heterocycloalkyl ring, for example, an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, or an optionally substituted 7-membered heterocycloalkyl ring.

[0437] In some embodiments of the compound of formula (I), the optionally substituted 3- to 7-membered heterocycloalkyl ring is optionally substituted 4-membered heterocycloalkyl ring.

[0438] In some embodiments of the compound of formula (I), the optionally substituted four-membered heterocycloalkyl ring is an azetidinyl ring.

[0439] Z is CR 4 R 4' And R 4 and R 4' However, in some embodiments of the compound of formula (I), both of these, together with the carbon atom to which they are bonded, form an azetidinyl ring which may be substituted, the azetidinyl ring is unsubstituted, i.e.,

[0440] [ka]

[0441] That is the case.

[0442] Z is CR 4 R 4' And R 4 and R 4' However, in some embodiments of the compound of formula (I), both of these, together with the carbon atom to which they are bonded, form an optionally substituted azetidinyl ring,

[0443] [ka]

[0444] That is the case.

[0445] Z is CR 4 R 4' and R 4 and R 4' In other embodiments of the compound of formula (I), both of these, together with the carbon atom to which they are bonded, form an optionally substituted azetidinyl ring, the azetidinyl ring may be nitrogen-substituted.

[0446] Z is CR 4 R 4' And R 4 and R 4' However, in some embodiments of the compounds of formula (I), both of these atoms together with the bonded carbon atom to form an N-substituted azetidinyl ring, the N substituent is -C1~C6 alkyl, -C1~C6 haloalkyl, -C(O)C1~C6 haloalkyl, -C(O)OC1~C6 alkyl, -C(O)C1~C6 alkyl, -C(O)N(C1~C6 alkyl)2, or -SO2-C1~C6 alkyl.

[0447] Z is CR 4 R 4' And R 4 and R 4' However, in some embodiments of the compounds of formula (I), both of these atoms together with the bonded carbon atom to form an N-substituted azetidinyl ring, the N substituent is -C1~C6 alkyl, -C(O)OC1~C6 alkyl, -C(O)C1~C6 alkyl, -C(O)N(C1~C6 alkyl)2, or -SO2-C1~C6 alkyl.

[0448] In some embodiments of the compound of formula (I), the N substituent is -CH3, -CH(CH3)2, -C(O)N(CH3)2, or -SO2CH3, i.e.,

[0449] [ka]

[0450] That is the case.

[0451] In other embodiments of the compound of formula (I), the N substituent is -CH2CF3, -CH2CHF2, -C(O)CF3, -C(O)OCH3, -C(O)OCH2CH3, or -SO2CH2CH3, for example,

[0452] [ka]

[0453] That is the case.

[0454] Z is CR 4 R 4' And R 4 and R 4' However, in some embodiments of the compound of formula (I), both of these combine with the carbon atom to which they are bonded to form an N-substituted azetidinyl ring,

[0455] [ka]

[0456] That is the case.

[0457] Z is CR 4 R 4' And R 4 and R 4' However, in some embodiments of the compound of formula (I), both of these substituents, together with the carbon atom to which they are bonded, form an N-substituted azetidinyl ring, the N substituent is -C(O)OCH2CH3, -SO2CH(CH3)2, or -SO2CH2CH3.

[0458] Z is CR 4 R 4' And R 4 and R 4' However, in some embodiments of the compound of formula (I), both of these combine with the carbon atom to which they are bonded to form an N-substituted azetidinyl ring,

[0459] [ka]

[0460] That is the case.

[0461] Z is CR 4 R 4' In some embodiments of the compound of formula (I), R 4 and R 4' These, together with the carbon atom to which they are bonded, form a thethane 1,1-dioxide ring, which may be substituted in some cases.

[0462] In some embodiments of the compound of formula (I), Z is:

[0463] [ka]

[0464] That is the case.

[0465] Z is CR 4 R 4' And R 4 and R 4' However, in some embodiments of the compound of formula (I), both of these, together with the carbon atom to which they are bonded, form an optionally substituted four-membered heterocycloalkyl ring, the optionally substituted four-membered heterocycloalkyl ring is an optionally substituted oxetane ring, for example,

[0466] [ka]

[0467] That is the case.

[0468] Z is CR 4 R 4' And R 4 and R 4'However, in some embodiments of the compound of formula (I), both of these combine with the carbon atom to which they are bonded to form an optionally substituted 3- to 7-membered heterocycloalkyl ring, the optionally substituted 3- to 7-membered heterocycloalkyl ring is an optionally substituted 5-membered heterocycloalkyl ring.

[0469] Z is CR 4 R 4' And R 4 and R 4' However, in some embodiments of the compounds of formula (I), both of these, together with the carbon atom to which they are bonded, form an optionally substituted five-membered heterocycloalkyl ring, the optionally substituted five-membered heterocycloalkyl ring is an unsubstituted pyrrolidinyl ring, an N-substituted pyrrolidinyl ring, an unsubstituted pyrrolidinyl-2-one ring, an N-substituted pyrrolidinyl-2-one ring, an unsubstituted pyrrolo-2,5-dione ring, an N-substituted pyrrolo-2,5-dione ring, an unsubstituted imidazolidinyl-2-one ring, an N-substituted imidazolidinyl-2-one ring, a tetrahydrofuranyl ring, or a tetrahydrothiophene-1,1-dioxide ring.

[0470] In some embodiments of the compound of formula (I), the N substituent is a -C1-C6 alkyl group, for example, -CH3.

[0471] In some embodiments, the N substituent is -C1~C6 alkyl, -C(O)OC1~C6 alkyl, -C(O)C1~C6 alkyl, -C(O)N(C1~C6 alkyl)2, or -SO2-C1~C6 alkyl.

[0472] In some embodiments, the N substituent is a -C(O)OC1~C6 alkyl group, for example, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, or a -SO2C1~C6 alkyl group, for example, -SO2CH3.

[0473] In some embodiments of the compound of formula (I), Z is

[0474] [ka]

[0475] That is the case.

[0476] In other embodiments of the compound of formula (I), Z is

[0477] [ka]

[0478] That is the case.

[0479] Z is CR 4 R 4' And R 4 and R 4' However, in some embodiments of the compound of formula (I), both of these combine with the carbon atom to which they are bonded to form an optionally substituted 3- to 7-membered heterocycloalkyl ring, the optionally substituted 3- to 7-membered heterocycloalkyl ring is an optionally substituted 6-membered heterocycloalkyl ring.

[0480] In some embodiments of the compound of formula (I), the optionally substituted six-membered heterocycloalkyl ring is either an unsubstituted piperidini-2-one ring or an N-substituted piperidini-2-one ring.

[0481] In some embodiments of the compound of formula (I), the N-substituent is -CH3.

[0482] In some embodiments of the compound of formula (I), Z is

[0483] [ka]

[0484] That is the case.

[0485] In other embodiments of the compound of formula (I), the optionally substituted six-membered heterocycloalkyl ring is a substituted or unsubstituted piperidine ring, or a tetrahydro-2H-thiopyran 1,1-dioxide ring.

[0486] In some embodiments of the compound of formula (I), the piperidine ring is N-substituted with -C(O)OC1~C6 alkyl, for example -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -C1~C6 alkyl, -C(O)C1~C6 alkyl, or -SO2C1~C6 alkyl, for example -SO2CH3, -SO2CH2CH3.

[0487] In some embodiments of the compound of formula (I), the piperidine ring is N-substituted with -C(O)OC1~C6 alkyl, for example -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -C1~C6 alkyl, -C(O)C1~C6 alkyl, or -SO2C1~C6 alkyl, for example -SO2CH3.

[0488] In some embodiments of the compound of formula (I), Z is

[0489] [ka]

[0490] That is the case.

[0491] In some embodiments of other compounds of formula (I), Z is

[0492] [ka]

[0493] That is the case.

[0494] Compound of formula (II) In some embodiments, the present disclosure relates to compounds of formula (II).

[0495] [ka]

[0496] or a pharmaceutically acceptable salt thereof [In the formula, n = 1, 2, or 3, m = 1, 2, or 3, Each R 1 These are independently H; or optionally substituted C1-C6 alkyl groups. Each R 2 These are independently H; or optionally substituted C1-C6 alkyl groups. or two R atoms bonded to the same carbon atom 1 The groups, together with the carbon atoms to which both are bonded, optionally form a substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring. or two R atoms bonded to the same carbon atom 1 The group, together with its carbon atom, represents a carbonyl group (C=O), or two R atoms bonded to the same carbon atom 2 The groups, together with the carbon atoms to which both are bonded, optionally form a substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring. or two R atoms bonded to the same carbon atom 2 The group, together with its carbon atom, represents a carbonyl group (C=O), or two R atoms bonded to different carbon atoms 1 The groups, together with the carbon atoms to which they are bonded, form a 3- to 7-membered cycloalkyl ring, or two R atoms bonded to different carbon atoms 2 The groups, together with the carbon atoms to which they are bonded, form a 3- to 7-membered cycloalkyl ring, or R 1 Base and R 2 The bases combine to form a 6-9 membered bridged biring ring, A = N or CH, Z = S(O)2; S(O); O, NR 3 or CR 4 R 4' and R 3 is H; optionally substituted -C1-C6 alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O)2R c ; or -S(O)2NR a R b and R a is H or C1-C6 alkyl, or R b is H or C1-C6 alkyl, or or R a and R b together with the N atom to which they are both attached form an optionally substituted 3-7 membered heterocycloalkyl ring, R c is optionally substituted C1-C6 alkyl, or cycloalkyl, or R 4 is H or optionally substituted C1-C6 alkyl, or R 4' is H, -OH, or optionally substituted C1-C6 alkyl, or or R 4 and R 4' together with the C atom to which they are both attached form an optionally substituted 3-7 membered heterocycloalkyl ring, Y is a 5- or 6-membered heteroaryl ring, Q 5 、Q 6 、Q 7 、Q 8 [[ID=7o]]、and Q 9 are each independently CR 5 and ​​These are H, halogen, C1-C3 alkyl; C1-C3 alkoxyl, or cycloalkyl. X = O, S, or NR, and R is H or C1-C3 alkyl. R 6 This applies to C1-C6 alkyl groups.

[0497] In some aspects of this disclosure, the compound of formula (II) is the compound of formula (IIA):

[0498] [ka]

[0499] [In the formula, Q 1 Q 2 Q 3 Q 4 One or two of them are N, and the rest are CR 5a And each R 5a [The elements are independently H, halogen, or C1-C3 alkyl, and the other variable elements are as described for formula (II)].

[0500] In some embodiments, the compound of formula (II) is the compound of formula (IIB):

[0501] [ka]

[0502] [In the formula, the variable elements have the values ​​listed above for formula (II)].

[0503] In some embodiments of the compound of formula (II), Q 6 and Q 8 Each of them operates independently, CR 5 And each R 5 is a halogen, Q 5 Q 7 , and Q 9 Each is independently CR 5 And each R 5 H is H.

[0504] In some embodiments of the compound of formula (II), Q 6 and Q 8 Each is independently CR 5 And each R 5 is -F and Q 5 Q 7 , and Q 9 Each is independently CR 5 And each R 5 H is H.

[0505] In some embodiments of the compound of formula (II), Q 5 and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 Q 7 , and Q 8 Each is independently CR 5 And R 5 H is H.

[0506] In some embodiments of the compound of formula (II), Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 Q 7 , and Q 8 Each is independently CR 5 And each R 5 H is H.

[0507] In some embodiments, this disclosure covers the following compounds or pharmaceutically acceptable salts thereof:

[0508] [ka]

[0509] In other embodiments, this disclosure covers the following compounds or pharmaceutically acceptable salts thereof:

[0510] [Table 1A]

[0511] [Table 1B]

[0512] [Table 1C]

[0513] [Table 1D]

[0514] [Table 1E]

[0515] [Table 1F]

[0516] [Table 1G]

[0517] [Table 1H]

[0518] [Table 1I]

[0519] In other embodiments, this disclosure covers the following compounds or pharmaceutically acceptable salts thereof:

[0520] [ka]

[0521] In some embodiments, this disclosure covers the compounds shown in the following examples, or pharmaceutically acceptable salts thereof.

[0522] References to formula (I) or formula (II) or their subgenus herein are intended to encompass the identified formula and all subgenus of those formulas disclosed herein. For example, references to formula (I) also encompass the subgenus formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IB, IB-1, and IB-2. References to formula (I) also encompass the subgenus formula IA-8.

[0523] Stereoisomers of compounds of formula (I) or formula (II) are also contemplated in this disclosure. Thus, this disclosure encompasses all stereoisomers and structural isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers, or mixtures thereof.

[0524] pharmaceutically acceptable salts and solvates of compounds of formula (I) or formula (II) are also within the scope of this disclosure.

[0525] For clarity, it should be recognized that certain features of the Invention described herein in the context of separate embodiments can also be provided in combination with a single embodiment. That is, unless they are obviously incompatible or specifically excluded, each individual embodiment is considered combinatable with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, for brevity, various features of the Invention described in the context of a single embodiment may also be provided separately or in any subordinate combination. Although embodiments are described as part of a series of steps or as part of a more general structure, each of the steps may also be considered an independent embodiment in itself that can be combined with other embodiments.

[0526] Pharmaceutical composition and method of administration The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the compound of the Disclosure as an active ingredient, or as a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. In some embodiments, the pharmaceutical composition contains the compound of the Disclosure or a pharmaceutically acceptable salt thereof, as well as a carrier comprising one or more pharmaceutically acceptable excipients, an inert solid diluent and filler, a diluent comprising a sterile aqueous solution and various organic solvents, a permeation enhancer, a solubilizer, and an adjuvant.

[0527] The pharmaceutical composition in question can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. If desired, one or more compounds of the present invention and the other agents may be mixed to form a preparation, or both components may be formulated into separate preparations for use separately or simultaneously.

[0528] In some embodiments, the concentrations of one or more compounds provided in the pharmaceutical composition of the present invention are 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0. The percentages are 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or less than 0.0001% (or any two of the above numbers within a range that includes both numbers) w / w, w / v, or v / v.

[0529] In some embodiments, the concentrations of one or more compounds of the present invention are 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%. 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0. The values ​​are greater than 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or any two of the above numbers within a range that includes both numbers) w / w, w / v, or v / v.

[0530] In some embodiments, the concentrations of one or more compounds of the present invention are approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately The percentages are approximately 23%, 0.09% to 22%, 0.1% to 21%, 0.2% to 20%, 0.3% to 19%, 0.4% to 18%, 0.5% to 17%, 0.6% to 16%, 0.7% to 15%, 0.8% to 14%, 0.9% to 12%, and 1% to 10%, all within the range of w / w, w / v, or v / v.

[0531] In some embodiments, the concentration of one or more compounds of the present invention is in the range of approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, and approximately 0.1% to approximately 0.9% w / w, w / v, or v / v.

[0532] In some embodiments, the amounts of one or more compounds of the present invention are 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.0 Equal to or less than 8g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g (or any two of the above numbers, within the range including those two numbers).

[0533] In some embodiments, the amounts of one or more compounds of the present invention are 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.003g 5g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0 .0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.04 5g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1 g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.7 Greater than 5g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g (or any two of the above numbers defined within the range including those two numbers).

[0534] In some embodiments, the amount of one or more compounds of the present invention is in the range of 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0535] In some embodiments, the compounds according to the present invention are effective over a wide dose range. For example, in the treatment of adult humans, usable dosages include 0.01–1000 mg, 0.5–100 mg, 1–50 mg, and 5–40 mg per day. Exemplary dosages are 10–30 mg per day. The exact dosage depends on the route of administration, the form in which the compound is administered, the subject being treated, the subject's body weight, and the physician's preference and experience.

[0536] Unless otherwise specified, the amounts of compounds described herein are given on a free base basis. That is, the amount refers to the amount of the administered compound excluding, for example, the solvent (e.g., in the solvate) or the counterion (e.g., in the pharmaceutically acceptable salt).

[0537] Non-limiting exemplary pharmaceutical compositions and methods for preparing them are described below.

[0538] Pharmaceutical composition for oral administration In some embodiments, the present invention provides a pharmaceutical composition for oral administration containing the compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0539] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration, comprising (i) an effective amount of the compound of the present invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises (iv) an effective amount of a third agent.

[0540] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical compositions of the present invention suitable for oral administration may also be presented in separate dosage forms, such as capsules, cachets, or tablets, or as liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder, or as granules, liquids, or as a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms may be prepared by any pharmaceutical method, all of which involve a step that brings about the association of the active ingredient with a carrier, which constitutes one or more required components. Generally, the composition is prepared by uniformly and densely mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into a desired appearance. For example, tablets may be prepared by compression or molding together with one or more auxiliary components as may be used. Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form into, for example, a powder or granules in suitable equipment, and optionally mixing it with excipients, for example, but not limited to binders, lubricants, inert diluents, and / or surfactants or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in suitable equipment.

[0541] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water may accelerate the decomposition of some compounds. For example, water may be added (e.g., 5%) as a means of simulating long-term storage in the pharmaceutical field to determine characteristics such as shelf life and stability of the formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. The pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored so as to maintain their anhydrous properties. Therefore, anhydrous compositions may be packaged using materials known to prevent exposure to water so as to be included in appropriate formulation kits. Examples of appropriate packaging, but not limited to, include sealed foil, plastic, unit dose containers, blister packs, and strip packs.

[0542] The active ingredient can be combined with a pharmaceutical carrier in a close mixture according to conventional pharmaceutical formulation techniques. The carrier can take a wide variety of forms depending on the desired form of the preparation for administration. In the preparation of compositions for oral dosage forms, for oral liquid preparations (e.g., suspensions, solutions, and elixirs) or aerosols, any of the usual pharmaceutical media can be used as a carrier, such as water, glycol, oil, alcohol, flavoring agent, preservative, coloring agent, etc. Alternatively, for oral solid preparations, in some embodiments, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants can be used without the use of lactose. For example, suitable carriers for solid oral preparations include powders, capsules, and tablets. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0543] Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums, such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0544] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powders), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0545] By using a disintegrant in the composition of the present invention, tablets that decompose when exposed to an aqueous environment can be obtained. Too much disintegrant may produce tablets that decompose in the bottle. Too little may be insufficient for disintegration, which may alter the rate and range of release of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant, neither too little nor too much, that would negatively alter the release of the active ingredient, may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary depending on the type of formulation and mode of administration, which will be readily apparent to those skilled in the art. About 0.5 to about 15 mass percent of disintegrant, or about 1 to about 5 mass percent of disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polaritrin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clay, other algins, other celluloses, gums, or mixtures thereof.

[0546] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, siloid silica gel, aerosols of synthetic silica, or mixtures thereof. Lubricants may optionally be added in amounts of less than about 1 mass percent of the pharmaceutical composition.

[0547] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredients therein may be various sweeteners or flavoring agents, coloring agents or dyes, and, if so desired, emulsifiers and / or suspending agents, which may be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0548] The tablets may be uncoated or coated by known techniques to slow their disintegration and absorption in the gastrointestinal tract, thereby obtaining a longer-lasting effect. For example, time-delaying substances, such as glyceryl monostearate or glyceryl distearate, can be used. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0549] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

[0550] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while a suitable lipophilic surfactant may generally have an HLB value of about 10 or less. The experimentally based parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions.

[0551] Hydrophilic surfactants are generally considered to be compounds with HLB values ​​greater than approximately 10, and which are anionic, cationic, or zwitterionic compounds to which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with HLB values ​​equal to or less than approximately 10. However, the HLB values ​​of surfactants are merely rough guides commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0552] Hydrophilic surfactants may be either ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidicates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; sodium docusate; acyl lactylates; mono- and diacetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0553] Among the above-mentioned group, examples of ionic surfactants include: lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinyl mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0554] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactylic esters, stearoyl-2-lactylate, and stearoyl lactyl esters. This may include tilates, succinyl monoglycerides, mono / diacetylated tartrates of mono / diglycerides, citrates of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, lysine oleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, ionized forms of lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts thereof, as well as mixtures thereof.

[0555] Examples of hydrophilic nonionic surfactants, though not limited to these, include alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers, e.g., polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, e.g., polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, e.g., polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, e.g., polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols with at least one member from the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, their derivatives, and analogs; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters, and hydrophilic transesterification products of polyols with at least one member from the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or sugars.

[0556] Other hydrophilic-nonionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, and PEG-1 stearate. 00, PEG-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, Glyceryl PEG-20 Oleate, Glyceryl PEG-30 Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric Acid / Caprylic Acid Glyceride, PEG-8 Capric Acid / Caprylic Acid Glyceride, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soybean Sterol, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, PO Examples include E-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween40, Tween60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG-10 to PEG-100 nonylphenol series, PEG-15 to PEG-100 octylphenol series, and poloxamer.

[0557] Suitable lipophilic surfactants include, but are not limited to, the following: aliphatic alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Among these, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or preferred lipophilic surfactants are hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0558] In one embodiment, the composition may contain a solubilizer to ensure good solubilization and / or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This may be particularly important for compositions for parenteral use, such as compositions for injection. Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0559] Examples of suitable solubilizers, but not limited to, include: alcohols and polyols, e.g., ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transkitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of about 200 to about 6000, e.g., tetrahydrofurfuryl alcohol PEG ether (glycoflor) or methoxyPEG; amides and other nitrogen-containing compounds, e.g., 2-pyrrolidone, 2 -Piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters, for example, ethyl propionate, tributyl citrate, triethyl acetyl citrate, tributyl acetyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art, for example, dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether and water.

[0560] Mixtures of solubilizers may also be used. Examples, but not limited to, include triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycoflor, transkitol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycoflor, and propylene glycol.

[0561] The amount of solubilizer that can be included is not particularly limited. A given amount of solubilizer may be limited to a biotolerable amount, which can be easily determined by those skilled in the art. In some situations, for example, it may be advantageous to include an amount of solubilizer far exceeding the biotolerable amount in order to maximize the concentration of the drug, but the prior art, for example, by using distillation or evaporation, removes the excess solubilizer before providing the composition to the target. Thus, if present, the solubilizer may be in a mass ratio of up to 10% by mass, 25% by mass, 50% by mass, 100% by mass, or about 200% by mass> relative to the combined mass of the drug and other excipients. If desired, very small amounts of solubilizer, for example, 5%>, 2%>, 1%, or even less may be used. Typically, the solubilizer may be present in an amount of about 1% by mass> to about 100% by mass, and more typically, about 5% by mass> to about 25% by mass>.

[0562] The composition may further contain one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, anti-tack agents, defoamers, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tension modifiers, flavoring agents, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0563] In addition, acids or bases may be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid, are also suitable. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, can also be used. When the base is a salt, the cation can be any convenient, pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, etc. Examples, but not limited to, include sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0564] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid.

[0565] Pharmaceutical composition for injection

[0566] In some embodiments, the present invention provides an injectable pharmaceutical composition containing the compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of the drug in the composition are as described herein.

[0567] Forms into which the novel compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions, emulsions using sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0568] Aqueous solutions in physiological saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Appropriate fluidity can be maintained, for example, in the case of dispersions, by using coatings such as lecithin to maintain the required particle size, and by using surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0569] Injectable sterile solutions are prepared by incorporating the required amount of the compound of the present invention, along with various other components listed above, into a suitable solvent, and subsequently sterilizing by filtration, if necessary. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other required components from those listed above. In the case of sterile powders for preparing injectable sterile solutions, certain preferred preparation methods are vacuum drying and freeze-drying techniques, which produce the active ingredient powder and any additional desired components from a pre-sterilized filtered solution.

[0570] Pharmaceutical compositions for topical (e.g., transdermal) delivery.

[0571] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery containing the compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0572] The compositions of the present invention can be formulated into solid, semi-solid, or liquid preparations suitable for localized or topical administration, such as gels, water-soluble jelly preparations, creams, lotions, suspensions, foaming agents, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, and dimethyl sulfoxide (DMSO)-based solutions. Generally, carriers with higher density can provide longer exposure to the active ingredient in a given area. In contrast, solution formulations can provide more immediate exposure to the active ingredient in a selected area.

[0573] Pharmaceutical compositions may also contain suitable solid or gel phase supports or excipients, which are compounds that enable increased penetration of therapeutic molecules through the permeability barrier of the stratum corneum of the skin, or that assist in their delivery. Many of these penetration-enhancing molecules are known to our industry in the field of topical formulations.

[0574] Examples of such carriers and excipients, but not limited to these, include humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers, such as polyethylene glycol.

[0575] Another exemplary formulation for use in the method of the present invention utilizes a transdermal delivery device ("patch"). Such a transdermal patch can be used to provide a controlled amount of the compound of the present invention, either in conjunction with or without another agent, in a continuous or discontinuous infusion.

[0576] The construction and use of transdermal patches for the delivery of pharmaceuticals are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be constructed for continuous, pulsed, or on-demand delivery of pharmaceuticals.

[0577] Inhalation pharmaceutical composition Compositions for inhalation or inhalation include pharmaceutically acceptable solutions and suspensions in aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, compositions are administered orally or via nasal respiratory routes for localized or systemic action. Preferably, compositions in pharmaceutically acceptable solvents can be sprayed using an inert gas. Sprayed solutions can be inhaled directly from a spraying device, or the spraying device can be attached to a face mask tent or an intermittent positive pressure (PAP) respiration device. Solutions, suspensions, or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0578] Other pharmaceutical compositions Pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, oral buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intrathecal administration. Preparations for such pharmaceutical compositions are well known in the art. For example, see Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th edition, McGraw-Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th edition, McGraw-Hill, 2001; Remingtons Pharmaceutical Sciences, 20th edition ed., Lippincott Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia, 32nd edition (The Pharmaceutical Press, London, 1999).

[0579] The compound or pharmaceutical composition of the present invention may be administered by any method that enables delivery of the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, intra-arterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or intravenous infusion), topical administration (e.g., percutaneous application), rectal administration, administration via localized delivery by catheter or stent, or administration by inhalation. The compound may also be administered intrafatally or intrathecally.

[0580] The amount of compound administered depends on the subject being treated, the severity of the disorder or condition, the administration rate, the pharmacokinetics of the compound, and the discretion of the prescribing physician. However, the effective dosage is in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg person, this is about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, but in other cases, even higher doses may be used, for example, by dividing such higher doses into several smaller doses for administration throughout the day, without causing any adverse side effects.

[0581] In some embodiments, the compound of the present invention is administered in a single dose.

[0582] Typically, such administration is carried out by injection, for example, intravenous injection, to rapidly deliver the drug. However, other routes may be used if necessary. A single dose of the compound of the present invention can also be used for the treatment of acute conditions.

[0583] In some embodiments, the compounds of the present invention are administered in multiple doses. Dosage may be approximately once, twice, three times, four times, five times, six times, or more than six times per day. Dosage may be approximately once a month, once every two weeks, once every week, or once every two days. In another embodiment, the compounds of the present invention and another agent are administered together approximately once to approximately six times per day. In yet another embodiment, administration of the compounds of the present invention and the agent continues for less than approximately seven days. In yet another embodiment, administration continues for approximately six, ten, fourteen, or twenty-eight days, two months, six months, or more than one year. In some cases, continuous dosing is achieved and maintained for as long as necessary.

[0584] The administration of the compounds of the present invention can be continued for as long as necessary. In some embodiments, the compounds of the present invention are administered for longer than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the present invention are administered for 28, 14, 7, 6, 5, 4, 3, 2, or less than 1 day. In some embodiments, the compounds of the present invention are administered on a continuous basis, for example, chronically for the treatment of chronic effects.

[0585] The effective amount of the compound of the present invention can be administered in single or multiple doses by any of the generally accepted administration modes of drugs having similar utility, which include administration via rectal, oral buccal, nasal and percutaneous routes, intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation.

[0586] The compositions of the present invention may also be delivered, for example, via an impregnated or coated device such as a stent, or via a cylindrical polymer inserted into an artery. Such methods of administration, for example, in accordance with procedures such as balloon angiogenesis, are useful in preventing or improving restenosis. Without being constrained by theory, the compounds of the present invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall, which contribute to restenosis. The compounds of the present invention may be administered by localized delivery, for example, from a stent support, from a stent graft, from a graft, or from a stent cover or sheath. In some embodiments, the compounds of the present invention are miscible with a matrix. Such a matrix may be a polymer matrix and may also function to bind the compounds to the stent. Suitable polymeric matrices for such use include, for example, lactone-based polyesters or copolyesters, e.g., polylactic acid, polycaprolactonglycolide, polyorthoesters, polyacid anhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxanes, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethyl methyl methacrylate, polyvinylpyrrolidinone), fluorinated polymers, e.g., polytetrafluoroethylene and cellulose esters. A suitable matrix may be non-degradable or degradable over time, releasing one or more compounds. The compounds of the present invention can be applied to the surface of the stent by various methods, e.g., dip / spin coating, spray coating, dip coating, and / or brush coating. The compounds may be applied in a solvent, which may be evaporated to form a layer of the compound on the stent. Alternatively, the compounds may be located within the body of the stent or graft, for example, in microchannels or micropores. If implanted, the compound diffuses from the stent body and comes into contact with the artery wall.Such stents can be prepared by dipping a stent, manufactured to contain such micropores or microchannels, into a solution of the compound of the present invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent can be removed by washing with additional solvent. In yet another embodiment, the compound of the present invention may be covalently bonded to the stent or graft. Release of the compound of the present invention can be brought about using a covalent linker that degrades in vivo. Any biologically unstable linkage, such as ester, amide, or anhydride linkage, can be used for this purpose. The compound of the present invention may be further administered intravascularly from a balloon used during angiogenesis. Extravascular administration of the compound via pericardial or adventitia application of the formulation of the present invention can also be performed to reduce restenosis.

[0587] Various stent devices that can be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: U.S. Patent No. 5451233; U.S. Patent No. 5040548; U.S. Patent No. 5061273; U.S. Patent No. 5496346; U.S. Patent No. 5292331; U.S. Patent No. 5674278; U.S. Patent No. 3657744; U.S. Patent No. 4739762; U.S. Patent No. 5195984; U.S. Patent No. 5292331; U.S. Patent No. 5674278; U.S. Patent No. 5879382; U.S. Patent No. 6344053.

[0588] The compounds of the present invention are administered in prescribed doses. It is well known in the art that individualization of the administration regimen is necessary for optimal therapy due to variability in the pharmacokinetics of the compounds among subjects. The dosage of the compounds of the present invention can be determined through routine experiments, taking this disclosure into consideration.

[0589] When the compound of the present invention is administered in a composition containing one or more agents, and these agents have a shorter half-life than the compound of the present invention, the unit dose forms of these agents and the compound of the present invention can be adjusted as appropriate.

[0590] The pharmaceutical composition may be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, or suspensions; for parenteral injection, such as sterile solutions, suspensions, or emulsions; for topical administration, such as ointments or creams; or for rectal administration, such as suppositories. The pharmaceutical composition may also be in a unit dosage form suitable for single-dose administration of a precise dosage. The pharmaceutical composition contains conventional pharmaceutical carriers or excipients and the compound according to the present invention as an active ingredient. In addition, the pharmaceutical composition may contain other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0591] Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, such as aqueous propylene glycol or dextrose solution. Such dosage forms can be appropriately buffered if desired.

[0592] How to use FGFR receptors (FGFR1, FGFR2, FGFR3, and FGFR4) share several common structural features, including an intracellular tyrosine kinase domain separated by three extracellular immunoglobulin-like (Ig) domains, a hydrophobic transmembrane domain, and a kinase insertion domain, followed by a cytoplasmic C-terminal tail (Johnson et al., Adv. Cancer Res. 60:pp. 1-40, 1993; and Wilkie et al., Curr. Biol. 5:pp. 500-507, 1995). In FGFR1, the kinase insertion domain extends from position 582 to 595 of the alpha-Al isoform of FGFR1. In FGFR2, the kinase insertion domain extends from position 585 to 598 of the FGFR2 Ille isoform. In FGFR3, the kinase insertion domain extends from position 576 to 589 of the FGFR3 Ille isoform. In FGFR4, the kinase insertion domain extends from position 571 to 58 in FGFR4 isoform 1. The C-terminal tail of FGFR begins immediately following the end of the tyrosine kinase domain and extends to the C-terminus of the protein. Several isoforms of each FGFR have been identified, and these are the result of alternative splicing of these mRNAs. (Johnson et al., Mol. Cell. Biol. 11: pp. 4627-4634, 1995; and Chellaiah et al., J. Biol. Chem. 269: pp. 11620-11627, 1994).

[0593] Some receptor variants resulting from this alternative splicing exhibit different ligand-binding specificities and affinities (Zimmer et al., J. Biol. Chem. 268:7899-7903, 1993; Cheon et al., Proc. Natl. Acad. Sci. USA 91:989-993, 1994; and Miki et al., Proc. Natl. Acad. Sci. USA 89:246-250, 1992). The protein sequences for the FGFR protein and the nucleic acid encoding the FGFR protein are publicly known in the art. FGFR signaling regulates major biological processes, including cell proliferation, survival, migration, and differentiation. Abnormal regulation of the FGFR gene, FGFR protein, or their expression, activity, or levels is associated with many types of cancer. For example, abnormal regulation of FGFR can result from numerous mechanisms, such as overexpression of the FGFR gene, amplification of the FGFR gene, activating mutations (e.g., point mutations or truncations), and chromosomal rearrangements that lead to FGFR fusion proteins. Abnormal regulation of the FGFR gene, FGFR protein, or their expression, activity, or levels can lead to (or partially cause) the development of various different FGFR-related cancers.

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Note that deletion of residues 795-808 of the FGFR3 isoform Ille also eliminates the stop codon, allowing the protein to be elongated by 99 amino acids (ATGPQQCEGSLAAHPAAGAQPLPGMRLSADGETATQSFGLCVCVCVCVCVCTSACACVRAHLASRCRGTLGVPAAVQRSPDWCCSTEGPLFWGDPVQNVSGPTRWDPVGQGAGPDMARPLPLHHGTSQGALGPSHTQS); Ge et al., Am J Cancer Res. 7(7):1540-1553, 2017. 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[0596] The compounds of this disclosure have been found to inhibit FGFR1, FGFR2, FGFR3, and / or FGFR4, and are therefore considered useful in treating diseases and disorders that can be treated with inhibitors of FGFR1, FGFR2, FGFR3, and / or FGFR4. For example, the compounds of this disclosure may be useful in treating FGFR-related diseases and disorders, such as proliferative disorders, including cancers such as hematological malignancies and solid tumors, and disorders related to angiogenesis. The compounds of this disclosure may also be useful in treating disorders resulting from major autosomal mutations in FGFR, such as FGFR3, including developmental disorders. Developmental disorders that should be treated with the compounds of this disclosure include achondroplasia (Ach) and related achondroplasic syndromes, including hypochondrodysplasia (Hch), severe achondroplasia with growth retardation and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD).

[0597] Non-limiting examples of diseases and disorders associated with FGFR include acanthosis nigricans, achondroplasia, Apert syndrome, Bea Stevenson syndrome (BSS), stunted-tall-hearing-deafness (CATSHL) syndrome, cleft lip and palate, congenital heart disease (e.g., associated with unspecified genitalia), craniosynostosis, Crouzon syndrome, cleft hand and foot, craniocranial lipomatosis, Hartsfield syndrome, achondroplasia, and hypogonadotropic hyposexuality (e.g., with anosmia or These include hypogonadotropic hyposexuality without sympathetic symptoms (Kallmann syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, fatal acinar dysplasia of the lung, microphthalmia, Muenke's coronary dysplasia, syringostosis, Pfeiffer syndrome, seborrheic keratometriosis, syndactyly, thanatophoric dysplasia (e.g., type I or type II), trigonocephaly (also known as frontocraniosynostosis), and tumor-induced osteomalacia.

[0598] Non-exclusive examples of diseases and disorders associated with FGFR1 include congenital heart defects (e.g., with unidentifiable genitalia), craniosynostosis, craniocranial lipomatosis, Hartsfield syndrome, hypogonadotropic hyposexuality (e.g., hypogonadotropic hyposexuality with or without anosmia², Kallmann syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, syringostosis, Pfeiffer syndrome, trigonocephaly¹ (also known as frontocraniosynostosis), and tumor-induced osteomalacia.

[0599] Non-exclusive examples of diseases and disorders associated with FGFR2 include Apert syndrome, Bea Stevenson syndrome (BSS), Crouzon syndrome, cleft hand and foot, Jackson-Weiss syndrome, fatal acinar dysplasia, Pfeiffer syndrome, and syndactyly. Non-exclusive examples of diseases and disorders associated with FGFR3 include acanthosis nigricans, achondroplasia, feline SHL syndrome, cleft lip and palate, craniosynostosis, achondroplasia, microphthalmia, Muenke's coronary suture fusion, seborrheic keratomeliopathy, and thanatophoric dysplasia (e.g., type I or type II). UniParc entry UPI00000534B8; UniParc entry UPI000000lCOF; UniPare entry UPI000002A99A; UniParc entry UPI000012A72A; Yong-Xing et al., Hum. Mol. Genet. 9(13): pp. 2001-2008, 2000; Eeva-Maria Laitinen et al., PLoS One 7(6): e39450, 2012; Hart et al., Oncogene 19(29): pp. 3309-3320, 2000; Shiang et al., Cell 76: pp. 335-342, 1994; Rosseau et al., Nature 371: pp. 252-254, 1994; Tavormina et al., Nature Genet. 9: pp. 321-328, 1995; Bellus et al., Nature Genet. 10: pp. 357-359, 1995; Muenke et al., Nature Genet. 8: pp. 269-274, 1994; Rutland et al., Nature Genet. 9: pp. 173-176, 1995; Reardon et al., Nature Genet. 8: pp. 98-103, 1994; Wilkie et al., Nature Genet. 9: pp. 165-172, 1995; Jabs et al., Nature Genet. 8: pp. 275-279, 1994; Japanese Patent No. JP05868992; Ye et al., Plast. Reconstr. Surg., 137(3): pp. 952-961, 2016; U.S. Patent No. 9447098B2; Bellus et al., Am. J. Med. Genet.85(1): pp. 53-65, 1999; PCT Patent Application Publication No. WO2016139227Al; Australian Patent Application Publication No. AU2014362227Al; Chinese Patent No. CN102741256B; Ohishi et al., Am. J. Med. Genet. A., doi: 10.1002 / ajmg.a.37992, 2016; Nagahara et al., Clin. Pediatr. Endocrinol., 25(3): pp. 103-106, 2016; Hibberd et al., Am. J. Med. Genet. A., doi: 10.1002 / ajmg.a.37862, 2016; Dias et al., Exp. Mol. Pathol., 101(1): pp. 116-1123, 2016; Lin et al., Mol. Med. Rep., 14(3): pp. 1941-1946, 2016; Barnett et al., Hum. Mutat., 37(9): pp. 955-953, 2016; Krstevska-Konstantinova et al., Med. Arch., 70(2): pp. 148-1450, 2016; Kuentz et al., Br. J. Dermatol., doi: 10.1111 / bjd.14681, 2016; Ron et al., Am. J. Case Rep., 15; 17: pp. 254-258, 2016; Fernandes et al., Am. J. Med. Genet. A., 170(6): pp. 1532-1537, 2016; Lindy et al., Am. J. Med. Genet. A., 170(6): pp. 1573-1579, 2016; Bennett et al., Am. J. Hum. Genet., 98(3):579~87, 2016; lchiyama et al., J. Eur. Acad. Dermatol. Venereal., 30(3):442~5, 2016; Zhao et al., Int. J. Clin. Exp. Med., 8(10):19241~9, 2015; Hasegawa et al., Am. J. Med. Genet. A., 170A(5):1370~2, 2016; Legeai-Mallet, Endocr. Dev., 30:98~105, 2016; Takagi, Am. J. Med. Genet. A., 167A(ll):2851~4, 2015; Goncalves, Fertil. Steril., 104(5): 1261 - 1267 pages. el, 2015; Miller et al., Journal of Clinical Oncology, 34: Supp. Supplement 15, iii93 pages. AbstractNumber: e22500, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Sarabipour et al., J. Mol. Biol., 428(20): 3903 - 3910 pages, 2016; Escobar et al., Am. J. Med. Genet. A., 170(7): 1908 - 1911 pages, 2016; Mazen et al., Sex Dev., 10(1): 16 - 22 pages, 2016; Taylan et al., J Allergy Clin Immunol, 136(2): 507 - 509 pages, 2015. doi: 10.1016 / j.jaci.2015.02.010; Kant et al., EuroJourn Endocrinol, 172(6): 763 - 770 pages, 2015. doi: 10.1530 / EJE - 14 - 0945; Gonzalez - Del Angel et al., Am J med Genet A, 176(1): 161 - 166 pages, 2018. doi: 10.1002 / ajmg.a.38526; Lei and Deng, Int J Biol Sci 13(9): 1163 - 1171, 2017. doi: 10.7150 / ijbs.20792; Lajeunie et al., Eur J Hum Genet, 14(3): 289 - 298 pages, 2006. doi: 10.1038 / sj.ejhg.5201558; Karadimas et al., Prenat Diagn, 26(3): 258 - 261 pages, 2006. doi: 10.1002 / pd.1392; lbrahimi et al., Hum Mol Genet 13(19): 2313 - 2324 pages, 2004. doi: 10.1093 / hmg / ddh235; Trarbach et al., J Clin Endocrinol Metab., 91(10): 4006 - 4012 pages, 2006. doi: 10.1210 / jc.2005 - 2793; Dode et al., Nat Genet, 33(4): 463 - 465 pages, 2003.See also doi: 10.1038 / ng1122. Each of these is incorporated herein by reference.

[0600] The term “angiogenic disorders” means diseases that are partially characterized by an increased number or size of blood vessels in the tissue of a subject or patient compared to similar tissue from a non-disease-affected subject. Non-exclusive examples of angiogenic disorders include cancer (e.g., any of the exemplary cancers described herein, e.g., prostate cancer, lung cancer, breast cancer, bladder cancer, kidney cancer, colon cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, liver cancer, sarcoma, and lymphoma), exudative macular degeneration, proliferative diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, iris rubeosis, corneal neovascularization, cyclitis, sickle cell retinopathy, and pterygium.

[0601] The compounds of the Disclosure inhibit wild-type FGFR1, FGFR2, FGFR3, and / or FGFR4. In other embodiments, the compounds of the Disclosure inhibit mutated FGFR1, FGFR2, FGFR3, and / or FGFR4. In other embodiments, the compounds of the Disclosure inhibit FGFR1, FGFR2, FGFR3, and / or FGFR4, including FGFR kinase inhibitor mutations.

[0602] In some embodiments of the methods or uses described herein, the cancer (e.g., FGFR-related cancer) is a hematological cancer. In some embodiments of the methods or uses described herein, the cancer (e.g., FGFR-related cancer) is a solid tumor.

[0603] In some embodiments of the methods or uses described herein, cancer (e.g., cancers associated with FGFR) is lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, lung adenocarcinoma, large cell carcinoma, mesothelioma, pulmonary neuroendocrine carcinoma, smoking-related lung cancer), prostate cancer, colorectal cancer (e.g., rectal adenocarcinoma), endometrial cancer (e.g., endometrioid endometrial cancer, endometrial adenocarcinoma), breast cancer (e.g., hormone receptor-positive breast cancer, triple-negative breast cancer, neuroendocrine carcinoma of the breast), skin cancer (e.g., For example, melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma, giant squamous cell carcinoma), gallbladder cancer, liposarcoma (e.g., dedifferentiated liposarcoma, myxoid liposarcoma), pheochromocytoma, myoepithelial carcinoma, urothelial carcinoma, spermatogenic seminoma, gastric cancer, head and neck cancer (e.g., head and neck (squamous) carcinoma, head and neck adenoid cystic carcinoma), brain cancer (e.g., glial cell tumor, glioma, neuroblastoma, glioblastoma, pilocytic astrocytoma, rosette-forming glial cell tumor, germinal dysplastic neuroepithelial tumor, undifferentiated astrocytoma, medulloblastoma, ganglioglioma, oligodendroglioma), malignant Peripheral nerve sheath tumors, sarcomas (e.g., soft tissue sarcomas (e.g., leiomyosarcoma), osteosarcoma), esophageal cancer (e.g., esophageal adenocarcinoma), lymphoma, bladder cancer (e.g., urothelial (metastatic cell) carcinoma of the bladder), cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma), fallopian tube cancer (e.g., fallopian tube cancer), ovarian cancer (e.g., serous ovarian carcinoma, mucinous ovarian carcinoma), bile duct cancer, adenoid cystic carcinoma, pancreatic cancer (e.g., exocrine pancreatic carcinoma, tubular adenocarcinoma of the pancreas, intraepithelial neoplasm of pancreatic cancer), salivary gland cancer (e.g., pleomorphic salivary gland carcinoma, salivary gland cystic carcinoma), oral cancer (e.g., oral squamous cell carcinoma), uterine cancer, stomach cancer or gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors, myeloma (e.g., multiple myeloma), lymphoblastoma, anal cancer (e.g., anal squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), renal alveolar carcinoma, thymic carcinoma, gastroesophageal junction adenocarcinoma, testicular cancer, rhabdomyosarcoma (e.g., alveolar rhabdomyosarcoma, fetal rhabdomyosarcoma), papillary renal carcinoma, liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), carcinoid, myeloid proliferative disorders (also called myeloid proliferative neoplasms (MPNs));For example, 8pll myeloproliferative syndrome (EMS, also known as stem cell leukemia / lymphoma), acute myeloid leukemia (AML), chronic myeloid leukemia (CML)), lymphoma (e.g., T-cell lymphoma, T-lymphoblastic lymphoma, acute lymphoblastic leukemia (ALL), B-cell lymphoma), myeloid and lymphoneoplasms, chronic neutrophilic leukemia, phosphateuric mesenchymal neoplasms, thyroid cancer (e.g., anaplastic thyroid carcinoma), or ductal carcinoma of the bile duct.

[0604] In some embodiments of the methods or uses described herein, cancer (e.g., FGFR-related cancers) includes: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adolescent cancers, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratomatoid / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoma Idoid tumor, cancer of unknown primary origin, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, neoplasms of a specific site, neoplasm, colon cancer, rectal and colon cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, cholangiocarcinoma, ductal carcinoma in situ, fetal tumor, endometrial cancer, ependymal cell tumor, esophageal cancer, sensory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, Extrahepatic cholangiocarcinoma, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic neoplasm, head and neck neoplasm, CNS tumor, primary CNS tumor, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, neuroendocrine tumor of the pancreas, Kaposi's sarcoma Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, neoplasms of any site, neoplasms, myelogenous leukemia, myeloid leukemiaLeukemia, multiple myeloma, myeloproliferative neoplasms, nasal and parasinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, lung neoplasms, lung cancer, lung neoplasms, respiratory neoplasms, bronchogenic lung cancer, bronchial neoplasms, oral cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleuroblastoma, pregnancy-related breast cancer, primary The following are selected from the group of central nervous system lymphomas, primary peritoneal cancers, prostate cancers, rectal cancers, colon cancers, neoplasms of the colon, renal cell carcinomas, retinoblastomas, rhabdomyosarcomas, salivary gland cancers, sarcomas, Sézary syndromes, skin cancers, Spitz tumors, small cell lung cancers, small intestine cancers, soft tissue sarcomas, squamous cell carcinomas, squamous neck cancers, gastric cancers, T-cell lymphomas, testicular cancers, pharyngeal cancers, thymomas and thymic carcinomas, thyroid cancers, transitional cell carcinomas of the renal pelvis and ureters, cancers of unknown primary origin, urethral cancers, uterine cancers, uterine sarcomas, vaginal cancers, vulvar cancers, and Wilms' tumors.

[0605] In some embodiments, hematological cancers (e.g., hematological cancers that are associated with FGFR) include leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also called Hodgkin lymphoma), and myeloma, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and chronic myelomonocytic leukemia (CMML). The group consists of chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonuclear leukemia (JMML), AML with myeloplastic abnormalities of three blood cell lines (AML / TMDS), adult T-cell ALL, mixed-phenotype leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), and multiple myeloma (MM).

[0606] Additional examples of hematological cancers include myeloproliferative disorders (MPDs), such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological cancer (e.g., a hematological cancer that is associated with FGFR) is AML or CMML. In some embodiments, the cancer (e.g., a cancer associated with FGFR) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are associated with FGFR) include, for example, lung cancer (e.g., adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer), bladder cancer, colorectal cancer, brain cancer, testicular cancer, cholangiocarcinoma, cervical cancer, prostate cancer, and spermatogenic seminoma. See, for example, Turner and Grose, Nat. Rev. Cancer, 10(2): pp. 116-129, 2010.

[0607] In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.

[0608] In some embodiments, cancers associated with FGFR1 are selected from the group consisting of lung cancer, breast cancer, and brain cancer.

[0609] In some embodiments, the cancer is selected from the group consisting of breast cancer, uterine cancer, bile duct cancer, and lung cancer.

[0610] In some embodiments, cancers associated with FGFR2 are selected from the group consisting of breast cancer, uterine cancer, bile duct cancer, and lung cancer. In some embodiments, cancers are selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.

[0611] In some embodiments, cancers associated with FGFR3 are selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.

[0612] In some embodiments, the cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0613] In some embodiments, cancers associated with FGFR4 are selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0614] In some embodiments, the compounds of the Disclosure are used to treat cancers associated with the amplification or overexpression of FGFR1, such as breast cancer or carcinoma (e.g., hormone receptor-positive breast cancer, ductal carcinoma in situ (mammary gland)), tubular adenocarcinoma of the pancreas, exocrine pancreatic carcinoma, smoking-related lung cancer, small cell lung cancer, lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer or carcinoma, prostate cancer or carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, rhabdomyosarcoma, head and neck cancer (e.g., squamous cell carcinoma of the head and neck), and esophageal cancer. It is useful for treating cancer (e.g., squamous cell carcinoma of the esophagus), sarcomas (e.g., osteosarcoma), hepatocellular carcinoma, elvic carcinoma, colorectal cancer (e.g., adenocarcinoma of the colon), prostate cancer, salivary gland tumors, glioblastoma multiforme, bladder cancer, urothelial carcinoma, cancer of unknown primary origin, squamous non-lung tumors, gastric cancer, gastroesophageal junction cancer, adenoid cystic carcinoma, anal squamous cell carcinoma, oral squamous cell carcinoma, bile duct cancer, hemangioendothelioma, leiomyosarcoma, melanoma, neuroendocrine carcinoma, squamous cell carcinoma, and carcinosarcoma of the uterus.

[0615] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR2 amplification, such as gastric cancer, gastroesophageal junction adenocarcinoma, breast cancer (e.g., triple-negative breast cancer), colon cancer, colorectal cancer (e.g., colorectal adenocarcinoma), urothelial carcinoma, bladder adenocarcinoma, cancer of unknown primary origin, cholangiocarcinoma, endometrial adenocarcinoma, esophageal adenocarcinoma, gallbladder cancer, ovarian cancer, fallopian tube cancer, pancreatic exocrine carcinoma, sarcoma, and squamous cell carcinoma.

[0616] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR2 overexpression, such as myxoid lipocarcinoma, colorectal cancer, elliptic carcinoma, and breast cancer.

[0617] In some embodiments, the compounds of the Disclosure are useful for treating cancers associated with upregulation of FGFR3 activity, such as colorectal cancer, hepatocellular carcinoma, and exocrine pancreatic carcinoma. In some embodiments, the compounds of the Disclosure are useful for treating cancers associated with overexpression of FGFR3 activity, such as multiple myeloma and thyroid cancer. In some embodiments, the compounds of the Disclosure are useful for treating cancers associated with amplification of FGFR3 activity, such as bladder cancer and adenoid cystic carcinoma of the salivary gland, urothelial carcinoma, breast cancer, carcinoid cancer, cancer of unknown primary origin, colorectal cancer (e.g., colorectal adenocarcinoma), gallbladder cancer, gastric cancer, gastroesophageal junction adenocarcinoma, glioma, mesothelioma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, fallopian tube cancer, and exocrine pancreatic carcinoma.

[0618] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR4 amplification, such as rhabdomyosarcoma, prostate cancer or carcinoma, breast cancer, urothelial carcinoma, carcinoid, cancer of unknown primary origin, esophageal adenocarcinoma, head and neck cancer, hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, and renal alveolar carcinoma.

[0619] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with the upregulation of FGFR4 activity, such as colorectal cancer, hepatocellular carcinoma, adrenal carcinoma, and breast cancer.

[0620] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with the overexpression of FGFR4 activity, such as pancreatic carcinoma in situ and tubular adenocarcinoma of the pancreas.

[0621] In some embodiments, the compounds of this disclosure are more selective to certain FGFRs than to other FGFRs. As used herein, “selectivity” of a compound to a first target over a second target means that the compound has more potent activity at the first target than at the second target. The selectivity factor can be calculated by any method known in the art. For example, the selectivity factor can be calculated by dividing the IC50 value (or Kd value) of the compound for a second target (e.g., FGFR1) by the IC50 value of the same compound for a first target (e.g., FGFR2 or FGFR3). The IC50 value can be determined by any method known in the art. In some embodiments, it is initially determined that the compound has an activity of less than 500 nM for the first target. In some embodiments, it is initially determined that the compound has an activity of less than 500 nM for the second target.

[0622] For example, in some embodiments, the compounds of the Disclosure are more selective to FGFR3 than to FGFR1. In some embodiments, the compounds are at least three times more selective to FGFR3 than to FGFR1. In some embodiments, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000 times more selective to FGFR3 than to FGFR1.

[0623] In some embodiments, the compounds of the Disclosure are more selective to FGFR2 than to FGFR1. In some embodiments, the compounds are at least three times more selective to FGFR2 than to FGFR1. In some embodiments, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000 more selective to FGFR2 than to FGFR1.

[0624] In some embodiments, the compounds of the Disclosure are more selective than a first FGFR family member (e.g., FGFR2 or FGFR3) compared to a second FGFR family member (e.g., FGFR1 or FGFR4). In some embodiments, the compounds of the Disclosure are at least three times more selective than a first FGFR family member compared to a second FGFR family member. In some embodiments, the compounds are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000 times more selective than a first FGFR family member compared to a second FGFR family member.

[0625] In some embodiments, the compounds of the Disclosure are more selective to FGFR kinases than other kinases that are not FGFR kinases. For example, the compounds of the Disclosure are at least three times more selective to FGFR kinases than other kinases that are not FGFR kinases. In some embodiments, the compounds of the Disclosure are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000 times more selective to FGFR kinases than other kinases that are not FGFR kinases. Examples of kinases that are not FGFR kinases include KDR kinase and Aurora B kinase.

[0626] In some embodiments, the compounds of this disclosure exhibit brain and / or central nervous system (CNS) permeability. Such compounds can cross the blood-brain barrier and inhibit FGFR kinases in the brain and / or other CNS structures. In some embodiments, the compounds provided herein can cross the blood-brain barrier in therapeutically effective doses. For example, treatment of a subject having cancer (e.g., FGFR-related cancer, e.g., FGFR-related brain or CNS cancer) may include administration of the compound to the subject (e.g., orally). In some such embodiments, the compounds provided herein are useful for treating primary or metastatic brain tumors, e.g., FGFR-related primary or metastatic brain tumors.

[0627] In some embodiments, the compounds of this disclosure exhibit one or more of the following: high GI absorption, low clearance, and low likelihood of drug-drug interactions.

[0628] In some embodiments, the compounds of the Disclosure may be used to treat a subject diagnosed with (or identified as having) a disease or disorder related to FGFR (e.g., FGFR-related cancer), comprising administering a therapeutically effective amount of the compounds of the Disclosure to the subject. Methods for treating a subject identified or diagnosed with a disease or disorder related to FGFR (e.g., FGFR-related cancer), comprising the step of administering a therapeutically effective amount of the compounds of the Disclosure to the subject, are also provided herein. In some embodiments, the subject is identified or diagnosed with a disease or disorder related to FGFR (e.g., FGFR-related cancer) by using a regulatory authority-approved, e.g., FDA-approved test or assay to identify abnormal regulation of the expression, activity, or level of the FGFR gene, FGFR kinase, or any of these in the subject or in a biopsy sample obtained from the subject, or by performing any non-limiting example of the assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the disease or disorder related to FGFR is FGFR-related cancer. For example, cancers associated with FGFR may be cancers that contain one or more FGFR inhibitor resistance mutations.

[0629] Methods are also provided for treating a disease or disorder in a subject requiring such treatment, comprising the steps of (a) detecting an FGFR-related disease or disorder in the subject; and (b) administering a therapeutically effective amount of a compound of the Disclosure to the subject. Some embodiments of these methods further include administering an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the Disclosure, or an immunotherapy) to the subject. In some embodiments, the subject has been pre-treated with a first FGFR inhibitor or another treatment. In some embodiments, the subject is determined to have an FGFR-related disease or disorder by using an FDA-approved test or assay, e.g., an FDA-approved test or assay to identify abnormal regulation of the expression, activity, or level of the FGFR gene, FGFR kinase, or any of these in or in a biopsy sample obtained from the subject, or by performing any non-limiting example of an assay described herein. In some embodiments, the test or assay is provided as a kit.

[0630] Methods for treating cancer in subjects requiring such treatment are also provided, comprising the steps of (a) detecting FGFR-related cancer in a subject; and (b) administering a therapeutically effective amount of a compound of the Disclosure to the subject. Some embodiments of these methods further include administering an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the Disclosure, or an immunotherapy) to the subject. In some embodiments, the subject has been pre-treated with a first FGFR inhibitor or with another anti-cancer treatment, e.g., at least partial resection of a tumor or radiotherapy. In some embodiments, the subject is determined to have FGFR-related cancer by using an FDA-approved test or assay to identify abnormal regulation of the expression, activity or level of the FGFR gene, FGFR kinase, or any of these in or in a biopsy sample obtained from the subject, or by performing any non-limiting example of an assay described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is FGFR-related cancer. For example, an FGFR-related cancer may be a cancer containing one or more FGFR inhibitor resistance mutations. In some embodiments, the cancer is an FGFR-related cancer. For example, an FGFR-related cancer may be a cancer containing one or more FGFR activating mutations.

[0631] Also provided are methods for treating a subject, comprising the steps of: performing an assay on a sample obtained from the subject to determine whether the subject has abnormal regulation of the expression, activity, or level of the FGFR gene, FGFR kinase, or either thereof; and administering (e.g., specifically or selectively) a therapeutically effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt or solvate thereof to the subject determined to have abnormal regulation of the expression, activity, or level of the FGFR gene, FGFR kinase, or either thereof. Some embodiments of these methods further include administering an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the Disclosure, or immunotherapy) to the subject. In some embodiments of these methods, the subject had been previously treated with a first FGFR inhibitor or with another anti-cancer treatment, such as at least partial tumor resection or radiotherapy. In some embodiments, the subjects are suspected to have an FGFR-related disease or disorder (e.g., FGFR-related cancer), exhibit one or more symptoms of an FGFR-related disease or disorder (e.g., FGFR-related cancer), or are at increased risk of developing an FGFR-related disease or disorder (e.g., FGFR-related cancer). In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory authority-approved assay, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional, non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, abnormal regulation of the expression, activity, or level of the FGFR gene, FGFR kinase, or any of these includes one or more FGFR inhibitor resistance mutations.

[0632] Also provided herein is a method for selecting a treatment for a subject, comprising the steps of: performing an assay on a sample obtained from the subject to determine whether the subject has an abnormal regulation of the expression, activity, or level of the FGFR gene, FGFR kinase, or any of these (e.g., one or more FGFR inhibitor resistance mutations); and identifying or diagnosing a subject who has been determined to have an FGFR-related cancer having an abnormal regulation of the expression, activity, or level of the FGFR gene, FGFR kinase, or any of these. Some embodiments further include administering the selected treatment to a subject identified or diagnosed with an FGFR-related cancer. For example, in some embodiments, the selected treatment may include administering a therapeutically effective amount of a compound of the present disclosure to a subject identified or diagnosed with an FGFR-related cancer. In some embodiments, the assay is an in vitro assay, for example, an assay utilizing next-generation sequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory authority-approved kit, for example, FDA-approved. In some embodiments, the assay is a liquid biopsy.

[0633] A method for treating FGFR-related cancer in a subject is also provided herein, comprising the steps of (a) administering one or more (e.g., two or more, three or more, four or more, five or more, or ten or more) doses of a first FGFR kinase inhibitor to a subject identified or diagnosed with having FGFR-related cancer (e.g., any of the types of FGFR-related cancers described herein) (e.g., identified or diagnosed with FGFR-related cancer using any exemplary method described herein or known in the art); (b) determining the level of circulating tumor DNA in a biological sample obtained from the subject after step (a) (e.g., a biological sample including blood, serum, or plasma); and (c) administering a therapeutically effective dose of a second FGFR inhibitor or a compound of the Disclosure to a subject identified as having a level of circulating tumor DNA that is approximately the same as or elevated compared to a reference level of circulating tumor DNA (e.g., any of the reference levels of circulating tumor DNA described herein), either as monotherapy or in combination with additional therapies or therapeutic agents. In some examples of these methods, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from a subject prior to step (a). Some embodiments of these methods further include a step of determining the level of circulating tumor DNA in a biological sample obtained from a subject prior to step (a). In some examples of these methods, the reference level of circulating tumor DNA is the threshold level of circulating tumor DNA (for example, the mean level of circulating tumor DNA in a population of subjects having similar FGFR-associated cancers and similar stages of FGFR-associated cancers, but who have received ineffective treatments or placebos, or who have not yet received therapeutic treatment, or the level of circulating tumor DNA in subjects having similar FGFR-associated cancers and similar stages of FGFR-associated cancers, but who have received ineffective treatments or placebos, or who have not yet received therapeutic treatment).In some examples of these methods, the first FGFR inhibitor is ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, olantinib, pemigatinib, ponatinib, PRN1371, logaratinib, sulfatinib, TAS-120, or RLY-4008.

[0634] The compounds of this disclosure may also be administered in conjunction with additional therapies or therapeutic agents. In some embodiments, the additional therapies or therapeutic agents include radiotherapy, chemotherapeutic agents (e.g., any of the exemplary chemotherapeutic agents described herein or known in the art), checkpoint inhibitors (e.g., any of the exemplary checkpoint inhibitors described herein or known in the art), surgery (e.g., at least partial resection of a tumor), and one or more other kinase inhibitors (e.g., any of the kinase inhibitors described herein or known in the art).

[0635] The compounds of the Disclosure may also be useful as adjuvants for the treatment of cancer; that is, the compounds of the Disclosure may be used in combination with one or more additional therapies or therapeutic agents, for example, chemotherapeutic agents that act by the same or different mechanisms of action. In some embodiments, the compounds of the Disclosure may be used before the administration of additional therapeutic agents or additional therapies. For example, a subject in need may be administered one or more doses of the compounds of the Disclosure for a period of time, and then undergo at least partial resection of the tumor. In some embodiments, treatment with one or more doses of the compounds of the Disclosure reduces the size of the tumor (e.g., tumor burden) before at least partial resection of the tumor. In some embodiments, a subject has cancer (e.g., locally advanced or metastatic tumor) that is resistant to or intolerant of standard therapies (e.g., administration of chemotherapeutic agents, e.g., a first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation, or platinum-based agents (e.g., cisplatin)). In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) that is resistant to or untolerable to previous therapies (e.g., administration of chemotherapeutic agents, e.g., a first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation, or platinum-based agents (e.g., cisplatin)).

[0636] In some embodiments of any of the methods described herein, the compounds of the Disclosure are administered in combination with at least one additional therapeutic agent selected from one or more additional therapeutic or therapeutic (e.g., chemotherapy) agents in a therapeutic dose. Non-limiting examples of additional therapeutic agents include other FGFR-targeting therapeutic agents (i.e., first or second FGFR kinase inhibitors), other kinase inhibitors (e.g., receptor tyrosine kinase-targeting therapeutic agents (e.g., Trk inhibitors or EGFR inhibitors)), signaling pathway inhibitors, checkpoint inhibitors, apoptotic pathway modulators (e.g., obataclax); cytotoxic chemotherapy agents, angiogenesis-targeted therapies, immuno-targeted agents, which include immunotherapy and radiotherapy.

[0637] A method for treating a disease or disorder is also provided herein, comprising the step of administering a pharmaceutically effective combination for treating the disease or disorder to a subject in need thereof, comprising (a) a compound of the Disclosure, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate, or sequential use for treating the disease or disorder, wherein the amounts of the compound of the Disclosure and the additional therapeutic agent together are effective for treating the disease or disorder. In some embodiments, the compound of the Disclosure and the additional therapeutic agent are administered simultaneously as separate doses. In some embodiments, the compound of the Disclosure and the additional therapeutic agent are administered sequentially in any order as separate doses, together as a therapeutically effective dose, for example, in daily or intermittent doses. In some embodiments, the compound of the Disclosure and the additional therapeutic agent are administered simultaneously as a combined dose. In some embodiments, the disease or disorder is a disease or disorder related to FGFR. In some embodiments, the subject is administered one or more doses of the compound of the Disclosure before administration of the pharmaceutically effective combination.

[0638] In some embodiments, the treatment period is at least 7 days (for example, at least or about 8 days, at least or about 9 days, at least or about 10 days, at least or about 11 days, at least or about 12 days, at least or about 13 days, at least or about 14 days, at least or about 15 days, at least or about 16 days, at least or about 17 days, at least or about 18 days, at least or about 19 days, at least or about 20 days, at least or about 21 days, at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, or at least or about 30 days).

[0639] In some embodiments, the treatment period is at least 21 days (for example, at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, at least or about 30 days, at least or about 31 days, at least or about 32 days, at least or about 33 days, at least or about 34 days, at least or about 35 days, at least or about 36 days, at least or about 37 days, at least or about 38 days, at least or about 39 days, or at least or about 40 days).

[0640] Pharmaceutical compositions containing the compounds of this disclosure as active ingredients in combination with one or more pharmaceutically acceptable carriers (excipients) are also provided herein. In some embodiments, the compositions are suitable for topical administration. In the preparation of the compositions provided herein, the active ingredient is usually mixed with an excipient, diluted with the excipient, or encapsulated in such carriers or in other containers, for example, in the form of capsules, sachets, or paper. When the excipient functions as a diluent, the excipient can be a solid, semi-solid, or liquid material and acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, suppositories, injectable sterile solutions, and sterile packaged powders containing up to 10% by mass of the active compound. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is formulated as tablets or capsules.

[0641] Compositions comprising the compounds of this disclosure can be formulated into unit dosage forms, each dose containing approximately 5 to approximately 1,000 mg (1 g), more typically approximately 100 mg to approximately 500 mg of the active ingredient. The term "unit dosage form" refers to physically distinct units for human and other subjects, each unit containing a predetermined amount of the active substance (i.e., the compounds of this disclosure) together with appropriate pharmaceutical excipients to produce the desired therapeutic effect.

[0642] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of the active ingredient, i.e., the compounds of the disclosure. Those skilled in the art will recognize that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of the active ingredient. Those skilled in the art will recognize that this embodies compounds or compositions containing approximately 50 mg to 100 mg, 100 mg to 150 mg, 150 mg to 200 mg, 200 mg to 250 mg, 250 mg to 300 mg, 350 mg to 400 mg, or 450 mg to 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain approximately 500 mg to 1,000 mg of the active ingredient. Those skilled in the art will recognize that this embodies a compound or composition containing an active ingredient in amounts of approximately 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1,000 mg.

[0643] Active compounds can be effective across a wide range of dosages and are generally administered at a pharmacokinetic dose. However, it should be understood that the actual amount of compound administered is usually determined by a physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

[0644] In some embodiments, the compounds provided herein can be administered in amounts ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein can be administered in amounts of approximately 1 mg / kg to approximately 20 mg / kg, approximately 5 mg / kg to approximately 50 mg / kg, approximately 10 mg / kg to approximately 40 mg / kg, approximately 15 mg / kg to approximately 45 mg / kg, approximately 20 mg / kg to approximately 60 mg / kg, or approximately 40 mg / kg to approximately 70 mg / kg. For example, approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 55 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 70 mg / kg, approximately 75 mg / kg, approximately 80 mg / kg, approximately 85 mg / kg, approximately 90 mg / kg, approximately 95 mg / kg, or approximately 100 mg / kg. In some embodiments, such administration may be once daily or twice daily (BID). [Examples]

[0645] The examples and preparations provided below further illustrate and demonstrate the compounds of the present invention and methods for preparing such compounds. It should be understood that the scope of the present invention is by no means limited to the following examples and preparations.

[0646] In some embodiments where a single enantiomer is provided, the enantiomer can be separated by conventional means (chiral chromatography, preparation of diastereomer salts, chiral derivatization, crystallization, enzymatic reactions, etc.). In some embodiments, the chiral intermediate compound is purified to prepare an intermediate that is pure as an enantiomer (or substantially pure as an enantiomer, enantiomer-enriched, etc.).

[0647] [ka]

[0648] (Example 1) 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-1,4-thiadinane 1,1-dioxide

[0649] [ka]

[0650] Step 1. 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A mixture of 3-iodo-1-tetrahydropyran-2-yl-indazole-5-ol (1.0 g, 2.90 mmol, 1.0 equivalent), [(1S)-1-(3,5-dichloro-4-pyridyl)ethyl]methanesulfonate (780 mg, 2.90 mmol, 1.0 equivalent), and cesium carbonate (1.41 g, 14.45 mmol, 1.5 equivalents) in N,N-dimethylformamide (20 mL) was heated at 130 °C for 16 hours. Volatile substances were removed under reduced pressure, and the residue was suspended in saturated ammonium chloride (50 mL). The solution was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on a Buchi automated chromatography system (Sorbtech 40g silica gel column) using a gradient of 0-30% ethyl acetate in heptane to obtain a white solid (1.01g, 88% yield). Analysis: LC-MS: m / z = 517.2 (M + H).

[0651] Step 2. 3-(6-chloro-3-pyridyl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazole. A solution of 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.32 g, 2.55 mmol, 1.0 equivalent), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (790 mg, 3.31 mmol, 1.3 equivalents), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (190 mg, 0.255 mmol, 0.1 equivalent), and potassium carbonate (700 mg, 5.1 mmol, 2.0 equivalents) in 1,4-dioxane (20 mL) and water (1 mL) was sparged with nitrogen for 15 minutes. After heating at 90°C for 16 hours, the reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was suspended in saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 25 g silica gel column) with elution gradient of 0-50% ethyl acetate in heptane to obtain a white solid (870 mg, yield 68%). Analysis: LC-MS: m / z = 503.1 (M + H).

[0652] Step 3. 4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)pyridine-2-yl)thiomorpholine 1,1-dioxide. A solution of the product from Step 2 (280 mg, 0.56 mmol, 1.0 equivalent), (150 mg, 1.12 mmol, 2.0 equivalents), xanthophos (64 mg, 0.11 mmol, 0.2 equivalents), tris(dibenzylideneacetone)dipalladium (0) (51 mg, 0.06 mmol, 0.1 equivalent), and cesium carbonate (364 mg, 1.1 mmol, 2.0 equivalents) in N,N-dimethylformamide (10 mL) was sparged with nitrogen for 15 minutes. After heating at 95°C for 16 hours, the reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 40g column) with elution in a gradient of 0-100% ethyl acetate in heptane to obtain a brown solid (290 mg, 89% yield). Analysis: LC-MS: m / z = 601.2 (M + H).

[0653] Step 4. 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-1,4-thiadinane 1,1-dioxide. A solution of the product from Step 3 (290 mg, 0.47 mmol, 1.0 equivalent) in 1,4-dioxane (2.0 mL) and water (0.5 mL) was treated with 4 M HCl (0.95 mL, 3.79 mmol, 8.0 equivalents) in 1,4-dioxane and heated at 100 °C for 1 hour in a CEM microwave reactor. Volatile substances were removed under reduced pressure. The residue was dissolved in 20% methanol (10 mL) in dichloromethane, followed by the addition of MP-carbonate (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50g column) with elution under a 0-80% acetonitrile gradient in water to obtain a white solid (29 mg, 12% yield). Analysis: LC-MS: m / z = 518.1 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.60 (s, 2H), 8.59 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 2.4, 8.9 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.20 - 7.15 (m, 2H), 7.10 (dd, J = 2.3, 9.0 Hz, 1H), 6.10 (q, J = 6.7 Hz, 1H), 4.18 - 4.11 (m, 4H), 3.20 - 3.15 (m, 4H), 1.76 (d, J = 6.6Hz, 3H).

[0654] [ka]

[0655] (Example 2) (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-(piperazine-1-yl)pyridine-3-yl)-1H-indazole dihydrochloride

[0656] [ka]

[0657] Step 1. tert-butyl 4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)pyridine-2-yl)piperazine-1-carboxylate. A solution of 5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.1 g, 5.99 mmol, 1 equivalent) and tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1-carboxylate (3.03 g, 7.78 mmol, 1.3 equivalents) in a 20:1 mixture of 1,4-dioxane and water (50 mL) was sparged with nitrogen for 10 minutes. Potassium carbonate (1.65 g, 11.98 mmol, 2.0 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.44 g, 0.6 mmol, 0.1 equivalents) were added, and the reaction mixture was sparged with nitrogen for a further 5 minutes. The reaction mixture was heated at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and dichloromethane (100 mL). The organic layer was separated, dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was pre-absorbed onto silica gel (5 g) and purified on an Interchim automated chromatography system (Sorbtech 120 g silica gel cartridge) with elution in a gradient of 0-30% ethyl acetate in heptane to obtain a white solid (2.19 g, yield 56%). Analysis: LC-MS: m / z = 653 (M + H).

[0658] Step 2. (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-(piperazine-1-yl)pyridine-3-yl)-1H-indazole dihydrochloride. A solution of the Step 1 product (70.0 mg, 0.11 mmol, 1.0 equivalent) in 1,4-dioxane (1.0 mL) was treated overnight at room temperature with 4 M HCl in dioxane (0.27 mL, 1.1 mmol, 10.0 equivalents). Volatile substances were removed under reduced pressure. The residue was ground with a 1:3 mixture of dichloromethane and methanol (2.8 mL) to obtain a white solid (23.0 mg, 40% yield). Analysis: LC-MS: m / z = 469.2 (free base M + H). 1 H NMR (400 MHz, DMSO-d6) δ 9.47 (br s, 2H), 8.59 (s, 2H), 8.50 (d, J = 2.1 Hz, 1H), 8.13 (dd, J = 2.0, 9.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 2.2, 9.0 Hz, 1H), 6.12 (q, J = 6.6 Hz, 1H), 3.97 - 3.93 (m, 4H), 3.27 (br s, 4H), 1.76 (d, J = 6.6 Hz, 3H).

[0659] (Example 3) [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]piperazine-1-yl]-morpholino-methanone

[0660] [ka]

[0661] Step 1. (4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)pyridine-2-yl)piperazin-1-yl)(morpholino)methanone. Triethylamine (28.0 uL, 0.204 mmol, 1.1 equivalents) and morpholine-4-carbonyl chloride (30.5 mg, 0.204 mmol, 1.1 equivalents) were added to the solution of Example 2 (102.6 mg, 0.185 mmol, 1 equivalent) in anhydrous THF (3 mL) at room temperature. After stirring for 1 hour, the reaction was diluted with saturated brine (20 mL) and dichloromethane (20 mL). The organic layer was separated, dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid (90 mg, 73% yield). Analysis: LC-MS: m / z = 666 (M + H).

[0662] Step 2. (R)-(4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)piperazin-1-yl)(morpholino)methanone. Example 3 Step 1 (90 mg, 0.135 mmol, 1 equivalent) was treated with 4M HCl (0.27 mL, 1.08 mmol, 8.0 equivalents) in 1,4-dioxane (4.0 mL) and water (1 mL), and heated in a CEM microwave reactor at 60°C for 20 minutes. Additional 4M HCl (0.27 mL, 1.08 mmol, 8.0 equivalents) in 1,4-dioxane was added, and the reaction was heated further in a CEM microwave reactor at 60°C for 20 minutes. After cooling to room temperature, volatiles were removed under reduced pressure. The residue was dissolved in methanol (20 mL), treated with MP-carbonate resin (3.2 mmol / g, 1 g), stirred for 30 minutes, filtered, and concentrated under reduced pressure. The residue was pre-absorbed onto Celite (1 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) using a 0-100% acetonitrile gradient in water. The fraction containing the product was collected and lyophilized to obtain a white solid (36.9 mg, 47% yield). Analysis: LCMS: m / z = 582.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.01 (br s, 1H), 8.60 (s, 2H), 8.56 (d, J = 2.2 Hz, 1H), 7.89 (dd, J = 2.4, 8.9 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.10 (q, J = 6.6 Hz, 1H), 3.63 - 3.57 (m, 8H), 3.33 - 3.30 (m, 4H), 3.22 - 3.18 (m, 4H), 1.76 (d, J = 6.6 Hz, 3H).

[0663] Examples 4-9 were synthesized using the procedure for Example 3.

[0664] [Table 2A]

[0665] [Table 2B]

[0666] (Example 10) 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(5-fluoro-6-piperazine-1-yl-3-pyridyl)-1H-indazole

[0667] [ka]

[0668] This example was synthesized using the procedure for Example 1, with 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and BOC-piperazine to obtain a white solid. Analysis: LCMS: m / z = 487.0 (M+H);1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.44 (s, 2H), 7.66 (dd, J = 1.7, 14.1 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 2.2, 9.0 Hz, 1H), 6.06 (q, J = 6.6 Hz, 1H), 3.61 - 3.53 (m, 4H), 3.12 - 3.01 (m, 4H), 1.83 (d, J = 6.7 Hz, 3H).

[0669] (Example 11) 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(2-piperazine-1-ylpyrimidine-5-yl)-1H-indazole

[0670] [ka]

[0671] Example 11 was synthesized using tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl]piperazine-1-carboxylate and the procedure for Example 2 to obtain an off-white solid (150 mg, 64% yield). Analysis: LC-MS: m / z = 470.1 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (br s, 1H), 8.75 (s, 2H), 8.57 (s, 2H), 7.47 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 2.2, 9.0 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 3.82 - 3.67 (m, 4H), 2.87 - 2.68 (m, 4H), 1.75 (d, J = 6.7 Hz, 3H).

[0672] (Example 12) 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]piperazine-1-carboxamide

[0673] [ka]

[0674] (R)-4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)piperazine-1-carboxamide. (Trimethylsilyl)isocyanate (66 μL, 0.49 mmol, 1.1 equivalents) and triethylamine (68 μL, 0.49 mmol, 1.1 equivalents) were sequentially added to a solution of Example 2 (208 mg, 0.45 mmol, 1 equivalent) in anhydrous THF (5 mL) at room temperature. After stirring for 20 hours, volatiles were removed under reduced pressure, and the crude product was pre-absorbed onto Celite (0.5 g) and then purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) with elution using a gradient of 0-100% acetonitrile in water. The fraction containing the product was collected and freeze-dried to obtain a white solid (36.0 mg, 16% yield). Analysis: LC-MS: m / z = 512.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (br s, 1H), 8.60 (s, 2H), 8.56 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.4, 8.8 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 6.14 - 6.02 (m, 3H), 3.62 - 3.50 (m, 5H), 3.50 - 3.39 (m, 4H), 1.76 (d, J = 6.6 Hz, 3H).

[0675] (Example 13) [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]piperazine-1-yl]-(4-methylpiperazine-1-yl)methanone

[0676] [ka]

[0677] (R)-(4-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)-3-fluoropyridine-2-yl)piperazin-1-yl)(4-methylpiperazin-1-yl)methanone. Triethylamine (21.6 μL, 0.156 mmol, 2.0 equivalents) and 4-methylpiperazin-1-carbonyl chloride hydrochloride (17.6 mg, 0.089 mmol, 1.0 equivalent) were sequentially added to a solution of Example 10 (43 mg, 0.089 mmol, 1 equivalent) in anhydrous THF (5 mL) at room temperature. After stirring for 1 hour, additional triethylamine (21.6 μL, 0.156 mmol, 2.0 equivalents) and 4-methylpiperazine-1-carbonyl chloride hydrochloride (17.6 mg, 0.089 mmol, 1.0 equivalent) were added, and the reaction mixture was stirred at room temperature for 20 hours. Volatile substances were removed under reduced pressure. The crude product was pre-absorbed onto Celite (0.5 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) eluting with a gradient of 0-100% acetonitrile in water. Further purification was performed on an Interchim automated chromatography system (Sorbtech 25 g silica gel cartridge) eluting with a gradient of 0-15% methanol in dichloromethane to obtain a white solid (12.0 mg, yield 22%). Analysis: LCMS: m / z = 613.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 10.51 (br s, 1H), 8.50 (t, J = 1.5 Hz, 1H), 8.43 (s, 2H), 7.69 (dd, J = 1.8, 13.9 Hz, 1H), 7.37 (dd, J = 0.4, 8.9 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 7.14 (d, J = 9.3 Hz, 1H), 6.05 (q, J = 6.7 Hz, 1H), 3.62 - 3.57 (m, 4H), 3.47 - 3.42 (m, 4H), 3.40 - 3.34 (m, 4H), 2.44 (br t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 1.82 (d, J = 6.7 Hz, 3H).

[0678] (Example 14) 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(4-methylsulfonylpiperazin-1-yl)pyrimidine-5-yl]-1H-indazole

[0679] [ka]

[0680] (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine-5-yl)-1H-indazole. Methanesulfonyl chloride (25 mg, 0.22 mmol, 1 equivalent) in acetonitrile (1 mL) was added dropwise at 0°C to a solution of Example 11 (104 mg, 0.22 mmol, 1 equivalent) in pyridine (10 mL). After stirring at room temperature for 16 hours, methanesulfonyl chloride (13 mg, 0.11 mmol, 0.5 equivalent) in an additional acetonitrile (0.5 mL) was added. After stirring for 70 hours, the reaction was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and purified on an InterChim automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) using a 0-100% acetonitrile gradient in water to obtain an off-white solid (20 mg, 17% yield). Analysis: LC-MS: m / z = 548.1 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ = 13.12 (br s, 1H), 8.82 (s, 2H), 8.57 (s, 2H), 7.48 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 2.3, 9.0 Hz, 1H), 6.15 (q, J = 6.7 Hz, 1H), 4.00 - 3.91 (m, 4H), 3.27 - 3.22 (m, 4H), 2.92 (s, 3H), 1.76 (d, J = 6.6 Hz, 3H).

[0681] (Example 15) [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]pyrimidine-2-yl]piperazine-1-yl]-(4-methylpiperazine-1-yl)methanone

[0682] [ka]

[0683] 4-Methylpiperazine-1-carbonyl chloride (44 mg, 0.22 mmol, 1 equivalent) was added to a solution of Example 11 (104 mg, 0.22 mmol, 1 equivalent) in pyridine (10 mL) at room temperature. After stirring for 16 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and purified on an InterChim automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) with elution under a 0-100% acetonitrile gradient to obtain an off-white solid (30 mg, 23% yield). Analysis: LCMS: m / z = 596.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.05 (br s, 1H), 8.79 (s, 2H), 8.57 (s, 2H), 7.48 (d, J = 9.2 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 2.3, 9.0 Hz, 1H), 6.14 (q, J = 6.7 Hz, 1H), 3.88 - 3.79 (m, 4H), 3.29 - 3.25 (m, 4H), 3.24 - 3.17 (m, 4H), 2.31 (br t, J = 4.6 Hz, 4H), 2.19 (s, 3H), 1.76 (d, J = 6.6 Hz, 3H).

[0684] [ka]

[0685] (Example 16) 3-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0686] [ka]

[0687] Step 1. tert-butyl3-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate. 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (170 mg, 0.33 mmol, 1.0 equivalent) in 1,4-dioxane (10 mL) and water (1 mL), tert-butyl3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3,6-di A solution of azabicyclo[3.1.1]heptane-6-carboxylate (128 mg, 0.40 mmol, 1.2 equivalents), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24 mg, 0.04 mmol, 0.1 equivalents), and potassium carbonate (91 mg, 0.66 mmol, 2.0 equivalents) was sparged with nitrogen for 15 minutes and then heated at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 25 g silica gel column) eluting with a gradient of 0-70% ethyl acetate in heptane to obtain a white solid (80 mg, yield 36%). Analysis: LC-MS: m / z = 665.1 (M + H).

[0688] Step 2. 3-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane. A solution of the product from Step 1 (80 mg, 0.13 mmol, 1.0 equivalent) in 1,4-dioxane (2.0 mL) and water (0.5 mL) was treated with 4 M HCl (0.65 mL, 2.65 mmol, 20.0 equivalents) in 1,4-dioxane and heated at 100 °C for 1 hour in a CEM microwave reactor. After cooling to room temperature, volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol (10 mL) in dichloromethane, followed by the addition of MP-carbonate resin (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50g column) using a 0-100% acetonitrile gradient in water. The fraction containing the product was freeze-dried to obtain an off-white solid (8 mg, 14% yield). Analysis: LC-MS: m / z = 481.1 (M+H); 1 H NMR (400 MHz, METHANOL-d4) δ 8.55 (dd, J = 0.5, 2.3 Hz, 1H), 8.46 (s, 2H), 7.97 (ddd, J = 2.0, 4.5, 8.6 Hz, 2H), 7.48 - 7.35 (m, 2H), 7.17 (dd, J = 2.3, 9.0 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.12 (q, J = 6.6 Hz, 1H), 4.52 (br d, J = 6.1 Hz, 2H), 4.12 - 3.99 (m, 4H), 3.18 - 3.06 (m, 1H), 1.97 (d, J = 10.3 Hz, 1H), 1.82 (d, J = 6.7 Hz, 3H).

[0689] (Example 17) 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[5-fluoro-6-(4-methylsulfonylpiperazine-1-yl)-3-pyridyl]-1H-indazole

[0690] [ka]

[0691] Step 1. 3-(6-chloro-4-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A solution of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (0.4 g, 0.77 mmol, 1 equivalent) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.258 g, 1.0 mmol, 1.3 equivalents) in a 20:1 mixture (10 mL) of 1,4-dioxane and water was sparged with nitrogen for 15 minutes. Potassium carbonate (0.28 g, 2.0 mmol, 2.6 equivalents) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (56 mg, 0.077 mmol, 0.01 equivalents) were added, and the reaction mixture was sparged with nitrogen for a further 5 minutes. The reaction mixture was heated at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and diluted with saturated brine (20 mL) and dichloromethane (20 mL). The layers were separated, the organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was pre-absorbed onto silica gel (1 g) and purified on an Interchim automated chromatography system (Sorbtech 40 g silica gel cartridge) with elution using a gradient of 5-50% ethyl acetate in heptane to obtain a white solid (360 mg, yield 89%). Analysis: LC-MS: m / z = 521.8 (M + H).

[0692] Step 2. A solution of the Step 1 product (360 mg, 0.69 mmol, 1 equivalent), BOC-piperazine (193 mg, 1.04 mmol, 1.5 equivalents), xanthophos (80 mg, 0.14 mmol, 0.2 equivalents), tris(dibenzylideneacetone)dipalladium(0) (63 mg, 0.07 mmol, 0.1 equivalents), and cesium carbonate (450 mg, 1.4 mmol, 2.0 equivalents) in N,N-dimethylformamide (10 mL) was sparged with nitrogen for 10 minutes. After heating at 95°C for 16 hours, the reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 25g silica gel column) eluting with a gradient of 0-15% methanol in dichloromethane to obtain a brown solid (107 mg, yield 23%). Analysis: LC-MS: m / z = 653.1 (M + H).

[0693] Step 3. (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(4-fluoro-6-(piperazin-1-yl)pyridine-3-yl)-1H-indazole. A solution of the Step 2 product (90 mg, 0.14 mmol, 1 equivalent) in 1,4-dioxane (2.0 mL) and water (0.2 mL) was treated with 4 M HCl (0.7 mL, 2.68 mmol, 20 equivalents) in 1,4-dioxane and heated at 100 °C for 1 hour in a CEM microwave reactor. Volatile substances were removed under reduced pressure. The residue was dissolved in 20% methanol (10 mL) in dichloromethane, followed by the addition of MP-carbonate (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 25g column) using a 0-80% acetonitrile gradient in water to obtain an off-white solid (15 mg, 20% yield). Analysis: LC-MS: m / z = 487.1 (M + H).

[0694] Step 4. (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(4-fluoro-6-(4-(methylsulfonyl)piperazin-1-yl)pyridine-3-yl)-1H-indazole. Methanesulfonyl chloride (3 μL, 0.04 mmol, 1.5 equivalents) was added to a solution of the Step 3 product (15 mg, 0.03 mmol, 1.0 equivalent) in pyridine (2.0 mL) at room temperature. After stirring for 16 hours, volatile matter was removed under reduced pressure. The residue was first purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50g column) eluting with a gradient of 0-80% acetonitrile in water, and then re-purified on a Teledyne ACCQPrep automated chromatography system (Waters Atlantis T3 Prep OBD column, 5μm, 19×250mm) eluting with a gradient of 0-80% acetonitrile in water containing 0.1% formic acid. The fraction containing the product was freeze-dried to obtain a white solid (R)-ADE-163 (12mg, 70% yield). Analysis: LCMS: m / z = 565.1 (M+H); 1 H NMR (400 MHz, CD3OD) δ 8.47 (s, 2H), 8.36 (d, J = 10.8 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.17 (dd, J = 2.4, 9.0 Hz, 1H), 6.86 (t, J = 2.4 Hz, 1H), 6.78 (d, J = 13.7 Hz, 1H), 6.05 (q, J = 6.7 Hz, 1H), 3.81 - 3.76 (m, 4H), 3.38 - 3.34 (m, 4H), 2.89 (s, 3H), 1.80 (d, J = 6.6 Hz, 3H).

[0695] (Example 18) 3-(6-chloro-3-pyridyl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0696] [ka]

[0697] 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-chloro-1-tetrahydropyran-2-yl-indazole was deprotected using the conditions for Step 4 of Example 1. Analysis: LCMS: m / z = 421.1 (M+H); 1 H NMR (400 MHz, DMSO) δ 13.42 (br s, 1H), 8.84 )dd, J = 0.6, 2.4 Hz, 1H), 8.59 (s, 2H), 8.21 (dd, J = 2.6, 8.3 Hz, 1H), 7.67 (dd, J = 0.6, 8.3 Hz, 1H), 7.54 (d, J - 9.2 Hz, 1H), 7.24 d, J = 2.2 Hz, 1H), 7.13 (dd, J = 2.2, 9 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 1.77 (d, J = 6.6 Hz, 3H).

[0698] (Example 19) 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]pyrimidine-2-yl]-N,N-dimethylpiperazine-1-carboxamide

[0699] [ka]

[0700] 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]pyrimidine-2-yl]-N,N-dimethylpiperazine-1-carboxamide. Triethylamine (65 mg, 0.638 mmol, 3 equivalents) and N,N-dimethylcarbamoyl chloride (23 mg, 0.213 mmol, 1 equivalent) in acetonitrile (1 mL) were added dropwise to a solution of Example 11 (100 mg, 0.213 mmol, 1 equivalent) in THF (10 mL) at room temperature. After stirring for 16 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and purified on an InterChim automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) using a 0-100% acetonitrile gradient in water to obtain an off-white solid (40 mg, 35% yield). Analysis: LC-MS: m / z = 541.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.13 (br s, 1H), 8.79 (s, 2H), 8.57 (s, 2H), 7.47 (d, J = 9.0 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 2.2, 9.0 Hz, 1H), 6.14 (q, J = 6.7 Hz, 1H), 3.87 - 3.80 (m, 4H), 3.26 - 3.21 (m, 4H), 2.80 (s, 6H), 1.76 (d, J = 6.6 Hz, 3H).

[0701] (Example 20) 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(6-methylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-1H-indazole

[0702] [ka]

[0703] 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(6-methylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-1H-indazole. Triethylamine (24.8 μL, 0.178 mmol, 1.2 equivalents) and methanesulfonyl chloride (11.5 μL, 0.149 mmol, 1 equivalent) were sequentially added to a solution of Example 16 (71 mg, 0.149 mmol, 1 equivalent) in anhydrous THF (2 mL) at room temperature. After stirring for 16 hours, additional methanesulfonyl chloride (2 × 11.5 μL, 0.149 mmol, 2 equivalents) and triethylamine (24.8 μL, 0.178 mmol, 1.2 equivalents) were added at 24-hour intervals, and the mixture was stirred for a total of 72 hours. Volatile components were removed under reduced pressure, and the crude product was pre-absorbed onto Celite (0.5 g). It was then purified using an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) with elution using a gradient of 0–100% acetonitrile in water. The fraction containing the product was collected and lyophilized to obtain a white solid. Analysis: LCMS: m / z = 559.1 (M+H); 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 2.3 Hz, 1H), 8.43 (s, 2H), 7.97 (dd, J = 2.1, 8.7 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.26 (s, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 1.9, 9.0 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.05 (q, J = 6.7 Hz, 1H), 4.57 (br d, J = 6.2 Hz, 2H), 4.10 (br d, J = 11.7 Hz, 2H), 3.88 (br d, J = 11.7 Hz, 2H), 3.14 - 3.08 (m, 1H), 2.95 (s, 3H), 1.82 (d, J = 6.6 Hz, 3H).

[0704] [ka]

[0705] (Example 21) 3-[6-(4,7-diazaspiro[2,5]octan-7-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0706] [ka]

[0707] Step 1. (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-fluoropyridine-3-yl)-1H-indazole. A solution of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (3.0 g, 5.80 mmol, 1.0 equivalent), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.6 g, 6.96 mmol, 1.2 equivalents), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (430 mg, 0.58 mmol, 0.1 equivalent), and potassium carbonate (1.6 g, 11.66 mmol, 2.0 equivalents) in 1,4-dioxane (30 mL) and water (3 mL) was spurged with nitrogen for 15 minutes and then heated at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 40g silica gel column) with elution in a gradient of 0-60% ethyl acetate in heptane to obtain a white solid (2.5g, 88% yield). Analysis: LC-MS: m / z = 487.1 (M + H).

[0708] Step 2. tert-butyl 7-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)pyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. A suspension of product Step 1 (350 mg, 0.72 mmol, 1.0 equivalent), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (310 mg, 1.44 mmol, 2.0 equivalents), and potassium carbonate (400 mg, 2.88 mmol, 4.0 equivalents) in DMSO (5.0 mL) was heated in a sealed tube at 120°C for 20 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50g column) using a 0-100% acetonitrile gradient in water to obtain an off-white solid (417 mg, 87% yield). Analysis: LC-MS: m / z = 679.1 (M + H).

[0709] Step 3. 3-[6-(4,7-diazaspiro[2.5]octan-7-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole. A solution of the Step 2 product (25 mg, 0.04 mmol, 1.0 equivalent) in 1,4-dioxane (1.0 mL) and water (0.4 mL) was treated with 4 M HCl (0.2 mL, 0.75 mmol, 20.0 equivalents) in 1,4-dioxane and heated in a microwave at 100 °C for 1 hour. After cooling to room temperature, volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol (10 mL) in dichloromethane, followed by the addition of MP-carbonate (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50g column) with elution under a 0-80% acetonitrile gradient. The product fraction was freeze-dried to obtain an off-white solid (7.5 mg, 20% yield). Analysis: LC-MS: m / z = 495.1 (M+H); 1H NMR (400 MHz, CD3OD) δ 8.50 - 8.44 (m, 3H), 7.88 (dd, J = 2.4, 8.8 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.16 (dd, J = 2.3, 9.0 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 3.66 - 3.62 (m, 2H), 3.51 (s, 2H), 3.08 - 3.02 (m, 2H), 1.82 (d, J = 6.6 Hz, 3H), 0.72 - 0.65 (m, 4H).

[0710] (Example 22) 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(4-methylsulfonyl-4,7-diazaspiro[2.5]octan-7-yl)-3-pyridyl]-1H-indazole

[0711] [ka]

[0712] Methanesulfonyl chloride (21 μL, 0.26 mmol, 1.5 equivalents) was added to a solution of Example 21 (100 mg, 0.17 mmol, 1.0 equivalent) in pyridine (5.0 mL) at room temperature. After stirring for 16 hours, an additional methanesulfonyl chloride (21 μL, 0.26 mmol, 1.5 equivalents) was added together with N,N-diisopropylethylamine (0.1 mL) at room temperature. After stirring for a further 2 hours, volatile matter was removed under reduced pressure. The residue was first purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a 0-80% acetonitrile gradient in water, and then re-purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 4 g column) eluting with a 0-80% acetonitrile gradient in water. The fraction containing the product was freeze-dried to obtain an off-white solid (16.0 mg, 16% yield). Analysis: LC-MS: m / z = 573.2 (M+H); 1 H NMR (400 MHz, CD3OD) δ 8.48 (s, 3H), 7.90 (dd, J = 2.4, 8.9 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.17 (dd, J = 2.3, 9.0 Hz, 1H), 7.11 (d, J = 1.7 Hz, 1H), 6.93 (dd, J = 0.5, 8.9 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 3.80 - 3.74 (m, 4H), 3.04 (s, 3H), 1.82 (d, J = 6.7 Hz, 3H), 1.29 (s, 3H), 1.23 - 1.20 (m, 2H), 1.00 - 0.96 (m, 2H).

[0713] (Example 23) (R)-7-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-N,N-dimethyl-4,7-diazaspiro[2.5]octane-4-carboxamide

[0714] [ka]

[0715] Dimethylcarbamate chloride (23 μL, 0.26 mmol, 1.5 equivalents) was added to a solution of Example 21 (100 mg, 0.17 mmol, 1.0 equivalent) in pyridine (5.0 mL) at room temperature. After stirring for 16 hours, an additional dimethylcarbamate chloride (23 μL, 0.26 mmol, 1.5 equivalents) was added together with N,N-diisopropylethylamine (0.1 mL) at room temperature. After stirring for a further 2 hours, volatile matter was removed under reduced pressure. The residue was first purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a 0-80% acetonitrile gradient in water, and then re-purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 4 g column) eluting with a 0-80% acetonitrile gradient in water to obtain an off-white solid (5 mg, 5% yield). Analysis: LCMS: m / z = 566.3 (M+H); 1 H NMR (400 MHz, CD3OD) δ 8.52 (dd, J = 0.6, 2.4 Hz, 1H), 8.47 (s, 2H), 7.93 (dd, J = 2.4, 8.9 Hz, 1H), 7.88 (dd, J = 0.4, 9.2 Hz, 1H), 7.24 (dd, J = 2.4, 9.1 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 6.92 (dd, J = 0.5, 8.9 Hz, 1H), 6.16 (q, J = 6.6 Hz, 1H), 3.70 - 3.65 (m, 2H), 3.55 (s, 2H), 3.24 (s, 6H), 3.08 - 3.01 (m, 2H), 1.83 (d, J = 6.7 Hz, 3H), 0.76 - 0.61 (m, 4H).

[0716] (Example 24) 7-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-4,7-diazaspiro[2.5]octane-4-carboxamide

[0717] [ka]

[0718] Step 1. 4-Nitrophenyl(R)-7-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. p-nitrophenyl chloroformate (48.8 mg, 0.242 mmol, 1.1 equivalents) and triethylamine (150 μL, 1.1 mmol, 5 equivalents) were sequentially added to a solution of Example 21 (119 mg, 0.22 mmol, 1 equivalent) in anhydrous THF (3 mL) at room temperature. After stirring overnight, the brown solution was diluted with water (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dehydrated with sodium sulfate and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 4g column) using a 0-100% acetonitrile gradient in water to obtain a white solid (40 mg, 28% yield). Analysis: LC-MS: m / z = 660.1 (M + H).

[0719] Step 2. 7-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-4,7-diazaspiro[2.5]octan-4-carboxamide. Concentrated ammonium hydroxide (71 μL, 0.515 mmol, 10 equivalents) was added to the solution of product Step 1 (34 mg, 0.0515 mmol, 1 equivalent) in DMSO (2 mL). The yellow solution was heated overnight at 90°C, cooled to room temperature, and diluted with water (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dehydrated with sodium sulfate and concentrated under reduced pressure. The residue was purified using an Interchim automated chromatography system (RediSep Rf Gold HP C18, 4g column) with elution under a 0-100% acetonitrile gradient in water to obtain a white solid (40 mg, 28% yield). Analysis: LC-MS: m / z = 538.2 (M+H). 1 H NMR (400 MHz, CDCl3) δ 10.12 (br s, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.42 (s, 2H), 7.93 (dd, J = 2.3, 8.8 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 2.3, 9.0 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.05 (q, J = 6.6 Hz, 1H), 5.08 (s, 2H), 3.85 (br s, 2H), 3.61 (s, 4H), 1.81 (d, J = 6.7 Hz, 3H), 1.14 - 1.05 (m, 4H).

[0720] (Example 25) 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(6-fluoro-3-pyridyl)-1H-indazole

[0721] [ka]

[0722] Step 1. (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-iodo-1H-indazole. A mixture of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (1.0 g, 1.93 mmol, 1 equivalent) in dichloromethane (10 mL) was treated with trifluoroacetic acid (3 mL, 39.2 mmol, 20 equivalents) at room temperature for 24 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with saturated sodium bicarbonate (100 mL), dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The product was dried overnight under vacuum at room temperature to obtain an orange solid (1.05 g), which was then used. Analysis: LCMS (ESI) m / z = 434 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.37 (br s, 1H), 8.60 (s, 2H), 7.46 (d, J = 8.9 Hz, 1H), 7.13 (dd, J = 2.4, 9.0 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.07 (q, J = 6.6 Hz, 1H), 1.75 (d, J = 6.6 Hz, 3H).

[0723] Step 2. (R)-5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-3-(6-fluoropyridine-3-yl)-1H-indazole. A solution of Product Step 1 (1.0 g, 2.3 mmol, 1 equivalent) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.67 g, 2.995 mmol, 1.3 equivalents) in a 20:1 mixture of 1,4-dioxane and water (21 mL) was sparged with nitrogen for 15 minutes. Potassium carbonate (0.825 g, 5.98 mmol, 2.6 equivalents) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (168 mg, 0.23 mmol, 0.01 equivalents) were added, and the reaction mixture was sparged with nitrogen for a further 5 minutes. The reaction mixture was heated at 90°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). The layers were separated, the organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was absorbed onto silica gel (2 g) and purified on an Interchim automated chromatography system (Sorbtech 40 g silica gel cartridge) with elution under a gradient of 20-80% ethyl acetate in heptane to obtain a yellow solid (0.42 g, yield 45%). Analysis: LC-MS (ESI) m / z = 403.1 (M+H); 1 H NMR (400 MHz, CDCl3) δ 10.55 (br s, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.43 (s, 2H), 8.24 (dt, J = 2.4, 8.1 Hz, 1H), 7.39 (dd, J = 0.8, 8.7 Hz, 1H), 7.20 - 7.14 (m, 2H), 7.06 (dd, J = 2.8, 8.4 Hz, 1H), 6.06 (q, J = 6.7 Hz, 1H), 1.82 (d, J = 6.6 Hz, 3H).

[0724] (Example 26) 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-1-oxa-8-azaspiro[4.5]decane

[0725] [ka]

[0726] Step 1. 8-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)pyridine-2-yl)-1-oxa-8-azaspiro[4.5]decane. A suspension of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(6-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-indazole (100 mg, 0.21 mmol, 1.0 equivalent), 1-oxa-8-azaspiro[4.5]decane (110 mg, 0.42 mmol, 3.0 equivalents), and potassium carbonate (145 mg, 1.05 mmol, 5.0 equivalents) in 1-methyl-2-pyrrolidone (5 mL) was heated in a sealed tube at 120 °C for 16 hours. The reaction mixture was cooled to room temperature and absorbed under reduced pressure using Celite. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) using a 0-100% acetonitrile gradient in water to obtain a white solid (105 mg, yield 84%). Analysis: LCMS (ESI) m / z=608.1 (M+H).

[0727] Step 2. (R)-8-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-1-oxa-8-azaspiro[4.5]decane. A solution of the Step 1 product (105 mg, 0.18 mmol, 1.0 equivalent) in 1,4-dioxane (2.0 mL) and water (0.1 mL) was treated with 4 M HCl (0.86 mL, 3.45 mmol, 20.0 equivalents) in 1,4-dioxane and heated in a microwave at 100 °C for 1 hour. After cooling to room temperature, volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol (10 mL) in dichloromethane, followed by the addition of MP-carbonate resin (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50g column) with elution under a 0-80% acetonitrile gradient in water. The fraction containing the product was freeze-dried to obtain a white solid (40.1 mg, 44% yield). Analysis: LC-MS (ESI) m / z = 524.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.01 (br s, 1H), 8.60 (s, 2H), 8.53 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 2.4, 8.9 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 2.1Hz, 1H), 7.08 (dd, J = 2.3, 8.9 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.10 (q, J = 6.7 Hz, 1H), 3.80 - 3.73 (m, 4H), 3.58 - 3.51 (m, 2H), 1.94 - 1.86 (m, 2H), 1.76 (d, J = 6.6 Hz, 3H), 1.74 - 1.68 (m, 2H), 1.61 (t, J = 5.6 Hz, 4H).

[0728] Examples 27-34 were synthesized using the procedure for Example 26.

[0729] [Table 3A]

[0730] [Table 3B]

[0731] [Table 3C]

[0732] [Table 3D]

[0733] (Example 41) 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-1,8-diazaspiro[4.5]decane-2-one

[0734] [ka]

[0735] This example was synthesized using 3-(6-chloro-4-fluoropyridine-3-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole by the method for Example 17 to obtain a white solid (49 mg, yield 35%). Analysis: LCMS: m / z = 555.2 (M+H); 1H NMR (400 MHz, CDCL3) δ 10.57 (br s, 1H), 8.47 (t, J = 1.6 Hz, 1H), 8.44 (s, 2H), 7.64 (dd, J = 2.0, 14.1 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 2.3, 9.0 Hz, 1H), 6.09 - 5.97 (m, 2H), 4.16 (td, J = 3.8, 13.4 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 3.21 (br t, J = 11.7 Hz, 2H), 2.22 - 2.10 (m, 4H), 1.82 (d, J = 6.7 Hz, 3H), 1.66 - 1.52 (m, 2H).

[0736] (Example 42) 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-1,8-diazaspiro[4.5]decane-2-one

[0737] [ka]

[0738] This example was synthesized using 3-(6-chloro-4-fluoropyridine-3-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole by the method for Example 17 to obtain a white solid (45 mg, yield 58%). Analysis: LCMS: m / z = 555.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 11.91 (br s, 1H), 8.42 (s, 2H), 8.39 (t, J = 1.6 Hz, 1H), 7.80 (s, 1H), 7.57 (dd, J = 1.9, 14.0 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.14 (dd, J = 2.2, 8.9 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.03 (q, J = 6.7 Hz, 1H), 3.84 - 3.71 (m, 2H), 3.36 - 3.24 (m, 2H), 2.51 (t, J = 8.1 Hz, 2H), 2.05 (t, J = 8.1 Hz, 2H), 1.90 - 1.78 (m, 7H).

[0739] (Example 43) 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-1-methyl-1,8-diazaspiro[4.5]decane-2-one

[0740] [ka]

[0741] This example was synthesized using 3-(6-chloro-4-fluoropyridine-3-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole by the method for Example 17. Analysis: LCMS: m / z = 569.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.57 (s, 2H), 8.46 (t, J = 1.7 Hz, 1H), 7.78 (dd, J = 2.0, 14.4 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 2.3, 9.0 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 4.11 (br d, J = 13.4 Hz, 2H), 3.12 - 3.03 (m, 2H), 2.64 (s, 3H), 2.32 - 2.26 (m, 2H), 2.06 - 1.97 (m, 4H), 1.76 (d, J = 6.6 Hz, 3H), 1.49 (br d, J = 12.5 Hz, 2H).

[0742] (Example 44) 9-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-3-fluoro-2-pyridyl]-1-methyl-1,4,9-triazaspiro[5.5]undecane-5-one

[0743] [ka]

[0744] This example was synthesized using 3-(6-chloro-4-fluoropyridine-3-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole by the method for Example 17. Analysis: LCMS: m / z = 584.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.16 (br s, 1H), 8.57 (s, 2H), 8.44 (t, J = 1.7 Hz, 1H), 7.74 (dd, J = 2.0, 14.5 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.45 (s, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 2.3, 9.0 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 3.85 (br d, J = 12.8 Hz, 2H), 3.38 - 3.32 (m, 2H), 3.06 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H), 2.05 - 1.91 (m, 4H), 1.76 (d, J = 6.7 Hz, 3H).

[0745] (Example 45) 3-[6-(2,6-diazaspiro[3,3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0746] [ka]

[0747] Step 1. tert-butyl(R)-6-(5-(5-(1-(3,5-dichloropyridine-4-yl)ethoxy)-1H-indazole-3-yl)pyridine-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate. A mixture of Example 25 (0.295 g, 0.732 mmol, 1 equivalent), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.29 g, 1.464 mmol, 2 equivalents), and potassium carbonate (0.4 g, 2.93 mmol, 4 equivalents) in anhydrous N-methylpyrrolidone was heated at 120°C for 16 hours. The reaction mixture was filtered through a syringe filter, and the filtrate was pre-absorbed onto Celite (5 g). The substance was purified using an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5g cartridge) with elution under a 0-100% acetonitrile gradient in water. The fraction containing the product was collected and freeze-dried to obtain a yellowish solid (0.3g, 71% yield). Analysis: LC-MS (ESI) m / z=581 (M+H).

[0748] Step 2. 3-[6-(2,6-diazaspiro[3,3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole. A solution of the Step 1 product (50 mg, 0.086 mmol, 1 equivalent) in anhydrous dichloromethane (2 mL) was treated with trifluoroacetic acid (0.53 mL, 6.88 mmol, 80 equivalents) at room temperature for 16 hours. Additional trifluoroacetic acid (0.23 mL, 3.01 mmol, 35 equivalents) was added and the mixture was stirred for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methanol (10 mL), treated with MP-carbonate resin (3.2 mmol / g, 1 g), stirred for 30 minutes, filtered, and concentrated under reduced pressure. The residue was absorbed onto Celite (1 g) and purified using an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) with elution under a 0-100% acetonitrile gradient in water. The fraction containing the product was collected and freeze-dried to obtain a white solid (30 mg, 73% yield). Analysis: LCMS: m / z = 481.1 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.00 (br s, 1H), 8.59 (s, 2H), 8.50 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 2.3, 8.7 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 2.3, 9.0 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.10 (q, J = 6.6 Hz, 1H), 4.20 - 3.82 (m, 5H), 3.66 (br s, 4H), 1.76 (d, J = 6.6 Hz, 3H).

[0749] (Example 46) 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3,3]heptan-6-yl)-3-pyridyl]-1H-indazole

[0750] [ka]

[0751] (5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole. Triethylamine (20.5 uL, 0.148 mmol, 1.2 equivalents) and methylsulfonyl chloride (9.5 uL, 0.123 mmol, 1.0 equivalent) in anhydrous THF (3 mL) in Example 45 (59.0 mg, The solution (0.123 mmol, 1 equivalent) was sequentially added at room temperature. After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). The layers were separated. The organic layer was dehydrated with sodium sulfate, filtered, and concentrated on Celite (1 g) under reduced pressure. The product was eluted using an Interchim automated chromatography system (RediSep) with a gradient of 0-100% acetonitrile in water. The product was purified on an Rf Gold HP C18 (15.5g cartridge). The fraction containing the product was collected and lyophilized to obtain a white solid (45.0 mg, 65% yield). Analysis: LCMS: m / z = 559.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.02 (br s, 1H), 8.59 (s, 2H), 8.52 (dd, J = 0.6, 2.2 Hz, 1H), 7.87 (dd, J = 2.4, 8.6 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 6.54 (dd, J = 0.4, 8.6 Hz, 1H), 6.10 (q, J = 6.6 Hz, 1H), 4.17 (s, 4H), 4.12 (s, 4H), 3.03 (s, 3H), 1.76 (d, J = 6.6 Hz, 3H).

[0752] (Example 47) 6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-N,N-dimethyl-2,6-diazaspiro[3,3]heptan-2-carboxamide

[0753] [ka]

[0754] 6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]-2-pyridyl]-N,N-dimethyl-2,6-diazaspiro[3.3]heptan-2-carboxamide. Triethylamine (24.4 μL, 0.175 mmol, 1.2 equivalents) and dimethylcarbamate chloride (14.8 μL, 0.161 mmol, 1.1 equivalents) were sequentially added to a solution of Example 45 (70.0 mg, 0.146 mmol, 1 equivalent) in anhydrous THF (3 mL) at room temperature. After stirring for 2 hours, additional dimethylcarbamate chloride (4 μL, 0.044 mmol, 0.3 equivalents) and triethylamine (8.1 μL, 0.058 mmol, 0.4 equivalents) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). The layers were separated. The organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was absorbed onto Celite (1 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) with elution using a gradient of 0-100% acetonitrile in water. The fraction containing the product was collected and lyophilized to obtain a white solid (33.0 mg, yield 41%). Analysis: LCMS: m / z = 552.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 2H), 8.51 (dd, J = 0.7, 2.3 Hz, 1H), 7.86 (dd, J = 2.3, 8.6 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 6.53 (dd, J = 0.6, 8.7 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 4.14 (s, 4H), 4.10 (s, 4H), 2.77 (s, 6H), 1.76 (d, J = 6.6 Hz, 3H), 1.36 (s, 1H).

[0755] [ka]

[0756] (Example 48) 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]pyrimidine-2-yl]-1,8-diazaspiro[4.5]decane-2-one

[0757] [ka]

[0758] Step 1. 3-(2-chloropyrimidine-5-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A mixture of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (1.5 g, 2.89 mmol, 1 equivalent), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (904 mg, 3.76 mmol, 1.3 equivalents), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (211 mg, 0.289 mmol, 0.1 equivalent), potassium carbonate (798 mg, 5.79 mmol, 2 equivalents), and water (2 mL) in 1,4-dioxane (24 mL) was sparged with nitrogen for 10 minutes. The mixture was vigorously stirred overnight at 90°C under a nitrogen atmosphere. The brown reaction mixture was cooled to room temperature and diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dehydrated with sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto Celite (10 g) and purified on an Interchim automated chromatography system (Sorbtech 80 g silica gel cartridge) with elution in a gradient of 0-50% ethyl acetate in heptane to obtain a white solid (1.17 g, yield 80%). Analysis: LC-MS: m / z = 504.1 (M + H).

[0759] Step 2. 8-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)pyrimidine-2-yl)-1,8-diazaspiro[4.5]decan-2-one. A mixture of product Step 1 (185 mg, 0.366 mmol, 1 equivalent), 1,8-diazaspiro[4.5]decan-2-one (62 mg, 0.403 mmol, 1.1 equivalents), and potassium carbonate (76 mg, 0.549 mmol, 1.5 equivalents) in anhydrous NMP (3 mL) was heated overnight at 120 °C. The reaction mixture was cooled to room temperature and diluted with water (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dehydrated with sodium sulfate and concentrated under reduced pressure to obtain a white solid (290 mg), which was then used. Analysis: LCMS m / z = 622.1 (M + H).

[0760] Step 3. 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]pyrimidine-2-yl]-1,8-diazaspiro[4.5]decan-2-one. Product Step 2 (290 mg) was dissolved in a 1:1 mixture of trifluoroacetic acid and dichloromethane (2 mL) at room temperature, and the red solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dehydrated with sodium sulfate and concentrated under reduced pressure. The brown residue was adsorbed onto Celite (1g) and purified using an Interchim automated chromatography system (RediSep Rf GOLD HP C18, 15g column) with a 0-100% methanol gradient in water. After lyophilization, a white solid was obtained (100mg, 40% yield, 2 steps). Analysis: LCMS: m / z = 538.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 12.24 (br s, 1H), 8.61 (s, 2H), 8.55 (s, 1H), 8.41 (s, 2H), 7.43 (dd, J = 0.5, 9.0 Hz, 1H), 7.14 (dd, J = 2.3, 9.0 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 6.03 (q, J = 6.7 Hz, 1H), 4.44 - 4.34 (m, 2H), 3.36 - 3.21 (m, 2H), 2.51 (t, J = 8.1 Hz, 2H), 2.02 (t, J = 8.1 Hz, 2H), 1.80 (d, J = 6.7 Hz, 3H), 1.74 - 1.69 (m, 4H).

[0761] Examples 49-58 were synthesized using the procedure for Example 26.

[0762] [Table 4A]

[0763] [Table 4B]

[0764] [Table 4C]

[0765] (Example 59) 3-(2-chloropyrimidine-5-yl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0766] [ka]

[0767] The product of Step 1 of Example 48 (60 mg, 0.12 mmol, 1 equivalent) in dichloromethane (0.6 mL) was treated with trifluoroacetic acid (0.6 mL, 7.84 mmol, 65 equivalents) overnight at room temperature. Volatile substances were removed under reduced pressure. The residue was dissolved in a 3:1 mixture of dichloromethane and methanol (2.4 mL) and treated with MP-Carbonate® (2.42 g) for 2 hours. The resin was filtered, and the filtrate was concentrated directly onto Celite. The residue was purified using a Biotage automated chromatography system (RediSep HP Gold C18 50 g column) with elution under a 0-100% acetonitrile gradient in water to obtain an off-white solid (17.6 mg, 36% yield). Analysis: LCMS: m / z = 422.0 (M+H); 1 H NMR (400 MHz, CDCl3) δ 10.41 (br s, 1H), 9.11 (s, 2H), 8.45 (s, 2H), 7.45 (dd, J = 0.5, 9.0 Hz, 1H), 7.21 (dd, J = 2.3, 9.0 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 6.08 (q, J = 6.6 Hz, 1H), 1.84 (d, J = 6.6 Hz, 3H).

[0768] (Example 60) 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]pyrimidine-5-yl]-1H-indazole

[0769] [ka]

[0770] 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]pyrimidine-5-yl]-1H-indazole. A mixture of Example 59 (135 mg, 0.321 mmol, 1.0 equivalent), 1-(oxetan-3-yl)-1,4-diazepane (136 mg, 0.354 mmol, 1.1 equivalent), and potassium carbonate (444 mg, 3.22 mmol, 10 equivalents) in N-methylpyrrolidinone was heated overnight at 120°C. The brown reaction mixture was cooled to room temperature and diluted with water (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dehydrated with sodium sulfate and concentrated under reduced pressure. The brown oily substance was adsorbed onto Celite (1 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18 15 g column) using a 0-100% methanol and water gradient to obtain a white solid (100 mg, 57% yield). Analysis: LC-MS: m / z = 541.2 (M+H); 1 H NMR (400 MHz, CDCl3) δ 10.11 (br s, 1H), 8.75 (s, 2H), 8.42 (s, 2H), 7.36 (dd, J = 0.6, 9.0 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 2.3, 9.0 Hz, 1H), 6.05 (q, J = 6.7 Hz, 1H), 4.69 - 4.63 (m, 2H), 4.63 - 4.56 (m, 2H), 4.03 - 3.98 (m, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.71 (quintet, J = 6.5 Hz, 1H), 2.65 - 2.58 (m, 2H), 2.49 - 2.42 (m, 2H), 2.07 - 2.00 (m, 2H), 1.82 (d, J = 6.6 Hz, 3H).

[0771] (Example 61) 3-[2-(1,4-diazepan-1-yl)pyrimidine-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0772] [ka]

[0773] Step 1. tert-butyl4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)pyrimidine-2-yl)-1,4-diazepan-1-carboxylate. Potassium carbonate (164.1 mg, 1.2 mmol, 4 equivalents) and 1-Boc-hexahydro-1,4-diazepine (117 μL, 0.6 mmol, 2 equivalents) were sequentially added at room temperature to a nitrogen-purged solution of 3-(2-chloropyrimidine-5-yl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazole (149.8 mg, 0.30 mmol, 1 equivalent) in N-methyl-2-pyrrolidone (3.0 mL) at room temperature. The resulting mixture was heated overnight at 120 °C. After cooling to room temperature, the reaction product was concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar 60 μm 15.5 g silica gel cartridge) using a gradient of 0-100% ethyl acetate in heptane to obtain a yellow solid (179 mg, 90% yield). Analysis: LC-MS: m / z = 668.2 (M + H).

[0774] Step 2. 3-[2-(1,4-diazepan-1-yl)pyrimidine-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole trifluoroacetate. The product from Step 1 (178.6 mg, 0.27 mmol, 1 equivalent) in dichloromethane (2.0 mL) was treated with trifluoroacetic acid (2.0 mL, 26.1 mmol, 96 equivalents) for 2 hours at room temperature. The reaction mixture was concentrated directly onto Celite and purified on a Biotage automated chromatography system (RediSep Gold HP C18 column 50 g) with elution under a 0-100% acetonitrile gradient in water to obtain an off-white solid (103 mg, yield 72%). Analysis: LCMS: m / z = 484.2 (M+H), 1 H NMR (400 MHz, CD3OD) δ 8.76 (s, 2H), 8.47 (s, 2H), 7.47 (dd, J = 0.4, 9.1 Hz, 1H), 7.19 (dd, J = 2.3, 9.0 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 4.56 (br s, 1H), 4.22 - 4.17 (m, 2H), 4.06 (t, J = 6.2 Hz, 2H), 3.49 - 3.46 (m, 2H), 3.38 - 3.35 (m, 2H), 2.21 (td, J = 5.9, 11.5 Hz, 2H), 1.83 (d, J = 6.6 Hz, 3H).

[0775] (Example 62) 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]pyrimidine-2-yl]-1,4-diazepan-1-carboxamide

[0776] [ka]

[0777] Step 1. A suspension of 3-(2-(1,4-diazepan-1-yl)pyrimidine-5-yl)-5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydropyran-2-yl)-1H-indazole:1-methyl-2-pyrrolidone (2 mL) containing 3-(2-chloropyrimidine-5-yl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazole (145 mg, 0.28 mmol, 1 equivalent) and potassium carbonate (160 mg, 1.12 mmol, 4 equivalents) was treated with 1,4-diazepane dihydrochloride (97 mg, 0.57 mmol, 2 equivalents). After heating at 120°C for 16 hours, the reaction mixture was cooled to room temperature and diluted with water (10 mL). The resulting solid was stirred at room temperature for 30 minutes and filtered to obtain a light brown solid (86 mg, yield 53%), which was then used. Analysis: LC-MS (ESI) m / z = 568.1 (M + H).

[0778] Step 2. 4-(5-(5-((R)-1-(3,5-dichloropyridine-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-yl)pyrimidine-2-yl)-1,4-diazepan-1-carboxamide (209-4):(trimethylsilyl)isocyanate (23 μL, 0.17 mmol, 1.1 equivalents) was added at room temperature to a solution of product Step 1 (86 mg, 0.15 mmol, 1 equivalent) and triethylamine (24 μL, 0.17 mmol, 1.1 equivalents) in THF (2 mL). After 4 hours, volatile matter was removed under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 24g silica gel column) using a gradient of 0-80% ethyl acetate in heptane to obtain a light brown solid (25 mg, yield 27%). Analysis: LC-MS (ESI) m / z = 611.1 (M + H).

[0779] Step 3. (4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole-3-yl]pyrimidine-2-yl]-1,4-diazepan-1-carboxamide. The product from Step 2 (25 mg, 0.04 mmol, 1 equivalent) was treated with a 1:1 mixture of dichloromethane-trifluoroacetic acid (0.5 mL) at room temperature for 2 hours. Volatile substances were removed under reduced pressure. The residue was diluted with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) with elution under a 0-80% acetonitrile gradient in water. The fraction containing the product was lyophilized to obtain a white solid (11 mg, 53% yield). Analysis: LC-MS (ESI) m / z = 527.2 (M+H); 1 H NMR (400 MHz, CD3OD) δ 8.70 - 8.67 (m, 2H), 8.48 (s, 2H), 7.45 (d, J = 9.0 Hz, 1H), 7.17 (dd, J = 2.3, 9.0 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 4.55 (br s, 2H), 4.02 (t, J = 5.5 Hz, 2H), 3.91 (t, J = 6.1 Hz, 2H), 3.69 - 3.64 (m, 2H), 3.49 - 3.45 (m, 2H), 2.05 - 1.99 (m, 2H), 1.82 (d, J = 6.6 Hz, 3H).

[0780] (Example 63) 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(4-methylsulfonyl-1,4-diazepan-1-yl)pyrimidine-5-yl]-1H-indazole

[0781] [ka]

[0782] Example 61 (76.5 mg, 0.16 mmol, 1 equivalent) in THF (1.6 mL) was treated with triethylamine (22.0 μL, 0.63 mmol, 4 equivalents) and methanesulfonyl chloride (12.2 μL, 0.63 mmol, 4 equivalents) at 40°C for 4 days. The reaction mixture was concentrated directly onto Celite and then purified on a Biotage automated chromatography system (RediSep Gold HP C18 50 g column) using a 0-100% acetonitrile gradient in water to obtain a white solid (14.8 mg, 17% yield). Analysis: LC-MS: m / z = 562.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.77 (s, 2H), 8.56 (s, 2H), 7.47 (d, J = 8.9 Hz, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 6.14 (q, J = 6.7 Hz, 1H), 3.97 (t, J = 5.6 Hz, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.50 (t, J = 5.5 Hz, 2H), 3.34 - 3.31 (m, 2H), 2.84 (s, 3H), 1.90 (quintet, J = 5.7 Hz, 2H), 1.76 (d, J = 6.7 Hz, 3H).

[0783] Examples 64-68 were synthesized using the procedures and methods for Examples 3-9, with tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]piperidine-1-carboxylate or 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]piperidine.

[0784] [Table 5A]

[0785] [Table 5B]

[0786] Examples 69-72 were synthesized using tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperidine-1-carboxylate, following the procedures and methods for Examples 3-9.

[0787] [Table 6]

[0788] Examples 73-76 were synthesized using the procedures and methods for Examples 3-9, with tert-butyl 6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylate and tert-butyl 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate.

[0789] [Table 7]

[0790] (Example 77) 8-[5-[5-[(1R)-1-(3,5-d...

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, [In the formula, n = 1, 2, or 3, m = 0, 1, 2, or 3, Each R 1 These are independently H, CN, or C which may be substituted. 1 ~C 6 It is alkyl, Each R 2 These are independently H, CN, or C which may be substituted. 1 ~C 6 Is it alkyl? or two R atoms bonded to the same carbon atom 1 The groups, together with the carbon atoms to which both are bonded, optionally form a substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or two R atoms bonded to the same carbon atom 1 The group, together with its carbon atom, represents a carbonyl group (C=O), or two Rs attached to the same carbon atom 2 together with the carbon atom to which both are attached form a 3- to 7-membered spirocycloalkyl ring optionally substituted or a 3- to 7-membered spiroheterocycloalkyl ring optionally substituted, or or two R atoms bonded to the same carbon atom 2 The group, together with its carbon atom, represents a carbonyl group (C=O), or two R atoms bonded to different carbon atoms 1 The groups, together with the carbon atoms to which they are bonded, form a 3- to 7-membered cycloalkyl ring, or two R atoms bonded to different carbon atoms 2 The groups, together with the carbon atoms to which they are bonded, form a 3- to 7-membered cycloalkyl ring, or R 1 Base and R 2 The bases combine to form a 6-9 membered bridged biring ring, A=N or CH Z=S(O) 2 ;S(O);O, NR 3 or CR 4 R 4' And, R 3 H is replaced by C depending on the case. 1 ~C 6 Alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O) 2 R c ; or -S(O) 2 NR a R b Is it, or R 3 R 1 Or R 2 Together with it, it forms a 3- to 7-membered heterocycloalkyl ring which may be substituted in some cases. R a is H or C 1 ~C 6 Is it alkyl? R b is H or C 1 ~C 6 Is it alkyl? or R a and R b These, together with the N atom to which they are bonded, form a optionally substituted 3- to 7-membered heterocycloalkyl ring. R c C is replaced in some cases. 1 ~C 6 Is it alkyl or cycloalkyl? R 4 C is replaced by H, -F, or as may be the case. 1 ~C 6 Is it alkyl? R 4' These are H, -F, -OH, -CN, -NH 2 , -NH(C 1 ~C 3 Alkyl), -N(C 1 ~C 3 Alkyl) 2 , -N(C 1 ~C 3 Alkyl)-SO 2 (C 1 ~C 3 Alkyl), -C 1 ~C 6 Haloalkyl, and optionally substituted C 1 ~C 6 Alkyl, or optionally substituted C 1 ~C 6 Is it an alkoxyl? or R 4 and R 4' These, together with the C atom to which they are bonded, may form a substituted 3- to 7-membered heterocycloalkyl ring or a substituted 3- to 7-membered cycloalkyl ring, or R 4 and R 4' These two, together with the carbon atom to which they are bonded, either form an oxo group, or R 4' R 1 Or R 2 Together with, it forms an optionally substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring, Y is a 5- or 6-membered heteroaryl ring, or a 6-membered aryl ring. Q 5 Q 6 Q 7 Q 8 , and Q 9 These are, independently, N or CR. 5 Q 5 Q 6 Q 7 Q 8 , and Q 9 One or two of them are N, and the rest are CR 5 And, R 5 H, halogen, C 1 ~C 3 Alkyl; C 1 ~C 3 It is an alkoxyl or cycloalkyl, X = O, S, or NR, where R is H or C 1 ~C 3 is alkyl, R 6 is C 1 ~C 6 It is alkyl, R 7 is H, halogen, -C 1 ~C 6 alkyl; -C 1 ~C 6 alkoxyl, or -cycloalkyl, and R 8 H, halogen, -C 1 ~C 6 Alkyl;-C 1 ~C 6 [It is alkoxyl or cycloalkyl.]

2. Compound according to claim 1 [In the formula, n = 1, 2, or 3, m = 1, 2, or 3, Each R 1 This is independently H or, depending on the case, C which is substituted. 1 ~C 6 It is alkyl, Each R 2 This is independently H or, depending on the case, C which is substituted. 1 ~C 6 Is it alkyl? or two R atoms bonded to the same carbon atom 1 The groups, together with the carbon atoms to which both are bonded, optionally form a substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or two R atoms bonded to the same carbon atom 1 The group, together with its carbon atom, represents a carbonyl group (C=O), or two R atoms bonded to the same carbon atom 2 The groups, together with the carbon atoms to which both are bonded, optionally form a substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or two R atoms bonded to the same carbon atom 2 The group, together with its carbon atom, represents a carbonyl group (C=O), or two R atoms bonded to different carbon atoms 1 The groups, together with the carbon atoms to which they are bonded, form a 3- to 7-membered cycloalkyl ring, or two R atoms bonded to different carbon atoms 2 The groups, together with the carbon atoms to which they are bonded, form a 3- to 7-membered cycloalkyl ring, or R 1 Base and R 2 The bases combine to form a 6-9 membered bridged biring ring, A=N or CH Z=S(O) 2 ;S(O);O, NR 3 or CR 4 R 4' And, R 3 H is replaced by C depending on the case. 1 ~C 6 Alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O) 2 R c ; or -S(O) 2 NR a R b And, R a is H or C 1 ~C 6 It is alkyl, R b is H or C 1 ~C 6 Is it alkyl? or R a and R b These, together with the N atom to which they are bonded, form a optionally substituted 3- to 7-membered heterocycloalkyl ring. R c C is replaced in some cases. 1 ~C 6 Alkyl or cycloalkyl, R 4 is H, or C which may be substituted. 1 ~C 6 It is alkyl, R 4' is H, -OH, or optionally substituted C 1 ~C 6 Is it alkyl? or R 4 and R 4' These, together with the C atom to which they are bonded, form a optionally substituted 3- to 7-membered heterocycloalkyl ring. Y is a 5- or 6-membered heteroaryl ring, Q 5 Q 6 Q 7 Q 8 , and Q 9 These are, independently, N or CR. 5 Q 5 Q 6 Q 7 Q 8 , and Q 9 One or two of them are N, and the rest are CR 5 And, R 5 H, halogen, C 1 ~C 3 Alkyl; C 1 ~C 3 It is an alkoxyl or cycloalkyl, X = O, S, or NR, and R is H or C 1 ~C 3 It is alkyl, R 6 is C 1 ~C 6 It is alkyl, R 7 H, halogen, -C 1 ~C 6 Alkyl;-C 1 ~C 6 It is an alkoxyl or cycloalkyl, R 8 H, halogen, -C 1 ~C 6 Alkyl;-C 1 ~C 6 [It is alkoxyl or cycloalkyl.]

3. The compound according to claim 1 or claim 2, wherein Y is a 6-membered heteroaryl ring.

4. The compound of formula (I) is the compound of formula (IA): 【Chemistry 2】 [In the formula, Q 1 Q 2 Q 3 Q 4 One or two of them are N, and the others are each independently CR 5a And R 5a is H, halogen, -CN, or C 1 ~C 3 The compound according to claim 3, wherein it is alkyl.

5. The compound according to any one of claims 1 to 4, wherein X is O.

6. Q 5 and Q 9 These are CR 5 And each R 5 is a halogen, Q 6 and Q 8 These are CR 5 And each R 5 H is Q 7 The compound according to any one of claims 1 to 5, wherein is N.

7. Q 5 and Q 9 These are CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 8 CR 5 And R 5 is C 1 ~C 3 It is alkyl, Q 7 The compound according to any one of claims 1 to 5, wherein is N.

8. Q 5 and Q 9 These are CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 CR 5 And R 5 ha-CH 3 Q 7 The compound according to any one of claims 1 to 5, wherein is N.

9. Q 5 and Q 9 These are CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 CR 5 And R 5 The compound according to any one of claims 1 to 5, wherein is H.

10. Q 5 and Q 9 These are CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 CR 5 And R 5 The compound according to any one of claims 1 to 5, wherein is H.

11. Q 5 and Q 9 These are CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 The compound according to any one of claims 1 to 5, wherein is N.

12. Q 5 and Q 9 These are CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 The compound according to any one of claims 1 to 5, wherein is N.

13. Q 5 and Q 9 These are CR 5 And each R 5 is C 1 ~C 3 It is alkyl, Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 The compound according to any one of claims 1 to 5, wherein is N.

14. Q 5 and Q 9 These are CR 5 And each R 5 ha-CH 3 Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 The compound according to any one of claims 1 to 5, wherein is N.

15. Q 5 Q 8 , and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 7 The compound according to any one of claims 1 to 5, wherein is N.

16. Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 CR 5 And R 5 is -F and Q 7 The compound according to any one of claims 1 to 5, wherein is N.

17. The compound of formula (IA) is the compound of formula (IA-1): 【Transformation 3】 The compound according to any one of claims 4 to 6.

18. R 6 ha-CH 3 The compound according to any one of claims 1 to 17.

19. Q 3 CR 5a The compound according to any one of claims 4 to 18.

20. R 5a The compound according to claim 19, wherein is a halogen.

21. The compound according to claim 20, wherein the halogen is -F.

22. The compound of formula (IA-1) is the compound of formula (IA-2): 【Chemistry 4】 The compound according to claim 17.

23. The compound according to any one of claims 1 to 22, wherein n=2 and m=2.

24. The compound according to any one of claims 1 to 22, wherein n=1 and m=1.

25. The compound according to any one of claims 1 to 22, wherein n=1 and m=2.

26. The compound according to any one of claims 1 to 22, wherein n=3 and m=2.

27. The compound of formula (IA-2) is the compound of formula (IA-3): 【Transformation 5】 The compound according to claim 22.

28. Each R 1 and each R 2 C is independently substituted for H or, in some cases, C. 1 ~C 6 The compound according to claim 27, wherein it is alkyl.

29. Each R 1 and each R 2 The compound according to claim 27, wherein is H.

30. Each R 1 It is H, and two Rs bonded to the same carbon atom. 2 The compound according to claim 27, wherein the groups, together with the carbon atoms to which both are bonded, form a 3- to 7-membered spirocycloalkyl ring.

31. The compound according to claim 30, wherein the 3- to 7-membered spirocycloalkyl ring is a 3-membered spirocycloalkyl ring.

32. On the other hand, R 1 Base and one of the R 2 The groups combine to form a 6- to 9-membered bridging bicyclic ring, and the other R 1 H is H, and the other R is R 2 The compound according to claim 27, wherein is H.

33. The compound according to claim 32, wherein the 6- to 9-membered bridging bicyclic ring is a 7-membered bridging bicyclic ring.

34. Each R 1 It is H, and two Rs bonded to the same carbon atom. 2 The compound according to claim 27, wherein the group represents a carbonyl group (C=O).

35. The compound of formula (IA-2) is the compound of formula (IA-4): 【Transformation 6】 The compound according to claim 22.

36. Two R atoms bonded to the same carbon atom 2 The compound according to claim 35, wherein the group represents a carbonyl group (C=O).

37. The compound of formula (IA-2) is the same as the compound of formula (IA-5): 【Transformation 7】 The compound according to claim 22.

38. Each R 1 and each R 2 This is independently H or optionally replaced by C. 1 ~C 6 The compound according to claim 37, wherein it is alkyl.

39. Each R 1 and each R 2 The compound according to claim 37, wherein is H.

40. Each R 1 It is H, and two Rs bonded to the same carbon atom. 2 The compound according to 37, wherein the groups, together with the carbon atoms to which both are bonded, form a 3- to 7-membered spirocycloalkyl ring.

41. The compound according to claim 40, wherein the 3- to 7-membered spirocycloalkyl ring is a 3-membered spirocycloalkyl ring.

42. On the other hand, R 1 Base and one of the R 2 The groups combine to form a 6- to 9-membered bridging bicyclic ring, and the other R 1 H is H, and the other R is R 2 The compound according to claim 37, wherein is H.

43. The compound according to claim 42, wherein the 6- to 9-membered bridging bicyclic ring is a 7-membered bridging bicyclic ring.

44. The compound of formula (IA-2) is the compound of formula (IA-6): 【Transformation 8】 The compound according to claim 22.

45. Two R atoms bonded to the same carbon atom 1 The compound according to claim 44, wherein the group represents a carbonyl group (C=O).

46. Two R atoms bonded to the same carbon atom 2 The compound according to claim 44 or claim 45, wherein the groups, together with the carbon atoms to which both are bonded, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring.

47. Two R atoms bonded to the same carbon atom 2 The compound according to claim 46, wherein the groups, together with the carbon atom to which both are bonded, form an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring.

48. The compound according to claim 47, wherein the optionally substituted 3- to 7-membered spiroheterocycloalkyl ring is optionally substituted azethinyl ring, optionally substituted pyrrolidinyl ring, or optionally substituted piperidinyl ring.

49. The compound according to claim 48, wherein the 3- to 7-membered spiroheterocycloalkyl ring substituted in the above case is an azethinyl ring, a pyrrolidinyl ring, a piperidinyl ring, an N-methylpiperidinyl ring, or an N-(methylsulfonyl)piperidinyl ring.

50. Compound (IA-2) corresponds to compound (IA-7): 【Chemistry 9】 The compound according to claim 22.

51. Each R 1 The compound according to claim 50, wherein is H.

52. Two R atoms bonded to the same carbon atom 1 The compound according to claim 50, wherein the group represents a carbonyl group (C=O).

53. Each R 2 The compound according to any one of claims 50 to 52, wherein is H.

54. Two R atoms bonded to the same carbon atom 2 The compound according to any one of claims 50 to 52, wherein the group represents a carbonyl group (C=O).

55. The compound of formula (I) is the compound of formula (IA-8): 【Chemistry 10】 [In the formula, R 9 is -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -C(O)C 1 ~C 6 Haloalkyl, -C(O)OC 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, -C(O)N(C 1 ~C 6 Alkyl) 2 , or -SO 2 -C 1 ~C 6 The compound according to claim 1 or claim 2, wherein it is alkyl.

56. R 9 ha-CH 2 CF 3 , -CH 2 CHF 2 , -C(O)CF 3 ,-C(O)OCH 3 ,-C(O)OCH 2 CH 3 , -SO 2 CH 2 CH 3 , or -SO 2 CH(CH 3 ) 2 The compound according to claim 55.

57. Q 2 The compound according to any one of claims 17 to 56, wherein is N.

58. Q 4 The compound according to any one of claims 17 to 56, wherein is N.

59. Q 4 CR 5a The compound according to any one of claims 17 to 56.

60. R 5a The compound according to claim 59, wherein is H.

61. R 5a The compound according to claim 59, wherein is a halogen.

62. The compound according to claim 59, wherein the halogen is -F.

63. The compound according to claim 1, wherein Y is a 5-membered heteroaryl ring.

64. The compound of formula (I) is the compound of formula IB: 【Chemistry 11】 The compound according to claim 63.

65. The compound according to claim 63 or 64, wherein X is O.

66. Q 5 and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 and Q 8 CR 5 And R 5 H is Q 7 The compound according to any one of claims 63 to 65, wherein is N.

67. Q 5 and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 8 CR 5 And R 5 is C 1 ~C 3 It is alkyl, Q 7 The compound according to any one of claims 63 to 65, wherein is N.

68. Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 CR 5 And R 5 ha-CH 3 Q 7 The compound according to any one of claims 63 to 65, wherein is N.

69. Q 5 and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 CR 5 And R 5 The compound according to any one of claims 63 to 65, wherein is H.

70. Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 CR 5 And R 5 The compound according to any one of claims 63 to 65, wherein is H.

71. Q 5 and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 The compound according to any one of claims 63 to 65, wherein is N.

72. Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 The compound according to any one of claims 63 to 65, wherein is N.

73. Q 5 and Q 9 Each is independently CR 5 And each R 5 is C 1 ~C 3 It is alkyl, Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 The compound according to any one of claims 63 to 65, wherein is N.

74. Q 5 and Q 9 Each is independently CR 5 And each R 5 ha-CH 3 Q 6 CR 5 And R 5 H is Q 8 is N and Q 7 The compound according to any one of claims 63 to 65, wherein is N.

75. Q 5 Q 8 , and Q 9 Each is independently CR 5 And each R 5 is a halogen, Q 6 CR 5 And R 5 H is Q 7 The compound according to any one of claims 63 to 65, wherein is N.

76. Q 5 and Q 9 Each is independently CR 5 And each R 5 is -Cl, and Q 6 CR 5 And R 5 H is Q 8 CR 5 And R 5 is -F and Q 7 The compound according to any one of claims 63 to 65, wherein is N.

77. Compounds of formula (IB) are compounds of formula IB-1: 【Chemistry 12】 The compound according to claim 64.

78. The compound of formula (IB-1) is the compound of formula IB-2: 【Chemistry 13】 The compound according to claim 77.

79. The compound according to any one of claims 64 to 78, wherein n=2 and m=2.

80. The compound according to any one of claims 64 to 78, wherein n=1 and m=1.

81. The compound according to any one of claims 64 to 78, wherein n=1 and m=2.

82. The compound according to any one of claims 64 to 78, wherein n=3 and m=2.

83. Each R 1 H is H, and each R 2 The compound according to any one of claims 64 to 78, wherein is H.

84. A is N, the compound according to any one of claims 1 to 83.

85. A is CH, the compound according to any one of claims 1 to 84.

86. Z is S(O) 2 The compound according to any one of claims 1 to 85.

87. The compound according to any one of claims 1 to 85, wherein Z is S(O).

88. The compound according to any one of claims 1 to 85, wherein Z is O.

89. Z is NR 3 The compound according to any one of claims 1 to 85.

90. R 3 The compound according to claim 89, wherein is H.

91. R 3 -C(O)NR a R b The compound according to claim 89.

92. R 3 -S(O) 2 NR a R b The compound according to claim 89.

93. R a H is R b The compound according to any one of claims 91 or 92, wherein is H.

94. R a H is R b C 1 ~C 6 The compound according to claim 91 or 92, wherein it is alkyl.

95. R a is C 1 ~C 6 It is alkyl, R b C 1 ~C 6 The compound according to claim 91 or 92, wherein it is alkyl.

96. R a and R b The compound according to claim 91 or 92, wherein both of these, together with the N atom to which they are bonded, form an optionally substituted 3- to 7-membered heterocycloalkyl ring.

97. The compound according to claim 96, wherein the optionally substituted 3- to 7-membered heterocycloalkyl ring is optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted morpholinyl ring.

98. The compound according to claim 97, wherein the 3- to 7-membered heterocycloalkyl ring substituted in the above case is 4-methylpiperazine-1-yl or a morpholinyl ring.

99. R 3 is -C(O)OR c The compound according to claim 89.

100. R 3 -C(O)R c The compound according to claim 89.

101. R 3 -S(O) 2 R c The compound according to claim 89.

102. The aforementioned R c ha-CH 3 The compound according to any one of claims 99 to 101.

103. The aforementioned R c ha-CH 2 CH 3 The compound according to any one of claims 99 to 101.

104. R 3 is C 1 ~C 6 The compound according to claim 89, wherein it is alkyl.

105. Said C 1 ~C 6 Alkyl is -CH 3 The compound according to claim 104.

106. R 3 The compound according to claim 89, wherein is a 3- to 5-membered heterocycloalkyl group.

107. The compound according to claim 106, wherein the 3- to 5-membered heterocycloalkyl group is oxetanyl.

108. Z is CR 4 R 4' The compound according to any one of claims 1 to 85.

109. R 4 and R 4' The compound according to claim 108, wherein each of the elements is H.

110. R 4 and R 4' C is substituted in each case. 1 ~C 6 The compound according to claim 108, wherein it is alkyl.

111. R 4 H is R 4' The compound according to claim 108, wherein is -OH.

112. R 4 and R 4' The compound according to claim 108, wherein both of these, together with the C atom to which they are bonded, form an optionally substituted 3- to 7-membered heterocycloalkyl ring.

113. The compound according to claim 112, wherein the optionally substituted 3- to 7-membered heterocycloalkyl ring is optionally a substituted 4-membered heterocycloalkyl ring.

114. The compound according to claim 113, wherein the substituted four-membered heterocycloalkyl ring is an azetidinyl ring.

115. The compound according to claim 114, wherein the azetidinyl ring is not substituted.

116. The compound according to claim 114, wherein the azetidinyl ring is N-substituted.

117. N substituent is -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -C(O)C 1 ~C 6 Haloalkyl, -C(O)OC 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, -C(O)N(C 1 ~C 6 Alkyl) 2 , or -SO 2 -C 1 ~C 6 The compound according to claim 116, wherein it is alkyl.

118. The N substituent is -CH 2 CF 3 , -CH 2 CHF 2 , -C(O)CF 3 ,-C(O)OCH 3 ,-C(O)OCH 2 CH 3 , -SO 2 CH 2 CH 3 , -SO 2 CH(CH 3 ) 2 , -CH 3 , -CH(CH 3 ) 2 , -C(O)N(CH 3 ) 2 , or -SO 2 CH 3 The compound according to claim 117.

119. N substituent is C 1 ~C 6 Alkyl, -C(O)OC 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, -C(O)N(C 1 ~C 6 Alkyl) 2 , or -SO 2 -C 1 ~C 6 The compound according to claim 116, wherein it is alkyl.

120. The N substituent is -CH 3 -CH(CH3) 2 ,-C(O)OCH 2 CH 3 , -C(O)N(CH 3 ) 2 , -SO 2 CH 3 , -SO 2 CH(CH 3 ) 2 , or -SO 2 CH 2 CH 3 The compound according to claim 119.

121. The compound according to claim 113, wherein the optionally substituted four-membered heterocycloalkyl ring is optionally a substituted thietan 1,1-dioxide ring.

122. The compound according to claim 112, wherein the optionally substituted 3- to 7-membered heterocycloalkyl ring is optionally a substituted 5-membered heterocycloalkyl ring.

123. The compound according to claim 122, wherein the optionally substituted five-membered heterocycloalkyl ring is an unsubstituted pyrrolidinyl ring, an N-substituted pyrrolidinyl ring, an unsubstituted pyrrolidinyl-2-one ring, an N-substituted pyrrolidinyl-2-one ring, an unsubstituted pyrrolo-2,5-dione ring, an N-substituted pyrrolo-2,5-dione ring, an unsubstituted imidazolidinyl-2-one ring, an N-substituted imidazolidinyl-2-one ring, a tetrahydrofuranyl ring, or a tetrahydrothiophene-1,1-dioxide ring.

124. The aforementioned N substituent is -C 1 ~C 6 Alkyl, -C(O)OC 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, or -SO 2 C 1 ~C 6 The compound according to claim 123, wherein it is alkyl.

125. The aforementioned N substituent is -CH 3 ,-C(O)OCH 3 ,-C(O)OCH 2 CH 3 ,-C(O)OCH(CH 3 ) 2 , or -SO 2 CH 3 The compound according to claim 124.

126. The compound according to claim 112, wherein the optionally substituted 3- to 7-membered heterocycloalkyl ring is optionally a substituted 6-membered heterocycloalkyl ring.

127. The compound according to claim 126, wherein the substituted six-membered heterocycloalkyl ring is an unsubstituted piperidinyl-2-one ring, an N-substituted piperidinyl-2-one ring, an N-substituted or unsubstituted piperidine ring, or a tetrahydro-2H-thiopyran-1,1-dioxide ring.

128. N-substituted, -C 1 ~C 6 Alkyl, -C(O)OC 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, or -SO 2 C 1 ~C 6 The compound according to claim 127, wherein it is alkyl.

129. The N substituent is -CH 3 ,-C(O)OCH 3 ,-C(O)OCH 2 CH 3 ,-C(O)OCH(CH 3 ) 2 , -SO 2 CH 2 CH 3 , or -SO 2 CH 3 The compound according to claim 128.

130. The N substituent is -SO 2 CH 2 CH 3 The compound according to claim 128.

131. A pharmaceutical composition comprising a compound according to any one of claims 1 to 130, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

132. A method for treating cancer in a subject requiring such treatment, comprising the step of administering to the subject a compound according to any one of claims 1 to 130, or a pharmaceutically acceptable salt thereof.

133. The method according to claim 132, wherein the cancer is urothelial carcinoma, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, pancreatic exocrine carcinoma, oral, prostate, bladder, colorectal cancer, renal elliptic carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous), melanoma, leiomyosarcoma, and / or sarcoma.

134. The method according to claim 133, wherein the cancer is intrahepatic cholangiocarcinoma.

135. The method according to any one of claims 132 to 134, wherein the cancer is an FGFR-mutated cancer.

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