Inhibitors of FGFR2 and FGFR3 and their use

Abstract

This specification describes FGFR2 and FGFR3 inhibitors, as well as pharmaceutical compositions containing such inhibitors. The compounds and compositions described herein are useful for treating diseases or disorders related to FGFR2 and / or FGFR3.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This patent application claims the interests of International Application PCT / CN2023 / 082529 filed on 20 March 2023, International Application PCT / CN2023 / 121183 filed on 25 September 2023, and International Application PCT / CN2024 / 078391 filed on 23 February 2024, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3, and FGFR4) are a subfamily of receptor tyrosine kinases (RTKs) consisting of an extracellular ligand-binding domain and an intracellular kinase domain. Binding of FGF ligands induces receptor dimerization, followed by phosphorylation of substrates such as FGFR substrate 2 (FRS2) and phospholipase Cγ (PLC-γ), further activating downstream signaling cascades and regulating major cellular functions including cell survival, proliferation, differentiation, migration, and angiogenesis (Clin. Cancer Res. 21(12) Jun. 15). th (2015). Abnormal activation of the FGFR signaling pathway due to FGFR fusion, mutation, and / or amplification may lead to tumor development, progression, and resistance to conventional cancer therapies. While pan-FGFR inhibitors have achieved clear clinical responses in several FGFR-modified cancers, on-target toxicities have also been observed, including FGFR1-mediated dose-limiting toxicities (e.g., hyperphosphatemia and tissue calcification) and FGFR4-mediated dose-limiting toxicities (e.g., diarrhea). Therefore, the development of next-generation dual FGFR2 / 3 inhibitors with higher selectivity, particularly against FGFR1, is desired for use in the treatment of cancer and other disorders. [Overview of the project]

[0003] In one embodiment, the foregoing provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof as described herein. [ka]

[0004] In another embodiment, provided herein are pharmaceutical compositions comprising any compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0005] In another embodiment, the foregoing provides a method for modulating the activity of fibroblast growth factor receptor (FGFR) or mutant FGFR in a subject, comprising administering any of the compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, or any pharmaceutical composition disclosed herein, to the subject.

[0006] In another embodiment, the foregoing provides a method for inhibiting fibroblast growth factor receptor (FGFR) activity or mutant FGFR activity in a subject, comprising administering any of the compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, or any pharmaceutical composition disclosed herein, to the subject.

[0007] In yet another aspect, what is provided herein is a method for treating cancer in a subject requiring treatment, comprising administering any of the substances disclosed herein, or any pharmaceutically acceptable salts or stereoisomers thereof, or any pharmaceutical composition disclosed herein, to the subject.

[0008] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference. [Modes for carrying out the invention]

[0009] definition The following description includes certain specific details to provide a complete understanding of various embodiments. However, those skilled in the art will understand that the invention can be carried out without these details. In other examples, well-known structures are not illustrated or described in detail to avoid unnecessarily obscuring the description of embodiments. Unless the context requires otherwise, the word “comprise” and its variations such as “comprises” and “comprising” throughout this specification and the subsequent claims should be interpreted as having an open and inclusive meaning, i.e., “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute an interpretation of the scope or meaning of the claimed invention.

[0010] Throughout this specification, any reference to “several embodiments” or “one embodiment” means that any particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment. Thus, although the phrase “in one embodiment” or “in one embodiment” appears in various places throughout this specification, not all of them necessarily refer to the same embodiment. Furthermore, any particular feature, structure, or characteristic can be combined in any preferred manner in one or more embodiments. Also, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” refer to multiple objects unless the context explicitly indicates otherwise. It should also be noted that the term “or” is generally used to mean “and / or” unless the context explicitly indicates otherwise.

[0011] As used herein, the following terms have the meanings set forth below unless otherwise indicated.

[0012] "Oxo" refers to O.

[0013] "Carboxyl" refers to the -COOH group.

[0014] "Cyano" refers to -CN.

[0015] "Alkyl" refers to a monovalent group of a linear or branched saturated hydrocarbon having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. "C1-C6 alkyl" or "C 1~6 Whenever a numerical range such as “alkyl” appears herein, it means that an alkyl group may consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms; however, this definition also includes the existence of the term “alkyl” without a specified numerical range. In some embodiments, alkyl is C 1~10 It is alkyl. In some embodiments, alkyl is C 1~6 It is alkyl. In some embodiments, alkyl is C 1~5 It is alkyl. In some embodiments, alkyl is C 1~4 It is alkyl. In some embodiments, alkyl is C 1~3It is alkyl. Unless otherwise specified herein, alkyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0016] "Alkenyl" refers to a monovalent group of a linear or branched hydrocarbon having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. This group can be in either a cis or trans conformation with respect to the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, and 1,3-butadienyl. Whenever numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl" appear herein, it means that the alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also includes the existence of the term "alkenyl" without a specified numerical range. Unless otherwise specified herein, alkenyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0017] "Alkynyl" refers to a monovalent group of a linear or branched hydrocarbon having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiinyl. Whenever numerical ranges such as "C2-C6 alkynyl" or "C2-6 alkynyl" appear herein, it means that the alkynyl group may consist of 2, 3, 4, 5, or 6 carbon atoms; however, this definition also includes the existence of the term "alkynyl" without a specified numerical range. Unless otherwise specified herein, the alkynyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0018] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified herein, alkylene groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0019] "Alkoxy" refers to a group of the formula -OR a wherein, in the formula, R a is an alkyl group as defined. Unless otherwise specifically stated herein, the alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0020] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems (where the aryl is bonded via aromatic ring atoms when fused with a cycloalkyl or heterocycloalkyl ring) or bridging ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Examples of aryl groups include, but are not limited to, aryl groups derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, aryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, aryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryls are optionally substituted with halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe. In some embodiments, aryls are optionally substituted with halogens. As used herein, "arylene" refers to the divalent aryl group described herein. Arylenes can be bonded via any suitable position of the aryl. In some embodiments, if the arylene contains an aryl condensed with a cycloalkyl ring or a heterocycloalkyl ring, the arylene is bonded in an aryl-cycloalkyl or aryl-heterocycloalkyl configuration. In some embodiments, when the arylene contains an aryl ring condensed with a cycloalkyl ring or a heterocycloalkyl ring, the arylene is bonded only at the aryl ring.

[0021] "Cycloalkyl" refers to a partially or completely saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded via non-aromatic ring atoms), spirocyclic systems, or bridging ring systems. In some embodiments, the cycloalkyl is completely saturated. Typical cycloalkyls include those with 3 to 15 carbon atoms (e.g., C3-C3). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), 3 to 10 carbon atoms (e.g., C3-C3) 10 Fully saturated cycloalkyl or C3-C 10Examples of cycloalkyls include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 to 10-membered fully saturated cycloalkyl or a 3 to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6-membered fully saturated cycloalkyl or a 3 to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6-membered fully saturated cycloalkyl or a 5 to 6-membered cycloalkenyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, dekalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen. As used herein, "cycloalkylene" refers to the divalent cycloalkyl groups described herein. In some embodiments, if the cycloalkylene includes a cycloalkyl group condensed with an aryl or heteroaryl ring, the cycloalkylene is bonded in a cycloalkyl and aryl, or cycloalkyl and heteroaryl. In some embodiments, if the cycloalkylene includes a cycloalkyl group condensed with an aryl or heteroaryl ring, the cycloalkylene is bonded only in the cycloalkyl group.

[0022] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0023] "Haloalkyl" refers to an alkyl group defined above that is substituted with one or more halo groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0024] "Hydroxyalkyl" refers to an alkyl group defined above, which is substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0025] "Aminoalkyl" refers to an alkyl group defined above, which is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Examples of aminoalkyls include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0026] A "heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. In a heteroalkyl group, the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, the heteroalkyl group is a C1-C6 heteroalkyl group, which consists of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, and the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified herein, heteroalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyls are optionally substituted with halogens.

[0027] "Heteroalkylene" refers to a linear or branched divalent alkylene group in which one or more skeletal atoms of alkylene are selected from heteroatoms, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. In some embodiments, the heteroalkylene is bonded to the rest of the molecule at two carbon atoms at both ends of the heteroalkylene. In some embodiments, the heteroalkylene is bonded to the rest of the molecule at two heteroatoms at both ends of the heteroalkylene. In some embodiments, the heteroalkylene is bonded to the rest of the molecule at one end carbon atom and the other end heteroatom. Unless otherwise specified herein, heteroalkylene groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the heteroalkylene is optionally substituted with halogen.

[0028] A "heterocycloalkyl" refers to a partially or fully saturated ring group with 3 to 24 members, comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1 to 3 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom and 1 oxygen atom. Unless otherwise specified herein, heterocycloalkyl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems (where the heterocycloalkyl group is bonded via a non-aromatic ring atom when fused with an aryl or heteroaryl ring), spirocyclic ring systems, or bridging ring systems. Nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group may be optionally oxidized, and nitrogen atoms may be optionally quaternized. Typical heterocycloalkyl groups include those with 2 to 15 carbon atoms (e.g., C2-C2). 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl), 2 to 10 carbon atoms (e.g., C2 to C2) 10 Fully saturated heterocycloalkyl or C2-C 10Examples of heterocycloalkyls include, but are not limited to, heterocycloalkenyls having 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyls or C2-C8 heterocycloalkenyls), 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyls or C2-C7 heterocycloalkenyls), 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyls or C2-C7 heterocycloalkenyls), 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyls or C2-C5 heterocycloalkenyls), or 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyls or C2-C4 heterocycloalkenyls). Examples of such heterocycloalkyl groups include azilidinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperadinyl, 4-piperidonyl, pyrrolidinyl Examples include, but are not limited to, 1,2-2,3In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specified herein, heterocycloalkyls may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. In some embodiments, heterocycloalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyls are optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyls are optionally substituted with halogen. As used herein, "heterocycloalkylene" refers to the divalent heterocycloalkyl groups described herein. In some embodiments, when the heterocycloalkylene includes an aryl ring or a heterocycloalkyl condensed with a heteroaryl ring, the heterocycloalkylene is bonded to the heterocycloalkyl and aryl, or to the heterocycloalkyl and heteroaryl.In some embodiments, when the heterocycloalkylene includes an aryl ring or a heterocycloalkyl condensed with a heteroaryl ring, the heterocycloalkylene is bonded only at the heterocycloalkyl.

[0029] A "heteroaryl" refers to a 5-14 membered ring group comprising 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused ring system (when fused with a cycloalkyl ring or heterocycloalkyl ring, the heteroaryl is bonded via an aromatic ring atom) or a bridging ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized, and the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indazolyl, isoindolyl, in Examples include, but are not limited to, dolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, heteroaryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryls are optionally substituted with halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with a halogen. As used herein, “heteroarylene” refers to the divalent heteroaryl group described herein. In some embodiments, if the heteroarylene includes a heteroaryl condensed with a cycloalkyl ring or a heterocycloalkyl ring, the heteroarylene is bonded in the heteroaryl and cycloalkyl, or in the heteroaryl and heterocycloalkyl. In some embodiments, if the heteroarylene includes a heteroaryl condensed with a cycloalkyl ring or a heterocycloalkyl ring, the heteroarylene is bonded only in the heteroaryl.

[0030] The terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur, and that the description includes both cases in which such event or situation occurs and cases in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Furthermore, the optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such a group is not intended to introduce substituents or substitution patterns that are sterically impractical and / or synthetically unrealizable. Therefore, it should be understood that any substituent described has a maximum molecular weight of approximately 1,000 daltons, more typically approximately 500 daltons.

[0031] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, that is effective in producing the desired therapeutic effect.

[0032] "Treatment" of an individual (e.g., a mammal such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes the administration of a pharmaceutical composition after the onset of a pathological event or contact with a pathogen, and includes stabilization of the condition (e.g., preventing the condition from worsening) or mitigation of the condition.

[0033] compound Described herein are compounds of formula (I) or (Ia) to (If), or pharmaceutically acceptable salts or stereoisomers thereof, which are useful in the treatment of diseases or disorders associated with FGFR2 and FGFR3 inhibition. In some embodiments, compounds of formula (I) or (Ia) to (If), or pharmaceutically acceptable salts or stereoisomers thereof, are useful in the treatment of diseases or disorders associated with mutant FGFR2 and mutant FGFR3 inhibition. In some embodiments, compounds of formula (I) or (Ia) to (If), or pharmaceutically acceptable salts or stereoisomers thereof, are useful in the treatment of cancer. In some embodiments, the cancer is selected from intrahepatic cholangiocarcinoma, urothelial carcinoma, gastric cancer, esophageal gastric cancer, colorectal cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, vaginal cancer, cervical cancer, glioma, head and neck cancer, other brain tumors, ovarian cancer, anal cancer, non-melanoma skin cancer, penile cancer, adrenocortical carcinoma, melanoma, ampulla cancer, Wilms' tumor, small intestine cancer, uterine sarcoma, salivary gland cancer, soft tissue sarcoma, retinoblastoma, or thyroid cancer.

[0034] In some embodiments, disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof. [ka] [In the formula, [ka] This represents a single bond or a double bond. Z 1 C(R 6 ), C(R 6 )(R 6a), O, S, N, or N(R 6N ) and Z 2 C(R 7 ), C(R 7 )(R 7a ), O, S, N, or N(R 7N ) and Z 3 C(R 8 ), C(R 8 )(R 8a ), O, S, N, or N(R 8N ) and R 1 and R 2 These are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R 3 These are, independently, halogen, -CN, -NO2, -OH, oxo, and -OR. a -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, -C(=O)R a -OC(=O)R a , -C(=O)OR b -C(=O)NR c R d -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR bC(=O)OR b 、 -NR b S(=O)2R a 、 -N=S(=O)(R b )2、 C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, C1 - C6 aminoalkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl, or C2 - C6 alkynyl, and each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 3a ; each R 3a is independently halogen, -CN, -NO2, -OH, oxo, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2. C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rs, L is a bond, -O-, -S-, -NH-, C1-C4 alkylene, or C1-C4 heteroalkylene, and the alkylene or heteroalkylene is optionally substituted with one or more Rs, n is 0, 1, 2, 3, 4, or 5, L 1 is a bond, C1-C4 alkylene, C1-C4 heteroalkylene, C2-C4 alkenylene, C2-C4 alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, and each of the alkylene, heteroalkylene, alkenylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is independently optionally substituted with one or more Rs 4a optionally substituted with, R 4 is selected from cycloalkylene, heterocycloalkylene, arylene, and heteroarylene, and the cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is optionally substituted with one or more Rs 4a optionally substituted with, Each R 4a is independently halogen, -CN, -NO2, -OH, oxo, -OR a , -OC(=O)R[[ID=​​​​​​​​​​​​​​​​b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. X is a bond, -C(=O)-, -OC(=O)-, -NR X C(=O)-, N(=NR) X ), -NR X P(=O)OR X -, -C(=S)-, -N(=O)-, -S(=O)-, -S(=O)2-, -OS(=O)-, -OS(O)2-, -NR X S(=O)-, or -NR X S(=O)²- R X Each of these is independently hydrogen, a C1-C6 haloalkyl, or a C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more Rs. R W Halogen, CN, [ka] Selected from, R11 , R 12 , and R 13 Each of these is independently selected from hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 heteroalkylene (cycloalkyl), C1-C6 heteroalkylene (heterocycloalkyl), heteroaryl, aryl, cycloalkyl, and heterocycloalkyl, and each of the alkyl, heteroalkyl, alkylene, heteroalkyl, heteroaryl, aryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R. R 6 and R 6a These are, independently, hydrogen, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b)2, selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, or R 6 and R 6a These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups. R 7 and R 7a These are, independently, hydrogen, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b)2, selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, or R 7 and R 7a These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups. R 8 and R 8a These are, independently, hydrogen, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b)2, selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, or R 8 and R 8a These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups. R 6N , R 7N , and R 8N Each of them independently consists of hydrogen, -C(=O)OR b -C(=O)R a -S(=O)R a -S(=O)2R a -C(=O)NR c R d Selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more Rs, or R 6 Or R 6N and R 7 Or R 7N These, together with the atoms to which they are bonded, form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which can be independently and optionally substituted with one or more R groups, or R 7 Or R 7N and R 8 Or R8N These, together with the atoms to which they are bonded, form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which can be independently and optionally substituted with one or more R groups. Each R a These are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. Each R b Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. R c and R dEach of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. Or, R c and R d These, together with the atoms to which they are bonded, form heterocycloalkyl groups that are optionally substituted with one or more R atoms. Each R independently represents halogen, -CN, -OH, -SF5, -SH, -S(=O)C1~C3 alkyl, -S(=O)2C1~C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1~C3 alkyl, -S(=O)2N(C1~C3 alkyl)2, -S(=O)(=NC1~C3 alkyl)(C1~C3 alkyl), -NH2, -NHC1~C3 alkyl, -N(C1~C3 alkyl)2, -N=S(=O)(C1~C3 alkyl)2, -O-C1~C4 alkylene-OH, -O-C1~C4 alkylene-NH2, -C(=O) C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, 3-6 member cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, Alternatively, two R atoms on the same atom can form an oxo.

[0035] In some embodiments, disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof. [ka] [In the formula, [ka] This represents a single bond or a double bond. Z 1 C(R 6 ), C(R 6 )(R 6a ), O, S, N, or N(R 6N ) and Z 2 C(R 7 ), C(R 7 )(R 7a ), O, S, N, or N(R 7N ) and Z 3 C(R 8 ), C(R 8 )(R 8a ), O, S, N, or N(R 8N ) and R 1 and R 2 These are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R 3 These are, independently, halogen, -CN, -NO2, -OH, oxo, and -OR. a -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, -C(=O)R a -OC(=O)R a , -C(=O)OR b -C(=O)NR c R d -OC(=O)NR c Rd -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently, one or more R 3a Replaced by optional selection, Each R 3a These are, independently, halogen, -CN, -NO2, -OH, oxo, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR bC(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. L is a bond, -O-, -S-, -NH-, C1-C4 alkylene, or C1-C4 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more Rs. n is 0, 1, 2, 3, 4, or 5. L 1 The bonds are C1-C4 alkylene, C1-C4 heteroalkylene, C2-C4 alkenylene, C2-C4 alkylylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, and each of the alkylene, heteroalkylene, alkenylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is independently one or more R 4a Replaced by optional selection, R 4 is selected from cycloalkylene, heterocycloalkylene, arylene, and heteroarylene, and the cycloalkylene, the heterocycloalkylene, the arylene, or the heteroarylene is one or more R 4a Replaced by optional selection, Each R 4a These are, independently, halogen, -CN, -NO2, -OH, oxo, and -OR. a -OC(=O)R a, -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. X is a bond, -C(=O)-, -OC(=O)-, -NR X C(=O)-, N(=NR) X ), -NR X P(=O)OR X -, -C(=S)-, -N(=O)-, -S(=O)-, -S(=O)2-, -OS(=O)-, -OS(O)2-, -NR X S(=O)-, or -NR X S(=O)²- R XEach of these is independently hydrogen, a C1-C6 haloalkyl, or a C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more Rs. R W Halogen, CN, [ka] Selected from, R 11 , R 12 , and R 13 Each is independently selected from hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, heteroaryl, aryl, cycloalkyl, and heterocycloalkyl, and each of the alkyl, heteroalkyl, heteroaryl, aryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R. R 6 and R 6a These are, independently, hydrogen, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)ORb -C(=O)NR c R d -P(=O)(R b )2, selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, or R 6 and R 6a These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups. R 7 and R 7a These are, independently, hydrogen, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR cR d -P(=O)(R b )2, selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, or R 7 and R 7a These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups. R 8 and R 8a These are, independently, hydrogen, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(Rb )2, selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, or R 8 and R 8a These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups. R 6N , R 7N , and R 8N Each of them independently consists of hydrogen, -C(=O)OR b -C(=O)R a -S(=O)R a -S(=O)2R a -C(=O)NR c R d Selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more Rs, or R 6 Or R 6N and R 7 Or R 7N These, together with the atoms to which they are bonded, form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which can be independently and optionally substituted with one or more R groups, or R 7 Or R 7N and R 8Or R 8N These, together with the atoms to which they are bonded, form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which can be independently and optionally substituted with one or more R groups. Each R a These are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. Each R b Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. R c and R dEach of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. Or, R c and R d These, together with the atoms to which they are bonded, form heterocycloalkyl groups that are optionally substituted with one or more R atoms. Each R independently represents halogen, -CN, -OH, -SF5, -SH, -S(=O)C1~C3 alkyl, -S(=O)2C1~C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1~C3 alkyl, -S(=O)2N(C1~C3 alkyl)2, -S(=O)(=NC1~C3 alkyl)(C1~C3 alkyl), -NH2, -NHC1~C3 alkyl, -N(C1~C3 alkyl)2, -N=S(=O)(C1~C3 alkyl)2, -O-C1~C4 alkylene-OH, -O-C1~C4 alkylene-NH2, -C(=O) C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, 3-6 member cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, Alternatively, two R atoms on the same atom can form an oxo.

[0036] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, each [ka] These are, independently, single or double bonds.

[0037] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] In some embodiments, Z 1 C(R 6 ) or N, Z 2 C(R 7 )(R 7a ), O, S, or N(R 7N ) and Z 3 C(R 8 )(R 8a ), O, S, or N(R 8N )

[0038] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] In some embodiments, Z 1 C(R 6 )(R 6a ), O, S, or N(R 6N ) and Z 2 C(R 7 ) or N, Z 3 C(R 8 ) or N.

[0039] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] (that is, both) [ka] ( is a double bond). In some embodiments, Z 1 C(R 6 ) or N, Z 2 C(R 7 ) or N, Z 3 C(R 8 ) or N.

[0040] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, Z 1 C(R 6 ) is. In some embodiments, Z 1 is C(R 6 )(R 6a ) is. In some embodiments, Z 1 In some embodiments, Z 1 In some embodiments, Z 1 In some embodiments, Z 1 is N(R 6N )

[0041] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, Z 2 C(R 7 ) is. In some embodiments, Z 2 is C(R 7 )(R 7a ) is. In some embodiments, Z 2 In some embodiments, Z 2 In some embodiments, Z2 In some embodiments, Z 2 is N(R 7N )

[0042] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, Z 3 C(R 8 ) is. In some embodiments, Z 3 is C(R 8 )(R 8a ) is. In some embodiments, Z 3 In some embodiments, Z 3 In some embodiments, Z 3 In some embodiments, Z 3 is N(R 8N )

[0043] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, R 1 and R 2 R is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 1 and R 2 R is independently selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, R 1 is hydrogen, R 2 R is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 1 is hydrogen, R 2 R is selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, R 1 and R 2 Both are hydrogen.

[0044] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, the compound has the structure of formula (Ia). [ka]

[0045] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, the compound has the structure of formula (Ib). [ka]

[0046] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, the compound has the structure of formula (Ic). [ka]

[0047] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, the compound has the structure of formula (Id). [ka]

[0048] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, the compound has the structure of formula (Ie). [ka]

[0049] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, the compound has the structure of formula (If). [ka]

[0050] In some embodiments, disclosed herein are compounds of formula (I-1), pharmaceutically acceptable salts thereof, or stereoisomers. [ka] [In the formula, R Z4 R 8 And, Ring A, R 1 , R 2 , R 3 , R 4 , R 8 , R W , L 1 X, Z 1 , Z 2 , Z 3 , and n have the meanings described herein. In some embodiments, R Z4 It is either hydrogen or a halogen.

[0051] In some embodiments, disclosed herein are compounds of formula (II-1), (II-2), or (II-3), or pharmaceutically acceptable salts or stereoisomers thereof. [ka] [In the formula, Z 4 C(R Z4 ), C(R Z4 )(R Z4a ), O, S, N, or N(R Z4N ) and R Z4 R 8 And R Z4a R 8a And R Z4N R 8N And, Ring A, R 1 , R 2 , R 3 , R 4 , R 8 , R 8a , R 8N , R W , L 1 X, Z 1 , Z 2 , Z 3 , and n have the meanings described herein. In some embodiments, R Z4 and R Z4aEach is independently hydrogen or halogen. In some embodiments, R Z4N It is hydrogen.

[0052] In some embodiments, disclosed herein are compounds of formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or pharmaceutically acceptable salts or stereoisomers thereof. [ka] [In the formula, rings A, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R W , L 1 X and n have the meanings set forth herein.

[0053] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 R is selected from hydrogen, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R.

[0054] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 R is selected from hydrogen, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl, where each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R.

[0055] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 It is hydrogen.

[0056] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 It is a halogen.

[0057] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 は-OR a In some embodiments, R a is a C1-C6 alkyl group. In some embodiments, R ais a C1-C3 alkyl group. In some embodiments, R a is CH3. In some embodiments, R in the formula 6 It is -OCH3.

[0058] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 R is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, or C1-C6 hydroxyalkyl, and the alkyl is independently and optionally substituted with one or more R. In some embodiments, R 6 R is a C1-C6 alkyl or C1-C6 hydroxyalkyl, and the alkyl is independently and optionally substituted with one or more R. In some embodiments, R 6 R is a C1-C6 alkyl, a C1-C6 heteroalkyl, or a C1-C6 hydroxyalkyl, and the alkyl is independently and optionally substituted with one or more R. In some embodiments, R 6 is a C1-C6 alkyl group. In some embodiments, R 6 is CH3. In some embodiments, R 6 is a C1-C6 heteroalkyl group. In some embodiments, the C1-C6 heteroalkyl group contains one or more heteroatoms selected from N, S, and O. In some embodiments, the C1-C6 heteroalkyl group contains one or two oxygen atoms. In some embodiments, R 6 is -CH2CH2OCH3. In some embodiments, R 6 is a C1-C6 hydroxyalkyl group. In some embodiments, R 6 It is -CH2CH2OH.

[0059] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 R is a C2-C6 alkynyl, and the alkynyl is optionally replaced by one or more R. In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] That is the case.

[0060] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 R is a 3-6 member cycloalkyl or 3-6 member heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is independently and optionally substituted with one or more Rs.

[0061] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 R is a 3-6 membered cycloalkyl group, and the cycloalkyl group is independently and optionally substituted with one or more R groups. In some embodiments, R 6 teeth, [ka] That is the case.

[0062] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 R is a 3- to 6-membered heterocycloalkyl group, and the heterocycloalkyl group is independently and optionally substituted with one or more R groups. In some embodiments, R 6 R is a 3-6 membered heterocycloalkyl, which is independently and optionally substituted with one or more Rs, and which contains one or two heteroatoms selected from N, S, and O. In some embodiments, R 6 R is a 3-6 member heterocycloalkyl, which is independently and optionally substituted with one or more Rs, and which contains one or two Ns. In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] That is the case.

[0063] In some embodiments of compounds of formula (I), (Ib), (Ic), (Id), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIb), (IId), (IIe), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 6 R is a phenyl or a 5-membered or 6-membered heteroaryl, which is independently and optionally substituted with one or more Rs. In some embodiments, R 6 R is a phenyl or a five-membered or six-membered heteroaryl, which is independently and optionally substituted with one or more Rs, and the heteroaryl contains one, two, three or four heteroatoms selected from N, S and O. In some embodiments, R 6 R is a 6-membered heteroaryl, which is independently and optionally substituted with one or more Rs. In some embodiments, R 6 is a 5-membered heteroaryl, which is independently and optionally substituted with one or more Rs, and which contains one, two or three heteroatoms selected from N, S, and O. In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] That is the case.

[0064] In some embodiments of compounds of formula (I), (Ia), (Ic), (Ie), (If), (I-1), (II-1), (II-2), (II-3), (IIb), (IIc), (IId), or (IIf), or their pharmaceutically acceptable salts or stereoisomers, R 7 R is selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and the alkyl is independently and optionally substituted with one or more R. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 R is a C1-C6 alkyl or C1-C6 haloalkyl, and the alkyl is independently and optionally substituted with one or more R. In some embodiments, R 7 R is a C1-C6 alkyl group, and the alkyl group is independently and optionally substituted with one or more R groups. In some embodiments, R 7 This is CH3.

[0065] In some embodiments of compounds of formula (I), (Ia), (Ib), (If), (I-1), (II-1), (II-2), (II-3), (IIa), (IIc), or (IIe), or their pharmaceutically acceptable salts or stereoisomers, R 8 R is selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and the alkyl is independently and optionally substituted with one or more R. In some embodiments, R 8 It is hydrogen.

[0066] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), or (II-3), or their pharmaceutically acceptable salts or stereoisomers, R 6a R is selected from hydrogen, halogens, C1-C6 alkyls, and C1-C6 haloalkyls. In some embodiments, R 6a It is hydrogen.

[0067] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), or (II-3), or their pharmaceutically acceptable salts or stereoisomers, R 7a R is selected from hydrogen, halogens, C1-C6 alkyls, and C1-C6 haloalkyls. In some embodiments, R 7a It is hydrogen.

[0068] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), or (II-3), or their pharmaceutically acceptable salts or stereoisomers, R 8a R is selected from hydrogen, halogens, C1-C6 alkyls, and C1-C6 haloalkyls. In some embodiments, R 8a It is hydrogen.

[0069] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), or (II-3), or their pharmaceutically acceptable salts or stereoisomers, R 6 and R 6a These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups.

[0070] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), or (II-3), or their pharmaceutically acceptable salts or stereoisomers, R 7 and R 7a These, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups.

[0071] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), or (II-3), or their pharmaceutically acceptable salts or stereoisomers, R 8 and R 8aThese, together with the carbon atoms to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups.

[0072] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), or (II-3), or their pharmaceutically acceptable salts or stereoisomers, R 6N R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some embodiments, R 6N R is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 6N It is hydrogen.

[0073] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), or (II-3), or their pharmaceutically acceptable salts or stereoisomers, R 7N R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some embodiments, R 7N R is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 7N It is hydrogen.

[0074] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), or (II-3), or their pharmaceutically acceptable salts or stereoisomers, R 8NR is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some embodiments, R 8N R is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 8N It is hydrogen.

[0075] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia), or (If), or their pharmaceutically acceptable salts or stereoisomers, R 7 or R 7N and R 8 or R 8N These, together with the atoms to which they are bonded, form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which can be independently and optionally substituted with one or more R groups.

[0076] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ic), or (If), or their pharmaceutically acceptable salts or stereoisomers, R 6 or R 6N and R 7 or R 7N These, together with the atoms to which they are bonded, form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which can be independently and optionally substituted with one or more R groups.

[0077] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3) or (Ia)-(If) or (IIa)-(IIf), or their pharmaceutically acceptable salts or stereoisomers, ring A is a cycloalkyl or heterocycloalkyl. In some embodiments, ring A is a 3- to 6-membered cycloalkyl. In some embodiments, ring A is a 3- to 6-membered heterocycloalkyl.

[0078] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), (II-3) or (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, ring A is phenyl. In some embodiments, [ka] teeth, [ka] In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] And R 31 and R 32 Each of these is independently R 3 Selected from: In some embodiments, [ka] teeth, [ka] And R 31 and R 33 Each of these is independently R 3 Selected from: In some embodiments, [ka] teeth, [ka] And R 32 and R 34 Each of these is independently R 3 Selected from. In some embodiments, R 32 These are halogen, -CN, -NO2, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, and each alkyl or heteroalkyl independently contains one or more R 3a It is optionally replaced by R. In some embodiments, 32 is a halogen. In some embodiments, R 32 is -F. In some embodiments, R 31 -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently comprises one or more R 3a It is optionally replaced by R. In some embodiments, 31 is one or more R 3a It is an -O-heteroaryl that is optionally substituted. In some embodiments, R 31 is one or more R 3a It is an optional substitution -O- (5-membered or 6-membered heteroaryl). In some embodiments, R 31 is one or more R 3a It is a -O-6 member heteroaryl that is optionally substituted.

[0079] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3) or (Ia)-(If) or (IIa)-(IIf), or their pharmaceutically acceptable salts or stereoisomers, ring A is a 5- to 6-membered heteroaryl. In some embodiments, ring A is a 6-membered heteroaryl. In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] That is the case.

[0080] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3) or (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, each R 3 These are, independently, halogen, -CN, -NO2, -OH, oxo, and -OR. a -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, -C(=O)R a -OC(=O)R a , -C(=O)OR b -C(=O)NR c R d -OC(=O)NR c Rd -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a The C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, and each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently comprises one or more R 3a It is optionally replaced by R. In some embodiments, each R 3 These are, independently, halogen, -CN, -OH, and -OR a -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, -C(=O)R a -C(=O)NR c R d -S(=O)R a -S(=O)2R a , -NR c R d , -NR b C(=O)R a The C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, and each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently comprises one or more R 3a It is optionally replaced by R. In some embodiments, each R 3 These are independently halogens, -L-phenyls, -L-5-membered or 6-membered heteroaryls, -L-3-membered or 6-membered heterocycloalkyls, and -C(=O)NR c R d , and selected from C1-C6 alkyl groups, each alkyl, heterocycloalkyl, phenyl, and heteroaryl independently, one or more R 3a It is optionally replaced by R. In some embodiments, each R 3These are independently halogens, -L-5-membered or 6-membered heteroaryls, -L-3-membered or 6-membered heterocycloalkyls, and -C(=O)NR c R d , and selected from C1-C6 alkyl groups, each alkyl, heterocycloalkyl, and heteroaryl group independently comprises one or more R 3a It will be replaced by an optional choice.

[0081] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, one or more R 3 is a halogen. In some embodiments, one or more R 3 is F. In some embodiments, one or more R 3 It is Cl.

[0082] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, one or more R 3 The alkyl group is C1-C6 alkyl, and the alkyl group may have one or more R 3a It is optionally replaced. In some embodiments, one or more R 3 The alkyl group is C1-C3 alkyl, and the alkyl group may have one or more R 3a It is optionally replaced. In some embodiments, one or more R 3 This is CH3.

[0083] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, one or more R 3 is a -L-heterocycloalkyl, and the heterocycloalkyl is one or more R 3a It is optionally replaced. In some embodiments, one or more R3 is an -L-heterocycloalkyl, the heterocycloalkyl is a monocyclic or bicyclic ring, and the heterocycloalkyl is one or more R 3a It is optionally replaced. In some embodiments, one or more R 3 is a -L-heterocycloalkyl, wherein the heterocycloalkyl is a fused ring, a spiro ring, a crosslinking ring, or any combination thereof, and the heterocycloalkyl is one or more R 3a It is optionally replaced. In some embodiments, one or more R 3 is a -L-heterocycloalkyl, wherein the heterocycloalkyl comprises one, two, or three heteroatoms selected from N, S, and O, and the heterocycloalkyl comprises one or more R 3a It is optionally replaced. In some embodiments, one or more R 3 is a -L-heterocycloalkyl, and the heterocycloalkyl is one or more R 3a Replaced by choice [ka] That is the case.

[0084] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, one or more R 3 is a -L-5-membered or 6-membered heteroaryl, wherein the heteroaryl is one or more R 3a It is optionally replaced. In some embodiments, one or more R 3 is a -L-5-membered or 6-membered heteroaryl, wherein the heteroaryl is one or more R 3a The heteroaryl is optionally substituted, and the heteroaryl comprises one, two, three, or four heteroatoms selected from the group consisting of N, S, and O. In some embodiments, one or more R 3 is a -L-5-membered or 6-membered heteroaryl, wherein the heteroaryl is one or more R3a The heteroaryl is optionally substituted, and contains one, two, or three Ns. In some embodiments, one or more Rs 3 is a -L-5-membered or 6-membered heteroaryl, wherein the heteroaryl is one or more R 3a The heteroaryl is optionally substituted and contains one N. In some embodiments, one or more R 3 is a -L-5-membered or 6-membered heteroaryl, wherein the heteroaryl is one or more R 3a The heteroaryl is optionally substituted and contains two Ns. In some embodiments, one or more Rs 3 is a -L-5 member heteroaryl, and the heteroaryl is one or more R 3a It is optionally replaced. In some embodiments, one or more R 3 is a -L-6 member heteroaryl, and the heteroaryl is one or more R 3a It is optionally replaced. In some embodiments, one or more R 3 is a -L-6 member heteroaryl, and the 6 member heteroaryl is one or more R 3a Replaced by choice [ka] That is the case.

[0085] In some embodiments of the compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If), or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, each R 3a R is independently selected from halogens, C1-C6 alkyls, or C1-C6 haloalkyls. In some embodiments, each R 3a is a halogen. In some embodiments, R 3a is F. In some embodiments, each R 3a R is a C1-C6 alkyl group. In some embodiments, each R 3a is a C1-C3 alkyl group. In some embodiments, R3a This is CH3.

[0086] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, one or more R 3 is a -L-6 member heteroaryl, and this 6 member heteroaryl is [ka] It is selected from the group consisting of the following.

[0087] In some embodiments of the compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If), or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, L is a bond, -O-, -S-, -NH-, a C1~C4 alkylene, or a C1~C4 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more Rs. In some embodiments, L is -O-. In some embodiments, L is a C1~C4 alkylene optionally substituted with one or more Rs (e.g., L is -C(=O)-). In some embodiments, L is a C1~C4 heteroalkylene optionally substituted with one or more Rs (e.g., L is -C(=O)NHCH2-).

[0088] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, one or more R 3 is -C(=O)NR c R d In some embodiments, one or more R 3 is -C(=O)NR c R d And each R c and R dHowever, each alkyl, alkyl, cycloalkyl, and heterocycloalkyl are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl), and C1-C6 alkylene (heterocycloalkyl), and each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments, one or more R 3 is -C(=O)NR c R d And each R c and R d However, each alkyl, alkylene, and heterocycloalkyl group is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 alkylene (heterocycloalkyl), and each alkyl, alkylene, and heterocycloalkyl group is independently optionally substituted with one or more R groups.

[0089] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, one or more R 3 is -C(=O)NHR d In some embodiments, one or more R 3 -C(=O)NHR d And R d R is a C1-C6 alkyl group, and the alkyl group is optionally substituted with one or more R groups. In some embodiments, R 3 teeth, [ka] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, one or more R 3 is -C(=O)NHR d In some embodiments, one or more R 3is -C(=O)NHR d And R d However, the R is C1-C6 alkylene (heterocycloalkyl), and each alkyl, alkylene, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments, one or more R 3 is -C(=O)NHR d And R d However, the C1-C6 alkylene (heterocycloalkyl) is a C1-C6 alkylene (heterocycloalkyl), and each alkyl, alkylene, and heterocycloalkyl is independently and optionally substituted with one or more R, and the heterocycloalkyl is a 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N, S, and O. In some embodiments, R 3 is -C(=O)NHR d And each R d However, it is a C1-C6 alkylene (heterocycloalkyl), and the heterocycloalkyl is optionally substituted with one or more Rs, and the heterocycloalkyl is [ka] Each R is independently selected from halogens, C1-C3 alkyls, and C1-C3 haloalkyls. In some embodiments, R 3 teeth, [ka] That is the case.

[0090] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, one or more R 3 is -C(=O)NR c R d And R c and R d However, together with the atoms to which they are bonded, they form heterocycloalkyl groups that are optionally substituted with one or more R groups. In some embodiments, one or more R groups3 is -C(=O)NR c R d And R c and R d However, together with the atoms to which they are bonded, they form a heterocycloalkyl that is optionally substituted with one or more R atoms, and the heterocycloalkyl contains one, two or three heteroatoms selected from the group consisting of N, O and S. In some embodiments, one or more R 3 is -C(=O)NR c R d And R c and R d However, together with the atoms to which they are bonded, they form a heterocycloalkyl that is optionally substituted with one or more R atoms, and the heterocycloalkyl contains one, two or three heteroatoms selected from the group consisting of N and O. In some embodiments, one or more R 3 is -C(=O)NR c R d And R c and R d However, together with the atoms to which they are bonded, they form a heterocycloalkyl that is optionally substituted with one or more R atoms, and the heterocycloalkyl contains one nitrogen atom and one oxygen atom. In some embodiments, one or more R atoms 3 is -C(=O)NR c R d And R c and R d However, together with the atoms to which they are bonded, they form a heterocycloalkyl that is optionally substituted with one or more R, and the heterocycloalkyl is a monocyclic, bicyclic, or tricyclic ring system. In some embodiments, R 3 is -C(=O)NR c R d And R c and R d However, together with the atoms to which they are bonded, they form a heterocycloalkyl that is optionally substituted with one or more R, and the heterocycloalkyl is a fused ring system, a spiro ring system, or a bridging ring system. In some embodiments, R 3 is -C(=O)NRc R d And R c and R d However, together with the atoms to which they are bonded, they form a heterocycloalkyl that is optionally substituted with one or more R atoms, and the heterocycloalkyl is [ka] In some embodiments, R 3 teeth, [ka] That is the case.

[0091] In some embodiments of the compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If), or (IIa)-(IIf), or their pharmaceutically acceptable salts or stereoisomers, R is independently selected from halogens, C1-C3 alkyls, or C1-C3 haloalkyls. In some embodiments, R is a halogen. In some embodiments, R is F. In some embodiments, R is a C1-C3 alkyl. In some embodiments, R is CH3.

[0092] In some embodiments of the compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 0.

[0093] In some embodiments of compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If), or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0094] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, L 1The bonds are C1-C4 alkylene, C1-C4 heteroalkylene, C2-C4 alkenylene, C2-C4 alkylylene, 3-6 membered cycloalkylene, 3-6 membered heterocycloalkylene, phenylene, or 5-6 membered heteroarylene, and each of the alkylene, heteroalkylene, alkenylene, cycloalkylene, heterocycloalkylene, phenylene, or heteroarylene is independently one or more R 4a It will be replaced by an optional choice.

[0095] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, L 1 It is a combination.

[0096] In some embodiments of the compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia) to (If), or their pharmaceutically acceptable salts or stereoisomers, L 1 is a C2-C4 alkynylene. In some embodiments, L 1 teeth, [ka] That is the case.

[0097] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, L 1 is one or more R 4a This is phenylene that is optionally substituted.

[0098] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, L 1 is one or more R 4aIn some embodiments, L 1 is one or more R 4a A 5-6 membered heteroarylene is optionally substituted, and the 5-6 membered heteroarylene contains one, two, three, or four heteroatoms selected from the group consisting of N, S, and O. In some embodiments, L 1 is one or more R 4a A 5-6 member heteroarylene is optionally substituted, and the 5-6 member heteroarylene contains 1, 2, 3, or 4 N atoms. In some embodiments, L 1 is one or more R 4a It is a 6-membered heteroarylene that is optionally substituted. In some embodiments, L 1 is one or more R 4a It is a 5-membered heteroarylene that is optionally substituted. In some embodiments, L 1 R 4a Replaced by choice [ka] That is the case.

[0099] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 4 It is a monocyclic ring. In some embodiments, R 4 It is a biring ring. In some embodiments, R 4 It is a triring ring.

[0100] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 4 R is a fused ring, a spiro ring, or a crosslinking ring. In some embodiments, R 4 It is a 6-5 or 5-6 fused ring.

[0101] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 4 is one or more R 4a It is an arylene that is optionally replaced by R. In some embodiments, 4 is one or more R 4a It is phenylene which is optionally substituted. In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0102] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 4 is one or more R 4a It is a bicyclic arylene that is optionally substituted. In some embodiments, the bicyclic arylene is one or more R 4a The arylene comprises phenyl condensed with a cycloalkyl or heterocycloalkyl which is optionally substituted. In some embodiments, the arylene is one or more R 4aIt includes phenyl condensed with a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl optionally substituted with 4 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0103] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If) or (IIa)-(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 4 is heteroarylene optionally substituted with one or more R 4a In some embodiments, R 4 is heteroarylene optionally substituted with one or more R 4aIt is a bicyclic heteroarylene that is optionally substituted. In some embodiments, the heteroarylene is a monocyclic ring. In some embodiments, the bicyclic heteroarylene is one or more R 4a The heteroaryl is condensed with a cycloalkyl or heterocycloalkyl which is optionally substituted. In some embodiments, the bicyclic heteroarylene is one or more R 4a The heteroaryl comprises a heteroaryl condensed with a 5-6 member cycloalkyl or 5-6 member heterocycloalkyl which is optionally substituted. In some embodiments, the bicyclic heteroarylene comprises a heteroaryl condensed with a cycloalkyl or heterocycloalkyl, wherein the heteroaryl is L 1 A cycloalkyl or heterocycloalkyl is bonded to X. In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0104] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 4 is one or more R 4a It is a cycloalkylene that is optionally substituted. In some embodiments, R 4 is one or more R4a A cycloalkylene is optionally substituted, and the cycloalkylene is a condensed ring. In some embodiments, R 4 is one or more R 4a A cycloalkylene which is optionally substituted, wherein the cycloalkylene comprises a cycloalkyl ring fused with a heteroaryl ring. In some embodiments, L 1 The R of the cycloalkyl ring 4 Binding to, on the other hand, X is R of the heteroaryl ring. 4 It is coupled to R. In some embodiments, 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0105] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 4 is one or more R 4a It is a heterocycloalkylene that is optionally substituted. In some embodiments, R 4 is one or more R 4a It is a 4-6 member monocyclic heterocycloalkylene that is optionally substituted. In some embodiments, R 4 is one or more R 4a It is a bicyclic heterocycloalkylene that is optionally substituted with R. In some embodiments, 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0106] In some embodiments of the compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If), or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, each R 4a These are, independently, halogen, -CN, -NO2, -OH, oxo, and -OR. a -OC(=O)R a , -OC(=O)OR b , -NR c R d -C(=O)R a The R groups are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, and each alkyl or heteroalkyl group is independently and optionally substituted with one or more R groups. In some embodiments, each R group is... 4a R is independently selected from halogens, C1-C6 alkyls, and C1-C6 haloalkyls. In some embodiments, R4a is a halogen. In some embodiments, R 4a is a C1-C6 alkyl group. In some embodiments, R 4a These are C1-C6 haloalkyl groups.

[0107] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, -L 1 -R 4 -teeth, [ka] Selected from. In some embodiments, -L 1 -R 4 -teeth, [ka] Selected from. In some embodiments, -L 1 -R 4 -teeth, [ka] In some embodiments, -L 1 -R 4 -teeth, [ka] In some embodiments, -L 1 -R 4 -teeth, [ka] In some embodiments, -L 1 -R 4 -teeth, [ka] In some embodiments, -L 1 -R 4 -teeth,

Chem.

Chem.

Chem.

Chem.

Chem.

[0108] In some embodiments of the compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, X is a bond.

[0109] In some embodiments of the compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If), or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, X is -C(=O)-.

[0110] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, X is -NR X C(=O)- is the case in some embodiments, each R X R is independently hydrogen, a C1-C6 haloalkyl, or a C1-C6 alkyl. In some embodiments, R X is hydrogen. In some embodiments, X is -NHC(=O)-. In some embodiments, X is -S(=O)- or -S(=O)2-. In some embodiments, X is -NR X S(=O)- or -NR X S(=O)²⁻

[0111] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R W teeth [ka] That is the case.

[0112] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R W teeth [ka] And here, R 11 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments, R W teeth, [ka] And here, R 11 It is hydrogen.

[0113] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 12 R is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl, and the alkyl and heteroalkyl are optionally substituted with one or more R. In some embodiments, R 12 R is selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 hydroxyalkyl, and the alkyl and heteroalkyl are optionally substituted with one or more R.

[0114] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 12 It is hydrogen.

[0115] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 12 This is a halogen (for example, F).

[0116] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 12 R is a C1-C6 alkyl group, and the alkyl group is optionally substituted with one or more R groups. In some embodiments, R 12 It is CH3.

[0117] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 12 R is a C1-C6 alkyl group, which is optionally substituted with one or more R groups, where R is selected from -CN, -OH, SH, -NH2, -NHC1-C3 alkyl groups, and -N(C1-C3 alkyl)2. In some embodiments, R 12 is a C1-C6 hydroxyalkyl group. In some embodiments, R 12 It is -CH2OH.

[0118] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 13 R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 heteroalkylene (cycloalkyl), and C1-C6 heteroalkylene (heterocycloalkyl), and the alkyl, heteroalkyl, alkylene, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments, R 13 The elements are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 heteroalkylene (cycloalkyl), or C1-C6 heteroalkylene (heterocycloalkyl), and each of these can be optionally substituted.

[0119] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R13 R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl, and the alkyl and heteroalkyl are optionally substituted with one or more R.

[0120] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 13 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl.

[0121] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 13 It is hydrogen.

[0122] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 13 R is a C1-C6 heteroalkyl. In some embodiments, R 13 R is a C1-C6 alkyl group, which is optionally substituted with one or more R groups, where R is selected from -CN, -OH, SH, -NH2, -NHC1-C3 alkyl groups, and -N(C1-C3 alkyl)2. In some embodiments, R 13 The alkyl group is C1-C6 alkyl, and this alkyl group is optionally substituted with -N(C1-C3 alkyl)2.

[0123] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 13is a C1-C6 heteroalkyl that is optionally substituted. In some embodiments, R 13 is a C1-C6 heteroalkyl group, and the heteroalkyl group contains one, two, or three heteroatoms selected from N, S, and O. In some embodiments, R 13 is a C1-C6 heteroalkyl group, and the heteroalkyl group contains one or two N atoms. In some embodiments, R 13 is a C1-C6 heteroalkyl group, and the heteroalkyl group contains N. In some embodiments, R 13 This is -CH2CH2N(CH3)2.

[0124] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 13 The elements are C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 heteroalkylene (cycloalkyl), and C1-C6 heteroalkylene (heterocycloalkyl), where each of the alkylene, heteroalkylene, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R.

[0125] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R 13 R is a C1-C6 alkylene (heterocycloalkyl) or a C1-C6 heteroalkylene (heterocycloalkyl), where each of the alkylene, the heteroalkylene, and the heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R 13 This is a C1-C6 alkylene (heterocycloalkyl) that can be optionally substituted, for example, [ka] In some embodiments, R 13 These are C1-C6 heteroalkylenes (heterocycloalkyls) that are optionally substituted, for example, [ka] That is the case.

[0126] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R W teeth [ka] In some embodiments, R W teeth, [ka] In some embodiments, R W teeth, [ka] And here, R 11 is a C1-C6 alkyl group. In some embodiments, R W teeth, [ka] That is the case.

[0127] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, R W is CN. In some embodiments, R W It is a halogen.

[0128] In some embodiments of compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf), or their pharmaceutically acceptable salts or stereoisomers, -XR W , CN, [ka] Selected from. In some embodiments, -XR W , CN, [ka] Selected from. In some embodiments, -XR W is CN. In some embodiments, -XR W teeth, [ka] In some embodiments, or in pharmaceutically acceptable salts or stereoisomers thereof, -XR W teeth, [ka] In some embodiments, -XR W teeth, [ka] In some embodiments, -XR W teeth, [ka] In some embodiments, -XR W teeth, [ka] In some embodiments, -XR W teeth, [ka] In some embodiments, -XRW teeth, [ka] In some embodiments, -XR W teeth, [ka] In some embodiments, -XR W teeth, [ka] In some embodiments, -XR W teeth, [ka] In some embodiments, -XR W teeth, [ka] In some embodiments, -XR W teeth, [ka] In some embodiments, -XR W teeth, [ka] That is the case.

[0129] In some embodiments of the compounds disclosed herein, each R aR is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl), or C1-C6 alkylene (heterocycloalkyl), and each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, a C1-C6 haloalkyl, a cycloalkyl, or a heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a These are independently C1-C6 alkyl groups.

[0130] In some embodiments of the compounds disclosed herein, each R bR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl), or C1-C6 alkylene (heterocycloalkyl), and each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each R b These are independently C1-C6 alkyl groups.

[0131] In some embodiments of the compounds disclosed herein, R c and R dEach of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl), or C1-C6 alkylene (heterocycloalkyl), and each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a cycloalkyl, or a heterocycloalkyl. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, R c and R d R is hydrogen, respectively. In some embodiments of the compounds disclosed herein, c and R d Each of these is independently a C1-C6 alkyl group.

[0132] In some embodiments of the compounds disclosed herein, R c and R d These atoms, together with the atoms to which they are bonded, form heterocycloalkyl groups that are optionally substituted with one or more R atoms.

[0133] In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -NH2, -NHC1~C3 alkyl, -N(C1~C3 alkyl)2, -C(=O)C1~C3 alkyl, -C(=O)OH, -C(=O)OC1~C3 alkyl, -C(=O)NH2, -C(=O)NHC1~C3 alkyl, -C(=O)N(C1~C3 alkyl)2, C1~C3 alkyl, C1~C3 alkoxy, C1~C3 haloalkyl, C1~C3 haloalkoxy, C1~C3 hydroxyalkyl, C1~C3 aminoalkyl, C1~C3 heteroalkyl, or a C3~C6 cycloalkyl optionally substituted with one or more halogens. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or a C3-C6 cycloalkyl optionally substituted with one or more halogens. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -NH2, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -NH2, or C1-C3 alkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen or a C1-C3 alkyl.

[0134] In one embodiment, the compounds disclosed herein are those of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If), or (IIa)~(IIf). In one embodiment, the compounds disclosed herein are those of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If), or (IIa)~(IIf). In one embodiment, the stereoisomers of the compounds of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If), or (IIa)~(IIf).

[0135] In some embodiments of the compounds disclosed herein, R, R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , R 6 , R 6a , R 6N , R 7 , R 7a , R 7N , R 8 , R 8a , R 8N , R 11 , R 12 , R 13 X, L, L 1 , R W , R a , R b , R c , and / or R d One or more of the groups contain deuterium at a higher percentage than the naturally occurring abundance of deuterium.

[0136] In some embodiments of the compounds disclosed herein, the following groups are present: R, R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , R 6 , R 6a , R 6N , R 7 , R 7a , R 7N , R 8, R 8a , R 8N , R 11 , R 12 , R 13 X, L, L 1 , R W , R a , R b , R c , and R d In one or more of these, one or more 1 H is replaced by one or more deuterium atoms.

[0137] In some embodiments of the compounds disclosed herein, R, R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , R 6 , R 6a , R 6N , R 7 , R 7a , R 7N , R 8 , R 8a , R 8N , R 11 , R 12 , R 13 X, L, L 1 , R W , R a , R b , R c , and / or R d The amount of deuterium present in each of these is, independently, at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0138] In some embodiments of the compounds disclosed herein, one or more rings A 1 H can be replaced by one or more deuterium atoms.

[0139] Any combination of the above groups for various variables is contemplated herein. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0140] Any combination of the above groups for various variables is contemplated herein. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0141] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts or stereoisomers, are one of the compounds listed in Table 1. [Table 1-1] [Table 1-2]

[0142] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts or stereoisomers, are one of the compounds listed in Table 2 or Table 3. [Table 2-1] [Table 2-2] [Table 3]

[0143] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, as well as corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered together with a resolving agent by any practical means that does not result in racemization.

[0144] isotopically enriched compounds Unless otherwise stated, the compounds described herein may exhibit their natural isotopic abundances, or one or more of their atoms may be artificially enriched as specific isotopes having the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure. For example, hydrogen has three naturally occurring isotopes, 1 H (protium), 2 H (deuterium), and 3 It is called H (tritium). Protium is the most abundant isotope of hydrogen in nature. The enrichment of deuterium may yield several therapeutic benefits, such as increased in vivo half-life and / or exposure, or may yield compounds useful for studying the in vivo pathways of drug excretion and metabolism.

[0145] For example, the compounds described herein may be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes that are not primarily found in nature. In some embodiments, the compounds described herein may be artificially enriched with deuterium ( 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 One or more isotopes selected from C) can be artificially enriched. In some embodiments, the compounds described herein are 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S,35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 One or more isotopes selected from I are artificially enriched. In some embodiments, the abundance of the enriched isotope is, independently, at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0146] In some embodiments, the compound is deuterated at at least one position. In some embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 It can be replaced by an H atom.

[0147] Methods for synthesizing deuterium-containing compounds are known in the art and include, but are not limited to, the procedures described in U.S. Patents No. 5,846,514 and No. 6,334,997, as well as the following synthesis methods. For example, deuterium-substituted compounds can be synthesized using various methods, including those described below: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0148] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0149] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a number of inorganic or organic bases, as well as either inorganic or organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified compound in its free form separately with a suitable acid or base and then isolating the salts thus formed.

[0150] Examples of pharmaceutically acceptable salts include salts prepared by the reaction of the compounds described herein with minerals, organic acids, or inorganic bases, such as acetates, acrylates, adipicates, alginates, aspartates, benzoates, benzenesulfons, bisulfites, bromides, butyrates, butyn-1,4-dioate, camphorates, camphorsulfons, capronates, caprylates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-dioate, hydroxybenzoates, γ-hydroxybutyrates, hydrochlorides, and bromine. Examples include hydrochlorides, hydroiodides, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malons, methanesulfonates, mandelates, metaphosphates, methanesulfonates, methoxybenzoates, methylbenzoates, monohydrogen phosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, palmoate, pectinates, persulfates, 3-phenylpropionates, phosphates, picrinates, pivalates, propions, pyrosulfates, pyrophosphates, propiolates, phthalates, phenylacetates, phenylbutyrates, propanesulfonates, salicylates, succinates, sulfates, sulfites, succinates, suberinates, sebacinates, sulfonates, tartrates, thiocyanates, tosylates, undecanoates, and xylenesulfonates.

[0151] Furthermore, the compounds described herein include inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc., and organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy These compounds can be prepared as pharmaceutically acceptable salts formed by reacting them with pharmaceutically acceptable inorganic or organic acids, including but not limited to ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octa-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, which are not pharmaceutically acceptable in themselves, are used to prepare salts that are useful as intermediates in obtaining the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.

[0152] In some embodiments, the compounds described herein that contain free acid groups react with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, or sulfate, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Typical salts include alkali salts or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Specific examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2. + (C 1~4 Examples include alkyl(4) and others.

[0153] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing group contained in the compound. In some embodiments, water-soluble or oil-soluble or water-dispersible or oil-dispersible products are obtained by such quaternization.

[0154] solvate In some embodiments, the compounds described herein exist as solvates. In some embodiments, the disclosure provides a method for treating a disease by administering a compound in such a solvate form. In some embodiments, the disclosure provides a method for treating a disease by administering a composition comprising a compound in such a solvate form. The solvates contain either stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during a crystallization process with a pharmaceutically acceptable solvent.

[0155] Tautomers In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the movement of hydrogen atoms, involving the exchange of a single bond with an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomer forms of the compounds disclosed herein are intended. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0156] Treatment method Disclosed herein are methods for treating diseases in which inhibition of FGFR2, FGFR3, mutant FGFR2 (e.g., FGFR2-V564I, FGFR2-V564F, FGFR2-N549H, FGFR2-N549K, FGFR2-E565G, FGFR2-K641R, or FGFR2-K659N, etc.) and / or mutant FGFR3 (e.g., FGFR3-V555M, or FGFR3-V555L, etc.) is beneficial, the method comprising administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If), or (IIa)~(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, disclosed herein are methods for treating diseases in which inhibition of FGFR2 or mutant FGFR2 (e.g., FGFR2-V564I, FGFR2-V564F, FGFR2-N549H, FGFR2-N549K, FGFR2-E565G, FGFR2-K641R, or FGFR2-K659N, etc.) is beneficial, the method comprising administering compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If), or (IIa)-(IIf) disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, disclosed herein are methods for treating diseases in which inhibition of FGFR3 or mutant FGFR3 (e.g., FGFR3-V555M or FGFR3-V555L) is beneficial, the method comprising administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, disclosed herein are methods for treating diseases in which inhibition of FGFR2 and FGFR3 is beneficial, the method comprising administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.In some embodiments, disclosed herein are methods for treating diseases in which inhibition of mutant FGFR2 (e.g., FGFR2-V564I, FGFR2-V564F, FGFR2-N549H, FGFR2-N549K, FGFR2-E565G, FGFR2-K641R, or FGFR2-K659N, etc.) and mutant FGFR3 (e.g., FGFR3-V555M or FGFR3-V555L, etc.) is beneficial, the method comprising administering compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)~(If) or (IIa)~(IIf) disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof.

[0157] Disclosed herein are methods for treating diseases or disorders associated with FGFR2, FGFR3, variant FGFR2 (e.g., FGFR2-V564I, FGFR2-V564F, FGFR2-N549H, FGFR2-N549K, FGFR2-E565G, FGFR2-K641R, or FGFR2-K659N, etc.) and / or variant FGFR3 (e.g., FGFR3-V555M or FGFR3-V555L, etc.), comprising administering compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If) or (IIa)-(IIf) disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, disclosed herein are methods for treating diseases or disorders associated with FGFR2 or variant FGFR2 (e.g., FGFR2-V564I, FGFR2-V564F, FGFR2-N549H, FGFR2-N549K, FGFR2-E565G, FGFR2-K641R, or FGFR2-K659N), comprising administering compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If), or (IIa)-(IIf) disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, methods for treating diseases or disorders associated with FGFR3 or mutant FGFR3 (e.g., FGFR3-V555M or FGFR3-V555L) include administering compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If), or (IIa)-(IIf) disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, methods for treating diseases or disorders associated with FGFR2 and FGFR3 include administering compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If), or (IIa)-(IIf) disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof.In some embodiments, disclosed herein are methods for treating diseases or disorders associated with mutant FGFR2 (e.g., FGFR2-V564I, FGFR2-V564F, FGFR2-N549H, FGFR2-N549K, FGFR2-E565G, FGFR2-K641R, or FGFR2-K659N, etc.) and mutant FGFR3 (e.g., FGFR3-V555M or FGFR3-V555L, etc.), comprising administering compounds of formulas (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If) or (IIa)-(IIf) disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, to the target.

[0158] Disclosed herein are methods for treating a target cancer, comprising administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If), or (IIa)-(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the target. In some embodiments, the method for treating a target cancer comprises administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If) or (IIa)-(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is selected from intrahepatic cholangiocarcinoma, urothelial carcinoma, gastric cancer, esophageal gastric cancer, colorectal cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, vaginal cancer, cervical cancer, glioma, head and neck cancer, other brain tumors, ovarian cancer, anal cancer, non-melanoma skin cancer, penile cancer, adrenocortical carcinoma, melanoma, ampulla cancer, Wilms' tumor, small intestine cancer, uterine sarcoma, salivary gland cancer, soft tissue sarcoma, retinoblastoma, or thyroid cancer. In some embodiments, a method for treating a target cancer comprises administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If) or (IIa)-(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is selected from intrahepatic cholangiocarcinoma, urothelial carcinoma, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer. In some embodiments, a method for treating a target intrahepatic cholangiocarcinoma comprises administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If) or (IIa)-(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a method for treating a target urothelial carcinoma comprises administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If), or (IIa)-(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, to the target.In some embodiments, a method for treating a target gastric cancer is provided, comprising administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If), or (IIa)-(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a method for treating a target bladder cancer is provided, comprising administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If), or (IIa)-(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a method for treating a target breast cancer comprises administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If) or (IIa)-(IIf) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a method for treating a target endometrial cancer comprises administering a compound of formula (I), (I-1), (II-1), (II-2), (II-3), (Ia)-(If) or (IIa)-(IIf) to a target.

[0159] In one embodiment, the method disclosed herein is a method for modulating the activity of fibroblast growth factor receptor (FGFR) in a subject, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein, to the subject. In another embodiment, the method disclosed herein is a method for inhibiting the activity of fibroblast growth factor receptor (FGFR) in a subject, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein, to the subject. In some embodiments, the subject has cancer.

[0160] In one embodiment, the foregoing describes a method for modulating the activity of mutant fibroblast growth factor receptor (FGFR) in a subject, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In another embodiment, the foregoing describes a method for inhibiting the activity of mutant fibroblast growth factor receptor (FGFR) in a subject, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the subject has cancer.

[0161] In one embodiment, the foregoing discloses a method for treating cancer in a subject requiring treatment, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein, to the subject. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is intrahepatic cholangiocarcinoma, urothelial carcinoma, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.

[0162] dosage In certain embodiments, compositions containing the compounds described herein are administered for therapeutic purposes. In certain therapeutic uses, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially cessate at least one of the symptoms of the disease or condition. The effective amount for this use depends on the severity and course of the disease or condition, past treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The amount of a given drug equivalent to such an amount varies depending on factors such as the specific compound, the disease condition and its severity, and the unique characteristics of the subject or host requiring treatment (e.g., weight, sex), but is still determined by the specific circumstances surrounding the case, including, for example, the specific drug being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0163] In various embodiments, the dosage is modified depending on many variables, including but not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the healthcare professional.

[0164] Route of administration Preferred routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, transvaginal, intraocular, transnasal, and local administration. Furthermore, as mere examples, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, lymphatic, and intranasal injection.

[0165] Pharmaceutical composition / formulation The compounds described herein are administered to subjects requiring them, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in pharmaceutical compositions, according to standard pharmaceutical practices. In some embodiments, the compounds described herein are administered to animals.

[0166] In another embodiment, provided herein are pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. The appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), and such disclosures are incorporated herein by reference. [Examples]

[0167] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0168] Throughout the above and this disclosure, the following abbreviations shall be understood to have the following meanings unless otherwise indicated. [Table 4] Example 1 [ka]

[0169] Compound 1.2 (1.7g, 5.33 mmol), 1,4-diazabicyclo[2.2.2]octane (919 mg, 8.19 mmol), and Pd(dppf)Cl2 (149.86 mg, 0.21 mmol) were added to a solution of compound 1.1 (1.0 g, 4.10 mmol) in toluene (12 mL) and ethanol (4 mL). The reaction mixture was stirred at 100 °C for 2 hours under N2 and microwave. After cooling to room temperature, the reaction mixture was filtered through a short plug of silica gel, and the silica was subsequently washed with EA (30 mL x 3). The combined organic layers were concentrated under vacuum to obtain the crude product, which was purified by preparative TLC to obtain compound 1.3 (500 mg, yield 33.7%). LCMS: 384.0[M+Na] + .

[0170] To a solution of compound 1.3 (500 mg, 1.38 mmol) in MeCN (20 mL), K2CO3 (210 mg, 1.52 mmol) and NBS (271 mg, 1.52 mmol) were added at 0°C, and the mixture was stirred at 0°C to room temperature for 5 minutes. The reaction product was diluted with H2O (100 mL), extracted with EA (100 mL x 3), and the combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by column chromatography on silica gel to obtain compound 1.4 (480 mg, yield 78.99%). 1 H NMR: (400MHz, CDCl3) δ10.26(s,1H),7.48(d,J=8.0Hz,2H),7.31(d,J=8.0Hz,2H),6.59(s,1H),4.00(s,3H),1.54(s,9H).

[0171] To a solution of compound 1.4 (440 mg, 1.0 mmol) in EtOH (10 mL) and H2O (2 mL), iron (167 mg, 3.0 mmol) and NH4Cl (160 mg, 3.0 mmol) were added at room temperature. The mixture was stirred at 60 °C for 18 hours. After cooling to room temperature, the reaction product was diluted with H2O (50 mL), extracted with EA (100 mL x 3), and the combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by column chromatography on silica gel to obtain compound 1.5 (240 mg, yield 58.0%). LCMS: 412.2[M+H] + .

[0172] Compound 1.6 (0.265 mL, 1.61 mmol) was added to a solution of compound 1.5 (220 mg, 0.54 mmol) in AcOH (10 mL), and the mixture was stirred at 70°C for 3 hours. The mixture was evaporated to obtain a residue, which was dissolved in EA (20 mL), washed with water (30 mL x 3), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel to obtain compound 1.7 (150 mg, yield 62.96%). LCMS: 446.0[M+H] + .

[0173] Compound 1.8 (125 mg, 0.40 mmol), XPhos Pd G2 (4.40 mg, 0.006 mmol), and K2CO3 (111 mg, 0.81 mmol) were added to a solution of compound 1.7 (120 mg, 0.27 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL). The mixture was stirred at 100°C under N2 for 2 hours. After cooling to room temperature, the reaction product was diluted with water (100 mL), extracted with EA (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel to obtain compound 1.9 (140 mg, yield 92.6%). LCMS: 551.2[M+H] + .

[0174] To a solution of compound 1.9 (130 mg, 0.24 mmol) in MeOH (10 mL) and H2O (5 mL), LiOH (49.5 mg, 1.2 mmol) was added. After addition, the mixture was stirred at 70°C for 3 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL), the pH was adjusted to approximately 7 with AcOH, the aqueous layer was extracted with EA (10 mL x 3), the combined organic layers were dried, filtered, and evaporated to obtain compound 1.10 (110 mg, yield 85.4%). LCMS: 537.2[M+H] + .

[0175] To a solution of compound 1.10 (100 mg, 0.19 mmol) in DMF (10 mL), NH4Cl (25 mg, 0.47 mmol), HATU (106 mg, 0.28 mmol), and DIEA (0.123 mL, 0.75 mmol) were added. After addition, the mixture was stirred at room temperature for 3 hours. The reaction product was diluted with H2O (50 mL), extracted with EA (50 mL x 3), washed with saturated NH4Cl solution (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by preparative TLC to obtain compound 1.11. LCMS: 536.2[M+H] + .

[0176] To a solution of compound 1.11 (72 mg, 0.13 mmol) in DCM (8 mL), TFA (2 mL) was added. After addition, the mixture was stirred at room temperature for 2 hours. The mixture was evaporated, the residue was dissolved in DCM (20 mL), washed with saturated NaHCO3 solution (100 mL), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 1.12. LCMS: 436.2[M+H] + .

[0177] To a solution of compound 1.12 (50 mg, 0.115 mmol) in acetone (5 mL), K2CO3 (0.34 mL, 0.34 mmol, 1.0 mol / L in water) and acryloyl chloride (0.13 mL, 0.13 mmol, 1.0 mol / L in acetone) were added at 0°C. After addition, the mixture was stirred at room temperature for 1 hour. The reaction product was diluted with H2O (50 mL), extracted with EA (50 mL x 3), and the combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by preparative HPLC to obtain Example 1. LCMS: 490.2 [M + H] + . 1 H NMR:(400MHz,DMSO-d6)δ10.10(s,1H),9.70(dd,J=7.2,2.0Hz,1H),8.39(dd,J=4.0,1.6Hz, 1H),7.76(t,J=7.2Hz,1H),7.55(d,J=7.2Hz,2H),7.47(s,1H),7.39-7.36(m,2H),7.27-7.25 (m,2H),7.19-7.17(m,2H),7.05-7.02(m,2H),6.81(d,J=8.0Hz,1H),6.42(dd,J=16.8,10.0H z,1H),6.24(dd,J=17.2,2.0Hz,1H),5.80(s,1H),5.72(dd,J=10.0,2.0Hz,1H),2.36(s,3H). Example 2 [ka]

[0178] A solution of compound 1.5 (480.0 mg, 1.17 mmol) and 1,1,3,3-tetraethoxy-2-methylpropane (822.3 mg, 3.51 mmol) in AcOH (8 mL) was stirred at 70°C for 3 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue, which was dissolved in ethyl acetate (20 mL). The solution was washed with water (30 mL x 3). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 2.2 (300 mg, 55.7%). LCMS: 460.1; 462.1 [M+H] + .

[0179] To a solution of compounds 2.2 (290.0 mg, 0.63 mmol) and 2.3 (416.1 mg, 1.26 mmol) in dioxane (1 mL) and H2O (0.40 mL), K2CO3 (261.2 mg, 1.89 mmol) was added. Then, XPhos Pd G2 (9.00 mg, 0.063 mmol) was added to the solution under N2. The reaction mixture was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by flash column chromatography on silica gel to obtain compound 2.4 (80.0 mg, yield 21.8%). LCMS: 584.2[M+H] + .

[0180] To a solution of compound 2.4 (80.0 mg, 0.14 mmol) in THF (3 mL) and H2O (0.6 mL), LiOH (28.8 mg, 0.69 mmol) was added. The reaction mixture was then stirred at 70°C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (5 mL) and the pH was adjusted to 7 with 1 M HCl (aqueous solution). The solution was then extracted with ethyl acetate (5 mL x 3), the combined organic layers were dried, filtered, and concentrated to obtain compound 2.5 (70.0 mg, crude). LCMS: 570.4[M+H] + .

[0181] To a solution of compound 2.5 (70.0 mg, 0.12 mmol) in DMF (1 mL), NH4Cl (17.8 mg, 0.33 mmol), HATU (74.8 mg, 0.20 mmol), and DIEA (0.09 mL, 0.52 mmol) were added. The reaction mixture was then stirred at 25°C for 3 hours. The reaction product was diluted with H2O (5 mL), extracted with ethyl acetate (10 mL x 3), washed with brine (5 mL x 3), dried over Na2SO4, filtered, and concentrated to obtain compound 2.6. LCMS: 569.2[M+H] + .

[0182] To a solution of compound 2.6 (60.0 mg, 0.11 mmol) in DCM (2 mL), TFA (0.5 mL) was added, and the reaction mixture was stirred at 25°C for 2 hours. The solution was diluted with H2O (5 mL), and the pH of the solution was adjusted to 7 with NaHCO3. The solution was extracted with ethyl acetate (5 mL x 3), the combined organic layers were dried, filtered, and concentrated to obtain compound 2.7. LCMS: 469.1 [M + H] + .

[0183] To a solution of compound 2.7 (40.0 mg, 0.09 mmol) and 2-fluoropropa-2-enoic acid (15.4 mg, 0.18 mmol) in pyridine (2 mL), EDCI (49.1 mg, 0.26 mmol) was added. The reaction mixture was then stirred at 50°C for 3 hours. After cooling to room temperature, the reaction solution was concentrated and purified by preparative HPLC to obtain Example 2. LCMS: 540.9 [M+H] + . 1 H NMR:(400MHz,DMSO-d6)δ10.29(s,1H),9.38(s,1H),8.51(d,J=4.1Hz,1H),8.30(s,1H),7.64(d,J=7.9Hz, 2H),7.49-7.16(m,7H),6.48-5.87(m,1H),5.79-5.60(m,1H),5.47-5.35(m,1H),2.44(s,3H),2.34(s,3H).

[0184] Example 3 [ka]

[0185] Compound 2.3 (9.70 g, 29.4 mmol) was added to a solution of compound 3.1 (5.00 g, 24.5 mmol) in dioxane (60 mL) and H2O (20 mL). Then, Pd(dppf)Cl2 (1.80 g, 2.45 mmol) and K2CO3 (6.80 g, 49.0 mmol) were added to the solution, and the mixture was stirred at 90°C under N2 for 2 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by flash column chromatography on silica gel to obtain compound 3.2 (5.20 g, 64.8%). LCMS: 328.1[M+H] + ; 1 H NMR:(400MHz,DMSO-d6)δ11.99(br s,1H),8.48(d,J=5.1Hz,1H),7.55(dd,J=12.3,2.0Hz,1H),7.43-7.38(m,1H),7.35-7.28(m,1H) ),7.19(d,J=4.8Hz,1H),7.06(t,J=2.8Hz,1H),6.41(t,J=2.4Hz,1H),3.74(s,3H),2.43(s,3H).

[0186] In a round-bottom flask, POCl3 (4.26 mL, 45.830 mmol) was added dropwise to DMF (3.53 mL, 45.8 mmol), and the mixture was maintained at 40°C for 15 minutes. DME (20 mL) was added to the solution at 0°C, and compound 3.2 (5.00 g, 15.3 mmol) dissolved in DME (20 mL) was added to the solution. The reaction mixture was stirred at 90°C for 3 hours. After cooling to room temperature, sodium acetate (6.90 g, 84.0 mmol) in distilled H2O (20 mL) was added, and the resulting mixture was stirred at 100°C for 1 hour. The organic layer was washed with distilled H2O (100 mL), saturated Na2CO3 aqueous solution (100 mL x 2), and brine (100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel to obtain compound 3.3 (1.77 g, 32.6%). LCMS:356.1[M+H] + ; 1H NMR:(400MHz,DMSO-d6)δ13.15(br s,1H),9.76(s,1H),8.49(d,J=4.8Hz,1H),7.58(dd,J=12.0,1.9Hz,1H),7.4 4-7.32(m,2H),7.20(d,J=5.2Hz,1H),7.16(s,1H),3.80(s,3H),2.43(s,3H).

[0187] To a solution of compound 3.3 (500.0 mg, 1.41 mmol) in DMF (5 mL), NBS (350.6 mg, 1.97 mmol) was added at 0°C. The reaction mixture was stirred at 30°C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum and purified by flash column chromatography on silica gel to obtain compound 3.4 (600.0 mg, 98.4%). LCMS: 436.0 [M+H] + .

[0188] To a solution of compound 3.4 (600.0 mg, 1.38 mmol) in acetone (6 mL), potassium iodide (458.8 mg, 2.76 mmol) and K2CO3 (286.5 mg, 2.073 mmol) were added. Then, 1-chloropropan-2-one (383.5 mg, 4.15 mmol) was added to the solution, and the mixture was stirred at 25°C for 12 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain compound 3.5 (650.0 mg, crude product). LCMS: 492.0 [M + H] + .

[0189] To a solution of compound 3.5 (650.0 mg, 1.33 mmol) in AcOH (7 mL), ammonium acetate (511.1 mg, 6.63 mmol) was added. The mixture was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was concentrated under vacuum and purified by flash column chromatography on silica gel to obtain compound 3.6. LCMS: 471.0 [M+H] + .

[0190] To a solution of compound 3.6 (200.0 mg, 0.424 mmol) in THF (2 mL) and H2O (0.4 mL), LiOH (89.1 mg, 2.12 mmol) was added. The reaction mixture was then stirred at 70°C for 3 hours. After cooling to room temperature, the mixture was diluted with H2O (5 mL) and adjusted to approximately pH 7 with 1N HCl. The solution was extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried, filtered, and concentrated to obtain compound 3.7. LCMS: 459.0 [M + H] + .

[0191] To a solution of compound 3.7 (160.0 mg, 0.35 mmol) and NH4Cl (56.1 mg, 1.05 mmol) in DMF (2 mL), DIEA (0.17 mL, 1.05 mmol) was added. Then, HATU (146.3 mg, 0.385 mmol) was added to the solution, and the mixture was stirred at 25°C for 4 hours. The mixture was concentrated and purified by flash column chromatography on silica gel to obtain compound 3.8. LCMS: 458.0 [M+H] + .

[0192] Compound 3.9 (34.4 mg, 0.118 mmol) and K2CO3 (32.7 mg, 0.237 mmol) were added to a solution of compound 3.8 (54.0 mg, 0.118 mmol) in dioxane (1.5 mL) and H2O (0.5 mL). Then, Pd(PPh3)4 (13.7 mg, 0.012 mmol) was added to the solution under N2. The reaction mixture was stirred at 100°C for 1 hour. After cooling to room temperature, the solution was concentrated under vacuum. The residue was purified by preparative HPLC to obtain Example 3. LCMS: 541.1[M+H] + ; 1 H NMR:(400MHz,DMSO-d6)δ10.36(s,1H),8.82(s,1H),8.73(s,1H),8.48(d,J=5. 2Hz,1H),7.77-7.69(m,3H),7.38(t,J=8.4Hz,1H),7.30-7.11(m,5H),6.68(br s,1H),5.72(dd,J=47.6,3.6Hz,1H),5.43(dd,J=15.6,3.6Hz,1H),2.42(s,6H).

[0193] Example 4 [ka]

[0194] Compound 4.1 was synthesized by coupling compound 1.5 and compound 2.3 in the same manner as described in the preparation of compound 3.2.

[0195] To a solution of compound 4.1 (600.0 mg, 1.12 mmol) in EtOH (6 mL) and AcOH (2 mL), 4,4-dimethoxybutan-2-one (297.3 mg, 2.25 mmol) was added. The mixture was stirred at 70°C for 3 hours. After cooling to room temperature, the reaction solution was concentrated and purified by flash column chromatography on silica gel to obtain compound 4.2 (400.0 mg, 61%). LCMS: 584.2[M+H] + . 1 H NMR(400MHz,CDCl3)δ9.67(d,J=7.2Hz,1H),8.42(d,J=4.8Hz,1H),7.37-7.34(m,2H),7.31-7.28(m,2H),7.21(t,J=8.0Hz,1H),7.14(dd,J=11.2, 2.0Hz,1H),7.04(d,J=8.2Hz,1H),6.94(d,J=4.8Hz,1H),6.80(d,J=7.2H z,1H),6.48(s,1H),3.71(s,3H),2.61(s,3H),2.52(s,3H),1.53(s,9H).

[0196] Example 4 was synthesized from compound 4.2 (200.0 mg, 0.343 mmol) in the same manner as in Example 2. LCMS: 540.9[M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.47(d,J=7.2Hz,1H),8.50(d,J=5.2Hz,1H),7.62(d,J=8.8Hz,2H),7.56-7.3 7(m,2H),7.33(dd,J=11.2,1.6Hz,1H),7.26(d,J=8.8Hz,2H),7.20(d,J=5.2Hz,2H),6.93(d,J=7.2Hz,1H),6.03(br s,1H),5.70(dd,J=47.6,3.6Hz,1H),5.42(dd,J=15.6,3.6Hz,1H),2.49(s,3H),2.43(s,3H).

[0197] Example 5 [ka]

[0198] To a solution of compound 4.1 (1.00 g, 1.87 mmol) in EtOH (10 mL), 2-bromopropanedial (566.0 mg, 3.75 mmol) and AcOH (3 mL, 52.4 mmol) were added. The mixture was stirred at 80°C for 6 hours. After cooling to room temperature, the mixture was diluted with H2O (50 mL), and the aqueous layer was extracted with EA (50 mL x 3). The combined organic layers were dried, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 5.1 (334.0 mg, 28%). LCMS: 650.0 [M + H] + .

[0199] To a solution of compound 5.1 (310.0 mg, 0.478 mmol) and cyclopropylboronic acid (123.2 mg, 1.43 mmol) in dioxane (4 mL) and H2O (1 mL), K2CO3 (165.2 mg, 1.19 mmol) was added. Then, Pd(OAc)2 (10.7 mg, 0.048 mmol) and PCy3 (26.8 mg, 0.096 mmol) were added to the mixture. The solution was stirred at 100°C under N2 for 12 hours. After cooling to room temperature, the mixture was concentrated under vacuum and purified by flash column chromatography on silica gel to obtain compound 5.2 (77.0 mg, 26%). LCMS: 610.2[M+H] + .

[0200] Example 5 was synthesized from compound 5.2 (77.0 mg, 0.126 mmol) in the same manner as in Example 2. LCMS: 567.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.30(d,J=2.0Hz,1H),8.50(d,J=5.2Hz,1H),8.24(d,J=2.0Hz,1H),7.63(d,J=8.8Hz,2H),7.54(br s,1H),7.42(t,J=8.4Hz,1H),7.33(dd,J=11.2,1.6Hz,1H),7.26(d,J=8.4Hz,2H),7.23-7.16(m,2H),6.13(br s,1H),5.70(dd,J=48.0,3.6Hz,1H),5.42(dd,J=15.6,3.6Hz,1H),2.43(s,3H),2.11-2.02(m,1H),1.05-0.98(m,2H),0.81-0.76(m,2H).

[0201] Example 6 [ka]

[0202] To a solution of compound 1.5 (8 g, 19.498 mmol) and compound 6.1 (9.1 g, 29.247 mmol) in dioxane (120 mL) and H2O (40 mL), K2CO3 (6.7 g, 48.745 mmol) was added, followed by the addition of Pd-118 (1.3 g, 1.950 mmol) to the solution. The mixture was stirred at 90°C under N2 for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (80 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by flash column chromatography on silica gel to obtain compound 6.2 (4.20 g, 42%). LCMS: 516.3[M+H] + .

[0203] A solution of compound 6.2 (1.90 g, 3.69 mmol) and 2-chloropropanedial (784.9 mg, 7.37 mmol) in EtOH (0.6 mL) and AcOH (20 mL) was stirred at 80°C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by flash column chromatography on silica gel to obtain compound 6.3 (1.10 g, 49%). LCMS: 586.2[M+H] + .

[0204] To a solution of compound 6.3 (300.0 mg, 0.51 mmol) and 1-methylpiperazine (256.5 mg, 2.56 mmol) in dioxane (5 mL), K3PO4 (543.4 mg, 2.56 mmol) was added. Then, Johnphos (30.6 mg, 0.10 mmol) and Pd2(dba)3 (46.9 mg, 0.05 mmol) were added to the solution. The mixture was stirred at 100°C under N2 for 18 hours. After cooling to room temperature, the reaction solution was poured into ice water (10 mL). The solution was extracted with EA (15 mL x 3), washed with brine, dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to obtain compound 6.4 (150.0 mg, 45%). LCMS: 650.4[M+H] + .

[0205] Example 6 was synthesized from compound 6.4 (130.0 mg, 0.20 mmol) in the same manner as in Example 2. LCMS: 607.5[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.22(s,1H),8.59-8.44(m,2H),8.17(s,1H),7.60(d,J=8.4Hz,2H),7.39(d,J=8.4Hz,2H),7.27(d,J= 8.4Hz,4H),7.18(d,J=4.8Hz,1H),5.87-5.54(m,2H),5.41(dd,J=15.6,2.8Hz,1H),3.13(s,4H)2.56-2.52(m,4H),2.43(s,3H),2.27(s,3H).

[0206] Example 7 [ka]

[0207] Compound 7.1 was synthesized in the same manner as described in the preparation of Compound 6.3.

[0208] To a solution of compounds 7.1 (800.0 mg, 1.33 mmol) and 7.2 (293.6 mg, 3.97 mmol) in dioxane (9 mL) and H2O (3 mL), K2CO3 (457.6 mg, 3.31 mmol) was added. Then, Xphos Pd-G3 (112.1 mg, 0.132 mmol) was added to the solution, and the mixture was stirred at 110°C under N2 for 18 hours. After cooling to room temperature, the reaction solution was poured into ice water (30 mL). The solution was extracted with EA (30 mL x 3), washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 7.3 (150.0 mg, 19%). LCMS: 598.3[M+H] + .

[0209] Example 7 was synthesized from compound 7.3 (150.0 mg, 0.18 mmol) in the same manner as in Example 2. LCMS: 555.2[M+H] + .1 H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.38(d,J=1.6Hz,1H),8.51(d,J=4.8Hz,1H),8.36 (d,J=2.0Hz,1H),7.47-7.68(m,3H),7.43(t,J=8.2Hz,1H),7.34(dd,J=11.2,1.4Hz,1H) ,7.28(d,J=8.6Hz,2H),7.22(d,J=5.1Hz,2H),6.24-6.03(m,1H),5.66(dd,J=47.6,3.6H z,1H),5.42(dd,J=15.7,3.6Hz,1H),2.74-2.66(m,2H),2.44(s,3H),1.29-1.25(m,3H).

[0210] Example 8 [ka]

[0211] To a solution of compound 7.1 (1.20 g, 1.99 mmol) and compound 8.1 (0.3 mL, 3.97 mmol) in dioxane (2 mL), K3PO4 (1.05 g, 4.97 mmol) was added. Then, JohnPhos (118.6 mg, 0.40 mmol) and Pd2(dba)3 (181.9 mg, 0.20 mmol) were added to the solution under N2. The reaction mixture was stirred at 110°C for 18 hours. After cooling to room temperature, the reaction solution was diluted with water (15 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 8.2 (700.0 mg, 54%). LCMS: 655.3[M+H] + .

[0212] Example 8 was synthesized from compound 8.2 (300.0 mg, 0.46 mmol) in the same manner as in Example 2. LC-MS: 612.3[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.07(s,1H),8.60-8.42(m,2H)7.63(d,J=8.4Hz,2H),7.43(t,J=8.4Hz,2H),7.37-7.18 (m,5H),6.14-5.81(m,1H),5.70(dd,J=48.0,2.8Hz,1H),5.42(dd,J=15.6,2.8Hz,1H),3.82(s,4H),3.12(s,4H),2.44(s,3H).

[0213] Example 9 [ka]

[0214] To a solution of compound 5.1 (400 mg, 0.617 mmol) and compound 9.1 (192.5 mg, 0.925 mmol) in dioxane (2 mL) and H2O (0.6 mL), K2CO3 (213.1 mg, 1.542 mmol) was added, followed by the addition of Pd-118 (40.5 mg, 0.062 mmol) to the solution. The mixture was stirred at 100°C under N2 for 1.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel to obtain compound 9.2 (360 mg, 90%). LCMS: 650.3[M+H] + .

[0215] Example 9 was synthesized from compound 9.2 (340 mg, 0.523 mmol) in the same manner as in Example 2. LCMS: 607.2[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),9.63(d,J=2.0Hz,1H),8.68(d,J=2.0Hz,1H),8.51(d,J=5.2Hz,1H),8. 33(s,1H),7.98(s,1H),7.68-7.63(m,4H),7.44-7.37(m,1H),7.34-7.29(m,2H),7.24-7.21(m,2H),6.26(br s,1H),5.71(dd,J=47.6,3.6Hz,1H),5.43(dd,J=15.6,3.6Hz,1H),3.92(s,3H),2.44(s,3H).

[0216] Example 10 [ka]

[0217] To a solution of compound 5.1 (550 mg, 0.848 mmol) and compound 10.1 (558.2 mg, 1.696 mmol) in toluene (2 mL), Pd(PPh3)4 (98.0 mg, 0.085 mmol) was added, and the mixture was stirred at 100 °C for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (15 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 10.2 (300 mg, 58%). LCMS: 508.1[M+H-Boc] + .

[0218] Example 10 was synthesized from compound 10.2 (350 mg, 0.576 mmol) in the same manner as in Example 2. LCMS: 565.2[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),9.57(s,1H),8.51(d,J=5.2Hz,1H),8.34(d,J=1.6Hz,1H ),7.67-7.64(m,3H),7.42(t,J=8.4Hz,1H),7.35(d,J=12.0Hz,1H),7.28-7.21(m,4H),6.24(br s,1H),5.71(dd,J=48.0,3.6Hz,1H),5.43(dd,J=15.6,3.2Hz,1H),2.44(s,3H),2.14(s,3H).

[0219] Example 11 [ka]

[0220] To a solution of compound 4.1 (350.0 mg, 0.656 mmol) and 1,1,3,3-tetramethoxypropane (129.0 mg, 0.787 mmol) in EtOH (1 mL), AcOH (3 mL, 52.4 mmol) was added. The mixture was stirred at 80°C for 4 hours. After cooling to room temperature, the mixture was concentrated under vacuum and purified by flash column chromatography on silica gel to obtain compound 11.1 (250.0 mg, 67%). LCMS: 570.3 [M+H] + .

[0221] Example 11 was synthesized from compound 11.1 (250.0 mg, 0.439 mmol) in the same manner as in Example 2. LCMS: 527.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.55(dd,J=7.2,1.2Hz,1H),8.50(d,J=4.8Hz,1H),8.38(dd,J=3.6,1.6Hz,1H),7.65(d,J=8.8Hz,2H),7.57(br s,1 H)7.44(t,J=8.4Hz,1H),7.35(dd,J=11.2,1.6Hz,1H),7.29(d,J=8.8Hz,2H),7.25-7.18(m,2H),7.03(dd,J=7.2,4.0Hz,1H),6.18(br s,1H),5.70(dd,J=48.0,3.6Hz,1H),5.42(dd,J=15.6,3.6Hz,1H),2.43(s,3H).

[0222] Example 12 [ka]

[0223] Compound 12.1 (6.00 g, 63.1 mmol) and K2CO3 (13.1 g, 94.6 mmol) were added to a solution of CTAB (2.30 g, 6.31 mmol) in H2O (25 mL) at 25 °C. The reaction mixture was stirred for 15 minutes. Then, compound 12.2 (15.0 g, 69.4 mmol) was added to the mixture, and the solution was stirred at 70 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with EA (25 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 12.3 (6.10 g, 42%). LCMS: 231.0 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=8.8Hz,2H),7.86(dd,J=6.8,2.0Hz,1H),7.55-7.44(m,3H),6.45(d,J=9.2Hz,1H),6.32-6.28(m,1H),5.24(s,2H).

[0224] To a solution of compound 12.3 (6.10 g, 26.5 mmol) in DCE (20 mL), POCl3 (7.39 mL, 79.50 mmol) in DCE (20 mL) was added dropwise. The reaction solution was stirred at 60°C for 18 hours. After cooling to room temperature, the reaction solution was concentrated under vacuum to obtain crude compound 12.4 (7.0 g, 93%). LC-MS: 249.0 [M] + .

[0225] To a solution of propanedinitrile (4.10 g, 61.4 mmol) in THF (20 mL), NaH (1.50 g, 61.4 mmol) was added. The reaction mixture was stirred at 25°C for 30 minutes. Next, compound 12.4 (7.00 g, 24.56 mmol) in THF (20 mL) was added to the mixture, and the solution was stirred at 25°C for 1 hour. The reaction solution was quenched with H2O (40 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 12.5 (3.62 g, 53%). LCMS: 279.1 [M+H] + .

[0226] To a solution of compound 12.5 (3.62 g, 13.01 mmol) in THF (50 mL), t-BuOK (13.0 mL, 13.0 mmol, 1.0 M in THF) was added dropwise at 0°C for 10 minutes. The reaction mixture was stirred at 0°C for 2 hours. The reaction solution was diluted with water (50 mL) and extracted with DCM (100 mL x 5). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 12.6 (990.0 mg, 27%). LCMS: 279.1 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ8.43(d,J=7.2Hz,1H),8.35-8.32(m,2H),7.83-7.80(m,2H) ),7.46(d,J=8.8Hz,1H),7.22-7.17(m,1H),6.86-6.82(m,1H),5.62-5.57(m,2H).

[0227] To a solution of compound 12.6 (850.0 mg, 3.05 mmol) in CH3CN (10 mL), diiodomethane (12.5 g, 46.7 mmol) and 3-methyl-1-(nitrosoxydanyl)butane (1.07 g, 9.16 mmol) were added. The mixture was then stirred at 40°C for 1 hour. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with EA (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 12.7 (700.0 mg, 59%). LCMS: 390.0 [M+H] + .

[0228] Compound 2.3 (865.4 mg, 2.62 mmol) and K2CO3 (603.6 mg, 4.37 mmol) were added to a solution of compound 12.7 (680.0 mg, 1.75 mmol) in dioxane (6 mL) and H2O (1 mL). Then, Pd-118 (114.8 mg, 0.18 mmol) was added to the mixture, and the solution was stirred at 90°C under N2 for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 12.8. LCMS: 466.1[M+H] + .

[0229] To a solution of compound 12.8 (350.0 mg, 0.75 mmol) in EtOH (1 mL) and H2O (0.3 mL), Fe (209.8 mg, 3.76 mmol) and CaCl2 (16.7 mg, 0.15 mmol) were added. The reaction mixture was then stirred at 80°C for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and concentrated to obtain crude compound 12.9. LCMS: 436.1[M+H] + .

[0230] To a solution of compound 12.9 (327.0 mg, 0.75 mmol) and compound 2.8 (135.3 mg, 1.50 mmol) in pyridine (10 mL), EDCI (431.8 mg, 2.25 mmol) was added. The mixture was stirred at 50°C for 3 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 12.10. LCMS: 508.1[M+H] + .

[0231] A solution of compound 12.10 (140.0 mg, 0.28 mmol) in H2SO4 (1 mL) was stirred at 25°C for 18 hours. The reaction solution was poured onto ice (5 mL) and the pH was adjusted to 7 with Na2CO3 (aqueous solution). The solution was extracted with EA (8 mL x 3), washed with brine, dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to obtain Example 12. LCMS: 526.1 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.47(d,J=4.8Hz,1H),8.07(d,J=9.2Hz,1H),8.01(d,J=7.6Hz, 1H),8.00-7.82(m,2H),7.35-7.30(m,4H),7.27(s,1H),7.19-7.10(m,3H),6.79-6.76(m,1H),6.31(br s,1H),5.74(dd,J=47.2,2.8Hz,1H),5.46(dd,J=15.6,3.6Hz,1H),2.42(s,3H).

[0232] Example 13 [ka]

[0233] Example 13 was synthesized in the same manner as in Example 2, from compound 2.7 (100 mg, 0.213 mmol) and compound 13.1 (26.9 mg, 0.32 mmol). LCMS: 535.0 [M+H]+ . 1 H NMR(400MHz,DMSO-d6)δ10.59(s,1H),9.38(s,1H),8.51(d,J=4.8Hz,1H),8.29(d, J=2.0Hz,1H),7.52-7.31(m,4H),7.24(d,J=8.8Hz,1H),7.23-7.19(m,4H),6.12(br s,1H),2.44(s,3H),2.34(s,3H),2.05(s,3H).

[0234] Example 14 [ka]

[0235] Example 14 was synthesized in the same manner as in Example 2, from compound 2.7 (100 mg, 0.213 mmol) and compound 14.1 (26.9 mg, 0.32 mmol). LCMS: 580.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.38(s,1H),8.51(d,J=5.2Hz,1H),8.29(s,1H),7.58-7.31( m,4H),7.24(d,J=8.4Hz,1H),7.23-7.19(m,4H),6.75-6.67(m,1H),6.27(d,J=15.6Hz,1H),6.16(br s, 1H), 3.05 (d, J=5.2Hz, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 2.18 (s, 6H).

[0236] Example 15 [ka]

[0237] To a solution of compound 2.2 (40.0 g, 86.9 mmol) in THF (300 mL), TMSOK (16.7 g, 130.4 mmol) was added. The reaction mixture was stirred at 50°C for 3 hours. After cooling to room temperature, the reaction solution was concentrated under vacuum to obtain compound 15.1 (38.0 g, 98%). LCMS: 446.2; 448.2 [M+H] + .

[0238] To a solution of compound 15.1 (38.0 g, 85.1 mmol) and NH4Cl (22.8 g, 425.7 mmol) in DMF (300 mL), DIEA (33.0 g, 255.4 mmol) was added. Then, HATU (38.8 g, 102.1 mmol) was added to the solution, and the mixture was stirred at 25°C for 3 hours. Water (200 mL) was added to the solution, and a brown solid precipitated. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain compound 15.2 (37.0 g, 98%). LCMS: 445.2; 447.2 [M+H] + .

[0239] To a solution of compound 15.2 (400 mg, 0.898 mmol) and compound 15.3 (467.0 mg, 1.347 mmol) in dioxane (3 mL) and H2O (1 mL), K2CO3 (372.4 mg, 2.695 mmol) was added, followed by the addition of Pd-118 (59.0 mg, 0.090 mmol) to the solution. The mixture was stirred at 100°C under N2 for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (150 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 15.4 (300 mg, 57%). LCMS: 585.0 [M + H] + .

[0240] Example 15 was synthesized from compound 15.4 (200.0 mg, 0.17 mmol) in the same manner as in Example 2. LCMS: 579.1[M+Na] + . 1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.58(s,1H),8.53(d,J=4.8Hz,1H),8.34(s,1H),7.63-7.51(m,5H) ,7.32-7.21(m,5H),5.70(dd,J=47.6,3.6Hz,1H),5.42(dd,J=15.6,3.6Hz,1H),2.44(s,3H),2.37(s,3H).

[0241] Example 16 [ka]

[0242] Example 16 was synthesized from compound 7.1 (240 mg, 0.398 mmol) in the same manner as in Example 2. LCMS: 561.3[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.66(d,J=2.4Hz,1H),8.51(d,J=5.2Hz,1H),8. 42(d,J=2.4Hz,1H),7.68-7.64(m,3H),7.37-7.28(m,2H),7.26-7.20(m,4H),6.27(br s,1H),5.76(dd,J=48.0,3.6Hz,1H),5.43(dd,J=15.6,3.6Hz,1H),2.44(s,3H).

[0243] Example 17 [ka]

[0244] To a solution of compound 1.1 (7 g, 28.112 mmol) and compound 17.1 (10.2 g, 29.518 mmol) in dioxane (200 mL) and H2O (30 mL), K2CO3 (9.7 g, 70.281 mmol) was added, followed by the addition of Pd-118 (1.8 g, 2.811 mmol) to the solution. The mixture was stirred at 100°C under N2 for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel to obtain compound 17.2 (4.54 g, 42%). LCMS: 388.3[M+H] + .

[0245] To a solution of compound 17.2 (4.54 g, 11.719 mmol) in CH3CN (100 mL), K2CO3 (1.8 g, 12.891 mmol) was added, followed by the addition of NBS (2.2 g, 12.305 mmol) in CH3CN (100 mL). The mixture was stirred at 25°C for 20 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel to obtain compound 17.3 (3 g, 55%). LCMS: 489.1[M+Na] + .

[0246] To a solution of compound 17.3 (3 g, 6.633 mmol) in EtOH (60 mL) and H2O (20 mL), Fe (1.9 g, 33.164 mmol) and CaCl2 (0.1 g, 1.327 mmol) were added, and the mixture was stirred at 80°C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel to obtain compound 17.4 (1.4 g, 48%). LCMS: 436.0 [M+H] + .

[0247] To a solution of compound 17.4 (1.4 g, 3.209 mmol) and compound 2.3 (2.1 g, 6.418 mmol) in dioxane (50 mL) and H2O (5 mL), K2CO3 (1.1 g, 8.022 mmol) was added, followed by the addition of Pd-118 (0.2 g, 0.321 mmol) to the solution. The mixture was stirred at 100°C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel to obtain compound 17.5 (740 mg, 41%). LCMS: 560.2 [M+H] + .

[0248] Compound 2.1 (433.8 mg, 1.851 mmol) was added to a solution of compound 17.5 (740 mg, 1.322 mmol) in AcOH (5 mL), and the reaction mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by flash column chromatography on silica gel to obtain compound 17.6 (480 mg, 60%). LCMS: 610.1[M+H] + .

[0249] Example 17 was synthesized from compound 17.6 (300 mg, 0.492 mmol) in the same manner as in Example 2. LC-MS: 566.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.50(d,J=5.2Hz,1H),8.31(d,J=2.0Hz,1H),7.86(br s,1H),7.43(br s,1H),7.35(d,J=1.6Hz,1H),7.32(d,J=1.6Hz,1H),7.28(s,1H),7.22-7.20(m,2H),7.09(d,J=8.4Hz,1H),6.15(br s,1H),5.57-5.40(m,2H),4.26-4.21(m,2H),3.11(t,J=8.0Hz,2H),2.44(s,3H),2.35(s,3H).

[0250] Example 18 [ka]

[0251] Compound 18.1 was synthesized in the same manner as described in the preparation of Compound 17.5.

[0252] Compound 2.1 (441.8 mg, 1.885 mmol) was added to a solution of compound 18.1 (800 mg, 1.450 mmol) in AcOH (3 mL), and the mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (15 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain compound 18.2 (450 mg, 52%). LCMS: 602.2[M+H] + .

[0253] Example 18 was synthesized from compound 18.2 (500 mg, 0.831 mmol) in the same manner as in Example 2. LCMS: 559.3[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),9.31(s,1H),8.48(d,J=5.2Hz,1H),8.26(s,1H),7.63(s,1H),7.5 3(s,1H),7.51(d,J=2.0Hz,1H),7.37-7.28(m,3H),7.25(d,J=2.8Hz,1H),7.20(d,J=4.8Hz,1H),6.21(br s,1H),5.74(dd,J=47.6,3.6Hz,1H),5.47(dd,J=15.6,3.6Hz,1H),2.42(s,3H),2.34(s,3H).

[0254] Example 19 [ka]

[0255] Example 19 was synthesized from compound 18.2 (1.3 g, 2.161 mmol) in the same manner as in Example 2. LC-MS: 555.1[M+H] + .1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),9.32(s,1H),8.48(d,J=4.4Hz,1H),8.26(s,1H),7.63(d,J=12.0Hz,1H),7.43-7.13(m,7H),6.38(br s, 1H), 5.82 (s, 1H), 5.55 (s, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 1.96 (s, 3H).

[0256] Example 20 [ka]

[0257] Example 20 was synthesized from compound 15.2 (500 mg, 1.12 mmol) in the same manner as in Example 15. LCMS: 523.3[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.52(d,J=1.2Hz,1H),8.50(d,J=4.8Hz,1H),8.31(d,J=2.4Hz,1H),7.66-7.44(m,3H),7.40(d,J=8.4Hz,2 H),7.31-7.24(m,4H),7.18(d,J=5.2Hz,1H),5.79(s,1H),5.70(dd,J=48.0,3.6Hz,1H),5.42(dd,J=15.6,3.6Hz,1H),2.43(s,3H),2.35(s,3H).

[0258] Example 21 [ka]

[0259] To a solution of compound 2.7 (200.0 mg, 0.427 mmol) and compound 21.1 (125.6 mg, 0.854 mmol) in pyridine (8 mL), EDCI (245.5 mg, 1.281 mmol) was added. The reaction mixture was stirred at 50°C for 2 hours. After cooling to room temperature, the reaction solution was concentrated and purified by preparative HPLC to obtain Example 21. LCMS: 598.5 [M+H]+ . 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.37(s,1H),8.51(d,J=4.8Hz,1H),8.30(d,J=2.2Hz,1H),7.67-7.39(m,4H),7.34(dd, J=11.2,1.8Hz,1H),7.30-7.18(m,4H),6.21-6.06(m,2H),3.14(dd,J=7.2,2.0Hz,2H),2.44(s,3H),2.35(s,3H),2.19(s,6H).

[0260] Example 22 [ka]

[0261] Compound 22.1 (352 mg, 0.213 mmol) was added at 0°C to a solution of compound 2.7 (500.0 mg, 1.07 mmol) and DIEA (415.0 mg, 0.321 mmol) in DCM (8 mL). The mixture was stirred at 25°C for 1 hour. Water (20 mL) was added to the solution, and the solution was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine, dried, and concentrated to obtain compound 22.2.

[0262] To a solution of compound 22.2 (150.0 mg, 0.244 mmol) and compound 22.3 (89.1 mg, 1.219 mmol) in THF (5 mL), DIEA (0.1 mL, 0.731 mmol) was added. The mixture was stirred at 25°C for 12 hours. Water (10 mL) was added to the solution, and the solution was extracted with EA (8 mL x 3). The combined organic phase was concentrated and purified by preparative HPLC to obtain Example 22. LCMS: 608.4 [M + H] + . 1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.37(s,1H),8.51(d,J=5.2Hz,1H),8.29(d,J=2.0Hz,1H),7.63-7.38 (m,4H),7.33(dd,J=11.2,1.8Hz,1H),7.27-7.16(m,4H),6.78-6.73(m,1H),6.25(d,J=15.4Hz,1H),6.15(br s,1H),4.62(t,J=6.4Hz,2H),4.34(t,J=6.4Hz,2H),3.91-3.84(m,1H),3.35-3.22(m,3H),2.44(s,3H),2.34(s,3H).

[0263] Example 23 [ka]

[0264] Example 23 was synthesized in the same manner as in Example 23 from compound 22.2 (150.0 mg, 0.244 mmol) and compound 23.1 (59.4 mg, 0.812 mmol). LCMS: 608.4[M+H] + . 1 1H NMR (400MHz, DMSO-d6)δ 10.03(s,1H),9.37(s,1H),8.51(d,J=4.8Hz,1H),8.29(d,J=2.0Hz,1H),7.6 4-7.39(m,4H),7.33(dd,J=11.2,1.6Hz,1H),7.28-7.17(m,4H),6.67-6.63(m ,1H),6.32-6.05(m,2H),5.34(d,J=6.4Hz,1H),4.25-4.14(m,1H),3.59-3.5 5(m,2H),3.19(d,J=3.2Hz,2H),2.77-2.73(m,2H),2.44(s,3H),2.34(s,3H).

[0265] Example A: FGFR biochemical assay The compounds described herein were tested using the following procedure. The test compound is diluted with 100% DMSO to 100 times the desired final maximum concentration in the reaction. In a 384-well source plate, serial dilutions are performed to a total of 10 concentrations by transferring 15 μL of the solution to 30 μL of 100% DMSO in the next well, for example. Echo(Labcyte) dispenses 100 nL of compound solution into each well from the source plate into a 384-well assay plate in a double-barreled manner. Prepare a solution of 2×FGFR enzyme (Carna) in kinase buffer (50 mM HEPES, pH 7.5, 10 mM MgCl2, 4 mM DTT, 0.01% Tween®-20, and 0.01% BSA). The final concentrations of FGFR1 / 2 / 3 / 4 are 0.01 nM, 0.01 nM, 0.1 nM, and 1 nM, respectively. Except for the low control well which does not contain the enzyme, add 5 μL of kinase solution to each well of the compound-containing assay plate (add 5 μL of 1× kinase buffer to the low control well which does not contain the enzyme). Shake the plate and incubate at room temperature for 10 minutes (Example 1) (or incubate for 60 minutes for the remaining examples in Table 4). Prepare substrate solutions of fluorescein-Poly GT (Invitrogen) and ATP (Sigma) in 1× kinase reaction buffer to twice the final concentration of each reagent desired in the assay (the final concentrations of ATP are 28 μM, 22 μM, 35 μM, and 238 μM for FGFR1 / 2 / 3 / 4, respectively, and fluorescein-Poly GT is fixed at 20 nM). Add 5 μL of substrate solution to each well of the assay plate to initiate the kinase reaction. Shake the plate briefly and incubate at room temperature for 30 minutes. - Prepare a 2× detection solution in antibody dilution buffer (LanthaScreen® Tb-PY20 antibody kit, Invitrogen). Add 10 μL of the detection solution to each well of the assay plate to stop the reaction. Gently mix in a centrifuge, incubate at room temperature for 60 minutes, then read with a microplate reader. Data will be collected using Envision with excitation at 340 nm and emission at 520 nm and 495 nm. Calculate the ratio of RFU 520nm / RFU 495nm. Convert the ratio value to an inhibition percentage (inhibition percentage = (maximum - sample ratio) / (maximum - minimum)). * 100) [In the formula, "minimum" refers to the ratio of the enzyme-free control, and "maximum" refers to the ratio of the DMSO control]. The data is analyzed and curve fitting is performed using the XLFit Excel add-in version 5.4.0.8. 50 The formula for calculating it is Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)^HillSlope

[0266] The data from Example A is shown in Table 4. [Table 5] 0 <A≦10nM; 10nM <B≦100nM; 100nM <C≦1000nM; D > 1000 nM; NT=Not tested

[0267] Example B: Pharmacokinetics in SD rats Male SD rats were administered the compound as a cocktail formulation either as a single intravenous injection or as a single oral dose. Doses of 1 mg / kg (per compound, intravenous administration) and 10 mg / kg (per compound, oral administration) were given as solutions in different formulations as needed (e.g., 5% DMSO + 10% Solutol + 85% (6% HP-β-CD in water)). Blood samples were collected sequentially from n=3 animals via the submandibular vein or other suitable vein at 0.083 hours (intravenous administration only), 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours, and these were further processed to obtain plasma.

[0268] This study demonstrated that the compounds described herein exhibit favorable pharmacokinetic profiles.

[0269] Example C: In vivo efficacy test All animal experiment procedures were carried out in accordance with AAALAC guidelines and IACUC rules. Female Balb / c nude mice were acclimated for approximately one week before use. Human gastric cancer cell lines, e.g., SNU-16, RT4, AN3CA, BaF3-TEL-FGFR3, BaF3-TEL-FGFR2-V564F, BaF3-TEL-FGFR3 V555L, or BaF3-TEL-FGFR3 V555M, were cultured and 1 million to 10 million cells were subcutaneously inoculated into the right flank of the animals (n=5-6 in each group). Animals were randomized. Treatment was started when the mean tumor volume reached approximately 100-150 mm3 (day 0) and continued for 12-21 days. The compound was weighed before use and dissolved as a clear solution in 5% DMSO + 10% Solutol + 85% (6% HP-β-CD). The animals were administered orally once or twice daily. Tumors were measured with calipers twice a week, and body weight was recorded.

[0270] This study demonstrated that the compounds described herein exhibit potent antitumor effects in vivo.

[0271] Example D: KinEASE biochemical assay of mutant FGFR HTRF The compounds described herein were tested using the following procedure. Dilute the test compound with 100% DMSO to the desired final concentration for the reaction. Using assay buffers, prepare 2× ATP and substrate solutions, as well as 2× kinase (e.g., FGFR2-V564I, FGFR2-V564F, FGFR2-N549H, FGFR2-N549K, FGFR2-E565G, FGFR2-K641R, FGFR2-K659N, FGFR3-V555M, FGFR3-V555L) and metal solutions. 50 nL of the compound was transferred to a 384 assay plate. 2.5 μL of 2× kinase and metal solution were added and mixed, and the mixture was incubated in a polystyrene-coated 384 assay plate at 25°C for 60 minutes. 2×XL665 and antibody solutions were prepared using detection buffer. Add 5 μL of kinase detection reagent to each well and incubate at 25°C for 60 minutes. The fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) are read using a microtiter plate reader. The logarithm of the % inhibition value and compound concentration is fitted to a nonlinear regression (dose-response - variable gradient) using GraphPad 8.0 to obtain IC. 50 Calculate. Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X) * (paraslope)) Inhibition percentage (%inh) in compound wells = 100 * (Negative control mean - Compound well) / (Negative control mean - Positive control mean)

[0272] This study demonstrated that the compounds described herein exhibit potent inhibitory activity in mutant FGFR2 / 3.

[0273] Example E: Cell proliferation assay The compounds were tested in growth assays using the following cell lines: SNU-16, KATO-III, SNU-1, AGS, AN3CA, MFE280, MKN45, KLE, RT112-84, RT4, T24, UM-UC-3, KMS11, OPM-2, RAPI8226, U266, SUM 52PE, MCF7, and BaF3. The test compounds were prepared as 10 mM DMSO stock solutions. 2 μL of the 1000× stock solution was added to 98 μL of growth medium to obtain a 20× final concentration, followed by a 3-fold 9-point dilution. 95 μL of the cell line suspension was seeded into 96-well plates and incubated at 37°C for 24 hours. Using an Echo550 liquid handler, 5 μL of the 20× compound solution was added to the 96-well plates according to the plate map. The final DMSO concentration in each well was 0.1%. Cell lines were incubated at 37°C for 72 hours, and then the assay plate was equilibrated to room temperature before measurement. 50 μL of CellTiter-Glo® reagent was added to each well. The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis, incubated at room temperature for 10 minutes to stabilize the luminescence signal, and then chemiluminescence was read using an EnVision reader. The inhibition rate (Inh.%) was calculated using the following formula relative to the vehicle (DMSO)-treated control well: Inhibition rate (Inh%) = 100 - (RLU compound - RLU blank) / (RLU control - RLU blank) * 100%. The data were analyzed using Graphpad Prism 7.0 and fitted to a four-parameter equation to create concentration-response curves.

[0274] This study demonstrated that the compounds described herein exhibit potent antiproliferative activity in multiple cell lines. See Table 5. [Table 6] 0 <A≦10nM; 10nM <B≦100nM; 100nM <C≦1000nM; D > 1000 nM; NT=Not tested

[0275] Example F: Permeability in Caco-2 assay Caco-2 cells purchased from ATCC were placed on a polyethylene membrane (PET) in a 96-well Corning insert plate in a 3.5 × 10⁶ arrangement. 4 cells / cm 2 Cells were seeded, and the medium was changed every 4–5 days until day 21–28 to allow for confluent cell monolayer formation. The transport buffer in this study was HBSS containing 10.0 mM HEPES at pH 7.40 ± 0.05. The test compounds were tested bidirectionally in a double-barrel at 2.00 μM. Digoxin was tested bidirectionally in a double-barrel at 10.0 μM, while nadolol and metoprolol were tested bidirectionally in a double-barrel from A to B at 2.00 μM. The final DMSO concentration was adjusted to less than 1%. Plates were incubated in a CO2 incubator at 37.0°C, 5% CO2, and saturated humidity for 2 hours without shaking. All samples were mixed with acetonitrile containing an internal standard and then centrifuged at 3220 × g for 10 minutes. The concentrations of the test compound and control compound in the starting solution, donor solution, and receiver solution were quantified by LC-MS / MS using the analyte / internal standard peak area ratio. After the transport assay, the integrity of the Caco-2 cell monolayer was determined by applying the Lucifer Yellow exclusion assay.

[0276] This study demonstrated that the compounds described herein exhibit the desired permeability.

Claims

1. Compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof. 【Chemistry 1】 [In the formula, 【Chemistry 2】 This represents a single bond or a double bond. Z １ is C(R ６ ), C (R ６ ) (Caution ６ａ ), O, S, N, or N(R ６Ｎ ) and Z ２ is C(R ７ ), C(R ７ )(R ７ａ ), O, S, N, or N(R ７Ｎ ), and Z ３ is C(R ８ ), C (R ８ ) (Caution ８ａ ), O, S, N, or N(R ８Ｎ ) and R １ and R ２ These are, independently, hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ Selected from haloalkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R groups. Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R ３ These are, independently, halogen, -CN, and -NO ２ -OH, oxo, -OR ａ -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, -C(=O)R ａ -OC(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ Each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently comprises one or more R ３ａ Replaced by optional selection, Each R ３ａ is independently halogen, -CN, -NO ２ , -OH, oxo, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ [[ID=2​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​The alkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl groups are independently and optionally substituted with one or more R groups. L is a bond, -O-, -S-, -NH-, C １ ~C ４ Alkylene, or C １ ~C ４ It is a heteroalkylene, wherein the alkylene or the heteroalkylene is optionally substituted with one or more Rs. n is 0, 1, 2, 3, 4, or 5. L １ C １ ~C ４ Alkylene, C １ ~C ４ Heteroalkylene, C ２ ~C ４ Alkenylene, C ２ ~C ４ Alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, wherein each of the alkylene, heteroalkylene, alkenylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene independently comprises one or more R ４ａ Replaced by optional selection, R ４ is selected from cycloalkylene, heterocycloalkylene, arylene, and heteroarylene, and the cycloalkylene, the heterocycloalkylene, the arylene, or the heteroarylene is one or more R ４ａ Replaced by optional selection, Each R ４ａ These are, independently, halogen, -CN, and -NO ２ -OH, oxo, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl groups are independently and optionally substituted with one or more R groups. X is a bond, -C(=O)-, -OC(=O)-, -NR Ｘ C(=O)-, N(=NR Ｘ ), -NR Ｘ P(=O)OR Ｘ -, -C(=S)-, -N(=O)-, -S(=O)-, -S(=O) ２ -, -OS(=O)-, -OS(O) ２ -, -NR Ｘ S(=O)-, or -NR Ｘ S (=O) ２ - and R Ｘ Each of them independently contains hydrogen and C １ ~C ６ Haloalkyl, or C １ ~C ６ It is an alkyl group, and the alkyl group is optionally substituted with one or more R groups. R Ｗ Halogen, CN, 【Transformation 3】 Selected from, R １１ , R １２ , and R １３ These are, independently, hydrogen, halogen, -CN, and C. １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Heteroalkylene (cycloalkyl), C １ ~C ６ A heteroalkylene (heterocycloalkyl), heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are selected, and each of the alkyl, heteroalkyl, heteroaryl, aryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Rs. R ６ and R ６ａ These are, independently, hydrogen, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Selected from alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, or R ６ and R ６ａ These, together with the carbon to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups. R ７ and R ７ａ These are, independently, hydrogen, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Selected from alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, or R ７ and R ７ａ These, together with the carbon to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups. R ８ and R ８ａ These are, independently, hydrogen, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Selected from alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, or R ８ and R ８ａ These, together with the carbon to which they are bonded, form cycloalkyl or heterocycloalkyl groups, each of which can be independently and optionally substituted with one or more R groups. R ６Ｎ , R ７Ｎ , and R ８Ｎ Each of them independently consists of hydrogen, -C(=O)OR ｂ , -C(=O)R ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Selected from alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, R ６ Or R ６Ｎ and R ７ Or R ７Ｎ These, together with the atoms to which they are bonded, form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which can be independently and optionally substituted with one or more R atoms, or R ７ Or R ７Ｎ and R ８ Or R ８Ｎ These, together with the atoms to which they are bonded, form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which can be independently and optionally substituted with one or more R groups. Each R ａ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ The alkylene (heteroaryl) is such that each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R groups. Each R ｂ These are, independently, hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ The alkylene (heteroaryl) is such that each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R groups. R ｃ and R ｄ These are, independently, hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ The alkylene (heteroaryl) is such that each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R groups. Or, R ｃ and R ｄ These, together with the atoms to which they are bonded, form heterocycloalkyl groups that are optionally substituted with one or more R atoms. Each R is independently halogen, -CN, -OH, -SF ５ , -SH, -S(=O)C １ ~C ３ Alkyl, -S (=O) ２ C １ ~C ３ Alkyl, -S (=O) ２ NH ２ , -S (=O) ２ NHC １ ~C ３ Alkyl, -S (=O) ２ N(C) １ ~C ３ Alkyl) ２ , -S(=O)(=NC １ ~C ３ (Alkyl) (C １ ~C ３ Alkyl), -NH ２ , - NHC １ ~C ３ Alkyl, -N(C) １ ~C ３ Alkyl) ２ , -N=S(=O)(C １ ~C ３ Alkyl) ２ , -O-C １ ~C ４ Alkylene-OH,-O-C １ ~C ４ Alkylene-NH ２ , -C(=O)C １ ~C ３ Alkyl, -C(=O)OH, -C(=O)OC １ ~C ３ Alkyl, -C(=O)NH ２ , -C(=O)NHC １ ~C ３ Alkyl, -C(=O)N(C １ ~C ３ Alkyl) ２ , -P(=O)(C １ ~C ３ Alkyl) ２ , C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Aminoalkyl, C １ ~C ３ It is a heteroalkyl, a 3-6 membered cycloalkyl, a 3-6 membered heterocycloalkyl, a phenyl, or a 5-6 membered heteroaryl. Alternatively, two R atoms on the same atom form an oxo. 【Request Item 2】 【Chemistry 4】 The compound according to claim 1, wherein the bond is a double bond, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. Z １ However, C(R ６ ) or N, Z ２ However, C(R ７ ) or N, Z ３ However, C(R ８ The compound according to claim 1 or 2, which is N, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. R １ and R ２ However, independently, hydrogen, C １ ~C ６ Alkyl and C １ ~C ６ A compound selected from haloalkyls, according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

5. Equation (Ia) 【Transformation 5】 A compound according to any one of claims 1 to 4 having the structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. Formula (Ib) 【Transformation 6】 A compound according to any one of claims 1 to 4 having the structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. Formula (Ic) 【Transformation 7】 A compound according to any one of claims 1 to 4 having the structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. Formula (Id) 【Transformation 8】 A compound according to any one of claims 1 to 4 having the structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

9. Equation (Ie) 【Chemistry 9】 A compound according to any one of claims 1 to 4 having the structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. Equation (If) 【Chemistry 10】 A compound according to any one of claims 1 to 4 having the structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

11. R ６ However, hydrogen, halogen, -OH, -OR ａ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ A compound according to any one of claims 1 to 4, 6 to 8, or 10, selected from alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and 5- or 6 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R groups, or a pharmaceutically acceptable salt or stereoisomer thereof.

12. R ６ A compound according to any one of claims 1 to 4, 6 to 8, 10 or 11, wherein is hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof.

13. R ６ A compound according to any one of claims 1 to 4, 6 to 8, 10 or 11, wherein is a halogen, or a pharmaceutically acceptable salt or stereoisomer thereof.

14. R ６ ga- OR ａ The compound according to any one of claims 1 to 4, 6 to 8, 10, or 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

15. R ６ ga-OCH ３ The compound according to any one of claims 1 to 4, 6 to 8, 10, 11, or 14, or a pharmaceutically acceptable salt or stereoisomer thereof.

16. R ６ However, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ A compound according to any one of claims 1 to 4, 6 to 8, 10, or 11, wherein the alkyl and heteroalkyl are independently and optionally substituted with one or more R groups, or a pharmaceutically acceptable salt or stereoisomer thereof.

17. R ６ However, CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ OCH ３ , or -CH ２ CH ２ A compound according to any one of claims 1 to 4, 6 to 8, 10, 11, or 16, which is an OH group, or a pharmaceutically acceptable salt or stereoisomer thereof.

18. R ６ C ２ ~C ６ It is an alkynyl, and the alkynyl is optionally replaced by one or more R (for example, R ６ teeth 【Chemistry 11】 A compound according to any one of claims 1 to 4, 6 to 8, 10 or 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

19. R ６ However, C is replaced by one or more R at will. １ ~C ６ It is alkyl (for example, R ６ CH ３ A compound according to any one of claims 1 to 4, 6 to 8, 10 or 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

20. R ６ A compound according to any one of claims 1 to 4, 6 to 8, 10 or 11, wherein is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is independently optionally substituted with one or more Rs. A pharmaceutically acceptable salt or stereoisomer thereof.

21. R ６ but, 【Chemistry 12】 The compound according to any one of claims 1 to 4, 6 to 8, 10, 11, or 20, or a pharmaceutically acceptable salt or stereoisomer thereof.

22. R ６ The compound according to any one of claims 1 to 4, 6 to 8, 10 or 11, wherein the compound is phenyl or a five-membered or six-membered heteroaryl, and the phenyl or heteroaryl is independently and optionally substituted with one or more Rs.

23. R ６ but 【Chemistry 13】 The compound according to any one of claims 1 to 4, 6 to 8, 10, 11, or 22, or a pharmaceutically acceptable salt or stereoisomer thereof.

24. R ７ However, hydrogen, halogen, C １ ~C ６ Alkyl and C １ ~C ６ A compound according to any one of claims 1 to 5, 7, or 9 to 23, selected from a haloalkyl group, wherein the alkyl group is independently and optionally substituted with one or more R groups, or a pharmaceutically acceptable salt or stereoisomer thereof.

25. R ７ A compound according to any one of claims 1 to 5, 7, or 9 to 24, wherein is hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof.

26. R ７ However, C １ ~C ６ Alkyl and C １ ~C ６ A compound according to any one of claims 1 to 5, 7, or 9 to 24, which is a haloalkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

27. R ８ However, hydrogen, halogen, C １ ~C ６ Alkyl and C １ ~C ６ A compound selected from haloalkyls, according to any one of claims 1 to 6 and 10 to 26, or a pharmaceutically acceptable salt or stereoisomer thereof.

28. R ８ A compound according to any one of claims 1 to 6 and 10 to 27, wherein is hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof.

29. Each R independently controls halogen and C. １ ~C ３ Alkyl, or C １ ~C ３ A compound according to any one of claims 1 to 28, selected from haloalkyls, or a pharmaceutically acceptable salt or stereoisomer thereof.

30. A compound according to any one of claims 1 to 29, wherein ring A is a cycloalkyl or heterocycloalkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

31. A compound according to any one of claims 1 to 29, wherein ring A is phenyl, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 32】 【Chemistry 14】 but 【Chemistry 15】 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 33】 【Chemistry 16】 but 【Chemistry 17】 The compound according to any one of claims 1 to 29 or 32, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 34】 【Chemistry 18】 but 【Chemistry 19】 And R ３１ and R ３２ Each of them independently, R ３ A compound according to any one of claims 1 to 29 or 32, selected from the above, or a pharmaceutically acceptable salt or stereoisomer thereof.

35. A compound according to any one of claims 1 to 29, wherein ring A is a 5- to 6-membered heteroaryl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

36. A compound according to any one of claims 1 to 29 or 35, wherein ring A is a six-membered heteroaryl compound, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 37】 【Chemistry 20】 but, 【Chemistry 21】 A compound according to any one of claims 1 to 29, 35, or 36, selected from the above, or a pharmaceutically acceptable salt or stereoisomer thereof.

38. Each R ３ However, independently, halogen, -CN, -NO ２ -OH, oxo, -OR ａ -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, -C(=O)R ａ -OC(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -OC(=O)NR ｃ R ｄ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)R ａ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ It is a heteroalkyl, and each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has one or more R ３ａ A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt or stereoisomer thereof, which is optionally substituted by [the specified compound].

39. Each R ３ However, independently, halogen, -CN, -OH, -OR ａ -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, -C(=O)R ａ , -C(=O)NR ｃ R ｄ , -S(=O)R ａ , -S (=O) ２ R ａ , -NR ｃ R ｄ , -NR ｂ C(=O)R ａ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ It is a heteroalkyl, and each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently has one or more R ３ａ A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt or stereoisomer thereof, which is optionally substituted by [the specified compound].

40. Each R ３ However, independently, halogens, -L-5-membered or 6-membered heteroaryls, -L-3-membered or 6-membered heterocycloalkyls, and -C(=O)NR ｃ R ｄ , and C １ ~C ６ Selected from alkyl groups, each alkyl, heterocycloalkyl, and heteroaryl group independently comprises one or more R groups. ３ａ A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt or stereoisomer thereof, which is optionally substituted by [the specified compound].

41. Each R ３ａ However, independently, halogen, C １ ~C ６ Alkyl and C １ ~C ６ A compound according to any one of claims 1 to 40, optionally selected from haloalkyls, or a pharmaceutically acceptable salt or stereoisomer thereof.

42. L is a bond, -O-, -S-, -NH-, C １ ~C ４ Alkylene, or C １ ~C ４ A compound according to any one of claims 1 to 41, wherein the alkylene or the heteroalkylene is optionally substituted with one or more Rs, or a pharmaceutically acceptable salt or stereoisomer thereof.

43. A compound according to any one of claims 1 to 42, wherein L is -O-, or a pharmaceutically acceptable salt or stereoisomer thereof.

44. C where L is optionally replaced by one or more R's. １ ~C ４ A compound according to any one of claims 1 to 42, which is alkylene (for example, L is -C(=O)-), or a pharmaceutically acceptable salt or stereoisomer thereof.

45. C where L is optionally replaced by one or more R's. １ ~C ４ It is a heteroalkylene (for example, L is -C(=O)NHCH) ２ A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or stereoisomer thereof.

46. A compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 0, 1, 2, or 3.

47. A compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1 or 2. 【Request Item 48】 【Chemistry 22】 but, 【Chemistry 23】 A compound according to any one of claims 1 to 29, 38 to 42, 46, or 47, selected from among, or a pharmaceutically acceptable salt or stereoisomer thereof.

49. L １ However, bond, C １ ~C ４ Alkylene, C １ ~C ４ Heteroalkylene, C ２ ~C ４ Alkenylene, C ２ ~C ４ Alkynylene, 3-6 membered cycloalkylene, 3-6 membered heterocycloalkylene, phenylene, or 5-6 membered heteroarylene, wherein each of the alkylene, heteroalkylene, alkenylene, cycloalkylene, heterocycloalkylene, phenylene, or heteroarylene independently comprises one or more R ４ａ A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt or stereoisomer thereof, which is optionally substituted by [the specified compound].

50. L １ A compound according to any one of claims 1 to 49, wherein the bond is a compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

51. L １ However, C ２ ~C ４ A compound according to any one of claims 1 to 49, which is an alkynylene, or a pharmaceutically acceptable salt or stereoisomer thereof.

52. L １ However, one or more R ４ａ A compound according to any one of claims 1 to 49, wherein phenylene is optionally substituted, or a pharmaceutically acceptable salt or stereoisomer thereof.

53. L １ However, one or more R ４ａ A compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a 5-6 membered heteroarylene that is optionally substituted.

54. R ４ A compound according to any one of claims 1 to 53, wherein the ring is a monocyclic ring, or a pharmaceutically acceptable salt or stereoisomer thereof.

55. R ４ A compound according to any one of claims 1 to 53, wherein the ring is a bicyclic ring, or a pharmaceutically acceptable salt or stereoisomer thereof.

56. R ４ However, one or more R ４ａ It is an arrine that is optionally replaced (for example, R ４ teeth, 【Chemistry 24】 A compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or stereoisomer thereof.

57. R ４ However, it is a biring arylene, and the biring arylene is one or more R ４ａ A compound according to any one of claims 1 to 53, 55, or 56, comprising a phenyl compound condensed with a 5-6 member cycloalkyl group or a 5-6 member heterocycloalkyl group that is optionally substituted, or a pharmaceutically acceptable salt or stereoisomer thereof.

58. R ４ but, 【Chemistry 25】 The compound according to any one of claims 1 to 53 or 55 to 57, or a pharmaceutically acceptable salt or stereoisomer thereof.

59. R ４ However, one or more R ４ａ A compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heteroarylene is optionally substituted.

60. R ４ but, 【Chemistry 26】 The compound according to any one of claims 1 to 55 or 59, or a pharmaceutically acceptable salt or stereoisomer thereof.

61. R ４ However, one or more R ４ａ A compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cycloalkylene is optionally substituted.

62. R ４ but, 【Chemistry 27】 The compound according to any one of claims 1 to 55 or 61, or a pharmaceutically acceptable salt or stereoisomer thereof.

63. R ４ However, one or more R ４ａ A compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heterocycloalkylene is optionally substituted.

64. R ４ but, 【Chemistry 28】 The compound according to any one of claims 1 to 55 or 63, or a pharmaceutically acceptable salt or stereoisomer thereof.

65. Each R ４ａ However, independently, halogen, C １ ~C ６ Alkyl and C １ ~C ６ A compound selected from haloalkyls, according to any one of claims 1 to 64, or a pharmaceutically acceptable salt or stereoisomer thereof.

66. -L １ -R ４ -but, 【Chemistry 29】 A compound according to any one of claims 1 to 49 or 65, selected from the above, or a pharmaceutically acceptable salt or stereoisomer thereof.

67. A compound according to any one of claims 1 to 66, wherein X is a bond, or a pharmaceutically acceptable salt or stereoisomer thereof.

68. A compound according to any one of claims 1 to 66, wherein X is -C(=O)-, or a pharmaceutically acceptable salt or stereoisomer thereof.

69. A compound according to any one of claims 1 to 66, wherein X is -NHC(=O)-, or a pharmaceutically acceptable salt or stereoisomer thereof.

70. R Ｗ but 【Transformation 30】 The compound according to any one of claims 1 to 69, or a pharmaceutically acceptable salt or stereoisomer thereof.

71. R Ｗ but 【Chemistry 31】 The compound according to any one of claims 1 to 69, or a pharmaceutically acceptable salt or stereoisomer thereof.

72. R Ｗ A compound according to any one of claims 1 to 69, wherein is CN, or a pharmaceutically acceptable salt or stereoisomer thereof.

73. R １１ However, hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, and C １ ~C ６ A compound according to any one of claims 1 to 71, selected from heteroalkyls, wherein the alkyl and the heteroalkyl are optionally substituted with one or more Rs, or a pharmaceutically acceptable salt or stereoisomer thereof.

74. R １１ The compound according to any one of claims 1 to 71 and 73, wherein the compound is hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof.

75. R １１ However, C １ ~C ６ A compound according to any one of claims 1 to 71 and 73, which is alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

76. R １２ However, hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, and C １ ~C ６ A compound according to any one of claims 1 to 70 and 73 to 75, selected from heteroalkyls, wherein the alkyl and the heteroalkyl are optionally substituted with one or more Rs, or a pharmaceutically acceptable salt or stereoisomer thereof.

77. R １２ However, hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ A compound according to any one of claims 1 to 70 and 73 to 76, which is a haloalkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

78. R １２ A compound according to any one of claims 1 to 70 and 73 to 77, wherein is hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof.

79. R １２ A compound according to any one of claims 1 to 70 and 73 to 77, wherein is a halogen (for example, F), or a pharmaceutically acceptable salt or stereoisomer thereof.

80. R １３ However, hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Heteroalkylenes (cycloalkyls), and C １ ~C ６ A compound according to any one of claims 1 to 70 or 73 to 79, wherein the alkyl, the heteroalkyl, the alkylene, the heteroalkyl, the cycloalkyl, and the heterocycloalkyl are optionally substituted with one or more Rs, or a pharmaceutically acceptable salt or stereoisomer thereof.

81. R １３ However, hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Heteroalkylene (cycloalkyl), C １ ~C ６ A compound according to any one of claims 1 to 70 or 73 to 80, wherein the alkyl, the heteroalkyl, the alkylene, the heteroalkyl, the cycloalkyl, and the heterocycloalkyl are optionally substituted with one or more R, or a pharmaceutically acceptable salt or stereoisomer thereof.

82. R １３ A compound according to any one of claims 1 to 70 or 73 to 81, wherein is hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof.

83. - X - R Ｗ が、CN、 【Chemistry 32】 A compound according to any one of claims 1 to 82, selected from, or a pharmaceutically acceptable salt or stereoisomer thereof.

84. A compound according to claim 1, selected from the compounds in Table 1 or Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

85. A pharmaceutical composition comprising a compound according to any one of claims 1 to 84 or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

86. A method for regulating the activity of fibroblast growth factor receptor (FGFR) in a subject, comprising administering to the subject a compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 85.

87. A method for inhibiting the activity of fibroblast growth factor receptor (FGFR) in a subject, comprising administering to the subject a compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 85.

88. A method for inhibiting the activity of mutant fibroblast growth factor receptor (FGFR) in a subject, comprising administering to the subject a compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 85.

89. A method for treating cancer in a subject requiring treatment, comprising administering to the subject a compound according to any one of claims 1 to 84 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 85.

90. The method according to claim 89, wherein the cancer is a solid tumor.

91. The method according to claim 90, wherein the cancer is intrahepatic cholangiocarcinoma, urothelial carcinoma, gastric cancer, esophageal gastric cancer, colorectal cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, vaginal cancer, cervical cancer, glioma, head and neck cancer, other brain tumors, ovarian cancer, anal cancer, non-melanoma skin cancer, penile cancer, adrenocortical carcinoma, melanoma, ampulla cancer, Wilms' tumor, small intestine cancer, uterine sarcoma, salivary gland cancer, soft tissue sarcoma, retinoblastoma, or thyroid cancer.

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