Inhibitors of FGFR2 and FGFR3 and their use

Abstract

There are provided FGFR2 and FGFR3 inhibitors of formula (I) and pharmaceutical compositions comprising said inhibitors. The compounds and compositions are useful for treating diseases or disorders associated with FGFR2 and / or FGFR3. [Chemical 1] TIFF2025523588000225.tif40161

Description

Technical Field

[0001] Cross-reference This patent application claims the benefit of International Application No. PCT / CN2022 / 102136, filed on June 29, 2022, International Application No. PCT / CN2023 / 082796, filed on March 21, 2023, and International Application No. PCT / CN2023 / 097992, filed on June 2, 2023, which are hereby incorporated by reference in their entirety.

Background Art

[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 the FGF ligand causes receptor dimerization and subsequent phosphorylation of substrates such as FGFR substrate 2 (FRS2) and phospholipase Cγ (PLC-γ), further activating the downstream signaling cascade and leading to the regulation of important cellular functions including cell survival, proliferation, differentiation, migration, and angiogenesis (Clin. Cancer Res. 21(12), June 15, 2015). Aberrant activation of the FGFR signaling pathway due to FGFR fusions, mutations, and / or amplifications can lead to tumorigenesis, progression, and resistance to conventional cancer therapies. Pan-FGFR inhibitors have achieved significant clinical responses in multiple FGFR-altered cancers, but off-target toxicities including FGFR1-mediated dose-limiting toxicities such as hyperphosphatemia and tissue calcification, and FGFR4-mediated dose-limiting toxicities such as diarrhea have also been observed. 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.

Summary of the Invention

[0003] Formula (I):

Chemical Formula

Chemical formula

Chemical Structure

[0004] In some embodiments, formula (Ia):

Chemical Structure

[0005] In some embodiments, formula (Ib):

Chemical Formula

[0006] In some embodiments, formula (Ic):

Chemical Formula

[0007] In some embodiments, formula (Id):

Chemical Formula

[0008] In some embodiments, formula (Ie):

Chemical formula

[0009] In some embodiments, formula (Ia') or formula (Ia"):

Chemical formula

[0010] In some embodiments, formula (Ib') or formula (Ib"):

Chemical formula

[0011] In some embodiments, formula (Ic') or formula (Ic"): [Chemical formula] (wherein R 1 , R 2 , R 4 , R 4a , R 5 , R 6 , R 7 , R 10 , R 15aa , and L 1 (have the meanings defined herein) Compounds having the structure of , or pharmaceutically acceptable salts or stereoisomers thereof, are disclosed herein.

[0012] In some embodiments, pharmaceutical compositions comprising a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient are disclosed herein.

[0013] In some embodiments, provided herein is a method of treating cancer in a mammal in need thereof, the method comprising administering to the mammal a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, provided herein is a method of treating cancer in a mammal in need thereof, the method comprising administering to the mammal a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is a solid tumor. In some embodiments, provided herein is a method of treating cancer in a mammal in need thereof, the method comprising administering to the mammal a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is intrahepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.

[0014] Incorporation by reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Definitions In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the disclosed technology can be practiced without these specific details. In other instances, well-known structures have not been shown in detail and have not been described in order to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires a different interpretation, throughout this specification and the following claims, the word "comprise" and its variations, such as "comprises" and "comprising", are to be construed in an open and inclusive sense, that is, "including, but not limited to". Further, the headings provided herein are for convenience only and do not explain the scope or meaning of the claimed invention.

[0016] Throughout this specification, references to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Further, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" include plural referents. It should also be noted that the term "or" is generally used in its sense including "and / or" unless the context clearly dictates otherwise.

[0017] The following terms, when used in this specification, have the following meanings unless otherwise indicated.

[0018] "Oxo" refers to =O.

[0019] "Carboxyl" refers to -COOH.

[0020] "Cyano" refers to -CN.

[0021] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon monovalent group having from 1 to about 10 carbon atoms, more preferably from 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, and longer alkyl groups such as heptyl, octyl, etc. Whenever a numerical range, such as "C1-C6 alkyl" or "C 1~6 alkyl", appears in this specification, it means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses the presence of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C 1~10 alkyl. In some embodiments, alkyl is C 1~6 alkyl. In some embodiments, alkyl is C 1~5 alkyl. In some embodiments, alkyl is C 1~4 alkyl. In some embodiments, alkyl is C 1~3It is alkyl. Unless specifically specified otherwise in this specification, the alkyl 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 alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0022] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon monovalent group having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group may be in either the cis or trans configuration about the double bond(s), and it should be understood that both isomers are included. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever a numerical range, e.g., "C2-C6 alkenyl" or "C2-6 alkenyl", appears herein, it means that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also encompasses the presence of the term "alkenyl" when no numerical range is specified. Unless specifically stated otherwise herein, the alkenyl 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 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.

[0023] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever a numerical range, e.g., "C2-C6 alkynyl" or "C2-6 alkynyl", appears herein, it means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the presence of the term "alkynyl" where no numerical range is specified. Unless specifically stated otherwise herein, the alkynyl 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, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0024] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless specifically stated otherwise herein, the alkylene 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, 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.

[0025] "Alkoxy" is a group of the formula -OR a wherein R a is an alkyl group as defined. Unless specifically specified otherwise 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, and the like. 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.

[0026] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl group may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, aryl is a 6- to 10-membered aryl. In some embodiments, aryl is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, preiadene, pyrene, and triphenylene. Unless specifically specified otherwise herein, aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen. As used herein, "arylene" refers to a divalent aryl group as described herein. Arylene can be bonded through aryl at any suitable position. In some embodiments, when arylene contains an aryl fused with a cycloalkyl or heterocycloalkyl ring, arylene is bonded to aryl and cycloalkyl, or aryl and heterocycloalkyl. In some embodiments, when arylene contains an aryl fused with a cycloalkyl or heterocycloalkyl ring, arylene is bonded only to aryl.

[0027] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached via a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls have 3 to 15 carbon atoms (e.g., C3-C 15 fully saturated cycloalkyl or C3-C 15 cycloalkenyl), 3 to 10 carbon atoms (e.g., C3-C 10 fully saturated cycloalkyl or C3-C 10cycloalkyl 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), but not limited thereto. 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. Monocyclic cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl includes, for example, adamantyl, norbornyl, decalinyl, 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. Partially saturated cycloalkyl includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically specified herein, the cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. As used herein, "cycloalkylene" refers to a divalent cycloalkyl group described herein. In some embodiments, when the cycloalkylene contains a cycloalkyl fused to an aryl or heteroaryl ring, the cycloalkylene is bonded to the cycloalkyl and the aryl, or the cycloalkyl and the heteroaryl. In some embodiments, when the cycloalkylene contains a cycloalkyl fused to an aryl or heteroaryl ring, the cycloalkylene is bonded only to the cycloalkyl.

[0028] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0029] "Haloalkyl" refers to an alkyl group as defined above substituted by one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0030] "Hydroxyalkyl" refers to an alkyl group as defined above substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted by one hydroxyl. In some embodiments, the alkyl is substituted by 1, 2, or 3 hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0031] "Aminoalkyl" refers to an alkyl group as defined above, substituted by one or more amines. In some embodiments, the alkyl is substituted by one amine. In some embodiments, the alkyl is substituted by 1, 2, or 3 amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0032] "Heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms of the alkyl are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is bonded to the remainder of the molecule through a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is C1-C6 heteroalkyl, and the heteroalkyl is composed of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and the heteroalkyl is bonded to the remainder of the molecule through a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless specifically specified otherwise herein, heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0033] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring group containing 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 nitrogens. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, the heterocycloalkyl contains 1 nitrogen. In some embodiments, the heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless specifically specified herein, the heterocycloalkyl group may include a fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached via a non-aromatic ring atom), spiro, or bridged ring system, and may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. The nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Representative heterocycloalkyls have 2 to 15 carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl), 2 to 10 carbon atoms (e.g., C2-C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkyl having 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl), including but not limited to such heterocycloalkyl. Examples of such heterocycloalkyl groups include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl, including but not limited to these. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyl has 2 to 10 carbons in the ring. When referring to the number of carbon atoms in heterocycloalkyl, it is understood that the number of carbon atoms in heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, 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 specifically specified otherwise herein, the heterocycloalkyl may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. as follows. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. As used herein, "heterocycloalkylene" refers to a divalent heterocycloalkyl group described herein. In some embodiments, when heterocycloalkylene includes a heterocycloalkyl fused to an aryl or heteroaryl ring, the heterocycloalkylene is attached to the heterocycloalkyl and aryl, or the heterocycloalkyl and heteroaryl. In some embodiments, when heterocycloalkylene includes a heterocycloalkyl fused to an aryl or heteroaryl ring, the heterocycloalkylene is attached only to the heterocycloalkyl.

[0034] "Heteroaryl" refers to a 5- to 14-membered ring system group containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, heteroaryl contains 1 to 3 nitrogens. In some embodiments, heteroaryl contains 1 or 2 nitrogens. In some embodiments, heteroaryl contains 1 nitrogen. The heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system which may include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached via an aromatic ring atom) or bridged ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. In some embodiments, heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, heteroaryl is a 6-membered heteroaryl. In some embodiments, heteroaryl is a 5-membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4 - benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2 - a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2 - oxoazepinyl, oxazolyl, oxiranyl, 1 - oxidopyridinyl, 1 - oxidopyrimidinyl, 1 - oxidopyrazinyl, 1 - oxidopyridazinyl, 1 - phenyl - 1H - pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise herein, heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, - CN, - COOH, COOMe, - CF3, - OH, - OMe, - NH2, or - NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, - 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 groups described herein. In some embodiments, when the heteroarylene includes a heteroaryl fused to a cycloalkyl or heterocycloalkyl ring, the heteroarylene is attached to the heteroaryl and cycloalkyl, or the heteroaryl and heterocycloalkyl. In some embodiments, when the heteroarylene includes a heteroaryl fused to a cycloalkyl or heterocycloalkyl ring, the heteroarylene is attached only to the heteroaryl.

[0035] The terms "optional" or "optionally" mean that the event or circumstance described thereafter may or may not occur, and that the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "optionally substituted alkyl" means either "alkyl" as defined above or "substituted alkyl". Further, an optionally substituted group may not be substituted (e.g., -CH2CH3), may be fully substituted (e.g., -CF2CF3), may be monosubstituted (e.g., -CH2CH2F) or substituted at some level between full substitution and monosubstitution (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically infeasible and / or synthetically unrealizable. Thus, any substituents described are generally understood to have a maximum molecular weight of about 1,000 daltons, more typically about 500 daltons.

[0036] "Effective amount" or "therapeutically effective amount" 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 to produce the desired therapeutic effect.

[0037] "Treatment" of an individual (e.g., a mammal, e.g., a human) or a cell is any type of intervention used in an attempt to modify the natural course of the individual or cell. In some embodiments, the treatment includes 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., the condition does not worsen) or alleviation of the condition.

[0038] Compound Compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, useful in the treatment of diseases or disorders associated with FGFR2 and FGFR3 inhibition are described herein. In some embodiments, compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), 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 cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.

[0039] In some embodiments, formula (I): [Chemical formula] (wherein, Z 1 is absent, C(R 5 ), C(R 5 )(R 5a ), N, or N(R 9 ), Z 2 is C(R 6 ), C(R 6 )(R 6a ), O, S, N, or N(R 9 ), Z 3 is C(R 7 ), C(R 7 )(R 7a ), O, S, N, or N(R9 ) and Z 4 is C(R 8 ), C(R 8 )(R 8a ), O, S, N, or N(R 9 ), and Z 1 is C(R 5 ), C(R 5 )(R 5a ), N, or N(R 9 ), when Z 1 , Z 2 , Z 3 , and Z 4 are two or less of N or N(R 9 ), and when Z 1 is absent, Z 2 , Z 3 , and Z 4 are one or less of O, S, N, or N(R 9 ), and R 1 and R 2 are independently selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl, R 3 is selected from C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, C 6~10 aryl, and C 1~9 heteroaryl, and C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, C 6~10 aryl, and C 1~9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15a , and R 4 is selected from C 3~6 cycloalkylene, C 2~9 heterocycloalkylene, C 6~10 arylene, and C 1~9 heteroarylene, and C 3~6 cycloalkylene, C 2~9 heterocycloalkylene, C 6~10 arylene, and C1~9 The heteroarylene is optionally substituted with one, two, or three groups selected from R 15b and is optionally substituted with one, two, or three groups selected from R L 1 is a bond, -N(R 9a )-, -N(R 9a )C(O)-, -C(O)N(R 9a )-, -N(R 9a )S(O)2-, -S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1~6 alkylene, C 2~6 alkenylene, C 2~6 alkynylene, C 3~6 cycloalkylene, C 2~9 heterocycloalkylene, or C 1~9 heteroarylene, and C 1~6 alkylene, C 2~6 alkenylene, C 2~6 alkynylene, C 3~6 cycloalkylene, C 2~9 heterocycloalkylene, and C 1~9 heteroarylene is optionally substituted with one, two, or three groups selected from R 15c and is optionally substituted with one, two, or three groups selected from R L 2 is a bond, C 1~6 alkylene, C 2~6 alkenylene, or C 2~6 alkynylene, and C 1~6 alkylene, C 2~6 alkenylene, or C 2~6 alkynylene is optionally substituted with one, two, or three groups selected from R 15c and is optionally substituted with one, two, or three groups selected from R R 4a is halogen, -CN,

Chemical formula

[0040] In some embodiments of the compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, Z 1 is C(R 5 ), Z 2 is N, Z 3 is C(R 7 ), Z 4 is C(R 8 ). In some embodiments of the compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, Z 1 is C(R 5 ), Z 2 is C(R 6 ), Z 3 is N, Z 4 is C(R 8 ). In some embodiments of the compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, Z 1 is N, Z 2 is C(R 6 ), Z 3 is C(R 7 ), Z 4 is C(R 8 ). In some embodiments of the compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, Z 1 is C(R 5 ), Z 2 is C(R 6 ), Z 3 is C(R 7 ), Z 4 is N. In some embodiments of the compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, Z 1 is C(R 5 )(R 5a ), Z 2 is N(R 9 ), Z3 is C(R 7 )(R 7a ), and Z 4 is C(R 8 )(R 8a ). In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, Z 1 is absent, Z 2 is S, Z 3 is C(R 7 ), and Z 4 is C(R 8 ). In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, Z 1 is absent, Z 2 is O, Z 3 is C(R 7 ), and Z 4 is C(R 8 ). In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, Z 1 is absent, Z 2 is N(R 9 ), Z 3 is C(R 7 ), and Z 4 is C(R 8 ).

[0041] In some embodiments, formula (Ia):

Chemical Formula

Chemical formula

[0042] In some embodiments, formula (Ia'): [Chemical formula] (wherein, R 1 , R 2 , R 4 , R 4a , R 5, R 7 , R 8 , and L 1 have the same meaning as in formula (Ia), R 10 is halogen, -CN, hydroxy, C 1~6 alkyl, C 1~6 haloalkyl, and C 1~6 heteroaryl optionally substituted with one, two, or three groups selected from alkoxy) 1~9 Compounds of formula (Ia) having the structure of) , or a pharmaceutically acceptable salt or stereoisomer thereof, are disclosed herein.

[0043] In some embodiments, formula (Ia"):

Chemical formula

[0044] In some embodiments, formula (Ib):

Chemical formula

Chemical formula

[0045] In some embodiments, formula (Ib'): [Chemical formula] (wherein R 1 、R 2 、R 4 、R 4a 、R 5 、R 6 、R 8 、and L 1 have the same meanings as in formula (Ib), R 10 is a C 1~6 alkyl, C 1~6 haloalkyl, and C 1~6 alkoxy, optionally substituted with one, two, or three groups selected from these, and is a C 1~9 heteroaryl) Compounds of formula (Ib) having the structure of

[0046] [Chemical formula] (wherein R 1 、R 2 、R 4 、R 4a 、R 5 、R 6 、R 8 、R 10 、and L 1 have the same meanings as in formula (Ib), R 15aa has the same meaning as R 15a in formula (Ib)) Compounds of formula (Ib) having the structure of

[0047] In some embodiments, formula (Ic): [Chemical formula] (wherein, R 1 and R 2 are each independently selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl, R 3 is selected from C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, C 6~10 aryl, and C 1~9 heteroaryl, and C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, C 6~10 aryl, and C 1~9 heteroaryl are each optionally substituted with one, two, or three groups selected from R 15a , R 4 is selected from C 3~6 cycloalkylene, C 2~9 heterocycloalkylene, C 6~10 arylene, and C 1~9 heteroarylene, and C 3~6 cycloalkylene, C 2~9 heterocycloalkylene, C 6~10 arylene, and C 1~9 heteroarylene are each optionally substituted with one, two, or three groups selected from R 15b , L 1 is a bond, -N(R 9a )-, -N(R 9a )C(O)-, -C(O)N(R 9a )-, -N(R 9a )S(O)2-, -S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1~6 alkylene, C 2~6 alkenylene, C 2~6 alkynylene, C 3~6 cycloalkylene, C 2~9 heterocycloalkylene, or C 1~9 heteroarylene, and C1~6 alkylene, C 2~6 alkenylene, C 2~6 alkynylene, C 3~6 cycloalkylene, C 2~9 heterocycloalkylene, and C 1~9 heteroarylene is optionally substituted with one, two, or three groups selected from R 15c and is optionally substituted with one, two, or three groups selected from R L 2 is a bond, C 1~6 alkylene, C 2~6 alkenylene, or C 2~6 alkynylene, and C 1~6 alkylene, C 2~6 alkenylene, or C 2~6 alkynylene is optionally substituted with one, two, or three groups selected from R 15c and is optionally substituted with one, two, or three groups selected from R R 4a is halogen, -CN,

Chemical formula

[0048] In some embodiments, formula (Ic'):

Chemical formula

[0049] In some embodiments, formula (Ic"):

Chemical formula

[0050] In some embodiments of the compounds of formula (Ia"), (Ib"), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, R 15aa is halogen, -CN, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, -CH2-C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, -CH2-C 2~9 heterocycloalkyl, C 6~10 aryl, -CH2-C 6~10 aryl, C 1~9 heteroaryl, -CH2-C 1~9 heteroaryl, -OR 10 , -SR 10 , -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 ), -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R11 )、 -S(=O)(=NH)(R 13 )、 -S(=O)(=NR 13 )R 13 、 -CH2C(O)N(R 10 )(R 11 )、 -CH2N(R 12 )C(O)R 13 、 -CH2S(O)2R 13 、 -CH2S(O)2N(R 10 )(R 11 )、 -Si(C 1~6 alkyl)3、 and -P(O)(R 10 )2, selected from C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, -CH2-C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, -CH2-C 2~9 heterocycloalkyl, C 6~10 aryl, -CH2-C 6~10 aryl, -CH2-C 1~9 heteroaryl, and C 1~9 heteroaryl are halogen, oxo, -CN, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, -OR 10 、 -SR 10 、 -SF5、 -N(R 10 )(R 11 )、 -C(O)OR 10 、 -OC(O)N(R 10 )(R 11 )、 -N(R 12 )C(O)N(R 10 )(R 11 )、 -N(R 12 )C(O)OR 13 、 -N(R 12 )S(O)2R 13 、 -C(O)R 13 、 -S(O)R 13 、 -OC(O)R 13 、 -C(O)N(R 10 )(R 11)、 -C(O)C(O)N(R 10 )(R 11 )、 -N(R 12 )C(O)R 13 、 -S(O)2R 13 、 -S(O)2N(R 10 )(R 11 ) -、 -N=S(=O)(R 13 )2、 -S(=O)(=NH)N(R 10 )(R 11 )、 -S(=O)(=NH)(R 13 )、 -S(=O)(=NR 13 )R 13 、 -CH2C(O)N(R 10 )(R 11 )、 -CH2N(R 12 )C(O)R 13 、 -CH2S(O)2R 13 、 -CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2, and is optionally substituted with one, two, or three groups independently selected from the following. In some embodiments of the compounds of formula (Ia"), (Ib''), or (Ic''), or pharmaceutically acceptable salts or stereoisomers thereof, R 15aa is halogen, -CN, C 1~6 alkyl, -OR 10 、 -N(R 10 )(R 11 )、 -C(O)OR 10 、 -N(R 12 )S(O)2R 13 、 -C(O)R 13 、 -S(O)R 13 、 -C(O)N(R 10 )(R 11 )、 -C(O)C(O)N(R 10 )(R 11 )、 -N(R 12 )C(O)R 13 、 -S(O)2R 13 、 and -S(O)2N(R 10 )(R 11 ) -, and is selected from C 1~6 alkyl is halogen, -CN, C 1~6 alkyl, C 1~6Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 10 , and -N(R 10 )(R 11 ) and is optionally substituted with one, two, or three groups independently selected from. In some embodiments, R 15aa is halogen, C 1~6 alkyl, and -OCH3, a compound of formula (Ia"), (Ib"), or (Ic"), or a pharmaceutically acceptable salt or stereoisomer thereof is disclosed herein. In some embodiments, R 15aa is halogen, a compound of formula (Ia"), (Ib"), or (Ic"), or a pharmaceutically acceptable salt or stereoisomer thereof is disclosed herein. In some embodiments, R 15aa is methyl or fluorine, a compound of formula (Ia"), (Ib"), or (Ic"), or a pharmaceutically acceptable salt or stereoisomer thereof is disclosed herein. In some embodiments, R 15aa is fluorine, a compound of formula (Ia"), (Ib"), or (Ic"), or a pharmaceutically acceptable salt or stereoisomer thereof is disclosed herein.

[0051] In some embodiments, R 10 is optionally substituted with one, two, or three groups independently selected from halogen, -CN, hydroxy, C 1~6 alkyl, C 1~6 haloalkyl, and C 1~6 alkoxy. A compound of formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic"), or a pharmaceutically acceptable salt or stereoisomer thereof is disclosed herein. In some embodiments, R 1~9 is optionally substituted with one, two, or three groups independently selected from halogen, -CN, hydroxy, C 10 alkyl, C 1~6 haloalkyl, and C 1~6 alkoxy. A compound of formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic"), or a pharmaceutically acceptable salt or stereoisomer thereof is disclosed herein. In some embodiments, R 1~6Compounds of formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic") which are 5- to 6-membered heteroaryl optionally substituted with 1, 2, or 3 groups selected from alkoxy, or a pharmaceutically acceptable salt or stereoisomer thereof are disclosed herein. In some embodiments, R 10 is 1~6 Compounds of formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic") which are 5- to 6-membered heteroaryl optionally substituted with 1 group selected from C 10 alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof are disclosed herein. In some embodiments, R 1~6 is pyridyl or pyrimidinyl, and pyridyl and pyrimidinyl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, hydroxy, C 1~6 alkyl, C 1~6 haloalkyl, and C 10 alkoxy, or a pharmaceutically acceptable salt or stereoisomer thereof are disclosed herein. In some embodiments, R 1~6 is pyridyl or pyrimidinyl, and pyridyl and pyrimidinyl are substituted with 1, 2, or 3 groups selected from C 10is a compound of formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic") optionally substituted with one or more substituents selected from 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, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl, or a pharmaceutically acceptable salt or stereoisomer thereof is disclosed herein. In some embodiments, R 10is a compound of formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic") optionally substituted with one or more substituents selected from halogen, -CN, -OH, -SF5, -SH, -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, -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, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl, or a pharmaceutically acceptable salt or stereoisomer thereof is disclosed herein. In some embodiments, R 10 is

Chemical formula

Chemical formula

Chemical formula

[0052] In some embodiments, formula (Id):

Chemical formula

Chemical formula

[0053] In some embodiments, the compound of formula (Ie): [ka] (In the formula, R 1 and R 2 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; R 3 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl and C 1~9 heteroaryl; C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl and C 1~9 Heteroaryl is R 15a and optionally substituted with one, two, or three groups selected from R 4 is C 3~6 Cycloalkylene, C 2~9 Heterocycloalkylene, C 6~10 Arylene, and C 1~9 heteroarylene; C 3~6 Cycloalkylene, C 2~9 Heterocycloalkylene, C6~10 Arylene, and C 1~9 Heteroarylene is optionally substituted with 1, 2, or 3 groups selected from R 15b and is optionally substituted with 1, 2, or 3 groups selected from R L 1 is a bond, -N(R 9a )-, -N(R 9a )C(O)-, -C(O)N(R 9a )-, -N(R 9a )S(O)2-, -S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1~6 alkylene, C 2~6 alkenylene, C 2~6 alkynylene, C 3~6 cycloalkylene, C 2~9 heterocycloalkylene, or C 1~9 heteroarylene, and C 1~6 alkylene, C 2~6 alkenylene, C 2~6 alkynylene, C 3~6 cycloalkylene, C 2~9 heterocycloalkylene, and C 1~9 heteroarylene is optionally substituted with 1, 2, or 3 groups selected from R 15c and is optionally substituted with 1, 2, or 3 groups selected from R L 2 is a bond, C 1~6 alkylene, C 2~6 alkenylene, or C 2~6 alkynylene, and C 1~6 alkylene, C 2~6 alkenylene, or C 2~6 alkynylene is optionally substituted with 1, 2, or 3 groups selected from R 15c and is optionally substituted with 1, 2, or 3 groups selected from R R 4a is halogen, -CN,

Chemical formula

[0054] In some embodiments of the compound of formula (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 9 is hydrogen, and R 15f is C optionally substituted with one, two or three groups selected from 1~6 alkyl. In some embodiments of the compound of formula (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 9 is hydrogen and unsubstituted C 1~6 alkyl. In some embodiments of the compound of formula (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 9 is hydrogen. In some embodiments of the compound of formula (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 9 is R 15f is C optionally substituted with one, two or three groups selected from 1~6 alkyl. In some embodiments of the compound of formula (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 9 is unsubstituted C 1~6 alkyl.

[0055] In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 5 is selected from hydrogen, halogen, -OR 10 , and C 1~6 alkyl, where C 1~6 alkyl is R 15eis optionally substituted with one, two, or three groups selected from. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 5 is hydrogen, and R 15e is optionally substituted with one, two, or three groups selected from C 1~6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 5 is hydrogen and unsubstituted C 1~6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 5 is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 5 is R 15e is optionally substituted with one, two, or three groups selected from C 1~6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 5 is unsubstituted C 1~6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 5is a halogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 5 is -OR 10 In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 5 is -OR 10 and R 10 is selected from hydrogen and C 1~6 alkyl.

[0056] In some embodiments of the compounds of formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or pharmaceutically acceptable salts or stereoisomers thereof, R 6 is selected from hydrogen, halogen, -OR 10 , and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with one, two, or three groups selected from R 15e In some embodiments of the compounds of formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or pharmaceutically acceptable salts or stereoisomers thereof, R 6 is selected from hydrogen and C 15e alkyl optionally substituted with one, two, or three groups selected from R 1~6 In some embodiments of the compounds of formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or pharmaceutically acceptable salts or stereoisomers thereof, R 6 is selected from hydrogen and unsubstituted C 1~6 alkyl. In some embodiments of the compounds of formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or pharmaceutically acceptable salts or stereoisomers thereof, R6 is hydrogen. In some embodiments of the compound of formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 is R 15e alkyl optionally substituted with one, two, or three groups selected from R 1~6 is alkyl. In some embodiments of the compound of formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 is unsubstituted C 1~6 alkyl. In some embodiments of the compound of formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 is unsubstituted C 1~3 alkyl. In some embodiments of the compound of formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 is methyl. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 is halogen. In some embodiments of the compound of formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 is -OR 10 . In some embodiments of the compound of formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 is -OR 10 and R 10 is selected from hydrogen and C 1~6 alkyl.

[0057] In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 is selected from hydrogen, halogen, -OR 10 , and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with one, two, or three groups selected from R 15e . In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 is selected from hydrogen and C 15e alkyl optionally substituted with one, two, or three groups selected from R 1~6 . In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 is selected from hydrogen and unsubstituted C 1~6 alkyl. In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 is hydrogen. In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 is C 15e alkyl optionally substituted with one, two, or three groups selected from R 1~6 . In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 is unsubstituted C 1~6is alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 7 is halogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 7 is -OR 10 In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 7 is -OR 10 wherein R 10 is selected from hydrogen and C 1~6 alkyl.

[0058] In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 8 is selected from hydrogen, halogen, -OR 10 and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with one, two, or three groups selected from R 15e In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 8 is selected from hydrogen and C 15e alkyl optionally substituted with one, two, or three groups selected from R 1~6 In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 8 is selected from hydrogen and unsubstituted C 1~6is selected from alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 8 is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 8 is R 15e is C optionally substituted with one, two, or three groups selected from 1~6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 8 is unsubstituted C 1~6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 8 is halogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 8 is -OR 10 . In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 8 is -OR 10 and R 10 is selected from hydrogen and C 1~6 alkyl.

[0059] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, L 2 is a bond or R 15cC optionally substituted with 1, 2, or 3 groups selected from 1~6 is alkylene. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, L 2 is a bond. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, L 2 is 15c C optionally substituted with 1, 2, or 3 groups selected from 1~6 is alkylene. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, L 2 is unsubstituted C 1~6 alkylene.

[0060] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 3 is 6~10 selected from aryl and C 1~9 heteroaryl, wherein aryl and C 6~10 heteroaryl are optionally substituted with 1, 2, or 3 groups selected from 1~9 In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 15a is 3 C optionally substituted with 1, 2, or 3 groups selected from 15a In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 6~10 is aryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 3 is 15aphenyl optionally substituted with one, two, or three groups selected from 3 is phenyl substituted with one, two, or three groups selected from 15a In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 3 is 15a C 1~9 heteroaryl optionally substituted with one, two, or three groups selected from 3 is 15a C 1~9 heteroaryl substituted with one, two, or three groups selected from

[0061] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 3 is substituted with R 15a wherein R 15a is -OCH3,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0062] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 3 is

Chemical formula

[0063] In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4 is C 6~10 arylene and C 1~9 heteroarylene, selected from C 6~10 arylene and C 1~9 heteroarylene is optionally substituted with one, two, or three groups selected from R 15b . In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4 is C 2~9 heterocycloalkylene, C 6~10 arylene, and C 1~9 heteroarylene, selected from C 2~9 heterocycloalkylene, C 6~10 arylene and C 1~9 heteroarylene is optionally substituted with one, two, or three groups selected from R 15b . In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4 is optionally substituted with one, two, or three groups selected from R 15b a C 6~10It is arylene. In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is phenylene optionally substituted with one, two, or three groups selected from R 15b In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is phenylene substituted with one, two, or three groups selected from R 15b In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is unsubstituted phenylene. In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is

Chemical formula

Chemical formula

Chemical formula

Chemical Structure

[0064] In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is C 15b cycloalkylene optionally substituted with one, two, or three groups selected from R 3~6 is as follows.

[0065] In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is C 15b cycloalkylene optionally substituted with one, two, or three groups selected from R 3~10 is as follows. In some embodiments, C 3~10 cycloalkylene is a bicyclic ring. In some embodiments, C 3~10 cycloalkylene contains a cycloalkyl fused to an aryl or heteroaryl. In some embodiments, C 3~10 cycloalkylene contains a cycloalkyl fused to an aryl or heteroaryl, and the cycloalkyl is bonded to the carbon marked with an asterisk

Chemical Structure

[0066] In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is 15b C 2~9 heterocycloalkylene optionally substituted with one, two, or three groups selected from 2~9 In some embodiments, C 4 heterocycloalkylene is a monocyclic ring. In some embodiments, R

Chemical formula

Chemical formula

Chemical formula

[0067] In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is 15b C 6~10It is an arylene. In some embodiments, C 6~10 The arylene is a monocyclic ring. In some embodiments, R 4 is optionally substituted phenylene. In some embodiments, R 4 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0068] In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is 15b C optionally substituted with one, two, or three groups selected from 1~9 is heteroarylene. In some embodiments, C 1~9 heteroarylene is a monocyclic ring. In some embodiments, R 4 is [Chemistry] is as follows. In some embodiments, R 4 is [Chemistry] is as follows. In some embodiments, R 4 is [Chemistry] is as follows. In some embodiments, C 1~9 heteroarylene is a bicyclic ring. In some embodiments, C 1~9 heteroarylene includes heteroaryl fused to cycloalkyl or heterocycloalkyl. In some embodiments, C 1~9 heteroarylene includes heteroaryl fused to a 5- to 6-membered cycloalkyl or a 5- to 6-membered heterocycloalkyl. In some embodiments, C 1~9 heteroarylene includes heteroaryl fused to cycloalkyl or heterocycloalkyl, and the heteroaryl is bonded to the carbon marked with an asterisk [Chemistry] , cycloalkyl or heterocycloalkyl is attached to L 1 and is attached to R 4 In some embodiments, R

Chemical Formula

Chemical formula

[0069] In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4a is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0070] In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b , R 4c , and R 4d are each independently hydrogen, halogen, -CN, -C(O)R 13 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), -N(R 10 )(R 11 ), -C 1~6 alkyl-N(R 10 )(R 11 ), -C(O)N(R 10 )OR 10 , C 1~6 alkyl, phenyl, 3- to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b , R 4c , and R 4d are each independently hydrogen, C 1~6 alkyl, or -C 1~6 alkyl-N(R 10 )(R 11 ). In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b , R 4c , and R 4dis, independently of each other, hydrogen, halogen, C 1~6 alkyl, or -C 1~6 alkyl-N(R 10 )(R 11 ), and the alkyl is optionally substituted with 1, 2, or 3 R 15d . In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b is hydrogen, halogen, or C 1~6 alkyl, and the alkyl is optionally substituted with 1, 2, or 3 R 15d . In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b is halogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b is F. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b is C 1~6is alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b is C 15d alkyl optionally substituted with one, two, or three R 1~6 is alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b is C 1~3 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b is CH3. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b is C 15d alkyl substituted with one, two, or three R 1~6 is alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b is C 1~6 alkyl-OR 10 is C 4b alkyl-OR 1~3 is C 10is as follows. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b is -CH2OH or CH2OCH3. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c is C 1~6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c is -C 1~6 alkyl-N(R 10 )(R 11 ). In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c is -CH2-N(CH3)2. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4d is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4d is C1~6 is alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4d is -C 1~6 alkyl-N(R 10 )(R 11 ) is. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4d is -CH2-N(CH3)2. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c and R 4d are each independently hydrogen or -C 1~6 alkyl-N(R 10 )(R 11 ) is. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c and R 4d are each independently hydrogen or -CH2-N(CH3)2. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c and R 4d are each independently hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c is -CH2-N(CH3)2, and R4d is hydrogen. In some embodiments, R 4b , R 4c , and / or R 4d is hydrogen that contains deuterium at a percentage higher than the natural abundance ratio of deuterium. In some embodiments, R 4b , R 4c , and / or R 4d is hydrogen in which one or more protons are replaced by one or more deuteriums.

[0071] In some embodiments of the compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0072] In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 1 and R 2 are independently selected from hydrogen and C 1~6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 1 and R 2 are hydrogen. In some embodiments of the compounds of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, R 1 is hydrogen and R 2 is C 1~6 alkyl.

[0073] In some embodiments, R 10is a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, optionally substituted with one or more substituents selected from 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, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl. In some embodiments, R 10is a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, optionally substituted with one or more substituents selected from halogen, -CN, -OH, -SF5, -SH, -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, -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, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl, is disclosed herein.

[0074] In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, each R 11 is independently selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl.

[0075] In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 10 and R 11 together with the nitrogen to which they are attached form a C 2~9forms a heterocycloalkyl. In some embodiments of a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 10 and R 11 together with the nitrogen to which they are attached form

Chemical formula

[0076] In some embodiments of a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, each R 13 is independently selected from C 1~6 alkyl, C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, and C 1~6 alkyl, C 3~6 cycloalkyl, C 2~9 heterocycloalkyl is optionally substituted with one, two, or three groups selected from halogen, C 1~6 alkyl, and C 1~6 haloalkyl. In some embodiments of a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, each R 13 is

Chemical formula

[0077] In some embodiments of a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, each R 15bis independently halogen, oxo, -CN, C 1~6 alkyl, C 3~10 cycloalkyl, -CH2-C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, -CH2-C 2~9 heterocycloalkyl, -OR 10 , -SR 10 , -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 selected from, C 1~6 alkyl, C 3~10 cycloalkyl, -CH2-C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, and -CH2-C 2~9 heterocycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, oxo, -CN, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, -OH, -SH, and amino. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15b is independently selected from halogen, C 1~6 alkyl, -OR 10 selected from, C 1~6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, -OH, -SH, and amino. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15bis a halogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15b is C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, -OH, -SH, and amino. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15b is a halogen. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15b is C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with one, two, or three groups independently selected from -OH. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15b is -OR 10 .

[0078] In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15c is independently halogen, oxo, -CN, C 1~6 alkyl, C 3~10Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, -OR 10 , -SR 10 , -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 selected from, C 1~6 alkyl, C 3~10 cycloalkyl, -CH2-C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, and -CH2-C 2~9 heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, -OH, -SH, and amino. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15c is independently selected from halogen, oxo, -OH, -CN, C 1~6 alkyl, C 1~6 alkoxyl, and amino, and C 1~6 alkyl is optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, -OH, -SH, and amino. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15c is independently selected from halogen, -OH, C 1~6 alkoxyl, and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with one, two, or three halogens.

[0079] In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15d is independently halogen, oxo, -CN, C 1~6 alkyl, C 3~10 cycloalkyl, -CH2-C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, -CH2-C 2~9 heterocycloalkyl, -OR 10 , -SR 10 , -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 selected from, C 1~6 alkyl, C 3~10 cycloalkyl, -CH2-C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, and -CH2-C 2~9 heterocycloalkyl are optionally substituted with 1, 2, or 3 groups independently selected from halogen, oxo, -CN, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, -OH, -SH, and amino. In some embodiments of the compounds of formula ((I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15d is independently halogen, oxo, -OH, -CN, C 1~6 alkyl, C 1~6 alkoxyl, and amino selected from, C 1~6Alkyl is optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, -OH, -SH, and amino. In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15d is independently selected from halogen, -OH, and C 1~6 alkyl, where C 1~6 alkyl is optionally substituted with one, two, or three halogens.

[0080] In some embodiments of the compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15e is independently selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl.

[0081] In some embodiments of the compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15f is independently selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl.

[0082] In some embodiments of the compounds of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, each R 15g is independently selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl.

[0083] Any combination of the above groups for the various variable elements is contemplated herein. Throughout this specification, the groups and their substituents are selected by one of ordinary skill in the art to obtain stable moieties and compounds.

[0084] In some embodiments, [Chemistry] Compounds selected from TIFF2025523588000099.tif223165, TIFF2025523588000100.tif244160, TIFF2025523588000101.tif255159, TIFF2025523588000102.tif111161, or pharmaceutically acceptable salts or stereoisomers thereof are disclosed herein.

[0085] In some embodiments, [Chemistry] Compounds selected from TIFF2025523588000104.tif84162, or pharmaceutically acceptable salts or stereoisomers thereof are disclosed herein.

[0086] 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 provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some situations, the compounds described herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers obtained from a single preparative step, combination, or interconversion are useful for the uses described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, separable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by taking advantage of 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 from the resolving agent by any practical means that does not result in racemization.

[0087] Labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, respectively 2 H(D), 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds described herein, and pharmaceutically acceptable salts or stereoisomers thereof, containing the foregoing isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically labeled compounds, for example, radioactive isotopes, such as 3 H and 14 C incorporated ones are useful in drug and / or substrate tissue distribution assays. Tritiation, i.e., 3 H and carbon-14, i.e., 14 C isotopes are particularly preferred because of the ease of their preparation and detectability.

[0088] In some embodiments, the abundance ratio of deuterium in each of the substituents disclosed herein 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%. In some embodiments, one or more of the substituents disclosed herein contain deuterium at a percentage higher than the natural abundance ratio of deuterium. In some embodiments, one or more 1 H is replaced by one or more deuteriums in one or more of the substituents disclosed herein.

[0089] In some embodiments, the compounds described herein are labeled by other means including, but not limited to, the use of a chromophore or fluorophore, a bioluminescent label, or a chemiluminescent label.

[0090] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0091] In some embodiments, the compounds described herein have acidic or basic groups and thus react with some inorganic or organic bases and with either inorganic or organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared by reacting in situ during the final isolation and purification of the compounds disclosed herein, or of their stereoisomers, or by separately reacting the purified compound in free form with a suitable acid or base and isolating the salt thus formed.

[0092] Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds described herein with a mineral, organic acid, or inorganic base, such salts being acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0093] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, 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-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, which is not itself pharmaceutically acceptable, are used in the preparation of salts useful as intermediates to obtain the compounds disclosed herein or their stereoisomers and their pharmaceutically acceptable acid addition salts.

[0094] In some embodiments, compounds described herein that contain a free acid group react with a suitable base, such as a hydroxide, carbonate, bicarbonate, sulfate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, etc. Examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 alkyl)4, etc.

[0095] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0096] Tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the scope of the formulas described herein. Tautomers are compounds that are interconvertible by the movement of a hydrogen atom accompanied by the switching of a single bond and an adjacent double bond. In bond arrangements where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors including temperature, solvent, and pH.

[0097] Methods of treatment A method of treating a disease in which inhibition of FGFR2 and / or FGFR3 is beneficial, the method comprising administering a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating a disease in which inhibition of FGFR2 is beneficial, the method comprising administering a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating a disease in which inhibition of FGFR3 is beneficial, the method comprising administering a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating a disease in which inhibition of FGFR2 and FGFR3 is beneficial, the method comprising administering a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein.

[0098] A method of treating a disease or disorder associated with FGFR2 and / or FGFR3, comprising the step of administering to a subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating a disease or disorder associated with FGFR2, comprising the step of administering to a subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating a disease or disorder associated with FGFR3, comprising the step of administering to a subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating a disease or disorder associated with FGFR2 and FGFR3, comprising the step of administering to a subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein.

[0099] A method of treating cancer in a subject, comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating cancer in a subject, comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is selected from intrahepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer, is disclosed herein. In some embodiments, a method of treating intrahepatic cholangiocarcinoma in a subject, comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating urothelial cancer in a subject, comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating gastric cancer in a subject, comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein.In some embodiments, a method of treating bladder cancer in a subject, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating breast cancer in a subject, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating endometrial cancer in a subject, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating kidney cancer in a subject, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating liver cancer in a subject, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein.In some embodiments, a method of treating lung cancer in a subject, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating melanoma in a subject, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating pancreatic cancer in a subject, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating prostate cancer in a subject, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein. In some embodiments, a method of treating thyroid cancer in a subject, the method comprising administering to the subject a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is disclosed herein.

[0100] Administration In certain embodiments, the composition(s) containing the compound(s) described herein is administered for prophylactic and / or therapeutic treatment. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous therapy, the health status, weight, and response of the patient to the drug, as well as the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0101] In prophylactic use, the composition containing the compound described herein is administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount is likewise dependent on the health status, weight, etc. of the patient. When used in a patient, the effective amount for this use depends on the severity and course of the disease, disorder or condition, previous therapy, the health status of the patient and response to the drug, as well as the judgment of the treating physician. In one aspect, prophylactic treatment is carried out by administering to a mammal that has previously experienced at least one symptom of the disease to be treated or a risk factor thereof and is currently in remission, a pharmaceutical composition comprising the compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent recurrence of the symptoms of the disease or condition.

[0102] In certain embodiments where the patient's condition does not improve, the administration of the compound is carried out chronically, i.e., over an extended period including the entire lifetime of the patient, at the discretion of the physician, in order to improve or otherwise control or limit the symptoms of the patient's disease or condition.

[0103] The amount of a given agent corresponding to such an amount will vary depending on factors such as a particular compound, disease state and its severity, identification of the subject or host in need of treatment (e.g., weight, gender), but nevertheless is determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0104] However, generally, the dosage used for the treatment of adults is typically in the range of 0.01 mg to 5000 mg per day. In one aspect, the dosage used for the treatment of adults is from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently provided as a single dose or as divided doses administered simultaneously or at appropriate intervals, e.g., as two, three, four or more partial doses per day.

[0105] In one embodiment, a suitable daily dosage of the compounds described herein, or a pharmaceutically acceptable salt thereof, is from about 0.01 to about 50 mg per kg of body weight. In some embodiments, the daily dosage, or the amount of the active substance in the dosage form, is less than or more than the ranges indicated herein, based on several variable factors regarding the individual treatment regimen. In various embodiments, the daily and unit dosages may be varied according to several variable factors including, but not limited to, the activity of the compound being used, the disease or condition being treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0106] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of LD 10 and ED 90 The dose ratio between the toxic and therapeutic effects is the therapeutic index and is LD 50 versus ED 50It is expressed as a ratio to. In certain embodiments, data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dosage range and / or therapeutically effective unit dosage for use in mammals including humans. In some embodiments, the daily dosage of the compounds described herein is the ED with minimal toxicity 50 is within the range of circulating concentrations including. In certain embodiments, the daily dosage range and / or unit dosage vary within this range depending on the dosage form used and the route of administration utilized.

[0107] In any of the foregoing aspects, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered to a mammal by injection, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal, which are further embodiments.

[0108] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of a compound, including (i) the compound is administered once a day, or (ii) the compound is administered to a mammal multiple times over a period of one day.

[0109] In any of the foregoing aspects, further embodiments include multiple administrations of an effective amount of a compound, including (i) the compound is administered continuously or intermittently, such as in a single dose or multiple doses, (ii) the time between multiple administrations is every 6 to 12 hours, (iii) the compound is administered to a mammal every 1 to 2 days, or (iv) the compound is administered to a subject weekly or monthly.

[0110] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intracerebroventricular, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0111] In certain embodiments, the compounds described herein are administered in a local rather than a systemic manner, often as depot or sustained release formulations, for example, by direct injection of the compound into an organ. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Further, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in liposomes coated with an organ-specific antibody. In such embodiments, the liposomes are targeted to and selectively taken up by the organ. Still further, in other embodiments, the compounds described herein are provided in the form of immediate release formulations, extended release formulations, or intermediate release formulations. Still further, in other embodiments, the compounds described herein are administered topically.

[0112] Pharmaceutical Composition / Formulation The compounds described herein are administered to a subject in need thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition, according to standard pharmaceutical practices. In some embodiments, the compounds of this disclosure may be administered to animals. The compounds can be administered orally or parenterally, including by intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0113] In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprising a compound of formula (I) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient is disclosed herein. In some embodiments, a pharmaceutical composition comprising a compound of formula (Ia) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient is disclosed herein. In some embodiments, a pharmaceutical composition comprising a compound of formula (Ib) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient is disclosed herein. In some embodiments, a pharmaceutical composition comprising a compound of formula (Ic) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient is disclosed herein. In some embodiments, a pharmaceutical composition comprising a compound of formula (Id) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient is disclosed herein. In some embodiments, a pharmaceutical composition comprising a compound of formula (Ie) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient is disclosed herein.

[0114] 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 preparation. Suitable formulations depend on the chosen route of administration. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (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, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0115] In some embodiments, the pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizers, humectants, plasticizers, stabilizers, permeation enhancers, wetting agents, defoaming agents, antioxidants, preservatives, and any combination thereof.

[0116] The pharmaceutical compositions described herein are administered to a subject by a suitable route of administration including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, solutions, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, rapidly dissolving formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0117] Pharmaceutical compositions containing the compounds described herein, or pharmaceutically acceptable salts or stereoisomers thereof, are manufactured in conventional manner, e.g., by merely way of example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0118] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if necessary, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, crystalline cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, etc.; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Disintegrants such as cross-linked sodium carboxymethyl cellulose, polyvinylpyrrolidone, agar, or alginic acid or salts thereof, such as sodium alginate, are added if necessary. In some embodiments, dyes or pigments are added to the tablet or dragee coating for the identification or characterization of different combinations of the active compound dosage.

[0119] The pharmaceutical composition for oral administration includes push-fit capsule agents made of gelatin, as well as soft-sealed capsule agents made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsule agents contain an active ingredient mixed with a filler, such as lactose, a binder, such as starch and / or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In the soft capsule agents, the active compound is dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0120] The pharmaceutical composition for parenteral use is formulated as an injectable or infusion agent. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes a sterile aqueous solution, or a dispersant, or a sterile powder containing the compounds described herein, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium including, for example, water, physiological saline, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, the pharmaceutical composition further includes a preservative to prevent the growth of microorganisms.

Examples

[0121] The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0122] When used above and throughout the description of the present disclosure, the following abbreviations are understood to have the following meanings unless otherwise indicated: ACN or MeCN Acetonitrile AcOH Acetic acid Ac Acetyl Bn Benzyl BOC or Boc tert-butyl carbamate i-Bu iso-butyl t-Bu tert-butyl CDI 1,1-carbonyl diimidazole DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE dichloroethane (ClCH2CH2Cl) DCM dichloromethane (CH2Cl2) DIBAL-H diisobutylaluminum hydride DIPEA or DIEA diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMA N,N-dimethylacetamide DMPU N,N'-dimethylpropyleneurea DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide Dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene EDC or EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride eq equivalent Et ethyl Et2O diethyl ether EtOH ethanol EA or EtOAc ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt 1-hydroxybenzotriazole HPLC high performance liquid chromatography KOAc potassium acetate KOtBu potassium tert-butoxide KHMDS potassium bis(trimethylsilyl)amide NaHMDS Sodium bis(trimethylsilyl)amide LiHMDS Lithium bis(trimethylsilyl)amide LAH / LiAlH4 Lithium aluminum anhydride LCMS Liquid chromatography mass spectrometry Me Methyl MeOH Methanol MS Mass spectrometry MTBE Methyl tert-butyl ether NBS N-Bromosuccinimide NMP N-Methylpyrrolidin-2-one NMR Nuclear magnetic resonance PE Petroleum ether Ph Phenyl iPr / i-Pr Iso-propyl PyAOP (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate RP-HPLC Reverse-phase high performance liquid chromatography rt Room temperature SEM 2-(Trimethylsilyl)ethoxymethyl TBS tert-Butyldimethylsilyl TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilyl [Example 1] 6-(4-Acrylamidophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0123] Step 1. tert-Butyl 2-cyano-2-(pyrazin-2-yl)acetate To a solution of 2-chloropyrazine (8.0 g, 69.85 mmol) in THF (250 mL) were added tert-butyl cyanoacetate (19.72 g, 139.70 mmol) and t-BuOK (19.59 g, 174.62 mmol). The reaction mixture was stirred at 80 °C for 48 h. After cooling to room temperature, the mixture was poured into water (300 mL) and extracted with EtOAc (3 × 300 mL) to remove impurities. The pH of the aqueous layer was adjusted to approximately 3 with 1N HCl solution and extracted with DCM (3 × 300 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (9.5 g, 62%). LC-MS (ESI+): m / z 164.0 [M+H-56] + .

[0124] Step 2. 2-(Pyrazin-2-yl)acetonitrile To a solution of tert-butyl 2-cyano-2-(pyrazin-2-yl)acetate (4.5 g, 20.53 mmol) in DCM (20 mL) was added TFA (20 mL). The reaction mixture was stirred at room temperature for 5 h. Next, the mixture was slowly poured into saturated NaHCO3 solution (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with PE:EtOAc = 1:1) to give the title compound (1.1 g, 45%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.78 - 8.53 (m, 3H), 4.33 (s, 2H).

[0125] Step 3. 6-Amino-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile To a solution of 2-(pyrazin-2-yl)acetonitrile (500 mg, 4.20 mmol) in MeOH (15 mL) were added 4-((6-methylpyridin-2-yl)oxy)benzaldehyde (895 mg, 4.20 mmol), DBU (1.9 g, 12.60 mmol), and acetyl cyanide (290 mg, 4.20 mmol). The reaction mixture was stirred at 120 °C for 20 minutes under microwave irradiation. After cooling to room temperature, the mixture was quenched with water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with MeOH:DCM = 10:1) to afford the title compound (0.9 g, 63%). LC-MS (ESI+): m / z 342.2 [M+H] + .

[0126] Step 4. 6-Bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile To a solution of 6-amino-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (1.3 g, 3.81 mmol) in MeCN (40 mL) were added tert-butyl nitrite (1.18 g, 11.42 mmol) and CuBr2 (1.28 g, 5.71 mmol). The reaction mixture was stirred at room temperature for 0.5 hour. Next, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (eluting with 5% - 70% MeCN in H2O containing 0.1% NH4OH) to afford the title compound (170 mg, 11%). LC-MS (ESI+): m / z 405.0 [M+H] + .

[0127] Step 5. 6-(4-Aminophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile A solution of 6-bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (170 mg, 0.42 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added with 4-aminophenylboronic acid pinacol ester (137.86 mg, 0.63 mmol), K2CO3 (116 mg, 0.84 mmol) and Pd(dppf)Cl2 (31 mg, 0.04 mmol). Under microwave irradiation and N2, this mixture was stirred at 100 °C for 1 h. After cooling to room temperature, this mixture was quenched with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with MeOH:DCM = 20:1) to give the title compound (140 mg, 81%). LC-MS (ESI+): m / z 418.2 [M+H] + .

[0128] Step 6. 6-(4-Aminophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide A mixture consisting of 6-(4-aminophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (130 mg, 0.31 mmol) and concentrated H2SO4 (6 mL) was stirred at 30 °C for 8 h. This mixture was slowly poured into water (100 mL), adjusted to pH ~8 with 6N NaOH solution and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product (130 mg, 97%). LC-MS (ESI+): m / z 436.2 [M+H] + .

[0129] Step 7. 6-(4-Acrylamidophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide To a solution of 6-(4-aminophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (130 mg, 0.30 mmol) in acetone (5 mL) were added a K2CO3 solution (1.65 mL, 0.5 mol / L in water) and acryloyl chloride (0.55 mL, 0.5 mol / L in acetone) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was quenched with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (eluted with 26% - 36% MeCN in H2O containing 0.1% FA) to give the title compound (16 mg, 12%). LC-MS (ESI+): m / z 490.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.33 (s, 1H), 8.05 (m, 1H), 7.84 - 7.71 (m, 3H), 7.67 (m, 1H), 7.41 (bs, 1H), 7.36 - 7.25 (m, 4H), 7.07 (m, 2H), 7.02 (m, 1H), 6.76 (m, 1H), 6.65 (bs, 1H), 6.45 (m, 1H), 6.28 (m, 1H), 5.78 (m, 1H), 2.34 (s, 3H). [Example 2] 6-(4-Acrylamidophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0130] Step 1. 4-((4-Methylpyrimidin-2-yl)oxy)benzaldehyde A solution of 4-hydroxybenzaldehyde (500 mg, 4.09 mmol) and 2-chloro-4-methylpyrimidine (632 mg, 4.91 mmol) in DMF (10 mL) was added with CsF (1.87 g, 12.28 mmol). The reaction mixture was stirred at 120 °C for 12 h. 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 (eluted with 0 - 50% ethyl acetate in petroleum ether) to obtain the title compound (380 mg, 43%). LC-MS (ESI+): m / z 215.4 [M+H] + .

[0131] Step 2. 6-Amino-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile To a mixture of 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde (576 mg, 2.69 mmol) and 2-(pyrazin-2-yl)acetonitrile (320 mg, 2.69 mmol) in MeOH (10 mL) were added DBU (1.23 g, 8.06 mmol) and acetyl cyanide (186 mg, 2.69 mmol). The reaction mixture was stirred at 100 °C for 20 min under microwave irradiation under N2. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dehydrated over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 10% methanol in dichloromethane) to obtain the title compound (450 mg, 49%). LC-MS (ESI+): m / z 343.0 [M+H] + .

[0132] Step 3. 6-Bromo-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile To a solution of 6-amino-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (450 mg, 1.31 mmol) in HBr (10 mL, 33% in AcOH) was added CuBr2 (382 mg, 1.71 mmol) at 0 °C. Next, a solution of NaNO2 (454 mg, 6.57 mmol) in H2O (4 mL) was added to this mixture. The reaction mixture was stirred at 0 °C for 0.5 h. Next, the pH of the solution was adjusted to 7 - 8 with Na2CO3 (aqueous). The mixture was extracted with DCM (20 ml * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluting with 0 - 10% methanol in dichloromethane) to give the title compound (280 mg, 53%). LC-MS (ESI+): m / z 405.8 [M+H] + .

[0133] Step 4. 6-(4-Aminophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile A mixture consisting of 6-bromo-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (280 mg, 689 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (302 mg, 1.38 mmol), Na2CO3 (219 mg, 2.07 mmol) and Pd-118 (45 mg, 68.9 μmol) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N2 three times. The mixture was stirred at 90 °C for 2 h under a N2 atmosphere. 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 (eluting with 0 - 30% ethyl acetate in petroleum ether) to give the title compound (180 mg, 62%). LC-MS (ESI+): m / z 419.1 [M+H] + .

[0134] Step 5. 6-(4-Aminophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide A mixture of 6-(4-Aminophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (180 mg, 430 μmol) in concentrated H2SO4 (3 mL) was stirred at 30 °C for 8 h. Next, this mixture was slowly poured into water (20 mL), the pH was adjusted to about 7 with Na2CO3, and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (160 mg, 85%). LC-MS (ESI+): m / z 437.2 [M+H] + .

[0135] Step 6. 6-(4-Acrylamidophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide To a solution of 6-(4-Aminophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (160 mg, 367 μmol) in acetone (2 mL) and H2O (0.4 mL) was added K2CO3 (102 mg, 734.8 μmol). Next, prop-2-enoyl chloride (40 mg, 440.9 μmol) was added to this solution at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Next, 10 mL of water was added to this mixture. After extraction with ethyl acetate (10 mL * 3), the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 10% MeOH in DCM) to obtain the title compound (26 mg, 15%). LC-MS (ESI+): m / z 491.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.28 (d, J = 1.5 Hz, 1H), 8.47 (d, J = 5.0 Hz, 1H), 7.99 (dd, J = 1.4, 4.9 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 4.8 Hz, 1H), 7.44 (br s, 1H), 7.32 (m, 4H), 7.20 - 7.11 (m, 3H), 6.75 (br s, 1H), 6.51 - 6.39 (m, 1H), 6.33 - 6.20 (m, 1H), 5.83 - 5.75 (m, 1H), 2.41 (s, 3H). [Example 3] 6-(6-Acrylamidopyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0136] Step 1. N-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acrylamide To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (200 mg, 908.8 μmol) and TEA (138 mg, 1.36 mmol, 189.7 μL) in DCM (3 mL) was added prop-2-enoyl chloride (82 mg, 908.8 μmol, 74.1 μL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Next, the mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 30% ethyl acetate in petroleum ether) to give the title compound (100 mg, 40%) as a colorless oil. 11H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.55 (d, J = 0.8 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.01 (dd, J = 1.8, 8.3 Hz, 1H), 6.68 - 6.54 (m, 1H), 6.33 (dd, J = 1.8, 17.1 Hz, 1H), 5.84 - 5.72 (m, 1H), 1.31 (s, 12H).

[0137] Step 2. 6-Bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide A mixture of 6-bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (100 mg, 246.8 μmol) in H2SO4 (2 mL) was stirred at 30 °C for 12 h. Then the mixture was slowly poured into water (20 mL), the pH was adjusted to about 7 with Na2CO3, and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (100 mg). LC-MS (ESI+): m / z 423.0 [M+H] + .

[0138] Step 3. 6-(6-Acrylamidopyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide A mixture consisting of 6-bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (100 mg, 236.3 μmol), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acrylamide (65 mg, 236.3 μmol), K2CO3 (82 mg, 590.7 μmol) and Pd-118 (15 mg, 23.6 μmol) in dioxane (4 mL) and H2O (1 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Boston Prime C 18 150 * 30 mm * 5 um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 30% - 50%, for 9 min) to obtain the title compound (18 mg, 15%). LC-MS (ESI+): m / z 491.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.35 (d, J = 1.3 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 1.8 Hz, 1H), 8.11 (m, 1H), 7.87 (dd, J = 2.3, 8.5 Hz, 1H), 7.79 - 7.67 (m, 2H), 7.43 (br s, 1H), 7.36 - 7.28 (m, 2H), 7.09 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.69 - 6.56 (m, 2H), 6.34 (m, 1H), 5.86 - 5.77 (m, 1H), 2.34 (s, 3H). [Example 4] 6-(6-Acrylamido-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

Chem.

[0139] Step 1. 6-(6-Amino-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile To a solution of 6-bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (100 mg, 0.24 mmol) in 1,4-dioxane (10 mL) and water (0.1 mL) were added 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (300 mg, 1.28 mmol), K2CO3 (102 mg, 0.74 mmol), and XPhos Pd G2 (19 mg, 0.03 mmol). The mixture was stirred at 100 °C for 1 h under microwave irradiation and N2. After cooling to room temperature, the mixture was quenched with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with DCM:MeOH = 20:1) to afford the title compound (65 mg, 63%). LC-MS (ESI+): m / z 433.2 [M+H] + .

[0140] Step 2. 6-(6-Amino-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide A mixture consisting of 6-(6-amino-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (65 mg, 0.15 mmol) and concentrated H2SO4 (3 mL) was stirred at 30 °C for 8 hours. Next, this mixture was slowly poured into water (20 mL), the pH was adjusted to about 8 with 6N NaOH solution, and extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated to obtain the title compound (30 mg, 45%). LC-MS (ESI+): m / z 451.2 [M+H] + .

[0141] Step 3. 6-(6-Acrylamido-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide To a solution of 6-(6-amino-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (20 mg, 0.044 mmol) in DCM (2 mL) were added TEA (0.1 mL, 0.67 mmol), acrylic acid (3.1 mL, 0.1 M in DCM, 0.31 mmol), and T3P (200 mg, 50% in EtOAc, 0.31 mmol) at 0 °C. This mixture was stirred at 25 °C for 1 hour. Next, this mixture was quenched with water (15 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (eluted with 30% - 46% MeCN in H2O containing 0.1% FA) to obtain the title compound (0.59 mg, 2%). LC-MS (ESI+): m / z 505.3 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.85 (s, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.25 (m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.33 (dd, J = 16.0, 8.0 Hz, 1H), 5.90 (d, J = 8.0 Hz, 1H), 5.78 - 5.63 (m, 1H), 2.45 (s, 3H), 2.06 (s, 3H). [Example 5] 6-(4-Acrylamidophenyl)-4-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0142] Preparation of tert-butyl 2-cyano-2-(6-methylpyrazin-2-yl)acetate (Intermediate 5.1) [Chemical formula]

[0143] Intermediate 5.1 was synthesized by replacing 2-chloropyrazine with 2-chloro-6-methylpyrazine in a similar manner according to the procedure of Intermediate 1.1.

[0144] Preparation of 2-(6-methylpyrazin-2-yl)acetonitrile (Intermediate 5.2) To a solution of tert-butyl 2-cyano-2-(6-methylpyrazin-2-yl)acetate (7.0 g, 30.01 mmol) in DMSO (70 mL) and H2O (70 mL) was added LiBr (3.92 g, 45.01 mmol). The mixture was stirred at 130 °C for 1 h. After cooling to room temperature, the mixture was slowly poured into saturated NaHCO3 solution (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and the solvent was evaporated to give the title compound (3.5 g, 88%) as a yellow oil. LC-MS (ESI+): m / z 134.2 [M+H] + .

[0145] Preparation of 6-(4-acrylamidophenyl)-4-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (Example 5) Example 5 was synthesized by replacing 2-(pyrazin-2-yl)acetonitrile with 2-(6-methylpyrazin-2-yl)acetonitrile (Intermediate 5.2) in a similar manner according to the procedure of Example 1. The residue was purified by preparative HPLC (eluting with 55% - 60% MeCN in H2O containing 0.1% FA) to give the title compound (17 mg, 19%). LC-MS (ESI+): m / z 504.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.29 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.44 (s, 1H), 7.35 (d, J = 8.0 Hz, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 3H), 6.71 (d, J = 8.0 Hz, 1H), 6.44 (dd, J1= 16.8, J2= 10.0 Hz, 2H), 6.27 (dd, J1= 16.0, J2= 2.0 Hz, 1H), 5.77 (dd, J1= 10.0, J2= 2.0 Hz, 1H), 2.31 (s, 3H), 1.98 (s, 3H). [Example 6] 6-(4-Acrylamidophenyl)-4-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0146] Preparation of Intermediate 6.2 [Chemical formula]

[0147] Step 1. 2-(6-Methylpyrazin-2-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)acrylonitrile To a solution of 2-(6-methylpyrazin-2-yl)acetonitrile (2 g, 15.02 mmol) in MeOH (200 mL) were added 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde (Intermediate 2.1) (3.86 g, 18.02 mmol) and NH4OAc (8.34 g, 108.15 mmol). The mixture was stirred at 70 °C for 3 h. After cooling to room temperature, the precipitate was filtered. The solid was washed with water (20 mL) and dried under vacuum to give the title compound (3.5 g, 71%). LC-MS (ESI+): m / z 330.3 [M+H] + .

[0148] Step 2. 6-Amino-4-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile To a solution of 2-(6-methylpyrazin-2-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)acrylonitrile (1.0 g, 3.04 mmol) in MeOH (20 mL) were added DBU (1.39 g, 9.11 mmol) and acetyl cyanide (0.21 g, 3.04 mmol). Under microwave irradiation and N2, the mixture was stirred at 120 °C for 20 min. After cooling to room temperature, the mixture was quenched with water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with MeOH:DCM = 20:1) to give the title compound (1 g, 92%). LC-MS (ESI+): m / z 357.2 [M+H] + .

[0149] In a similar manner according to the procedure of Example 2, 6-amino-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile was replaced with 6-amino-4-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile to synthesize Example 6. The residue was purified by preparative HPLC (eluted with 55% - 60% MeCN in H2O containing 0.1% FA) to obtain the title compound (6 mg, 8% yield in 2 steps). LC-MS (ESI+): m / z 505.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.25 (s, 1H), 8.44 (d, J =8.0 Hz, 1H), 8.37 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.43 (s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.53 (s, 1H), 6.44 (dd, J1= 16.0, J2= 12.0 Hz, 1H), 6.30 - 6.22 (m, 1H), 5.79 - 5.74 (m, 1H), 2.38 (s, 3H), 1.97 (s, 3H). [Example 7] 6-(4-Acrylamidophenyl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical Structure Diagram]

[0150] Preparation of Intermediate 7.1 Step 1. 2-(5-Methylpyrazin-2-yl)acetonitrile [Chemical Structure Diagram] A mixture consisting of 2-(chloromethyl)-5-methylpyrazine hydrochloride (4.00 g, 22.3 mmol), KI (1.11 g, 6.70 mmol) and KCN (2.18 g, 33.51 mmol) in EtOH (200 mL) and H2O (40 mL) was degassed and purged with N2 three times. This mixture was stirred at 80 °C for 5 h under a N2 atmosphere. After cooling to room temperature, 200 mL of aqueous Na2CO3 was added to this solution. This solution was diluted with 200 mL of water and extracted with ethyl acetate (250 mL × 2). The combined organic layers were washed with brine, dehydrated over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 30% ethyl acetate in petroleum ether) to give the title compound (2.10 g, 71%). 1 1H NMR: (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.51 - 8.40 (m, 1H), 3.94 (s, 2H), 2.67 - 2.57 (m, 3H).

[0151] Example 7 was synthesized by replacing 2-(pyrazin-2-yl)acetonitrile with 2-(5-methylpyrazin-2-yl)acetonitrile and 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde with 4-((6-methylpyridin-2-yl)oxy)benzaldehyde in a similar manner according to the procedure of Example 2. The residue was purified by preparative HPLC (FA conditions; column: Boston Prime C 18 150 * 30 mm * 5 μm; mobile phase: [water (FA)-ACN]; B%: 20% - 40%, 2 min) to give the title compound (26 mg, 13% yield). LC-MS (ESI+): m / z 504.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.27 (s, 1H), 7.85 (s, 1H), 7.79 - 7.70 (m, 3H), 7.42 - 7.24 (m, 5H), 7.12 - 6.98 (m, 3H), 6.76 (d, J = 8.0 Hz, 1H), 6.45 (dd, J = 10.0, 17.1 Hz, 2H), 6.33 - 6.23 (m, 1H), 5.79 (d, J = 10.5 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H). [Example 8] 6-(4-Acrylamidophenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0152] Example 8 was synthesized by replacing 2-(pyrazin-2-yl)acetonitrile with 2-(5-methylpyrazin-2-yl)acetonitrile in a similar manner according to the procedure of Example 2. The residue was purified by preparative HPLC (eluted with 20% - 36% MeCN in H2O containing 0.1% FA) to obtain the title compound (40 mg, 38%). LC-MS (ESI+): m / z 505.2 [M + H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.24 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.37 - 7.28 (m, 5H), 7.16 (s, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.57 (br s, 1H), 6.48 - 6.39 (m, 1H), 6.28 (dd, J1 = 16.0, J2 = 2.0 Hz, 1H), 5.81 - 5.75 (m, 1H), 2.41 (s, 3H), 2.34 (s, 3H). [Example 9] (E)-6-(4-(4-(Dimethylamino)but-2-enamide)phenyl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0153] Step 1. (E)-4-(Dimethylamino)but-2-enoyl chloride hydrochloride To a solution of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (200 mg, 1.212 mmol) in THF (2 mL) was added oxalyl chloride (0.1 mL, 1.212 mmol) and DMF (0.001 mL, 0.012 mmol) at 0 °C. The mixture was stirred at 30 °C for 1.5 h. The mixture was used directly in the next step.

[0154] Step 2. (E)-6-(4-(4-(Dimethylamino)but-2-enamide)phenyl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide Intermediate 9.2 was synthesized in a similar manner following the procedure of Intermediate 2.5, replacing 2-(pyrazin-2-yl)acetonitrile with 2-(5-methylpyrazin-2-yl)acetonitrile and 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde with 4-((6-methylpyridin-2-yl)oxy)benzaldehyde.

[0155] To a solution of 6-(4-aminophenyl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (80 mg, 0.18 mmol) in DCM (3 mL) were added TEA (0.074 mL, 0.534 mmol) and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (0.44 mL, 0.26 mmol from step 1) at 0 °C. The mixture was stirred at 0 °C for 3 h. Next, the mixture was quenched with water (50 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (eluting with 25% - 37% MeCN in H2O containing 0.1% FA) to give the title compound (6.5 mg, 7%). LC-MS (ESI+): m / z 561.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.27 (s, 1H), 7.83 (s, 1H), 7.77 - 7.69 (m, 3H), 7.33 - 7.22 (m, 4H), 7.06 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 1H), 6.80 - 6.70 (m, 2H), 6.46 (br s, 1H), 6.28 (d, J = 16.0 Hz, 1H), 3.06 (d, J = 8.0 Hz, 2H), 2.34 (s, 6H), 2.18 (s, 6H). [Example 10] (E)-6-(6-(4-(Dimethylamino)but-2-enamide)pyridin-3-yl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical Structure]

[0156] Step 1. (E)-6-(6-(4-Bromobut-2-enamide)pyridin-3-yl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide Intermediate 10.1 was synthesized by replacing 2-(pyrazin-2-yl)acetonitrile with 2-(5-methylpyrazin-2-yl)acetonitrile, 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde with 4-((6-methylpyridin-2-yl)oxy)benzaldehyde, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine in a similar manner according to the procedure of Intermediate 2.5.

[0157] To a solution of 6-(6-aminopyridin-3-yl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (80 mg, 0.18 mmol) in DCM (2 mL) were added TEA (54 mg, 0.36 mmol) and (E)-4-bromobut-2-enoyl chloride (65 mg, 0.36 mmol) at 0 °C. The mixture was stirred at room temperature for 18 h. The mixture was quenched with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (DCM:MeOH = 20:1) to afford the title compound (12 mg, 0.02 mmol, 11%) as a yellow oil. LC-MS (ESI+): m / z 597.1 [M+H] + + .

[0158] Step 2. (E)-6-(6-(4-(Dimethylamino)but-2-enamide)pyridin-3-yl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (E)-6-(6-(4-Bromobuta-2-enamide)pyridin-3-yl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (12 mg, 0.02 mmol) in MeCN (2 mL) was added with K2CO3 (3 mg, 0.02 mmol) and dimethylamine hydrochloride (0.1 mL, 0.2 M in MeCN). The mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the mixture was quenched with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (eluted with 22% - 35% MeCN in H2O containing 0.1% FA) to give the title compound (0.6 mg, 5%). LC-MS (ESI+): m / z 562.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.30 (s, 1H), 8.43 - 8.22 (m, 3H), 8.19 (s, 1H), 7.94 (s, 1H), 7.82 (dd, J = 8.0, 2.0 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.90 - 6.65 (m, 2H), 6.45 (d, J = 16.0 Hz, 1H), 3.05 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.17 (s, 6H). [Example 11] 6-(4-Acrylamidophenyl)-3-(hydroxymethyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

Chemical Structure

[0159] Preparation of Methyl 5-(cyanomethyl)pyrazine-2-carboxylate (Intermediate 11.2) [Chemical formula] Intermediate 11.1 was synthesized by replacing 2-chloropyrazine with methyl 5-chloropyrazine-2-carboxylate in a similar manner according to the procedure of Intermediate 1.1.

[0160] p-TsOH (5.71 g, 33.18 mmol) was added to a mixture consisting of methyl 5-(2-(tert-butoxy)-1-cyano-2-oxoethyl)pyrazine-2-carboxylate (9.2 g, 33.18 mmol) in toluene (200 mL). The reaction mixture was stirred at 120 °C for 18 h. After cooling to room temperature, the mixture was slowly poured into water (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with PE:EtOAc = 1:1) to give Intermediate 11.2 (900 mg, 15%). LC-MS (ESI+): m / z 178.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 1.3 Hz, 1H), 8.81 (s, 1H), 4.48 (s, 2H), 3.94 (s, 3H).

[0161] Step 1. 6-(4-Aminophenyl)-3-(hydroxymethyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide Intermediate 11.3 was synthesized by replacing 2-(pyrazin-2-yl)acetonitrile with methyl 5-(cyanomethyl)pyrazine-2-carboxylate and 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde with 4-((6-methylpyridin-2-yl)oxy)benzaldehyde in a similar manner according to the procedure of Intermediate 2.5.

[0162] To a solution of methyl 6-(4-aminophenyl)-8-carbamoyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-3-carboxylate (150 mg, 0.30 mmol) in DCM (5 mL) and MeOH (5 mL) were added NaBH4 (57.49 mg, 1.52 mmol) and CaCl2 (3.37 mg, 0.03 mmol) at 0 °C. The mixture was stirred at 25 °C for 5 h. Then the mixture was quenched with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with MeOH:DCM = 20:1) to afford the title compound (15 mg, 10%) as a yellow oil. LC-MS (ESI+): m / z 466.2 [M+H] + .

[0163] Step 2. 6-(4-Acrylamidophenyl)-3-(hydroxymethyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide To a solution of 6-(4-aminophenyl)-3-(hydroxymethyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (15 mg, 0.03 mmol) in acetone (5 mL) were added K2CO3 (13 mg, 0.10 mmol, 0.5 M in water) and acryloyl chloride (0.1 mL, 0.3 M in acetone) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Next, the mixture was quenched with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (eluted with 35% - 40% MeCN in H2O containing 0.1% FA) to give the title compound (1.3 mg, 7%). LC-MS (ESI+): m / z 520.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.27 (s, 1H), 7.89 (s, 1H), 7.79 - 7.71 (m, 3H), 7.40 - 7.25 (m, 5H), 7.07 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 7.2 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.55 (br s, 1H), 6.45 (dd, J1= 16.0, J2= 12.0 Hz, 1H), 6.28 (dd, J1= 16.0, J2= 2.0 Hz, 1H), 5.78 (dd, J1= 10.0, J2= 2.0 Hz, 1H), 5.40 (br s, 1H), 4.53 (s, 2H), 2.34 (s, 3H). [Example 12] 6-(4-Acrylamidophenyl)-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0164] Step 1. tert-Butyl 2-(3-chloropyrazin-2-yl)-2-cyanoacetate To a solution of 2,3-dichloropyrazine (10.0 g, 67.1 mmol) in DMF (100 mL) was added Cs2CO3 (43.7 g, 134.3 mmol). Next, tert-butyl 2-cyanoacetate (12.3 g, 87.3 mmol, 12.5 mL) was added. The reaction mixture was stirred at 80 °C for 4 hours. After cooling to room temperature, 300 mL of water was added to this mixture. The pH of this mixture was adjusted to 3 - 5 with 1N HCl (aqueous). This mixture was extracted with EtOAc (200 mL * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 50% ethyl acetate in petroleum ether) to obtain the title compound (15.0 g, 88%) as a yellow oil.

[0165] Step 2. 2-(3-Chloropyrazin-2-yl)acetonitrile To a solution of tert-butyl 2-(3-chloropyrazin-2-yl)-2-cyanoacetate (15.0 g, 59.1 mmol) in toluene (170 mL) was added p-TsOH (815 mg, 4.73 mmol). The reaction mixture was stirred at 120 °C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash column chromatography on silica gel (eluted with 0 - 50% ethyl acetate in petroleum ether) to obtain the title compound (6.0 g, 66%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 2.5 Hz, 1H), 8.54 (d, J = 2.5 Hz, 1H), 4.47 (s, 2H).

[0166] Step 3. 6-Amino-1-chloro-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile A mixture consisting of 4-((6-methylpyridin-2-yl)oxy)benzaldehyde (694 mg, 3.26 mmol) and 2-(3-chloropyrazin-2-yl)acetonitrile (500 mg, 3.26 mmol) in MeOH (10 mL) was added with DBU (1.49 g, 9.77 mmol, 1.47 mL) and acetyl cyanide (225 mg, 3.26 mmol) at 25 °C. The reaction mixture was purged with N2 three times, stirred, and heated at 100 °C for 20 minutes under microwave irradiation. 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 (eluted with 0 - 80% ethyl acetate in petroleum ether) to obtain the title compound (600 mg, 49%). LC-MS (ESI+): m / z 376.0 [M+H] + .

[0167] Step 4. 6-Bromo-1-chloro-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile To a solution of 6-amino-1-chloro-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (300 mg, 798.3 μmol) in HBr / AcOH (10 mL) was added CuBr2 (232 mg, 1.04 mmol, 48.6 μL) at 0 °C. The mixture was stirred for 20 minutes. Next, a solution of NaNO2 (275 mg, 3.99 mmol) in H2O (4 mL) was added. The reaction mixture was stirred at 0 °C for 0.5 hour. Then, the pH of the solution was adjusted to 7 with aqueous Na2CO3. After extraction with ethyl acetate (20 mL * 3), the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 2% MeOH in DCM) to obtain the title compound (300 mg, 86%). LC-MS (ESI+): m / z 438.8 [M+H] + .

[0168] Step 5. 6-Bromo-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile To a mixture of 6-bromo-1-chloro-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (300 mg, 682.3 μmol) and methanamine hydrochloride (138 mg, 2.05 mmol) in THF (3 mL) was added DBU (519 mg, 3.41 mmol) at 25 °C. The reaction mixture was purged with N2 three times and stirred, and then heated at 120 °C for 3 h under microwave irradiation. 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 (eluted with 0 - 30% ethyl acetate in petroleum ether) to give the title compound (210 mg, 71%). LC-MS (ESI+): m / z 433.8 [M+H] + .

[0169] Step 6. 6-Bromo-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide A mixture of 6-bromo-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (250 mg, 575.7 μmol) in H2SO4 (5.52 g, 56.3 mmol, 3 mL) was stirred at 30 °C for 16 h. Next, the mixture was slowly poured into water (100 mL), the pH was adjusted to about 7 with Na2CO3, and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (260 mg). LC-MS (ESI+): m / z 451.9 [M+H] + .

[0170] Step 7. 6-(4-Acrylamidophenyl)-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide To a solution of 6-bromo-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (140 mg, 309.5 μmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (169 mg, 619.1 μmol) in dioxane (3 mL) and H2O (1 mL) were added K2CO3 (128 mg, 928.6 μmol) and Pd-118 (20 mg, 31.0 μmol). The mixture was degassed and purged with N2 three times, and then stirred at 90 °C for 2 h under a N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by reverse-phase HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 20% - 40%, 9 min) to give the title compound (23 mg, 15%). LC-MS (ESI+): m / z 519.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.35 - 10.18 (m, 1H), 9.13 - 8.82 (m, 1H), 7.78 - 7.68 (m, 3H), 7.62 (br s, 1H), 7.28 - 7.15 (m, 6H), 7.11 - 6.95 (m, 3H), 6.74 (d, J = 8.1 Hz, 1H), 6.50 - 6.22 (m, 3H), 5.82 - 5.73 (m, 1H), 2.98 (d, J = 4.6 Hz, 3H), 2.34 (s, 3H). [Example 13] 6-(4-Acrylamidophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide

Chemical Structure

[0171] Step 1. 1-(tert-Butyl) 3-methyl 4-(4-nitrobenzoyl) piperazine-1,3-dicarboxylate To a solution of 1-(tert-butyl) 3-methylpiperazine-1,3-dicarboxylate (17.4 g, 71.23 mmol) in DCM (600 mL) was added TEA (21.8 mL, 156.69 mmol). The mixture was stirred at 0 °C for 30 minutes. 4-Nitrobenzoyl chloride (14.54 g, 78.35 mmol in 85 mL of DCM) was added and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with water (500 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated to give the title compound (27 g), which was used directly in the next step. LC-MS (ESI+): m / z 338.2 (M+H-56) + .

[0172] Step 2. Sodium 4-(tert-butoxycarbonyl)-1-(4-nitrobenzoyl) piperazine-2-carboxylate To a solution of 1-(tert-butyl) 3-methyl 4-(4-nitrobenzoyl) piperazine-1,3-dicarboxylate (27 g) in MeOH (300 mL) was slowly added NaOH solution (2N, 41 mL, 82.00 mmol) at 0 °C. The mixture was stirred at room temperature for 18 hours. Next, the mixture was evaporated to dryness in vacuo to give the title compound (30 g), which was used directly in the next step. LC-MS (ESI+): m / z 378.1 (M-Na) - .

[0173] Step 3. tert-Butyl 8-cyano-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate To a mixture of sodium 4-(tert-butoxycarbonyl)-1-(4-nitrobenzoyl)piperazine-2-carboxylate (15 g) in DCM (300 mL) was added 4-toluenesulfonyl chloride (7.84 g, 41.11 mmol) at 0 °C. After stirring at room temperature for 1 hour, 2-chloroacrylonitrile (3.0 mL, 37.37 mmol) and TEA (11.94 mL, 85.96 mmol) were sequentially added. The mixture was stirred at room temperature for 18 hours. Next, the mixture was quenched with water (400 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with PE:EtOAc = 1:1) to afford the title compound (3.7 g, total yield of 3 steps 28%). LC-MS (ESI+): m / z 369.1 [M+H] + .

[0174] Step 4. tert-Butyl 7-bromo-8-cyano-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate To a solution of tert-butyl 8-cyano-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (3.0 g, 8.14 mmol) in DCM (30 mL) was added NBS (1.59 g, 8.958 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. Next, the mixture was diluted with DCM (100 mL) and washed with saturated NaHCO3 solution (2 × 100 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated to give the title compound (3.6 g, 82%). LC-MS (ESI+): m / z 469.0 (M+Na) + .

[0175] Step 5. tert-Butyl 8-cyano-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate A solution of tert-butyl 7-bromo-8-cyano-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (4.27 g, 9.54 mmol) and 2-methyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (3.24 g, 10.42 mmol) in 1,4-dioxane (85 mL) and water (17 mL) was added with K2CO3 (3.60 g, 26.06 mmol) and XPhos Pd G2 (0.38 g, 0.47 mmol). The mixture was stirred at 100 °C for 1 h under N2. After cooling to room temperature, the mixture was slowly poured into water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with DCM:MeOH = 20:1) to give the title compound (1.4 g, 27%). LC-MS (ESI+): m / z 552.1 [M+H] + .

[0176] Step 6. 7-(4-((6-Methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile TFA (3.5 mL) was added to a solution of tert-butyl 8-cyano-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (0.7 g, 1.27 mmol) in DCM (7 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. Then, the mixture was slowly poured into saturated NaHCO3 solution (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated to give the title compound (570 mg, 99%). LC-MS (ESI+): m / z 452.2 [M+H] + .

[0177] Step 7. 2-Methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile To a solution of 7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile (525 mg, 1.16 mmol) in DMF (12 mL) were added K2CO3 (193 mg, 1.39 mmol) and MeI (2.3 mL, 1.16 mmol). The mixture was stirred at 30 °C for 1.5 h. Then, the mixture was poured into water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated NH4Cl solution (3 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with DCM:MeOH = 50:1) to give the title compound (300 mg, 55%). LC-MS (ESI+): m / z 466.2 [M+H] + .

[0178] Step 8. 6-(4-Aminophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile To a solution of 2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile (200 mg, 0.43 mmol) in EtOH (18 mL) and water (4.5 mL) were added NH4Cl (115 mg, 2.15 mmol) and iron (120 mg, 2.15 mmol). The mixture was stirred at 70 °C for 5 h. Then, the mixture was filtered at 70 °C. The filtrate was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated to give the title compound (120 mg, 63%). LC-MS (ESI+): m / z 436.1 [M+H]+ .

[0179] Step 9. 6-(4-Aminophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide A mixture consisting of 6-(4-aminophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile (120 mg, 0.27 mmol) and concentrated H2SO4 (10 mL) was stirred at 30 °C for 18 h. Next, this mixture was slowly poured into water (100 mL), the pH was adjusted to about 8 with 6N NaOH solution, and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (DCM:MeOH = 20:1) to give the title compound (70 mg, 56%). LC-MS (ESI+): m / z 454.2 [M+H] + .

[0180] Step 10. 6-(4-Acrylamidophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide To a solution of 6-(4-aminophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide (70 mg, 0.154 mmol) in acetone (5 mL) were added K2CO3 (0.92 mL, 0.46 mmol, 0.5 mol / L in water) and acryloyl chloride (0.37 mL, 0.18 mmol, 0.5 mol / L in acetone) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (eluting with 20% - 25% MeCN in H2O containing 0.1% FA) to give the title compound (22 mg, 28%). LC-MS (ESI+): m / z 508.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.57 (t, J = 8.0 Hz, 1H), 7.55 - 7.37 (m, 3H), 7.19 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 6.25 (dd, J = 16.0, 8.0 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 5.26 (br s, 2H), 4.20 (br s, 2H), 3.94 (br s, 2H), 2.89 (br s, 2H), 2.60 (s, 3H), 2.44 (s, 3H). [Example 14] 6-(1-Acryloylindolin-5-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0181] Step 1. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indoline To a solution of 5-bromoindoline (2.0 g, 10.1 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.85 g, 15.1 mmol) in dioxane (20 mL) were sequentially added KOAc (2.97 g, 30.3 mmol) and Pd(dppf)Cl2 (0.74 g, 1.01 mmol). The reaction mixture was stirred at 80 °C for 16 h under a N2 atmosphere. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 30% ethyl acetate in petroleum ether) to give the title compound (2.0 g, 81%). LC-MS (ESI+): m / z 245.8 [M+H] + .

[0182] Step 2. 1-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)prop-2-en-1-one To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (1.9 g, 7.75 mmol) in THF (20 mL) was added TEA (2.16 mL, 15.5 mmol). A solution of prop-2-enoyl chloride (0.84 g, 9.30 mmol) in THF (5 mL) was added dropwise to this mixture. Next, the solution was stirred at 0 °C for 0.5 h. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 30% ethyl acetate in petroleum ether) to give the title compound (1.0 g, 43%). LC-MS (ESI+): m / z 300.2 [M+H] + .

[0183] Step 3. 6-(1-Acryloylindolin-5-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide To a solution of 6-bromo-7-[4-[(6-methyl-2-pyridyl)oxy]phenyl]pyrrolo[1,2-a]pyrazine-8-carboxamide (150 mg, 354.4 μmol) and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl]prop-2-en-1-one (159.0 mg, 531.6 μmol) in dioxane (6 mL) and H2O (2 mL), K2CO3 (123 mg, 886.0 μmol) and Pd-118 (23 mg, 35.4 μmol) were sequentially added. The reaction mixture was stirred at 90 °C for 2 h under a N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: YMC-Triart Prep C 18 150*40 mm*7 μm; mobile phase: [water (FA)-ACN]; B%: 13% - 53%, 9 min) to give the title compound (44 mg, 24%). LC-MS (ESI+): m / z 516.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.18 (d, J=8.3 Hz, 1H), 8.06 - 7.99 (m, 1H), 7.80 - 7.70 (m, 1H), 7.67 (d, J=4.9 Hz, 1H), 7.40 (br s, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.26 (s, 1H), 7.13 (dd, J=1.5, 8.4 Hz, 1H), 7.08 (d, J=8.6 Hz, 2H), 7.02 (d, J=7.4 Hz, 1H), 6.85 - 6.70 (m, 2H), 6.61 (br s, 1H), 6.32 (dd, J=1.6, 16.7 Hz, 1H), 5.89 - 5.79 (m, 1H), 4.25 (t, J=8.3 Hz, 2H), 3.17 (t, J=8.4 Hz, 2H), 2.34 (s, 3H). [Example 15] 7-(4-Acrylamidophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carboxamide [Chemical formula]

[0184] Step 1. N,N-Dimethyl-2-(pyrimidin-4-yl)ethen-1-amine To a solution of 4-methylpyrimidine (8.0 g, 85.0 mmol) in DMF (39.2 mL) was added DMF-DMA (30.4 g, 255.0 mmol, 33.9 mL). The reaction mixture was stirred at 140 °C for 12 h. Next, the mixture was concentrated in vacuo to give the title compound (15.0 g) as a brown liquid.

[0185] Step 2. 2-(Pyrimidin-4-yl)acetonitrile To a solution of N,N-dimethyl-2-(pyrimidin-4-yl)ethen-1-amine (8.0 g, 53.6 mmol) in H2O (80 mL) was added hydroxylamine-O-sulfonic acid (15.2 g, 134.1 mmol). The reaction mixture was stirred at 50 °C for 0.5 h. After cooling to room temperature, the pH of the reaction solution was adjusted to 7 with aqueous sodium carbonate solution. After extraction with ethyl acetate (200 ml * 3), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 30% ethyl acetate in petroleum ether) to give the title compound (2.0 g, 31%). 1 H NMR (400MHz, DMSO-d6) δ 9.19 (d, J = 0.8 Hz, 1H), 8.83 (d, J = 5.0 Hz, 1H), 7.61 - 7.49 (m, 1H), 4.40 - 4.28 (m, 2H).

[0186] Step 3. 7-Amino-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carbonitrile To a mixture of 2-(pyrimidin-4-yl)acetonitrile (400 mg, 3.36 mmol) and 4-((6-methylpyridin-2-yl)oxy)benzaldehyde (716.0 mg, 3.36 mmol) in MeOH (12 mL) were added DBU (1.53 g, 10.1 mmol) and acetyl cyanide (231.9 mg, 3.36 mmol) at 25 °C. The reaction mixture was purged with N2 three times, stirred, and heated at 100 °C for 20 min under microwave irradiation. After cooling to room temperature, water (50 mL) was added to the reaction mixture. After extraction with ethyl acetate (50 mL × 3), the combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 3% MeOH in DCM) to give the title compound (410 mg, 36%). LC-MS (ESI+): m / z 342.1 [M + H] + .

[0187] Step 4. 7-Iodo-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carbonitrile To a solution of 7-amino-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carbonitrile (280 mg, 820.2 μmol) and CH2I2 (3.36 g, 12.6 mmol, 1.01 mL) in CHCl3 (5 mL) stirred at 70 °C, isopentyl nitrite (384 mg, 3.28 mmol) was added portionwise over 30 minutes while maintaining the internal temperature at 70 °C. The reaction mixture was stirred at 70 °C for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with 0-20% ethyl acetate in petroleum ether) to afford the title compound (200 mg, 54%). LC-MS (ESI+): m / z 453.0 [M+H] + .

[0188] Step 5. N-(4-(5-Cyano-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidin-7-yl)phenyl)acrylamide A mixture of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (181 mg, 663.4 μmol) and 7-iodo-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carbonitrile (200 mg, 442.2 μmol) in dioxane (3 mL) and H2O (1 mL) was sequentially added with K2CO3 (183 mg, 1.33 mmol) and Pd-118 (29 mg, 44.2 μmol) under N2. The reaction mixture was stirred at 90 °C for 2 h under N2. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 20% ethyl acetate in petroleum ether) to give the title compound (90 mg, 43%). LC-MS (ESI+): m / z 472.1 [M+H] + .

[0189] Step 6. 7-(4-Acrylamidophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carboxamide A mixture of N-(4-(5-cyano-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidin-7-yl)phenyl)acrylamide (90 mg, 190.9 μmol) in concentrated H2SO4 (3 mL) was stirred at 30 °C for 16 h. Next, the pH of the reaction mixture was adjusted to 7 with an aqueous sodium carbonate solution. After extraction with ethyl acetate (20 ml * 3), the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5um; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 25% - 55%, 10 min) to give the title compound (21 mg, 22%). LC-MS (ESI+): m / z 490.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.87 (d, J = 1.3 Hz, 1H), 7.94 (d, J = 6.4 Hz, 1H), 7.78 - 7.65 (m, 4H), 7.38 - 7.16 (m, 5H), 7.11 - 6.99 (m, 3H), 6.77 (d, J = 8.1 Hz, 1H), 6.50 - 6.40 (m, 1H), 6.32 - 6.12 (m, 2H), 5.82 - 5.71 (m, 1H), 2.34 (s, 3H). [Example 16] 6-(4-Acrylamidophenyl)-7-(4-(((1-fluorocyclobutyl)methyl)carbamoyl)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0190] Step 1. 4-(6-Bromo-8-cyanopyrrolo[1,2-a]pyrazin-7-yl)benzoic acid In a similar manner according to the procedure of Intermediate 2.2, Intermediate 16.1 was synthesized by replacing 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde with methyl 4-formylbenzoate.

[0191] To a solution of methyl 4-(6-bromo-8-cyanopyrrolo[1,2-a]pyrazin-7-yl)benzoate (Intermediate 16.1) (480 mg, 1.35 mmol) in THF (10.0 mL) was added LiOH·H2O (2 M in water, 3.37 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. Next, the mixture was extracted with DCM (20.0 mL). The pH of this aqueous phase was adjusted to 7 with 1N HCl. After extraction with DCM (20.0 mL * 3), the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (300 mg, 43%). LC-MS (ESI+): m / z 341.8 [M + H] + .

[0192] Step 2. 4-(6-Bromo-8-cyanopyrrolo[1,2-a]pyrazin-7-yl)-N-((1-fluorocyclobutyl)methyl)benzamide To a solution of 4-(6-bromo-8-cyanopyrrolo[1,2-a]pyrazin-7-yl)benzoic acid (370 mg, 1.08 mmol) in DCM (10 mL) were added DIPEA (698 mg, 5.41 mmol), (1-fluorocyclobutyl)methanamine hydrochloride (166 mg, 1.19 mmol) and HATU (616 mg, 1.62 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. Next, the mixture was diluted with H2O (50 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 1 - 50% EtOAc in petroleum ether) to give the title compound (500 mg). LC-MS (ESI+): m / z 426.8 [M + H] + .

[0193] Step 3. 6-Bromo-7-(4-(((1-fluorocyclobutyl)methyl)carbamoyl)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide To a solution of 4-(6-bromo-8-cyanopyrrolo[1,2-a]pyrazin-7-yl)-N-((1-fluorocyclobutyl)methyl)benzamide (100 mg, 234.0 μmol) in DMSO (25.0 mL) was added K2CO3 (113 mg, 819.0 μmol). H2O2 (1.09 mL, 11.3 mmol, 30% purity) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 5 h. Next, the mixture was quenched by the addition of aqueous Na2SO3 (40.0 mL). After extraction with DCM (30.0 mL × 3), the combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure to give the title compound (100 mg) as a yellow oil. LC-MS (ESI+): m / z 444.9 [M + H] + .

[0194] Step 4. 6-(4-Acrylamidophenyl)-7-(4-(((1-fluorocyclobutyl)methyl)carbamoyl)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide To a mixture consisting of 6-bromo-7-(4-(((1-fluorocyclobutyl)methyl)carbamoyl)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (100 mg, 224.0 μmol) in dioxane (4.0 mL) and H2O (1.0 mL), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (122 mg, 449 μmol), Na2CO3 (71 mg, 673.0 μmol) and Pd(PPh3)4 (26 mg, 22.4 μmol) were added under N2 at 25 °C. The reaction mixture was stirred at 70 °C for 12 h under a N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (HCl)-MeOH]; B%: 16% - 46%, 10 min) to give the title compound (20 mg, 17%). LC-MS (ESI+): m / z 512.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.26 (d, J = 1.3 Hz, 1H), 8.71 (m, 1H), 8.04 - 7.97 (m, 1H), 7.85 - 7.62 (m, 5H), 7.41 - 7.25 (m, 5H), 6.82 - 6.71 (m, 1H), 6.48 - 6.39 (m, 1H), 6.31 - 6.23 (m, 1H), 5.81 - 5.73 (m, 1H), 3.68 - 3.56 (m, 2H), 2.23 - 2.10 (m, 4H), 1.81 - 1.70 (m, 1H), 1.58 - 1.42 (m, 1H).

[0195] Preparation of 6-Iodo-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (Intermediate 17.6) [Chemical Formula]

[0196] Step 1. (5-Methoxypyrazin-2-yl)methanol To a solution of (5-chloropyrazin-2-yl)methanol (4.0 g, 27.67 mmol) in methanol (120 mL) was added sodium methoxide (14.95 g, 276.70 mmol) portionwise over 10 minutes at 25 °C. The reaction mixture was stirred at 25 °C for 18 hours. Next, water (50 mL) was added to the reaction mixture. After extraction with ethyl acetate (50 mL × 3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 25% ethyl acetate in petroleum ether) to give the title compound (2.6 g, 67%). LC-MS (ESI+): m / z 141.0 [M+H] + .

[0197] Step 2. 2-(Chloromethyl)-5-methoxypyrazine To a solution of (5-methoxypyrazin-2-yl)methanol (2.6 g, 18.55 mmol) in dichloromethane (52 mL) was slowly added thionyl dichloride (6.73 mL, 92.76 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 18 hours. Next, the mixture was concentrated under reduced pressure to give the title compound (2.7 g, 92%) as a yellow oil, which was used directly in the next step. LC-MS (ESI+): m / z 159.0 [M+H] + .

[0198] Step 3. 2-(5-Methoxypyrazin-2-yl)acetonitrile A solution of 2-(chloromethyl)-5-methoxypyrazine (2.7 g, 17.02 mmol) in ethanol (150 mL) and H2O (50 mL) was added with potassium iodide (0.85 g, 5.11 mmol), K2CO3 (2.35 g, 17.03 mmol) and KCN (1.22 g, 18.73 mmol). The reaction mixture was stirred at 80 °C for 18 h. After cooling to room temperature, saturated Na2CO3 solution (100 mL) was added to this mixture. After extraction with ethyl acetate (100 mL × 3), the combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluted with 0 - 25% ethyl acetate in petroleum ether) to obtain the title compound (1.7 g, 67%). LC-MS (ESI+): m / z 150.0 [M+H] + .

[0199] Step 4. 2-(5-Methoxypyrazin-2-yl)-3-(4-((6-methylpyridin-2-yl)oxy)phenyl)acrylonitrile To a solution of 2-(5-methoxypyrazin-2-yl)acetonitrile (1.80 g, 12.07 mmol) in methanol (20 mL) were added 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde (3.09 g, 14.48 mmol) and DBU (5.51 g, 36.20 mmol). The reaction mixture was stirred at 80 °C for 3 h. After cooling to room temperature, the precipitate was filtered. The solid was washed with water (20 mL) and dried under reduced pressure to obtain the title compound (3 g, 72%). LC-MS (ESI+): m / z 345.0 [M+H] + .

[0200] Step 5. 6-Amino-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile A mixture consisting of 2-(5-methoxypyrazin-2-yl)-3-(4-((6-methylpyridin-2-yl)oxy)phenyl)acrylonitrile (3 g, 8.71 mmol) in methanol (90 mL) was added with DBU (4 g, 26.14 mmol) and acetyl cyanide (0.72 g, 10.45 mmol). The reaction mixture was stirred at 120 °C for 20 minutes under microwave irradiation. After cooling to room temperature, water (200 mL) was added to this reaction. After extraction with ethyl acetate (200 mL × 3), the combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluted with 0 - 5% methanol in dichloromethane) to obtain the title compound (740 mg, 23%). LC-MS (ESI+): m / z 372.3 [M+H] + .

[0201] Step 6. 6-Iodo-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile To a solution of 6-amino-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (560 mg, 1.51 mmol) in chloroform (50 mL) were added 3-methyl-1-(nitrosooxy)butane (530 mg, 4.5 mmol) and diiodomethane (606 mg, 2.26 mmol). The reaction mixture was stirred at 70 °C for 1 hour. After cooling to room temperature, water (50 mL) was added to this reaction. After extraction with DCM (50 mL × 3), the combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluted with 0% - 50% ethyl acetate in petroleum ether) to obtain the title compound (50 mg, 7%). LC-MS(ESI+): m / z 482.8 [M+H] + . [Example 17] 6-(4-Acrylamidophenyl)-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

Chem.

[0202] Preparation of Intermediate 18.5

Chem.

[0203] Step 1. 2-(Benzylthio)-5-chloropyrazine To a solution of 2,5-dichloropyrazine (7.85 g, 52.70 mmol) in 1,4-dioxane (160 mL) were added phenylmethanethiol (6.54 g, 52.70 mmol), Xantphos (6.10 g, 10.54 mmol), Pd2(dba)3 (4.83 g, 5.27 mmol), and DIPEA (26.13 mL, 158.08 mmol). The reaction mixture was stirred at 100 °C for 2 h under N2. After cooling to room temperature, the mixture was diluted with brine (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with petroleum ether to afford the title compound (3.77 g, 30%) as a yellow oil. LC-MS (ESI+): m / z 237.2 [M+H] + .

[0204] Step 2. 5-Chloropyrazine-2-sulfonyl chloride To a solution of 2-(benzylthio)-5-chloropyrazine (3.1 g, 13.09 mmol) in DCM (60 mL) and H2O (6 mL) was added sulfuryl chloride (11.84 g, 87.74 mmol) at 0 - 10 °C. The reaction mixture was stirred at 0 °C for 2 h under N2. Water (100 mL) was added to the reaction mixture. After extraction with DCM (100 mL × 3), the combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether (0% - 10%) to afford the title compound (1.99 g, 71%). 1 1H NMR (400 MHz, CDCl3) δ 9.095 (d, J = 4.0 Hz, 1H), 8.775 (d, J = 4.0 Hz, 1H).

[0205] Step 3. 5-Chloro-N-methylpyrazine-2-sulfonamide A suspension of methylamine hydrochloride (0.60 g, 8.92 mmol) in DCM (10 mL) was added with triethylamine (1.24 mL, 8.92 mmol) and 5-chloropyrazine-2-sulfonyl chloride (1.9 g, 8.92 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. Brine (100 mL) was added to the reaction mixture. After extraction with DCM (100 mL × 3), the combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (0% - 50%) in petroleum ether to obtain the title compound (1.46 g, 79%) as an oil. 1 H NMR (400 MHz, CDCl3) δ 8.985 (d, J = 4.0 Hz, 1H), 8.66 (d, J = 1.3 Hz, 1H), 4.82 (br s, 1H), 2.835 (d, J = 4.0 Hz, 3H).

[0206] Step 4. tert-Butyl 2-cyano-2-(5-(N-methylsulfamoyl)pyrazin-2-yl)acetate To a solution of 5-chloro-N-methylpyrazine-2-sulfonamide (650 mg, 3.13 mmol) in THF (20 mL) were added tert-butyl 2-cyanoacetate (884 mg, 6.26 mmol) and Cs2CO3 (2.55 g, 7.82 mmol). The reaction mixture was stirred at 80 °C for 1 h. After cooling to room temperature, water (100 mL) was added to the mixture. After extraction with ethyl acetate (50 mL × 3), the pH of the aqueous layer was adjusted to 3 with dilute HCl solution (1 N). After extraction with DCM (100 mL × 3), the combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with DCM to obtain the title compound (850 mg, 87%). LC-MS (ESI+): m / z 313.2 [M+H] + .

[0207] Step 5. 5-(Cyanomethyl)-N-methylpyrazine-2-sulfonamide To a solution of tert-butyl 2-cyano-2-(5-(N-methylsulfamoyl)pyrazin-2-yl)acetate (840 mg, 2.69 mmol) in toluene (25 mL) was added 4-methylbenzenesulfonic acid (463 mg, 2.69 mmol). The reaction mixture was stirred at 120 °C for 1 h under N2. After cooling to room temperature, water (100 mL) was added to the mixture. After extraction with DCM (100 mL × 3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with dichloromethane to afford the title compound (260 mg, 46%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.83 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 4.49 (s, 2H), 2.585 (d, J = 4.0 Hz, 3H). [Example 18] 6-(4-Acrylamidophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-3-(N-methylsulfamoyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0208] Example 18 was synthesized in a similar manner following the procedure of Example 1 by replacing 2-(pyrazin-2-yl)acetonitrile with 5-(cyanomethyl)-N-methylpyrazine-2-sulfonamide (Intermediate 18.5). The crude product was purified by preparative HPLC (eluted with 40% - 50% MeCN in H2O containing 0.1% FA) to afford the title compound (8 mg, 16%). LC-MS (ESI+): m / z 583.2 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 9.84 (d, J = 1.2 Hz, 1H), 8.59 (d, J = 1.2 Hz, 1H), 7.69 - 7.62 (m, 3H), 7.37 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.46 (d, J = 20.0 Hz, 1H), 6.35 - 6.20 (m, 1H), 5.82 (d, J = 12.0 Hz, 1H), 5.67 - 5.35 (m, 2H), 5.02 - 4.92 (m, 1H), 2.71 (d, J = 4.0 Hz, 3H), 2.47 (s, 3H). [Example 19] 6-(4-Acrylamidophenyl)-7-(4-((4-methylthiazol-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0209] Preparation of Intermediate 19.1 [Chemical formula] To a solution of 4-hydroxybenzaldehyde (10.0 g, 81.9 mmol) in DMF (100 mL) were added 2-bromo-4-methylthiazole (16.0 g, 90.0 mmol) and CsF (37.3 g, 245.0 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 12 h. Next, the mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (50.0 mL * 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with EtOAc (1% - 50%) in petroleum ether to afford the title compound (2.50 g, 12%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.05 - 7.96 (m, 2H), 7.57 - 7.47 (m, 2H), 6.90 (s, 1H), 2.22 (s, 3H).

[0210] Example 19 was synthesized in a similar manner following the procedure of Example 15, replacing 4-((6-methylpyridin-2-yl)oxy)benzaldehyde with 4-((4-methylthiazol-2-yl)oxy)benzaldehyde and 2-(pyrimidin-4-yl)acetonitrile with 2-(pyrazin-2-yl)acetonitrile. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 * 25 mm * 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25% - 55%, 8 min) to give the title compound (25 mg, 12%). LC-MS (ESI+): m / z 496.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.26 (d, J = 1.3 Hz, 1H), 8.00 (dd, J = 1.4, 4.9 Hz, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 4.9 Hz, 1H), 7.40 - 7.27 (m, 7H), 6.84 - 6.68 (m, 2H), 6.49 - 6.39 (m, 1H), 6.32 - 6.24 (m, 1H), 5.82 - 5.74 (m, 1H), 2.21 (d, J = 1.0 Hz, 3H). [Example 20] 7-(4-Acrylamidophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide [Chemical formula]

[0211] Step 1. 1-(4-Nitrobenzyl)pyridazin-1-ium bromide To a mixture of pyridazine (5.87 g, 73.2 mmol) in EtOAc (30.0 mL) was added 1-(bromomethyl)-4-nitro-benzene (19.0 g, 87.9 mmol) in one portion at 25 °C under N2. The mixture was stirred at 80 °C for 12 h. Next, the mixture was cooled to room temperature and filtered. The filter cake was dried under reduced pressure to give the title compound (15.0 g) LC-MS (ESI+): m / z 216.0 (M + ).

[0212] Step 2. 7-(4-Nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carbonitrile To a solution of 1-(4-nitrobenzyl)pyridazin-1-ium bromide (10.0 g, 33.9 mmol) in DME (100 mL) was added prop-2-enenitrile (9.31 g, 175 mmol). Next, to this solution were added MnO2 (15.2 g, 175 mmol) and TEA (10.7 g, 106 mmol, 14.8 mL) at room temperature. Then, the reaction mixture was stirred at 80 °C for 7 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel eluted with EtOAc (1% - 10%) in petroleum ether to give the title compound (6.40 g, 72%). 1 H NMR (400MHz, DMSO-d6) δ 8.72 - 8.68 (m, 1H), 8.45 - 8.39 (m, 3H), 8.39 - 8.34 (m, 2H), 8.15 (s, 1H), 7.34 - 7.29 (m, 1H).

[0213] Step 3. 6-Bromo-7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide To a solution of 7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carbonitrile (2.00 g, 7.57 mmol) in H2SO4 (15.0 mL) was added NBS (2.69 g, 15.1 mmol). The reaction mixture was stirred at 25 °C for 4 hours. The mixture was poured into ice and the pH was adjusted to 7 by dropwise addition of saturated aqueous Na2CO3. After extraction with ethyl acetate (50 mL * 3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (800 mg, 29%).

[0214] Step 4. 6-(4-((6-Methylpyridin-2-yl)oxy)phenyl)-7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide A solution of 6-bromo-7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide (526 mg, 1.46 mmol) in DMF (16 mL) and H2O (1 mL) was added with 2-methyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (498 mg, 1.60 mmol), Pd(DtBPF)Cl2 (95 mg, 145 μmol) and K3PO4 (927 mg, 4.37 mmol). The reaction mixture was stirred at 95 °C for 4 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex C18 250 * 50 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 37% - 67%, 8 min) to obtain the title compound (50 mg, 7%). LC-MS (ESI+): m / z 466.1 [M+H] + .

[0215] Step 5. 7-(4-Aminophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide To a solution of 6-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide (35 mg, 75.1 μmol) in EtOH (2 mL) and H2O (2 mL) was added Fe (27 mg, 488 μmol) and CaCl2 (25 mg, 225 μmol) at room temperature. The reaction mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (30 mg). LC-MS (ESI+): m / z 436.3 [M+H] + .

[0216] Step 6. 7-(4-Acrylamidophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide A solution of 7-(4-aminophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide (30 mg, 68.8 μmol) in acetone (2 mL) and H2O (0.4 mL) was added with K2CO3 (19.0 mg, 137.0 μmol) at 0 °C. Next, prop-2-enenoyl chloride (7.48 mg, 82.6 μmol) was added to this solution at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Next, this mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain a residue, which was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1) to obtain the title compound (10 mg, 29%). LC-MS (ESI+): m / z 490.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (d, J = 8.1 Hz, 1H), 8.50 - 8.44 (m, 1H), 8.35 - 8.29 (m, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.36 - 7.28 (m, 4H), 7.25 (br s, 1H), 7.13 (d, J = 8.6 Hz, 2H), 7.06 - 6.94 (m, 2H), 6.77 (d, J = 8.1 Hz, 1H), 6.53 - 6.40 (m, 1H), 6.35 - 6.15 (m, 2H), 5.81 - 5.70 (m, 1H), 2.36 (s, 3H). [Example 21] 6-(4-Acrylamidophenyl)-3-(1-methylazetidin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0217] Step 1. tert-Butyl 3-(6-amino-8-cyano-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazin-3-yl)azetidine-1-carboxylate Intermediate 21.1 was synthesized by replacing 2,3-dichloropyrazine with 2,5-dibromopyrazine in a similar manner according to the procedure of Intermediate 12.3.

[0218] To a mixture of Zn (498 mg, 7.61 mmol) in THF (10 mL) were added 1,2-dibromoethane (27 mg, 142.77 μmol) and TMSCl (31 mg, 285.54 μmol). The reaction mixture was warmed to 65 °C. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (808 mg, 2.86 mmol) in THF (2 mL) was added. Next, the mixture was stirred at 65 °C for 1 h under N2. Then, 6-amino-3-bromo-7-[4-[(6-methyl-2-pyridyl)oxy]phenyl]pyrrolo[1,2-a]pyrazine-8-carbonitrile (400 mg, 951.8 μmol), CuI (22.7 mg, 119.0 μmol), and Pd(dppf)Cl2·CH2Cl2 (47 mg, 57.1 μmol) were added. The reaction mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with 0 - 10% MeOH in DCM) to give the title compound (400 mg, 85%). LC-MS (ESI+): m / z 441.1 (M+H-56) + .

[0219] Step 2. tert-Butyl 3-(8-cyano-6-iodo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazin-3-yl)azetidine-1-carboxylate A mixture consisting of tert-butyl 3-(6-amino-8-cyano-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazin-3-yl)azetidine-1-carboxylate (500 mg, 1.01 mmol) in CHCl3 (5 mL) was sequentially added with CH2I2 (4.13 g, 15.4 mmol) and isopentyl nitrite (472 mg, 4.03 mmol). The reaction mixture was stirred at 70 °C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel (eluted with 0 - 35% ethyl acetate in petroleum ether) to give the title compound (230 mg, 38%). LC-MS (ESI+): m / z 607.8 [M+H] + .

[0220] Step 3. 3-(Azetidin-3-yl)-6-iodo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide A mixture of tert-butyl 3-(8-cyano-6-iodo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazin-3-yl)azetidine-1-carboxylate (220 mg, 362.2 μmol) in H2SO4 (4.40 mL, 82.5 mmol) was stirred at 30 °C for 12 hours. After cooling to room temperature, the mixture was poured into ice water (30 mL) and the pH was adjusted to 7 with aqueous sodium carbonate solution. After extraction with ethyl acetate (20 mL * 3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (150 mg). LC-MS (ESI+): m / z 526.1 [M+H] + .

[0221] Step 4. 6-Iodo-3-(1-methylazetidin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide A solution of 3-(azetidin-3-yl)-6-iodo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (150 mg, 285.5 μmol) and HCHO (43 mg, 571.1 μmol, 40% purity) in MeOH (5 mL) was added with NaBH3CN (63 mg, 999.4 μmol). The reaction mixture was stirred at 25 °C for 2 hours. Next, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (120 mg). LC-MS (ESI+): m / z 540.0 [M+H] + .

[0222] Step 5. 6-(4-Acrylamidophenyl)-3-(1-methylazetidin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide To a solution of 6-iodo-3-(1-methylazetidin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (100 mg, 185.4 μmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (61 mg, 222.5 μmol) in dioxane (3 mL) and H2O (1 mL), K2CO3 (64 mg, 463.5 μmol) and Pd-118 (12 mg, 18.5 μmol) were sequentially added. The reaction mixture was stirred at 90 °C for 2 hours under a N2 atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC (column: Boston Prime C 18150 * 30 mm * 5 um; Mobile phase: [Water (ammonia hydroxide v / v) - ACN]; B%: 25% - 47% (for 22 minutes), and the title compound (1.6 mg, 2%) was obtained after purification. LC-MS (ESI+): m / z 559.4 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.77 (s, 1H), 7.70 - 7.60 (m, 3H), 7.52 (s, 1H), 7.30 - 7.25 (m, 2H), 7.22 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 7.3 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 6.52 - 6.44 (m, 1H), 6.30 (dd, J = 10.2, 16.7 Hz, 1H), 5.83 (d, J = 10.0 Hz, 1H), 5.60 - 5.26 (m, 2H), 3.97 - 3.89 (m, 2H), 3.82 - 3.73 (m, 1H), 3.63 - 3.55 (m, 2H), 2.57 (s, 3H), 2.47 (s, 3H). [Example 22] Preparation of 6-(4 - acrylamidophenyl)-7-(4 - methoxyphenyl)pyrrolo[1,2 - a]pyrazine - 8 - carboxamide

Chemical Structure

[0223] Step 1: Preparation of Example 22 Example 22 was synthesized from compound 22.1 in a similar manner following the procedure of Example 15. Spectral data of Example 22: LCMS: 413.1 [M + H] + ; 11H NMR: (400 MHz, DMSO-d6) δ 10.30 (br s, 1H), 9.35 (s, 1H), 8.00 (d, J = 4.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 4.8 Hz, 1H), 7.35 - 7.25 (m, 3H), 7.21 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.49 - 6.38 (m, 1H), 6.35 - 6.23 (m, 2H), 5.78 (dd, J = 10.2, 1.6 Hz, 1H), 3.75 (s, 3H). [Example 23] Preparation of 5-(4-Acrylamidophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[2,1-b]thiazole-7-carboxamide [Chemical formula]

[0224] Step 1: Preparation of Example 23 A solution of Example 24 (45.0 mg, 0.094 mmol) in H2SO4 (1 mL) was stirred at 30 °C for 16 h. The reaction solution was poured into ice, and the pH of the reaction solution was adjusted to 7 with an aqueous sodium carbonate solution. After extraction with EA (10 mL × 3), the combined organic layers were washed with brine (10 mL), dehydrated over Na2SO4, filtered, concentrated, and purified by preparative HPLC to obtain Example 23. LCMS: m / z 495.1 [M+H] + ; 11H NMR: (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.85 (d, J = 4.2 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 4.2 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.47 - 6.37 (m, 1H), 6.30 - 6.21 (m, 1H), 5.81 - 5.72 (m, 1H), 2.35 (s, 3H). [Example 24] Preparation of N-(4-(7-cyano-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[2,1-b]thiazol-5-yl)phenyl)acrylamide [Chemical formula]

[0225] Step 1: Preparation of Compound 24.3 To a solution of Compound 24.1 (10.0 g, 61.0 mmol) in DMF (100 mL) was added Cs2CO3 (39.7 g, 121.9 mmol). Next, Compound 24.2 (11.2 g, 79.3 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered, the filtrate was concentrated, and purified by flash column chromatography on silica gel to obtain Compound 24.3 (8.00 g, 58.51%) as a yellow solid. LCMS: 168.8 [M+H-56] + .

[0226] Step 2: Preparation of Compound 24.4 To a solution of compound 24.3 (6.00 g, 26.8 mmol) in toluene (90 mL) was added 4-methylbenzenesulfonic acid (0.37 g, 2.14 mmol), and the solution was stirred at 140 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated and purified by flash column chromatography on silica gel to give compound 24.4 (1.50 g, 45.16%) as a yellow solid. LCMS: 124.8 [M+H] + .

[0227] Step 3: Preparation of compound 24.6 To a solution of compound 24.4 (1.50 g, 12.1 mmol) in MeOH (60 mL) were added compound 24.5 (2.58 g, 12.1 mmol) and DBU (5.52 g, 36.2 mmol). Next, acetyl cyanide (0.83 g, 12.1 mmol) was added dropwise to this solution under N2, and the reaction mixture was stirred under microwave at 100 °C for 20 min. After cooling to room temperature, the reaction mixture was concentrated and purified by flash column chromatography on silica gel to give compound 24.6. LCMS: 347.2 [M+H] +

[0228] Step 4: Preparation of compound 24.7 To a solution of compound 24.6 (500.0 mg, 1.44 mmol) in chloroform (8 mL) was added diiodomethane (5.80 g, 21.7 mmol). Next, 3-methyl-1-(nitrosooxy)butane (676.4 mg, 5.77 mmol) in chloroform (2 mL) was added to this solution at 70 °C, and the reaction solution was stirred at 70 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated and purified by flash column chromatography on silica gel to give compound 24.7. LCMS: m / z 457.9 [M+H] +

[0229] Step 5: Preparation of Example 24 A solution of compound 24.7 (100.0 mg, 0.219 mmol) and compound 24.8 (71.7 mg, 0.262 mmol) in dioxane (2 mL) and H2O (0.4 mL) was added with K2CO3 (60.4 mg, 0.437 mmol). Next, Pd(PPh3)4 (25.3 mg, 0.022 mmol) was added to this solution under N2, and the reaction solution was stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction solution was diluted with water (2 mL) and extracted with EA (2 mL × 3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to obtain Example 24. LCMS: 477.2 [M+H] + ; 1 H NMR: (400 MHz, CD3OD) δ 7.78 (d, J = 4.3 Hz, 1H), 7.76 - 7.69 (m, 3H), 7.38 (dd, J = 15.6, 8.5 Hz, 4H), 7.27 (d, J = 4.1 Hz, 1H), 7.08 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.49 - 6.37 (m, 2H), 5.81 (dd, J = 9.4, 2.1 Hz, 1H), 2.45 (s, 3H). [Example 25] Preparation of 6-(4 - acrylamidophenyl)-7-(3 - methoxy - 4 - ((6 - methylpyridin - 2 - yl)oxy)phenyl)pyrrolo[1,2 - a]pyrazine - 8 - carboxamide

Chemical Structure

[0230] Step 1: Preparation of compound 25.3 To a solution of Compound 25.1 (11.70 mL, 113.38 mmol) in DMF (110 mL) were added Compound 25.2 (34.50 g, 226.75 mmol) and Cs2CO3 (110.82 g, 340.13 mmol). The mixture was stirred at 130 °C for 18 h. NaOH (40 mL, 2.00 mmol) was added to the reaction mixture, and it was stirred at 25 °C for 0.5 h and then extracted with EA (3 × 100 mL). The organic layer was washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and the solvent was evaporated to obtain the crude product, which was purified by flash chromatography to give Compound 25.3 (1.68 g). 1 H NMR: (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.78 (s, 3H), 2.27 (s, 3H).

[0231] Step 2: Preparation of Compound 25.4 To a solution of Compound 1.2 (587.67 mg, 4.93 mmol) in methanol (16 mL) were added Compound 25.3 (1.2 g, 4.93 mmol), acetyl cyanide (0.350 mL, 4.93 mmol), and DBU (2.21 mL, 14.80 mmol), and the reaction was stirred under microwave irradiation at 100 °C for 20 min. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EA (3 × 70 mL). The organic layer was washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and the solvent was evaporated to give Compound 25.4 (1.83 g, 99.0% yield). LCMS: 371.9 [M+H] + .

[0232] Step 3: Preparation of Example 25 Example 25 was synthesized from Compound 25.4 in a similar manner according to the procedure of Example 15. Spectral data for Example 25: LCMS: 520.3 [M+H] +; 1 H NMR: (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.34 (d, J = 1.32 Hz, 1H), 8.03 (dd, J = 4.8, 1.4 Hz, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.66 (dd, J = 6.2, 5.0 Hz, 2H), 7.41 (s, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.05 (dd, J = 12.2, 8.1 Hz, 2H), 6.95 - 6.87 (m, 2H), 6.61 (d, J = 8.2 Hz, 2H), 6.45 (dd, J = 16.9, 10.0 Hz, 1H), 6.28 (dd, J = 17.0, 2.0 Hz, 1H), 5.78 (dd, J = 10.0, 1.9 Hz, 1H), 3.52 (s, 3H), 2.29 (s, 3H). [Example 26] Preparation of 6-(4 - acrylamidophenyl)-7-(4-(pyridin - 2 - yloxy)phenyl)pyrrolo[1,2 - a]pyrazine - 8 - carboxamide [Chemical Structure]

[0233] Step 1: Preparation of Compound 26.3 To a solution of Compound 26.1 (4.17 mL, 44.04 mmol) in DMF (50 mL) were added Compound 26.2 (8.07 g, 66.06 mmol), potassium carbonate (18.26 g, 132.11 mmol), and copper(II) oxide (1.28 g, 8.81 mmol). The mixture was stirred at 150 °C for 18 hours. After cooling to room temperature, the reaction mixture was poured into water (80 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel to give Compound 26.3 (4.79 g, 54.61% yield). LCMS: 241.0 [M + 42] + .

[0234] Step 2: Preparation of Compound 26.4 To a solution of Compound 26.3 (836.08 mg, 4.20 mmol) in MeOH (15 mL) were added Compound 1.2 (500 mg, 4.20 mmol), DBU (1.88 mL, 12.59 mmol), and acetyl cyanide (0.30 mL, 4.20 mmol). The mixture was stirred at 120 °C for 20 minutes. After cooling to room temperature, the reaction mixture was poured into water (80 mL) and extracted with EA (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel to give Compound 26.4 (695 mg, 50.48% yield). LCMS: 328.2 [M+H] + .

[0235] Step 3: Preparation of Example 26 Example 26 was synthesized from Compound 26.4 in a similar manner following the procedure of Example 15. Spectral data of Example 26: LCMS: 476.3[M+H] + . 1 H NMR: (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.30 (s, 1H), 8.19 (dd, J = 5.0, 1.6 Hz, 1H), 7.99 (dd, J = 4.8, 0.8 Hz, 1H), 7.91-7.83 (m, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 4.8 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J = 8.4 Hz, 4H), 7.15 (dd, J = 4.8, 0.8 Hz, 1H), 7.12-7.07 (dt, J = 8.8 Hz, 2.4 Hz, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 6.45 (dd, J = 16.8, 10.0 Hz, 1H), 6.28 (dd, J = 17.2, 2.0 Hz, 1H), 5.78 (dd, J = 10.0, 2.0 Hz, 1H). [Example 27] Preparation of 6-(4-Acrylamidophenyl)-7-(4-(cyclopropylsulfonyl)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical Structure]

[0236] Step 1: Preparation of Example 27 Example 27 was synthesized from Compound 27.1 in a similar manner following the procedure of Example 12. Spectrum data of Example 27: LCMS: 487.3 [M+H] + ; 1 H NMR: (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.18 (s, 1H), 8.01 - 7.97 (m, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 4.8 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.42 (br s, 1H), 7.28 (d, J = 8.5 Hz, 3H), 6.49 - 6.39 (m, 1H), 6.32 - 6.24 (m, 1H), 5.82 - 5.75 (m, 1H), 2.93 - 2.83 (m, 1H), 1.15 - 1.10 (m, 2H), 1.08 - 1.01 (m, 2H). [Example 28] Preparation of 6-(4-Acrylamidophenyl)-7-(4-(cyclopentyloxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical Structure]

[0237] Step 1: Preparation of Compound 28.1 To a solution of compound 26.2 (5 g, 40.94 mmol) in DMF (60 mL) was added potassium carbonate (11.32 g, 81.88 mmol). The mixture was heated to 65 °C and bromocyclopentane (12.20 g, 81.88 mmol) was added. The reaction mixture was stirred at 100 °C for 5 h under N2. After cooling to room temperature, the reaction was diluted with H2O (300 mL) and extracted with EA (3 × 300 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 28.1 (6.94 g, 89.10% yield). LCMS: 191.2 [M+H] +

[0238] Step 2: Preparation of compound 28.2 To a solution of compound 1.2 (500 mg, 4.19 mmol) in MeOH (15 mL) were added compound 28.1 (798.46 mg, 4.19 mmol), DBU (1916.90 mg, 12.59 mmol), and 2-hydroxy-2-methylpropanenitrile (357.21 mg, 4.19 mmol). The mixture was stirred at 120 °C for 20 min under microwave and N2. After cooling to room temperature, the mixture was quenched with water (100 mL), extracted with dichloromethane (3 × 100 mL), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to give compound 28.2 (800 mg, 59.87% yield). LCMS: 319.2 [M+H] + .

[0239] Step 3: Preparation of Example 28 Example 28 was synthesized from compound 28.2 in a similar manner according to the procedure of Example 1. Spectral data for Example 28: LCMS: 467.2 [M+H] + ; 11H NMR: (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.34 (s, 1H), 7.99 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 4.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 3H), 7.18 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.44 (dd, J = 16.8, 10.0 Hz, 1H), 6.27 (d, J = 16.8 Hz, 2H), 5.78 (d, J = 12 Hz, 1H), 4.80 - 4.78 (m, 1H), 1.92 - 1.88 (3, 2H), 1.73 - 1.67 (m, 4H), 1.65 - 1.52 (m, 2H). [Example 29] Preparation of 6-(4-Acrylamidophenyl)-3-((dimethylamino)methyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0240] Step 1: Preparation of Example 29 Compound 29.1 was synthesized in a similar manner following the procedure of Example 15.

[0241] A solution of Compound 29.1 (130 mg, 248 μmol), Compound 29.2 (81.9 mg, 496 μmol), Cs2CO3 (162.0 mg, 496.0 μmol), and Xphos Pd G3 (21.0 mg, 24.8 μmol) in dioxane (2.5 mL) and H2O (0.5 mL) was stirred at 100 °C for 12 h under N2. The reaction solution was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give Example 29. LCMS: 547.4 [M+H] + . 11H NMR: (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.27 (s, 1H), 7.89 (s, 1H), 7.82 - 7.69 (m, 3H), 7.38 (br s, 1H), 7.29 (dd, J = 8.0, 5.5 Hz, 4H), 7.06 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.58 (br s, 1H), 6.49 - 6.41 (m, 1H), 6.32 - 6.23 (m, 1H), 5.79 (d, J = 11.0 Hz, 1H), 3.54 (s, 2H), 2.33 (s, 3H), 2.23 (s, 6H). [Example 30] Preparation of 7-(4-(2-Azaspiro[3.3]heptane-2-carbonyl)phenyl)-6-(4-acrylamidophenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0242] Step 1: Preparation of Example 30 Example 30 was synthesized from Compound 30.1 in a similar manner following the procedure of Example 12. Spectral data for Example 30: LCMS: 506.3 [M+H] + ; 11H NMR: (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.24 (s, 1H), 7.99 (d, J = 5.0 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 5.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.37 (br s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 6.84 (br s, 1H), 6.50 - 6.38 (m, 1H), 6.35 - 6.19 (m, 1H), 5.78 (d, J = 10.3 Hz, 1H), 4.26 (s, 2H), 3.99 (s, 2H), 2.13 (t, J = 7.7 Hz, 4H), 1.84 - 1.64 (m, 2H). [Example 32] Preparation of 6-(4-Acrylamidophenyl)-7-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0243] Step 1: Preparation of Compound 32.2 To a suspension of Compound 25.1 (6 g, 54.00 mmol) in NMP (200 mL) was added Compound 32.1 (10.31 g, 53.60 mmol) and Cs2CO3 (52.78 g, 161.99 mmol). The reaction mixture was stirred at 150 °C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with saturated brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel to give Compound 32.2 (7.7 g, 48.16% yield). LCMS: 281.8 [M+H] + .

[0244] Step 2: Preparation of Compound 32.3 To a solution of Compound 32.2 (3 g, 10.63 mmol) in THF (150 mL) was added a solution of BuLi (7.31 mL, 11.70 mmol) in THF at -78 °C. The reaction mixture was stirred at -78 °C for 30 minutes, then DMF (0.98 mL, 12.76 mmol) was added to this mixture, and the reaction mixture was stirred at -78 °C for 30 minutes. After warming to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with saturated brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel to give Compound 32.3 (460 mg, 18.71% yield). LCMS: 232.0 [M+H] + .

[0245] Step 3: Preparation of Compound 32.4 To a solution of Compound 1.2 (400 mg, 3.36 mmol) and Compound 32.3 (776 mg, 3.36 mmol) in MeOH (15 mL) were added DBU (1533 mg, 10.07 mmol) and 2-oxopropanenitrile (255 mg, 3.69 mmol). The reaction mixture was stirred at 100 °C for 20 minutes under microwave and N2. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel to give Compound 32.4 (900 mg, 74.59% yield). LCMS: 360.0 [M+H] + .

[0246] Step 4: Preparation of Example 32 Example 32 was synthesized from Compound 32.4 in a similar manner according to the procedure of Example 15. Spectrum data of Example 32: LCMS: 508.3 [M+H] + . 11H NMR: (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.26 (d, J = 1.2 Hz, 1H), 8.41 (s, 1H), 7.83 - 7.76 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.44 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.28 - 7.17 (m, 2H), 7.09 (d, J = 9.2 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.93 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.46 (dd, J = 16.0, 10.1 Hz, 1H), 6.28 (dd, J = 16.0, 1.9 Hz, 1H), 5.78 (dd, J = 10.0, 1.9 Hz, 1H), 2.29 (s, 3H). [Example 33] Preparation of 6-(4-acrylamidophenyl)-7-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0247] Step 1: Preparation of Compound 33.3 To a solution of Compound 33.1 (15.0 g, 107.1 mmol) and Compound 33.2 (16.5 g, 128.5 mmol) in DMF (250 mL) was added CsF (32.5 g, 214.1 mmol). The reaction mixture was stirred at 120 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered, the filtrate was concentrated, and purified by flash column chromatography on silica gel to obtain Compound 33.3 (6.00 g, 24.14%) as a yellow solid. LCMS: 232.9 [M+H] + .

[0248] Step 2: Preparation of Compound 33.4 To a mixture of Compound 33.3 (974.7 mg, 4.20 mmol) and Compound 1.2 (500.0 mg, 4.20 mmol) in n-BuOH (10 mL) was added DBU (1.28 g, 8.39 mmol, 1.27 mL). Next, acetyl cyanide (322.1 mg, 4.20 mmol, 90% purity) was added to this solution at 25 °C, and N2 was purged three times. After the addition, the reaction mixture was heated to 100 °C under microwave for 20 minutes. The reaction solution was cooled to room temperature and diluted with water (100 mL). After extraction with EA (50 mL × 3), the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain Compound 33.4 (400.0 mg, 26.45% yield) as a yellow solid. LCMS: 361.0 [M+H] + .

[0249] Step 3: Preparation of Example 33 Example 33 was synthesized from Compound 33.4 in a similar manner according to the procedure of Example 15. Spectral data of Example 33: LCMS: 509.1 [M+H] + ; 1 H NMR: (400 MHz, DMSO-d6) δ 10.36 (s, 1 H), 9.23 (s, 1 H), 8.48 (d, J = 4.8 Hz, 1 H), 7.99 (d, J = 4.3 Hz, 1 H), 7.79 (d, J = 8.3 Hz, 2 H), 7.66 (d, J = 4.8 Hz, 1 H), 7.48 (br s, 1 H), 7.38 - 7.29 (m, 3 H), 7.26 (d, J = 11.8 Hz, 1 H), 7.19 (d, J = 5.0 Hz, 1 H), 7.11 (d, J = 8.5 Hz, 2 H), 6.52 - 6.38 (m, 1 H), 6.35 - 6.21 (m, 1 H), 5.85 - 5.73 (m, 1 H), 2.42 (s, 3 H). [Example 34] Preparation of 7-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(4-methacrylamidophenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

Chemical Structure

[0250] Step 1: Preparation of Compound 34.3 To a mixture of Compound 34.1 (2.00 g, 9.13 mmol) in DCM (20 mL) was added TEA (2.77 g, 27.4 mmol). Next, Compound 34.2 (1.05 g, 10.0 mmol) dissolved in DCM (10 mL) was added to this solution at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain Compound 34.3 (1.20 g, 45.78% yield) as a white solid. LCMS: 288.2 [M+H] +

[0251] Step 2: Preparation of Example 34 Compound 34.4 was synthesized from Compound 33.4 in a similar manner following the procedure of Example 15.

[0252] To a solution of Compound 34.4 (240.0 mg, 490.6 μmol) and Compound 34.3 (211.3 mg, 735.8 μmol) in dioxane (6 mL) and H2O (3 mL) was added Na2CO3 (104.0 mg, 981.1 μmol). Next, Pd(PPh3)4 (56.7 mg, 49.1 μmol) was added to this mixture under N2, and the reaction mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to obtain Example 34. LCMS: 523.4 [M+H] +; 1 H NMR: (400 MHz, DMSO-d6) δ 9.98 (s, 1 H), 9.23 (s, 1 H), 8.48 (d, J = 5.0 Hz, 1 H), 7.98 (dd, J = 4.9, 1.2 Hz, 1 H), 7.82 (d, J = 8.6 Hz, 2 H), 7.66 (d, J = 4.9 Hz, 1 H), 7.59 - 7.37 (m, 1 H), 7.36 - 7.29 (m, 3 H), 7.26 (dd, J = 11.6, 1.8 Hz, 1 H), 7.19 (d, J = 5.0 Hz, 1 H), 7.15 - 7.01 (m, 2 H), 5.82 (s, 1 H), 5.55 (s, 1 H), 2.43 (s, 3 H), 1.96 (s, 3 H). [Example 35] Preparation of 6-(4-Acrylamidophenyl)-7-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-3-methylpyrrolo[1,2-a]pyrazine-8-carboxamide

Chemical Structure

[0253] Step 1: Preparation of Compound 35.1 To a solution of Compound 33.3 (872.0 mg, 3.76 mmol) and Compound 7.1 (500.0 mg, 3.76 mmol) in n-BuOH (10 mL) was added DBU (1.14 g, 7.51 mmol, 1.13 mL). Next, acetyl cyanide (288.2 mg, 3.76 mmol, 90% purity) was added to this solution at 25 °C, and N2 was purged three times. After the addition, the reaction mixture was heated to 100 °C under microwave for 20 minutes. The reaction solution was cooled to room temperature and diluted with water (100 mL). After extraction with EA (50 mL × 3), the combined organic layers were washed with brine (100 mL), dehydrated with Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain Compound 35.1 (300.0 mg, 21.34% yield) as a yellow solid. LCMS: 374.8 [M+H]+ .

[0254] Step 2: Preparation of Compound 35.2 To a mixture of Compound 35.1 (280.0 mg, 747.9 μmol) in CH3CN (5 mL) was added CH2I2 (3.06 g, 11.44 mmol). Next, isopentyl nitrite (350.5 mg, 2.99 mmol) was added to this mixture, and the reaction was stirred at 40 °C for 1 hour. After cooling to room temperature, the reaction solution was concentrated and purified by flash column chromatography on silica gel to obtain Compound 35.2. LCMS: 485.9 [M+H] + .

[0255] Step 3: Preparation of Compound 35.3 A solution of Compound 35.2 (140.0 mg, 288.5 μmol) in H2SO4 (9.20 g, 93.8 mmol, 5 mL) was stirred at 30 °C for 16 hours. After cooling to room temperature, the reaction solution was diluted with ice water (30 mL), and the pH of the reaction solution was adjusted to 7 with NaHCO3 (saturated aqueous solution). After extraction with EA (20 mL × 3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain Compound 35.3. LCMS: 504.0 [M+H] + .

[0256] Step 4: Preparation of Example 35 To a solution of Compound 35.3 (90.0 mg, 178.8 μmol) and Compound 24.8 (63.5 mg, 232.5 μmol) in dioxane (3 mL) and H2O (1 mL) was added Na2CO3 (37.9 mg, 357.7 μmol). Next, Pd(PPh3)4 (20.7 mg, 17.9 μmol) was added to this mixture under N2, and the mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to obtain Example 35. LCMS: 523.1[M+H] + . 11H NMR: (400 MHz, DMSO-d6) δ 10.35 (s, 1 H), 9.18 (s, 1 H), 8.47 (d, J = 5.0 Hz, 1 H), 7.84 - 7.76 (m, 3 H), 7.50 - 7.38 (m, 1 H), 7.34 - 7.28 (m, 3 H), 7.27 - 7.21 (m, 1 H), 7.19 (d, J = 5.0 Hz, 1 H), 7.10 (d, J = 8.4 Hz, 1 H), 7.03 - 6.90 (m, 1 H), 6.50 - 6.41 (m, 1 H), 6.33 - 6.25 (m, 1 H), 5.83 - 5.77 (m, 1 H), 2.42 (s, 3 H), 2.35 (s, 3 H).

[0257] Examples 36 - 55 were prepared using the same procedure as described in Example 35. [Table 1] TIFF2025523588000147.tif232163TIFF2025523588000148.tif239163TIFF2025523588000149.tif239163TIFF2025523588000150.tif247163TIFF2025523588000151.tif249163TIFF2025523588000152.tif177163[Example 50] Preparation of 6-(5-(2-Fluoroacrylamide)pyridin-2-yl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical Structure]

[0258] Step 1: Preparation of Compound 50.3 Compound 50.1 was synthesized in a similar manner following the procedures of Example 15 and Example 35.

[0259] A solution of Compound 50.1 (150.0 mg, 0.342 mmol), Compound 50.2 (88.8 mg, 0.513 mmol), 4,4,5,5 - tetramethyl - 2-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)-1,3,2 - dioxaborolane (156 mg, 0.616 mmol), K2CO3 (94.6 mg, 0.684 mmol) and Pd(dppf)Cl2 (37.6 mg, 0.051 mmol) in dioxane (3 mL) was stirred at 100 °C for 16 h under N2. After cooling to room temperature, the reaction mixture was diluted with EA (50 mL), washed with brine (15 mL), dried over Na2SO4, filtered and purified by flash column chromatography on silica gel to give Compound 50.3. LCMS: 451.0[M + H] + .

[0260] Step 2: Preparation of Example 50 EDCI (127 mg, 0.664 mmol) was added to a solution of Compound 50.3 (100 mg, 0.221 mmol) and 2 - fluoroprop - 2 - enoic acid (39.9 mg, 0.443 mmol) in pyridine (3 mL). The mixture was stirred at 50 °C for 2 h. The mixture was diluted with DCM (20 mL), washed with water (10 mL×2) and brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by preparative HPLC to give Example 50. LCMS: 524.2[M + H] + . 11H NMR: (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.31 (s, 1H), 9.11 (d, J = 2.3 Hz, 1H), 8.63 (s, 1H), 8.49 (d, J = 4.8 Hz, 1H), 8.03 (dd, J = 8.9, 2.4 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.23 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 5.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.66 - 6.48 (m, 1H), 5.85 - 5.69 (m, 1H), 5.54 - 5.46 (m, 1H), 2.43 (s, 3H), 2.41 (s, 3H). [Example 57] (E)-6-(4-(4-(Dimethylamino)but-2-enamide)phenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide Preparation [Chemical Structure]

[0261] Step 1: Preparation of Compound 57.2 To a solution of Compound 34.1 (600.0 mg, 2.74 mmol) and Compound 57.1 (540.0 mg, 3.29 mmol) in DCM (10 mL) was added DIEA (1.06 g, 8.22 mmol). Next, HATU (1.09 g, 2.88 mmol) was added to this solution, and the solution was stirred at 25 °C for 3 hours. The reaction solution was diluted with water (30 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain Compound 57.2 (300.0 mg, 33.17%) as a white solid. LCMS: 331.3 [M+H] + .

[0262] Step 2: Preparation of Example 57 Compound 57.3 was synthesized in a similar manner following the procedure of compound 35.3.

[0263] To a solution of compound 57.3 (120.0 mg, 0.247 mmol) and compound 57.2 (163.3 mg, 0.495 mmol) in dioxane (3 mL) and H2O (1.5 mL) was added K2CO3 (102.5 mg, 0.742 mmol). Next, Pd(PPh3)4 (28.5 mg, 0.025 mmol) was added to this mixture under N2, and the mixture was stirred at 90 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were concentrated and purified by preparative HPLC to obtain Example 57. LCMS: 562.3 [M+H] + . 1 H NMR: (400 MHz, DMSO-d6) δ 10.22 (s, 1 H), 9.24 (s, 1 H), 8.46 (d, J = 4.8 Hz, 1 H), 7.84 - 7.70 (m, 3 H), 7.33 - 7.26 (m, 5 H), 7.18 - 7.12 (m, 3 H), 6.78 - 6.71 (m, 1 H), 6.32 - 6.29 (m, 1 H), 3.07 (d, J = 4.5 Hz, 2 H), 2.41 (s, 3 H), 2.35 (s, 3 H), 2.19 (s, 6 H). [Example 58] Preparation of 6-(4-(2-(Hydroxymethyl)acrylamide)phenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

Chemical Structure

[0264] Step 1: Preparation of compound 58.1 To a solution of Compound 50.1 (250.0 mg, 0.497 mmol) and Compound 24.8 (187.0 mg, 0.684 mmol) in dioxane (5 mL) and H2O (1 mL) was added K2CO3 (189.2 mg, 1.37 mmol). Next, Pd-118 (30.0 mg, 0.046 mmol) was added to this mixture under N2, and the mixture was stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with EA (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography on silica gel to obtain Compound 58.1. LCMS: 505.1 [M+H] + .

[0265] Step 2: Preparation of Example 58 To a solution of Compound 58.1 (70.0 mg, 0.139 mmol) and formaldehyde (56.3 mg, 0.694 mmol, 37%) in dioxane (1 mL) and H2O (0.3 mL) was added DABCO (46.7 mg, 0.416 mmol). The mixture was stirred at 80 °C for 8 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (5 mL) and extracted with EA (10 mL × 3). The combined organic layers were concentrated and purified by preparative HPLC to obtain Example 58. LCMS: 535.1 [M+H] + ; 1 H NMR: (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.19 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.11 (t, J = 6.3 Hz, 1H), 7.84 - 7.74 (m, 3H), 7.33 - 7.26 (m, 4H), 7.17 - 7.10 (m, 3H), 6.50 - 6.41 (m, 1H), 6.32 - 6.25 (m, 1H), 5.82 - 5.77 (m, 1H), 5.73 - 5.64 (m, 1H), 4.65 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H), 2.35 (s, 3H). [Example 59] Preparation of 6-(4-(2-((Dimethylamino)methyl)acrylamide)phenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

Chemical Structure

[0266] Step 1: Preparation of Example 59 Compound 59.1 was synthesized in a similar manner following the procedures of Example 1 and Example 35.

[0267] Example 59 was synthesized from Compound 59.1 in a similar manner following the procedure of Example 50. LCMS: 562.3 [M+H] + . 1 H NMR: (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.25 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 7.81 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.33 - 7.29 (m, 5H), 7.20 - 7.13 (m, 3H), 6.58 (br s, 1H), 6.02 (s, 1H), 5.59 (s, 1H), 3.23 (s, 2H), 2.41 (s, 3H), 2.35 (s, 3H), 2.25 (s, 6H). [Example 60] Preparation of 6-(4-(2-(Methoxymethyl)acrylamide)phenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

Chemical Structure

[0268] Step 1: Preparation of Example 60 Example 60 was synthesized from Compound 50.1 in a similar manner following the procedure of Example 35. LCMS: 549.3 [M+H] +. 1 1H NMR: (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.25 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H), 7.84 - 7.74 (m, 3H), 7.41 - 7.25 (m, 5H), 7.18 - 7.13 (m, 3H), 6.56 (br s, 1H), 5.95 (s, 1H), 5.71 (s, 1H), 4.18 - 4.14 (m, 2H), 3.30 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H). [Example 61] (E)-3-Methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(4-(3-(1-methylpyrrolidin-2-yl)acrylamido)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide Preparation

Chemical Structure

[0269] Step 1: Preparation of Compound 61.2 To a solution of Compound 61.1 (500.0 mg, 2.07 mmol) in DCM (5 mL) were added Compound 34.1 (454.00 mg, 2.07 mmol), DIEA (1.03 mL, 6.22 mmol) and HATU (866.7 mg, 2.28 mmol). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into H2O (10 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (50 mL), concentrated and purified by flash column chromatography on silica gel to give Compound 61.2 (690.0 mg, 75.3%) as a white solid. LCMS: 443.2 [M+H] + .

[0270] Step 2: Preparation of Compound 61.3 To a solution of Compound 50.1 (200.0 mg, 0.456 mmol) in dioxane (5 mL) and H2O (1 mL), Compound 61.2 (242.2 mg, 0.548 mmol) was added. Next, to this solution, Pd-118 (29.7 mg, 0.046 mmol) and K2CO3 (189.2 mg, 1.37 mmol) were added under N2. The solution was stirred at 90 °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 61.3. LCMS: 674.3 [M+H] + .

[0271] Step 3: Preparation of Compound 61.4 To a solution of Compound 61.3 (160.0 mg, 0.24 mmol) in DCM (2 mL), TFA (0.5 mL, 0.007 mmol) was added and the solution was stirred at 25 °C for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to obtain Compound 61.4. LCMS: 574.4 [M+H] + .

[0272] Step 4: Preparation of Example 61 To a solution of Compound 61.4 (160.0 mg, 0.279 mmol) and HCHO (45.3 mg, 0.558 mmol) in MeOH (2 mL), NaBH3CN (61.3 mg, 0.976 mmol) and DIEA (0.138 mL, 0.837 mmol) were added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with EA (8 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to obtain Example 61. LCMS: 588.3 [M+H] + ; 11H NMR: (400 MHz, DMSO-d6) δ 10.21 (s, 1 H), 9.24 (s, 1 H), 8.46 (d, J = 5.1 Hz, 1 H), 7.81 (s, 1 H), 7.73 (d, J = 8.6 Hz, 2 H), 7.36 (br s, 1 H), 7.31 - 7.25 (m, 4 H), 7.17 - 7.11 (m, 3 H), 6.65 (dd, J = 15.2, 7.5 Hz, 1 H), 6.58 (br s, 1 H), 6.26 (d, J = 15.2 Hz, 1 H), 3.06 - 2.99 (m, 1 H), 2.77 - 2.73 (m, 1 H), 2.40 (s, 3 H), 2.34 (s, 3 H), 2.26 - 2.13 (m, 4 H), 2.06 - 1.95 (m, 1 H), 1.79 - 1.68 (m, 2 H), 1.61 - 1.49 (m, 1 H). [Example 62] Preparation of 6-(4-(but-2-ynamide)phenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide [Chemical formula]

[0273] Step 1: Preparation of Compound 62.2 To a solution of Compound 34.1 (700.0 mg, 3.65 mmol) and Compound 62.1 (340.0 mg, 4.02 mmol) in DCM (10 mL) was added DIEA (1.42 g, 10.9 mmol). Next, HATU (1.46 g, 3.83 mmol) was added to this solution, and the solution was stirred at 25 °C for 3 hours. The reaction solution was diluted with water (30 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel to obtain Compound 62.2 (650.0 mg, 62.43%) as a white solid. LCMS: 286.2 [M+H] + .

[0274] Step 2: Preparation of Example 62 To a solution of Compound 57.3 (120.0 mg, 0.247 mmol) and Compound 62.2 (105.8 mg, 0.371 mmol) in dioxane (3 mL) and H2O (1.5 mL) was added K2CO3 (102.5 mg, 0.742 mmol). Next, Pd(PPh3)4 (28.5 mg, 0.025 mmol) was added to this mixture under N2, and the mixture was stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with EA (10 mL × 3). The combined organic layers ...

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, Z 1 C(R) does not exist. 5 ), C(R 5 )(R 5a ), N, or N(R 9 ) and Z 2 is C(R 6 ), C(R 6 )(R 6a ), O, S, N, or N(R 9 ), and Z 3 C(R 7 ), C(R 7 )(R 7a ), O, S, N, or N(R 9 ) and Z 4 C(R 8 ), C(R 8 )(R 8a ), O, S, N, or N(R 9 ) and Z 1 However, C(R 5 ), C(R 5 )(R 5a ), N, or N(R 9 ) if Z 1 , Z 2 , Z 3 , and Z 4 If there are two or fewer of these, then N or N(R 9 ) and Z 1 If Z does not exist, 2 , Z 3 , and Z 4 One or fewer of these are O, S, N, or N(R) 9 ) and R 1 and R 2 Independently, hydrogen and C 1～6 Alkyl and C 1～6 Selected from haloalkyl groups, R 3 C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Aryl, and C 1～9 Selected from heteroaryls, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Aryl, and C 1～9 Heteroaryls are R 15a It is optionally substituted with one, two, or three groups selected from the following: R 4 C 3～6 Cycloalkylene, C 2～9 Heterocycloalkylene, C 6～10 Arylene and C 1～9 Selected from heteroarrenes, C 3～6 Cycloalkylene, C 2～9 Heterocycloalkylene, C 6～10 Arylene and C 1～9 Heteroarrenes are R 15b It is optionally substituted with one, two, or three groups selected from the following: L 1 This is a bond, -N(R 9a )-,-N(R 9a )C(O)-, -C(O)N(R 9a )-,-N(R 9a )S(O) 2 -, -S(O) 2 N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O) 2 -, -OS(O)-, -OS(O) 2 -, C 1～6 Alkilen, C 2～6 Alkenylene, C 2～6 Alkinylene, C 3～6 Cycloalkylene, C 2～9 Heterocycloalkylene, or C 1～9 It is a heteroarylene, C 1～6 Alkilen, C 2～6 Alkenylene, C 2～6 Alkinylene, C 3～6 Cycloalkylene, C 2～9 Heterocycloalkylenes, and C 1～9 Heteroarrenes are R 15c It is optionally substituted with one, two, or three groups selected from the following: L 2 is a bond, C 1～6 alkylene, C 2～6 alkenylene, or C 2～6 alkynylene, and C 1～6 alkylene, C 2～6 alkenylene, or C 2～6 alkynylene is optionally substituted with one, two, or three groups selected from R 15c and R 4a Halogen, -CN, 【Chemistry 2】 Selected from, R 4b 、R 4c 、and R 4d are each independently hydrogen, halogen, -CN, -C(O)R 13 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), -N(R 10 )(R 11 ), -C 1～6 alkyl-N(R 10 )(R 11 ), -C(O)N(R 10 )OR 10 , C 1～6 alkyl, phenyl, 3- to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and C 1～6 alkyl, phenyl, 3- to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, or 3 groups selected from R 15d or R 4b and R 4c These atoms, together with the atoms to which they are bonded, form a 3- to 14-membered cycloalkyl or 3- to 14-membered heterocycloalkyl group, and the 3- to 14-membered cycloalkyl and 3- to 14-membered heterocycloalkyl groups have 1, 2, 3, or 4 R atoms. 15d It is either optionally replaced by R 4d and R 4c These atoms, together with the atoms to which they are bonded, form a 3- to 14-membered cycloalkyl or 3- to 14-membered heterocycloalkyl group, and the 3- to 14-membered cycloalkyl and 3- to 14-membered heterocycloalkyl groups have 1, 2, 3, or 4 R atoms. 15d It is optionally replaced by R 4e is halogen or -OS(O) 2 R 13 And, R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , and R 8a These are independently hydrogen, halogen, -CN, and C 1～6 Alkyl, C 1～6 Haloalkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Ariel, C 1～9 Heteroaryl, -OR 10 , -SR 10 ,-SCIENCE FICTION 5 , -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, -N=S(=O)(R 13 ) 2 -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)(R 13 ), -S(=O)(=NR 13 )R 13 , -CH 2 C(O)N(R 10 )(R 11 ), -CH 2 N(R 12 )C(O)R 13 , -CH 2 S(O) 2 R 13 , -CH 2 S(O) 2 N(R 10 )(R 11 ), -Si(C 1～6 Alkyl) 3 , and -P(O)(R 10 ) 2 Selected from, C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Aryl, and C 1～9 Heteroaryls are R 15e It is optionally substituted with one, two, or three groups selected from the following: R 9 is hydrogen, C 1～6 Alkyl, C 1～6 Haloalkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Ariel, C 1～9 Heteroaryl, -C(O)OR 10 , -C(O)R 13 ,-S(O)R 13 ,-C(O)N(R 10 )(R 11 ), and -S(O) 2 R 13 Selected from, C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Aryl, and C 1～9 Heteroaryls are R 15f It is optionally substituted with one, two, or three groups selected from the following: R 9a is hydrogen, C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Aryl, and C 1～9 Selected from heteroaryls, C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Aryl, and C 1～9 Heteroaryls are R 15g It is optionally substituted with one, two, or three groups selected from the following: Each R 10 Independently, hydrogen and C 1～6 Alkyl, C 1～6 Haloalkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～6 Cycloalkyl, -CH 2 -C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, -CH 2 -C 2～9 Heterocycloalkyl, -CH 2 -C 6～10 Ariel, C 6～10 Ariel, C 1～9 Heteroaryls and -CH 2 -C 1～9 Selected from heteroaryls, C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～6 Cycloalkyl, -CH 2 -C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, -CH 2 -C 2～9 Heterocycloalkyl, -CH 2 -C 6～10 Ariel, C 6～10 Ariel, C 1～9 Heteroaryls and -CH 2 -C 1～9 Heteroaryls include halogen, -CN, hydroxy, and C. 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Aryl, and C 1～9 It is optionally substituted with one, two, or three groups selected from heteroaryl groups. Each R 11 Independently, hydrogen and C 1～6 Alkyl and C 1～6 Selected from haloalkyls, or R 10 and R 11 Together with the nitrogen to which they are bonded, C 2～9 Forms heterocycloalkyl groups, Each R 12 Independently, hydrogen and C 1～6 Alkyl and C 1～6 Selected from haloalkyl groups, Each R 13 Independently, C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Aryl, and C 1～9 Selected from heteroaryls, C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Aryl, and C 1～9 Heteroaryls include halogen, -CN, hydroxy, and C. 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, C 6～10 Aryl, and C 1～9 It is optionally substituted with one, two, or three groups selected from heteroaryl groups. Each R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , and R 15g Each of these is independently: halogen, oxo, -CN, C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～10 Cycloalkyl, -CH 2 -C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, -CH 2 -C 2～9 Heterocycloalkyl, C 6～10 Ariel, -CH 2 -C 6～10 Ariel, C 1～9 Heteroaryl, -CH 2 -C 1～9 Heteroaryl, -OR 10 , -SR 10 ,-SCIENCE FICTION 5 , -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, -N=S(=O)(R 13 ) 2 -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)(R 13 ), -S(=O)(=NR 13 )R 13 , -CH 2 C(O)N(R 10 )(R 11 ), -CH 2 N(R 12 )C(O)R 13 , -CH 2 S(O) 2 R 13 , -CH 2 S(O) 2 N(R 10 )(R 11 ), -Si(C 1～6 Alkyl) 3 , and -P(O)(R 10 ) 2 Selected from, C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～10 Cycloalkyl, -CH 2 -C 3～6 Cycloalkyl, C 2～9 Heterocycloalkyl, -CH 2 -C 2～9 Heterocycloalkyl, C 6～10 Ariel, -CH 2 -C 6～10 Ariel, -CH 2 -C 1～9 Heteroaryls, and C 1～9 Heteroaryls include halogens, oxo, -CN, and C. 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, -OR 10 , -SR 10 ,-SCIENCE FICTION 5 , -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, -N=S(=O)(R 13 ) 2 -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)(R 13 ), -S(=O)(=NR 13 )R 13 , -CH 2 C(O)N(R 10 )(R 11 ), -CH 2 N(R 12 )C(O)R 13 , -CH 2 S(O) 2 R 13 , -CH 2 S(O) 2 N(R 10 )(R 11 ) and -P(O)(R 10 ) 2 It is optionally substituted with one, two, or three groups independently selected from the above, 【Transformation 3】 (This indicates a single or double bond in which all valencies are satisfied.) Compounds thereof, or pharmaceutically acceptable salts or stereoisomers thereof.

2. Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Formula (Ie): 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. R 5 , R 6 , R 7 , and R 8 These independently produce hydrogen, halogen, and -OR 10 , and C 1～6 Selected from alkyl groups, C 1～6 Alkyl, R 15e The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, which is optionally substituted with one, two, or three groups selected from the above.

4. R 5 , R 6 , R 7 , and R 8 These independently consist of hydrogen and unsubstituted C 1～6 A compound according to claim 1 or 2, selected from alkyl groups, or a pharmaceutically acceptable salt or stereoisomer thereof.

5. R 5 , R 6 , R 7 , and R 8 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each of the atoms is hydrogen.

6. The compound according to claim 1 or 2, wherein L2 is a bond, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. R 3 However, C 6～10 Aryl and C 1～9 Selected from heteroaryls, C 6～10 Aryl and C 1～9 Heteroaryls, 15a The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, which is optionally substituted with one, two, or three groups selected from the above.

8. R 3 However, R 15a The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, which is a phenyl optionally substituted with one, two, or three groups selected from the above.

9. Expression (Ia'), expression (Ia"), expression (Ib'), expression (Ib"), expression (Ic'), or expression (Ic): 【Chemistry 9】 【Chemistry 10】 【change】 【Chemistry 11】 (In the formula, R 10 is halogen, -CN, hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl and C 1～6 C is optionally substituted with one, two, or three groups selected from alkoxy groups. 1～9 It is a heteroaryl, R 15aa These include halogens, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -CH2-C3-6 cycloalkyl, C2-9 heterocycloalkyl, -CH2-C2-9 heterocycloalkyl, C6-10 aryl, -CH2-C6-10 aryl, C1-9 heteroaryl, -CH2-C1-9 heteroaryl, -OR 10, -SR 10, -SF 5, -N(R 10)(R 11), -C(O)OR 10, -OC(O)N(R 10)(R 11), -N(R 12)C(O)N(R 10)(R 11), -N(R 12)C(O)C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, -N=S(=O)(R 13 ) 2 , -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)(R 13 ), -S(=O)(=NR 13 )R 13 , -CH Selected from 2 C(O)N(R 10)(R 11), -CH 2 N(R 12)C(O)R 13, -CH 2 S(O) 2 R 13, -CH 2 S(O) 2 N(R 10)(R 11), -Si(C1-6 alkyl) 3, and -P(O)(R 10) 2, including C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -CH 2-C3-6 cycloalkyl, C2-9 heterocycloalkyl, -CH 2-C2-9 heterocycloalkyl, C6-10 aryl, -CH 2-C6-10 aryl, -CH 2-C1-9 heteroaryl, and C1-9 Heteroaryls include halogens, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -OR 10, -SR 10, -SF 5, -N(R 10)(R 11), and -C(O)OR 10., -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, -N=S(=O)(R 13 ) 2 (These are arbitrarily substituted with one, two, or three groups independently selected from -S(=O)(=NH)N(R 10)(R 11), -S(=O)(=NH)(R 13), -S(=O)(=NR 13)R 13, -CH 2 C(O)N(R 10)(R 11), -CH 2 N(R 12)C(O)R 13, -CH 2 S(O) 2 R 13, -CH 2 S(O) 2 N(R 10)(R 11), and -P(O)(R 10) 2.) A compound according to claim 8 having the structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. R 15aa However, halogen, C 1～6 Alkyl and -OCH 3 A compound according to claim 9, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from the above.

11. R 10 is pyridyl or pyrimidinyl, and pyridyl and pyrimidinyl are halogen, -CN, hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl and C 1～6 The compound according to claim 9, or a pharmaceutically acceptable salt or stereoisomer thereof, optionally substituted with one, two, or three groups selected from alkoxys.

12. R 4 However, R 15b The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, which is a phenyl optionally substituted with one, two, or three groups selected from the above.

13. L 1 However, the bond, -N(R 9a )-,-N(R 9a )C(O)-, -C(O)N(R 9a )-,-N(R 9a )S(O) 2 -, -S(O) 2 N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) 2 -, or R 15c C is optionally substituted with one, two, or three groups selected from the above. 1～6 A compound according to claim 1 or 2, which is alkylene, or a pharmaceutically acceptable salt or stereoisomer thereof.

14. L 1 ga-N(R 9a The compound according to claim 1 or 2, wherein R 9a is hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof.

15. R 4a but, 【Chemistry 12】 A compound according to claim 1 or 2, selected from, or a pharmaceutically acceptable salt or stereoisomer thereof.

16. R 4c and R 4d Each of them independently, hydrogen or -C 1～6 Alkyl-N(R 10 )(R 11 The compound according to claim 1 or 2, wherein R 4b is hydrogen, a halogen, or a C1-6 alkyl group, and the alkyl group is optionally substituted with 1, 2, or 3 R 15d groups, or a pharmaceutically acceptable salt or stereoisomer thereof.

17. R 1 and R 2 The compound according to claim 1 or 2, wherein the compound is hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 18】 【Chemistry 13】 【change】 【change】 【change】 【change】 A compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from the above.

19. A pharmaceutical composition comprising the compound described in claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

20. Use of the compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a pharmaceutical for treating cancer in mammals that require it.

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