Indazole compounds as PKMYT1 kinase inhibitors

Abstract

The present invention relates to a compound of general formula (I): TIFF2026507114000428.tif49170, wherein R 1 , R 2 , R 3 , R 4 , A1, A2, A3, and A4 provide novel compounds, or pharmaceutically acceptable salts thereof, compositions comprising the compounds, and methods of using the compounds, which are as described herein.

Description

[Technical Field]

[0001] The present invention relates to organic compounds, particularly PKMYT1 (protein kinase, membrane-bound tyrosine and threonine kinase) kinase inhibitors, that are useful in the treatment of mammalian cancer. In particular, the present invention relates to indazole compounds that have PKMYT1 kinase inhibitory activity, as well as their preparation, pharmaceutical compositions containing them, and their potential use as medicaments. [Background technology]

[0002] Cells frequently experience endogenous and exogenous genotoxic stresses that cause DNA damage and compromise genome integrity. To counteract potential genetic alterations caused by these DNA-damaging agents, cells must establish various mechanisms to detect DNA damage, repair DNA damage, and maintain genome stability. This sophisticated network, called the DNA damage response (DDR), is evolutionarily highly conserved and orchestrated by multiple coordinated signaling pathways, capable of repairing various types of DNA damage. One of the key components involved in the DDR mechanism is the activation of cell cycle checkpoints, which arrest the cell cycle at specific stages until the damaged DNA is repaired. At least two types of checkpoints, G1 / S and G2 / M, are involved in DDR signaling. They sense DNA damage and pause the cell cycle before DNA replication and chromosome segregation, respectively, thereby ensuring the fidelity of genetic information in dividing cells. In cancer cells, genomic instability and replication stress are commonly observed due to dysregulation of the DDR mechanism, which is usually induced by endogenous genetic alterations in cancer cells or genotoxic agents. For example, G1 / S checkpoints, such as p53, are frequently mutated and disrupted in cancer cells. As a result, the survival of cancer cells with replication stress and a dysfunctional G1 / S checkpoint is highly dependent on the G2 / M checkpoint for DNA damage repair processing. Therefore, disruption of the G2 / M checkpoint via inhibition of PKMYT1 kinase activity has become a promising therapeutic approach, especially for genetically targeted cancer treatment. Summary of the Invention

[0003] The present invention provides a novel compound of formula (I), its preparation, a pharmaceutical composition based on the compound according to the present invention and its preparation, and the use of the compound of formula (I) as a PKMYT1 kinase inhibitor for treating a wide range of cancers. The compound of formula (I) exhibits excellent PKMYT1 kinase inhibitory activity. Furthermore, the compound of formula (I) also exhibits good safety and a good PK profile, such as good microsomal stability, hepatic clearance, and safety margin.

[0004] One aspect of the present invention is a compound represented by formula (I): TIFF2026507114000002.tif49170, wherein: R 1 is H, halogen or C 1-6 is alkyl, R 2 But H, halogen, cyano, C 3-7 Cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy or HaloC 1-6 is alkyl, R 3 is H or a halogen, R 4 is H, halogen or C 1-6 is alkyl, A1 is N or CR 5 and A2 is N or CR 6 and A3 is N or CR 7 and A4 is N or CR 8 and R 5 , R 6 , R 7 and R 8 each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl C 1-6 Alkoxy, C 3-7 Cycloalkyl C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 1-6 Alkyl C 3-7 Cycloalkoxy, C 1-6 Alkoxy-oxo-C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkynyl, C 1-6 Alkyl C 2-6Alkynyl, aryl, deuterated C 1-6 alkyl, carbonyl, carboxyl, sulfanyl, sulfinyl, sulfonyl, sulfamoyl, cyano, benzyloxy, 5- to 8-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, and 5- to 8-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; R 5 , R 6 , R 7 , and R 8 each independently optionally selected from halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, cyano C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbamoyl, Amino, C 1-6 Alkylamino, HaloC 1-6 substituted with alkyl, hydroxyl, cyano, or a 5- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; 5 , R 6 , R 7 and R 8 each of which is independently optionally further substituted with hydroxyl; or R 5 , R 6 , R 7 and R 8 Each of these is H, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-7 Cycloalkyl C 1-6 Alkyl, (C 1-6 Alkylamino)C 1-6 Alkyl, hydroxy C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-7 Cycloalkyl, HaloC 3-7 Cycloalkyl, C 1-6 Alkyl C 3-7 Cycloalkyl, C1-6 Alkoxy, C 3-7 Cycloalkyl C 1-6 Alkoxy, (C 1-6 Alkylamino)C 1-6 Alkoxy, (C 1-6 Alkyl)C 1-6 Alkoxy, (cyano C 3-7 Cycloalkyl)C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-7 Cycloalkoxy, Cyano C 3-7 Cycloalkoxy, HaloC 3-7 Cycloalkoxy, (hydroxyl)(C 1-6 Alkyl)C 3-7 Cycloalkoxy, C 1-6 Alkoxycarbonyl C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxy C 2-6 Alkynyl, C 1-6 Alkoxy C 2-6 Alkynyl, Morpholino C 2-6 Alkynyl, (hydroxyl)(C 1-6 Alkyl)C 2-6 Alkynyl, (C 1-6 Alkoxy)(C 1-6 Alkyl)C 2-6 Alkynyl, (hydroxytetrahydrofuranyl)C 2-6 Alkynyl, (C 1-6 Alkylamino)C 2-6 Alkynyl, (amino)(C 1-6 Alkynyl)C 2-6 Alkynyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkyl C 2-6 Alkynyl, (hydroxyl)(C 1-6 Alkyl)C 2-6 Alkynyl, oxetanyl C 2-6 Alkynyl, C 1-6 Alkylamino, acyl, cyano, carboxy, C 1-6 Alkylsulfanyl, C 1-6Alkylsulfinyl, C 1-6 alkylsulfonyl, benzyloxy, aryl, 5- to 8-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, and 5- to 8-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, each of the aryl, heterocyclyl, and heteroaryl independently optionally containing halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkylcarbamoyl, HaloC 1-6 alkyl- or hydroxyl-substituted compounds, or a pharmaceutically acceptable salt thereof.

[0005] Another aspect of the present invention relates to a process for preparing a compound of formula (I), and to a compound of formula (I) or a pharmaceutically acceptable salt thereof when prepared according to this process.

[0006] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0007] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

[0008] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[0009] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer.

[0010] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the inhibition of PKMYT1 kinase.

[0011] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer.

[0012] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the inhibition of PKMYT1 kinase.

[0013] Another aspect of the present invention relates to a method for treating cancer, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0014] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Furthermore, the following definitions are set forth to illustrate and define the meaning and scope of various terms used to describe the present invention.

[0015] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0016] The terms "compound(s) of this invention" and "compound(s) of the present invention" refer to compounds of formula (I) and stereoisomers, solvates or salts (e.g., pharmaceutically acceptable salts) thereof.

[0017] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom in a parent molecule.

[0018] The term "aryl" means a monovalent aromatic carbocyclic mono- or bicyclic ring system containing 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl.

[0019] As used herein, "C 1-6 The term "alkyl", alone or in combination, means a saturated, straight or branched chain alkyl group containing 1 to 6, especially 2 to 6 or 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. 1-6 "Alkyl" groups are methyl, ethyl, propyl, isopropyl and isopentyl.

[0020] "C 1-6 The term "alkoxy" refers to C 1-6 It represents alkyl-O-.

[0021] "C 2-6 The term "alkenyl" refers to a monovalent linear or branched hydrocarbon group of 2 to 6 carbon atoms having at least one double bond. In certain embodiments, an alkenyl has 2 to 4 carbon atoms having at least one double bond. 2-6 Examples of alkenyl include ethenyl (or vinyl), propenyl, prop-2-enyl, isopropenyl, n-butenyl, and iso-butenyl.

[0022] "C 3-7 The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more carbon atoms in common. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.

[0023] "C 3ー7 The term "cycloalkoxy" refers to C 3ー7 This represents cycloalkyl-O-.

[0024] The term "halogen" or "halo" means fluoro, chloro, bromo, or iodo.

[0025] "Haro C 1-6 The term "alkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced with the same or different halogen atom, in particular a fluoro atom. 1-6 Examples of alkyl include monochloro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, eg difluoromethyl.

[0026] The term "heteroaryl" refers to a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heteroaryl moieties include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl. Heteroaryl is substituted with halogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, Cyano, C 3-7 Cycloalkyl, (C 1-6 Alkyl)2amino or C 1-6 It may be further substituted with alkoxy.

[0027] The term "heterocyclyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 9 ring atoms containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In certain embodiments, a heterocyclyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples for monocyclic saturated heterocyclyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, oxopiperidinyl, oxopiperazinyl or oxopyrrolidinyl. Examples of bicyclic saturated heterocyclyls are azaspiro[3.3]heptanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocyclyls are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl.

[0028] The compounds according to the present invention can exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to conventional acid or base addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as those derived from organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, formic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, and fumaric acid. Base addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical modification of pharmaceutical compounds into salts is a technique well known to medicinal chemists to improve the physical and chemical stability, hygroscopicity, flowability, and solubility of the compounds. This is described, for example, in Bastin RJ, et al., Organic Process Research & Development 2000, 4, 427-435. In particular, the sodium salt of the compound of formula (I).

[0029] The term "therapeutically effective amount" means an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder, as described herein. A therapeutically effective amount will vary depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0030] The term "pharmaceutical composition" means a mixture or solution containing a therapeutically effective amount of an active ingredient together with pharmaceutically acceptable excipients, for administration to a mammal, e.g., a human, in need thereof.

[0031] PKMYT1 kinase inhibitors The present invention relates to a compound of formula (I): TIFF2026507114000003.tif49170, wherein: R 1 is H, halogen or C 1-6 is alkyl, R 2 But H, halogen, cyano, C 3-7 Cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy or HaloC 1-6 is alkyl, R 3 is H or a halogen, R 4 is H, halogen or C 1-6 is alkyl, A1 is N or CR 5 and A2 is N or CR 6 and A3 is N or CR 7 and A4 is N or CR 8 and R 5 , R 6 , R 7 and R 8 each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl C 1-6 Alkoxy, C 3-7 Cycloalkyl C 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 1-6 Alkyl C 3-7 Cycloalkoxy, C1-6 Alkoxy-oxo-C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkynyl, C 1-6 Alkyl C 2-6 Alkynyl, aryl, deuterated C 1-6 alkyl, carbonyl, carboxyl, sulfanyl, sulfinyl, sulfonyl, sulfamoyl, cyano, benzyloxy, 5- to 8-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, and 5- to 8-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; R 5 , R 6 , R 7 , and R 8 each independently optionally selected from halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, cyano C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbamoyl, Amino, C 1-6 Alkylamino, HaloC 1-6 substituted with alkyl, hydroxyl, cyano, or a 5- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; 5 , R 6 , R 7 and R 8 each of which is independently optionally further substituted with hydroxyl; or R 5 , R 6 , R 7 and R 8 Each of these is H, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-7 Cycloalkyl C 1-6 Alkyl, (C 1-6 Alkylamino)C 1-6 Alkyl, hydroxy C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6Alkoxy C 1-6 Alkyl, C 3-7 Cycloalkyl, HaloC 3-7 Cycloalkyl, C 1-6 Alkyl C 3-7 Cycloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl C 1-6 Alkoxy, (C 1-6 Alkylamino)C 1-6 Alkoxy, (C 1-6 Alkyl)C 1-6 Alkoxy, (cyano C 3-7 Cycloalkyl)C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-7 Cycloalkoxy, Cyano C 3-7 Cycloalkoxy, HaloC 3-7 Cycloalkoxy, (hydroxyl)(C 1-6 Alkyl)C 3-7 Cycloalkoxy, C 1-6 Alkoxycarbonyl C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxy C 2-6 Alkynyl, C 1-6 Alkoxy C 2-6 Alkynyl, Morpholino C 2-6 Alkynyl, (hydroxyl)(C 1-6 Alkyl)C 2-6 Alkynyl, (C 1-6 Alkoxy)(C 1-6 Alkyl)C 2-6 Alkynyl, (hydroxytetrahydrofuranyl)C 2-6 Alkynyl, (C 1-6 Alkylamino)C 2-6 Alkynyl, (amino)(C 1-6 Alkynyl)C 2-6 Alkynyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkyl C 2-6 Alkynyl, (hydroxyl)(C 1-6 Alkyl)C 2-6Alkynyl, oxetanyl C 2-6 Alkynyl, C 1-6 Alkylamino, acyl, cyano, carboxy, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 alkylsulfonyl, benzyloxy, aryl, 5- to 8-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, and 5- to 8-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, each of the aryl, heterocyclyl, and heteroaryl independently optionally containing halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkylcarbamoyl, HaloC 1-6 alkyl- or hydroxyl-substituted compounds, or a pharmaceutically acceptable salt thereof.

[0032] A further embodiment of the present invention is (ii) a compound of formula (I), wherein: R 1 But H or C 1-6 is alkyl, R 2 But H, halogen, C 1-6 Alkyl or haloC 1-6 is alkyl, R 3 is H or a halogen, R 4 is H, halogen or C 1-6 is alkyl, A1 is N or CR 5 and R 5 , H, halogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 is cycloalkyl, A2 is N or CR 6 and R 6 H, halogen, C 1-6Alkyl, hydroxy C 1-6 Alkyl, deuterated C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-7 Cycloalkyl C 1-6 Alkyl, C 3-7 Cycloalkyl, HaloC 3-7 Cycloalkyl, C 1-6 Alkyl C 3-7 Cycloalkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-7 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, Cyano, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 alkylsulfonyl, aryl, 5- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, wherein each aryl, heterocyclyl, and heteroaryl is independently selected from halogen, C 1-6 Alkyl, halogen C 1-6 Alkyl, or C 1-6 optionally substituted with alkylcarbamoyl; A3 is N or CR 7 and R 7 H, halogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, HaloC 1-6 Alkyl, (C 1-6 Alkylamino)C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-7 Cycloalkyl C 1-6 Alkoxy, (C 1-6 Alkylamino)C 1-6 Alkoxy, (hydroxyl) (C 1-6 Alkyl)C 1-6 Alkoxy, (cyano C 3-7 Cycloalkyl)C1-6 Alkoxy, C 1-6 Alkoxy-oxo-C 1-6 Alkoxy, C 3-7 Cycloalkoxy, Cyano C 3-7 Cycloalkoxy, HaloC 3-7 Cycloalkoxy, (hydroxyl)(C 1-6 Alkyl)C 3-7 Cycloalkoxy, C 1-6 Alkoxycarbonyl C 3-7 Cycloalkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxy C 2-6 Alkynyl, C 1-6 Alkoxy C 2-6 Alkynyl, Morpholino C 2-6 Alkynyl, (hydroxy)(C 1-6 Alkyl)C 2-6 Alkynyl, (C 1-6 Alkoxy)(C 1-6 Alkyl)C 2-6 Alkynyl, (hydroxytetrahydrofuranyl)C 2-6 Alkynyl, (C 1-6 Alkylamino)C 2-6 Alkynyl, (amino)(C 1-6 Alkyl)C 2-6 Alkynyl, C 1-6 Alkyl C 2-6 Alkynyl, (hydroxyl)(C 1-6 Alkyl)C 2-6 Alkynyl, oxetanyl C 2-6 Alkynyl, C 1-6 alkoxycarbonyl, acyl, carboxy, cyano, or 5- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, and each of the heterocyclyl and heteroaryl is independently C 1-6 Alkyl, C 3-7 Cycloalkyl, halogenated C 1-6 optionally substituted with alkyl or hydroxy groups; A4 is N or CR 8 and R 8But H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-7 Cycloalkyl C 1-6 Alkoxy, C 3-7 a compound which is cycloalkoxy, cyano, or benzyloxy; or a pharmaceutically acceptable salt thereof.

[0033] A further embodiment of the present invention is (iii) R 1 is H or methyl.

[0034] A further embodiment of the present invention is (iv) R 1 is H.

[0035] A further embodiment of the present invention is (v) R 2 is H, fluoro, chloro, methyl or trifluoromethyl.

[0036] A further embodiment of the present invention is (vi) R 2 is a halogen.

[0037] A further embodiment of the present invention is (vi) R 2 is fluoro or chloro.

[0038] A further embodiment of the present invention is a compound represented by the formula (viii) R 3 is H or fluoro.

[0039] A further embodiment of the present invention is (ix) R 3 is H.

[0040] A further embodiment of the present invention is (x)R 4 is H, fluoro, chloro, or methyl.

[0041] A further embodiment of the present invention is a compound represented by the formula (xi) R 4 is H.

[0042] A further embodiment of the present invention is (xii) R 5 is H, chloro, fluoro, methyl, difluoromethyl, methoxy, or cyclopropyl.

[0043] A further embodiment of the present invention is (xiii) R 5 is H, halogen, or C 1-6 alkyl, preferably H or C 1-6 The compound according to any one of (i) to (xi), wherein the aryl group is alkyl.

[0044] A further embodiment of the present invention is (xiv) R 5 is H, chloro or methyl, preferably H or methyl.

[0045] A further embodiment of the present invention is (xv) R 6is H, fluoro, chloro, bromo, iodo, methyl, trideuteriomethyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, difluoroethyl, hydroxyisopropyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, cyclobutyl, fluorocyclopropyl, methylcyclopropyl, dimethylcyclopropyl, methoxy, ethoxy, isopropoxy, trifluoroethoxy, cyclobutoxy, vinyl, isopropenyl, ethynyl, azetidinyl, oxetanyl, morpholino, cyano, methylsulfanyl, methylsulfinyl, methylsulfonyl, phenyl, or heteroaryl selected from imidazolyl, pyrazolyl, isothiazolyl, pyridyl, pyridazinyl, and thiazolyl, wherein each of phenyl and heteroaryl is independently optionally substituted with fluoro, methyl, trifluoromethyl, or dimethylcarbamoyl.

[0046] A further embodiment of the present invention is (xvi) R 6 is H, chloro, fluoro, bromo, iodo, methyl, trideuteriomethyl, ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1-hydroxy-1-methyl-ethyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, cyclobutyl, 2-fluorocyclopropyl, 1-methylcyclopropyl, (1R,2R)-2-methylcyclopropyl, methoxy, ethoxy, isopropoxy, 2,2,2-trifluoroethoxy, cyclobutoxy, vinyl, The compound is any one of (i) to (xv) above, which is isopropenyl, ethynyl, azetidin-1-yl, oxetan-3-yl, morpholino, cyano, methylsulfanyl, methylsulfinyl, methylsulfonyl, 4-(dimethylcarbamoyl)phenyl, 3-methylimidazol-4-yl, 1H-pyrazol-5-yl, isothiazol-5-yl, 2-(trifluoromethyl)-4-pyridyl, 5-fluoro-2-pyridyl, 2-pyridyl, pyridazin-4-yl, or thiazol-2-yl.

[0047] A further embodiment of the present invention is (xvii) R 6 But H, halogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-7 Cycloalkyl, or C 1-6 alkylsulfanyl, preferably C 1-6 Alkyl, deuterated C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-7 Cycloalkyl, or C 1-6 The compound is any one of (i) to (xiv) above, which is alkylsulfanyl.

[0048] A further embodiment of the present invention is (xviii) R 6 is H, chloro, methyl, trideuteriomethyl, ethyl, isopropyl, difluoroethyl, trifluoroethyl, cyclopropyl, or methylsulfanyl, preferably methyl, ethyl, isopropyl, trideuteriomethyl, difluoroethyl, trifluoroethyl, cyclopropyl, or methylsulfanyl.

[0049] A further embodiment of the present invention is (xix) R 7where H, chloro, bromo, methyl, ethyl, hydroxyisopentyl, hydroxyisopropyl, trifluoromethyl, cyclopropyl, 3-(dimethylamino)propyl, methoxy, propoxy, isopropoxy, 1-bicyclo[1.1.1]pentanylmethoxy, difluoromethoxy, trifluoroethoxy, difluoroethoxy, difluoropropoxy, (dimethylamino)ethoxy, methylpropoxy, cyclopropylmethoxy, (1-cyanocyclopropyl)methoxy, 2-ethoxy-2-oxo-ethoxy, cyclobutoxy, cyanocyclobutoxy, fluorocyclobutoxy, 3-(1-methylethyl)cyclobutoxy, 3-methoxycarbonylcyclobutoxy, isopropylamino, vinyl, ethynyl, hydroxybutynyl, methoxypropynyl, morpholinopropynyl, (hydroxyl)(methyl)butynyl, methoxymethylbutynyl, 2-(4-hydroxytetrahydrofuran-3-yl)-1-ethynyl methylbutynyl, 3-hydroxy-3-methylbutynyl, 3-methoxy-3-methylbutynyl, 2-(oxetan-3-yl)ethynyl, methoxycarbonyl, carboxy, cyano, acetyl, thienyl, thiazolyl, oxazolyl, pyridyl, or pyrrolidinyl, morpholino, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2 ,5-diazabicyclo[2.2.1]heptanyl, piperazinyl, 2,5-diazabicyclo[2.2.2]octanyl, piperidyl, oxetanyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, wherein the heterocyclyl is optionally substituted with methyl, isopropyl, cyclopropyl, trifluoroethyl, or hydroxyl.

[0050] A further embodiment of the present invention is (xx)R 7H, chloro, bromo, methyl, ethyl, 3-hydroxy-3-methyl-1-butyl, 1-hydroxy-1-methyl-ethyl, trifluoromethyl, cyclopropyl, 3-(dimethylamino)propyl, methoxy, propoxy, isopropoxy, 1-bicyclo[1.1.1]pentanylmethoxy, difluoromethoxy, trifluoroethoxy, 2,2-difluoroethoxy, 3,3-difluoropropoxy, 2-(dimethylamino)ethoxy, 2-hydroxy-2-methylpropoxy, cyclopropyl Pyrimoxy, (1-cyanocyclopropyl)methoxy, 2-ethoxy-2-oxo-ethoxy, cyclobutoxy, 3-cyanocyclobutoxy, 3-fluorocyclobutoxy, 3-(1-hydroxy-1-methyl-ethyl)cyclobutoxy, 3-methoxycarbonylcyclobutoxy, isopropylamino, vinyl, ethynyl, 3-hydroxybut-1-ynyl, 3-methoxyprop-1-ynyl, 3-morpholinoprop-1-ynyl, 3-hydroxy-3-methyl-1-but-1-ynyl, 3-methoxy thiazol-3-yl, 2-(4-hydroxytetrahydrofuran-3-yl)-1-ethynyl, 3-(dimethylamino)prop-1-ynyl, 3-amino-3-methylbut-1-ynyl, 3-methylbut-1-ynyl, 3-hydroxy-3-methylbut-1-ynyl, 3-methoxy-3-methylbut-1-ynyl, 2-(oxetan-3-yl)ethynyl, methoxycarbonyl, carboxy, cyano, acetyl, 2-thienyl, thiazol-4-yl, thiazol-2-yl , oxazol-2-yl, 2-pyridyl, 3-hydroxypyrrolidin-1-yl, morpholino, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-methyl-2,6-diazaspiro[3.3]heptan-6-yl, 5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, 5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl.2]octan-2-yl, 4-piperidyl, 1-methyl-4-piperidyl, 1-(2,2,2-trifluoroethyl)-4-piperidyl, oxetan-3-yl, 1-methylazetidin-3-yl, or 2-oxa-6-azaspiro[3.3]heptan-6-yl.

[0051] A further embodiment of the present invention is (xxi) R 7 But H, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkoxy, C 3-7 Cycloalkyl C 1-6 Alkoxy, (hydroxyl) (C 1-6 Alkyl)C 2-6 Alkynyl, or hydroxy C 2-6 Alkynyl, preferably H or C 1-6 The compound is any one of (i) to (xviii) above, wherein the aryl group is alkyl.

[0052] A further embodiment of the present invention is (xxii) R 7 is H, chloro, methyl, cyclopropyl, cyclobutoxy, cyclopropylmethoxy, 3-hydroxy-3-methyl-1-but-1-ynyl, or 3-hydroxybut-1-ynyl, preferably H or methyl.

[0053] A further embodiment of the present invention is (xxiii) R 8 is H, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 3,3-difluoropropoxy, cyclopropylmethoxy, cyclopropoxy, cyclobutoxy, cyano, or benzyloxy.

[0054] A further embodiment of the present invention is (xxiv) R 8 But C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-7 cycloalkoxy, or cyano, preferably C 1-6 Alkoxy, HaloC 1-6 Alkoxy, or C 3-7 The compound according to any one of the above (i) to (xxii), which is cycloalkoxy.

[0055] A further embodiment of the present invention is (xxv) R 8 is ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, cyclopropoxy, cyclobutoxy, or cyano. Preferably, it is the compound described in (xxiv) above, wherein is ethoxy, difluoromethoxy, trifluoroethoxy, cyclopropoxy, or cyclobutoxy.

[0056] A further embodiment of the present invention is (xxvi) R 1 is H, R 2 is a halogen, R 3 is H, R 4 is H, A1 is CR 5 and R 5 is H, halogen, or C 1-6 alkyl, preferably H or C 1-6 is alkyl, A2 is N or CR 6 and R 6 But hydrogen, halogens, C 1-6 Alkyl, C 3-7 Cycloalkyl, HaloC 1-6 Alkyl, deuterated C 1-6 Alkyl, or C 1-6 alkylsulfanyl, preferably C 1-6 Alkyl, deuterated C 1-6Alkyl, HaloC 1-6 Alkyl, C 3-7 Cycloalkyl, or C 1-6 alkylsulfanyl, A3 is N or CR 7 and R 7 But H, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkoxy, C 3-7 Cycloalkyl C 1-6 Alkoxy, (hydroxyl) (C 1-6 Alkyl)C 2-6 Alkynyl, or hydroxy C 2-6 Alkynyl; preferably H or C 1-6 is alkyl, A4 is N or CR 8 and R 8 But C 1-6 Alkoxy, halogen C 1-6 Alkoxy, C 3-7 cycloalkoxy, or cyano, preferably C 1-6 Alkoxy, halogen C 1-6 Alkoxy, or C 3-7 is cycloalkoxy, The compound is described in (i) or (ii) above. A further embodiment of the present invention is (xxvii) R 1 is H, R 2 is fluoro or chloro, R 3 is H, R 4 is H, A1 is N or CR 5 and R 5 is H, chloro or methyl, preferably H or methyl; A2 is N or CR 6 and R 6is H, chloro, methyl, trideuteriomethyl, ethyl, isopropyl, difluoroethyl, trifluoroethyl, cyclopropyl, or methylsulfanyl, preferably methyl, ethyl, isopropyl, trideuteriomethyl, difluoroethyl, trifluoroethyl, cyclopropyl, or methylsulfanyl, A3 is N or CR 7 and R 7 is hydrogen, chloro, methyl, cyclopropyl, cyclobutoxy, cyclopropylmethoxy, 3-hydroxy-3-methyl-1-but-1-ynyl, or 3-hydroxybut-1-ynyl, preferably hydrogen or methyl, A4 is N or CR 8 and R 8 is ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, cyclopropoxy, cyclobutoxy, or cyano, preferably ethoxy, difluoromethoxy, trifluoroethoxy, cyclopropoxy, or cyclobutoxy; The compound is described in (xxvi) above.

[0057] A further embodiment of the present invention is (xxviii) a compound selected from the following compounds: 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-fluoro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(trifluoromethyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methoxy-1H-1,5-naphthyridin-2-one, 4-[7-amino-8-(7-fluoro-1H-indazol-4-yl)-6-oxo-5H-1,5-naphthyridin-3-yl]-N,N-dimethyl-benzamide, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(3-methylimidazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(1H-pyrazol-5-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-isothiazol-5-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-[2-(trifluoromethyl)-4-pyridyl]-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-pyridazin-4-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(2-pyridyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(5-fluoro-2-pyridyl)-1H-1,5-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-thiazol-2-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,7-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-morpholino-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(1-hydroxy-1-methyl-ethyl)-1H-1,5-naphthyridin-2-one, 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(4-methylpiperazin-1-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(isopropylamino)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxypyrrolidin-1-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-morpholino-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(4-isopropylpiperazin-1-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-(4-cyclopropylpiperazin-1-yl)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methyl-butyl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(1H-indazol-4-yl)-7-thiazol-2-yl-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(6-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-chloro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-methyl-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(6,7-difluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(5-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-[7-(trifluoromethyl)-1H-indazol-4-yl]-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-fluoro-5-methyl-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(5-chloro-7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-piperazin-1-yl-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(3-methyl-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-6-(cyclobutoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-(cyclopropylmethoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,7-dimethyl-1H-quinolin-2-one, 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-7,8-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methoxy-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7,8-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-6,8-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-6,7-dimethyl-1H-1,5-naphthyridin-2-one, 1-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxymethyl]cyclopropanecarbonitrile, 3-amino-6-(2,2-difluoroethoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-7-methyl-1H-1,5-naphthyridin-2-one, ethyl 2-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxy]acetate, 3-amino-6-(difluoromethoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-(1-bicyclo[1.1.1]pentanylmethoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-isopropoxy-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-propoxy-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2,2,2-trifluoroethoxy)-1H-1,5-naphthyridin-2-one, methyl 3-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxy]cyclobutanecarboxylate, 3-amino-6-[2-(dimethylamino)ethoxy]-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(4-piperidyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methyl-but-1-ynyl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-methoxyprop-1-ynyl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-methoxy-3-methyl-but-1-ynyl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-[2-(4-hydroxytetrahydrofuran-3-yl)ethynyl]-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxybut-1-ynyl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-[3-(dimethylamino)prop-1-ynyl]-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(3-morpholinoprop-1-ynyl)-1H-1,5-naphthyridin-2-one, 3-amino-6-(3-amino-3-methyl-but-1-ynyl)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(2-hydroxy-2-methyl-propoxy)-7-methyl-1H-1,5-naphthyridin-2-one, 3-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxy]cyclobutanecarbonitrile, trans-3-amino-6-(3-fluorocyclobutoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-(3,3-difluoropropoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(1-methyl-4-piperidyl)-1H-1,5-naphthyridin-2-one, 7-amino-8-(7-fluoro-1H-indazol-4-yl)-2,3-dimethyl-5H-pyrido[2,3-b]pyrazin-6-one, 7-amino-8-(7-fluoro-1H-indazol-4-yl)-2,4-dimethyl-5H-pyrido[3,2-d]pyrimidin-6-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-[3-(dimethylamino)propyl]-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, methyl 7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridine-2-carboxylate, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(1-hydroxy-1-methyl-ethyl)-7-methyl-1H-1,5-naphthyridin-2-one, 7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridine-2-carboxylic acid, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridine-2-carbonitrile, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(oxetan-3-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,8-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-6-chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-[3-(1-hydroxy-1-methyl-ethyl)cyclobutoxy]-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(trifluoromethyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(1-methylazetidin-3-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, or 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(trideuteriomethyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-7-methyl-1H-quinolin-2-one, 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-quinolin-2-one, 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-quinolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-quinolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-1H-quinolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,7-dimethyl-1H-1,8-naphthyridin-2-one, 3-amino-6-bromo-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,7,8-trimethyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-6-ethynyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 6-acetyl-3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-vinyl-1H-1,5-naphthyridin-2-one, 3-amino-6,8-dicyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-bromo-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-iodo-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-(azetidin-1-yl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 7-amino-8-(7-fluoro-1H-indazol-4-yl)-4-methyl-6-oxo-5H-1,5-naphthyridine-3-carbonitrile, 3-amino-7-cyclobutyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-pyridazin-4-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-thiazol-2-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(oxetan-3-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-vinyl-1H-1,5-naphthyridin-2-one, 3-amino-7-ethynyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-isopropenyl-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-cyclopentyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-isopropyl-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-ethyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(1-methylcyclopropyl)-1H-1,5-naphthyridin-2-one, 3-amino-7-(2,2-dimethylcyclopropyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-(cyclopropylmethyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-(2-fluorocyclopropyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-1H-1,5-naphthyridin-2-one, 3-amino-7-(1,1-difluoroethyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-fluoro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methoxy-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(2,2,2-trifluoroethoxy)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-isopropoxy-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-(cyclobutoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-ethoxy-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-methylsulfanyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-methylsulfinyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-methylsulfonyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-[rac-(1R,2R)-2-methylcyclopropyl]-1H-1,5-naphthyridin-2-one, 3-amino-8-(difluoromethyl)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-7,8-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methyl-but-1-ynyl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-methoxy-3-methyl-but-1-ynyl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-6-[2-(oxetan-3-yl)ethynyl]-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2-thienyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-thiazol-4-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-thiazol-2-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-oxazol-2-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2-pyridyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(3-methylbut-1-ynyl)-1H-1,5-naphthyridin-2-one, 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6,7-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-7,8-dimethyl-1H-1,6-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7,8-dimethyl-2-oxo-1H-1,6-naphthyridine-5-carbonitrile, 3-amino-5-chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,6-naphthyridin-2-one, 3-amino-5-chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,6-naphthyridin-2-one, 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,6-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,6-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-5-methyl-1H-1,6-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-2-oxo-1H-1,6-naphthyridine-5-carbonitrile, 3-amino-7-cyclopropyl-5-(difluoromethoxy)-4-(7-fluoro-1H-indazol-4-yl)-1H-1,6-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-1H-1,6-naphthyridin-2-one, 3-amino-8-fluoro-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-1H-1,6-naphthyridin-2-one, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-1H-1,6-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-8-methyl-1H-1,6-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-6,8-dimethyl-1H-1,7-naphthyridin-2-one, 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5,8-dimethyl-1H-1,7-naphthyridin-2-one, 3-amino-5-ethyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-fluoro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-benzyloxy-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-naphthyridin-2-one, 3-amino-5-benzyloxy-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-isopropoxy-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-5-(2,2,2-trifluoroethoxy)-1H-1,7-naphthyridin-2-one, 3-amino-5-ethoxy-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-(difluoromethoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-(2,2-difluoroethoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-(cyclopropoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-(3,3-difluoropropoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-(cyclobutoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-5-propoxy-1H-1,7-naphthyridin-2-one, 3-amino-5-(cyclopropylmethoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-5-(trifluoromethoxy)-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-(methoxymethyl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-7-bromo-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-ethyl-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one, or a pharmaceutically acceptable salt thereof.

[0058] A further embodiment of the present invention is (xxix) a compound of formula (I) 1. A method for preparing a compound having the structure of TIFF2026507114000004.tif49170, comprising the steps of: (a) Formula (IX) Decomposition of the pyridinium salt of TIFF2026507114000005.tif49170 with hydrazine hydrate; (b) Formula (XVII) TIFF2026507114000006.tif29170 and a compound of formula (XVIII) The compound of formula (XIX) is obtained by subjecting the compound of formula (XIX) to a cross-coupling reaction in the presence of a catalyst. TIFF2026507114000008.tif54170, followed by deprotection of the compound of formula (XIX) in the presence of an acid; (c) Formula (XXIV) The pyridinium salt of TIFF2026507114000009.tif54170 was decomposed with hydrazine hydrate to give the compound of formula (XIX). TIFF2026507114000010.tif60170, and then deprotecting the compound of formula (XIX) in the presence of an acid. including one of the following: In the formula, B 3 is a halogen, preferably bromine or iodide, and B 4 is a boronic acid, a boronic ester or tributyltin, PG is hydrogen or a protecting group, preferably a tetrahydropyranyl group, the acid is preferably trifluoroacetic acid or HCl, the catalyst is preferably Pd(dtbpf)Cl, Pd(dppf)Cl or Pd(PPh), In the formula, B 3is a halogen, preferably bromine or chlorine, B 4 is a boronic acid, a boronic ester or tributyltin, PG is hydrogen or a protecting group, preferably a tetrahydropyranyl group, the acid is preferably trifluoroacetic acid or HCl, the catalyst is preferably Pd(dtbpf)Cl, Pd(dppf)Cl or Pd(PPh), In the formula, R 1 , R 2 , R 3 , R 4 , A1, A2, A3, and A4 are as defined herein.

[0059] A further embodiment of the present invention is a compound corresponding to any one of (i) to (xxviii) or a pharmaceutically acceptable salt thereof, produced by the production method described in (xxx)(xxix).

[0060] A further embodiment of the present invention is (xxxi) a pharmaceutical composition comprising a compound according to any one of the above (i) to (xxviii) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0061] Pharmaceutical Compositions and Administration In another embodiment, pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments, are provided. In one example, a compound of formula (I) can be formulated into a galenic dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosage amounts and concentrations employed, at ambient temperature, at an appropriate pH, and at the desired degree of purity. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably somewhere in the range of about 3 to about 8. In one example, a compound of formula (I) is formulated in acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0062] The composition is formulated, dosed, and administered in a manner consistent with good medical practice.Factors to be considered in this regard include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of each patient, the cause of the disorder, the drug delivery site, the administration method, the administration schedule, and other factors known to medical professionals.The "effective amount" of the compound to be administered is determined based on these considerations and is the minimum amount required to suppress the growth of PKMYT1-dependent cancer (i.e., cancer that depends on PKMYT1 kinase activity to survive).For example, this amount may be below the amount that is toxic to normal cells or the whole mammal.

[0063] In one embodiment, a pharmaceutically effective amount of a compound of the invention administered parenterally per dose ranges from about 0.1 to 1000 mg / kg, or about 0.1 to 1000 mg per kg of patient body weight per day, with a typical initial range of compound used being 0.3 to 15 mg / kg / day. In another embodiment, an oral dosage unit, such as a tablet or capsule, preferably contains from about 1 to about 1000 mg of a compound of the invention.

[0064] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0065] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients conventional in pharmaceutical preparations, such as diluents, carriers, pH modifiers, sweeteners, fillers, and additional active agents.

[0066] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide a superior presentation of the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0067] An example of a suitable oral dosage form is a tablet containing approximately 1-1000 mg of a compound of the present invention formulated with approximately 1-1000 mg of anhydrous lactose, approximately 1-1000 mg of croscarmellose sodium, approximately 1-1000 mg of polyvinylpyrrolidone (PVP) K30, and approximately 1-1000 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. An example aerosol formulation can be prepared, for example, by dissolving 5-400 mg of a compound of the present invention in a suitable buffer solution, such as phosphate buffer, and adding an isotonicity agent (e.g., a salt such as sodium chloride) if desired. The solution can be filtered, for example, through a 0.2 micron filter, to remove impurities and contaminants.

[0068] Thus, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0069] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of PKMYT1 dependent cancers.Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of PKMYT1 dependent cancers.

[0070] Compositions A and B below show typical compositions of the present invention and serve merely as representative thereof.

[0071] Composition A The compounds of the invention can be used in a manner known per se as the active ingredient for producing tablets of the following composition: Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0072] Composition B The compounds of the invention can be used in a manner known per se as active ingredients for the manufacture of capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0073] Indications and Treatment Methods The compounds of the present invention bind to the kinase domain of PKMYT1 and inhibit its kinase activity, thereby reducing inhibitory CDK1 phosphorylation at Thr14 without significantly affecting CDK1 phosphorylation at Tyr15. Inhibition of PKMYT1, a negative regulator of CDK1, leads to unscheduled CDK1 activation and cell entry into mitosis. For example, in cancer cells with high levels of replication stress and DNA damage, such as those with cyclin E1 (CCNE1) amplification, PKMYT1 inhibition further induces CDK1 imbalance, promoting early mitotic entry in cells undergoing DNA synthesis and DNA repair, ultimately leading to accumulated replication stress and catastrophic genomic instability. Therefore, the compounds of the present invention are useful for treating cancers with high levels of replication stress and genomic instability. Alternatively, the compounds of the present invention are useful in combination therapeutic approaches with agents that induce DNA damage or disrupt DNA replication or DNA damage repair processes.

[0074] Another embodiment includes a method of treating or preventing cancer in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound of Formula (I), stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof. Cancers include, but are not limited to, sarcomas, adenocarcinomas, blastomas, and carcinomas of various organ systems, such as those affecting the pancreas, liver, lung, breast, stomach, small intestine (e.g., colon), genitourinary tract (e.g., renal urothelial cells), and ovaries.

[0075] A further embodiment of the present invention is (XXXII) a compound of the present invention for use as a therapeutically active substance.

[0076] A further embodiment of the present invention is (xxxiii) a compound of the present invention for use in the treatment or treatment of cancer.

[0077] A further embodiment of the present invention is (xxxiv) the use of a compound of the present invention for the treatment of cancer.

[0078] A further embodiment of the present invention is (xxxv) the use of a compound of the present invention for the inhibition of PKMYT1.

[0079] A further embodiment of the invention is (xxxvi) the use of a compound of the invention for the preparation of a medicament for the treatment of cancer.

[0080] A further embodiment of the invention is (xxxvii) the use of a compound of the invention for the preparation of a medicament for inhibiting PKMYT1.

[0081] A further embodiment of the invention is (xxxviii) a method for the treatment of cancer, which method comprises administering an effective amount of a compound of the invention.

[0082] A further embodiment of the invention is the use according to (xxxix) (xxxiv) or (xxxvi) or the method according to (xxxviii), wherein the cancer is pancreatic, liver, lung, breast, gastric, biliary, genitourinary, or ovarian cancer.

[0083] synthesis The compounds of the present invention may be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are illustrated in the following schemes and examples. All substituents, particularly R 1 , R 2 , R 3 , R 4 , A1, A2, A3, and A4 are defined above. Furthermore, unless otherwise specified, all reactions, reaction conditions, abbreviations, and symbols have meanings well known to one skilled in the art of organic chemistry.

[0084] A general synthetic route for preparing compounds of formula (I) is shown below. TIFF2026507114000011.tif111170, B 1 is a halogen, for example, Br or I, and B2 is an ester such as -OMe or -OEt, or an amide such as a Weinreb amide; TIFF2026507114000012.tif16170PG 1 is a protecting group such as tert-butoxycarbonyl, and PG 2 is hydrogen or a protecting group such as a tetrahydropyranyl group.

[0085] Compounds of formula (V) can be obtained by metal-halogen exchange reaction of compounds of formula (II) in the presence of an organometallic reagent such as n-BuLi or i-PrMgBr, followed by nucleophilic addition reaction with compounds of formula (III). Compounds of formula (VI) can be obtained by oxidation of the alcohol of compounds of formula (V) using a suitable oxidizing agent such as Dess-Martin periodinane or MnO. Alternatively, compounds of formula (VI) can be obtained directly by metal-halogen exchange reaction of compounds of formula (II) in the presence of an organometallic reagent such as n-BuLi or i-PrMgBr, followed by nucleophilic addition reaction with compounds of formula (IV). Compounds of formula (VII) can be obtained by deprotection of compounds of formula (VI) in the presence of a suitable acid such as TFA or HCl. Compounds of formula (VIII) can be prepared by acylation of compounds of formula (VII) with 2-chloroacetyl chloride in the presence of a suitable base such as pyridine, DMAP, TEA, or DIPEA. The compound of formula (VIII) can be cyclized in the presence of pyridine to give the compound of formula (IX). The compound of formula (I) can be obtained by decomposing the pyridinium salt of formula (IX) with hydrazine hydrate.

[0086] TIFF2026507114000013.tif152170

[0087] Alternatively, compounds of formula (I) can also be prepared by the process shown in Scheme 2. Compounds of formula (XI) could be obtained from a metal-halogen exchange reaction of compounds of formula (X) with a Grignard reagent such as PhMgBr or i-PrMgBr, followed by a Grignard reaction with compounds of formula (III). Compounds of formula (XII) could be obtained by oxidation of compounds of formula (XI) in the presence of a suitable oxidizing reagent such as Dess-Martin periodinane or MnO2. Compounds of formula (XIII) could be prepared by reduction of compounds of formula (XII) with hydrogen in the presence of a suitable reducing reagent such as iron powder, sodium dithionite or Pd / C. XIIIDeprotection of PG2 of the compound of formula (VII) in the presence of a suitable acid, such as TFA or HCl, can give a compound of formula (VII). Compounds of formula (VIII) can be prepared by acylation of the compound of formula (VII) with 2-chloroacetyl chloride in the presence of a suitable base, such as pyridine, DMAP, TEA, or DIPEA. Compounds of formula (IX) can be obtained by cyclization of the compound of formula (VIII) in the presence of pyridine. Compounds of formula (I) can be obtained by decomposing the pyridinium salt of formula (IX) with hydrazine hydrate.

[0088] TIFF2026507114000014.tif91170, B 3 is a halogen, such as bromo or iodide, and B 4 is a boronic acid, a boronic ester, or tributyltin.

[0089] Alternatively, compounds of formula (I) can be prepared according to Scheme 3. Nitration of compounds of formula (XIV) in the presence of a suitable nitrating agent, such as nitric acid, gave compounds of formula (XV). Reduction of compounds of formula (XV) with hydrogen in the presence of a suitable reducing agent, such as iron powder, sodium dithionite, or Pd / C, gave compounds of formula (XVI). Halogenation of compounds of formula (XVI) in the presence of a suitable reagent, such as NBS or NIS, gave compounds of formula (XVII). Cross-coupling of compounds of formula (XVII) and compounds of formula (XVIII) in the presence of a suitable catalyst, such as Pd(dtbpf)Cl2, Pd(dppf)Cl2, or Pd(PPh3)4, gave compounds of formula (XIX). Compounds of formula (I) could be obtained by deprotection of compounds of formula (XIX) in the presence of a suitable acid, such as TFA or HCl.

[0090] TIFF2026507114000015.tif111170

[0091] Alternatively, compounds of formula (I) can be prepared according to Scheme 4. Compounds of formula (XXII) can be obtained by metal-halogen exchange reaction of compounds of formula (XXI) in the presence of an organometallic reagent such as n-BuLi or i-PrMgBr, followed by nucleophilic addition to react with compounds of formula (XX). Compounds of formula (XXIII) can be prepared by acylation of compounds of formula (XXII) with 2-chloroacetyl chloride in the presence of a suitable base such as pyridine, DMAP, TEA, or DIPEA. Compounds of formula (XXIV) can be obtained by cyclization of compounds of formula (XXIII) in the presence of pyridine. Decomposition of the pyridinium salt of formula (XXIV) with hydrazine hydrate can give compounds of formula (XIX). Compounds of formula (I) can be obtained by deprotection of compounds of formula (XIX) in the presence of a suitable acid, such as TFA or HCl.

[0092] The compounds of the present invention may be obtained as mixtures of diastereomers or enantiomers which may be separated by methods well known in the art, for example (chiral) HPLC or SFC.

[0093] The present invention also relates to a process for the preparation of a compound of formula (I), comprising: a) Formula (I) The compound of formula (IX) It is produced by the decomposition reaction of the compound TIFF2026507114000017.tif44170 in the presence of hydrazine hydrate, b) Formula (I) TIFF2026507114000018.tif44170, by reacting the compound of formula (XVII) TIFF2026507114000019.tif29170 and a compound of formula (XVIII) via cross-coupling of the compound of formula TIFF2026507114000020.tif34170, followed by deprotection of PG2, In the formula, B 3is a halogen, e.g., bromo or iodide, and B 4 is a boronic acid, a boronic ester or tributyltin, and PG2 is hydrogen or a protecting group, such as a tetrahydropyranyl group. [Example]

[0094] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0095] List of Abbreviations The abbreviations used herein are as follows: aq.:Aqueous solution BAST: bis(2-methoxyethyl)aminosulfur trifluoride BNMO: Bis(naphthalen-1-ylmethyl)oxalamide Boc: tert-butoxycarbonyl group DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMP: Dess-Martin periodinane DMF: N,N-dimethylformamide EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc: ethyl acetate NCS: N-chlorosuccinimide NBS: N-bromosuccinimide NIS: N-iodosuccinimide NMP: N-methyl-2-pyrrolidone NaHMDS Sodium bis(trimethylsilyl)amide NADPH: reduced nicotinamide adenine dinucleotide phosphate FA: Formic acid THF: tetrahydrofuran TFA: Trifluoroacetic acid TEA: Triethylamine TsOH: p-toluenesulfonic acid KOAc: Potassium acetate Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride Pd(dtbpf)Cl2 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride PhMgBr: Phenyl magnesium bromide i-PrMgBr: Isopropyl magnesium bromide LiHMDS: lithium bis(trimethylsilyl)amide Na2CO3: Sodium carbonate HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid EGTA: Ethylene glycol bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid DTT: dithiothreitol IPA: Isopropyl alcohol rt: room temperature I C 50 : The molar concentration of an inhibitor that produces 50% of the maximum possible response for that inhibitor. HPLC: High-performance liquid chromatography Preparative TLC: Preparative thin layer chromatography MS(ESI): Mass spectrometry (electrospray ionization) obsd:actual measurement PE: Petroleum ether δ: chemical shift SFC: Supercritical Fluid Chromatography

[0096] General experimental conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) a Biotage SP1 system and Quad12 / 25 cartridge module; ii) an ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60Å, particle size: 40-60 μm; ii) CAS Registry Number: Silica Gel: 63231-67-4, particle size: 47-60 micron; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0097] Alternatively, intermediates and final compounds were purified by preparative HPLC on reversed-phase columns using an XBridge™ preparative C18 (5 μm, OBD™ 30×100 mm) column, a SunFire™ preparative C18 (5 μm, OBD™ 30×100 mm) column, a Phenomenex Synergi-C18 (10 μm, 25×150 mm) or a Phenomenex Gemini-C18 (10 μm, 25×150 mm). Purification was performed by preparative HPLC on a reversed-phase column using a Waters AutoP purification system (sample manager 2767, pump 2525, detectors: Micromass ZQ and UV 2487, solvent systems: acetonitrile and 0.1% ammonium hydroxide in water, acetonitrile and 0.1% FA in water, or acetonitrile and 0.1% TFA in water); or a Gilson-281 purification system (pump 322, detector: UV 156, solvent systems: acetonitrile and 0.05% ammonium hydroxide in water, acetonitrile and 0.225% FA in water, acetonitrile and 0.05% HCl in water, acetonitrile and 0.075% TFA in water, or acetonitrile and water).

[0098] For SFC chiral separations, intermediates and final compounds were separated by chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) on a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC, or Thar80 preparative SFC, solvent systems: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure 100 bar, UV detection at 254 or 220 nm.

[0099] The LC / MS spectra of the compounds were obtained using an LC / MS (Waters™ Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ) under the following LC / MS conditions (run time: 3 minutes or 1.5 minutes). Acidic conditions I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic conditions II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH3·H2O in H2O; B: acetonitrile; Basic conditions II: A: 0.025% NH3·H2O in H2O; B: acetonitrile; Neutral conditions: A: H2O; B: acetonitrile. Mass spectra (MS): Generally, only ions representing the parent mass are reported, and unless otherwise stated, the mass ions quoted are positive mass ions (M−H). + is.

[0100] NMR spectra were obtained using a Bruker Avance 400 / 500 MHz.

[0101] Microwave-assisted reactions were performed on a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

[0102] Preparation example The following examples are intended to illustrate the meaning of the present invention but do not in any way represent a limitation within the meaning of the present invention.

[0103] Intermediate 1: 7-Fluoro-N-methoxy-N-methyl-1-tetrahydropyran-2-yl-indazole-4-carboxamide TIFF2026507114000021.tif39170 Step 1: Methyl 7-fluoro-1H-indazole-4-carboxylate A mixture of 4-bromo-7-fluoro-1H-indazole (20.0 g, 93.0 mmol), TEA (25.86 mL, 186 mmol), and Pd(dppf)Cl2 (6.81 g, 9.3 mmol) in methanol (200 mL) was stirred at 80 °C under a CO atmosphere (50 psi) for 12 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound Int-1a (18.0 g, 99.6% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:195.2.

[0104] Step 2: 7-Fluoro-1H-indazole-4-carboxylic acid A mixture of compound Int-1a (10.0 g, 51.5 mmol) and NaOH (0.8 g, 200 mmol) in methanol (50 mL) and water (50 mL) was stirred at 25° C. for 2 hours. After completion, the pH of the mixture was adjusted to approximately 3 using aqueous HCl (1 M). The suspension was collected by filtration to give a solid, which was washed with water (30 mL) and concentrated in vacuo to give compound Int-1b (9.0 g, 97.0% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H)+]:181.1

[0105] Step 3: 7-Fluoro-N-methoxy-N-methyl-1H-indazole-4-carboxamide A mixture of Int-1b (8.0 g, 44.4 mmol), O,N-dimethylhydroxylamine HCl salt (5.2 g, 53.3 mmol), TEA (9.26 mL, 66.6 mmol), and EDCI (12.7 g, 66.6 mmol) in DCM (100 mL) was stirred at 25 °C for 2 h. After completion, the mixture was poured into water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound Int-1 (7.0 g, 70.6% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:224.1.

[0106] Intermediate 2: tert-butyl N-(2-bromo-5-chloro-3-pyridyl)carbamate To a solution of 2-bromo-5-chloro-pyridin-3-amine (1.0 g, 4.82 mmol) in THF (20 mL) was added NaHMDS (9.64 mL, 9.64 mmol) dropwise at 0° C. Then, a solution of di-tert-butyl dicarbonate (1.05 g, 4.82 mmol) in THF (5 mL) was added dropwise to the mixture at 0° C. The mixture was then warmed to 25° C. and stirred for an additional 2 h. Upon completion, the reaction was quenched with saturated ammonium chloride (10 mL) at 0° C. and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-10%) to give compound Int-2 (1.2 g, 80.9% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:307.0.

[0107] Intermediate 3: tert-butyl (2-bromo-5-methylpyridin-3-yl)carbamate The title compound TIFF2026507114000026.tif23170 was prepared similarly to the preparation of compound Int-2, substituting 2-bromo-5-chloro-pyridin-3-amine with 2-bromo-5-methyl-pyridin-3-amine. Compound Int-3 (9.5 g) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:287.1.

[0108] Intermediate 4: tert-butyl N-(2-bromo-5-fluoro-3-pyridyl)carbamate The title compound TIFF2026507114000027.tif23170 was prepared similarly to the preparation of compound Int-2, substituting 2-bromo-5-chloro-pyridin-3-amine for 2-bromo-5-fluoro-pyridin-3-amine. Compound Int-4 (1.5 g) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:291.1.

[0109] Intermediate 5: tert-butyl N-[2-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate The title compound, TIFF2026507114000028.tif23170, was prepared similarly to the preparation of compound Int-2, substituting 2-bromo-5-chloro-pyridin-3-amine with 2-bromo-5-(trifluoromethyl)pyridin-3-amine. Compound Int-5 (1.2 g) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:341.1.

[0110] Intermediate 6: tert-butyl N-(2-bromo-5-methoxy-3-pyridyl)carbamate The title compound, TIFF2026507114000029.tif24170, was prepared similarly to the preparation of compound Int-2, substituting 2-bromo-5-chloro-pyridin-3-amine with 2-bromo-5-methoxy-pyridin-3-amine. Compound Int-6 (1.0 g) was obtained as a white solid. MS (ESI) + )obsd.[(M+H) + ]:303.1.

[0111] Intermediate 7: tert-butyl N-[2-bromo-6-(cyclobutoxy)-5-methyl-3-pyridyl]carbamate TIFF2026507114000030.tif23170 Step 1: 2-(cyclobutoxy)-3-methyl-5-nitro-pyridine To a mixture of cyclobutanol (1.0 g, 13.9 mmol) in THF (10 mL) was added NaH (0.83 g, 20.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then, a solution of 2-chloro-3-methyl-5-nitropyridine (3.6 g, 20.8 mmol) in THF (25 mL) was added to the mixture and stirred at 25 °C for 12 h. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-10%) to give compound Int-7a (1.7 g, 58.2% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:209.1.

[0112] Step 2: 6-(cyclobutoxy)-5-methyl-pyridin-3-amine TIFF2026507114000032.tif23170 Compound Int-7a (1.7 g, 8.1 mmol), NHCl (2.16 g, 40.3 mmol), and iron powder (3.8 g, 40.4 mmol) in ethanol (15 mL) and water (15 mL) were stirred at 80 °C for 2 h. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give compound Int-7b (1.4 g, 97.4% yield) as a brown oil. MS (ESI) + )obsd.[(M+H) + ]:179.1.

[0113] Step 3: 2-Bromo-6-(cyclobutoxy)-5-methylpyridin-3-amine To a solution of compound Int-7b (1.3 g, 7.3 mmol) in MeCN (15 mL) was added a suspension of NBS (1.4 g, 7.7 mmol) in MeCN (5 mL) at 0 °C. The mixture was warmed to 25 °C and stirred for 1 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (20 mL) and saturated Na2CO3 (50 mL). The resulting mixture was then extracted with EtOAc (1.2 L × 3). The combined organic layers were washed with brine (1.2 L), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give compound Int-7c (1.8 g, 96.0% yield) as a brown oil. MS (ESI) + )obsd.[(M+H) + ]:257.0.

[0114] Step 4: tert-Butyl N-[2-bromo-6-(cyclobutoxy)-5-methyl-3-pyridyl]carbamate The title compound TIFF2026507114000034.tif23170 was prepared in a similar manner to the preparation of compound Int-2, substituting compound Int-7c for 2-bromo-5-chloro-pyridin-3-amine. Compound Int-7 (1.0 g) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:357.2.

[0115] Intermediate 8: tert-butyl N-[2-bromo-6-(cyclopropylmethoxy)-5-methyl-3-pyridyl]carbamate The title compound was prepared in a similar manner to the preparation of compound Int-7, substituting cyclopropylmethanol for cyclobutanol. Compound Int-8 (1.0 g) was obtained as a white solid. MS (ESI) + )obsd.[(M+H) + ]:357.2.

[0116] Intermediate 9: tert-butyl N-[6-chloro-2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-5-methyl-3-pyridyl]carbamate TIFF2026507114000036.tif44170 Step 1: 2-Bromo-4-chloro-5-methyl-aniline To a mixture of 2-bromo-5-methylaniline (20.0 g, 107.5 mmol) in DMF (300 mL) was added a solution of NCS (15.8 g, 118.3 mmol) in DMF (20 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (500 mL) and saturated Na2CO3 (200 mL) and extracted with EtOAc (600 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give compound Int-9a (21.0 g, 88.6% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:221.0.

[0117] Step 2: tert-butyl N-(2-bromo-6-chloro-5-methyl-3-pyridyl)carbamate The title compound TIFF2026507114000038.tif23170 was prepared in a similar manner to the preparation of compound Int-2, substituting compound Int-9a for 2-bromo-5-chloro-pyridin-3-amine. Compound Int-19b (6.7 g) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:322.9.

[0118] Step 3: tert-butyl N-[6-chloro-2-(7-fluoro-1-tetrahydropyran-2-ylindazole-4-carbonyl)-5-methyl-3-pyridyl]carbamate TIFF2026507114000039.tif44170 To a solution of compound Int-9b (1.1 g, 3.58 mmol) in tetrahydrofuran (15 mL) was added NaH (156.2 mg, 3.9 mmol) at 0 ° C. The reaction mixture was then cooled to -78 ° C., and n-BuLi (1.4 mL, 3.6 mmol) was added dropwise at -78 ° C. and stirred for an additional 30 minutes. A solution of compound Int-1 (1.0 g, 3.3 mmol) in tetrahydrofuran (2 mL) was then added, and the mixture was stirred for an additional 30 minutes at -78 ° C. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-10%) to give compound Int-9 (470.0 mg, 29.5% yield) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:489.1.

[0119] Intermediate 10: 3-amino-4-bromo-7-chloro-1H-1,5-naphthyridin-2-one TIFF2026507114000040.tif29170 Step 1: 7-Chloro-3-nitro-1H-1,5-naphthyridin-2-one To a solution of 7-chloro-1H-1,5-naphthyridin-2-one (3.5 g, 19.4 mmol) in HCl (40 mL) was added KNO (3.9 g, 38.8 mmol). The mixture was stirred at 120 °C, and KNO (2.0 g, 19.4 mmol) was added every 6 h until the starting material was completely consumed. Upon completion, the resulting mixture was poured into ice water (200 mL). The suspension was filtered to obtain a solid, which was washed with water and dried in vacuo to give crude compound Int-10a (2.8 g, 63.8% yield) as a yellow solid, which was used in the next step without further purification. MS (ESI) + )obsd.[(M+H) + ]:226.0.

[0120] Step 2: 3-Amino-7-chloro-1H-1,5-naphthyridin-2-one A mixture of compound Int-10a (2.70 g, 12.0 mmol), ammonium chloride (6.4 g, 119.7 mmol), and iron powder (5.4 g, 95.8 mmol) in MeOH (100 mL) and water (20 mL) was stirred at 75 °C for 2 h. After completion, the resulting mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was washed with water and dried in vacuo to give crude compound Int-10b (1.5 g, 63.9% yield) as a yellow solid, which was used in the next step without further purification. MS (ESI) + )obsd.[(M+H) + ]:196.0.

[0121] Step 3: 3-Amino-4-bromo-7-chloro-1H-1,5-naphthyridin-2-one To a suspension of compound Int-10b (420.0 mg, 2.2 mmol) in acetonitrile (30 mL) at 0° C. was added NBS (401.0 mg, 2.3 mmol). The mixture was stirred at 0° C. for 1 hour. After completion, the mixture was concentrated in vacuo to give a residue, which was washed with water and MeOH. The solid was dried in vacuo to give crude compound Int-10 (280.0 mg, 46.5% yield) as a brown solid, which was used in the next step without further purification. MS (ESI) + )obsd.[(M+H) + ]:273.9.

[0122] Intermediate 11: 4-Bromo-7-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole TIFF2026507114000044.tif34170 Step 1: 2-Bromo-5,6-difluoro-3-methyl-benzaldehyde To a solution of 2,2,6,6-tetramethylpiperidine (3.6 g, 25.4 mmol) in anhydrous THF (50 mL) was added n-BuLi (2.0 M in hexane, 12.7 mL) dropwise at -70 °C under a N atmosphere, and the mixture was stirred for 10 min. A solution of 1-bromo-4,5-difluoro-2-methyl-benzene (5.0 g, 24.2 mmol) in THF (15 mL) was then added dropwise, and the mixture was stirred at -70 °C for an additional 2 h, after which DMF (2.0 g, 26.6 mmol) was added dropwise. Upon completion, the mixture was warmed to -20 °C and quenched by the dropwise addition of HCl (1 M aqueous solution, 20 mL). The mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with hydrochloric acid (1 M) and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give compound Int-11a (5.2 g, 87.1% yield) as a yellow solid, which was used in the next step without further purification.

[0123] Step 2: 4-Bromo-7-fluoro-5-methyl-1H-indazole TIFF2026507114000046.tif34170 A mixture of compound Int-11a (5.2 g, 22.0 mmol), hydrazine monohydrate (3.3 g, 3.2 mL), and 1,4-dioxane (50 mL) was stirred at 110 °C for 12 hours. After completion, the resulting mixture was concentrated in vacuo to give a crude residue, which was redissolved in EtOAc (100 mL) and washed with water (100 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give compound Int-11b (4.9 g, 97.3% yield) as a yellow solid, which was used in the next step without further purification. MS (ESI) + )obsd.[(M+H) + ]:228.9.

[0124] Step 3: 4-Bromo-7-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole A mixture of Int-11b (4.5 g, 19.7 mmol), 3,4-dihydro-2H-pyran (5.0 g, 59.0 mmol), and p-toluenesulfonic acid monohydrate (374.0 mg, 2.0 mmol) in anhydrous DCM (90 mL) was stirred at rt for 2 h. After completion, the reaction was quenched with a saturated solution of NaHCO3 and extracted with DCM (100 mL × 3). The combined organic layers were concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-10%) to give compound Int-11 (3.8 g, 61.6% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:313.1.

[0125] Intermediate 12: 4-Bromo-5-chloro-7-fluoro-1-tetrahydropyran-2-yl-indazole TIFF2026507114000048.tif34170 Step 1: N-benzyl-7-fluoro-1-tetrahydropyran-2-yl-indazol-4-amine Compound 4-bromo-7-fluoro-1-tetrahydropyran-2-yl-indazole (4.1 g, 13.7 mmol), benzylamine (2.2 g, 20.6 mmol), CsCO (11.2 g, 34.2 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (1.4 g, 1.4 mmol), and RuPhos (959.3 mg, 2.1 mmol) were stirred in toluene (100 mL) under a N atmosphere at 100 °C for 12 h. After completion, the resulting mixture was filtered, and the filtrate was concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-25%) to give compound Int-12a (4.1 g, 91.8% yield) as a yellow oil. MS(ESI + )obsd.[(M+H) + ]:326.1.

[0126] Step 2: 7-Fluoro-1-tetrahydropyran-2-yl-indazol-4-amine A mixture of compound Int-12a (4.4 g, 13.6 mmol), Pd / C (440 mg, 10 wt%) in THF (100 mL) was stirred at rt under an H atmosphere for 48 h. After completion, the resulting mixture was filtered, and the filtrate was concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 5-50%) to give compound Int-12b (2.5 g, 78.4% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:236.1.

[0127] Step 3: 5-chloro-7-fluoro-1-tetrahydropyran-2-yl-indazol-4-amine To a cooled solution of compound Int-12b (500.0 mg, 2.1 mmol) in anhydrous DCM (15 mL) was added NCS (284.0 mg, 2.13 mmol). The mixture was stirred at room temperature for 2 h. After completion, the mixture was quenched with saturated NaHCO3 solution and extracted with DCM (15 mL x 3). The combined organic layers were concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound Int-12c (510.0 mg, 88.7% yield) as a pale yellow solid. MS (ESI) + )obsd.[(M+H) + ]:270.0.

[0128] Step 4: 4-Bromo-5-chloro-7-fluoro-1-tetrahydropyran-2-yl-indazole To a suspension of CuBr (745.0 mg, 5.2 mmol) in anhydrous acetonitrile (15 mL) was added dropwise tert-butyl nitrite (1.34 g, 12.98 mmol) at 50 °C. The mixture was stirred at 50 °C for 30 min. Compound Int-12c (700 mg, 2.6 mmol) in anhydrous acetonitrile (5 mL) was then added dropwise, and the mixture was stirred at 80 °C for 6 h. After completion, the mixture was concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluted with EA: PE = 0-10%) to give compound Int-12 (400.0 mg, 46.1% yield) as a white solid. MS (ESI) + )obsd.[(M-THP+H)+]:248.9.

[0129] Intermediate 13: tert-butyl (2-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-6-hydroxy-5-methylpyridin-3-yl)carbamate TIFF2026507114000053.tif44170 Step 1: 2-Benzyloxy-3-methyl-5-nitro-pyridine The title compound was prepared in a similar manner to the preparation of compound Int-7a, substituting benzyl alcohol for 2-cyclobutanol. Compound Int-13a (8.0 g) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:245.1.

[0130] Step 2: 6-(benzyloxy)-5-methylpyridin-3-amine The title compound was prepared similarly to the preparation of Int-7b, replacing compound Int-7a with compound Int-13a. Compound Int-13b (4.7 g) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:215.3.

[0131] Step 3: 6-(benzyloxy)-2-bromo-5-methylpyridin-3-amine The title compound was prepared similarly to the preparation of Int-7c, replacing compound Int-7b with compound Int-13b. Compound Int-13c (3.6 g) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:215.3.

[0132] Step 4: tert-butyl (6-(benzyloxy)-2-bromo-5-methylpyridin-3-yl)carbamate The title compound was prepared similarly to the preparation of Int-2, replacing 2-bromo-5-chloro-pyridin-3-amine with compound Int-13c. Compound Int-13d (4.3 g) was obtained as a pale yellow solid. MS (ESI + )obsd.[(M+H) + ]:393.1.

[0133] Step 5: tert-butyl (6-(benzyloxy)-2-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)(hydroxy)methyl)-5-methylpyridin-3-yl)carbamate To a solution of compound Int-13d (4.3 g, 10.9 mmol) in THF (40 mL) was added n-BuLi (9.1 mL, 22.8 mmol) at −78° C., and the mixture was stirred at −78° C. for 1 h. Then, 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde (2.3 g, 9.1 mmol) (Vendor: PharmaBlock (Nanjing) R&D Co. Ltd., Cat. No. PCS1710) dissolved in THF (30 mL) was added, and the mixture was stirred at −78° C. for an additional 30 min. After completion, the reaction mixture was quenched with saturated ammonium chloride (40 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound Int-13e (4.1 g, 66.9% yield) as a pale yellow oil. MS (ESI) + )obsd.[(M+H) + ]:563.3.

[0134] Step 6: tert-butyl (6-(benzyloxy)-2-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-5-methylpyridin-3-yl)carbamate A mixture of compound Int-13e (4.1 g, 7.3 mmol) and MnO2 (12.7 g, 145.7 mmol) in chloroform (50 mL) was stirred at 50 °C for 3 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-10%) to give compound Int-13f (3.4 g, 83.0% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:561.4.

[0135] Step 7: tert-butyl (2-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-6-hydroxy-5-methylpyridin-3-yl)carbamate A mixture of compound Int-13f (3.4 g, 6.1 mmol) and Pd / C (0.81 g, 5% on wet carbon) in EtOAc (60.0 mL) under H₂O (15 psi) was stirred at room temperature for 1 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound Int-13 (2.4 g, 84.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:471.4.

[0136] Intermediate 14: tert-butyl N-(2-bromo-6-chloro-4,5-dimethyl-3-pyridyl)carbamate TIFF2026507114000061.tif24170 Step 1: 5-Bromo-6-chloro-4-methyl-pyridin-3-amine To a solution of compound 3-bromo-2-chloro-4-methyl-5-nitro-pyridine (2.0 g, 7.9 mmol) in MeOH (20 mL) and water (6 mL) was added Fe powder (4.4 g, 79.5 mmol) and NH4Cl (4.3 g, 79.5 mmol) at 25°C. The mixture was stirred at 75°C for 2 hours. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give compound Int-14a (1.7 g, 94.2% yield) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:220.9.

[0137] Step 2: 6-Chloro-4,5-dimethyl-pyridin-3-amine To a solution of compound Int-14a (2.0 g, 8.9 mmol) in 1,4-dioxane (25 mL) and water (2.5 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.7 g, 13.3 mmol), potassium carbonate (3.7 g, 26.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (647.0 mg, 885.0 μmol). The mixture was stirred at 80°C for 3 hours. Upon completion, the mixture was filtered, and the filtrate was concentrated under vacuum to give compound Int-14b (1.4 g, 100% yield) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:157.0.

[0138] Step 3: 2-Bromo-6-chloro-4,5-dimethyl-pyridin-3-amine To a solution of compound Int-14b (400.0 mg, 2.6 mmol) in acetonitrile (12 mL) was added NBS (500.0 mg, 2.8 mmol). The mixture was stirred at 25 °C for 1 h. After completion, the mixture was poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound Int-14c (400.0 mg, 66.5% yield) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:235.0.

[0139] Step 4: tert-butyl-N-(2-bromo-6-chloro-4,5-dimethyl-3-pyridyl)carbamate TIFF2026507114000065.tif24170 To a solution of compound Int-14c (800 mg, 3.40 mmol) in THF (20 mL), (Boc)2O (2.97 g, 13.6 mmol) and 4-dimethylaminopyridine (830 mg, 6.79 mmol) were added at room temperature. The mixture was stirred at 70 °C for 2 hours. After completion, the mixture was poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a residue. The residue was redissolved in THF (7 mL), methanol (21 mL), and water (7 mL). Lithium hydroxide hydrate (2.48 g, 59.1 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. After completion, the mixture was poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound Int-14 (1.1 g, 90.8% yield) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:335.0.

[0140] Intermediate 15: tert-butyl N-(2-bromo-4-methoxy-5-methyl-3-pyridyl)carbamate TIFF2026507114000066.tif29170 Step 1: 3-Bromo-4-methoxy-5-nitropyridine A mixture of 3-bromo-4-chloro-5-nitropyridine (7.7 g, 32.4 mmol) and MeONa (7.2 mL, 38.9 mmol) in methanol (100 mL) was stirred at 25 °C for 2 h. After completion, the mixture was poured into water (120 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound Int-15a (7.0 g, 92.7% yield) as a yellow gum.

[0141] Step 2: 4-Methoxy-3-methyl-5-nitropyridine A mixture of compound Int-15a (1.0 g, 4.29 mmol), trimethylboroxine (2.45 mL, 8.58 mmol), Pd(dppf)Cl (313.71 mg, 0.43 mmol), and KCO (1186.25 mg, 8.58 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 12 h under N protection. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound Int-15b (600.0 mg, 83.15% yield) as a yellow gum. MS(ESI + )obsd.[(M+H) + ]:169.1.

[0142] Step 3: 4-Methoxy-5-methylpyridin-3-amine A mixture of compound Int-15b (2.0 g, 13.1 mmol), Fe (4.4 g, 78.9 mmol), and NH4Cl (4.2 g, 78.9 mmol) in ethanol (30 mL) and water (10 mL) was stirred at 80 °C for 3 h. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound Int-15c (0.5 g, 27.4% yield) as a yellow gum. MS (ESI) + )obsd.[(M+H) + ]:139.2.

[0143] Step 4: 2-Bromo-4-methoxy-5-methylpyridin-3-amine To a solution of compound Int-15c (1.2 g, 8.7 mmol) in MeCN (15 mL) was added NBS (1.5 g, 8.7 mmol) dropwise at 0 °C. The mixture was then warmed to 25 °C and stirred for 1 h. Upon completion, the reaction was quenched with saturated sodium sulfite (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound Int-15d (310.0 mg, 16.4% yield) as a yellow gum. MS (ESI) + )obsd.[(M+H) + ]:217.0

[0144] Step 5: tert-butyl (2-bromo-4-methoxy-5-methylpyridin-3-yl)carbamate The title compound TIFF2026507114000071.tif24170 was prepared in a manner similar to the preparation of compound Int-2, substituting compound Int-15d for 2-bromo-5-chloro-pyridin-3-amine. Compound Int-15 (310.0 mg) was obtained as a yellow gum. MS (ESI + )obsd.[(M+H) + ]:317.0.

[0145] Intermediate 16: tert-butyl N-(2-bromo-5-chloro-6-methyl-3-pyridyl)carbamate The title compound was prepared in a manner similar to the preparation of compound Int-15, substituting 3-chloro-2-methyl-5-nitropyridine for compound Int-15b in step 3. Compound Int-16 (1.5 g) was obtained as a yellow gum. MS (ESI + )obsd.[(M+H) + ]:321.0.

[0146] Intermediate 17: tert-butyl N-(2-bromo-4,5-dimethyl-3-pyridyl)carbamate The title compound was prepared similarly to the preparation of compound Int-15, replacing compound Int-15b with 3,4-dimethyl-5-nitropyridine in step 3. Compound Int-17 (1.6 g) was obtained as a yellow gum. MS (ESI + )obsd.[(M+H) + ]:301.2.

[0147] Intermediate 18: tert-butyl N-(2-bromo-5-chloro-6-cyclopropyl-3-pyridyl)carbamate TIFF2026507114000074.tif29170 Step 1: 5-Chloro-6-cyclopropylpyridin-3-amine A mixture of 6-bromo-5-chloro-pyridin-3-amine (10.0 g, 48.2 mmol), cyclopropylboronic acid (4.1 g, 48.2 mmol), Pd(dppf)Cl2 (3.5 g, 4.8 mmol), and Cs2CO3 (3.1 g, 96.4 mmol) in 1,4-dioxane (100 mL) was stirred at 100 °C for 1 h under N2 protection. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 20-40%) to give compound Int-18a (9.5 g, 71.8% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:169.1.

[0148] Step 2: 2-Bromo-5-chloro-6-cyclopropylpyridin-3-amine To a mixture of compound Int-18a (700.0 mg, 4.1 mmol) in DMF (7 mL), NBS (665.0 mg, 3.7 mmol) was added portionwise. The reaction mixture was stirred at 0 °C for 0.5 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 20-40%) to give compound Int-18b (790.0 mg, 76.9% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:246.9.

[0149] Step 3: tert-butyl (2-bromo-5-chloro-6-cyclopropylpyridin-3-yl)carbamate The title compound TIFF2026507114000077.tif29170 was prepared in a manner similar to the preparation of compound Int-2, substituting compound Int-18b for 2-bromo-5-chloro-pyridin-3-amine. Compound Int-18 (940.0 mg) was obtained as a yellow gum. MS (ESI + )obsd.[(M+H) + ]:347.1.

[0150] Intermediate 19: tert-butyl N-(2-bromo-5-chloro-4,6-dimethyl-3-pyridyl)carbamate The title compound, TIFF2026507114000078.tif24170, was prepared in a manner similar to the preparation of compound Int-15, substituting 2-bromo-3-chloro-4-methyl-5-nitro-pyridine for compound Int-15a in step 2. Compound Int-19 (1.5 g) was obtained as a yellow gum. MS (ESI + )obsd.[(M+H) + ]:335.0.

[0151] Intermediate 20: tert-butyl N-(2-bromo-4-chloro-5,6-dimethyl-3-pyridyl)carbamate TIFF2026507114000079.tif29170 Step 1: 2-Bromo-5,6-dimethylpyridin-3-amine To a solution of 5,6-dimethylpyridin-3-amine (4.0 g, 32.7 mmol) in DCM (40 mL) was added a solution of NBS (6.4 g, 36.0 mmol) in DCM (60 mL) dropwise at 0 °C. The reaction was stirred at 0 °C for 1.5 h. Upon completion, the reaction mixture was quenched with sodium sulfite solution (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE / EA = 5 / 1) to give compound Int-20a (4.3 g, 65.3% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:201.0.

[0152] Step 2: 2-Bromo-4-chloro-5,6-dimethylpyridin-3-amine To a solution of compound Int-20a (4.2 g, 20.9 mmol) in NMP (50 mL) was added a solution of NCS (3.1 g, 23.0 mmol) in NMP (30 mL) dropwise at 25 °C. The mixture was then heated to 80 °C and stirred for 12 h. Upon completion, the reaction mixture was quenched with saturated sodium sulfite (40 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound Int-20b (500.0 mg, 10.2% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:235.0

[0153] Step 3: tert-butyl (2-bromo-4-chloro-5,6-dimethylpyridin-3-yl)carbamate The title compound TIFF2026507114000082.tif29170 was prepared in a similar manner to the preparation of compound Int-2, substituting compound Int-20b for 2-bromo-5-chloro-pyridin-3-amine. Compound Int-20 (518.0 mg) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:335.0.

[0154] Intermediate 21: tert-butyl N-[2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-4-methyl-3-pyridyl]carbamate The title compound, TIFF2026507114000083.tif49170, was prepared in a manner similar to the preparation of compound Int-13f, substituting 2-bromo-4-methyl-pyridin-3-amine for compound Int-13c in step 4. Compound Int-21 (1.5 g) was obtained as a yellow gum. MS (ESI + )obsd.[(M+H) + ]:455.2.

[0155] Intermediate 22: (5-cyclopropyl-4-methyl-3-nitro-2-pyridyl)-(7-fluoro-1-tetrahydropyran-2-yl-indazol-4-yl)methanone TIFF2026507114000084.tif44170 Step 1: (5-bromo-4-methyl-3-nitropyridin-2-yl)(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanol To a solution of 5-bromo-2-iodo-4-methyl-3-nitropyridine (1.1 g, 3.2 mmol) in THF (10 mL) was added PhMgBr (1.2 mL, 3.5 mmol) under a nitrogen atmosphere at −40° C. Then, a solution of 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde (1.1 g, 4.5 mmol) in THF (10 mL) was added to the mixture at −40° C. The reaction mixture was slowly warmed to 25° C. and stirred for an additional 30 minutes. Upon completion, the reaction mixture was quenched with saturated ammonium chloride (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give compound Int-22a (680.0 mg, 83.5% yield) as an orange solid. MS (ESI) + )obsd.[(M+H) + ]:465.0.

[0156] Step 2: (5-bromo-4-methyl-3-nitropyridin-2-yl)(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanone To a mixture of compound Int-22a (680.0 mg, 1.5 mmol) in chloroform (10 mL) was added MnO (1.9 g, 21.9 mmol), and the mixture was stirred at 50 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give compound Int-22b (650.0 mg, crude) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:463.0.

[0157] Step 3: (5-cyclopropyl-4-methyl-3-nitropyridin-2-yl)(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanone A mixture of compound Int-22b (300 mg, 0.65 mmol), cyclopropylboronic acid (61.2 mg, 0.71 mmol), Pd(dppf)Cl2 (47.3 mg, 0.06 mmol), and K2CO3 (179 mg, 1.3 mmol) in 1,4-dioxane (5 mL) was stirred at 80 °C for 12 h under N2 protection. After completion, the mixture was poured into water (20 mL), and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give compound Int-22 (170 mg, 61.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:425.1.

[0158] Intermediate 23: [3-amino-4-methyl-5-(trideuteriomethyl)-2-pyridyl]-(7-fluoro-1-tetrahydropyran-2-yl-indazol-4-yl)methanone TIFF2026507114000088.tif49170 Step 1: (3-amino-5-bromo-4-methylpyridin-2-yl)(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanone The title compound was prepared in a manner similar to that used to prepare compound Int-15c, substituting compound Int-22b for compound Int-15b. Compound Int-23a (0.5 g) was obtained as a yellow gum. MS (ESI + )obsd.[(M+H) + ]:433.1.

[0159] Step 2: (3-amino-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanone A mixture of compound Int-23a (260.0 mg, 0.6 mmol), bis(pinacolato)diboron (304.8 mg, 1.2 mmol), Pd(dppf)Cl (43.9 mg, 0.06 mmol), and KOAc (206.1 mg, 2.1 mmol) in 1,4-dioxane (5 mL) was stirred at 110 °C for 12 hours under N protection. Upon completion, the suspension was filtered, and the filtrate was concentrated in vacuo to give compound Int-23b (280.0 mg, crude) as a black oil. MS (ESI) + )obsd.[(M+H) + ]:481.4.

[0160] Step 3: [3-amino-4-methyl-5-(trideuteriomethyl)-2-pyridyl]-(7-fluoro-1-tetrahydropyran-2-yl-indazol-4-yl)methanone A mixture of compound Int-23b (280.0 mg, 0.58 mmol), iodomethane-d3 (0.11 mL, 1.8 mmol), Pd(dppf)Cl2 (42.7 mg, 0.06 mmol), and K3PO4 (371.2 mg, 1.8 mmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) was stirred at 80 °C for 2 h under N2 protection. After completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give compound Int-23 (65.0 mg, 30.0% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:372.3.

[0161] Intermediate 24: tert-butyl N-(2-chloro-3-iodo-5,6-dimethyl-4-pyridyl)carbamate TIFF2026507114000092.tif34170 Step 1: 6-Chloro-3-iodo-2-methylpyridin-4-amine To a solution of 2-chloro-6-methyl-pyridin-4-amine (4.0 g, 28.05 mmol) and toluene-4-sulfonic acid (241.54 mg, 1.4 mmol) in MeCN (40 mL) was added NIS (7.57 g, 33.66 mmol), and the mixture was stirred at 70 °C for 12 h. After completion, the mixture was quenched with saturated sodium sulfite (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give Int-24a (2.6 g, 34.5% yield) as a yellow solid.

[0162] Step 2: 6-Chloro-2,3-dimethylpyridin-4-amine A mixture of Int-24a (2.4 g, 8.94 mmol), trimethylboroxine (3.83 mL, 13.41 mmol), Pd(dppf)Cl2 (654.1 mg, 0.89 mmol), and Cs2CO3 (5.83 g, 17.88 mmol) in 1,4-dioxane (30 mL) was stirred at 80 °C for 2 h under N2 protection. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give Int-24b (1.05 g, 75.0% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:157.1.

[0163] Step 3: 2-Chloro-3-iodo-5,6-dimethylpyridin-4-amine To a solution of Int-24b (1.0 g, 6.39 mmol) and toluene-4-sulfonic acid (54.98 mg, 0.32 mmol) in MeCN (10 mL) was added NIS (1.72 g, 7.66 mmol), and the mixture was stirred at 70 °C for 2 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give Int-24c (1.8 g, 99.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:282.9.

[0164] Step 4: tert-butyl (2-chloro-3-iodo-5,6-dimethylpyridin-4-yl)carbamate To a solution of Int-24c (1.7 g, 6.02 mmol) in THF (20 mL) was added NaHMDS (12.03 mL, 12.03 mmol) dropwise at 0 °C. After stirring at 0 °C for 30 min, a solution of di-t-butyl dicarbonate (1.44 g, 6.62 mmol) in THF (20 mL) was added dropwise to the above mixture at 0 °C, and the mixture was then stirred at 0 °C for an additional 1 h. Upon completion, the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give Int-24 (1.8 g, 78.2% yield) as a yellow solid. MS(ESI + )obsd.[(M+H) + ]:383.1.

[0165] Intermediate 25: tert-butyl (2-chloro-6-cyclopropyl-3-iodopyridin-4-yl)carbamate TIFF2026507114000097.tif34170 Step 1: 2-Chloro-6-cyclopropyl-3-iodopyridin-4-amine To a solution of 2-chloro-6-cyclopropyl-pyridin-4-amine (1.86 g, 11.0 mmol) and toluene-4-sulfonic acid (95.2 mg, 0.55 mmol) in MeCN (3 mL) was added NIS (2.5 g, 11.0 mmol), and the mixture was stirred at 70 °C for 2 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give Int-25a (2.1 g, 64.43% yield) as a yellow solid. MS (ESI) + ) and observed. [(M+H) + ]:295.1.

[0166] Step 2: tert-butyl (2-chloro-6-cyclopropyl-3-iodopyridin-4-yl)carbamate The title compound was prepared in a manner similar to the preparation of Int-24, substituting compound Int-25a for compound Int-24c in step 4. Int-25 (2.4 g) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:395.1.

[0167] Intermediate 26: tert-butyl N-[4-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-5-hydroxy-2-methyl-3-pyridyl]carbamate TIFF2026507114000100.tif49170

[0168] Step 1: 5-(benzyloxy)-3-bromo-2-chloropyridine A mixture of 5-bromo-6-chloro-pyridin-3-ol (10.0 g, 47.98 mmol), bromomethylbenzene (8.55 mL, 71.96 mmol), and potassium carbonate (13.26 g, 95.95 mmol) in MeCN (100 mL) was stirred at 25 °C for 12 h. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-10%) to give compound Int-26a (13.5 g, 94.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:299.9.

[0169] Step 2: tert-butyl (5-(benzyloxy)-2-chloropyridin-3-yl)carbamate A mixture of compound Int-26a (16.0 g, 53.6 mmol), CsCO (52.4 g, 160.8 mmol), tert-butyl carbamate (6.3 g, 53.6 mmol), Pd(dba) (4.9 g, 5.4 mmol), and Xantphos (3.1 g, 5.36 mmol) in 1,4-dioxane (180 mL) was stirred at 100 °C under N protection for 12 h. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give Int-26b (13.0 g, 72.5% yield) as a pale yellow solid. MS (ESI) + )obsd.[(M+H) + ]:335.1.

[0170] Step 3: tert-butyl (5-(benzyloxy)-2-chloro-4-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)(hydroxy)methyl)pyridin-3-yl)carbamate To a solution of Int-26b (5.4 g, 16.13 mmol) in tetrahydrofuran (50 mL), n-BuLi (14.19 mL, 35.48 mmol) was added dropwise at −78° C. The mixture was then stirred at −78° C. for 1 hour. A solution of 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde (4.8 g, 19.35 mmol) in tetrahydrofuran (15 mL) was added dropwise to the above mixture at −78° C. The mixture was then stirred at −78° C. for an additional 0.5 hour. After completion, the reaction mixture was quenched with saturated ammonium chloride (40 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound Int-26c (5.0 g, 53.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:583.2.

[0171] Step 4: tert-butyl (5-(benzyloxy)-2-chloro-4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)pyridin-3-yl)carbamate To a solution of compound Int-26c (5.0 g, 8.58 mmol) in DCM (50 mL) was added DMP (4.36 g, 10.29 mmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound Int-26d (2.0 g, 40.1% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:581.3.

[0172] Step 5: tert-butyl (5-(benzyloxy)-4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-2-methylpyridin-3-yl)carbamate A mixture of compound Int-26d (1.6 g, 2.75 mmol), CsCO (1.79 g, 5.51 mmol), trimethylboroxine (1.57 mL, 5.51 mmol), and Pd(dppf)Cl (201.49 mg, 0.28 mmol) in 1,4-dioxane (30 mL) was stirred at 100 °C for 2 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound Int-26e (1.1 g, 68.1% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:561.3.

[0173] Step 6: tert-butyl (4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-5-hydroxy-2-methylpyridin-3-yl)carbamate A mixture of compound Int-26e (1.05 g, 1.87 mmol) and Pd / C (210 mg, 10% purity) in EtOAc (20 mL) was stirred under a H balloon for 2 h at 25 °C. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-60%) to give compound Int-26 (700.0 mg, 83.4% yield) as a yellow solid. MS (ESI) + ) and observed by [(M+H) + ]:471.2.

[0174] Intermediate 27: tert-butyl (2-chloro-5-(methoxymethyl)pyridin-3-yl)carbamate TIFF2026507114000107.tif39170 Step 1: (5-Bromo-6-chloropyridin-3-yl)methanol To a solution of methyl 5-bromo-6-chloronicotinate (2.0 g, 7.98 mmol) in tetrahydrofuran (20 mL) was added diisobutylaluminum hydride (19.96 mL, 19.96 mmol) at -78 °C. The reaction was stirred at 0 °C for 1 h. After completion, the mixture was quenched with hydrochloric acid (3 M, 20 mL) at 0 °C and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give Int-27a (1.5 g, 84.4% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:223.9.

[0175] Step 2: 3-Bromo-2-chloro-5-(methoxymethyl)pyridine To a solution of Int-27a (1.5 g, 6.74 mmol) in THF (20 mL), NaH (350.61 mg, 8.77 mmol) was added portionwise at 0 °C, and the mixture was stirred at 0 °C for 30 min. Iodomethane (0.63 mL, 10.11 mmol) was then added to the above mixture at 0 °C, and the mixture was stirred at 25 °C for an additional 1 h. After completion, the mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give Int-27b (1.5 g, crude) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:237.9.

[0176] Step 3: tert-butyl (2-chloro-5-(methoxymethyl)pyridin-3-yl)carbamate A mixture of compound Int-27b (1.55 g, 6.55 mmol), CsCO (6.41 g, 19.66 mmol), tert-butyl carbamate (767.82 mg, 6.55 mmol), Pd(dba) (0.6 g, 0.66 mmol), and Xantphos (0.38 g, 0.66 mmol) in 1,4-dioxane (1 mL) was stirred at 100 °C for 12 h. After completion, the suspension was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NHHCO as an additive) to give Int-27 (470.0 mg, 26.3% yield) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:273.1.

[0177] Example 001: 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000111.tif44170 Step 1: tert-Butyl N-[5-chloro-2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-3-pyridyl]carbamate TIFF2026507114000112.tif44170 To a solution of compound Int-2 (4.9 g, 15.9 mmol) in THF (50 mL) was added NaH (60%, 794.0 mg, 19.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. n-BuLi (2.0 M in cyclohexane, 9.3 mL) was added dropwise to the mixture at -78 °C, and the mixture was stirred at -78 °C for another 30 minutes. Then, a solution of compound Int-1 (4.1 g, 13.2 mmol) in THF (50 mL) was added to the mixture at -78 °C. The mixture was slowly warmed to 25 °C and stirred for an additional 1 hour. Upon completion, the mixture was poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (eluted with EtOAc: PE = 0-10%) to give compound 001a (2.5 g, 40.0% yield) as a yellow oil. + )obsd.[(M+H) + ]:475.1.

[0178] Step 2: (3-amino-5-chloro-2-pyridyl)-(7-fluoro-1H-indazol-4-yl)methanone A mixture of compound 001a (1.6 g, 3.4 mmol) in DCM (15 mL) and TFA (2.6 mL, 33.7 mmol) was stirred at 25 °C for 2 h. After completion, the mixture was concentrated in vacuo to give crude compound 001b (0.98 g, 100% yield) as a yellow solid, which was used in the next step without further purification. MS (ESI) + )obsd.[(M+H) + ]:290.9.

[0179] Step 3: 2-chloro-N-[5-chloro-2-(7-fluoro-1H-indazole-4-carbonyl)-3-pyridyl]acetamide To a solution of compound 001b (980.0 mg, 3.4 mmol) in DCM (10 mL) and DMF (10 mL) was added TEA (0.94 mL, 6.7 mmol) and chloroacetyl chloride (0.30 mL, 3.7 mmol) dropwise. The mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated in vacuo to afford crude compound 001c (1.3 g, 100% yield) as a yellow oil, which was used in the next step without further purification. MS (ESI) + )obsd.[(M+H) + ]:367.0.

[0180] Step 4: 7-Chloro-4-(7-fluoro-1H-indazol-4-yl)-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride A solution of crude compound 001c (1.3 g, 3.4 mmol) in pyridine (10 mL) was stirred at 120° C. for 5 hours. After completion, the mixture was concentrated in vacuo to give crude compound 001d (1.3 g, 100% yield) as a brown oil, which was used in the next step without further purification. MS (ESI) + )obsd.[(M-Cl)+]:392.0.

[0181] Step 5: 3-Amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000116.tif44170 A mixture of compound 001d (1.31 g, 3.37 mmol) and hydrazine monohydrate (1.6 mL, 33.7 mmol) in ethanol (10 mL) was stirred at 70 °C for 2 h. After completion, the mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (NH3 addition) to give Example 001 (453 mg, 40.8% yield) as a yellow solid. MS (ESI) +)obsd.[(M+H) + ]:330.0.

[0182] Example 1: 1 H NMR (400MHz, DMSO-d6)δppm 13.62(brs, 1H), 12.25(brs, 1H), 8.13(d, J=2.25Hz, 1H), 7.63(d, J=2.25Hz, 2H) , 7.28(dd, J=11.07, 7.94Hz, 1H), 7.00(dd, J=7.75, 4.13Hz, 1H), 5.44(brs, 2H). 19 F NMR (376MHz, DMSO-d6)δppm-132.64(s, 1F).

[0183] The following Examples 002-006 were prepared in a manner similar to the procedure described for the preparation of Example 001, with compound Int-2 in Step 1 being replaced with HALOCPD as shown in Table 1. [Table 1] TIFF2026507114000118.tif162170

[0184] Example 007: 4-[7-amino-8-(7-fluoro-1H-indazol-4-yl)-6-oxo-5H-1,5-naphthyridin-3-yl]-N,N-dimethylbenzamide To a solution of Example 001 (30.0 mg, 91.0 μmol) in 1,4-dioxane (2.0 mL) and HO (0.2 mL) was added 4-(N,N-dimethylaminocarbonyl)phenylboronic acid (21.1 mg, 109.2 μmol), tribasic potassium phosphate (48.3 mg, 227.5 μmol), and 1,1′-bis(di-t-butylphosphino)ferrocenepalladium dichloride (5.9 mg, 9.1 μmol). The mixture was stirred at 100° C. for 2 hours. Upon completion, the mixture was filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (FA as an additive) to give Example 007 (10.0 mg, 24.8% yield) as a yellow powder. MS (ESI) + )obsd.[(M+H) + ]:443.1.

[0185] Example 7: 1 H NMR (400MHz, DMSO-d6)δppm 13.63(brs, 1H), 12.22(brs, 1H), 8.51(d, J=1.88Hz, 1H), 7.85(d, J=1.88Hz, 1H), 7.71(d, J=8.25Hz, 2H), 7.52(d, J=8 .13Hz, 2H), 7.30(dd, J=10.94, 7.94Hz, 1H), 7.04(dd, J=7.69, 4.06Hz, 1H), 5.41(brs, 2H), 2.99(s, 3H), 2.96(s, 3H). 19 F NMR (376MHz, DMSO-d6)δppm-132.81(s, 1F).

[0186] Following a procedure similar to that described for the preparation of Example 007, the following Examples 008-014 were prepared, substituting BORONICCPD as shown in Table 2 for the compound 4-(N,N-dimethylaminocarbonyl)phenyl-boronic acid. [Table 2] TIFF2026507114000121.tif255170TIFF2026507114000122.tif181170

[0187] Example 015: 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000123.tif44170 Step 1: tert-Butyl N-[5-cyclopropyl-2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-3-pyridyl]carbamate A mixture of compound 001a (300.0 mg, 0.63 mmol), cyclopropylboronic acid (108.53 mg, 1.26 mmol, 2.0 eq), Pd(dppf)Cl2 (46.22 mg, 0.06 mmol), and K2CO3 (174.6 mg, 1.26 mmol) in 1,4-dioxane (6 mL) was stirred at 100 °C for 12 h under N2 protection. After completion, the mixture was diluted with water (10 mL) and extracted with EtOAc (7 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound 015a (300.0 mg, 98.8% yield) as a white solid. MS(ESI + )obsd.[(M+H-Me) + ]:481.3.

[0188] Step 2: (3-amino-5-cyclopropylpyridin-2-yl)(7-fluoro-1H-indazol-4-yl)methanone The title compound TIFF2026507114000125.tif44170 was prepared in a similar manner to the preparation of compound 001b, substituting compound 015a for compound 001a. Compound 015b (120.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:297.1.

[0189] Step 3: 2-chloro-N-[5-cyclopropyl-2-(7-fluoro-1H-indazole-4-carbonyl)-3-pyridyl]acetamide The title compound was prepared in a similar manner to the preparation of compound 001c, substituting compound 015b for compound 001b. Compound 015c (110.0 mg, crude) was obtained as a gray solid. MS (ESI + )obsd.[(M+H) + ]:373.1.

[0190] Step 4: 7-chloro-4-(7-fluoro-1H-indazol-4-yl)-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride The title compound was prepared similarly to the preparation of compound 001d, replacing compound 001c with compound 015c. Compound 015d (80.0 mg, crude) was obtained as a black solid. MS (ESI + )obsd.[(M-Cl) + ]:398.1.

[0191] Step 5: 3-Amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000128.tif44170 was prepared in a manner similar to the preparation of Example 001, substituting compound 015d for compound 001d in step 5. Example 115 (80.0 mg, crude) was obtained as a pale red solid. MS (ESI + )obsd.[(M+H) + ]:336.2.

[0192] Example 015: 1H NMR (400MHz, DMSO-d6) δ ppm 13.60(brs, 1H), 12.00(brd, J=5.6Hz, 1H), 7.98(d, J=2.0Hz, 1H), 7.59(s, 1H), 7.27(dd, J=7.6, 10.8Hz, 1H), 7.22(d, J =2.0Hz, 1H), 6.98(dd, J=4.4, 7.6Hz, 1H), 5.14(s, 2H), 2.00-1.91(m, 1H), 1.02-0.96(m, 2H), 0.67-0.65-0.96(m, 2H). 19 F NMR(376MHz, DMSO-d6)δ ppm-132.931

[0193] Prepare the following Examples 016-018 by a similar procedure to that described in the preparation of Example 015, except that in Step 1, compound 001a is replaced with an intermediate, cyclopropylboronic acid is replaced with a tail, and the intermediates and tails are as shown in Table 3. [Table 3] TIFF2026507114000130.tif18170

[0194] Example 019: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-morpholino-1H-1,5-naphthyridin-2-one TIFF2026507114000131.tif49170 Step 1: tert-Butyl N-[2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-5-morpholino-3-pyridyl]carbamate A mixture of compound 001a (200.0 mg, 0.42 mmol), RuPhos-Pd-G4 (35.81 mg, 0.04 mmol), morpholine (36.69 mg, 0.42 mmol), and t-BuONa (0.42 mL, 0.84 mmol) in 1,4-dioxane (2 mL) was stirred at 90 °C for 6 h under N2 protection. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-40%) to give compound 019a (120.0 mg, 54.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:526.5.

[0195] Step 2: (3-amino-5-morpholino-2-pyridyl)-(7-fluoro-1H-indazol-4-yl)methanone The title compound TIFF2026507114000133.tif49170 was prepared in a similar manner to the preparation of compound 001b, substituting compound 019a for compound 001a. Compound 019b (120.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:342.1.

[0196] Step 3: 2-chloro-N-[2-(7-fluoro-1H-indazole-4-carbonyl)-5-morpholino-3-pyridyl]acetamide The title compound TIFF2026507114000134.tif49170 was prepared in a similar manner to the preparation of compound 001c, substituting compound 019b for compound 001b. Compound 019c (80.0 mg, crude) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:418.1.

[0197] Step 4: 4-(7-Fluoro-1H-indazol-4-yl)-7-morpholino-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride The title compound was prepared similarly to the preparation of compound 001d, replacing compound 001c with compound 019c. Compound 019d (70.0 mg, crude) was obtained as a black solid. MS (ESI + )obsd.[(M-Cl) + ]:443.3.

[0198] Step 5: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-morpholino-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000136.tif49170 was prepared in a manner similar to the preparation of Example 001, substituting Compound 019d for Compound 001d in Step 5. Example 019 (29.7 mg) was obtained as a pale red solid. MS (ESI + )obsd.[(M+H) + ]:381.1.

[0199] Example 019: 1 H NMR (400MHz, DMSO-d6) δ ppm 8.04(d, J=2.4Hz, 1H), 7.60(d, J=3.2Hz, 1H), 7.27(dd, J=8.0, 11.6Hz, 1H), 7.05(d, J=2. 8Hz, 1H), 6.99(dd, J=4.4, 8.0Hz, 1H), 4.89(s, 2H), 3.78-3.72(m, 4H), 3.14-3.08(m, 4H). 19 F NMR(376MHz, DMSO-d6)δ ppm-132.876.

[0200] Example 020: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(1-hydroxy-1-methylethyl)-1H-1,5-naphthyridin-2-one TIFF2026507114000137.tif49170 Step 1: Ethyl 5-(tert-butoxycarbonylamino)-6-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)pyridine-3-carboxylate A mixture of compound 001a (300.0 mg, 0.63 mmol), Pd(dppf)Cl2 (46.22 mg, 0.06 mmol, 0.1 eq), and TEA (0.18 mL, 1.26 mmol) in ethyl alcohol (29.1 mg, 0.63 mmol) was stirred at 80 °C under a CO atmosphere (50 psi) for 12 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound 020a (320.0 mg, 98.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H)+]:513.3.

[0201] Step 2: Ethyl 5-amino-6-(7-fluoro-1H-indazole-4-carbonyl)pyridine-3-carboxylate The title compound was prepared in a similar manner to the preparation of compound 001b, substituting compound 020a for compound 001a. Compound 020b (200.0 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:329.0.

[0202] Step 3: Ethyl 5-[(2-chloroacetyl)amino]-6-(7-fluoro-1H-indazole-4-carbonyl)pyridine-3-carboxylate The title compound TIFF2026507114000140.tif49170 was prepared in a similar manner to the preparation of compound 001c, substituting compound 020b for compound 001b. Compound 020c (210.0 mg, crude) was obtained as a brown solid. MS (ESI + )obsd.[(M+H)+ ]:405.0.

[0203] Step 4: Ethyl 8-(7-fluoro-1H-indazol-4-yl)-6-oxo-7-pyridin-1-ium-1-yl-5H-1,5-naphthyridine-3-carboxylate; chloride The title compound was prepared similarly to the preparation of compound 001d, replacing compound 001c with compound 020c. Compound 020d (70.0 mg, crude) was obtained as a black solid. MS (ESI + )obsd.[(M-Cl) + ]:430.0.

[0204] Step 5: Ethyl 7-amino-8-(7-fluoro-1H-indazol-4-yl)-6-oxo-5H-1,5-naphthyridine-3-carboxylate The title compound, TIFF2026507114000142.tif49170, was prepared in a manner similar to the preparation of Example 001, substituting compound 020d for compound 001d in step 5. Compound 020e (97.0 mg) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:368.1.

[0205] Step 6: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(1-hydroxy-1-methylethyl)-1H-1,5-naphthyridin-2-one To a solution of compound 020e (40.0 mg, 0.11 mmol) in THF (3 mL) was added methylmagnesium bromide (0.36 mL, 1.09 mmol) under a nitrogen atmosphere at 0° C., and the mixture was then stirred at 0° C. for 2 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride (5 mL), and the resulting mixture was extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by preparative HPLC (NH3 added) and lyophilized to give Example 020 (8.2 mg, 0.02 mmol, 20.76% yield) as a light gray solid. MS (ESI) + )obsd.[(M+H) + ]:354.3 Example 020: 1 H NMR (400MHz, MeOD-d4) δ ppm 8.31(d, J=2.0Hz, 1H), 7.84(d, J=2.0Hz, 1H), 7.64(d, J=2.8Hz, 1H), 7.29(dd, J=7.6, 10.8Hz, 1H), 7.12(dd, J=4.0, 8.0Hz, 1H), 1.57(s, 6H). 19 F NMR (376MHz, MeOD-d4)δ ppm-134.560.

[0206] Example 021: 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000144.tif44170 Step 1: tert-Butyl N-[2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-5-methyl-3-pyridyl]carbamate The title compound TIFF2026507114000145.tif44170 was prepared in a similar manner to the preparation of compound 001a, substituting compound Int-3 for compound Int-2. Compound 021a (400 mg) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:455.2.

[0207] Step 2: (3-amino-5-methyl-2-pyridyl)-(7-fluoro-1H-indazol-4-yl)methanone The title compound was prepared in a similar manner to the preparation of compound 001b, substituting compound 021a for compound 001a. Compound 021b (400 mg) was obtained as a white solid. MS (ESI) + )obsd.[(M+H) + ]:271.1.

[0208] Step 3: (3-amino-6-bromo-5-methyl-2-pyridyl)-(7-fluoro-1H-indazol-4-yl)methanone To a mixture of compound 021b (400.0 mg, 1.5 mmol) in DMF (5 mL) was added NBS (263.0 mg, 1.5 mmol). The reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by preparative HPLC (TFA as an additive) and lyophilized to give compound 021c (340.0 mg, 65.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:349.0.

[0209] Step 4: N-[6-bromo-2-(7-fluoro-1H-indazole-4-carbonyl)-5-methyl-3-pyridyl]-2-chloroacetamide The title compound was prepared in a similar manner to the preparation of compound 001c, substituting compound 021c for compound 001b. Compound 021d (420.0 mg, crude) was obtained as a gray solid. MS (ESI + )obsd.[(M+H) + ]:425.1.

[0210] Step 5: 6-Bromo-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride The title compound TIFF2026507114000149.tif49170 was prepared in a similar manner to the preparation of compound 001d, substituting compound 021d for compound 001c. Compound 021e (400.0 mg, crude) was obtained as a brown solid. MS (ESI + )obsd.[(M-Cl) + ]:451.9.

[0211] Step 6: 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one The title compound TIFF2026507114000150.tif44170 was prepared in a manner similar to the preparation of Example 001, substituting Compound 021e for Compound 001d in Step 5. Example 021 (190.0 mg) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:388.0. Example 021: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.65(s, 1H), 12.25(s, 1H), 7.66(s, 1H), 7.51(s, 1H), 7.30(dd, J=8.0, 11.2Hz, 1H), 7.02(dd, J=4.0, 7.6Hz, 1H), 5.40(s, 2H), 2.31(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.42(s, 1F).

[0212] Example 022: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(4-methylpiperazin-1-yl)-1H-1,5-naphthyridin-2-one A mixture of Example 021 (50.0 mg, 0.13 mmol), 1-methylpiperazine (19.4 mg, 0.19 mmol), t-BuONa (0.64 mL, 1.3 mmol), and CPhos-Pd-G3 (10.4 mg, 0.01 mmol) in 1,4-dioxane (1 mL) was stirred at 100 °C for 2 h under N2 protection. After completion, the reaction mixture was poured into saturated ammonium chloride (15 mL), and the resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue that was purified by preparative HPLC (NH3 added) and lyophilized to give Example 022 (8.1 mg, 15.3% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:408.2.

[0213] Example 022: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.49(s, 1H), 11.94(s, 1H), 7.59(d, J=3.2Hz, 1H), 7.35(s, 1H), 7.27(dd, J=8.0, 11.2Hz, 1 H), 7.08(dd, J=4.0, 7.6Hz, 1H), 5.14(s, 2H), 2.64-2.59(m, 4H), 2.23(s, 7H), 2.09(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.96(s, 1F).

[0214] The following Examples 023-031 were prepared in an analogous manner to the procedure described for the preparation of Example 022, substituting the amines shown in Table 4 for 1-methylpiperazine. [Table 4] TIFF2026507114000153.tif255170TIFF2026507114000154.tif255170TIFF2026507114000155.tif36170

[0215] Example 032: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methyl-butyl)-7-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000156.tif44170 Step 1: [3-amino-6-(3-hydroxy-3-methyl-but-1-ynyl)-5-methyl-2-pyridyl]-(7-fluoro-1H-indazol-4-yl)methanone A mixture of compound 021c (150.0 mg, 0.43 mmol), 2-methyl-3-butyn-2-ol (144.6 mg, 1.7 mmol), TEA (2.0 mL, 14.4 mmol), Pd(PPh)Cl (15.1 mg, 0.02 mmol), and CuI (8.2 mg, 0.04 mmol) in THF (2 mL) was stirred at 60 °C for 12 h under N protection. After completion, the reaction mixture was quenched with saturated ammonium chloride (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-40%) to give compound 032a (120.0 mg, 79.3% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:353.2.

[0216] Step 2: 2-chloro-N-[2-(7-fluoro-1H-indazole-4-carbonyl)-6-(3-hydroxy-3-methyl-but-1-ynyl)-5-methyl-3-pyridyl]acetamide The title compound was prepared in a manner similar to that used to prepare compound 001c, substituting compound 032a for compound 001b. Compound 032b (140.0 mg, crude) was obtained as a brown solid. MS (ESI) + )obsd.[(M+H) + ]:429.1.

[0217] Step 3: 1-(4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-7-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-3-yl)pyridin-1-ium chloride The title compound was prepared in a manner similar to that used to prepare compound 001d, substituting compound 032b for compound 001c. Compound 032c (150.0 mg, crude) was obtained as a brown solid. MS (ESI) + )obsd.[(M-Cl) + ]:454.0.

[0218] Step 4: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methylbutyl)-7-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000160.tif44170 A mixture of compound 032c (300 mg, 0.05 mmol) and hydrazine monohydrate (1 mL) in ethanol (5 mL) was stirred at 70 °C for 2 hours. After completion, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were concentrated in vacuo to give a residue, which was purified by preparative HPLC (NH4HCO3 added) and lyophilized to give Example 032 (6.9 mg, 3.5% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:396.1.

[0219] Example 032: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.56(s, 1H), 11.99(s, 1H), 7.56(s, 1H), 7.33(s, 1H), 7.27(dd, J=8.0, 11.2Hz, 1H), 7.04(dd, J=4.4, 8.0Hz, 1H) , 5.11(s, 2H), 4.01(s, 1H), 2.53(t, J=8.4Hz, 2H), 2.28(s, 3H), 1.39(t, J=8.4Hz, 2H), 0.94(s, 3H), 0.91(s, 3H). 19F NMR (376MHz, DMSO-d6)δ ppm-133.04(s, 1F). Example 033: 3-amino-4-(1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000161.tif44170

[0220] Step 1: tert-butyl N-[2-(7-fluoro-1H-indazole-4-carbonyl)-5-methyl-3-pyridyl]carbamate To a solution of Int-3 (785.9 mg, 2.7 mmol) in THF (5 mL) was added n-BuLi (2.3 mL, 5.8 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 30 min. Next, a solution of 1H-indazole-4-carbaldehyde (200.0 mg, 1.4 mmol) in THF (5 mL) was added dropwise to the above mixture at −78° C., and the mixture was stirred at −78° C. for another 30 min. After completion, the reaction was quenched with saturated ammonium chloride (5 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give compound 033a (238.0 mg, 24.7% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:355.2.

[0221] Step 2: tert-butyl N-[2-(1H-indazole-4-carbonyl)-5-methyl-3-pyridyl]carbamate To a solution of compound 033a (630.0 mg, 1.7 mmol) in DCM (3 mL) was added DMP (904.8 mg, 2.1 mmol). The mixture was stirred at 25 °C for 1 h. After completion, the mixture was quenched with saturated sodium sulfite (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound 033b (605.0 mg, 96.0% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:353.2.

[0222] Step 3: (3-amino-5-methylpyridin-2-yl)(1H-indazol-4-yl)methanone The title compound TIFF2026507114000164.tif39170 was prepared in a similar manner to the preparation of compound 001b, substituting compound 033b for compound 001a. Compound 033c (380.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:253.1.

[0223] Step 4: 2-chloro-N-[2-(1H-indazole-4-carbonyl)-5-methyl-3-pyridyl]acetamide The title compound TIFF2026507114000165.tif49170 was prepared in a similar manner to the preparation of compound 001c, substituting compound 033c for compound 001b. Compound 033d (350.0 mg, crude) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:329.1.

[0224] Step 5: 4-(1H-indazol-4-yl)-7-methyl-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride The title compound TIFF2026507114000166.tif44170 was prepared in a similar manner to the preparation of compound 001d, substituting compound 033d for compound 001c. Compound 033e (345.0 mg, crude) was obtained as a black solid. MS (ESI + )obsd.[(M-Cl) + ]:354.1.

[0225] Step 6: 3-amino-4-(1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one The title compound, TIFF2026507114000167.tif44170, was prepared in a manner similar to the preparation of Example 001, substituting Compound 033e for Compound 001d in Step 5. Example 033 (68.7 mg) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:292.1. Example 033: 1 H NMR (400MHz, DMSO-d6) δ ppm 7.98(s, 1H), 7.57-7.55(d, J=8.0Hz, 1H), 7.50(s, 1H), 7.47-7.43(m, 1H), 7.41(s, 1H), 7.05-7.03(m, 1H), 5.03(s, 2H), 2.30(s, 3H).

[0226] Example 034: 3-amino-7-cyclopropyl-4-(1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000168.tif44170

[0227] Step 1: tert-butyl N-[5-chloro-2-[hydroxy(1H-indazol-4-yl)methyl]-3-pyridyl]carbamate The title compound TIFF2026507114000169.tif44170 was prepared in a similar manner to the preparation of compound 033a, substituting compound Int-2 for compound Int-3. Compound 034a (3.0 g) was obtained as a white solid. MS (ESI +)obsd.[(M+H) + ]:375.1.

[0228] Step 2: tert-butyl N-[5-chloro-2-(1H-indazole-4-carbonyl)-3-pyridyl]carbamate The title compound was prepared in a similar manner to the preparation of compound 033b, substituting compound 034a for compound 033a. Compound 034b (940.0 mg) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:373.1.

[0229] Step 3: tert-butyl (5-chloro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)pyridin-3-yl)carbamate A mixture of compound 034b (200.0 mg, 0.54 mmol), dihydropyran (0.98 mL, 10.7 mmol), and TsOH (9.2 mg, 0.05 mmol) in DCM (2.5 mL) and THF (2.5 mL) was stirred at 25 °C for 12 h. After completion, the mixture was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-10%) to give compound 034c (200.0 mg, 81.6% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:457.2.

[0230] Step 4: tert-butyl N-[5-cyclopropyl-2-(1-tetrahydropyran-2-ylindazole-4-carbonyl)-3-pyridyl]carbamate A mixture of compound 034c (100.0 mg, 0.22 mmol), cyclopropylboronic acid (75.2 mg, 0.88 mmol), Pd(dppf)Cl2 (16.01 mg, 0.02 mmol), and K2CO3 (120.99 mg, 0.88 mmol, 4.0 eq) in 1,4-dioxane (1 mL) was stirred at 100 °C for 12 h under N2 protection. After completion, the mixture was poured into water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-10%) to give compound 034d (80.0 mg, 79% yield) as a yellow solid. MS(ESI + )obsd.[(M+H) + ]:463.3.

[0231] Step 5: (3-Amino-5-cyclopropyl-2-pyridyl)-(1H-indazol-4-yl)methanone The title compound TIFF2026507114000173.tif44170 was prepared in a manner similar to the preparation of compound 001b, substituting compound 034d for compound 001a. Compound 034e (380.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:279.1.

[0232] Step 6: 2-chloro-N-[5-cyclopropyl-2-(1H-indazole-4-carbonyl)-3-pyridyl]acetamide The title compound TIFF2026507114000174.tif49170 was prepared in a manner similar to the preparation of compound 001c, substituting compound 034e for compound 001b. Compound 034f (120.0 mg, crude) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:355.1.

[0233] Step 7: 7-Cyclopropyl-4-(1H-indazol-4-yl)-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride The title compound TIFF2026507114000175.tif44170 was prepared in a manner similar to the preparation of compound 001d, substituting compound 034f for compound 001c. Compound 034e (345.0 mg, crude) was obtained as a black solid. MS (ESI + )obsd.[(M-Cl) + ]:380.2.

[0234] Step 8: 3-Amino-7-cyclopropyl-4-(1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one The title compound, TIFF2026507114000176.tif44170, was prepared in a manner similar to the preparation of Example 001, substituting Compound 034e for Compound 001d in Step 5. Example 034 (68.7 mg) was obtained as a white solid. MS (ESI + )obsd.[(M+H) + ]:318.1.

[0235] Example 034: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.06(s, 1H), 11.99(s, 1H), 7.98(d, J=2.0Hz, 1H), 7.56(d, J=8.4Hz, 1H), 7.52-7.41(m, 2H), 7. 25-7.21(m, 1H), 7.04(d, J=6.8Hz, 1H), 2.02-1.89(s, 1H), 1.04-0.95(m, 2H), 0.71-0.64(s, 2H).

[0236] Example 035: 3-amino-4-(1H-indazol-4-yl)-7-thiazol-2-yl-1H-1,5-naphthyridin-2-one The title compound, TIFF2026507114000177.tif44170, was prepared in a manner similar to the preparation of Example 034, substituting tetrabutyl(thiazol-2-yl)tin for cyclopropylboronic acid in step 4. Example 035 (9.3 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:361.1.

[0237] Example 035: 1 H NMR (400MHz, DMSO-d6) δ ppm 12.87(s, 1H), 8.52(d, J=1.6Hz, 1H), 8.43(s, 1H), 8.00(d, J=3.2Hz, 1H), 7.90 (d, J=2.8Hz, 1H), 7.76-7.67(m, 2H), 7.58-7.51(m, 1H), 7.15(d, J=6.8Hz, 1H).

[0238] Example 036: 3-amino-7-chloro-4-(6-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000178.tif44170

[0239] Step 1: 6-Fluoro-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole A mixture of 4-bromo-6-fluoro-1-tetrahydropyran-2-yl-indazole (500 mg, 1.7 mmol), bis(pinacolato)diboron (488.0 mg, 1.9 mmol), AcOK (492 mg, 5.0 mmol), and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (124.0 mg, 0.17 mmol) in 1,4-dioxane (8 mL) was stirred under N protection at 100 °C for 4 h. After completion, the mixture was diluted with EtOAc (50 mL) and washed with water and brine. The organic layer was concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-12%) to give compound 036a (350.0 mg, 60% yield) as a yellow oil. + )obsd.[(M+H) + ]:347.1.

[0240] Step 2: 3-amino-7-chloro-4-(6-fluoro-1-tetrahydropyran-2-yl-indazol-4-yl)-1H-1,5-naphthyridin-2-one A mixture of compound 036a (37.8 mg, 109.3 μmol), CsCO (89.0 mg, 273.2 μmol), Pd(dtbpf)Cl (7.1 mg, 10.9 μmol), and compound Int-10 (30.0 mg, 109.3 μmol) in 1,4-dioxane (4 mL) and water was stirred at 90 °C under a N atmosphere for 1 h. After completion, the resulting mixture was quenched with water and extracted with DCM / MeOH (9 / 1, 20 mL × 3). The combined organic layers were concentrated in vacuo to give crude compound 036b (50 mg, 49% purity, 54% yield), which was used in the next step without further purification. MS (ESI) + )obsd.[(M+H) + ]:414.0.

[0241] Step 3: 3-amino-7-chloro-4-(6-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one To a solution of compound 036b (50 mg, 49% purified, 59.3 μmol) in DCM (10 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 4 hours. After completion, the mixture was concentrated in vacuo to give a crude residue, which was purified by preparative HPLC (NH3 as an additive) to give Example 036 (1.0 mg, 2.4% yield) as a white powder. MS (ESI) + )obsd.[(M+H) + ]:330.0.

[0242] Example 036: 1 H NMR (500MHz, DMSO-d6) δ ppm 13.13(s, 1H), 12.29(brs, 1H), 8.16(d, J=2.3Hz, 1H), 7.63(d, J=2.3Hz, 1H) , 7.56(s, 1H), 7.36-7.32(m, 1H), 6.93(dd, J=2.1, 9.9Hz, 1H), 5.59(s, 2H). 19 F NMR (471MHz, DMSO-d6)δ ppm-115.97(s, 1F).

[0243] In a manner similar to the procedure described in the preparation of Example 036, by replacing 4-bromo-6-fluoro-1-tetrahydropyran-2-yl-indazole with the head shown in Table 5 in Step 1, the following Examples 037 to 043 were prepared. [Table 5] TIFF2026507114000183.tif253170TIFF2026507114000184.tif43170

[0244] Example 044: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-piperazin-1-yl-1H-1,5-naphthyridin-2-one TIFF2026507114000185.tif44170

[0245] Step 1: tert-butyl 4-(7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-2-yl)piperazine-1-carboxylate The title compound TIFF2026507114000186.tif44170 was prepared in a manner similar to the preparation of Example 022, substituting 1-Boc-piperazine for compound 1-methylpiperazine to afford compound 044a (20.0 mg, crude) as a yellow oil. MS (ESI + )obsd.[(M+H) + ]:494.4

[0246] Step 2: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(piperazin-1-yl)-1,5-naphthyridin-2(1H)-one A mixture of compound 044a (20.0 mg, 0.04 mmol) in HCl / EtOAc (1.0 mL, 4 M) was stirred at 25° C. for 1 hour. After completion, the mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC (NH as an additive) and lyophilized to give Example 044 (2.0 mg, 12.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:394.3.

[0247] Example 044: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.57(s, 1H), 11.92(s, 1H), 7.60(d, J=3.2Hz, 1H), 7.35(s, 1H), 7.27(dd, J=8.0, 11 .2Hz, 1H), 7.08(dd, J=4.0, 7.6Hz, 1H), 5.12(s, 2H), 2.62-2.54(m, 8H), 2.23(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.96(s, 1F). Example 045: 3-amino-7-chloro-4-(3-methyl-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000188.tif44170

[0248] Step 1: 3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbaldehyde To a mixture of compound 4-bromo-3-methyl-1-tetrahydropyran-2-yl-indazole (2.0 g, 6.8 mmol) in THF (20 mL) was added n-BuLi (3.0 mL, 7.5 mmol) at −78° C., and the mixture was stirred at −78° C. for 0.5 h. DMF (2.6 mL, 33.9 mmol) was then added to the mixture, and the mixture was stirred at 25° C. for an additional 1 h. After completion, the mixture was quenched with saturated aqueous NH4Cl (40 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 5-50%) to give compound 045a (1.4 g, 84.3% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:245.1.

[0249] Step 2: tert-butyl (5-chloro-2-(hydroxy(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methyl)pyridin-3-yl)carbamate To a solution of Int-2 (475.0 mg, 1.5 mmol) in tetrahydrofuran (5 mL) was added NaH (67.5 mg, 1.7 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 min. Then, n-BuLi (0.68 mL, 1.7 mmol) was added dropwise at -78 °C and stirred for an additional 30 min. Next, a solution of 045a (300.0 mg, 1.2 mmol) in tetrahydrofuran (2 mL) was added to the mixture, and the mixture was stirred at -78 °C for an additional 30 min. After completion, the mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give 045b (550.0 mg, 1.16 mmol, 77.3% yield) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:473.2.

[0250] Step 3: tert-butyl (5-chloro-2-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)pyridin-3-yl)carbamate A mixture of compound 045b (850.0 mg, 1.8 mmol) and DMP (1.0 g, 5.39 mmol) in DCM (15 mL) was stirred at 25 °C for 6 h. After completion, the mixture was quenched with saturated aqueous sodium sulfite (30 mL) and saturated aqueous Na2CO3 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 5-40%) to give compound 045c (730.0 mg, 86.1% yield) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:471.2.

[0251] Step 4: (3-amino-5-chloropyridin-2-yl)(3-methyl-1H-indazol-4-yl)methanone The title compound was prepared similarly to the preparation of compound 001b, replacing compound 001a with compound 045c. Compound 045d (420.0 mg, crude) was obtained as a yellow oil. MS (ESI + )obsd.[(M+H) + ]:287.0.

[0252] Step 5: 2-chloro-N-(5-chloro-2-(3-methyl-1H-indazole-4-carbonyl)pyridin-3-yl)acetamide The title compound TIFF2026507114000193.tif49170 was prepared in a manner similar to the preparation of compound 001c, substituting compound 045d for compound 001b. Compound 045e (540 mg, crude) was obtained as a brown oil. MS (ESI + )obsd.[(M+H) + ]:363.0.

[0253] Step 6: 1-(7-chloro-4-(3-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydro-1,5-naphthyridin-3-yl)pyridin-1-ium chloride The title compound TIFF2026507114000194.tif44170 was prepared in a manner similar to the preparation of compound 001d, substituting compound 045e for compound 001c. Compound 045f (440.0 mg, crude) was obtained as a brown oil. MS (ESI + )obsd.[(M-Cl) + ]:388.1.

[0254] Step 7: 3-amino-7-chloro-4-(3-methyl-1H-indazol-4-yl)-1,5-naphthyridin-2(1H)-one The title compound TIFF2026507114000195.tif44170 was prepared in a manner similar to the preparation of Example 001 in Step 5, substituting compound 045f for compound 001d. Compound 045 (270.0 mg) was obtained as a brown solid. MS (ESI + )obsd.[(M+H) + ]:326.1. Example 045: 1 H NMR (400MHz, DMSO+D2O) δ ppm 8.12(d, J=2.4Hz, 1H), 7.70(d, J=2.0Hz, 1H), 7.55-7.49(m, 1H), 7.48-7.39(m, 1H), 6.88(d, J=6.4Hz, 1H), 1.79(s, 3H).

[0255] Prepare the following Examples 046-057 by a procedure similar to that described for the preparation of Example 045, except that in Step 2, Int-2 was replaced with HALOCPD as shown in Table 6, and compound 045a was replaced with 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde. [Table 6] TIFF2026507114000197.tif253170TIFF2026507114000198.tif254170TIFF2026507114000199.tif253170TIFF2026507114000200.tif45170

[0256] Example 058: 1-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxymethyl]cyclopropanecarbonitrile TIFF2026507114000201.tif44170

[0257] Step 1: tert-butyl (6-((1-cyanocyclopropyl)methoxy)-2-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-5-methylpyridin-3-yl)carbamate A mixture of Int-13 (50.0 mg, 0.11 mmol), 1-(bromomethyl)cyclopropanecarbonitrile (34.01 mg, 0.21 mmol), and K2CO3 (44.32 mg, 0.32 mmol) in DMF (2 mL) was stirred at 80 °C for 2 h. After completion, the mixture was poured into water (10 mL), and the suspension was collected by filtration. The filter cake was washed with water (30 mL) and concentrated under reduced pressure to give compound 058a (50.0 mg, 81.8% yield) as a pale yellow oil. MS (ESI) + )obsd.[(M+H) + ]:550.2.

[0258] Step 2: 1-(((5-amino-6-(7-fluoro-1H-indazole-4-carbonyl)-3-methylpyridin-2-yl)oxy)methyl)cyclopropane-1-carbonitrile The title compound TIFF2026507114000203.tif44170 was prepared in a similar manner to the preparation of compound 001b, substituting compound 058a for compound 001a. Compound 058b (30.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:366.2.

[0259] Step 3: 2-chloro-N-(6-((1-cyanocyclopropyl)methoxy)-2-(7-fluoro-1H-indazole-4-carbonyl)-5-methylpyridin-3-yl)acetamide The title compound was prepared in a similar manner to the preparation of compound 001c, substituting compound 058b for compound 001b. Compound 058c (35.0 mg, crude) was obtained as a black solid. MS (ESI + )obsd.[(M+H)+ ]:442.1.

[0260] Step 4: 1-[[8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-7-pyridin-1-ium-1-yl-5H-1,5-naphthyridin-2-yl]oxymethyl]cyclopropanecarbonitrile; chloride The title compound TIFF2026507114000205.tif44170 was prepared in a similar manner to the preparation of compound 001d, substituting compound 058c for compound 001c. Compound 058d (30.0 mg) was obtained as a brown solid. MS (ESI + )obsd.[(M-Cl) + ]:467.3.

[0261] Step 5: 1-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxymethyl]cyclopropanecarbonitrile The title compound of TIFF2026507114000206.tif44170 was prepared in a manner similar to the preparation of Example 001 in Step 5, substituting Compound 058d for Compound 001d. Example 058 (5.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:405.2.

[0262] Example 058: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.61(s, 1H), 12.04(s, 1H), 7.65(d, J=2.4Hz, 1H), 7.44(s, 1H), 7.29(dd, J=8.4, 10.8Hz, 1H), 7.07(dd, J=4.4, 8 .0Hz, 1H), 5.25(s, 2H), 3.84-3.76(m, 2H), 2.19(s, 3H), 1.05-0.98(m, 2H), 0.57-0.53(m, 1H), 0.42-0.38(m, 1H). 19 F NMR (400MHz, DMSO-d6)δ ppm-132.66(s, 1F).

[0263] The following Examples 059 to 068 were prepared by procedures similar to those described in the preparation of Example 058, substituting the branch shown in Table 7 for 1-(bromomethyl)cyclopropanecarbonitrile in Step 1. [Table 7] TIFF2026507114000208.tif253170TIFF2026507114000209.tif255170TIFF2026507114000210.tif85170

[0264] Example 069: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(4-piperidyl)-1H-1,5-naphthyridin-2-one TIFF2026507114000211.tif44170

[0265] Step 1: tert-butyl 4-[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate Example 021 (50.0 mg, 0.13 mmol), Pd(dppf)Cl (9.4 mg, 0.01 mmol), KCO (35.6 mg, 0.26 mmol), and 1-N-Boc-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (59.7 mg, 0.19 mmol) were stirred in 1,4-dioxane (1 mL) and water (0.3 mL) under N protection at 80 °C for 2 h. After completion, the mixture was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound 069a (30.0 mg, 47.5% yield) as a yellow solid. MS(ESI + )obsd.[(M+H) + ]:491.4.

[0266] Step 2: tert-butyl 4-[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]piperidine-1-carboxylate A mixture of compound 069a (30.0 mg, 0.06 mmol) and Pd / C (289.72 mg, 10% wt) in 3 mL of EtOAc was stirred under H (15 psi) at 25 °C for 1 h. After completion, the mixture was filtered and the filtrate was concentrated in vacuo to give compound 069b (30.0 mg, 100% yield) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:493.2.

[0267] Step 3: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(4-piperidyl)-1H-1,5-naphthyridin-2-one To a solution of compound 069b (23.0 mg, 0.05 mmol) in EtOAc (0.5 mL) was added EtOAc / HCl (4.0 mL, 16.0 mmol). The mixture was stirred at 25° C. for 3 hours. After completion, the solvent was evaporated and the residue was purified by preparative HPLC (NH3 as an additive) to give Example 069 (12.5 mg, 52.3% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:393.1.

[0268] Example 069: 1 H NMR (400MHz, DMSO-d6) δ ppm 7.57(d, J=3.2Hz, 1H), 7.33-7.31(m, 1H), 7.30-7.22(m, 1H), 7.07(dd, J=4.4, 8.0Hz, 1H), 5.12(s, 2H), 2. 83-2.72(m, 3H), 2.45-2.38(m, 2H), 2.30(s, 3H), 1.42-1.38(m, 1H), 1.32-1.21(m, 2H), 1.15-1.05(m, 1H).19 F NMR (376MHz, DMSO-d6)δ ppm-132.91(s, 1F).

[0269] Example 070: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methyl-but-1-ynyl)-7-methyl-1H-1,5-naphthyridin-2-one A mixture of Example 021 (20.0 mg, 0.05 mmol), 2-methyl-3-butyn-2-ol (17.34 mg, 0.21 mmol), TEA (1.46 mL, 7.19 mmol), Pd(PPh)Cl (1.81 mg), and CuI (0.98 mg, 0.01 mmol) in THF (0.5 mL) was stirred at 60 °C for 12 h under N protection. After completion, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 added) and lyophilized to give Example 070 (6.1 mg, 28.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:392.1.

[0270] Example 070: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.66(s, 1H), 12.12(s, 1H), 7.64(s, 1H), 7.45(s, 1H), 7.30(dd, J=8.0, 11.2Hz, 1H ), 6.97(dd, J=4.0, 7.6Hz, 1H), 5.43(s, 1H), 5.18(s, 2H), 2.36(s, 3H), 1.38(s, 6H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.65(s, 1F).

[0271] By procedures similar to those described in the preparation of Example 071, substituting the alkynes shown in Table 8 for 2-methyl-3-butyn-2-ol, the following Examples 071-077 were prepared. [Table 8] TIFF2026507114000217.tif255170TIFF2026507114000218.tif86170

[0272] Example 078: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(2-hydroxy-2-methylpropoxy)-7-methyl-1H-1,5-naphthyridin-2-one To a solution of Example 061 (20.0 mg, 0.05 mmol) in THF (1 mL) under N2 atmosphere at 0 °C, methylmagnesium bromide (0.16 mL, 0.49 mmol) was added, and the mixture was stirred at 0 °C for 2 h. After completion, the reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 added) and lyophilized to give Example 078 (8.0 mg, 40.5% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:398.3.

[0273] Example 078: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.57(s, 1H), 11.98(s, 1H), 7.63(d, J=2.0Hz, 1H), 7.39(s, 1H), 7.28(dd, J=7.6, 10.4Hz, 1H), 7.07(dd, J= 4.0, 7.6Hz, 1H), 5.16-5.15(m, 2H), 4.31(s, 1H), 3.54-3.41(m, 2H), 2.17(s, 3H), 0.97(s, 3H), 0.94(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.90(s, 1F).

[0274] Example 079: 3-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxy]cyclobutanecarbonitrile A mixture of Example 021 (100.0 mg, 0.26 mmol), 3-hydroxycyclobutanecarbonitrile (50.0 mg, 0.52 mmol), BNMO (9.49 mg, 0.03 mmol), CuI (4.9 mg, 0.03 mmol), and t-BuONa (1.3 mL, 2.6 mmol) in 1,4-dioxane (1 mL) was stirred under N protection at 60° C. for 12 hours. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (NH4HCO3 added) and lyophilized to give Example 079 (15.2 mg, 13.9% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:405.1.

[0275] Example 079: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.62(brs, 1H), 12.00(brs, 1H), 7.63(t, J=3.2Hz, 1H), 7.40(d, J=3.6Hz, 1H ), 7.33-7.26(m, 1H), 7.08-7.01(m, 1H), 5.19(d, J=11.6Hz, 2H), 4.65-4.61(m , 0.5H), 4.37-4.29(m, 0.5H), 3.15-3.07(m, 0.5H), 2.81-2.72(m, 0.5H), 2.3 7-2.19(m, 1.5H), 2.16-2.09(m, 4H), 2.02-1.96(m, 1H), 1.83-1.76(m, 0.5H). 19 F NMR (400MHz, DMSO-d6) δ ppm -132.59(s, 0.5F), -132.77(s, 0.5F).

[0276] Example 080: trans-3-amino-6-(3-fluorocyclobutoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000221.tif44170

[0277] Step 1: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-iodo-7-methyl-1H-1,5-naphthyridin-2-one A mixture of Example 021 (600.0 mg, 1.55 mmol), NaI (463.4 mg, 3.1 mmol), N1,N2-dimethylethane-1,2-diamine (68.1 mg, 0.77 mmol), and CuI (147.2 mg, 0.77 mmol) in 1,4-dioxane (10 mL) was stirred at 110 °C for 3 h under N2 protection. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 25-70%) to give compound 080a (300.0 mg, 44.6% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:436.1.

[0278] Step 2: trans-3-amino-6-(3-fluorocyclobutoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one A mixture of compound 080a (50.0 mg, 0.11 mmol), 3-fluorocyclobutanol (20.7 mg, 0.23 mmol), BNMO (4.23 mg, 0.01 mmol), t-BuONa (0.57 mL, 1.15 mmol), and CuI (2.19 mg, 0.01 mmol) in 1,4-dioxane (1 mL) was stirred at 60 °C for 12 h under N protection. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue which was purified by preparative HPLC (NH4HCO3 added) and lyophilized to give Example 080 (1.6 mg, 3.2% yield) as an off-white solid. MS (ESI) + )obsd.[(M+H) + ]:398.2.

[0279] Example 080: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.58(s, 1H), 11.99(s, 1H), 7.61(s, 1H), 7.39(s, 1H), 7.29(dd, J=8.0, 11.2Hz, 1H), 7.03(dd, J=4.0, 7. 6Hz, 1H), 5.22-5.09(m, 2.5H), 5.02-4.97(m, 0.5H), 4.66-4.56(m, 1H), 2.13(s, 3H), 2.09-1.95(m, 4H). 19 F NMR (400MHz, DMSO-d6) δ ppm -132.97(s, 1F), -176.79(s, 1F).

[0280] Example 081: 3-amino-6-(3,3-difluoropropoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000224.tif44170

[0281] Step 1: tert-butyl N-[2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-6-(3-hydroxypropoxy)-5-methyl-3-pyridyl]carbamate A mixture of Int-13 (500.0 mg, 1.06 mmol), 3-iodopropanol (790.6 mg, 4.3 mmol), and KCO (587.5 mg, 4.3 mmol) in DMF (5 mL) was stirred at 100 °C for 2 h. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 081a (560.0 mg, 100% yield) as a pale yellow oil. MS (ESI) + )obsd.[(M+H) + ]:529.2.

[0282] Step 2: tert-butyl N-[2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-5-methyl-6-(3-oxopropoxy)-3-pyridyl]carbamate A mixture of compound 081a (560.0 mg, 1.06 mmol) and DMP (674.06 mg, 1.59 mmol) in DCM (6 mL) was stirred at 25 °C for 1 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with EtOAc: PE = 0-15%) to give compound 081b (150.0 mg, 26.9% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:527.3.

[0283] Step 3: tert-butyl N-[6-(3,3-difluoropropoxy)-2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-5-methyl-3-pyridyl]carbamate A mixture of compound 081b (170.0 mg, 0.32 mmol) and BAST (0.6 mL, 3.23 mmol) in DCM (5 mL) was stirred at 0 °C for 1 h. After completion, the reaction mixture was quenched with saturated sodium bicarbonate (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (eluted with EtOAc: PE = 0-10%) to give compound 081c (50.0 mg, 28.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:549.4.

[0284] Step 4: [3-amino-6-(3,3-difluoropropoxy)-5-methyl-2-pyridyl]-(7-fluoro-1H-indazol-4-yl)methanone The title compound TIFF2026507114000228.tif44170 was prepared in a similar manner to the preparation of compound 001b, substituting compound 081c for compound 001a. Compound 081d (28.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:365.2.

[0285] Step 5: 2-chloro-N-[6-(3,3-difluoropropoxy)-2-(7-fluoro-1H-indazole-4-carbonyl)-5-methyl-3-pyridyl]acetamide The title compound TIFF2026507114000229.tif49170 was prepared in a similar manner to the preparation of compound 001c, substituting compound 081d for compound 001b. Compound 081e (27.0 mg, crude) was obtained as a black solid. MS (ESI +)obsd.[(M+H) + ]:441.2.

[0286] Step 6: 6-(3,3-difluoropropoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride The title compound TIFF2026507114000230.tif49170 was prepared in a similar manner to the preparation of compound 001d, substituting compound 081e for compound 001c. Compound 081f (30 mg) was obtained as a brown solid. MS (ESI + )obsd.[(M-Cl) + ]:466.3.

[0287] Step 7: 3-amino-6-(3,3-difluoropropoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000231.tif44170 was prepared in a manner similar to the preparation of Example 001 in Step 5, substituting Compound 081f for Compound 001d. Example 081 (4.9 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:404.0.

[0288] Example 081: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.58(s, 1H), 12.01(s, 1H), 7.64(s, 1H), 7.41(s, 1H), 7.27(dd, J=8.0, 10.8Hz, 1H), 7.07(dd, J=4 .0, 8.0Hz, 1H), 6.07-5.66(m, 1H), 5.19(s, 2H), 3.94-3.72(m, 2H), 2.14(s, 3H), 1.99-1.88(m, 2H). 19 F NMR (400MHz, DMSO-d6) δ ppm -115.78(s, 2F), -132.87(s, 1F).

[0289] Example 082: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(1-methyl-4-piperidyl)-1H-1,5-naphthyridin-2-one TIFF2026507114000232.tif44170

[0290] Step 1: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000233.tif441701-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (43.1 mg, 0.19 mmol), K2CO3 (35.6 mg, 0.26 mmol), Example 021 (50.0 mg, 0.13 mmol), and Pd(dppf)Cl2 (9.4 mg, 0.01 mmol) were stirred in 1,4-dioxane (1 mL) and water (0.30 mL) under N2 protection at 80 °C for 2 hours. Upon completion, the reaction mixture was evaporated in vacuo to give a residue, which was purified by preparative HPLC (NH4HCO3 as additive) and lyophilized to give compound 082a (35.0 mg, 67.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:405.4.

[0291] Step 2: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(1-methyl-4-piperidyl)-1H-1,5-naphthyridin-2-one A mixture of compound 082a (25.0 mg, 0.06 mmol) and Pd / C (30.0 mg, 10 wt% on carbon) in ethyl acetate (1 mL) was stirred under H (15 psi) at 25 °C for 12 h. Upon completion, the suspension was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (NHHCO as additive) and lyophilized to give Example 082 (10.4 mg, 39.8% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:407.2.

[0292] Example 082: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.57(s, 1H), 11.99(s, 1H), 7.55(d, J=3.2Hz, 1H), 7.32(s, 1H), 7.28(dd, J=7.6, 11.2Hz, 1H), 7.06(dd, J=4.4 , 8.0Hz, 1H), 5.13(s, 2H), 2.64-2.58(m, 2H), 2.30(s, 3H), 2.03(s, 3H), 1.86-1.75(m, 2H), 1.40-1.21(m, 5H). 19 F NMR (400MHz, DMSO-d6)δ ppm-132.95(s, 1F).

[0293] Example 083: 7-amino-8-(7-fluoro-1H-indazol-4-yl)-2,3-dimethyl-5H-pyrido[2,3-b]pyrazin-6-one TIFF2026507114000235.tif44170

[0294] Step 1: 3-Amino-N-methoxy-N,5,6-trimethylpyrazine-2-carboxamide To a solution of N,O-dimethylhydroxylamine hydrochloride (2.5 g, 25.4 mmol) in THF (30 mL), LiHMDS (50.8 mL, 50.8 mmol) was added dropwise at 0 °C. After 30 min, methyl 3-amino-5,6-dimethylpyrazine-2-carboxylate (2.3 g, 12.7 mmol) in THF (20 mL) was added dropwise to the above mixture at 0 °C. The mixture was then warmed to 20 °C and stirred for 0.5 h. After completion, the mixture was quenched by the slow addition of saturated ammonium chloride (30 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-50%) to give compound 083a (1.07 g, 40.1% yield) as an off-white solid. MS (ESI) + )obsd.[(M+H) + ]:211.2.

[0295] Step 2: (3-amino-5,6-dimethylpyrazin-2-yl)(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanone To a solution of 4-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.8 g, 6.02 mmol) in THF (20 mL) was added n-BuLi (2.89 mL, 7.22 mmol) dropwise at −78° C. under a N atmosphere. The mixture was then stirred at −78° C. for 0.5 h. Then, a solution of compound 083a (1.01 g, 4.8 mmol) in THF (10 mL) was added dropwise to the above mixture at −78° C. and stirred at −78° C. for another 0.5 h. After completion, the reaction mixture was quenched with saturated ammonium chloride (30 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 30-50%) to give compound 083b (145.0 mg, 6.5% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:370.2.

[0296] Step 3: 2-chloro-N-(3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-5,6-dimethylpyrazin-2-yl)acetamide To a solution of compound 083b (50.0 mg, 0.14 mmol) and TEA (0.08 mL, 0.54 mmol) in chloroform (1.5 mL) at 0° C., chloroacetyl chloride (0.02 mL, 0.27 mmol) was added dropwise. The mixture was then stirred at 20° C. for 1 hour. Upon completion, the mixture was concentrated in vacuo to afford compound 083c (50.0 mg, crude) as a light gray solid, which was used directly in the next step. MS (ESI) + )obsd.[(M-THP+H)+]:362.0.

[0297] Step 4: 8-(7-Fluoro-1-tetrahydropyran-2-yl-indazol-4-yl)-2,3-dimethyl-7-pyridin-1-ium-1-yl-5H-pyrido[2,3-b]pyrazin-6-one; chloride A solution of compound 083c (50.0 mg, 0.11 mmol) in pyridine (2.5 mL) was stirred at 70 °C for 12 hours. The mixture was concentrated under reduced pressure to give compound 083d (40.0 mg, 70.4% yield) as a black solid, which was used directly in the next step. MS (ESI) + )obsd.[(M-Cl) + ]:471.4.

[0298] Step 5: 7-amino-8-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2,3-dimethylpyrido[2,3-b]pyrazin-6(5H)-one TIFF2026507114000240.tif44170 A solution of compound 083d (90.0 mg, 0.18 mmol) and hydrazine hydrate (0.5 mL, 85% purity) in ethanol (1 mL) was stirred at 50 °C for 12 h. After completion, the reaction mixture was poured into water (4 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 added) and lyophilized to give compound 083e (30.0 mg, 41.4% yield) as a light brown solid. MS (ESI) + )obsd.[(M+H) + ]:409.3.

[0299] Step 6: 7-Amino-8-(7-fluoro-1H-indazol-4-yl)-2,3-dimethyl-5H-pyrido[2,3-b]pyrazin-6-one A solution of compound 083e (30.0 mg, 0.07 mmol) in TIFF2026507114000241.tif44170 HCl / EA (2.0 mL, 4 M) was stirred at 25 °C for 1 hour. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 as additive) and lyophilized to give Example 083 (2.1 mg, 8.2% yield) as a white solid. MS (ESI + )obsd.[(M+H) + ]:325.0.

[0300] Example 083: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.63(s, 1H), 7.66(d, J=0.8Hz, 1H), 7.29(dd, J=7.6, 10.8Hz, 1H), 7.02(dd, J=4.0, 7.6Hz, 1H), 5.38(s, 2H), 2.44(s, 3H), 2.23(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.60(s, 1F).

[0301] Example 084: 7-amino-8-(7-fluoro-1H-indazol-4-yl)-2,4-dimethyl-5H-pyrido[3,2-d]pyrimidin-6-one TIFF2026507114000242.tif49170 The title compound was prepared in a manner similar to the preparation of Example 083, substituting methyl 5-amino-2,6-dimethyl-pyrimidine-4-carboxylate for methyl 3-amino-5,6-dimethylpyrazine-2-carboxylate in Step 1. Example 084 (4.9 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:325.2.

[0302] Example 084: 1H NMR (400MHz, DMSO-d6) δ ppm 13.62(s, 1H), 11.70(s, 1H), 7.66(d, J=2.4Hz, 1H), 7.28(dd, J=11.2, 7.6H z, 1H), 6.99(dd, J=7.6, 4.0Hz, 1H), 5.82(s, 2H), 2.60(s, 3H), 2.26(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.69(s, 1F).

[0303] Example 085: 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000243.tif44170

[0304] Step 1: (3-amino-6-bromo-5-cyclopropylpyridin-2-yl)(7-fluoro-1H-indazol-4-yl)methanone A mixture of compound 015b (340.0 mg, 1.2 mmol) and NBS (214.0 mg, 1.2 mmol) in DMF (3 mL) was stirred at 25 °C for 1 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 added) and lyophilized to give compound 085a (210.0 mg, 48.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:375.0.

[0305] Step 2: N-(6-bromo-5-cyclopropyl-2-(7-fluoro-1H-indazole-4-carbonyl)pyridin-3-yl)-2-chloroacetamide The title compound TIFF2026507114000245.tif49170 was prepared in a similar manner to the preparation of compound 001c, substituting compound 085a for compound 001b. Compound 085b (220.0 mg) was obtained as a brown oil. MS (ESI + )obsd.[(M+H) + ]:451.0.

[0306] Step 3: 6-Bromo-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride The title compound TIFF2026507114000246.tif49170 was prepared in a manner similar to the preparation of compound 001d, substituting compound 085b for compound 001c. Compound 085c (200 mg, crude) was obtained as a brown oil. MS (ESI + )obsd.[(M-Cl) + ]:478.0.

[0307] Step 4: 3-Amino-6-bromo-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1,5-naphthyridin-2(1H)-one The title compound, TIFF2026507114000247.tif44170, was prepared in a manner similar to the preparation of Example 001 in Step 5, substituting compound 085c for compound 001d. Compound 085d (200.0 mg, crude) was obtained as a brown oil. MS (ESI + )obsd.MS(ESI + )obsd.[(M+H) + ]:414.2.

[0308] Step 5: 3-Amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1,5-naphthyridin-2(1H)-one TIFF2026507114000248.tif44170 A mixture of compound 085d (60.0 mg, 0.14 mmol), trimethylboroxine (0.05 mL, 0.16 mmol), Pd(dppf)Cl (10.6 mg, 0.01 mmol), and KCO (40.04 mg, 0.29 mmol) in 1,4-dioxane (3 mL) was stirred at 100 °C for 12 hours under N protection. Upon completion, the mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NHHCO as an additive) and lyophilized to give Example 085 (28.3 mg, 54.1% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:350.3.

[0309] Example 085: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.61(s, 1H)11.95(s, 1H), 7.62(s, 1H), 7.29(dd, J=11.2, 8.0Hz, 1H), 7.21(s, 1H), 7.01(dd, J=7.6, 4.0Hz , 1H), 4.49-5.57(m, 2H), 2.33(s, 3H) 1.91-1.95(m, 1H) 0.97(dd, J=8.4, 1.8Hz, 2H), 0.57(d, J=3.6Hz, 2H). 19 F NMR (377MHz, DMSO-d6)δ ppm-132.91(m, 1F).

[0310] Example 086: 3-amino-6-[3-(dimethylamino)propyl]-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one A mixture of Example 075 (50.0 mg, 0.13 mmol) and Pd / C (24 mg, 10% purity) in methanol (4 mL) was stirred at rt under an atmosphere of H (15 psi) for 0.5 h. Upon completion, the mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (NHHCO as an additive) and lyophilized to give Example 086 (40.0 mg, 79.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:395.2.

[0311] Example 086: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.57(brs, 1H), 11.99(brs, 1H), 7.56(d, J=3.4Hz, 1H), 7.33(s, 1H), 7.26(d, J=19.2Hz, 1H), 7.03(dd, J=4.0 , 8.0Hz, 1H), 5.11(s, 2H), 2.46-2.39(m, 1H), 2.26(s, 3H), 2.00-1.95(m, 2H), 1.90(s, 6H), 1.46-1.38(m, 2H). 19 F NMR (376MHz, DMSO-d6)δ ppm-133.086(s, 1F).

[0312] Example 087: Methyl 7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridine-2-carboxylate A mixture of Example 021 (100.0 mg, 0.26 mmol), Pd(dppf)Cl (37.7 mg, 0.05 mmol), and TEA (0.07 mL, 0.52 mmol) in methanol (2 mL) was stirred at 80 °C under a CO (50 psi) atmosphere for 12 hours. After completion, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (HCl as additive) and lyophilized to give Example 087 (47.0 mg, 44.1% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:368.2.

[0313] Example 087: 1 H NMR (400MHz, DMSO-d6) δ ppm 12.32(s, 1H), 7.65(d, J=3.2Hz, 1H), 7.49(s, 1H), 7.29(dd, J=8.0, 11.2Hz, 1H), 7.03(dd, J=4.4, 8.0Hz, 1H), 3.65(s, 3H), 2.41(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.57(s, 1F).

[0314] Example 088: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(1-hydroxy-1-methylethyl)-7-methyl-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000251.tif44170 was prepared similarly to the preparation of Example 078, substituting Example 087 for Example 061. Example 088 (10.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:368.3.

[0315] Example 089: 1H NMR (400MHz, MeOD-d4) δ ppm 7.95(s, 1H), 7.93(d, J=3.2Hz, 1H), 7.31(dd, J=8.0, 10.8Hz, 1H), 7.07(dd, J=4.0, 7.6Hz, 1H), 2.59(s, 3H), 1.62(s, 3H), 1.53(s, 3H). 19 F NMR (376MHz, MeOD-d4)δ ppm-130.91(s, 1F).

[0316] Example 089: 7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridine-2-carboxylic acid TIFF2026507114000252.tif44170 A mixture of Example 087 (6.0 mg, 0.01 mmol) and NaOH (0.5 mL, 2.0 mmol) in methanol (1 mL) and water (1 mL) was stirred at 25°C for 1 hour. After completion, the mixture was acidified with HCl (1M) to a pH of 3. The mixture was then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl as additive) and lyophilized to give Example 089 (5.2 mg, 91.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:354.2. Example 089: 1 H NMR (400MHz, DMSO-d6) δ ppm 12.39(s, 1H), 7.68(d, J=3.2Hz, 1H), 7.52(s, 1H), 7.31(dd, J=8.0, 11.2Hz, 1H), 7.07(dd, J=4.0, 8.0Hz, 1H), 2.48(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.24(s, 1F).

[0317] Example 090: 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000253.tif49170

[0318] Step 1: (3-amino-4-chloropyridin-2-yl)(7-fluoro-1-tosyl-1H-indazol-4-yl)methanone To a solution of (3-amino-4-chloro-2-pyridyl)-(7-fluoro-1H-indazol-4-yl)methanone (150.0 mg, 0.52 mmol) in THF (10 mL) was added NaH (22.7 mg, 0.57 mmol) at 0 °C. After stirring at 0 °C for 30 min, a solution of p-toluenesulfonyl chloride (103.3 mg, 0.54 mmol) in THF (2 mL) was added dropwise to the mixture at 0 °C. The mixture was then warmed to 25 °C and stirred for an additional 1 h. Upon completion, the reaction mixture was quenched with saturated sodium bicarbonate (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with EtOAc: PE = 0-50%) to give compound 090a (150.0 mg, 65.34% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:445.1.

[0319] Step 2: (3-amino-6-bromo-4-chloropyridin-2-yl)(7-fluoro-1-tosyl-1H-indazol-4-yl)methanone A mixture of compound 090a (140.0 mg, 0.31 mmol) and NBS (67.21 mg, 0.38 mmol) in DMF (1 mL) was stirred at 50 °C for 4 h. After completion, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-80%) to give compound 090b (160.0 mg, 97.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:523.2.

[0320] Step 3: (3-amino-4-chloro-6-methylpyridin-2-yl)(7-fluoro-1-tosyl-1H-indazol-4-yl)methanone A mixture of compound 090b (145.0 mg, 0.28 mmol), trimethylboroxine (0.12 mL, 0.42 mmol), Pd(dppf)Cl2 (20.26 mg, 0.03 mmol), and K2CO3 (76.52 mg, 0.55 mmol) in 1,4-dioxane (10 mL) was stirred at 80 °C for 12 h. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-80%) to give compound 090c (120.0 mg, 94.5% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:459.2

[0321] Step 4: 2-chloro-N-(4-chloro-2-(7-fluoro-1-tosyl-1H-indazole-4-carbonyl)-6-methylpyridin-3-yl)acetamide The title compound was prepared in a similar manner to the preparation of compound 001c, substituting compound 090c for compound 001b. Compound 090d (110 mg, crude) was obtained as a black solid. MS (ESI) + )obsd.[(M+H) + ]:535.1.

[0322] Step 5: 8-chloro-4-[7-fluoro-1-(p-tolylsulfonyl)indazol-4-yl]-6-methyl-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride The title compound was prepared in a similar manner to the preparation of compound 001d, substituting compound 090d for compound 001c. Compound 090e (120 mg, crude) was obtained as a black solid. MS (ESI) + )obsd.[(M-Cl) + ]:560.1.

[0323] Step 6: 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000259.tif49170 A mixture of compound 090e (120.0 mg, 0.2 mmol) and hydrazine monohydrate (1.0 mL) in ethanol (1 mL) was stirred at 50 °C for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 as additive) and lyophilized to give Example 090 (27.0 mg, 37.8% yield) as a brown solid. MS (ESI) + )obsd.[(M+H) + ]:344.2.

[0324] Example 090: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.60(brs, 1H), 11.61(brs, 1H), 7.64(s, 1H), 7.28(dd, J=8.0, 10.8Hz, 1H), 7.22(s, 1H), 7.00(dd, J=4.0, 7.6Hz, 1H), 5.43(s, 2H), 2.19(s, 3H). 19 F NMR (400MHz, DMSO-d6)δ ppm-132.76(s, 1F).

[0325] Example 091: 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000260.tif49170

[0326] Step 1: (3-amino-4-methylpyridin-2-yl)(7-fluoro-1H-indazol-4-yl)methanone A solution of compound Int-21 (400.0 mg, 0.88 mmol) in HCl / EA (6.0 mL, 4 M) was stirred at 25° C. for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to give compound 091a (210.0 mg, 88.0% yield) as a yellow solid. MS (ESI+) obsd. [(M+H) + ]:271.2.

[0327] Step 2: (3-amino-4-methylpyridin-2-yl)(7-fluoro-1-tosyl-1H-indazol-4-yl)methanone The title compound TIFF2026507114000262.tif49170 was prepared in a manner similar to that used to prepare compound 090a, substituting (3-amino-4-chloro-2-pyridyl)-(7-fluoro-1H-indazol-4-yl)methanone for compound 091a. Compound 091b (100.0 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:425.2.

[0328] Step 3: (3-amino-6-chloro-4-methylpyridin-2-yl)(7-fluoro-1-tosyl-1H-indazol-4-yl)methanone A mixture of compound 091b (50.0 mg, 0.12 mmol) and NCS (17.3 mg, 0.13 mmol) in DMF (1 mL) was stirred at 80 °C for 0.5 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (6 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NHHCO) and lyophilized to give compound 091c (20.0 mg, 37.0% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) +]:459.3.

[0329] Step 4: 2-chloro-N-(6-chloro-2-(7-fluoro-1-tosyl-1H-indazole-4-carbonyl)-4-methylpyridin-3-yl)acetamide The title compound TIFF2026507114000264.tif49170 was prepared in a similar manner to the preparation of compound 001c, substituting compound 091c for compound 001b. Compound 091d (15.0 mg, crude) was obtained as a brown solid. MS (ESI + )obsd.[(M+H) + ]:535.2.

[0330] Step 5: 6-chloro-4-[7-fluoro-1-(p-tolylsulfonyl)indazol-4-yl]-8-methyl-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride The title compound TIFF2026507114000265.tif49170 was prepared in a similar manner to the preparation of compound 001d, substituting compound 091d for compound 001c. Compound 091e (16.0 mg, crude) was obtained as a brown solid. MS (ESI + )obsd.[(M-Cl) + ]:560.2.

[0331] Step 6: 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one The title compound was prepared in a manner similar to the preparation of Example 090, substituting Compound 091e for Compound 090e in Step 6. Example 091 (6.4 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H) + ]:344.1.

[0332] Example 091: 1H NMR (400MHz, DMSO-d6) δ ppm 13.64(s, 1H), 11.63(brs, 1H), 7.66(d, J=1.2Hz, 1H), 7.26-7.33(m, 1H), 7.11(s, 1H), 6.99(dd, J=7.6, 4.4Hz, 1H)5.47(s, 2H)2.48(s, 3H). 19 F NMR (377MHz, DMSO-d6)δ ppm-132.57(s, 1F).

[0333] Example 092: 7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridine-2-carbonitrile TIFF2026507114000267.tif44170

[0334] Step 1: (3-amino-6-bromo-5-methyl-2-pyridyl)-[7-fluoro-1-(p-tolylsulfonyl)indazol-4-yl]methanone The title compound TIFF2026507114000268.tif44170 was prepared in a manner similar to that used to prepare compound 090a, substituting compound 021c for (3-amino-4-chloro-2-pyridyl)-(7-fluoro-1H-indazol-4-yl)methanone. Compound 092a (500.0 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:503.2.

[0335] Step 2: 5-amino-6-[7-fluoro-1-(p-tolylsulfonyl)indazole-4-carbonyl]-3-methylpyridine-2-carbonitrile A mixture of compound 092a (500.0 mg, 0.99 mmol), DPPF (110.1 mg, 0.2 mmol), Zn(CN) (350.0 mg, 3.0 mmol), Pd(PPh) (229.6 mg, 0.2 mmol), and Zn (130.0 mg, 2.0 mmol) in DMA (10 mL) was stirred at 100 °C for 2 h under N protection. After completion, the reaction mixture was quenched with saturated sodium sulfite (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-100%) to give compound 092b (100.0 mg, 22.4% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:450.1.

[0336] Step 3: 2-chloro-N-[6-cyano-2-[7-fluoro-1-(p-tolylsulfonyl)indazole-4-carbonyl]-5-methyl-3-pyridyl]acetamide The title compound was prepared in a manner similar to that used to prepare compound 001c, substituting compound 092b for compound 001b. Compound 092c (110.0 mg, crude) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:526.3.

[0337] Step 4: 8-(7-Fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-7-pyridin-1-ium-1-yl-5H-1,5-naphthyridine-2-carbonitrile; chloride A mixture of compound 092c (110.0 mg, 0.21 mmol) in pyridine (3.0 mL) was stirred at 50° C. for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure to give compound 092d (90.0 mg, crude) as a brown solid. MS (ESI)+ ) is unclear. [(M-Cl) + ]:397.2.

[0338] Step 5: 7-Amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridine-2-carbonitrile TIFF2026507114000272.tif44170 Compound 092d (90.0 mg, 0.21 mmol) and hydrazine monohydrate (0.1 mL, 98% purity) were dissolved in ethanol (1 mL) and stirred at 50°C for 1 hour. After completion, the mixture was poured into water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (HCl as additive) and lyophilized to give Example 092 (11.2 mg, 13.4% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:335.0.

[0339] Example 092: 1 H NMR (400MHz, DMSO-d6)δ ppm 12.52(s, 1H), 7.67(d, J=3.2Hz, 1H), 7.56(s, 1H), 7.31(dd, J=7.6, 10.8Hz, 1H), 7.01(dd, J=4.0, 7.6Hz, 1H), 2.46(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.20(s, 1F).

[0340] Example 093: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(oxetan-3-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000273.tif44170 Pyridine-2,6-bis(carboximidamide); hydrogen chloride (257.1 mg, 1.3 mmol), NiCl (66.8 mg, 0.52 mmol), NaI (193.1 mg, 1.3 mmol), 3-bromooxetane (176.4 mg, 1.3 mmol), Example 021 (100.0 mg, 0.26 mmol), and Zn (168.4 mg, 2.6 mmol) were added to DMA (3 mL) at 25 °C with the addition of TFA (25.0 mg, 0.26 mmol). The mixture was then stirred at 60 °C for 16 h. Upon completion, the mixture was poured into water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (NH4HCO3 added) and lyophilized to give Example 093 (2.7 mg, 2.6% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:366.1.

[0341] Example 093: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.57(m, 1H), 12.08(s, 1H), 7.62(s, 1H), 7.37(s, 1H), 7.30(dd, J=8.0, 11.2Hz, 1H), 7.10(dd, J=4.4, 8.0Hz , 1H), 5.23(s, 2H), 4.61-4.55(m, 2H), 4.49-4.47(m, 1H), 4.45-4.42(m, 1H), 4.41-4.35(m, 1H), 2.10(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.88(s, 1F).

[0342] Example 094: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,8-dimethyl-1H-1,5-naphthyridin-2-one A mixture of Example 090 (15.0 mg, 0.04 mmol), trimethylboroxine (0.02 mL, 0.07 mmol), Pd(dppf)Cl (3.19 mg), and KCO (12.06 mg, 0.09 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C under N protection for 2 h. Upon completion, the suspension was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (NHHCO as an additive) and lyophilized to give Example 094 (3.0 mg, 14.7% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:324.1.

[0343] Example 094: 1 H NMR (400MHz, DMSO-d6) δ=13.60(s, 1H), 11.42(s, 1H), 7.59(d, J=3.2Hz, 1H), 7.34-7 .22(m, 1H), 7.01-6.97(m, 1H), 6.90(s, 1H), 5.14(s, 2H), 2.44(s, 3H), 2.16(s, 3H). 19 F NMR(376MHz, DMSO-d6)δ ppm-133.068(s, 1F).

[0344] Example 095: 3-amino-6-chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000275.tif44170

[0345] Step 1: (3-amino-6-chloro-5-cyclopropylpyridin-2-yl)(7-fluoro-1H-indazol-4-yl)methanone To a mixture of compound 015b (350.0 mg, 1.2 mmol) in DMF (2.5 mL) was added NCS (165.6 mg, 1.2 mmol) in portions at 0 °C. The mixture was slowly heated to 50 °C and stirred for 1 h. Upon completion, the reaction mixture was quenched with saturated sodium sulfite (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (with NH4HCO3) and lyophilized to give compound 095a (210.0 mg, 53.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:331.0.

[0346] Step 2: 2-chloro-N-(6-chloro-5-cyclopropyl-2-(7-fluoro-1H-indazole-4-carbonyl)pyridin-3-yl)acetamide The title compound was prepared in a manner similar to that used to prepare compound 001c, substituting compound 095a for compound 001b. Compound 095b (80.0 mg, crude) was obtained as a yellow gum. MS (ESI + )obsd.[(M+H) + ]:407.2.

[0347] Step 3: 6-Chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-3-pyridin-1-ium-1-yl-1H-1,5-naphthyridin-2-one; chloride The title compound was prepared in a manner similar to that used to prepare compound 001d, substituting compound 095b for compound 001c. Compound 095c (70.0 mg, crude) was obtained as a brown solid. MS (ESI + )obsd.[(M-Cl) + ]:432.2.

[0348] Step 4: 3-amino-6-chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one The title compound was prepared in a manner similar to the preparation of Example 001 in Step 5, substituting Compound 095c for Compound 001d. Example 095 (29.3 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M) + ]:370.0.

[0349] Example 095: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.64(s, 1H)12.10(s, H)7.66(s, 1H)7.27-7.34(m, 1H)7.26(s, 1H)7.01(dd, J=7.6, 4.0Hz, 1H)5.39(s, 2H)2.02-2.09(m, 1H)1.04(d, J =6.8Hz, 2H)0.64(d, J=4.0Hz, 2H). 19 F NMR(377MHz, DMSO-d6)δ ppm-132.46(s, 1F).

[0350] Example 096: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-[3-(1-hydroxy-1-methylethyl)cyclobutoxy]-7-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000280.tif44170 The title compound was prepared similarly to the preparation of Example 078, substituting Example 067 for Example 061. Example 096 (20.1 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:438.3.

[0351] Example 096: 1H NMR (400MHz, DMSO-d6) δ ppm 13.55(s, 1H), 11.94(s, 1H), 77.61(s, 1H), 7.36(s, 1H), 7.27(dd, J=11.2, 7.6Hz, 1H), 7.03(dd, J=7.6, 4.4Hz, 1H), 5.14(s, 2H)4.14-4.09(m, 1H)3.99(s, 1H)2.11(s, 3H)1.64-1.55(m, 3H), 1.48-1.36(m, 2H), 0.86(d, J=4.4Hz, 6H). 19 F NMR (376MHz, DMSO-d6)δ ppm-133.23(s, 1F).

[0352] Example 097: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(trifluoromethyl)-1H-1,5-naphthyridin-2-one TIFF2026507114000281.tif44170 Compound 080a (130.0 mg, 0.3 mmol) and (1,10-phenanthroline-κN 1 ,κN 10 A mixture of (trifluoromethyl)copper (184.5 mg, 0.6 mmol) in DMF (3 mL) was stirred at 80° C. for 3 hours. After completion, the reaction mixture was poured into water (40 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 as additive) and lyophilized to give Example 097 (23.3 mg, 18.6% yield) as a gray solid. MS (ESI) + )obsd.[(M+H) + ]:378.0.

[0353] Example 097: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.60(s, 1H), 7.65(d, J=1.2Hz, 1H), 7.57(s, 1H), 7.32-7.26(m, 1H), 7.05(dd, J=4.0, 8.0Hz, 1H), 5.50(s, 2H), 2.43(s, 3H). 19F NMR (376MHz, DMSO-d6) δ ppm -62.83(s, 1F), -132.54(s, 1F).

[0354] Example 098: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(1-methylazetidin-3-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000282.tif44170

[0355] Step 1: tert-butyl 3-(7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-2-yl)azetidine-1-carboxylate The title compound TIFF2026507114000283.tif44170 was prepared in a manner similar to the preparation of Example 093, substituting tert-butyl 3-bromoazetidine-1-carboxylate for 3-bromooxetane. Compound 098a (60.1 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:465.2.

[0356] Step 2: 3-amino-6-(azetidin-3-yl)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1,5-naphthyridin-2(1H)-one A solution of compound 098a (60.1 mg, 0.12 mmol) in TFA (2 mL) was stirred at room temperature for 1 hour. After completion, the solvent was evaporated in vacuo to give a residue, which was purified by preparative HPLC (NH4HCO3 as an additive) to give compound 098b (30.0 mg, 68.4% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:365.1.

[0357] Step 3: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(1-methylazetidin-3-yl)-1H-1,5-naphthyridin-2-one To a solution of compound 098b (30.0 mg, 0.08 mmol), formaldehyde (12.36 mg, 0.41 mmol) in methanol (3 mL) was added NaBHCN (26.28 mg, 0.41 mmol) at 20 °C and stirred for 7 hours. Upon completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NHHCO as an additive) and lyophilized to give Example 098 (10.0 mg, 31.2% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:379.1.

[0358] Example 098: 1 H NMR (400MHz, DMSO-d6) δ ppm 7.61(d, J=3.6Hz, 1H), 7.31(s, 1H), 7.30-7.24(m, 1H), 7.10(dd, J=4.0, 8.0Hz, 1H), 5.22( s, 2H), 3.72-3.64(m, 1H), 3.40-3.37(m, 2H), 2.78-2.70(m, 2H), 2.18(s, 3H), 1.87(s, 3H). 19 F NMR (376MHz, DMSO-d6) δ ppm -73.43(s, 3F), -132.96(s, 1F).

[0359] Example 099: 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000286.tif44170

[0360] Step 1: 5-chloro-2-iodo-4-methyl-3-nitropyridine A mixture of 5-chloro-4-methyl-3-nitro-pyridin-2-amine (10.0 g, 53.3 mmol), CuI (3.1 g, 16.0 mmol), and KI (17.7 g, 106.6 mmol) in DME (60 mL) and toluene (24 mL) was heated to 65 °C under N protection. tert-Butyl nitrite (17.3 mL, 143.9 mmol) was added portionwise over 10 min at 65 °C, and the mixture was stirred at 65 °C for an additional 12 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (50 mL), and the resulting mixture was extracted with ethyl acetate (25 mL × 3). The combined organic layers were washed with brine (70 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound 099a (6.5 g, 40.9% yield) as a pale yellow solid. MS (ESI) + )obsd.[(M+H) + ]:299.1.

[0361] Step 2: (5-chloro-4-methyl-3-nitropyridin-2-yl)(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanol To a solution of compound 099a (4.5 g, 15.1 mmol) in THF (20 mL) was added PhMgBr (3 M, 5.53 mL) under a nitrogen atmosphere at −40° C. Then, a solution of 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbaldehyde (5.2 g, 21.1 mmol) in THF (20 mL) was added to the above mixture at −40° C. The mixture was slowly warmed to RT and stirred for 30 min. After completion, the reaction mixture was quenched with saturated ammonium chloride (30 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (45 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with THF: PE = 0-30%) to give compound 099b (1.6 g, 45.4% yield) as a pale yellow solid. MS (ESI) + )obsd.[(M+H) + ]:421.1.

[0362] Step 3: (5-chloro-4-methyl-3-nitropyridin-2-yl)(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanone TIFF2026507114000289.tif44170 Compound 099b (300.0 mg, 0.71 mmol) and MnO2 (1.24 g, 14.26 mmol) were dissolved in chloroform (4 mL) and stirred at 50 °C for 2 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give compound 099c (290.0 mg, crude) as an orange solid. MS (ESI) + )obsd.[(M-THP+H)+]:335.1.

[0363] Step 4: (3-amino-5-chloro-4-methylpyridin-2-yl)(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanone A mixture of compound 099c (290.0 mg, 0.69 mmol), Fe (386.7 mg, 6.9 mmol), and NH4Cl (370.4 mg, 6.9 mmol) in ethanol (1.5 mL) and water (0.5 mL) was stirred at 80 °C for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with THF; PE = 0-30%) to give compound 099d (130.0 mg, 48.3% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:389.1

[0364] Step 5: (3-amino-5-chloro-4-methylpyridin-2-yl)(7-fluoro-1H-indazol-4-yl)methanone A solution of compound 099d (130.0 mg, 0.33 mmol) in HCl / EA (4 M, 4.0 mL) was stirred at 20° C. for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to give compound 099e (110.0 mg, crude) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:305.2.

[0365] Step 6: 2-chloro-N-(5-chloro-2-(7-fluoro-1H-indazole-4-carbonyl)-4-methylpyridin-3-yl)acetamide The title compound was prepared in a manner similar to that used to prepare compound 001c, substituting compound 099e for compound 001b. Compound 099f (150.0 mg, crude) was obtained as a light gray solid. MS (ESI) + )obsd.[(M+H) + ]:381.0.

[0366] Step 7: 1-(7-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-3-yl)pyridin-1-ium chloride The title compound was prepared in a manner similar to that used to prepare compound 001d, substituting compound 099f for compound 001c. Compound 099g (150.0 mg, crude) was obtained as a black solid. MS (ESI) + )obsd.[(M-Cl) + ]:406.1.

[0367] Step 8: 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1,5-naphthyridin-2(1H)-one The title compound, TIFF2026507114000294.tif49170, was prepared in a manner similar to the preparation of Example 001 in Step 5, substituting Compound 099g for Compound 001d. Example 099 (15.3 mg) was obtained as a pale red solid. MS (ESI + )obsd.[(M+H) + ]:344.0.

[0368] Example 099: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.64(s, 1H), 11.67(s, 1H), 8.12(s, 1H), 7.63(d, J=2.4Hz, 1H), 7.28(dd, J=8.0, 11.2Hz, 1H), 6.98(dd, J=4.4, 8.0Hz, 1H), 2.56(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.66(s, 1F).

[0369] Example 100: 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000295.tif44170 was prepared in a manner similar to the preparation of Example 099, substituting Compound Int-22 for Compound 099c in Step 4. Example 100 (15.3 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:350.0.

[0370] Example 100: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.05(s, 1H), 12.21(s, 1H), 7.85(d, J=3.2Hz, 1H), 7.60(s, 1H), 7.39(dd, J=7.6, 11.2Hz, 1H), 7.09(dd , J=4.4, 8.0Hz, 1H), 6.71(s, 2H), 2.76(s, 3H), 2.07-1.99(m, 1H), 1.03-0.99(m, 2H), 0.69-0.65(m, 2H). 19 F NMR (376MHz, DMSO-d6)δ ppm-130.42(s, 1F).

[0371] Example 101: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(trideuteriomethyl)-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000296.tif49170 was prepared in a manner similar to the preparation of Example 099, substituting Compound Int-23 for Compound 099d in Step 5. Example 101 (6.3 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:326.9.

[0372] Example 101: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.87(s, 1H), 7.86(d, J=3.2Hz, 1H), 7.40(dd, J=7.6, 10.8Hz, 1H), 7.23(dd, J=4.0, 8.0Hz, 1H), 2.67(s, 3H). 19F NMR (376MHz, MeOD-d4)δ ppm-131.47(s, 1F).

[0373] Example 102: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-7-methyl-1H-quinolin-2-one The title compound of TIFF2026507114000297.tif49170 was prepared in a manner similar to the preparation of Example 045, substituting tert-butyl N-3-methoxy-5-methyl-phenyl)carbamate for Int-2 and 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a in step 2. Example 102 (7.7 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:339.1.

[0374] Example 102: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.54(brs, 1H), 11.96(s, 1H), 7.60(d, J=3.6Hz, 1H), 7.21(dd, J=8.0, 11.2Hz, 1H) , 6.84(dd, J=4.0, 8.0Hz, 1H), 6.76(s, 1H), 6.37(s, 1H), 2.98(s, 3H), 2.28(s, 3H). 19 F NMR (377MHz, DMSO-d6)δ ppm-133.94(s, 1F).

[0375] Example 103: 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-quinolin-2-one The title compound of TIFF2026507114000298.tif49170 was prepared in a manner similar to the preparation of Example 045, substituting tert-butyl N-(3-chloro-5-methyl-phenyl)carbamate for Int-2 and 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a in step 2. Example 103 (19.8 mg) was obtained as a yellow solid. MS (ESI +)obsd.[(M+H) + ]:343.1.

[0376] Example 103: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.65(s, 1H), 12.21(s, 1H), 7.68(s, 1H), 7.28-7.23(m, 1H), 7.12(s, 1H), 6.9 1(dd, J=4.4Hz, J=7.6Hz, 1H), 6.87(d, J=1.6Hz, 1H), 4.78(s, 2H), 2.28(s, 3H). 19 F NMR (377MHz, DMSO-d6)δ ppm-132.740(s, 1F).

[0377] Example 104: 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-quinolin-2-one The title compound of TIFF2026507114000299.tif49170 was prepared in a manner similar to the preparation of Example 021, substituting tert-butyl N-(2-bromo-5-methyl-phenyl)carbamate for Int-3 in Step 1. Example 104 (69.5 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:387.0.

[0378] Example 104: 1 H NMR (400MHz, DMSO-d6) δ ppm 7.71(d, J=3.2Hz, 1H), 7.36(dd, J=7.6, 11.2Hz, 1H), 7.24(s, 1H), 7.02(dd, J=4.0, 7.6Hz, 1H), 6.81(s, 1H), 4.99(s, 2H), 2.32(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-131.43(s, 1F).

[0379] Example 105: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-quinolin-2-one A mixture of Example 104 (50.0 mg, 0.13 mmol), 2-oxa-6-azaspiro[3.3]heptane (60.0 mg, 0.61 mmol), t-BuONa (0.8 mL, 0.8 mmol), and CPhos-Pd-G3 (5.2 mg, 0.01 mmol) in degassed 1,4-dioxane (4 mL) was stirred at 100 °C for 12 h under N2 protection. Upon completion, the suspension was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (NH4HCO3 as an additive) to give Example 105 (12.7 mg, 25.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:406.2.

[0380] Example 105: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.78(s, 1H), 11.80(s, 1H), 7.66(d, J=3.2Hz, 1H), 7.36(dd, J=7.6, 11.2Hz, 1H), 7.00(dd, J=4.0, 7.6Hz, 1H), 6.9 7(s, 1H), 5.80(s, 1H), 4.72(s, 2H), 4.59-4.55(m, 4H), 3.68(d, J=7.2Hz, 2H), 3.62(d, J=7.2Hz, 2H), 2.14(s, 3H).

[0381] Example 106: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-1H-quinolin-2-one TIFF2026507114000301.tif49170

[0382] Step 1: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-[1-(2,2,2-trifluoroethyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-quinolin-2-one A mixture of Example 104 (30.0 mg, 0.077 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-3,6-dihydro-2H-pyridine (27.1 mg, 0.093 mmol), Pd(dppf)Cl (6.3 mg, 7.8 μmol), and KCO (32.1 mg, 0.23 mmol) in 1,4-dioxane (3 mL) and water (600 μL) was stirred in a sealed tube under a N atmosphere at 100° C. for 2 hours. Upon completion, the resulting mixture was concentrated to give a residue that was suspended in ethyl acetate and filtered. The filtrate was concentrated to give compound 106a (36.0 mg, 98.6% yield) as a yellow solid, which was used in the next step without purification. + )obsd.[(M+H) + ]:472.4.

[0383] Step 2: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-1H-quinolin-2-one A mixture of compound 106a (36.0 mg, 0.076 mmol) and Pd / C (9 mg) in MeOH (10 mL) was stirred under a H balloon at room temperature for 16 hours. After completion, the resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (FA as an additive) to give Example 106 (4.3 mg, 11.1% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:474.7.

[0384] Example 106: 1H NMR (400MHz, DMSO-d6) δ ppm 13.76(s, 1H), 11.89(s, 1H), 7.63(brd, J=1.9Hz, 1H), 7.38(dd, J=8.0, 11.0H z, 1H), 7.08(s, 1H), 7.03(dd, J=4.0, 7.6Hz, 1H), 6.62(s, 1H), 4.74(brs, 2H) , 3.09(q, J=10.4Hz, 2H), 2.92-2.79(m, 2H), 2.41-2.31(m, 2H), 2.29(s, 3H), 2.04-1.94(m, 1H), 1.58-1.50(m, 1H), 1.48-1.40(m, 1H), 1.20-0.98(m, 2H).

[0385] Example 107: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,7-dimethyl-1H-1,8-naphthyridin-2-one The title compound of TIFF2026507114000304.tif49170 was prepared in a manner similar to the preparation of Example 045, substituting 3-bromo-5,6-dimethyl-pyridin-2-amine for Int-2 and 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a in step 2. Example 107 (44.7 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:324.3.

[0386] Example 107: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.75(d, J=3.2Hz, 1H), 7.42(s, 1H), 7.37(dd, J=7.6, 10.8Hz, 1H), 7.16(dd, J=4.0, 7.6Hz, 1H), 2.66(s, 3H), 2.25(s, 3H). 19 F NMR (376MHz, MeOD-d4)δ ppm-132.82(s, 1F).

[0387] Example 108: 3-amino-6-bromo-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000305.tif49170 was prepared in a manner similar to the preparation of Example 021, substituting tert-butyl N-(2-bromo-4-chloro-5-methyl-3-pyridyl)carbamate for Int-3 in Step 1. Example 108 (10.5 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:421.9.

[0388] Example 108: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.64(brs, 1H), 11.67-11.80(m, 1H), 7.69(brs, 1H), 7.30(dd, J=11.13, 7.63Hz, 1H), 7.01(dd, J=7.82, 3.94Hz, 1H), 5.63(s, 2H), 2.45(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.28(s, 1F).

[0389] Example 109: 3-amino-8-chloro-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one A mixture of Example 108 compound (100.0 mg, 0.23 mmol), cyclopropylboronic acid (30.5 mg, 0.35 mmol), potassium carbonate (81.7 mg, 0.59 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (38.6 mg, 0.047 mmol) in degassed 1,4-dioxane (4 mL) was stirred at 80°C for 3 hours. Upon completion, the mixture was filtered and concentrated in vacuo to give a residue that was purified by preparative HPLC (FA as an additive) to give Example 109 (18.3 mg, 20.7% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:384.0.

[0390] Example 109: 1H NMR (400MHz, DMSO-d6) δ ppm 13.55(brs, 1H), 11.26-11.41(m, 1H), 7.55(brs, 1H), 7.27(dd, J=7.9, 11.1Hz, 1H), 7.00(dd, J=4.1, 7.7Hz, 1H), 5.35(brs, 2H), 2.47(s, 3H), 2.00-2.09(m, 1H), 0.58(dd, J=3.6, 8.1Hz, 2H), 0.35(dt, J=4.2, 8.9Hz, 1H), 0.23(dt, J=4.3, 8.7Hz, 1H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.84(s, 1F).

[0391] By procedures similar to those described for the preparation of Example 109, substituting CLREAG as shown in Table 9 for cyclopropylboronic acid, the following Examples 110 to 114 were prepared. [Table 9] TIFF2026507114000308.tif143170

[0392] Example 115: 3-amino-7-bromo-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000309.tif49170 was prepared in a manner similar to the preparation of Example 045, substituting tert-butyl N-(5-bromo-2-iodo-4-methyl-3-pyridyl)carbamate for Int-2 and 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a in step 2. Example 115 (30.5 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:388.0.

[0393] Example 115: 1H NMR (400MHz, DMSO-d6) δ ppm 13.64(s, 1H), 11.67(s, 1H), 8.12(s, 1H), 7.63(d, J=2.4Hz, 1H), 7.28(dd, J=8.0, 11.2Hz, 1H), 6.98(dd, J=4.4, 8.0Hz, 1H), 2.56(s, 3H).

[0394] Example 116: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-iodo-8-methyl-1H-1,5-naphthyridin-2-one A mixture of Example 115 (20.0 mg, 0.05 mmol), CuI (4.91 mg, 0.03 mmol), NaI (77.23 mg, 0.52 mmol), and N,N-dimethylethylenediamine (6.81 mg, 0.08 mmol) in 1,4-dioxane (2 mL) was stirred at 110 °C for 12 hours. After completion, the mixture was poured into water (3 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (NHHCO) to give Example 116 (1.3 mg, 5.7% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:436.2.

[0395] Example 116: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.62(s, 1H), 11.43(s, 1H), 8.35(s, 1H), 7.62(d, J=1.6Hz, 1H), 7.27(d, J=8.4, 11.8Hz, 1H), 6.97-6.94(m, 1H), 5.37(s, 2H), 2.62(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.78(s, 1F).

[0396] Example 117: 3-amino-7-(azetidin-1-yl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one A mixture of Example 115 (60.0 mg, 0.15 mmol), azetidine (13.24 mg, 0.23 mmol), t-BuONa (1.55 mL, 3.09 mmol), and CPhos-Pd-G3 (12.46 mg, 0.02 mmol) in degassed 1,4-dioxane (2 mL) was stirred at 100 °C for 2 h. After completion, the reaction mixture was quenched with saturated sodium bicarbonate (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (NH4HCO3 added) to give Example 117 (13.9 mg, 24.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:365.2.

[0397] Example 117: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.54(s, 1H), 11.22(d, J=2.4Hz, 1H), 7.58(s, 1H), 7.52(s, 1H), 7.28-7.24(m, 1H), 6 .96-6.93(m, 1H), 4.82(s, 2H), 3.90(t, J=7.2Hz, 4H), 2.25(s, 3H), 2.24-2.17(m, 2H). 19 F NMR (400MHz, DMSO-d6)δ ppm-133.127(s, 1F).

[0398] Example 118: 7-amino-8-(7-fluoro-1H-indazol-4-yl)-4-methyl-6-oxo-5H-1,5-naphthyridine-3-carbonitrile A mixture of Example 115 (20.0 mg, 0.06 mmol), Zn (0.84 mg, 0.01 mmol), Zn(CN) (4.54 mg, 0.04 mmol), and Pd(PPh) (5.95 mg, 0.01 mmol) in degassed DMF (2 mL) was stirred at 100 °C for 3 h. After completion, the mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were concentrated in vacuo to give the crude product, which was purified by preparative HPLC (NHHCO) to give Example 118 as a yellow solid (3.5 mg, 17.5% yield). MS (ESI) + )obsd.[(M+H) + ]:335.2.

[0399] Example 118: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.32(s, 1H), 11.33(s, 1H), 8.31(s, 1H), 7.58(d, J=1.6Hz, 1H), 7.23(d, J=8.4, 11.8Hz, 1H), 6.97-6.94(m, 1H), 5.34(s, 2H), 2.32(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.18(s, 1F).

[0400] Example 119: 3-amino-7-cyclobutyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000313.tif49170 Example 115 (50.0 mg, 0.13 mmol), 2,6-lutidine (27.6 mg, 0.26 mmol), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate A mixture of 119 (14.5 mg, 0.013 mmol), potassium cyclobutyltrifluoroborate (31.3 mg, 0.19 mmol), and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride (10.3 mg, 0.026 mmol) in 1,4-dioxane (4 mL) was stirred at rt for 16 h under 450 nm light (16 W) in a sealed tube under a N2 atmosphere. The resulting mixture was filtered and purified by preparative HPLC (FA as an additive) to give Example 119 (2.2 mg, 4.5% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:364.4.

[0401] Example 119: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.54(brs, 1H), 11.14(s, 1H), 7.95(s, 1H), 7.53(brd, J=2.8Hz, 1H), 7.21(dd, J=7.8, 11.2Hz, 1H), 6.90(dd, J=4.1, 7.7Hz, 1H), 5.05(s, 2H), 3.62(quin, J=8.7Hz, 1H), 2.28(s, 3H), 2.26-2.20(m, 2H), 2.11-1.97(m, 1H), 1.97-1.85(m, 1H), 1.76-1.62(m, 1H). 19 F NMR (376MHz, DMSO-d6)δ ppm-131.75(s, 1F).

[0402] Example 120: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-pyridazin-4-yl-1H-1,5-naphthyridin-2-one A mixture of Example 115 (20.0 mg, 0.06 mmol), tributyl(pyridazin-4-yl)stannane (40.0 mg, 0.10 mmol), and Pd(PPh) (18.0 mg, 0.03 mmol) in degassed dioxane (4 mL) was stirred at 100 °C for 3 h under N protection. After completion, the mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were concentrated in vacuo to give the crude product, which was purified by preparative HPLC (NHHCO) to give Example 120 as a yellow solid (3.5 mg, 15.0% yield). MS (ESI) + )obsd.[(M+H) + ]:388.2.

[0403] Example 120: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.62(brs, 1H), 11.64(s, 1H), 9.42-9.14(m, 2H), 8.09(s, 1H), 7.78(dd, J=2.4, 5.4Hz, 1H), 7.66( brs, 1H), 7.29(brdd, J=7.9, 11.0Hz, 1H), 7.00(dd, J=4.1, 7.7Hz, 1H), 5.47(brs, 2H), 2.46(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.83(s, 1F).

[0404] By procedures similar to those described for the preparation of Example 120, substituting TINCPD as shown in Table 10 for tributyl(pyridazin-4-yl)stannane, the following Examples 121, 123-125 were prepared. [Table 10] TIFF2026507114000316.tif75170

[0405] Example 122: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(oxetan-3-yl)-1H-1,5-naphthyridin-2-one TIFF2026507114000317.tif49170 Example 115 (50.0 mg, 0.13 mmol), 2,6-lutidine (27.6 mg, 0.26 mmol), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate (14.5 mg, 0. A mixture of 1,4-dioxane (4 mL), 3-bromooxetane (26.5 mg, 0.19 mmol), tris(trimethylsilyl)silane (32.0 mg, 0.13 mmol), and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride (10.3 mg, 0.026 mmol) was stirred at rt for 16 h in a sealed tube under N2 atmosphere and 450 nm light (16 W). The resulting mixture was filtered and purified by preparative HPLC (FA as an additive) to give Example 122 (1.6 mg, 3.4% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:366.1.

[0406] Example 122: 1 H NMR (500MHz, DMSO-d6) δ ppm 13.54(brs, 1H), 11.32(s, 1H), 8.04(s, 1H), 7.53(brs, 1H), 7.22(brdd, J=7.9, 11.1Hz, 1H), 6.91(dd, J=4.0, 7.7Hz, 1H), 5 .13(s, 2H), 4.85(ddd, J=2.1, 5.9, 8.3Hz, 2H), 4.67(ddd, J=5.9, 7.6, 11.9Hz, 2H), 4.50(quin, J=8.0Hz, 1H), 2.20(s, 3H).

[0407] Example 126: 3-amino-7-cyclopentyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000318.tif49170

[0408] Step 1: 3-amino-7-(cyclopent-1-en-1-yl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1,5-naphthyridin-2(1H)-one A mixture of Example 115 (100.0 mg, 0.26 mmol), cyclopenten-1-ylboronic acid (86.5 mg, 0.77 mmol), Pd(dppf)Cl (18.85 mg, 0.03 mmol), and CsCO (167.87 mg, 0.52 mmol) in degassed 1,4-dioxane (2 mL) and water (0.2 mL) was stirred at 100 °C for 6 h. After completion, the reaction mixture was quenched with saturated ammonium chloride (4 mL) and extracted with ethyl acetate (4 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound 126a (80.0 mg, 82.7% yield) as a light brown solid. MS(ESI + )obsd.[(M+H) + ]:376.2

[0409] Step 2: 3-amino-7-cyclopentyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one A mixture of compound 126a (80.0 mg, 0.21 mmol), Pd / C (68.04 mg, 0.06 mmol) in methanol (2 mL) was stirred at 25 °C for 1 h under a H balloon. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl as additive) to give Example 126 (22.6 mg, 27.3% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:378.1.

[0410] Example 126: 1H NMR (400MHz, DMSO-d6) δ ppm 13.75(s, 1H), 11.78(s, 1H), 7.86(s, 1H), 7.75(s, 1H), 7.35(dd, J=7.7, 10.1Hz, 1H), 7.04(dd, J=3.9, 7.6Hz, 1H), 3.28-3.24(m, 1H), 2.57(s, 3H), 2.04-1.97(m, 2H), 1.76-1.63(m, 4H), 1.57-1.49(m, 2H). 19 F NMR(376MHz, DMSO-d6)δ ppm-130.870(s, 1F).

[0411] Example 127: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-isopropyl-8-methyl-1H-1,5-naphthyridin-2-one The title compound was prepared in a manner similar to the preparation of Example 126, substituting Example 125 for Compound 126a in Step 2. Example 127 (27.4 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:352.1.

[0412] Example 127: 1 H NMR (400MHz, DMSO-d6) δ ppm 7.81(d, J=3.6Hz, 1H), 7.78(s, 1H), 7.37(dd, J=7.6, 11.2Hz, 1H), 7.09(dd, J =4.0, 8.0Hz, 1H), 3.31-3.25(m, 1H), 2.61(s, 3H), 1.20(s, 3H), 1.19(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-130.24(s, 1F).

[0413] Example 128: 3-amino-7-ethyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000322.tif49170 was prepared in a manner similar to the preparation of Example 126, substituting Example 123 for Compound 126a in Step 2. Example 128 (27.4 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:338.1.

[0414] Example 128: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.86(d, J=3.2Hz, 1H), 7.84(s, 1H), 7.40(dd, J=7.6, 10.8Hz, 1H), 7.23(dd, J =4.0, 7.6Hz, 1H), 2.88(q, J=7.6Hz, 2H), 2.70(s, 3H), 1.27(t, J=7.6Hz, 3H). 19 F NMR (400MHz, MeOD-d4)δ ppm-131.48(s, 1F).

[0415] Example 129: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(1-methylcyclopropyl)-1H-1,5-naphthyridin-2-one TIFF2026507114000323.tif50170

[0416] Step 1: tert-butyl N-[5-bromo-2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-4-methyl-3-pyridyl]carbamate A mixture of Int-23a (1.0 g, 2.3 mmol), Boc anhydride (0.6 g, 2.8 mmol), DIPEA (0.5 g, 3.8 mmol), and DMAP (0.1 g, 0.83 mmol) in DCM (20 mL) was stirred at room temperature for 10 h. After completion, the mixture was washed with saturated aqueous NH4Cl (20 mL x 3). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound 129a (1.0 g, 81.5% yield) as a light brown oil. MS (ESI) + )obsd.[(M+H) + ]:533.3.

[0417] Step 2: tert-butyl (2-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-4-methyl-5-(1-methylcyclopropyl)pyridin-3-yl)carbamate TIFF2026507114000325.tif49170

[0418] Compound 129a (300.0 mg, 0.56 mmol), 4,4,5,5-tetramethyl-2-(1-methylcyclopropyl)-1,3,2-dioxaborolane (307.21 mg, 1.69 mmol), Pd(dppf)Cl (41.15 mg, 0.06 mmol), and CsCO (549.76 mg, 1.69 mmol) were dissolved in degassed 1,4-dioxane (5 mL) and water (0.5 mL) and stirred at 100 °C for 12 h. After the reaction was complete, the mixture was filtered, and the filtrate was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (15 mL), dried over NaSO, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-30%) to give compound 129b (190.0 mg, 66.4% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:509.3.

[0419] Step 3: (3-amino-4-methyl-5-(1-methylcyclopropyl)pyridin-2-yl)(7-fluoro-1H-indazol-4-yl)methanone A solution of compound 129b (190.0 mg, 0.37 mmol) in HCl / EtOAc (3.0 mL, 4 M) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give crude compound 129c (120.0 mg, unpurified) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:325.2.

[0420] Step 4: 2-chloro-N-(2-(7-fluoro-1H-indazole-4-carbonyl)-4-methyl-5-(1-methylcyclopropyl)pyridin-3-yl)acetamide The title compound was prepared in a similar manner to the preparation of compound 001c, substituting compound 129c for compound 001b. Compound 129d (140.0 mg, crude) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:401.0.

[0421] Step 5: 1-(4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(1-methylcyclopropyl)-2-oxo-1,2-dihydro-1,5-naphthyridin-3-yl)pyridin-1-ium chloride The title compound was prepared in a similar manner to the preparation of compound 001d, substituting compound 129d for compound 001c. Compound 129e (160.0 mg, crude) was obtained as a yellow solid. MS (ESI + )obsd.[(M-Cl) + ]:426.3.

[0422] Step 6: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(1-methylcyclopropyl)-1H-1,5-naphthyridin-2-one The title compound, TIFF2026507114000329.tif49170, was prepared in a manner similar to the preparation of compound 001, substituting compound 129e for compound 001d. Example 129 (140.0 mg, crude) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:364.1.

[0423] Example 129: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.09(s, 1H), 12.21(s, 1H), 7.87(d, J=3.6Hz, 1H), 7.82(s, 1H), 7.40(dd, J=7.6, 11.2Hz, 1H), 7.08( dd, J=4.0, 7.6Hz, 1H), 6.75(s, 2H), 2.79(s, 3H), 1.31(s, 3H), 0.87-0.84(m, 2H), 0.81-0.78(m, 2H). 19 F NMR (376MHz, DMSO-d6)δ=-130.40(s, 1F).

[0424] Prepare the following Examples 130-132 and 144 by procedures similar to those described for the preparation of Example 129, substituting BOROCPD as shown in Table 11 for 4,4,5,5-tetramethyl-2-(1-methylcyclopropyl)-1,3,2-dioxaborolane in Step 2. [Table 11] TIFF2026507114000331.tif86170

[0425] Example 133: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-1H-1,5-naphthyridin-2-one The title compound, TIFF2026507114000332.tif49170, was prepared in a manner similar to the preparation of Example 101, substituting 1,1,1-trifluoro-2-iodo-ethane for iodomethane-d3 in step 3 of the synthesis of Int-23. Example 133 (14.7 mg, crude) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:392.1.

[0426] Example 133: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.81(s, 1H), 12.06(s, 1H), 8.07(s, 1H), 7.83(s, 1H), 7.37(dd, J=8.0, 1 1.6Hz, 1H), 7.08(dd, J=4.0, 7.6Hz, 1H), 4.01-3.93(m, 2H), 2.62(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ=-63.92(s, 3F), -130.98(s, 1F).

[0427] Example 134: 3-amino-7-(1,1-difluoroethyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000333.tif49170

[0428] Step 1: 3-amino-7-(1-ethoxyvinyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1,5-naphthyridin-2(1H)-one A mixture of Example 115 (150.0 mg, 0.39 mmol), Pd(PPh3)4 (44.65 mg, 0.04 mmol), and tributyl(1-ethoxyvinyl)tin (230.0 mg, 0.64 mmol) in degassed 1,4-dioxane (5 mL) was stirred at 100 °C for 4 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 134a (150.0 mg, crude) as a dark brown oil, which was used directly in the next step. MS (ESI)+ )obsd.[(M+H) + ]:380.0

[0429] Step 2: 7-acetyl-3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1,5-naphthyridin-2(1H)-one A solution of compound 134a (150.0 mg, 0.4 mmol) in HCl / EA (4 M, 2.0 mL) and THF (2 mL) was stirred at 25° C. for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (aqueous ammonia hydroxide as an additive) to give compound 134b (50.0 mg, 36.0% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:352.0.

[0430] Step 3: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(2-methyl-1,3-dithiolan-2-yl)-1,5-naphthyridin-2(1H)-one A mixture of compound 134b (20.0 mg, 0.06 mmol), BF3.Et2O (0.03 mL, 0.23 mmol), and 1,2-ethanedithiol (21.45 mg, 0.23 mmol) in DCM (2 mL) was stirred at 40 °C for 10 h. After completion, the mixture was concentrated under reduced pressure to give a crude residue, which was purified by preparative HPLC (aqueous ammonium hydroxide as an additive) to give compound 134c (9.0 mg, 37.0% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:428.1.

[0431] Step 4: 3-amino-7-(1,1-difluoroethyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one To a solution of TIFF2026507114000337.tif49170NIS (18.42 mg, 0.08 mmol) in DCM (2.0 mL) was added fluorinated pyridine (0.02 mL, 0.16 mmol) dropwise at −60° C., and the reaction mixture was stirred at −60° C. for 1 hour. Compound 134c (7.0 mg, 0.02 mmol) dissolved in DCM (0.1 mL) was added dropwise to the above solution at −60° C. The reaction mixture was then stirred at −60° C. for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by preparative HPLC (HCl as an additive) to give Example 134 (2.33 mg, 34.0% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:374.1.

[0432] Example 134: 1 H NMR (400MHz, MeOD-d4) δ ppm 8.04(s, 1H), 7.86(d, J=3.2Hz, 1H), 7.41-7.36(m, 1H), 7.24-7.21(m, 1H), 2.80(s, 3H), 2.08(t, J=18.8Hz, 3H). 19 F NMR (376MHz, MeOD-d4) δ ppm -85.378(m, 2F), -131.65(s, 1F).

[0433] Example 135: 3-amino-7-fluoro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000338.tif54170 was prepared in a manner similar to the preparation of Example 045, substituting tert-butyl N-(2-bromo-5-fluoro-4-methyl-3-pyridyl)carbamate for Int-2 and 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a in step 2. Example 135 (26.5 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H) + ]:328.1.

[0434] Example 135: 1H NMR (400MHz, MeOD-d4) δ ppm 8.08(d, J=2.4Hz, 1H), 7.80(d, J=3.2Hz, 1H), 7.36(dd, J=7.6, 10.8Hz, 1H), 7.19(dd, J=4.0, 7.6Hz, 1H), 2.62(d, J=1.6Hz, 3H). 19 F NMR (376MHz, MeOD-d4) δ ppm -132.27(s, 1F), -135.80(s, 1F).

[0435] Example 136: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methoxy-8-methyl-1H-1,5-naphthyridin-2-one A mixture of Example 116 (100.0 mg, 0.23 mmol), MeONa (0.13 mL, 0.69 mmol), CuI (8.75 mg, 0.05 mmol), and 1,10-phenanthroline (8.28 mg, 0.05 mmol) in degassed DMF (2 mL) was stirred at 100° C. for 16 hours. After completion, the mixture was filtered, and the filtrate was purified by preparative HPLC (NHHCO as an additive) to give Example 136 (5.93 mg, 7.6% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:340.1.

[0436] Example 136: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.60(s, 1H), 11.35(s, 1H), 8.00(s, 1H), 7.60(s, 1H), 7.28(dd, J=7.6, 11.2 Hz, 1H), 6.98(dd, J=4.0, 7.6Hz, 1H), 4.98(s, 2H), 3.85(s, 3H), 2.34(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-133.01(s, 1F).

[0437] Example 137: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(2,2,2-trifluoroethoxy)-1H-1,5-naphthyridin-2-one TIFF2026507114000340.tif44170

[0438] Step 1: tert-butyl (2-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)carbamate A mixture of compound 129a (1.6 g, 3.0 mmol), bis(pinacolato)diboron (1.52 g, 6.0 mmol), Pd(dppf)Cl2 (219 mg, 0.3 mmol), and KOAc (1.0 g, 10.5 mmol) in degassed 1,4-dioxane (20 mL) was stirred at 110 °C for 12 h under N2 protection. Upon completion, the reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 137a (1.7 g, 97.6% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:581.4.

[0439] Step 2: tert-butyl (2-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-5-hydroxy-4-methylpyridin-3-yl)carbamate To a solution of compound 137a (1.7 g, 2.9 mmol) in THF (20 mL) and water (3 mL) was added HO (7.0 g, 61.7 mmol) dropwise at room temperature and stirred at 25 °C for 2 h. After completion, the reaction mixture was quenched with saturated NaSO (40 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound 137b (1.3 g, 97.8% yield) as a yellow gum. MS (ESI) + )obsd.[(M+H) + ]:471.3.

[0440] Step 3: tert-butyl N-[2-(7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbonyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-3-pyridyl]carbamate A mixture of compound 137b (200 mg, 0.43 mmol), K2CO3 (117 mg, 0.85 mmol), 1,1,1-trifluoro-2-iodo-ethane (394 mg, 1.9 mmol), and NaI (23.0 mg, 0.13 mmol) in DMF (3 mL) was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound 137c (200.0 mg, 85.1% yield) as a yellow oil. MS (ESI) + )obsd.[(M+H) + ]:553.3.

[0441] Step 4: (3-amino-4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)(7-fluoro-1H-indazol-4-yl)methanone A solution of compound 137c (200 mg, 0.36 mmol) in HCl / EA (4.0 mL, 4 M) was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (EtOAc / PE = 1:2) to give compound 137d (130.0 mg, 97.5% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:369.3.

[0442] Step 5: 2-chloro-N-(2-(7-fluoro-1H-indazole-4-carbonyl)-4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-3-yl)acetamide The title compound was prepared in a similar manner to the preparation of compound 001c, substituting compound 137d for compound 001b. Compound 137e (140.0 mg, crude) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:445.2.

[0443] Step 6: 1-(4-(7-fluoro-1H-indazol-4-yl)-8-methyl-2-oxo-7-(2,2,2-trifluoroethoxy)-1,2-dihydro-1,5-naphthyridin-3-yl)pyridin-1-ium chloride The title compound TIFF2026507114000346.tif49170 was prepared in a manner similar to the preparation of compound 001d, substituting compound 137e for compound 001c. Compound 137f (160.0 mg, crude) was obtained as a yellow solid. MS (ESI + )obsd.[(M-Cl) + ]:470.2.

[0444] Step 7: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(2,2,2-trifluoroethoxy)-1H-1,5-naphthyridin-2-one The title compound, TIFF2026507114000347.tif49170, was prepared in a manner similar to the preparation of compound 001, substituting compound 137f for compound 001d. Example 137 (140.0 mg, crude) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:408.3.

[0445] Example 137: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.61(s, 1H), 11.45(s, 1H), 8.05(s, 1H), 7.61(d, J=3.2Hz, 1H), 7.28(dd, J=7.6, 11.2 Hz, 1H), 6.96(dd, J=4.0, 7.6Hz, 1H), 5.09(s, 2H), 4.82(q, J=8.8Hz, 2H), 2.38(s, 3H). 19 F NMR (376MHz, DMSO-d6) δ ppm -72.98(s, 1F), -132.89(s, 1F).

[0446] Prepare the following Examples 138-140 by a procedure similar to that described in the preparation of Example 137, replacing 1,1,1-trifluoro-2-iodo-ethane in Step 3 with IODOCPD as shown in Table 12. [Table 12]

[0447] Example 141: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-methylsulfanyl-1H-1,5-naphthyridin-2-one A mixture of Example 115 (100.0 mg, 0.26 mmol), sodium thiomethoxide (72.22 mg, 1.03 mmol), t-BuONa (1.29 mL, 2.58 mmol), and Pd(PPh) (29.77 mg, 0.03 mmol) in degassed DMSO (2 mL) was stirred at 100 °C for 12 h under N protection. After completion, the reaction mixture was quenched with aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl as additive) to give Example 141 (93.0 mg, 91.7% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:356.1.

[0448] Example 141: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.88(d, J=3.2Hz, 1H), 7.81(s, 1H), 7.40(dd, J=7.6, 10.8Hz, 1H), 7.24(dd, J=4.0, 8.0Hz, 1H), 2.76(s, 3H), 2.54(s, 3H). 19 F NMR (376MHz, MeOD-d4)δ ppm-131.39(s, 1F).

[0449] Examples 142 and 143: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-methylsulfinyl-1H-1,5-naphthyridin-2-one (142) and 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-methylsulfonyl-1H-1,5-naphthyridin-2-one (143) A mixture of Example 141 (18.0 mg, 45.9 μmol) and 3-chloroperoxybenzoic acid (25.7 mg, 114.8 μmol) in DCM (5.0 mL) and DMF (2.0 mL) was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was quenched with saturated NaSO solution and extracted four times with ethyl acetate (5 mL × 3). The organic layer was dried over anhydrous NaSO and concentrated under vacuum to give a crude residue, which was purified by preparative HPLC (FA as an additive) to give Example 142 (5.9 mg, 34% yield) as a white powder and Example 143 (1.8 mg, 10% yield) as a white powder.

[0450] Example 142: 1 H NMR (500MHz, DMSO-d6) δ ppm 13.63(brs, 1H), 11.69(s, 1H), 8.40(s, 1H), 7.63(brs, 1H), 7.34-7.25(m, 1H) , 7.03-6.94(m, 1H), 5.57(brs, 2H), 2.79(d, J=4.6Hz, 3H), 2.52(s, 3H).MS(ESI + )obsd.[(M+H) + ]:372.1.

[0451] Example 143: 1 H NMR (500MHz, DMSO-d6) δ ppm 13.63(brs, 1H), 11.75(s, 1H), 8.48(s, 1H), 7.64(brs, 1H), 7.29(brdd, J=8.0, 10.9H z, 1H), 6.97(dd, J=4.0, 7.6Hz, 1H), 5.86(brs, 2H), 3.26(s, 3H), 2.81(s, 3H).MS(ESI + )obsd.[(M+H) + ]:388.1.

[0452] Example 145: 3-amino-8-(difluoromethyl)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000351.tif49170 was prepared in a manner similar to the preparation of Example 045, substituting tert-butyl N-[4-(difluoromethyl)-2-iodo-5-methyl-3-pyridyl]carbamate for Int-2 and 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a in step 2. Example 145 (46.1 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:360.3.

[0453] Example 145: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.98(s, 1H), 7.90(d, J=3.2Hz, 1H), 7.85-7.52(m, 1H), 7.40(dd, J=7.6, 10.8Hz, 1H), 7.24(dd, J=4.0, 7.6Hz, 1H), 2.60(s, 3H). 19 F NMR (376MHz, MeOD-d4) δ ppm -118.09(s, 2F), -131.14(s, 1F).

[0454] Example 146: 3-amino-4-(7-chloro-1H-indazol-4-yl)-7,8-dimethyl-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000352.tif49170 was prepared in a manner similar to the preparation of Example 045, substituting tert-butyl N-(2-bromo-4,5-dimethyl-3-pyridyl)carbamate for Int-2 and 7-chloro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a in step 2. Example 146 (38.1 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:340.8.

[0455] Example 146: 1H NMR (500MHz, DMSO-d6) δ ppm 13.55(s, 1H), 11.38(s, 1H), 7.92(s, 1H), 7.60(s, 1H), 7.53(d, J=7.5Hz, 1H), 7.02(d, J=7.5Hz, 1H), 5.17(s, 2H), 2.40(s, 3H), 2.24(s, 3H).

[0456] Example 147: 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000353.tif49170 The title compound was prepared similarly to the preparation of Example 091, except that NCS was replaced with NBS in step 4. Example 147 (44.7 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:388.0.

[0457] Example 147: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.71(s, 1H), 11.56(brs, 1H), 7.59(d, J=1.2Hz, 1H), 7.21-7.36(m, 1H), 7.07(s, 1H), 6.87(dd, J=7.6, 4.4Hz, 1H)5.45(s, 2H)2.43(s, 3H).

[0458] Example 148: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methyl-but-1-ynyl)-8-methyl-1H-1,5-naphthyridin-2-one A mixture of Example 147 (60.0 mg, 0.15 mmol), 2-methyl-3-butyn-2-ol (26.0 mg, 0.31 mmol), diisopropylamine (4.01 mL, 23.09 mmol), Pd(PPh)Cl (5.42 mg, 0.01 mmol), and CuI (2.94 mg, 0.02 mmol) in degassed 1,4-dioxane (1 mL) was stirred at 80 °C for 3 h under N protection. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (with NHHCO) to give Example 148 (45.3 mg, 71.0% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:392.2.

[0459] Example 148: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.65(s, 1H), 7.65(s, 1H), 7.30(dd, J=8.0, 11.2Hz, 1H), 7.13(s, 1H), 6.95(d d, J=4.0, 8.0Hz, 1H), 5.42(s, 1H), 5.27(s, 2H), 2.46(s, 3H), 1.35(s, 6H).19F NMR(376MHz, DMSO- d6 )δ ppm-132.78(s, 1F).

[0460] By procedures similar to those described in the preparation of Example 148, substituting the alkynes shown in Table 13 for 2-methyl-3-butyn-2-ol, the following Examples 149 and 150 were prepared. [Table 13]

[0461] Example 151: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2-thienyl)-1H-1,5-naphthyridin-2-one A mixture of Example 021 (20.0 mg, 0.05 mmol), tributyl(2-thienyl)stannane (40.0 mg, 0.10 mmol), and Pd(PPh) (4.0 mg) in degassed 1,4-dioxane (2 mL) was stirred at 100 °C under N protection for 2 h. After completion, the mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (NHHCO as additive) to give Example 151 (6.1 mg, 31.6% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:392.1.

[0462] Example 151: 1 H NMR (400MHz, MeOH-d4) δ ppm 9.15(d, J=2.1Hz, 1H), 8.53(brd, J=2.8Hz, 1H), 8.39(s, 1H), 8.26(d, J=2.1Hz, 1H), 8.14-8.03(m, 3H), 3.65(s, 3H).

[0463] By procedures similar to those described for the preparation of Example 151, substituting TINCPD as shown in Table 14 for tributyl(2-thienyl)stannane, the following Examples 152-155 were prepared. [Table 14] TIFF2026507114000358.tif65170

[0464] Example 156: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(3-methylbut-1-ynyl)-1H-1,5-naphthyridin-2-one The title compound, TIFF2026507114000359.tif49170, was prepared in a manner similar to the preparation of Example 070, substituting 3-methylbutan-1-ine for 2-methyl-3-butyn-2-ol. Example 156 (11.7 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) +]:376.2.

[0465] Example 156: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.65(brs, 1H), 12.21(s, 1H), 7.64(d, J=3.2Hz, 1H), 7.45(s, 1H), 7.30(dd, J=8.0, 11.2H z, 1H), 6.98(dd, J=4.0, 8.0Hz, 1H), 2.76-2.69(m, 1H), 2.34(s, 3H), 1.14(d, J=6.8Hz, 6H). 19 F NMR(376MHz, DMSO-d6)δ ppm-132.64(s, 1F).

[0466] Example 157: 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000360.tif49170

[0467] Step 1: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-vinyl-1,5-naphthyridin-2(1H)-one A mixture of Example 021 (200.0 mg, 0.52 mmol), vinylboronic acid pinacol ester (119.03 mg, 0.77 mmol), Pd(dppf)Cl (37.7 mg, 0.05 mmol), and CsCO (335.72 mg, 1.03 mmol) in degassed 1,4-dioxane (3 mL) and water (0.300 mL) was stirred at 100 °C for 12 h under N protection. After completion, the mixture was poured into water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound 157a (100.0 mg, 57.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:336.2.

[0468] Step 2: 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one A suspension of Pd / C (100.0 mg, 0.09 mmol) and compound 157a (100.0 mg, 0.3 mmol) in methanol (3 mL) was stirred under an atmosphere of H (15 psi) at 25 °C for 0.5 h. Upon completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (HCl as an additive) to give Example 157 (14.7 mg, 14.6% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:338.1.

[0469] Example 157: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.95(s, 1H), 7.86(d, J=3.2Hz, 1H), 7.39(dd, J=7.6, 10.8Hz, 1H), 7.25(dd, J =4.0, 7.6Hz, 1H), 2.87(q, J=7.6Hz, 2H), 2.49(s, 3H), 1.11(t, J=7.6Hz, 3H). 19 F NMR (376MHz, MeOD-d4)δ ppm-131.64(s, 1F).

[0470] Example 158: 3-amino-7-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one The title compound, TIFF2026507114000363.tif49170, was prepared in a manner similar to the preparation of Example 157, substituting Example 001 for Example 021 in Step 1. Example 158 (48.9 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:324.1.

[0471] Example 158: 1H NMR (400MHz, MeOD-d4) δ ppm 7.98(d, J=1.6Hz, 1H), 7.92(d, J=1.6Hz, 1H), 7.86(d, J=3.2Hz, 1H), 7.39(dd, J=7.6, 1 0.8Hz, 1H), 7.23(dd, J=3.6, 7.6Hz, 1H), 2.82(q, J=7.6Hz, 2H), 1.32(t, J=7.6Hz, 3H). 19 F NMR (377MHz, MeOD-d4)δ ppm-131.73(s, 1F).

[0472] Example 159: 3-amino-4-(7-chloro-1H-indazol-4-yl)-6,7-dimethyl-1H-1,5-naphthyridin-2-one The title compound of TIFF2026507114000364.tif49170 was prepared in a manner similar to the preparation of Example 045, substituting tert-butyl N-(2-bromo-5,6-dimethyl-3-pyridyl)carbamate for Int-2 and 7-chloro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a in step 2. Example 159 (17.1 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:324.3.

[0473] Example 159: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.95(s, 1H), 7.88(s, 1H), 7.68(d, J=7.6Hz, 1H), 7.24(d, J=7.6Hz, 1H), 2.50(s, 3H), 2.45(s, 3H).

[0474] Example 160: 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-7,8-dimethyl-1H-1,6-naphthyridin-2-one The title compound of TIFF2026507114000365.tif49170 was prepared in a manner similar to the preparation of Example 045, substituting Int-24 for Int-2 and 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a in step 2. Example 160 (9.9 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:358.1.

[0475] Example 160: 1 H NMR (400MHz, DMSO-d6) δ ppm 11.52(s, 1H), 7.74(d, J=3.6Hz, 1H), 7.26(dd, J=8.0, 11.2Hz, 1H), 6.91(dd, J=4.0, 7.6Hz, 1H), 2.40(s, 3H), 2.37(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-132.41(s, 1F).

[0476] Example 161: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7,8-dimethyl-2-oxo-1H-1,6-naphthyridine-5-carbonitrile A mixture of Example 160 (40.0 mg, 0.11 mmol), Zn (14.62 mg, 0.22 mmol), Pd(dppf)Cl (16.36 mg, 0.02 mmol), and Zn(CN) (39.39 mg, 0.34 mmol) in DMF (3 mL) was stirred at 100 °C for 12 h under N protection. After completion, the reaction mixture was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NHCO added) to give Example 161 (13.9 mg, 34.3% yield) as an off-white solid. MS (ESI) + )obsd.[(M+H) + ]:349.1.

[0477] Example 161:1 H NMR (400MHz, DMSO-d6) δ ppm 13.71(s, 1H), 11.69(s, 1H), 7.75(s, 1H), 7.29(dd, J=8.0, 10.8Hz, 1H), 7.03(dd, J=4.0, 7.6Hz, 1H), 5.43(s, 2H), 2.46(s, 3H), 2.45(s, 3H). 19 F NMR (376MHz, DMSO-d6)δ ppm-131.10(s, 1F).

[0478] Example 162: 3-amino-5-chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,6-naphthyridin-2-one The title compound of TIFF2026507114000367.tif49170 was prepared in a manner similar to the preparation of Example 160, substituting 2-chloro-6-cyclopropyl-pyridin-4-amine for 2-chloro-6-methyl-pyridin-4-amine in step 1 of the synthesis of Int-24. Example 162 (11.9 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:384.3.

[0479] Example 162: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.72(d, J=3.2Hz, 1H), 7.24(dd, J=7.6, 11.2Hz, 1H), 7.00(dd, J=4.0, 7.6Hz, 1H), 2.57(s, 3H), 2.28-2.18(m, 1H), 1.00-0.90(m, 4H). 19 F NMR (376MHz, MeOD-d4)δ ppm-134.49(s, 1F).

[0480] Example 163: 3-amino-5-chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,6-naphthyridin-2-one The title compound of TIFF2026507114000368.tif49170 was prepared in a manner similar to the preparation of Example 045, substituting Int-25 for Int-2 and 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a in step 2. Example 163 (4.3 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:370.2.

[0481] Example 163: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.79(d, J=3.2Hz, 1H), 7.26(dd, J=7.6, 11.2Hz, 1H), 7.05-7.02(m, 2H), 2.11(d, J=16.4Hz, 1H), 1.13-1.09(m, 2H), 1.00-0.97(m, 2H). 19 F NMR (376MHz, MeOD-d4)δ ppm-133.84(s, 1F).

[0482] Example 164: 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,6-naphthyridin-2-one The title compound, TIFF2026507114000369.tif49170, was prepared in a manner similar to the preparation of Example 163, substituting 2-chloro-5-methyl-pyridin-4-amine for 2-chloro-6-cyclopropyl-pyridin-4-amine in step 1 of the synthesis of Int-25. Example 164 (4.3 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:344.1.

[0483] Example 164: 1 H NMR (400MHz, DMSO-d6) δ=13.67(s, 1H), 11.70(s, 1H), 7.89(d, J=0.4Hz, 1H), 7.75(s, 1H), 7.29-7.24(m, 1H), 6.94-6.91(m, 1H), 5.12(s, 2H), 2.41(s, 3H). 19F NMR (377MHz, DMSO-d6)δ ppm-131.44(s, 1F).

[0484] Example 165: 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,6-naphthyridin-2-one A mixture of Example 162 (60.0 mg, 0.16 mmol) and Pd / C (60 mg, 0.16 mmol) in methanol (2 mL) was stirred under a H balloon at 25 °C for 3 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (HCl as additive) to give Example 165 (3.53 mg, 6.4% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:350.3.

[0485] Example 165: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.80(d, J=2.4Hz, 1H), 7.63(s, 1H), 7.36(dd, J=8.0, 10.8Hz, 1H), 7.17(dd, J=4.0, 7.8Hz, 1H), 2.70(s, 3H), 2.38-2.34(m, 1H), 1.26-1.23(m, 2H), 1.00-0.97(m, 2H). 19 F NMR (376MHz, MeOD-d4)δ ppm-134.49(s, 1F).

[0486] Example 166: 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-5-methyl-1H-1,6-naphthyridin-2-one A mixture of Example 163 (200 mg, 0.54 mmol), trimethylboroxine (0.31 mL, 1.08 mmol), Pd(dppf)Cl (39.5 mg, 0.05 mmol), and CsCO (440 mg, 1.35 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 12 h under N protection. Upon completion, the reaction mixture was poured into saturated ammonium chloride (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl as additive) to give Example 166 (122.6 mg, 56.4% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:350.3.

[0487] Example 166: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.88-7.87(m, 1H), 7.32(dd, J=7.6, 10.8Hz, 1H), 7.13(dd, J=3.9, 7.8Hz, 1H), 7. 02(s, 1H), 2.27-2.23(m, 1H), 1.94(s, 3H), 1.35-1.29(m, 2H), 1.08-1.04(m, 2H). 19 F NMR (376MHz, MeOD-d4)δ ppm-132.34(s, 1F).

[0488] Example 167: 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-2-oxo-1H-1,6-naphthyridine-5-carbonitrile A mixture of Example 163 (100 mg, 0.27 mmol), Zn(CN) (94.9 mg, 0.81 mmol), Pd(dppf)Cl (19.7 mg, 0.03 mmol), and Zn (43.9 mg, 0.68 mmol) in DMF (3 mL) was stirred at 130 °C for 12 h under N protection. After completion, the reaction mixture was poured into saturated ammonium chloride (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NHHCO added) to give Example 167 (22.1 mg, 22.4% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:361.3.

[0489] Example 167: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.74(d, J=3.2Hz, 1H), 7.28-7.26(m, 1H), 7.24(s, 1H), 7.12(dd, J=4.0, 7.6Hz, 1H), 2.09-2.05(m, 1H), 1.00-0.94(m, 4H). 19 F NMR (376MHz, MeOD-d4)δ ppm-132.74(s, 1F).

[0490] Example 168: 3-amino-7-cyclopropyl-5-(difluoromethoxy)-4-(7-fluoro-1H-indazol-4-yl)-1H-1,6-naphthyridin-2-one TIFF2026507114000373.tif49170

[0491] Step 1: 3-amino-5-benzyloxy-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,6-naphthyridin-2-one A mixture of Example 163 (110 mg, 0.30 mmol) and benzyloxysodium (50 mg, 0.38 mmol) in toluene (2 mL) was stirred at 120 °C for 12 hours. After completion, the mixture was poured into saturated NH4Cl solution (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl as additive) to give compound 168a (30.8 mg, 23.2% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:442.2.

[0492] Step 2: 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-5-hydroxy-1H-1,6-naphthyridin-2-one A mixture of compound 168a (30.8 mg) and Pd / C (20 mg) in 10 mL of EtOAc was stirred under a H balloon at 25 °C for 0.5 h. After completion, the mixture was filtered and the filtrate was concentrated in vacuo to give crude compound 168b (30.0 mg, 100% yield), which was used directly in the next step. MS (ESI) + )obsd.[(M+H) + ]:352.1

[0493] Step 3: 3-amino-7-cyclopropyl-5-(difluoromethoxy)-4-(7-fluoro-1H-indazol-4-yl)-1H-1,6-naphthyridin-2-one A mixture of compound 168b (crude product 30.0 mg, 0.085 mmol), NaSO (20.2 mg, 0.16 mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (118.35 mg, 0.66 mmol) in MeCN (2 mL) was stirred at 25 °C for 1 h. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate (5 mL) and extracted with ethyl acetate (8 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give Example 168 (5.4 mg, 15.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:402.2.

[0494] Example 168: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.69(d, J=2.4Hz, 1H), 7.23-7.18(m, 1H), 7.02(t, J=73.2Hz, 1H), 7.00-6.98(m, 2H), 2.01-1.95(m, 1H), 0.97-0.86(m, 4H). 19 F NMR (376MHz, MeOD-d4) δ ppm -91.59(dd, J=176, 564Hz, 2F), -135.37(s, 1F).

[0495] Example 169: 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-1H-1,6-naphthyridin-2-one The title compound was prepared in a manner similar to that used to prepare compound 168a, substituting sodium methylate for sodium benzyloxysodium. Example 169 (41.9 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:366.3.

[0496] Example 169: 1H NMR (400MHz, MeOD-d4) δ ppm 7.68(d, J=3.3Hz, 1H), 7.21(dd, J=7.6, 11.2Hz, 1H), 6.96(dd, J=4.0, 7.6Hz, 1H), 6 .79(s, 1H), 3.23(s, 3H), 2.00-1.93(m, 1H), 0.99-0.95(m, 2H), 0.92-0.87(m, 2H). 19 F NMR (376MHz, MeOD-d4)δ ppm-135.44(s, 1F).

[0497] Example 170: 3-amino-8-fluoro-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-1H-1,6-naphthyridin-2-one The title compound, TIFF2026507114000378.tif49170, was prepared in a manner similar to the preparation of Example 163, substituting 5-fluoro-2-methoxy-pyridin-4-amine for 2-chloro-6-cyclopropyl-pyridin-4-amine in step 1 of the synthesis of Int-25. Example 170 (11.2 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:344.1.

[0498] Example 170: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.76(d, J=1.6Hz, 1H), 7.71(d, J=3.6Hz, 1H), 7.22(dd, J=8.0, 11.2Hz, 1H), 6.98(dd, J=4.0, 8.0Hz, 1H), 3.25(s, 3H). 19 F NMR (376MHz, MeOD-d4) δ ppm -135.39(s, 1F), -159.76(s, 1F).

[0499] Example 171: 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-1H-1,6-naphthyridin-2-one The title compound, TIFF2026507114000379.tif49170, was prepared in a manner similar to the preparation of Example 163, substituting 5-chloro-2-methoxy-pyridin-4-amine for 2-chloro-6-cyclopropyl-pyridin-4-amine in step 1 of the synthesis of Int-25. Example 171 (60.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:360.0.

[0500] Example 171: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.90(s, 1H), 7.70(d, J=3.2Hz, 1H), 7.23(dd, J=8.0, 11.2Hz, 1H), 6.98(dd, J=4.0, 7.6Hz, 1H), 3.26(s, 3H). 19 F NMR (376MHz, MeOD-d4)δ ppm-135.45(s, 1F).

[0501] Example 172: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-8-methyl-1H-1,6-naphthyridin-2-one A mixture of Example 171 (100.0 mg, 0.28 mmol), Catacurium A palladium G2 (92.93 mg, 0.14 mmol), K3PO4 (271.71 mg, 0.83 mmol), and methylboronic acid (133.11 mg, 2.22 mmol) in 1,4-dioxane (2 mL) and water (0.40 mL) was stirred at 100 °C for 12 hours under N2 protection. Upon completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (NH4HCO3 as an additive) to give Example 172 (51.1 mg, 52.4% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:340.1.

[0502] Example 172: 1H NMR (400MHz, DMSO-d6) δ ppm 13.81-13.31(m, 1H), 11.43(brs, 1H), 7.67-7.64(m, 2H), 7.22(dd, J=8.0, 11. 2Hz, 1H), 6.86(dd, J=4.0, 7.6Hz, 1H), 4.74(s, 2H), 3.12(s, 3H), 2.33(s, 3H). 19 F NMR(376MHz, DMSO-d6)δ ppm-133.55(s, 1F).

[0503] Example 173: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-8-methyl-1H-1,7-naphthyridin-2-one The title compound of TIFF2026507114000381.tif49170 was prepared in a manner similar to the preparation of Example 163, substituting 5-methoxy-2-methyl-pyridin-3-amine for 2-chloro-6-cyclopropyl-pyridin-4-amine in step 1 of the synthesis of Int-25. Example 173 (2.4 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:340.0.

[0504] Example 173: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.73(d, J=2.8Hz, 1H), 7.68(s, 1H), 7.23(dd, J=7.6, 10.8Hz, 1H), 7.00(dd, J=4.0, 7.6Hz, 1H), 3.25(s, 3H), 2.82(s, 3H).

[0505] 19 F NMR (376MHz, MeOD-d4)δ=-134.82(s, 1F). Example 174: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-6,8-dimethyl-1H-1,7-naphthyridin-2-one TIFF2026507114000382.tif49170

[0506] Step 1: tert-butyl (4-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)(hydroxy)methyl)-5-methoxypyridin-3-yl)carbamate The title compound TIFF2026507114000383.tif44170 was prepared in a manner similar to the preparation of compound 045b, substituting tert-butyl N-(5-methoxy-3-pyridyl)carbamate for Int-2 and 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a. Compound 174a (8.4 g) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:473.2.

[0507] Step 2: tert-butyl (4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-5-methoxypyridin-3-yl)carbamate The title compound was prepared in a manner similar to that used to prepare compound 045c, substituting compound 174a for compound 045b. Compound 174b (0.9 g) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:471.3.

[0508] Step 3: (3-amino-5-methoxypyridin-4-yl)(7-fluoro-1H-indazol-4-yl)methanone The title compound was prepared in a manner similar to that used to prepare compound 045d, substituting compound 174b for compound 045c. Compound 174c (0.54 g) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:287.1.

[0509] Step 4: (3-amino-2,6-dibromo-5-methoxypyridin-4-yl)(7-fluoro-1H-indazol-4-yl)methanone To a solution of compound 174 (1.3 g, 4.54 mmol) in MeCN (15 mL) at -20 °C was added NBS (1.21 g, 6.81 mmol). The mixture was stirred at -20 °C for 0.5 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-100%) to give compound 174d (600.0 mg, 29.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:445.0.

[0510] Step 5: 2-chloro-N-(2,6-dibromo-4-(7-fluoro-1H-indazole-4-carbonyl)-5-methoxypyridin-3-yl)acetamide TIFF2026507114000387.tif49170 To a solution of compound 174d (100.0 mg, 0.23 mmol) in toluene (3 mL) was added chloroacetyl chloride (0.05 mL, 0.68 mmol). The mixture was stirred at 100°C for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure to give compound 174e (115.0 mg, crude) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:521.0.

[0511] Step 6: 1-(6,8-dibromo-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-2-oxo-1,2-dihydro-1,7-naphthyridin-3-yl)pyridin-1-ium chloride A solution of compound 174e (115.0 mg, 0.22 mmol) in pyridine (3.0 mL) was stirred at 50 °C for 3 hours, and the mixture was concentrated under reduced pressure to give compound 174f (120.0 mg, crude) as a brown solid. MS (ESI) + )obsd.[(M-Cl)+ ]:546.0.

[0512] Step 7: 3-amino-6,8-dibromo-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-1,7-naphthyridin-2(1H)-one A mixture of compound 174f (120.0 mg, 0.21 mmol) and hydrazine hydrate (0.1 mL, 2.06 mmol) in ethanol (5 mL) was stirred at 70 °C for 1 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-100%) to give compound 174f (90.0 mg, 90.3% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:484.1.

[0513] Step 8: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-6,8-dimethyl-1H-1,7-naphthyridin-2-one A mixture of compound 174g (30.0 mg, 0.06 mmol), trimethylboroxine (0.09 mL, 0.31 mmol), Pd(dppf)Cl (4.54 mg, 0.01 mmol), and CsCO (40.47 mg, 0.12 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 12 hours under N protection. Upon completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (HCl as an additive) to give Example 174 (6.8 mg, 28.0% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:354.2.

[0514] Example 174: 1H NMR (400MHz, MeOD-d4) δ ppm 7.72(d, J=2.8Hz, 1H), 7.27(dd, J=7.6, 10.8Hz, 1H), 7.13(dd, J=4.0, 7.6Hz, 1H), 2.93(s, 3H), 2.83(s, 3H), 2.43(s, 3H). 19 F NMR (376MHz, MeOD-d4)δ=-134.22(s, 1F).

[0515] Example 175: 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one The title compound, TIFF2026507114000391.tif49170, was prepared in a manner similar to the preparation of Example 163, substituting 6-chloro-2-methyl-pyridin-3-amine for 2-chloro-6-cyclopropyl-pyridin-4-amine in step 1 of the synthesis of Int-25. Example 175 (60.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:344.1.

[0516] Example 175: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.77(d, J=3.2Hz, 1H), 7.35(dd, J=7.6, 10.8Hz, 1H), 7.12(dd, J=3.6, 7.6Hz, 1H), 6.77(s, 1H), 2.80(s, 3H). 19 F NMR (376MHz, MeOD-d4)δ ppm-132.47(s, 1F).

[0517] Example 176: 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one The title compound, TIFF2026507114000392.tif49170, was prepared in a manner similar to the preparation of Example 163, substituting 5-chloro-2-methyl-pyridin-3-amine for 2-chloro-6-cyclopropyl-pyridin-4-amine in step 1 of the synthesis of Int-25. Example 176 (60.0 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:344.0.

[0518] Example 176: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.67(brs, 1H), 11.17(brs, 1H), 7.89(s, 1H), 7.76(d, J=3.2Hz, 1H), 7.25(d d, J=8.0, 11.2Hz, 1H), 6.93(dd, J=4.0, 8.0Hz, 1H), 5.54(s, 2H), 2.67(s, 3H). 19 F NMR(376MHz, DMSO-d6)δ ppm-132.25.

[0519] Example 177: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5,8-dimethyl-1H-1,7-naphthyridin-2-one The title compound, TIFF2026507114000393.tif49170, was prepared in a manner similar to the preparation of Example 163, substituting 2,5-dimethylpyridin-3-amine for 2-chloro-6-cyclopropyl-pyridin-4-amine in step 1 of the synthesis of Int-25. Example 177 (19.1 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:324.1.

[0520] Example 177: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.83(d, J=3.6Hz, 1H), 7.79(s, 1H), 7.30(dd, J=8.0, 11.2Hz, 1H), 7.12(dd, J=4.0, 8.0Hz, 1H), 2.88(s, 3H), 1.63(s, 3H). 19F NMR (376MHz, MeOD-d4)δ ppm-132.57(s, 1F).

[0521] Example 178: 3-amino-5-ethyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one The title compound, TIFF2026507114000394.tif49170, was prepared in a manner similar to the preparation of Example 058, substituting Example 176 for Example 001 in Step 1. Example 178 (9.2 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:338.0.

[0522] Example 178: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.82(s, 1H), 7.77(s, 1H), 7.34-7.29(m, 1H), 7.17-7.14(m, 1H), 2.87(s, 3H), 2.03-1.90(m, 2H), 0.75(t, J=7.6Hz, 3H). 19 F NMR (376MHz, MeOD-d4)δ ppm-132.54(s, 1F).

[0523] Example 179: 3-amino-5-fluoro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one The title compound, TIFF2026507114000395.tif49170, was prepared in a manner similar to the preparation of Example 163, substituting 5-fluoro-2-methyl-3-pyridinamine for 2-chloro-6-cyclopropyl-pyridin-4-amine in step 1 of the synthesis of Int-25. Example 179 (10.1 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:328.1.

[0524] Example 179: 1H NMR (400MHz, MeOD-d4) δ ppm 8.10(d, J=6.0Hz, 1H), 7.84(d, J=3.2Hz, 1H), 7.27(dd, J=8.0, 10.8Hz, 1H), 7.11(dd, J=4.0, 8.0Hz, 1H), 2.87(s, 3H). 19 F NMR (376MHz, MeOD-d4) δ ppm -130.82(s, 1F), -133.50(s, 1F).

[0525] Example 180: 3-amino-5-benzyloxy-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-naphthyridin-2-one The title compound of TIFF2026507114000396.tif49170 was prepared in a manner similar to the preparation of Example 001, substituting compound Int-26d for compound 001a in step 2. Example 180 (21.8 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:436.0.

[0526] Example 180: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.41(s, 1H), 11.44(s, 1H), 7.74(s, 1H), 7.70(d, J=2.4Hz, 1H), 7.24-7.18(m, 1H), 7.14-7.07(m, 2H), 6.90( dd, J=7.6, 11.2Hz, 1H), 6.77(dd, J=4.0, 7.6Hz, 1H), 6.43(d, J=7.2Hz, 2H), 5.35(brs, 2H), 4.76-4.46(m, 2H). 19 F NMR(400MHz, DMSO-d6)δ ppm-132.86(s, 1F).

[0527] Example 181: 3-amino-5-benzyloxy-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one The title compound of TIFF2026507114000397.tif49170 was prepared in a manner similar to the preparation of Example 001, substituting compound Int-26e for compound 001a in step 2. Example 181 (16.5 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:416.1.

[0528] Example 181: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.43(brs, 1H), 7.78(s, 1H), 7.64(brs, 1H), 7.22-7.15(m, 1H), 7.14-7.05(m, 2H), 6.92(dd, J=7.2, 11.2 Hz, 1H), 6.77(dd, J=4.4, 7.2Hz, 1H), 6.42(d, J=7.2Hz, 2H), 5.07(s, 2H), 4.72-4.31(m, 2H), 2.61(s, 3H). 19 F NMR (400MHz, DMSO-d6)δ ppm-133.15(s, 1F).

[0529] Example 182: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-isopropoxy-8-methyl-1H-1,7-naphthyridin-2-one TIFF2026507114000398.tif49170

[0530] Step 1: tert-butyl (4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)-5-isopropoxy-2-methylpyridin-3-yl)carbamate A mixture of compound Int-26 (100 mg, 0.21 mmol), 2-bromopropane (78.42 mg, 0.64 mmol), and K2CO3 (88.12 mg, 0.64 mmol) in DMF (1 mL) was stirred at 80 °C for 2 h. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-20%) to give compound 182a (100 mg, 91.8% yield) as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:513.3.

[0531] Step 2: (3-amino-5-isopropoxy-2-methylpyridin-4-yl)(7-fluoro-1H-indazol-4-yl)methanone The title compound was prepared in a similar manner to the preparation of compound 001b, substituting compound 182a for compound 001a. Compound 182b (60.0 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:329.1.

[0532] Step 3: 2-chloro-N-(4-(7-fluoro-1H-indazole-4-carbonyl)-5-isopropoxy-2-methylpyridin-3-yl)acetamide The title compound was prepared in a similar manner to the preparation of compound 001c, substituting compound 182b for compound 001b. Compound 182c (60.0 mg, crude) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:405.1.

[0533] Step 4: 1-(4-(7-fluoro-1H-indazol-4-yl)-5-isopropoxy-8-methyl-2-oxo-1,2-dihydro-1,7-naphthyridin-3-yl)pyridin-1-ium chloride The title compound was prepared in a similar manner to the preparation of compound 001d, substituting compound 182c for compound 001c. Compound 182d (80.0 mg, crude) was obtained as a brown solid. MS (ESI + )obsd.[(M-Cl) + ]:430.2.

[0534] Step 5: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-isopropoxy-8-methyl-1H-1,7-naphthyridin-2-one The title compound, TIFF2026507114000403.tif49170, was prepared in a manner similar to the preparation of Example 001, substituting Compound 182d for Compound 001d. Example 182 (33.2 mg) was obtained as a yellow solid. MS (ESI + )obsd.[(M+H) + ]:368.1.

[0535] Example 182: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.75(d, J=3.2Hz, 1H), 7.66(s, 1H), 7.24(dd, J=7.6, 10.8Hz, 1H), 6.98(dd, J=4.0, 7.6 Hz, 1H), 4.34-4.27(m, 1H), 2.84(s, 3H), 0.66(d, J=6.0Hz, 3H), 0.42(d, J=6.0Hz, 3H). 19 F NMR (376MHz, MeOD-d4)δ ppm-135.09(s, 1F).

[0536] Following a procedure similar to that described for the preparation of Example 182, but replacing 2-bromopropane in Step 1 with HALOCPD as shown in Table 15, the following Examples 183-192 were prepared. [Table 15] TIFF2026507114000405.tif255170TIFF2026507114000406.tif255170TIFF2026507114000407.tif91170

[0537] Example 193: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-(methoxymethyl)-8-methyl-1H-1,7-naphthyridin-2-one The title compound of TIFF2026507114000408.tif39170 was prepared in a manner similar to the preparation of Example 045, substituting Int-2 with Int-27 in Step 2 and 7-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde for compound 045a. Example 193 (11.1 mg) was obtained as a yellow solid. MS (ESI) + )obsd.[(M+H) + ]:354.1.

[0538] Example 193: 1 H NMR (400MHz, MeOD-d4) δ ppm 8.03(s, 1H), 7.82(d, J=3.2Hz, 1H), 7.33(dd, J=7.6, 10.8Hz, 1H), 7.13(dd, J=4.0, 7 .6Hz, 1H), 3.83(d, J=12.8Hz, 1H), 3.43(d, J=13.2Hz, 1H), 2.90(s, 3H), 2.83(s, 3H). 19 F NMR (376MHz, MeOD-d4)δ ppm-132.03(s, 1F).

[0539] Example 194: 3-amino-7-bromo-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one The title compound, TIFF2026507114000409.tif39170, was prepared in a manner similar to the preparation of Example 163, substituting 5-bromo-6-methyl-pyridin-3-amine for 2-chloro-6-cyclopropyl-pyridin-4-amine in step 1 of the synthesis of Int-25. Example 194 (10.1 mg) was obtained as a yellow solid. MS (ESI+ )obsd.[(M+H) + ]:388.3.

[0540] Example 194: 1 H NMR (400MHz, DMSO-d6) δ ppm 13.45(s, 1H), 12.10(s, 1H), 7.71(s, 1H), 7.59(s, 1H), 7.34(dd, J=8.0, 11.2Hz, 1H), 7.11(dd, J=4.0, 7.6Hz, 1H), 5.40(s, 2H), 2.47(s, 3H).

[0541] Example 195: 3-amino-7-ethyl-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000410.tif39170

[0542] Step 1: 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-7-vinyl-1,5-naphthyridin-2(1H)-one A mixture of Example 194 (200 mg, 0.52 mmol), vinylboronic acid pinacol ester (159 mg, 1.03 mmol), Pd(dppf)Cl2 (37.7 mg, 0.05 mmol), and Cs2CO3 (336 mg, 1.03 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. Upon completion, the reaction was concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluted with EtOAc: PE = 0-40%) to give compound 195a (80.0 mg, 46.3% yield) as a yellow solid. MS (ESI) + ) and observed by [(M+H) + ]:336.1.

[0543] Step 2: 3-amino-7-ethyl-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one TIFF2026507114000412.tif39170 A mixture of compound 195a (25.0 mg, 0.07 mmol) and Pd / C (25.0 mg) in methanol (2 mL) / THF (2 mL) was stirred under a hydrogen atmosphere (15 Psi) at 25 °C for 0.2 h. Upon completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (NH4HCO3 as eluent) to give Example 195 (5.39 mg, 21.4% yield) as a white solid. MS (ESI) + )obsd.[(M+H) + ]:338.1.

[0544] Example 195: 1 H NMR (400MHz, MeOD-d4) δ ppm 7.62(d, J=2.8Hz, 1H), 7.47(s, 1H), 7.28(dd, J=8.0, 10.8Hz, 1H), 7.15(dd, J =4.0, 8.0Hz, 1H), 2.71(q, J=7.6Hz, 2H), 2.31(s, 3H), 1.28(t, J=7.6Hz, 3H). 19 F NMR (377MHz, MeOD-d4)δ ppm-134.89(s, 1F).

[0545] biological example Example 200: ADP-Glo ​​Assay: Myt1 kinase activity was detected using a recombinant human Myt1 kinase assay that measures ATP hydrolysis using a commercially available ADP-Glo ​​assay (Promega ADP-Glo™ Kinase Assay, 10000 assay, #V9102). Briefly, 50 nL of compound (diluted in DMSO) was added to the microplate using an ECHO Liquid Handler. After this, 2.5 μL of recombinant human Myt1 (full-length PKMYT1 recombinant human protein expressed in insect cells) was prepared in reaction buffer (50 mM HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid), 10 mM MgCl, 1 mM EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid), 0.1 mg / ml BSA (bovine serum albumin), 1 mM DTT (dithiothreitol)) and added to a 384-well white microplate (Corning #4512) and incubated at 22 °C for 15 min. Ultrapure adenosine triphosphate (ATP) solution (Promega, ADP-Glo ​​kit) was diluted in the reaction buffer, and 2.5 μL was added to the microplate. The plate was briefly spun down and incubated at 30 °C for 60 min. The final Myt1 enzyme concentration was 20 nM, and the final ATP concentration was 300 μM. After a 60-minute incubation, 5 μL of ADP-Glo ​​reagent was added, the plate was briefly swirled, sealed, and incubated in the dark at 22°C for 60 minutes. After this, 10 μL of kinase detection reagent was added per well, the plate was briefly swirled, sealed, and incubated in the dark at 22°C for 30 minutes. Luminescence was read using an Envision (250 ms integration). The IC for each inhibitor compound tested was calculated. 50 and % maximum inhibition were calculated.

[0546] Exemplary prepared compounds and their activities are shown in Table 16 below. [Table 16] TIFF2026507114000414.tif173170

[0547] Example 201: Human microsome stability assay The human microsomal stability assay is used to rapidly evaluate the metabolic stability of compounds of the present invention in human liver microsomes. Human liver microsomes (Cat. No.: 452117, Corning, USA) were preincubated with test compounds in 100 mM potassium phosphate buffer, pH 7.4, at 37°C for 10 minutes. The reaction was initiated by adding an NADPH-regenerating system. 1 μM compound, 0.5 mg / mL liver microsomal protein, 1 mM MgCl2, and 1 mM NADPH were incubated in 100 mM potassium phosphate buffer (pH 7.4). After incubation at 37°C for 0, 3, 6, 9, 15, and 30 minutes, the reaction was stopped by adding 300 μL of cold acetonitrile (containing an internal standard) to 100 μL of the incubation mixture. After precipitation and centrifugation, the amount of compound remaining in the sample was determined by LC-MS / MS. Controls without NADPH regeneration were also prepared and analyzed at 0 and 30 minutes. The compounds of the present invention showed good stability to human liver microsomes in the above assay, and the results are shown in Table 17 below.

number

[0548] TIFF2026507114000416.tif251170TIFF2026507114000417.tif14170

[0549] Example 202: Human hepatocyte stability assay Thawing medium and incubation medium were warmed to 37°C, and human frozen hepatocytes (product number X008001, Bioreclamation IVT) were thawed. Cell viability and density were measured, and the cell suspension was diluted to 2 × 10 in incubation medium (William's E medium containing 10% FBS (fetal bovine serum), 50 U / mL pen-strep, 0.004 mg / mL insulin, and 0.4 mM L-glutamine). 6Adjust to cells / mL. Place 50 μl of cell suspension into an incubation plate (Thermo 96 Deep Well PP Plate Cat. No. 260251). Preincubate the incubation plate at 37°C in a CO2 incubator with an appropriate shaking speed (typically 900 rpm) for a minimum of 30 minutes. Dilute compounds in incubation medium to obtain 2x the incubation concentration (1 μM incubation should yield 2 μM compound). After preincubation, start the kinetic analysis by adding 50 μl of compound. A 100 μL incubation yields 1x10 6 The wells contained 1 μM of cells / mL and 1 μM compound. Samples were single (one compound per well for each time point). At the appropriate sampling time, 200 μl of acetonitrile containing the internal standard was added directly to the well to stop the reaction. Single copies were taken at t=2, 10, 20, 40, 60, and 120 min. Samples were centrifuged at 4000 rpm for 10 min. Samples were assayed by LC / MS / MS. [Table 18]

[0550] Example 203: GSH adduct screening assay All compounds, including positive controls (e.g., diclofenac, troglitazone, and nefazodone) and solvent controls (pure DMSO), are incubated in 450 μl of 0.1 M sodium phosphate buffer, pH 7.4, containing human liver microsomes (HLMs) at 20 μM (1 μl of 10 mM DMSO stock solution added) in a 96-deep-well plate (Eppendorf). The microsomal protein concentration is 1 mg / ml. Pipetting is performed with a TECAN pipetting robot. After a 5-minute preincubation at 37°C, the reaction is initiated by adding 50 μl of buffer containing GSH (100 mM) and NADPH (20 mM). Fresh stock solutions of GSH and NADPH are prepared before each experiment. The final concentrations are 5 mM for GSH and 1 mM for NADPH. After incubation at 37° C. for 60 min (shaking at 800 rpm), the reaction is quenched with 500 μl of cold acetonitrile and centrifuged at 5000×g for 11 min at 25° C. Before analysis, the supernatant is divided into two fractions of 450 and 400 μl, respectively, and subsequently evaporated to a volume of approximately 150 μl using a stream of N at 35° C.

[0551] Analysis was performed by UPLC using a quadrupole time-of-flight mass spectrometer. Data analysis and evaluation were accomplished using an automated approach using software (MassMetaSite and WebMetaBase) to extract and identify GSH conjugates based on the presence of multiple collision-induced neutral losses and fragment ions specific to glutathione conjugates in the MS spectrum. The GSH assay provides a qualitative endpoint. The assay readout is binary: GSH adducts are either found (flag) or not (no flag). [Table 19]

Claims

1. Formula (I) A compound of the formula: R １ is H, halogen or C １－６ is alkyl, R ２ H, halogen, cyano, C ３－７ Cycloalkoxy, C １－６ Alkyl, C １－６ Alkoxy or halo C １－６ is alkyl, R ３ is H or a halogen, R ４ is H, halogen or C １－６ is alkyl, A １ But N or CR ５ and A ２ But N or CR ６ and A ３ But N or CR ７ and A ４ But N or CR ８ and R ５ , R ６ , R ７ and R ８ each independently represents H, a halogen, C １－６ Alkyl, deuterated C １－６ Alkyl, C ３－７ Cycloalkyl C １－６ Alkyl, (C １－６ alkylamino)C １－６ Alkyl, hydroxy C １－６ Alkyl, haloC １－６ Alkyl, C １－６ Alkoxy C １－６ Alkyl, C ３－７ Cycloalkyl, haloC ３－７ Cycloalkyl, C １－６ Alkyl C ３－７ Cycloalkyl, C １－６ Alkoxy, C ３－７ Cycloalkyl C １－６ Alkoxy, (C １－６ alkylamino)C １－６ Alkoxy, (hydroxyl) (C １－６ alkyl) C １－６ Alkoxy, (cyano C ３－７ Cycloalkyl)C １－６ Alkoxy, C １－６ Alkoxy-oxo-C １－６ Alkoxy, HaloC １－６ Alkoxy, C ３－７ Cycloalkoxy, cyano C ３－７ Cycloalkoxy, halo C ３－７ Cycloalkoxy, (hydroxyl) (C １－６ alkyl) C ３－７ Cycloalkoxy, C １－６ Alkoxycarbonyl C ３－７ Cycloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, hydroxy C ２－６ Alkynyl, C １－６ Alkoxy C ２－６ Alkynyl, Morpholino C ２－６ Alkynyl, (hydroxyl) (C １－６ alkyl) C ２－６ Alkynyl, (C １－６ Alkoxy) (C １－６ alkyl) C ２－６ Alkynyl, (hydroxytetrahydrofuranyl)C ２－６ Alkynyl, (C １－６ alkylamino)C ２－６ Alkynyl, (amino) (C １－６ alkynyl)C ２－６ Alkynyl, C １－６ Alkoxycarbonyl, C １－６ Alkyl C ２－６ Alkynyl, (hydroxyl) (C １－６ alkyl) C ２－６ Alkynyl, oxetanyl C ２－６ Alkynyl, C １－６ Alkylamino, acyl, cyano, carboxy, C １－６ Alkylsulfanyl, C １－６ Alkylsulfinyl, C １－６ alkylsulfonyl, benzyloxy, aryl, a 5- to 8-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, and a 5- to 8-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, wherein each of the aryl, heterocyclyl, and heteroaryl is independently selected from halogen, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Alkylcarbamoyl, haloC １－６ a compound optionally substituted with alkyl or hydroxyl, or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1 , R １ is H or C １－６ is alkyl, R ２ H, halogen, C １－６ Alkyl or halo C １－６ is alkyl, R ３ is H or a halogen, R ４ is H, halogen or C １－６ is alkyl, A １ But N or CR ５ and R ５ H, halogen, C １－６ Alkyl, haloC １－６ Alkyl, C １－６ Alkoxy or C ３－７ is cycloalkyl, A ２ But N or CR ６ and R ６ H, halogen, C １－６ Alkyl, hydroxy C １－６ Alkyl, deuterated C １－６ Alkyl, haloC １－６ Alkyl, C ３－７ Cycloalkyl C １－６ Alkyl, C ３－７ Cycloalkyl, haloC ３－７ Cycloalkyl, C １－６ Alkyl C ３－７ Cycloalkyl, C １－６ Alkoxy, HaloC １－６ Alkoxy, C ３－７ Cycloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, cyano, C １－６ Alkylsulfanyl, C １－６ Alkylsulfinyl, C １－６ alkylsulfonyl, aryl, a 5- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, wherein each of the aryl, heterocyclyl, and heteroaryl is independently selected from halogen, C １－６ Alkyl, haloC １－６ Alkyl, or C １－６ optionally substituted with alkylcarbamoyl; A ３ But N or CR ７ and R ７ H, halogen, C １－６ Alkyl, hydroxy C １－６ Alkyl, haloC １－６ Alkyl, (C １－６ alkylamino)C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Alkoxy, HaloC １－６ Alkoxy, C ３－７ Cycloalkyl C １－６ Alkoxy, (C １－６ alkylamino)C １－６ Alkoxy, (hydroxyl) (C １－６ alkyl) C １－６ Alkoxy, (cyano C ３－７ Cycloalkyl)C １－６ Alkoxy, C １－６ Alkoxy-oxo-C １－６ Alkoxy, C ３－７ Cycloalkoxy, cyano C ３－７ Cycloalkoxy, halo C ３－７ Cycloalkoxy, (hydroxyl) (C １－６ alkyl) C ３－７ Cycloalkoxy, C １－６ Alkoxycarbonyl C ３－７ Cycloalkoxy, C １－６ Alkylamino, C ２－６ Alkenyl, C ２－６ Alkynyl, hydroxy C ２－６ Alkynyl, C １－６ Alkoxy C ２－６ Alkynyl, Morpholino C ２－６ Alkynyl, (hydroxyl) (C １－６ alkyl) C ２－６ Alkynyl, (C １－６ Alkoxy) (C １－６ alkyl) C ２－６ Alkynyl, (hydroxytetrahydrofuranyl)C ２－６ Alkynyl, (C １－６ alkylamino)C ２－６ Alkynyl, (amino) (C １－６ alkyl) C ２－６ Alkynyl, C １－６ Alkyl C ２－６ Alkynyl, (hydroxyl) (C １－６ alkyl) C ２－６ Alkynyl, oxetanyl C ２－６ Alkynyl, C １－６ alkoxycarbonyl, acyl, carboxy, cyano, or a 5-8 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein each of the heterocyclyl and heteroaryl is independently selected from C １－６ Alkyl, C ３－７ Cycloalkyl, haloC １－６ optionally substituted with alkyl or hydroxyl; A ４ But N or CR ８ and R ８ H, halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkoxy C １－６ Alkyl, haloC １－６ Alkoxy, C ３－７ Cycloalkyl C １－６ Alkoxy, C ３－７ a compound which is cycloalkoxy, cyano, or benzyloxy; or a pharmaceutically acceptable salt thereof.

3. R １ 3. The compound of claim 1 or 2, wherein is H or methyl.

4. R １ The compound according to any one of claims 1 to 3, wherein is H.

5. R ２ The compound of any one of claims 1 to 4, wherein is H, fluoro, chloro, methyl, or trifluoromethyl.

6. R ２ The compound according to any one of claims 1 to 4, wherein is a halogen.

7. R ２ The compound of claim 6, wherein is fluoro or chloro.

8. R ３ The compound of any one of claims 1 to 7, wherein is H or fluoro.

9. R ３ The compound of any one of claims 1 to 8, wherein is H.

10. R ４ The compound of any one of claims 1 to 9, wherein is H, fluoro, chloro, or methyl.

11. R ４ The compound of any one of claims 1 to 10, wherein is H.

12. R ５ The compound of any one of claims 1 to 11, wherein is H, chloro, fluoro, methyl, difluoromethyl, methoxy, or cyclopropyl.

13. R ５ is H, halogen, or C １－６ The compound of any one of claims 1 to 11, which is alkyl.

14. R ５ 14. The compound of claim 13, wherein is H, chloro, or methyl.

15. R ６ is H, fluoro, chloro, bromo, iodo, methyl, trideuteriomethyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, difluoroethyl, hydroxyisopropyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, cyclobutyl, fluorocyclopropyl, methylcyclopropyl, dimethylcyclopropyl, methoxy, ethoxy, isopropoxy, trifluoroethoxy, cyclobutoxy, vinyl, isopropenyl, ethynyl, azetidinyl, oxetanyl, morpholino, cyano, methylsulfanyl, methylsulfinyl, methylsulfonyl, phenyl, or heteroaryl selected from imidazolyl, pyrazolyl, isothiazolyl, pyridyl, pyridazinyl, and thiazolyl, wherein each of phenyl and heteroaryl is independently optionally substituted with fluoro, methyl, trifluoromethyl, or dimethylcarbamoyl.

16. R ６ is H, chloro, fluoro, bromo, iodo, methyl, trideuteriomethyl, ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1-hydroxy-1-methyl-ethyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, cyclobutyl, 2-fluorocyclopropyl, 1-methylcyclopropyl, (1R,2R)-2-methylcyclopropyl, methoxy, ethoxy, isopropoxy, 2,2,2-trifluoroethoxy, cyclobutoxy, biphenyl, 16. The compound of any one of claims 1 to 15, wherein the compound is phenyl, isopropenyl, ethynyl, azetidin-1-yl, oxetan-3-yl, morpholino, cyano, methylsulfanyl, methylsulfinyl, methylsulfonyl, 4-(dimethylcarbamoyl)phenyl, 3-methylimidazol-4-yl, 1H-pyrazol-5-yl, isothiazol-5-yl, 2-(trifluoromethyl)-4-pyridyl, 5-fluoro-2-pyridyl, 2-pyridyl, pyridazin-4-yl, or thiazol-2-yl.

17. R ６ H, halogen, C １－６ Alkyl, haloC １－６ Alkyl, deuterated C １－６ Alkyl, C ３－７ Cycloalkyl or C １－６ The compound of any one of claims 1 to 14, which is alkylsulfanyl.

18. R ６ 18. The compound of claim 17, wherein is H, chloro, methyl, trideuteriomethyl, ethyl, isopropyl, difluoroethyl, trifluoroethyl, cyclopropyl, or methylsulfanyl.

19. R ７ is H, chloro, bromo, methyl, ethyl, hydroxyisopentyl, hydroxyisopropyl, trifluoromethyl, cyclopropyl, 3-(dimethylamino)propyl, methoxy, propoxy, isopropoxy, 1-bicyclo[1.1.1]pentanylmethoxy, difluoromethoxy, trifluoroethoxy, difluoroethoxy, difluoropropoxy, (dimethylamino)ethoxy, methylpropoxy, cyclopropylmethoxy, (1-cyanocyclopropyl)methoxy, 2-ethoxy-2-oxo-ethoxy, cyclobutoxy, cyanocyclobutoxy, fluorocyclobutoxy, 3-(1-methylethyl)cyclobutoxy, 3-methoxycarbonylcyclobutoxy, isopropylamino, vinyl, ethynyl, hydroxybutynyl, methoxypropynyl, morpholinopropynyl, (hydroxyl)(methyl)butynyl, methoxymethylbutynyl, 2-(4-hydroxytetrahydrofuran-3-yl)- 1-ethynyl, dimethylaminopropynyl, 3-methyl-1-but-1-ynyl, methylbutynyl, 3-hydroxy-3-methyl-butynyl, 3-methoxy-3-methyl-butynyl, 2-(octan-3-yl)-ethynyl, methoxycarbonyl, carboxy, cyano, acetyl, thienyl, thiazolyl, oxazolyl, pyridyl, or pyrrolidinyl, morpholino, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 19. The compound of any one of claims 1 to 18, wherein the heterocyclyl is selected from butanyl, 2,5-diazabicyclo[2.2.1]heptanyl, piperazinyl, 2,5-diazabicyclo[2.2.2]octanyl, piperidyl, oxetanyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, wherein the heterocyclyl is optionally substituted with methyl, isopropyl, cyclopropyl, trifluoroethyl, or hydroxyl.

20. R ７ is H, chloro, bromo, methyl, ethyl, 3-hydroxy-3-methyl-1-butyl, 1-hydroxy-1-methyl-ethyl, trifluoromethyl, cyclopropyl, 3-(dimethylamino)propyl, methoxy, propoxy, isopropoxy, 1-bicyclo[1.1.1]pentanylmethoxy, difluoromethoxy, trifluoroethoxy, 2,2-difluoroethoxy, 3,3-difluoropropoxy, 2-(dimethylamino)ethoxy, 2-hydroxy-2-methylpropoxy, cyclopropylmethoxy, (1- cyanocyclopropyl)methoxy, 2-ethoxy-2-oxo-ethoxy, cyclobutoxy, 3-cyanocyclobutoxy, 3-fluorocyclobutoxy, 3-(1-hydroxy-1-methyl-ethyl)cyclobutoxy, 3-methoxycarbonylcyclobutoxy, isopropylamino, vinyl, ethynyl, 3-hydroxybut-1-ynyl, 3-methoxyprop-1-ynyl, 3-morpholinoprop-1-ynyl, 3-hydroxy-3-methyl-1-but-1-ynyl, 3-methoxy-3-methyl-but-1-ynyl, 2-( 4-hydroxytetrahydrofuran-3-yl)-1-ethynyl, 3-(dimethylamino)prop-1-ynyl, 3-amino-3-methyl-but-1-ynyl, 3-methylbut-1-ynyl, 3-hydroxy-3-methyl-but-1-ynyl, 3-methoxy-3-methyl-but-1-ynyl, 2-(oxetan-3-yl)-ethynyl, methoxycarbonyl, carboxy, cyano, acetyl, 2-thienyl, thiazol-4-yl, thiazol-2-yl, oxazol-2-yl, 2-pyridyl, 3-hydroxypyrrolidine octan-1-yl, morpholino, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-methyl-2,6-diazaspiro[3.3]heptan-6-yl, 5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, 5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl, 4-piperidyl, 1-methyl-4-piperidyl, 1-(2,2,The compound according to any one of claims 1 to 19, which is 2-trifluoroethyl)-4-piperidyl, oxetan-3-yl, 1-methylazetidin-3-yl, or 2-oxa-6-azaspiro[3.3]heptan-6-yl.

21. R ７ H, halogen, C １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkoxy, C ３－７ Cycloalkyl C １－６ Alkoxy, (hydroxyl) (C １－６ alkyl) C ２－６ Alkynyl or hydroxy C ２－６ The compound of any one of claims 1 to 18, which is alkynyl.

22. R ７ 22. The compound of claim 21, wherein is H, chloro, methyl, cyclopropyl, cyclobutoxy, cyclopropylmethoxy, 3-hydroxy-3-methyl-1-but-1-ynyl, or 3-hydroxybut-1-ynyl.

23. R ８ is H, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 3,3-difluoropropoxy, cyclopropylmethoxy, cyclopropoxy, cyclobutoxy, cyano, or benzyloxy.

24. R ８ But C １－６ Alkoxy, HaloC １－６ Alkoxy, C ３－７ The compound of any one of claims 1 to 22, which is cycloalkoxy or cyano.

25. R ８ 25. The compound of claim 24, wherein is ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, cyclopropoxy, cyclobutoxy, or cyano.

26. 3. A compound according to claim 1 or 2, R １ is H, R ２ is a halogen, R ３ is H, R ４ is H, A １ But, CR ５ and R ５ is H, halogen or C １－６ is alkyl, A ２ But N or CR ６ and R ６ H, halogen, C １－６ Alkyl, deuterated C １－６ Alkyl, haloC １－６ Alkyl, C ３－７ cycloalkyl, or C １－６ alkylsulfanyl, A ３ But N or CR ７ and R ７ H, halogen, C １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkoxy, C ３－７ Cycloalkyl C １－６ Alkoxy, (hydroxyl) (C １－６ alkyl) C ２－６ Alkynyl or hydroxy C ２－６ is alkynyl, A ４ But N or CR ８ and R ８ But C １－６ Alkoxy, HaloC １－６ Alkoxy, C ３－７ A compound which is cycloalkoxy or cyano.

27. 27. The compound of claim 26, R １ is H, R ２ is fluoro or chloro, R ３ is H, R ４ is H, A １ But, CR ５ and R ５ is H, chloro or methyl, A ２ But N or CR ６ and R ６ is H, chloro, methyl, trideuteriomethyl, ethyl, isopropyl, difluoroethyl, trifluoroethyl, cyclopropyl or methylsulfanyl, A ３ But N or CR ７ and R ７ is H, chloro, methyl, cyclopropyl, cyclobutoxy, cyclopropylmethoxy, 3-hydroxy-3-methyl-1-but-1-ynyl, or 3-hydroxybut-1-ynyl; A ４ But N or CR ８ and R ８ is ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, cyclopropoxy, cyclobutoxy, or cyano.

28. A compound selected from: 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-fluoro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(trifluoromethyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methoxy-1H-1,5-naphthyridin-2-one, 4-[7-amino-8-(7-fluoro-1H-indazol-4-yl)-6-oxo-5H-1,5-naphthyridin-3-yl]-N,N-dimethyl-benzamide, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(3-methylimidazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(1H-pyrazol-5-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-isothiazol-5-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-[2-(trifluoromethyl)-4-pyridyl]-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-pyridazin-4-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(2-pyridyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(5-fluoro-2-pyridyl)-1H-1,5-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-thiazol-2-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,7-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-morpholino-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-(1-hydroxy-1-methyl-ethyl)-1H-1,5-naphthyridin-2-one, 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(4-methylpiperazin-1-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(isopropylamino)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxypyrrolidin-1-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-morpholino-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(4-isopropylpiperazin-1-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-(4-cyclopropylpiperazin-1-yl)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methyl-butyl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(1H-indazol-4-yl)-7-thiazol-2-yl-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(6-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-chloro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-methyl-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(6,7-difluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(5-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-[7-(trifluoromethyl)-1H-indazol-4-yl]-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-fluoro-5-methyl-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(5-chloro-7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-piperazin-1-yl-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(3-methyl-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-6-(cyclobutoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-(cyclopropylmethoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,7-dimethyl-1H-quinolin-2-one, 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-7,8-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methoxy-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7,8-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-6,8-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-6,7-dimethyl-1H-1,5-naphthyridin-2-one, 1-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxymethyl]cyclopropanecarbonitrile, 3-amino-6-(2,2-difluoroethoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-7-methyl-1H-1,5-naphthyridin-2-one, ethyl 2-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxy]acetate, 3-amino-6-(difluoromethoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-(1-bicyclo[1.1.1]pentanylmethoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-isopropoxy-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-propoxy-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2,2,2-trifluoroethoxy)-1H-1,5-naphthyridin-2-one, methyl 3-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxy]cyclobutanecarboxylate, 3-amino-6-[2-(dimethylamino)ethoxy]-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(4-piperidyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methyl-but-1-ynyl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-methoxyprop-1-ynyl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-methoxy-3-methyl-but-1-ynyl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-[2-(4-hydroxytetrahydrofuran-3-yl)ethynyl]-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxybut-1-ynyl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-[3-(dimethylamino)prop-1-ynyl]-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(3-morpholinoprop-1-ynyl)-1H-1,5-naphthyridin-2-one, 3-amino-6-(3-amino-3-methyl-but-1-ynyl)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(2-hydroxy-2-methyl-propoxy)-7-methyl-1H-1,5-naphthyridin-2-one, 3-[[7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridin-2-yl]oxy]cyclobutanecarbonitrile, trans-3-amino-6-(3-fluorocyclobutoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-(3,3-difluoropropoxy)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(1-methyl-4-piperidyl)-1H-1,5-naphthyridin-2-one, 7-amino-8-(7-fluoro-1H-indazol-4-yl)-2,3-dimethyl-5H-pyrido[2,3-b]pyrazin-6-one, 7-amino-8-(7-fluoro-1H-indazol-4-yl)-2,4-dimethyl-5H-pyrido[3,2-d]pyrimidin-6-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-[3-(dimethylamino)propyl]-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, methyl 7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridine-2-carboxylate, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(1-hydroxy-1-methyl-ethyl)-7-methyl-1H-1,5-naphthyridin-2-one, 7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridine-2-carboxylic acid, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one, 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 7-amino-8-(7-fluoro-1H-indazol-4-yl)-3-methyl-6-oxo-5H-1,5-naphthyridine-2-carbonitrile, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(oxetan-3-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,8-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-6-chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-[3-(1-hydroxy-1-methyl-ethyl)cyclobutoxy]-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(trifluoromethyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(1-methylazetidin-3-yl)-1H-1,5-naphthyridin-2-one, 3-amino-7-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, or 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(trideuteriomethyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-7-methyl-1H-quinolin-2-one, 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-quinolin-2-one, 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-quinolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-quinolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-1H-quinolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,7-dimethyl-1H-1,8-naphthyridin-2-one, 3-amino-6-bromo-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6,7,8-trimethyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-6-ethynyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 6-acetyl-3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-vinyl-1H-1,5-naphthyridin-2-one, 3-amino-6,8-dicyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-bromo-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-iodo-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-(azetidin-1-yl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 7-amino-8-(7-fluoro-1H-indazol-4-yl)-4-methyl-6-oxo-5H-1,5-naphthyridine-3-carbonitrile, 3-amino-7-cyclobutyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-pyridazin-4-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-thiazol-2-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(oxetan-3-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-vinyl-1H-1,5-naphthyridin-2-one, 3-amino-7-ethynyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-isopropenyl-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-cyclopentyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-isopropyl-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-ethyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(1-methylcyclopropyl)-1H-1,5-naphthyridin-2-one, 3-amino-7-(2,2-dimethylcyclopropyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-(cyclopropylmethyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-(2-fluorocyclopropyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-1H-1,5-naphthyridin-2-one, 3-amino-7-(1,1-difluoroethyl)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-fluoro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methoxy-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-(2,2,2-trifluoroethoxy)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-isopropoxy-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-(cyclobutoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-ethoxy-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-methylsulfanyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-methylsulfinyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-methylsulfonyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-7-[rac-(1R,2R)-2-methylcyclopropyl]-1H-1,5-naphthyridin-2-one, 3-amino-8-(difluoromethyl)-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-7,8-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-hydroxy-3-methyl-but-1-ynyl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-(3-methoxy-3-methyl-but-1-ynyl)-8-methyl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-6-[2-(oxetan-3-yl)ethynyl]-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2-thienyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-thiazol-4-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-thiazol-2-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-oxazol-2-yl-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(2-pyridyl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-6-(3-methylbut-1-ynyl)-1H-1,5-naphthyridin-2-one, 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-7-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,5-naphthyridin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6,7-dimethyl-1H-1,5-naphthyridin-2-one, 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-7,8-dimethyl-1H-1,6-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-7,8-dimethyl-2-oxo-1H-1,6-naphthyridine-5-carbonitrile, 3-amino-5-chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,6-naphthyridin-2-one, 3-amino-5-chloro-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,6-naphthyridin-2-one, 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,6-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,6-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-5-methyl-1H-1,6-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-2-oxo-1H-1,6-naphthyridine-5-carbonitrile, 3-amino-7-cyclopropyl-5-(difluoromethoxy)-4-(7-fluoro-1H-indazol-4-yl)-1H-1,6-naphthyridin-2-one, 3-amino-7-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-1H-1,6-naphthyridin-2-one, 3-amino-8-fluoro-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-1H-1,6-naphthyridin-2-one, 3-amino-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-1H-1,6-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-8-methyl-1H-1,6-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-methoxy-6,8-dimethyl-1H-1,7-naphthyridin-2-one, 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-chloro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5,8-dimethyl-1H-1,7-naphthyridin-2-one, 3-amino-5-ethyl-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-fluoro-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-benzyloxy-8-chloro-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-naphthyridin-2-one, 3-amino-5-benzyloxy-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-isopropoxy-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-5-(2,2,2-trifluoroethoxy)-1H-1,7-naphthyridin-2-one, 3-amino-5-ethoxy-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-(difluoromethoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-(2,2-difluoroethoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-(cyclopropoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-(3,3-difluoropropoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-5-(cyclobutoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-5-propoxy-1H-1,7-naphthyridin-2-one, 3-amino-5-(cyclopropylmethoxy)-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-8-methyl-5-(trifluoromethoxy)-1H-1,7-naphthyridin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-5-(methoxymethyl)-8-methyl-1H-1,7-naphthyridin-2-one, 3-amino-7-bromo-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one, 3-amino-7-ethyl-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,5-naphthyridin-2-one, or a pharmaceutically acceptable salt thereof.

29. Formula (I) 1. A method for preparing a compound having the structure: (a) Formula (IX) decomposition of the pyridinium salt of the compound of formula (I) with hydrazine hydrate; (b) Formula (XVII) and a compound of formula (XVIII) is subjected to a cross-coupling reaction in the presence of a catalyst to give a compound of formula (XIX): and then deprotecting said compound of formula (XIX) in the presence of an acid; (c) Formula (XXIV) Decomposition of the pyridinium salt of formula (XIX) with hydrazine hydrate and then deprotecting the compound of formula (XIX) in the presence of an acid including one of In the formula, B ３ is a halogen, preferably bromine or iodide, B ４ is a boronic acid, a boronic acid ester, or tributyltin, and PG ２ is hydrogen or a protecting group, preferably a tetrahydropyranyl group, the acid is preferably trifluoroacetic acid or HCl, and the catalyst is preferably Pd(dtbpf)Cl ２ , Pd(dppf)Cl ２ or Pd(PPh ３ ) ４ and In the formula, R １ , R ２ , R ３ , R ４ , A １ , A ２ , A ３ , and A ４ is as defined in any one of claims 1 to 27.

30. 30. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, when produced according to the method of claim 29.

31. A pharmaceutical composition comprising the compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

32. 29. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

33. 29. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

34. 30. Use of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof for the treatment of cancer.

35. Use of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof for inhibiting PKMYT1.

36. 30. Use of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer.

37. Use of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the inhibition of PKMYT1.

38. 30. A method for the treatment of cancer, comprising administering an effective amount of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

39. 39. The use of claim 34 or 36, or the method of claim 38, wherein the cancer is a cancer of the pancreas, liver, lung, breast, stomach, colon, urogenital tract or ovary.

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