Substituted pyridazinone compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a substituted pyridazinone compound as well as a preparation method and application thereof. The invention discloses a compound as shown in a formula (I), and pharmaceutically acceptable salts or stereoisomers thereof, wherein the definition of each group in the formula is shown in the specification. In addition, the invention also discloses a pharmaceutical composition containing the compound, and application of the pharmaceutical composition in preparation of drugs for treating RIPK1 related diseases or symptoms.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Chinese patent application CN202410571617.2 filed on May 9, 2024; the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to the field of medical technology, and in particular to a substituted pyridazinone compound and its use as an RIPK1 inhibitor. Background Art

[0004] Necroptosis (programmed necrosis) is a recently discovered, caspase-independent form of programmed cell death, distinct from apoptosis. It is regulated by death signals and exhibits necrosis-like structural features. Unlike apoptosis, programmed necrosis does not form apoptotic bodies or chromatin condensation. In contrast to necrosis, programmed necrosis is a controlled cell death regulated by multiple genes. Following the addition of the caspase inhibitor Z-VAD-FMK to the in vitro culture system, TNF can induce programmed necrosis. Necrotic morphology is characterized by cell swelling, rupture, and release of cellular contents, which in turn triggers inflammation and immune responses. In addition to TNF, TLR3 and TLR4 ligands, as well as certain bacterial and viral infections, can also induce programmed necrosis.

[0005] Programmed necroptosis (necroptosis) is closely associated with the development and progression of diseases such as inflammation, autoimmune diseases, neurodegenerative diseases, and tumors. For example, studies have shown that programmed necroptosis (necroptosis) is a key cause of systemic inflammatory response syndrome (SIRS). SIRS is a systemic inflammatory response caused by infectious or non-infectious factors, leading to an uncontrolled and self-destructive response. Critically ill patients are often susceptible to SIRS due to reduced compensatory anti-inflammatory responses and metabolic dysfunction. Long-term studies have shown that the TNFα-induced SIRS model is highly correlated with RIPK1-dependent necroptosis. Inflammatory bowel disease (IBD) refers to abnormal immune-mediated intestinal inflammation caused by environmental, genetic, infectious, or immune factors. It is a chronic, nonspecific intestinal inflammatory disease. While its pathogenesis remains unclear, excessive apoptosis of intestinal epithelial cells, impaired intestinal mucosal barrier, and increased intestinal epithelial permeability are believed to contribute to the development of IBD. Studies have shown that programmed necroptosis plays a key role in the pathogenesis of IBD. In addition, programmed cell necrosis also plays an important role in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Activated microglia play a key role in the development of Alzheimer's disease (AD), and RIPK1 is highly expressed in microglia. RIPK1 inhibitors can effectively protect Aβ-induced neuronal cell programmed necrosis in vitro. In addition to Alzheimer's disease, programmed necrosis is also involved in the occurrence and development of many neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD). In 2016, Strilic et al. first revealed that tumor cells can induce programmed necrosis of vascular endothelial cells, and then tumor cells pass through the vascular wall and achieve distal metastasis through the blood circulation. This is an important cause of tumor metastasis. Experiments have shown that RIPK1 inhibitors can effectively inhibit tumor metastasis. In addition, studies have shown that RIPK1 kinase can promote the differentiation of tolerant macrophages in the pancreatic cancer tumor microenvironment, and RIPK1 inhibition can differentiate immunogenic macrophages in the pancreatic cancer tumor microenvironment, leading to adaptive immune activation and tumor protection. Summary of the Invention

[0006] The present invention provides a class of RIPK1 inhibitors. The RIPK1 inhibitors of the present invention have the advantages of high activity, low toxicity and side effects, and good physicochemical properties and drug-forming properties.

[0007] In one aspect of the present invention, there is provided a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof:

[0008]

[0009] Where,

[0010] G1, G2, G3, G4 are each independently selected from CH2, CR C R D , NH, N, O or S;

[0011] p is 0, 1, 2, or 3;

[0012] Ring C is absent or is a ring formed by connecting G1, G2, G3, and G4; when ring C is absent, R 1 is connected to ring B at any one of the carbon atoms shared by ring B and ring C, and ring B is optionally replaced by R B replace;

[0013] R B 、R C 、R D Each is independently selected from hydrogen, =O, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0014] X1 is N or CH;

[0015] R X is hydrogen or halogen;

[0016] Ring A is

[0017] A1 is N or CH;

[0018] A2 is N or CR A2 ; A3 is N or CR A3 ; A4 is N or CR A4 ; A5 is N or CR A5 ; A6 is N or CR A6 ;

[0019] R 2 、R 5 Each independently selected from hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl;

[0020] R 3 、R 4 Each is independently selected from hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 8-membered heteroaryl, -4- to 10-membered heterocyclyl-4- to 10-membered heterocyclyl, -5- to 8-membered heteroaryl-C1-C6 alkyl, -5- to 8-membered heteroaryl-4- to 10-membered heterocyclyl, -5- to 8-membered heteroaryl-C1-C6 alkylene-C3-C 10 Cycloalkyl, -5 to 8 membered heteroaryl-C1-C6 alkylene-4 to 10 membered heterocyclic group, -NR a R b 、-C(O)R 31 、-NR c -R 32 、-NR c -C(O)R 33 、-C(O)NR c -R 34 or -C(O)NR c -NR c -C(O)-R 35 wherein the C1-C6 alkyl, -C1-C6 alkylene, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4 to 10 membered heterocyclyl or 5 to 8 membered heteroaryl are optionally substituted by one or more R * replaced by;

[0021] Or, R 3 、R 4 The carbon atoms connected to it together form a 4- to 8-membered partially unsaturated carbon ring, C 6- C 10 aromatic ring or 5 to 8 membered heteroaromatic ring, said 4 to 8 membered partially unsaturated carbon ring, C 6- C 10 The aromatic ring or 5- to 8-membered heteroaromatic ring is optionally substituted with one or more R ** replace;

[0022] R 31 、R 32 、R 33 、R 34 、R 35 Each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C6-C8 aryl, 4- to 10-membered heterocyclic group, 5- to 8-membered heteroaryl, 6- to 12-membered partially unsaturated carbocyclic group, -C3-C6 cycloalkyl-C6-C8 aryl, -C1-C6 alkylene-C1-C6 alkoxy, -C1-C6 alkylene-C3-C 10Cycloalkyl, -C1-C6 alkylene-C6-C8 aryl, -C1-C6 alkylene-4 to 10-membered heterocyclyl, -C1-C6 alkylene-C(O)-4 to 10-membered heterocyclyl, -C1-C6 alkylene-5 to 8-membered heteroaryl, -4 to 10-membered heterocyclyl-4 to 10-membered heterocyclyl, -4 to 10-membered heterocyclyl-NR a C(O)-C1-C6 alkylene-C6-C8 aryl, -5 to 8-membered heteroaryl-C1-C6 alkyl, -5 to 8-membered heteroaryl-C1-C6 alkylene-C(O)-4 to 10-membered heterocyclyl, -5 to 8-membered heteroaryl-C1-C6 alkylene-C6-C8 aryl, -5 to 8-membered heteroaryl-4 to 10-membered heterocyclyl, or -NR a R b wherein the C1-C6 alkyl, C1-C6 alkylene, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C6-C8 aryl, 4 to 10 membered heterocyclyl, 5 to 8 membered heteroaryl, 6 to 12 membered partially unsaturated carbocyclyl, optionally substituted with one or more R *** replace;

[0023] R * Halogen, hydroxy, cyano, C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, -NR a R b or -C(O)R d ;

[0024] R ** Halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 5 to 8 membered heteroaryl; the 5 to 8 membered heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl or C3-C 10 Substitution of cycloalkyl groups;

[0025] R *** =O, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, -NR a R b 、-P(O)R e R f 、-S(O)2R e 、-C(O)OR e 、-C(O)NR a R b 、-OC(O)-R g 、-O-C1-C6 alkylene-R h or -NR c C(O)-R g;

[0026] R 6 is hydrogen, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl;

[0027] R A2 、R A3 、R A4 、R A5 or R A6 Each is independently selected from hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, -NR a R b 、-C(O)NR a R b 、-NR c -C(O)-R H1 、-NR c -C(=NH)-NR c -R H1 、-NR c -C(=S)-NR c -R H1 or -NR c -C(=O)-NR c -R H1 ;

[0028] R H1 C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl or 4- to 10-membered heterocycloalkyl, the 4- to 10-membered heterocycloalkyl being optionally substituted with one or more hydroxy groups;

[0029] In the above groups, R a 、R b 、R d 、R e 、R f 、R g 、R h Each is independently selected from hydrogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy;

[0030] R 1 Selected from

[0031] Among them, R 7 C 6-8 Aryl, the C 6-8 Aryl is optionally substituted with one or more selected from R 71 Substituents substituted;

[0032] R 71is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy or C 3-6 Cycloalkyl;

[0033] Ring D is selected from a 5- or 6-membered monocyclic heteroaryl group or a 4- to 8-membered nitrogen-containing heterocyclic group;

[0034] R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 1f are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl;

[0035] Or, R 1a 、R 1b The carbon atom and nitrogen atom connected thereto together form a 4- to 8-membered nitrogen-containing heterocyclic group;

[0036] Or, R 1b 、R 1e The carbon atoms connected to it together form C 3-6 Cycloalkyl;

[0037] t1 and t2 are each independently selected from 0, 1 or 2;

[0038] In the above groups, the 4- to 10-membered heterocyclic group contains 1, 2, 3 or 4 heterocyclic ring atoms selected from N, O or S; the 5- to 8-membered heteroaryl group contains 1, 2 or 3 heterocyclic ring atoms selected from N, O or S; the 5- or 6-membered monocyclic heteroaryl group contains 1, 2 or 3 heterocyclic ring atoms selected from N, O or S; and the 4- to 8-membered nitrogen-containing heterocyclic group contains at least 1 nitrogen heteroatom as a ring atom.

[0039] In one embodiment, R B 、R C 、R D Each is independently selected from hydrogen, =0 or C1-C6 alkyl.

[0040] In one embodiment, R B 、R C 、R D are each independently selected from hydrogen, =0 or methyl.

[0041] In one embodiment, Formula (IA):

[0042]

[0043] In formula (IA), X1 is N or CH; G1, G2, G3, and G4 are each independently selected from CH2, C(CH3)2, C═O, NH, O, or S; and p is 0, 1, 2, or 3.

[0044] In a preferred embodiment, G1, G2, G3, and G4 are each independently selected from CH2, C═O, NH, O, or S.

[0045] In one example, G4 is C=O.

[0046] In one embodiment, Formula (IB):

[0047]

[0048] In formula (IB), G3 and G4 are each independently selected from CH or N; R C It is hydrogen, =O, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl.

[0049] In one example, G3 is CH and G4 is CH.

[0050] In one example, R C is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl.

[0051] Preferably, R C is hydrogen, methyl, ethyl, propyl or isopropyl.

[0052] More preferably, R C It is a methyl group.

[0053] In one embodiment, Formula (IC):

[0054]

[0055] In formula (IC), X1 is N or CH; R B It is hydrogen, =O, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl.

[0056] Preferably, X1 is N, R B For hydrogen.

[0057] Preferably, X1 is CH, R B is hydrogen, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl.

[0058] In one example, R B is hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy.

[0059] Preferably, RB is ethyl or methoxy.

[0060] In one embodiment, Selected from:

[0061] In one embodiment, Selected from:

[0062] In one embodiment, R X is hydrogen, fluorine, chlorine or bromine, more preferably hydrogen or fluorine.

[0063] In one embodiment, for

[0064] In one embodiment, for

[0065] In one embodiment, Ring A is R 2 、R 3 、R 4 The respective definitions are the same as before;

[0066] In one example, R 2 is hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl.

[0067] Preferably, R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropyl or cyclopentyl.

[0068] More preferably, R 2 is hydrogen or cyclopropyl.

[0069] In one example, R 4 For hydrogen.

[0070] In one example, R 3 is hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 8-membered heteroaryl, -4- to 10-membered heterocyclyl-4- to 10-membered heterocyclyl, -5- to 8-membered heteroaryl-C1-C6 alkyl, -5- to 8-membered heteroaryl-4- to 10-membered heterocyclyl, -5- to 8-membered heteroaryl-C1-C6 alkylene-C3-C 10 Cycloalkyl, -5 to 8 membered heteroaryl-C1-C6 alkylene-4 to 10 membered heterocyclic group, -NR a R b、-C(O)R 31 、-NR c -R 32 、-NR c -C(O)R 33 、-C(O)NR c -R 34 or -C(O)NR c -NR c -C(O)-R 35 wherein the C1-C6 alkyl, -C1-C6 alkylene, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4 to 10 membered heterocyclyl or 5 to 8 membered heteroaryl are optionally substituted with one or more halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 alkyl, 10 Cycloalkyl, -NR a R b or -C(O)R d substituted by a substituent.

[0071] R 31 、R 32 、R 33 、R 34 、R 35 Each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C6-C8 aryl, 4- to 10-membered heterocyclic group, 5- to 8-membered heteroaryl, 6- to 12-membered partially unsaturated carbocyclic group, -C3-C6 cycloalkyl-C6-C8 aryl, -C1-C6 alkylene-C1-C6 alkoxy, -C1-C6 alkylene-C3-C 10 Cycloalkyl, -C1-C6 alkylene-C6-C8 aryl, -C1-C6 alkylene-4 to 10-membered heterocyclyl, -C1-C6 alkylene-C(O)-4 to 10-membered heterocyclyl, -C1-C6 alkylene-5 to 8-membered heteroaryl, -4 to 10-membered heterocyclyl-4 to 10-membered heterocyclyl, -4 to 10-membered heterocyclyl-NR a C(O)-C1-C6 alkylene-C6-C8 aryl, -5 to 8-membered heteroaryl-C1-C6 alkyl, -5 to 8-membered heteroaryl-C1-C6 alkylene-C(O)-4 to 10-membered heterocyclyl, -5 to 8-membered heteroaryl-C1-C6 alkylene-C6-C8 aryl, -5 to 8-membered heteroaryl-4 to 10-membered heterocyclyl, or -NR a R b wherein the C1-C6 alkyl, C1-C6 alkylene, C1-C6 alkoxy, C3-C 10Cycloalkyl, C6-C8 aryl, 4 to 10 membered heterocyclyl, 5 to 8 membered heteroaryl, 6 to 12 membered partially unsaturated carbocyclyl, optionally substituted by one or more selected from =O, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, -NR a R b 、-P(O)R e R f 、-S(O)2R e 、-C(O)OR e 、-C(O)NR a R b 、-OC(O)-R g 、-O-C1-C6 alkylene-R h or -NR c C(O)-R g substituted by a substituent.

[0072] In the above groups, R a 、R b 、R d 、R e 、R f 、R g 、R h Each is independently selected from hydrogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy.

[0073] In one embodiment, R 3 is hydrogen, methyl, ethyl, isopropyl, methoxy, ethoxy, -CH2CH(CH3)2, -(CH2)2C(CH3)3, tert-butyl, amino, cyano, cyclopropyl, cyclopentyl, -(CH2)2OCH2CH3, -CH2OH, -C(CH3)2OH, -C(O)CH3, -C(O)NH2, -C(O)NHOH, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)(CH2)3CH3, -C(O)NH(CH2)3CH3, -C(O)NHC(CH3)3, -C(O)N(CH3)2, -C(O)NHCH2CF3, -C(O)NHCH2CHF2, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -C(O)NHCH(CH3)2,

[0074]

[0075]

[0076]

[0077] In one embodiment, Ring A is R 3 、R 4 Together with the carbon atoms it is connected to form described Optionally, one or more R *** replace.

[0078] In one embodiment, R *** is fluoro, methyl, methoxy, cyclopropyl, -CH2CH(CH3)2 or

[0079] In one embodiment, Ring A is R 2 、R 3 、R 4 The definitions are the same as before.

[0080] In one example, R 2 is hydrogen;

[0081] In one example, R 3 is hydrogen, halogen, cyano, C1-C6 alkyl or -C(O)NR a R b .

[0082] Preferably, R 3 It is hydrogen, cyano or -C(O)NH2.

[0083] More preferably, R 3 It is cyano or -C(O)NH2.

[0084] In one example, R 4 For hydrogen.

[0085] In one embodiment, Ring A is R 2 、R 3 The definitions are the same as before.

[0086] In one example, R 2 For hydrogen.

[0087] In one example, R 3 is hydrogen or -C(O)-C1-C6 alkoxy;

[0088] Preferably, R 3 is -C(O)-C1-C6 alkoxy;

[0089] More preferably, R 3is -C(O)-OCH3, -C(O)-OCH2CH3 or -C(O)-O(CH2)2CH3;

[0090] More preferably, R 3 It is -C(O)-OCH3.

[0091] In one embodiment, Ring A is R 5 、R 6 The definitions are the same as before.

[0092] In one example, R 5 For hydrogen.

[0093] In one example, R 6 is hydrogen or halogen.

[0094] More preferably, R 6 is hydrogen, fluorine or chlorine.

[0095] More preferably, R 6 For chlorine.

[0096] In one embodiment, Ring A is R A6 Same definition as above.

[0097] In one example, R A6 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, 4- to 10-membered heterocycloalkyl, -NR a R b or -NR c -C(O)-C3-C 10 Cycloalkyl.

[0098] Preferably, R A6 is hydrogen, C1-C6 alkoxy, -NR a R b or -NR c -C(O)-C3-C 10 Cycloalkyl.

[0099] More preferably, R A6 is hydrogen, methoxy, amino, morpholinyl or -NHC(O)-cyclopropyl.

[0100] In one embodiment, Ring A is R A6 Same definition as above.

[0101] In one example, R A6 is hydrogen or hydroxy, more preferably, R A6 It is a hydroxyl group.

[0102] In one embodiment, Ring A is R A5 、R A6 The definitions are the same as before.

[0103] Preferably, R A5 is hydrogen, -NR a R b or -NR c -C(O)-C3-C 10 Cycloalkyl; more preferably, R A5 is amino or -NHC(O)-cyclopropyl.

[0104] Preferably, R A6 is hydrogen or halogen; more preferably, R A6 is fluorine, chlorine or bromine; more preferably, R A6 For fluorine.

[0105] In one embodiment, Ring A is R A2 Same definition as above.

[0106] Preferably, R A2 is hydrogen or C1-C6 alkyl;

[0107] More preferably, R A2 For hydrogen.

[0108] In one embodiment, Ring A is R A1 、R A4 The definitions are the same as before.

[0109] Preferably, R A1 It is a halogen.

[0110] More preferably, R A1 is fluorine, chlorine or bromine.

[0111] More preferably, R A1 For chlorine.

[0112] Preferably, R A4 -NR a R b .

[0113] More preferably, R A4 It is an amino group.

[0114] In one embodiment, Ring A is R A5 、R A6 The definitions are the same as before.

[0115] Preferably, R A5 is hydrogen or halogen.

[0116] More preferably, R A5is hydrogen, fluorine, chlorine or bromine.

[0117] More preferably, R A5 is hydrogen or fluorine.

[0118] Preferably, R A6 For hydrogen, halogen, hydroxyl, -NR c -C(O)-R H1 、-NR c -C(=NH)-NR c -R H1 、-NR c -C(=S)-NR c -R H1 、-NR c -C(=O)-NR c -R H1 .

[0119] Preferably, R H1 It is a C1-C6 alkyl group, a C1-C6 alkoxy group or a 4- to 10-membered heterocycloalkyl group.

[0120] More preferably, R H1 It is hydroxy, isopropyl, methoxy, azacyclohexyl or azacyclohexyl substituted with hydroxy.

[0121] More preferably, R A6 For hydroxyl,

[0122] In one embodiment, R A2 、R A3 、R A4 or R A5 Each is independently selected from fluorine, chlorine, hydroxyl, amino, cyano, methoxy, morpholinyl, -C(O)NH2,

[0123] In one embodiment, R 1 Selected from

[0124] Among them, R 7 is phenyl, said phenyl being optionally substituted by one or more selected from R 71 substituted by a substituent.

[0125] Preferably, R 71 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogen substituted C 1-6 alkyl.

[0126] More preferably, R 71is fluorine, chlorine, -OCF3 or -OCH3.

[0127] Preferably, R 1a 、R 1b 、R 1c 、R 1d 、R 1e are each independently selected from hydrogen, halogen, C 1-6 Alkyl or C 2-6 Alkynyl.

[0128] More preferably, R 1a 、R 1b 、R 1c 、R 1d 、R 1e Each is independently selected from hydrogen, methyl, and ethynyl.

[0129] Preferably, R 1a 、R 1b The carbon atom and nitrogen atom to which it is connected together form an aziridine group, an aziridine group or a morpholinyl group.

[0130] Preferably, R 1b 、R 1e The carbon atom to which it is attached together forms a cyclopropyl, cyclobutyl or cyclopentyl group;

[0131] Preferably, ring D is selected from

[0132] t1 and t2 are each independently selected from 0, 1 or 2.

[0133] In one embodiment, R 1 for

[0134] Among them, R 7 is phenyl, said phenyl being optionally substituted by one or more selected from R 71 substituted by a substituent.

[0135] Preferably, R 71 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogen substituted C 1-6 alkyl.

[0136] More preferably, R 71 is fluorine or -OCF3.

[0137] Preferably, R 1f is hydrogen or C 1-6 alkyl.

[0138] More preferably, R 1f is hydrogen or methyl.

[0139] In one embodiment, R 1 for

[0140] In one embodiment, the compound of formula (I) is represented by the following formula (II):

[0141] Where R 1 、R 2 、R 3 、R 4 The definitions are the same as before.

[0142] In one embodiment, the compound of formula (I) is represented by the following formula (IIA):

[0143] Where R 2 、R 3 、R 4 Each is defined as above;

[0144] R 1a 、R 1b 、R 1c , t1, R 7 Respective definitions are as described above.

[0145] In one embodiment, the compound of formula (I) is represented by the following formula (IIB):

[0146]

[0147] Where R 2 、R 3 、R 4 Each is defined as above;

[0148] Ring D, R 1d 、R 1e , t2, R 7 Respective definitions are as described above.

[0149] In one embodiment, the compound of formula (I) is represented by the following formula (VI):

[0150]

[0151] Where R 2 、R 3 、R 4 Each is defined as above;

[0152] R 1a 、R 1b 、R 1c , t1, R 7 Respective definitions are as described above.

[0153] In one embodiment, the compound of formula (I) is represented by the following formula (III):

[0154]

[0155] Where R 1 、R 2 、R 3 、R 4 、R X The respective definitions are the same as before;

[0156] Furthermore, the compound of formula (III) has the structure shown in formula (IIIA):

[0157]

[0158] Where R 1 、R 2 、R 3 、R 4 The respective definitions are the same as before;

[0159] G1 is selected from CH2, C(CH3)2, C=O, NH, O or S; preferably, G1 is selected from CH2, C(CH3)2 or O; preferably CH2.

[0160] Preferably, R 1 for Among them, R 7 is phenyl, said phenyl being optionally substituted by one or more selected from R 71 Substituents substituted;

[0161] R 71 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogen substituted C 1-6 alkyl;

[0162] Preferably, R 71 is fluorine or -OCF3.

[0163] Preferably, R 1f is hydrogen or C 1-6 alkyl.

[0164] More preferably, R 1f is hydrogen or methyl.

[0165] Preferably, R 1 for

[0166] In one embodiment, the compound of formula (I) is represented by the following formula (IIIB):

[0167]

[0168] Where R 2 、R 3 、R 4 Each is defined as above;

[0169] R G1 、R G2 Each independently selected from H, C 1-3 Alkyl or halogen;

[0170] R 7 is phenyl, said phenyl being optionally substituted by one or more selected from R 71 Substituents substituted;

[0171] R 71 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogen substituted C 1-6 alkyl.

[0172] In one embodiment, R G1 、R G2 are each independently selected from H or methyl.

[0173] In one embodiment, R 71 is fluorine or -OCF3;

[0174] R 1f is hydrogen or C 1-6 Alkyl; More preferably, R 1f is hydrogen or methyl.

[0175] In one embodiment, for

[0176] In one embodiment, the compound of formula (I) is represented by the following formula (IIIC):

[0177]

[0178] Where R 2 、R 3 、R 4 Each is defined as above;

[0179] R G1 、R G2 Each independently selected from H, C 1-3 Alkyl or halogen;

[0180] R 7 is phenyl, said phenyl being optionally substituted by one or more selected from R 71 Substituents substituted;

[0181] R71 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogen substituted C 1-6 alkyl.

[0182] In one embodiment, R G1 、R G2 are each independently selected from H or methyl.

[0183] In one embodiment, R 71 is fluorine or -OCF3;

[0184] R 1f is hydrogen or C 1-6 Alkyl; More preferably, R 1f is hydrogen or methyl.

[0185] In one embodiment, for

[0186] In one embodiment, the compound of formula (I) is represented by the following formula (IV) or formula (V):

[0187]

[0188] Where R 1 、R 2 、R 3 、R 4 、R B The definitions are the same as before.

[0189] In one embodiment, the compound of formula (I) is represented by the following formula (IVA):

[0190]

[0191] Where R 2 、R 3 、R 4 Each is defined as above;

[0192] R B The definitions are as above;

[0193] R 1a 、R 1b 、R 1c , t1, R 7 Respective definitions are as described above.

[0194] In one embodiment, the compound of formula (I) is represented by the following formula (VA):

[0195]

[0196] Where R2 、R 3 、R 4 Each is defined as above;

[0197] R 1a 、R 1b 、R 1c , t1, R 7 Respective definitions are as described above.

[0198] The present invention provides the following compounds, their pharmaceutically acceptable salts, solvates or stereoisomers:

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222] In another aspect of the present invention, a pharmaceutical composition is provided, which comprises the aforementioned compound, a pharmaceutically acceptable salt or stereoisomer thereof.

[0223] In another aspect of the present invention, there is provided use of the aforementioned compound, its pharmaceutically acceptable salt or stereoisomer or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating inflammation, autoimmune diseases, neurodegenerative diseases and cancer.

[0224] In another aspect of the present invention, there is provided use of the aforementioned compound, a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or the aforementioned pharmaceutical composition in the preparation of a RIPK inhibitor.

[0225] In a preferred embodiment, the RIPK inhibitor is a RIPK1 inhibitor.

[0226] In another aspect of the present invention, a method for preventing and / or treating diseases associated with abnormal RIPK expression is provided, comprising the step of administering the aforementioned compound, its pharmaceutically acceptable salt, or stereoisomer, or the aforementioned pharmaceutical composition to a patient in need thereof.

[0227] In this application, RIPK-mediated diseases refer to diseases associated with abnormal RIPK expression.

[0228] In some embodiments, the invention is used in a medicament for treating a disease associated with abnormal RIPK expression selected from inflammation, autoimmune disease, neurodegenerative disease and cancer.

[0229] In some specific embodiments, the disease associated with abnormal RIPK expression is cancer.

[0230] In some embodiments, the cancer is colon cancer.

[0231] In another aspect of the present invention, the aforementioned compound, its pharmaceutically acceptable salt, solvate or stereoisomer or the aforementioned pharmaceutical composition is provided for use in treatment.

[0232] In another aspect of the present invention, the aforementioned compound, a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or the aforementioned pharmaceutical composition is provided for use in treating diseases associated with abnormal RIPK expression.

[0233] In another aspect of the present invention, there is provided use of the aforementioned compound, a pharmaceutically acceptable salt or stereoisomer thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating diseases associated with abnormal RIPK expression. DETAILED DESCRIPTION

[0234] I. Definition

[0235] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the relevant terms and laboratory procedures used herein are those widely used in the relevant fields and routine procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0236] In the description herein, references to “some embodiments,” “some implementation schemes,” or “some implementation plans” describe a subset of all possible embodiments, but it will be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0237] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0238] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic or organic acids, such as nitric, phosphoric, and carbonic acids; organic acids, such as propionic, hexanoic, cyclopentylpropionic, glycolic, pyruvic, gluconic, stearic, and muconic acids; salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal or alkaline earth metal ion; or coordination compounds formed with an organic base, such as ethanolamine. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid or base groups by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of both. Generally, non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, are preferred. In addition to salt forms, the compounds provided herein also exist in prodrug form. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

[0239] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers, etc. The compounds of the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesomorphs, racemates, equal mixtures of atropisomers, etc. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes cis-isomers and trans-isomers, and any combination thereof. The atropisomers of the present invention are stereoisomers with axial or planar chirality based on restricted intramolecular rotation. And as a drug, stereoisomers with excellent activity are preferred. The compounds of the present invention have optical isomers arising from asymmetric carbon atoms, etc., and individual isomers can be resolved and obtained, if necessary, by methods known in the art, such as crystallization or chiral chromatography.

[0240] As used herein, the term "heteroatom" is selected from nitrogen, oxygen, or sulfur, wherein the nitrogen may be optionally substituted; the sulfur may also be optionally substituted, for example, oxo, i.e., forming S(O)m3 (wherein m3 is an integer from 0 to 2).

[0241] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. 1-10 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 10 carbon atoms. Preferably, C 1-6 Alkyl (i.e., linear or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms). More preferably, C 1-4 More preferably, C 1-3 Alkyl. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof.

[0242] As used herein, the term "alkoxy" refers to a group having the structure -O-alkyl, wherein alkyl is as defined above. 1-6 "Alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms. Preferably, it is C1-4 Alkoxy, more preferably C 1-3 Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, and the like.

[0243] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group, including, for example, monocyclic cycloalkyl, spirocyclic alkyl, fused cycloalkyl and bridged cycloalkyl. The ring carbon atoms of the cycloalkyl group described in the present invention may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure. The term "C 3-10 "Cycloalkyl" refers to a cycloalkyl group having 3 to 10 ring carbon atoms, including monocyclic cycloalkyl, spirocyclic alkyl, fused cycloalkyl and bridged cycloalkyl. Preferably, C 3-8 Cycloalkyl, more preferably C 3-6 Monocyclic cycloalkyl.

[0244] As used herein, the term "bridged cycloalkyl" refers to a saturated or partially unsaturated polycyclic hydrocarbon group in which any two rings share two carbon atoms that are not directly connected. The term "bridged heterocycloalkyl" refers to a bridged cycloalkyl group containing a carbon atom and at least one heteroatom such as nitrogen, oxygen, or sulfur as ring members.

[0245] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated ring substituent containing heteroatoms in the ring backbone, wherein one or more (preferably 1 to 4 or 1 to 3 or 1 to 2) ring atoms are heteroatoms selected from N, O, and S. The term "4- to 10-membered heterocyclyl" refers to a saturated or partially unsaturated ring substituent optionally containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring atoms. The term "4- to 8-membered nitrogen-containing heterocyclyl" refers to a 4- to 8-membered heterocyclyl in which one of the ring atoms must be a nitrogen atom, and the remaining ring atoms are all carbon atoms, or 1, 2, or 3 of the remaining ring atoms are independently heteroatoms selected from N, O, and S. The "4- to 8-membered nitrogen-containing heterocycloalkyl" is preferably attached to the rest of the molecule via the required nitrogen atom.

[0246] As used herein, the term "partially unsaturated carbocycle" or "partially unsaturated carbocyclyl" refers to a carbocyclic ring containing at least one double bond between ring atoms, wherein at least one ring of the carbocyclyl is not aromatic. Partially unsaturated carbocyclyls can be characterized by the number of ring carbon atoms. Partially unsaturated carbocyclyls can be in the form of monocyclic carbocycles, bicyclic carbocycles, tricyclic carbocycles, bridged carbocycles, spirocyclic carbocycles, or other carbocyclic ring systems.

[0247] As used herein, the term "aryl" refers to an all-carbon monocyclic, all-carbon non-fused polycyclic (rings are connected by covalent bonds and are not fused) or all-carbon fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, in which at least one ring is aromatic, i.e., has a conjugated π electron system. The term "C 6-8"Aryl" refers to an aromatic group having 6 to 8 ring atoms. Preferably it is phenyl or naphthyl.

[0248] As used herein, the term "5- or 6-membered monocyclic heteroaryl" refers to a group having 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S(=O). m m' (wherein m' is an integer from 0 to 2). Specific examples of monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

[0249] "Optionally substituted by one or more..." means that it may be substituted by one or more specified substituents (preferably 1, 2 or 3), or it may be unsubstituted; the "multiple" in "one or more", if not limited, has a minimum value of 2 and a maximum value of the number of substitutable sites of the substituted group.

[0250] If substituents are described as being "individually selected" or "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (or other) substituent.

[0251] "Substitution" means that a hydrogen atom in a molecule is replaced by another different group.

[0252] The term "membered" refers to the number of skeletal atoms constituting the ring.

[0253] The "bond" mentioned in the present invention means that there is only one connecting bond, and can also be understood as "none".

[0254] Unless otherwise specified, the ring formed by "connecting to form a ring" in the present invention includes unsubstituted rings and rings substituted with substituents.

[0255] "Alkoxy" refers to an -O-alkyl group.

[0256] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0257] "(O)" means =0.

[0258] The two carbon atoms represented as being connected are adjacent pairs of carbon atoms that are shared when fused to other rings.

[0259] When the double ring appears When the connection position is uncertain, it means that the connection site is limited to Any atom in the monocyclic ring, as long as the valence permits.

[0260] II. Examples

[0261] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below. The described embodiments should not be regarded as limiting the present invention. All other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0262] Before further explaining the embodiments of the present invention in detail, the nouns and terms involved in the embodiments of the present invention are explained. The nouns and terms involved in the embodiments of the present invention are subject to the following interpretations.

[0263] The raw materials and equipment used in the specific embodiments of the present disclosure are all known products and are obtained by purchasing commercially available products.

[0264] Example 1: Preparation of intermediates

[0265] Preparation of intermediate INT-1:

[0266]

[0267] Preparation of intermediate INT-1-2: 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxylic acid:

[0268] Intermediate INT-1-1 (1.32 g, 4.2 mmol) was dissolved in methanol (15 mL), and water (15 mL) and sodium hydroxide (1.20 g, 30 mmol) were added. The mixture was heated to reflux and stirred for 3 h. The reaction solution was concentrated under reduced pressure and the pH was adjusted to 4-5 with dilute hydrochloric acid (3 M). The solid was filtered and dried to obtain intermediate INT-1-2 in a 62% yield. MS (ESI, positive ion) m / z: 302.1 [M+H] + .

[0269] Preparation of intermediate INT-1-3: (S)-N-(1-(4-fluorophenyl)ethyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxamide:

[0270] Intermediate INT-1-2 (604 mg, 2.0 mmol) was dispersed in 5 ml of tetrahydrofuran, and (S)-(-)-1-(4-fluorophenyl)ethanamine (333 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to obtain intermediate INT-1-3 in a 70% yield. MS (ESI, positive ion) m / z: 423.3 [M+H] + .

[0271] Preparation of intermediate INT-1: (S)-5-(6-amino-5-fluoropyridin-3-yl)-N-(1-(4-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide:

[0272] Intermediate INT-1-3 (200 mg, 0.47 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 2-amino-3-fluoro-5-chloropyridine (68.6 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 40%) to obtain intermediate INT-1 in 80% yield. MS (ESI, positive ion) m / z: 407.4 [M+H] + .

[0273] Preparation of intermediate INT-2:

[0274]

[0275] Intermediate INT-2-1: Preparation of (S)-6-(3-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-methyl-1H-indol-5-yl)-3-oxo-2,3-dihydropyridazinone-4-carboxylic acid methyl ester:

[0276] Intermediate INT-1-3 (2.0 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to obtain intermediate INT-2-1 in 80% yield. MS (ESI, positive ion) m / z: 449.5 [M+H] + .

[0277] Intermediate INT-2: Preparation of (S)-6-(3-((1-(4-fluorophenyl)ethyl)formamido)-1-methyl-1H-indol-5-yl)-3-oxo-2,3-dihydropyridazinone-4-carboxylic acid

[0278] Intermediate INT-2-1 (900 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to 4-5 with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain intermediate INT-2 in a 92% yield. MS (ESI, positive ion) m / z: 435.4 [M+H] + .

[0279] Preparation of intermediate INT-3:

[0280]

[0281] Preparation of intermediate INT-3-1: (S)-(2-(4-fluorophenyl)pyrrolidin-1-yl)(1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)methanone:

[0282] Intermediate INT-1-2 (1.95 g, 6.5 mmol) was dispersed in tetrahydrofuran (55 mL), and (S)-2-(4-fluorophenyl)pyrrolidine (1.29 g, 7.8 mmol), diisopropylethylamine (1.00 g, 7.8 mmol), and HATU (2.96 g, 7.8 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford intermediate INT-3-1 in a 72% yield. MS (ESI, positive ion) m / z: 449.2 [M+H] +.

[0283] Intermediate INT-3-2: Preparation of methyl (S)-6-(3-(2-(4-fluorophenyl)pyrrolidinyl-1-carbonyl)-1-methyl-1H-indol-5-yl)-3-oxo-2,3-dihydropyridazinone-4-carboxylate:

[0284] Intermediate INT-3-1 (2.1 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to obtain intermediate INT-2-1 in 82% yield. MS (ESI, positive ion) m / z: 475.5 [M+H] + .

[0285] Preparation of intermediate INT-3: (S)-6-(3-(2-(4-fluorophenyl)pyrrolidinyl-1-carbonyl)-1-methyl-1H-indol-5-yl)-3-oxo-2,3-dihydropyridazinone-4-carboxylic acid:

[0286] Intermediate INT-3-2 (950 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain intermediate INT-2 in a 90% yield. MS (ESI, positive ion) m / z: 461.5 [M+H] + .

[0287] Example 2: Preparation of compounds disclosed herein

[0288] Preparation of compound 1:

[0289]

[0290] Preparation of compound 1-2:

[0291] 1-1 (604 mg, 2.0 mmol) was dispersed in 5 ml of tetrahydrofuran, and 1-(4-fluorophenyl)ethanamine (333 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford intermediate 1-2 in a 70% yield. MS (ESI, positive ion) m / z: 423.3 [M+H] + .

[0292] Preparation of compound 1:

[0293] Intermediate 1-2 (200 mg, 0.47 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 3-hydroxy-6-chloropyridazine (61 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 40%) to obtain compound 1 in an 80% yield. MS (ESI, positive ion) m / z: 449.5 [M+H] + .

[0294] 1 H NMR (400MHz, DMSO-d6) δ13.10(s,1H),8.61(d,J=2.0Hz,1H),8.33(d,J=8.0Hz,1H),8.19(s,1H),8.02(d,J=9.9Hz,1H),7.74(dd,J=8.7,1.9Hz,1H), 7.61(d,J=8.7Hz,1H),7.50–7.42(m,2H),7.22–7.11(m,2H),6.99(dd,J=9 .9,2.2Hz,1H),5.21(p,J=7.2Hz,1H),3.89(s,3H),1.49(d,J=7.1Hz,3H).

[0295] Preparation of compound 2:

[0296]

[0297] Intermediate INT-1-3 (100 mg, 0.2 mmol) was dissolved in 1,4-dioxane:water (1.5 mL:0.15 mL). 3-Hydroxy-6-chloropyridazine (39 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), and Pd(dppf)2Cl2 (20 mg, 0.03 mmol) were added. The mixture was heated to 90°C and stirred for 10 h. The reaction solution was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to obtain compound 2 in a 65% yield. MS (ESI, positive ion) m / z: 391.2 [M+H] + .

[0298] Preparation of compound 3:

[0299]

[0300] The intermediate INT-1-3 (100 mg, 0.2 mmol) was dissolved in 1,4-dioxane: water (1.5 mL: 0.15 mL), and 3-amino-6-chloropyridazine (39 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), Pd(dppf) 2 Cl2 (20 mg, 0.03 mmol) was added, heated to 90°C, and stirred for 10 h. The reaction solution was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to obtain compound 3 in a 65% yield. MS (ESI, positive ion) m / z: 390.2 [M+H] + .

[0301] Preparation of compound 4:

[0302]

[0303] Intermediate INT-1-3 (100 mg, 0.2 mmol) was dissolved in 1,4-dioxane:water (1.5 mL:0.15 mL). 4-(6-chloropyridazin-3-yl)morpholine (60 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), and Pd(dppf)2Cl2 (20 mg, 0.03 mmol) were added. The mixture was heated to 90°C and stirred for 10 h. The reaction mixture was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to afford compound 4 in a 65% yield. MS (ESI, positive ion) m / z: 460.2 [M+H] + .

[0304] 1H NMR (400MHz, DMSO) δ8.72(s,1H),8.31(dd,J=8.8,4.3Hz,1H),8.19(s,1H),8.00–7.89(m,2H),7.61(d,J=8.7Hz,1H),7.47(dd,J=8.5,5.7Hz,2H ),7.36(d,J=9.6Hz,1H),7.16(t,J=8.9Hz,2H),5.22(t,J=7.6Hz,1H),3 .89(s,3H),3.79–3.76(m,4H),3.63–3.57(m,4H),1.50(d,J=7.0Hz,3H).

[0305] Preparation of compound 5:

[0306]

[0307] Intermediate INT-1-3 (100 mg, 0.2 mmol) was dissolved in 1,4-dioxane:water (1.5 mL:0.15 mL). 6-Chloro-4-methyl-3-pyridazinone (43 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), and Pd(dppf)2Cl2 (20 mg, 0.03 mmol) were added. The mixture was heated to 90°C and stirred for 10 h. The reaction mixture was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to afford compound 5 in a 65% yield. MS (ESI, positive ion) m / z: 405.2 [M+H] + .

[0308] 1 H NMR (400MHz, DMSO) δ12.96(s,1H),8.60(s,1H),8.34(d,J=7.9Hz,1H),8.20(s,1H),7.91(s,1H),7.73(t,J=11.0Hz,1H),7.59(d,J=8.7Hz, 1H),7.46(dd,J=8.4,5.7Hz,2H),7.16(t,J=8.8Hz,2H),5.20(t,J=7.5Hz,1H),3.90(d,J=13.6Hz,3H),2.17(s,3H),1.49(d,J=7.1Hz,3H).

[0309] Preparation of compound 6:

[0310]

[0311] Preparation of compound 6-1:

[0312] Intermediate INT-1 (203 mg, 0.5 mmol) was dissolved in tetrahydrofuran (10 mL), and N,N-diisopropylethylamine (129 mg, 1.0 mmol) and isopropyl isothiocyanate (60.7 mg, 0.6 mmol) were added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain intermediate 6-1 in 80% yield. MS (ESI, positive ion) m / z: 508.2 [M+H] + .

[0313] Preparation of compound 6:

[0314] Intermediate 6-1 (202 mg, 0.4 mmol) was dissolved in acetonitrile (5 mL). 2-Iodoacylbenzoic acid (336 mg, 1.2 mmol) was dissolved in aqueous ammonia (2 mL) and added dropwise to the reaction mixture. The temperature was raised to 70°C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 45%) to afford compound 6 in a 40% yield. MS (ESI, positive ion) m / z: 491.2 [M+H] + .

[0315] 1 H NMR (400MHz, DMSO) δ8.33(s,1H),8.29(d,J=8.0Hz,1H),8.23(s,1H),8.17(s,1H),7.69(d,J=11.6Hz,1H),7.63–7.39(m,6H),7.16(t,J =8.9Hz,2H),5.21(p,J=7.0Hz,1H),3.99(d,J=6.8Hz,1H),3.88(s,3H),2.52–2.52(m,1H),1.50(d,J=7.0Hz,3H),1.18(d,J=6.4Hz,6H).

[0316] Preparation of compound 7:

[0317]

[0318] Intermediate INT-1 (203 mg, 0.2 mmol) was dissolved in tetrahydrofuran (10 mL), and N,N-diisopropylethylamine (51.6 mg, 0.4 mmol) and isopropyl isothiocyanate (30.3 mg, 0.3 mmol) were added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain Intermediate 7 in 80% yield. MS (ESI, positive ion) m / z: 508.2 [M+H] + .

[0319] 1 H NMR(400MHz,DMSO)δ11.10(d,J=7.5Hz,1H),9.59(s,1H),8.49–8.40(m,2H),8 .33(d,J=8.0Hz,1H),8.20(s,1H),8.11(dd,J=11.9,1.8Hz,1H),7.67–7.56(m, 2H),7.46(dd,J=8.6,5.6Hz,2H),7.16(t,J=8.9Hz,2H),5.20(p,J=7.2Hz,1H) ,4.52–4.39(m,1H),3.89(s,3H),1.49(d,J=7.1Hz,3H),1.30(d,J=6.5Hz,6H).

[0320] Preparation of compound 8:

[0321]

[0322] Preparation of compound 8-1:

[0323] Compound INT-1 (50 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and ethyl chloroformate (12.5 mg, 0.12 mmol) and N,N-diisopropylethylamine (15.5 mg, 0.12 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (30 mL) was added to the reaction solution for crystallization. The solid was filtered, washed with water, and dried to obtain compound 8-1 in a 50% yield. MS (ESI, positive) m / z: 479.2 [M+H] + .

[0324] Preparation of compound 8:

[0325] Compound 8-1 (20 mg, 0.042 mmol) was dissolved in acetonitrile (1 mL), and piperidine (3.5 mg, 0.042 mmol) was added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to obtain compound 8 in a 25% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[0326] 1H NMR (400MHz, DMSO) δ9.04 (s, 1H), 8.45 (d, J = 17.1Hz, 2H), 8.33 (d, J = 8.2Hz, 1 H),8.21(s,1H),7.94(dd,J=11.5,1.9Hz,1H),7.68–7.57(m,2H),7.47(dd,J= 8.6,5.6Hz,2H),7.17(t,J=8.9Hz,2H),5.23(dd,J=14.8,7.5Hz,1H),3.90(s ,3H),3.52–3.39(m,4H),1.57(dd,J=32.6,4.5Hz,6H),1.50(d,J=7.1Hz,3H).

[0327] Preparation of compound 9:

[0328]

[0329] Compound 8-1 (20 mg, 0.042 mmol) was dissolved in acetonitrile (1 mL), and piperidin-4-ol (4.3 mg, 0.042 mmol) was added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 60%) to afford compound 9 in a 25% yield. MS (ESI, positive ion) m / z: 534.2 [M+H] + .

[0330] 1 H NMR (400MHz, DMSO) δ9.09 (s, 1H), 8.44 (d, J = 17.6Hz, 2H), 8.33 (d, J = 8.0Hz, 1H), 8.21 (s, 1H), 7.94 (dd,J=11.5,1.8Hz,1H),7.68–7.56(m,2H),7.47(dd,J=8.6,5.6Hz,2H),7.16(t,J=8.9Hz,2H),5. 21(t,J=7.3Hz,1H),4.73(d,J=4.3Hz,1H),3.90(s,3H),3.86(d,J=13.6Hz,2H),3.70(dd,J=8.5,4 .4Hz,1H),3.10(t,J=10.1Hz,2H),1.77(d,J=9.6Hz,2H),1.50(d,J=7.0Hz,3H),1.42–1.31(m,2H).

[0331] Preparation of compound 10:

[0332]

[0333] Intermediate INT-1 (203 mg, 0.2 mmol) was dissolved in tetrahydrofuran (10 mL), and N,N-diisopropylethylamine (51.6 mg, 0.4 mmol) and isopropyl isocyanate (25.53 mg, 0.3 mmol) were added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 10 in a 75% yield. MS (ESI, positive ion) m / z: 492.2 [M+H] + .

[0334] 1 H NMR (400MHz, DMSO) δ9.02 (s, 1H), 8.76 (d, J = 7.1Hz, 1H), 8.40 (s, 2H), 8.31 (d, J = 8 .0Hz,1H),8.19(s,1H),7.99(dd,J=11.9,1.9Hz,1H),7.59(dt,J=8.6,5.1Hz,2H) ,7.46(dd,J=8.6,5.6Hz,2H),7.16(t,J=8.9Hz,2H),5.21(p,J=7.0Hz,1H),3.93( dd,J=13.5,6.8Hz,1H),3.89(s,3H),1.49(d,J=7.0Hz,3H),1.21(d,J=6.5Hz,6H).

[0335] Preparation of compound 11:

[0336]

[0337] Intermediate INT-1-3 (20 mg, 0.047 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.3 mL). 5-Bromopyridin-2-ol (9.8 mg, 0.056 mmol) was added, along with potassium phosphate (7.8 mg, 0.056 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (5 mg, 0.0061 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 11 in a 55% yield. MS (ESI, positive ion) m / z: 390.4 [M+H] + .

[0338] Preparation of compound 12:

[0339]

[0340] Intermediate INT-1 (10 mg, 0.025 mmol) was dissolved in dichloromethane (1 mL), and ethyl chloroformate (2.7 mg, 0.025 mmol) and N,N-diisopropylethylamine (3.2 mg, 0.025 mmol) were added. The mixture was stirred for 6 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 50%) to obtain compound 12 in a 30% yield. MS (ESI, positive ion) m / z: 479.5 [M+H] + .

[0341] Preparation of compound 13:

[0342]

[0343] Intermediate INT-1-3 (200 mg, 0.47 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 5,6-dichloropyridazin-3(2H)-one (77.6 mg, 0.47 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 40%) to obtain compound 13 in an 80% yield. MS (ESI, positive ion) m / z: 425.2 [M+H] + .

[0344] 1 H NMR(400MHz, DMSO-d6)δ13.26(s,1H),8.33(d,J=8.0Hz,1H),8.28–8.22(m,2H),7.67–7.60(m,1H),7.50–7.40(m,2H), 7.35(dd,J=8.5,1.8Hz,1H),7.21–7.10(m,2H),6.92(s,1H),5.20(p,J=7.2Hz,1H),3.90(s,3H),1.49(d,J=7.1Hz,3H).

[0345] Preparation of compound 14:

[0346]

[0347] Intermediate INT-1-3 (80 mg, 0.19 mmol) was dissolved in 1,4-dioxane (2 mL). Potassium phosphate (80 mg, 0.38 mmol), 4-bromo-6-chloro-3-pyridazinone (40 mg, 0.19 mmol), PdCl2(dppf)2 (15 mg), and water (0.2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 40%) to obtain compound 14 in a 75% yield. MS (ESI, positiveion) m / z: 425.9 [M+H] + .

[0348] 1 H NMR (400MHz, DMSO-d6) δ13.17(s,1H),8.73(d,J=1.7Hz,1H),8.32(d,J=8.0Hz,1H),8.19(s,1H),7.76(dd,J=8.7,1.8Hz,1H),7.6 5(s,1H),7.59(d,J=8.7Hz,1H),7.51–7.41(m,2H),7.21–7.11(m,2H),5.20(p,J=7.2Hz,1H),3.89(s,3H),1.49(d,J=7.1Hz,3H).

[0349] Preparation of compound 15:

[0350]

[0351] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and ammonium chloride (16 mg, 0.3 mmol), diisopropylethylamine (56 mg, 0.4 mmol), and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 50%) to provide compound 15 in a 42% yield. MS (ESI, positive ion) m / z: 434.4 [M+H] + .

[0352] 1H NMR (400MHz, DMSO-d6) δ8.94(d,J=3.8Hz,1H),8.65(d,J=1.8Hz,1H),8.58(s,1H),8.36(d,J=8.0Hz,1H),8.21(s,1H),8.11(d,J=3.9Hz,1H),7.8 0(dd,J=8.7,1.9Hz,1H),7.64(d,J=8.7Hz,1H),7.51–7.43(m,2H),7.22 –7.12(m,2H),5.21(q,J=7.2Hz,1H),3.90(s,3H),1.49(d,J=7.0Hz,3H).

[0353] Preparation of compound 16:

[0354]

[0355] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in ethanol (5 mL). Hydrochloric acid / 1,4-dioxane (2 mL, 8 mmol) was added and the mixture was heated to reflux for 3 h. The mixture was concentrated to 2 mL, filtered, and the filter cake was washed with sodium bicarbonate solution, water, and dried. Compound 16 was obtained in a 42% yield. MS (ESI, positive ion) m / z: 463.5 [M+H] + .

[0356] 1 H NMR(400MHz, DMSO-d6)δ8.60(d,J=1.8Hz,1H),8.38–8.29(m,2H),8.21(s,1H),7.76(dd,J=8.6,1.9Hz,1H),7.62(d,J=8.7Hz,1H),7.50–7 .36(m,3H),7.16(t,J=8.9Hz,2H),5.21(t,J=7.4Hz,1H),4.34(q,J=7.1Hz,2H),3.89(s,3H),1.49(d,J=7.1Hz,3H),1.34(d,J=7.1Hz,3H).

[0357] Preparation of compound 17:

[0358]

[0359] Compound 15 (22 mg, 0.05 mmol) was dissolved in pyridine (1 mL) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%), heated to 120°C, and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 50%) to obtain compound 17 in a 71% yield. MS (ESI, positive ion) m / z: 416.4 [M+H] + .

[0360] Preparation of compound 18:

[0361]

[0362] Intermediate INT-1-3 (80 mg, 0.19 mmol) was dissolved in 1,4-dioxane (2 mL), and potassium phosphate (80 mg, 0.38 mmol), 5-bromo-3-cyano-2(1H)-pyridone (29 mg, 0.19 mmol), PdCl2(dppf)2 (15 mg), and water (0.2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 40%) to obtain compound 18 in a 75% yield. MS (ESI, positiveion) m / z: 415.4 [M+H] + .

[0363] 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=2.8Hz,1H),8.29(d,J=8.0Hz,1H),8.24(d,J=1.8Hz,1H),8.17(s,1H),8.02(d,J=2.8Hz, 1H),7.57(d,J=8.6Hz,1H),7.51–7.41(m,3H),7.21–7.11(m,2H),5.21(p,J=7.2Hz,1H),3.87(s,3H),1.49(d,J=7.1Hz,3H).

[0364] Preparation of compound 19:

[0365]

[0366] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and methylamine hydrochloride (20 mg, 0.3 mmol), diisopropylethylamine (56 mg, 0.4 mmol), and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 19 in a 62% yield. MS (ESI, positive ion) m / z: 448.3 [M+H] + .

[0367] 1 H NMR (400MHz, DMSO-d6) δ13.52(s,1H),9.51(q,J=4.8Hz,1H),8.66(d,J=1.8 Hz,1H),8.57(s,1H),8.37(d,J=8.0Hz,1H),8.22(s,1H),7.80(dd,J=8.7,1. 9Hz,1H),7.65(d,J=8.7Hz,1H),7.52–7.43(m,2H),7.22–7.12(m,2H),5.22 (p,J=7.2Hz,1H),3.90(s,3H),2.92(d,J=4.9Hz,3H),1.50(d,J=7.0Hz,3H).

[0368] Preparation of compound 20:

[0369]

[0370] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and morpholine (26 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 50%) to afford compound 20 in a 55% yield. MS (ESI, positive) m / z: 504.2 [M+H] + .

[0371] Preparation of compound 21:

[0372]

[0373] Intermediate INT-1-3 (84 mg, 0.2 mmol) was dissolved in 1,4-dioxane:water (1.5 mL:0.15 mL). 7-Chloro-3-methyl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one (55 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), and Pd(dppf)2Cl2 (20 mg, 0.03 mmol) were added. The mixture was heated to 90°C and stirred for 10 h. The reaction mixture was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to afford compound 21 in a 65% yield. MS (ESI, positive ion) m / z: 445.2 [M+H] + .

[0374] 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),9.23(dd,J=1.8,0.7Hz,1H),8.42(s,1H),8.29–8.22(m,2H),8.17(s,1H),7.60(dd,J=8 .7,0.7Hz,1H),7.49–7.45(m,2H),7.19–7.14(m,2H),5.21(p,J=7.2Hz,1H),4.12(s,3H),3.89(s,3H),1.49(d,J=7.0Hz,3H).

[0375] Preparation of compound 22:

[0376]

[0377] Preparation of intermediate 22-1:

[0378] Intermediate INT-1-3 (84 mg, 0.2 mmol) was dissolved in 1,4-dioxane:water (1.5 mL:0.15 mL). 5-Chloro-2-hydroxynicotinonitrile (46 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), and Pd(dppf)2Cl2 (20 mg, 0.03 mmol) were added. The mixture was heated to 90°C and stirred for 10 h. The reaction mixture was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to afford intermediate 22-1 in a 65% yield. MS (ESI, positive ion) m / z: 415.2 [M+H] + .

[0379] Preparation of compound 22:

[0380] Intermediate 22-1 (50 mg, 0.12 mmol) was dissolved in ethanol:tetrahydrofuran:water (1 mL:1 mL:10 mL). Sodium hydroxide (48 mg, 1.2 mmol) was added, the temperature was raised to 60°C, and the mixture was stirred for 20 h. The reaction mixture was adjusted to pH 7 by adding acetic acid, and extracted three times with dichloromethane / methanol (10 / 1). The organic phase was concentrated and purified on a normal phase silica gel column (dichloromethane / methanol = 30 / 1) to obtain compound 22 in an 80% yield. MS (ESI, positive ion) m / z: 433.2 [M+H] + .

[0381] Preparation of compound 23:

[0382]

[0383] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylmethylamine (14.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (63.6 mg, 0.2 mmol) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 45%) to afford compound 23 in a 51% yield. MS (ESI, positive ion) m / z: 488.2 [M+H] + .

[0384] 1 H NMR (400MHz, DMSO-d6) δ9.72(t,J=5.7Hz,1H),8.65(d,J=1.8Hz,1H),8.58(s,1H),8.36(d,J= 8.1Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.64(d,J=8.5Hz,1H),7.50–7.44(m,2H) ,7.20–7.13(m,2H),5.22(p,J=7.2Hz,1H),3.89(s,3H),3.27(dd,J=7.0,5.7Hz,2H),1.49(d, J=7.1Hz,3H),1.14–1.05(m,1H),1.02(d,J=6.6Hz,1H),0.54–0.46(m,2H),0.32–0.24(m,2H).

[0385] Preparation of compound 24:

[0386]

[0387] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (11.4 mg, 0.2 mmol) and 1-propylphosphonic anhydride (63.6 mg, 0.2 mmol) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 45%) to afford compound 24 in a 48% yield. MS (ESI, positive) m / z: 474.2 [M+H] + .

[0388] 1 H NMR(400MHz,DMSO-d6)δ9.62(d,J=4.6Hz,1H),8.65(d,J=1.9Hz,1H),8.55(s,1H), 8.37(d,J=8.0Hz,1H),8.22(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.64(d,J=8.7Hz,1 H),7.52–7.43(m,2H),7.22–7.12(m,2H),5.22(p,J=7.2Hz,1H),3.90(s,3H),3.00– 2.89(m,1H),1.50(d,J=7.1Hz,3H),0.82(td,J=7.1,4.9Hz,2H),0.65–0.57(m,2H).

[0389] Preparation of compound 25:

[0390]

[0391] Intermediate INT-1-3 (84 mg, 0.2 mmol) was dissolved in 1,4-dioxane:water (1.5 mL:0.15 mL). 7-Chloro-1-methyl-1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one (55 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), and Pd(dppf)2Cl2 (20 mg, 0.03 mmol) were added. The mixture was heated to 90°C and stirred for 10 h. The reaction mixture was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to afford compound 25 in a 65% yield. MS (ESI, positive ion) m / z: 445.2 [M+H] + .

[0392] Preparation of compound 26:

[0393]

[0394] Intermediate INT-1-3 (84 mg, 0.2 mmol) was dissolved in 1,4-dioxane:water (1.5 mL:0.15 mL). 6-methoxy-3-chloropyridazine (43 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), and Pd(dppf)2Cl2 (20 mg, 0.03 mmol) were added. The mixture was heated to 90°C and stirred for 10 h. The reaction mixture was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to afford compound 26 in a 65% yield. MS (ESI, positive ion) m / z: 405.2 [M+H] + .

[0395] Preparation of compound 27:

[0396]

[0397] Intermediate INT-1-3 (84 mg, 0.2 mmol) was dissolved in 1,4-dioxane:water (1.5 mL:0.15 mL). 5-Chloropyrazin-2-ol (39 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), and Pd(dppf)2Cl2 (20 mg, 0.03 mmol) were added. The mixture was heated to 90°C and stirred for 10 h. The reaction mixture was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to afford compound 27 in a 65% yield. MS (ESI, positive ion) m / z: 391.2 [M+H] + .

[0398] Preparation of compound 28:

[0399]

[0400] Intermediate INT-1-3 (8.4 mg, 0.024 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.3 mL). 4-Chloro-7-methyl-1,2-dihydrophthalazin-1-one (4.7 mg, 0.024 mmol) was added, along with potassium phosphate (3.98 mg, 0.029 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.55 mg, 0.0031 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 28 in a 46% yield. MS (ESI, positive ion) m / z: 455.3 [M+H] + .

[0401] 1H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.36–8.30(m,2H),8.26(s,1H),8.17(d,J=1.8Hz,1H),7.73(dd,J=8.6,1.9Hz,1H),7.66(dd,J=13.2,8. 4Hz,2H),7.48–7.41(m,3H),7.18–7.11(m,2H),5.19(p,J=7.1Hz,1H),3.94(s,3H),1.48(d,J=7.0Hz,3H),1.37(d,J=6.0Hz,1H),1.25(s,2H).

[0402] Preparation of compound 29:

[0403]

[0404] Intermediate INT-1-3 (8.4 mg, 0.024 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.3 mL). 4-Chloro-6-methyl-1,2-dihydrophthalazin-1-one (4.7 mg, 0.024 mmol) was added, along with potassium phosphate (3.98 mg, 0.029 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.55 mg, 0.0031 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 29 in a 46% yield. MS (ESI, positive ion) m / z: 455.3 [M+H] + .

[0405] Preparation of compound 30:

[0406]

[0407] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 4-(piperidin-4-yl)morpholine (34 mg, 0.2 mmol) and 1-propylphosphonic anhydride (63.6 mg, 0.2 mmol) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 45%) to afford compound 30 in a 50% yield. MS (ESI, positive ion) m / z: 587.2 [M+H] + .

[0408] 1H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.39(d,J=8.0Hz,1H),8.24(s,1H),8.05(s,1H),7.78(dt,J=8.7, 1.4Hz,1H),7.61(d,J=8.8Hz,1H),7.49–7.45(m,3H),7.18–7.14(m,2H),5.21(q,J=7.2Hz,1H),4.43(d ,J=13.2Hz,1H),3.89(s,3H),3.58(t,J=4.5Hz,4H),3.55–3.48(m,1H),3.06(t,J=12.1Hz,1H),2.83(t ,J=11.5Hz,1H),2.49–2.39(m,5H),1.87(d,J=12.3Hz,1H),1.74(d,J=12.4Hz,1H),1.54–1.34(m,5H).

[0409] Preparation of compound 31:

[0410]

[0411] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methyl-1H-pyrazol-4-amine (29 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 50%) to afford compound 31 in a 58% yield. MS (ESI, positive ion) m / z: 514.5 [M+H] + .

[0412] 1 H NMR (400MHz, DMSO-d6) δ11.61 (s, 1H), 8.69 (d, J = 1.8Hz, 1H), 8.64 (s, 1H), 8.38 (d,J=8.1Hz,1H),8.23(s,1H),8.16(s,1H),7.82(dd,J=8.7,1.9Hz,1H),7.74(d ,J=0.7Hz,1H),7.66(d,J=8.7Hz,1H),7.53–7.43(m,2H),7.23–7.12(m,2H),5. 23(p,J=7.2Hz,1H),3.89(d,J=15.6Hz,6H),1.51(d,J=7.0Hz,3H),1.12(s,1H).

[0413] Preparation of compound 32:

[0414]

[0415] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and acetic acid hydrazide (22 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 50%) to afford compound 32 in a 60% yield. MS (ESI, positive) m / z: 491.5 [M+H] + .

[0416] 1 H NMR (400MHz, DMSO-d6) δ8.81(d,J=1.3Hz,1H),8.70–8.65(m,1H),8.48–8.41(m,1H),8.28(d,J=1.6Hz,1H),7.81(dq,J=8.7,1.7Hz,2H),7.65( dd,J=8.7,2.4Hz,2H),7.49–7.46(m,3H),7.18–7.14(m,2H),5.22(p,J=7.3Hz,1H),3.89(s,3H),2.03(d,J=32.0Hz,3H),1.50(d,J=7.0Hz,3H).

[0417] Preparation of compound 33:

[0418]

[0419] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in DMSO (1 mL), and (S)-(+)-2-amino-1-propanol (38 mg, 0.5 mmol) and HATU (114 mg, 0.3 mmol) were added. The mixture was stirred at room temperature for 2 h. Sodium hydroxide solution (0.5 ml, 20%) was added, and the reaction was stirred at room temperature for 20 min. Compound 33 was purified by C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 50%) to obtain compound 33 in a 16% yield. MS (ESI, positive ion) m / z: 492.5 [M+H] + .

[0420] Preparation of compound 34:

[0421]

[0422] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-methoxyethylamine (23 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 50%) to afford compound 34 in a 65% yield. MS (ESI, positive ion) m / z: 492.5 [M+H] + .

[0423] 1 H NMR(400MHz,DMSO-d6)δ9.76(t,J=5.5Hz,1H),8.66(d,J=1.8Hz,1H),8.58(s,1 H),8.43(d,J=8.1Hz,1H),8.27(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.64(d,J=8 .7Hz,1H),7.51–7.46(m,2H),7.19–7.14(m,2H),5.22(p,J=7.2Hz,1H),3.90(s ,3H),3.59–3.54(m,2H),3.53–3.49(m,2H),3.35(s,4H),1.50(d,J=7.1Hz,3H).

[0424] Preparation of compound 35:

[0425]

[0426] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and N-tert-butyloxycarbonyl-1,2-ethylenediamine (48 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 50%) to afford compound 35 in a 63% yield. MS (ESI, positive ion) m / z: 577.6 [M+H] + .

[0427] 1H NMR (400MHz, DMSO-d6) δ9.66(t,J=6.0Hz,1H),8.66(d,J=1.8Hz,1H),8.57(s,1H),8.40(d ,J=8.1Hz,1H),8.24(s,1H),7.79(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.51–7.45 (m,2H),7.20–7.13(m,2H),6.97(d,J=5.8Hz,1H),5.22(p,J=7.1Hz,1H),3.90(s,3H),3.4 3(q,J=6.1Hz,2H),3.30(s,1H),3.15(q,J=6.0Hz,2H),1.50(d,J=7.1Hz,3H),1.39(s,9H).

[0428] Preparation of compound 36:

[0429]

[0430] Intermediate INT-1-3 (8.4 mg, 0.024 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.3 mL). 4-Chloro-6-methoxy-1,2-dihydrophthalazin-1-one (5.1 mg, 0.024 mmol) was added, along with potassium phosphate (3.98 mg, 0.029 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.55 mg, 0.0031 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 36 in a 44% yield. MS (ESI, positive ion) m / z: 471.5 [M+H] + .

[0431] 1 H NMR (400MHz, DMSO-d6) δ12.68(d,J=23.7Hz,1H),8.39–8.26(m,3H),8.25(d,J=4.9Hz,1H),7.76–7.65(m,2H),7.51–7. 42(m,4H),7.16–7.12(m,2H),5.18(h,J=6.7,6.2Hz,1H),3.98–3.91(m,5H),3.78(s,1H),1.48(dd,J=7.0,1.5Hz,3H).

[0432] Preparation of compound 37:

[0433]

[0434] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and piperidin-4-ol (4.65 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to afford compound 37 in a 35% yield. MS (ESI, positive ion) m / z: 518.5 [M+H] + .

[0435] 1 H NMR (400MHz, DMSO-d6) δ8.62(d,J=1.8Hz,1H),8.33(d,J=8.0Hz,1H),8.19(s,1H),8.03(d,J=0.7Hz,1H),7.78(dd ,J=8.7,1.8Hz,1H),7.61(d,J=8.7Hz,1H),7.49–7.43(m,2H),7.19–7.14(m,2H),5.20(p,J=7.2Hz,1H),4.78(dd, J=4.0,1.5Hz,1H),4.03–3.96(m,1H),3.89(s,3H),3.80–3.71(m,1H),3.48–3.40(m,1H),3.29–3.21(m,1H),3.11 (dd,J=11.8,7.8Hz,1H),1.76(d,J=25.3Hz,2H),1.49(d,J=7.1Hz,3H),1.43(dq,J=8.6,4.2Hz,2H),0.99(s,1H).

[0436] Preparation of compound 38:

[0437]

[0438] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and (R)-3-pyrrolidinol (5.7 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 38 in a 30% yield. MS (ESI, positive ion) m / z: 503.2 [M+H] + .

[0439] 1H NMR (400MHz, DMSO-d6) δ8.63(d,J=1.8Hz,1H),8.34(d,J=8.0Hz,1H),8.20(s,1H),8.03(s,1H),7.7 9(dd,J=8.8,1.9Hz,1H),7.61(d,J=8.7Hz,1H),7.46(dd,J=8.4,5.6Hz,2H),7.21–7.13(m,2H),5.2 0(p,J=7.2Hz,1H),5.01(dd,J=16.5,3.7Hz,1H),4.32(d,J=27.7Hz,1H),3.89(s,3H),3.53(dq,J=1 3.6,9.0,7.9Hz,3H),3.41(d,J=10.8Hz,1H),2.00–1.75(m,2H),1.49(d,J=7.1Hz,3H),0.98(s,1H).

[0440] Preparation of compound 39:

[0441]

[0442] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and 3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine (5.7 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 39 in a 30% yield. MS (ESI, positive ion) m / z: 540.5 [M+H] + .

[0443] Preparation of compound 40:

[0444]

[0445] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and isopropylamine (18 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 55%) to afford compound 40 in a 65% yield. MS (ESI, positive ion) m / z: 476.2 [M+H] + .

[0446] 1H NMR(400MHz,DMSO-d6)δ9.61(d,J=7.6Hz,1H),8.65(d,J=1.8Hz,1H),8.56(s,1H), 8.37(d,J=8.0Hz,1H),8.22(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.64(d,J=8.7Hz, 1H),7.52–7.41(m,2H),7.20–7.14(m,2H),5.22(p,J=7.1Hz,1H),4.19–4.05(m,1H ), 3.90 (s, 3H), 1.50 (d, J = 7.1Hz, 3H), 1.23 (d, J = 6.6Hz, 6H), 1.21 (d, J = 6.4Hz, 1H).

[0447] Preparation of compound 41:

[0448]

[0449] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and trifluoroethylamine (4.6 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 41 in a 40% yield. MS (ESI, positive ion) m / z: 516.4 [M+H] + .

[0450] Preparation of compound 42:

[0451]

[0452] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and 2R-oxolan-2-amine (4 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 42 in a 41% yield. MS (ESI, positive ion) m / z: 504.5 [M+H] + .

[0453] Preparation of compound 43:

[0454]

[0455] Preparation of compound 43:

[0456] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and 3-aminooxolan-2-one (4.7 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 43 in a 43% yield. MS (ESI, positive ion) m / z: 518.5 [M+H] + .

[0457] Preparation of compound 44:

[0458]

[0459] Preparation of compound 44:

[0460] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and N,N-dimethyl-1,2-cyclohexanediamine (6.5 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 44 in a 40% yield. MS (ESI, positive ion) m / z: 559.6 [M+H] + .

[0461] Preparation of compound 45:

[0462]

[0463] Preparation of compound 45:

[0464] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and methyl 2-aminobenzoate (7 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 45 in a 58% yield. MS (ESI, positive ion) m / z: 568.6 [M+H] + .

[0465] Preparation of compound 46:

[0466]

[0467] Preparation of compound 46:

[0468] Intermediate INT-2 (84 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and hydroxylamine hydrochloride (21 mg, 0.3 mmol), N,N-diisopropylethylamine (0.1 mL), and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 100°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 60%) to afford compound 46 in a 65% yield. MS (ESI, positive ion) m / z: 450.2 [M+H] + .

[0469] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=1.9Hz,1H),8.55(s,1H),8.37(d,J=8.1Hz,1H),8.22(s,1H),7.82(dd,J=8.7,1.9Hz,1H),7.65(d,J= 8.7Hz,1H),7.47(dd,J=8.6,5.6Hz,2H),7.17(t,J=8.9Hz,2H),5.22(t,J=7.2Hz,1H),3.90(s,3H),1.50(d,J=7.0Hz,3H),1.08(s,3H).

[0470] Preparation of compound 47:

[0471]

[0472] Preparation of intermediate 47-1:

[0473] Intermediate INT-2 (200 mg, 0.4 mmol) was dissolved in pyridine (2 mL), and methoxymethylamine (36 mg, 0.6 mmol) and 1-propylphosphonic anhydride (222 mg, 0.35 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 55%) to afford intermediate 47-1 in a 75% yield. MS (ESI, positive ion) m / z: 478.2 [M+H] + .

[0474] Preparation of compound 47:

[0475] Intermediate 47-1 (95 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and methylmagnesium bromide (0.4 mL, 0.4 mmol, 1 mol / L) was added dropwise at 0°C. The mixture was stirred for 30 min. Saturated ammonium chloride solution (1 mL) was added to the reaction solution, concentrated under reduced pressure, and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to obtain compound 47 in a 65% yield. MS (ESI, positive ion) m / z: 433.2 [M+H] + .

[0476] 1 H NMR (400MHz, DMSO-d6) δ8.62(d,J=1.9Hz,1H),8.35(d,J=8.1Hz,1H),8.20(d,J=4.0Hz,2H),7.77(dd,J=8.7,1.8Hz,1H),7.63( d,J=8.7Hz,1H),7.49–7.44(m,2H),7.19–7.13(m,2H),5.20(q,J=7.3Hz,1H),3.89(s,3H),2.66(s,3H),1.49(d,J=7.1Hz,3H).

[0477] Preparation of compound 48:

[0478]

[0479] Preparation of compound 48:

[0480] Intermediate INT-2-1 (99 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL). Methylmagnesium bromide (0.6 mL, 0.6 mmol, 1 mol / L) was added dropwise at 0°C and stirred for 30 min. Saturated ammonium chloride solution (1 mL) was added to the reaction solution, which was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to afford compound 48 in a 70% yield. MS (ESI, positive ion) m / z: 449.2 [M+H] + .

[0481] 1H NMR (400MHz, DMSO-d6) δ12.98(s,1H),8.63(d,J=1.8Hz,1H),8.35(d,J=7.9Hz,1H),8.20(s,1H),8.06(s,1H),7.76(dd,J=8.7,1.8Hz,1H),7.6 2(d,J=8.7Hz,1H),7.50–7.43(m,2H),7.19–7.13(m,2H),5.46(s,1H), 5.21(p,J=7.1Hz,1H),3.89(s,3H),1.54(s,6H),1.49(d,J=7.1Hz,3H).

[0482] Preparation of compound 49:

[0483]

[0484] Preparation of compound 49:

[0485] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 4-aminotetrahydropyran (30 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 49 in a 58% yield. MS (ESI, positive ion) m / z: 518.5 [M+H] + .

[0486] 1 H NMR (400MHz, DMSO-d6) δ9.72(d,J=7.6Hz,1H),8.65(d,J=1.8Hz,1H),8.57(s,1H),8.36(d, J=8.0Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.64(d,J=8.7Hz,1H),7.50–7.45(m ,2H),7.20–7.14(m,2H),5.22(p,J=7.2Hz,1H),4.14–4.02(m,1H),3.90(s,3H),3.86(dd,J =11.5,4.1Hz,2H),3.49(td,J=11.3,2.4Hz,2H),1.91(d,J=12.5Hz,2H),1.59–1.48(m,5H).

[0487] Preparation of compound 50:

[0488]

[0489] Preparation of compound 50:

[0490] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and adamantaneamine (45 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 50%) to afford compound 50 in a 68% yield. MS (ESI, positive ion) m / z: 568.7 [M+H] + .

[0491] 1 H NMR (400MHz, DMSO-d6) δ9.62(s,1H),8.65(d,J=1.8Hz,1H),8.55(s,1H),8.35(d,J=8.0Hz,1H),8.21(s,1H),7.79(dd,J=8.7,1.9Hz,1H),7.64 (d,J=8.7Hz,1H),7.51–7.44(m,2H),7.21–7.14(m,2H),5.22(p,J=7.2Hz,1H),3.90(s,3H),2.09(s,10H),1.70(s,6H),1.50(d,J=7.0Hz,3H).

[0492] Preparation of compound 51:

[0493]

[0494] Preparation of compound 51:

[0495] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and methyl glycine (27 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 51 in a 12% yield. MS (ESI, positive ion) m / z: 506.5 [M+H] + .

[0496] 1H NMR (400MHz, DMSO-d6) δ9.97(t,J=5.7Hz,1H),8.66(d,J=1.8Hz,1H),8.58(s,1H),8.36(d,J=8.1Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.6 5(d,J=8.7Hz,1H),7.50–7.44(m,2H),7.19–7.14(m,2H),5.22(p,J=7.2Hz, 1H), 4.23 (d, J = 5.7Hz, 2H), 3.90 (s, 3H), 3.70 (s, 3H), 1.50 (d, J = 7.1Hz, 3H).

[0497] Preparation of compound 52:

[0498]

[0499] Preparation of compound 52:

[0500] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclobutylmethylamine (26 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 52 in a 60% yield. MS (ESI, positive ion) m / z: 502.5 [M+H] + .

[0501] 1 H NMR (400MHz, DMSO-d6) δ9.67(t,J=5.8Hz,1H),8.66(d,J=1.8Hz,1H),8.57(s,1H),8.36(d, J=8.1Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.64(d,J=8.7Hz,1H),7.50–7.45(m ,2H),7.19–7.14(m,2H),5.22(p,J=7.3Hz,1H),3.90(s,3H),3.46–3.40(m,2H),2.62–2.55 (m,1H),2.04(p,J=7.8Hz,2H),1.93–1.84(m,2H),1.80–1.70(m,2H),1.50(d,J=7.0Hz,3H).

[0502] Preparation of compound 53:

[0503]

[0504] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and N-(2-aminoethyl)morpholine (39 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 50%) to afford compound 53 in a 55% yield. MS (ESI, positive ion) m / z: 547.6 [M+H] + .

[0505] 1 H NMR(400MHz, DMSO-d6)δ9.81(t,J=5.4Hz,1H),8.66(d,J=1.8Hz,1H),8.57(s,1H),8.36( d,J=8.0Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.50–7. 45(m,2H),7.20–7.14(m,2H),5.22(p,J=7.3Hz,1H),3.90(s,3H),3.62(t,J=4.6Hz,4H),3 .51(q,J=6.1Hz,2H),2.54(d,J=4.3Hz,2H),2.46(t,J=4.7Hz,4H),1.50(d,J=7.1Hz,3H).

[0506] Preparation of compound 54:

[0507]

[0508] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (51 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 54 in a 57% yield. MS (ESI, positive ion) m / z: 586.6 [M+H] + .

[0509] 1H NMR (400MHz, DMSO-d6) δ13.77(s,1H),9.80(d,J=4.5Hz,1H),8.66(d,J=1.8Hz,1H),8.56(s ,1H),8.36(d,J=8.0Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.64(d,J=8.7Hz,1H) ,7.52–7.40(m,2H),7.40–7.26(m,2H),7.22–7.07(m,2H),5.22(p,J=7.2Hz,1H),3.90(s,3H ),3.14–3.05(m,1H),2.24(td,J=7.9,3.4Hz,1H),1.50(d,J=7.0Hz,3H),1.43–1.35(m,2H).

[0510] Preparation of compound 55:

[0511]

[0512] Compound 3 (80 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropanecarboxylic acid (26 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 55%) to afford compound 55 in a 65% yield. MS (ESI, positive) m / z: 458.2 [M+H] + .

[0513] 1 H NMR (400MHz, DMSO-d6) δ11.47(s,1H),8.87(d,J=1.8Hz,1H),8.38(d,J=9.4Hz,1H),8.35(d, J=8.0Hz,1H),8.22(s,1H),8.18(d,J=9.4Hz,1H),7.99(dd,J=8.7,1.8Hz,1H),7.66(d,J=8. 7Hz,1H),7.47(dd,J=8.7,5.6Hz,2H),7.16(t,J=8.9Hz,2H),5.26–5.18(m,1H),3.91(s,3H) ,2.12(p,J=6.5Hz,1H),1.50(d,J=7.0Hz,3H),1.37(d,J=6.0Hz,1H),1.25(d,J=2.7Hz,3H).

[0514] Preparation of compound 56:

[0515]

[0516] Intermediate INT-2-1 (89.6 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (11.4 mg, 0.3 mmol) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched by adding 0.1 mL of water, 0.1 mL of 1 mol / L NaOH solution, and 0.3 mL of water. Anhydrous magnesium sulfate (0.5 g) was added, and the mixture was stirred at room temperature for 10 minutes. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 56 in a 29% yield. MS (ESI, positive ion) m / z: 421.2 [M+H] + .

[0517] 1 H NMR (400MHz, DMSO-d6) δ13.04(s,1H),8.63(d,J=1.8Hz,1H),8.35(d,J=7.9Hz, 1H),8.21(s,1H),7.92(d,J=1.8Hz,1H),7.77(dd,J=8.7,1.8Hz,1H),7.62(d,J= 8.8Hz,1H),7.47(dd,J=8.6,5.5Hz,2H),7.16(t,J=8.9Hz,2H),5.51(t,J=5.5Hz ,1H),5.25–5.17(m,1H),4.51–4.44(m,2H),3.89(s,3H),1.49(d,J=7.0Hz,3H).

[0518] Preparation of compound 57:

[0519]

[0520] Intermediate INT-3 (46 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (34 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 45%) to afford compound 57 in a 46% yield. MS (ESI, positive ion) m / z: 500.2 [M+H] + .

[0521] 1H NMR (400MHz, DMSO-d6) δ13.87(s,1H),9.64(s,1H),8.58(d,J=1.8Hz,1H),8.51(s,1H),7.80(d,J=8.2Hz,1H),7.68–7.61(m,1H),7.34(t, J=7.0Hz,2H),7.16(d,J=8.9Hz,2H),3.90(s,3H),3.59(s,6H),1.95(s,2H),1.80(s,1H),0.80(dd,J=7.2,4.9Hz,2H),0.63–0.57(m,2H).

[0522] Preparation of compound 58:

[0523]

[0524] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and 2-(1H-indol-3-yl)ethane-1-amine (7.4 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 58 in a 57% yield. MS (ESI, positive ion) m / z: 577.6 [M+H] + .

[0525] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),9.74(t,J=5.8Hz,1H),8.66(d,J=1.9Hz,1H),8.59(s,1H),8.36(d,J=8.0 Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.64(dd,J=8.3,4.8Hz,2H),7.51–7.45(m,2H),7.36(d,J=8.2 Hz,1H),7.24(d,J=2.4Hz,1H),7.20–7.14(m,2H),7.09(ddd,J=8.1,7.0,1.2Hz,1H),7.00(ddd,J=7.9,7.0,1.1 Hz,1H),5.23(t,J=7.4Hz,1H),3.90(s,3H),3.69(q,J=6.8Hz,2H),3.01(t,J=7.2Hz,2H),1.50(d,J=7.0Hz,3H).

[0526] Preparation of compound 59:

[0527]

[0528] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and 4-butylaniline (6.9 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 59 in a 39% yield. MS (ESI, positive ion) m / z: 566.6 [M+H] + .

[0529] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),8.70(d,J=1.8Hz,1H),8.67(s,1H),8.37(d,J=8.0Hz, 1H),8.23(s,1H),7.84(dd,J=8.7,1.9Hz,1H),7.69–7.65(m,3H),7.51–7.45(m,2H),7.25(d ,J=8.3Hz,2H),7.18(t,J=8.9Hz,2H),5.28–5.18(m,1H),3.91(s,3H),2.60(t,J=7.6Hz,2H) ,1.58(p,J=7.6Hz,2H),1.51(d,J=7.0Hz,3H),1.34(h,J=7.3Hz,2H),0.93(t,J=7.3Hz,3H).

[0530] Preparation of compound 60:

[0531]

[0532] Preparation of intermediate 60-1:

[0533] Intermediate INT-1-3 (422 mg, 1.0 mmol) and methyl 6-chloropyridazine-4-carboxylate (172 mg, 1.0 mmol) were dissolved in 1,4-dioxane (10 mL). Potassium phosphate (424 mg, 2.0 mmol), PdCl2(dppf)2 (42 mg), and water (1.0 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the mixture was stirred for 8 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to afford Intermediate 60-1 in a 65% yield. MS (ESI, positive ion) m / z: 419.2 [M+H] + .

[0534] Preparation of compound 60:

[0535] Intermediate 60-1 (42 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (11.4 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 60 in a 42% yield. MS (ESI, positive) m / z: 458.2 [M+H] + .

[0536] 1 H NMR (400MHz, DMSO) δ9.42(d,J=1.9Hz,1H),9.10(d,J=4.0Hz,1H),8.97(d,J=1.5Hz,1H),8.43(d,J =2.0Hz,1H),8.38(d,J=7.9Hz,1H),8.24(s,1H),8.13(dd,J=8.7,1.8Hz,1H),7.72(d,J=8.7Hz,1H ),7.48(dd,J=8.6,5.6Hz,2H),7.17(t,J=8.9Hz,2H),5.24(dd,J=14.6,7.1Hz,1H),3.93(s,3H),2 .94(tq,J=7.6,3.9Hz,1H),1.51(d,J=7.0Hz,3H),0.80(td,J=7.1,4.8Hz,2H),0.70–0.63(m,2H).

[0537] Preparation of compound 61:

[0538]

[0539] Intermediate INT-2-1 (89.6 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (11.4 mg, 0.3 mmol) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched by adding 0.1 mL of water, 0.1 mL of 1 mol / L NaOH solution, and 0.3 mL of water. Anhydrous magnesium sulfate (0.5 g) was added, and the mixture was stirred at room temperature for 10 minutes. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to afford compound 61 in a 20% yield. MS (ESI, positive ion) m / z: 451.2 [M+H] + .

[0540] 1H NMR (400MHz, DMSO) δ11.15(s,1H),8.51(s,1H),8.33(d,J=7.9Hz,1H),8.18(s,1H),7.72(dd,J=8.8,1.6Hz,1H),7.55(d,J=8.8Hz,1H),7.48–7.43 (m,2H),7.16(t,J=8.8Hz,2H),5.23–5.14(m,1H),3.87(s,3H),3.78–3.7 1(m,1H),3.69(d,J=0.8Hz,3H),3.31–3.17(m,2H),1.49(d,J=7.1Hz,3H).

[0541] Preparation of compound 62:

[0542]

[0543] Intermediate INT-2 (300 mg, 0.2 mmol) was dissolved in methanol (10 mL). A solution of hydrogen chloride in 1,4-dioxane (1 mL) was added, and the mixture was heated to 60°C and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and filtered. The filter cake was retained to obtain compound 62 in an 80% yield. MS (ESI, positive ion) m / z: 449.2 [M+H] + .

[0544] 1 H NMR (400MHz, DMSO) δ13.55(s,1H),8.61(d,J=1.6Hz,1H),8.35(d,J=6.3Hz,2H),8.21(d,J=3.8Hz,1H),7.77(dd,J=8.7,1.8Hz,1H), 7.63(d,J=8.7Hz,1H),7.49–7.42(m,2H),7.16(t,J=8.9Hz,2H),5.21(p,J=7.0Hz,1H),3.88(d,J=7.5Hz,6H),1.49(d,J=7.0Hz,3H).

[0545] Preparation of compound 63:

[0546]

[0547] Intermediate INT-2 (84 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2,2-difluoroethylamine (24 mg, 0.3 mmol) and 1-propylphosphonic anhydride (111 mg, 0.351 mmol) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 55%) to afford compound 63 in a 65% yield. MS (ESI, positive ion) m / z: 498.2 [M+H] + .

[0548] 1 H NMR(400MHz,DMSO)δ13.49(s,0H),9.90(t,J=6.1Hz,1H),8.66(d,J=1.6Hz,1H),8 .59(s,1H),8.37(d,J=8.0Hz,1H),8.22(s,1H),7.80(dd,J=8.7,1.8Hz,1H),7.64 (d,J=8.7Hz,1H),7.52–7.40(m,2H),7.20–7.11(m,2H),6.23(tt,J=55.7,3.7Hz, 1H), 5.22 (p, J = 7.0Hz, 1H), 3.89 (s, 3H), 3.88–3.80 (m, 2H), 1.49 (d, J = 7.1Hz, 3H).

[0549] Preparation of compound 64:

[0550]

[0551] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and N-methyl-3-aminopyrazole (29 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 64 in a 65% yield. MS (ESI, positive ion) m / z: 514.5 [M+H] + .

[0552] 1H NMR (400MHz, DMSO-d6) δ13.94(s,1H),12.07(s,1H),8.69(d,J=9.0Hz,2H),8.37(d,J=8.0Hz,1H),8.22(s,1H),7.86–7.78(m,1H),7.71–7.63(m,2H ),7.48(dd,J=8.5,5.5Hz,2H),7.17(t,J=8.7Hz,2H),6.67(d,J=2.3Hz,1H ),5.23(t,J=7.4Hz,1H),3.90(s,3H),3.81(s,3H),1.50(d,J=7.1Hz,3H).

[0553] Preparation of compound 65:

[0554]

[0555] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-aminopyrazole (25 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 65 in a 10% yield. MS (ESI, positive ion) m / z: 500.5 [M+H] + .

[0556] 1 H NMR(400MHz,DMSO-d6)δ14.04(s,1H),12.61(s,1H),12.09(s,1H),8.75–8.6 6(m,2H),8.37(d,J=8.0Hz,1H),8.22(s,1H),7.84(dd,J=8.7,1.9Hz,1H),7. 74(s,1H),7.67(d,J=8.7Hz,1H),7.53–7.44(m,2H),7.23–7.12(m,2H),6.74 (t,J=2.1Hz,1H),5.23(p,J=7.1Hz,1H),3.91(s,3H),1.51(d,J=7.1Hz,3H).

[0557] Preparation of compound 66:

[0558]

[0559] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methyl-1H-1,2,4-triazol-3-amine (29 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 66 in a 56% yield. MS (ESI, positive ion) m / z: 515.2 [M+H] + .

[0560] 1 H NMR(400MHz,DMSO-d6)δ13.85(s,1H),12.09(s,1H),8.71–8.63(m,2H),8.43–8.34(m,2H),8.22(s,1H),7.83(dd,J=8.7,1.9Hz,1H), 7.66(d,J=8.7Hz,1H),7.52–7.42(m,2H),7.22–7.12(m,2H),5.23(p,J=7.1Hz,1H),3.91(s,3H),3.87(s,3H),1.50(d,J=7.0Hz,3H).

[0561] Preparation of compound 67:

[0562]

[0563] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-aminopyridine (28 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 67 in a 65% yield. MS (ESI, positive ion) m / z: 511.2 [M+H] + .

[0564] 1H NMR (400MHz, DMSO-d6) δ14.12(s,1H),12.38(s,1H),8.72–8.67(m,2H),8.42(ddd,J=4 .9,1.9,0.9Hz,1H),8.38(d,J=8.1Hz,1H),8.33(dt,J=8.3,1.1Hz,1H),8.23(s,1H),7 .93(ddd,J=8.9,7.4,1.9Hz,1H),7.88–7.79(m,1H),7.67(d,J=8.7Hz,1H),7.51–7.46 (m,2H),7.28–7.11(m,3H),5.23(h,J=7.0Hz,1H),3.91(s,3H),1.51(d,J=7.1Hz,3H).

[0565] Preparation of compound 68:

[0566]

[0567] Intermediate INT-2 (84 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-amino-6-fluoropyridine (34 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 55%) to afford compound 68 in a 65% yield. MS (ESI, positive ion) m / z: 529.2 [M+H] + .

[0568] 1 H NMR(400MHz,DMSO-d6)δ14.26(s,1H),12.74(s,-1H),8.71–8.66(m,1H),8.61(s,1 H),8.43(d,J=8.0Hz,1H),8.30–8.20(m,2H),8.10(q,J=8.2Hz,1H),7.85(dd,J=8. 7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.53–7.45(m,2H),7.17(t,J=8.9Hz,2H),6.9 8(dd,J=8.2,2.3Hz,1H),5.23(p,J=7.1Hz,1H),3.90(s,3H),1.51(d,J=7.0Hz,3H).

[0569] Preparation of compound 69:

[0570]

[0571] Intermediate INT-1-3 (42.2 mg, 0.1 mmol) and 5-bromopyrimidin-2(1H)-one (17.4 mg, 0.1 mmol) were dissolved in 1,4-dioxane (2 mL). Potassium phosphate (42.4 mg, 0.2 mmol), PdCl2(dppf)2 (5 mg), and water (0.2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the mixture was stirred for 8 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to afford compound 69 in a 49% yield. MS (ESI, positive ion) m / z: 391.2 [M+H] + .

[0572] 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.56(s,1H),8.43(s,3H),8.32–8.22(m,2H),8.17(d,J=6.4Hz,1H),7.62–7.5 3(m,1H),7.53–7.41(m,3H),7.21–7.11(m,2H),5.21(p,J=7.2Hz,1H),3.88(d,J=2.9Hz,3H),1.49(d,J=7.1Hz,3H).

[0573] Preparation of compound 70:

[0574]

[0575] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and (1S,3S)-3-aminomethylcyclobutane-1-ol (4.7 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 70 in a 46% yield. MS (ESI, positive ion) m / z: 518.5 [M+H] + .

[0576] 1H NMR (400MHz, DMSO-d6) δ13.92(s,1H),9.65(t,J=5.9Hz,1H),8.65(d,J=1.8Hz,1H),8.57(s,1H),8 .36(d,J=8.0Hz,1H),8.21(s,1H),7.80(dd,J=8.6,1.9Hz,1H),7.64(d,J=8.7Hz,1H),7.57–7.40(m ,3H),7.16(t,J=8.7Hz,2H),5.26–5.13(m,1H),3.89(s,3H),3.39(t,J=6.2Hz,2H),2.27(q,J=8.1, 5.6Hz,2H),2.02–1.88(m,1H),1.56(q,J=9.4Hz,2H),1.49(d,J=7.0Hz,3H),1.46(d,J=7.3Hz,1H).

[0577] Preparation of compound 71:

[0578]

[0579] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and tert-butyl N-(2-aminoethyl)-N-methylcarbamate (8 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 60%) to afford compound 71 in a 74% yield. MS (ESI, positive ion) m / z: 591.6 [M+H] + .

[0580] 1 H NMR (400MHz, DMSO-d6) δ9.65(d,J=6.4Hz,1H),8.66(d,J=1.8Hz,1H),8.58(s,1H),8.36(d ,J=8.0Hz,1H),8.21(s,1H),7.79(dd,J=8.7,1.9Hz,1H),7.64(d,J=8.7Hz,1H),7.53–7.40 (m,2H),7.22–7.11(m,2H),5.22(p,J=7.2Hz,1H),3.90(s,3H),3.54(q,J=6.0Hz,2H),3.4 1(d,J=6.1Hz,2H),2.84(s,3H),1.50(d,J=7.0Hz,3H),1.41(d,J=3.0Hz,1H),1.35(s,9H).

[0581] Preparation of compound 72:

[0582]

[0583] Intermediate INT-1-3 (50 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.3 mL). 4-Chloro-5,6,7,8-tetrahydrophthalazin-1(2H)-one (22 mg, 0.12 mmol) was added, along with potassium phosphate (20 mg, 0.14 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (13 mg, 0.016 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 72 in a 47% yield. MS (ESI, positive ion) m / z: 445.5 [M+H] + .

[0584] 1 H NMR (400MHz, DMSO-d6) δ8.35–8.28(m,2H),8.24(s,1H),7.64(d,J=8.5Hz,1H),7.43(dddd,J=16.5,9.8,6.8,2.4Hz,4H),7.19–7.10(m,2H),5. 19(p,J=7.0Hz,1H),3.92(s,3H),2.77(t,J=6.3Hz,2H),2.63(t,J=6.2Hz,2H),1.85(d,J=6.0Hz,2H),1.69–1.64(m,2H),1.48(d,J=7.1Hz,3H).

[0585] Preparation of compound 73:

[0586]

[0587] Intermediate INT-1-3 (50 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.3 mL). 6-Chloro-4,5-diethyl-2,3-dihydropyridazin-3-one (22 mg, 0.12 mmol) was added, along with potassium phosphate (20 mg, 0.14 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (13 mg, 0.016 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 73 in a 46% yield. MS (ESI, positive ion) m / z: 447.5 [M+H]+ .

[0588] 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),8.30(d,J=8.0Hz,1H),8.22(s,1H),8.13(d,J=1. 7Hz,1H),7.58(d,J=8.4Hz,1H),7.44(ddd,J=11.1,6.7,3.8Hz,2H),7.25(dd,J=8.4,1. 7Hz,1H),7.20–7.10(m,2H),5.19(p,J=7.1Hz,1H),3.90(s,3H),2.59(q,J=7.6Hz,2H), 2.50–2.42(m,2H),1.48(d,J=7.1Hz,3H),1.13(t,J=7.4Hz,3H),0.85(t,J=7.5Hz,3H).

[0589] Preparation of compound 74:

[0590]

[0591] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (S)-2-(aminomethyl)-1-ethylpyrrolidine (38 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 74 in a 65% yield. MS (ESI, positive ion) m / z: 545.2 [M+H] + .

[0592] 1H NMR (400MHz, DMSO-d6) δ13.88(s,1H),9.79(s,1H),8.65(d,J=1.9Hz,1H),8.58(s,1H),8.37(d,J=8 .0Hz,1H),8.22(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.51–7.42(m,2H),7.22– 7.11(m,2H),5.22(p,J=7.2Hz,1H),3.90(s,3H),3.87(s,1H),3.69–3.41(m,2H),3.25–2.81(m,2H) ,2.80–2.58(m,1H),2.44–2.20(m,1H),2.02–1.54(m,4H),1.50(d,J=7.0Hz,3H),1.21–1.02(m,3H).

[0593] Preparation of compound 75:

[0594]

[0595] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (50 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 75 in a 65% yield. MS (ESI, positive ion) m / z: 584.2 [M+H] + .

[0596] 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.69(d,J=1.9Hz,1H),8.64(s,1H),8.37(d,J=8.0 Hz,1H),8.23(d,J=4.2Hz,2H),7.86–7.79(m,2H),7.66(d,J=8.7Hz,1H),7.52–7.44(m,2H ),7.23–7.13(m,2H),5.23(p,J=7.1Hz,1H),4.43(tt,J=10.1,5.2Hz,1H),4.02–3.95(m, 2H),3.91(s,3H),3.49(td,J=11.3,3.2Hz,2H),2.05–1.97(m,4H),1.50(d,J=7.1Hz,4H).

[0597] Preparation of compound 76:

[0598]

[0599] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-amino-1-morpholinoethan-1-one (28.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (63.6 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 45%) to afford compound 76 in a 49% yield. MS (ESI, positive ion) m / z: 562.2 [M+H] + .

[0600] 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),10.12(t,J=4.8Hz,1H),8.65(d,J=1.8Hz,1H),8.58( s,1H),8.37(d,J=8.0Hz,1H),8.22(s,1H),7.81(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1 H),7.51–7.42(m,2H),7.22–7.11(m,2H),5.22(p,J=7.2Hz,1H),4.32(d,J=4.8Hz,2H),3.9 0(s,3H),3.62(dt,J=11.3,4.4Hz,4H),3.49(dt,J=10.1,4.5Hz,4H),1.50(d,J=7.0Hz,3H).

[0601] Preparation of compound 77:

[0602]

[0603] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and pyrazin-2-amine (28.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (63.6 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 45%) to afford compound 77 in a 55% yield. MS (ESI, positive ion) m / z: 512.2 [M+H] + .

[0604] Preparation of compound 78:

[0605]

[0606] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and pyridazin-3-amine (28.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (63.6 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 45%) to afford compound 78 in a 51% yield. MS (ESI, positive ion) m / z: 512.2 [M+H] + .

[0607] Preparation of compound 79:

[0608]

[0609] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-aminopyridine (28 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 55%) to afford compound 79 in a 65% yield. MS (ESI, positive ion) m / z: 511.2 [M+H] + .

[0610] 1 H NMR (400MHz, DMSO-d6) δ13.93 (s, 1H), 12.06 (s, 1H), 8.93 (d, J = 2.6Hz, 1H) ,8.73–8.64(m,2H),8.43–8.35(m,2H),8.27–8.18(m,2H),7.85(dd,J=8.7 ,1.9Hz,1H),7.66(d,J=8.7Hz,1H),7.48(td,J=6.0,2.8Hz,3H),7.22–7.1 3(m,2H),5.24(q,J=7.2Hz,1H),3.93–3.86(m,3H),1.50(d,J=7.0Hz,3H).

[0611] Preparation of compound 80:

[0612]

[0613] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 4-amino-2-fluoropyridine (34 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 80 in a 65% yield. MS (ESI, positive ion) m / z: 529.2 [M+H] + .

[0614] 1 H NMR(400MHz,DMSO-d6)δ14.12(s,1H),12.68(s,-1H),8.72–8.63(m,3H),8 .48(dt,J=11.4,5.4Hz,2H),8.37(d,J=8.1Hz,1H),8.22(s,1H),7.85(dd,J =8.7,1.9Hz,1H),7.67(d,J=8.7Hz,1H),7.47(dd,J=8.6,5.6Hz,2H),7.17( t,J=8.9Hz,2H),5.22(q,J=7.2Hz,1H),3.90(s,3H),1.50(d,J=7.0Hz,3H).

[0615] Preparation of compound 81:

[0616]

[0617] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 5-amino-2-methoxypyridine (37 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 55%) to afford compound 81 in a 65% yield. MS (ESI, positive ion) m / z: 541.2 [M+H] + .

[0618] 1H NMR (400MHz, DMSO-d6) δ13.80(s,1H),11.86(s,1H),8.69(d,J=1.9Hz,1H),8.65(s,1H),8. 58(d,J=2.8Hz,1H),8.37(d,J=8.0Hz,1H),8.22(s,1H),8.10(dd,J=8.9,2.7Hz,1H),7.84( dd,J=8.7,1.8Hz,1H),7.66(d,J=8.7Hz,1H),7.52–7.44(m,2H),7.17(t,J=8.9Hz,2H),6.9 1(d,J=8.9Hz,1H),5.22(t,J=7.4Hz,1H),3.90(s,3H),3.88(s,3H),1.50(d,J=7.0Hz,3H).

[0619] Preparation of compound 82:

[0620]

[0621] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and pyrimidin-5-amine (28.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 45%) to afford compound 82 in a 51% yield. MS (ESI, positive ion) m / z: 512.2 [M+H] + .

[0622] 1 H NMR (400MHz, DMSO-d6) δ14.16(s,1H),11.99(s,1H),9.23(s,2H),9.01(s,1H),8.73–8.66(m,2H),8.38(d,J=8.0Hz,1H),8.23(s,1H),7.85(dd,J=8 .7,1.9Hz,1H),7.67(d,J=8.8Hz,1H),7.48(dd,J=8.6,5.6Hz,2H),7.17(t ,J=8.9Hz,2H),5.23(t,J=7.3Hz,1H),3.91(s,3H),1.50(d,J=7.0Hz,3H).

[0623] Preparation of compound 83:

[0624]

[0625] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 5-amino-2-fluoropyridine (34 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 83 in a 65% yield. MS (ESI, positive ion) m / z: 529.2 [M+H] + .

[0626] 1 H NMR (400MHz, DMSO-d6) δ13.89(s,1H),11.97(s,1H),8.72–8.61(m,3H),8.38(ddd,J=9.9,7.3,2.6Hz,2H),8.23(s,1H),7.84(dd,J=8.7,1.9Hz,1H),7 .67(d,J=8.7Hz,1H),7.52–7.44(m,2H),7.28(dd,J=8.8,3.2Hz,1H),7.17( t,J=8.9Hz,2H),5.23(p,J=7.1Hz,1H),3.91(s,3H),1.50(d,J=7.1Hz,3H).

[0627] Preparation of compound 84:

[0628]

[0629] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and cyclopentylamine (3.9 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 84 in a 66% yield. MS (ESI, positive ion) m / z: 502.5 [M+H] + .

[0630] 1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),9.70(d,J=7.4Hz,1H),8.66(d,J=1.8Hz,1H),8 .56(s,1H),8.36(d,J=8.0Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.64(d,J =8.7Hz,1H),7.53–7.40(m,2H),7.22–7.11(m,2H),5.22(p,J=7.2Hz,1H),4.27(h,J= 6.8Hz,1H),3.90(s,3H),2.05–1.69(m,4H),1.68–1.52(m,4H),1.50(d,J=7.1Hz,3H).

[0631] Preparation of compound 85:

[0632]

[0633] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and cyclohexylamine (4.6 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 85 in a 64% yield. MS (ESI, positive ion) m / z: 516.6 [M+H] + .

[0634] 1 H NMR (400MHz, DMSO-d6) δ13.91(s,1H),9.70(d,J=7.8Hz,1H),8.65(d,J=1.9Hz,1H),8.57(s,1 H),8.36(d,J=8.0Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7. 54–7.42(m,2H),7.22–7.11(m,2H),5.22(p,J=7.3Hz,1H),3.90(s,3H),3.89–3.80(m,2H),1. 80(dd,J=75.4,9.8Hz,4H),1.57(s,1H),1.50(d,J=7.0Hz,3H),1.38(q,J=12.3,11.1Hz,4H).

[0635] Preparation of compound 86:

[0636]

[0637] Intermediate INT-1-3 (50 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.3 mL). 4-Amino-6-chloro-2,3-dihydropyridazin-3-one (17 mg, 0.12 mmol) was added, along with potassium phosphate (20 mg, 0.14 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (13 mg, 0.016 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 86 in a 71% yield. MS (ESI, positive ion) m / z: 406.2 [M+H] + .

[0638] 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),8.55(d,J=1.8Hz,1H),8.32(d,J=7.9Hz,1H),8.17(s,1H),7.71(dd,J=8.7,1.8Hz,1H),7.55(d,J =8.7Hz,1H),7.52–7.41(m,2H),7.22–7.11(m,2H),6.86(s,1H),6.38(s,2H),5.20(p,J=7.2Hz,1H),3.87(s,3H),1.49(d,J=7.0Hz,3H).

[0639] Preparation of compound 87:

[0640]

[0641] Intermediate INT-1-3 (50 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.3 mL). 1-Chloropyrido[3,4-D]pyridazin-4(3H)-one (22 mg, 0.12 mmol) was added, along with potassium phosphate (20 mg, 0.14 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (13 mg, 0.016 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 87 in a 61% yield. MS (ESI, positive ion) m / z: 442.6 [M+H] + .

[0642] 1H NMR (400MHz, DMSO-d6) δ13.13(d,J=6.6Hz,1H),9.10(s,1H),9.02(dd,J=5.4,3.0Hz,1 H),8.40(dd,J=15.9,1.7Hz,1H),8.35(dd,J=8.0,3.5Hz,1H),8.27(s,1H),8.19(dd,J =5.2,0.9Hz,1H),7.71(dd,J=8.6,5.4Hz,1H),7.56–7.48(m,1H),7.47–7.43(m,2H),7 .20–7.09(m,2H),5.19(p,J=7.1Hz,1H),3.94(d,J=2.6Hz,3H),1.48(d,J=7.1Hz,3H).

[0643] Preparation of compound 88:

[0644]

[0645] Preparation of intermediate 88-1:

[0646] Intermediate INT-2-1 (89 mg, 0.2 mmol) was dissolved in 1,2-dichloroethane (10 mL). N,N-diisopropylethylamine (0.1 mL), pyridine (0.1 mL), copper acetate (120 mg, 0.6 mmol), and cyclopropaneboronic acid (34 mg, 0.4 mmol) were added. The mixture was heated to 80°C and stirred for 1 hour. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain intermediate 88-1 in 80% yield. MS (ESI, positive ion) m / z: 489.2 [M+H] + .

[0647] Preparation of intermediate 88-2:

[0648] Intermediate 88-1 (49 mg, 0.1 mmol) was dissolved in ethanol (5 mL), and water (1 mL) and sodium hydroxide (24 mg, 0.6 mmol) were added. The mixture was heated to 60°C and stirred for 1 h. The pH of the reaction solution was adjusted to a weakly acidic state. The solid precipitated, was filtered, and dried to obtain Intermediate 88-2 in a 90% yield. MS (ESI, positive ion) m / z: 475.2 [M+H] + .

[0649] Preparation of compound 88:

[0650] Intermediate 88-2 (47 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and methylamine hydrochloride (13.5 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 46%) to afford compound 88 in a 55% yield. MS (ESI, positive ion) m / z: 488.3 [M+H] + .

[0651] 1 H NMR (400MHz, DMSO-d6) δ9.55(d,J=5.0Hz,1H),8.64(d,J=1.8Hz,1H),8.54(s,1H),8.36( d,J=8.0Hz,1H),8.22(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.52–7. 44(m,2H),7.22–7.13(m,2H),5.24(p,J=7.1Hz,1H),4.26(tt,J=7.7,4.0Hz,1H),3.90(s ,3H),2.93(d,J=4.8Hz,3H),1.50(d,J=7.1Hz,3H),1.27–1.20(m,2H),1.20–1.07(m,2H).

[0652] Preparation of compound 89:

[0653]

[0654] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and 2-(4-fluorophenyl)ethylamine (6.4 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 60%) to afford compound 89 in a 39% yield. MS (ESI, positive ion) m / z: 556.5 [M+H] + .

[0655] 1H NMR(400MHz, DMSO-d6)δ9.69(t,J=5.8Hz,1H),8.65(d,J=1.8Hz,1H),8.56(s,1H), 8.36(d,J=8.0Hz,1H),8.21(s,1H),7.79(dd,J=8.7,1.9Hz,1H),7.64(d,J=8.7Hz, 1H),7.52–7.43(m,2H),7.37–7.30(m,2H),7.20–7.10(m,5H),5.22(p,J=7.1Hz,1H ), 3.90 (s, 3H), 3.62 (q, J = 6.8Hz, 2H), 2.88 (t, J = 7.2Hz, 2H), 1.50 (d, J = 7.1Hz, 3H).

[0656] Preparation of compound 90:

[0657]

[0658] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and 3-amino-5,7-dihydroadamantan-1-ol (7.7 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 90 in a 37% yield. MS (ESI, positive ion) m / z: 584.6 [M+H] + .

[0659] 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 8.66 (d, J = 1.8Hz, 1H), 8.55 (s, 1H), 8.36 ( d,J=8.0Hz,1H),8.21(s,1H),7.79(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.8Hz,1H ),7.53–7.44(m,2H),7.22–7.13(m,2H),5.22(p,J=7.0Hz,1H),4.60(s,1H),3. 90(s,3H),2.22(s,2H),1.96(s,5H),1.61(d,J=6.6Hz,4H),1.59–1.47(m,6H).

[0660] Preparation of compound 91:

[0661]

[0662] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and 4-aminooxolan-2-one (4.7 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 60%) to afford compound 91 in a 43% yield. MS (ESI, positive ion) m / z: 518.5 [M+H] + .

[0663] 1 H NMR (400MHz, DMSO-d6) δ9.94(d,J=6.8Hz,1H),8.66(d,J=2.0Hz,1H),8.55(s,1H),8.37(d,J=8.0Hz,1H) ,8.22(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.50–7.45(m,2H),7.20–7.14(m,2H),5 .22(p,J=7.2Hz,1H),4.78(dtt,J=8.6,6.7,4.2Hz,1H),4.58(dd,J=9.4,6.7Hz,1H),4.27(dd,J=9.3,4. 0Hz, 1H), 3.90 (s, 3H), 3.00 (dd, J=17.6, 8.4Hz, 1H), 2.64 (dd, J=17.6, 4.5Hz, 1H), 1.50 (d, J=7.0Hz, 3H).

[0664] Preparation of compound 92:

[0665]

[0666] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and (3S)-oxolan-3-amine (4.0 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 60%) to afford compound 92 in a 58% yield. MS (ESI, positive ion) m / z: 504.5 [M+H] + .

[0667] 1H NMR (400MHz, DMSO-d6) δ9.84(d,J=7.2Hz,1H),8.66(d,J=1.8Hz,1H),8.57(s,1H),8.37(d,J=8.0 Hz,1H),8.22(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.50–7.45(m,2H),7.20 –7.14(m,2H),5.22(p,J=7.2Hz,1H),4.54(dh,J=10.9,3.5Hz,1H),3.90(s,3H),3.91–3.83(m,5H ),3.66(d,J=3.3Hz,1H),2.28(dq,J=12.8,7.6Hz,1H),1.91–1.82(m,1H),1.50(d,J=7.1Hz,3H).

[0668] Preparation of compound 93:

[0669]

[0670] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and 4-aminopyridine (4.3 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 60%) to afford compound 93 in a 43% yield. MS (ESI, positive ion) m / z: 511.5 [M+H] + .

[0671] 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),8.70(d,J=1.8Hz,1H),8.66(s,1H),8.56(d,J=5.4Hz,2H),8.38(d,J=8.0Hz,1H),8.23(s,1H),7.84(dd,J=8.7, 1.9Hz,1H),7.75(d,J=5.7Hz,2H),7.67(d,J=8.7Hz,1H),7.50–7.46(m,2H) ,7.20–7.15(m,2H),5.25–5.20(m,1H),3.91(s,3H),1.50(d,J=7.1Hz,3H).

[0672] Preparation of compound 94:

[0673]

[0674] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2,4-difluorobenzylamine (43 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 94 in a 65% yield. MS (ESI, positive ion) m / z: 560.2 [M+H] + .

[0675] 1 H NMR(400MHz, DMSO-d6)δ13.93(s,1H),10.02(t,J=6.0Hz,1H),8.66(d,J=1.8Hz,1H), 8.58(s,1H),8.36(d,J=8.1Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.64(d ,J=8.7Hz,1H),7.49–7.46(m,2H),7.31–7.25(m,1H),7.19–7.14(m,2H),7.12–7.07( m,1H),5.25–5.19(m,1H),4.62(d,J=5.9Hz,2H),3.90(s,3H),1.50(d,J=7.1Hz,3H).

[0676] Preparation of compound 95:

[0677]

[0678] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and trans-3-aminocyclobutanol hydrochloride (37 mg, 0.3 mmol), diisopropylethylamine (56 mg, 0.4 mmol), and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 95 in a 57% yield. MS (ESI, positive ion) m / z: 504.6 [M+H] + .

[0679] 1H NMR (400MHz, DMSO) δ10.71 (s, 1H), 8.61 (d, J = 1.4Hz, 1H), 8.33 (t, J = 3.9Hz, 2H) ,8.18(s,1H),7.84(dd,J=8.7,1.7Hz,1H),7.60(d,J=8.7Hz,1H),7.52–7.43(m ,2H),7.17(dd,J=12.4,5.5Hz,2H),5.23(p,J=7.1Hz,2H),4.49–4.27(m,2H),4 .04(t,J=6.7Hz,1H),3.88(s,3H),2.23(t,J=5.4Hz,4H),1.50(d,J=7.1Hz,3H).

[0680] Preparation of compound 96:

[0681]

[0682] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cis-3-aminocyclobutanol hydrochloride (37 mg, 0.3 mmol), diisopropylethylamine (56 mg, 0.4 mmol), and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 96 in a 58% yield. MS (ESI, positive ion) m / z: 504.6 [M+H] + .

[0683] 1 H NMR (400MHz, DMSO) δ9.95(s,1H),8.63(d,J=1.5Hz,1H),8.49(s,1H),8.35(d,J=8.0Hz,1H),8.20(s ,1H),7.80(dd,J=8.7,1.7Hz,1H),7.63(d,J=8.7Hz,1H),7.47(dd,J=8.6,5.6Hz,2H),7.16(t,J=8. 9Hz,2H),5.21(p,J=7.1Hz,1H),5.14(d,J=6.4Hz,1H),3.96(td,J=16.4,7.7Hz,2H),3.89(s,3H),2 .87(s,1H),2.68(dt,J=9.4,7.1Hz,2H),1.83(ddd,J=17.0,8.9,2.9Hz,2H),1.49(d,J=7.1Hz,3H).

[0684] Preparation of compound 97:

[0685]

[0686] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methyl-1-cyclobutaneamine hydrochloride (36 mg, 0.3 mmol), diisopropylethylamine (56 mg, 0.4 mmol), and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 50%) to afford compound 97 in a 60% yield. MS (ESI, positive ion) m / z: 502.6 [M+H] + .

[0687] 1 H NMR(400MHz,DMSO)δ13.93(s,1H),9.98(s,1H),8.66(d,J=1.5Hz,1H),8.55(s,1H),8 .36(d,J=8.0Hz,1H),8.21(s,1H),7.79(dd,J=8.7,1.7Hz,1H),7.65(d,J=8.7Hz,1H) ,7.47(dd,J=8.6,5.6Hz,2H),7.17(t,J=8.9Hz,2H),5.21(t,J=7.4Hz,1H),4.73(d,J =6.4Hz,2H),4.44(d,J=6.4Hz,2H),3.90(s,3H),1.67(s,3H),1.50(d,J=7.1Hz,3H).

[0688] Preparation of compound 98:

[0689]

[0690] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and bicyclo[1.1.1]pentane-1-amine hydrochloride (36 mg, 0.3 mmol), diisopropylethylamine (56 mg, 0.4 mmol), and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 50%) to afford compound 98 in a 62% yield. MS (ESI, positive ion) m / z: 500.5 [M+H] + .

[0691] 1H NMR (400MHz, DMSO) δ13.85(s,1H),9.99(s,1H),8.66(d,J=1.5Hz,1H),8.56(s,1H),8.37(d,J=8.0Hz,1H),8.22(s,1H),7.79(dd,J=8.7,1.7Hz,1H) ,7.65(d,J=8.7Hz,1H),7.49(dd,J=8.6,5.6Hz,2H),7.18(t,J=8.9Hz,2H ),5.23(p,J=7.0Hz,1H),3.91(s,3H),2.16(s,7H),1.51(d,J=7.0Hz,3H).

[0692] Preparation of compound 99:

[0693]

[0694] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-(4-amino-1H-pyrazol-1-yl)acetonitrile (24.4 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 45%) to afford compound 99 in a 56% yield. MS (ESI, positive ion) m / z: 539.2 [M+H] + .

[0695] Preparation of compound 100:

[0696]

[0697] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-(4-amino-1H-pyrazol-1-yl)propionitrile (26 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 45%) to afford compound 100 in a 53% yield. MS (ESI, positive ion) m / z: 553.2 [M+H] + .

[0698] 1H NMR(400MHz,DMSO)δ14.24–13.92(m,1H),11.64(s,1H),8.70(s,1H),8.64(s,1H),8 .37(d,J=7.9Hz,1H),8.31(s,1H),8.22(s,1H),7.86–7.80(m,2H),7.66(d,J=8.8Hz ,1H),7.48(dd,J=8.6,5.7Hz,2H),7.17(t,J=8.9Hz,2H),5.24(dd,J=14.3,6.9Hz,1 H), 4.43 (t, J = 6.4Hz, 2H), 3.91 (s, 3H), 3.09 (t, J = 6.4Hz, 2H), 1.50 (d, J = 7.0Hz, 3H).

[0699] Preparation of compound 101:

[0700]

[0701] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2,3-dihydro-1H-inden-2-amine (26.6 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 48%) to afford compound 101 in a 50% yield. MS (ESI, positive ion) m / z: 550.2 [M+H] + .

[0702] 1 H NMR (400MHz, DMSO) δ9.87(d,J=7.1Hz,1H),8.65(d,J=1.6Hz,1H),8.57(s,1H),8.36(d,J=8.1H z,1H),8.21(s,1H),7.79(dd,J=8.7,1.7Hz,1H),7.64(d,J=8.7Hz,1H),7.47(dd,J=8.6,5.6Hz, 2H),7.29(dd,J=5.2,3.3Hz,2H),7.23–7.11(m,5H),5.22(p,J=7.3Hz,1H),4.73(dt,J=12.4,6 .3Hz,1H),3.89(s,3H),3.38–3.34(m,2H),2.93(dd,J=16.0,5.1Hz,2H),1.49(d,J=7.0Hz,3H).

[0703] Preparation of compound 102:

[0704]

[0705] Preparation of intermediate 102-1:

[0706] Compound 47 (86 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and S-tert-butylsulfenamide (36 mg, 0.3 mmol) and tetraethyl titanate (0.3 mL) were added. The temperature was raised to 65°C and stirred for 6 h. The reaction solution was cooled to 0°C, and borane tetrahydrofuran complex (0.2 mL) was added dropwise and stirred for 30 min. 3 mL of methanol was added to the reaction solution, which was concentrated under reduced pressure and purified on a normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 102-1 in 80% yield. MS (ESI, positive ion) m / z: 538.2 [M+H] + .

[0707] Preparation of compound 102:

[0708] Intermediate 102-1 (70 mg, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (0.5 mL) was added and stirred for 30 min. The reaction mixture was concentrated under reduced pressure and extracted with water / dichloromethane (10 mL / 10 mL). The aqueous phase was retained and the pH was adjusted to 7. Dichloromethane / methanol (10 mL / 1 mL) was added for further extraction. The organic phase was retained and the solvent was evaporated to afford compound 102 in an 80% yield. MS (ESI, positive ion) m / z: 434.2 [M+H] + .

[0709] 1 H NMR (400MHz, DMSO) δ13.20–12.81(m,1H),9.05(s,1H),8.64(d,J=1.3Hz,1H),8.61(d,J =8.0Hz,1H),8.35(d,J=7.9Hz,1H),8.21(s,1H),8.03(s,1H),7.77(dd,J=8.7,1.7Hz,1H ),7.61(d,J=8.7Hz,1H),7.46(dd,J=8.6,5.6Hz,2H),7.16(t,J=8.9Hz,2H),5.26–5.12( m,1H),4.13(q,J=6.6Hz,1H),3.89(s,3H),1.49(d,J=7.0Hz,3H),1.25(d,J=3.3Hz,3H).

[0710] Preparation of compound 103:

[0711]

[0712] Preparation of intermediate 103-1:

[0713] Compound 47 (86 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and R-tert-butylsulfenamide (36 mg, 0.3 mmol) and tetraethyl titanate (0.3 mL) were added. The temperature was raised to 65°C and stirred for 6 h. The reaction solution was cooled to 0°C, and borane tetrahydrofuran complex (0.2 mL) was added dropwise and stirred for 30 min. 3 mL of methanol was added to the reaction solution, which was concentrated under reduced pressure and purified on a normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 103-1 in 80% yield. MS (ESI, positive ion) m / z: 538.2 [M+H] + .

[0714] Preparation of compound 103:

[0715] Intermediate 103-1 (70 mg, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (0.5 mL) was added and stirred for 30 min. The reaction solution was concentrated under reduced pressure and extracted with water / dichloromethane (10 mL / 10 mL). The aqueous phase was retained and the pH was adjusted to 7. Dichloromethane / methanol (10 mL / 1 mL) was added for further extraction. The organic phase was retained and the solvent was evaporated to afford compound 103 in 80% yield. MS (ESI, positive ion) m / z: 434.2 [M+H] + .

[0716] 1 H NMR (400MHz, DMSO) δ13.14–12.89(m,1H),8.64(d,J=1.4Hz,1H),8.62–8.61(m,1H),8.3 4(d,J=8.0Hz,1H),8.21(s,1H),8.20(s,1H),8.01(s,1H),7.77(dd,J=8.7,1.6Hz,1H),7 .61(d,J=8.7Hz,1H),7.46(dd,J=8.6,5.7Hz,2H),7.16(t,J=8.9Hz,2H),5.20(t,J=7.4H z,1H),4.10(d,J=6.8Hz,1H),3.89(s,3H),1.49(d,J=7.1Hz,3H),1.30(d,J=6.5Hz,3H).

[0717] Preparation of compound 104:

[0718]

[0719] Intermediate INT-2 (20 mg, 0.046 mmol) was dissolved in pyridine (1 mL), and N-methylethylenediamine (6 mg, 0.046 mmol) and 1-propylphosphonic anhydride (64 mg, 0.1 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous hydrochloric acid = 60%) to afford compound 104 in a 31% yield. MS (ESI, positive ion) m / z: 491.5 [M+H] + .

[0720] 1 H NMR(400MHz,DMSO)δ13.95(s,1H),9.75(s,1H),8.65(s,1H),8.58(s,1H),8.53(s,1H) ,8.40(d,J=7.7Hz,1H),8.28(d,J=26.7Hz,1H),7.80(d,J=6.9Hz,1H),7.68(dd,J=16.3 ,9.0Hz,1H),7.45(d,J=5.9Hz,2H),7.18(d,J=9.0Hz,2H),5.20(s,1H),3.87(dd,J=16. 3,8.0Hz,3H),3.68(s,2H),3.14(s,2H),1.50(d,J=7.0Hz,3H),1.29(d,J=24.9Hz,3H).

[0721] Preparation of compound 105:

[0722]

[0723] Intermediate INT-1-3 (84 mg, 0.2 mmol) was dissolved in 1,4-dioxane:water (1.5 mL:0.15 mL). 3-Amino-4-bromo-6-chloropyridazine (62 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), and Pd(dppf)2Cl2 (20 mg, 0.03 mmol) were added. The mixture was heated to 90°C and stirred for 10 h. The reaction mixture was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to afford compound 105 in a 65% yield. MS (ESI, positive ion) m / z: 424.2 [M+H] + .

[0724] 1H NMR (400MHz, DMSO) δ8.32(d,J=8.0Hz,1H),8.27(s,1H),8.21(s,1H),7.67(d,J=8.5Hz,1H),7.45(dd,J=8.5,5.6Hz,2H),7.38(d d,J=8.5,1.5Hz,1H),7.34(s,1H),7.16(t,J=8.9Hz,2H),6.30(s,2H),5.19(p,J=7.2Hz,1H),3.90(s,3H),1.48(d,J=7.0Hz,3H).

[0725] Preparation of compound 106:

[0726]

[0727] Intermediate INT-1-3 (84 mg, 0.2 mmol) was dissolved in 1,4-dioxane:water (1.5 mL:0.15 mL). 4-Amino-2-chloro-5-fluoropyrimidine (44 mg, 0.3 mmol), potassium carbonate (55 mg, 0.4 mmol), and Pd(dppf)2Cl2 (20 mg, 0.03 mmol) were added. The mixture was heated to 90°C and stirred for 10 h. The reaction mixture was concentrated under reduced pressure and purified on a normal phase silica gel column (dichloromethane / methanol = 40 / 1) to afford compound 106 in a 65% yield. MS (ESI, positive ion) m / z: 408.2 [M+H] + .

[0728] 1 H NMR (400MHz, DMSO-d6) δ9.08(d,J=1.6Hz,1H),8.31(d,J=7.9Hz,1H),8.22(d,J=3.5Hz,1H),8.19(dd,J=8.7,1.7Hz,1H),8.15(s,1H) ,7.53(d,J=8.7Hz,1H),7.47–7.43(m,2H),7.27(s,2H),7.18–7.14(m,2H),5.18(t,J=7.3Hz,1H),3.88(s,3H),1.49(d,J=7.0Hz,3H).

[0729] Preparation of compound 107:

[0730]

[0731] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-isopropyl-1H-pyrazol-4-amine (38 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 107 in a 65% yield. MS (ESI, positive ion) m / z: 542.2 [M+H] + .

[0732] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.69(d,J=1.8Hz,1H),8.63(s,1H),8.37(d, J=8.0Hz,1H),8.21(d,J=6.5Hz,2H),7.82(dd,J=8.7,1.9Hz,1H),7.76(s,1H),7.66 (d,J=8.7Hz,1H),7.48(dd,J=8.7,5.6Hz,2H),7.17(t,J=8.9Hz,2H),5.25–5.20(m ,1H),4.54–4.49(m,1H),3.90(s,3H),1.50(d,J=7.0Hz,3H),1.44(d,J=6.7Hz,6H).

[0733] Preparation of compound 108:

[0734]

[0735] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-ethyl-3-methyl-1H-pyrazol-4-amine (38 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 108 in a 65% yield. MS (ESI, positive ion) m / z: 542.2 [M+H] + .

[0736] 1H NMR (400MHz, DMSO-d6) δ11.73(s,1H),8.70(d,J=1.8Hz,1H),8.65(s,1H),8.38(d, J=8.1Hz,1H),8.22(s,1H),8.17(s,1H),7.83(dd,J=8.7,1.9Hz,1H),7.67(d,J=8.7 Hz,1H),7.50–7.46(m,2H),7.19(d,J=8.9Hz,2H),5.23(t,J=7.4Hz,1H),4.10(d,J= 7.2Hz,2H),3.91(s,3H),2.24(s,3H),1.51(d,J=7.1Hz,3H),1.39(d,J=7.2Hz,3H).

[0737] Preparation of compound 109:

[0738]

[0739] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-(tert-butyl)-1H-pyrazol-4-amine (42 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 109 in a 65% yield. MS (ESI, positive ion) m / z: 556.2 [M+H] + .

[0740] 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.69(d,J=1.9Hz,1H),8.64(s,1H),8 .37(d,J=8.0Hz,1H),8.21(d,J=7.2Hz,2H),7.82(dd,J=8.7,1.9Hz,1H),7.7 7(s,1H),7.66(d,J=8.7Hz,1H),7.50–7.46(m,2H),7.20–7.15(m,2H),5.25– 5.20(m,1H),4.55–4.49(m,1H),3.90(s,3H),1.47(dd,J=24.4,6.8Hz,12H).

[0741] Preparation of compound 110:

[0742]

[0743] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methyl-3-trifluoromethyl-1H-pyrazol-4-amine (50 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 110 in a 65% yield. MS (ESI, positive ion) m / z: 582.5 [M+H] + .

[0744] 1 H NMR(400MHz,DMSO-d6)δ14.13(s,1H),12.24(s,1H),8.69(d,J=1.8Hz,1H) ,8.66(s,1H),8.55(s,1H),8.38(d,J=8.0Hz,1H),8.22(s,1H),7.83(dd,J= 8.7,1.8Hz,1H),7.66(d,J=8.7Hz,1H),7.50–7.46(m,2H),7.20–7.15(m,2 H), 5.23 (t, J = 7.4Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H), 1.50 (d, J = 7.1Hz, 3H).

[0745] Preparation of compound 111:

[0746]

[0747] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-pyrazol-1-ylethylamine (33 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 55%) to afford compound 111 in a 65% yield. MS (ESI, positive ion) m / z: 528.2 [M+H] + .

[0748] 1H NMR (400MHz, DMSO-d6) δ9.69(t,J=5.9Hz,1H),8.65(d,J=1.8Hz,1H),8.56(s,1H),8.36( d,J=8.1Hz,1H),8.21(s,1H),7.79(dd,J=8.7,1.9Hz,1H),7.75(d,J=2.3Hz,1H),7.65(d ,J=8.6Hz,1H),7.49–7.46(m,3H),7.19–7.15(m,2H),6.25(t,J=2.1Hz,1H),5.24–5.20( m,1H),4.35(t,J=6.1Hz,2H),3.90(s,3H),3.80(t,J=6.0Hz,2H),1.50(d,J=7.1Hz,3H).

[0749] Preparation of compound 112:

[0750]

[0751] Intermediate INT-3-1 (11 mg, 0.024 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.3 mL). 4-Chloro-7-methyl-1,2-dihydrophthalazin-1-one (4.7 mg, 0.024 mmol) was added, along with potassium phosphate (4 mg, 0.029 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.6 mg, 0.0031 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 112 in a 17% yield. MS (ESI, positive ion) m / z: 481.5 [M+H] + .

[0752] Preparation of compound 113:

[0753]

[0754] Intermediate INT-3-1 (20 mg, 0.045 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL). 4-Chloro-7-methyl-1,2-dihydrophthalazin-1-one (8.8 mg, 0.045 mmol) was added, along with potassium phosphate (7.5 mg, 0.054 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (4.9 mg, 0.0058 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 113 in a 46% yield. MS (ESI, positive ion) m / z: 481.5 [M+H] + .

[0755] 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),8.25(d,J=1.7Hz,1H),8.16(d,J=1.7Hz,1H ),7.73–7.70(m,1H),7.65(d,J=8.6Hz,1H),7.62(s,1H),7.44–7.42(m,1H),7.32 –7.28(m,3H),7.12(q,J=3.3,2.2Hz,2H),5.29(s,1H),4.06(s,1H),3.93(s,4H), 2.85(s,2H),2.01(d,J=55.7Hz,3H),1.77(d,J=6.5Hz,1H),1.53(q,J=7.5Hz,1H).

[0756] Preparation of compound 114:

[0757]

[0758] Intermediate 114-1 (10 mg, 0.022 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.3 mL). 4-Chloro-7-methyl-1,2-dihydrophthalazin-1-one (4.3 mg, 0.022 mmol) was added, along with potassium phosphate (3.7 mg, 0.026 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.3 mg, 0.0029 mmol). The mixture was heated to 85°C and stirred for 4 h. Silica gel was added to the reaction mixture and the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to afford compound 114 in a 28% yield. MS (ESI, positive ion) m / z: 497.53 [M+H] + .

[0759] 1H NMR (400MHz, DMSO-d6) δ12.71(s,1H),8.18(s,1H),7.95(dd,J=8.3,1.7Hz,1H),7.90(s,1 H),7.73(dd,J=8.0,2.2Hz,1H),7.68(d,J=8.5Hz,1H),7.66–7.61(m,1H),7.55–7.52(m,1 H),7.49–7.46(m,2H),7.20–7.15(m,2H),5.61(s,1H),4.45(d,J=11.9Hz,1H),3.91(d,J= 2.2Hz,3H),3.86(d,J=5.5Hz,2H),3.61–3.55(m,1H),2.55(s,2H),1.36(d,J=6.0Hz,3H).

[0760] Preparation of compound 115:

[0761]

[0762] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methyl-4-ethylaminopyrazole (38 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 115 in a 65% yield. MS (ESI, positive ion) m / z: 542.2 [M+H] + .

[0763] 1 H NMR(400MHz, DMSO-d6)δ9.70(t,J=5.8Hz,1H),8.66(d,J=1.8Hz,1H),8.57(s,1H),8.37(d, J=8.0Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.8Hz,1H),7.65(d,J=8.6Hz,1H),7.56(s,1H) ,7.48(dt,J=6.5,2.8Hz,2H),7.33(d,J=0.8Hz,1H),7.19–7.15(m,2H),5.25–5.20(m,1H), 3.90(s,3H),3.80(s,3H),3.56–3.51(m,2H),2.70(t,J=7.0Hz,2H),1.50(d,J=7.1Hz,3H).

[0764] Preparation of compound 116:

[0765]

[0766] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylhistamine (38 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 116 in a 65% yield. MS (ESI, positive ion) m / z: 542.2 [M+H] + .

[0767] 1 H NMR(400MHz, DMSO-d6)δ9.70(t,J=5.8Hz,1H),8.66(d,J=1.8Hz,1H),8.57(s,1H),8.37(d, J=8.0Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.8Hz,1H),7.65(d,J=8.6Hz,1H),7.56(s,1H) ,7.48(dt,J=6.5,2.8Hz,2H),7.33(d,J=0.8Hz,1H),7.19–7.15(m,2H),5.25–5.20(m,1H), 3.90(s,3H),3.80(s,3H),3.56–3.51(m,2H),2.70(t,J=7.0Hz,2H),1.50(d,J=7.1Hz,3H).

[0768] Preparation of compound 117:

[0769]

[0770] Preparation of compound 117:

[0771] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 1-benzyl-1H-pyrazol-4-amine (34.6 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 117 in a 55% yield. MS (ESI, positive ion) m / z: 590.2 [M+H] + .

[0772] 1H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.68(d,J=1.9Hz,1H),8.62(s,1H),8.38(d,J=8.0Hz,1H ),8.29(d,J=0.7Hz,1H),8.22(s,1H),7.81(dd,J=8.7,1.9Hz,1H),7.79(d,J=0.8Hz,1H),7.66( d,J=8.8Hz,1H),7.49–7.46(m,2H),7.37(dd,J=6.9,1.3Hz,2H),7.34–7.31(m,1H),7.30–7.25 (m,3H),7.19–7.15(m,2H),5.36(s,2H),5.25–5.20(m,1H),3.90(s,3H),1.50(d,J=7.0Hz,3H).

[0773] Preparation of compound 118:

[0774]

[0775] Compound 106 (81 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropanecarboxylic acid (26 mg, 0.3 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 55%) to afford compound 118 in a 65% yield. MS (ESI, positive ion) m / z: 576.2 [M+H] + .

[0776] 1 H NMR (400MHz, DMSO-d6) δ9.19(d,J=1.7Hz,1H),8.81(d,J=2.8Hz,1H),8.36(d,J=7.9Hz,1H),8.25(dd,J=8.7,1.8Hz,1H),8.20(s,1H),7.61(d,J=8.7Hz ,1H),7.51–7.43(m,2H),7.22–7.12(m,2H),5.20(p,J=7.2Hz,1H),3.90(s, 3H), 2.11 (tt, J=7.9, 4.6Hz, 1H), 1.50 (d, J=7.1Hz, 3H), 0.99–0.86 (m, 4H).

[0777] Preparation of compound 119:

[0778]

[0779] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (55 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 119 in a 65% yield. MS (ESI, positive ion) m / z: 599.2 [M+H] + .

[0780] 1 H NMR (400MHz, DMSO-d6) δ11.19(s,1H),8.68(d,J=1.8Hz,1H),8.59(s,1H),8.39(d,J= 8.0Hz,1H),8.23(s,1H),7.84(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.8Hz,2H),7.47(dd, J=8.4,5.4Hz,2H),7.19–7.14(m,2H),5.22(p,J=7.1Hz,1H),3.92(d,J=11.1Hz,7H),1 .64–1.58(m,2H),1.50(d,J=7.1Hz,3H),1.37(d,J=6.1Hz,2H),1.25(d,J=3.5Hz,4H).

[0781] Preparation of compound 120:

[0782]

[0783] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (55 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 65%) to provide compound 120 in a 65% yield. MS (ESI, positive ion) m / z: 581.2 [M+H] + .

[0784] 1H NMR (400MHz, DMSO-d6) δ12.05(s,1H),8.72(d,J=1.8Hz,1H),8.64(s,1H),8.39(d,J=8. 0Hz,1H),8.24(s,1H),7.86(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.48(t,J=3.2 Hz,2H),7.19–7.15(m,2H),5.26–5.21(m,1H),3.99(s,3H),3.90(s,3H),2.62(d,J=7.5H z, 2H), 1.67 (q, J = 7.4Hz, 2H), 1.50 (d, J = 7.0Hz, 3H), 1.36 (s, 1H), 0.96 (d, J = 7.3Hz, 3H).

[0785] Preparation of compound 121:

[0786]

[0787] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 5-(tert-butyl)isoxazol-3-amine (42 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 121 in a 65% yield. MS (ESI, positive ion) m / z: 557.2 [M+H] + .

[0788] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=1.8Hz,1H),8.63(s,1H),8.40(d,J=8.0Hz,1H),8.24(s,1H),7.83(dd,J=8.7,1.9Hz,1H),7.66(d, J=8.7Hz,1H),7.51–7.45(m,3H),7.19–7.15(m,2H),6.79(s,1H),5.24–5.20(m,1H),3.90(s,3H),1.50(d,J=7.1Hz,3H),1.36(s,9H).

[0789] Preparation of compound 122:

[0790]

[0791] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 1-(methylsulfonyl)-1H-pyrazol-4-amine (32.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 52%) to afford compound 122 in a 50% yield. MS (ESI, positive ion) m / z: 590.2 [M+H] + .

[0792] 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),8.70(d,J=1.9Hz,1H),8.65(d,J=6.3Hz,2H),8.38(d,J=9.8Hz,2H),8.23(s,1H),7.84(dd,J=8.7,1.8Hz,1H) ,7.67(d,J=8.7Hz,1H),7.48(dd,J=8.6,5.6Hz,2H),7.18(t,J=8.9Hz,2H ),5.23(t,J=7.4Hz,1H),3.91(s,3H),3.58(s,3H),1.51(d,J=7.1Hz,3H).

[0793] Preparation of compound 123:

[0794]

[0795] Intermediate INT-2 (43 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-(4-amino-1H-pyrazol-1-yl)-1-morpholinoethan-1-one (42 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 50%) to afford compound 123 in a 51% yield. MS (ESI, positive ion) m / z: 627.2 [M+H] + .

[0796] 1H NMR (400MHz, DMSO-d6) δ11.65(s,1H),8.69(d,J=2.0Hz,1H),8.63(s,1H),8.38(d,J= 8.1Hz,1H),8.22(s,1H),8.15(s,1H),7.83(dd,J=8.6,1.9Hz,1H),7.75(s,1H),7.66 (d,J=8.7Hz,1H),7.52–7.44(m,2H),7.17(t,J=8.9Hz,2H),5.27–5.19(m,1H),5.17( s,2H),3.91(s,3H),3.66–3.58(m,4H),3.50(d,J=21.8Hz,4H),1.50(d,J=7.1Hz,3H).

[0797] Preparation of compound 124:

[0798]

[0799] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-ethyl-1H-pyrazol-4-amine (33 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 124 in a 65% yield. MS (ESI, positive ion) m / z: 528.2 [M+H] + .

[0800] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),8.69(d,J=1.9Hz,1H),8.63(s,1H),8.38(d ,J=8.1Hz,1H),8.21(d,J=12.3Hz,2H),7.82(dd,J=8.7,1.9Hz,1H),7.75(s,1H),7 .66(d,J=8.8Hz,1H),7.52–7.44(m,2H),7.23–7.12(m,2H),5.22(h,J=7.3Hz,1H) ,4.16(q,J=7.2Hz,2H),3.91(s,3H),1.50(d,J=7.0Hz,3H),1.40(t,J=7.3Hz,3H).

[0801] Preparation of compound 125:

[0802]

[0803] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-(2-methoxyethyl)-1H-pyrazol-4-amine (42 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 125 in a 65% yield. MS (ESI, positive ion) m / z: 558.2 [M+H] + .

[0804] Preparation of compound 126:

[0805]

[0806] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and tert-butylamine (22 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 126 in a 65% yield. MS (ESI, positive ion) m / z: 490.2 [M+H] + .

[0807] 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),8.66(d,J=1.8Hz,1H),8.58(s,1H),8.37(d,J=8.0Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H ),7.65(d,J=8.7Hz,1H),7.53–7.43(m,2H),7.22–7.12(m,2H),5.22(p,J=7.2Hz,1H),3.90(s,3H),1.50(d,J=7.1Hz,3H),1.43(s,9H).

[0808] Preparation of compound 127:

[0809]

[0810] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-(methylsulfonyl)ethane-1-amine (37 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 127 in a 65% yield. MS (ESI, positive ion) m / z: 540.2 [M+H] + .

[0811] 1 H NMR(400MHz,DMSO-d6)δ9.85(t,J=6.0Hz,1H),8.66(d,J=1.8Hz,1H),8.58(s,1H) ,8.37(d,J=8.0Hz,1H),8.21(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7H z,1H),7.52–7.43(m,2H),7.22–7.11(m,2H),5.22(p,J=7.4Hz,1H),3.90(s,3H), 3.83(q,J=6.7Hz,2H),3.44(t,J=6.6Hz,2H),3.07(s,3H),1.50(d,J=7.1Hz,3H).

[0812] Preparation of compound 128:

[0813]

[0814] Preparation of intermediate 128-1:

[0815] Intermediate INT-1-3 (42.2 mg, 0.1 mmol) and 4-amino-6-chloropyridazin-3(2H)-one (29 mg, 0.1 mmol) were dissolved in 1,4-dioxane (2 mL). Potassium phosphate (42.4 mg, 0.2 mmol), PdCl2(dppf)2 (5 mg), and water (0.2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the mixture was stirred for 8 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to afford Intermediate 128-1 in 35% yield. MS (ESI, positive ion) m / z: 406.2 [M+H] + .

[0816] Preparation of compound 128:

[0817] Intermediate 128-1 (40.5 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and nicotinic acid (24.6 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 128 in a 35% yield. MS (ESI, positive ion) m / z: 511.2 [M+H] + .

[0818] 1 H NMR(400MHz, DMSO-d6)δ9.12(d,J=2.4Hz,1H),8.85–8.77(m,2H),8.63(d,J=1.8Hz,1H),8.39–8.31(m,2H),8.22(s,1H),7.76(dd,J=8.6,1.9Hz,1 H),7.62(dd,J=13.6,8.4Hz,2H),7.47(ddd,J=8.8,5.5,2.7Hz,2H),7.21–7.12(m,2H),5.22(p,J=7.1Hz,1H),3.90(s,3H),1.50(d,J=7.1Hz,3H).

[0819] Preparation of compound 129:

[0820]

[0821] Intermediate 128-1 (81 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and morpholineacetic acid (43 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 129 in a 65% yield. MS (ESI, positive ion) m / z: 533.2 [M+H] + .

[0822] 1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.63–8.51(m,2H),8.34(d,J=8.1Hz,1H ),8.20(s,1H),7.71(dd,J=8.7,1.7Hz,1H),7.62(d,J=8.7Hz,1H),7.47(dd,J= 8.6,5.6Hz,2H),7.16(t,J=8.9Hz,2H),5.21(p,J=7.1Hz,1H),3.89(s,3H),3. 67(t,J=4.6Hz,4H),3.29(s,2H),2.58(t,J=4.6Hz,4H),1.49(d,J=7.1Hz,3H).

[0823] Preparation of compound 130:

[0824]

[0825] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 4-amino-3,5-dimethylisoxazole (33 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 130 in a 59% yield. MS (ESI, positive ion) m / z: 529.2 [M+H] + .

[0826] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.68(d,J=1.8Hz,1H),8.62(s,1H),8.38(d,J=8.0Hz,1H),8.22(s,1H),7.83(dd,J=8.7,1.9Hz,1H),7.65(d,J =8.7Hz,1H),7.47(dd,J=8.6,5.6Hz,2H),7.16(t,J=8.9Hz,2H),5.21(p,J =7.1Hz,1H),3.90(s,3H),2.38(s,3H),2.19(s,3H),1.49(d,J=7.0Hz,3H).

[0827] Preparation of compound 131:

[0828]

[0829] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-tert-butyl-5-aminoisoxazole (42 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 131 in a 61% yield. MS (ESI, positive ion) m / z: 557.2 [M+H] + .

[0830] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=1.8Hz,1H),8.60(s,1H),8.37(d,J=8.1Hz,1H),8.22(s,1H),7.84(dd,J=8.7,1.8Hz,1H),7.66(d,J=8.7H z,1H),7.48(dd,J=8.7,5.6Hz,2H),7.17(t,J=8.9Hz,2H),6.47(s,1H),5.27–5.18(m,1H),3.91(s,3H),1.50(d,J=7.0Hz,3H),1.32(s,9H).

[0831] Preparation of compound 132:

[0832]

[0833] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 4-aminoisoxazole (25 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 132 in a 59% yield. MS (ESI, positive ion) m / z: 501.2 [M+H] + .

[0834] 1H NMR (400MHz, DMSO-d6) δ11.71(s,1H),9.39(s,1H),9.06(s,1H),8.69(d,J=1.8Hz,1H),8.64(s,1H),8.37(d,J=8.0Hz,1H),8.22(s,1H),7.83(d d,J=8.7,1.9Hz,1H),7.66(d,J=8.8Hz,1H),7.49–7.45(m,2H),7.17(t, J=8.9Hz,2H),5.22(p,J=7.2Hz,1H),3.90(s,3H),1.50(d,J=7.1Hz,3H).

[0835] Preparation of compound 133:

[0836]

[0837] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 5-methylisoxazol-4-amine (29 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 133 in a 66% yield. MS (ESI, positive ion) m / z: 515.2 [M+H] + .

[0838] 1 H NMR (400MHz, DMSO) δ14.22 (s, 1H), 12.94 (s, 1H), 8.69 (d, J = 1.4Hz, 1H), 8.65 (s,1H),8.38(d,J=8.1Hz,1H),8.23(s,1H),7.84(dd,J=8.7,1.7Hz,1H),7.66 (d,J=8.7Hz,1H),7.48(dd,J=8.6,5.6Hz,2H),7.17(t,J=8.9Hz,2H),6.39(s ,1H),5.23(p,J=7.1Hz,1H),3.90(s,3H),2.27(s,3H),1.50(d,J=7.0Hz,3H).

[0839] Preparation of compound 134:

[0840]

[0841] Intermediate 128-1 (81 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and pyrimidine-5-carboxylic acid (37 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 134 in a 62% yield. MS (ESI, positive ion) m / z: 512.2 [M+H] + .

[0842] 1 H NMR(400MHz,DMSO)δ13.69–13.22(m,1H),9.70(s,1H),9.39(s,1H),9.26(s,2H) ,8.83(s,1H),8.64(d,J=1.5Hz,1H),8.37(d,J=8.0Hz,1H),8.23(s,1H),7.77(d d,J=8.7,1.7Hz,1H),7.65(d,J=8.7Hz,1H),7.48(dd,J=8.6,5.7Hz,2H),7.17(t ,J=8.9Hz,2H),5.22(dd,J=14.6,7.1Hz,1H),3.91(s,3H),1.51(d,J=7.1Hz,3H).

[0843] Preparation of compound 135:

[0844]

[0845] Intermediate 128-1 (81 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 5-methylnicotinic acid (41 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 135 in a 67% yield. MS (ESI, positive ion) m / z: 525.2 [M+H] + .

[0846] 1H NMR (400MHz, DMSO) δ13.82–13.16(m,1H),10.23–9.84(m,1H),8.93(d,J=1.8Hz,1H),8 .80(s,1H),8.65(dd,J=12.6,1.4Hz,2H),8.36(d,J=7.9Hz,1H),8.20(d,J=14.4Hz,2H ),7.77(dd,J=8.7,1.7Hz,1H),7.64(d,J=8.7Hz,1H),7.48(dd,J=8.6,5.6Hz,2H),7.1 7(t,J=8.9Hz,2H),5.30–5.15(m,1H),3.90(s,3H),2.43(s,3H),1.50(d,J=7.0Hz,3H).

[0847] Preparation of compound 136:

[0848]

[0849] Intermediate 128-1 (81 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 5-methylisoxazole-4-carboxylic acid (38 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 136 in a 61% yield. MS (ESI, positive ion) m / z: 515.2 [M+H] + .

[0850] 1 H NMR (400MHz, DMSO) δ12.94(s,1H),12.40(s,1H),8.74(s,1H),8.59(d,J=1.3Hz,1H),8.30(d,J=8.1Hz,1H),8.17(s,1H),7.68(dd,J=8.7,1.7Hz,1H ),7.58(d,J=8.7Hz,1H),7.49(dd,J=8.6,5.6Hz,2H),7.16(t,J=8.9Hz,3H ),5.24(t,J=7.4Hz,1H),3.88(s,3H),2.05(s,3H),1.49(d,J=7.0Hz,3H).

[0851] Preparation of compound 137:

[0852]

[0853] Intermediate 128-1 (81 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropanecarboxylic acid (26 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 137 in a 69% yield. MS (ESI, positive ion) m / z: 474.2 [M+H] + .

[0854] 1 H NMR (400MHz, DMSO) δ9.00(d,J=9.7Hz,1H),8.58(d,J=6.9Hz,1H),8.53–8.36(m,2H),7.79(dd,J=8.5,5.5Hz,2H),7.75–7.63( m,2H),7.58(d,J=1.3Hz,1H),7.32(t,J=8.9Hz,2H),7.21(dd,J=7.0,1.9Hz,1H),6.21–6.08(m,1H),6.01(s,2H),3.93(s,3H).

[0855] Preparation of compound 138:

[0856]

[0857] Preparation of intermediate 138-1:

[0858] Intermediate INT-1-2 (1.95 g, 6.5 mmol) was dispersed in tetrahydrofuran (55 mL), and (S)-1-(4-(methylsulfonyl)phenyl)ethan-1-amine (1.55 g, 7.8 mmol), diisopropylethylamine (1.00 g, 7.8 mmol), and HATU (2.96 g, 7.8 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 138-1 in 64% yield. MS (ESI, positive ion) m / z: 483.2 [M+H] + .

[0859] Preparation of intermediate 138-2:

[0860] Intermediate 138-1 (2.3 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to afford Intermediate 138-2 in a 39% yield. MS (ESI, positive ion) m / z: 527.1 [M+H] + .

[0861] Preparation of intermediate 138-3

[0862] Intermediate 138-2 (1054 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 138-3 in an 86% yield. MS (ESI, positive ion) m / z: 495.2 [M+H] + .

[0863] Preparation of compound 138:

[0864] Intermediate 138-3 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (15.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 138 in a 69% yield. MS (ESI, positive ion) m / z: 534.2 [M+H] + .

[0865] 1H NMR (400MHz, DMSO) δ14.09(s,1H),11.98(s,1H),8.92(d,J=2.4Hz,1H),8.70–8.64(m ,2H),8.51(d,J=7.6Hz,1H),8.40(dd,J=4.6,1.2Hz,1H),8.27–8.21(m,2H),7.92(d,J =8.4Hz,2H),7.85(dd,J=8.7,1.7Hz,1H),7.69(dd,J=12.3,8.6Hz,3H),7.47(dd,J=8. 3,4.7Hz,1H),5.28(p,J=7.2Hz,1H),3.92(s,3H),3.20(s,3H),1.54(d,J=7.1Hz,3H).

[0866] Preparation of compound 139:

[0867]

[0868] Preparation of intermediate 139-1:

[0869] Intermediate INT-1-2 (1.95 g, 6.5 mmol) was dispersed in tetrahydrofuran (55 mL), and (R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine (1.51 g, 7.8 mmol), diisopropylethylamine (1.00 g, 7.8 mmol), and HATU (2.96 g, 7.8 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 139-1 in 73% yield. MS (ESI, positive ion) m / z: 477.2 [M+H] + .

[0870] Preparation of intermediate 139-2:

[0871] Intermediate 139-1 (2.2 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to obtain Intermediate 139-2 in a 59% yield. MS (ESI, positive ion) m / z: 503.1 [M+H] + .

[0872] Preparation of intermediate 139-3

[0873] Intermediate 139-2 (1006 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 139-3 in an 83% yield. MS (ESI, positive ion) m / z: 489.1 [M+H] + .

[0874] Preparation of compound 139:

[0875] Intermediate 139-3 (98 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (15.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 139 in a 79% yield. MS (ESI, positive ion) m / z: 528.2 [M+H] + .

[0876] 1 H NMR (400MHz, DMSO) δ13.90(s,1H),9.63(d,J=4.1Hz,1H),9.01(d,J=9.6Hz,1H),8.66(d,J=1.5Hz,1H),8.56(s,1H),8.43(s,1H), 7.87–7.63(m,4H),7.32(t,J=8.9Hz,2H),6.15(t,J=8.9Hz,1H),3.93(s,3H),1.25(s,1H),0.85–0.79(m,2H),0.65–0.56(m,2H).

[0877] Preparation of compound 140:

[0878]

[0879] Intermediate 128-1 (81 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazole-4-carboxylic acid (38 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 140 in a 59% yield. MS (ESI, positive ion) m / z: 514.2 [M+H] + .

[0880] Preparation of compound 141:

[0881]

[0882] Intermediate 128-1 (81 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 6-fluoronicotinic acid (42 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 141 in a 63% yield. MS (ESI, positive ion) m / z: 529.2 [M+H] + .

[0883] Preparation of compound 142:

[0884]

[0885] Intermediate 128-1 (81 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 5-bromonicotinic acid (60 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 142 in a 61% yield. MS (ESI, positive ion) m / z: 589.1 [M+H] + .

[0886] Preparation of compound 143:

[0887]

[0888] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and n-butylamine (22 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 143 in a 53% yield. MS (ESI, positive ion) m / z: 516.2 [M+H] + .

[0889] Preparation of compound 144:

[0890]

[0891] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-methoxyethylamine (22 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 144 in a 55% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[0892] Preparation of compound 145:

[0893]

[0894] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-(2-methoxyethyl)-1H-pyrazol-4-amine (42 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 145 in a 63% yield. MS (ESI, positive ion) m / z: 584.2 [M+H] + .

[0895] Preparation of compound 146:

[0896]

[0897] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-aminotetrahydrofuran (26 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 146 in a 52% yield. MS (ESI, positive ion) m / z: 530.2 [M+H] + .

[0898] Preparation of compound 147:

[0899]

[0900] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-(1H-pyrazol-1-yl)ethane-1-amine (33 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 147 in a 53% yield. MS (ESI, positive ion) m / z: 553.2 [M+H] + .

[0901] Preparation of compound 148:

[0902]

[0903] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methyl-4-ethylaminopyrazole (37 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 148 in a 59% yield. MS (ESI, positive ion) m / z: 568.2 [M+H] + .

[0904] Preparation of compound 149:

[0905]

[0906] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and methylamine hydrochloride (20 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 149 in a 48% yield. MS (ESI, positive ion) m / z: 474.2 [M+H] + .

[0907] Preparation of compound 150:

[0908]

[0909] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-aminothiophene (30 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 150 in a 68% yield. MS (ESI, positive ion) m / z: 542.2 [M+H] + .

[0910] Preparation of compound 151:

[0911]

[0912] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-aminomethyl-tetrahydrofuran (30 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 151 in a 68% yield. MS (ESI, positive ion) m / z: 544.2 [M+H] + .

[0913] Preparation of compound 152:

[0914]

[0915] Preparation of intermediate 152-1:

[0916] Intermediate INT-13-1 (44.8 mg, 0.1 mmol) and 4-amino-6-chloropyridazin-3(2H)-one (29 mg, 0.1 mmol) were dissolved in 1,4-dioxane (2 mL). Potassium phosphate (42.4 mg, 0.2 mmol), PdCl2(dppf)2 (5 mg), and water (0.2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the mixture was stirred for 8 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to afford Intermediate 152-1 in 47% yield. MS (ESI, positive ion) m / z: 432.2 [M+H] + .

[0917] Preparation of compound 152:

[0918] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylcarboxylic acid (26.1 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 152 in a 49% yield. MS (ESI, positive ion) m / z: 500.2 [M+H] + .

[0919] Preparation of compound 153:

[0920]

[0921] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and morpholineacetic acid (29 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 153 in a 56% yield. MS (ESI, positive ion) m / z: 559.2 [M+H] + .

[0922] 1H NMR (400MHz, DMSO-d6) δ10.23(s,1H),8.65(s,1H),8.44(d,J=1.8Hz,1H),7.70(dd,J=8.7,1.8Hz,1H),7.57(d,J=8.7Hz,1H),7 .35–7.27(m,3H),7.16–7.08(m,3H),5.32(s,1H),4.14–3.78(m,7H),2.44–2.32(m,2H),1.99–1.70(m,5H),0.90–0.82(m,4H).

[0923] Preparation of compound 154:

[0924]

[0925] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and pyrazolo[1,5-A]4,5,6,7-tetrahydropyridine-3-carboxylic acid (33.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 154 in a 51% yield. MS (ESI, positive ion) m / z: 580.2 [M+H] + .

[0926] 1 H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.64(s,1H),8.48(d,J=1.8Hz,1H),8 .08(s,1H),7.76–7.71(m,1H),7.59(d,J=8.8Hz,1H),7.33(dd,J=8.6,5.5H z,3H),7.13(t,J=8.8Hz,3H),5.33(d,J=6.3Hz,1H),4.12(t,J=6.0Hz,3H) ,3.92(s,2H),3.08(t,J=6.4Hz,2H),2.40–2.33(m,1H),2.03–1.82(m,9H).

[0927] Preparation of compound 155:

[0928]

[0929] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-(2-aminoethyl)pyrrolidine (34 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 155 in a 63% yield. MS (ESI, positive ion) m / z: 557.2 [M+H] + .

[0930] Preparation of compound 156:

[0931]

[0932] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-aminomethylpyridine (32.4 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 156 in a 66% yield. MS (ESI, positive ion) m / z: 551.2 [M+H] + .

[0933] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),9.39(s,1H),9.06(s,1H),8.63(d,J=6.7Hz,2H),7.83(dd,J=8.8,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.34(dd ,J=8.6,5.5Hz,2H),7.16(d,J=8.9Hz,2H),5.35(s,1H),4.07(s,1H),3.9 1(s,4H),2.53(s,3H),2.40–2.34(m,1H),1.96(s,2H),1.85–1.77(m,1H).

[0934] Preparation of compound 157:

[0935]

[0936] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 4-aminoisoxazole (25.2 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 157 in a 61% yield. MS (ESI, positive ion) m / z: 527.2 [M+H] + .

[0937] 1 H NMR (400MHz, DMSO-d6) δ10.26(t,J=5.6Hz,1H),8.62–8.56(m,3H),7.80(td,J=7.7,1.8Hz,2H),7.64(d,J=8.7Hz,1H),7.42(d,J=7.9Hz,1H),7. 36–7.30(m,3H),7.18–7.12(m,2H),4.72(d,J=5.7Hz,2H),3.92(d,J=19 .3Hz,4H),2.44–2.31(m,1H),1.96(s,2H),1.80(dd,J=12.1,6.0Hz,1H).

[0938] Preparation of compound 158:

[0939]

[0940] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-(1-methyl-4-piperidinyl)-1H-pyrazol-4-amine (54 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 158 in a 68% yield. MS (ESI, positive ion) m / z: 623.3 [M+H] + .

[0941] 1H NMR (400MHz, DMSO-d6) δ11.73 (s, 1H), 8.64–8.59 (m, 2H), 8.51 (d, J = 2.7Hz, 1H), 7.96 (dd, J = 9. 1,2.8Hz,1H),7.84(d,J=9.0Hz,1H),7.65(d,J=8.7Hz,1H),7.35(dd,J=8.5,5.4Hz,2H),7.15( t,J=8.9Hz,2H),6.91(d,J=9.2Hz,1H),5.35(s,1H),4.07(s,1H),3.91(s,4H),3.51–3.47(m,4 H),2.42(t,J=5.1Hz,4H),2.39–2.34(m,1H),2.24(s,3H),1.96(s,2H),1.80(d,J=7.0Hz,1H).

[0942] Preparation of compound 159:

[0943]

[0944] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-amino-6-(4-methylpiperazin-1-yl)pyridine (57.6 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 159 in a 68% yield. MS (ESI, positive ion) m / z: 635.3 [M+H] + .

[0945] 1 H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.61(d,J=8.9Hz,2H),8.19(s,1H),7.85–7.80( m,1H),7.78(s,1H),7.64(d,J=8.6Hz,1H),7.34(t,J=7.1Hz,2H),7.14(t,J=8.8Hz,2H) ,5.34(s,1H),4.12(dt,J=10.4,5.2Hz,2H),3.90(s,4H),2.86(d,J=10.9Hz,2H),2.37 (dd,J=12.3,7.3Hz,1H),2.06(t,J=10.2Hz,2H),2.00–1.89(m,6H),1.85–1.74(m,1H).

[0946] Preparation of compound 160:

[0947]

[0948] Intermediate INT-13-1 (44.8 mg, 0.1 mmol) and 4-chloro-7-fluorophthalazin-1(2H)-one (20 mg, 0.1 mmol) were dissolved in 1,4-dioxane (2 mL). Potassium phosphate (42.4 mg, 0.2 mmol), PdCl2(dppf)2 (5 mg), and water (0.2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the mixture was stirred for 8 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to afford compound 160 in 50% yield. MS (ESI, positive ion) m / z: 485.2 [M+H] + .

[0949] 1 H NMR(400MHz, DMSO-d6)δ12.87(d,J=6.5Hz,1H),8.47–8.24(m,2H),7.82–7.63(m,3H),7.48–7.43(m,1H),7.34(dd,J=9.8,2.5Hz,1H),7.32–7.27(m, 2H),7.12(td,J=7.9,6.8,3.2Hz,2H),5.31(s,1H),4.07(s,1H),3.94(s,4 H), 2.36 (dd, J=12.7, 7.0Hz, 1H), 1.94 (d, J=5.6Hz, 2H), 1.83–1.75 (m, 1H).

[0950] Preparation of compound 161:

[0951]

[0952] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (5-methylfuran-2-yl)methanamine (33.3 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 161 in a 68% yield. MS (ESI, positive ion) m / z: 554.2 [M+H] + .

[0953] 1H NMR(400MHz,DMSO-d6)δ9.90(t,J=5.7Hz,1H),8.63–8.52(m,2H),7.80(dd,J=8.8,1.9Hz,1H), 7.63(d,J=8.7Hz,1H),7.34(dd,J=8.4,5.5Hz,2H),7.14(dd,J=10.0,7.6Hz,2H),6.24(d,J=3.1 Hz,1H),6.03(d,J=3.1Hz,1H),5.35(s,1H),4.54(d,J=5.7Hz,2H),4.06(s,1H),3.92(d,J=17. 1Hz,5H),2.37(dq,J=14.4,7.3Hz,1H),2.26(s,3H),1.94(d,J=11.0Hz,2H),1.86–1.74(m,1H).

[0954] Preparation of compound 162:

[0955]

[0956] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 5-methylnicotinic acid (27.4 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 162 in a 71% yield. MS (ESI, positive ion) m / z: 551.2 [M+H] + .

[0957] 1 H NMR (400MHz, DMSO-d6) δ8.93(d,J=2.2Hz,1H),8.77(s,1H),8.67(d,J=2.1Hz,1H),8. 55(d,J=1.8Hz,1H),8.18(t,J=2.3Hz,1H),7.77(dd,J=8.8,1.8Hz,1H),7.63(d,J=8.7 Hz,1H),7.39–7.31(m,2H),7.19–7.12(m,2H),5.35(d,J=5.9Hz,1H),4.07(s,1H),3. 93(d,J=21.3Hz,4H),2.43(s,3H),2.41–2.33(m,1H),1.96(s,2H),1.84–1.74(m,1H).

[0958] Preparation of compound 163:

[0959]

[0960] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and pyrimidine-5-carboxylic acid (24.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 163 in a 69% yield. MS (ESI, positive ion) m / z: 538.2 [M+H] + .

[0961] 1 H NMR (400MHz, DMSO-d6) δ13.44(s,1H),10.57(s,1H),9.38(s,1H),9.25(s,2H),8.80(s,1H),8.55(d,J=1.8Hz,1H),7.80–7.75(m,1H),7.63(d,J=8 .8Hz,1H),7.36–7.32(m,2H),7.15(t,J=8.8Hz,2H),5.35(s,1H),4.07(s ,1H),3.90(s,5H),2.40–2.34(m,1H),1.96(s,2H),1.79(d,J=6.3Hz,1H).

[0962] Preparation of compound 164:

[0963]

[0964] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and nicotinic acid (24.6 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 164 in a 63% yield. MS (ESI, positive ion) m / z: 537.2 [M+H] + .

[0965] 1H NMR (400MHz, DMSO-d6) δ13.45(s,1H),10.08(s,1H),9.12(d,J=2.3Hz,1H),8.82(dd,J=4.8,1.6 Hz,1H),8.77(s,1H),8.55(d,J=1.8Hz,1H),8.36–8.31(m,1H),7.78(dd,J=8.7,1.8Hz,1H),7.66 –7.58(m,2H),7.38–7.32(m,2H),7.15(t,J=8.9Hz,2H),5.36(s,1H),4.07(s,1H),3.93(d,J=22 .7Hz,4H),2.54(s,1H),2.37(dt,J=14.5,7.2Hz,1H),1.96(s,2H),1.80(dd,J=12.0,6.0Hz,1H).

[0966] Preparation of compound 165:

[0967]

[0968] Preparation of intermediate 165-1:

[0969] 4-Bromo-6-chloropyridazin-3(2H)-one (208 mg, 1.0 mmol) and methylamine hydrochloride (135 mg, 2.0 mmol) were dissolved in 1,4-dioxane (20 mL). Cesium carbonate (625 mg, 2.0 mmol), X-phos (20 mg), and Pd(OAc)2 (20 mg) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 100°C. The reaction mixture was stirred and reacted overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to obtain intermediate 165-1 in a 42% yield. MS (ESI, positive ion) m / z: 160.2 [M+H] + .

[0970] Preparation of compound 165:

[0971] Intermediate 165-1 (32.0 mg, 0.2 mmol) and INT-3-1 (89.6 mg, 0.2 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium phosphate (97 mg, 0.46 mmol), PdCl2(dppf)2 (7 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to obtain compound 165 in a 61% yield. MS (ESI, positive ion) m / z: 446.4 [M+H]+ .

[0972] Preparation of compound 166:

[0973]

[0974] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-(1H-pyrazol-1-yl)acetic acid (25.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 166 in a 67% yield. MS (ESI, positive ion) m / z: 540.2 [M+H] + .

[0975] 1 H NMR (400MHz, DMSO-d6) δ13.33(s,1H),10.26(s,1H),8.63(s,1H),8.47(d,J=1.8Hz,1H),7.8 1(d,J=2.3Hz,1H),7.71(dd,J=8.7,1.8Hz,1H),7.58(d,J=8.8Hz,1H),7.53(d,J=1.9Hz,1H), 7.36–7.30(m,2H),7.16–7.09(m,2H),6.33(t,J=2.1Hz,1H),5.35(s,1H),5.29(s,2H),4.04( s,1H),3.90(d,J=17.6Hz,4H),2.35(dq,J=14.6,7.2Hz,1H),1.93(s,2H),1.82–1.72(m,1H).

[0976] Preparation of compound 167:

[0977]

[0978] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-(4-methyl-1H-pyrazol-1-yl)acetic acid (28 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 167 in a 69% yield. MS (ESI, positive ion) m / z: 554.2 [M+H] + .

[0979] 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.46(d,J=1.9Hz,1H),7.71(dd,J=8.7,1 .8Hz,1H),7.62–7.55(m,2H),7.36–7.31(m,3H),7.16–7.10(m,2H),5.35(s,1H ),5.20(s,2H),4.04(s,1H),3.90(d,J=16.7Hz,4H),2.57–2.53(m,1H),2.35(d t,J=12.0,7.2Hz,1H),2.06(s,3H),1.94(s,2H),1.77(dd,J=11.7,6.3Hz,1H).

[0980] Preparation of compound 168:

[0981]

[0982] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-(pyridin-3-yl)acetic acid (27.4 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 168 in a 66% yield. MS (ESI, positive ion) m / z: 551.2 [M+H] + .

[0983] 1 H NMR (400MHz, DMSO-d6) δ13.70(s,1H),10.06(t,J=6.1Hz,1H),8.60(dd,J=5.9,2.0Hz,2H),8.56(s,1 H),8.50(dd,J=4.8,1.7Hz,1H),7.80(dq,J=7.8,2.0Hz,2H),7.63(d,J=8.7Hz,1H),7.39(ddd,J=7.9 ,4.8,0.8Hz,1H),7.36–7.31(m,2H),7.17–7.12(m,2H),5.34(s,1H),4.64(d,J=6.0Hz,2H),4.06(s, 1H), 3.92 (d, J = 19.1Hz, 4H), 2.37 (dq, J = 12.2, 7.3Hz, 1H), 1.95 (s, 2H), 1.81 (dt, J = 9.3, 4.4Hz, 1H).

[0984] Preparation of compound 169:

[0985]

[0986] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and imidazo[1,2-a]pyridin-6-amine (39.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 169 in a 61% yield. MS (ESI, positive ion) m / z: 576.2 [M+H] + .

[0987] 1 H NMR (400MHz, DMSO-d6) δ11.89 (s, 1H), 9.44–9.39 (m, 1H), 8.65 (d, J = 7.7Hz, 2H),8.08(s,1H),7.85(d,J=8.2Hz,1H),7.63(dd,J=18.2,7.9Hz,3H),7.35( dd,J=8.4,6.0Hz,3H),7.15(t,J=8.8Hz,2H),5.35(s,1H),4.07(s,1H),3.9 1(s,4H),2.38(dd,J=12.4,7.4Hz,1H),1.97(s,2H),1.79(d,J=12.1Hz,1H).

[0988] Preparation of compound 170:

[0989]

[0990] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (tetrahydro-2H-pyran-4-yl)methanamine (34.5 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 170 in a 63% yield. MS (ESI, positive ion) m / z: 558.2 [M+H] + .

[0991] 1H NMR (400MHz, DMSO-d6) δ9.71(t,J=6.0Hz,1H),8.59(d,J=1.8Hz,1H),8.54(s,1H),7.80(dd,J =8.7,1.9Hz,1H),7.63(d,J=8.7Hz,1H),7.34(td,J=5.6,2.5Hz,2H),7.19–7.11(m,2H),5.34 (s,1H),4.06(s,1H),3.99–3.74(m,6H),3.32–3.24(m,4H),2.37(dq,J=12.3,7.3Hz,1H),1.9 6(s,2H),1.87–1.75(m,2H),1.61(ddd,J=12.8,4.1,2.0Hz,2H),1.26(qd,J=12.1,4.5Hz,2H).

[0992] Preparation of compound 171:

[0993]

[0994] Preparation of intermediate 171-1:

[0995] Intermediate INT-1-2 (604 mg, 2.0 mmol) was dispersed in 5 mL of tetrahydrofuran, and 1-(4-fluorophenyl)prop-2-yn-1-amine (358 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 171-1 in a 72% yield. MS (ESI, positive ion) m / z: 433.3 [M+H] + .

[0996] Preparation of compound 171:

[0997] Intermediate 171-1 (200 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 40%) to obtain compound 171 in a 71% yield. MS (ESI, positive) m / z: 416.4 [M+H] + .

[0998] 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),8.91(d,J=8.4Hz,1H),8.59(d,J=1.8Hz,1H),8.20(s,1H),7.72(dd,J=8.7,1.8Hz,1H),7 .61–7.55(m,3H),7.26–7.21(m,2H),6.87(s,1H),6.40(s,2H),6.15(dd,J=8.4,2.5Hz,1H),3.86(s,3H),3.55(d,J=2.5Hz,1H).

[0999] Preparation of compound 172:

[1000]

[1001] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-(4-methylpiperazin-1-yl)acetic acid (31.6 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 172 in a 59% yield. MS (ESI, positive ion) m / z: 572.3 [M+H] + .

[1002] 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),10.12(s,1H),8.59(s,1H),8.49(s,1H ),7.71(d,J=8.7Hz,1H),7.61(d,J=8.9Hz,1H),7.34(t,J=7.0Hz,2H),7.15(t ,J=8.6Hz,2H),5.34(s,1H),4.05(s,1H),3.98–3.81(m,4H),3.26(s,2H),2. 72–2.54(m,6H),2.39(d,J=18.4Hz,4H),2.22(s,3H),1.87(d,J=64.4Hz,3H).

[1003] Preparation of compound 173:

[1004]

[1005] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and tetrahydrofuran-3-carboxylic acid (23.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 173 in a 60% yield. MS (ESI, positive ion) m / z: 530.2 [M+H] + .

[1006] 1 H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.70(s,1H),8.48(d,J=1.8Hz,1H),7.76– 7.69(m,1H),7.60(d,J=8.7Hz,1H),7.39–7.30(m,2H),7.18–7.11(m,2H),5.35(d ,J=6.7Hz,1H),4.06(s,1H),3.97–3.71(m,8H),3.60(p,J=7.5Hz,1H),2.37(dq, J=12.2,7.2Hz,1H),2.11(q,J=7.2Hz,2H),2.04–1.91(m,2H),1.83–1.73(m,1H).

[1007] Preparation of compound 174:

[1008]

[1009] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2,2-difluorocyclopropane-1-carboxylic acid (24.4 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 174 in a 58% yield. MS (ESI, positive ion) m / z: 536.2 [M+H] + .

[1010] 1H NMR(400MHz,DMSO-d6)δ13.33(s,1H),10.60(s,1H),8.67(d,J=5.6Hz,1H),8.49– 8.45(m,1H),7.73(t,J=6.8Hz,1H),7.59(d,J=8.7Hz,1H),7.33(dd,J=8.3,5.5Hz ,2H),7.14(t,J=8.7Hz,2H),5.34(s,1H),4.05(s,1H),3.88(s,4H),3.48(d,J=11 .2Hz,1H),2.36(dd,J=12.6,6.6Hz,1H),2.16–1.86(m,5H),1.78(d,J=6.0Hz,1H).

[1011] Preparation of compound 175:

[1012]

[1013] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrrolidine-3-carboxylic acid (25.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 175 in a 62% yield. MS (ESI, positive ion) m / z: 543.2 [M+H] + .

[1014] Preparation of compound 176:

[1015]

[1016] Compound 171 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylcarboxylic acid (17.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 48%) to afford compound 176 in a 61% yield. MS (ESI, positive ion) m / z: 484.2 [M+H] + .

[1017] 1H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.93(d,J=8.4Hz,1H),8.73(s,1H),8.61(d,J=1.8Hz,1H),8.23(s,1H),7.73(dd,J=8.6,1.8Hz,1H),7.62(d,J= 4.8Hz,1H),7.61–7.58(m,2H),7.24(t,J=8.9Hz,2H),6.16(d,J=7.0Hz,1H) ,3.87(s,3H),3.54(d,J=2.5Hz,1H),2.47–2.41(m,1H),0.93–0.87(m,4H).

[1018] Preparation of compound 177:

[1019]

[1020] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpiperidin-4-amine (34.2 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 177 in a 68% yield. MS (ESI, positive ion) m / z: 557.3 [M+H] + .

[1021] Preparation of compound 178:

[1022]

[1023] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-(4-methylpiperazin-1-yl)ethan-1-amine (42.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 178 in a 68% yield. MS (ESI, positive ion) m / z: 586.3 [M+H] + .

[1024] 1H NMR(400MHz,DMSO-d6)δ9.79(t,J=5.6Hz,1H),8.59(d,J=1.8Hz,1H),8.54(s,1H), 7.85–7.76(m,1H),7.63(d,J=8.8Hz,1H),7.34(dd,J=8.5,5.5Hz,2H),7.15(t,J=8 .8Hz,2H),5.34(s,1H),4.07(s,1H),3.90(s,4H),3.48(q,J=6.1Hz,2H),2.52–2.4 1(m,8H),2.37(q,J=6.5,5.7Hz,5H),2.17(s,3H),1.96(s,2H),1.85–1.74(m,1H).

[1025] Preparation of compound 179:

[1026]

[1027] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and (1R)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid (46.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 179 in a 55% yield. MS (ESI, positive ion) m / z: 645.2 [M+H] + .

[1028] 1 H NMR (400MHz, DMSO-d6) δ9.55(s,1H),8.64(d,J=2.1Hz,1H),8.52(d,J=1.8Hz,1H),7.76(d,J=8 .7Hz,1H),7.62(d,J=8.6Hz,1H),7.34(dd,J=8.5,5.5Hz,2H),7.15(t,J=8.8Hz,2H),5.34(s,1H ),4.07(s,1H),3.89(d,J=11.7Hz,5H),3.17(d,J=12.3Hz,1H),2.73(dd,J=19.1,9.1Hz,1H),2. 60–2.54(m,1H),2.48–2.34(m,6H),1.96(s,2H),1.78(d,J=6.7Hz,1H),1.60(d,J=10.5Hz,2H).

[1029] Preparation of compound 180:

[1030]

[1031] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and dimethylglycine (20.6 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 180 in a 65% yield. MS (ESI, positive ion) m / z: 517.2 [M+H] + .

[1032] 1 H NMR(400MHz,DMSO-d6)δ13.40(s,1H),10.01(s,1H),8.61(s,1H),8.50(d,J= 1.8Hz,1H),7.72(dd,J=8.6,1.8Hz,1H),7.62(d,J=8.8Hz,1H),7.35(dd,J=8. 6,5.6Hz,2H),7.15(t,J=8.8Hz,2H),5.35(s,1H),4.07(s,1H),3.90(s,4H), 3.22(s,2H),2.45–2.37(m,1H),2.35(s,7H),1.96(s,2H),1.88–1.74(m,1H).

[1033] Preparation of compound 181:

[1034]

[1035] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-methoxypropionic acid (20.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 181 in a 71% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[1036] 1H NMR (400MHz, DMSO-d6) δ13.42(s,1H),9.61(s,1H),8.63(d,J=1.1Hz,1H),8.50(d,J=1.7 Hz,1H),7.73(dd,J=8.6,1.8Hz,1H),7.61(d,J=8.6Hz,1H),7.37–7.30(m,2H),7.19–7.11 (m,2H),5.35(s,1H),4.14(t,J=6.7Hz,1H),4.06(s,1H),3.92(d,J=19.8Hz,4H),3.43(s, 3H), 2.37(dq,J=12.2,7.2Hz,1H),1.95(s,2H),1.84–1.74(m,1H),1.38(d,J=6.7Hz,3H).

[1037] Preparation of compound 182:

[1038]

[1039] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and pivalic acid (20.4 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 182 in a 59% yield. MS (ESI, positive ion) m / z: 516.2 [M+H] + .

[1040] 1 H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.61(s,1H),8.50(d,J=1.8Hz,1H),7.79–7.72(m,1H),7.61(d,J=8.7Hz,1H),7.37–7.33(m,2H),7.16(t, J=8.8Hz,2H),5.36(s,1H),4.07(s,1H),3.92(d,J=18.8Hz,4H),2.37(dt,J=14.4,7.2Hz,1H),1.95(s,2H),1.79(d,J=9.2Hz,1H),1.30(s,9H).

[1041] Preparation of compound 183:

[1042]

[1043] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and n-butyric acid (20.4 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 183 in a 66% yield. MS (ESI, positive ion) m / z: 516.2 [M+H] + .

[1044] 1 H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.70(s,1H),8.48(s,1H),7.72(d,J=8.7Hz,1H) ,7.64–7.52(m,2H),7.35(dd,J=8.4,5.4Hz,2H),7.15(t,J=8.7Hz,2H),5.35(s,1H), 4.06(s,1H),3.89(s,4H),2.59(t,J=7.4Hz,2H),2.37(dd,J=12.7,6.9Hz,1H),1.95( s,2H),1.80(s,1H),1.62–1.55(m,2H),1.34(q,J=7.4Hz,2H),0.91(t,J=7.4Hz,3H).

[1045] Preparation of compound 184:

[1046]

[1047] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-aminopropyl pivalate (47.7 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 184 in a 66% yield. MS (ESI, positive ion) m / z: 602.3 [M+H] + .

[1048] Preparation of compound 185:

[1049]

[1050] Intermediate INT-13-1 (44.8 mg, 0.1 mmol) and 4-chlorobenzo[g]phthalazin-1(2H)-one (23 mg, 0.1 mmol) were dissolved in 1,4-dioxane (2 mL). Potassium phosphate (42.4 mg, 0.2 mmol), PdCl2(dppf)2 (5 mg), and water (0.2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the mixture was stirred for 8 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to afford compound 185 in a 45% yield. MS (ESI, positive ion) m / z: 517.2 [M+H] + .

[1051] 1 H NMR(400MHz,DMSO-d6)δ12.56(s,1H),9.04(s,1H),8.36–8.31(m,2H),8.26(s ,1H),8.10(d,J=8.1Hz,1H),7.73(dt,J=14.9,6.8Hz,3H),7.53(d,J=8.4Hz,1 H),7.29(dd,J=8.5,5.5Hz,2H),7.11(q,J=8.7,6.2Hz,2H),5.29(s,1H),3.95 (s,5H),2.55(s,1H),2.35(dq,J=14.5,7.5Hz,1H),1.93(s,2H),1.77(s,1H).

[1052] Preparation of compound 186:

[1053]

[1054] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-(2-methoxyethoxy)acetic acid (26.6 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 186 in a 71% yield. MS (ESI, positive ion) m / z: 548.2 [M+H] + .

[1055] 1H NMR (400MHz, DMSO-d6) δ13.39(s,1H),9.64(s,1H),8.63(s,1H),8.51(d,J=1.8Hz,1H),7.7 3(dd,J=8.7,1.8Hz,1H),7.62(d,J=8.6Hz,1H),7.39–7.30(m,2H),7.19–7.12(m,2H),5.35 (s,1H),4.26(s,2H),4.07(s,1H),3.93(d,J=18.8Hz,4H),3.78–3.72(m,2H),3.59–3.54(m ,2H),3.32(s,3H),2.38(dq,J=12.2,7.3Hz,1H),1.96(s,2H),1.79(dd,J=12.2,6.0Hz,1H).

[1056] Preparation of compound 187:

[1057]

[1058] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and acetic acid (12 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 187 in a 71% yield. MS (ESI, positive ion) m / z: 474.2 [M+H] + .

[1059] 1 H NMR (400MHz, DMSO-d6) δ13.25(s,1H),9.95(s,1H),8.66(s,1H),8.48(d,J=1.8 Hz,1H),8.09(s,1H),7.70(dd,J=8.6,1.8Hz,1H),7.60(d,J=8.7Hz,1H),7.38–7 .30(m,2H),7.18–7.10(m,2H),5.34(s,1H),4.05(s,1H),3.91(d,J=21.5Hz,4H) ,2.37(dq,J=12.2,7.1Hz,1H),2.25(s,3H),1.95(s,2H),1.78(q,J=6.2Hz,1H).

[1060] Preparation of compound 188:

[1061]

[1062] Intermediate INT-13-1 (44.8 mg, 0.1 mmol) and 4-chloro-7-(1-cyclopropyl-1H-pyrazol-4-yl)phthalazin-1(2H)-one (29 mg, 0.1 mmol) were dissolved in 1,4-dioxane (2 mL). Potassium phosphate (42.4 mg, 0.2 mmol), PdCl2(dppf)2 (5 mg), and water (0.2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the mixture was stirred for 8 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to afford compound 188 in a 49% yield. MS (ESI, positive) m / z: 573.2 [M+H] + .

[1063] 1 H NMR(400MHz,DMSO-d6)δ12.75–12.63(m,1H),8.57–8.46(m,1H),8.38–8.26(m,2H),8.14–8.04(m,2H),7 .91–7.81(m,1H),7.70–7.66(m,1H),7.56–7.43(m,1H),7.30(ddd,J=8.0,5.4,2.2Hz,2H),7.17–7.07(m ,2H),5.32(s,1H),4.05(d,J=14.2Hz,1H),3.80(tt,J=7.6,3.9Hz,1H),2.35(dd,J=12.7,6.8Hz,1H),1. 94(s,2H),1.78(s,1H),1.25(d,J=3.1Hz,2H),1.20–1.12(m,2H),1.08–0.99(m,3H),0.97–0.91(m,1H).

[1064] Preparation of compound 189:

[1065]

[1066] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclobutanoic acid (20 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 189 in a 68% yield. MS (ESI, positive ion) m / z: 513.2 [M+H] + .

[1067] 1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.73(s,1H),8.49(d,J=1.8Hz,1H),7.78–7.70 (m,1H),7.61(d,J=8.8Hz,1H),7.35(dd,J=8.4,5.4Hz,2H),7.16(t,J=8.8Hz,2H),5 .36(s,1H),4.07(s,1H),3.92(d,J=19.6Hz,4H),3.66(p,J=8.4Hz,1H),2.38(dd,J= 12.7,7.0Hz,1H),2.29–2.12(m,4H),1.95(q,J=9.3,8.7Hz,3H),1.90–1.75(m,2H).

[1068] Preparation of compound 190:

[1069]

[1070] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (1,3-dimethyl-1H-pyrazol-4-yl)methanamine (37.5 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 190 in a 66% yield. MS (ESI, positive ion) m / z: 568.2 [M+H] + .

[1071] 1 H NMR (400MHz, DMSO-d6) δ9.74(t,J=5.6Hz,1H),8.59(d,J=1.8Hz,1H),8.56(s,1H),7.8 0(dd,J=8.6,1.8Hz,1H),7.63(d,J=8.7Hz,1H),7.58(s,1H),7.37–7.31(m,2H),7.18–7 .12(m,2H),5.34(s,1H),4.36(d,J=5.5Hz,2H),4.06(s,1H),3.90(s,4H),3.73(s,3H) ,2.36(dt,J=12.5,7.3Hz,1H),2.15(s,3H),1.95(s,2H),1.80(dd,J=11.4,5.3Hz,1H).

[1072] Preparation of compound 191:

[1073]

[1074] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (1-methyl-1H-pyrazol-4-yl)methanamine (33.3 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 191 in a 76% yield. MS (ESI, positive ion) m / z: 554.2 [M+H] + .

[1075] 1 H NMR (400MHz, DMSO-d6) δ9.81(t,J=5.7Hz,1H),8.60(d,J=1.8Hz,1H),8.57(s,1H),7.81( dd,J=8.6,1.9Hz,1H),7.69(s,1H),7.64(d,J=8.7Hz,1H),7.42(s,1H),7.34(dd,J=8.5,5 .5Hz,2H),7.18–7.12(m,2H),5.35(s,1H),4.41(d,J=5.6Hz,2H),4.07(s,1H),3.90(s,4 H),3.82(s,3H),2.36(dt,J=12.2,7.2Hz,1H),1.96(s,2H),1.80(dd,J=11.9,5.8Hz,1H).

[1076] Preparation of compound 192:

[1077]

[1078] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and chloroacetic acid (18.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 192 in a 58% yield. MS (ESI, positive ion) m / z: 508.2 [M+H] + .

[1079] 1H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.58–8.47(m,1H),8.10(s,1H),7.73(dd,J=8.6,1.8Hz,1H),7.61(d,J=8.6Hz,1H),7.35(dd,J=8.8,5.4Hz,2H ),7.18–7.12(m,2H),5.35(s,1H),4.59(s,2H),4.06(s,1H),3.92(d,J=1 7.9Hz, 4H), 2.37 (dd, J=12.5, 7.1Hz, 1H), 1.95 (s, 2H), 1.84–1.72 (m, 1H).

[1080] Preparation of compound 193:

[1081]

[1082] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 4-methyl-1,2,5-oxadiazol-3-amine (29.7 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 193 in a 64% yield. MS (ESI, positive ion) m / z: 542.2 [M+H] + .

[1083] 1 H NMR (400MHz, DMSO-d6) δ8.64(d,J=2.1Hz,2H),8.14(s,1H),7.86(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.34(dd,J=8.5,5.5Hz,2 H),7.17–7.12(m,2H),5.34(s,1H),4.07(s,1H),3.91(s,4H),2.43(s,3H),2.40–2.32(m,1H),1.96(s,2H),1.80(dd,J=12.8,6.0Hz,1H).

[1084] Preparation of compound 194:

[1085]

[1086] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 5-methyl-1,3,4-oxadiazol-2-amine (29.7 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 194 in a 60% yield. MS (ESI, positive ion) m / z: 542.2 [M+H] + .

[1087] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=16.1Hz,1H),8.14(s,1H),7.83(t,J=10.3Hz,1H),7.65(d,J=8.6Hz,1H),7.33(d,J=6.0Hz,2H),7.15(t,J=8. 7Hz,2H),5.34(s,1H),4.07(s,1H),3.89(d,J=17.3Hz,4H),2.60–2.53( m,3H),2.45–2.25(m,2H),1.94(d,J=10.8Hz,2H),1.79(d,J=8.4Hz,1H).

[1088] Preparation of compound 195:

[1089]

[1090] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (1R,2S)-2-fluorocyclopropane-1-amine (22.5 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 195 in a 60% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[1091] 1H NMR (400MHz, DMSO-d6) δ13.94(s,1H),9.87(d,J=5.3Hz,1H),8.59(d,J=1.8Hz,1H),8.55(s,1H),8.13(s,1H),7.8 0(dd,J=8.7,1.9Hz,1H),7.62(d,J=8.7Hz,1H),7.34(dd,J=8.4,5.5Hz,2H),7.14(t,J=8.7Hz,2H),5.34(s,1H),4 .92(dtd,J=64.8,5.8,3.0Hz,1H),4.05(s,1H),3.90(q,J=16.9Hz,4H),3.06(ddt,J=10.8,6.0,3.6Hz,1H),2.36( dq,J=12.4,7.3Hz,1H),1.95(s,2H),1.81(dq,J=12.3,6.7,6.0Hz,1H),1.36(d,J=6.3Hz,1H),1.07–0.94(m,1H).

[1092] Preparation of compound 196:

[1093]

[1094] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (28.0 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 196 in a 61% yield. MS (ESI, positive ion) m / z: 554.2 [M+H] + .

[1095] 1H NMR (400MHz, DMSO-d6) δ9.93 (s, 1H), 8.65 (s, 1H), 8.46 (d, J = 1.8Hz, 1H), 7.70 ( dd,J=8.9,1.7Hz,1H),7.63(s,1H),7.59(d,J=8.8Hz,1H),7.37–7.30(m,3H),7. 14(t,J=8.9Hz,2H),5.34(s,1H),4.05(s,1H),3.90(d,J=18.5Hz,4H),3.81(s, 3H),3.75(s,2H),2.35(dt,J=14.5,7.3Hz,1H),1.94(s,2H),1.84–1.72(m,1H).

[1096] Preparation of compound 197:

[1097]

[1098] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2,2-difluorocyclopropane-1-amine (27.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 197 in a 64% yield. MS (ESI, positive ion) m / z: 536.2 [M+H] + .

[1099] 1 H NMR (400MHz, DMSO-d6) δ8.60–8.52(m,2H),7.81(d,J=8.7Hz,1H),7.63(d,J=8.9Hz,1H),7.35(d,J=8.7Hz,3 H),7.15(t,J=8.7Hz,3H),5.34(s,1H),4.07(s,1H),3.90(s,5H),2.40–2.36(m,1H),1.94(t,J=55.6Hz,6H).

[1100] Preparation of compound 198:

[1101]

[1102] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyanoacetic acid (16.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 198 in a 71% yield. MS (ESI, positive ion) m / z: 499.2 [M+H] + .

[1103] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.50(s,1H),7.72(d,J=8.8Hz,1H),7.61(d,J=8.8Hz,1H),7.35(s,2H),7.15(s,2H),5.34(d,J=4. 9Hz,1H),4.06(s,1H),3.90(s,4H),2.91(d,J=7.2Hz,1H),2.42–2.37(m,1H),2.35(s,1H),2.06–2.00(m,2H),1.96(s,3H),1.78(s,1H).

[1104] Preparation of compound 199:

[1105]

[1106] Preparation of intermediate 199-1:

[1107] Intermediate INT-1-2 (604 mg, 2.0 mmol) was dispersed in 5 ml of tetrahydrofuran, and (S)-2-benzylaziridine (319 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 199-1 in 75% yield. MS (ESI, positive ion) m / z: 417.2 [M+H] + .

[1108] Preparation of compound 199:

[1109] Intermediate 199-1 (192 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 40%) to obtain compound 199 in a 66% yield. MS (ESI, positive) m / z: 400.2 [M+H] + .

[1110] 1 H NMR (400MHz, DMSO-d6) δ12.60(s,1H),8.57–8.46(m,1H),7.83(s,1H),7.72(dd,J=8.6,1.8Hz,1H),7.59(d,J=8.7Hz,1H),7.41–7.34(m,4H),7.32 –7.24(m,2H),6.84(d,J=8.1Hz,1H),6.41(s,2H),3.90–3.85(m,1H),3.8 3(s,3H),3.13–2.98(m,1H),2.87(d,J=2.0Hz,1H),2.55(d,J=5.6Hz,1H).

[1111] Preparation of compound 200:

[1112]

[1113] Preparation of intermediate 200-1:

[1114] Intermediate INT-1-2 (604 mg, 2.0 mmol) was dispersed in 5 ml of tetrahydrofuran, and (S)-2-(4-chlorophenyl)pyrrolidine (437 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 200-1 in a 77% yield. MS (ESI, positive ion) m / z: 465.2 [M+H] + .

[1115] Preparation of compound 200:

[1116] Intermediate 200-1 (214 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to obtain compound 200 in a 66% yield. MS (ESI, positive) m / z: 448.2 [M+H] + .

[1117] 1 H NMR (400MHz, DMSO-d6) δ12.56(s,1H),8.49(d,J=1.8Hz,1H),7.72(d,J=8.8Hz,1H),7.54(d,J=8.5Hz,1H),7.38(d,J=8.5Hz,2H),7.32(d,J=8.2H z,2H),6.83(s,1H),6.34(d,J=20.5Hz,2H),5.30(s,1H),4.06(s,1H),3. 99–3.81(m,5H),2.38(dd,J=12.7,7.2Hz,1H),1.96(s,2H),1.79(s,1H).

[1118] Preparation of compound 201:

[1119]

[1120] Preparation of intermediate 201-1:

[1121] Intermediate INT-1-2 (604 mg, 2.0 mmol) was dispersed in 5 mL of tetrahydrofuran, and (S)-2-(4-trifluoromethoxyphenyl)pyrrolidine (554 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 201-1 in a 67% yield. MS (ESI, positive ion) m / z: 515.2 [M+H] + .

[1122] Preparation of compound 201:

[1123] Intermediate 201-1 (237 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 40%) to obtain compound 201 in a 56% yield. MS (ESI, positive) m / z: 498.2 [M+H] + .

[1124] Preparation of compound 202:

[1125]

[1126] Preparation of intermediate 202-1:

[1127] Intermediate INT-1-2 (1.95 g, 6.5 mmol) was dispersed in tetrahydrofuran (55 mL), and (S)-2-(2,5-difluorophenyl)pyrrolidine (1.43 g, 7.8 mmol), diisopropylethylamine (1.00 g, 7.8 mmol), and HATU (2.96 g, 7.8 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 202-1 in 74% yield. MS (ESI, positive ion) m / z: 467.2 [M+H] + .

[1128] Preparation of intermediate 202-2:

[1129] Intermediate 202-1 (2.2 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to obtain Intermediate 202-2 in a 62% yield. MS (ESI, positive ion) m / z: 493.2 [M+H] + .

[1130] Preparation of Intermediate 202-3

[1131] Intermediate 202-2 (985 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 202-3 in a 90% yield. MS (ESI, positive ion) m / z: 477.2 [M+H] + .

[1132] Preparation of compound 202:

[1133] Intermediate 202-3 (95 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and methylamine hydrochloride (20.2 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 202 in a 64% yield. MS (ESI, positive ion) m / z: 492.2 [M+H] + .

[1134] 1 H NMR(400MHz,DMSO-d6)δ12.58(s,1H),9.49(d,J=5.1Hz,1H),8.57(s,1H),8.53(s,1H),8.1 7(s,1H),7.81(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.26(td,J=9.1,4.3Hz,1H),7 .10(td,J=9.6,8.8,4.5Hz,2H),5.45(t,J=6.8Hz,1H),4.14(s,1H),3.94(d,J=15.3Hz,4H) ,2.91(d,J=4.9Hz,3H),2.45–2.33(m,1H),2.05–1.95(m,2H),1.80(dd,J=12.4,6.2Hz,1H).

[1135] Preparation of compound 203:

[1136]

[1137] Intermediate 202-3 (95 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (12.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 203 in a 71% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[1138] 1 H NMR (400MHz, DMSO-d6) δ13.89(s,1H),9.61(d,J=4.6Hz,1H),8.58(s,1H),8.52(s,1H),7.81(dd,J=8.7, 1.8Hz,1H),7.66(d,J=8.7Hz,1H),7.27(td,J=9.2,4.4Hz,1H),7.11(td,J=11.3,9.7,5.0Hz,2H),5.46(t ,J=6.7Hz,1H),4.14(s,1H),3.93(s,4H),3.31(s,1H),2.94(tq,J=8.0,4.2Hz,1H),2.41(dt,J=14.1,7.1 Hz,1H),2.06–1.95(m,2H),1.81(dd,J=12.4,6.3Hz,1H),0.81(td,J=7.1,4.9Hz,2H),0.64–0.58(m,2H).

[1139] Preparation of compound 204:

[1140]

[1141] Intermediate 200 (47.7 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylcarboxylic acid (17.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 204 in a 71% yield. MS (ESI, positive ion) m / z: 516.2 [M+H] + .

[1142] Preparation of compound 205:

[1143]

[1144] Preparation of intermediate 205-1:

[1145] Intermediate 202-1 (2.2 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to obtain Intermediate 205-1 in a 66% yield. MS (ESI, positive ion) m / z: 491.2 [M+H] + .

[1146] Preparation of intermediate 205-2

[1147] Intermediate 205-1 (980 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 205-2 in a 90% yield. MS (ESI, positive ion) m / z: 477.1 [M+H] + .

[1148] Preparation of compound 205:

[1149] Intermediate 205-2 (95 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (24.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 205 in a 75% yield. MS (ESI, positive ion) m / z: 516.2 [M+H] + .

[1150] Preparation of compound 206:

[1151]

[1152] Intermediate 201 (49.7 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylcarboxylic acid (17.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 206 in a 63% yield. MS (ESI, positive ion) m / z: 566.2 [M+H] + .

[1153] 1 H NMR (400MHz, DMSO-d6) δ13.67(s,1H),9.62(d,J=4.5Hz,1H),8.58(d,J=1.8Hz,1H),8.51(s,1H) ,8.13(s,1H),7.80(dd,J=8.6,1.9Hz,1H),7.63(d,J=8.6Hz,1H),7.38(d,J=8.6Hz,2H),7.33(d, J=8.4Hz,2H),5.32(s,1H),4.07(s,1H),3.90(s,4H),2.93(tq,J=7.9,4.1Hz,1H),2.37(dt,J=1 4.4,7.1Hz,1H),1.96(s,2H),1.85–1.71(m,1H),0.81(td,J=7.1,4.9Hz,2H),0.63–0.58(m,2H).

[1154] Preparation of compound 207:

[1155]

[1156] Preparation of intermediate 207-1:

[1157] Intermediate 202-1 (2.4 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to obtain Intermediate 207-1 in a 56% yield. MS (ESI, positive ion) m / z: 541.2 [M+H] + .

[1158] Preparation of intermediate 207-2

[1159] Intermediate 207-2 (1.08 g, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 207-2 in an 85% yield. MS (ESI, positive ion) m / z: 527.1 [M+H] + .

[1160] Preparation of compound 207:

[1161] Intermediate 207-2 (105 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (24.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 207 in a 65% yield. MS (ESI, positive ion) m / z: 566.2 [M+H] + .

[1162] 1 H NMR(400MHz, DMSO-d6)δ9.61(d,J=4.6Hz,1H),8.58(d,J=1.8Hz,1H),8.52(s,1H),8.21–8.08(m ,1H),7.80(dd,J=8.7,1.8Hz,1H),7.64(d,J=8.7Hz,1H),7.45–7.41(m,2H),7.32(d,J=8.2Hz,2 H),5.35(s,1H),4.09(s,1H),3.91(s,4H),2.92(ddt,J=13.8,9.8,5.2Hz,1H),2.39(dt,J=14.7 ,7.7Hz,1H),1.97(s,2H),1.81(d,J=6.0Hz,1H),0.81(td,J=7.1,5.0Hz,2H),0.66–0.57(m,2H).

[1163] Preparation of compound 208:

[1164]

[1165] Preparation of intermediate 208-1:

[1166] Intermediate INT-1-2 (604 mg, 2.0 mmol) was dispersed in 5 mL of tetrahydrofuran, and (S)-1-(4-(trifluoromethoxy)phenyl)ethan-1-amine (492 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 208-1 in a 77% yield. MS (ESI, positive ion) m / z: 489.2 [M+H] + .

[1167] Preparation of compound 208:

[1168] Intermediate 208-1 (225 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 40%) to obtain compound 208 in a 56% yield. MS (ESI, positive) m / z: 471.2 [M+H] + .

[1169] Preparation of compound 209:

[1170]

[1171] Intermediate 200 (47.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylcarboxylic acid (17.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 209 in a 71% yield. MS (ESI, positive ion) m / z: 540.2 [M+H] + .

[1172] 1H NMR (400MHz, DMSO-d6) δ12.59(s,1H),8.55(d,J=1.8Hz,1H),8.38(d,J=7.8Hz,1H),8.19(s,1H),7.71(dd,J=8.6,1.8Hz,1H),7.55 (dd,J=8.7,2.3Hz,3H),7.34(d,J=8.2Hz,2H),6.87(s,1H),6.38(s,2H),5.23(p,J=7.1Hz,1H),3.88(s,3H),1.51(d,J=7.0Hz,3H).

[1173] Preparation of compound 210:

[1174]

[1175] Preparation of intermediate 210-1:

[1176] Intermediate INT-1-2 (604 mg, 2.0 mmol) was dispersed in 5 ml of tetrahydrofuran, and (S)-2-(2,5-difluorophenyl)pyrrolidine (439 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 210-1 in a 67% yield. MS (ESI, positive ion) m / z: 467.2 [M+H] + .

[1177] Preparation of compound 210:

[1178] Intermediate 210-1 (214 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to obtain compound 210 in a 53% yield. MS (ESI, positive) m / z: 450.2 [M+H] + .

[1179] 1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.49(s,1H),8.13(s,1H),7.77–7.71(m,1H) ),7.57(d,J=8.6Hz,1H),7.27(td,J=9.3,4.4Hz,1H),7.19–7.01(m,2H),6.85(s, 1H),6.36(s,1H),5.45(s,1H),4.15(s,1H),3.95(d,J=25.0Hz,4H),2.41(tt,J=1 4.8,7.3Hz,1H),2.02(t,J=7.0Hz,2H),1.86–1.73(m,1H),1.38(d,J=6.1Hz,1H).

[1180] Preparation of compound 211:

[1181]

[1182] Intermediate INT-2 (87 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (1R,2S)-2-fluorocyclopropane-1-amine (22 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 211 in a 65% yield. MS (ESI, positive ion) m / z: 492.2 [M+H] + .

[1183] 1 H NMR (400MHz, DMSO-d6) δ13.95(s,1H),9.90(d,J=5.3Hz,1H),8.68(d,J=1.8Hz,1H),8.60(s,1H),8.38 (d,J=8.0Hz,1H),8.23(s,1H),7.81(dd,J=8.7,1.8Hz,1H),7.65(d,J=8.7Hz,1H),7.52–7.44(m,2H), 7.22–7.13(m,2H),5.24(p,J=7.2Hz,1H),4.93(dtd,J=64.7,5.7,3.0Hz,1H),3.90(s,3H),3.13–3.04 (m,1H),1.51(d,J=7.0Hz,3H),1.24(dt,J=6.2,3.7Hz,1H),1.03(dddd,J=25.6,8.3,5.8,3.0Hz,1H).

[1184] Preparation of compound 212:

[1185]

[1186] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and (1R,2R)-2-fluorocyclopropane-1-carboxylic acid (21 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 212 in a 73% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[1187] 1 H NMR(400MHz,DMSO-d6)δ13.97(s,1H),10.31(s,1H),8.67(s,1H),8.50–8.45(m,1H),8.08(s,1H),7.7 2(dd,J=8.7,1.8Hz,1H),7.59(d,J=8.7Hz,1H),7.34(dd,J=8.5,5.5Hz,2H),7.14(t,J=8.8Hz,2H),5.3 5(s,1H),4.96(dq,J=66.0,5.7Hz,1H),4.05(s,1H),3.91(d,J=20.6Hz,4H),2.64(dt,J=14.1,7.6Hz,1 H),2.36(dq,J=14.3,7.3Hz,1H),1.94(s,2H),1.84–1.64(m,2H),1.24(ddd,J=15.0,12.4,6.4Hz,1H).

[1188] Preparation of compound 213:

[1189]

[1190] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (21 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 213 in a 63% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[1191] 1 H NMR(400MHz,DMSO-d6)δ13.37(s,1H),10.32(s,1H),8.69(d,J=6.5Hz,1H),8.49(s,1H),8 .01(s,1H),7.79–7.69(m,1H),7.60(d,J=8.7Hz,1H),7.35(t,J=6.7Hz,2H),7.15(t,J=8.7 Hz,2H),5.36(s,1H),5.10–4.85(m,1H),4.06(s,1H),3.90(s,4H),2.65(p,J=7.0Hz,1H),2 .36(dt,J=14.2,7.2Hz,1H),1.95(s,2H),1.84–1.66(m,2H),1.25(dq,J=14.0,6.5Hz,1H).

[1192] Preparation of compound 214:

[1193]

[1194] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 4,5,6,7-tetrahydropyrazolo[1,5-A]pyridine-2-carboxylic acid (33.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 214 in a 53% yield. MS (ESI, positive ion) m / z: 580.2 [M+H] + .

[1195] 1H NMR (400MHz, DMSO-d6) δ13.32(s,1H),9.13(s,1H),8.69(s,1H),8.60(d,J=1.8Hz,1H),8.36(d, J=8.0Hz,1H),8.22(s,1H),8.10(s,1H),7.75(dd,J=8.7,1.8Hz,1H),7.62(d,J=8.7Hz,1H),7.47 (dd,J=8.5,5.6Hz,2H),7.16(t,J=8.8Hz,2H),5.22(p,J=7.2Hz,1H),4.13(t,J=6.0Hz,2H),3.8 9(s,3H),3.10(t,J=6.4Hz,2H),2.00(d,J=7.3Hz,2H),1.92–1.82(m,2H),1.49(d,J=7.1Hz,3H).

[1196] Preparation of compound 215:

[1197]

[1198] Preparation of intermediate 215-2:

[1199] Intermediate 215-1 (3.0 g, 14.4 mmol) was dissolved in methanol (45 mL), and ethanolamine (1.3 g, 21.6 mmol) and 100 mg of glacial acetic acid were added. The mixture was stirred at room temperature for 3 hours. Sodium borohydride (1.1 g) was added in portions, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 2 / 1) to obtain Intermediate 215-2 in a 68.1% yield. MS (ESI, positive ion) m / z: 254.0 [M+H] + .

[1200] Preparation of intermediate 215-3:

[1201] Intermediate 215-2 (2 g, 2.0 mmol) and N,N-diisopropylethylamine (1.8 g, 14.1 mmol) were dissolved in 35 ml of dimethyl sulfoxide. HATU (5.4 g, 14.2 mmol) was added and stirred at room temperature for 4 h to stop the reaction. The reaction mixture was added with 70 ml of water and extracted with ethyl acetate (35 ml x 3). The organic phases were combined, washed with 30 ml of water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (EA / PE = 1 / 1) to obtain Intermediate 215-3 in 90% yield. MS (ESI, positive) m / z: 455.0 [M+H] + .

[1202] Preparation of intermediate 215-4:

[1203] Intermediate 215-3 (2.0 g, 4.4 mmol) was dissolved in DMF (30 mL) and sodium hydroxide (353 g, 8.8 mmol) was added. The reaction was allowed to react at room temperature for 1-2 h. The reaction was stopped and poured into 50 mL of ice water. The mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with 40 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated to a thick consistency. The crude product was purified by silica gel column chromatography (EA / PE = 1 / 2) to afford Intermediate 215-4 in a 51% yield. MS (ESI, positive ion) m / z: 435.0 [M+H] + .

[1204] Preparation of intermediate 215-5:

[1205] Intermediate 215-4 (290 g, 0.665 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium acetate (200 mg, 2 mmol), bis(pinacolato) borate (254 mg, 1 mmol), and PdCl2(dppf)2 (50 mg, 0.07 mmol) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred for 2-3 hours. The reaction mixture was concentrated under reduced pressure, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 10 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (EA / PE = 1 / 1) to afford Intermediate 215-5 in a 15% yield. MS (ESI, positive ion) m / z: 483.1 [M+H] + .

[1206] Preparation of intermediate 215-6

[1207] Intermediate 215-5 (390 mg, 0.81 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (343 mg, 1.62 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (152 mg, 0.81 mmol), PdCl2(dppf)2 (40 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to afford Intermediate 215-6 in 80% yield. MS (ESI, positive ion) m / z: 495.1 [M+H] + .

[1208] Preparation of compound 215:

[1209] Intermediate 215-6 (99 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (17.1 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 215 in a 70% yield. MS (ESI, positive ion) m / z: 534.2 [M+H] + .

[1210] 1 H NMR (400MHz, DMSO-d6) δ13.99(s,1H),9.80(s,1H),8.94(d,J=2.6Hz,1H),8.76(d,J=2.6Hz,1H),8.49(s,1H),7.42(dd,J=9.8,5.8Hz,3H),4. 88(s,2H),4.56(t,J=4.4Hz,2H),3.82(t,J=4.7Hz,2H),2.92(tt,J=7.9,3.9Hz,1H),0.80(td,J=7.1,4.9Hz,2H),0.59(dt,J=6.9,4.7Hz,2H).

[1211] Preparation of compound 216:

[1212]

[1213] Preparation of intermediate 216-1:

[1214] Intermediate INT-1-2 (1.95 g, 6.5 mmol) was dispersed in tetrahydrofuran (55 mL), and (S)-1-(4-chlorophenyl)ethan-1-amine (1.21 g, 7.8 mmol), diisopropylethylamine (1.00 g, 7.8 mmol), and HATU (2.96 g, 7.8 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 216-1 in a 64% yield. MS (ESI, positive ion) m / z: 439.2 [M+H] + .

[1215] Preparation of intermediate 216-2:

[1216] Intermediate 216-1 (2.0 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to afford Intermediate 216-2 in a 72% yield. MS (ESI, positive ion) m / z: 464.1 [M+H] + .

[1217] Preparation of intermediate 216-3

[1218] Intermediate 216-2 (928 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 216-3 in a 90% yield. MS (ESI, positive ion) m / z: 451.2 [M+H] + .

[1219] Preparation of compound 216:

[1220] Intermediate 216-3 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (15.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 216 in a 64% yield. MS (ESI, positive ion) m / z: 490.2 [M+H] + .

[1221] 1H NMR (400MHz, DMSO-d6) δ13.53(s,-1H),9.62(d,J=4.6Hz,1H),8.64(d,J=1.9Hz,1H),8.55( s,1H),8.39(d,J=7.9Hz,1H),8.22(s,1H),7.79(dd,J=8.7,1.9Hz,1H),7.64(d,J=8.7Hz,1H ),7.46(d,J=8.6Hz,2H),7.40(d,J=8.6Hz,2H),5.20(p,J=7.2Hz,1H),3.90(s,3H),2.94(t t,J=7.3,3.9Hz,1H),1.49(d,J=7.1Hz,3H),0.81(dt,J=7.0,3.4Hz,2H),0.65–0.57(m,2H).

[1222] Preparation of compound 217:

[1223]

[1224] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (30.4 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 217 in a 53% yield. MS (ESI, positive ion) m / z: 566.2 [M+H] + .

[1225] 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),9.08(s,1H),8.67(s,1H),8.52(d,J=1.8Hz,1H),8.10( s,1H),7.76(d,J=8.6Hz,1H),7.62(d,J=8.7Hz,1H),7.35(dd,J=8.5,5.5Hz,2H),7.16(t,J=8 .8Hz,2H),5.36(s,1H),4.17(t,J=7.4Hz,2H),4.01(d,J=46.8Hz,3H),3.90(s,3H),3.16(t,J =7.4Hz,2H),2.70–2.65(m,2H),2.37(dt,J=14.2,7.1Hz,1H),1.95(s,2H),1.84–1.76(m,1H).

[1226] Preparation of compound 218:

[1227]

[1228] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-fluoroethane-1-amine (18.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 218 in a 74% yield. MS (ESI, positive ion) m / z: 506.2 [M+H] + .

[1229] 1 H NMR(400MHz, DMSO-d6)δ13.80(s,-1H),9.84(t,J=5.8Hz,1H),8.62–8.53(m,2H),8.21(d,J= 75.1Hz,1H),7.80(dd,J=8.7,1.8Hz,1H),7.63(d,J=8.7Hz,1H),7.34(dd,J=8.4,5.5Hz,2H) ,7.14(t,J=8.8Hz,2H),5.34(s,1H),4.60(dt,J=47.4,5.0Hz,2H),4.06(s,2H),3.90(s,3H) ,3.71(dq,J=27.1,5.3Hz,2H),2.36(dt,J=14.5,7.3Hz,1H),1.95(s,2H),1.84–1.76(m,1H).

[1230] Preparation of compound 219:

[1231]

[1232] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (1R,2R)-2-fluorocyclopropane-1-amine (22.5 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 219 in a 66% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[1233] 1H NMR (400MHz, DMSO-d6) δ13.50(s,-1H),9.54(t,J=3.3Hz,1H),8.58(d,J=1.9Hz,1H),8.51(s,1H),8.09(d,J=19.0H z,1H),7.79(dd,J=8.8,1.9Hz,1H),7.63(d,J=8.7Hz,1H),7.34(dd,J=8.5,5.5Hz,2H),7.14(t,J=8.8Hz,2H),5.34 (s,1H),5.03–4.79(m,1H),4.06(s,2H),3.90(s,3H),3.27(dd,J=10.5,5.1Hz,1H),2.37(dq,J=12.1,7.3Hz,1H),1 .95(s,2H),1.80(p,J=5.7Hz,1H),1.47(dddd,J=24.0,10.8,8.1,3.2Hz,1H),1.15(dddd,J=14.1,12.3,6.7Hz,1H).

[1234] Preparation of compound 220:

[1235]

[1236] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylcyclopropane-1-amine (21.3 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 220 in a 66% yield. MS (ESI, positive ion) m / z: 514.2 [M+H] + .

[1237] 1H NMR (400MHz, DMSO-d6) δ13.32(s,-1H),9.79(s,1H),8.59(d,J=1.8Hz,1H),8.52(s,1H),8.09(d,J=1 9.1Hz,1H),7.79(dd,J=8.8,1.8Hz,1H),7.63(d,J=8.7Hz,1H),7.34(dd,J=8.4,5.5Hz,2H),7.15(t,J =8.7Hz,2H),5.34(s,1H),4.01(d,J=47.8Hz,2H),3.91(d,J=11.3Hz,3H),2.37(dq,J=12.4,7.3Hz,1 H),1.96(s,2H),1.80(dt,J=12.6,6.1Hz,1H),1.42(s,3H),0.79(d,J=4.8Hz,2H),0.72–0.66(m,2H).

[1238] Preparation of compound 221:

[1239]

[1240] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-1-cyclopropylethane-1-amine (25.5 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 221 in a 66% yield. MS (ESI, positive ion) m / z: 528.2 [M+H] + .

[1241] 1H NMR (400MHz, DMSO-d6) δ13.57(s,-1H),9.67(d,J=8.0Hz,1H),8.59(d,J=1.8Hz,1H),8.54(s,1H),8.09(d,J=20 .3Hz,1H),7.80(dd,J=8.6,1.8Hz,1H),7.63(d,J=8.7Hz,1H),7.34(dd,J=8.5,5.4Hz,2H),7.14(t,J=8.8Hz,2H ),5.34(s,1H),4.00(d,J=48.8Hz,2H),3.90(s,3H),3.54(p,J=7.1Hz,1H),2.43–2.30(m,1H),1.95(s,2H),1.8 4–1.76(m,1H),1.27(d,J=6.6Hz,3H),1.11–0.97(m,1H),0.47(ddp,J=12.4,8.1,3.8Hz,2H),0.38–0.23(m,2H).

[1242] Preparation of compound 222:

[1243]

[1244] Intermediate INT-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (1S,3S)-3-fluorocyclobutane-1-amine (26.7 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 222 in a 66% yield. MS (ESI, positive ion) m / z: 532.2 [M+H] + .

[1245] 1H NMR (400MHz, DMSO-d6) δ13.74(s,-1H),9.84(d,J=6.9Hz,1H),8.58(d,J=1.8Hz,1H),8.50(s,1H),8. 08(d,J=14.7Hz,1H),7.78(dd,J=8.7,1.9Hz,1H),7.61(d,J=8.7Hz,1H),7.33(dd,J=8.4,5.5Hz,2H) ,7.15(d,J=8.8Hz,2H),5.41–5.17(m,2H),4.66–4.52(m,1H),4.15–3.93(m,2H),3.89(s,3H),2.60( tdd,J=13.5,7.1,3.5Hz,2H),2.47(t,J=6.7Hz,1H),1.99–1.91(m,2H),1.79(dt,J=12.1,6.0Hz,1H).

[1246] Preparation of compound 223:

[1247]

[1248] Intermediate 216-1 (201 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to obtain compound 223-1 in a 67% yield. MS (ESI, positive) m / z: 422.2 [M+H] + .

[1249] 1H NMR (400MHz, DMSO-d6) δ13.26(s,1H),10.26(s,1H),8.70(s,1H),8.55(d,J=1.8Hz,1 H),8.38(d,J=7.9Hz,1H),8.21(s,1H),7.72(dd,J=8.7,1.8Hz,1H),7.60(d,J=8.7Hz, 1H),7.47(s,1H),7.43–7.33(m,2H),7.29(dt,J=6.4,2.3Hz,1H),5.19(p,J=7.1Hz,1H ),3.89(s,3H),2.43(tt,J=7.8,4.6Hz,1H),1.49(d,J=7.0Hz,3H),0.92–0.85(m,4H).

[1250] Preparation of compound 224:

[1251]

[1252] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and (1R,2S)-2-fluorocyclopropane-1-carboxylic acid (20.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 224 in a 53% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[1253] 1H NMR (400MHz, DMSO-d6) δ13.30(s,1H),10.53(s,1H),8.65(s,1H),8.46(d,J=1.8Hz,1H),8.09(s,1H),7.72 (dd,J=8.7,1.8Hz,1H),7.59(d,J=8.7Hz,1H),7.36–7.31(m,2H),7.15(d,J=8.8Hz,2H),5.33(s,1H),4.96 (dt,J=64.9,4.9Hz,1H),3.99(d,J=46.5Hz,2H),3.89(s,3H),3.13–2.99(m,1H),2.36(dt,J=12.2,7.2Hz, 1H),1.94(s,2H),1.82–1.75(m,1H),1.56(dtd,J=24.4,9.1,7.8,4.2Hz,1H),1.31(dq,J=12.9,6.4Hz,1H).

[1254] Preparation of compound 225:

[1255]

[1256] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and (1S,2R)-2-fluorocyclopropane-1-carboxylic acid (20.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 225 in a 53% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[1257] 1H NMR (400MHz, DMSO-d6) δ13.31(s,1H),10.55(s,1H),8.66(d,J=1.7Hz,1H),8.47(d,J=1.8Hz,1H),7. 74(d,J=8.7Hz,1H),7.60(d,J=8.7Hz,1H),7.34(dd,J=8.5,5.5Hz,2H),7.17(d,J=8.8Hz,2H),5.35(s ,1H),5.11–4.84(m,1H),4.06(s,1H),3.95(s,2H),3.90(s,3H),3.07(ddd,J=17.7,10.5,6.2Hz,1H) ,2.38(dq,J=12.1,7.3Hz,1H),1.95(s,2H),1.87–1.71(m,1H),1.65–1.50(m,1H),1.39–1.26(m,1H).

[1258] Preparation of compound 226:

[1259]

[1260] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 4,5,6,7-tetrahydrobenzothiophene-2-carboxylic acid (36.4 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 226 in a 53% yield. MS (ESI, positive ion) m / z: 596.2 [M+H] + .

[1261] 1 H NMR (400MHz, DMSO-d6) δ13.42(s,1H),9.45(s,1H),8.62(s,1H),8.52(d,J=1.8Hz,1H) ,8.09(s,1H),7.75(d,J=13.6Hz,2H),7.61(d,J=8.7Hz,1H),7.34(dd,J=8.3,5.4Hz,2H ),7.15(t,J=8.8Hz,2H),5.36(s,1H),4.16–3.91(m,3H),3.89(s,3H),2.81(t,J=5.9Hz ,2H),2.68–2.60(m,2H),2.36(dt,J=14.4,7.1Hz,1H),1.95(s,2H),1.83–1.76(m,4H).

[1262] Preparation of compound 227:

[1263]

[1264] Intermediate 223 (42.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylcarboxylic acid (17.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 227 in a 63% yield. MS (ESI, positive ion) m / z: 490.2 [M+H] + .

[1265] 1 H NMR (400MHz, DMSO-d6) δ12.56(s,1H),8.52(s,1H),8.36(d,J=7.8Hz,1H),8.17(s,1H),7.70(dd,J=8.8,1.8Hz,1H),7.55(d,J=8.7Hz,1H),7.4 7(s,1H),7.37(dd,J=7.7,5.4Hz,2H),7.33–7.26(m,1H),6.84(s,1H),6.36(s,2H),5.17(p,J=7.0Hz,1H),3.88(s,3H),1.49(d,J=7.1Hz,3H).

[1266] Preparation of compound 228:

[1267]

[1268] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (66.8 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 228 in a 53% yield. MS (ESI, positive ion) m / z: 748.2 [M+H] + .

[1269] 1H NMR (400MHz, DMSO-d6) δ13.41(s,-1H),10.48(s,1H),8.80(d,J=7.4Hz,1H),8.68(s,1H),8.48(d,J=1.8Hz,1H), 7.77–7.70(m,1H),7.61(d,J=8.7Hz,1H),7.41–7.34(m,2H),7.32(d,J=1.6Hz,4H),7.31–7.22(m,2H),7.15(t,J= 8.8Hz,2H),5.64(d,J=4.0Hz,1H),5.50(dd,J=7.3,4.0Hz,1H),5.36(s,1H),5.12(s,1H),4.17–3.93(m,2H),3.89 (s,3H),3.67–3.55(m,2H),2.38(p,J=7.2Hz,1H),1.94(s,2H),1.79(d,J=12.7Hz,1H),1.65(s,3H),1.46(s,3H).

[1270] Preparation of compound 229:

[1271]

[1272] Preparation of intermediate 229-1:

[1273] Methyl 5-bromo-1-methyl-1H-indole-3-carboxylate (20.1 g, 75 mmol) was dispersed in methanol (200 mL). Hydrazine hydrate (6.9 g, 150 mmol) and potassium carbonate (10.3 g, 75 mmol) were added. The mixture was heated to reflux and stirred overnight. The reaction mixture was concentrated under reduced pressure and filtered. The filter cake was washed with 30 ml of ethyl acetate, filtered, and air-dried to obtain Intermediate 229-1 in a 75% yield. MS (ESI, positive ion) m / z: 269.1 [M+H] + .

[1274] Preparation of intermediate 229-2:

[1275] Intermediate 229-1 (2 g, 7.4 mmol) was dispersed in n-butanol (14 mL). Potassium carbonate (1 g, 7.4 mmol) and 2-(3,4-difluorophenyl)acetonitrile (1.7 g, 11.1 mmol) were added. The mixture was heated to reflux and stirred overnight. The mixture was cooled and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA / PE = 1 / 3) to obtain Intermediate 229-2 in 85% yield. MS (ESI, positive ion) m / z: 404.2 [M+H] + .

[1276] Preparation of intermediate 229-3:

[1277] Intermediate 229-2 (500 mg, 1.24 mmol) was dissolved in 1,4-dioxane (10 mL). Potassium acetate (248 mg, 2.48 mmol), bis(pinacolato) borate (630 mg, 2.48 mmol), and PdCl2(dppf)2 (60 mg, 0.08 mmol) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 100°C. The reaction mixture was stirred and reacted overnight. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 3) to obtain Intermediate 229-3 in 83% yield. MS (ESI, positive ion) m / z: 451.3 [M+H] + .

[1278] Preparation of compound 229:

[1279] Intermediate 229-3 (207 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 40%) to obtain compound 229 in a 55% yield. MS (ESI, positive) m / z: 434.2 [M+H] + .

[1280] 1 H NMR(400MHz, DMSO-d6)δ13.70(s,1H),12.61(s,1H),8.65–8.54(m,1H),7.95(d,J=31.1Hz,1H),7.71–7.54(m,2H), 7.50–7.35(m,2H),7.22(s,1H),6.85(d,J=8.3Hz,1H),6.42(s,2H),4.15(d,J=36.3Hz,2H),3.90(d,J=15.8Hz,3H).

[1281] Preparation of compound 230:

[1282]

[1283] Preparation of intermediate 230-1:

[1284] Intermediate 229-3 (2.11 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to afford Intermediate 230-1 in 49% yield. MS (ESI, positive ion) m / z: 477.2 [M+H] + .

[1285] Preparation of Intermediate 230-2

[1286] Intermediate 230-1 (954 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 230-2 in a 78% yield. MS (ESI, positive ion) m / z: 463.2 [M+H] + .

[1287] Preparation of compound 230:

[1288] Intermediate 230-2 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (15.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 230 in a 65% yield. MS (ESI, positive ion) m / z: 502.2 [M+H] + .

[1289] 1H NMR (400MHz, DMSO-d6) δ13.81(s,1H),9.65(d,J=4.5Hz,1H),8.73(s,1H),8.64(s,1H),8.00(s,1H),7.83(d,J=8.8Hz,1H),7.66(d,J=8 .7Hz,1H),7.55–7.37(m,3H),7.25(s,1H),4.15(s,2H),3.91(s,3H),2.95(dq,J=7.7,3.8Hz,1H),0.87–0.78(m,2H),0.66–0.58(m,2H).

[1290] Preparation of compound 231:

[1291]

[1292] Compound 229 (43.4 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and acetic acid (18.0 mg, 0.3 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 231 in a 73% yield. MS (ESI, positive ion) m / z: 476.2 [M+H] + .

[1293] 1 H NMR (400MHz, DMSO-d6) δ13.74(s,-1H),13.27(s,-1H),9.98(s,1H),8.76(s,1H),8.71–8.66(m,1H),7.97(s,1H),7.72 (dd,J=8.7,1.8Hz,1H),7.64(d,J=8.7Hz,1H),7.53–7.35(m,2H),7.26(s,1H),4.15(s,2H),3.91(s,3H),2.28(s,3H).

[1294] Preparation of compound 232:

[1295]

[1296] Preparation of intermediate 232-1:

[1297] Intermediate INT-1-2 (604 mg, 2.0 mmol) was dispersed in 5 mL of tetrahydrofuran, and 2-(3-chlorophenyl)pyrrolidine (434 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 232-1 in a 77% yield. MS (ESI, positive ion) m / z: 465.2 [M+H] + .

[1298] Preparation of compound 232:

[1299] Intermediate 232-1 (214 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to obtain compound 232 in a 56% yield. MS (ESI, positive) m / z: 448.2 [M+H] + .

[1300] 1 H NMR (400MHz, DMSO-d6) δ12.56(s,1H),8.48(s,1H),7.72(d,J=8.7Hz,1H),7.55(d,J=8.7Hz,1H),7.35(dd,J=15.6,7.8Hz,2H),7.29–7.26(m ,2H),6.83(s,1H),6.36(s,2H),5.29(s,-1H),4.15–3.93(m,2H),3.89 (s,3H),2.40(dt,J=12.7,7.1Hz,1H),2.00–1.78(m,2H),1.25(s,2H).

[1301] Preparation of compound 233:

[1302]

[1303] Intermediate 232 (44.7 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylcarboxylic acid (17.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 233 in a 73% yield. MS (ESI, positive ion) m / z: 516.2 [M+H] + .

[1304] 1 H NMR (400MHz, DMSO-d6) δ13.27(s,1H),10.26(s,1H),8.68(s,1H),8.47(d,J=1.9Hz,1H),7.7 3(dd,J=8.7,1.8Hz,1H),7.60(d,J=8.7Hz,1H),7.34(dd,J=4.0,2.3Hz,2H),7.30–7.26(m,2H ),5.32(s,1H),3.95(dd,J=10.2,5.1Hz,1H),3.90(s,3H),3.31(s,1H),2.42(ddt,J=19.1,12 .6,5.8Hz,2H),2.03–1.88(m,2H),1.79(dq,J=8.8,4.8Hz,1H),0.89(dt,J=13.4,4.1Hz,5H).

[1305] Preparation of compound 234:

[1306]

[1307] Preparation of intermediate 234-1:

[1308] Intermediate INT-1-2 (1.95 g, 6.5 mmol) was dispersed in tetrahydrofuran (55 mL), and 1-(3-fluoro-4-methoxyphenyl)ethan-1-amine (1.32 g, 7.8 mmol), diisopropylethylamine (1.00 g, 7.8 mmol), and HATU (2.96 g, 7.8 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 234-1 in 74% yield. MS (ESI, positive ion) m / z: 453.2 [M+H] + .

[1309] Preparation of intermediate 234-2:

[1310] Intermediate 234-1 (2.1 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to obtain Intermediate 234-2 in a 69% yield. MS (ESI, positive ion) m / z: 479.2 [M+H] + .

[1311] Preparation of intermediate 234-3

[1312] Intermediate 234-2 (956 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 234-3 in an 84% yield. MS (ESI, positive ion) m / z: 465.2 [M+H] + .

[1313] Preparation of compound 234:

[1314] Intermediate 234-3 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (15.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 234 in a 73% yield. MS (ESI, positive ion) m / z: 504.2 [M+H] + .

[1315] 1H NMR (400MHz, DMSO-d6) δ13.20(s,-1H),9.64(d,J=4.6Hz,1H),8.66(d,J=1.8Hz,1H),8.55(s,1H),8.34 (d,J=8.1Hz,1H),8.22(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.65(d,J=8.7Hz,1H),7.27(dd,J=12.8,2.1 Hz,1H),7.20(dd,J=8.5,2.1Hz,1H),7.13(t,J=8.6Hz,1H),5.17(p,J=7.1Hz,1H),3.90(s,3H),3.83(s, 3H), 2.94 (tt, J=7.8, 3.9Hz, 1H), 1.48 (d, J=7.0Hz, 3H), 0.82 (td, J=7.1, 4.9Hz, 2H), 0.65–0.57 (m, 2H).

[1316] Preparation of compound 235:

[1317]

[1318] Preparation of intermediate 235-1:

[1319] 5-Bromo-2-methoxynicotinic acid (1.50 g, 6.5 mmol) was dispersed in tetrahydrofuran (55 mL), and (2,5-difluorophenyl)methanamine (1.11 g, 7.8 mmol), diisopropylethylamine (1.00 g, 7.8 mmol), and HATU (2.96 g, 7.8 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 235-1 in 68% yield. MS (ESI, positive ion) m / z: 357.1 [M+H] + .

[1320] Preparation of intermediate 235-2:

[1321] Intermediate 235-1 (357 mg, 1.0 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium acetate (245 mg, 2.5 mmol), pinacol diboronate (330 mg, 1.3 mmol), and PdCl2(dppf)2 (50 mg) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred and reacted overnight. The reaction solution was concentrated under reduced pressure and purified on a normal silica gel column (petroleum ether / ethyl acetate = 4 / 1) to obtain Intermediate 235-2 in a 71% yield. MS (ESI, positive ion) m / z: 405.2 [M+H] + .

[1322] Preparation of compound 235:

[1323] Intermediate 235-2 (186 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to obtain compound 235 in a 46% yield. MS (ESI, positiveion) m / z: 388.2 [M+H] + .

[1324] 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.67(d,J=2.5Hz,1H),8.46(d,J=2.5Hz,1H),7.28(td,J=9.2,4.5Hz,1H) ,7.19(dtd,J=17.1,8.8,3.7Hz,2H),6.77(s,1H),6.53(s,2H),6.31(s,1H),4.57(d,J=6.0Hz,2H),4.06(s,3H).

[1325] Preparation of compound 236:

[1326]

[1327] Compound 235 (38.8 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylcarboxylic acid (17.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 236 in a 67% yield. MS (ESI, positive ion) m / z: 516.2 [M+H] + .

[1328] 1H NMR (400MHz, DMSO-d6) δ13.27(s,-1H),10.35(s,1H),8.94(t,J=6.1Hz,1H),8.69(d,J=2.5Hz,1H),8.58(s,1H),8.45( d,J=2.5Hz,1H),7.33–7.12(m,3H),4.57(d,J=6.0Hz,2H),4.07(s,3H),2.44(tt,J=7.0,3.6Hz,1H),0.92–0.84(m,4H).

[1329] Preparation of compound 237:

[1330]

[1331] Intermediate 230-2 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (1R,2R)-2-fluorocyclopropane-1-amine (22.5 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 237 in a 67% yield. MS (ESI, positive ion) m / z: 520.2 [M+H] + .

[1332] Preparation of compound 238:

[1333]

[1334] Preparation of intermediate 238-1:

[1335] Intermediate INT-1-2 (604 mg, 2.0 mmol) was dispersed in 5 mL of tetrahydrofuran, and 1-(3,5-difluorophenyl)ethan-1-amine (377 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 238-1 in a 72% yield. MS (ESI, positive ion) m / z: 441.2 [M+H] + .

[1336] Preparation of compound 238:

[1337] Intermediate 238-1 (202 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to obtain compound 238 in a 51% yield. MS (ESI, positive) m / z: 423.2 [M+H] + .

[1338] 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),8.53(d,J=1.8Hz,1H),8.38(d,J=7.8Hz,1H),8.19(s,1H),7.71(dd,J=8.7,1.8Hz,1H),7.56(d,J=8.7Hz,1H), 7.13(tdd,J=8.4,5.4,2.3Hz,2H),7.07(dt,J=9.3,2.4Hz,1H),6.85(s,1H ), 6.38 (s, 2H), 5.19 (p, J = 7.1Hz, 1H), 3.89 (s, 3H), 1.49 (d, J = 7.1Hz, 3H).

[1339] Preparation of compound 239:

[1340]

[1341] Preparation of intermediate 239-1:

[1342] Intermediate INT-1-2 (1.95 g, 6.5 mmol) was dispersed in tetrahydrofuran (55 mL), and 1-(3,5-difluorophenyl)ethan-1-amine (1.22 g, 7.8 mmol), diisopropylethylamine (1.00 g, 7.8 mmol), and HATU (2.96 g, 7.8 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 239-1 in 78% yield. MS (ESI, positive ion) m / z: 441.2 [M+H] + .

[1343] Preparation of intermediate 239-2:

[1344] Intermediate 239-1 (2.1 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to obtain Intermediate 239-2 in a 69% yield. MS (ESI, positive ion) m / z: 466.2 [M+H] + .

[1345] Preparation of intermediate 239-3

[1346] Intermediate 239-2 (932 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 234-3 in an 81% yield. MS (ESI, positive ion) m / z: 453.2 [M+H] + .

[1347] Preparation of compound 239:

[1348] Intermediate 239-3 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (15.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 239 in a 75% yield. MS (ESI, positive ion) m / z: 492.2 [M+H] + .

[1349] 1H NMR(400MHz,DMSO-d6)δ13.37(s,-1H),9.62(d,J=4.6Hz,1H),8.65(d,J=1.8Hz,1H),8 .54(s,1H),8.42(d,J=7.9Hz,1H),8.24(s,1H),7.80(dd,J=8.7,1.9Hz,1H),7.65(d,J= 8.7Hz,1H),7.20–7.03(m,3H),5.22(p,J=7.2Hz,1H),3.91(s,3H),2.94(ddt,J=10.6, 6.8,3.7Hz,1H),1.50(d,J=7.1Hz,3H),0.81(dt,J=7.0,3.4Hz,2H),0.65–0.57(m,2H).

[1350] Preparation of compound 240:

[1351]

[1352] Intermediate 39-3 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylcyclopropane-1-amine (21.3 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 240 in a 66% yield. MS (ESI, positive ion) m / z: 505.2 [M+H] + .

[1353] 1 H NMR (400MHz, DMSO-d6) δ13.40(s,-1H),9.79(s,1H),8.65(d,J=1.8Hz,1H),8.55(s ,1H),8.43(d,J=7.9Hz,1H),8.25(s,1H),7.79(dd,J=8.7,1.9Hz,1H),7.65(d,J=8. 7Hz,1H),7.16–7.13(m,2H),7.08(tt,J=9.3,2.5Hz,1H),5.22(p,J=7.1Hz,1H),3.9 1(s,3H),1.50(d,J=7.2Hz,3H),1.43(s,3H),0.83–0.73(m,2H),0.73–0.67(m,2H).

[1354] Preparation of compound 241:

[1355]

[1356] Compound 238 (42.3 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and acetic acid (12.0 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 241 in a 75% yield. MS (ESI, positive ion) m / z: 465.2 [M+H] + .

[1357] 1 H NMR (400MHz, DMSO-d6) δ13.15(s,-1H),9.95(s,1H),8.69(s,1H),8.56(d,J= 1.8Hz,1H),8.40(d,J=7.8Hz,1H),8.23(s,1H),7.71(dd,J=8.7,1.8Hz,1H),7 .62(d,J=8.7Hz,1H),7.15(tq,J=6.1,4.0,3.0Hz,2H),7.08(tt,J=9.3,2.4Hz ,1H),5.21(p,J=7.2Hz,1H),3.90(s,3H),2.25(s,3H),1.49(d,J=7.0Hz,3H).

[1358] Preparation of compound 242:

[1359]

[1360] Preparation of intermediate 242-1:

[1361] Intermediate 235-2 (404 mg, 1.0 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (434 g, 2.0 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (187 mg, 1.0 mmol), PdCl2(dppf)2 (50 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to obtain Intermediate 242-1 in a 69% yield. MS (ESI, positive ion) m / z: 431.2 [M+H] + .

[1362] Preparation of intermediate 242-2

[1363] Intermediate 242-1 (431 mg, 1.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.24 g, 6.0 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 242-2 in an 89% yield. MS (ESI, positive ion) m / z: 417.1 [M+H] + .

[1364] Preparation of compound 242:

[1365] Intermediate 242-2 (83 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and methylamine hydrochloride (20.2 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 242 in a 77% yield. MS (ESI, positive ion) m / z: 430.1 [M+H] + .

[1366] 1 H NMR (400MHz, DMSO-d6) δ13.64(s,-1H),9.55(d,J=5.4Hz,1H),9.06(t,J=5.8Hz,1H),8.98–8.90(m,1H),8.71–8.63(m ,2H),7.33(dddd,J=33.6,17.0,8.9,4.6Hz,3H),4.68(d,J=5.8Hz,2H),4.18(d,J=2.6Hz,3H),3.00(t,J=4.3Hz,3H).

[1367] Preparation of compound 243:

[1368]

[1369] Intermediate 242-2 (83 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (15.9 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 243 in a 67% yield. MS (ESI, positive ion) m / z: 456.1 [M+H] + .

[1370] 1 H NMR (400MHz, DMSO-d6) δ13.05(s,-1H),9.61(d,J=4.6Hz,1H),8.96(t,J=6.0Hz,1H),8.85(d,J=2.5Hz,1H),8.58(d,J=2.5Hz,1H),8.54(s,1H) ,7.29–7.18(m,3H),4.57(d,J=6.0Hz,2H),4.08(s,3H),2.92(td,J=7.5,3.9Hz,1H),0.81(dd,J=7.2,2.2Hz,2H),0.60(dd,J=4.2,2.2Hz,2H).

[1371] Preparation of compound 244:

[1372]

[1373] Preparation of intermediate 244-1:

[1374] Intermediate INT-1-2 (604 mg, 2.0 mmol) was dispersed in 5 mL of tetrahydrofuran, and (S)-1-(3,4-difluorophenyl)ethan-1-amine (377 mg, 2.4 mmol), diisopropylethylamine (310 mg, 2.4 mmol), and HATU (912 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 244-1 in a 79% yield. MS (ESI, positive ion) m / z: 441.2 [M+H] + .

[1375] Preparation of compound 244:

[1376] Intermediate 244-1 (203 mg, 0.46 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (195 mg, 0.92 mmol), 4-amino-6-chloropyridazin-3(2H)-one (68.1 mg, 0.47 mmol), PdCl2(dppf)2 (15 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 40%) to obtain compound 244 in a 51% yield. MS (ESI, positive) m / z: 424.2 [M+H] + .

[1377] 1H NMR (400MHz, DMSO-d6) δ12.57(s,1H),8.52(d,J=1.8Hz,1H),8.34(d,J=7.8Hz,1H),8.17(s,1H),7.77–7.63(m,1H),7.55(d,J=8 .6Hz,1H),7.51–7.34(m,2H),7.27(s,1H),6.84(s,1H),6.37(s,2H),5.19(h,J=7.6Hz,1H),3.88(s,3H),1.48(d,J=7.1Hz,3H).

[1378] Preparation of compound 245:

[1379]

[1380] Compound 244 (42.4 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and cyclopropylcarboxylic acid (17.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 245 in a 73% yield. MS (ESI, positive ion) m / z: 492.2 [M+H] + .

[1381] Preparation of compound 246:

[1382]

[1383] Preparation of intermediate 246-1:

[1384] 4-Bromo-6-chloropyridazin-3(2H)-one (208 mg, 1.0 mmol) and tert-butylboronic acid pinacol ester were added.

[1385] The product (276 mg, 1.5 mmol) was dissolved in 1,4-dioxane (40 mL), and potassium phosphate (421 mg, 2.0 mmol), PdCl2(dppf)2 (50 mg), and water (4 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C, with stirring, and the reaction was allowed to proceed overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 40%) to afford intermediate 246-1 in a 44% yield. MS (ESI, positive ion) m / z: 187.1 [M+H] + .

[1386] Preparation of compound 246:

[1387] Intermediate 246-1 (37.4 mg, 0.2 mmol) and INT-3-1 (89.6 mg, 0.2 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium phosphate (97 mg, 0.46 mmol), PdCl2(dppf)2 (7 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred and reacted overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 40%) to obtain compound 246 in a 61% yield. MS (ESI, positive ion) m / z: 473.2 [M+H] + .

[1388] 1 H NMR (400MHz, DMSO-d6) δ12.97(s,1H),8.01(d,J=1.7Hz,1H),7.53(d,J=8.4H z,1H),7.34–7.26(m,2H),7.18(td,J=8.4,2.1Hz,1H),7.14–7.06(m,2H),6. 81(d,J=2.0Hz,1H),5.46(d,J=127.9Hz,-1H),4.13–3.94(m,2H),3.90(s,3H ), 2.34(dt,J=12.2,7.3Hz,1H),1.93(s,2H),1.85–1.44(m,2H),1.07(s,9H).

[1389] Preparation of compound 247:

[1390]

[1391] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and tetrahydro-2H-pyran-4-carboxylic acid (26.0 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 247 in a 56% yield. MS (ESI, positive ion) m / z: 544.2 [M+H] + .

[1392] 1H NMR (400MHz, DMSO-d6) δ13.28(s,-1H),9.89(s,1H),8.70(s,1H),8.49(d,J=1.8Hz,1H),7 .73(dd,J=8.6,1.8Hz,1H),7.60(d,J=8.7Hz,1H),7.39–7.31(m,2H),7.21–7.11(m,2H),5 .36(s,1H),3.97–3.90(m,4H),3.90(s,3H),3.41–3.35(m,2H),3.08(ddt,J=11.3,7.9,4. 0Hz,1H),2.37(dq,J=14.4,7.3Hz,1H),1.95(s,2H),1.86–1.68(m,4H),1.68–1.59(m,2H).

[1393] Preparation of compound 248:

[1394]

[1395] Preparation of intermediate 248-1:

[1396] 7-Bromo-3,4-dihydronaphthalen-1(2H)-one (5.0 g, 22.3 mmol) was dispersed in ethanol (100 mL), potassium acetate (4.37 g, 44.6 mmol) and hydroxylamine hydrochloride (3.1 g, 44.6 mmol) were added, and the mixture was heated to 80°C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure, and water (250 mL) was added. The solid was filtered, washed with water (250 mL), and dried to obtain Intermediate 248-1 in a 95% yield. MS (ESI, positive ion) m / z: 240.2 [M+H] + .

[1397] Preparation of intermediate 248-2:

[1398] Intermediate 248-1 (3.0 g, 12.5 mmol) was dispersed in thionyl chloride (50 mL) and heated to 50°C with stirring for 3 h. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried and concentrated, and then purified by silica gel column chromatography (EA / PE = 1 / 5) to obtain Intermediate 248-2 in a 60% yield. MS (ESI, positiveion) m / z: 240.2 [M+H] + .

[1399] Preparation of intermediate 248-3:

[1400] Intermediate 248-2 (1.0 g, 4.2 mmol) was dispersed in tetrahydrofuran (15 mL), and sodium hydride (252 mg, 6.3 mmol) was added. The mixture was stirred at room temperature for 10 minutes, followed by the addition of 2-fluoro-5-(trifluoromethoxy)benzyl methanesulfonate (1.33 g, 4.62 mmol). The mixture was heated to 55°C and stirred for 1 hour. The reaction was quenched by the addition of water (30 mL), and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried, concentrated, and purified by silica gel chromatography (EA / PE = 1 / 4) to afford Intermediate 248-3 in 76% yield. MS (ESI, positive ion) m / z: 432.2 [M+H] + .

[1401] Preparation of intermediate 248-4:

[1402] Intermediate 248-3 (500 mg, 1.04 mmol) was dissolved in 1,4-dioxane (10 mL). Potassium acetate (204.5 mg, 2.1 mmol), PdCl2(dppf)2 (30 mg), and bipyralidin (396 mg, 1.56 mmol) were added. The atmosphere was replaced with argon three times, the temperature was raised to 100°C, and the mixture was stirred for 8 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 248-4 in 83% yield. MS (ESI, positive ion) m / z: 480.3 [M+H] + .

[1403] Preparation of intermediate 248-5

[1404] Intermediate 248-4 (400 mg, 0.81 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (343 mg, 1.62 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (152 mg, 0.81 mmol), PdCl2(dppf)2 (40 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to afford Intermediate 248-5 in 80% yield. MS (ESI, positive ion) m / z: 492.2 [M+H] + .

[1405] Preparation of compound 248:

[1406] Intermediate 248-5 (98 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylamine (17.1 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 55%) to afford compound 248 in a 70% yield. MS (ESI, positive ion) m / z: 531.2 [M+H] + .

[1407] 1 H NMR(400MHz,DMSO-d6)δ13.03(s,-1H),9.60(d,J=4.6Hz,1H),8.52(s,1H),8.06 (d,J=2.1Hz,1H),7.98(dd,J=7.9,2.1Hz,1H),7.48(d,J=6.2Hz,1H),7.42(t,J=7 .6Hz,3H),4.83(s,2H),3.30–3.27(m,2H),2.93(td,J=7.2,3.6Hz,1H),2.75(t, J=7.0Hz,2H),1.88–1.80(m,2H),0.81(td,J=7.1,4.9Hz,2H),0.65–0.56(m,2H).

[1408] Preparation of compound 249:

[1409]

[1410] Intermediate 152-1 (43.1 mg, 0.1 mmol) was dissolved in pyridine (1 mL), and 2-(diethoxyphosphoryl)acetic acid (39.2 mg, 0.2 mmol) and 1-propylphosphonic anhydride (127 mg, 0.2 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 48%) to afford compound 249 in a 49% yield. MS (ESI, positive ion) m / z: 610.2 [M+H] + .

[1411] 1H NMR (400MHz, DMSO-d6) δ13.23(s,-1H),10.03(d,J=60.1Hz,-1H),8.64(s,1H),8.48(d,J=1.8 Hz,1H),7.72(dd,J=8.7,1.8Hz,1H),7.61(d,J=8.7Hz,1H),7.34(dd,J=8.6,5.4Hz,2H),7.19 –7.10(m,2H),5.35(s,1H),4.15–4.07(m,4H),4.07–3.93(m,2H),3.90(s,3H),3.50(d,J=21. 7Hz,2H),2.52–2.29(m,2H),1.95(s,2H),1.79(dd,J=12.5,6.2Hz,1H),1.27(t,J=7.0Hz,6H).

[1412] Preparation of compound 250:

[1413]

[1414] Preparation of intermediate 250-1:

[1415] 1-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxylic acid (2.05 g, 6.5 mmol) was dispersed in tetrahydrofuran (55 mL). (S)-2-(4-fluorophenyl)pyrrolidine (1.29 g, 7.8 mmol), diisopropylethylamine (1.00 g, 7.8 mmol), and HATU (2.96 g, 7.8 mmol) were added and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE = 1 / 4) to afford Intermediate 250-1 in 76% yield. MS (ESI, positive ion) m / z: 463.2 [M+H] + .

[1416] Preparation of intermediate 250-2:

[1417] Intermediate 250-1 (2.2 g, 4.7 mmol) was dissolved in 1,4-dioxane (20 mL). Potassium phosphate (1.95 g, 9.2 mmol), methyl 3-oxo-6-chloro-2,3-dihydropyridazine-4-carboxylate (0.88 g, 4.7 mmol), PdCl2(dppf)2 (150 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate = 40%) to afford Intermediate 250-2 in 78% yield. MS (ESI, positive ion) m / z: 489.5 [M+H] + .

[1418] Preparation of intermediate 250-3

[1419] Intermediate 250-2 (978 mg, 2.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.48 g, 12 mmol) was added, the temperature was raised to 75°C, and the mixture was stirred for 5 h. The pH was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M). The solid was filtered and dried to obtain Intermediate 250-3 in a 90% yield. MS (ESI, positive ion) m / z: 461.5 [M+H] + .

[1420] Preparation of compound 250:

[1421] Intermediate 250-3 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (1R,2S)-2-fluorocyclopropane-1-amine (22.5 mg, 0.3 mmol) and 1-propylphosphonic anhydride (191 mg, 0.3 mmol, 50%) were added. The mixture was heated to 80°C and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 55%) to afford compound 250 in a 60% yield. MS (ESI, positive ion) m / z: 532.2 [M+H] + .

[1422] Preparation of compound 251:

[1423]

[1424] Preparation of intermediate 251-1:

[1425] 4-Bromo-6-chloropyridazin-3(2H)-one (208 mg, 1.0 mmol) and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (399 mg, 1.5 mmol) were dissolved in 1,4-dioxane (40 mL). Potassium phosphate (421 mg, 2.0 mmol), PdCl2(dppf)2 (50 mg), and water (4 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to afford Intermediate 251-1 in 56% yield. MS (ESI, positive ion) m / z: 268.1 [M+H] + .

[1426] Preparation of compound 251:

[1427] Intermediate 251-1 (53.6 mg, 0.2 mmol) and INT-3-1 (89.6 mg, 0.2 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium phosphate (97 mg, 0.46 mmol), PdCl2(dppf)2 (7 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 40%) to obtain compound 251 in a 63% yield. MS (ESI, positive ion) m / z: 555.2 [M+H] + .

[1428] 1 H NMR (400MHz, DMSO-d6) δ13.15(s,-1H),8.69(s,1H),8.61(d,J=1.8Hz,1H),8.39(s,1H) ,8.23(s,1H),7.84(dd,J=8.7,1.8Hz,1H),7.61(t,J=7.9Hz,1H),7.34(dd,J=8.4,5.5Hz ,2H),7.20–7.10(m,2H),5.34(s,1H),4.75(s,1H),4.11(s,2H),4.00(d,J=46.7Hz,2H), 3.89(s,3H),2.51–2.29(m,2H),1.95(s,2H),1.79(dd,J=12.2,6.1Hz,1H),1.11(s,6H).

[1429] Preparation of compound 252:

[1430]

[1431] Preparation of intermediate 252-1:

[1432] 4-Bromo-6-chloropyridazin-3(2H)-one (208 mg, 1.0 mmol) and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (352 mg, 1.5 mmol) were dissolved in 1,4-dioxane (40 mL). Potassium phosphate (421 mg, 2.0 mmol), PdCl2(dppf)2 (50 mg), and water (4 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to afford Intermediate 252-1 in a 61% yield. MS (ESI, positive ion) m / z: 238.1 [M+H] + .

[1433] Preparation of compound 252:

[1434] Intermediate 252-1 (47.6 mg, 0.2 mmol) and INT-3-1 (89.6 mg, 0.2 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium phosphate (97 mg, 0.46 mmol), PdCl2(dppf)2 (7 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C. The reaction mixture was stirred and allowed to react overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 40%) to obtain compound 252 in a 61% yield. MS (ESI, positive ion) m / z: 524.2 [M+H] + .

[1435] 1H NMR (400MHz, DMSO-d6) δ13.26(s,1H),8.86(d,J=2.4Hz,1H),8.63(d,J=1.8Hz,1H),8.35(d d,J=8.7,2.5Hz,1H),8.16(s,1H),7.91–7.84(m,1H),7.61(d,J=8.7Hz,1H),7.33(dd,J=8.3 ,5.4Hz,2H),7.14(t,J=8.7Hz,2H),6.95(d,J=8.7Hz,1H),5.33(s,1H),4.09(d,J=26.4Hz,1 H),3.94(s,3H),3.90(s,3H),2.37(dq,J=14.3,7.3Hz,2H),1.94(s,2H),1.94–1.66(m,2H).

[1436] Preparation of compound 253:

[1437]

[1438] Preparation of intermediate 253-1:

[1439] 4-Bromo-6-chloropyridazin-3(2H)-one (208 mg, 1.0 mmol) and cyclopropylboronic acid pinacol ester were added.

[1440] The product (252 mg, 1.5 mmol) was dissolved in 1,4-dioxane (40 mL), and potassium phosphate (421 mg, 2.0 mmol), PdCl2(dppf)2 (50 mg), and water (4 mL) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 95°C, with stirring, and the reaction was allowed to proceed overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to afford intermediate 253-1 in a 41% yield. MS (ESI, positive ion) m / z: 170.0 [M+H] + .

[1441] Preparation of compound 253:

[1442] Intermediate 253-1 (34.0 mg, 0.2 mmol) and INT-3-1 (89.6 mg, 0.2 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium phosphate (97 mg, 0.46 mmol), PdCl2(dppf)2 (7 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 40%) to obtain compound 253 in a 61% yield. MS (ESI, positive ion) m / z: 457.2 [M+H] + .

[1443] 1 H NMR (400MHz, DMSO-d6) δ12.93(s,1H),8.51(d,J=1.8Hz,1H),7.74(dd,J=8.8,1.9Hz,1 H),7.56(d,J=8.7Hz,1H),7.40(s,1H),7.33(dd,J=8.5,5.5Hz,2H),7.14(td,J=6.5,3 .3Hz,2H),5.33(s,1H),4.11–3.99(m,1H),3.88(s,3H),2.42–2.17(m,2H),2.17(p,J= 6.9Hz, 1H), 1.93 (d, J = 7.8Hz, 2H), 1.78 (dd, J = 12.2, 6.1Hz, 2H), 1.04 (d, J = 6.8Hz, 4H).

[1444] Preparation of compound 254:

[1445]

[1446] Preparation of intermediate 254-1:

[1447] 4-Bromo-6-chloropyridazin-3(2H)-one (208 mg, 1.0 mmol) and 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (334 mg, 2.0 mmol) were dissolved in 1,4-dioxane (20 mL). Cesium carbonate (625 mg, 2.0 mmol), X-phos (20 mg), and Pd(OAc)2 (20 mg) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 100°C. The reaction mixture was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% aqueous ammonium bicarbonate solution = 40%) to afford Intermediate 254-1 in 44% yield. MS (ESI, positive ion) m / z: 296.1 [M+H] + .

[1448] Preparation of compound 254:

[1449] Intermediate 254-1 (59.0 mg, 0.2 mmol) and INT-3-1 (89.6 mg, 0.2 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium phosphate (97 mg, 0.46 mmol), PdCl2(dppf)2 (7 mg), and water (2 mL) were added. The atmosphere was replaced with argon three times, the temperature was raised to 95°C, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure and purified on a C-18 reverse-phase silica gel column (acetonitrile / 0.1% ammonium bicarbonate solution = 40%) to obtain compound 254 in a 52% yield. MS (ESI, positive ion) m / z: 582.2.4 [M+H] + .

[1450] 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),8.54(s,1H),8.45(d,J=1.8Hz,1H),8.03(d,J=13.1Hz, 2H),7.73(dd,J=8.5,1.8Hz,1H),7.61(d,J=7.9Hz,2H),7.32(dd,J=8.5,5.5Hz,2H),7.14(t,J =8.8Hz,2H),6.85(s,1H),4.46–4.40(m,1H),3.98(dq,J=10.6,3.4Hz,4H),3.87(s,3H),3.53– 3.42(m,4H),2.36(dq,J=14.6,7.3Hz,1H),1.98–1.96(m,2H),1.93(s,2H),1.90–1.72(m,2H).

[1451] Preparation of compound 255:

[1452]

[1453] Preparation of intermediate 255-1:

[1454] 4-Bromo-6-chloropyridazin-3(2H)-one (208 mg, 1.0 mmol) and 1-[2-(pyrrolidin-1-yl)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (436 mg, 1.5 mmol) were dissolved in 1,4-dioxane (40 mL). Potassium phosphate (421 mg, 2.0 mmol), PdCl2(dppf)2 (50 mg), and water (4 mL) were added. The ...

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof: Where, G1, G2, G3, G4 are each independently selected from CH2, CR C R D , NH, N, O or S; p is 0, 1, 2, or 3; Ring C is absent or is a ring formed by connecting G1, G2, G3, and G4; when ring C is absent, R 1 is connected to ring B at any one of the carbon atoms shared by ring B and ring C, and ring B is optionally replaced by R B replace; R B 、R C 、R D Each is independently selected from hydrogen, =O, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; X1 is N or CH; R X is hydrogen or halogen; Ring A is A1 is N or CH; A2 is N or CR A2 ; A3 is N or CR A3 ; A4 is N or CR A4 ; A5 is N or CR A5 ; A6 is N or CR A6 ; R 2 、R 5 Each independently selected from hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl; R 3 、R 4 Each is independently selected from hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 8-membered heteroaryl, -4- to 10-membered heterocyclyl-4- to 10-membered heterocyclyl, -5- to 8-membered heteroaryl-C1-C6 alkyl, -5- to 8-membered heteroaryl-4- to 10-membered heterocyclyl, -5- to 8-membered heteroaryl-C1-C6 alkylene-C3-C 10 Cycloalkyl, -5 to 8 membered heteroaryl-C1-C6 alkylene-4 to 10 membered heterocyclic group, -NR a R b 、-C(O)R 31 、-NR c -R 32 、-NR c -C(O)R 33 、-C(O)NR c -R 34 or -C(O)NR c -NR c -C(O)-R 35 wherein the C1-C6 alkyl, -C1-C6 alkylene, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4 to 10 membered heterocyclyl or 5 to 8 membered heteroaryl are optionally substituted by one or more R * replaced by; Or, R 3 、R 4 The carbon atoms connected to it together form a 4- to 8-membered partially unsaturated carbon ring, C 6- C 10 aromatic ring or 5 to 8 membered heteroaromatic ring, said 4 to 8 membered partially unsaturated carbon ring, C 6- C 10 The aromatic ring or 5- to 8-membered heteroaromatic ring is optionally substituted with one or more R ** replace; R 31 、R 32 、R 33 、R 34 、R 35 Each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C6-C8 aryl, 4- to 10-membered heterocyclic group, 5- to 8-membered heteroaryl, 6- to 12-membered partially unsaturated carbocyclic group, -C3-C6 cycloalkyl-C6-C8 aryl, -C1-C6 alkylene-C1-C6 alkoxy, -C1-C6 alkylene-C3-C 10 Cycloalkyl, -C1-C6 alkylene-C6-C8 aryl, -C1-C6 alkylene-4 to 10-membered heterocyclyl, -C1-C6 alkylene-C(O)-4 to 10-membered heterocyclyl, -C1-C6 alkylene-5 to 8-membered heteroaryl, -4 to 10-membered heterocyclyl-4 to 10-membered heterocyclyl, -4 to 10-membered heterocyclyl-NR a C(O)-C1-C6 alkylene-C6-C8 aryl, -5 to 8-membered heteroaryl-C1-C6 alkyl, -5 to 8-membered heteroaryl-C1-C6 alkylene-C(O)-4 to 10-membered heterocyclyl, -5 to 8-membered heteroaryl-C1-C6 alkylene-C6-C8 aryl, -5 to 8-membered heteroaryl-4 to 10-membered heterocyclyl, or -NR a R b wherein the C1-C6 alkyl, C1-C6 alkylene, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C6-C8 aryl, 4 to 10 membered heterocyclyl, 5 to 8 membered heteroaryl, 6 to 12 membered partially unsaturated carbocyclyl, optionally substituted with one or more R *** replace; R * Halogen, hydroxy, cyano, C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, -NR a R b or -C(O)R d ; R ** Halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 5 to 8 membered heteroaryl; the 5 to 8 membered heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl or C3-C 10 Substitution of cycloalkyl groups; R *** =O, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, -NR a R b 、-P(O)R e R f 、-S(O)2R e 、-C(O)OR e 、-C(O)NR a R b 、-OC(O)-R g 、-O-C1-C6 alkylene-R h or -NR c C(O)-R g ; R 6 is hydrogen, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl; R A2 、R A3 、R A4 、R A5 or R A6 Each is independently selected from hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, -NR a R b 、-C(O)NR a R b 、-NR c -C(O)-R H1 、-NR c -C(=NH)-NR c -R H1 、-NR c -C(=S)-NR c -R H1 or -NR c -C(=O)-NR c -R H1 ; R H1 C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl or 4- to 10-membered heterocycloalkyl, the 4- to 10-membered heterocycloalkyl being optionally substituted with one or more hydroxy groups; In the above groups, R a 、R b 、R d 、R e 、R f 、R g 、R h Each is independently selected from hydrogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy; R 1 Selected from in, R 7 C 6-8 Aryl, the C 6-8 Aryl is optionally substituted with one or more selected from R 71 Substituents substituted; R 71 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy or C 3-6 Cycloalkyl; Ring D is selected from a 5- or 6-membered monocyclic heteroaryl group or a 4- to 8-membered nitrogen-containing heterocyclic group; R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 1f are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; Or, R 1a 、R 1b The carbon atom and nitrogen atom connected thereto together form a 4- to 8-membered nitrogen-containing heterocyclic group; Or, R 1b 、R 1e The carbon atoms connected to it together form C 3-6 Cycloalkyl; t1 and t2 are each independently selected from 0, 1 or 2; In the above groups, the 4- to 10-membered heterocyclic group contains 1, 2, 3 or 4 heterocyclic ring atoms selected from N, O or S; the 5- to 8-membered heteroaryl group contains 1, 2 or 3 heterocyclic ring atoms selected from N, O or S; the 5- or 6-membered monocyclic heteroaryl group contains 1, 2 or 3 heterocyclic ring atoms selected from N, O or S; and the 4- to 8-membered nitrogen-containing heterocyclic group contains at least 1 nitrogen heteroatom as a ring atom.

2. The compound according to claim 1, wherein Selected from Formula (IA), Formula (IB) or Formula (IC): In formula (IA), X1 is N or CH; G1, G2, G3, and G4 are each independently selected from CH2, C(CH3)2, C=O, NH, O, or S; p is 0, 1, 2, or 3; Preferably, G4 is C=O; In formula (IB), G3 and G4 are each independently selected from CH or N; R C is hydrogen, ═O, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; Preferably, G3 is CH, G4 is CH; Preferably, R C is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; more preferably, R C is hydrogen, methyl, ethyl, propyl or isopropyl; more preferably, R C is methyl; In formula (IC), X1 is N or CH; R B is hydrogen, ═O, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; Preferably, X1 is N, R B is hydrogen; Preferably, X1 is CH, R B is hydrogen, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; more preferably, R B is hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy; more preferably, R B is ethyl or methoxy; Preferably, Selected from: Preferably, for Preferably, R X is hydrogen, fluorine, chlorine or bromine, more preferably hydrogen or fluorine; Preferably, for Preferably, wherein ring A is R 2 、R 3 、R 4 Each of the following claims: Preferably, R 2 is hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl; more preferably, R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropyl or cyclopentyl; more preferably, R 2 is hydrogen or cyclopropyl; Preferably, R 4 is hydrogen; Preferably, R 3 is hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 8-membered heteroaryl, -4- to 10-membered heterocyclyl-4- to 10-membered heterocyclyl, -5- to 8-membered heteroaryl-C1-C6 alkyl, -5- to 8-membered heteroaryl-4- to 10-membered heterocyclyl, -5- to 8-membered heteroaryl-C1-C6 alkylene-C3-C 10 Cycloalkyl, -5 to 8 membered heteroaryl-C1-C6 alkylene-4 to 10 membered heterocyclic group, -NR a R b 、-C(O)R 31 、-NR c -R 32 、-NR c -C(O)R 33 、-C(O)NR c -R 34 or -C(O)NR c -NR c -C(O)-R 35 wherein the C1-C6 alkyl, -C1-C6 alkylene, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4 to 10 membered heterocyclyl or 5 to 8 membered heteroaryl are optionally substituted with one or more halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 alkyl, 10 Cycloalkyl, -NR a R b or -C(O)R d Substituents substituted; R 31 、R 32 、R 33 、R 34 、R 35 Each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C6-C8 aryl, 4- to 10-membered heterocyclic group, 5- to 8-membered heteroaryl, 6- to 12-membered partially unsaturated carbocyclic group, -C3-C6 cycloalkyl-C6-C8 aryl, -C1-C6 alkylene-C1-C6 alkoxy, -C1-C6 alkylene-C3-C 10 Cycloalkyl, -C1-C6 alkylene-C6-C8 aryl, -C1-C6 alkylene-4 to 10-membered heterocyclyl, -C1-C6 alkylene-C(O)-4 to 10-membered heterocyclyl, -C1-C6 alkylene-5 to 8-membered heteroaryl, -4 to 10-membered heterocyclyl-4 to 10-membered heterocyclyl, -4 to 10-membered heterocyclyl-NR a C(O)-C1-C6 alkylene-C6-C8 aryl, -5 to 8-membered heteroaryl-C1-C6 alkyl, -5 to 8-membered heteroaryl-C1-C6 alkylene-C(O)-4 to 10-membered heterocyclyl, -5 to 8-membered heteroaryl-C1-C6 alkylene-C6-C8 aryl, -5 to 8-membered heteroaryl-4 to 10-membered heterocyclyl, or -NR a R b wherein the C1-C6 alkyl, C1-C6 alkylene, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C6-C8 aryl, 4 to 10 membered heterocyclyl, 5 to 8 membered heteroaryl, 6 to 12 membered partially unsaturated carbocyclyl, optionally substituted by one or more selected from =O, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, -NR a R b 、-P(O)R e R f 、-S(O)2R e 、-C(O)OR e 、-C(O)NR a R b 、-OC(O)-R g 、-O-C1-C6 alkylene-R h or -NR c C(O)-R g Substituents substituted; In the above groups, R a 、R b 、R d 、R e 、R f 、R g 、R h Each is independently selected from hydrogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy; Preferably, wherein R 3 is hydrogen, methyl, ethyl, isopropyl, methoxy, ethoxy, -CH2CH(CH3)2, -(CH2)2C(CH3)3, tert-butyl, amino, cyano, cyclopropyl, cyclopentyl, -(CH2)2OCH2CH3, -CH2OH, -C(CH3)2OH, -C(O)CH3, -C(O)NH2, -C(O)NHOH, -C(O)NHCH3, -NHC(O)CH3, -NHC(O)(CH2)3CH3, -C(O)NH(CH2)3CH3, -C(O)NHC(CH3)3, -C(O)N(CH3)2, -C(O)NHCH2CF3, -C(O)NHCH2CHF2, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -C(O)NHCH(CH3)2, Preferably, wherein ring A is R 3 、R 4 Together with the carbon atoms it is connected to form described Optionally, one or more R *** replace; Preferably, R *** is fluoro, methyl, methoxy, cyclopropyl, -CH2CH(CH3)2 or Preferably, wherein ring A is R 2 、R 3 、R 4 Each of the following claims: Preferably, R 2 is hydrogen; Preferably, R 3 is hydrogen, halogen, cyano, C1-C6 alkyl or -C(O)NR a R b More preferably, R 3 is hydrogen, cyano or -C(O)NH2; more preferably, R 3 is cyano or -C(O)NH2; Preferably, R 4 is hydrogen; Preferably, wherein ring A is R 2 、R 3 Each of the following claims: Preferably, R 2 is hydrogen; Preferably, R 3 is hydrogen or -C(O)-C1-C6 alkoxy; more preferably, R 3 is -C(O)-C1-C6 alkoxy; more preferably, R 3 is -C(O)-OCH3, -C(O)-OCH2CH3 or -C(O)-O(CH2)2CH3; more preferably, R 3 is -C(O)-OCH3; Preferably, wherein ring A is R 5 、R 6 Each of the following claims: Preferably, R 5 is hydrogen; Preferably, R 6 is hydrogen or halogen; more preferably, R 6 is hydrogen, fluorine or chlorine; more preferably, R 6 For chlorine; Preferably, wherein ring A is R A6 The definition is the same as claim 1; Preferably, R A6 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, 4- to 10-membered heterocycloalkyl, -NR a R b or -NR c -C(O)-C3-C 10 Cycloalkyl; more preferably, R A6 is hydrogen, C1-C6 alkoxy, -NR a R b or -NR c -C(O)-C3-C 10 Cycloalkyl; more preferably, R A6 is hydrogen, methoxy, amino, morpholinyl or -NHC(O)-cyclopropyl; Or; Ring A is R A6 The definition is the same as claim 1; Preferably, R A6 is hydrogen or hydroxy, more preferably, R A6 is hydroxyl group; Or; Ring A is R A5 、R A6 Each of the following claims: Preferably, R A5 is hydrogen, -NR a R b or -NR c -C(O)-C3-C 10 Cycloalkyl; more preferably, R A5 is amino or -NHC(O)-cyclopropyl; Preferably, R A6 is hydrogen or halogen; more preferably, R A6 is fluorine, chlorine or bromine; more preferably, R A6 For fluorine; Or; Ring A is R A2 The definition is the same as claim 1; Preferably, R A2 is hydrogen or C1-C6 alkyl; more preferably, R A2 is hydrogen; Or; Ring A is R A1 、R A4 Each of the following claims: Preferably, R A1 is halogen; more preferably, R A1 is fluorine, chlorine or bromine; more preferably, R A1 For chlorine; Preferably, R A4 -NR a R b More preferably, R A4 It is amino; Or; Ring A is R A5 、R A6 Each of the following claims: Preferably, R A5 is hydrogen or halogen; more preferably, R A5 is hydrogen, fluorine, chlorine or bromine; more preferably, R A5 is hydrogen or fluorine; Preferably, R A6 For hydrogen, halogen, hydroxyl, -NR c -C(O)-R H1 、-NR c -C(=NH)-NR c -R H1 、-NR c -C(=S)-NR c -R H1 、-NR c -C(=O)-NR c -R H1 ; Preferably, R H1 is C1-C6 alkyl, C1-C6 alkoxy or 4 to 10 membered heterocycloalkyl; more preferably, R H1 is hydroxy, isopropyl, methoxy, azacyclohexyl or azacyclohexyl substituted with hydroxy; More preferably, R A6 For hydroxyl, Preferably, wherein R A2 、R A3 、R A4 or R A5 Each is independently selected from fluorine, chlorine, hydroxyl, amino, cyano, methoxy, morpholinyl, -C(O)NH2, Preferably, wherein R 1 Selected from Among them, R 7 is phenyl, said phenyl being optionally substituted by one or more selected from R 71 Substituents substituted; Preferably, R 71 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogen substituted C 1-6 Alkyl; More preferably, R 71 is fluorine, chlorine, -OCF3 or -OCH3; Preferably, R 1a 、R 1b 、R 1c 、R 1d 、R 1e are each independently selected from hydrogen, halogen, C 1-6 Alkyl or C 2-6 Alkynyl; more preferably, R 1a 、R 1b 、R 1c 、R 1d 、R 1e are each independently selected from hydrogen, methyl, ethynyl; Preferably, R 1a 、R 1b The carbon atom and nitrogen atom to which it is connected together form an aziridine group, an azocyclopentyl group or a morpholinyl group; Preferably, R 1b 、R 1e The carbon atom to which it is attached together forms a cyclopropyl, cyclobutyl or cyclopentyl group; Preferably, ring D is selected from t1 and t2 are each independently selected from 0, 1 or 2; Preferably, wherein R 1 for Among them, R 7 is phenyl, said phenyl being optionally substituted by one or more selected from R 71 Substituents substituted; Preferably, R 71 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogen substituted C 1-6 Alkyl; More preferably, R 71 is fluorine or -OCF3; Preferably, R 1f is hydrogen or C 1-6 Alkyl; More preferably, R 1f is hydrogen or methyl; Preferably, wherein R 1 for 3. The compound according to any one of claims 1 or 2, wherein The compound of formula (I) is shown in the following formula (II): Where R 1 、R 2 、R 3 、R 4 Each claim 1 or 2; Preferably, the compound of formula (I) is represented by the following formula (IIA): Where R 2 、R 3 、R 4 Each claim 1 or 2; R 1a 、R 1b 、R 1c , t1, R 7 Each is as defined in claim 2; Preferably, the compound of formula (I) is represented by the following formula (IIB): Where R 2 、R 3 、R 4 Each claim 1 or 2; Ring D, R 1d 、R 1e , t2, R 7 Each is as defined in claim 2; Preferably, the compound of formula (I) is represented by the following formula (VI): Where R 2 、R 3 、R 4 Each claim 1 or 2; R 1a 、R 1b 、R 1c , t1, R 7 Each is as defined in claim 2.

4. The compound according to any one of claims 1 to 3, wherein The compound of formula (I) is shown in the following formula (III): Where R 1 、R 2 、R 3 、R 4 、R X Each claim 1 or 2; G1 is selected from CH2, C(CH3)2, C=O, NH, O or S; preferably, G1 is selected from CH2, C(CH3)2 or O; preferably, CH2; Preferably, R 1 for Among them, R 7 is phenyl, said phenyl being optionally substituted by one or more selected from R 71 Substituents substituted; R 71 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogen substituted C 1-6 alkyl; Preferably, R 71 is fluorine or -OCF3; Preferably, R 1f is hydrogen or C 1-6 Alkyl; More preferably, R 1f is hydrogen or methyl; Preferably, R 1 for Preferably, the compound of formula (I) is represented by the following formula (IIIB): Where R 2 、R 3 、R 4 、R X Each claim 1 or 2; R G1 、R G2 Each independently selected from H, C 1-3 Alkyl or halogen; Preferably, R G1 、R G2 Each independently selected from H or methyl; R 7 is phenyl, said phenyl being optionally substituted by one or more selected from R 71 Substituents substituted; R 71 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogen substituted C 1-6 alkyl; Preferably, R 71 is fluorine or -OCF3; R 1f is hydrogen or C 1-6 Alkyl; More preferably, R 1f is hydrogen or methyl; Preferably, for Preferably, the compound of formula (I) is represented by the following formula (IIIC): Where R 2 、R 3 、R 4 、R X Each claim 1 or 2; R G1 、R G2 Each independently selected from H, C 1-3 Alkyl or halogen; Preferably, R G1 、R G2 Each independently selected from H or methyl; R 7 is phenyl, said phenyl being optionally substituted by one or more selected from R 71 Substituents substituted; R 71 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogen substituted C 1-6 alkyl; Preferably, R 71 is fluorine or -OCF3; R 1f is hydrogen or C 1-6 Alkyl; More preferably, R 1f is hydrogen or methyl; Preferably, for 5. The compound according to claim 1, wherein The compound of formula (I) is represented by the following formula (IV) or formula (V): Where R 1 、R 2 、R 3 、R 4 、R B Each claim 1 or 2; Preferably, the compound of formula (I) is represented by the following formula (IVA): Where R 2 、R 3 、R 4 Each claim 1 or 2; R B The definition is the same as that in claim 2; R 1a 、R 1b 、R 1c , t1, R 7 Each is as defined in claim 2; Preferably, the compound of formula (I) is represented by the following formula (VA): Where R 2 、R 3 、R 4 Each claim 1 or 2; R 1a 、R 1b 、R 1c , t1, R 7 Each is as defined in claim 2.

6. The following compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. Use of the compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and / or treating inflammation, autoimmune diseases, neurodegenerative diseases and cancer.

9. Use of the compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, solvate or stereoisomer, or the pharmaceutical composition according to claim 7 in the preparation of a RIPK inhibitor; Preferably, the RIPK inhibitor is a RIPK1 inhibitor.

10. Use of the compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt or stereoisomer, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and / or treating diseases associated with abnormal RIPK expression; Preferably, the disease associated with abnormal RIPK expression is selected from inflammation, autoimmune disease, neurodegenerative disease and cancer in a drug; Preferably, the disease associated with abnormal RIPK expression is cancer; Preferably, the cancer is colon cancer.

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