Substituted pyridotriazole compounds, their preparation methods and uses

Abstract

This invention relates to the field of pharmaceutical technology, specifically to a substituted pyridotriazole compound, its preparation method, and its uses. This specification discloses a substituted pyridotriazole compound that inhibits RIPK1 and / or MLK, as well as its pharmaceutically acceptable salts, stereoisomers, solvent compounds, or prodrugs. The compound is shown in formula (I), where the definitions of each group are detailed in the specification. Furthermore, this invention also discloses pharmaceutical compositions comprising this compound and their use in the preparation of medicaments for treating RIPK1-related diseases or conditions.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to a substituted pyridotriazole derivative and its use as an inhibitor of RIPK1 and / or MLK. Background Technology

[0002] Programmed necrosis (PCN) is a novel, caspase-independent form of programmed cell death, distinct from apoptosis, discovered in recent years. It is regulated by death signals and exhibits necrosis-like structural characteristics. Compared to apoptosis, PCN does not form apoptotic bodies, and chromatin does not condense; unlike necrosis, PCN is a controlled cell death process regulated by multiple genes. In vitro culture systems incorporating the caspase inhibitor z-VAD-FMK, followed by TNF, can induce PCN, resulting in morphological characteristics such as cell swelling, rupture, and release of cellular contents, subsequently triggering inflammatory and immune responses. Besides TNF, ligands of TLR3 and TLR4, certain bacterial and viral infections, and other factors can also induce PCN.

[0003] Receptor-interacting protein kinase 1 (RIPK1) is a protein with specific serine / threonine kinase activity. It possesses an N-terminal kinase domain similar to other protein kinases, but with a different binding domain. Studies have shown that RIPK1 is a key regulator of programmed cell death (CCD), modulating it through the RIPK1 / RIPK3 / MLKL signaling axis. Various death receptors, such as TNFR, FAS, TRAILR, and Toll-like receptors, can trigger upstream signals in CCD under conditions of inflammatory cytokine stimulation or exogenous infection. When cIAPs and caspase activity are restricted, RIPK1 and RIPK3 form necrosomes. RIPK3 further recruits MLKL; phosphorylated MLKL oligomerizes and migrates to the cell membrane, "perforating" it, leading to leakage of cellular contents and disruption of ionization balance, ultimately resulting in cell necrosis.

[0004] Programmed necrosis is closely related to the development and progression of diseases such as inflammation, autoimmune diseases, neurodegenerative diseases, and tumors. For example, studies have shown that programmed necrosis is an important cause of systemic inflammatory response syndrome (SIRS). SIRS is a systemic inflammatory response caused by infectious or non-infectious factors, leading to uncontrolled self-destruction. Critically ill patients are prone to SIRS due to reduced compensatory anti-inflammatory capacity and metabolic disorders. A TNFα-induced SIRS disease model has been shown in long-term studies to be highly correlated with RIPK1-dependent necroptosis. Inflammatory bowel disease (IBD) refers to abnormal immune-mediated intestinal inflammation caused by environmental, genetic, infectious, and immune factors. It is a chronic, non-specific inflammatory bowel disease. Its pathogenesis is still unclear, but excessive apoptosis of intestinal epithelial cells, damage to the intestinal mucosal barrier, and increased permeability of intestinal epithelial cells are considered to be among the causes of IBD. Studies have shown that programmed necrosis plays an important role in the pathogenesis of IBD. Furthermore, programmed necrosis plays a crucial role in the pathogenesis of various autoimmune diseases, including 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 against Aβ-induced programmed necrosis of neurons in vitro. Besides Alzheimer's disease, programmed necrosis is also involved in the development of numerous 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 in vascular endothelial cells, subsequently allowing tumor cells to cross the blood vessel wall and metastasize to distant sites via blood circulation. This is a significant cause of tumor metastasis, and 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, while RIPK1 inhibition can lead to the differentiation of immunogenic macrophages in the pancreatic cancer tumor microenvironment, thereby resulting in adaptive immune activation and tumor protection.

[0005] Mixed lineage kinases (MLKs) are MAPK kinases that target JNK and p38MAPK and are activated in response to various stimuli that cause cellular stress. Thus, MLKs regulate a wide range of cellular processes. The MLK family consists of six members: MLK1, MLK2, MLK3, MLK6, double leucine zipper kinase (DLK), and leucine zipper kinase (LZK). MLK2 is also known as MST. MLK3 is the most widely expressed member of the MLK family and is found in neurons and resident mononuclear phagocytes in the brain.

[0006] MLK3 can modulate neuroinflammation by influencing cytokines produced by microglia and brain macrophages. In particular, CEP-1347-mediated MLK3 inhibition leads to a significant reduction in the release of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 from Tat-stimulated macrophages and microglia. The potent brain-permeable MLK3 inhibitor URMC-099 has been shown to be effective in protecting normal synaptic structure and reversing neuroinflammation in vivo after CNS exposure to HIV-1 Tat (Journal of Neuroscience the Official Journal of the Society for Neuroscience 33.24(2013): 9998-10010.).

[0007] Blocking the MLK3 pathway may interfere with the neurotoxic effects of β-amyloid oligomers and inhibit tau hyperphosphorylation in cultured hippocampal neurons with C-jun / JNK pathway blockade (Journal of Neuroscience, 2009, 29(28): 9078-9089). Therefore, MLK3 inhibitors may be valuable for the treatment of Alzheimer's disease and other neurodegenerative diseases involving the C-jun / JNK pathway.

[0008] MLK3 inhibition can also be used to treat a variety of cancers, such as pancreatic and breast cancers. MLK3 regulates the proliferation of some tumor cell types that overexpress MLK3, including human schwannomas and meningiomas and breast cancer cells (Oncogene 29.31(2010):4399-4411).

[0009] In summary, RIPK1 and MLK are important therapeutic targets for diseases related to programmed cell death, such as inflammation, autoimmune diseases, neurodegenerative diseases, and tumors. RIPK1 inhibitors are expected to become potential therapeutic drugs for these diseases. Summary of the Invention

[0010] The purpose of this invention is to provide a novel class of RIPK1 kinase inhibitors.

[0011] A first aspect of the present invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof:

[0012]

[0013] In the formula.

[0014] X1 is selected from N or CH;

[0015] X2, X3, and X4 are each independently selected from N or CH, provided that at least one of X1, X2, and X3 is N;

[0016] R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkoxy or C 3-6 cycloalkyl, the C 1-6 Alkyl groups may optionally be replaced by halogens;

[0017] R 2 Selected from

[0018] Among them, R 4 Selected from C 1-6 Alkyl, C 5-8 Aryl, 8- to 12-membered partially unsaturated bicyclic, 5- or 6-membered monocyclic heteroaryl, wherein C 5-8 aryl, 8 to 12-membered partially unsaturated bicyclic, 5 or 6-membered monocyclic heteroaryl, optionally separated by one or more members selected from R 41 Substituents of the substituents;

[0019] R 41 Selected from halogen, cyano, -NR 4a R 4b C 1-6 Alkyl or C 3-6 cycloalkyl;

[0020] Ring F is selected from 5- or 6-membered monocyclic heteroaryl groups or 4- to 8-membered nitrogen-containing partially unsaturated heterocyclic groups;

[0021] R 2a R 2b R 2c R 2d Each is independently selected from hydrogen, tritium, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens or hydroxyl groups;

[0022] Or, R2b R 2c Together with the carbon atoms attached to it, they form C 3-6 Cycloalkyl or 4- to 12-membered heterocyclic alkyl;

[0023] Or, R 2a R 2b The carbon and nitrogen atoms attached to it together form 4 to 12-membered nitrogen-containing heterocyclic alkyl groups or 4 to 8-membered nitrogen-containing partially unsaturated heterocyclic groups;

[0024] Or, R 2b R 2d Together with the carbon atoms attached to it, they form C 3-6 Cycloalkyl or 4- to 12-membered heterocyclic alkyl;

[0025] The C 3-6 The cycloalkyl, 4- to 12-membered heterocycloalkyl, 4- to 12-membered nitrogen-containing heterocycloalkyl or 4- to 8-membered nitrogen-containing partially unsaturated heterocycloalkyl group is optionally substituted by one or more substituents selected from halogens;

[0026] t1, t2, and t3 are each independently selected from integers between 0 and 6:

[0027] R 3 Selected from 4- to 12-membered heterocyclic alkyl groups, -NH-C 1-6 Alkyl, -NH-4 to 12-membered heterocyclic alkyl or -NH-C(O)R 5 The C 1-6 Alkyl or 4- to 12-membered heterocyclic alkyl groups optionally surrounded by one or more C 3-6 Cycloalkyl substitution;

[0028] R 5 Selected from hydrogen, tritium, and C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4- to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -NR 5a R 5b -C(O)OC 1-6 Alkyl, -C(O)NR 5a R 5b -NR 5a R 5b -C(O)OC 1-6 Alkyl, -C(O)-4 to 12-membered heterocyclic alkyl, -C 1-6 Alkyl-(OCH2CH2) m OCH3, -C 1-6 Alkyl NR 5a R 5b -C 1-6 Alkyl NH-C 1-6 Alkyl-OC1-6 Alkyl, -C 1-6 Alkyl-4 to 12-membered heterocyclic alkyl, -C 1-6 Alkyl-NH-4 to 12-membered heterocyclic alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-4 to 12-membered heterocyclic alkyl, or -C 1-6 alkyl-5 or 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4 to 12-membered heterocycloalkyl, 5 or 6-membered heteroaryl, optionally separated by one or more groups selected from tritium, halogen, cyano, oxo, hydroxyl, carboxyl, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 3-6 Substitution with a cycloalkyl or 4- to 12-membered heterocyclic alkyl group, wherein the C 1-6 Two hydrogen atoms on any one carbon atom of an alkyl group are substituted to form a C12 group. 3-6 cycloalkyl;

[0029] m is selected from integers from 1 to 4;

[0030] R 4a R 4b R 5a R 5b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl groups are optionally surrounded by one or more elements selected from halogens, hydroxyl groups, or C. 3-6 Substitution of cycloalkyl groups.

[0031] In one implementation scheme, R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0032] Preferably, R 1 Selected from C 1-6 Alkyl or -C 1-3 Alkyl-C 1-3 Alkoxy;

[0033] Preferably, R 1 Selected from methyl, ethyl or -CH2CH2OCH3.

[0034] In one embodiment, t1, t2, and t3 are each independently selected from 0, 1, 2, or 3;

[0035] In one implementation scheme, R 2 Selected from

[0036] R 4 Selected from C 1-6 alkyl, Wherein R 41 Define compounds of formula (I); X 5 Selected from N, O, or S;

[0037] Preferably, R 41 Selected from halogen, cyano, or amino groups;

[0038] Preferably, R 41 Selected from fluorine, chlorine, or cyano groups;

[0039] Preferably, ring F is selected from 5- or 6-membered monocyclic heteroaryl or 4- to 8-membered nitrogen-containing partially unsaturated heterocyclic groups, wherein the 5- or 6-membered monocyclic heteroaryl or 4- to 8-membered nitrogen-containing partially unsaturated heterocyclic group optionally contains 1, 2, or 3 heteroatoms selected from N or O atoms as ring atoms;

[0040] Preferably, ring F is selected from 5- or 6-membered monocyclic heteroaryl or 4- to 6-membered nitrogen-containing partially unsaturated heterocyclic groups, wherein the 5- or 6-membered monocyclic heteroaryl or 4- to 8-membered nitrogen-containing partially unsaturated heterocyclic group optionally contains 1, 2, or 3 heteroatoms selected from N or O atoms as ring atoms;

[0041] Preferably, ring F is selected from triazolyl or dihydrooxazolyl.

[0042] In one implementation scheme, R 2a R 2b R 2c R 2d Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, halogen-substituted C 1-6 alkyl or hydroxy substituted C 1-6 Alkyl; more preferably hydrogen, deuterium, halogen, methyl, ethyl, fluoroethyl, difluoroethyl or hydroxymethyl;

[0043] Preferably, R 2a Selected from hydrogen, deuterium, or methyl;

[0044] Preferably, R 2b R 2c R 2d Each is independently selected from methyl, ethyl, fluoroethyl, difluoroethyl, or hydroxymethyl;

[0045] Preferably, R2b R 2c Together with the carbon atoms attached to it, they form C 3-6 Cycloalkyl or 4- to 12-membered heterocyclic alkyl;

[0046] Preferably, R 2b R 2c Together with the carbon atoms attached to it, they form C 3-6 Cycloalkyl or 4- to 12-membered heterocyclic alkyl;

[0047] Preferably, R 2b R 2c The carbon atoms attached thereto form a 4- to 8-membered heterocyclic alkyl group, wherein the 4- to 8-membered heterocyclic alkyl group optionally contains one or two heteroatoms selected from N, O or S as ring atoms;

[0048] Preferably, the 4- to 12-membered heterocyclic alkyl group is a 4- to 6-membered oxygen-containing heterocyclic alkyl group, more preferably an oxocyclic butyl group;

[0049] Or, R 2a R 2b The carbon and nitrogen atoms attached thereto together form a 4 to 12-membered nitrogen-containing heterocyclic alkyl group or a 4 to 8-membered nitrogen-containing partially unsaturated heterocyclic group, wherein the 4 to 12-membered nitrogen-containing heterocyclic alkyl group is preferably an azacyclopentyl or morpholinyl; the 4 to 8-membered nitrogen-containing partially unsaturated heterocyclic group is preferably a dihydropyrazolyl, wherein the azacyclopentyl is optionally substituted by one or more halogens;

[0050] Or, R 2b R 2d Together with the carbon atoms attached to it, they form C 3-6 Cycloalkyl groups, preferably cyclopropyl groups;

[0051] Preferably, R 2 Selected from

[0052] In one implementation scheme, R 3 Selected from 4- to 6-membered heterocyclic alkyl groups, -NH-C 1-6 Alkyl, -NH-4 to 12-membered heterocyclic alkyl or -NH-C(O)R 5 The C 1-6 Alkyl groups are optionally surrounded by one or more Cs 3-6 Cycloalkyl substitution, wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted with one or more oxo groups;

[0053] Preferably, R 3 Selected from morpholino or oxomorpholino;

[0054] Preferably, R 3Selected from -NH-isopropyl, -NH-CH2-cyclopropyl, or -NH-tetrahydrofuran-3-yl;

[0055] Preferably, R 5 Selected from methyl, ethoxy, -CH2CH2COOH, -CH2Cl, -CH2CN, -CH2OCH3, -CH(CH3)OCH3, -C(O)OCH2CH3, -C(O)NH2, -CH2(OCH2CH2)2OCH3, -CH2(OCH2CH2)3OCH3,

[0056]

[0057] In one implementation scheme, R 3 Selected from:

[0058]

[0059]

[0060] Preferably, R 3 Selected from:

[0061]

[0062]

[0063] Among them, X 6 X 7 X 8 X 9 Each is independently selected from N, NH, O, S, CH or CH2;

[0064] t4 and t5 are each independently selected from integers from 0 to 6;

[0065] t6 and t7 are each independently selected from 0, 1, or 2;

[0066] R 3a R 3b R 3c R 3d R 3e R 3f R 3g Each is independently selected from hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, carboxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, -(OCH2CH2) m OCH3, -NRX3a R X3b -C(O)R X3c The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from halogen, hydroxyl, C 1-6 Substitution of alkoxy groups;

[0067] Or, R 3d R 3e Together with the carbon atoms attached to it, they form C 3-6 cycloalkyl;

[0068] R X3a R X3b R X3c Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0069] m is selected from an integer from 1 to 4; preferably 2 or 3.

[0070] In one implementation scheme, R 3a Selected from hydrogen, deuterium, oxo group or C 1-6 Alkyl group; preferably derived from hydrogen, oxo group or methyl group;

[0071] Preferably, R 3b Selected from hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, -C(O)C 1-6 Alkyl, -C(O)C 3-6 cycloalkyl, C 3-6 Cycloalkyl or 4- to 12-membered heterocyclic alkyl; the 4- to 12-membered heterocyclic alkyl optionally contains 1, 2 or 3 heteroatoms selected from N or O as ring atoms;

[0072] Preferably, R 3b Selected from hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, carboxyl, methyl, methoxy, -CH2OH, -C(O)CH3, -C(O)cyclopropyl, cyclopropyl or morpholino;

[0073] Preferably, R 3c Selected from hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, carboxyl, amino, and -(OCH2CH2). m OCH3, -NR X3a R X3b C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C1-6 Alkyl, C 3-6 Cycloalkyl, halogen-substituted C 3-6 cycloalkyl, the C 1-6 Alkyl or C 1-6 Alkyl groups are optionally surrounded by one or more molecules selected from hydroxyl, C 1-6 Substitution of alkoxy groups;

[0074] Preferably, R 3c Selected from hydrogen, deuterium, halogen, cyano, oxo, hydroxyl, carboxyl, amino, dimethylamino, diethylamino, trifluoromethyl, methoxy, ethoxy, isopropyl, cyclopropyl, halogen-substituted cyclopropyl, -CH(OCH3)2, -OCH2CH2OH, -(OCH2CH2)2OCH3 or -(OCH2CH2)3OCH3;

[0075] Or, R 3d R 3e Together with the carbon atoms attached to it, they form C 3-6 cycloalkyl; preferably, R 3d R 3e The carbon atom attached to it forms a cyclopropyl group.

[0076] In one embodiment, R 3f It is hydrogen.

[0077] In one embodiment, the compound of formula (I) is the compound of formula (II):

[0078]

[0079] In the formula, X 1 R 1 R 2 Each is a custom compound of formula (I);

[0080] R 6 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4- to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -C(O)NR 5a R 5b -C(O)OC 1-6 Alkyl or -C(O)-4 to 12-membered heterocyclic alkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 12-membered heterocycloalkyl, 5 or 6-membered heteroaryl, optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, carboxyl, cyano, C 1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy, C3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 3-6 Substitution with a cycloalkyl or 4- to 12-membered heterocyclic alkyl group, wherein the C 1-6 Two hydrogen atoms on any one carbon atom of an alkyl group are substituted to form a C12 group. 3-6 cycloalkyl;

[0081] R 5a R 5b Each is independently selected from hydrogen and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl groups are optionally oxidized by one or more halogens or C 3-6 Cycloalkyl substitution.

[0082] In one embodiment, R 6 Selected from methyl, ethoxy, -CH2CH2COOH, -CH2Cl, -CH2CN, -CH2OCH3, -CH(CH3)OCH3, -C(O)OCH2CH3、-C(O)NH2 -CH2-(OCH2CH2)2OCH3, -CH2(OCH2CH2)3OCH3,

[0083] In one embodiment, the compound of formula (I) is the compound shown in formula (III):

[0084]

[0085] In the formula, X 1 R 1 R 2 Each is a custom compound of formula (I);

[0086] R 7 Selected from -NR 5a R 5b -(OCH2CH2) m OCH3, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, -4 to 12-membered heterocyclic alkyl, -NH-4 to 12-membered heterocyclic alkyl, -NH-C 1-6 Alkyl-4 to 12-membered heterocyclic alkyl or 5 or 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 12-membered heterocycloalkyl, 5 or 6-membered heteroaryl, optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, carboxyl, cyano, C1-6 Alkyl, -C 1-6 Alkyl-OH, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 3-6 Substitution with cycloalkyl or 4- to 12-membered heterocyclic alkyl groups;

[0087] R 5a R 5b Each is independently selected from hydrogen and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl groups are optionally oxidized by one or more halogens or C 3-6 Cycloalkyl substitution.

[0088] In one embodiment, R 7 Selected from

[0089]

[0090] In one embodiment, the compound of formula (III) is the compound shown in formula (IIIa):

[0091]

[0092] In the formula, X 1 R 1 R 2 Each is a custom compound of formula (I);

[0093] R 71 R 72 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 alkoxy, 4- to 12-membered heterocyclic alkyl, 5- or 6-membered heteroaryl, wherein the C 1-6 Alkyl groups are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkoxy, C 3-6 Substitution with cycloalkyl, 4- to 12-membered heterocycloalkyl or -CH(OCH3)2 groups.

[0094] In one embodiment, the compound of formula (III) is the compound shown in formula (IIIb):

[0095]

[0096] In the formula, X 1 R 1 R 2Each is a custom compound of formula (I);

[0097] Ring G is selected from 5- or 6-membered nitrogen-containing heteroaryl groups or 5 to 12-membered nitrogen-containing heterocyclic alkyl groups;

[0098] R 8 Selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl or -C(O)-C 3-6 cycloalkyl;

[0099] p is selected from 0, 1, 2 or 3, preferably 1 or 2;

[0100] Preferably, R 8 Selected from hydrogen, fluorine, cyano, hydroxyl, carboxyl, oxo, methyl, methoxy, hydroxymethyl, -C(O)CH3, -C(O)-cyclopropyl or -C(O)OCH(CH3)3;

[0101] In one embodiment, ring G is selected from...

[0102]

[0103] Among them, X b Let N, X c X d Each is independently selected from CH2, NH, N, O, or S;

[0104] q is selected from 1, 2 or 3, preferably 1 or 2.

[0105] Preferably, ring G is selected from

[0106] In one embodiment, the 4- to 12-membered heterocyclic alkyl group is selected from 4- to 7-membered monocyclic heterocyclic alkyl groups, 6- to 8-membered bicyclic heterocyclic alkyl groups, 6- to 10-membered bridged heterocyclic alkyl groups, or 6- to 10-membered spirocyclic alkyl groups; the 4- to 7-membered monocyclic heterocyclic alkyl group, 6- to 8-membered bicyclic heterocyclic alkyl group, 6- to 10-membered bridged heterocyclic alkyl group, or 6- to 10-membered spirocyclic alkyl group preferably contains 1, 2, or 3 heteroatoms selected from N, S, or O as ring atoms.

[0107] In one embodiment, the 4- to 12-membered heterocyclic alkyl group is selected from...

[0108] Among them, X a X b Xc X d Each is independently selected from CH2, NH, N, O or S; q is selected from 1, 2 or 3, preferably 1 or 2.

[0109] Preferably, X b Let N be the number of elements in the array.

[0110] Preferably, the 4 to 12-membered heterocyclic alkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, oxetyl, oxetyl, oxetyl, isoxazolyl, morpholinyl, oxazhepyl, oxet ...

[0111] Preferably, the 4- to 12-membered heterocyclic alkyl group is selected from...

[0112] In one embodiment, the 5- or 6-membered heteroaryl group is selected from 5- or 6-membered nitrogen-containing heteroaryl groups, wherein the 5- or 6-membered nitrogen-containing heteroaryl group optionally includes 1, 2 or 3 nitrogen atoms as atoms;

[0113] Preferably, the 5- or 6-membered heteroaryl group is selected from imidazolyl, pyrazolyl, triazolyl, or pyridyl;

[0114] Preferably, the 5- or 6-membered heteroaryl group is selected from...

[0115] This invention provides the following compounds, their pharmaceutically acceptable salts, solvates, or stereoisomers:

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125] In another aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0126] In another aspect of the present invention, the use of the aforementioned compounds, their pharmaceutically acceptable salts, solvates, stereoisomers, or pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of inflammation, autoimmune diseases, neurodegenerative diseases, and tumor-related diseases is provided.

[0127] Preferred use is in the preparation of medicaments for treating tumor-related diseases.

[0128] In another aspect of the invention, the use of the aforementioned compounds, their pharmaceutically acceptable salts, solvates, stereoisomers, or pharmaceutical compositions in the preparation of RIPK1 and / or MLK inhibitors is provided.

[0129] Preferably, the MLK inhibitor is an MLK2 / 3 inhibitor.

[0130] A method for preventing and / or treating inflammation, autoimmune diseases, neurodegenerative diseases, and tumor-related diseases, comprising the step of administering the aforementioned compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutical composition thereof to a patient in need.

[0131] Preferably, the procedure includes administering a therapeutically effective amount of the aforementioned compound, its pharmaceutically acceptable salt, solvate, stereoisomer, or pharmaceutical composition to a patient in need. Detailed Implementation

[0132] I. Definition

[0133] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the related terms and laboratory procedures used herein are all widely used terms and routine procedures in the respective fields. To better understand this invention, definitions and explanations of related terms are provided below.

[0134] As used herein and unless otherwise stated, the terms “about” or “approximately” mean within 10% of a given value or range. Where an integer is required, the term means within 10% of a given value or range, rounded up or down to the nearest integer.

[0135] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is 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.

[0136] As used herein and unless otherwise stated, the terms “comprising,” “including,” “having,” “containing,” and their grammatical equivalents, including their grammatical equivalents, should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps.

[0137] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include: salts formed by addition to an inorganic acid or an organic acid, such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, mucoacinic acid, etc.; or salts formed when an acidic proton present on the parent compound is replaced by a metal ion, such as an alkali metal ion or an alkaline earth metal ion; or coordination compounds formed with an organic base, such as ethanolamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid radical or a base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in their free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In addition to the salt form, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention in the in vivo environment via chemical or biochemical methods.

[0138] As used herein, the term "solvent" refers to a substance formed by combining a compound of the present invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include acetic acid, etc. Solvents include stoichiometric solvates and non-stoichiometric solvates. Some compounds of the present invention may exist in either a solvated or non-solventized form. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of the present invention.

[0139] As used in this text, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers primarily include cis-trans isomers and optical isomers. The compounds of this invention can exist in stereoisomer form and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, and trans-blocked isomers. The compounds of this invention can also exist in any combination or mixture of the aforementioned stereoisomers, such as meso compounds, racemic compounds, and equal mixtures of trans-blocked isomers. Examples include a single enantiomer, a single diastereomer or a mixture of more than one, or a single trans-blocked isomer or a mixture thereof. When the compounds of this invention contain an olefinic double bond, unless otherwise specified, they include cis and trans isomers, and any combination thereof. The trans-blocked isomers of this invention are stereoisomers with axial or planar chirality resulting from restricted intramolecular rotation. Furthermore, stereoisomers with excellent activity are preferred as pharmaceuticals. The compounds of the present invention have optical isomers derived from asymmetric carbon, etc., and if necessary, a single isomer can be obtained by separation by methods known in the art, such as crystallization or chiral chromatography.

[0140] As used herein, the term "heteroatom" is selected from nitrogen, oxygen, or sulfur. Nitrogen may optionally be substituted; sulfur may also optionally be substituted, for example, by oxygenation, to form S(O)m3 (where m3 is an integer from 0 to 2).

[0141] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. The term "C"... 1-20 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 20 carbon atoms. Preferably, it is C10. 1-10 Alkyl group. More preferably C10. 1-6 Alkyl groups (i.e., straight-chain or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms). More preferably, C10 is used. 1-4 Alkyl group. More preferably C10. 1-3 Alkyl groups. 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 their various branched isomers.

[0142] As used herein, the term "alkoxy" refers to a group having an -O-alkyl structure, wherein the definition of alkyl is as described above. The term "C" 1-6"Alkoxy group" refers to an alkoxy group having 1 to 6 carbon atoms. Preferably, it is C64-66. 1-4 Alkyl groups, more preferably C 1-3 Alkyl groups. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, and n-pentoxy.

[0143] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group, including, for example, monocyclic cycloalkyl, spirocyclic cycloalkyl, fused cycloalkyl, and bridged cycloalkyl. The cycloalkyl group described in this invention may optionally have its cyclic carbon atom replaced by one, two, or three oxo groups to form a cyclic ketone structure. The terms "3- to 20-membered cycloalkyl" or "C" are also used. 3-20 "Cycloalkyl" refers to a cycloalkyl group having 3 to 20 ring carbon atoms, including monocyclic cycloalkyl, spirocyclic cycloalkyl, fused cycloalkyl, and bridged cycloalkyl. Preferably, it has 3 carbon atoms. 3-12 cycloalkyl, C 5-20 Spirocycloalkyl, C 5-20 fused cycloalkyl or C 5-20 Bridged cycloalkyl. More preferably C 3-8 Monocyclic cycloalkyl.

[0144] As used herein, the term "spirocycloalkyl" refers to a saturated or partially unsaturated polycyclic cyclic hydrocarbon group in which the rings share a single carbon atom (called a spiro atom). The term "spiroheterocycloalkyl" refers to a spirocycloalkyl group containing at least one of a C atom and a heteroatom such as N, O, or S as a ring member. Non-limiting examples of spiroheterocycloalkyl groups include:

[0145]

[0146] As used herein, the term "bridged cycloalkyl" refers to a saturated or partially unsaturated polycyclic cyclic hydrocarbon group in which any two rings share two non-directly connected carbon atoms. The term "bridged heterocyclic alkyl" refers to a bridged cycloalkyl group containing at least one of a C atom and a heteroatom such as N, O, or S as ring members.

[0147] As used herein, the term "heterocyclic alkyl" refers to a saturated ring substituent containing heteroatoms on a ring backbone, wherein one or more (preferably 1 to 4, 1 to 3, or 1 to 2) ring atoms are heteroatoms selected from N, O, and S. The term "4 to 12-membered heterocyclic alkyl" refers to a saturated ring substituent optionally containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring atoms. The term "4 to 12-membered nitrogen-containing heterocyclic alkyl" means that one ring atom in a 4 to 12-membered heterocyclic alkyl group must be a nitrogen atom, and the remaining ring atoms are all carbon atoms, or that 0, 1, 2, or 3 of the remaining ring atoms are each independently a heteroatom selected from N, O, and S. The "4 to 12-membered nitrogen-containing heterocyclic alkyl" is preferably linked to the rest of the molecule through the required nitrogen atom.

[0148] As used herein, the term "partially unsaturated heterocycle" refers to a cyclic group comprising at least one heteroatom selected from C and N, O, S, etc., as ring members, wherein the bicyclic group is partially unsaturated and contains at least one C-C double bond, preferably one C-C double bond. As used herein, the term "partially unsaturated bicycle" includes both "partially unsaturated bicyclic carbocyclic rings" and "partially unsaturated bicyclic heterocycles," wherein the term "partially unsaturated bicyclic carbocyclic ring" refers to a bicyclic group comprising only C atoms as ring members, wherein the bicyclic group is partially unsaturated and contains at least one C-C double bond, the largest unsaturated carbocyclic ring containing the most conjugated C-C double bonds allowed by the ring size, and the partially unsaturated bicyclic carbocyclic ring containing fewer C-C double bonds than the largest allowed by the ring size. The "partially unsaturated bicyclic carbocyclic ring" is preferably composed of C... 5-8 An aryl group is fused with a 5- or 6-membered monocyclic ring to form the aryl group, wherein the 5- or 6-membered monocyclic ring is selected from the group consisting of:

[0149]

[0150] As used herein, the term "partially unsaturated bicyclic heterocycle" refers to a bicyclic group that comprises at least one of a C atom and a heteroatom such as N, O, or S as ring members, and that is partially unsaturated, containing at least one C-C double bond. The most unsaturated heterocycle contains the maximum number of C-C double bonds allowed by the ring size, as well as double bonds between the C atom and the heteroatom. The partially unsaturated bicyclic heterocycle contains fewer double bonds than allowed by the ring size.

[0151] As used herein, the term "aryl" refers to an all-carbon monocyclic, all-carbon non-fused polycyclic (rings connected by covalent bonds, not fused), or all-carbon fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group, wherein at least one ring in the group is aromatic, i.e., has a conjugated π-electron system. The term "C" 6-14 "Aryl" refers to an aryl group having 6 to 14 ring atoms. C is preferred. 6-10 Aryl. In this invention, C 6-14 Aryl groups include monocyclic aryl groups, non-fused polycyclic aryl groups, and aromatic fused polycyclic groups. Examples of monocyclic aryl groups include phenyl groups, and examples of non-fused polycyclic aryl groups include biphenyl groups.

[0152] As used herein, the term "5- or 6-membered monocyclic heteroaryl" refers to a group having 5 or 6 ring atoms, of which 1, 2, or 3 ring atoms are selected from nitrogen, oxygen, or S (=O). mMonocyclic heteroaryl groups with heteroatoms (where 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, tetrazolium, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.

[0153] "Optionally substituted by one or more..." means that it can be substituted by one or more specified substituents (preferably 1, 2 or 3), or it can be unsubstituted; the "multiple" in "one or more" is not limited, and the minimum value is 2, and the maximum value is the number of substituted sites of the substituted group.

[0154] If a substituent is described as being "selected from" or "independently selected from" a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (or other) substituent.

[0155] "Substitution" refers to the replacement of hydrogen atoms in a molecule with other different groups.

[0156] “Element” refers to the number of skeleton atoms that make up the ring.

[0157] In this invention, "key" refers to a single connection key at that location, or it can be understood as "none".

[0158] "Azacycloalkyl" refers to cycloalkyl groups whose ring skeleton contains nitrogen atoms.

[0159] "Bridged cycloalkyl" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.

[0160] "Spirocycloalkyl" refers to a heterocyclic alkyl group in which two carbon rings in the molecule share a carbon atom, and the shared carbon atom is called "spirocarbon atom".

[0161] Unless otherwise specified, the rings formed by "linking together" in this invention include unsubstituted rings and rings substituted with substituents.

[0162] "Alkoxy" refers to -O-alkyl.

[0163] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0164] “(O)” or “oxy group” means =O.

[0165] This represents the location of a chemical bond.

[0166] Although the term "optionally substituted" is not used, if substitution occurs at any position on a ring (e.g., an aliphatic or aromatic ring), it should be understood that the position and number of substitutions are arbitrary, as long as it is chemically feasible.

[0167] II. Examples

[0168] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be described in further detail below. The described embodiments should not be considered as limitations on the invention. All other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0169] Before providing a further detailed description of the embodiments of the present invention, the nouns and terms involved in the embodiments of the present invention will be explained, and the nouns and terms involved in the embodiments of the present invention shall be interpreted as follows.

[0170] The raw materials and equipment used in the specific embodiments of this disclosure are all known products, obtained by purchasing commercially available products.

[0171] Preparation example:

[0172] Preparation of intermediate INT-1:

[0173]

[0174] Preparation of intermediate INT-1-2: methyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole-3-carboxylic acid ester:

[0175] Under argon protection, intermediate INT-1-1 (1335 mg, 5.0 mmol) and pinacol diborate (1651 mg, 6.5 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of potassium acetate (4.9 g, 10.0 mmol) and PdCl2(dppf)2 (160 mg). The mixture was purged three times with argon, heated to 100 °C, and stirred for 10 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate INT-1-2 in 80% yield. MS (ESI, positive ion) m / z: 316.3 [M+H] + .

[0176] Preparation of intermediate INT-1-3: methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indole-3-carboxylic acid:

[0177] Under argon protection, intermediate INT-1-2 (1260 mg, 4.0 mmol) and 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (848 mg, 4.0 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of potassium phosphate (1.7 g, 8.0 mmol), PdCl2(dppf)2 (120 mg), and water (2.0 mL). The mixture was purged three times with argon, heated to 95 °C, and stirred for 8 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain intermediate INT-1-3 in 70% yield. MS (ESI, positive ion) m / z: 322.2 [M+H] + .

[0178] Preparation of intermediate INT-1: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indole-3-carboxylic acid:

[0179] Intermediate INT-1-3 (963 mg, 3.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.96 g, 24 mmol) was added, and the mixture was heated to 75 °C and stirred for 5 h. The pH was adjusted to weakly acidic with dilute hydrochloric acid (1 M), filtered, and dried to obtain intermediate INT-1 in 92% yield. MS (ESI, positive ion) m / z: 308.3 [M+H] + .

[0180] Preparation of intermediate INT-2:

[0181]

[0182] Preparation of intermediate INT-2-2: methyl 5-bromo-1-ethyl-1H-indole-3-carboxylic acid:

[0183] Intermediate INT-1-1 (2.0 g, 8.0 mmol) was dissolved in N,N-dimethylformamide (20 mL). Iodoethane (2.5 g, 16.0 mmol) and sodium hydride (640 mg, 16 mmol, 60%) were added under ice bath conditions, and the mixture was stirred at room temperature for 2 h. 20 mL of water was added under ice bath conditions, and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give intermediate INT-2-2 in 83% yield. MS (ESI, positive ion) m / z: 282.2. [M+H] + .

[0184] Preparation of intermediate INT-2-3: methyl 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-1H-indole-3-carboxylic acid:

[0185] Under argon protection, intermediate INT-2-2 (1.4 g, 5.0 mmol) and pinacol diborate (1651 mg, 6.5 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium acetate (4.9 g, 10.0 mmol) and PdCl2(dppf)2 (160 mg) were added. The mixture was purged with argon three times, heated to 100 °C, and stirred for 10 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate INT-2-3 in 80% yield. MS (ESI, positive ion) m / z: 330.4 [M+H] + .

[0186] Preparation of intermediate INT-2-4 methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-ethyl-1H-indole-3-carboxylic acid:

[0187] Under argon protection, intermediate INT-2-3 (1.3 g, 4.0 mmol) and 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (848 mg, 4.0 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of potassium phosphate (1.7 g, 8.0 mmol), PdCl2(dppf)2 (120 mg), and water (2.0 mL). The mixture was purged three times with argon, heated to 95 °C, and stirred for 8 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain intermediate INT-2-4 in 70% yield. MS (ESI, positive ion) m / z: 322.2 [M+H] + .

[0188] Preparation of intermediate INT-2: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-ethyl-1H-indole-3-carboxylic acid:

[0189] Intermediate INT-2-4 (1.0 g, 3.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.96 g, 24 mmol) was added, and the mixture was heated to 75 °C and stirred for 5 h. The pH was adjusted to weakly acidic with dilute hydrochloric acid (1 M), filtered, and dried to obtain intermediate INT-2, with a yield of 92%. MS (ESI, positive ion) m / z: 322.2 [M+H] + .

[0190] Preparation of intermediate INT-3:

[0191]

[0192] Preparation of intermediate INT-3: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide:

[0193] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-(4-fluorophenyl)ethane-1-amine (167 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-3 in 70% yield. MS (ESI, positive ion) m / z: 429.3 [M+H] + .

[0194] Preparation of intermediate INT-4:

[0195]

[0196] Preparation of intermediate INT-4: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide:

[0197] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-(3-fluorophenyl)ethane-1-amine (167 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-4 in 71% yield. MS (ESI, positive ion) m / z: 429.3 [M+H] + .

[0198] Preparation of intermediate INT-5:

[0199]

[0200] Preparation of intermediate INT-5: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-indole-3-carboxamide:

[0201] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-6-fluoro-2,3-dihydro-1H-indene-1-amine (181 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-5 in 73% yield. MS (ESI, positive ion) m / z: 441.2 [M+H] + .

[0202] Preparation of intermediate INT-6:

[0203]

[0204] Preparation of intermediate INT-6: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-methyl-1H-indole-3-carboxamide:

[0205] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (1R,2S)-2-(3,4-difluorophenyl)cyclopropane-1-amine (202 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-6-2 in 68% yield. MS (ESI, positive ion) m / z: 459.3 [M+H] + .

[0206] Preparation of intermediate INT-7:

[0207]

[0208] Preparation of intermediate INT-7: (R)-5-(2-amino-[1,2,4]triazol-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-indole-3-carboxamide[1,5-a]pyridin-7-yl):

[0209] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then, (R)-5-fluoro-2,3-dihydro-1H-indene-1-amine (181 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-7 in 68% yield. MS (ESI, positive ion) m / z: 443.3 [M+H] + .

[0210] Preparation of intermediate INT-8:

[0211]

[0212] Preparation of intermediate INT-8: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-indole-3-carboxamide:

[0213] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-amino-2,3-dihydro-1H-inden-5-onitrile (181 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-8 in 66% yield. MS (ESI, positive ion) m / z: 448.3 [M+H] + .

[0214] Preparation of intermediate INT-9:

[0215]

[0216] Preparation of intermediate INT-9: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(6-fluoro-1,2,3,4-tetrahydronaphth-1-yl)-1-methyl-1H-indole-3-carboxamide:

[0217] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-6-fluoro-1,2,3,4-tetrahydronaphthyl-1-amine (198 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-9, with a yield of 69%. MS (ESI, positive ion) m / z: 455.3 [M+H] + .

[0218] Preparation of intermediate INT-10:

[0219]

[0220] Preparation of intermediate INT-10: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(7-fluoro-1,2,3,4-tetrahydronaphth-1-yl)-1-methyl-1H-indole-3-carboxamide:

[0221] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-7-fluoro-1,2,3,4-tetrahydronaphthyl-1-amine (198 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-10, with a yield of 68%. MS (ESI, positive ion) m / z: 455.3 [M+H] + .

[0222] Preparation of intermediate INT-11:

[0223]

[0224] Preparation of intermediate INT-11: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-indole-3-carboxamide:

[0225] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-5,6-difluoro-2,3-dihydro-1H-indene-1-amine (203 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-11, with a yield of 65%. MS (ESI, positive ion) m / z: 459.3 [M+H] + .

[0226] Preparation of intermediate INT-12:

[0227]

[0228] Preparation of intermediate INT-12: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-fluorophenyl)oxetane-3-yl)-1-methyl-1H-indole-3-carboxamide:

[0229] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then, 3-(4-fluorophenyl)oxetane-3-amine (200 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. After filtration and drying, intermediate INT-12 was obtained, with a yield of 65%. MS (ESI, positive ion) m / z: 457.3 [M+H] + .

[0230] Preparation of intermediate INT-13:

[0231]

[0232] Preparation of intermediate INT-13: (S)-(5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indol-3-yl)(3-(4-fluorophenyl)morpholino) ketone:

[0233] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-3-(4-fluorophenyl)morpholine (217 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-13, with a yield of 71%. MS (ESI, positive ion) m / z: 471.3 [M+H] + .

[0234] Preparation of intermediate INT-14:

[0235]

[0236] Preparation of intermediate INT-14: (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2-fluoro-1-(3-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide:

[0237] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (R)-2-fluoro-1-(3-fluorophenyl)ethane-1-amine (188 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-14, with a yield of 72%. MS (ESI, positive ion) m / z: 447.3 [M+H] + .

[0238] Preparation of intermediate INT-15:

[0239]

[0240] Preparation of intermediate INT-15: (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2-fluoro-1-(4-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide:

[0241] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (R)-2-fluoro-1-(4-fluorophenyl)ethane-1-amine (188 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-15 in 72% yield. MS (ESI, positive ion) m / z: 447.3 [M+H] + .

[0242] Preparation of intermediate INT-16:

[0243]

[0244] Preparation of intermediate INT-16: (S)-(5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indol-3-yl)(2-(4-fluorophenyl)pyrrolidine-1-yl) methyl ketone:

[0245] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-2-(4-fluorophenyl)pyrrolidine (198 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-16, with a yield of 73%. MS (ESI, positive ion) m / z: 455.3 [M+H] + .

[0246] Preparation of intermediate INT-17:

[0247]

[0248] Preparation of intermediate INT-17: (5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indol-3-yl)((2S)-4-fluoro-2-(4-fluorophenyl)pyrrolidine-1-yl) methyl ketone:

[0249] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (2S)-4-fluoro-2-(4-fluorophenyl)pyrrolidine (220 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-17 in 70% yield. MS (ESI, positive ion) m / z: 473.3 [M+H] + .

[0250] Preparation of intermediate INT-18:

[0251]

[0252] Preparation of intermediate INT-18: (S)-(5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indol-3-yl)(4,4-difluoro-2-(4-fluorophenyl)pyrrolidine-1-yl) methyl ketone:

[0253] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-4,4-difluoro-2-(4-fluorophenyl)pyrrolidine (241 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-18 in 70% yield. MS (ESI, positive ion) m / z: 491.3 [M+H] + .

[0254] Preparation of intermediate INT-19:

[0255]

[0256] Preparation of intermediate INT-19: (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-1-(4-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide:

[0257] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then, (R)-2,2-difluoro-1-(4-fluorophenyl)ethane-1-amine (210 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-19, with a yield of 70%. MS (ESI, positive ion) m / z: 464.3 [M+H] + .

[0258] Preparation of intermediate INT-20:

[0259]

[0260] Preparation of intermediate INT-20: (S)-(5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indol-3-yl)(5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl) methyl ketone:

[0261] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole (197 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-20, with a yield of 70%. MS (ESI, positive ion) m / z: 464.3 [M+H] + .

[0262] Preparation of intermediate INT-21:

[0263]

[0264] Preparation of intermediate INT-21: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-fluorophenyl)ethyl)-N,1-dimethyl-1H-indole-3-carboxamide:

[0265] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-(4-fluorophenyl)-N-methylethane-1-amine (184 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-21 in 70% yield. MS (ESI, positive ion) m / z: 443.3 [M+H] + .

[0266] Preparation of intermediate INT-22:

[0267]

[0268] Preparation of intermediate INT-22-2: 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole-3-amine:

[0269] Under argon protection, intermediate INT-22-1 (1.12 g, 5.0 mmol) and pinacol diborate (1651 mg, 6.5 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium acetate (4.9 g, 10.0 mmol) and PdCl2(dppf)2 (160 mg) were added. The mixture was purged with argon three times, heated to 100 °C, and stirred for 10 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate INT-22-2 in 70% yield. MS (ESI, positive ion) m / z: 273.3 [M+H] + .

[0270] Preparation of intermediate INT-22-3: 7-(3-amino-1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine:

[0271] Under argon protection, intermediate INT-22-2 (1.09 g, 4.0 mmol) and 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (848 mg, 4.0 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of potassium phosphate (1.7 g, 8.0 mmol), PdCl2(dppf)2 (120 mg), and water (2.0 mL). The mixture was purged three times with argon, heated to 95 °C, and stirred for 8 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain intermediate INT-22-3 in 61% yield. MS (ESI, positive ion) m / z: 279.2 [M+H] + .

[0272] Preparation of intermediate INT-22: N-(5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indol-3-yl)-2-(4-fluorophenyl)propionamide:

[0273] Intermediate INT-22-3 (278 mg, 1.0 mmol) and 2-(4-fluorophenyl)propionic acid (168 mg, 1.0 mmol) were dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 2 h. The reaction mixture was added dropwise to water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give intermediate INT-22 in 73% yield. MS (ESI, positive ion) m / z: 429.3. [M+H] + .

[0274] Preparation of intermediate INT-23:

[0275]

[0276] Preparation of intermediate INT-23-2: 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole-3-amine:

[0277] Under argon protection, intermediate INT-23-1 (1.12 g, 5.0 mmol) and pinacol diborate (1651 mg, 6.5 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium acetate (4.9 g, 10.0 mmol) and PdCl2(dppf)2 (160 mg) were added. The mixture was purged with argon three times, heated to 100 °C, and stirred for 10 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate INT-23-2 in 67% yield. MS (ESI, positive ion) m / z: 274.3 [M+H] + .

[0278] Preparation of intermediate INT-23-3: 7-(3-amino-1-methyl-1H-indazol-5-yl)-[1,2,4]triazol[1,5-a]pyridine-2-amine:

[0279] Under argon protection, intermediate INT-23-2 (1.09 g, 4.0 mmol) and 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (848 mg, 4.0 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of potassium phosphate (1.7 g, 8.0 mmol), PdCl2(dppf)2 (120 mg), and water (2.0 mL). The mixture was purged three times with argon, heated to 95 °C, and stirred for 8 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain intermediate INT-23-3 in 61% yield. MS (ESI, positive ion) m / z: 280.2 [M+H] + .

[0280] Preparation of intermediate INT-23: N-(5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indazol-3-yl)-2-(4-fluorophenyl)propionamide:

[0281] Intermediate INT-23-3 (278 mg, 1.0 mmol) and 2-(4-fluorophenyl)propionic acid (168 mg, 1.0 mmol) were dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 2 h. The reaction mixture was added dropwise to water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give intermediate INT-23 in 70% yield. MS (ESI, positive ion) m / z: 430.3. [M+H] + .

[0282] Preparation of intermediate INT-24:

[0283]

[0284] Preparation of intermediate INT-24: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-chlorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide:

[0285] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-(4-chlorophenyl)ethane-1-amine (186 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-24 in 70% yield. MS (ESI, positive ion) m / z: 445.1 [M+H] + .

[0286] Preparation of intermediate INT-25:

[0287]

[0288] Preparation of intermediate INT-25: (S)-5-(2-amino-[1,2,4]triazol-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-indole-3-carboxamide[1,5-a]pyridin-7-yl):

[0289] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-5-fluoro-2,3-dihydro-1H-indene-1-amine (181 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to obtain intermediate INT-25 in 68% yield. MS (ESI, positive ion) m / z: 443.3 [M+H] + .

[0290] Preparation of intermediate INT-26:

[0291]

[0292] Preparation of intermediate INT-26:

[0293] Intermediate INT-3 (42.8 g, 100 mmol) was dissolved in dichloromethane (1 L), and chloroacetyl chloride (13.5 g, 120 mmol) and N,N-diisopropylethylamine (25.8 g, 200 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give intermediate INT-26 in 82% yield. MS (ESI, positive ion) m / z: 505.2 [M+H] + .

[0294] Preparation of intermediate INT-27:

[0295]

[0296] Preparation of intermediate INT-27:

[0297] Intermediate INT-24 (44.4 g, 100 mmol) was dissolved in dichloromethane (1 L), and chloroacetyl chloride (13.5 g, 120 mmol) and N,N-diisopropylethylamine (25.8 g, 200 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give intermediate INT-27 in 78% yield. MS (ESI, positive ion) m / z: 521.2 [M+H] + .

[0298] Preparation of intermediate INT-28:

[0299]

[0300] Preparation of intermediate INT-28:

[0301] Intermediate INT-15 (44.6 g, 100 mmol) was dissolved in dichloromethane (1 L), and chloroacetyl chloride (13.5 g, 120 mmol) and N,N-diisopropylethylamine (25.8 g, 200 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give intermediate INT-28 in 75% yield. MS (ESI, positive ion) m / z: 523.2 [M+H] + .

[0302] Preparation of intermediate INT-29:

[0303]

[0304] Preparation of intermediate INT-29-2: methyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole-3-carboxylic acid ester:

[0305] Under argon protection, intermediate INT-29-1 (1335 mg, 5.0 mmol) and pinacol diborate (1651 mg, 6.5 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of potassium acetate (4.9 g, 10.0 mmol) and PdCl2 (dppf)22 (160 mg). The mixture was purged three times with argon, heated to 100 °C, and stirred for 10 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate INT-29-2 in 68% yield. MS (ESI, positive ion) m / z: 317.3 [M+H] + .

[0306] Preparation of intermediate INT-29-3: methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indazole-3-carboxylic acid:

[0307] Under argon protection, intermediate INT-29-2 (1260 mg, 4.0 mmol) and 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (848 mg, 4.0 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of potassium phosphate (1.7 g, 8.0 mmol), PdCl2(dppt)2 (120 mg), and water (2.0 mL). The mixture was purged three times with argon, heated to 95 °C, and stirred for 8 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain intermediate INT-29-3 in 70% yield. MS (ESI, positive ion) m / z: 323.2 [M+H] + .

[0308] Preparation of intermediate INT-29: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl).1-methyl-1H-indazole-3-carboxylic acid:

[0309] Intermediate INT-29-3 (963 mg, 3.0 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL), and water (15 mL). Sodium hydroxide (0.96 g, 24 mmol) was added, and the mixture was heated to 75 °C and stirred for 5 h. The pH was adjusted to weakly acidic with dilute hydrochloric acid (1 M), filtered, and dried to obtain intermediate INT-29 in 62% yield. MS (ESI, positive ion) m / z: 309.3 [M+H] +.

[0310] Example 1: Preparation of Compound 1:

[0311]

[0312] Preparation of compound 1-1:

[0313] Intermediate INT-3 (214 mg, 0.5 mmol) was dissolved in pyridine (2 mL), and 2-chloropropionic acid (65 mg, 0.6 mmol) and 1-propylphosphonic anhydride (316 mg, 1.0 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 1-1 in 61% yield. MS (ESI, positive ion) m / z: 519.2 [M+H] + .

[0314] Preparation of compound 1:

[0315] Compound 1-1 (100 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (S)-3-pyrrolidone (43 mg, 0.5 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 1 in 45% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0316] 1HNMR (400MHz, DMSO-d6) δ10.62 (s, 1H), 8.89 (dd, J=7.1, 0.8Hz, 1H), 8.56 (d, J=1.9Hz, 1H), 8.3 6 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d , J=8.6Hz, 1H), 7.48 (dd, J=7.4, 2.0Hz, 3H), 7.21-7.14 (m, 2H), 5.25-5.20 (m, 1H), 3.92 (s, 3H), 3.67 (m, 1H), 2.48-2.34 (m, 4H), 1.82-1.63 (m, 4H), 1.51 (d, J=7.1Hz, 3H), 1.29 (d, J=7.4Hz, 3H).

[0317] Example 2: Preparation of compound 2:

[0318]

[0319] Preparation of compound 2:

[0320] Compound 1-1 (100 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (43 mg, 0.5 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 1 in 62% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0321] 1 H NMR (400MHz, DMSO-d6) δ10.62 (s, 1H), 8.89 (dd, J=7.1, 0.8Hz, 1H), 8.56 (d, J=1.9Hz, 1H), 8.36 ( d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.48 (dd, J=7.4, 2.0Hz, 3H), 7.21-7.14 (m, 2H), 5.25-5.20 (m, 1H), 3.92 (s, 3H), 3 .67 (m, 1H), 3.48-3.34 (m, 4H), 2.82-2.63 (m, 4H), 1.51 (d, J = 7.1Hz, 3H), 1.29 (d, J = 7.4Hz, 3H).

[0322] Example 3: Preparation of compound 3:

[0323]

[0324] Preparation of compound 3:

[0325] (R)-4-hydroxy-2-pyrrolidone (101 mg, 1 mmol) was dissolved in dry tetrahydrofuran (2 mL), sodium hydrogen (80 mg, 2 mmol) was added, and after five minutes, intermediate INT-26 (252 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 3 h. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The solution was purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 3, in 41% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0326] 1H NMR (400MHz, DMSO-d6) δ10.62 (s, 1H), 8.89 (dd, J=7.1, 0.8Hz, 1H), 8.56 (d, J=1.9Hz, 1H), 8.36 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 ( d, J=8.6Hz, 1H), 7.48 (dd, J=7.4, 2.0Hz, 3H), 7.21-7.14 (m, 2H), 5.40 (s, 1H), 5.25-5.20 (m, 1H) ), 3.92 (s, 3H), 3.56-3.43 (m, 3H), 3.67-3.42 (m, 2H), 2.50-2.25 (m, 2H), 1.51 (d, J=7.1Hz, 3H).

[0327] Example 4: Preparation of compound 4:

[0328]

[0329] Preparation of compound 4:

[0330] (S)-4-hydroxy-2-pyrrolidone (101 mg, 1 mmol) was dissolved in dry tetrahydrofuran (2 mL), sodium hydrogen (80 mg, 2 mmol) was added, and after five minutes, intermediate INT-26 (252 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 3 h. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The solution was purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 4, in 43% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0331] 1H NMR (400MHz, DMSO-d6) δ10.62 (s, 1H), 8.89 (dd, J=7.1, 0.8Hz, 1H), 8.56 (d, J=1.9Hz, 1H), 8.36 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 ( d, J=8.6Hz, 1H), 7.48 (dd, J=7.4, 2.0Hz, 3H), 7.21-7.14 (m, 2H), 5.40 (s, 1H), 5.25-5.20 (m, 1H) ), 3.92 (s, 3H), 3.56-3.43 (m, 3H), 3.67-3.42 (m, 2H), 2.50-2.25 (m, 2H), 1.51 (d, J=7.1Hz, 3H).

[0332] Example 5: Preparation of compound 5:

[0333]

[0334] Preparation of compound 5:

[0335] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 4,4-piperidinediol hydrochloride (60 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 5 in 32% yield. MS (ESI, positive ion) m / z: 586.2 [M+H] + .

[0336] 1 H NMR (400MHz, DMSO-d6) δ10.62 (s, 1H), 8.89 (dd, J=7.1, 0.8Hz, 1H), 8.56 (d, J=1.9Hz, 1H), 8.36 ( d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J =8.6Hz, 1H), 7.48 (dd, J = 7.4, 2.0Hz, 3H), 7.21-7.14 (m, 2H), 5.25-5.20 (m, 1H), 3.92 (s, 3H), 3.4 6 (s, 2H), 2.92 (t, J = 6.0Hz, 4H), 2.55 (d, J = 6.8Hz, 2H), 2.48-2.34 (m, 4H), 1.51 (d, J = 7.1Hz, 3H).

[0337] Example 6: Preparation of compound 6:

[0338]

[0339] Preparation of compound 6:

[0340] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 4-piperidinol (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 6, yield 42%. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0341] 1 H NMR (400MHz, DMSO-d6) δ10.38 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.36 (d, J = 8.0Hz, 1 H), 8.22 (s, 1H), 7.90 (dd, J=1.9, 0.9Hz, 1H), 7.73 (d, J=1.9Hz, 1H), 7.68 (d, J=8.7Hz, 1H), 7.50-7.46 ( m, 3H), 7.17 (t, J = 8.9Hz, 2H), 5.28-5.18 (m, 1H), 4.58 (d, J = 4.2Hz, 1H), 3.92 (s, 3H), 3.55-3.45 (m, 1H) , 3.21 (s, 2H), 2.85-2.76 (m, 2H), 2.30 (t, J=10.2Hz, 2H), 1.76 (d, J=10.9Hz, 2H), 1.51 (d, J=7.0Hz, 5H).

[0342] Example 7: Preparation of Compound 7:

[0343]

[0344] Preparation of compound 7:

[0345] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and S-3-hydroxypiperidine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 7, yield 46%. MS (ESI, positive ion) m / z: 570.2 [M+H] +.

[0346] 1 H NMR (400MHz, DMSO-d6) δ10.42 (s, 1H), 8.89 (dd, J=7.1, 0.8Hz, 1H), 8.55 (d, J=1.8Hz, 1H), 8.36 (d, J=8.0Hz, 1H), 8.22 (s, 1H), 7.90 (dd, J=1.9, 0.9Hz, 1H), 7.74 (dd, J=8.7, 1.8Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.50-7.46 (m, 3H), 7.17 (t, J=8.9Hz, 2H), 5.28-5.18 (m , 1H), 4.74 (d, J=5.5Hz, 1H), 3.92 (s, 3H), 3.58 (dd, J=9.0, 4.6Hz, 1H), 3.22 (d, J=8.7Hz, 2H), 2.83 (d, J=9.6Hz, 1H), 2.66 (dd, J=15 .1, 9.2Hz, 1H), 2.23 (t, J=10.2Hz, 1H), 2.12 (t, J=9.4Hz, 1H), 1.80-1.66 (m, 2H), 1.50 (d, J=7.0Hz, 4H), 1.18 (q, J=9.0, 8.3Hz, 1H).

[0347] Example 8: Preparation of Compound 8:

[0348]

[0349] Preparation of compound 8-1:

[0350] Intermediate INT-2 (321 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-(4-fluorophenyl)ethane-1-amine (167 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give compound 8-1 in 73% yield. MS (ESI, positive ion) m / z: 443.3 [M+H] + .

[0351] Preparation of compound 8-2:

[0352] Compound 8-1 (442 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), and chloroacetyl chloride (135 mg, 1.2 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (30 mL) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 8-2, with a yield of 79%. MS (ESI, positive ion) m / z: 519.2 [M+H] + .

[0353] Preparation of compound 8:

[0354] Compound 8-2 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (43 mg, 0.5 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 8, in 52% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0355] 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 8.89 (d, J=7.1Hz, 1H), 8.56 (s, 1H), 8.3 5(d, J=8.0Hz, 1H), 8.30 (s, 1H), 7.89 (d, J=1.9Hz, 1H), 7.72 (d, J=1.3Hz, 2H), 7 .48 (dd, J=8.4, 5.4Hz, 3H), 7.20-7.15 (m, 2H), 5.23 (t, J=7.3Hz, 1H), 4.32 (q, J=7.3Hz, 2H), 3.65 (t, J=4.6Hz, 4H), 2.57 (t, J=4.4Hz, 4H), 1.52-1.46 (m, 6H).

[0356] Example 9: Preparation of compound 9:

[0357]

[0358] Preparation of compound 9:

[0359] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-morpholino-4-yl-2-oxo-acetic acid (48 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 9, yield 56%. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0360] 1 H NMR (400MHz, DMSO-d6) δ11.60 (s, 1H), 8.89 (d, J = 7.3Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.36 ( d, J=8.0Hz, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.74 (dd, J=8.5, 1.9Hz, 1H), 7.66 (d, J=8.6Hz, 1 H), 7.48 (dtd, J=12.1, 6.4, 5.7, 2.0Hz, 3H), 7.19-7.13 (m, 2H), 5.22 (t, J=7.3Hz, 1H), 3.91 (s, 3H), 3.70 (d, J = 22.8Hz, 4H), 3.56 (t, J = 4.9Hz, 2H), 3.46 (s, 2H), 1.50 (d, J = 7.0Hz, 3H).

[0361] Example 10: Preparation of compound 10:

[0362]

[0363] Preparation of compound 10:

[0364] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and monoethyl oxalate (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 10, in 46% yield. MS (ESI, positive ion) m / z: 529.2 [M+H] + .

[0365] 1H NMR (400MHz, DMSO-d6) δ11.76-11.52 (m, 1H), 8.87 (d, J=6.9Hz, 1H), 8.53 (d, J=1.9 Hz, 1H), 8.34 (d, J=8.0Hz, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 7.69 (dd, J=8.7, 1.8Hz, 1H ), 7.61 (d, J = 8.6Hz, 1H), 7.49-7.41 (m, 3H), 7.15-7.09 (m, 2H), 5.19 (t, J = 7.3Hz, 1H ), 4.30 (q, J=7.1Hz, 2H), 3.86 (s, 3H), 1.46 (d, J=7.0Hz, 3H), 1.28 (t, J=7.0Hz, 3H).

[0366] Example 11: Preparation of compound 11:

[0367]

[0368] Preparation of compound 11:

[0369] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and oxalic acid (27 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 11 in 51% yield. MS (ESI, positive ion) m / z: 500.2 [M+H] + .

[0370] 1 H NMR (400MHz, DMSO-d6) δ10.87 (s, 1H), 8.93 (d, J = 7.2Hz, 1H), 8.56 (d, J = 1.8Hz, 1H), 8.36 (d, J = 7.8Hz, 2H), 8.22 (s, 1H), 8.08-7.95 (m, 2H), 7. 76 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.54-7.45 (m, 3H), 7.19-7.14 (m, 2H), 5.27-5.18 (m, 1H), 3.91 (s, 3H), 1.50 (d, J=7.0Hz, 3H).

[0371] Example 12: Preparation of compound 12:

[0372]

[0373] Preparation of compound 12:

[0374] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (R)-3-pyrrolidine (35 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 12 in 46% yield. MS (ESI, positive ion) m / z: 556.2 [M+H] + .

[0375] 1 H NMR (400MHz, DMSO-d6) δ10.44 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.36 (d, J = 8.0Hz, 1H), 8.23 (s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.507.45 (m, 3H), 7 .21-7.14 (m, 2H), 5.22 (p, J=7.1Hz, 1H), 4.83 (d, J=5.5Hz, 1H), 4.23 (s, 1H), 3.91 (s, 3H), 3.36 (s, 2H), 2.8 7-2.79 (m, 2H), 2.60-2.55 (m, 2H), 2.06 (dq, J=14.0, 7.2Hz, 1H), 1.69-1.59 (m, 1H), 1.50 (d, J=7.0Hz, 3H).

[0376] Example 13: Preparation of compound 13:

[0377]

[0378] Preparation of compound 13:

[0379] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclohexylacetic acid (42 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 13 in 61% yield. MS (ESI, positive ion) m / z: 553.2 [M+H] + .

[0380] 1H NMR (400MHz, DMSO-d6) δ10.78 (s, 1H), 8.86 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.37 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 7.88 (d, J=1.9Hz, 1H), 7.73 (dd, J=8.6, 1.9Hz, 1H), 7.66 (d, J=8.6Hz, 1H), 7.47 (ddd, J=8.6, 5.5, 2.4Hz, 3H), 7. 17 (t, J=8.9Hz, 2H), 5.27-5.17 (m, 1H), 3.91 (s, 3H), 3.85 (ddd, J=11.3, 4.4, 1.9Hz, 2H), 3.31 (dd, J=11.6, 2.1Hz, 2H ), 2.40 (s, 1H), 2.04 (dt, J=7.4, 3.5Hz, 1H), 1.67-1.59 (m, 2H), 1.50 (d, J=7.1Hz, 3H), 1.28 (tt, J=12.1, 6.0Hz, 2H).

[0381] Example 14: Preparation of compound 14:

[0382]

[0383] Preparation of compound 14:

[0384] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and L-pyroglutamic acid (39 mg, 0.3 mmol) and 1-propylphosphoric 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 14 in 53% yield. MS (ESI, positive ion) m / z: 540.2 [M+H] + .

[0385] 1 H NMR (400MHz, DMSO-d6) δ8.42 (t, J=1.2Hz, 1H), 8.31 (d, J=8.0Hz, 1H), 8.19 (s, 1H), 7.88 (d, J=1.6Hz, 1H), 7.66-7.59 (m, 4H), 7. 51-7.42 (m, 2H), 7.22-7.11 (m, 2H), 5.22 (p, J=7.1Hz, 1H), 4.11 (m, 1H), 3.90 (s, 3H), 2.46-2.08 (m, 4H), 1.50 (d, J=7.0Hz, 3H).

[0386] Example 15: Preparation of compound 15:

[0387]

[0388] Preparation of compound 15:

[0389] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclohexylcarboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 15 in 51% yield. MS (ESI, positive ion) m / z: 540.2 [M+H] + .

[0390] 1 H NMR (400MHz, DMSO-d6) δ8.42 (t, J=1.2Hz, 1H), 8.31 (d, J=8.0Hz, 1H), 8.19 (s, 1H), 7.88 (d, J=1.6Hz, 1H), 7.66-7.59 (m, 3H), 7.51-7 .42 (m, 2H), 7.22-7.11 (m, 2H), 5.22 (p, J=7.1Hz, 1H), 3.90 (s, 3H), 3.63 (t, J=4.6Hz, 4H), 2.60-2.55 (m, 4H), 1.50 (d, J=7.0Hz, 3H).

[0391] Example 16: Preparation of compound 16:

[0392]

[0393] Preparation of compound 16:

[0394] 3-Morpholinone (101 mg, 1 mmol) was dissolved in dry tetrahydrofuran (2 mL), sodium hydrogen (80 mg, 2 mmol) was added, and after five minutes, intermediate INT-26 (252 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 3 h. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The solution was purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 16, in 33% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0395] 1H NMR (400MHz, DMSO-d6) δ8.56 (d, J=1.9Hz, 1H), 8.37 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H ), 7.98 (s, 1H), 7.78-7.66 (m, 3H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.47 (dd, J=8.5, 5.6Hz, 3H), 7.18 (d, J=8.9Hz, 2H), 4.974.82 (m, 1H), 4.30 (s, 2H), 3.91 (s, 3H), 3 .65-3.52(m, 2H), 2.57(m, 2H), 2.35(s, 2H), 1.50(d, J=7.1Hz, 3H), 1.25(s, 6H),.

[0396] Example 17: Preparation of compound 17:

[0397]

[0398] Preparation of compound 17:

[0399] Intermediate INT-3 (43 mg, 0.10 mmol) was dissolved in dichloromethane (1 mL), and ethyl chloroformate (13 mg, 0.12 mmol) and N,N-diisopropylethylamine (26 mg, 0.20 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (3 mL) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 17, with a yield of 82%. MS (ESI, positive ion) m / z: 501.2 [M+H] + .

[0400] 1 H NMR (400MHz, DMSO-d6) δ10.46 (s, 1H), 8.83 (d, J = 7.1Hz, 1H), 8.52 (d, J = 1.8Hz, 1H), 8.34 (d, J=8.0Hz, 1H), 8.20 (s, 1H), 7.85 (d, J=1.9Hz, 1H), 7.71 (dd, J=8.6, 1.9Hz, 1H), 7.65 (d, J=8.7Hz, 1H), 7.49-7.37 (m, 3H), 7.19-7.10 (m, 2H), 5.25-5 .15 (m, 1H), 4.16 (q, J=7.1Hz, 2H), 1.48 (d, J=7.1Hz, 3H), 1.25 (t, J=7.1Hz, 3H).

[0401] Example 18: Preparation of compound 18:

[0402]

[0403] Preparation of compound 18:

[0404] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 2,2-methylmorpholine (45 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 18 in 66% yield. MS (ESI, positive ion) m / z: 584.2 [M+H] + .

[0405] 1 H NMR (400MHz, DMSO-d6) δ8.56 (d, J=1.9Hz, 1H), 8.37 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H ), 7.98 (s, 1H), 7.78-7.66 (m, 3H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.47 (dd, J=8.5, 5 .6Hz, 3H), 7.18(d, J=8.9Hz, 2H), 4.97-4.82(m, 1H), 3.91(s, 3H), 3.65-3.52(m, 2H), 3.25(s, 2H), 2.57(m, 2H), 2.35(s, 2H), 1.50(d, J=7.1Hz, 3H), 1.25(s, 6H),.

[0406] Example 19: Preparation of compound 19:

[0407]

[0408] Preparation of compound 19:

[0409] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 2-methoxypyrrolidine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 19, yield 76%. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0410] 1H NMR (400MHz, DMSO-d6) δ8.56 (d, J=1.9Hz, 1H), 8.37 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1 H), 7.98 (s, 1H), 7.78-7.66 (m, 3H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.47 (dd, J=8.5 , 5.6Hz, 3H), 7.18 (d, J=8.9Hz, 2H), 4.974.82 (m, 1H), 3.91 (s, 3H), 3.42-3.38 (m , 4H), 3.25 (s, 2H), 2.62-2.32 (m, 4H), 1.82-1.64 (m, 2H), 1.50 (d, J=7.1Hz, 3H).

[0411] Example 20: Preparation of compound 20:

[0412]

[0413] Preparation of compound 20:

[0414] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3-(S)-pyrrolidone (35 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 20 in 76% yield. MS (ESI, positive ion) m / z: 558.2 [M+H] + .

[0415] 1 H NMR (400MHz, DMSO-d6) δ8.56 (d, J=1.9Hz, 1H), 8.37 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H ), 7.98 (s, 1H), 7.78-7.66 (m, 3H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.47 (dd, J=8.5, 5.6Hz, 3H), 7.18(d, J=8.9Hz, 2H), 4.97-4.82(m, 1H), 3.91(s, 3H), 3.42-3.38(m , 1H), 3.25 (s, 2H), 2.62-2.32 (m, 4H), 1.82-1.64 (m, 2H), 1.50 (d, J=7.1Hz, 3H).

[0416] Example 21: Preparation of compound 21:

[0417]

[0418] Preparation of compound 21:

[0419] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3-(R)-pyrrolidone (35 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 21 in 66% yield. MS (ESI, positive ion) m / z: 558.2 [M+H] + .

[0420] 1 H NMR (400MHz, DMSO-d6) δ8.56 (d, J=1.9Hz, 1H), 8.37 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H ), 7.98 (s, 1H), 7.78-7.66 (m, 3H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.47 (dd, J=8.5, 5.6Hz, 3H), 7.18(d, J=8.9Hz, 2H), 4.97-4.82(m, 1H), 3.91(s, 3H), 3.42-3.38(m , 1H), 3.25 (s, 2H), 2.62-2.32 (m, 4H), 1.82-1.64 (m, 2H), 1.50 (d, J=7.1Hz, 3H).

[0421] Example 22 Preparation of compound 22:

[0422]

[0423] Preparation of compound 22:

[0424] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and isoxazolidine (29 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 22 in 56% yield. MS (ESI, positive ion) m / z: 541.2 [M+H] + .

[0425] 1H NMR (400MHz, DMSO-d6) δ8.56 (d, J=1.9Hz, 1H), 8.37 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.98 (s, 1H), 7.78-7.66 (m, 3H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.47 (dd, J=8.5, 5.6Hz, 3H), 7.18 (d, J=8.9Hz, 2H), 5.27-5.17 (m, 1H), 4.07-3.98 (m, 1H), 3.91 (s, 3H), 3.70 (s, 2H), 2.01 (s, 2H), 1.57 1.54 (m, 1H), 1.50 (d, J = 7.1Hz, 3H), 0.88 (d, J = 2.1Hz, 2H).

[0426] Example 23: Preparation of compound 23:

[0427]

[0428] Preparation of compound 23:

[0429] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 4-cyanopiperidine (44 mg, 0.4 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 by C.18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 23 in 66% yield. MS (ESI, positive ion) m / z: 579.2 [M+H] + .

[0430] 1 H NMR (400MHz, DMSO) δ10.52 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.4Hz, 1H), 8.39 (d, J = 8.0Hz , 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.1Hz, 1H), 7.78-7.64 (m, 2H), 7.51-7.43 (m, 3H), 7.17 (t, J=8.9Hz , 2H), 5.22 (p, J=6.9Hz, 1H), 3.91 (s, 3H), 3.26 (d, J=11.5Hz, 2H), 2.97-2.86 (m, 1H), 2.77-2.62 ( m, 2H), 2.48 (s, 2H), 2.01-1.84 (m, 2H), 1.79 (ddd, J=12.9, 8.4, 4.0Hz, 2H), 1.50 (d, J=7.0Hz, 3H).

[0431] Example 24: Preparation of compound 24:

[0432]

[0433] Preparation of compound 24:

[0434] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 4-methoxypiperidine (45 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 24 in 76% yield. MS (ESI, positive ion) m / z: 584.2 [M+H] + .

[0435] 1 H NMR (400MHz, DMSO) δ10.44 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.5Hz, 1H), 8.39 (d , J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.2Hz, 1H), 7.78-7.63 (m, 2H), 7.52-7.43 (m, 3H) , 7.26-7.11(m, 2H), 5.22(p, J=7.1Hz, 1H), 3.91(s, 3H), 3.38(s, 3H), 3.23(s, 3H), 2.77( dd, J=13.7, 8.1Hz, 2H), 2.38-2.29 (m, 2H), 1.87 (d, J=9.7Hz, 2H), 1.50 (d, J=7.0Hz, 5H).

[0436] Example 25: Preparation of compound 25:

[0437]

[0438] Preparation of compound 25:

[0439] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (53 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 25 in 51% yield. MS (ESI, positive ion) m / z: 589.2 [M+H] + .

[0440] 1 H NMR (400MHz, DMSO) δ10.56 (s, 1H), 8.90 (d, J = 7.1Hz, 1H), 8.56 (d, J = 1.2Hz, 1H), 8.39 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.91 (s, 1H), 7.79-7.64 (m, 2H), 7.47 (dd, J=8.2, 5.9Hz, 3H), 7 .17(t, J=8.9Hz, 2H), 5.22(p, J=7.1Hz, 1H), 4.37-4.19(m, 2H), 3.91(s, 3H), 3.72-3.66(m , 2H), 3.64-3.57 (m, 4H), 3.49 (dd, J=5.7, 3.7Hz, 2H), 3.26 (s, 3H), 1.50 (d, J=7.0Hz, 3H).

[0441] Example 26: Preparation of compound 26:

[0442]

[0443] Preparation of compound 26:

[0444] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and triethylene glycol monomethyl ether acetic acid (66 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 26 in 48% yield. MS (ESI, positive ion) m / z: 633.2 [M+H] + .

[0445] 1H NMR (400MHz, DMSO) δ10.54 (s, 1H), 8.90 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.2Hz, 1H), 8.38 (d, J = 8.0Hz, 1H), 8. 23 (s, 1H), 7.93 (d, J=15.9Hz, 1H), 7.78-7.64 (m, 2H), 7.47 (dd, J=8.1, 6.0Hz, 3H), 7.17 (t, J=8.9Hz, 2H), 5 .22 (p, J=7.0Hz, 1H), 4.25 (s, 2H), 3.91 (s, 3H), 3.70 (dd, J=5.8, 3.3Hz, 2H), 3.62 (dd, J=5.6, 3.4Hz, 2H), 3.58 (s, 4H), 3.53 (dd, J=5.8, 3.6Hz, 2H), 3.43 (dd, J=5.7, 3.8Hz, 2H), 3.23 (s, 3H), 1.50 (d, J=7.0Hz, 3H).

[0446] Example 27: Preparation of compound 27:

[0447]

[0448] Preparation of compound 27:

[0449] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 4-piperidinone ethylene glycol (57 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 27 in 86% yield. MS (ESI, positive ion) m / z: 612.2 [M+H] + .

[0450] 1 H NMR (400MHz, DMSO) δ10.48 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.4Hz, 1H), 8.39 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.2Hz, 1H), 7.78-7.64 (m, 2H), 7.5 2-7.43 (m, 3H), 7.17 (t, J=8.9Hz, 2H), 5.22 (p, J=7.1Hz, 1H), 3.90 (d, J=10.6Hz, 7 H), 3.27 (s, 2H), 2.68-2.58 (m, 4H), 1.69 (t, J=5.4Hz, 4H), 1.50 (d, J=7.0Hz, 3H).

[0451] Example 28: Preparation of compound 28:

[0452]

[0453] Preparation of compound 28:

[0454] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and thiomorpholine-1,1-dioxide (53 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 28 in 72% yield. MS (ESI, positive ion) m / z: 604.2 [M+H] + .

[0455] 1 H NMR (400MHz, DMSO) δ10.70 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.4Hz, 1H ), 8.39 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J = 1.2Hz, 1H), 7.78-7.59 (m, 2H) , 7.52-7.43 (m, 3H), 7.22-7.12 (m, 2H), 5.22 (p, J=7.0Hz, 1H), 3.91 (s, 3H), 3. 52 (s, 2H), 3.19 (d, J = 4.8Hz, 4H), 3.13 (d, J = 5.3Hz, 4H), 1.50 (d, J = 7.0Hz, 3H).

[0456] Example 29: Preparation of compound 29:

[0457]

[0458] Preparation of compound 29:

[0459] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3-methylazacyclobutane-3-carboxynitrile (38 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 29 in 68% yield. MS (ESI, positive ion) m / z: 565.2 [M+H] + .

[0460] 1H NMR (400MHz, DMSO) δ10.68 (s, 1H), 8.87 (d, J=7.1Hz, 1H), 8.54 (s, 1H), 8.38 (d, J=8.0Hz, 1H), 8.22(s, 1H), 7.89(s, 1H), 7.77-7.63(m, 2H), 7.52-7.42( m, 3H), 7.16 (t, J=8.9Hz, 2H), 5.21 (p, J=7.2Hz, 1H), 3.90 (s, 3H), 3.67 (d, J =7.2Hz, 2H), 3.45 (s, 2H), 3.33 (s, 2H), 1.58 (s, 3H), 1.49 (d, J = 7.0Hz, 3H).

[0461] Example 30: Preparation of compound 30:

[0462]

[0463] Preparation of compound 30:

[0464] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 1,4-oxazacycloheptanine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 30 in 78% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0465] 1 H NMR (400MHz, DMSO) δ10.47 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.5Hz, 1H), 8.39 (d, J =8.0Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J = 1.2Hz, 1H), 7.78-7.64 (m, 2H), 7.52-7.43 (m, 3H), 7. 17 (dd, J=12.4, 5.4Hz, 2H), 5.22 (p, J=7.1Hz, 1H), 3.91 (s, 3H), 3.73 (t, J=6.0Hz, 2H), 3.7 0-3.64 (m, 2H), 3.44 (s, 2H), 2.87-2.80 (m, 4H), 1.92-1.81 (m, 2H), 1.50 (d, J=7.0Hz, 3H).

[0466] Example 31: Preparation of compound 31:

[0467]

[0468] Preparation of compound 31:

[0469] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1,1-cyclopropyldicarboxylic acid (39 mg, 0.3 mmol) and 1-propylphosphoric 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 31 in 39% yield. MS (ESI, positive ion) m / z: 541.2 [M+H] + .

[0470] 1 H NMR (400MHz, DMSO-d6) δ8.81 (d, J=7.2Hz, 1H), 8.52 (s, 1H), 8.44 (d, J=7.9Hz, 1H), 8.28 (s, 1H), 7.86 (s, 1H), 7.64 (q, J=8.8Hz, 2 H), 7.43 (t, J=7.4Hz, 3H), 7.11 (t, J=8.7Hz, 2H), 5.24-5.11 (m, 1H), 3.85 (s, 3H), 1.45 (d, J=7.0Hz, 3H), 1.23 (d, J=41.5Hz, 4H).

[0471] Example 32: Preparation of compound 32:

[0472]

[0473] Preparation of compound 32:

[0474] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3,3-dimethylmorpholine (46 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 32 in 88% yield. MS (ESI, positive ion) m / z: 583.2 [M+H] + .

[0475] 1H NMR (400MHz, DMSO) δ10.32-10.25 (m, 1H), 8.94-8.87 (m, 1H), 8.58-8.52 (m, 1H), 8. 43-8.34(m, 1H), 8.26-8.21(m, 1H), 7.94-7.89(m, 1H), 7.78-7.64(m, 2H), 7.53-7. 43(m, 3H), 7.22-7.13(m, 2H), 5.23(p, J=7.0Hz, 1H), 3.92(s, 3H), 3.76-3.65(m, 2H ), 3.37(s, 2H), 3.22(s, 2H), 2.66-2.57(m, 2H), 1.50(d, J=7.0Hz, 3H), 1.04(s, 6H).

[0476] Example 33: Preparation of compound 33:

[0477]

[0478] Preparation of compound 33:

[0479] Intermediate INT-26 (108 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3-morpholine carboxylic acid (52 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 33, yield 48%. MS (ESI, positive ion) m / z: 600.2 [M+H] + .

[0480] 1 H NMR (400MHz, DMSO-d6) δ11.3 (s, 1H), 10.25 (s, 1H), 8.87 (d, J=7.1Hz, 1H), 8.54 (d, J=1.9 Hz, 1H), 8.39 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.88 (s, 1H), 7.76-7.64 (m, 2H), 7.47 (ddd, J= 8.9, 5.7, 2.8Hz, 3H), 7.20-7.14 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 3.91 (s, 3H), 3.85 (d, J=9 .8Hz, 1H), 3.72-3.50 (m, 5H), 3.18 (s, 2H), 2.90 (d, J=11.4Hz, 1H), 1.50 (d, J=7.0Hz, 3H).

[0481] Example 34: Preparation of compound 34:

[0482]

[0483] Preparation of compound 34:

[0484] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3-acetonitrile-azacyclobutane (32 mg, 0.4 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 by C.18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 34 in 38% yield. MS (ESI, positive ion) m / z: 551.2 [M+H] + .

[0485] 1 H NMR (400MHz, DMSO-d6) δ10.65 (s, 1H), 8.86 (d, J=7.1Hz, 1H), 8.54 (d, J=1.8Hz, 1H), 8.36 (d, J=8. 0Hz, 1H), 8.22 (s, 1H), 7.89 (d, J = 1.9Hz, 1H), 7.72 (d, J = 1.9Hz, 1H), 7.66 (d, J = 8.6Hz, 1H), 7.47 (t d, J=5.5, 2.5Hz, 3H), 7.16 (t, J=8.9Hz, 2H), 5.22 (t, J=7.3Hz, 1H), 3.91 (s, 3H), 3.64 (dd, J=7.8, 5 .9Hz, 2H), 3.59-3.53 (m, 1H), 3.48 (d, J=6.3Hz, 2H), 1.50 (d, J=7.1Hz, 3H), 0.95 (d, J=6.5Hz, 2H).

[0486] Preparation of compound 35 in Example 35:

[0487]

[0488] Preparation of compound 35:

[0489] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (S)-3-hydroxymethylmorpholine (46 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 35 in 58% yield. MS (ESI, positive ion) m / z: 586.2 [M+H] + .

[0490] 1H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.59-8.53 (m, 1H), 8.36 (t, J = 7.6Hz, 1H), 8.22 (d, J=7.6Hz, 1H), 7.90 (d, J=2.0Hz, 1H), 7.76-7.61 (m, 2H), 7.51-7.43 (m, 3H), 7.17 (t, J=8.8Hz, 2H ), 5.22 (p, J=7.1Hz, 1H), 4.71 (t, J=5.2Hz, 1H), 3.91 (d, J=4.8Hz, 3H), 3.80-3.38 (m, 6H), 3.27 (d, J=16 .3Hz, 2H), 3.06-2.77 (m, 1H), 2.60 (d, J=8.7Hz, 1H), 2.46 (q, J=7.2Hz, 1H), 1.50 (dd, J=7.1, 1.9Hz, 3H).

[0491] Example 36: Preparation of compound 36:

[0492]

[0493] Preparation of compound 36:

[0494] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-diethylaminoacetic acid (39 mg, 0.3 mmol) and 1-propylphosphonic anhydride were added.

[0495] (111 mg, 0.351 mmol), heated to 80 °C, stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 36, yield 39%. MS (ESI, positiveion) m / z: 542.2 [M+H] + .

[0496] 1H NMR (400MHz, DMSO-d6) δ10.28 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8. 37 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.73 (d, J=1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.50-7.46(m, 3H), 7.17(t, J=8.9Hz, 2H), 5.23(t, J=7.4Hz, 1H), 3.91(s , 3H), 3.28 (s, 2H), 2.65 (q, J=7.2Hz, 4H), 1.51 (d, J=7.1Hz, 3H), 1.05 (t, J=7.1Hz, 6H).

[0497] Example 37: Preparation of compound 37:

[0498]

[0499] Preparation of compound 37:

[0500] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and L-proline (34 mg, 0.4 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 by C.18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 37 in 48% yield. MS (ESI, positive ion) m / z: 584.2 [M+H] + .

[0501] 1 H NMR (400MHz, DMSO-d6) δ8.87 (d, J=7.2Hz, 1H), 8.55 (s, 1H), 8.37 (d, J=7.9Hz, 1 H), 8.22 (s, 1H), 7.89 (s, 1H), 7.78-7.64 (m, 2H), 7.47 (dd, J=8.6, 5.6Hz, 3H), 7. 17 (t, J=8.8Hz, 2H), 5.22 (t, J=7.3Hz, 1H), 3.91 (s, 3H), 3.50-3.42 (m, 2H), 3.28 -3.09 (m, 4H), 2.67 (d, J = 15.5Hz, 1H), 2.19-2.06 (m, 1H), 1.50 (d, J = 7.1Hz, 3H).

[0502] Example 38: Preparation of compound 38:

[0503]

[0504] Preparation of compound 38:

[0505] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 4-(4-piperidinyl)morpholine (68 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 38 in 78% yield. MS (ESI, positive ion) m / z: 639.2 [M+H] + .

[0506] 1 H NMR (400MHz, DMSO-d6) δ10.40 (s, 1H), 8.88 (dd, J=7.1, 0.8Hz, 1H), 8.55 (d, J=1.8Hz, 1H), 8.36 (d, J=8.0Hz , 1H), 8.22 (s, 1H), 7.90 (dd, J=2.0, 0.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.50-7. 45 (m, 3H), 7.21-7.13 (m, 2H), 5.23 (t, J=7.4Hz, 1H), 3.91 (s, 3H), 3.58 (t, J=4.6Hz, 4H), 3.22 (s, 2H), 2.95 (d, J=11.0Hz, 2H), 2.47 (t, J=4.7Hz, 4H), 2.24-2.16 (m, 2H), 1.77 (d, J=12.2Hz, 2H), 1.49 (t, J=8.3Hz, 5H).

[0507] Preparation of compound 39 in Example 39:

[0508]

[0509] Preparation of compound 39:

[0510] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane (39 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 39, yield 76%. MS (ESI, positive ion) m / z: 568.2 [M+H] + .

[0511] 1 H NMR (400MHz, DMSO-d6) δ10.39 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.37 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H) , 7.90 (d, J=1.9Hz, 1H), 7.77-7.71 (m, 1H), 7.67 (d, J=8.6Hz, 1H), 7.50-7.45 (m, 3H), 7.17 (t, J=8.7Hz, 2H), 5.23 (t, J=7 .3Hz, 1H), 4.40 (s, 1H), 3.90 (d, J=10.6Hz, 4H), 3.62 (s, 1H), 3.58 (dd, J=7.6, 1.7Hz, 1H), 3.48 (d, J=5.3Hz, 2H), 2.97 (d d, J=10.0, 1.7Hz, 1H), 2.57 (d, J=9.9Hz, 1H), 1.87 (dd, J=9.6, 2.1Hz, 1H), 1.65 (d, J=9.5Hz, 1H), 1.51 (d, J=7.0Hz, 3H).

[0512] Example 40: Preparation of compound 40:

[0513]

[0514] Preparation of compound 40:

[0515] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 mg, 0.3 mmol) and 1-propylphosphonic anhydride were added.

[0516] (111 mg, 0.351 mmol), heated to 80 °C, stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 40, yield 39%. MS (ESI, positive ion) m / z: 514.2 [M+H] + .

[0517] 1H NMR (400MHz, DMSO-d6) δ10.76 (s, 1H), 8.87 (d, J = 7.1Hz, 1H), 8.52 (d, J = 1.8Hz, 1H), 8.37 ( d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.89 (d, J=1.9Hz, 1H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.65 (d, J=8.6Hz, 1H), 7.57 (td, J=5.3, 2.4Hz, 3H), 7.19-7.14 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 3.91 (s, 3H), 3.80 (t, J=12.5Hz, 4H), 3.61 (s, 6H), 1.50 (d, J=7.0Hz, 3H), 0.97 (d, J=6.5Hz.2H).

[0518] Example 41: Preparation of compound 41:

[0519]

[0520] Preparation of compound 41:

[0521] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (S)-3-pyrrolidone (35 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 41 in 66% yield. MS (ESI, positive ion) m / z: 556.2 [M+H] + .

[0522] 1 H NMR (400MHz, DMSO-d6) δ10.74 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.54 (d, J = 1.8Hz, 1H), 8.36 (d, J =8.0Hz, 1H), 8.22 (s, 1H), 7.89 (d, J = 1.9Hz, 1H), 7.74 (dd, J = 8.6, 1.9Hz, 1H), 7.67 (d, J = 8.6H z, 1H), 7.47 (td, J=5.3, 2.4Hz, 3H), 7.19-7.14 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 3.91 (s, 3H), 3. 80 (t, J=12.5Hz, 4H), 2.06 (m, 1H), 1.50 (d, J=7.0Hz, 3H), 1.22 (m, 2H), 0.97 (d, J=6.5Hz, 2H).

[0523] Example 42: Preparation of compound 42:

[0524]

[0525] Preparation of compound 42:

[0526] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3,3-difluoroacetidine (37 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 42, yield 71%. MS (ESI, positive ion) m / z: 562.2 [M+H] + .

[0527] 1 H NMR (400MHz, DMSO-d6) δ10.74 (s, 1H), 8.87 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8. 37 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.89 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1H), 7. 67 (d, J=8.6Hz, 1H), 7.47 (td, J=5.3, 2.4Hz, 3H), 7.19-7.14 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 3.91 (s, 3H), 3.80 (t, J=12.5Hz, 4H), 1.50 (d, J=7.0Hz, 3H), 0.97 (d, J=6.5Hz, 2H).

[0528] Example 43: Preparation of compound 43:

[0529]

[0530] Preparation of compound 43:

[0531] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and thiomorpholine (41 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 43, yield 71%. MS (ESI, positive ion) m / z: 562.2 [M+H] + .

[0532] 1H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.56 (d, J = 1.9Hz, 1H), 8. 37 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1H), 7. 67 (d, J=8.6Hz, 1H), 7.48 (td, J=5.5, 2.5Hz, 3H), 7.22-7.12 (m, 2H), 5.23 (p, J=7.1Hz, 1 H), 3.91 (s, 3H), 2.84 (dd, J=6.5, 3.4Hz, 4H), 2.71-2.65 (m, 4H), 1.51 (d, J=7.0Hz, 3H).

[0533] Example 44: Preparation of compound 44:

[0534]

[0535] Preparation of compound 44:

[0536] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3-hydroxymethylpiperidine (46 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 44, yield 61%. MS (ESI, positive ion) m / z: 584.2 [M+H] + .

[0537] 1H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 8.89 (d, J = 7.3Hz, 1H), 8.55 (d, J = 2.0Hz, 1H), 8.38 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 7 .90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.52-7.43 (m, 3H), 7.22-7.12 (m, 2H), 5.22 (p, J= 7.2Hz, 1H), 4.48 (t, J=5.3Hz, 1H), 3.92 (s, 3H), 3.34-3.29 (m, 1H), 3.27-3.16 (m, 3H), 2.98-2.91 (m, 1H), 2.83 (d, J=11.0H z, 1H), 2.21-2.11 (m, 1H), 1.91 (t, J=10.4Hz, 1H), 1.75-1.62 (m, 3H), 1.50 (d, J=7.1Hz, 4H), 0.95 (dd, J=19.6, 9.2Hz, 1H).

[0538] Preparation of compound 45 in Example 45:

[0539]

[0540] Preparation of compound 45:

[0541] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3-hydroxymethylpiperidine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 45, yield 61%. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0542] 1H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.39 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 7 .90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.49-7.45 (m, 3H), 7.17 (t, J=8.9Hz, 2H), 5.22 (p , J=7.2Hz, 1H), 3.91 (s, 3H), 3.77 (dt, J=10.4, 2.5Hz, 1H), 3.64-3.54 (m, 2H), 3.26 (s, 2H), 2.82 (dd, J=11.1, 2.4Hz, 1H), 2 .75 (d, J=11.2Hz, 1H), 2.28 (td, J=11.3, 3.3Hz, 1H), 1.98 (t, J=10.5Hz, 1H), 1.50 (d, J=7.0Hz, 3H), 1.07 (d, J=6.3Hz, 3H).

[0543] Example 46: Preparation of compound 46:

[0544]

[0545] Preparation of compound 46:

[0546] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and cis-2,6-dimethylmorpholine (46 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 46, yield 74%. MS (ESI, positive ion) m / z: 584.2 [M+H] + .

[0547] 1H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 8.88 (dd, J=7.1, 0.8Hz, 1H), 8.55 (d, J=1.8Hz, 1H), 8.36 (d, J=8.0 Hz, 1H), 8.22 (s, 1H), 7.89 (dd, J=1.9, 0.9Hz, 1H), 7.73 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7. 49-7.44 (m, 3H), 7.21-7.12 (m, 2H), 5.22 (t, J=7.3Hz, 1H), 3.91 (s, 3H), 3.64 (ddd, J=10.0, 6.2, 2.0Hz, 2 H), 3.25 (s, 2H), 2.82-2.77 (m, 2H), 1.91 (t, J=10.6Hz, 2H), 1.50 (d, J=7.0Hz, 3H), 1.07 (d, J=6.2Hz, 6H).

[0548] Example 47: Preparation of compound 47:

[0549]

[0550] Preparation of compound 47:

[0551] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 4,4-difluoropiperidine (48 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 47, yield 74%. MS (ESI, positive ion) m / z: 590.2 [M+H] + .

[0552] 1H NMR (400MHz, DMSO-d6) δ10.60 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.9Hz, 1H), 8.39 (d, J=8.0Hz, 1H), 8.24 (s, 1H), 7.90 (d, J=2.0Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.50-7.45 (m, 3H), 7.22-7.12 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 3.91 (s, 3H), 2.72 (t, J =5.7Hz, 4H), 2.53 (d, J = 1.9Hz, 2H), 2.04 (dq, J = 14.3, 8.0, 6.8Hz, 4H), 1.50 (d, J = 7.0Hz, 3H).

[0553] Example 48: Preparation of compound 48:

[0554]

[0555] Preparation of compound 48:

[0556] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 4,4-difluoropiperidine (27 mg, 0.4 mmol) and potassium carbonate (55 mg, 0.4 mmol) were added. The mixture was heated to 80 °C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 48 in 69% yield. MS (ESI, positive ion) m / z: 537.2 [M+H] + .

[0557] 1 H NMR (400MHz, DMSO-d6) δ11.25 (s, 1H), 8.90 (d, J = 7.1Hz, 1H), 8.56 (d, J = 1.9Hz, 1H) , 8.38 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 7.93 (t, J = 1.4Hz, 1H), 7.76 (dd, J = 8.7, 1.9Hz, 1H), 7.71-7.64(m, 2H), 7.47(tt, J=9.0, 2.6Hz, 3H), 7.22-7.12(m, 3H), 6.92(t, J= 1.1Hz, 1H), 5.23 (q, J=7.3Hz, 1H), 3.92 (s, 3H), 2.56 (s, 2H), 1.50 (d, J=7.0Hz, 3H).

[0558] Example 49: Preparation of compound 49:

[0559]

[0560] Preparation of compound 49:

[0561] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (R)-3-piperidinol (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 49, yield 62%. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0562] 1 H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.38 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 7. 90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.48 (dt, J=6.6, 2.7Hz, 3H), 7.17 (dd, J=10.0, 7.8H z, 2H), 5.23 (q, J=7.3Hz, 1H), 4.77 (d, J=5.6Hz, 1H), 3.91 (s, 3H), 3.58 (s, 1H), 3.30-3.15 (m, 2H), 2.83 (d, J=10.0Hz, 1H), 2 .64 (d, J=10.9Hz, 1H), 2.17 (dt, J=42.9, 9.8Hz, 2H), 1.74 (q, J=12.9, 9.1Hz, 2H), 1.50 (d, J=7.0Hz, 4H), 1.24-1.12 (m, 1H).

[0563] Example 50: Preparation of compound 50:

[0564]

[0565] Preparation of compound 50:

[0566] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 1-cyclopropionylpiperazine (61 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 50, with a precision of 58%. MS (ESI, positive ion) m / z: 623.2 [M+H] + .

[0567] 1 H NMR (400MHz, DMSO-d6) δ10.58 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.9Hz, 1H), 8.38 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 7.91 (d, J=2.0Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7.50-7.4 5(m, 3H), 7.20-7.14(m, 2H), 5.22(p, J=7.2Hz, 1H), 3.91(s, 3H), 3.74(s, 2H), 3.53(s, 2H), 3.34(s, 4H ), 2.62 (s, 2H), 1.99 (tt, J=7.8, 4.9Hz, 1H), 1.50 (d, J=7.0Hz, 3H), 0.73 (ddt, J=10.7, 4.8, 2.9Hz, 4H).

[0568] Example 51: Preparation of compound 51:

[0569]

[0570] Preparation of compound 51:

[0571] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 1-methylpiperazine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 51 in 61% yield. MS (ESI, positive ion) m / z: 569.2 [M+H] + .

[0572] 1H NMR (400MHz, DMSO-d6) δ10.44 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.3 9 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=2.0Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1H), 7.6 7(d, J=8.6Hz, 1H), 7.48 (td, J=5.6, 2.6Hz, 3H), 7.17 (t, J=8.9Hz, 2H), 5.23 (p, J=7.1Hz , 1H), 3.92 (s, 3H), 3.36 (s, 6H), 2.79-2.54 (m, 4H), 2.38 (s, 3H), 1.50 (d, J=7.1Hz, 3H).

[0573] Preparation of compound 52 in Example 52:

[0574]

[0575] Preparation of compound 52:

[0576] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and triazole (27 mg, 0.4 mmol) and potassium carbonate (55 mg, 0.4 mmol) were added. The mixture was heated to 80 °C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 52, yield 41%. MS (ESI, positive ion) m / z: 538.2 [M+H] + .

[0577] 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.91 (d, J = 7.2Hz, 1H), 8.56 (d, J = 1.9Hz, 1H), 8.3 8(d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 8.19 (s, 1H), 7.97-7.93 (m, 1H), 7.79 (d, J=9.1Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.47 (dd, J=8.5, 5.7Hz, 3H), 7.17 (dd, J=10.1, 7.7Hz, 2H), 5.22 ( t, J=7.3Hz, 1H), 3.92 (s, 3H), 2.56 (s, 2H), 1.50 (d, J=7.0Hz, 3H), 0.97 (d, J=6.5Hz, 1H).

[0578] Preparation of compound 53 in Example 53:

[0579]

[0580] Preparation of compound 53:

[0581] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 1-acetylpiperazine (51 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 53 in 58% yield. MS (ESI, positive ion) m / z: 597.2 [M+H] + .

[0582] 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.39 ( d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.91 (d, J=2.0Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J =8.6Hz, 1H), 7.50-7.45 (m, 3H), 7.20-7.15 (m, 2H), 5.22 (p, J = 7.2Hz, 1H), 3.92 (s, 3H), 3.5 0 (q, J=5.1Hz, 4H), 3.32 (s, 4H), 2.58 (t, J=5.0Hz, 2H), 2.02 (s, 3H), 1.50 (d, J=7.0Hz, 3H).

[0583] Preparation of compound 54 in Example 54:

[0584]

[0585] Preparation of compound 54:

[0586] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (1-methyl-4-piperidin-)methylamine (51 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 54 in 54% yield. MS (ESI, positive ion) m / z: 597.2 [M+H] + .

[0587] 1H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.88 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.9Hz, 1H), 8.38 (d, J = 8.1Hz , 1H), 8.22 (s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.76 (dd, J=8.6, 1.8Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7.47 (dd t, J=5.8, 4.1, 1.7Hz, 3H), 7.22-7.12 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 4.32 (m, 1H), 3.91 (s, 3H), 3.64 (t , J=4.6Hz, 4H), 3.5 (s, 3H), 3.27 (s, 2H), 3.10 (m, 2H) 1.50 (d, J=7.0Hz, 3H). 1.23 (m, 4H), 1.15 (m, 1H).

[0588] Preparation of compound 55 in Example 55:

[0589]

[0590] Preparation of compound 55:

[0591] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and trifluoroethylamine (39 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 55 in 54% yield. MS (ESI, positive ion) m / z: 568.2 [M+H] + .

[0592] 1 H NMR (400MHz, DMSO-d6) δ10.74 (s, 1H), 8.91-8.87 (m, 1H), 8.55 (d, J=1.9Hz, 1H), 8.38 (d, J =8.0Hz, 1H), 8.23 ​​(s, 1H), 7.92-7.89 (m, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.7H z, 1H), 7.47 (td, J=5.5, 2.5Hz, 3H), 7.19-7.15 (m, 2H), 5.22 (t, J=7.3Hz, 1H), 3.91 (s, 3H) , 3.61 (s, 1H), 3.40 (td, J=10.1, 6.5Hz, 2H), 1.50 (d, J=7.1Hz, 3H), 0.97 (d, J=6.5Hz, 2H).

[0593] Example 56: Preparation of compound 56:

[0594]

[0595] Preparation of compound 56:

[0596] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and N-(2-aminoethyl)morpholine (52 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 56 in 64% yield. MS (ESI, positive ion) m / z: 599.2 [M+H] + .

[0597] 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=7.1Hz, 1H), 8.56 (d, J=1.8Hz, 1H), 8.37 (d, J=8.0Hz, 1H), 8. 23 (s, 1H), 7.90 (d, J=2.0Hz, 1H), 7.75 (dd, J=8.6, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.48 (td, J=5.4, 2.4Hz, 3H), 7.17 (t, J=8.8Hz, 2H), 5.23 (p, J=7.2Hz, 1H), 3.92 (s, 3H), 3.60 (t, J=4.7Hz , 4H), 3.47 (s, 2H), 2.70 (t, J=6.1Hz, 2H), 2.41 (dt, J=10.4, 5.4Hz, 6H), 1.51 (d, J=7.0Hz, 3H).

[0598] Preparation of compound 57 in Example 57:

[0599]

[0600] Preparation of compound 57:

[0601] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and m-triazole (27 mg, 0.4 mmol) and potassium carbonate (55 mg, 0.4 mmol) were added. The mixture was heated to 80 °C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 57, yield 41%. MS (ESI, positive ion) m / z: 538.2 [M+H] +.

[0602] 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=7.2Hz, 1H), 8.55 (d, J=1.9Hz, 1H), 8.52 (s, 1H), 8 .40 (d, J=8.0Hz, 1H), 8.22 (s, 1H), 7.93 (d, J=1.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H ), 7.67 (d, J=8.6Hz, 1H), 7.47 (dt, J=8.5, 4.0Hz, 3H), 7.19-7.14 (m, 2H), 5.78 (p, J= 7.1Hz, 2H), 5.21 (t, J=7.3Hz, 1H), 3.91 (s, 3H), 2.56 (s, 2H), 1.50 (d, J=7.0Hz, 3H).

[0603] Preparation of compound 58 in Example 58:

[0604]

[0605] Preparation of compound 58:

[0606] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and pyrazole (27 mg, 0.4 mmol) and potassium carbonate (55 mg, 0.4 mmol) were added. The mixture was heated to 80 °C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 58 in 57% yield. MS (ESI, positive ion) m / z: 537.2 [M+H] + .

[0607] 1 H NMR (400MHz, DMSO-d6) δ11.24 (d, J=13.2Hz, 1H), 8.91 (dd, J=7.0, 5.4Hz, 1H), 8.56 (d, J=1.9Hz, 1H), 8.38 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.96-7.91 (m, 1H), 7.83-7.7 2 (m, 2H), 7.68 (d, J=8.6Hz, 1H), 7.53-7.43 (m, 3H), 7.23-7.12 (m, 2H), 5.79 (p, J=7 .1Hz, 2H), 5.22 (p, J=7.1Hz, 1H), 3.92 (s, 3H), 2.55 (s, 2H), 1.50 (d, J=7.0Hz, 3H).

[0608] Preparation of compound 59 in Example 59:

[0609]

[0610] Preparation of compound 59:

[0611] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3-amino-1-adamantaneol (61 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 59, yield 34%. MS (ESI, positive ion) m / z: 622.2 [M+H] + .

[0612] 1 H NMR (400MHz, DMSO-d6) δ10.44 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.38 (d, J = 8 .0Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=2.0Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.7Hz, 1H) , 7.47 (td, J=5.3, 2.4Hz, 3H), 7.22-7.12 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 4.47 (s, 1H), 3.91 (s, 3H ), 3.35 (dd, J=7.1, 3.7Hz, 3H), 2.16 (d, J=4.4Hz, 2H), 1.55-1.47 (m, 13H), 1.44 (d, J=3.4Hz, 2H).

[0613] Example 60: Preparation of compound 60:

[0614]

[0615] Preparation of compound 60:

[0616] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (S)-3-methylmorpholine cis-2,6-dimethylmorpholine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 60, yield 71%. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0617] 1 H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.37 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 7.9 0 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.50-7.45 (m, 3H), 7.22-7.12 (m, 2H), 5.23 (p, J=7.2H z, 1H), 3.92 (s, 3H), 3.73 (dt, J=11.3, 3.0Hz, 1H), 3.66 (dd, J=11.1, 3.1Hz, 1H), 3.57 (td, J=10.7, 2.5Hz, 1H), 3.50 (d, J=16 .3Hz, 1H), 3.28-3.12 (m, 2H), 2.80 (dt, J=11.6, 2.7Hz, 1H), 2.68-2.54 (m, 2H), 1.51 (d, J=7.0Hz, 3H), 0.97 (d, J=6.3Hz, 3H).

[0618] Example 61: Preparation of compound 61:

[0619]

[0620] Preparation of compound 61:

[0621] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (S)-pyrrolidine-3-methanol (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 61 in 58% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0622] 1H NMR (400MHz, DMSO-d6) δ10.44 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.39 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 7. 90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.47 (td, J=5.5, 2.4Hz, 3H), 7.22-7.12 (m, 2H), 5.2 2 (p, J=7.1Hz, 1H), 4.60 (s, 1H), 3.91 (s, 3H), 3.35 (dd, J=7.1, 3.7Hz, 4H), 2.74 (dd, J=9.1, 7.7Hz, 1H), 2.64 (t, J=6.9Hz, 2 H), 2.45 (dd, J=9.1, 5.6Hz, 1H), 2.30-2.25 (m, 1H), 1.93-1.75 (m, 1H), 1.50 (d, J=7.1Hz, 3H), 1.44 (dt, J=12.9, 6.5Hz, 1H).

[0623] Example 62: Preparation of compound 62:

[0624]

[0625] Preparation of compound 62:

[0626] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (R)-pyrrolidine-3-methanol (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 62 in 54% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0627] 1H NMR (400MHz, DMSO-d6) δ10.44 (s, 1H), 8.86 (d, J = 7.1Hz, 1H), 8.54 (d, J = 1.8Hz, 1H), 8.41 (d, J = 8.0Hz, 1H), 8.21 (s, 1H), 7.89 (d, J=1.9Hz, 1H), 7.72 (dd, J=8.7, 1.8Hz, 1H), 7.66 (d, J=8.6Hz, 1H), 7.47 (td, J=6.9, 5.7, 2.2Hz, 3H), 7.20-7.11 (m, 2H), 5. 21 (p, J=7.2Hz, 1H), 4.68 (s, 1H), 3.90 (s, 3H), 3.35 (dd, J=7.1, 3.7Hz, 4H), 2.73 (dd, J=9.1, 7.8Hz, 1H), 2.64 (t, J=6.9Hz, 2H ), 2.44 (dd, J=9.1, 5.7Hz, 1H), 2.27 (t, J=7.8Hz, 1H), 1.93-1.76 (m, 1H), 1.49 (d, J=7.0Hz, 3H), 1.44 (dt, J=12.9, 6.4Hz, 1H).

[0628] Example 63: Preparation of compound 63:

[0629]

[0630] Preparation of compound 63:

[0631] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 63 in 35% yield. MS (ESI, positive ion) m / z: 515.2 [M+H] + .

[0632] 1H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 8.86 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.9Hz, 1H), 8.39 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.89 (d, J=2.0Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1 H), 7.67 (d, J=8.6Hz, 1H), 7.47 (qd, J=6.9, 6.3, 2.1Hz, 3H), 7.17 (t, J=8.9Hz, 2H), 5 .22 (p, J=7.2Hz, 1H), 3.91 (s, 3H), 2.70 (s, 2H), 2.50 (s, 2H), 1.50 (d, J=7.0Hz, 3H).

[0633] Example 64: Preparation of compound 64:

[0634]

[0635] Preparation of compound 64:

[0636] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (R)-4-Boc-2-methylpiperazine (80 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 64, yield 61%. MS (ESI, positive ion) m / z: 669.2 [M+H] + .

[0637] 1H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.88 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.9Hz, 1H), 8.36 (d, J = 8.1Hz, 1H), 8.22 ( s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7.49-7.45 (m, 3H), 7.17 (t, J=8 .9Hz, 2H), 5.22 (p, J=7.1Hz, 1H), 3.91 (s, 3H), 3.67 (d, J=13.0Hz, 2H), 3.46 (d, J=15.7Hz, 1H), 3.09 (d, J=11.9Hz , 1H), 2.83 (d, J=11.5Hz, 1H), 2.62 (s, 1H), 1.50 (d, J=7.1Hz, 3H), 1.41 (d, J=7.3Hz, 12H), 1.03 (d, J=6.2Hz, 3H).

[0638] Preparation of compound 65 in Example 65:

[0639]

[0640] Preparation of compound 65:

[0641] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and diethylene glycolamine (42 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 65 in 71% yield. MS (ESI, positive ion) m / z: 574.2 [M+H] + .

[0642] 1 H NMR (400MHz, DMSO-d6) δ8.92 (dd, J=23.7, 7.1Hz, 1H), 8.56 (d, J=1.9Hz, 1H), 8.3 7 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1H), 7.89 (t, J=1.3Hz, 1H), 7.75 (dd, J=8.7, 2.0Hz, 1 H), 7.71-7.64 (m, 1H), 7.56-7.44 (m, 3H), 7.22-7.13 (m, 2H), 5.23 (p, J=7.2Hz, 1 H), 3.92 (s, 3H), 3.58-3.43 (m, 8H), 2.75 (t, J=5.5Hz, 2H), 1.51 (d, J=7.0Hz, 3H).

[0643] Example 66: Preparation of compound 66:

[0644]

[0645] Preparation of compound 66:

[0646] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and cyclopropylmethylamine (28 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 66 in 75% yield. MS (ESI, positive ion) m / z: 540.2 [M+H] + .

[0647] 1 H NMR (400MHz, DMSO-d6) 610.43 (s, 1H), 8.93 (dd, J=13.2, 7.1Hz, 1H), 8.56 (dd, J=4.8, 1.8Hz, 1H), 8.48 (t, J=8. 1Hz, 1H), 8.31 (d, J=6.8Hz, 1H), 7.97 (dd, J=24.3, 1.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.7Hz, 2H ), 7.48 (d, J = 2.9Hz, 2H), 7.21-7.12 (m, 2H), 5.20 (q, J = 7.3Hz, 1H), 4.44 (t, J = 5.4Hz, 1H), 3.91 (s, 3H), 3.46 (s, 1H), 2.88 (d, J=7.3Hz, 1H), 2.74 (t, J=5.5Hz, 2H), 1.50 (d, J=7.1Hz, 3H), 1.17-0.85 (m, 1H), 0.63-0.16 (m, 4H).

[0648] Example 67: Preparation of compound 67:

[0649]

[0650] Preparation of compound 67:

[0651] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and isopropylamine (23 mg, 0.4 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 by C.18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 67 in 65% yield. MS (ESI, positive ion) m / z: 528.2 [M+H] + .

[0652] 1 H NMR (400MHz, DMSO-d6) δ8.91 (dd, J=22.1, 7.1Hz, 1H), 8.55 (d, J=1.9Hz, 1H), 8.36 (d, J=8. 0Hz, 1H), 8.22 (s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.7Hz , 1H), 7.47 (td, J=5.5, 2.5Hz, 3H), 7.22-7.13 (m, 2H), 5.24 (h, J=7.3, 6.7Hz, 1H), 3.92 (s, 3 H), 3.51-3.39 (m, 2H), 2.78 (p, J=6.2Hz, 1H), 1.51 (d, J=7.0Hz, 3H), 1.04 (d, J=6.2Hz, 6H).

[0653] Example 68: Preparation of compound 68:

[0654]

[0655] Preparation of compound 68:

[0656] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 2-methoxyethylamine (30 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 68 in 75% yield. MS (ESI, positive ion) m / z: 544.2 [M+H] + .

[0657] 1H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.89 (d, J = 7.2Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.38 (d, J = 7.9 Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=2.1Hz, 1H), 7.73 (d, J=1.9Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7.48 (dd, J=5.6, 3.2Hz, 3H), 7.19-7.16 (m, 2H), 5.21 (d, J=7.4Hz, 1H), 4.44 (t, J=5.4Hz, 1H), 3.91 (s, 3H), 3 .46 (s, 1H), 3.43 (t, J = 5.5Hz, 3H), 3.27-3.24 (m, 3H), 2.74 (t, J = 5.5Hz, 2H), 1.50 (d, J = 7.1Hz, 3H).

[0658] Example 69: Preparation of compound 69:

[0659]

[0660] Preparation of compound 69:

[0661] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and aminoacetaldehyde dimethyl acetal (42 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 69, yield 66%. MS (ESI, positive ion) m / z: 574.2 [M+H] + .

[0662] 1H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.89 (d, J=7.1Hz, 1H), 8.55 (d, J=1.9Hz, 1H), 8.38 (d, J=8. 0Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=2.0Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7 .47 (td, J=5.5, 2.5Hz, 3H), 7.23-7.13 (m, 2H), 5.22 (p, J=7.1Hz, 1H), 4.44 (t, J=5.4Hz, 1H), 3.92 ( s, 3H), 3.46 (s, 1H), 3.31 (s, 6H), 3.29-3.26 (m, 2H), 2.69 (d, J=5.4Hz, 2H), 1.50 (d, J=7.1Hz, 3H).

[0663] Example 70: Preparation of compound 70:

[0664]

[0665] Preparation of compound 70:

[0666] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and N-hydroxyethylpiperazine (52 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 70, yield 56%. MS (ESI, positive ion) m / z: 599.2 [M+H] + .

[0667] 1H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.38 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=2.0Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.51-7.4 2 (m, 3H), 7.22-7.12 (m, 2H), 5.22 (p, J=7.1Hz, 1H), 4.39 (t, J=5.4Hz, 1H), 3.91 (s, 3H), 3.51 (q, J=6.1 Hz, 2H), 3.23 (s, 2H), 2.56 (s, 3H), 2.47 (d, J=7.7Hz, 3H), 2.40 (t, J=6.3Hz, 2H), 1.50 (d, J=7.0Hz, 3H).

[0668] Example 71: Preparation of compound 71:

[0669]

[0670] Preparation of compound 71:

[0671] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 8-oxo-3-azabicyclo[3.2.1]octane hydrochloride (45 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 71 in 56% yield. MS (ESI, positive ion) m / z: 582.2 [M+H] + .

[0672] 1H NMR (400MHz, DMSO-d6) δ10.41 (s, 1H), 8.93-8.86 (m, 1H), 8.55 (d, J=1.9Hz, 1H), 8.38 (d, J=8.0H z, 1H), 8.23 ​​(s, 1H), 7.92 (dd, J=2.0, 0.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1 H), 7.49-7.45(m, 3H), 7.20-7.15(m, 2H), 5.22(p, J=7.1Hz, 1H), 4.25(s, 2H), 3.92(s, 4H), 3.22( s, 2H), 2.64 (d, J=10.7Hz, 2H), 2.47 (dd, J=11.1, 2.1Hz, 3H), 1.77 (s, 2H), 1.50 (d, J=7.1Hz, 3H).

[0673] Example 72: Preparation of compound 72:

[0674]

[0675] Preparation of compound 72:

[0676] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (R)-3-methylmorpholine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 72, yield 76%. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[0677] 1H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.89 (dd, J=7.1, 0.8Hz, 1H), 8.55 (d, J=1.8Hz, 1H), 8.37 (d, J=8.0Hz, 1H), 8.23 ​​(s, 1 H), 7.90 (dd, J=1.9, 0.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7.527.43 (m, 3H), 7.22-7.12 (m, 2H), 5. 23 (p, J=7.2Hz, 1H), 3.91 (s, 3H), 3.73 (dt, J=11.2, 3.1Hz, 1H), 3.66 (dd, J=11.0, 3.1Hz, 1H), 3.62-3.53 (m, 1H), 3.53-3.4 2 (m, 1H), 3.28-3.12 (m, 2H), 2.80 (dt, J=11.7, 2.7Hz, 1H), 2.70-2.54 (m, 2H), 1.50 (d, J=7.1Hz, 3H), 0.97 (d, J=6.3Hz, 3H).

[0678] Example 73: Preparation of compound 73:

[0679]

[0680] Preparation of compound 73:

[0681] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and notrocytic butylbromide (45 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 73, yield 65%. MS (ESI, positive ion) m / z: 582.2 [M+H] + .

[0682] 1H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.90 (d, J = 7.2Hz, 1H), 8.55 (d, J = 1.9Hz, 1H), 8.38 (d, J = 8.0Hz, 1 H), 8.22 (s, 1H), 7.91 (d, J=2.0Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.48 (dd, J=6 .5, 2.7Hz, 3H), 7.19-7.15 (m, 2H), 5.22 (t, J=7.3Hz, 1H), 3.91 (s, 4H), 3.69 (d, J=10.3Hz, 2H), 3.49 (dd, J=10.7, 2.1Hz, 2H), 3.15 (s, 3H), 1.90 (dd, J=9.0, 4.6Hz, 2H), 1.82-1.76 (m, 2H), 1.50 (d, J=7.0Hz, 3H).

[0683] Preparation of compound 74 in Example 74:

[0684]

[0685] Preparation of compound 74:

[0686] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and N-methyl-2-hydroxyethylamine (30 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 74, yield 55%. MS (ESI, positive ion) m / z: 544.2 [M+H] + .

[0687] 1H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 8.89 (d, J=7.1Hz, 1H), 8.60-8.52 (m, 1H), 8.37 (t, J=7.5 Hz, 1H), 8.22 (d, J=7.4Hz, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.71-7.62 (m , 1H), 7.51-7.43 (m, 3H), 7.23-7.12 (m, 2H), 5.22 (p, J=7.3Hz, 1H), 4.71 (s, 1H), 3.91 (d, J=4.8 Hz, 3H), 3.56-3.42 (m, 3H), 2.63-2.53 (m, 2H), 2.35 (s, 3H), 2.30 (s, 1H), 1.50 (d, J=7.1Hz, 3H).

[0688] Preparation of compound 75 in Example 75:

[0689]

[0690] Preparation of compound 75:

[0691] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (35 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 75 in 85% yield. MS (ESI, positive ion) m / z: 556.2 [M+H] + .

[0692] 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.9Hz, 1H), 8.38 (d, J=8.1Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.8Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.47 (ddt, J=5.8, 4.1, 1.7Hz, 3H), 7.22-7.12 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 3.91 (s , 3H), 3.64 (t, J=4.6Hz, 4H), 3.27 (s, 2H), 2.56 (dd, J=5.4, 3.4Hz, 4H), 1.50 (d, J=7.0Hz, 3H).

[0693] Example 76: Preparation of compound 76:

[0694]

[0695] Preparation of compound 76:

[0696] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and ethylamine hydrochloride (32 mg, 0.4 mmol) and DIPEA (103 mg, 0.8 mmol) were added. The mixture was heated to 80 °C and stirred for 6 h. The reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 76, in 68% yield. MS (ESI, positive ion) m / z: 514.2 [M+H] + .

[0697] 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.9Hz, 1H), 8.38 (d, J = 8.1Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.8Hz, 1H), 7.67 (d, J=8.7Hz, 1 H), 7.47 (ddt, J=5.8, 4.1, 1.7Hz, 3H), 7.22-7.12 (m, 2H), 4.97 (m, 1H), 3.91 (s, 3H), 3.44 (s, 1H) ), 3.22 (s, 2H), 2.63 (dd, J=6.6, 1.8Hz, 2H), 1.56 (d, J=5.4Hz, 3H), 1.10 (dd, J=7.6, 2.8Hz, 3H).

[0698] Example 77: Preparation of compound 77:

[0699]

[0700] Preparation of compound 77:

[0701] Intermediate INT-26 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3-aminotetrahydrofuran (35 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 77, yield 61%. MS (ESI, positive ion) m / z: 556.2 [M+H] + .

[0702] 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.9Hz, 1H), 8.38 (d, J = 8 .1Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.8Hz, 1H), 7.67 (d, J=8.7Hz, 1H ), 7.47(ddt, J=5.8, 4.1, 1.7Hz, 3H), 7.22-7.12(m, 2H), 5.13(s, 1H), 4.97(m, 1H), 3.91-3.75(m , 7H), 3.01-2.95 (m, 1H), 2.63 (dd, J=6.6, 1.8Hz, 2H), 2.06-1.83 (m, 2H), 1.56 (d, J=5.4Hz, 3H).

[0703] Preparation of compound 78 in Example 78:

[0704]

[0705] Preparation of compound 78:

[0706] Intermediate INT-3 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 78, yield 49%. MS (ESI, positive ion) m / z: 530.2 [M+H] + .

[0707] 1H NMR (400MHz, DMSO-d6) δ10.44 (s, 1H), 8.88 (dd, J=7.1, 0.8Hz, 1H), 8.55 (d, J=1.8 Hz, 1H), 8.39 (d, J=7.9Hz, 1H), 8.23 ​​(s, 1H), 7.90 (dd, J=2.0, 0.9Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.50-7.45 (m, 3H), 7.43-7.39 (m, 2H), 5. 21 (p, J=7.1Hz, 1H), 3.92 (s, 3H), 3.21 (s, 2H), 2.33 (s, 6H), 1.50 (d, J=7.1Hz, 3H).

[0708] Preparation of compound 79 in Example 79:

[0709]

[0710] Preparation of compound 79:

[0711] Intermediate INT-27 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 2-oxa-5-azabicyclo[2.2.1]heptane (39 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 79, yield 71%. MS (ESI, positive ion) m / z: 584.2 [M+H] + .

[0712] 1H NMR (400MHz, DMSO-d6) δ10.39 (s, 1H), 8.88 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.39 (d, J = 7.9Hz, 1H), 8.23 ​​(s, 1H), 7 .90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.49-7.45 (m, 3H), 7.42-7.39 (m, 2H), 5.26-5.15 (m, 1H), 4.39 (t, J = 2.1Hz, 1H), 3.90 (d, J = 11.3Hz, 4H), 3.62 (s, 1H), 3.58 (dd, J = 7.7, 1.8Hz, 1H), 3.48 (d, J = 5.2Hz, 2H), 2 .96 (dd, J=9.9, 1.7Hz, 1H), 2.57 (d, J=10.0Hz, 1H), 1.87 (dd, J=9.7, 2.2Hz, 1H), 1.68-1.61 (m, 1H), 1.50 (d, J=7.1Hz, 3H).

[0713] Example 80: Preparation of compound 80:

[0714]

[0715] Preparation of compound 80:

[0716] Intermediate INT-27 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3,3-difluoroacetidine (37 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 80, in 65% yield. MS (ESI, positive ion) m / z: 578.2 [M+H] + .

[0717] 1H NMR (400MHz, DMSO) δ10.77 (s, 1H), 8.89 (t, J = 10.7Hz, 1H), 8.55 (s, 1H), 8.41 (d, J = 7.9Hz, 1H), 8.24 (s, 1H), 7.91 (d, J = 11.7Hz, 1H), 7.79-7.64 (m, 2H ), 7.47 (dd, J=9.4, 5.0Hz, 3H), 7.41 (d, J=8.5Hz, 2H), 5.20 (p, J=7.0Hz, 1H ), 3.92 (s, 3H), 3.80 (t, J = 12.5Hz, 4H), 3.61 (s, 2H), 1.50 (d, J = 7.0Hz, 3H).

[0718] Example 81: Preparation of compound 81:

[0719]

[0720] Preparation of compound 81:

[0721] Intermediate INT-27 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (R)-3-methylmorpholine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 81 in 73% yield. MS (ESI, positive ion) m / z: 586.2 [M+H] + .

[0722] 1 H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.39 (d, J = 7.9Hz, 1H), 8. 24 (s, 1H), 7.90 (d, J=2.0Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.7Hz, 1H), 7.49-7.44 (m, 3H), 7.43 -7.38(m, 2H), 5.25-5.17(m, 1H), 3.92(s, 3H), 3.76-3.70(m, 1H), 3.66(dd, J=10.9, 3.1Hz, 1H), 3.61-3.46(m , 2H), 3.22-3.15 (m, 1H), 2.82-2.78 (m, 1H), 2.66-2.54 (m, 2H), 1.50 (d, J=7.1Hz, 3H), 0.97 (d, J=6.3Hz, 3H).

[0723] Example 82: Preparation of compound 82:

[0724]

[0725] Preparation of compound 82:

[0726] Intermediate INT-27 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and (S)-3-methylmorpholine cis-2,6-dimethylmorpholine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 82 in 68% yield. MS (ESI, positive ion) m / z: 586.2 [M+H] + .

[0727] 1 H NMR (400MHz, DMSO) δ10.45 (s, 1H), 8.89 (d, J=7.1Hz, 1H), 8.55 (s, 1H), 8.43 (t, J=13.8Hz, 1H), 8.2 4 (s, 1H), 7.90 (s, 1H), 7.71 (dd, J=25.0, 8.6Hz, 2H), 7.50-7.44 (m, 3H), 7.41 (d, J=8.4Hz, 2H), 5.20 (p, J=6.9Hz, 1H), 3.92 (s, 3H), 3.69 (dd, J=27.9, 9.8Hz, 2H), 3.61-3.46 (m, 2H), 3.34-3.10 (m, 2H), 2.79 (d, J=11.7Hz, 1H), 2.60 (dd, J=18.8, 8.3Hz, 2H), 1.50 (d, J=7.0Hz, 3H), 0.96 (d, J=6.3Hz, 3H).

[0728] Example 83: Preparation of compound 83:

[0729]

[0730] Preparation of compound 83:

[0731] Intermediate INT-27 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (35 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 83 in 82% yield. MS (ESI, positive ion) m / z: 572.2 [M+H] + .

[0732] 1 H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.54 (d, J = 2.0Hz, 1H), 8. 40 (d, J=7.9Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1H), 7 .67 (d, J=8.7Hz, 1H), 7.51-7.44 (m, 3H), 7.44-7.37 (m, 2H), 5.20 (p, J=7.2Hz, 1H), 3.9 1 (s, 3H), 3.64 (t, J = 4.6Hz, 4H), 3.27 (s, 2H), 2.58-2.54 (m, 4H), 1.50 (d, J = 7.1Hz, 3H).

[0733] Example 84: Preparation of compound 84:

[0734]

[0735] Preparation of compound 84:

[0736] Intermediate INT-27 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 3-hydroxymethylpiperidine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 84, yield 66%. MS (ESI, positive ion) m / z: 586.2 [M+H] + .

[0737] 1H NMR (400MHz, DMSO-d6) δ10.52 (s, 1H), 8.88 (d, J = 7.1Hz, 1H), 8.54 (d, J = 1.8Hz, 1H), 8.40 (d, J = 7.9Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7.49-7.44 (m, 3H), 7.40 (d, J=8.6Hz, 2H), 5.20 (p, J=7.2Hz, 1H) , 3.91 (s, 3H), 3.77 (dt, J = 10.0, 2.4Hz, 1H), 3.58 (ddd, J = 13.8, 8.9, 2.8Hz, 2H), 3.26 (s, 2H), 2.82 (dt, J = 11.1, 2.1Hz, 1H), 2.75 ( dd, J=11.1, 2.1Hz, 1H), 2.28 (td, J=11.3, 3.3Hz, 1H), 1.98 (dd, J=11.1, 9.9Hz, 1H), 1.50 (d, J=7.1Hz, 3H), 1.07 (d, J=6.2Hz, 3H).

[0738] Preparation of compound 85 in Example 85:

[0739]

[0740] Preparation of compound 85:

[0741] Intermediate INT-27 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and cis-2,6-dimethylmorpholine (46 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 85, yield 64%. MS (ESI, positive ion) m / z: 600.2 [M+H] + .

[0742] 1H NMR (400MHz, DMSO-d6) δ10.50 (s, 1H), 8.86 (d, J = 7.1Hz, 1H), 8.52 (d, J = 1.9Hz, 1H), 8.39 (d, J = 7.9 Hz, 1H), 8.21 (s, 1H), 7.88 (d, J=2.0Hz, 1H), 7.72 (dd, J=8.6, 1.9Hz, 1H), 7.66 (d, J=8.7Hz, 1H), 7. 47-7.42 (m, 3H), 7.38 (d, J=8.6Hz, 2H), 5.18 (t, J=7.3Hz, 1H), 3.90 (s, 3H), 3.67-3.59 (m, 2H), 3.2 3 (s, 2H), 2.81-2.77 (m, 2H), 1.89 (t, J=10.6Hz, 2H), 1.48 (d, J=7.0Hz, 3H), 1.05 (d, J=6.3Hz, 6H).

[0743] Example 86 Preparation of compound 86:

[0744]

[0745] Preparation of compound 86:

[0746] Intermediate INT-27 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and 4,4-difluoropiperidine (48 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 86, yield 71%. MS (ESI, positive ion) m / z: 606.2 [M+H] + .

[0747] 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=7.1Hz, 1H), 8.55 (d, J=1.9Hz, 1H), 8.42 (d, J=7.9Hz , 1H), 8.24 (s, 1H), 7.90 (d, J=2.0Hz, 1H), 7.74 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.7H z, 1H), 7.49-7.44 (m, 3H), 7.41 (d, J=8.5Hz, 2H), 5.20 (p, J=7.2Hz, 1H), 3.92 (s, 3H), 3 .39 (s, 2H), 2.72 (t, J=5.7Hz, 4H), 2.03 (dt, J=14.6, 7.8Hz, 4H), 1.50 (d, J=7.0Hz, 3H).

[0748] Example 87: Preparation of compound 87:

[0749]

[0750] Preparation of compound 87:

[0751] Intermediate INT-27 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and thiomorpholine (41 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 87, yield 61%. MS (ESI, positive ion) m / z: 588.2 [M+H] + .

[0752] 1 H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.88 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.3 9 (d, J=7.9Hz, 1H), 8.24 (s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1H), 7.68 (d, J=8.7Hz, 1H), 7.49-7.45 (m, 3H), 7.42-7.39 (m, 2H), 5.21 (p, J=7.2Hz, 1H), 3.92 (s, 3H), 3.31 (s, 2H), 2.84 (dd, J=6.4, 3.5Hz, 4H), 2.70-2.66 (m, 4H), 1.50 (d, J=7.1Hz, 3H).

[0753] Preparation of compound 88 in Example 88:

[0754]

[0755] Preparation of compound 88-1:

[0756] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-(furan-2-yl)ethyl-1-amine (133 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give intermediate compound 88-1 in 76% yield. MS (ESI, positive ion) m / z: 401.3 [M+H] +.

[0757] Preparation of compound 88:

[0758] Compound 88-1 (80 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and morpholino-4-ylacetic acid (43 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 88 in 69% yield. MS (ESI, positive ion) m / z: 528.2 [M+H] + .

[0759] 1 H NMR (400MHz, DMSO-d6) δ10.52 (s, 1H), 8.90 (d, J = 7.1Hz, 1H), 8.61 (d, J = 1.8Hz, 1H), 8.31 (d, J = 8.4Hz, 1H ), 8.19 (s, 1H), 7.92 (d, J = 1.8Hz, 1H), 7.75 (dd, J = 8.6, 1.9Hz, 1H), 7.67 (d, J = 8.6Hz, 1H), 7.60 (d, J = 1.8H z, 1H), 7.50 (dd, J=7.2, 2.0Hz, 1H), 6.42 (dd, J=3.3, 1.8Hz, 1H), 6.30 (d, J=3.2Hz, 1H), 5.34 (p, J=7.2Hz, 1H), 3.90 (s, 3H), 3.65 (t, J=4.6Hz, 4H), 3.28 (s, 2H), 2.57 (dd, J=5.6, 3.7Hz, 4H), 1.52 (d, J=7.0Hz, 3H).

[0760] Example 89: Preparation of compound 89:

[0761]

[0762] Preparation of compound 89:

[0763] Compound 88-1 (80 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 89, in 62% yield. MS (ESI, positive ion) m / z: 509.2 [M+H] + .

[0764] 1 H NMR (400MHz, DMSO-d6) δ10.93 (s, 1H), 8.96-8.90 (m, 1H), 8.62 (d, J = 1.9Hz, 1H), 8.43 (s, 1H), 8.33 (d, J = 8.4H z, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.96-7.91 (m, 1H), 7.77 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 7.65-

[0765] 7.58 (m, 1H), 7.51 (dd, J=7.2, 2.0Hz, 1H), 6.43 (dd, J=3.2, 1.8Hz, 1H), 6.31 (dt, J=3 .3, 1.0Hz, 1H), 5.34 (p, J=7.1Hz, 1H), 3.91 (d, J=5.9Hz, 6H), 1.52 (d, J=7.0Hz, 3H).

[0766] Example 90: Preparation of compound 90:

[0767]

[0768] Preparation of compound 90-1:

[0769] Intermediate INT-1-4 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-tert-butylethyl-1-amine (121 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give intermediate compound 90-1, with a yield of 56%. MS (ESI, positive ion) m / z: 391.3 [M+H] + .

[0770] Preparation of compound 90:

[0771] Compound 90-1 (78 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and morpholino-4-ylacetic acid (43 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 90 in 59% yield. MS (ESI, positive ion) m / z: 518.2 [M+H] + .

[0772] 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.92-8.89 (m, 1H), 8.57 (d, J=1.8Hz, 1H) , 8.22 (s, 1H), 7.91 (dd, J=2.0, 0.9Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.52-7.47 (m, 2H), 4.09-4.00 (m, 1H), 3.90 (s, 3H), 3.65 (t, J=4.6 Hz, 4H), 3.28 (s, 2H), 2.57 (t, J=4.7Hz, 4H), 1.12 (d, J=6.9Hz, 3H), 0.95 (s, 9H).

[0773] Example 91: Preparation of compound 91:

[0774]

[0775] Preparation of compound 91:

[0776] Compound 90-1 (78 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 91 in 58% yield. MS (ESI, positive ion) m / z: 499.2 [M+H] + .

[0777] 1 H NMR (400MHz, DMSO-d6) δ10.93 (s, 1H), 8.93 (d, J = 7.1Hz, 1H), 8.59 (d, J = 1.8Hz, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.93 (t, J = 1.3Hz, 1H), 7 .76 (dd, J=8.6, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.54-7.47 (m, 2H), 4.1 1-3.99 (m, 1H), 3.91 (d, J=4.1Hz, 6H), 1.12 (d, J=6.9Hz, 3H), 0.95 (s, 9H).

[0778] Example 92: Preparation of compound 92:

[0779]

[0780] Preparation of compound 92:

[0781] Compound 90-1 (78 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-fluorocyclopropanecarboxylic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 92 in 58% yield. MS (ESI, positive ion) m / z: 477.2 [M+H] + .

[0782] 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=7.1Hz, 1H), 8.58 (d, J=1.8Hz, 1H), 8.22 (s, 1H), 7.90 (d, J=2.2Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8 .7Hz, 1H), 7.55-7.45 (m, 2H), 4.05 (dd, J=9.3, 6.9Hz, 1H), 3.90 (s, 3H), 1 .75-1.60 (m, 1H), 1.26-1.16 (m, 1H), 1.12 (d, J=6.9Hz, 3H), 0.95 (s, 11H).

[0783] Example 93: Preparation of compound 93:

[0784]

[0785] Preparation of compound 93:

[0786] Compound 90-1 (78 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 93 in 58% yield. MS (ESI, positive ion) m / z: 459.2 [M+H] + .

[0787] 1H NMR (400MHz, DMSO-d6) δ11.10 (s, 1H), 8.88 (d, J=7.0Hz, 1H), 8.58 (d, J=1.8Hz, 1H), 8.22 (s, 1H), 7.92-7.87 (m, 1H), 7.74 (dd, J=8.7, 1.9Hz , 1H), 7.67 (d, J=8.6Hz, 1H), 7.53-7.46 (m, 2H), 4.09-4.00 (m, 1H), 3.90 (s, 3H), 1.12 (d, J=6.9Hz, 3H), 0.95 (s, 10H), 0.86 (d, J=6.1Hz, 4H).

[0788] Example 94: Preparation of compound 94:

[0789]

[0790] Preparation of compound 94:

[0791] Intermediate INT-15 (44.6 g, 100 mmol) was dissolved in dichloromethane (1 L), and chloroacetyl chloride (13.5 g, 120 mmol) and N,N-diisopropylethylamine (25.8 g, 200 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 94, yield 73%. MS (ESI, positive ion) m / z: 523.2 [M+H] + .

[0792] 1 H NMR (400MHz, DMSO-) d6 ) δ11.26 (s, 1H), 8.92 (d, J = 7.1Hz, 1H), 8.62 (d, J = 8.3Hz, 1H), 8.55 (d, J = 1.8Hz , 1H), 8.27 (s, 1H), 7.94 (d, J=1.9Hz, 1H), 7.77 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J =8.7Hz, 1H), 7.59-7.53 (m, 2H), 7.50 (dd, J = 7.2, 2.0Hz, 1H), 7.23 (t, J = 8.9Hz, 2H), 5.48 (dq, J=14.6, 7.2Hz, 1H), 4.84-4.58 (m, 2H), 4.46 (s, 2H), 3.93 (s, 3H).

[0793] Preparation of compound 95 in Example 95:

[0794]

[0795] Preparation of compound 95-1:

[0796] Intermediate INT-15 (44.6 g, 100 mmol) was dissolved in dichloromethane (1 L), and methyl chloroformate (11.2 g, 120 mmol) and N,N-diisopropylethylamine (25.8 g, 200 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 95-1, with a yield of 69%. MS (ESI, positive ion) m / z: 505.2 [M+H] + .

[0797] Preparation of compound 95:

[0798] Compound 95-1 (100 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and N-methylpiperazine (40 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 95 in 61% yield. MS (ESI, positive ion) m / z: 573.2 [M+H] + .

[0799] 1 H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 8.83 (d, J = 7.1Hz, 1H), 8.61 (d, J = 8.3Hz, 1H), 8.52 (d, J = 1.8Hz, 1H ), 8.27 (s, 1H), 7.86 (dd, J=1.9, 0.9Hz, 1H), 7.78 (dd, J=8.7, 1.9Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.59-7. 53 (m, 2H), 7.43 (dd, J=7.1, 2.0Hz, 1H), 7.23 (t, J=8.9Hz, 2H), 5.48 (dq, J=14.9, 7.2Hz, 1H), 4.75 (dd, J= 6.6, 3.3Hz, 1H), 4.68-4.60 (m, 1H), 4.23 (s, 3H), 3.93 (s, 3H), 3.55-3.60 (m, 4H), 3.48 (t, J=4.8Hz, 4H).

[0800] Example 96: Preparation of compound 96:

[0801]

[0802] Preparation of compound 96:

[0803] Intermediate compound 96 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and piperidine (34 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 96 in 58% yield. MS (ESI, positive ion) m / z: 572.2 [M+H] + .

[0804] 1 H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.85 (d, J = 7.1Hz, 1H), 8.61 (d, J = 8.3Hz, 1H), 8.54 (d, J = 1.8Hz, 1H) , 8.26 (s, 1H), 7.85 (dd, J=1.9, 0.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.56-7.53 (m, 2H), 7.43 (dd, J=7.1, 2.0Hz, 1H), 7.23 (t, J=8.9Hz, 2H), 5.46 (dq, J=14.9, 7.2Hz, 1H), 4.75 (dd, J=6. 6, 3.3Hz, 1H), 4.65-4.60 (m, 1H), 3.93 (s, 3H), 3.67 (m, 2H), 3.55-3.60 (m, 4H), 1.32 (m, 4H). 1.10 (m, 2H).

[0805] Example 97: Preparation of compound 97:

[0806]

[0807] Preparation of compound 97:

[0808] INT-15 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-methoxyacetic acid (26 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 97, in 68% yield. MS (ESI, positive ion) m / z: 519.2 [M+H] + .

[0809] 1H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 8.86 (d, J=7.1Hz, 1H), 8.65 (d, J=8.3Hz, 1H), 8.54 (d, J=1. 8Hz, 1H), 8.25 (s, 1H), 7.86 (dd, J=1.9, 0.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.72 (d, J=8.6Hz , 1H), 7.59-7.53 (m, 2H), 7.42 (dd, J=7.1, 2.0Hz, 1H), 7.21 (t, J=8.9Hz, 2H), 5.48 (dq, J=14.9, 7. 2Hz, 1H), 4.75 (dd, J=6.6, 3.3Hz, 1H), 4.68-4.60 (m, 1H), 3.93 (s, 3H), 3.12 (m, 2H), 2.87 (m, 2H).

[0810] Preparation of compound 98 in Example 98:

[0811]

[0812] Preparation of compound 98:

[0813] INT-15 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (S)-2-methoxypropionic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 98, yield 61%. MS (ESI, positive ion) m / z: 533.2 [M+H] + .

[0814] 1H NMR (400MHz, DMSO-d6) δ8.61 (t, J=8.3Hz, 2H), 8.49 (d, J=1.8Hz, 1H), 8.25 (s, 1H), 7.73-7.6 3 (m, 2H), 7.61 (d, J=2.0Hz, 1H), 7.55 (dd, J=8.6, 5.6Hz, 2H), 7.27-7.17 (m, 3H), 6.58 (t, J=6 .1Hz, 1H), 5.49 (dt, J=15.5, 7.0Hz, 1H), 4.75 (d, J=7.7Hz, 1H), 4.67-4.60 (m, 1H), 3.92 (s, 3 H), 3.55 (q, J=6.1Hz, 1H), 3.22 (dt, J=12.9, 6.1Hz, 1H), 1.25 (s, 3H), 1.13 (d, J=6.1Hz, 3H).

[0815] Preparation of compound 99 in Example 99:

[0816]

[0817] Preparation of compound 99:

[0818] INT-15 (89 mg, 0.2 mmol) was dissolved in THF (1 mL), and acetone (0.2 mL) and tetraisopropyl titanate (0.1 mL) were added. The mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, sodium borohydride (23 mg, 0.6 mmol) was added. After 1 hour, the reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 99, yield 21%. MS (ESI, positive ion) m / z: 489.2 [M+H] + .

[0819] 1 H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.85 (d, J = 7.1Hz, 1H), 8.64 (d, J = 8.3Hz, 1H), 8.53 (d , J=1.8Hz, 1H), 8.27 (s, 1H), 7.86 (dd, J=1.9, 0.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.6 7 (d, J=8.6Hz, 1H), 7.61-7.53 (m, 2H), 7.45 (dd, J=7.1, 2.0Hz, 1H), 7.22 (t, J=8.9Hz, 2H), 4.75 (dd, J=6.6, 3.3Hz, 1H), 3.96 (m, 1H), 3.76 (m, 2H), 3.50 (s, 3H), 1.21 (d, J=8.6Hz.6H).

[0820] Example 100: Preparation of compound 100:

[0821]

[0822] Preparation of compound 100:

[0823] INT-15 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and R-1-methyl-3-pyrrolidone carboxylic acid (39 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 100, yield 78%. MS (ESI, positive ion) m / z: 558.2 [M+H] + .

[0824] 1 H NMR (400MHz, DMSO-d6) δ9.63 (s, 1H), 8.85 (d, J = 7.1Hz, 1H), 8.64 (d, J = 8.3Hz, 1H), 8.55 (d, J=1.8Hz, 1H), 8.27 (s, 1H), 7.83 (dd, J=1.9, 0.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.69 ( d, J=8.6Hz, 1H), 7.59-7.53 (m, 2H), 7.43 (dd, J=7.1, 2.0Hz, 1H), 7.24 (t, J=8.9Hz, 2H), 5.4 8 (dq, J=14.9, 7.2Hz, 1H), 4.75 (dd, J=6.6, 3.3Hz, 1H), 3.59 (m, 1H), 1.50 (d, J=7.1Hz.6H).

[0825] Example 101: Preparation of compound 101:

[0826]

[0827] Preparation of compound 101:

[0828] INT-15 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 101 in 78% yield. MS (ESI, positive ion) m / z: 532.2 [M+H] + .

[0829] 1 H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.85 (d, J = 7.1Hz, 1H), 8.64 (d, J = 8.3Hz, 1H), 8.53 (d, J = 1.8H z, 1H), 8.27 (s, 1H), 7.86 (dd, J=1.9, 0.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H ), 7.61-7.53 (m, 2H), 7.45 (dd, J=7.1, 2.0Hz, 1H), 7.22 (t, J=8.9Hz, 2H), 5.49 (dq, J=14.9, 7.2Hz, 1H), 4.75 (dd, J=6.6, 3.3Hz, 1H), 3.76 (m, 2H), 3.66 (m, 2H), 3.50 (s, 3H), 2.87 (m, 2H), 2.32 (m, 1H).

[0830] Example 102: Preparation of compound 102:

[0831]

[0832] Preparation of compound 102:

[0833] INT-15 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyanoacetic acid (29 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 102 in 78% yield. MS (ESI, positive ion) m / z: 500.2 [M+H] + .

[0834] 1H NMR (400MHz, DMSO-d6) δ11.29 (s, 1H), 8.92 (d, J = 7.1Hz, 1H), 8.62 (d, J = 8.2Hz, 1H), 8 .55 (d, J=1.8Hz, 1H), 8.27 (s, 1H), 7.94 (d, J=1.8Hz, 1H), 7.77 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 7.57-7.49 (m, 3H), 7.23 (t, J=8.8Hz, 2H), 5.53-5.43 (m, 1H), 4 .76(d, J=8.0Hz, 1H), 4.67-4.61(m, 1H), 3.93(s, 3H), 2.72-2.55(m, 1H), 2.35(s, 1H).

[0835] Preparation of compound 103 in Example 103:

[0836]

[0837] Preparation of compound 103:

[0838] Compound 95-1 (100 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (32 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 103, in 61% yield. MS (ESI, positive ion) m / z: 560.2 [M+H] + .

[0839] 1 H NMR (400MHz, DMSO-d6) δ9.63 (s, 1H), 8.84 (d, J = 7.1Hz, 1H), 8.69 (d, J = 8.3Hz, 1H), 8.54 (d, J = 1.3Hz, 1H) , 8.26 (s, 1H), 7.86 (dd, J=1.9, 0.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.72 (d, J=8.6Hz, 1H), 7.59-7.5 3 (m, 2H), 7.43 (dd, J=7.1, 2.0Hz, 1H), 7.21 (t, J=8.7Hz, 2H), 5.49 (dq, J=14.9, 7.2Hz, 1H), 4.76 (dd, J=6 .6, 3.3Hz, 1H), 4.68-4.60 (m, 1H), 3.93 (s, 3H), 3.55 (dd, J=7.6, 3.8Hz, 4H), 3.31 (dd, J=7.4, 3.7Hz, 4H).

[0840] Example 104: Preparation of compound 104:

[0841]

[0842] Preparation of compound 104:

[0843] INT-15 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 104 in 71% yield. MS (ESI, positive ion) m / z: 545.2 [M+H] + .

[0844] 1 H NMR (400MHz, DMSO-d6) δ9.63 (s, 1H), 8.84 (d, J = 7.1Hz, 1H), 8.69 (d, J = 8.3Hz, 1H), 8.54 (d, J = 1.3Hz , 1H), 8.26 (s, 1H), 7.86 (dd, J=1.9, 0.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.72 (d, J=8.6Hz, 1H), 7 .59-7.53 (m, 2H), 7.43 (dd, J=7.1, 2.0Hz, 1H), 7.21 (t, J=8.7Hz, 2H), 5.49 (dq, J=14.9, 7.2Hz, 1H), 4.76 (dd, J=6.6, 3.3Hz, 1H), 4.68-4.60 (m, 1H), 3.93 (s, 3H), 3.67 (m, 2H), 3.53 (m, 1H), 1.88 (m, 4H).

[0845] Preparation of compound 105 in Example 105:

[0846]

[0847] Preparation of compound 105:

[0848] INT-15 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylcyclobutanecarboxylic acid (34 mg, 0.3 mmol) and 1-propylphosphoric 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 105 in 71% yield. MS (ESI, positive ion) m / z: 543.2 [M+H] + .

[0849] 1 H NMR (400MHz, DMSO-d6) δ9.62 (s, 1H), 8.83 (d, J = 7.1Hz, 1H), 8.62 (d, J = 8.3Hz, 1H), 8.54 (d, J = 1. 8Hz, 1H), 8.27 (s, 1H), 7.85 (dd, J=1.9, 0.9Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.69 (d, J=8.6Hz , 1H), 7.59-7.53 (m, 2H), 7.43 (dd, J=7.1, 2.0Hz, 1H), 7.23 (t, J=8.9Hz, 2H), 5.48 (dq, J=14.9, 7. 2Hz, 1H), 4.75 (dd, J=6.6, 3.3Hz, 1H), 4.68-4.60 (m, 1H), 3.93 (s, 3H), 2.78 (m, 4H), 1.23 (s, 3H).

[0850] Example 106: Preparation of compound 106:

[0851]

[0852] Preparation of compound 106:

[0853] Intermediate INT-3 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-tetrahydrofuranic acid (30 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 106 in 55% yield. MS (ESI, positive ion) m / z: 527.2 [M+H] + .

[0854] 1H NMR (400MHz, DMSO-d6) δ10.44 (s, 1H), 8.79 (d, J = 7.4Hz, 1H), 8.56 (d, J = 1.4Hz, 1H), 8.34 (d, J =8.1Hz, 1H), 8.22 (s, 1H), 7.92 (d, J = 1.9Hz, 1H), 7.72 (dd, J = 8.6, 1.8Hz, 1H), 7.61 (d, J = 8.7H z, 1H), 7.43 (ddt, J=5.8, 4.1, 1.7Hz, 3H), 7.24-7.12 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 3.91 (s, 3 H), 3.27 (s, 2H), 2.56 (dd, J=5.4, 3.6Hz, 4H), 2.1 (m, 2H), 1.87 (m, 1H), 1.50 (d, J=7.0Hz, 3H).

[0855] Example 107: Preparation of compound 107:

[0856]

[0857] Preparation of compound 107:

[0858] INT-3 (89 mg, 0.2 mmol) was dissolved in THF (1 mL), and dihydro-3(2H)-furanone (0.2 mL) and tetraisopropyl titanate (0.1 mL) were added. The mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, sodium borohydride (23 mg, 0.6 mmol) was added. After 1 hour, the reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 107, yield 18%. MS (ESI, positive ion) m / z: 499.2 [M+H]+.

[0859] 1 H NMR (400MHz, DMSO-d6) δ10.56 (s, 1H), 8.87 (d, J = 7.1Hz, 1H), 8.53 (d, J = 1.9Hz, 1H), 8.3 8(d, J=8.1Hz, 1H), 8.22 (s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.8Hz, 1H), 7.6 7(d, J=8.7Hz, 1H), 7.47 (ddt, J=5.8, 4.1, 1.7Hz, 3H), 7.23-7.11 (m, 2H), 5.24 (p, J=7.2 Hz, 1H), 3.92 (s, 3H), 3.76 (m, 1H), 2.56 (dd, J=5.4, 3.4Hz, 4H), 2.15 (m, 2H), 1.50 (d, J=

[0860] 7.0Hz, 3H).

[0861] Example 108: Preparation of compound 108:

[0862]

[0863] Preparation of compound 108:

[0864] INT-15 (89 mg, 0.2 mmol) was dissolved in THF (1 mL), and cyclopropylformaldehyde (0.2 mL) and tetraisopropyl titanate (0.1 mL) were added. The mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, sodium borohydride (23 mg, 0.6 mmol) was added. After 1 hour, the reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 108, in 23% yield. MS (ESI, positive ion) m / z: 501.2 [M+H] + .

[0865] 1 H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.84 (d, J = 7.1Hz, 1H), 8.65 (d, J = 8.2Hz, 1H), 8.55 (d, J = 1. 9Hz, 1H), 8.28 (s, 1H), 7.83 (dd, J=1.9, 0.9Hz, 1H), 7.75 (dd, J=8.6, 1.9Hz, 1H), 7.71 (d, J=8.6Hz , 1H), 7.62-7.53 (m, 2H), 7.46 (dd, J=7.1, 2.0Hz, 1H), 7.23 (t, J=8.8Hz, 2H), 5.48 (dq, J=14.9, 7 .2Hz, 1H), 4.75 (dd, J=6.6, 3.3Hz, 1H), 4.68-4.60 (m, 1H), 3.93 (s, 3H), 3.23 (m, 2H), 1.10 (m, 5H)

[0866] Example 109: Preparation of compound 109:

[0867]

[0868] Preparation of compound 109:

[0869] Intermediate INT-15 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-tetrahydrofuranic acid (30 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 109 in 65% yield. MS (ESI, positive ion) m / z: 545.2 [M+H] + .

[0870] 1 H NMR (400MHz, DMSO-d6) δ9.63 (s, 1H), 8.84 (d, J = 7.1Hz, 1H), 8.65 (d, J = 8.2Hz, 1H), 8.57 (d, J = 1.9Hz , 1H), 8.29 (s, 1H), 7.84 (dd, J=1.9, 0.9Hz, 1H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.73 (d, J=8.6Hz, 1H), 7 .63-7.53 (m, 2H), 7.44 (dd, J=7.1, 2.0Hz, 1H), 7.23 (t, J=8.8Hz, 2H), 5.48 (dq, J=14.9, 7.2Hz, 1H), 4.75(dd, J=6.6, 3.3Hz, 1H), 4.68-4.60(m, 1H), 3.93(s, 3H), 2.92(m, 4H), 1.67(m, 2H), 1.32(m, 1H).

[0871] Example 110: Preparation of compound 110:

[0872]

[0873] Preparation of compound 110:

[0874] Intermediate INT-15 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2,2-difluorocyclopropanecarboxylic acid (36 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 110 in 65% yield. MS (ESI, positive ion) m / z: 551.2 [M+H] + .

[0875] 1H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.83 (d, J=7.2Hz, 1H), 8.64 (d, J=8.3Hz, 1H), 8.55 (d, J=1. 9Hz, 1H), 8.30 (s, 1H), 7.83 (dd, J=2.2, 0.9Hz, 1H), 7.73 (dd, J=8.6, 1.9Hz, 1H), 7.71 (d, J=8.4Hz , 1H), 7.63-7.53 (m, 2H), 7.44 (dd, J=7.1, 2.0Hz, 1H), 7.23 (t, J=8.8Hz, 2H), 5.48 (dq, J=14.9, 7. 2Hz, 1H), 4.75 (dd, J=6.6, 3.3Hz, 1H), 4.68-4.60 (m, 1H), 3.93 (s, 3H), 2.02 (m, 2H), 1.86 (m, 1H).

[0876] Example 111: Preparation of compound 111:

[0877]

[0878] Preparation of compound 111:

[0879] Intermediate INT-15 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 111 in 45% yield. MS (ESI, positive ion) m / z: 555.2 [M+H] + .

[0880] 1H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 8.81 (d, J = 7.2Hz, 1H), 8.64 (d, J = 8.3Hz, 1H), 8.61 (d, J = 1. 9Hz, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.83 (dd, J=2.2, 0.9Hz, 1H), 7.73 (dd, J=8.6, 1. 9Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 7.63-7.53 (m, 2H), 7.44 (dd, J=7.1, 2.0Hz, 1H), 7.23 (t, J=8.8Hz , 2H), 5.48 (dq, J=14.9, 7.2Hz, 1H), 4.75 (dd, J=6.6, 3.3Hz, 1H), 4.68-4.60 (m, 1H), 3.95 (s, 6H).

[0881] Example 112: Preparation of compound 112:

[0882]

[0883] Preparation of compound 112:

[0884] Intermediate INT-15 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-methoxypropionic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 112 in 45% yield. MS (ESI, positive ion) m / z: 533.2 [M+H] + .

[0885] 1H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 8.82 (d, J = 7.3Hz, 1H), 8.63 (d, J = 8.5Hz, 1H), 8.52 (d, J = 1.9Hz, 1 H), 8.30 (s, 1H), 7.83 (dd, J=2.2, 0.9Hz, 1H), 7.73 (dd, J=8.5, 1.9Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 7.63- 7.53 (m, 2H), 7.44 (dd, J=7.2, 2.0Hz, 1H), 7.22 (t, J=8.8Hz, 2H), 5.48 (dq, J=14.9, 7.2Hz, 1H), 4.75 (d d, J=6.6, 3.3Hz, 1H), 4.68-4.60 (m, 1H), 3.93 (s, 3H), 2.64 (s, 3H), 2.58 (m, 1H), 1.52 (d, J=2.8Hz, 3H).

[0886] Example 113: Preparation of compound 113:

[0887]

[0888] Preparation of compound 113:

[0889] Intermediate INT-15 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-fluorocyclopropanecarboxylic acid (31 mg, 0.3 mmol) and 1-propylphosphoric 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 113 in 55% yield. MS (ESI, positive ion) m / z: 533.2 [M+H] + .

[0890] 1H NMR (400MHz, DMSO-d6) δ10.56 (s, 1H), 8.91 (d, J = 7.2Hz, 1H), 8.57 (d, J = 1.6Hz, 1H) , 8.39 (d, J = 8.2Hz, 1H), 8.22 (s, 1H), 7.92 (d, J = 1.9Hz, 1H), 7.75 (dd, J = 8.4, 1.6Hz, 1H), 7.65 (d, J=8.7Hz, 1H), 7.44 (ddt, J=5.8, 4.1, 1.7Hz, 3H), 7.21-7.12 (m, 2H), 5 .23 (p, J=7.2Hz, 1H), 3.91 (s, 3H), 2.67 (m, 4H), 1.50 (d, J=7.0Hz, 3H), 1.20 (s, 3H).

[0891] Example 114: Preparation of compound 114:

[0892]

[0893] Preparation of compound 114:

[0894] Intermediate INT-15 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 114 in 55% yield. MS (ESI, positive ion) m / z: 515.2 [M+H] + .

[0895] 1 H NMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 8.86 (d, J = 7.1Hz, 1H), 8.67 (d, J = 8.3Hz, 1H), 8.55 (d, J = 1.8H z, 1H), 8.30 (s, 1H), 7.90 (d, J=2.0Hz, 1H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 7.45 (ddd, J=14.3, 6.8, 1.8Hz, 2H), 7.40-7.33 (m, 2H), 7.20-7.11 (m, 1H), 5.51 (dq, J=14.5, 6.6Hz, 1H), 4.78 (d, J=6.5Hz, 1H), 4.66 (d, J=6.5Hz, 1H), 3.94 (s, 3H), 2.15-1.97 (m, 1H), 1.25 (d, J=2.9Hz, 4H).

[0896] Example 115: Preparation of compound 115:

[0897]

[0898] Preparation of compound 115:

[0899] Intermediate INT-3 (83 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (39 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 115 in 55% yield. MS (ESI, positive ion) m / z: 552.2 [M+H] + .

[0900] 1 H NMR (400MHz, DMSO-d6) δ11.68 (s, 1H), 8.96 (dd, J=7.1, 0.8Hz, 1H), 8.58 (d, J=1.8Hz, 1H), 8. 47 (d, J=5.2Hz, 1H), 8.38 (d, J=8.0Hz, 1H), 8.24 (s, 1H), 7.97 (dd, J=2.0, 0.9Hz, 1H), 7.90 (dt , J=5.2, 1.7Hz, 1H), 7.807.71 (m, 2H), 7.68 (d, J=8.6Hz, 1H), 7.54 (dd, J=7.2, 2.0Hz, 1H), 7.5 0-7.42 (m, 2H), 7.22-7.12 (m, 2H), 5.23 (p, J=7.1Hz, 1H), 3.92 (s, 3H), 1.51 (d, J=7.1Hz, 3H).

[0901] Example 116: Preparation of compound 116:

[0902]

[0903] Preparation of compound 116-1:

[0904] Intermediate INT-3 (42.8 g, 100 mmol) was dissolved in dichloromethane (1 L), and methyl chloroformate (11.2 g, 120 mmol) and N,N-diisopropylethylamine (25.8 g, 200 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 116-1, with a yield of 65%. MS (ESI, positive ion) m / z: 487.2 [M+H] + .

[0905] Preparation of compound 116:

[0906] Compound 116-1 (97 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 116 in 58% yield. MS (ESI, positive ion) m / z: 542.2 [M+H] + .

[0907] 1 H NMR (400MHz, DMSO-d6) δ9.60 (s, 1H), 8.85-8.79 (m, 1H), 8.60-8.48 (m, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.23 ​​(s, 1H), 7.84 (dd, J=2.1, 0.8Hz, 1H), 7.74 (dd, J=8.6, 1.9Hz, 1H), 7.67 (d, J=8 .6Hz, 1H), 7.49-7.45 (m, 2H), 7.43 (dd, J=7.1, 2.0Hz, 1H), 7.17 (t, J=8.9Hz, 2H), 5.21 (q, J =7.2Hz, 1H), 3.91 (s, 3H), 3.66-3.58 (m, 4H), 3.48 (t, J = 4.8Hz, 4H), 1.50 (d, J = 7.1Hz, 3H).

[0908] Example 117: Preparation of compound 117:

[0909]

[0910] Preparation of compound 117:

[0911] INT-3 (83 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 117 in 69% yield. MS (ESI, positive ion) m / z: 527.2 [M+H] + .

[0912] 1 H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.93-8.86 (m, 1H), 8.56 (d, J = 1.9Hz, 1H), 8.37 (d, J = 8.0Hz, 1H), 8.23 (s, 1H), 7.94-7.89 (m, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.57-7.43 (m, 3H), 7.22-7.12 (m, 2H), 5.23 (p, J=7.1Hz, 1H), 4.54 (s, 1H), 4.02 (q, J=6.9Hz, 1H), 3.92 (s, 3H), 3.85 (ddd, J =7.9, 7.0, 5.9Hz, 1H), 2.31-2.18(m, 1H), 2.06-1.95(m, 1H), 1.95-1.81(m, 2H), 1.51(d, J=7.1Hz, 3H).

[0913] Example 118: Preparation of compound 118:

[0914]

[0915] Preparation of compound 118-1:

[0916] Intermediate INT-4 (42.8 g, 100 mmol) was dissolved in dichloromethane (1 L), and methyl chloroformate (11.2 g, 120 mmol) and N,N-diisopropylethylamine (25.8 g, 200 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 118-1, with a yield of 65%. MS (ESI, positive ion) m / z: 487.2 [M+H] + .

[0917] Preparation of compound 118:

[0918] Compound 118-1 (97 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 118 in 58% yield. MS (ESI, positive ion) m / z: 542.2 [M+H] + .

[0919] 1 H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.85 (d, J=7.2Hz, 1H), 8.53 (s, 1H), 8.42 (d, J= 8.0Hz, 1H), 8.24 (s, 1H), 7.93 (s, 1H), 7.76 (d, J=8.6Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 7 .48(d, J=7.2Hz, 1H), 7.42(q, J=7.5Hz, 1H), 7.27(t, J=9.0Hz, 2H), 7.11-7.02(m, 1H) , 5.25 (p, J=7.2Hz, 1H), 3.92 (s, 3H), 3.50 (m, 4H), 2.67 (m, 4H), 1.52 (d, J=7.1Hz, 3H).

[0920] Example 119: Preparation of compound 119:

[0921]

[0922] Preparation of compound 119:

[0923] INT-4 (83 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 119 in 69% yield. MS (ESI, positive ion) m / z: 527.2 [M+H] + .

[0924] 1H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.89 (d, J = 7.2Hz, 1H), 8.56 (s, 1H), 8.41 (d, J = 8.0Hz, 1H), 8.25 (s, 1 H), 7.91 (s, 1H), 7.75 (d, J = 8.6Hz, 1H), 7.68 (d, J = 8.7Hz, 1H), 7.49 (d, J = 7.2Hz, 1H), 7.40 (q, J = 7.5Hz, 1H), 7.27 (t, J=9.0Hz, 2H), 7.11-7.02 (m, 1H), 5.25 (p, J=7.2Hz, 1H), 4.01 (t, J=7.1Hz, 1H), 3.92 (s, 3H), 3.82 ( dt, J=14.0, 7.1Hz, 2H), 2.22 (ddq, J=26.5, 12.3, 7.3, 6.4Hz, 2H), 1.93-1.84 (m, 3H), 1.52 (d, J=7.1Hz, 3H).

[0925] Example 120: Preparation of compound 120:

[0926]

[0927] Preparation of compound 120:

[0928] Intermediate INT-4 (83 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 120 in 45% yield. MS (ESI, positive ion) m / z: 537.2 [M+H] + .

[0929] 1H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.91 (dd, J=7.2, 0.8Hz, 1H), 8.65 (d, J=1.9Hz, 1H), 8.38 (d, J=8.2Hz, 1H), 8.18 (s, 1H), 7.95 (dd, J=1.9, 0.9Hz, 1H), 7.76 (dd, J=8.7, 1.9Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.32 (dd , J=8.1, 5.4Hz, 1H), 7.06 (td, J=8.6, 7.6, 1.7Hz, 2H), 5.60 (q, J=8.1Hz, 1H), 4.54 (s, 1H), 4.07-3.94 (m, 1H), 3.90 (s, 3H) , 3.88-3.82 (m, 1H), 3.05-2.94 (m, 1H), 2.85 (dt, J=16.1, 8.5Hz, 1H), 2.56 (dd, J=7.9, 3.1Hz, 1H), 2.32-2.16 (m, 1H), 2.09 1.88(m,4H).

[0930] Example 121 Preparation of compound 121:

[0931]

[0932] Preparation of compound 121:

[0933] INT-5 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 121 in 71% yield. MS (ESI, positive ion) m / z: 539.2 [M+H] + .

[0934] 1H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.91 (dd, J=7.2, 0.8Hz, 1H), 8.65 (d, J=1.9Hz, 1H), 8.38 (d, J=8.2Hz, 1H), 8.18 (s, 1H) , 7.95 (dd, J=1.9, 0.9Hz, 1H), 7.76 (dd, J=8.7, 1.9Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.32 (dd, J=8.1 , 5.4Hz, 1H), 7.06 (td, J=8.6, 7.6, 1.7Hz, 2H), 5.60 (q, J=8.1Hz, 1H), 4.54 (s, 1H), 4.07-3.94 (m, 1H), 3.90 (s, 3H), 3.88-3.8 2 (m, 1H), 3.05-2.94 (m, 1H), 2.85 (dt, J=16.1, 8.5Hz, 1H), 2.56 (dd, J=7.9, 3.1Hz, 1H), 2.32-2.16 (m, 1H), 2.09-1.88 (m, 4H).

[0935] Example 122: Preparation of compound 122:

[0936]

[0937] Preparation of compound 122:

[0938] Intermediate INT-5 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 122 in 44% yield. MS (ESI, positive ion) m / z: 549.2 [M+H] + .

[0939] 1H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 8.93 (d, J = 7.1Hz, 1H), 8.66 (d, J = 1.8Hz, 1H), 8.44 (s, 1H), 8.39 (d, J = 8.3 Hz, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.95 (d, J=1.9Hz, 1H), 7.77 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.5 3 (dd, J=7.2, 2.0Hz, 1H), 7.31 (dd, J=8.8, 5.2Hz, 1H), 7.06 (t, J=7.8Hz, 2H), 5.62 (t, J=8.1Hz, 1H), 3.91 (d, J=7 .9Hz, 6H), 3.05-2.94 (m, 1H), 2.85 (dt, J=16.4, 8.7Hz, 1H), 2.57 (d, J=8.8Hz, 1H), 2.05 (dq, J=12.3, 8.8Hz, 1H).

[0940] Preparation of compound 123 in Example 123:

[0941]

[0942] Preparation of compound 123:

[0943] Intermediate INT-5 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 mg, 0.3 mmol) and 1-propylphosphonic anhydride were added.

[0944] (111 mg, 0.351 mmol), heated to 80 °C, stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 123, yield 54%. MS (ESI, positiveion) m / z: 526.2 [M+H] + .

[0945] 1H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.91 (d, J = 7.1Hz, 1H), 8.65 (d, J = 1.9Hz, 1H), 8.38 (d, J = 8.2Hz, 1 H), 8.18 (s, 1H), 7.97-7.92 (m, 1H), 7.77 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 7.52 (dd, J=7.1, 2.0Hz, 1H), 7.36-7.28 (m, 1H), 7.06 (d, J=9.1Hz, 2H), 5.61 (q, J=8.1Hz, 1H), 3.90 (s, 3H), 3.22 (s, 2H), 3 .05-2.95 (m, 1H), 2.86 (dt, J=16.0, 8.5Hz, 1H), 2.56 (s, 1H), 2.33 (s, 6H), 2.05 (dq, J=12.5, 8.8Hz, 1H).

[0946] Example 124: Preparation of compound 124:

[0947]

[0948] Preparation of compound 124:

[0949] Intermediate INT-5 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and acetic acid (18 mg, 0.3 mmol) and 1-propylphosphoric 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 124 in 55% yield. MS (ESI, positive ion) m / z: 483.2 [M+H] + .

[0950] 1H NMR (400MHz, DMSO-d6) δ10.79 (s, 1H), 8.89 (dd, J=7.1, 0.9Hz, 1H), 8.64 (d, J=1.9Hz, 1H), 8.37 (d, J=8.2Hz, 1 H), 8.17 (s, 1H), 7.93 (dd, J=2.1, 0.9Hz, 1H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 7.50 (dd, J=7 .1, 2.0Hz, 1H), 7.35-7.29 (m, 1H), 7.06 (t, J=8.4Hz, 2H), 5.60 (q, J=8.1Hz, 1H), 3.90 (s, 3H), 3.00 (dd, J=13. 8, 8.6Hz, 1H), 2.86 (dt, J=16.0, 8.3Hz, 1H), 2.55 (d, J=5.6Hz, 1H), 2.18 (s, 3H), 2.05 (dq, J=12.4, 8.8Hz, 1H).

[0951] Example 125: Preparation of compound 125:

[0952]

[0953] Preparation of compound 125:

[0954] Intermediate INT-6 (91 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and acetic acid (18 mg, 0.3 mmol) and 1-propylphosphoric 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 125 in 55% yield. MS (ESI, positive ion) m / z: 501.2 [M+H] + .

[0955] 1H NMR (400MHz, DMSO-d6) δ10.79 (s, 1H), 8.88 (dd, J=7.1, 0.8Hz, 1H), 8.57 (d, J=1.8Hz, 1H), 8.30 (d, J=3.8Hz, 1H), 8.07 (s, 1H), 7.91 (dd, J=2.0, 0.9Hz, 1H), 7.75 (dd, J=8.6, 1.9Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7.48 (dd, J =7.2, 2.0Hz, 1H), 7.36 (dt, J = 10.9, 8.6Hz, 1H), 7.28 (ddd, J = 12.2, 7.8, 2.2Hz, 1H), 7.13-7.06 (m, 1H), 3.90 (s, 3H), 3.06-3.00 (m, 1H), 2.21 (d, J=21.2Hz, 3H), 2.13-2.05 (m, 1H), 1.41-1.35 (m, 1H), 1.33-1.23 (m, 1H).

[0956] Example 126: Preparation of compound 126:

[0957]

[0958] Preparation of compound 126:

[0959] Intermediate INT-6 (91 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 126 in 54% yield. MS (ESI, positive ion) m / z: 544.2 [M+H] + .

[0960] 1H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.93-8.86 (m, 1H), 8.57 (d, J = 1.9Hz, 1H), 8.30 (d, J = 3.9Hz, 1H), 8.07 (s, 1H), 7.92 (dd, J=2.0, 0.8Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.50 (dd, J=7.2, 2.0Hz, 1H), 7.42-7.23 (m, 2H), 7.10 (s, 1H), 3.91 (s, 3H), 3.21 (s, 2H), 3.02 (dd, J =8.0, 4.2Hz, 1H), 2.33 (s, 6H), 2.13-2.04 (m, 1H), 1.38 (dt, J = 9.8, 5.3Hz, 1H), 1.33-1.24 (m, 1H).

[0961] Example 127: Preparation of compound 127:

[0962]

[0963] Preparation of compound 127:

[0964] Intermediate INT-7 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and acetic acid (18 mg, 0.3 mmol) and 1-propylphosphoric 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 127 in 53% yield. MS (ESI, positive ion) m / z: 483.2 [M+H] + .

[0965] 1H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 8.90 (d, J = 7.0Hz, 1H), 8.64 (d, J = 1.9Hz, 1H), 8.33 (d, J = 8.3Hz, 1H), 8.16 (s, 1H), 7 .957.90 (m, 1H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.68 (d, J=8.7Hz, 1H), 7.50 (dd, J=7.1, 2.0Hz, 1H), 7.31 (dd, J=8.4, 5.4Hz, 1 H), 7.13 (d, J=9.5Hz, 1H), 7.03 (t, J=8.8Hz, 1H), 5.58 (q, J=8.0Hz, 1H), 3.89 (s, 3H), 3.03 (dd, J=13.2, 1 0.0Hz, 1H), 2.89 (dt, J=16.3, 8.5Hz, 1H), 2.60-2.54 (m, 1H), 2.18 (s, 3H), 2.05 (dq, J=12.6, 8.7Hz, 1H).

[0966] Example 128: Preparation of compound 128:

[0967]

[0968] Preparation of compound 128:

[0969] INT-7 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 128 in 71% yield. MS (ESI, positive ion) m / z: 539.2 [M+H] + .

[0970] 1H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.92 (d, J = 7.1Hz, 1H), 8.64 (d, J = 1.8Hz, 1H), 8.33 (d, J = 8.3Hz, 1H), 8.16 (s, 1H), 7.9 7-7.92 (m, 1H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.68 (d, J=8.7Hz, 1H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.31 (dd, J=8.3, 5.4Hz, 1H) , 7.13 (d, J=9.4Hz, 1H), 7.03 (t, J=8.9Hz, 1H), 5.58 (q, J=7.9Hz, 1H), 4.54 (s, 1H), 4.02 (q, J=7.0Hz, 1H), 3.89 (s, 3H), 3.85 (q, J=7.2Hz, 1H), 3.09-2.99 (m, 1H), 2.89 (dt, J=16.3, 8.5Hz, 1H), 2.59-2.54 (m, 1H), 2.31-2.16 (m, 1H), 2.11-1.83 (m, 4H).

[0971] Example 129: Preparation of compound 129:

[0972]

[0973] Preparation of compound 129:

[0974] INT-7 (88 mg, 0-2 mmol) was dissolved in pyridine (1 mL), and (S)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 129, yield 61%. MS (ESI, positive ion) m / z: 539.2 [M+H] + .

[0975] 1H NMR (400MHz, DMSO-d6) δ10.48 (s, 1H), 8.95-8.89 (m, 1H), 8.65 (d, J = 1.9Hz, 1H), 8.33 (d, J = 8.3Hz, 1H), 8.16 (s, 1H), 7.95 (dd, J =2.0, 0.9Hz, 1H), 7.77 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.31 (dd, J=8.3, 5.4Hz, 1H), 7 .13 (d, J=9.0Hz, 1H), 7.03 (t, J=8.9Hz, 1H), 5.58 (q, J=8.0Hz, 1H), 4.54 (s, 1H), 4.02 (q, J=7.0Hz, 1H), 3.89 (s, 3H), 3.85 (q, J=7 .0Hz, 1H), 3.09-2.99 (m, 1H), 2.89 (dt, J=16.2, 8.4Hz, 1H), 2.58-2.54 (m, 1H), 2.25 (dq, J=11.3, 7.8Hz, 1H), 2.09-1.87 (m, 4H).

[0976] Example 130: Preparation of compound 130:

[0977]

[0978] Preparation of compound 130:

[0979] INT-8 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (26 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 130 in 61% yield. MS (ESI, positive ion) m / z: 516.2 [M+H] + .

[0980] 1H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 8.88 (d, J=7.0Hz, 1H), 8.63 (d, J=1.9Hz, 1H), 8.43 (d, J=8.2Hz, 1H), 8.15 (s, 1H), 7.92 (d, J=1.9Hz, 1H), 7.80-7.73 (m, 2H), 7.69 (dd, J=8.5, 3.1Hz, 2H), 7.53-7.44 (m, 2H), 5.66 (q, J=8.5Hz, 1H), 3.90 (s, 3H), 3.13-3.03 (m, 1H), 2.95 (dt, J=1 6.4, 8.7Hz, 1H), 2.14-2.02 (m, 2H), 1.30 (ddd, J=4.0, 3.0, 2.0Hz, 1H), 0.86 (d, J=6.1Hz, 4H).

[0981] Example 131: Preparation of compound 131:

[0982]

[0983] Preparation of compound 131:

[0984] INT-8 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 131 in 71% yield. MS (ESI, positive ion) m / z: 546.2 [M+H] + .

[0985] 1H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.92 (d, J = 7.3Hz, 1H), 8.64 (d, J = 1.9Hz, 1H), 8.43 (d, J = 8.3Hz, 1H), 8. 15 (s, 1H), 7.95 (dd, J=2.0, 0.8Hz, 1H), 7.81-7.74 (m, 2H), 7.73-7.65 (m, 2H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.4 8 (d, J=7.9Hz, 1H), 5.66 (q, J=8.3Hz, 1H), 4.54 (s, 1H), 4.02 (q, J=7.0Hz, 1H), 3.90 (s, 3H), 3.85 (q, J=7.0Hz, 1 H), 3.14-3.03 (m, 1H), 2.95 (dt, J=16.5, 8.7Hz, 1H), 2.59-2.54 (m, 1H), 2.32-2.18 (m, 1H), 2.14-1.83 (m, 4H).

[0986] Example 132: Preparation of compound 132:

[0987]

[0988] Preparation of compound 132:

[0989] Intermediate INT-8 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and acetic acid (18 mg, 0.3 mmol) and 1-propylphosphoric 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 132 in 53% yield. MS (ESI, positive ion) m / z: 490.2 [M+H] + .

[0990] 1H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 8.90 (dd, J=7.1, 0.8Hz, 1H), 8.63 (d, J=2.1Hz, 1H), 8.43 (d, J=8.3Hz, 1H), 8.15 (s, 1H), 7.93 (dd, J=1.9, 0.9Hz, 1H), 7.80-7.73 (m, 2H), 7.69 (dd, J=8.9 , 2.8Hz, 2H), 7.53-7.44(m, 2H), 5.66(q, J=8.3Hz, 1H), 3.90(s, 3H), 3.13-3.03(m, 1H), 2.95(d t, J=16.2, 8.5Hz, 1H), 2.57 (dd, J=8.1, 2.7Hz, 1H), 2.18 (s, 3H), 2.07 (dq, J=12.4, 8.9Hz, 1H).

[0991] Example 133: Preparation of compound 133:

[0992]

[0993] Preparation of compound 133:

[0994] Intermediate INT-8 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 133, yield 44%. MS (ESI, positive ion) m / z: 556.2 [M+H] + .

[0995] 1H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 8.94 (dd, J=7.1, 0.8Hz, 1H), 8.65 (d, J=2.0Hz, 1H), 8.44 (d, J =7.3Hz, 2H), 8.18-8.07(m, 2H), 7.96(dd, J=2.0, 0.9Hz, 1H), 7.82-7.75(m, 2H), 7.73-7.65(m, 2H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.48 (d, J=7.8Hz, 1H), 5.66 (q, J=8.4Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H) , 3.08 (dd, J=15.5, 9.1Hz, 1H), 2.95 (dt, J=16.5, 8.7Hz, 1H), 2.60-2.54 (m, 1H), 2.14-2.00 (m, 1H).

[0996] Example 134: Preparation of compound 134:

[0997]

[0998] Preparation of compound 134:

[0999] INT-8 (89 mg, 0-2 mmol) was dissolved in pyridine (1 mL), and (S)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 134 in 61% yield. MS (ESI, positive ion) m / z: 546.2 [M+H] + .

[1000] 1H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 8.93 (d, J = 7.1Hz, 1H), 8.64 (d, J = 1.8Hz, 1H), 8.45 (d, J = 8.2Hz, 1H), 8.16 (s, 1H), 7.98-7.93 (m, 1H), 7.81-7.74 (m, 2H), 7.73-7.66 (m, 2H), 7.53 (dd, J=7.1, 2.0Hz, 1H), 7.48 (d, J=7.8Hz, 1H), 5.67 (q, J=8.3Hz, 1H), 4.54 (s, 1H), 4.02 (q, J=6.9Hz, 1H), 3.91 (s, 3H), 3.85 (q, J=7.1Hz, 1H ), 3.143.03 (m, 1H), 2.95 (dt, J=16.4, 8.6Hz, 1H), 2.60-2.55 (m, 1H), 2.32-2.19 (m, 1H), 2.14-1.84 (m, 4H).

[1001] Example 135: Preparation of compound 135:

[1002]

[1003] Preparation of compound 135:

[1004] Intermediate INT-8 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 135 in 54% yield. MS (ESI, positive ion) m / z: 533.2 [M+H] + .

[1005] 1H NMR (400MHz, DMSO-d6) δ8.93 (d, J=7.2Hz, 1H), 8.64 (d, J=1.8Hz, 1H), 8.45 (d, J=8.3Hz, 1H), 8.1 6 (s, 1H), 7.99-7.94 (m, 1H), 7.81-7.74 (m, 2H), 7.73-7.66 (m, 2H), 7.55 (dd, J=7.2, 2.0Hz, 1H), 7 .47 (d, J=8.0Hz, 1H), 5.66 (q, J=8.4Hz, 1H), 3.90 (s, 3H), 3.72 (s, 2H), 3.08 (dd, J=15.1, 7.9Hz, 1H), 2.95 (dt, J=16.5, 8.6Hz, 1H), 2.60 (d, J=17.7Hz, 6H), 2.58-2.55 (m, 1H), 2.14-2.00 (m, 1H).

[1006] Example 136: Preparation of compound 136:

[1007]

[1008] Preparation of compound 136:

[1009] INT-9 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (26 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 136, in 61% yield. MS (ESI, positive ion) m / z: 523.2 [M+H] + .

[1010] 1H NMR (400MHz, DMSO-d6) δ11.16 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.67 (d, J = 1.8Hz, 1H), 8.33 (d, J = 8.6H z, 1H), 8.19 (s, 1H), 7.94 (d, J=2.4Hz, 1H), 7.75 (dd, J=8.7, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.50 ( dd, J=7.2, 2.0Hz, 1H), 7.31 (dd, J=8.2, 6.1Hz, 1H), 6.99 (t, J=8.8Hz, 2H), 5.27 (q, J=8.4, 7.5Hz, 1H ), 3.88 (s, 3H), 2.91-2.73 (m, 2H), 2.00 (p, J=7.4, 6.5Hz, 2H), 1.92-1.73 (m, 2H), 0.93-0.80 (m, 5H).

[1011] Example 137: Preparation of compound 137:

[1012]

[1013] Preparation of compound 137:

[1014] INT-9 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 137 in 71% yield. MS (ESI, positive ion) m / z: 553.2 [M+H] + .

[1015] 1H NMR (400MHz, DMSO-d6) δ10.48 (s, 1H), 8.92 (dd, J=7.2, 0.8Hz, 1H), 8.66 (d, J=1.8Hz, 1H), 8.32 (d, J=8.6Hz, 1H), 8.1 8 (s, 1H), 7.94 (dd, J=2.0, 0.9Hz, 1H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.52 (dd, J=7.1, 2.0Hz, 1H) , 7.36-7.27 (m, 1H), 6.99 (d, J=9.2Hz, 2H), 5.27 (t, J=6.5Hz, 1H), 4.02 (q, J=7.0Hz, 1H), 3.89 (s, 3H), 3.88-3.80 (m, 2H), 2.83 (dt, J=7.3, 4.2Hz, 2H), 1.99 (dt, J=15.2, 8.1Hz, 4H), 1.91 (q, J=7.0Hz, 2H), 1.84 (dd, J=18.7, 10.8Hz, 2H).

[1016] Example 138: Preparation of compound 138:

[1017]

[1018] Preparation of compound 138:

[1019] 1NT-9 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and acetic acid (18 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 138 in 61% yield. MS (ESI, positive ion) m / z: 497.2 [M+H] + .

[1020] 1H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 8.90 (d, J = 7.0Hz, 1H), 8.65 (d, J = 1.9Hz, 1H), 8.32 (d , J=8.6Hz, 1H), 8.17 (s, 1H), 7.95-7.90 (m, 1H), 7.76 (dd, J=8.7, 1.8Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.50 (dd, J=7.1, 2.0Hz, 1H), 7.36-7.28 (m, 1H), 7.00 (t, J=8.5Hz, 2H), 5.27 (s, 1H) , 3.89 (s, 3H), 2.82 (d, J = 6.9Hz, 2H), 2.18 (s, 3H), 2.00 (d, J = 4.9Hz, 2H), 1.91-1.75 (m, 2H).

[1021] Example 139: Preparation of compound 139:

[1022]

[1023] Preparation of compound 139:

[1024] INT-9 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 139 in 68% yield. MS (ESI, positive ion) m / z: 553.2 [M+H] + .

[1025] 1H NMR (400MHz, DMSO-d6) δ10.48 (s, 1H), 8.92 (dd, J=7.2, 0.8Hz, 1H), 8.66 (d, J=1.8Hz, 1H), 8.32 (d, J=8.6Hz, 1H), 8.1 8 (s, 1H), 7.94 (dd, J=2.0, 0.9Hz, 1H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.52 (dd, J=7.1, 2.0Hz, 1H ), 7.367.27 (m, 1H), 6.99 (d, J=9.2Hz, 2H), 5.27 (t, J=6.5Hz, 1H), 4.02 (q, J=7.0Hz, 1H), 3.89 (s, 3H), 3.883.80 (m, 2 H), 2.83 (dt, J=7.3, 4.2Hz, 2H), 1.99 (dt, J=15.2, 8.1Hz, 4H), 1.91 (q, J=7.0Hz, 2H), 1.84 (dd, J=18.7, 10.8Hz, 2H).

[1026] Example 140: Preparation of compound 140:

[1027]

[1028] Preparation of compound 140:

[1029] INT-9 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 140 in 56% yield. MS (ESI, positive ion) m / z: 540.2 [M+H] + .

[1030] 1H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.94-8.88 (m, 1H), 8.65 (d, J = 1.8Hz, 1H), 8.31 (d, J = 8.6Hz, 1 H), 8.17 (s, 1H), 7.93 (dd, J=2.0, 0.9Hz, 1H), 7.76 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.7Hz, 1H), 7. 51 (dd, J=7.2, 2.0Hz, 1H), 7.36-7.27 (m, 1H), 7.00 (t, J=8.5Hz, 2H), 5.27 (s, 1H), 3.89 (s, 3H), 3.21 (s, 2H), 2.82 (d, J=6.4Hz, 2H), 2.33 (s, 6H), 2.06-1.94 (m, 2H), 1.84 (td, J=16.8, 14.5, 9.2Hz, 2H).

[1031] Example 141: Preparation of compound 141:

[1032]

[1033] Preparation of compound 141:

[1034] INT-9 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 141 in 62% yield. MS (ESI, positive ion) m / z: 563.2 [M+H] + .

[1035] 1H NMR (400MHz, DMSO-d6) δ10.93 (s, 1H), 8.94 (d, J = 7.1Hz, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 8.33 ( d, J=8.7Hz, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.98-7.93 (m, 1H), 7.81-7.74 (m, 1H), 7.69 (d, J=8. 7Hz, 1H), 7.52 (dd, J=7.3, 2.0Hz, 1H), 7.36-7.28 (m, 1H), 6.99 (d, J=9.2Hz, 2H), 5.28 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.82 (s, 2H), 2.66-2.56 (m, 1H), 2.00 (d, J=5.3Hz, 2H), 1.83 (s, 1H).

[1036] Example 142: Preparation of compound 142:

[1037]

[1038] Preparation of compound 142:

[1039] INT-9 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyanoacetic acid (25 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 142 in 71% yield. MS (ESI, positive ion) m / z: 522.2 [M+H] + .

[1040] 1H NMR (400MHz, DMSO-d6) δ11.27 (s, -1H), 8.94 (d, J = 7.1Hz, 1H), 8.66 (d, J = 1.9Hz, 1H), 8.32 (d, J = 8.6Hz, 1 H), 8.17 (s, 1H), 7.97 (dd, J=2.1, 0.9Hz, 1H), 7.77 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.7Hz, 1H), 7.54 (dd , J=7.1, 2.0Hz, 1H), 7.36-7.28 (m, 1H), 7.00 (t, J=8.4Hz, 2H), 5.27 (s, 1H), 3.90-3.88 (m, 3H), 2.82 (d, J =6.4Hz, 2H), 2.80-2.57(m, 1H), 2.50-2.26(m, 1H), 2.04-1.97(m, 2H), 1.84(dq, J=15.1, 8.2, 5.6Hz, 2H).

[1041] Example 143: Preparation of compound 143:

[1042]

[1043] Preparation of compound 143:

[1044] INT-10 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 143 in 72% yield. MS (ESI, positive ion) m / z: 563.2 [M+H] + .

[1045] 1H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 8.94 (dd, J=7.1, 0.8Hz, 1H), 8.67 (d, J=1.9Hz, 1H), 8.44 (s, 1H), 8.32 (d, J= 8.7Hz, 1H), 8.18 (s, 1H), 8.13 (d, J=0.8Hz, 1H), 7.95 (dd, J=2.0, 0.9Hz, 1H), 7.77 (dd, J=8.7, 1.9Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 7.52 (dd, J=7.2, 2.0Hz, 1H), 7.32 (dd, J=8.2, 6.1Hz, 1H), 7.00 (t, J=8.7Hz, 2H), 5.31-5.23 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.82 (d, J=6.7Hz, 2H), 2.01 (dd, J=9.0, 4.7Hz, 2H), 1.83 (ddd, J=23.5, 11.1, 7.9Hz, 2H).

[1046] Example 144: Preparation of compound 144:

[1047]

[1048] Preparation of compound 144:

[1049] INT-10 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 144 in 58% yield. MS (ESI, positive ion) m / z: 540.2 [M+H] + .

[1050] 1H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.91 (d, J = 7.0Hz, 1H), 8.65 (d, J = 1.8Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.17 (s, 1H), 7.93 (dd, J=2.1, 0.9Hz, 1H), 7.76 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H ), 7.51 (dd, J=7.2, 2.0Hz, 1H), 7.36-7.28 (m, 1H), 7.00 (t, J=8.4Hz, 2H), 5.27 (s, 1H), 3.89 (s, 3H), 3.21 (s, 2H), 2.82 (d, J=6.4Hz, 2H), 2.33 (s, 6H), 2.04-1.97 (m, 2H), 1.86 (dd, J=22.3, 13.8Hz, 2H).

[1051] Example 145: Preparation of compound 145:

[1052]

[1053] Preparation of compound 145:

[1054] INT-10 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and acetic acid (18 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 145 in 61% yield. MS (ESI, positive ion) m / z: 497.2 [M+H] + .

[1055] 1H NMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 8.90 (dd, J=7.1, 0.8Hz, 1H), 8.66 (d, J=1.9Hz, 1H), 8.33 (d , J=8.6Hz, 1H), 8.18 (s, 1H), 7.93 (dd, J=1.9, 0.9Hz, 1H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.68 (d, J= 8.6Hz, 1H), 7.50 (dd, J=7.1, 2.0Hz, 1H), 7.36-7.27 (m, 1H), 7.00 (t, J=8.5Hz, 2H), 5.27 (s, 1H), 3 .89 (s, 3H), 2.82 (d, J = 6.8Hz, 2H), 2.18 (s, 3H), 2.06-1.95 (m, 2H), 1.85 (dt, J = 17.8, 10.0Hz, 2H).

[1056] Example 146: Preparation of compound 146:

[1057]

[1058] Preparation of compound 146:

[1059] INT-9 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 146 in 68% yield. MS (ESI, positive ion) m / z: 553.2 [M+H] + .

[1060] 1H NMR (400MHz, DMSO-d6) δ10.48 (s, 1H), 8.92 (d, J = 7.1Hz, 1H), 8.66 (d, J = 1.8Hz, 1H), 8.32 (d, J = 8.6Hz, 1H), 8.18 ( s, 1H), 7.95 (d, J=2.0Hz, 1H), 7.76 (dd, J=8.7, 1.9Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.52 (dd, J=7.2, 2.0Hz, 1H), 7. 36-7.29 (m, 1H), 7.00 (t, J=8.4Hz, 2H), 5.28 (s, 1H), 4.54 (s, 1H), 4.02 (q, J=7.0Hz, 1H), 3.89 (s, 3H), 3.883.82 ( m, 1H), 2.82 (d, J=6.6Hz, 2H), 2.30-2.21 (m, 1H), 2.00 (q, J=6.5, 6.1Hz, 3H), 1.88 (ddd, J=32.1, 17.2, 9.5Hz, 4H).

[1061] Example 147: Preparation of compound 147:

[1062]

[1063] Preparation of compound 147:

[1064] INT-11 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 147 in 68% yield. MS (ESI, positive ion) m / z: 553.2 [M+H] + .

[1065] 1H NMR (400MHz, DMSO-d6) δ11.27 (s, -1H), 8.94 (d, J = 7.1Hz, 1H), 8.66 (d, J = 1.9Hz, 1H), 8.32 (d, J = 8.6Hz, 1 H), 8.17 (s, 1H), 7.97 (dd, J=2.1, 0.9Hz, 1H), 7.77 (dd, J=8.7, 1.9Hz, 1H), 7.68 (d, J=8.7Hz, 1H), 7.54 (dd , J=7.1, 2.0Hz, 1H), 7.36-7.28 (m, 1H), 7.00 (t, J=8.4Hz, 2H), 5.27 (s, 1H), 3.90-3.88 (m, 3H), 2.82 (d, J =6.4Hz, 2H), 2.80-2.57(m, 1H), 2.50-2.26(m, 1H), 2.04-1.97(m, 2H), 1.84(dq, J=15.1, 8.2, 5.6Hz, 2H).

[1066] Example 148: Preparation of compound 148:

[1067]

[1068] Preparation of compound 148:

[1069] INT-9 (91 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (26 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 148, in 61% yield. MS (ESI, positive ion) m / z: 525.2 [M+H] + .

[1070] 1H NMR (400MHz, DMSO-d6) δ11.10 (s, 1H), 9.22 (s, 1H), 8.93 (s, 1H), 8.63 (d, J=1.8Hz, 1H), 8.05 (s, 1H), 7.95 (d, J=1.9Hz, 1H), 7.81 (dd, J=8.7, 1.9Hz, 1H), 7.73 (d, J=8.6Hz, 1H), 7.61-7.57 (m, 2H), 7.51 (dd, J=7.1, 2.0Hz, 1H), 7.21 (d, J=8.9Hz, 2H), 5.13 (t, J=5.9Hz, 1H), 4.77 (d, J= 8.1Hz, 1H), 4.29 (d, J=8.1Hz, 1H), 3.93 (s, 3H), 3.66 (d, J=6.5Hz, 2H), 0.86 (d, J=6.2Hz, 5H).

[1071] Example 149: Preparation of compound 149:

[1072]

[1073] Preparation of compound 149:

[1074] INT-13 (94 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 149, yield 62%. MS (ESI, positive ion) m / z: 579.2 [M+H] + .

[1075] 1H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 8.95-8.85 (m, 1H), 8.44 (s, 1H), 8.19 (dd, J=9.3, 1.8Hz, 1H), 8.13 (s, 1H), 7.97-7.92 (m, 1H), 7.88 (d, J=9.6Hz, 1H), 7.78 (td, J=7.7, 6.8, 1.7Hz, 1H), 7.73-7.64 (m, 1H), 7.61-7.38 (m, 4H), 7.24 (t, J=8.9Hz, 2H), 5.63 (s, 1H), 4.50 (d, J=12.2Hz, 1H), 4.10 (d, J=1 3.4Hz, 1H), 3.98-3.93 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.87 (d, J=11.4Hz, 2H), 3.68-3.58 (m, 1H).

[1076] Example 150: Preparation of compound 150:

[1077]

[1078] Preparation of compound 150:

[1079] INT-13 (94 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 150, in 66% yield. MS (ESI, positive ion) m / z: 579.2 [M+H] + .

[1080] 1H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.90 (d, J=7.2Hz, 1H), 8.21-8.10 (m, 1H), 7.96-7.87 (m, 2H), 7.77 (dd, J=8.7, 1 .8Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.53 (dt, J=9.5, 4.7Hz, 2H), 7.48 (dd, J=7.2, 2.0Hz, 1H), 7.24 (t, J=8.9Hz, 2H), 5.63 (s, 1H), 4.49 (d, J=12.3Hz, 1H), 4.09 (d, J=13.5Hz, 1H), 4.02 (q, J=7.0Hz, 1H), 3.94 (dd, J=12.2, 3.5Hz, 2H), 3.89 (s, 3 H), 3.85 (q, J=7.1Hz, 2H), 3.63 (td, J=11.7, 2.9Hz, 1H), 3.29 (d, J=12.6Hz, 1H), 2.32-1.95 (m, 2H), 1.94-1.80 (m, 2H).

[1081] Example 151: Preparation of compound 151:

[1082]

[1083] Preparation of compound 151:

[1084] INT-13 (94 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (26 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 151 in 56% yield. MS (ESI, positive ion) m / z: 539.2 [M+H] + .

[1085] 1H NMR (400MHz, DMSO-d6) δ10.46 (s, 1H), 8.92 (d, J=7.3Hz, 1H), 8.22-8.11 (m, 1H), 7.97-7.88 ( m, 2H), 7.76 (dd, J=8.7, 1.8Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.53 (dt, J=9.5, 4.7Hz, 2H), 7.48 (dd, J=7.2, 2.0Hz, 1H), 7.24 (t, J=8.9Hz, 2H), 5.63 (s, 1H), 4.49 (d, J=12.3Hz, 1H), 3.94 (dd , J=12.2, 3.5Hz, 2H), 3.89 (s, 3H),, 3.29 (d, J=12.6Hz, 1H), 1.94-1.80 (m, 2H).1.35 (m, 5H).

[1086] Example 152: Preparation of compound 152:

[1087]

[1088] Preparation of compound 152-1:

[1089] Intermediate INT-14 (44.6 g, 100 mmol) was dissolved in dichloromethane (1 L), and methyl chloroformate (11.2 g, 120 mmol) and N,N-diisopropylethylamine (25.8 g, 200 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 152-1, yield 71%. MS (ESI, positive ion) m / z: 505.2 [M+H] + .

[1090] Preparation of compound 152:

[1091] Compound 152-1 (100 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 152, in 64% yield. MS (ESI, positive ion) m / z: 560.2 [M+H] + .

[1092] 1H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 9.21 (d, J = 8.6Hz, 1H), 8.86 (d, J = 7.1Hz, 1H), 8. 52(s, 1H), 8.03-7.97(m, 1H), 7.98-7.90(m, 2H), 7.63-7.54(m, 2H), 7.49-7.42(m, 1H ), 7.22 (t, J=8.9Hz, 2H), 5.50 (dq, J=13.5, 8.4, 6.8Hz, 1H), 5.01-4.73 (m, 1H), 4.69 ( ddd, J=46.3, 9.5, 5.6Hz, 1H), 4.24 (s, 3H), 3.66-3.59 (m, 4H), 3.47 (t, J=4.7Hz, 4H).

[1093] Preparation of compound 153 in Example 153:

[1094]

[1095] Preparation of compound 153-1:

[1096] Intermediate INT-16 (4.5 g, 10 mmol) was dissolved in dichloromethane (0.3 L), and methyl chloroformate (1.12 g, 12 mmol) and N,N-diisopropylethylamine (2.58 g, 20 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 153-1, yield 71%. MS (ESI, positive ion) m / z: 513.2 [M+H] + .

[1097] Preparation of compound 153:

[1098] Compound 152-1 (100 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 153, yield 64%. MS (ESI, positive ion) m / z: 568.2 [M+H] + .

[1099] 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 1H), 8.48 (d, J = 1.8Hz, 1H), 8.35 (s, 1H), 7.85 (m, 2H), 7.73 (d, J = 8.6Hz, 1H), 7.59-7.49 (m, 1H) ), 7.42 (dd, J=7.1, 2.0Hz, 1H), 7.32 (m, 1H), 7.13 (t, J=8.7Hz, 2H),, 4.71-4.52 (m, 2H), 3.74 (s, 3H), 3.55-3.31 (m, 10H), 2.10-1.74 (m, 4H).

[1100] Example 154: Preparation of compound 154:

[1101]

[1102] Preparation of compound 154:

[1103] INT-16 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and tetrahydrofuran-2-carboxylic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 154 in 78% yield. MS (ESI, positive ion) m / z: 553.2 [M+H] + .

[1104] 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 1H), 8.48 (d, J = 1.8Hz, 1H), 8.35 (s, 1H), 7.85 (m, 2H), 7.73 (d, J = 8.6Hz, 1H), 7.59-7.49 (m, 1H), 7.42 (dd, J=7.1, 2.0Hz, 1H), 7.32 (m, 1H), 7.13 (t, J=8.7Hz, 2H),, 4.71 -4.52(m, 2H), 3.86-3.70(m, 5H), 3.51-3.40(m, 2H), 2.10-1.74(m, 6H).

[1105] Example 155: Preparation of compound 155:

[1106]

[1107] Preparation of compound 155:

[1108] Intermediate INT-14 (86 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 155 in 45% yield. MS (ESI, positive ion) m / z: 555.2 [M+H] + .

[1109] 1 H NMR (400MHz, DMSO-d6) δ10.88 (s, 1H), 8.85 (d, J = 7.2Hz, 1H), 8.61 (d, J = 8.3Hz, 1H), 8.50 (d , J=1.9Hz, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.86 (s, 1H), 7.70 (d, J=1.8Hz, 1H), 7 .64 (d, J=8.7Hz, 1H), 7.45-7.35 (m, 2H), 7.33-7.26 (m, 2H), 7.09 (t, J=8.6Hz, 1H), 5.44 (dq, J=15.0, 7.0Hz, 1H), 4.71 (d, J=6.5Hz, 1H), 4.60 (d, J=6.4Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H).

[1110] Example 156: Preparation of compound 156:

[1111]

[1112] Preparation of compound 156:

[1113] INT-17 (94 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (26 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 156 in 66% yield. MS (ESI, positive ion) m / z: 541.2 [M+H] + .

[1114] Example 157: Preparation of compound 157:

[1115]

[1116] Preparation of compound 157:

[1117] INT-17 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and tetrahydrofuran-2-carboxylic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 157 in 78% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[1118] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 1H), 8.35 (s, 1H), 7.85 (m, 2H), 7.73 (d, J=8.6Hz, 1H), 7.59-7.49 (m, 2H), 7.42 (dd , J=7.1, 2.0Hz, 1H), 7.32 (dd, J=8.5, 5.5Hz, 2H), 7.13 (t, J=8.7Hz, 2H), 4.81-4.75 (m, 1H), 3.8-3.75 (m, 7H), 2.51-1.83 (m, 4H).

[1119] Example 158: Preparation of compound 158:

[1120]

[1121] Preparation of compound 158:

[1122] INT-18 (98 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (26 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 158 in 56% yield. MS (ESI, positive ion) m / z: 559.2 [M+H] + .

[1123] 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 1H), 8.35 (s, 1H), 7.85 (m, 2H), 7.73 (d, J=8.6Hz, 1H), 7.59-7.49 (m, 2H), 7.42 (dd, J=7.1, 2.0Hz, 1H) , 7.32 (dd, J=8.5, 5.5Hz, 2H), 7.13 (t, J=8.7Hz, 2H), 4.81-4.75 (m, 1H), 3 .8-3.75(s, 5H), 2.51-2.42(m, 2H), 1.51-1.43(m, 1H), 1.12-1.06(m, 4H).

[1124] Example 159: Preparation of compound 159:

[1125]

[1126] Preparation of compound 159:

[1127] INT-18 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and tetrahydrofuran-2-carboxylic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 159 in 72% yield. MS (ESI, positive ion) m / z: 589.2 [M+H] + .

[1128] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 1H), 8.35 (s, 1H), 7.85 (m, 2H), 7.73 (d, J=8.6Hz, 1H), 7.59-7.49 (m, 2H), 7.42 (dd , J=7.1, 2.0Hz, 1H), 7.32 (dd, J=8.5, 5.5Hz, 2H), 7.13 (t, J=8.7Hz, 2H), 4.81-4.75 (m, 1H), 3.8-3.75 (m, 7H), 2.51-1.83 (m, 4H).

[1129] Example 160: Preparation of compound 160:

[1130]

[1131] Preparation of compound 160-1:

[1132] Intermediate INT-18 (490 mg, 1 mmol) was dissolved in dichloromethane (0.3 L), and methyl chloroformate (112 mg, 1.2 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (0.3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 160-1, yield 61%. MS (ESI, positive ion) m / z: 549.2 [M+H] + .

[1133] Preparation of compound 160:

[1134] Compound 160-1 (110 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 160 in 68% yield. MS (ESI, positive ion) m / z: 604.2 [M+H] + .

[1135] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 1H), 8.35 (s, 1H), 7.85 (m, 2H), 7.73 (d, J=8.6Hz, 1H), 7.59

[1136] 7.49 (m, 2H), 7.42 (dd, J=7.1, 2.0Hz, 1H), 7.32 (dd, J=8.5, 5.5Hz, 2H), 7.13 (t, J=8.7Hz, 2H), 4.82-4.70(m, 1H), 3.89-3.71(m, 3H), 3.64(m, 4H), 3.31(m, 4H), 2.52-2.28(m, 2H).

[1137] Example 161: Preparation of compound 161:

[1138]

[1139] Preparation of compound 161:

[1140] Intermediate INT-19 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 161 in 65% yield. MS (ESI, positive ion) m / z: 533.2 [M+H] + .

[1141] 1 H NMR (400MHz, DMSO-d6) δ11.28 (s, 1H), 8.92 (d, J=7.2Hz, 1H), 8.78 (d, J=9.1Hz, 1H), 8.55 (d, J=1. 9Hz, 1H), 8.36 (s, 1H), 7.94 (d, J=1.9Hz, 1H), 7.77 (dd, J=8.7, 1.9Hz, 1H), 7.70 (d, J=8.7Hz, 1H), 7 .66-7.62 (m, 2H), 7.50 (dd, J=7.1, 2.0Hz, 1H), 7.27 (t, J=8.9Hz, 2H), 6.37-6.12 (m, 2H), 4.02 (d, J=8.5Hz, 5H), 3.85 (q, J=7.0Hz, 1H), 2.32-2.19 (m, 1H), 2.07-1.84 (m, 3H), 1.50 (d, J=7.0Hz, 3H).

[1142] Example 162: Preparation of compound 162:

[1143]

[1144] Preparation of compound 162:

[1145] Intermediate INT-19 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-tetrahydrofuranic acid (30 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 162 in 55% yield. MS (ESI, positive ion) m / z: 564.2 [M+H] + .

[1146] 1H NMR (400MHz, DMSO-d6) δ11.28 (s, 1H), 8.92 (d, J = 7.2Hz, 1H), 8.78 (d, J = 9.1Hz, 1H), 8 .55 (d, J=1.9Hz, 1H), 8.36 (s, 1H), 7.94 (d, J=1.9Hz, 1H), 7.77 (dd, J=8.7, 1.9Hz, 1H) , 7.70 (d, J=8.7Hz, 1H), 7.66-7.62 (m, 2H), 7.50 (dd, J=7.1, 2.0Hz, 1H), 7.27 (t, J=8. 9Hz, 2H), 6.37-6.12(m, 2H), 4.12-3.75(m, 7H), 2.72-2.63(m, 1H), 2.17-1.94(m, 2H).

[1147] Example 163: Preparation of compound 163:

[1148]

[1149] Preparation of compound 163:

[1150] Intermediate INT-19 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-piperidinylacetic acid (42 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 163 in 55% yield. MS (ESI, positive ion) m / z: 590.2 [M+H] + .

[1151] 1 H NMR (400MHz, DMSO-d6) δ11.28 (s, 1H), 8.92 (d, J = 7.2Hz, 1H), 8.78 (d, J = 9.1Hz, 1H), 8. 55 (d, J=1.9Hz, 1H), 8.36 (s, 1H), 7.94 (d, J=1.9Hz, 1H), 7.77 (dd, J=8.7, 1.9Hz, 1H), 7. 70 (d, J=8.7Hz, 1H), 7.66-7.62 (m, 2H), 7.50 (dd, J=7.1, 2.0Hz, 1H), 7.27 (t, J=8.9Hz, 2 H), 6.37-6.12(m, 2H), 3.81(s, 3H), 3.35(s, 2H), 2.51-3.36(m, 4H), 1.62-1.42(m, 6H).

[1152] Example 164: Preparation of compound 164:

[1153]

[1154] Preparation of compound 164:

[1155] INT-19 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyanoacetic acid (29 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 164 in 58% yield. MS (ESI, positive ion) m / z: 532.2 [M+H] + .

[1156] 1 H NMR (400MHz, DMSO-d6) δ11.28 (s, 1H), 8.92 (d, J = 7.2Hz, 1H), 8.78 (d, J = 9.1Hz, 1H), 8.5 5 (d, J=1.9Hz, 1H), 8.36 (s, 1H), 7.94 (d, J=1.9Hz, 1H), 7.77 (dd, J=8.7, 1.9Hz, 1H), 7.7 0 (d, J=8.7Hz, 1H), 7.66-7.62 (m, 2H), 7.50 (dd, J=7.1, 2.0Hz, 1H), 7.27 (t, J=8.9Hz, 2H ), 6.37 (td, J=55.5, 4.2Hz, 1H), 5.61 (dt, J=14.6, 9.8Hz, 1H), 4.06 (s, 2H), 3.94 (s, 3H).

[1157] Example 165: Preparation of compound 165:

[1158]

[1159] Preparation of compound 165:

[1160] INT-19 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (S)-2-methoxypropionic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 165 in 62% yield. MS (ESI, positive ion) m / z: 551.2 [M+H] + .

[1161] 1 H NMR (400MHz, DMSO-d6) δ10.72 (s, 1H), 8.91 (d, J = 7.1Hz, 1H), 8.78 (d, J = 9.0Hz, 1H), 8.5 5 (d, J=1.8Hz, 1H), 8.36 (s, 1H), 7.92 (d, J=2.0Hz, 1H), 7.77 (dd, J=8.7, 1.9Hz, 1H), 7.74 -7.60 (m, 3H), 7.49 (dd, J=7.2, 2.0Hz, 1H), 7.27 (t, J=8.9Hz, 2H), 6.37 (td, J=55.6, 4.1H z, 1H), 5.66-5.58 (m, 1H), 4.05 (s, 1H), 3.94 (s, 3H), 3.32 (s, 3H), 1.34 (d, J=6.7Hz, 3H).

[1162] Example 166: Preparation of compound 166:

[1163]

[1164] Preparation of compound 166:

[1165] INT-19 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-methoxyacetic acid (26 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 166 in 69% yield. MS (ESI, positive ion) m / z: 537.2 [M+H] + .

[1166] 1H NMR (400MHz, DMSO-d6) δ10.68 (s, 1H), 8.90 (d, J = 7.1Hz, 1H), 8.77 (d, J = 9.1Hz, 1H), 8.55 ( d, J=1.8Hz, 1H), 8.36 (s, 1H), 7.92 (d, J=1.9Hz, 1H), 7.77 (dd, J=8.5, 1.9Hz, 1H), 7.70 (d, J =8.6Hz, 1H), 7.64 (dd, J=8.5, 5.5Hz, 2H), 7.49 (dd, J=7.2, 1.9Hz, 1H), 7.27 (t, J=8.8Hz, 2H ), 6.37 (td, J=55.5, 4.1Hz, 1H), 5.66-5.58 (m, 1H), 4.18 (s, 2H), 3.94 (s, 3H), 3.39 (s, 3H).

[1167] Example 167: Preparation of compound 167:

[1168]

[1169] Preparation of compound 167:

[1170] INT-19 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 167 in 73% yield. MS (ESI, positive ion) m / z: 550.2 [M+H] + .

[1171] 1 H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.89 (d, J = 7.2Hz, 1H), 8.76 (d, J = 9.0Hz, 1H), 8.53 (s, 1H), 8.35 (s, 1H), 7.90 (s, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.72-7.59 (m, 3H), 7.47 (d, J=7.1Hz, 1H), 7.26 (t, J=8.7Hz, 2H), 6.53-6. 19(m, 1H), 5.61(d, J=12.9Hz, 1H), 3.93(s, 3H), 3.20(s, 2H), 2.31(s, 6H).

[1172] Example 168: Preparation of compound 168:

[1173]

[1174] Preparation of compound 168:

[1175] INT-19 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and R-1-methyl-3-pyrrolidone carboxylic acid (39 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 168 in 68% yield. MS (ESI, positive ion) m / z: 576.2 [M+H] + .

[1176] 1 H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.78 (d, J = 9.0Hz, 1H), 8.55 (s, 1H), 8.36 (s, 1H ), 7.90 (d, J=1.9Hz, 1H), 7.77 (dd, J=8.7, 1.9Hz, 1H), 7.70 (d, J=8.6Hz, 1H), 7.64 (dd, J=8.4, 5.4Hz, 2H), 7. 48(dd, J=7.1, 2.0Hz, 1H), 7.27(t, J=8.7Hz, 2H), 6.55-6.19(m, 1H), 5.65-5.58(m, 1H), 3.94(s, 3H), 2.82(d t, J=8.1, 5.0Hz, 2H), 2.45 (s, 3H), 2.36 (s, 1H), 2.07 (ddd, J=20.3, 16.3, 9.0Hz, 2H), 1.37 (d, J=6.1Hz, 2H).

[1177] Example 169: Preparation of compound 169:

[1178]

[1179] Preparation of compound 162:

[1180] Intermediate INT-20 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 3-tetrahydrofuranic acid (30 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 169 in 55% yield. MS (ESI, positive ion) m / z: 552.2 [M+H] + .

[1181] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 2H), 8.35 (s, 1H), 7.85 (m, 2H) , 7.73 (d, J=8.6Hz, 1H), 7.59-7.49 (m, 1H), 7.42 (dd, J=7.1, 2.0Hz, 1H), 7.32 (dd, J=8.5, 5.5Hz, 2H), 7.13 (t, J=8.7Hz, 2H), 4.02 (d, J=8.5Hz, 5H), 3.85 (q , J=7.0Hz, 1H), 2.32-2.19 (m, 1H), 2.07-1.84 (m, 3H), 1.50 (d, J=7.0Hz, 3H).

[1182] Example 170: Preparation of compound 170:

[1183]

[1184] Preparation of compound 170:

[1185] Intermediate INT-20 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 170 in 61% yield. MS (ESI, positive ion) m / z: 522.2 [M+H] + .

[1186] 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 2H), 8.35 (s, 1H), 7.85 (m, 2H), 7.73 (d, J=8.6Hz, 1H), 7.59-7.49 (m, 1H), 7.42 (dd, J=7.1, 2.0Hz, 1 H), 7.32 (dd, J=8.5, 5.5Hz, 2H), 7.13 (t, J=8.7Hz, 2H), 4.82-4.70 (m, 1H ), 3.83(s, 3H), 2.81-2.56(m, 2H), 1.45-1.38(m, 1H), 1.12-0.96(m, 4H).

[1187] Example 171: Preparation of compound 171:

[1188]

[1189] Preparation of compound 171:

[1190] INT-20 (94 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 171 in 62% yield. MS (ESI, positive ion) m / z: 562.2 [M+H] + .

[1191] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 2H), 8.35 (s, 1H), 7.85 (m, 2H), 7.73 (d, J=8.6Hz, 1H), 7.59-7.49 (m, 1H), 7.42 (dd, J= 7.1, 2.0Hz, 1H), 7.32 (dd, J=8.5, 5.5Hz, 2H), 7.13 (t, J=8.7Hz, 2H), 4.82-4.70 (m, 1H), 3.95 (s, 3H), 3.73 (s, 3H), 2.81-2.56 (m, 2H).

[1192] Example 172: Preparation of compound 172:

[1193]

[1194] Preparation of compound 172-1:

[1195] Intermediate INT-20 (490 mg, 1 mmol) was dissolved in dichloromethane (0.3 L), and methyl chloroformate (112 mg, 1.2 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (0.3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 172-1, with a yield of 61%. MS (ESI, positive ion) m / z: 512.2 [M+H] + .

[1196] Preparation of compound 172:

[1197] Compound 172-1 (102 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 172, in 68% yield. MS (ESI, positive ion) m / z: 567.2 [M+H] + .

[1198] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 2H), 8.35 (s, 1H), 7.85 (m, 2H), 7.73 (d, J = 8.6Hz, 1H), 7.59-7.49 (m, 1H), 7.42 (dd, J = 7.1, 2. 0Hz, 1H), 7.32 (dd, J=8.5, 5.5Hz, 2H), 7.13 (t, J=8.7Hz, 2H), 4.82-4.70 (m, 1H), 3.83 (s, 3H), 3.64 (m, 4H), 3.31 (m, 4H), 2.81-2.56 (m, 2H).

[1199] Example 173: Preparation of compound 173:

[1200]

[1201] Preparation of compound 173:

[1202] INT-21 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 173, yield 71%. MS (ESI, positive ion) m / z: 543.2 [M+H] + .

[1203] 1 H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.29 (d, J = 1.8Hz, 1H), 7.95-7.87 (m, 2H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.48 (dd, J=7.2, 2.0Hz, 1H), 7.43 (dd, J=8 .5, 5.5Hz, 2H), 7.27-7.17 (m, 2H), 4.02 (q, J=7.0Hz, 1H), 3.90 (s, 3H), 3.86 (t, J=7.0Hz, 1H), 2.86 (s, 3H), 2.31-2.18 (m, 1H), 2.07-1.81 (m, 3H), 1.62 (d, J=7.0Hz, 3H), 1.29 (dd, J=10.4, 6.7Hz, 1H).

[1204] Example 174: Preparation of compound 174:

[1205]

[1206] Preparation of compound 174:

[1207] INT-21 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 174, yield 74%. MS (ESI, positive ion) m / z: 527.2 [M+H] + .

[1208] 1H NMR (400MHz, DMSO-d6) δ10.44 (s, 1H), 8.88 (d, J = 7.2Hz, 1H), 8.28 (s, 1H), 7.90 (d, J = 7.6Hz, 2H), 7.79-7.72 (m, 1H), 7.67 (d, J = 8.6Hz, 1H), 7.45 (ddd, J=14.6, 7.6, 3.6Hz, 3H), 7.22 (t, J=8.7Hz, 2H), 3.90 (s, 3H), 3.22 (s, 2H), 2.86 (s, 3H), 2.57-2.49 (m, 6H), 1.62 (d, J=7.1Hz, 3H).

[1209] Example 175: Preparation of compound 175:

[1210]

[1211] Preparation of compound 175:

[1212] Intermediate INT-20 (93 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 175, yield 61%. MS (ESI, positive ion) m / z: 511.2 [M+H] + .

[1213] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.88-8.84 (m, 1H), 8.28 (d, J=1.8Hz, 1H), 7.91 (dd, J=3.5, 1.9Hz, 2H), 7.77 (dd, J=8.6, 1.9Hz, 1H), 7.68 ( d, J=8.6Hz, 1H), 7.48-7.41 (m, 3H), 7.23 (t, J=8.9Hz, 2H), 5.88 (s, 1H), 3.90 (s, 3H), 2.86 (s, 3H), 1.63 (d, J = 7.0Hz, 3H), 0.86 (d, J = 5.6Hz, 5H).

[1214] Example 176: Preparation of compound 176:

[1215]

[1216] Preparation of compound 176:

[1217] INT-21 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (S)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 176, yield 71%. MS (ESI, positive ion) m / z: 543.2 [M+H] + .

[1218] 1 H NMR (400MHz, DMSO-d6) δ10.46 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.28 (d, J = 1.6Hz, 1H), 7.95-7.87 (m, 2 H), 7.77 (dd, J=8.7, 1.8Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.48 (dd, J=7.2, 2.0Hz, 1H), 7.43 (dd, J=8.5, 5.5Hz, 2H), 7.22 (t, J=8.8Hz, 2H), 5.88 (s, 1H), 4.53 (s, 1H), 4.01 (q, J=7.0Hz, 1H), 3.90 (s, 3H), 3.8 9-3.80 (m, 1H), 2.86 (s, 3H), 2.31-1.93 (m, 2H), 1.90 (dt, J=13.5, 6.6Hz, 2H), 1.62 (d, J=7.0Hz, 3H).

[1219] Example 177: Preparation of compound 177:

[1220]

[1221] Preparation of compound 177:

[1222] Intermediate INT-22 (84 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 177, yield 61%. MS (ESI, positive ion) m / z: 497.2 [M+H] + .

[1223] 1H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 10.16 (s, 1H), 8.92 (d, J=7.1Hz, 1H), 8.37 ( d, J=1.8Hz, 1H), 7.92 (d, J=1.9Hz, 1H), 7.86 (s, 1H), 7.72 (dd, J=8.7, 1.8Hz, 1H), 7 .56 (d, J=8.7Hz, 1H), 7.50 (td, J=5.6, 2.3Hz, 3H), 7.25-7.15 (m, 2H), 4.04 (q, J=7 .0Hz, 1H), 3.80 (s, 3H), 2.10 (s, 1H), 1.49 (d, J=7.0Hz, 3H), 0.87 (d, J=6.2Hz, 4H).

[1224] Example 178: Preparation of compound 178:

[1225]

[1226] Preparation of compound 178:

[1227] INT-22 (84 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (S)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 178, yield 71%. MS (ESI, positive ion) m / z: 527.2 [M+H] + .

[1228] 1 H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 10.17 (s, 1H), 8.94 (d, J = 7.1Hz, 1H), 8.38 (d, J = 1.8Hz, 1H), 7.94 (d, J = 2.0Hz, 1H), 7.85 (s, 1H), 7.72 (dd, J=8.7, 1.8Hz, 1H), 7.58-7.48 (m, 4H), 7.21-7.16 (m, 2H), 4.55 (s, 1H), 4.10

[1229] 3.97(m, 2H), 3.883.83(m, 1H), 3.80(s, 3H), 2.332.19(m, 1H), 2.02(td, J=7.1, 5.5Hz, 1H), 1.981.93 (m, 1H), 1.49 (d, J=7.0Hz, 3H), 1.44 (s, 1H).

[1230] Example 179: Preparation of compound 179:

[1231]

[1232] Preparation of compound 179:

[1233] INT-22 (84 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 179, yield 77%. MS (ESI, positive ion) m / z: 527.2 [M+H] + .

[1234] 1 H NMR (400MHz, DMSO-d6) δ10.72 (s, 1H), 10.47 (s, 1H), 8.94 (dd, J=7.1, 0.8Hz, 1H), 8. 22 (s, 1H), 7.96-7.89 (m, 2H), 7.73 (d, J=8.9Hz, 1H), 7.52 (dd, J=8.4, 5.5Hz, 2H), 7. 43 (dd, J=7.2, 2.0Hz, 1H), 7.21 (t, J=8.8Hz, 2H), 4.54 (s, 1H), 4.02 (d, J=8.5Hz, 6H) , 3.85 (q, J=7.0Hz, 1H), 2.32-2.19 (m, 1H), 2.07-1.84 (m, 3H), 1.50 (d, J=7.0Hz, 3H).

[1235] Example 180: Preparation of compound 180:

[1236]

[1237] Preparation of compound 180:

[1238] INT-23 (86 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 180 in 73% yield. MS (ESI, positive ion) m / z: 515.2 [M+H] + .

[1239] 1 H NMR (400MHz, DMSO-d6) δ10.76 (s, 2H), 8.94 (d, J=7.1Hz, 1H), 8.23 ​​(s, 1H), 7.91 (d, J=6.5Hz, 2H), 7.72 (d, J=8.9Hz, 1H), 7.52 (t, J=6 .9Hz, 2H), 7.43 (d, J=7.2Hz, 1H), 7.21 (t, J=8.7Hz, 2H), 4.06 (s, 1H), 4.00 (s, 3H), 3.39 (s, 2H), 2.42 (s, 6H), 1.50 (d, J=6.8Hz, 3H).

[1240] Example 181: Preparation of compound 181:

[1241]

[1242] Preparation of compound 181:

[1243] INT-23 (86 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 181 in 62% yield. MS (ESI, positive ion) m / z: 538.2 [M+H] + .

[1244] 1 H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 10.74 (s, 1H), 8.96 (d, J=7.1Hz, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.93 (td, J=4.9, 4.4, 1.8Hz, 2H), 7.73 (d, J=8. 9Hz, 1H), 7.52 (dd, J=8.5, 5.6Hz, 2H), 7.42 (dd, J=7.1, 2.0Hz, 1H), 7.22 (t, J=8. 8Hz, 2H), 4.04 (d, J=7.2Hz, 2H), 4.01 (s, 3H), 3.92 (s, 3H), 1.50 (d, J=7.0Hz, 3H).

[1245] Example 182: Preparation of compound 182:

[1246]

[1247] Preparation of compound 182:

[1248] Intermediate INT-23 (86 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 182 in 61% yield. MS (ESI, positive ion) m / z: 498.2 [M+H] + .

[1249] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 10.71 (s, 1H), 8.90 (d, J=7.0Hz, 1H), 8.21 (s, 1H), 7.90 (d, J=8.9Hz, 2H), 7.71 (d, J=8.9Hz, 1H), 7.52 (t, J=6. 9Hz, 2H), 7.39 (d, J=7.2Hz, 1H), 7.21 (t, J=8.6Hz, 2H), 4.01 (d, J=11.9Hz, 4H), 2.05 (d, J=41.0Hz, 1H), 1.50 (d, J=7.1Hz, 3H), 0.86 (d, J=6.3Hz, 4H).

[1250] Example 183: Preparation of compound 183:

[1251]

[1252] Preparation of compound 183:

[1253] INT-14 (86 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 183 in 67% yield. MS (ESI, positive ion) m / z: 545.2 [M+H] + .

[1254] 1H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 8.90 (d, J = 7.1Hz, 1H), 8.65 (d, J = 8.3Hz, 1H), 8.55 (d, J = 1.8Hz, 1H), 8.30 (s, 1H), 7.92 (dd, J=2.0, 0.9Hz, 1H), 7.77 (dd, J=8.7, 1.8Hz, 1H), 7.70 (d, J=8.6Hz, 1H), 7.52-7.47 (m, 1H), 7.44 (dd, J=7.9, 6.2 Hz, 1H), 7.36 (d, J=8.4Hz, 2H), 7.19-7.12 (m, 1H), 5.50 (dt, J=14.8, 7.4Hz, 1H), 4.78 (d, J=6.4Hz, 1H), 4.66 (d, J=6.4Hz , 1H), 4.53 (s, 1H), 4.01 (q, J=7.1, 6.7Hz, 1H), 3.94 (s, 3H), 3.84 (q, J=7.2Hz, 1H), 2.30-2.19 (m, 1H), 2.01-1.89 (m, 3H).

[1255] Example 184: Preparation of compound 184:

[1256]

[1257] Preparation of compound 184:

[1258] INT-6 (91 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 184 in 71% yield. MS (ESI, positive ion) m / z: 557.2 [M+H] + .

[1259] 1H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.90 (d, J = 7.2Hz, 1H), 8.58 (d, J = 1.8Hz, 1H), 8.31 (d, J = 3.8Hz, 1H), 8.08 (s, 1H), 7.93 (d, J = 1.9Hz, 1H), 7.75 (dd, J=8.6, 1.9Hz, 1H), 7.68 (d, J=8.7Hz, 1H), 7.51 (dd, J=7.1, 2.0Hz, 1H), 7.42-7.23 (m, 2H), 7.09 (dq, J=6.7, 2.8 , 2.2Hz, 1H), 4.54 (s, 1H), 4.02 (dt, J=8.1, 6.7Hz, 1H), 3.91 (s, 3H), 3.89-3.80 (m, 1H), 3.02 (dq, J=8.0, 3.9Hz, 1H), 2.25 (dtd, J=11 .4, 7.9, 6.1Hz, 1H), 2.09 (ddd, J=9.5, 6.2, 3.3Hz, 1H), 2.05-1.81 (m, 3H), 1.39 (dt, J=9.7, 5.3Hz, 1H), 1.29 (dt, J=7.9, 5.8Hz, 1H).

[1260] Example 185: Preparation of compound 185:

[1261]

[1262] Preparation of compound 185:

[1263] Compound 95-1 (100 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 185, in 66% yield. MS (ESI, positive ion) m / z: 560.2 [M+H] + .

[1264] 1H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.90 (dd, J=7.1, 0.8Hz, 1H), 8.62 (d, J=8.3Hz, 1H), 8.55 (d, J=1 .8Hz, 1H), 8.27 (s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.76 (dd, J=8.7, 1.8Hz, 1H), 7.69 (d, J=8.6Hz, 1H ), 7.607.53 (m, 2H), 7.48 (dd, J=7.2, 2.0Hz, 1H), 7.28-7.18 (m, 2H), 5.49 (dq, J=15.3, 7.3Hz, 1H), 4.8 2-4.70 (m, 1H), 4.70-4.60 (m, 1H), 3.93 (s, 3H), 3.64 (t, J=4.6Hz, 4H), 3.27 (s, 2H), 2.58-2.55 (m, 4H).

[1265] Example 186: Preparation of compound 186:

[1266]

[1267] Preparation of compound 186:

[1268] INT-16 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and tetrahydrofuran-3-carboxylic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 186 in 62% yield. MS (ESI, positive ion) m / z: 553.2 [M+H] + .

[1269] 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 1H), 8.48 (d, J=1.8Hz, 1H), 8.35 (s, 1H), 7.85 (m, 2H), 7.73 (d, J=8.6Hz, 1H), 7.59-7.49 (m, 1H), 7. 42 (dd, J=7.1, 2.0Hz, 1H), 7.32 (m, 1H), 7.13 (t, J=8.7Hz, 2H), 4.71-4.52 (m, 2H), 4.23 (s, 3H), 4.16-3.70 (m, 4H), 2.81 (m, 1H), 2.23-2.04 (m, 2H).

[1270] Example 187: Preparation of compound 187:

[1271]

[1272] Preparation of compound 187-1:

[1273] Intermediate INT-29 (321 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (R)-2-fluoro-1-(3-fluorophenyl)ethane-1-amine (188 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give compound 187-1 in 63% yield. MS (ESI, positive ion) m / z: 448.3 [M+H] + .

[1274] Preparation of compound 187:

[1275] Compound 187-1 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 187, in 52% yield. MS (ESI, positive ion) m / z: 556.2 [M+H] + .

[1276] 1 H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 8.94 (dd, J=7.1, 0.8Hz, 1H), 8.89 (d, J=8.4Hz , 1H), 8.78 (s, 1H), 8.55 (dd, J=1.8, 0.8Hz, 1H), 8.43 (s, 1H), 8.13 (d, J=0.8Hz, 1H), 8 .05-7.98 (m, 2H), 7.93 (d, J=9.1Hz, 1H), 7.78 (s, 1H), 7.52 (ddd, J=8.7, 3.6, 1.9Hz, 3 H), 7.17 (t, J=8.9Hz, 2H), 5.26 (m, 1H), 4.71-4.52 (m, 2H), 4.23 (s, 3H), 3.86 (s, 3H).

[1277] Example 188: Preparation of compound 188:

[1278]

[1279] Preparation of compound 188:

[1280] Compound 187-1 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and tetrahydrofuran-3-carboxylic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 188 in 52% yield. MS (ESI, positive ion) m / z: 546.2 [M+H] + .

[1281] 1 H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 8.94 (dd, J=7.1, 0.8Hz, 1H), 8.89 (d, J=8.4Hz, 1H ), 8.55 (dd, J=1.8, 0.8Hz, 1H), 8.43 (s, 1H), 8.13 (d, J=0.8Hz, 1H), 8.05-7.98 (m, 2H), 7 .93 (d, J=9.1Hz, 1H), 7.52 (ddd, J=8.7, 3.6, 1.9Hz, 3H), 7.17 (t, J=8.9Hz, 2H), 5.26 (m, 1H), 4.71-4.52(m, 2H), 4.23(s, 3H), 4.16-3.70(m, 4H), 2.81(m, 1H), 2.23-2.04(m, 2H).

[1282] Example 189: Preparation of compound 189:

[1283]

[1284] Preparation of compound 189-1:

[1285] Intermediate 187-1 (447 mg, 1 mmol) was dissolved in dichloromethane (0.3 L), and methyl chloroformate (112 mg, 1.2 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (0.3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 189-1, with a yield of 61%. MS (ESI, positive ion) m / z: 506.2 [M+H] + .

[1286] Preparation of compound 189:

[1287] Compound 189-1 (101 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 189, in 58% yield. MS (ESI, positive ion) m / z: 561.2 [M+H] + .

[1288] 1 H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 9.20 (d, J = 8.6Hz, 1H), 8.85 (d, J = 7.1Hz, 1H), 8. 52(s, 1H), 8.03-7.97(m, 1H), 7.97-7.90(m, 2H), 7.62-7.54(m, 2H), 7.49-7.43(m, 1H ), 7.22 (t, J=8.9Hz, 2H), 5.50 (dq, J=13.5, 8.4, 6.8Hz, 1H), 5.00-4.73 (m, 1H), 4.69 ( ddd, J=46.3, 9.5, 5.6Hz, 1H), 4.24 (s, 3H), 3.66-3.59 (m, 4H), 3.47 (t, J=4.7Hz, 4H).

[1289] Example 190: Preparation of compound 190:

[1290]

[1291] Preparation of compound 190:

[1292] Compound 187-1 (89 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 190, in 72% yield. MS (ESI, positive ion) m / z: 516.2 [M+H] + .

[1293] 1H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 8.94 (dd, J=7.1, 0.8Hz, 1H), 8.89 (d, J=8.4H z, 1H), 8.55 (dd, J=1.8, 0.8Hz, 1H), 8.43 (s, 1H), 8.13 (d, J=0.8Hz, 1H), 8.05-7.98 (m, 2H), 7.93 (d, J=9.1Hz, 1H), 7.52 (ddd, J=8.7, 3.6, 1.9Hz, 3H), 7.17 (t, J=8.9Hz , 2H), 5.26 (p, J=7.4Hz, 1H), 4.23 (s, 3H), 4.04-3.93 (m, 2H), 1.55 (d, J=7.1Hz, 3H).

[1294] Example 191: Preparation of compound 191:

[1295]

[1296] Preparation of compound 191-1:

[1297] Intermediate INT-29 (321 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-(3-fluorophenyl)ethane-1-amine (171 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give compound 191-1 in 61% yield. MS (ESI, positive ion) m / z: 430.3 [M+H] + .

[1298] Preparation of compound 191:

[1299] Compound 191-1 (86 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 191 in 52% yield. MS (ESI, positive ion) m / z: 538.2 [M+H] + .

[1300] 1H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 8.94 (dd, J=7.1, 0.8Hz, 1H), 8.89 (d, J=8.4 Hz, 1H), 8.55 (dd, J=1.8, 0.8Hz, 1H), 8.43 (s, 1H), 8.13 (d, J=0.8Hz, 1H), 8.05-7. 98 (m, 2H), 7.93 (d, J=9.1Hz, 1H), 7.52 (ddd, J=8.7, 3.6, 1.9Hz, 3H), 7.17 (t, J=8. 9Hz, 2H), 5.26 (p, J=7.4Hz, 1H), 4.23 (s, 3H), 3.92 (s, 3H), 1.55 (d, J=7.1Hz, 3H).

[1301] Example 192: Preparation of compound 192:

[1302]

[1303] Preparation of compound 192:

[1304] Compound 191-1 (86 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 192 in 62% yield. MS (ESI, positive ion) m / z: 498.2 [M+H] + .

[1305] 1 H NMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 8.92-8.86 (m, 2H), 8.56-8.51 (m, 1H), 8.04-7.95 (m, 2H), 7.92 (d, J=8.9Hz, 1H), 7.56-7.46 (m, 3H), 7.22-7.13 (m, 2H), 5.26 (p, J=7.3Hz, 1H), 4.22 (s, 3H), 2.45-1.65 (m, -1H), 1.55 (d, J=7.0Hz, 3H), 0.86 (d, J=6.2Hz, 4H).

[1306] Example 193: Preparation of compound 193:

[1307]

[1308] Preparation of compound 193:

[1309] Compound 191-1 (86 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 mg, 0.3 mmol) and 1,1-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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 193 in 72% yield. MS (ESI, positive ion) m / z: 528.2 [M+H] + .

[1310] 1 H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 8.92 (dd, J=7.1, 0.8Hz, 1H), 8.87 (d, J=8.4Hz, 1H), 8.56 -8.51 (m, 1H), 8.00 (ddd, J=5.5, 3.9, 1.8Hz, 2H), 7.92 (d, J=8.9Hz, 1H), 7.54-7.50 (m, 3H), 7.2 2-7.12 (m, 2H), 5.26 (p, J=7.1Hz, 1H), 4.54 (s, 1H), 4.22 (s, 3H), 4.02 (dt, J=8.0, 6.7Hz, 1H), 3 .90-3.80 (m, 1H), 2.25 (dtd, J=11.4, 8.0, 6.1Hz, 1H), 2.03-1.88 (m, 3H), 1.56 (d, J=7.1Hz, 3H).

[1311] Example 194: Preparation of compound 194:

[1312]

[1313] Preparation of compound 194:

[1314] Compound 191-1 (86 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (S)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 194 in 66% yield. MS (ESI, positive ion) m / z: 528.2 [M+H] + .

[1315] 1H NMR (400MHz, DMSO-d6) δ10.50 (s, 1H), 8.95-8.85 (m, 2H), 8.56-8.50 (m, 1H), 8.03 -7.96 (m, 2H), 7.92 (d, J=9.0Hz, 1H), 7.52 (td, J=5.6, 2.6Hz, 3H), 7.22-7.12 (m, 2H ), 5.26 (p, J=7.2Hz, 1H), 4.53 (s, 1H), 4.22 (s, 3H), 4.01 (q, J=6.9Hz, 1H), 3.84 (t d, J=7.6, 6.5Hz, 1H), 2.30-1.92 (m, 2H), 1.97-1.82 (m, 2H), 1.55 (d, J=7.1Hz, 3H).

[1316] Example 195: Preparation of compound 195:

[1317]

[1318] Preparation of compound 195-1:

[1319] Intermediate 191-1 (429 mg, 1 mmol) was dissolved in dichloromethane (0.3 L), and methyl chloroformate (112 mg, 1.2 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (0.3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 195-1, with a yield of 61%. MS (ESI, positive ion) m / z: 488.2 [M+H] + .

[1320] Preparation of compound 195:

[1321] Compound 195-1 (97 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 195 in 58% yield. MS (ESI, positive ion) m / z: 543.2 [M+H] + .

[1322] 1 H NMR (400MHz, DMSO-d6) δ9.63 (s, 1H), 8.86 (t, J=7.3Hz, 2H), 8.52 (d, J=1.8H z, 1H), 7.99 (dd, J=8.9, 1.8Hz, 1H), 7.95-7.85 (m, 2H), 7.57-7.49 (m, 2H), 7 .46 (dd, J=7.2, 2.0Hz, 1H), 7.21-7.12 (m, 2H), 5.26 (p, J=7.3Hz, 1H), 4.22 ( s, 3H), 3.63 (t, J=4.7Hz, 4H), 3.48 (t, J=4.8Hz, 4H), 1.55 (d, J=7.0Hz, 3H).

[1323] Example 196: Preparation of compound 196:

[1324]

[1325] Preparation of compound 196:

[1326] Compound 191-1 (86 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and morpholine acetic acid (43 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 196 in 71% yield. MS (ESI, positive ion) m / z: 557.2 [M+H] + .

[1327] 1 H NMR (400MHz, DMSO-) d 6) δ10.53 (s, 1H), 8.85 (dd, J=17.4, 7.7Hz, 2H), 8.49 (d, J=1.7Hz, 1H), 7.93 (dd, J=6.5, 1.9Hz, 2H), 7.86 (d, J=8.9Hz, 1H), 7.53-7.45 (m, 3H) , 7.14 (t, J=8.9Hz, 2H), 5.24 (t, J=7.5Hz, 1H), 4.18 (s, 3H), 3.62 (t, J=4.5Hz, 4H), 3.26 (s, 2H), 2.54 (t, J=4.6Hz, 4H), 1.53 (d, J=7.0Hz, 3H).

[1328] Example 197: Preparation of compound 197:

[1329]

[1330] Preparation of compound 197-1:

[1331] Intermediate INT-1 (306 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-(3-fluorophenyl)propane-1-amine (188 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give compound 197-1, with a yield of 64%. MS (ESI, positive ion) m / z: 443.3 [M+H] + .

[1332] Preparation of compound 197:

[1333] Compound 197-1 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and morpholine acetic acid (43 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 197, in 61% yield. MS (ESI, positive ion) m / z: 570.2 [M+H] + .

[1334] 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.89 (d, J = 7.1Hz, 1H), 8.55 (d, J = 1.9Hz, 1H), 8.38 (d, J=8.1Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.8Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.47 (ddt, J=5.8, 4.1, 1.7Hz, 3H), 7.22-7.12 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 3.91 (s , 3H), 3.64 (t, J=4.6Hz, 4H), 3.27 (s, 2H), 2.56 (dd, J=5.4, 3.4Hz, 4H), 1.50 (d, J=7.0Hz, 3H).

[1335] Example 198: Preparation of compound 198:

[1336]

[1337] Preparation of compound 198-1:

[1338] Intermediate INT-1 (306 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-1-(3-fluorophenyl)ethanol-1-amine (190 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give compound 198-1, with a yield of 54%. MS (ESI, positive ion) m / z: 443.3 [M+H] + .

[1339] Preparation of compound 198:

[1340] Compound 198-1 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and morpholine acetic acid (43 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 198 in 61% yield. MS (ESI, positive ion) m / z: 571.2 [M+H] + .

[1341] 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.89 (d, J=7.1Hz, 1H), 8.55 (d, J=1.9Hz, 1H), 8.38 (d, J=8. 1Hz, 1H), 8.23 ​​(s, 1H), 7.90 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6, 1.8Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7 .47 (ddt, J=5.8, 4.1, 1.7Hz, 3H), 7.22-7.12 (m, 2H), 5.22 (p, J=7.2Hz, 1H), 3.95 (s, 1H), 3.81-3. 72 (m, 2H), 3.64 (t, J=4.6Hz, 4H), 3.27 (s, 2H), 2.56 (dd, J=5.4, 3.4Hz, 4H), 1.50 (d, J=7.0Hz, 3H).

[1342] Example 199: Preparation of compound 199:

[1343]

[1344] Preparation of compound 199-1:

[1345] Intermediate INT-2 (320 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (R)-2-fluoro-1-(3-fluorophenyl)ethane-1-amine (188 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give compound 199-1, with a yield of 67%. MS (ESI, positive ion) m / z: 461.3 [M+H] + .

[1346] Preparation of compound 199:

[1347] Compound 199-1 (92 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyanoacetic acid (25 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 199, in 57% yield. MS (ESI, positive ion) m / z: 527.2 [M+H] + .

[1348] 1 H NMR (400MHz, DMSO-d6) δ11.29 (s, 1H), 8.92 (d, J = 7.1Hz, 1H), 8.62 (d, J = 8.2Hz, 1H), 8.55 (d, J=1.8Hz, 1H), 8.27 (s, 1H), 7.94 (d, J=1.8Hz, 1H), 7.77 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.57-7.49 (m, 3H), 7.23 (t, J=8.8Hz, 2H), 5.53-5.43 (m, 1H), 4.76 (d, J=8.0Hz, 1H), 4.67-4.61 (m, 1H), 4.04-3.93 (m, 2H), 2.72-2.55 (m, 1H), 2.35 (s, 1H), 1.50 (d, J=7.2Hz, 3H).

[1349] Example 200: Preparation of compound 200:

[1350]

[1351] Preparation of compound 200-1:

[1352] Intermediate 199-1 (460 mg, 1 mmol) was dissolved in dichloromethane (0.3 L), and methyl chloroformate (112 mg, 1.2 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (0.3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 200-1, yield 55%. MS (ESI, positive ion) m / z: 519.2 [M+H] + .

[1353] Preparation of compound 200:

[1354] Compound 200-1 (104 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 200 in 58% yield. MS (ESI, positive ion) m / z: 574.2 [M+H] + .

[1355] 1 H NMR (400MHz, DMSO-d6) δ11.29 (s, 1H), 8.92 (d, J = 7.1Hz, 1H), 8.62 (d, J = 8.2Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J=1.8Hz, 1H), 7.77 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 7. 577.49 (m, 3H), 7.23 (t, J=8.8Hz, 2H), 5.53-5.43 (m, 1H), 4.76 (d, J=8.0Hz, 1H), 4.67-4.61 (m, 1H) , 3.66-3.58 (m, 4H), 3.48 (t, J=4.8Hz, 4H), 2.72-2.55 (m, 1H), 2.35 (s, 1H), 1.50 (d, J=7.2Hz, 3H).

[1356] Example 201: Preparation of compound 201:

[1357]

[1358] Preparation of compound 201-1:

[1359] Intermediate INT-1 (306 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-5-fluoro-2,3-dihydro-1H-indene-1-amine (181 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give compound 201-1 in 58% yield. MS (ESI, positive ion) m / z: 441.3 [M+H] + .

[1360] Preparation of compound 201:

[1361] Compound 201-1 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 201 in 53% yield. MS (ESI, positive ion) m / z: 549.2 [M+H] + .

[1362] 1 H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 8.94 (dd, J=7.1, 0.8Hz, 1H), 8.66 (d, J=1.7Hz, 1H), 8.43 (s, 1H), 8.34 (d, J=8 .4Hz, 1H), 8.18-8.11 (m, 2H), 7.95 (dd, J=2.0, 0.9Hz, 1H), 7.78 (dd, J=8.7, 1.9Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.31 (dd, J=8.3, 5.4Hz, 1H), 7.167.10 (m, 1H), 7.076.99 (m, 1H), 5.58 (q, J=8.2Hz, 1H), 3.9 2 (s, 3H), 3.90 (s, 3H), 3.04 (t, J=11.8Hz, 1H), 2.89 (dt, J=16.5, 8.4Hz, 1H), 2.58-2.54 (m, 1H), 2.12-1.98 (m, 1H).

[1363] Example 202: Preparation of compound 202:

[1364]

[1365] Preparation of compound 202:

[1366] Compound 201-1 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-dimethylaminoacetic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 202 in 58% yield. MS (ESI, positive ion) m / z: 526.2 [M+H] + .

[1367] 1 H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.91 (d, J = 7.3Hz, 1H), 8.64 (d, J = 1.9Hz, 1H), 8.33 (d, J = 8.4Hz, 1H), 8. 16 (s, 1H), 7.93 (d, J=2.0Hz, 1H), 7.76 (dd, J=8.6, 1.9Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.51 (dd, J=7.1, 2.0Hz, 1 H), 7.31 (dd, J=8.4, 5.4Hz, 1H), 7.13 (d, J=9.9Hz, 1H), 7.03 (t, J=8.9Hz, 1H), 5.58 (q, J=7.9Hz, 1H), 3.89 (s, 4H), 3.21 (s, 2H), 3.09-2.99 (m, 1H), 2.89 (dt, J=16.4, 8.4Hz, 1H), 2.33 (s, 5H), 2.04 (dq, J=12.5, 8.7Hz, 1H).

[1368] Example 203: Preparation of compound 203:

[1369]

[1370] Preparation of compound 203:

[1371] Compound 201-1 (88 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 203 in 68% yield. MS (ESI, positive ion) m / z: 509.2 [M+H] +.

[1372] 1 H NMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.89 (d, J = 7.0Hz, 1H), 8.65 (d, J = 1.8Hz, 1H), 8.34 (d, J = 8.3Hz, 1H), 8.16 ( s, 1H), 7.93 (d, J=2.0Hz, 1H), 7.77 (dd, J=8.7, 2.0Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 7.50 (dd, J=7.1, 2.0Hz, 1H), 7. 32 (dd, J=8.4, 5.3Hz, 1H), 7.14 (d, J=10.0Hz, 1H), 7.08-6.99 (m, 1H), 5.58 (q, J=8.0Hz, 1H), 3.90 (s, 3H), 3.05 (d d, J=17.5, 8.1Hz, 1H), 2.90 (dt, J=16.5, 8.5Hz, 1H), 2.60-2.55 (m, 1H), 2.23-1.93 (m, 2H), 0.87 (d, J=6.1Hz, 4H).

[1373] Example 204: Preparation of compound 204:

[1374]

[1375] Preparation of compound 204-1:

[1376] Intermediate INT-1 (306 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-5-fluoro-2,3-dihydro-1H-inden-1-amine-1-methyl (197 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give compound 204-1 in 49% yield. MS (ESI, positive ion) m / z: 454.3 [M+H] + .

[1377] Preparation of compound 204:

[1378] Compound 204-1 (91 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 204, in 51% yield. MS (ESI, positive ion) m / z: 563.2 [M+H] + .

[1379] 1 H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 8.93 (d, J = 7.1Hz, 1H), 8.66 (d, J = 1.8Hz, 1H), 8.44 (s, 1H), 8.39 (d, J = 8.3Hz, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.95 (d, J=1.9Hz, 1H), 7.77 (dd, J=8.6, 1.9Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.53 (dd, J=7.2, 2.0Hz, 1H), 7.31 (dd, J=8.8, 5.2Hz, 1H), 7.06 (t, J=7.8Hz, 2H), 5.62 (t, J=8.1Hz, 1H), 3.91 (d, J=7.9Hz, 6H) , 3.05-2.94 (m, 1H), 3.26 (s, 3H), 2.85 (dt, J=16.4, 8.7Hz, 1H), 2.57 (d, J=8.8Hz, 1H), 2.05 (dq, J=12.3, 8.8Hz, 1H).

[1380] Example 205: Preparation of compound 205:

[1381]

[1382] Preparation of compound 205:

[1383] Compound 204-1 (91 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 205 in 67% yield. MS (ESI, positive ion) m / z: 523.2 [M+H] + .

[1384] 1 H NMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.89 (d, J = 7.0Hz, 1H), 8.65 (d, J = 1.8Hz, 1H), 8.34 (d, J = 8.3Hz, 1H), 8.1 6 (s, 1H), 7.93 (d, J=2.0Hz, 1H), 7.77 (dd, J=8.7, 2.0Hz, 1H), 7.50 (dd, J=7.1, 2.0Hz, 1H), 7.32 (dd, J=8.4, 5.3 Hz, 1H), 7.14 (d, J=10.0Hz, 1H), 7.08-6.99 (m, 1H), 5.58 (q, J=8.0Hz, 1H), 3.90 (s, 3H), 3.26 (s, 3H), 3.05 (dd, J=17.5, 8.1Hz, 1H), 2.90 (dt, J=16.5, 8.5Hz, 1H), 2.60-2.55 (m, 1H), 2.23-1.93 (m, 2H), 0.87 (d, J=6.1Hz, 4H).

[1385] Example 206: Preparation of compound 206:

[1386]

[1387] Preparation of compound 206:

[1388] Compound 204-1 (91 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and (R)-tetrahydrofuranic acid (35 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 206 in 67% yield. MS (ESI, positive ion) m / z: 553.2 [M+H] + .

[1389] 1H NMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 8.89 (d, J = 7.0Hz, 1H), 8.65 (d, J = 1.8Hz, 1H), 8.34 (d, J = 8.3Hz, 1H), 8.16 (s, 1H), 7 .93 (d, J=2.0Hz, 1H), 7.77 (dd, J=8.7, 2.0Hz, 1H), 7.50 (dd, J=7.1, 2.0Hz, 1H), 7.32 (dd, J=8.4, 5.3Hz, 1H), 7.14 (d, J=10. 0Hz, 1H), 7.08-6.99 (m, 1H), 5.58 (q, J=7.9Hz, 1H), 4.54 (s, 1H), 4.02 (q, J=7.0Hz, 1H), 3.89 (s, 3H), 3.31 (s, 3H), 3.85 (q , J=7.2Hz, 1H), 3.09-2.99 (m, 1H), 2.89 (dt, J=16.3, 8.5Hz, 1H), 2.59-2.54 (m, 1H), 2.31-2.16 (m, 1H), 2.11-1.83 (m, 4H).

[1390] Example 207: Preparation of compound 207:

[1391]

[1392] Preparation of compound 207-1:

[1393] Intermediate INT-29 (307 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. Then (S)-2-(4-fluorophenyl)pyrrolidine (198 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then added dropwise to water and stirred for 0.5 h. The mixture was filtered and dried to give compound 207-1, with a yield of 49%. MS (ESI, positive ion) m / z: 456.3 [M+H] + .

[1394] Preparation of compound 207:

[1395] Compound 207-1 (91 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 207, in 51% yield. MS (ESI, positive ion) m / z: 564.2 [M+H] + .

[1396] 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (m, 2H), 8.48 (d, J = 1.8Hz, 1H), 7.85 (m, 2H), 7.73 (d, J = 8.6Hz, 1H), 7.59-7.49 (m, 1H), 7.42 ( dd, J=7.1, 2.0Hz, 1H), 7.32 (dd, J=8.5, 5.5Hz, 2H), 7.13 (t, J=8.7Hz, 2H), 5.05 (m, 1H), 3.95 (s, 3H), 3.71 (s, 3H), 1.89 (d, J=6.8Hz, 3H).

[1397] Example 208: Preparation of compound 208:

[1398]

[1399] Preparation of compound 208:

[1400] Compound INT-30 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 208 in 53% yield. MS (ESI, positive ion) m / z: 561.2 [M+H] + .

[1401] 1H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 8.86 (d, J=7.0Hz, 1H), 8.50 (m, 2H), 8.19 (s, 1H), 7.95 (s, 1H), 7.89 (d, J=1.9Hz, 1H), 7.82 (m, 2H), 7.73 ( d, J=8.6Hz, 1H), 7.42 (m, 2H), 7.36 (dd, J=8.7, 5.5Hz, 2H), 7.18 (t, J=8.9Hz, 2H), 5.05 (m, 1H), 3.95 (s, 3H), 3.71 (s, 3H), 1.89 (d, J=6.8Hz, 3H).

[1402] Example 209: Preparation of compound 209:

[1403]

[1404] Preparation of compound 209:

[1405] Compound INT-30 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-fluorocyclopropanecarboxylic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 209, in 56% yield. MS (ESI, positive ion) m / z: 539.2 [M+H] + .

[1406] 1 H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 8.86 (d, J = 7.0Hz, 1H), 8.50 (d, J = 1.8Hz, 1H), 8. 19 (s, 1H), 7.95 (s, 1H), 7.89 (d, J=1.9Hz, 1H), 7.82 (m, 2H), 7.73 (d, J=8.6Hz, 1H), 7.4 2 (dd, J=7.2, 2.0Hz, 1H), 7.36 (dd, J=8.7, 5.5Hz, 2H), 7.18 (t, J=8.9Hz, 2H), 6.10 (d, J =6.8Hz, 1H), 4.71-4.59 (m, 1H), 3.95 (s, 3H), 1.89 (d, J = 6.8Hz, 3H), 0.92-0.78 (m, 3H).

[1407] Example 210: Preparation of compound 210:

[1408]

[1409] Preparation of compound 210:

[1410] Compound INT-30 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 210 in 69% yield. MS (ESI, positive ion) m / z: 521.2 [M+H] + .

[1411] 1 H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 8.86 (d, J = 7.0Hz, 1H), 8.50 (d, J = 1.8Hz, 1H ), 8.19 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 1.9Hz, 1H), 7.82 (m, 2H), 7.73 (d, J = 8.6Hz , 1H), 7.42 (dd, J=7.2, 2.0Hz, 1H), 7.36 (dd, J=8.7, 5.5Hz, 2H), 7.18 (t, J=8.9Hz, 2H), 6.10 (d, J=6.8Hz, 1H), 3.95 (s, 3H), 1.89 (d, J=6.8Hz, 3H), 0.92-0.78 (m, 5H).

[1412] Example 211 Preparation of compound 211:

[1413]

[1414] Preparation of compound 211:

[1415] Compound INT-32 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-fluorocyclopropanecarboxylic acid (31 mg, 0.3 mmol) and 1-propylphosphoric 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 211 in 64% yield. MS (ESI, positive ion) m / z: 513.2 [M+H] + .

[1416] 1H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.76 (m, 1H), 8.55 (d, J=1.8Hz, 1H), 8. 27 (s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=8.6Hz, 1H), 7 .60-7.53(m,1H),7.48(m,2H),7.28-7.18(m,2H),5.54-5.49(m,1H),4.71-4 .59(m, 3H), 3.72(s, 3H), 2.60-2.55(m, 1H), 1.42(m, 1H), 1.21-1.06(m, 2H).

[1417] Example 212: Preparation of compound 212:

[1418]

[1419] Preparation of compound 212:

[1420] Compound INT-32 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyclopropylformic acid (28 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 212 in 68% yield. MS (ESI, positive ion) m / z: 495.2 [M+H] + .

[1421] 1 H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.76 (m, 1H), 8.55 (d, J=1.8Hz, 1H), 8. 27 (s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=8.6Hz, 1H), 7 .60-7.53(m,1H),7.48(m,2H),7.28-7.18(m,2H),5.54-5.49(m,1H),4.71-4 .59(m, 2H), 3.72(s, 3H), 2.60-2.55(m, 1H), 1.42(m, 1H), 0.72-0.56(m, 4H).

[1422] Example 213 Preparation of compound 213:

[1423]

[1424] Preparation of compound 213:

[1425] Compound INT-32 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 1-methylpyrazol-4-carboxylic acid (38 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 213 in 58% yield. MS (ESI, positive ion) m / z: 535.2 [M+H] + .

[1426] 1 H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.76 (m, 2H), 8.55 (d, J=1.8Hz, 1H), 8.27 (s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=8.6Hz, 1H), 7.60-7.53 (m, 2H), 7.48 (m, 2H), 7.28-7.18 (m, 2H), 5.54-5.49 (m, 1H), 4.71-4.59 (m, 2H), 3.92 (s, 3H), 3.71 (s, 3H).

[1427] Example 214: Preparation of compound 214:

[1428]

[1429] Preparation of compound 214-1:

[1430] Intermediate INT-31 (490 mg, 1 mmol) was dissolved in dichloromethane (0.3 L), and methyl chloroformate (112 mg, 1.2 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol) were added. The mixture was stirred at room temperature for 2 h. Petroleum ether (0.3 L) was added to the reaction solution to induce crystallization. The solid was filtered, washed with water, and dried to give compound 214-1, with a yield of 65%. MS (ESI, positive ion) m / z: 549.2 [M+H] + .

[1431] Preparation of compound 214:

[1432] Compound 214-1 (110 mg, 0.2 mmol) was dissolved in acetonitrile (1 mL), and morpholine (36 mg, 0.4 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 214 in 58% yield. MS (ESI, positive ion) m / z: 604.2 [M+H] + .

[1433] 1 H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.90 (dd, J=7.1, 0.8Hz, 1H), 8.62 (d, J=8.3Hz, 1H), 8.55 (d, J=1.8Hz, 1H), 8.27 (s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.76 (dd, J=8.7, 1.8Hz, 1H), 7.69 (d , J=8.6Hz, 1H), 7.60-7.53(m, 2H), 7.48(dd, J=7.2, 2.0Hz, 1H), 7.28-7.18(m, 2H), 5.49(dq, J= 15.3, 7.3Hz, 1H), 4.70-4.60(m, 3H), 3.64(m, 6H), 3.43(s, 3H), 3.27(s, 2H), 2.58-2.55(m, 4H).

[1434] Example 215: Preparation of compound 215:

[1435]

[1436] Preparation of compound 215:

[1437] Compound INT-31 (85 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and cyanoacetic acid (25 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 215 in 58% yield. MS (ESI, positive ion) m / z: 558.2 [M+H] + .

[1438] 1H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.90 (dd, J=7.1, 0.8Hz, 1H), 8.62 (d, J=8.3Hz, 1H), 8.55 (d, J=1.8Hz, 1H), 8.27 (s, 1H), 7.91 (dd, J=1.9, 0.9Hz, 1H), 7.76 (dd, J=8.7, 1.8Hz, 1H), 7.69 (d , J=8.6Hz, 1H), 7.60-7.53(m, 2H), 7.48(dd, J=7.2, 2.0Hz, 1H), 7.28-7.18(m, 2H), 5.49(dq, J= 15.3, 7.3Hz, 1H), 4.70-4.60(m, 3H), 3.71-3.60(m, 2H), 3.34(s, 2H), 3.23(s, 3H), 3.27(s, 2H).

[1439] Example 216: Preparation of compound 216:

[1440]

[1441] Preparation of compound 216:

[1442] INT-33 (90 mg, 0.2 mmol) was dissolved in pyridine (1 mL), and 2-methoxypropionic acid (31 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 by C-18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution = 60%) to give compound 216 in 66% yield. MS (ESI, positive ion) m / z: 539.2 [M+H] + .

[1443] 1 H NMR (400MHz, DMSO-d6) δ10.50 (s, 1H), 8.95-8.85 (m, 2H), 8.66 (s, 1H), 8.56-8.50 (m, 1H), 8.03-7.96 (m, 2H), 7.92 (d, J=9.0Hz, 1H ), 7.52 (m, 3H), 7.22-7.12 (m, 2H), 5.26 (p, J = 7.2Hz, 1H), 4.18 (m, 1H), 3.39 (s, 3H), 1.55 (d, J = 7.1Hz, 3H), 1.35 (d, J = 6.6Hz, 3H).

[1444] Example 217 Preparation of compound 217:

[1445]

[1446] Preparation o...

Claims

1. The following compounds, pharmaceutically acceptable salts or stereoisomers thereof: 。 2. A pharmaceutical composition comprising the compound of claim 1, a pharmaceutically acceptable salt or stereoisomer thereof.

3. Use of the compound of claim 1, a pharmaceutically acceptable salt, stereoisomer thereof or the pharmaceutical composition of claim 2 for the manufacture of a medicament for the prevention and / or treatment of inflammation, autoimmune diseases, neurodegenerative diseases and tumor-related diseases.

4. Use of the compound of claim 1, a pharmaceutically acceptable salt, stereoisomer thereof or the pharmaceutical composition of claim 2 for the manufacture of a RIPK1 and / or MLK inhibitor.

5. Use according to claim 4, wherein, The MLK inhibitor is a MLK2 / 3 inhibitor.

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