Hydroxamic acid ester compounds, methods of making and using the same

Abstract

The application relates to a hydroxamic acid ester compound shown in formula (I), a preparation method and application thereof. The application also relates to a pharmaceutical composition containing the compound as an active ingredient and use of the compound or the pharmaceutical composition for treating and / or preventing a related disease mediated by TYK2.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to hydroxamic acid ester compounds, their preparation methods, and their applications. Background Technology

[0002] The Janus kinase (JAK) family is a class of non-receptor tyrosine kinases, with four members identified: JAK1, JAK2, JAK3, and TYK2. Signal transducer and activator of transcription (STAT) proteins are direct substrates of JAKs, with seven members identified (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). Many cytokines and growth factors transduce signals through the JAK-STAT signaling pathway: these cytokines and growth factors have corresponding receptors on the cell membrane, but these receptors themselves do not possess kinase activity; instead, they have JAK binding sites in their intracellular domains. Upon binding of the receptor to its ligand, the receptor molecule dimers, bringing the receptor-coupled JAKs closer together and activating them through phosphorylation of interacting tyrosine residues. The activated JAKs catalyze the phosphorylation of tyrosine residues on the receptor itself, forming corresponding STAT docking sites. This allows STATs to bind to the receptor and be phosphorylated and activated by JAKs. The STATs then enter the nucleus as dimers, binding to the promoters of target genes and activating their transcription and expression. A single JAK kinase can participate in the signal transduction of multiple cytokines, and a single cytokine signaling pathway can activate multiple JAK kinases; however, cytokines exhibit a degree of selectivity for activated STAT molecules.

[0003] The JAK-STAT signaling pathway is closely related to autoimmune and inflammatory diseases. Therefore, the JAK family has become a popular target for new drug development. Small molecule drugs inhibiting JAK1, JAK2, and JAK3 have been approved for the treatment of multiple related diseases. For example, pan-JAK inhibitors tofacitinib and peficitinib, the JAK1 / JAK2 inhibitor baricitinib are approved for the treatment of rheumatoid arthritis, and the JAK1 / JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis. However, all of these drugs have been given black box warnings by the US FDA due to risks such as infection and thrombosis, especially with high doses and long-term use. The inability to achieve highly selective inhibition of different JAK kinase subtypes is the reason for the significant side effects of first-generation JAK inhibitors; therefore, high selectivity has become the development direction for next-generation JAK inhibitors.

[0004] As a member of the JAK family, tyrosine kinase 2 (TYK2) is widely distributed in various tissues and cells. It can couple with receptors such as IFNAR1, IL10R2, IL12R-β1, and gp130, exerting its effects in TYK2 / JAK1, TYK2 / JAK2, and TYK2 / JAK1 / JAK2 pairings. It mediates signaling pathways involving type I interferon, interleukin-10 (IL-10), IL-12, and IL-23, but does not participate in cytokine responses mediated by other kinases. Although no TYK2 inhibitors have been approved for marketing, due to its unique molecular mechanism of action in diseases, it is considered a potential target with fewer side effects while maintaining the same therapeutic efficacy. Inhibition of the TYK2 signaling pathway can block signaling pathways induced by factors including type I interferon, IL-10, IL-12, and IL-23, producing positive therapeutic effects on diseases, including but not limited to those closely related to these factors. Summary of the Invention

[0005] The problem the invention aims to solve:

[0006] Although several patent applications for selective TYK2 inhibitors have been published, further development of new compounds is still needed, given the promising prospects of TYK2-specific inhibitors in treating inflammatory diseases, autoimmune diseases, and cancer. Through continuous efforts, the inventors of this application have designed compounds having the structures shown in general formula (I), formula (I'), or formula (I”), and discovered that compounds with such structures exhibit superior effects and functions, possessing better druggability, stronger efficacy, and higher TYK2 kinase selectivity.

[0007] Solution for solving the problem:

[0008] In order to solve the above problems, the inventors of this application have conducted in-depth research and discovered that specific hydroxyoxime ester compounds can achieve the desired purpose, resulting in the completion of this invention.

[0009] This invention relates to the following hydroxyoxime ester compounds.

[0010] This invention protects the following specific embodiments:

[0011] A compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0012]

[0013] in:

[0014] X is CR a Or N;

[0015] Y is CH or N;

[0016] R a Selected from hydrogen, deuterium, F, Cl, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0017] Preferably, R a It can be hydrogen or methyl;

[0018] More preferably, R a It is hydrogen;

[0019] R 0 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally selected from C 1-6 Alkyl or C 3-6 Substituents of cycloalkyl groups;

[0020] Preferably, R 0 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0021] More preferably, R 0 Selected from hydrogen, C 3-6 cycloalkyl;

[0022] Or more preferably, R 0 Selected from hydrogen, C 1-6 alkyl;

[0023] More preferably, R 0 Selected from hydrogen and methyl;

[0024] Most preferably, R 0 Selected from hydrogen;

[0025] R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl groups or C groups containing 1 to 4 heteroatoms 3-6 Heterocyclic alkyl groups, wherein the heteroatoms are selected from O, N, and S, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl groups or C groups containing 1 to 4 heteroatoms 3-6 Heterocyclic alkyl groups are each optionally surrounded by 1 to 7 R 1a replace;

[0026] Preferably, R 1 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 3-6Each cycloalkyl group is optionally surrounded by 1 to 7 (e.g., 1-5 or 1-3, specifically 2, 3, 4, 5 or 6) R 1a replace;

[0027] More preferably, R 1 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 3-6 Each cycloalkyl group is optionally surrounded by 1 to 3 R 1a replace;

[0028] Or more preferably, R 1 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally surrounded by 1 to 7 (e.g., 1-5 or 1-3, specifically 2, 3, 4, 5 or 6) R. 1a replace;

[0029] More preferably, R 1 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups 1a replace;

[0030] R 1a Selected from deuterium, F, Cl, or CN;

[0031] Preferably, R 1a Selected from deuterium, F, or Cl;

[0032] More preferably, R 1a Selected from deuterium or F;

[0033] Most preferably, R 1 The compound is selected from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl, 2,2,2-trifluoroethyl, and cyclopropyl, and preferably from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl, and 2,2,2-trifluoroethyl.

[0034] R 2 Selected from C 3-10 Cycloalkyl-C(O)-, C containing 1 to 4 heteroatoms selected from N, O and S 3-8 Heterocyclic groups -C(O)-, C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl groups, containing 1 to 4 heteroatoms selected from N, O, and S. 3-8 Heterocyclic group, C 6-10The aryl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S is optionally surrounded by 1 to 3 R atoms. 2a replace;

[0035] Preferably, R 2 Selected from C 3-10 Cycloalkyl-C(O)-, C containing 1 to 4 heteroatoms selected from N, O and S 3-8 Heterocyclic groups -C(O)-, C 6-10 aryl, a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the C 3-10 Cycloalkyl groups, containing 1 to 4 heteroatoms selected from N, O, and S. 3-8 Heterocyclic group, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S is optionally surrounded by 1 to 3 R atoms. 2a replace;

[0036] More preferably, R 2 Selected from C 3-6 Cycloalkyl-C(O)-, C containing one to two heteroatoms selected from N, O and S 3-6 Heterocyclic group -C(O)-, phenyl, 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, wherein C 3-6 Cycloalkyl groups, containing one to two heteroatoms selected from N, O, and S. 3-6 The heterocyclic group, phenyl group, or 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O, and S is each optionally surrounded by 1 to 2 R atoms. 2a replace;

[0037] Most preferably, R 2 Selected from C 3-6 Cycloalkyl-C(O)-, C containing one to two heteroatoms selected from N, O and S 3-6 Heterocyclic group -C(O)-, phenyl, 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms selected from N and S, wherein the 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms selected from N and S is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, and C 3-6 Cycloalkyl groups, containing one to two heteroatoms selected from N, O, and S. 3-6 The heterocyclic group, phenyl group, or 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms selected from N and S is optionally surrounded by 1 to 2 R atoms. 2a replace;

[0038] Preferably, the C containing one to two heteroatoms selected from N, O, and S... 3-6 The heterocyclic group is a nitrogen-containing heterocyclic butyl group;

[0039] Preferably, the C 3-8 Heterocyclic group -C(O)- or the C group described above 3-6 In the heterocyclic group -C(O)-, the heterocyclic group is connected to -C(O)- through a heteroatom on the heterocycle; preferably, the heteroatom is a nitrogen atom;

[0040] R 2a Selected from deuterium, =O (oxo), F, Cl, Br, I, CN, OCF3, NO2, -(CH2) r OR b -(CH2) r SR b -(CH2) r C(O)R b -(CH2) r C(O)OR b -(CH2) r NR b R c -(CH2) r C(O)NR b R c -(CH2) r NR b C(O)R c -(CH2) r NR b C(O)OR c -NR b C(O)NR c R c -NR b S(O) p R c -S(O) p R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 2-6 alkenyl, optionally surrounded by 1 to 3 R d Replacement C 2-6 Alkyne group, optionally surrounded by 1 to 3 R groups d Substituted -(CH2) r -3 to 10 yuan of carbon rings or optional 1 to 3 Rs d Substituted -(CH2) r -5 to 10-membered heterocyclic rings; wherein the heterocyclic rings comprise 1 to 4 nucleotides selected from O, N, or S(O). p heteroatoms;

[0041] Preferably, R2a Selected from halogen, cyano, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Alkyl-S(O)2-, -P(O)R b R c -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 1-6 alkyl;

[0042] More preferably, R 2a Selected from C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 3-6 Cycloalkyl, cyano, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkyl-S(O)2-;

[0043] Most preferably, R 2a Selected from methyl, F, methoxy, cyclopropyl, cyano, -CF3, hydroxymethyl, and methanesulfonyl;

[0044] R 3 Selected from C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the C 6-10 aryl or 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, optionally bounded by 1 to 4 R atoms. 3a replace;

[0045] Preferably, R 3 The phenyl group is selected from phenyl or a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O, and S, wherein the phenyl group or the 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O, and S is optionally surrounded by 1 to 3 R atoms. 3a replace;

[0046] More preferably, R 3 Selected from phenyl or 5- to 9-membered heteroaryl groups containing 1 to 2 heteroatoms selected from N or O, wherein the phenyl or 5- to 9-membered heteroaryl group containing 1 to 2 heteroatoms selected from N or O is optionally surrounded by 1 to 3 R... 3a replace;

[0047] More preferably, R 3 The group is selected from phenyl, pyridyl, pyridonel, 2-pyridonel, pyrazinyl, pyrimidinyl, pyridazinyl, indoleyl, or indazole, wherein the phenyl, pyridyl, pyridonel, 2-pyridonel, pyrazinyl, pyrimidinyl, pyridazinyl, indoleyl, or indazole is optionally surrounded by 1 to 3 R groups.3a replace;

[0048] Most preferably, R 3 The group is selected from phenyl, pyridyl, 2-pyridone, or indazole, wherein the phenyl, pyridyl, 2-pyridone, or indazole group is optionally surrounded by 1 to 3 R groups. 3a replace;

[0049] R 3a Selected from deuterium, =O, F, Cl, Br, I, CN, OCF3, NO2, -(CH2) r OR b -(CH2) r SR b -(CH2) r C(O)R b -(CH2) r C(O)OR b -(CH2) r NR b R c -(CH2) r C(O)NR b R c -(CH2) r NR b C(O)R c -(CH2) r NR b C(O)OR c -NR b C(O)NR c R c -NR b S(O) p R c -S(O) p R c -S(O) p NR c R c -P(O)R b R c , Choose 1 to 3 R d Substituted C1-C6 alkyl groups, optionally with 1 to 3 R d Replacement C 2-6 alkenyl, optionally surrounded by 1 to 3 R d Replacement C 2-6 Alkyne group, optionally surrounded by 1 to 3 R groups d Substituted -(CH2) r -3 to 10 yuan carbon rings, optionally coated with 1 to 3 Rs d Substituted -(CH2) r -5 to 10 yuan heterocyclic, randomly selected by 1 to 3 R dThe substituted 5- to 10-membered heteroaryl group; wherein the heterocycle or heteroaryl group comprises 1 to 4 ions selected from O, N, or S(O). p heteroatoms;

[0050] Or two Rs 3a The atoms bonded to it combine to form a fused ring, wherein the ring is selected from phenyl and heterocycles, and the heterocycle contains 1 to 4 atoms selected from N, N or S(O). p The heteroatoms, each fused ring optionally separated by 1 to 3 R atoms b replace;

[0051] Preferably, R 3a Selected from F, Cl, Br, I, CN, NO2, -OR b -SR b -C(O)OR b -C(O)NR b R c -NR b C(O)R c -NR b C(O)OR c -NR b C(O)NR c R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O and S;

[0052] More preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c, Choose 1 to 3 R d Replacement C 1-6 Alkyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O and S;

[0053] Most preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-6 Alkyl groups (such as trifluoromethyl, methyl, ethyl, propyl, isopropyl, etc.), C 2-6 Alkyne groups (such as ethynyl, propynyl, etc.), C 3-6 cycloalkyl groups (such as cyclopropyl, cyclobutyl, etc.), optionally R d The substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, or 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S are selected from thiazolyl groups (e.g., ...). ), benzimidazole group (e.g. ), pyrazolyl (e.g.) ), oxadiazole group (such as ), triazole (e.g. ), pyridyl (e.g.) ), pyrimidine group (such as ) or pyrazinyl (e.g.: The 5- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from N, O, and S is selected from morpholino (e.g., ), piperidinyl (e.g.) );

[0054] R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 3-6 cycloalkyl, optionally with 1 to 3 Rd Substituted -(CH2) r -Phenyl or optionally with 1 to 3 R d Substituted -(CH2) r -4 to 7-membered heterocycles; wherein the heterocycles contain 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0055] Preferably, R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl groups, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S;

[0056] More preferably, R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl groups, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 oxygen atoms;

[0057] Most preferably, R b Selected from hydrogen, optionally surrounded by 1 to 3 R... d Substituted methyl, ethyl, isopropyl,

[0058] R c Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted -(CH2) r -Phenyl or optionally with 1 to 3 R d Substituted -(CH2) r -5 to 7-membered heterocycles; wherein the heterocycles contain 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0059] Preferably, R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0060] More preferably, R c Selected from hydrogen, methyl, ethyl, and cyclopropyl;

[0061] Most preferably, R c Selected from hydrogen, methyl, and cyclopropyl;

[0062] R d Selected from hydrogen, deuterium, F, Cl, Br, I, OCF3, CF3, and -(CH2). r-CN, NO2, OR e -(CH2) r COR c -NR e R e -NR e C(O)OR c C1-C6 alkyl, C 3-6 cycloalkyl or optionally with 1 to 3 R f Substituted -(CH2) r -Phenyl;

[0063] Preferably, R d Selected from deuterium, F, Cl, Br, I, hydroxyl, C1-C6 alkyl, C 3-6 Cycloalkyl, -(CH2) p -CN;

[0064] More preferably, R d Selected from deuterium, F, Cl, Br, hydroxyl, C1-C6 alkyl, C 3-6 cycloalkyl;

[0065] Most preferably, R d Selected from deuterium, F, Cl, hydroxyl, methyl, cyclopropyl, and isopropyl;

[0066] R e Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or optionally with 1 to 3 R f Substituted -(CH2) r -Phenyl;

[0067] Preferably, R e It is hydrogen;

[0068] R f Selected from hydrogen, F, Cl, Br, NH2, OH, CF3, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or -(CH2) r -5 to 7-membered heterocycles, wherein the heterocycles comprise 1 to 4 ions selected from O, N, or S(O). p heteroatoms;

[0069] p is 0, 1, or 2, and

[0070] r can be 0, 1, 2, 3 or 4.

[0071] In some implementation schemes, wherein:

[0072] X is CR a Or N;

[0073] R aSelected from hydrogen and methyl;

[0074] Preferably, R a It is hydrogen;

[0075] R 0 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0076] Preferably, R 0 Selected from hydrogen, C 1-6 alkyl;

[0077] Or preferably, R 0 Selected from hydrogen, C 3-6 cycloalkyl;

[0078] More preferably, R 0 Selected from hydrogen and methyl;

[0079] Most preferably, R 0 Selected from hydrogen;

[0080] R 1 Selected from C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 Each cycloalkyl group is optionally surrounded by 1 to 3 R 1a replace;

[0081] Preferably, R 1 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups 1a replace;

[0082] R 1a Selected from deuterium, F, Cl, or CN;

[0083] Preferably, R 1a Selected from deuterium, F, or Cl;

[0084] More preferably, R 1a Selected from deuterium or F;

[0085] More preferably, R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl, 2,2,2-trifluoroethyl, and cyclopropyl;

[0086] Most preferably, R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl, and 2,2,2-trifluoroethyl;

[0087] R 2 Selected from cyclopropionyl, Phenyl, pyrazolyl, thiazolyl, furanyl, thiophene, imidazole, pyridyl, pyridone, pyrazinyl, pyrimidinyl, pyridazinyl, and cyclopropionicyl, Phenyl, pyrazolyl, thiazolyl, furanyl, thiophene, imidazolyl, pyridyl, pyridonel, pyrazinyl, pyrimidinyl, and pyridazinyl are each optionally surrounded by 1 to 3 R groups. 2a replace;

[0088] Preferably, R 2 Selected from cyclopropionyl, Phenyl, pyrazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and cyclopropionic acid, Phenyl, pyrazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl groups are optionally surrounded by one to two R groups. 2a replace;

[0089] R 2a Selected from deuterium, =O, F, Cl, Br, CN, OCF3, -(CH2) r OR b -(CH2) r C(O)OR b -(CH2) r NR b R c ,

[0090] -(CH2) r C(O)NR b R c -(CH2) r NR b C(O)R c -(CH2) r NR b C(O)OR c -S(O) p R c , Choose 1 to 3 R d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Substituted -(CH2) r -3 to 7 yuan carbon rings or optionally 1 to 3 R d Substituted -(CH2) r -5 to 7-membered heterocycles; wherein the heterocycles comprise 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0091] Preferably, R 2a Selected from F, Cl, Br, cyano, C 1-6 Alkoxy, C 3-6 cycloalkyl, C1-6 Alkyl-S(O)2-, optionally surrounded by 1 to 3 R d Replacement C 1-6 alkyl;

[0092] More preferably, R 2a Selected from C 1-6 Alkyl, F, Cl, Br, C 1-6 Alkoxy, C 3-6 Cycloalkyl, cyano, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkyl-S(O)2-;

[0093] Most preferably, R 2a Selected from methyl, F, methoxy, cyclopropyl, cyano, -CF3, hydroxymethyl, and methanesulfonyl;

[0094] R 3 The group is selected from phenyl, pyridinyl, pyridoneyl, 2-pyridoneyl, pyrazinyl, pyrimidinyl, pyridazinyl, or indazoleyl, wherein the phenylpyridinyl, pyridoneyl, 2-pyridoneyl, pyrazinyl, pyrimidinyl, pyridazinyl, or indazoleyl group is optionally surrounded by 1 to 3 R groups. 3a replace;

[0095] Preferably, R 3 The group is selected from phenyl, pyridyl, 2-pyridone, or indazole, wherein the phenyl, pyridyl, 2-pyridone, or indazole group is optionally surrounded by 1 to 3 R groups. 3a replace;

[0096] R 3a Selected from deuterium, =O, F, Cl, Br, CN, OCF3, NO2, -(CH2) r OR b -(CH2) r C(O)R b -(CH2) r C(O)OR b -(CH2) r NR b R c -(CH2) r C(O)NR b R c -(CH2) r NR b C(O)R c -(CH2) r NR b C(O)OR c -NR b C(O)NR c R c -NRb S(O) p R c -S(O) p R c -S(O) p NR c R c -P(O)R b R c , Choose 1 to 3 R d Substituted C1-C6 alkyl groups, optionally with 1 to 3 R d Replacement C 2-6 alkenyl, optionally surrounded by 1 to 3 R d Replacement C 2-6 Alkyne group, optionally surrounded by 1 to 3 R groups d Substituted -(CH2) r -3 to 7 yuan carbon rings, optionally coated with 1 to 3 Rs d The substituted 5 to 10 heteroaryl groups or optionally 1 to 3 R groups d Substituted -(CH2) r -5 to 10-membered heterocycles; wherein the heterocycle or heteroaryl group comprises 1 to 4 ions selected from O, N, or S(O). p heteroatoms;

[0097] Or two Rs 3a The atoms bonded to it combine to form a fused ring, wherein the ring is selected from phenyl and heterocycles, and the heterocycle contains 1 to 4 atoms selected from N, N or S(O). p The heteroatoms, each fused ring optionally separated by 1 to 3 R atoms b replace;

[0098] Preferably, R 3a Selected from F, Cl, Br, I, CN, NO2, -OR b -C(O)OR b -C(O)NR b R c -NR b C(O)R c -NR b C(O)OR c -NR b C(O)NR c R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Choose 1 to 3 R d Replacement C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O and S;

[0099] More preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-6 Alkyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O and S;

[0100] Most preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-6 Alkyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, optional R dThe substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, and the 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S are selected from thiazolyl, benzimidazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, and the 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S are selected from morpholinyl and piperidinyl;

[0101] R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted -(CH2) r -Phenyl or optionally with 1 to 3 R d Substituted -(CH2) r -4 to 7-membered heterocycles; wherein the heterocycles contain 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0102] Preferably, R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl groups, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S;

[0103] More preferably, R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl groups, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 oxygen atoms;

[0104] Most preferably, R b Selected from hydrogen, optionally surrounded by 1 to 3 R... d Substituted methyl, ethyl, isopropyl,

[0105] R c Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted -(CH2) r -Phenyl or optionally with 1 to 3 R d Substituted -(CH2) r -5 to 7-membered heterocycles; wherein the heterocycles contain 1 to 4 members selected from O, N, or S(O).p heteroatoms;

[0106] Preferably, R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0107] More preferably, R c Selected from hydrogen, methyl, ethyl, and cyclopropyl;

[0108] Most preferably, R c Selected from hydrogen, methyl, and cyclopropyl;

[0109] R d Selected from hydrogen, deuterium, F, Cl, Br, OCF3, CF3, and -(CH2). r -CN, NO2, OR e -(CH2) r COR c -NR e R e -NR e C(O)OR c C1-C6 alkyl, C 3-6 Cycloalkyl or optionally with 1 to 3 R f Substituted -(CH2) r -Phenyl;

[0110] Preferably, R d Selected from deuterium, F, Cl, Br, hydroxyl, C1-C6 alkyl, C 3-6 Cycloalkyl, -(CH2) p -CN;

[0111] More preferably, R d Selected from deuterium, F, Cl, Br, hydroxyl, C1-C6 alkyl, C 3-6 cycloalkyl;

[0112] Most preferably, R d Selected from deuterium, F, Cl, hydroxyl, methyl, cyclopropyl, and isopropyl;

[0113] R e Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or optionally with 1 to 3 R f Substituted -(CH2) r -Phenyl;

[0114] Preferably, R e It is hydrogen;

[0115] R f Selected from hydrogen, F, Cl, Br, NH2, OH, CF3, -OC1-6 Alkyl, C 3-6 Cycloalkyl or -(CH2) r -5 to 7-membered heterocycles, wherein the heterocycles comprise 1 to 4 ions selected from O, N, or S(O). p heteroatoms;

[0116] p is 0, 1, or 2, and

[0117] r is 0, 1, or 2.

[0118] In some implementation schemes, R 3a Selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, -CF3, methoxy, ethoxy, ethynyl,

[0119] In some implementation schemes, wherein:

[0120] R 0 Selected from hydrogen and methyl;

[0121] Preferably, R 0 Selected from hydrogen;

[0122] R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, trideuterated methyl or 2,2,2-trifluoroethyl;

[0123] Preferably, R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl or 2,2,2-trifluoroethyl;

[0124] R 2 Selected from cyclopropionyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, or pyrazolyl, wherein the cyclopropionyl group, Phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, or pyrazolyl is optionally surrounded by 1 to 3 (e.g., 1 to 2) R 2a replace;

[0125] R 3 The group is selected from phenyl, pyridyl, pyridone, 2-pyridone, or indazole, wherein the phenyl, pyridyl, pyridone, 2-pyridone, or indazole group is optionally surrounded by 1 to 3 R groups. 3a replace;

[0126] Preferably, R 3 The group is selected from phenyl, pyridyl, 2-pyridone, or indazole, wherein the phenyl, pyridyl, 2-pyridone, or indazole group is optionally surrounded by 1 to 3 R groups. 3a replace.

[0127] In some implementation schemes, wherein:

[0128] X is selected from CH or N;

[0129] R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl, and 2,2,2-trifluoroethyl;

[0130] R 2a Selected from F, Cl, Br, CN, OCF3, -(CH2) r OR b -S(O) p R c , Choose 1 to 3 R d Replacement C 1-3 Alkyl groups or optionally 1 to 3 R groups d Substituted -(CH2) r -3 to 5 element carbon rings;

[0131] Preferably, R 2a Selected from C 1-3 Alkyl, halogen, C 1-3 Alkoxy, C 3-5 Cycloalkyl, cyano, halogenated C 1-3 Alkyl, hydroxyl substituted C 1-3 Alkyl, C 1-3 Alkyl-S(O)2-;

[0132] More preferably, R 2a Selected from methyl, F, methoxy, cyclopropyl, cyano, -CF3, hydroxymethyl, and methanesulfonyl;

[0133] R 3a Selected from F, Cl, Br, CN, OCF3, -(CH2) r OR b -(CH2) r NR b R c -(CH2) r C(O)NR b R c -NR b C(O)NR c R c -NR b S(O) p R c -S(O) p R c -S(O) p NR c R c -P(O)R b R c , Choose 1 to 3 R dSubstituted C1-C3 alkyl groups, optionally with 1 to 3 R d Replacement C 2-4 Alkyne group, optionally surrounded by 1 to 3 R groups d Substituted -(CH2) r -3 to 5 yuan of carbon rings or optionally 1 to 3 R d Substituted -(CH2) r -5 to 9-membered heterocycles; wherein the heterocycles comprise 1 to 4 ions selected from O, N, or S(O). p heteroatoms;

[0134] Preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-3 Alkyl, C 2-4 alkynyl group, C 3-5 cycloalkyl, optionally with 1 to 3 R d Substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O and S;

[0135] More preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-3 Alkyl, C 2-4 alkynyl group, C 3-5 cycloalkyl, optional R dThe substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, and the 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S are selected from thiazolyl, benzimidazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, and the 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S are selected from morpholinyl or piperidinyl;

[0136] R b Selected from hydrogen, optionally surrounded by 1 to 3 R... d Substituted methyl, ethyl, isopropyl, cyclopropyl,

[0137] Preferably, R b Selected from hydrogen, optionally surrounded by 1 to 3 R... d Substituted methyl, ethyl, isopropyl,

[0138] R c Selected from hydrogen, methyl, ethyl, and cyclopropyl;

[0139] Preferably, R c Selected from hydrogen, methyl, and cyclopropyl;

[0140] R d Selected from hydrogen, deuterium, F, Cl, hydroxyl, methyl, ethyl, cyclopropyl, and isopropyl;

[0141] Preferably, R d Selected from deuterium, F, Cl, hydroxyl, methyl, cyclopropyl, and isopropyl.

[0142] In some implementation schemes, R 2 Selected from

[0143] R 4 R 5 R 6 R 7 R 8 Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl;

[0144] Preferably, R 4 R 5 R 6 R 7 R 8Each is independently selected from hydrogen, F, methoxy, cyclopropyl, cyano, methyl, trifluoromethyl, and hydroxymethyl;

[0145] Or preferably, R 5 R 6 R 7 R 8 Or R 4 R 6 R 7 R 8 In, any one (such as R) 4 R 6 R 7 Or R 8 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl groups, the remainder being hydrogen; or, R 5 R 6 R 7 R 8 Or R 4 R 6 R 7 R 8 Or R 4 R 5 R 7 R 8 In, any two independent ones (such as R) 6 and R 7 , or R 7 and R 8 , or R 5 and R 7 , or R 4 and R 8 Selected from halogens, C 1-6 Alkyl groups, the rest being hydrogen;

[0146] Or more preferably, R 5 R 6 R 7 R 8 Or R 4 R 6 R 7 R 8 In, any one (such as R) 4 R 6 R 7 Or R 8 The radicals are selected from hydrogen, F, methoxy, cyano, trifluoromethyl, methyl, hydroxymethyl, cyclopropyl, and the remainder is hydrogen; or, R 5 R 6 R7 R 8 Or R 4 R 6 R 7 R 8 Or R 4 R 5 R 7 R 8 In, any two (such as R) 6 and R 7 , or R 7 and R 8 , or R 5 and R 7 , or R 4 and R 8 Each is independently selected from F and methyl, and the rest are hydrogen;

[0147] R 10 R 11 R 12 Each is independently selected from hydrogen and C. 1-6 alkyl;

[0148] Preferably, R 10 R 11 R 12 Each is independently selected from hydrogen and methyl;

[0149] Or preferably, R 10 R 11 R 12 In, any one (such as R) 12 (Selected from C) 1-6 Alkyl groups, the rest being hydrogen;

[0150] Or more preferably, R 10 R 11 R 12 In, any one (such as R) 12 () is methyl, the rest are hydrogen;

[0151] R 13 R 14 R 15 R 16 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy groups, halogens;

[0152] Preferably, R 13 R 14 R 15 R 16 Each is independently selected from hydrogen, methyl, methoxy, F, and Cl;

[0153] Or preferably, R 14 R15 R 16 Or R 13 R 15 R 16 In, any one (such as R) 13 Or R 15 (Selected from C) 1-6 Alkyl, C 1-6 Alkoxy, halogen, and the rest are hydrogen; or, any two (such as R). 13 and R 16 , or R 14 and R 16 Each is independently selected from hydrogen, C 1-6 Alkyl groups, the rest being hydrogen;

[0154] Or more preferably, R 14 R 15 R 16 Or R 13 R 15 R 16 In, any one (such as R) 13 Or R 15 The radical is selected from methyl, methoxy, F, and Cl, preferably from methoxy, methyl, and F, with the remainder being hydrogen; or, any two (such as R) 13 and R 16 , or R 14 and R 16 Each of the elements is independently selected from hydrogen, methyl, methoxy, F, Cl (preferably hydrogen and methyl), and the remainder is hydrogen;

[0155] R 18 R 19 R 20 Each is independently selected from hydrogen and C. 1-6 alkyl;

[0156] Preferably, R 18 R 19 R 20 It is hydrogen;

[0157] R 21 R 22 R 23 R 24 Each is independently selected from hydrogen and C. 1-6 alkyl;

[0158] Preferably, R 21 R 22 R 23 R 24 Each is independently selected from hydrogen and methyl;

[0159] Or preferably, R 21 R 23 R24 Or R 21 R 22 R 24 Or R 21 R 22 R 23 In the middle, R 21 Selected from C 1-6 Alkyl groups, the rest being hydrogen;

[0160] Or more preferably, R 21 R 23 R 24 Or R 21 R 22 R 24 Or R 21 R 22 R 23 In the middle, R 21 One is methyl, the rest are hydrogen;

[0161] R 26 R 27 Each is independently selected from hydrogen and C. 1-6 alkyl;

[0162] Preferably, R 26 R 27 Each is independently selected from hydrogen and methyl;

[0163] Or preferably, R 26 R 27 In, any one is selected from hydrogen, C 1-6 The other is an alkyl group, and the third is hydrogen.

[0164] Or more preferably, R 26 R 27 In this context, one of the components is selected from hydrogen or methyl, and the other is hydrogen;

[0165] R 28 R 29 R 30 R 31 Each is independently selected from hydrogen and C. 1-6 Alkyl groups, halogens;

[0166] Preferably, R 28 R 29 R 30 R 31 Each is independently selected from hydrogen, methyl, F, and Cl;

[0167] More preferably, R 28 R 29 For hydrogen, R 30 R 31 Each is independently selected from hydrogen, methyl, and F;

[0168] R 32 R 33 R 34 R 35 R 36 Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy groups, and not all of them are hydrogen;

[0169] Preferably, R 32 R 33 R 34 R 35 R 36 Each is independently selected from hydrogen, F, methanesulfonyl, cyano, and methoxy, and they are not all hydrogen at the same time;

[0170] Or preferably, R 32 R 33 R 34 R 35 R 36 In, any one (such as R) 34 Selected from halogens, cyano groups, and C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy groups, the rest are hydrogen;

[0171] Or more preferably, R 32 R 33 R 34 R 35 R 36 In, any one (such as R) 34 The group is selected from F, methanesulfonyl, cyano, and methoxy, with the remainder being hydrogen.

[0172] R 55 R 56 R 57 R 58 R 59 R 60 Each is independently selected from hydrogen and C. 1-6 Alkyl groups, halogens;

[0173] Preferably, R 55 R 56 R 57 R 58 R 59 R 60 Each is independently selected from hydrogen, methyl, F, and Cl;

[0174] More preferably, R 55 R 56 R 59 R 60 For hydrogen, R57 R 58 Each is independently selected from hydrogen, methyl, F, and Cl;

[0175] Most preferably, R 55 R 56 R 59 R 60 For hydrogen, R 57 R 58 Each is independently selected from F and Cl.

[0176] In some implementation schemes, R 3 Selected from

[0177] R 37 R 38 R 39 R 40 R 41 Each is independently selected from hydrogen, -NR b S(O)2R c -S(O)2R c -P(O)R b R c -C(O)NR b R c -S(O)2NR c R c C 1-6 Alkyl, F, Cl, Br, I, cyano, optionally C 3-6 Cycloalkyl (e.g., cyclopropyl) substituted C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-6 Alkyne, morpholino, piperidinyl, optionally substituted with F, Cl, or C 1-6 Alkyl (such as methyl or isopropyl) C 3-6 Cycloalkyl (e.g., cyclopropyl) substituted indazole, pyrazolyl, oxadiazolyl, triazolyl, thiazolyl, benzimidazolyl, pyridyl, pyrimidinyl, or pyrazinyl groups, 4 to 6 membered saturated heterocyclic groups -O-, said saturated heterocyclic groups containing 1 to 2 oxygen atoms; R b Selected from hydrogen, C 1-6 Alkyl groups, preferably selected from hydrogen and methyl groups; R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, preferably selected from hydrogen, methyl, ethyl, cyclopropyl, more preferably selected from hydrogen, methyl, cyclopropyl; and R 37 R 38 R 39 R40 R 41 They are not both hydrogen;

[0178] Preferably, R 37 R 38 R 39 R 40 R 41 Each is independently selected from hydrogen, Methyl, ethyl, isopropyl, F, Cl, Br, cyano, methoxy, ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl Difluoromethoxy, And R 37 R 38 R 39 R 40 R 41 They are not both hydrogen;

[0179] More preferably, R 37 R 38 R 39 R 40 R 41 Each is independently selected from hydrogen, Methyl, ethyl, isopropyl, F, Cl, cyano, methoxy Ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl Difluoromethoxy, And R 37 R 38 R 39 R 40 R 41 They are not both hydrogen;

[0180] More preferably, R 37 R 38 R 39 R 40 R 41 Each is independently selected from hydrogen, Methyl, ethyl, isopropyl, F, Cl, cyano, methoxy, ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl

[0181]

[0182] And R 37 R 38 R 39 R 40R 41 They are not both hydrogen;

[0183] Or preferably, R 37 R 38 R 39 R 40 R 41 In, any one (such as R) 37 (Selected from -NR) b S(O)2R c -S(O)2R c , -P(O)R b R c -S(O)2NR c R c 4 to 6-membered saturated heterocyclic group -O-, the remainder being hydrogen, wherein the saturated heterocyclic group contains 1 to 2 oxygen atoms; R b Selected from hydrogen, C 1-6 Alkyl groups, preferably selected from hydrogen and methyl groups; R c Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl groups, preferably selected from methyl and cyclopropyl groups;

[0184] Or more preferably, R 37 R 38 R 39 R 40 R 41 In, any one (such as R) 37 (Selected from) The rest is hydrogen;

[0185] Or, most preferably, R 37 R 38 R 39 R 40 R 41 In, any one (such as R) 37 (Selected from) The rest is hydrogen;

[0186] Or preferably, R 37 R 38 R 39 R 40 R 41 In, any two (such as R) 37 R 38 , or R 37 R 39 , or R 37 R 40 Each is independently selected from -NR b S(O)2R c , -C(O)NR bR c C 1-6 Alkyl, F, Cl, Br, I, cyano, optionally C 3-6 Cycloalkyl (e.g., cyclopropyl) substituted C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-6 alkynyl, morpholinyl, piperidinyl C can be chosen 1-6 Alkyl groups (such as methyl or isopropyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), F or Cl substituted indazole, pyrazolyl, oxadiazolyl, triazolyl, thiazolyl, benzimidazolyl, pyridyl, pyrimidinyl, or pyrazinyl, with the remainder being hydrogen; R b Selected from hydrogen, C 1-6 Alkyl groups, preferably selected from hydrogen and methyl groups; R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, preferably selected from hydrogen, methyl, ethyl, and cyclopropyl groups, and more preferably selected from hydrogen, methyl, and cyclopropyl groups;

[0187] Or more preferably, R 37 R 38 R 39 R 40 R 41 In, any two (such as R) 37 R 38 , or R 37 R 39 , or R 37 R 40 Each independently selected Methyl, ethyl, isopropyl, F, Cl, Br, cyano, methoxy Ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl Difluoromethoxy, The rest is hydrogen;

[0188] Or, most preferably, R 37 R 38 R 39 R 40 R 41 In, any two (such as R) 37 R 38 , or R 37 R 39 , or R 37 R 40Each independently selected Methyl, ethyl, F, Cl, cyano, methoxy Ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl Difluoromethoxy, The rest is hydrogen;

[0189] Or, most preferably, R 37 R 38 R 39 R 40 R 41 In, any two (such as R) 37 R 38 , or R 37 R 39 , or R 37 R 40 Each independently selected F, Cl, cyano, methyl, ethyl, isopropyl, -CF3, cyclopropyl, methoxy, ethoxy, isopropoxy Acetylene group,

[0190] Or preferably, R 37 R 38 R 39 R 40 R 41 In, any three (such as R) 37 R 39 R 40 Or R 37 R 38 R 39 Or R 37 R 38 R 40 Each is independently selected from -NR b S(O)2R c F, Cl, Br, I, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkyne group, optionally C 1-6 Alkyl (such as methyl or isopropyl), F, CNCH2- or C 3-6 Cycloalkyl (e.g., cyclopropyl) substituted with a triazolyl, pyrimidinyl, or pyrazinyl group, with the remainder being hydrogen; R b Selected from C 1-6 Alkyl group, preferably methyl group; R c Selected from C 1-6 Alkyl, C3-6 cycloalkyl groups, preferably selected from C 1-6 Alkyl groups, or preferably selected from methyl, cyclopropyl, and more preferably methyl;

[0191] Or more preferably, R 37 R 38 R 39 R 40 R 41 In, any three (such as R) 37 R 39 R 40 Or R 37 R 38 R 39 Or R 37 R 38 R 40 Each independently selected Cyclopropyl, F, Cl, methyl, ethyl, isopropyl, methoxy Acetylene group, The rest is hydrogen;

[0192] Or, most preferably, R 37 R 38 R 39 R 40 R 41 In, any three (such as R) 37 R 39 R 40 Or R 37 R 38 R 39 Or R 37 R 38 R 40 Each independently selected Cyclopropyl, F, Cl, methyl, isopropyl, methoxy Acetylene group, The rest is hydrogen;

[0193] Or, most preferably, R 37 R 38 R 39 R 40 R 41 In, any three (such as R) 37 R 39 R 40 Or R 37 R 38 R 39 Or R 37 R 38 R 40 Each independently selected Cyclopropyl, F, Cl, methyl, ethyl, methoxy, ethynyl The rest is hydrogen;

[0194] Or preferably, R 37 R 38 R 39 R 40 R 41 Each is independently selected from hydrogen, Methyl, ethyl, isopropyl, F, Cl, cyano, methoxy, ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl

[0195] Or more preferably, R 37 R 38 R 39 R 40 R 41 In, any one (such as R) 37 (Selected from) Methyl, ethyl, isopropyl, F, Cl, cyano, methoxy, ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl The rest is hydrogen;

[0196] Or more preferably, R 37 R 38 R 39 R 40 R 41 In, any two (such as R) 37 R 38 , or R 37 R 39 Each independently selected Methyl, ethyl, isopropyl, F, Cl, cyano, methoxy, ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl The rest is hydrogen;

[0197] Or preferably, R 37 R 38 R 39 R 40 R 41 In, any three (such as R) 37 R 39 R 40 Or R 37 R 38 R 39 Each independently selected Methyl, ethyl, isopropyl, F, Cl, cyano, methoxy, ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl The rest is hydrogen;

[0198] R 42 R 43 R 44 R 45 Each is independently selected from hydrogen, -NR b S(O)2R c C 1-6 Alkyl, C 1-6 Alkoxy; R b Selected from hydrogen, C 1-6 Alkyl groups, preferably selected from hydrogen and methyl groups; R c Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl groups, preferably selected from methyl and cyclopropyl groups; and R 42 R 43 R 44 R 45 They are not both hydrogen;

[0199] Preferably, R 42 R 43 R 44 R 45 Each is independently selected from hydrogen, methyl, methoxy, and R 42 R 43 R 44 R 45 They are not both hydrogen;

[0200] Or preferably, R 42 R 43 R 44 R 45 In, any one (such as R) 42 Or R 43 (Selected from -NR) b S(O)2R c The rest are each independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy; R b Selected from hydrogen, C 1-6 Alkyl groups, preferably selected from hydrogen and methyl groups; R c Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl groups, preferably selected from methyl and cyclopropyl groups;

[0201] Or more preferably, R 42 R 43 R 44 R45 In, any one (such as R) 42 Or R 43 (Selected from) The others are each independently selected from hydrogen, methyl, and methoxy;

[0202] R 46 R 47 R 48 R 49 Each is independently selected from hydrogen and C. 1-6 alkyl, thiazolyl, and R 46 R 47 R 48 R 49 They are not both hydrogen;

[0203] More preferably, R 46 R 47 R 48 R 49 Each is independently selected from hydrogen, And R 46 R 47 R 48 R 49 They are not both hydrogen;

[0204] Or preferably, R 46 R 47 R 48 R 49 In, any one (such as R) 49 () is a thiazolyl group, and the rest are hydrogen atoms;

[0205] Or more preferably, R 46 R 47 R 48 R 49 In, any one (such as R) 49 )for The rest is hydrogen;

[0206] R 50 R 51 R 52 R 53 R 54 Each is independently selected from hydrogen and C. 1-6 Alkyl, and R 50 R 51 R 52 R 53 R 54 They are not both hydrogen;

[0207] Preferably, R 50 R 51 R 52 R 53 R54 Each is independently selected from hydrogen and methyl, and R 50 R 51 R 52 R 53 R 54 They are not both hydrogen;

[0208] Or preferably, R 50 R 51 R 52 R 53 R 54 In, any one (such as R) 50 (Selected from C) 1-6 Alkyl groups, the rest being hydrogen;

[0209] Or more preferably, R 50 R 51 R 52 R 53 R 54 In, any one (such as R) 50 () is selected from methyl, the rest are hydrogen.

[0210] In some implementations, R 2 Selected from:

[0211]

[0212]

[0213] In some preferred embodiments, R 2 Selected from

[0214] In some implementations, R 2 Selected from:

[0215] In some preferred embodiments, R 2 Selected from

[0216] In some implementations, R 3 Selected from:

[0217]

[0218]

[0219] In some preferred embodiments, R3 Selected from:

[0220]

[0221]

[0222] In some preferred embodiments, R 3 Selected from

[0223]

[0224]

[0225] In some implementation schemes, R 3 Selected from:

[0226]

[0227]

[0228] In some preferred embodiments, R 3 Selected from:

[0229]

[0230] On the other hand, the present invention also provides a compound of formula (I'), or a pharmaceutically acceptable salt thereof:

[0231]

[0232] in:

[0233] X is CR a Or N;

[0234] Y is CH or N;

[0235] R a Selected from hydrogen, deuterium, F, Cl, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0236] Preferably, R a It is hydrogen;

[0237] R 0 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally selected from C 1-6 Alkyl or C 3-6 Substituents of cycloalkyl groups;

[0238] Preferably, R0 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0239] More preferably, R 0 Selected from hydrogen, C 1-6 alkyl;

[0240] Most preferably, R 0 Selected from hydrogen and methyl;

[0241] R 1 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups, wherein the heteroatoms are selected from O, N, and S, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups are each optionally surrounded by 1 to 7 R 1a replace;

[0242] Preferably, R 1 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 3-6 Each cycloalkyl group is optionally surrounded by 1 to 7 (e.g., 1-5 or 1-3, specifically 2, 3, 4, 5 or 6) R 1a replace;

[0243] More preferably, R 1 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 3-6 Each cycloalkyl group is optionally surrounded by 1 to 3 R 1a replace;

[0244] Or more preferably, R 1 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally surrounded by 1 to 7 (e.g., 1-5 or 1-3, specifically 2, 3, 4, 5 or 6) R. 1a replace;

[0245] More preferably, R 1 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups 1a replace;

[0246] R 1a Selected from deuterium, F, Cl, or CN;

[0247] Preferably, R 1a Selected from deuterium, F, or Cl;

[0248] More preferably, R 1a Selected from deuterium or F;

[0249] Most preferably, R 1 The compound is selected from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl, 2,2,2-trifluoroethyl, and cyclopropyl, and preferably from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl, and 2,2,2-trifluoroethyl.

[0250] R 2 Selected from C 3-10 Cycloalkyl-C(O)-, C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S is optionally surrounded by 1 to 3 R atoms. 2a replace;

[0251] Preferably, R 2 Selected from C 3-10 Cycloalkyl-C(O)-, C 6-10 aryl, a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the C 3-10 cycloalkyl, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S is optionally surrounded by 1 to 3 R atoms. 2a replace;

[0252] More preferably, R 2 Selected from C 3-6 Cycloalkyl-C(O)-, phenyl, or a 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O, and S, wherein the C 3-6 Cycloalkyl, phenyl, or 5- to 6-membered heteroaryl groups containing 1 to 2 heteroatoms selected from N, O, and S are each optionally surrounded by 1 to 2 R atoms. 2a replace;

[0253] Most preferably, R 2 Selected from C 3-6 Cycloalkyl-C(O)-, phenyl, or a 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms selected from N and S, wherein the 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms selected from N and S is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, or pyrazolyl, wherein the C 3-6Cycloalkyl, phenyl, or 5- to 6-membered heteroaryl groups containing 1 to 2 heteroatoms selected from N and S are each optionally surrounded by 1 to 2 R atoms. 2a replace;

[0254] R 2a Selected from deuterium, =O (oxo), F, Cl, Br, I, CN, OCF3, NO2, -(CH2) r OR b -(CH2) r SR b -(CH2) r C(O)R b -(CH2) r C(O)OR b -(CH2) r NR b R c -(CH2) r C(O)NR b R c -(CH2) r NR b C(O)R c -(CH2) r NR b C(O)OR c -NR b C(O)NR c R c -NR b S(O) p R c -S(O) p R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 2-6 alkenyl, optionally surrounded by 1 to 3 R d Replacement C 2-6 Alkyne group, optionally surrounded by 1 to 3 R groups d Substituted -(CH2) r -3 to 10 yuan of carbon rings or optional 1 to 3 Rs d Substituted -(CH2) r -5 to 10-membered heterocyclic rings; wherein the heterocyclic rings comprise 1 to 4 nucleotides selected from O, N, or S(O). p heteroatoms;

[0255] Preferably, R 2a Selected from halogen, cyano, C 1-6 Alkoxy, C3-6 cycloalkyl, C 1-6 Alkyl-S(O)2-, -P(O)R b R c -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 1-6 alkyl;

[0256] More preferably, R 2a Selected from C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 3-6 Cycloalkyl, cyano, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkyl-S(O)2-;

[0257] Most preferably, R 2a Selected from methyl, F, methoxy, cyclopropyl, cyano, -CF3, hydroxymethyl, and methanesulfonyl;

[0258] R 3 Selected from C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the C 6-10 aryl or 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, optionally bounded by 1 to 4 R atoms. 3a replace;

[0259] Preferably, R 3 The phenyl group is selected from phenyl or a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O, and S, wherein the phenyl group or the 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O, and S is optionally surrounded by 1 to 3 R atoms. 3a replace;

[0260] More preferably, R 3 Selected from phenyl or 5- to 9-membered heteroaryl groups containing 1 to 2 heteroatoms selected from N or O, wherein the phenyl or 5- to 9-membered heteroaryl group containing 1 to 2 heteroatoms selected from N or O is optionally surrounded by 1 to 3 R... 3a replace;

[0261] More preferably, R 3 The group is selected from phenyl, pyridyl, pyridonel, 2-pyridonel, pyrazinyl, pyrimidinyl, pyridazinyl, indoleyl, or indazole, wherein the phenyl, pyridyl, pyridonel, 2-pyridonel, pyrazinyl, pyrimidinyl, pyridazinyl, indoleyl, or indazole is optionally surrounded by 1 to 3 R groups. 3a replace;

[0262] Most preferably, R 3 The group is selected from phenyl, pyridyl, 2-pyridone, or indazole, wherein the phenyl, pyridyl, 2-pyridone, or indazole group is optionally surrounded by 1 to 3 R groups. 3a replace;

[0263] R 3a Selected from deuterium, =O, F, Cl, Br, I, CN, OCF3, NO2, -(CH2) r OR b -(CH2) r SR b -(CH2) r C(O)R b -(CH2) r C(O)OR b -(CH2) r NR b R c -(CH2) r C(O)NR b R c -(CH2) r NR b C(O)R c -(CH2) r NR b C(O)OR c -NR b C(O)NR c R c -NR b S(O) p R c -S(O) p R c -S(O) p NR c R c -P(O)R b R c , Choose 1 to 3 R d Substituted C1-C6 alkyl groups, optionally with 1 to 3 R d Replacement C 2-6 alkenyl, optionally surrounded by 1 to 3 R d Replacement C 2-6 Alkyne group, optionally surrounded by 1 to 3 R groups d Substituted -(CH2) r -3 to 10 yuan carbon rings, optionally coated with 1 to 3 Rs d Substituted -(CH2) r -5 to 10 yuan heterocyclic, randomly selected by 1 to 3 R d The substituted 5- to 10-membered heteroaryl group; wherein the heterocycle or heteroaryl group comprises 1 to 4 ions selected from O, N, or S(O).p heteroatoms;

[0264] Or two Rs 3a The atoms bonded to it combine to form a fused ring, wherein the ring is selected from phenyl and heterocycles, and the heterocycle contains 1 to 4 atoms selected from N, N or S(O). p The heteroatoms, each fused ring optionally separated by 1 to 3 R atoms b replace;

[0265] Preferably, R 3a Selected from F, Cl, Br, I, CN, NO2, -OR b -SR b -C(O)OR b -C(O)NR b R c -NR b C(O)R c -NR b C(O)OR c -NR b C(O)NR c R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O and S;

[0266] More preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-6Alkyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O and S;

[0267] Most preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Choose 1 to 3 R d Replacement C 1-6 Alkyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, optional R d The substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, or 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S are selected from thiazolyl groups (e.g., ...). ), benzimidazole group (e.g. ), pyrazolyl (e.g.) ), oxadiazole group (such as ), triazole (e.g. The 5- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from N, O, and S is selected from morpholino (e.g., ), piperidinyl (e.g.) );

[0268] R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted -(CH2) r -Phenyl or optionally with 1 to 3 R d Substituted -(CH2) r -4 to 7-membered heterocycles; wherein the heterocycles contain 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0269] Preferably, R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl groups, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S;

[0270] More preferably, R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl groups, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 oxygen atoms;

[0271] Most preferably, R b Selected from hydrogen, optionally surrounded by 1 to 3 R... d Substituted methyl, ethyl, isopropyl,

[0272] R c Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted -(CH2) r -Phenyl or optionally with 1 to 3 R d Substituted -(CH2) r -5 to 7-membered heterocycles; wherein the heterocycles contain 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0273] Preferably, R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0274] More preferably, R c Selected from hydrogen, methyl, ethyl, and cyclopropyl;

[0275] Most preferably, R c Selected from hydrogen, methyl, and cyclopropyl;

[0276] R d Selected from hydrogen, deuterium, F, Cl, Br, I, OCF3, CF3, CN, NO2, OR e -(CH2) r COR c -NR e R e -NR e C(O)OR c C1-C6 alkyl, C 3-6 Cycloalkyl or optionally with 1 to 3 Rf Substituted -(CH2) r -Phenyl;

[0277] Preferably, R d Selected from F, Cl, Br, I, hydroxyl, C1-C6 alkyl, C 3-6 cycloalkyl;

[0278] More preferably, R d Selected from F, hydroxy, methyl, and cyclopropyl;

[0279] R e Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or optionally with 1 to 3 R f Substituted -(CH2) r -Phenyl;

[0280] Preferably, R e It is hydrogen;

[0281] R f Selected from hydrogen, F, Cl, Br, NH2, OH, CF3, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or -(CH2) r -5 to 7-membered heterocycles, wherein the heterocycles comprise 1 to 4 ions selected from O, N, or S(O). p heteroatoms;

[0282] p is 0, 1, or 2, and

[0283] r can be 0, 1, 2, 3 or 4.

[0284] In some implementation schemes, wherein:

[0285] X is CR a Or N;

[0286] R a Selected from hydrogen and methyl;

[0287] Preferably, R a It is hydrogen;

[0288] R 0 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0289] Preferably, R 0 Selected from hydrogen, C 1-6 alkyl;

[0290] More preferably, R 0 Selected from hydrogen and methyl;

[0291] R1 Selected from C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 Each cycloalkyl group is optionally surrounded by 1 to 3 R 1a replace;

[0292] Preferably, R 1 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups 1a replace;

[0293] R 1a Selected from deuterium, F, Cl, or CN;

[0294] Preferably, R 1a Selected from deuterium, F, or Cl;

[0295] More preferably, R 1a Selected from deuterium or F;

[0296] More preferably, R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl, 2,2,2-trifluoroethyl, and cyclopropyl;

[0297] Most preferably, R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl, and 2,2,2-trifluoroethyl;

[0298] R 2 The group is selected from cyclopropionyl, phenyl, pyrazolyl, thiazolyl, furanyl, thiophene, imidazole, pyridyl, pyridonel, pyrazinyl, pyrimidinyl, and pyridazinyl, wherein each of the cyclopropionyl, phenyl, pyrazolyl, thiazolyl, furanyl, thiophene, imidazole, pyridyl, pyridonel, pyrazinyl, pyrimidinyl, and pyridazinyl groups is optionally surrounded by 1 to 3 R groups. 2a replace;

[0299] Preferably, R 2 The group is selected from cyclopropionyl, phenyl, pyrazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl, wherein the cyclopropionyl, phenyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, and pyridazinyl groups are optionally surrounded by 1 to 2 R groups. 2a replace;

[0300] R 2a Selected from deuterium, =O, F, Cl, Br, CN, OCF3, -(CH2) r OR b -(CH2) r C(O)OR b -(CH2) r NRb R c ,

[0301] -(CH2) r C(O)NR b R c -(CH2) r NR b C(O)R c -(CH2) r NR b C(O)OR c -S(O) p R c , Select 1 to 3 R d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Substituted -(CH2) r -3 to 7 yuan carbon rings or optionally 1 to 3 R d Substituted -(CH2) r -5 to 7-membered heterocycles; wherein the heterocycles comprise 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0302] Preferably, R 2a Selected from F, Cl, Br, cyano, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Alkyl-S(O)2-, optionally surrounded by 1 to 3 R d Replacement C 1-6 alkyl;

[0303] More preferably, R 2a Selected from C 1-6 Alkyl, F, Cl, Br, C 1-6 Alkoxy, C 3-6 Cycloalkyl, cyano, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkyl-S(O)2-;

[0304] Most preferably, R 2a Selected from methyl, F, methoxy, cyclopropyl, cyano, -CF3, hydroxymethyl, and methanesulfonyl;

[0305] R 3 The group is selected from phenyl, pyridinyl, pyridoneyl, 2-pyridoneyl, pyrazinyl, pyrimidinyl, pyridazinyl, or indazoleyl, wherein the phenylpyridinyl, pyridoneyl, 2-pyridoneyl, pyrazinyl, pyrimidinyl, pyridazinyl, or indazoleyl group is optionally surrounded by 1 to 3 R groups. 3a replace;

[0306] Preferably, R 3 The group is selected from phenyl, pyridyl, 2-pyridone, or indazole, wherein the phenyl, pyridyl, 2-pyridone, or indazole is optionally surrounded by 1 to 3 R groups. 3a replace;

[0307] R 3a Selected from deuterium, =O, F, Cl, Br, CN, OCF3, NO2, -(CH2) r OR b -(CH2) r C(O)R b -(CH2) r C(O)OR b ,

[0308] -(CH2) r NR b R c -(CH2) r C(O)NR b R c -(CH2) r NR b C(O)R c -(CH2) r NR b C(O)OR c -NR b C(O)NR c R c -NR b S(O) p R c -S(O) p R c -S(O) p NR c R c -P(O)R b R c , Select 1 to 3 R d Substituted C1-C6 alkyl groups, optionally with 1 to 3 R d Replacement C 2-6 alkenyl, optionally surrounded by 1 to 3 R d Replacement C 2-6 Alkyne group, optionally surrounded by 1 to 3 R groups d Substituted -(CH2) r -3 to 7 yuan carbon rings, optionally coated with 1 to 3 Rs d The substituted 5 to 10 heteroaryl groups or optionally 1 to 3 R groups d Substituted -(CH2) r -5 to 10-membered heterocycles; wherein the heterocycle or heteroaryl group comprises 1 to 4 ions selected from O, N, or S(O).p heteroatoms;

[0309] Or two Rs 3a The atoms bonded to it combine to form a fused ring, wherein the ring is selected from phenyl and heterocycles, and the heterocycle contains 1 to 4 atoms selected from N, N or S(O). p The heteroatoms, each fused ring optionally separated by 1 to 3 R atoms b replace;

[0310] Preferably, R 3a Selected from F, Cl, Br, I, CN, NO2, -OR b -C(O)OR b -C(O)NR b R c -NR b C(O)R c -NR b C(O)OR c -NR b C(O)NR c R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Select 1 to 3 R d Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O and S;

[0311] More preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Select 1 to 3 R d Replacement C 1-6 Alkyl, C 2-6alkynyl group, C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O and S;

[0312] Most preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Select 1 to 3 R d Replacement C 1-6 Alkyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, optional R d The substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, and the 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S are selected from thiazolyl, benzimidazolyl, pyrazolyl, oxadiazolyl, and triazolyl, and the 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S are selected from morpholino and piperidinyl.

[0313] R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted -(CH2) r -Phenyl or optionally with 1 to 3 R d Substituted -(CH2) r -4 to 7-membered heterocycles; wherein the heterocycles contain 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0314] Preferably, R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl groups, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S;

[0315] More preferably, Rb Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl groups, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 oxygen atoms;

[0316] Most preferably, R b Selected from hydrogen, optionally surrounded by 1 to 3 R... d Substituted methyl, ethyl, isopropyl,

[0317] R c Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted -(CH2) r -Phenyl or optionally with 1 to 3 R d Substituted -(CH2) r -5 to 7-membered heterocycles; wherein the heterocycles contain 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0318] Preferably, R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0319] More preferably, R c Selected from hydrogen, methyl, ethyl, and cyclopropyl;

[0320] Most preferably, R c Selected from hydrogen, methyl, and cyclopropyl;

[0321] R d Selected from hydrogen, deuterium, F, Cl, Br, OCF3, CF3, CN, NO2, OR e -(CH2) r COR c -NR e R e -NR e C(O)OR c C1-C6 alkyl, C 3-6 Cycloalkyl or optionally with 1 to 3 R f Substituted -(CH2) r -Phenyl;

[0322] Preferably, R d Selected from F, Cl, Br, hydroxyl, C1-C6 alkyl, C 3-6 cycloalkyl;

[0323] More preferably, R d Selected from F, hydroxy, methyl, and cyclopropyl;

[0324] R e Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or optionally with 1 to 3 R f Substituted -(CH2) r -Phenyl;

[0325] Preferably, R e It is hydrogen;

[0326] R f Selected from hydrogen, F, Cl, Br, NH2, OH, CF3, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or -(CH2) r -5 to 7-membered heterocycles, wherein the heterocycles comprise 1 to 4 ions selected from O, N, or S(O). p heteroatoms;

[0327] p is 0, 1, or 2, and

[0328] r is 0, 1, or 2.

[0329] In some implementation schemes, wherein:

[0330] R 0 Selected from hydrogen and methyl;

[0331] R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, trideuterated methyl or 2,2,2-trifluoroethyl;

[0332] Preferably, R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl or 2,2,2-trifluoroethyl;

[0333] R 2 The group is selected from cyclopropionyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, or pyrazolyl, wherein the cyclopropionyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, or pyrazolyl group is optionally surrounded by 1 to 3 (e.g., 1 to 2) R groups. 2a replace;

[0334] R 3 The group is selected from phenyl, pyridyl, pyridone, 2-pyridone, or indazole, wherein the phenyl, pyridyl, pyridone, 2-pyridone, or indazole group is optionally surrounded by 1 to 3 R groups. 3a replace;

[0335] Preferably, R 3The group is selected from phenyl, pyridyl, 2-pyridone, or indazole, wherein the phenyl, pyridyl, 2-pyridone, or indazole is optionally surrounded by 1 to 3 R groups. 3a replace.

[0336] In some implementation schemes, wherein:

[0337] X is selected from CH or N;

[0338] R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, trideuterated methyl, and 2,2,2-trifluoroethyl;

[0339] R 2a Selected from F, Cl, Br, CN, OCF3, -(CH2) r OR b -S(O) p R c , Select 1 to 3 R d Replacement C 1-3 Alkyl groups or optionally 1 to 3 R groups d Substituted -(CH2) r -3 to 5 element carbon rings;

[0340] Preferably, R 2a Selected from C 1-3 Alkyl, halogen, C 1-3 Alkoxy, C 3-5 Cycloalkyl, cyano, halogenated C 1-3 Alkyl, hydroxyl substituted C 1-3 Alkyl, C 1-3 Alkyl-S(O)2-;

[0341] More preferably, R 2a Selected from methyl, F, methoxy, cyclopropyl, cyano, -CF3, hydroxymethyl, and methanesulfonyl;

[0342] R 3a Selected from F, Cl, Br, CN, OCF3, -(CH2) r OR b -(CH2) r NR b R c -(CH2) r C(O)NR b R c -NR b C(O)NR c R c -NR b S(O) p R c -S(O) p R c-S(O) p NR c R c -P(O)R b R c , Select 1 to 3 R d Substituted C1-C3 alkyl groups, optionally with 1 to 3 R d Replacement C 2-4 Alkyne group, optionally surrounded by 1 to 3 R groups d Substituted -(CH2) r -3 to 5 yuan of carbon rings or optionally 1 to 3 R d Substituted -(CH2) r -5 to 9-membered heterocycles; wherein the heterocycles comprise 1 to 4 ions selected from O, N, or S(O). p heteroatoms;

[0343] Preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Select 1 to 3 R d Replacement C 1-3 Alkyl, C 2-4 alkynyl group, C 3-5 cycloalkyl, optionally with 1 to 3 R d Substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, and 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O and S;

[0344] More preferably, R 3a Selected from F, Cl, Br, I, CN, -OR b -C(O)NR b R c -NR b S(O)2R c -S(O)2R c -S(O)2NR c R c -P(O)R b R c , Select 1 to 3 R d Replacement C 1-3 Alkyl, C 2-4 alkynyl group, C3-5 cycloalkyl, optional R d The substituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, and the 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S are selected from thiazolyl, benzimidazolyl, pyrazolyl, oxadiazolyl, and triazolyl, and the 5- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S are selected from morpholino and piperidinyl.

[0345] R b Selected from hydrogen, optionally surrounded by 1 to 3 R... d Substituted methyl, ethyl, isopropyl, cyclopropyl,

[0346] Preferably, R b Selected from hydrogen, optionally surrounded by 1 to 3 R... d Substituted methyl, ethyl, isopropyl,

[0347] R c Selected from hydrogen, methyl, ethyl, and cyclopropyl;

[0348] Preferably, R c Selected from hydrogen, methyl, and cyclopropyl;

[0349] R d Selected from hydrogen, F, Cl, hydroxyl, methyl, ethyl, and cyclopropyl;

[0350] Preferably, R d Selected from F, hydroxyl, methyl, and cyclopropyl.

[0351] In some implementation schemes, R 2 Selected from

[0352]

[0353] R 4 R 5 R 6 R 7 R 8 Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl;

[0354] Preferably, R 4 R 5 R 6 R7 R 8 Each is independently selected from hydrogen, F, methoxy, cyclopropyl, cyano, methyl, trifluoromethyl, and hydroxymethyl;

[0355] Or preferably, R 5 R 6 R 7 R 8 Or R 4 R 6 R 7 R 8 In, any one (such as R) 4 R 6 R 7 Or R 8 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl groups, the remainder being hydrogen; or, R 5 R 6 R 7 R 8 Or R 4 R 6 R 7 R 8 In, any two independent ones (such as R) 6 and R 7 Selected from halogens, C 1-6 Alkyl groups, the rest being hydrogen;

[0356] Or more preferably, R 5 R 6 R 7 R 8 Or R 4 R 6 R 7 R 8 In, any one (such as R) 4 R 6 R 7 Or R 8 The radicals are selected from hydrogen, F, methoxy, cyano, trifluoromethyl, methyl, hydroxymethyl, cyclopropyl, and the remainder is hydrogen; or, R 5 R 6 R 7 R 8 Or R 4 R 6 R 7 R 8 In, any two (such as R) 6 and R 7Each is independently selected from F and methyl, and the rest are hydrogen;

[0357] R 10 R 11 R 12 Each is independently selected from hydrogen and C. 1-6 alkyl;

[0358] Preferably, R 10 R 11 R 12 Each is independently selected from hydrogen and methyl;

[0359] Or preferably, R 10 R 11 R 12 In, any one (such as R) 12 (Selected from C) 1-6 Alkyl groups, the rest being hydrogen;

[0360] Or more preferably, R 10 R 11 R 12 In, any one (such as R) 12 () is methyl, the rest are hydrogen;

[0361] R 13 R 14 R 15 R 16 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy;

[0362] Preferably, R 13 R 14 R 15 R 16 Each is independently selected from hydrogen, methyl, and methoxy;

[0363] Or preferably, R 14 R 15 R 16 Or R 13 R 15 R 16 In, any one (such as R) 13 (Selected from C) 1-6 Alkyl, C 1-6 Alkyl groups, preferably selected from C 1-6 Alkoxy groups, the rest being hydrogen; or, any two (such as R). 13 and R 16 , or R 14 and R 16 Each is independently selected from hydrogen, C 1-6 Alkyl groups, the rest being hydrogen;

[0364] Or more preferably, R 14 R 15 R 16 Or R 13 R 15 R 16 In, any one (such as R) 13 The group is selected from methyl, methoxy, preferably methoxy, with the remainder being hydrogen; or, any two (such as R) 13 and R 16 , or R 14 and R 16 Each is independently selected from hydrogen and methyl, and the rest are hydrogen;

[0365] R 18 R 19 R 20 Each is independently selected from hydrogen and C. 1-6 alkyl;

[0366] Preferably, R 18 R 19 R 20 It is hydrogen;

[0367] R 21 R 22 R 23 R 24 Each is independently selected from hydrogen and C. 1-6 alkyl;

[0368] Preferably, R 21 R 22 R 23 R 24 Each is independently selected from hydrogen and methyl;

[0369] Or preferably, R 21 R 23 R 24 Or R 21 R 22 R 24 Or R 21 R 22 R 23 In the middle, R 21 Selected from C 1-6 Alkyl groups, the rest being hydrogen;

[0370] Or more preferably, R 21 R 23 R 24 Or R 21 R 22 R 24 Or R 21 R 22 R 23 In the middle, R 21One is methyl, the rest are hydrogen;

[0371] R 26 R 27 Each is independently selected from hydrogen and C. 1-6 alkyl;

[0372] Preferably, R 26 R 27 Each is independently selected from hydrogen and methyl;

[0373] Or preferably, R 26 R 27 In, any one is selected from hydrogen, C 1-6 Alkyl group, the other being hydrogen;

[0374] Or more preferably, R 26 R 27 In this context, one of the components is selected from hydrogen or methyl, and the other is hydrogen;

[0375] R 28 R 29 R 30 R 31 Each is independently selected from hydrogen and C. 1-6 alkyl;

[0376] Preferably, R 28 R 29 R 30 R 31 Each is independently selected from hydrogen and methyl;

[0377] More preferably, R 28 R 29 For hydrogen, R 30 R 31 Each is independently selected from hydrogen and methyl;

[0378] R 32 R 33 R 34 R 35 R 36 Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl groups, and not all of them are hydrogen;

[0379] Preferably, R 32 R 33 R 34 R 35 R 36 Each is independently selected from hydrogen, F, methanesulfonyl, cyano, and methoxy, and they are not all hydrogen at the same time;

[0380] Or preferably, R 32 R33 R 34 R 35 R 36 In, any one (such as R) 34 Selected from halogens, cyano groups, and C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy groups, the rest are hydrogen;

[0381] Or more preferably, R 32 R 33 R 34 R 35 R 36 In, any one (such as R) 34 The radical is selected from F, methanesulfonyl, cyano, methoxy, and the remainder is hydrogen.

[0382] In some implementation schemes, R 3 Selected from

[0383] R 37 R 38 R 39 R 40 R 41 Each is independently selected from hydrogen, -NR b S(O)2R c -S(O)2R c -P(O)R b R c -C(O)NR b R c , -S(O)2NR c R c C 1-6 Alkyl, F, Cl, Br, I, cyano, optionally C 3-6 Cycloalkyl (e.g., cyclopropyl) substituted C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-6 Alkyne, morpholino, piperidinyl, optionally C 1-6 Alkyl (e.g., methyl) substituted indazole, pyrazolyl, oxadiazolyl, triazolyl, 4- to 6-membered saturated heterocyclic group -O-, said saturated heterocyclic group containing 1 to 2 oxygen atoms; R b Selected from hydrogen, C 1-6 Alkyl groups, preferably selected from hydrogen and methyl groups; R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, preferably selected from hydrogen, methyl, ethyl, cyclopropyl, more preferably selected from hydrogen, methyl, cyclopropyl; and R 37 R38 R 39 R 40 R 41 They are not both hydrogen;

[0384] Preferably, R 37 R 38 R 39 R 40 R 41 Each is independently selected from hydrogen, Methyl, ethyl, isopropyl, F, Cl, Br, cyano, methoxy, ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl Difluoromethoxy, And R 37 R 38 R 39 R 40 R 41 They are not both hydrogen;

[0385] More preferably, R 37 R 38 R 39 R 40 R 41 Each is independently selected from hydrogen, Methyl, ethyl, F, Cl, cyano, methoxy, ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl Difluoromethoxy, And R 37 R 38 R 39 R 40 R 41 They are not both hydrogen;

[0386] Or preferably, R 37 R 38 R 39 R 40 R 41 In, any one (such as R) 37 (Selected from -NR) b S(O)2R c -S(O)2R c , -P(O)R b R c , -S(O)2NR c R c 4 to 6-membered saturated heterocyclic group -O-, the remainder being hydrogen, wherein the saturated heterocyclic group contains 1 to 2 oxygen atoms; R b Selected from hydrogen, C 1-6Alkyl groups, preferably selected from hydrogen and methyl groups; R c Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl groups, preferably selected from methyl and cyclopropyl groups;

[0387] Or more preferably, R 37 R 38 R 39 R 40 R 41 In, any one (such as R) 37 (Selected from) The rest is hydrogen;

[0388] Or preferably, R 37 R 38 R 39 R 40 R 41 In, any two (such as R) 37 R 38 , or R 37 R 39 Each is independently selected from -NR b S(O)2R c , -C(O)NR b R c C 1-6 Alkyl, F, Cl, Br, I, cyano, optionally C 3-6 Cycloalkyl (e.g., cyclopropyl) substituted C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-6 Alkyne, morpholino, piperidinyl, optionally C 1-6 Alkyl groups (such as methyl) substituted with indazole, pyrazol, oxadiazole, or triazole groups, with the remainder being hydrogen; R b Selected from hydrogen, C 1-6 Alkyl groups, preferably selected from hydrogen and methyl groups; R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, preferably selected from hydrogen, methyl, ethyl, and cyclopropyl groups, and more preferably selected from hydrogen, methyl, and cyclopropyl groups;

[0389] Or more preferably, R 37 R 38 R 39 R 40 R 41 In, any two (such as R) 37 R 38 , or R 37 R 39Each independently selected Methyl, ethyl, isopropyl, F, Cl, Br, cyano, methoxy, ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl Difluoromethoxy, The rest is hydrogen;

[0390] Or, most preferably, R 37 R 38 R 39 R 40 R 41 In, any two (such as R) 37 R 38 , or R 37 R 39 Each independently selected Methyl, ethyl, F, Cl, cyano, methoxy, ethoxy, isopropoxy, -CF3, cyclopropyl, ethynyl Difluoromethoxy, The rest is hydrogen;

[0391] Or preferably, R 37 R 38 R 39 R 40 R 41 In, any three (such as R) 37 R 39 R 40 Or R 37 R 38 R 39 Each is independently selected from -NR b S(O)2R c F, Cl, Br, I, C 3-6 cycloalkyl, C 1-6 Alkyl, C 2-6 Alkyne group, the rest are hydrogen; R b Selected from C 1-6 Alkyl group, preferably methyl group; R c Selected from C 1-6 Alkyl, C 3-6 cycloalkyl groups, preferably selected from C 1-6 Alkyl groups, or preferably selected from methyl, cyclopropyl, and more preferably methyl;

[0392] Or more preferably, R 37 R 38 R 39 R 40 R 41 In, any three (such as R) 37 R 39 R40 Or R 37 R 38 R 39 Each independently selected Cyclopropyl, F, Cl, methyl, ethyl, isopropyl, ethynyl, and the remainder are hydrogen;

[0393] Or, most preferably, R 37 R 38 R 39 R 40 R 41 In, any three (such as R) 37 R 39 R 40 Or R 37 R 38 R 39 Each independently selected Cyclopropyl, F, Cl, methyl, ethynyl, and the remainder are hydrogen;

[0394] R 42 R 43 R 44 R 45 Each is independently selected from hydrogen, -NR b S(O)2R c C 1-6 Alkyl; R b Selected from hydrogen, C 1-6 Alkyl groups, preferably selected from hydrogen and methyl groups; R c Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl groups, preferably selected from methyl and cyclopropyl groups; and R 42 R 43 R 44 R 45 They are not both hydrogen;

[0395] Preferably, R 42 R 43 R 44 R 45 Each is independently selected from hydrogen, Methyl, and R 42 R 43 R 44 R 45 They are not both hydrogen;

[0396] Or preferably, R 42 R 43 R 44 R 45 In, any one (such as R) 42 Or R 43 (Selected from -NR) bS(O)2R c The rest are each independently selected from hydrogen and C. 1-6 Alkyl; R b Selected from hydrogen, C 1-6 Alkyl groups, preferably selected from hydrogen and methyl groups; R c Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl groups, preferably selected from methyl and cyclopropyl groups;

[0397] Or more preferably, R 42 R 43 R 44 R 45 In, any one (such as R) 42 Or R 43 (Selected from) The remaining components are each independently selected from hydrogen and methyl groups;

[0398] R 46 R 47 R 48 R 49 Each is independently selected from hydrogen and C. 1-6 alkyl, thiazolyl, and R 46 R 47 R 48 R 49 They are not both hydrogen;

[0399] More preferably, R 46 R 47 R 48 R 49 Each is independently selected from hydrogen, And R 46 R 47 R 48 R 49 They are not both hydrogen;

[0400] Or preferably, R 46 R 47 R 48 R 49 In, any one (such as R) 49 () is a thiazolyl group, and the rest are hydrogen atoms;

[0401] Or more preferably, R 46 R 47 R 48 R 49 In, any one (such as R) 49 )for The rest is hydrogen;

[0402] R 50 R 51 R 52R 53 R 54 Each is independently selected from hydrogen and C. 1-6 Alkyl, and R 50 R 51 R 52 R 53 R 54 They are not both hydrogen;

[0403] Preferably, R 50 R 51 R 52 R 53 R 54 Each is independently selected from hydrogen and methyl, and R 50 R 51 R 52 R 53 R 54 They are not both hydrogen;

[0404] Or preferably, R 50 R 51 R 52 R 53 R 54 In, any one (such as R) 50 (Selected from C) 1-6 Alkyl groups, the rest being hydrogen;

[0405] Or more preferably, R 50 R 51 R 52 R 53 R 54 In, any one (such as R) 50 () is selected from methyl, the rest are hydrogen.

[0406] In some implementations, R 2 Selected from:

[0407]

[0408] In some preferred embodiments, R 2 Selected from

[0409]

[0410] In some implementations, R 3 Selected from:

[0411]

[0412]

[0413] In some preferred embodiments, R3 Selected from

[0414]

[0415] In some preferred embodiments, R 3 Selected from

[0416]

[0417]

[0418] Furthermore, in another aspect of the invention, a compound of formula (I”) or a pharmaceutically acceptable salt thereof is provided:

[0419]

[0420] X is CH;

[0421] Y is CH;

[0422] R 0 Selected from hydrogen;

[0423] R 1 Selected from ethyl;

[0424] R 2 Selected from pyridinyl, pyrimidinyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 3-8 Heterocyclic groups, the C 3-8 The saturated heterocyclic alkyl group contains 1 to 4 heteroatoms selected from N, O, and S; the C 3-6 cycloalkyl, C 3-8 Each saturated heterocyclic group is optionally surrounded by 1 to 3 R 2a replace;

[0425] Preferably, R 2 Selected from pyridinyl, pyrimidinyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 3-6 Heterocyclic groups, the C 3-6 The heterocyclic group contains one to two heteroatoms selected from N, O, and S; the C 3-6 cycloalkyl, C 3-6 Each heterocyclic group is optionally surrounded by 1 to 3 R 2a replace;

[0426] Preferably, the -C(O)-C 3-8 Heterocyclic groups, the aforementioned -C(O)-C 3-6In the heterocyclic group, the heterocyclic group is connected to -C(O)- through a heteroatom on the heterocycle; preferably, the heteroatom is a nitrogen atom;

[0427] R 2a Selected from deuterium, =O (oxo), F, Cl, Br, I, CN, OCF3, NO2, -(CH2) r OR b -(CH2) r SR b -(CH2) r C(O)R b -(CH2) r C(O)OR b -(CH2) r NR b R c -(CH2) r C(O)NR b R c -(CH2) r NR b C(O)R c -(CH2) r NR b C(O)OR c -NR b C(O)NR c R c -NR b S(O) p R c -S(O) p R c -P(O)R b R c , Select 1 to 3 R d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 2-6 alkenyl, optionally surrounded by 1 to 3 R d Replacement C 2-6 Alkyne group, optionally surrounded by 1 to 3 R groups d Substituted -(CH2) r -3 to 10 yuan of carbon rings or optional 1 to 3 Rs d Substituted -(CH2) r -5 to 10-membered heterocyclic rings; wherein the heterocyclic rings contain 1 to 4 nucleotides selected from O, N, or S(O). p heteroatoms;

[0428] Preferably, R 2a Selected from halogen, cyano, C 1-6 Alkoxy, C 3-6 cycloalkyl, C1-6 Alkyl-S(O)2-, -P(O)R b R c -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 1-6 alkyl;

[0429] More preferably, R 2a Selected from C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 3-6 Cycloalkyl, cyano, halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkyl-S(O)2-;

[0430] Most preferably, R 2a Selected from methyl, F, methoxy, cyclopropyl, cyano, -CF3, hydroxymethyl, and methanesulfonyl;

[0431] Preferably, R 2 Selected from the following structures:

[0432]

[0433] R 3 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1 to 3 R groups. 3a replace;

[0434] R 3a Selected from -(CH2) r OR b -NR b S(O) p R c , F, Cl, C 1-6 Alkyl, C 3-6 Cycloalkyl, triazolyl, pyrazolyl, pyrimidinyl, pyrazinyl; the C 1-6 Alkyl, C 3-6 Cycloalkyl, triazolyl, pyrazolyl, pyrimidinyl, and pyrazinyl groups, each optionally independently bounded by 1 to 3 R groups. d replace;

[0435] R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted -(CH2) r -Phenyl or optionally with 1 to 3 Rd Substituted -(CH2) r -4 to 7-membered heterocycles; wherein the heterocycles contain 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0436] Preferably, R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl groups, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from N, O, and S;

[0437] More preferably, R b Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl groups, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 oxygen atoms;

[0438] Most preferably, R b Selected from hydrogen, optionally surrounded by 1 to 3 R... d Substituted methyl, ethyl, isopropyl,

[0439] R c Selected from hydrogen, optionally coated with 1 to 3 R... d Replacement C 1-6 Alkyl, optionally with 1 to 3 R d Replacement C 3-6 cycloalkyl, optionally with 1 to 3 R d Substituted -(CH2) r -Phenyl or optionally with 1 to 3 R d Substituted -(CH2) r -5 to 7-membered heterocycles; wherein the heterocycles contain 1 to 4 members selected from O, N, or S(O). p heteroatoms;

[0440] Preferably, R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0441] More preferably, R c Selected from hydrogen, methyl, ethyl, and cyclopropyl;

[0442] Most preferably, R c Selected from hydrogen, methyl, and cyclopropyl;

[0443] R d Selected from hydrogen, deuterium, F, Cl, Br, I, OCF3, CF3, -(CH2)r, CN, NO2, OR e -(CH2) r COR c-NR e R e -NR e C(O)OR c C1-C6 alkyl, C 3-6 Cycloalkyl or optionally with 1 to 3 R f Substituted -(CH2) r -Phenyl;

[0444] Preferably, R d Selected from F, Cl, Br, I, hydroxyl, C1-C6 alkyl, C 3-6 Cycloalkyl, -(CH2)pCN;

[0445] More preferably, R d Selected from F, Cl, hydroxyl, methyl, cyclopropyl, -CH2CN;

[0446] R e Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or optionally with 1 to 3 R f Substituted -(CH2) r -Phenyl;

[0447] Preferably, R e It is hydrogen;

[0448] R f Selected from hydrogen, F, Cl, Br, NH2, OH, CF3, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or -(CH2) r -5 to 7-membered heterocycles, wherein the heterocycles comprise 1 to 4 ions selected from O, N, or S(O). p heteroatoms;

[0449] p is 0, 1, or 2, and

[0450] r can be 0, 1, 2, 3 or 4.

[0451] Preferably, R 3 Selected from the following structures:

[0452]

[0453] As exemplary compounds, the compounds represented by Formula I, Formula I', or Formula I'" of the present invention include:

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491] As used herein, an example of the term "pharmaceutically acceptable salt of a compound represented by formula (I) or formula (I') or formula (I")" is an organic acid adduct salt formed from an organic acid that forms a pharmaceutically acceptable anion.

[0492] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting an adequate amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.

[0493] Preparation method:

[0494] This invention also provides a method for preparing the compounds. The preparation of the compounds of general formula (I), (I'), or (I") of this invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered in any way as limiting the scope of this invention. The compounds of this invention can also be synthesized by synthetic techniques known to those skilled in the art, or by combining synthetic methods known in the art with the methods described in this invention. The products obtained from each reaction step are obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for synthesis can be conventionally synthesized according to literature (such as those provided by Scifinder) or purchased.

[0495] The compounds of general formula (I), formula (I'), or formula (I') of this invention can be synthesized according to the following route: 1) starting material A1 is condensed with hydroxylamines that have different substitutions on oxygen (i.e., 1) A2 is obtained; 2) A2 reacts with a (hetero)aromatic amine (i.e., R) containing a functional group under the action of a base. 2 -NH2) undergoes a substitution reaction to give A3; 3) A3 reacts with amides or aromatic amines containing different functional groups (R 3-NH2) generates the target compound A4 via the Buchwald coupling reaction:

[0496] Among them, X, Y, R 0 R 1 R 2 R 3 The definition is as stated above;

[0497]

[0498] The present invention also provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutical carrier and / or excipient and / or diluent.

[0499] In some embodiments, the pharmaceutical composition may also contain other medicines for treating and / or preventing TYK2-mediated related diseases.

[0500] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredient are known, or will be obvious to those skilled in the art according to the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, etc.

[0501] The present invention also provides a pharmaceutical formulation comprising the aforementioned compound or a pharmaceutically acceptable salt thereof, as well as a pharmaceutical carrier and / or excipients and / or diluents.

[0502] In another aspect, the present invention also provides the use of the said compound or a pharmaceutically acceptable salt thereof, or the said pharmaceutical composition or the said pharmaceutical preparation, in the preparation of a medicament for treating and / or preventing TYK2-mediated related diseases.

[0503] In another aspect, the present invention also provides the said compound or a pharmaceutically acceptable salt thereof, or the said pharmaceutical composition or the said pharmaceutical preparation, for the treatment and / or prevention of TYK2-mediated related diseases.

[0504] In another aspect, the present invention also provides a method for treating and / or preventing TYK2-mediated related diseases, comprising: administering to a subject in need a therapeutic and / or preventative effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition or the pharmaceutical preparation thereof.

[0505] In some implementation schemes, the aforementioned diseases include inflammatory diseases, autoimmune diseases, and cancer.

[0506] In this invention, "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect may be preventative based on the complete or partial prevention of the disease or its symptoms; and / or therapeutic based on the partial or complete stabilization or cure of the disease and / or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) preventing the occurrence of a disease or symptoms in a patient who is susceptible to the disease or symptoms but has not yet been diagnosed with the disease; (b) suppressing the symptoms of the disease, i.e., preventing its progression; or (c) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0507] In this invention, "subject" refers to a vertebrate. In some embodiments, vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, mammal refers to a human.

[0508] In this invention, "effective amount" refers to the amount that effectively achieves the desired therapeutic or preventative effect at the necessary dose and time. The "therapeutic effective amount" of the substance / molecule of this invention may vary depending on factors such as an individual's disease state, age, sex, weight, and the substance / molecule's ability to elicit the desired response in the individual. Therapeutic effective amount also encompasses the amount in which the beneficial therapeutic effect of the substance / molecule outweighs any toxic or harmful consequences. "Preventative effective amount" refers to the amount that effectively achieves the desired preventative effect at the necessary dose and time. Typically, but not necessarily, the preventative effective amount will be lower than the therapeutic effective amount because the preventative dose is administered to the subject before the onset of the disease or in its early stages. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; shrink the tumor volume; inhibit (i.e., slow down, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down, preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent.

[0509] Terminology definition:

[0510] According to the conventions of the art, In the structural formula of this paper, the bond is used to describe the connection point between the part or substituent and the parent nucleus or main structure.

[0511] The hyphen "-" that does not appear between two letters or symbols is used to indicate the connection point of a substituent. For example, -CONH2 is connected by a carbon atom.

[0512] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, or independently disclosed "C 1-4 "alkyl", or independently disclosed "C 1-3 alkyl".

[0513] As used herein, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, and C6. Additionally, for example, "C..." 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted, in which one or more of their hydrogen atoms are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc.

[0514] The term "alkoxy" refers to any of the above-mentioned alkyl groups (e.g., C10, C20, C30, C40, C50, C6 ... 1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl groups, etc., which are attached to the rest of the molecule by oxygen atoms (-O-).

[0515] The term "halogenated C" 1-6 Alkyl or halogenated C 1-6 "Alkoxy" refers to an alkyl or alkoxy group in which one or more (e.g., two or three) hydrogen atoms are replaced by a halogen atom, such as fluorine, chlorine, or bromine. The definition of the alkyl or alkoxy group is as described above. In some embodiments, the term "halogenated C" is used... 1-6 "Alkyl" is preferably fluorinated, and can be, for example, -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, etc. In some embodiments, the term "halogenated C" is used. 1-6 The alkoxy group is preferably fluorinated, for example, it can be -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, etc.

[0516] The term "hydroxy-substituted C" 1-6 "Alkyl" refers to an alkyl group in which one hydrogen atom is replaced by a hydroxyl group, as defined above. As an example, the "hydroxyl-substituted C..." 1-6 "alkyl" can be hydroxymethyl.

[0517] "Alkenyl" refers to a hydrocarbon chain that includes a straight-chain or branched configuration and has one or more carbon-carbon double bonds that can exist at any stable point along the chain. For example, "C 2-6 "Alkenyl" refers to compounds including C2, C3, C4, C5, and C6. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.

[0518] "Alkyne group" refers to a hydrocarbon group that includes a straight-chain or branched configuration and has one or more carbon-carbon triple bonds that can exist at any stable point along the chain. For example, "C 2-6 "Alkenyl" refers to alkynyl groups including C2, C3, C4, C5, and C6. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentylyl, and hexynyl.

[0519] Those skilled in the art will understand that when “CO2” is used herein, it refers to a functional group.

[0520] As used in this article, “substituted” means that any one or more hydrogen atoms on a specified atom or group are selectively substituted by a specified group, provided that the substitution does not exceed the normal valence state of the specified atom.

[0521] The term "cycloalkyl" refers to cyclic alkyl groups, including monocyclic, bicyclic, or polycyclic systems. 3-7 Cycloalkyl refers to C3, C4, C5, C6, and C7 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, “carbocyclic ring” or “carbocyclic residue” refers to any stable 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered monocyclic or bicyclic or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic or tricyclic ring, any of which may be saturated, partially saturated, unsaturated, or aromatic. Examples of such carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptenyl, adamantyl, cyclooctyl, phenyl, and naphthyl. As shown above, bridging rings are also included in the definition of a carbocyclic ring, such as [2,2,2]bicyclooctane. Unless otherwise specified, preferred carbocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl, and phenyl. A bridging ring is formed when one or more carbon atoms connect two non-adjacent carbon atoms. Preferably, the bridge consists of one or two carbon atoms. It should be noted that a bridge always transforms a monocyclic ring into a bicyclic ring. In ring bridging, the substituents described above for the ring may also be present on the bridge.

[0522] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring moiety, such as phenyl and naphthyl, each of which can be substituted.

[0523] The terms “heterocyclic,” “heterocyclic alkyl,” “heterocyclic,” or “heterocyclic group” are used interchangeably and refer to substituted and unsubstituted 3- to 7-membered monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, wherein at least one ring has at least one heteroatom (O, S, or N), and the heteroatom-containing ring preferably has one, two, or three heteroatoms selected from O, S, and N. Each heteroatom-containing ring in the group may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, with the limitation that the heteroatom count in each ring is generally four or less, and a further limitation that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocyclic group may be attached to any available nitrogen or carbon atom. All terms in this document that refer to “heterocyclic,” “heterocyclic alkyl,” “heterocyclic,” and “heterocyclic group” include “heteroaryl” as defined below.

[0524] In addition to the heteroaryl groups described below, exemplary monocyclic heterocyclic groups include azirrobutyl, oxacyclobutyl, pyrrolyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidyl, 2-oxopyrrolyl, 2-oxaazirroheptantrienyl, 1-pyridoneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, 1,3-dioxacyclopentyl, etc. Exemplary bicyclic heterocyclic groups expose quinine rings. Other monocyclic heterocyclic groups include:

[0525] The term "saturated heterocyclic group" refers to the monocyclic, bicyclic, or tricyclic group in the aforementioned "heterocyclic group" where the group is in a completely saturated state. The "heterocyclic group" is as described above. As an example, the saturated heterocyclic group can be a morpholino group (e.g., ...). ), piperidinyl (e.g.) ), piperazine group etc.

[0526] The term "heteroaryl" refers to a substituted or unsubstituted aromatic 5- or 6-membered monocyclic group, 9- or 10-membered bicyclic group, and 11- to 14-membered tricyclic group having at least one heteroatom (O, N, or S) in at least one ring, wherein the heteroatom-containing ring preferably has one, two, or three heteroatoms selected from O, N, or S. Each heteroatom-containing ring of the heteroaryl group may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, limited by the total number of heteroatoms in each ring being four or less and each ring having at least one carbon atom. Fused rings completing bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Nitrogen and sulfur atoms may optionally be oxidized and nitrogen atoms may optionally be quaternized. Heteroaryl groups that are bicyclic or tricyclic must include at least one fully aromatic ring, but the other one or more fused rings may be aromatic or non-aromatic. The heterocyclic group may be attached to any available nitrogen or carbon atom in any ring. If the valence allows, and the other ring is a cycloalkyl or heterocyclic ring, it may be optionally substituted with =O (oxo).

[0527] Exemplary monocyclic heteroaromatic rings include pyrrole, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophene, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, pyridoneyl, 2-pyridoneyl (e.g.) ), etc. It should be noted that, in this invention, the structural formula of pyridone is... The structural formula of 2-pyridone is

[0528] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzimidazolyl, benzo-m-dioxacyclopentenyl, benzoxazolyl, benzothiophenyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzofuranyl, inazinyl, benzopyranyl, crononeyl, coumarinyl, benzopyranyl, quinoxalinyl, indazoleyl, pyrrolopyrimidinyl, furanopyridyl, and isoindolyl, tetrahydroquinolinyl, etc.

[0529] Exemplary tricyclic heteroaryl groups include carbazolyl, benzoindolyl, phenanthrolinel, acridinel, etc.

[0530] In compounds of formula I, I', or I'', preferred heteroaryl groups include:

[0531]

[0532] etc., which can be optionally substituted on any available carbon or nitrogen atom.

[0533] Unless otherwise specified, when referring to a clearly named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclic (e.g., pyrrolidinyl, piperidinyl, morpholinyl) or heteroaryl (e.g., imidazolyl, pyrazolyl, triazolyl), the reference means a ring having 0 to 3, preferably 0 to 2, substituents selected as needed from the substituents described above for aryl, cycloalkyl, heterocyclic and / or heteroaryl.

[0534] The term "carbocyclic" or "carbocyclic" refers to a monocyclic or bicyclic ring in which all atoms of all rings are carbon, either saturated or unsaturated. Therefore, the term includes cycloalkyl and aryl rings. Monocyclic carbocyclic rings have 3 to 6 carbon atoms, more commonly 5 or 6. Bicyclic carbocyclic rings have 7-12 ring atoms, for example, arranged in a bicyclic [4,5], [5,5], [6,6] system, or 9 or 10 ring atoms arranged in a bicyclic [5,6] or [6,6] system. Examples of monocyclic and bicyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, and naphthyl. The carbocyclic ring can be substituted, in which case the substituent is selected from all the substituents mentioned above for cycloalkyl and aryl groups.

[0535] The term "heteroatoms" should include oxygen, sulfur, and nitrogen.

[0536] When the term "unsaturated" is used in the text to refer to a ring or group, the ring or group may be completely unsaturated or partially unsaturated.

[0537] From all the above descriptions, it will be apparent to those skilled in the art that its name is any group of a compound name, such as "C". 3-10 "Cycloalkyl-C(O)-" should refer to the part conventionally derived from it, such as from the C-shaped part. 3-10 It is constructed by substituting a carbonyl group with a cycloalkyl group, wherein the cycloalkyl group is as defined above. Other similar compound names can be understood with reference to the foregoing.

[0538] The term "optional" means that it is optional. For example, "optional is selected by 1 to 3 Rs". d Replacement C 1-6 "alkyl" indicates that the C 1-6 Alkyl groups can be 1 to 3 R d It can be replaced, or it can be replaced by 1 to 3 Rs. d It replaces [other definitions]. Other similar definitions can be understood by referring to the foregoing content.

[0539] Throughout the specification, groups and their substituents may be selected by those skilled in the art to provide stable moieties and compounds and compounds that can be used as pharmaceutically acceptable compounds and / or intermediate compounds that can be used to prepare pharmaceutically acceptable compounds.

[0540] Invention effects:

[0541] The hydroxamic acid esters of formula (I), (I'), or (I”) of the present invention exhibit good TYK2 inhibitory activity and can be used as drugs for the treatment and / or prevention of diseases related to this activity. Detailed Implementation

[0542] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. Furthermore, although any methods, apparatus, and materials similar to or equivalent to those described herein may be used to practice or test the invention, preferred methods, apparatus, and materials are described here.

[0543] The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker ASCENA-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were expressed in 10⁻¹⁰ increments. -6 (ppm) is given as the unit.

[0544] Reaction monitoring and MS determination were performed using a Thermofisher ESQ (ESI) mass spectrometer.

[0545] The HPLC determination was performed using a Thermo Fisher Scientific U3000 DAD high-performance liquid chromatograph (GL Sciences ODS-HL HP 3μm 3.0*100mm column).

[0546] Thin-layer chromatography (TLC) used Qingdao Ocean GF254 silica gel plates. The silica gel plates used in TLC had a diameter of 0.15–0.2 mm, while the purified products were separated using high-performance thin-layer chromatography (HPLC) preparative plates with a diameter of 0.9–1.0 mm. Column chromatography used Qingdao Ocean 200–300 mesh silica gel as the carrier. The developing solvent systems were A: dichloromethane and methanol; and B: petroleum ether and ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compounds. For medium-pressure preparative liquid chromatography (PLC) purification, a Biotage Isera One preparative PL was used.

[0547] In the following examples, unless otherwise specified, all reaction materials can be purchased from manufacturers such as Saen Chemical Technology (Shanghai) Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Jiangsu Aikon Biomedical R&D Co., Ltd., and Shanghai Bide Pharmaceutical Technology Co., Ltd.

[0548] intermediate int-1

[0549] 4,6-Dichloro-N-methoxynicotinamide

[0550]

[0551] 1) Dissolve 4,6-dichloronicotinic acid (int-1a, 1.92 g, 10 mmol) in dichloromethane (30 ml) and add to a 100 ml two-necked flask. Cool the reaction solution to 0℃~5℃ using an ice-water bath. Add the catalytic amount of DMF (0.1 ml) dropwise, then slowly add oxalyl chloride (1.52 g, 12 mmol). Stir at room temperature for 30 min. TLC shows that the reaction is complete. Concentrate the reaction solution under reduced pressure at 40℃. Add dichloromethane (20 ml) to the concentrated crude product and concentrate again under reduced pressure. Proceed directly to the next step of the reaction.

[0552] 2) Methoxyamine hydrochloride (1.25 g, 15 mmol) was added to an ethyl acetate / water (40 ml) (5:1) solution, followed by potassium carbonate (4.14 g, 30 mmol). The mixture was stirred at room temperature for 10 min. The crude product was dissolved in dichloromethane (10 ml) and added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction mixture was separated, the organic phase was concentrated, and column purification (petroleum ether / ethyl acetate = 2:1) was performed to obtain the product 4,6-dichloro-N-methoxynicotinamide (int-1, 2.0 g, 9 mmol, 90.5% yield for 2 steps). MS Calcd: 221; MS Found: 222 ([M+H) + ).

[0553] intermediate int-2

[0554] 4,6-Dichloro-N-ethoxynicotinamide

[0555]

[0556] Step 1: 1) Dissolve 4,6-dichloronicotinic acid (int-1a, 1.92 g, 10 mmol) in dichloromethane (30 ml) and add to a 100 ml two-necked flask. Cool the reaction solution to 0℃~5℃ using an ice-water bath. Add the catalytic amount of DMF (0.1 ml) dropwise, then slowly add oxaloyl chloride (1.52 g, 12 mmol). Stir at room temperature for 30 min. TLC shows that the reaction is complete. Concentrate the reaction solution under reduced pressure at 40℃. Add dichloromethane (20 ml) to the concentrated crude product and concentrate again under reduced pressure.

[0557] 2) Ethoxyamine hydrochloride (1.426 g, 15 mmol) was added to an ethyl acetate / water (40 ml) (5:1) solution, followed by potassium carbonate (4.14 g, 30 mmol). The mixture was stirred at room temperature for 10 min. The crude product was dissolved in dichloromethane (10 ml) and added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction mixture was separated, the organic phase was concentrated, and column purification (petroleum ether / ethyl acetate = 2:1) yielded 4,6-dichloro-N-ethoxynicotinamide (int-2, 1.6 g, 6.8 mmol, 68.3% yield). MS Calcd: 234; MS Found: 235 ([M+H) + ).

[0558] Example 1

[0559] 6-(Cyclopropylcarboxamide)-N-methoxy-4-((2-oxo-1-(thiazo-2-yl)-1,2-dihydropyridin-3-yl)amino)nicotinamide

[0560]

[0561] Step 1: Dissolve 3-amino-2-hydroxypyridine (1-a, 440 mg, 4.0 mmol) in dichloromethane (10 ml) and add it to a 50 ml reaction flask. Then, dissolve benzyl chlorocarbamate (750.60 mg, 4.4 mmol) in dichloromethane (5 ml) and slowly add it dropwise to the reaction flask at 0℃~5℃. Stir the reaction at room temperature for 3 h. The reaction was monitored by TLC until complete. The reaction solution was washed with water (10 ml x 1) and brine (10 ml x 1), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography yielded the product 2-oxo-1,2-dihydropyridine-3-ylcarbamate (1-b, 850 mg, 87% yield). MS Calcd: 244; MS Found: 245 ([M+H) + ).

[0562] Step 2: Add 2-oxo-1,2-dihydropyridine-3-ylcarbamate benzyl ester (1-b, 600 mg, 2.46 mmol). 2-Bromo Thiazole(524.2 mg, 3.20 mmol), CuI (93.7 mg, 0.492 mmol), N,N'-dimethylethylenediamine (86.74 mg, 0.987 mmol), and potassium carbonate (679 mg, 4.92 mmol) were suspended in dioxane (20 mL). The reaction mixture was purged with nitrogen three times, then heated to 115 °C and reacted for 5 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated, 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 4:1) to give benzyl (2-oxo-1-(thiazo-2-yl)-1,2-dihydropyridin-3-yl)carbamate (1-c, 525 mg, 1.60 mmol, 66% yield). MS Calcd: 327; MS Found: 328 ([M+H) + ).

[0563] Step 3: Benzyl (2-oxo-1-(thiazol-2-yl)-1,2-dihydropyridin-3-yl)carbamate (1-c, 500 mg, 1.53 mmol) was dissolved in glacial acetic acid (10 ml) and added to a 50 ml reaction flask. Then, 0.5 ml of 40% aqueous hydrogen bromide solution was added, and the mixture was heated to 90 °C and reacted for 3 h. The reaction was monitored by TLC until complete. Water and ethyl acetate were added to the reaction solution, and the pH was adjusted to 7–8 with sodium carbonate. The mixture was then extracted with ethyl acetate (10 ml x 3). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by silica gel column chromatography yielded 3-amino-1-(thiazol-2-yl)pyridin-2(1H)-one (1-d, 206 mg, 1.07 mmol, 70% yield). MS Calcd: 193; MS Found: 194 ([M+H) + ).

[0564] Step 4: 3-Amino-1-(thiazol-2-yl)pyridin-2(1H)-one (1-d, 150 mg, 0.78 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 169.4 mg, 0.78 mmol) were added to 5 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (2.34 mL, 2.34 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was confirmed to be complete by TLC. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography. 6-Chloro-N-methoxy-4-((2-oxo-1-(thiazol-2-yl)-1,2-dihydropyridin-3-yl)amino)nicotinamide (1-e, 200 mg, 0.53 mmol, 68% yield) was purified from the organic layers. MS Calcd:377;MS Found:378([M+H] + ).

[0565] Step 5: Administer 6-chloro-N-methoxy-4-((2-oxo-1-(thiazolyl-2-yl)-1,2-dihydropyridin-3-yl)amino)nicotinamide (1-e, 100 mg, 0.26 mmol), cyclopropylformamide (24.8 mg, 0.292 mmol), cesium carbonate (256.80 mg, 0.80 mmol), XantPhos (30 mg, 0.04 mmol), and Pd2(dba)3 (24 mg, 0.026 mmol) Added to anhydrous dioxane (5 ml) and evacuated, purged three times with nitrogen, heated to 100 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(cyclopropylformamide)-N-methoxy-4-((2-oxo-1-(thiazo-2-yl)-1,2-dihydropyridin-3-yl)amino)nicotinamide (1, 15 mg, 0.035 mmol, 13.5% yield). MS Calcd: 426; MS Found: 427 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.92(s,1H),10.98(s,1H),10.56(s,1H),8.49-8 .47(dd,J1=1.2Hz,J2=7.2Hz,1H),8.42(s,1H),8.27(s,1H),7.83-7.82(d,J =3.2Hz,1H),7.73-7.72(d,J=4Hz,1H),7.52-7.50(t,J=8.0Hz,1H),6.71-6. 67-7.50(t,J=16Hz,1H),3.74(s,3H),1.98-1.95(m,1H),0.85-0.82(m,4H).

[0566] Example 2

[0567] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide

[0568]

[0569] Step 1: Dissolve 1-fluoro-2-nitrobenzene (2-a, 1.0 g, 9.16 mmol) in acetonitrile (30 ml) and add it to a 100 ml reaction flask. Then add cesium carbonate (5.95 g, 18.32 mmol) and N-methylmethanesulfonamide (1.227 g, 8.702 mmol) to the reaction flask. Stir the mixture overnight at room temperature. The reaction was checked by TLC until complete. The reaction solution was washed with water (30 ml x 1) and brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purification was achieved by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the product N-methyl-N-(2-nitrophenyl)methanesulfonamide (2-b, 1.2 g, 73.6% yield). MS Calcd: 230; MS Found: 231 ([M+H) + ).

[0570] Step 2: N-methyl-N-(2-nitrophenyl)methanesulfonamide (2-b, 460 mg, 2 mmol) and 10% palladium on carbon 46 mg were added to methanol (15 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-(2-aminophenyl)-N-methylmethanesulfonamide (2-c, 350 mg, 1.75 mmol, 87.5% yield). No purification was required; the mixture was directly used in the next reaction. MS Calcd: 200; MS Found: 201 ([M+H]) + ).

[0571] Step 3: N-(2-aminophenyl)-N-methylmethanesulfonamide (2-c, 200 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 218 mg, 1 mmol) were added to 5 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (3 mL, 3 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC until complete. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography. 6-chloro-N-methoxy-4-((2-(N-methylmethanesulfonamide)phenyl)amino)nicotinamide (2-d, 150 mg, 0.39 mmol, 39% yield) was purified from the soluble solids. MS Calcd: 384; MS Found: 385 ([M+H) + ).

[0572] Step 4: 6-chloro-N-methoxy-4-((2-(N-methylmethanesulfonamido)phenyl)amino)nicotinamide (2-d, 39 mg, 0.1 mmol), cyclopropylformamide (9.4 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added to anhydrous dioxane (5 ml) and the mixture was evacuated. The mixture was purged with nitrogen three times, heated to 100 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain 6-(cyclopropylformamide)-N-methoxy-4-((2-(N-methylmethanesulfonamido)phenyl)amino)nicotinamide (2, 10 mg, 0.023 mmol, 23.1% yield). MS Calcd:433;MS Found:434([M+H] + ). 1 H NMR (400MHz, DMSO-d6): δ11.82(s,1H),10.81(s,1H),10.05(s,1H),8.33(s,1H),7.92(s,1H),7.58-7.53(m,1H),7.50-7.48 (m,1H),7.42-7.24(m,1H),7.23-7.20(m,1H),3.88(s,3H),3.14(s,3H),3.10(s,3H),1.97-1.94(m,1H),0.77-0.76(m,4H).

[0573] Example 3

[0574] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)amino)nicotinamide

[0575]

[0576] Step 1: 1-Bromo-2-methoxy-3-nitrobenzene (3-a, 1 g, 4.32 mmol), iron powder (1.21 g, 21.6 mmol), and glacial acetic acid (20 ml) were added to a 100 ml single-necked flask. The reaction mixture was heated to 85 °C and stirred for 3 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, ethyl acetate and water were added, and the mixture was filtered through diatomaceous earth. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate until no product was observed. The organic phases were combined, washed with saturated sodium carbonate solution (50 ml x 3), then washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 3-bromo-2-methoxyaniline (3-b, 750 mg, 3.73 mmol, 86.37% yield). No purification was required; the reaction proceeded directly to the next step. MS Calcd: 202; MS Found: 203 ([M+H) + ).

[0577] Step 2: 3-Bromo-2-methoxyaniline (3-b, 402 mg, 2 mmol), sodium carbonate (318 mg, 3 mmol), bis-pinacolborate (609.6 g, 2.4 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (146.2 mg, 0.2 mmol) were added to anhydrous dioxane (10 ml) and the mixture was evacuated under vacuum, purged three times with nitrogen, heated to 90 °C, stirred for 3 h, filtered, and the filtrate was purified by concentrated silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (3-c, 210 mg, 0.84 mmol, 42.2% yield). MS Calcd: 249; MS Found: 250 ([M+H) +Step 3: Dissolve 2-bromo-1H-benzo[d]imidazole (3-c, 392 mg, 2 mmol) in acetonitrile (15 ml) and add it to a 100 ml reaction flask. Then add cesium carbonate (975 mg, 3 mmol) and methyl iodoform (312.4 mg, 2.2 mmol) to the reaction flask. Stir the reaction mixture overnight at room temperature. The reaction was checked by TLC until complete. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 ml x 2), washed with brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification of 2-bromo-1-methyl-1H-benzo[d]imidazole (3-d, 400 mg, 1.90 mmol, 95.2% yield) by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) was performed. MS Calcd: 210; MS Found: 211 ([M+H) + ).

[0578] Step 4: 2-Bromo-1-methyl-1H-benzimidazole (3-d, 176.4 mg, 0.84 mmol), sodium carbonate (178 mg, 1.68 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (33067-c, 210 mg, 0.84 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (…) II (61.4 mg, 0.084 mmol) was added to anhydrous dioxane (15 ml) and the mixture was evacuated, purged three times with nitrogen, heated to 90 °C, stirred for 3 h, filtered, and the filtrate was purified by concentrated silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain 2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (3-e, 105 mg, 0.41 mmol, 49.4% yield). MS Calcd: 253; MS Found: 254 ([M+H) + ).

[0579] Step 5: 2-Methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (3-e, 105 mg, 0.41 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 90 mg, 0.41 mmol) were added to 5 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (1.23 mL, 1.23 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was confirmed to be complete by TLC. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography. 6-Chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)amino)nicotinamide (3-f, 70 mg, 0.16 mmol, 39% yield) was purified from the organic layers. MS Calcd:437;MS Found:438([M+H] + ).

[0580] Step 6: 6-Chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)amino)nicotinamide (3-f, 70 mg, 0.16 mmol), cyclopropylformamide (21.51 mg, 0.19 mmol), cesium carbonate (156 mg, 0.48 mmol), XantPhos (18 mg, 0.032 mmol), and Pd2(dba)3 (16.5 mg, 0.016 mmol) were administered. Added to anhydrous dioxane (5 ml) and evacuated, purged three times with nitrogen, heated to 100 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(cyclopropylcarbamoyl)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)amino)nicotinamide (3, 10 mg, 0.02 mmol, 10.8% yield). MS Calcd: 486; MS Found: 487 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),10.85(s,1H),10.18(s,1H),8.38(s,1H),8.05(s,1H),7.70(d,J=7.8Hz,1H),7. 63(d,J=7.8Hz,2H),7.37–7.24(m,4H).,3.73(s,3H),3.66(s,3H),3.40(s,3H),2.33-2.31(m,1H),0.85-0.79(m,4H).

[0581] Example 4

[0582] 6-((5-Fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide

[0583]

[0584] Step 1: 6-Chloro-N-methoxy-4-((2-(N-methylmethanesulfonamido)phenyl)amino)nicotinamide (2-d, 67 mg, 0.17 mmol), 5-fluoro-2-aminopyridine (21.51 mg, 0.19 mmol), cesium carbonate (166.7 mg, 0.51 mmol), XantPhos (18.6 mg, 0.034 mmol), and Pd2(dba)3 (16.6 mg, 0.017 mmol) were added. mol) was added to anhydrous dioxane (5 ml) and the mixture was evacuated, purged three times with nitrogen, heated to 100 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide (4, 17 mg, 0.037 mmol, 21.7% yield). MS Calcd: 460; MS Found: 461 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.71(s,1H),10.09(s,1H),9.84(s,1H),8.30(s,1H),8.15-8.14(d,J=2.8Hz,1H),7.67-7. 61(m,4H),7.55(dd,J=8.0,2.0Hz,1H),7.50-7.46(m,1H),7.20-7.19(m,1H),3.72(s,3H),3.16(s,3H),3.14(s,3H).

[0585] Example 5

[0586] N-Methoxy-6-(((2-Methoxypyridin-3-yl)amino)-4-((2-(N-Methylmethylsulfonamido)phenyl)amino)nicotinamide

[0587]

[0588] Step 1: Add 6-chloro-N-methoxy-4-((2-(N-methylmethanesulfonamido)phenyl)amino)nicotinamide (2-d, 60 mg, 0.16 mmol), 2-methoxy-3-aminopyridine (19.4 mg, 0.16 mmol), cesium carbonate (152 mg, 0.47 mmol), XantPhos (17.53 mg, 0.032 mmol), and Pd2(dba)3 (15.6 mg, 0.016 mmol) to anhydrous dioxin. The solution was placed in a hexacyclic container (5 ml) and evacuated, purged three times with nitrogen, heated to 100 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: N-methoxy-6-(((2-methoxypyridin-3-yl)amino)-4-((2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide (5, 15 mg, 0.032 mmol, 20.5% yield). MS Calcd: 472; MS Found: 473 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.68(s,1H),9.93(s,1H),8.58(s,1H),8.50-8.48(m,1H),8.33(s,1H),7.73-7.72(m,1H),7.56-7.53(m,2 H),7.44-7.40(m,1H),7.21-7.17(m,1H),6.95-6.91(m,1H),6.85-6.84(m,1H),3.91(s,3H),3.71(s,3H),3.16(s,3H),3.14(s,3H).

[0589] Example 6

[0590] 6-(Cyclopropylformamide)-N-methoxy-4-((4-methoxy-2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide

[0591]

[0592] Step 1: Dissolve 3-fluoro-4-nitrophenol (6-a, 628 mg, 4 mmol) in acetonitrile (30 ml) and add it to a 100 ml reaction flask. Then add cesium carbonate (1.95 g, 6 mmol) and methyl iodoform (624.8 mg, 4.4 mmol) to the reaction flask. Stir the reaction mixture overnight at room temperature. The reaction was monitored by TLC until complete. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 ml x 2), washed with brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification was achieved by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 2-fluoro-4-methoxy-1-nitrobenzene (6-b, 650 mg, 3.82 mmol, 95% yield). MS Calcd: 157; MS Found: 158 ([M+H) + Step 2: Dissolve 2-fluoro-4-methoxy-1-nitrobenzene (6-b, 600 g, 3.5 mmol) in dichloromethane (30 ml) and add it to a 100 ml reaction flask. Then add cesium carbonate (1.70 g, 5.25 mmol) and N-methylmethanesulfonamide (412 mg, 3.85 mmol) to the reaction flask. Stir the reaction mixture overnight at room temperature. The reaction was checked by TLC until complete. The reaction solution was washed with water (30 ml x 1) and brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain N-(5-methoxy-2-nitrophenyl)-N-methylmethanesulfonamide (6-c, 520 mg, 2 mmol, 57.1% yield). MS Calcd: 260; MS Found: 261 ([M+H) + ).

[0593] Step 3: N-(5-methoxy-2-nitrophenyl)-N-methylmethanesulfonamide (6-c, 520 mg, 2 mmol) and palladium on carbon 46 mg were added to methanol (20 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-(2-aminophenyl)-N-methylmethanesulfonamide (6-d, 440 mg, 1.87 mmol, 93.47% yield). No purification was required; the mixture was directly used in the next reaction. MS Calcd: 230; MS Found: 231 ([M+H]) + )

[0594] Step 4: N-(2-amino-5-methoxyphenyl)-N-methylmethanesulfonamide (6-d, 230 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 218 mg, 1 mmol) were added to 5 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (3 mL, 3 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC until complete. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography of 6-chloro-N-methoxy-4-((4-methoxy-2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide (6-e, 200 mg, 0.483 mmol, 48.3% yield). MS Calcd: 414; MS Found: 415 ([M+H) + ).

[0595] Step 5: Add 6-chloro-N-methoxy-4-((4-methoxy-2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide (6-e, 100 mg, 0.24 mmol), cyclopropylformamide (20.4 mg, 0.24 mmol), cesium carbonate (234 mg, 0.72 mmol), XantPhos (27.74 mg, 0.048 mmol), and Pd2(dba)3 (23.4 mg, 0.024 mmol) to the solution. mmol) was added to anhydrous dioxane (5 ml) and the mixture was evacuated, purged three times with nitrogen, heated to 100 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give 6-(cyclopropaneformamide)-N-methoxy-4-((4-methoxy-2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide (6, 15 mg, 0.032 mmol, 13.3% yield). MS Calcd: 463; MS Found: 464 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.72(s,1H),10.70(s,1H),9.70(s,1H),8.30(s,1H),7.62(s,1H),7.51(s,1H),7.35-7. 33(m,1H),7.14(s,1H),3.81(s,3H),3.71(s,3H),3.11(s,3H),3.09(s,3H),1.98-2.01(m,1H),0.75-0.73(m,4H).

[0596] Example 7

[0597] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((6-methoxy-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide

[0598]

[0599] Step 1: Dissolve 6-chloro-5-nitropyridin-2-ol (7-a, 696 mg, 4 mmol) in acetonitrile (30 mL) and add it to a 100 mL reaction flask. Then add cesium carbonate (1.95 g, 6 mmol) and iodomethane (624.8 mg, 4.4 mmol) to the reaction flask. Stir the reaction mixture overnight at room temperature. The reaction was confirmed to be complete by TLC. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2), washed with brine (30 mL x 1), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification was achieved by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 2-chloro-6-methoxy-3-nitropyridinium (7-b, 700 mg, 3.72 mmol, 93% yield). MS Calcd: 188; MS Found: 189 ([M+H) + ).

[0600] Step 2: Dissolve 2-chloro-6-methoxy-3-nitropyridine (7-b, 600 g, 3.19 mmol) in dichloromethane (30 ml) and add it to a 100 ml reaction flask. Then add cesium carbonate (1.57 g, 4.78 mmol) and N-methylmethanesulfonamide (379 mg, 3.51 mmol) to the reaction flask. Stir the mixture overnight at room temperature. The reaction was checked by TLC until complete. The reaction solution was washed with water (30 ml x 1) and brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purification was achieved by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give N-(6-methoxy-3-nitropyridine-2-yl)-N-methylmethanesulfonamide (7-c, 550 mg, 2.10 mmol, 65.8% yield). MS Calcd: 261; MS Found: 262 ([M+H) + ).

[0601] Step 3: N-(6-methoxy-3-nitropyridin-2-yl)-N-methylmethanesulfonamide (7-c, 550 mg, 2.1 mmol) and 46 mg palladium on carbon were added to methanol (20 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-(3-amino-6-methoxypyridin-2-yl)-N-methylmethanesulfonamide (7-d, 450 mg, 1.95 mmol, 92.76% yield). No purification was required; the mixture was directly used in the next reaction. MS Calcd: 231; MS Found: 232 ([M+H]+ ).

[0602] Step 4: N-(3-amino-6-methoxypyridin-2-yl)-N-methylmethanesulfonamide (7-d, 231 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 218 mg, 1 mmol) were added to 5 ml of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (3 ml, 3 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was detected by TLC to be complete. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (30 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography to obtain 6-chloro-N-methoxy-4-((6-methoxy-2-(N-methylmethanesulfonamide)pyridin-3-yl)amino)nicotinamide (7-e, 210 mg, 0.506 mmol, 50.6% yield). MS Calcd:415;MS Found:416([M+H] + ).

[0603] Step 5: Administer 6-chloro-N-methoxy-4-((6-methoxy-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (7-e, 100 mg, 0.24 mmol), cyclopropylformamide (20.4 mg, 0.24 mmol), cesium carbonate (234 mg, 0.72 mmol), XantPhos (27.74 mg, 0.048 mmol), and Pd2(dba)3 (23.4 mg, 0.024 mmol) to the following concentrations: l) Add to anhydrous dioxane (5 ml) and evacuate under vacuum. Replace with nitrogen three times, heat to 100 °C, stir for 5 h, filter, concentrate, and purify by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 6-(cyclopropylcarbamate)-N-methoxy-4-((6-methoxy-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (7.16 mg, 0.034 mmol, 14.3% yield). MS Calcd: 464; MS Found: 465 ([M+H) + ).

[0604] 1H NMR (400MHz, DMSO-d6): δ11.79(s,1H),10.76(s,1H),9.78(s,1H),8.34(s,1H),7.85(d,J=8.4Hz,1H),7.58(s,1H) ,6.94(d,J=8.4Hz,1H),3.88(s,3H),3.71(s,3H),3.18(s,3H),3.11(s,3H),1.98-2.01(m,1H),0.76-0.74(m,4H).

[0605] Example 8

[0606] 6-((5-Fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methoxy-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide

[0607]

[0608] Step 1: Add 6-chloro-N-methoxy-4-((6-methoxy-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (7-e, 50 mg, 0.12 mmol), 5-fluoropyridin-2-amine (14.87 mg, 0.13 mmol), cesium carbonate (117 mg, 0.36 mmol), XantPhos (13.9 mg, 0.024 mmol), and Pd2(dba)3 (11 mg, 0.012 mmol) to... The solution was added to anhydrous dioxane (5 ml) and evacuated. The mixture was purged three times with nitrogen, heated to 100 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methoxy-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (8.8 mg, 0.016 mmol, 13.6% yield). MS Calcd: 491; MS Found: 492 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.68(s,1H),9.79(s,1H),9.76(s,1H),8.30(s,1H),8.12(d,J=2.8Hz,1H),7.95(d,J=8.8 Hz, 1H), 7.68-7.67 (m, 2H), 7.24 (s, 1H), 7.03 (d, J = 8.8Hz, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 3.21 (s, 3H), 3.13 (s, 3H).

[0609] Example 9

[0610] N-Methoxy-4-((6-Methoxy-2-(N-Methylsulfonamido)pyridin-3-yl)amino)-6-((2-Methoxypyridin-3-yl)amino)nicotinamide

[0611]

[0612] Step 1: Add 6-chloro-N-methoxy-4-((6-methoxy-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (7-e, 50 mg, 0.12 mmol), 2-methoxypyridin-3-amine (16.12 mg, 0.13 mmol), cesium carbonate (117 mg, 0.36 mmol), XantPhos (13.9 mg, 0.024 mmol), and Pd2(dba)3 (11 mg, 0.012 mmol) to... The solution was added to anhydrous dioxane (5 ml) and evacuated. The mixture was purged three times with nitrogen, heated to 100 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: N-methoxy-4-((6-methoxy-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)-6-((2-methoxypyridin-3-yl)amino)nicotinamide (9.8 mg, 0.016 mmol, 13.6% yield). MS Calcd: 503; MS Found: 504 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.65(s,1H),9.59(s,1H)8.52(dd,J=8.0,1.6Hz,1H),8.43(s,1H),8.24(s,1H)7.88(d,J=8.8Hz,1H),7.71(dd,J=4.8 ,2.0Hz,1H),6.95(d,J=8.4Hz,1H),6.92(dd,J=8.0,4.8Hz,1H),6.44(s ,1H),3.90(s,3H),3.86(s,3H),3.71(s,3H),3.21(s,3H),3.12(s,3H).

[0613] Example 10

[0614] 6-(Cyclopropylcarbamate)-N-methoxy-4-((2-(N-methylmethanesulfonamide)-4-(trifluoromethyl)phenyl)amino)nicotinamide

[0615]

[0616] Step 1: Dissolve 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (10-a, 418 mg, 2 mmol) in DMF (20 ml) and add it to a 100 ml reaction flask. Then add 60% sodium hydroxide (120 °C g, 3 mmol) and N-methylmethanesulfonamide (261.6 mg, 2.4 mmol) to the reaction flask. Stir at 50 °C for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was then added to water (40 ml) / ethyl acetate (30 ml), and the mixture was extracted separately. The organic phase was washed with water (30 ml x 1) and brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the product N-methyl-N-(2-nitro-5-(trifluoromethyl)phenyl)methanesulfonamide (10-b, 420 mg, 70.4% yield). MS Calcd:298;MS Found:299([M+H] + ).

[0617] Step 2: N-methyl-N-(2-nitro-5-(trifluoromethyl)phenyl)methanesulfonamide (10-b, 400 mg, 1.34 mmol) and 40 mg palladium on carbon were added to methanol (15 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-(2-amino-5-(trifluoromethyl)phenyl)-N-methylmethanesulfonamide (10-c, 350 mg, 1.31 mmol, 97.4% yield). No purification was required; the mixture was directly used in the next reaction. MS Calcd: 268; MS Found: 269 ([M+H]) + Step 3: N-(2-amino-5-(trifluoromethyl)phenyl)-N-methylmethanesulfonamide (10-c, 350 mg, 1.31 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 285.6 mg, 1.31 mmol) were added to 5 ml of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (4 ml, 3.93 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was confirmed to be complete by TLC. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (30 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography of 6-chloro-N-methoxy-4-((2-(N-methylmethanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide (10-d, 110 mg, 0.24 mmol, 18.6% yield). MS Calcd:452;MS Found:453([M+H] + ).

[0618] Step 4: Add 6-chloro-N-methoxy-4-((2-(N-methylmethylsulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide (10-d, 60 mg, 0.13 mmol), cyclopropylformamide (12.4 mg, 0.15 mmol), cesium carbonate (126.7 mg, 0.39 mmol), XantPhos (11 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) to the solution. Add to anhydrous dioxane (5 ml) and evacuate. Replace with nitrogen three times, heat to 120 °C, stir for 5 h, filter, concentrate the filtrate, and purify by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 6-(cyclopropylcarboxamide)-N-methoxy-4-((2-(N-methylmethanesulfonamide)-4-(trifluoromethyl)phenyl)amino)nicotinamide (10.8 mg, 0.016 mmol, 12.3% yield).

[0619] MS Calcd:501;MS Found:502([M+H] + ). 1 H NMR (400MHz, DMSO-d6): δ11.91(s,1H),10.93(s,1H),10.37(s,1H),8.40(s,1H),8.17(s,1H),7.92(d,J =2.0Hz,1H),7.77–7.70(m,2H),3.92(s,3H),3.22(s,3H),3.20(s,3H),1.99(m,1H),0.85-0.79(m,4H).

[0620] Example 11

[0621] 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methylmethanesulfonyl)-4-(trifluoromethyl)phenyl)amino)nicotinamide

[0622]

[0623] Step 1: Add 6-chloro-N-methoxy-4-((2-(N-methylmethanesulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide (10-d, 50 mg, 0.11 mmol), 6-fluoro-2-aminopyridine (10.4 mg, 0.12 mmol), cesium carbonate (108.2 mg, 0.33 mmol), XantPhos (11 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) to... The solution was placed in anhydrous dioxane (5 ml) under vacuum, purged three times with nitrogen, heated to 120 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methylmethylsulfonamido)-4-(trifluoromethyl)phenyl)amino)nicotinamide (11, 15 mg, 0.028 mmol, 25.8% yield). MS Calcd: 528; MS Found: 529 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.84(s,1H),10.46(s,1H),10.16(s,1H),8.38(s,1H),7.92-7.89(m,3H),7.83(dd,J=16.4,8.0 Hz, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.45 (d, J = 8.0Hz, 1H), 6.61 (dd, J = 8.0, 2.4Hz, 1H), 3.71 (s, 3H), 3.22 (s, 3H), 3.13 (s, 3H).

[0624] Example 12

[0625] 6-(cyclopropylcarbamoyl)-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide

[0626]

[0627] Step 1: Dissolve methanesulfonyl methylamine (0.6 g, 5.5 mmol) in 10 mL of N,N-dimethylformamide, add sodium hydrogen (0.29 g, 7.5 mmol) in portions, then heat the reaction solution to 55 °C and continue stirring for 2 hours. Add 4-bromo-2-fluoro-1-nitrobenzene (12-a, 1.1 g, 5.0 mmol), and continue stirring at this temperature for 2 hours. Monitor the reaction by TLC until it is complete. Add water (40 mL) to the reaction solution, extract with ethyl acetate (30 mL x 2), wash with saturated brine (30 mL x 2), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (EA:PE = 1:5) to obtain a pale yellow solid N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (12-b, 1.6 g, 5.17 mmol, 94% yield). MS Calcd:307.95;MS Found:307.00([MH] - ).

[0628] Step 2: N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (12-b, 1.6 g, 5.17 mmol), cyclopropylboronic acid (0.53 g, 6.2 mmol), potassium phosphate (5.27 g, 15.6 mmol), and Pd(dppf)Cl2 (0.38 g, 0.52 mmol) were sequentially added to 30 mL of a 5 / 1 mixture of dioxane and water. The mixture was purged with nitrogen three times under vacuum and stirred at 110 °C for 6 hours. The reaction was monitored by TLC until completion. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE = 1:1) to obtain a yellow solid N-(5-cyclopropyl-2-nitrophenyl)-N-methylmethanesulfonamide (12-c, 1.1 g, 0.4 mmol, 77.3% yield). MS Calcd: 270.07; MS Found: 271.13 ([M+H] + ).

[0629] Step 3: N-(5-cyclopropyl-2-nitrophenyl)-N-methylmethanesulfonamide (12-c, 1 g, 3.7 mmol), ammonium chloride (0.98 g, 18 mmol), and iron powder (0.62 g, 11.1 mmol) were added sequentially to 10 mL of a mixed solvent of water and ethanol (1:4), and stirred under reflux for 6 hours. The reaction was monitored by TLC until completion. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain a colorless oily substance, N-(2-amino-5-cyclopropylphenyl)-N-methylmethanesulfonamide (12-d, 0.72 g, 2.98 mmol, 80.7% yield). MS Calcd: 240.09; MS Found: 241.22 ([M+H] + ).

[0630] Step 4: N-(2-amino-5-cyclopropylphenyl)-N-methylmethanesulfonamide (12-d, 165.8 mg, 0.69 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 150 mg, 0.69 mmol) were added to 10 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (2.0 mL, 2.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC until completion. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain a brown oily substance 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (12-e, 250 mg, 0.59 mmol, 85.6% yield). MSCalcd:424.10;MS Found:425.29([M+H] + ).

[0631] Step 5: Add 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (12-e, 127 mg, 0.3 mmol), cyclopropylformamide (28 mg, 0.33 mmol), cesium carbonate (293 mg, 0.9 mmol), XantPhos (34.7 mg, 0.06 mmol), and Pd2(dba)3 (28.4 mg, 0.03 mmol) to... The solution was added to anhydrous dioxane (5 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(cyclopropylcarbamoyl)-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (12, 40 mg, 0.085 mmol, 28.2% yield). MS Calcd: 473.17; MS Found: 472.36 ([MH]) - ). 1H NMR (400MHz, DMSO-d6): δ11.76(s,1H),10.74(s,1H),9.789(s,1H),8.30(s,1H),7.82(s,1H),7.33(d,J=8.4Hz,1H),7.26(d,J=2.0 Hz,1H),7.09(dd,J=8.4,2.0Hz,1H),3.71(s,3H),3.12(s,3H),3.07(s,3H),1.98–1.93(m,2H),1.00-0.95(m,2H)0.77-0.70(m,6H).

[0632] Example 13

[0633] 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0634]

[0635] Step 1: Add 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (12-e, 127 mg, 0.3 mmol), 5-fluoropyridine-2-amine (28 mg, 0.33 mmol), cesium carbonate (293 mg, 0.9 mmol), XantPhos (34.7 mg, 0.06 mmol), and Pd2(dba)3 (28.4 mg, 0.03 mmol) to... The solution was placed in anhydrous dioxane (5 ml) under vacuum, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (13, 50 mg, 0.085 mmol, 33.3% yield). MS Calcd: 500.17; MS Found: 501.36 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.67(s,1H),9.92(s,1H),9.78(s,1H),8.27(s,1 H), 8.15(d,J=7.2Hz,1H),7.67-7.64(m,2H),7.50(s,1H),7.46(d,J=8.4Hz, 1H),7.27(d,J=2.0Hz,1H),7.16(dd,J=8.4,2.0Hz,1H),3.70(s,3H),3.14( s,3H)3.10(s,3H),2.01-1.97(m,1H),1.01-0.97(m,2H),0.74-0.70(m,2H).

[0636] Example 14

[0637] 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0638]

[0639] Step 1: Add 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (12-e, 127 mg, 0.3 mmol), 6-fluoropyridine-2-amine (28 mg, 0.33 mmol), cesium carbonate (293 mg, 0.9 mmol), XantPhos (34.7 mg, 0.06 mmol), and Pd2(dba)3 (28.4 mg, 0.03 mmol) to... The solution was transferred to anhydrous dioxane (5 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (14, 45 mg, 0.085 mmol, 30% yield). MS Calcd: 500.17; MS Found: 501.36 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.69(s,1H),9.96(s,1H), 9.93(s,1H),8.30(s,1H) ,7.79(dd,J=16.8,8.4Hz,1H),7.76(s,1H),7.54-7.48(m,1H),7.46-7.44(m, 1H),7.28(s,1H),7.08(d,J=8.0Hz,1H),6.56-6.54(m,1H),3.70(s,3H),3.14 (s,3H)3.07(s,3H),2.01-1.97(m,1H),1.01-0.97(m,2H),0.74-0.70(m,2H).

[0640] Example 15

[0641] 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((4-fluorophenyl)amino)-N-methoxynicotinamide

[0642]

[0643] Step 1: 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (15-e, 100 mg, 0.24 mmol), 4-fluoroaniline (31.5 mg, 0.28 mmol), cesium carbonate (230 mg, 0.71 mmol), XantPhos (27.3 mg, 0.047 mmol), and Pd2(dba)3 (23.08 mg, 0.023 mmol) were added. Added to anhydrous dioxane (5 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-6-((4-fluorophenyl)amino)-N-methoxynicotinamide (15, 40 mg, 0.08 mmol, 33.3% yield). MS Calcd: 499.17; MS Found: 500.16 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.60(s,1H),9.67(s,1H),9.04(s,1H),8.22(s,1H),7.59-7.57(m,2H),7.37(d,J=8.4Hz,1H),7.27(d,J=2.0 Hz,1H),7.12-7.05(m,3H),6.28(s,1H),3.77(s,3H),3.14(s,3H)3.10(s,3H),2.01-1.97(m,1H),1.01-0.97(m,2H),0.74-0.70(m,2H).

[0644] Example 16

[0645] 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxy-6-((5-methoxypyridin-2-yl)amino)nicotinamide

[0646]

[0647] Step 1: 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (12-e, 80 mg, 0.189 mmol), 5-methoxypyridine-2-amine (25.8 mg, 0.208 mmol), cesium carbonate (184.3 mg, 0.567 mmol), XantPhos (21.97 mg, 0.038 mmol), and Pd2(dba)3 (18.58 mg, 0.019 mmol) were added. Add ol) to anhydrous dioxane (5 ml) and evacuate under vacuum. Replace with nitrogen, heat to 120 °C, stir for 6 hours, filter, concentrate, and purify by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-methoxy-6-((5-methoxypyridin-2-yl)amino)nicotinamide (16, 25 mg, 0.049 mmol, 25.8% yield). MS Calcd: 512.18; MS Found: 513.22 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.61(s,1H),9.90(s,1H),9.51(s,1H),8.25(s,1H),7 .87(d,J=2.8Hz,1H), 7.56(d,J=8.8Hz,1H),7.47-7.44(m,2H),7.35(dd,J=8.8,2 .8Hz,1H),7.26(d,J=2.4Hz,1H),7.15-7.13(m,1H),3.77(s,3H),3.70(s,3H),3. 14(s,3H),3.10(s,3H),2.01-1.97(m,1H),1.01-0.97(m,2H),0.74-0.70(m,2H).

[0648] Example 17

[0649] 6-((4-fluorophenyl)amino)-N-methoxy-4-((2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide

[0650]

[0651] Step 1: Dissolve methanesulfonyl methylamine (0.48 g, 4.4 mmol) in 10 mL of N,N-dimethylformamide, add sodium hydrogen (0.24 g, 6 mmol) in portions, then heat the reaction solution to 55 °C and continue stirring for 2 hours. Add 2-chloro-3-nitropyridine (17-a, 0.632 g, 4.0 mmol), and continue stirring at this temperature for 2 hours. Monitor the reaction by TLC until it is complete. Add water (40 mL) to the reaction solution, extract with ethyl acetate (30 mL x 2), wash with saturated brine (30 mL x 2), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (EA:PE = 1:5) to obtain a pale yellow solid N-methyl-N-(3-nitropyridine-2-yl)methanesulfonamide (17-b, 572 mg, 2.48 mmol, 61.9% yield). MS Calcd:231.07;MS Found:230.20([MH] - ).

[0652] Step 2: N-methyl-N-(3-nitropyridin-2-yl)methanesulfonamide (17-b, 572 mg, 2.48 mmol), ammonium chloride (0.67 g, 12.4 mmol), and iron powder (0.42 g, 7.44 mmol) were added sequentially to 10 mL of a mixed solvent of water and ethanol (1:4), and stirred under reflux for 6 hours. The reaction was monitored by TLC until completion. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain a colorless oily substance, N-(3-aminopyridin-2-yl)-N-methylmethanesulfonamide (17-c, 0.41 g, 2.19 mmol, 88.4% yield). MS Calcd: 201.06; MS Found: 202.06 ([M+H] + ).

[0653] Step 3: N-(3-aminopyridin-2-yl)-N-methylmethanesulfonamide (17-c, 150 mg, 0.80 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 174.8 mg, 0.80 mmol) were added to 5 ml of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (2.4 ml, 2.4 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC until completion. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (20 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain 6-chloro-N-methoxy-4-((2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (17-d, 180 mg, 0.467 mmol, 58.4% yield). MS Calcd:385.06; MS Found:386.22([M+H] +Step 4: 6-Chloro-N-methoxy-4-((2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (17-d, 53 mg, 0.13 mmol), 4-fluoroaniline (18.4 mg, 0.16 mmol), cesium carbonate (135 mg, 0.41 mmol), XantPhos (16.2 mg, 0.028 mmol), and Pd2(dba)3 (13.7 mg, 0.014 mmol) were administered. The solution was added to anhydrous dioxane (5 ml) and the mixture was evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-((4-fluorophenyl)amino)-N-methoxy-4-((2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (17, 15 mg, 0.032 mmol, 25% yield). MS Calcd: 460.13; MS Found: 459.2 ([MH]) - ). 1 H NMR (400MHz, DMSO-d6): δ11.67(s,1H),9.99(s,1H),9.13(s,1H),8.27(s,1H),8.24(dd,J=8.4,1.6Hz,1H), 8.02(dd,J=7.2,1.6 Hz,1H),7.61-7.57(m,2H),7.48(dd,J=8.4,4.8Hz,1H),7.12-7.09(m,2H),6.44(s,1H),3.71(s,3H),3.20(s,3H),3.15(s,3H).

[0654] Example 18

[0655] 4-((4-ethynyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxy-6-((5-methoxypyridin-2-yl)amino)nicotinamide

[0656]

[0657] Step 1: Dissolve methanesulfonyl methylamine (0.6 g, 5.5 mmol) in 10 mL of N,N-dimethylformamide, add sodium hydrogen (0.29 g, 7.5 mmol) in portions, then heat the reaction solution to 55 °C and continue stirring for 2 hours. Add 4-bromo-2-fluoro-1-nitrobenzene (18-a, 1.1 g, 5.0 mmol), and continue stirring at this temperature for 2 hours. Monitor the reaction by TLC until it is complete. Add water (40 mL) to the reaction solution, extract with ethyl acetate (30 mL x 2), wash with saturated brine (30 mL x 2), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (EA:PE = 1:5) to obtain a pale yellow solid N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (18-b, 1.6 g, 5.17 mmol, 94% yield). MS Calcd:307.95;MS Found:307.00([MH] - ).

[0658] Step 2: N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (18-b, 0.45 g, 1.46 mmol), ethynyltrimethylsilane (0.43 g, 4.38 mmol), cuprous iodide (23.04 mg, 0.15 mmol), and Pd(dppf)Cl2 (109.7 mg, 0.15 mmol) were sequentially added to 5 ml of triethylamine. The mixture was purged with nitrogen three times under vacuum and stirred at 60 °C for 4 hours. The reaction was monitored by TLC until completion. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE = 1:1) to obtain a yellow solid, N-methyl-N-(2-nitro-5-((trimethylsilyl)ethynyl)phenyl)methanesulfonamide (18-c, 0.375 g, 1.07 mmol, 73.2% yield). MSCalcd:326.08;MS Found:327.10([M+H] + ).

[0659] Step 3: N-methyl-N-(2-nitro-5-((trimethylsilyl)ethynyl)phenyl)methanesulfonamide (18-c, 0.3375 g, 1.07 mmol), ammonium chloride (0.322 g, 5.75 mmol), and iron powder (0.62 g, 11.1 mmol) were added sequentially to 10 mL of a mixed solvent of water and ethanol (1:4), and stirred under reflux for 6 hours. The reaction was monitored by TLC until completion. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain a colorless oily substance, N-(2-amino-5-((trimethylsilyl)ethynyl)phenyl)-N-methylmethanesulfonamide (18-d, 0.307 g, 1.03 mmol, 96.2% yield). MS Calcd: 296.09; MS Found: 297.22 ([M+H]+ ).

[0660] Step 4: N-(2-amino-5-((trimethylsilyl)ethynyl)phenyl)-N-methylmethanesulfonamide (18-d, 307 mg, 1.03 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 224.5 mg, 1.03 mmol) were added to 10 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (3.1 mL, 3.09 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC until completion. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (20 mL x 10 mL). 3) The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to give a brown oily substance, 6-chloro-4-((4-ethynyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-methoxynicotinamide (18-e, 197 mg, 0.48 mmol, 46.8% yield). MS Calcd: 408.10; MS Found: 409.29 ([M+H] + ).

[0661] Step 5: 6-chloro-4-((4-ethynyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-methoxynicotinamide (18-e, 100 mg, 0.245 mmol), 5-methoxypyridine-2-amine (33.43 mg, 0.27 mmol), cesium carbonate (239 mg, 0.74 mmol), XantPhos (28.9 mg, 0.05 mmol), and Pd2(dba)3 (24.45 mg, 0.025 mmol) were added. The solution was added to anhydrous dioxane (5 ml) and the mixture was evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-ethynyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxy-6-((5-methoxypyridin-2-yl)amino)nicotinamide (18, 10 mg, 0.02 mmol, 8.2% yield). MS Calcd: 496.15; MS Found: 497.20 ([M+H] + ). 1H NMR (400MHz, DMSO-d6): δ11.71(s,1H),10.32(s,1H),9.67(s,1H),8.31(s,1H),7.95(d,J=2.8Hz,1H),7.87(m,1H),7 .66-7.64(m,2H),7.59-7.54(m,2H),7.37(dd,J=8.8,2.8Hz,1H),4.23(s,1H),3.79(s,3H),3.71(s,3H),3.18(s,6H).

[0662] Example 19

[0663] 4-((4-ethynyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-(((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0664]

[0665] Step 1: Dissolve 6-chloro-4-((4-ethynyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (18-e, 90 mg, 0.22 mmol), 6-fluoropyridine-2-amine (27.13 mg, 0.24 mmol), cesium carbonate (215 mg, 0.66 mmol), XantPhos (25.4 mg, 0.04 mmol), and Pd2(dba)3 (21.5 mg, 0.022 mmol) in [the following concentrations]. Added to anhydrous dioxane (5 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-ethynyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-(((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (19, 5 mg, 0.01 mmol, 4.7% yield). MS Calcd: 484.13; MS Found: 485.20 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.78(s,1H),10.30(s,1H),10.08(s,1H),8.35(s,1H),7.84- 7.78(m,1H),7.70-7.66(m,1H),7.47-7.45(m,2H),7.40-7.29(m,2H),6.58(d,J=8.0Hz 1H),4.21(s,1H),3.71(s,3H),3.17(s,3H),3.16(s,3H).

[0666] Example 20

[0667] 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-ethoxy-6-((5-methoxypyridin-2-yl)amino)nicotinamide

[0668]

[0669] Step 1: N-(2-amino-5-cyclopropylphenyl)-N-methylmethanesulfonamide (18-b, 240 mg, 1.0 mmol) and 4,6-dichloro-N-ethoxynicotinamide (int-2, 234 mg, 1.0 mmol) were added to 10 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (3 mL, 3.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC until completion. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-ethoxynicotinamide (20-a, 325 mg, 0.74 mmol, 74.2% yield). MS Calcd:438;MS Found:439([M+H] + Step 2: 6-chloro-4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-ethoxynicotinamide (33169-c, 87 mg, 0.2 mmol), 5-methoxypyridine-2-amine (29.76 mg, 0.24 mmol), cesium carbonate (215 mg, 0.66 mmol), XantPhos (25.4 mg, 0.04 mmol), and Pd2(dba)3 (21.5 mg, 0.022 mmol) were added. l) Add to anhydrous dioxane (5 ml) and evacuate under vacuum, purge with nitrogen, heat to 120 °C, stir for 6 hours, filter, concentrate the filtrate, and purify by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-ethoxy-6-((5-methoxypyridin-2-yl)amino)nicotinamide (20, 20 mg, 0.038 mmol, 19% yield). MS Calcd: 526.20; MS Found: 527.20 ([M+H) + ).

[0670] 1H NMR (400MHz, DMSO-d6): δ9.86 (s, 1H), 9.50 (s, 1H), 8.27 (s, 1H), 7.87 (d, J = 3.2Hz, 1H ), 7.58(d,J=9.2Hz,1H),7.46-7.44(m,2H),7.36(dd,J=8.8,3.2Hz,1H),7.26(d,J=2 .0Hz,1H),7.14(d,J=8.4Hz,1H),3.93(q,J=7.2Hz,2H),3.77(s,3H),3.18–3.08(m,7 H), 2.01-1.95 (m, 1H), 1.227 (t, J = 7.2Hz, 3H), 1.01-0.96 (m, 2H), 0.74-0.70 (m, 2H).

[0671] Example 21

[0672] 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxynicotinamide

[0673]

[0674] Step 1: Add 6-chloro-4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-ethoxynicotinamide (20-a, 87 mg, 0.2 mmol), 2,6-dimethylpyrimidin-4-amine (29.7 mg, 0.24 mmol), cesium carbonate (215 mg, 0.66 mmol), XantPhos (25.4 mg, 0.04 mmol), and Pd2(dba)3 (21.5 mg, 0.022 mmol) to... The solution was added to anhydrous dioxane (5 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxynicotinamide (21, 25 mg, 0.047 mmol, 23.8% yield). MS Calcd: 525.20; MS Found: 526.20 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.59(s,1H),9.99(s,1H),9.85(s,1H),8.32(s,1H),7.82 (s,1H),7.45(d,J=8.4Hz,1H),7.31(d,J=2.4Hz,1H),7.11(dd,J=8.4,2.0Hz,1H),7 .04(s,1H),3.94(q,J=7.2Hz,2H),3.13(s,3H),3.09(s,3H),2.31(s,3H),2.26(s,3 H),1.98-1.94(m,1H),1.22(t,J=7.2Hz,3H),0.99-0.95(m,2H),0.72-0.698(m.2H).

[0675] Example 22

[0676] 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-ethoxy-6-((6-fluoropyridin-2-yl)amino)nicotinamide

[0677]

[0678] Step 1: Add 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-ethoxynicotinamide (20-a, 87 mg, 0.2 mmol), 6-fluoropyridine-2-amine (26.9 mg, 0.24 mmol), cesium carbonate (215 mg, 0.66 mmol), XantPhos (25.4 mg, 0.04 mmol), and Pd2(dba)3 (21.5 mg, 0.022 mmol) to... The solution was transferred to anhydrous dioxane (5 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-ethoxy-6-((6-fluoropyridin-2-yl)amino)nicotinamide (22, 20 mg, 0.039 mmol, 19.4% yield). MS Calcd: 514.18; MS Found: 515.20 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.10(s,1H),9.94(s,1H),9.85(s,1H),8.38(s,1H),7. 78(dd,J=16.4,8.4Hz,1H),7.51-7.44(m,3H),7.27(d,J=2.0Hz,1H),7.09-7.06(m ,1H),6.64(dd,J=8.0,2.8Hz,1H),3.93(q,J=7.2Hz,2H),3.13(s,3H),3.07(s,3H) ,1.96-1.94(m,1H),1.21(t,J=7.2Hz,3H),1.00-0.95(m,2H),0.72-0.698(m.2H).

[0679] Example 23

[0680]

[0681] 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-isopropoxynicotinamide Step 1: 1) Dissolve 4,6-dichloronicotinic acid (23-a, 288 mg, 1.5 mmol) in dichloromethane (10 ml) and add to a 50 ml two-necked flask. Cool the reaction solution to 0℃~5℃ using an ice-water bath. Add the catalytic amount of DMF (0.1 ml) dropwise, then slowly add oxaloyl chloride (229 mg, 1.8 mmol). Stir at room temperature for 30 min. TLC shows that the reaction is complete. Concentrate the reaction solution under reduced pressure at 40℃. Add dichloromethane (20 ml) to the concentrated crude product and concentrate again under reduced pressure.

[0682] 2) Isopropylamine hydrochloride (200.7 g, 1.8 mmol) was added to an ethyl acetate / water (40 ml) (5:1) solution, followed by potassium carbonate (828 mg, 6 mmol). The mixture was stirred at room temperature for 10 min. The crude product was dissolved in dichloromethane (5 ml) and added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction mixture was separated, the organic phase was concentrated, and column purification (petroleum ether / ethyl acetate = 2:1) was performed to obtain the product 4,6-dichloro-N-isopropoxynicotinamide (23-b, 350 mg, 1.42 mmol, 94.8% yield). MS Calcd: 248; MS Found: 249 ([M+H) + ).

[0683] Step 2: N-(2-amino-5-cyclopropylphenyl)-N-methylmethanesulfonamide (23-b, 120 mg, 0.5 mmol) and 4,6-dichloro-N-isopropoxynicotinamide (123 mg, 0.5 mmol) were added to 5 ml of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (1.5 ml, 1.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC until completion. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (20 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain a brown oily substance 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-isopropoxynicotinamide (23-c, 170 mg, 0.37 mmol, 75.2% yield). MS Calcd:452;MSFound:453([M+H] + ).

[0684] Step 3: Administer 6-chloro-4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-isopropoxynicotinamide (23-c, 71 mg, 0.16 mmol), 6-fluoropyridine-2-amine (21.18 mg, 0.19 mmol), cesium carbonate (153 mg, 0.47 mmol), XantPhos (18.5 mg, 0.03 mmol), and Pd2(dba)3 (15.2 mg, 0.015 mmol). Added to anhydrous dioxane (5 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-isopropoxynicotinamide (23, 15 mg, 0.028 mmol, 17.8% yield). MS Calcd: 528; MS Found: 529 ([M+H) +). 1H NMR (400MHz, DMSO-d6): δ11.10(s,1H),9.94(s,1H),9.85(s,1H),8.33(s,1H),7. 78(dd,J=16.4,8.4Hz,1H),7.50-7.47(m,3H),7.28(s,1H),7.08(dd,J=8.4,2.0Hz ,1H),6.55(dd,J=8.0,2.8Hz,1H),4.14(q,J=7.0Hz,1H),3.14(s,3H),3.07(s,3H ),1.98-1.96(m,1H),1.22(d,J=7.0Hz,6H),0.99-0.95(m,2H),0.72-0.69(m.2H).

[0685] Example 24

[0686] 4-((4-ethynyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-(((6-fluoropyridin-2-yl)amino)-N-isopropoxynicotinamide

[0687]

[0688] Step 1: N-(2-amino-5-((trimethylsilyl)ethynyl)phenyl)-N-methylmethanesulfonamide (226 mg, 0.76 mmol) and 4,6-dichloro-N-isopropoxynicotinamide (23-b, 187 mg, 0.76 mmol) were added to 5 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (2.3 mL, 2.28 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC until completion. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (20 mL x 10 mL). 3) The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain a brown oily substance 6-chloro-4-((4-ethynyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-isopropoxynicotinamide (24-a, 130 mg, 0.298 mmol, 39.2% yield).

[0689] MS Calcd:436.10; MS Found:437.29([M+H] + ).

[0690] Step 2: 6-Chloro-4-((4-ethynyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-isopropoxynicotinamide (24-a, 130 mg, 0.298 mmol), 6-fluoropyridine-2-amine (40.11 mg, 0.36 mmol), cesium carbonate (290.6 mg, 0.89 mmol), XantPhos (34.7 mg, 0.06 mmol), and Pd2(dba)3 (28.41 mg, 0.03 mmol) were added. Added to anhydrous dioxane (5 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-ethynyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-(((6-fluoropyridin-2-yl)amino)-N-isopropoxynicotinamide (24, 17.2 mg, 0.033 mmol, 11.2% yield). MS Calcd: 512.16; MS Found: 513.20 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.52(s,1H),10.24(s,1H),10.05(s,1H),8.35(s ,1H),7.82(dd,J=16.8,8.0Hz,1H),7.77(s,1H),7.68(d,J=8.4Hz,1H),7.6 6(d,J=2.0Hz,1H),7.48-7.46(m,2H),6.59(dd,J=8.0,2.4Hz,1H),4.23(s, 1H),4.17-4.11(m,1H),3.19(s,3H),3.17(s,3H),1.22(d,3H),1.21(s,3H).

[0691] Example 25

[0692] 6-((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide

[0693]

[0694] Step 1: 2-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline (203 mg, 1.0 mmol) and 4,6-dichloro-N-ethoxynicotinamide (int-2, 234 mg, 1.0 mmol) were added to 10 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (3 mL, 3.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC until completion. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain 6-chloro-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (25-a, 320 mg, 0.80 mmol, 80% yield). MS Calcd:401;MS Found:402([M+H] + ).

[0695] Step 2: 6-Chloro-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (25-a, 120 mg, 0.3 mmol), 2,6-dimethylpyrimidin-4-amine (40.59 mg, 0.33 mmol), cesium carbonate (292.5 mg, 0.9 mmol), XantPhos (34.68 mg, 0.06 mmol), and Pd2(dba)3 (27.47 mg, 0.03 mmol) were added. The solution was added to anhydrous dioxane (5 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (25, 6 mg, 0.012 mmol, 4% yield). MS Calcd: 488.23; MS Found: 489.20 ([M+H] + ). 1H NMR (400MHz, DMSO-d6): δ11.70(s,1H),10.23(s,1H),10.08(s,1H),8.38(s ,1H),8.17-8.16(m,2H),7.92(s,1H),7.44(dd,J=8.0,1.2Hz,1H),7.38(dd, J=8.0,1.6Hz,1H),7.19(t,J=8.0Hz,1H),7.07(s,1H),3.96(q,J=7.2Hz,2H) ,3.90(s,3H),3.61(s,3H),2.37(s,3H),2.27(s,3H),1.22(t,J=7.2Hz,3H).

[0696] Example 26

[0697] 6-(cyclopropylcarbamoyl)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide

[0698]

[0699] Step 1: 6-Chloro-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (25-a, 120 mg, 0.3 mmol), cyclopropylformamide (25.5 mg, 0.3 mmol), cesium carbonate (292.5 mg, 0.9 mmol), XantPhos (34.68 mg, 0.06 mmol), and Pd2(dba)3 (27.47 mg, 0.03 mmol) were administered. Added to anhydrous dioxane (5 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(cyclopropylcarbamoyl)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (26, 40 mg, 0.088 mmol, 29.5% yield). MS Calcd: 450.20; MS Found: 451.20 ([M+H] + ). 1H NMR (400MHz, DMSO-d6): δ11.76(s,1H),10.79(s,1H),10.14(s,1H),8.38(s,1H),8. 16(s,1H),8.06(s,1H),7.91(s,1H),7.36(dd,J=8.0,1.6Hz,1H),7.27(dd,J=8.0,1 .6Hz,1H),7.15(t,J=8.0Hz,1H),3.96(q,J=7.2Hz,2H),3.90(s,3H),3.58(s,3H),1 .98-1.97(m,1H),1.24-1.21(t,J=7.2Hz,3H),0.78-0.75(m,2H),0.64-0.58(m,2H).

[0700] Example 27

[0701] 6-((5-cyclopropylpyridin-2-yl)amino)-N-ethoxy-4-((2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide

[0702]

[0703] Step 1: N-(2-aminophenyl)-N-methylmethanesulfonamide (2-c, 201 mg, 1 mmol) and 4,6-dichloro-N-ethoxynicotinamide (int-2, 236 mg, 1 mmol) were added to 10 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (3 mL, 3 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was detected by TLC to be complete. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography to 6-chloro-N-ethoxy-4-((2-(N-methylmethanesulfonamide)phenyl)amino)nicotinamide (27-a, 380 mg, 0.76 mmol, 76% yield).

[0704] Step 2: Add 6-chloro-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (27-a, 92 mg, 0.185 mmol), 5-cyclopropylpyridine-2-amine (24.8 mg, 0.185 mmol, Tetrahedron Letters) 2017, 58, 1681), cesium carbonate (175.5 mg, 0.54 mmol), XantPhos (20.81 mg, 0.036 mmol), and Pd2(dba)3 (17.5 mg, 0.018 mmol) were added to anhydrous dioxane (5 mL) and the mixture was evacuated, purged with nitrogen, heated to 120 °C, stirred for 6 hours, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-((5-cyclopropylpyridin-2-yl)amino)-N-ethoxy-4-((2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide (27, 20 mg, 0.04 mmol, 21.7% yield). MS Calcd: 496.19.20; MS Found: 497.20 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6): δ11.57(s,1H),10.06(s,1H),9.65(s,1H),8.30(s,1H),8.00-7.99 (m,1H),7.73-7.68(m,1H),7.63(dd,J=8.4,1.6Hz,1H),7.55(d,J=8.0Hz,1H),7.48-7.44( m,2H),7.31(d,J=8.4Hz,1H),7.19(t,J=8.0Hz,1H),3.96(q,J=7.2Hz,2H),3.15(s,3H),3. 13(s,3H),1.89-1.83(m,1H),1.22(t,J=7.2Hz,3H),0.92-0.91(m,2H),0.65-0.61(m,2H).

[0705] Example 28

[0706] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((1-methyl-1H-indazol-6-yl)amino)nicotinamide

[0707]

[0708] Step 1: Add 1-methyl-6-amino-1H-indazole (28-a, 147 mg, 1 mmol), 4,6-dichloro-N-methoxynicotinamide (int-1, 218 mg, 1 mmol), and anhydrous tetrahydrofuran (5 mL) sequentially to a two-necked flask. Add a tetrahydrofuran solution of LiHMDS (3 mL, 1 mol / L) at room temperature and continue stirring at room temperature for 2 h. The reaction was monitored by TLC until complete, and the pH was adjusted to 5 with hydrochloric acid (1N). Extraction was performed with ethyl acetate (30 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography to obtain 6-chloro-N-methoxy-4-((1-methyl-1H-indazole-6-yl)amino)nicotinamide (28-b, 142 mg, 0.39 mmol, 43% yield). MS Calcd: 331; MS Found: 332 ([M+H) + ).

[0709] Step 2: 6-Chloro-N-methoxy-4-((1-methyl-1H-indazole-6-yl)amino)nicotinamide (28-b, 33 mg, 0.1 mmol), cyclopropylformamide (9.4 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added to anhydrous dioxane (5 ml). The mixture was purged with nitrogen three times, heated to 125 °C, stirred for 8 h, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 6-(cyclopropylformamido)-N-methoxy-4-((1-methyl-1H-indazole-6-yl)amino)nicotinamide (28, 12 mg, 0.032 mmol, 32% yield). MS Calcd:380; MS Found:381([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),10.74(s,1H),10.07(s,1H),8.37(s,1H),8.03(s,1H),8.00(d,J=1.2Hz,1H),7.75( d,J=8.4Hz,1H),7.52(s,1H),7.03(dd,J=8.4,2.0Hz,1H),3.99(s,3H),3.74(s,3H),1.99-1.93(m,1H),0.77–0.60(m,4H).

[0710] Example 29

[0711] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)nicotinamide

[0712]

[0713] Step 1: In a 100 mL single-necked flask, add 1-(2-hydroxy-3-nitrophenyl)ethyl-1-one (29-a, 1 g, 5.5 mmol), methyl iodoforme (1 g, 7 mmol), anhydrous potassium carbonate (1 g, 7.2 mmol), and N,N-dimethylformamide (5 mL) sequentially, and stir at room temperature. After the reaction is complete as determined by TLC, dilute the mother liquor with 20 mL of water, extract three times with ethyl acetate, combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain 1-(2-methoxy-3-nitrophenyl)ethyl-1-one (29-b, 1.03 g, 5.28 mmol, 96% yield). MS Calcd: 195; MS Found: 196 ([M+H) + ).

[0714] Step 2: Take 1-(2-methoxy-3-nitrophenyl)ethyl-1-one (29-b, 1.03 g, 5.28 mmol) into a single-necked flask, add 2 mL of DMF-DMA, stir at 90°C, and after TLC detection of complete reaction, directly remove DMF-DMA by rotation to obtain 3-(dimethylamino)-1-(2-methoxy-3-nitrophenyl)prop-2-en-1-one (29-c). Use directly in the next step without purification, adding a small amount of ethanol for later use. MS Calcd: 250; MS Found: 251 ([M+H]) + ).

[0715] Step 3: Take 0.5 mL of hydrazine monohydrate in a single-necked flask, add 5 mL of ethanol and 1 mL of acetic acid under ice bath conditions, stir for 5 minutes, then add the prepared solution from Step 2 above. Stir at room temperature, and after the reaction is complete as detected by TLC, remove the solvent by evaporation, wash with a small amount of water, extract with ethyl acetate, combine the organic phases, wash with saturated sodium chloride, and dry on anhydrous sodium sulfate. Remove the solvent by evaporation to give 3-(2-methoxy-3-nitrophenyl)-1H-pyrazole (29-d, 1.07 g, 4.88 mmol, 92% yield). MS Calcd: 219; MS Found: 220 ([M+H] + ).

[0716] Step 4: 3-(2-methoxy-3-nitrophenyl)-1H-pyrazole (29-d, 1.05 g, 4.82 mmol) was placed in a single-necked flask, and N,N-dimethylformamide (5 mL), anhydrous potassium carbonate (2 g, 14.4 mmol), and iodomethane (2 g, 14.1 mmol) were added sequentially. The mixture was stirred at room temperature. After the reaction was confirmed to be complete by TLC, a small amount of water was added to the mother liquor, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride (30 mL x 3), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-pyrazole (29-e, 1.07 g, 4.59 mmol, 95% yield). MS Calcd: 233; MS Found: 234 ([M+H] + ).

[0717] Step 5: Take 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-pyrazole (29-e, 1.07 g, 4.59 mmol), add iron powder (1.8 g, 32 mmol), saturated ammonium chloride aqueous solution (6 mL), and methanol (6 mL) sequentially. After completion, heat to 100°C and stir. After the reaction is complete, filter the mother liquor with diatomaceous earth, extract the filtrate with ethyl acetate, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain 2-methoxy-3-(1-methyl-1H-pyrazole-3-yl)aniline (29-f, 580 mg, 2.86 mmol, 62% yield). MS Calcd: 203; MS Found: 204 ([M+H] + ).

[0718] Step 6: Add 2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)aniline (29-f, 203 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (218 mg, 1 mmol) sequentially to a two-necked flask. Add 5 mL of anhydrous tetrahydrofuran as solvent, and add a tetrahydrofuran solution of LiHMDS (3 mL, 1 mol / L) at room temperature. Continue stirring at room temperature for 2 h. The reaction was checked by TLC until complete. Adjust the pH to 5 with hydrochloric acid (1N) and extract with ethyl acetate (30 mL x 3). Combine the organic layers, dry and concentrate, and purify by silica gel column chromatography to obtain 6-chloro-N-methoxy-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)nicotinamide (29-g, 138 mg, 0.36 mmol, 36% yield). MS Calcd: 387; MS Found: 388 ([M+H) + ).

[0719] Step 7: Add 6-chloro-N-methoxy-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)nicotinamide (29-g, 39 mg, 0.1 mmol), cyclopropylformamide (9.4 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) to the solution. Added to anhydrous dioxane (5 ml), purged three times with nitrogen, heated to 120 °C and stirred for 8 h, filtered, the filtrate was concentrated, and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 6-(cyclopropylcarbamate)-N-methoxy-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)nicotinamide (29, 14 mg, 0.033 mmol, 32% yield). MS Calcd: 436; MS Found: 437 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),10.82(s,1H),10.17(s,1H),8.37(s,1H),8.08(s,1H),7.78(d,J=2.4Hz,1H),7.61(dd,J=8.0,1.6Hz,1H),7.3 6(dd,J=8.0,1.6Hz,1H),7.18(t,J=8.0Hz,1H),6.72(d,J=2.4Hz,1H),3.9 1(s,3H),3.73(s,3H),3.59(s,3H),2.01–1.93(m,1H),0.81–0.75(m,4H).

[0720] Example 30

[0721] 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)nicotinamide

[0722]

[0723] Step 1: Add 6-chloro-N-methoxy-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)nicotinamide (29-g, 38.7 mg, 0.1 mmol), 6-fluoropyridine-2-amine (12.2 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) to... Add to anhydrous dioxane (5 ml), purge three times with nitrogen, heat to 120 °C and stir for 8 h, filter, concentrate the filtrate, and purify by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 6-(((6-fluoropyridin-2-yl)amino)-N-methoxy-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)nicotinamide (30, 11.8 mg, 0.025 mmol, 25% yield). MS Calcd: 463; MS Found: 464 ([M+H) + ). 1 H NMR(400MHz,DMSO-d6)δ11.81(s,1H),10.27(s,1H),10.07(s,1H),8.36(s,1H), 7.86–7.79(m,2H),7.78(d,J=2.4Hz,1H),7.60(dd,J=8.0,1.6Hz,1H),7.56(dd, J=8.0,1.6Hz,1H),7.49(dd,J=8.0,2.4Hz,1H),7.19(t,J=8.0Hz,1H),6.74(d,J =2.4Hz, 1H), 6.58 (dd, J = 7.8, 2.4Hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H), 3.62 (s, 3H).

[0724] Example 31

[0725] 4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropylcarbamoyl)-N-methoxynicotinamide

[0726]

[0727] Step 1: In a 100 mL single-necked flask, methyl 2-hydroxy-3-nitrobenzene (31-a, 3 g, 15 mmol), methyl iodoforme (2.8 g, 20 mmol), anhydrous potassium carbonate (3 g, 21.7 mmol), and N,N-dimethylformamide (5 mL) were added sequentially and stirred at room temperature. After the reaction was complete as determined by TLC, the mother liquor was diluted with water (20 mL), extracted three times with ethyl acetate (30 mL x 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give methyl 2-methoxy-3-nitrobenzene (31-b, 2.9 g, 13.7 mmol, 91.3% yield). MS Calcd: 211; MS Found: 212 ([M+H) + ).

[0728] Step 2: 2-Methoxy-3-nitrobenzoate (31-b, 2.9 g, 13.7 mmol) was added sequentially, followed by 10 mL of methanol, 2 mL of water, and sodium hydroxide (2 g, 40 mmol). The mixture was stirred at room temperature. After the reaction was complete as detected by TLC, a small amount of water was added to the mother liquor. The pH was adjusted to 5 with hydrochloric acid (1N), resulting in the precipitation of a large amount of solid. This solid was filtered and dried to obtain 2-methoxy-3-nitrobenzoic acid (31-c, 2.55 g, 12.9 mmol, 94.5% yield). MS Calcd: 197; MS Found: 198 ([M+H) + ).

[0729] Step 3; Take 2-methoxy-3-nitrobenzoic acid (31-b, 2.55 g, 12.9 mmol), add N,N-dimethylformamide (10 mL), and after complete dissolution, add tert-butyl hydrazide carboxylate (2.6 g, 20 mmol) and HATU (7.6 g, 20 mmol). Stir overnight at 45°C. After the reaction is complete as detected by TLC, wash with a small amount of water, extract with ethyl acetate, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and purify by column chromatography on silica gel to obtain tert-butyl 2-(2-methoxy-3-nitrobenzoyl)hydrazide-1-carboxylate (31-d, 2.31 g, 7.43 mmol, 57.6% yield). MS Calcd: 311; MS Found: 312 ([M+H) + ).

[0730] Step 4: Take 2-(2-methoxy-3-nitrobenzoyl)hydrazine-1-carboxylic acid tert-butyl ester (31-d, 2.3 g, 7.43 mmol), add dichloromethane (6 mL), and add trifluoroacetic acid (3 mL) dropwise under ice bath conditions. Heat to room temperature and stir. After the reaction is complete as detected by TLC, directly remove the solvent by rotary evaporation to obtain 2-methoxy-3-nitrobenzohydrazine (31-e, 1.56 g, 7.4 mmol, 99% yield). MS Calcd: 211; MS Found: 212 ([M+H] + ).

[0731] Step 5: Take 2-methoxy-3-nitrobenzohydrazine (31-e, 0.63 g, 3 mmol), add trimethyl orthoformate (3 mL), heat to 105 °C under nitrogen protection and stir. After the reaction is complete as detected by TLC, remove the solvent by rotary evaporation, wash with a small amount of water (30 mL x 3), extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated sodium chloride (30 mL x 3), and dry with anhydrous sodium sulfate to obtain 2-(2-methoxy-3-nitrophenyl)-1,3,4-oxadiazole (31-f, 521 mg, 2.36 mmol, 78.7% yield). MS Calcd: 221; MS Found: 222 ([M+H) + ).

[0732] Step 6: Take 2-(2-methoxy-3-nitrophenyl)-1,3,4-oxadiazole (31-f, 300 mg, 1.35 mmol), add palladium on carbon (20 mg) and 5 mL of methanol, and react at room temperature under hydrogen protection. After the reaction is complete, filter the mother liquor and remove the filtrate by rotary evaporation to obtain 2-methoxy-3-(1,3,4-oxadiazole-2-yl)aniline (31-g, 223 mg, 1.16 mmol, 86% yield). MS Calcd: 191; MS Found: 192 ([M+H) + Step 7: Add 2-methoxy-3-(1,3,4-oxadiazol-2-yl)aniline (31 g, 191 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 218 mg, 1 mmol) sequentially to a two-necked flask. Add 5 ml of anhydrous tetrahydrofuran as solvent, and add a tetrahydrofuran solution of LiHMDS (3 ml, 3 mmol) at room temperature. Continue stirring at room temperature for 2 h. The reaction was checked by TLC until complete. Adjust the pH to 5 with hydrochloric acid (1N) and extract with ethyl acetate (30 ml x 3). Combine the organic layers, dry and concentrate, and purify by silica gel column chromatography to obtain 6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-methoxynicotinamide (31 g, 156 mg, 0.47 mmol, 47% yield). MS Calcd: 332; MS Found: 333 ([M+H)+ ).

[0733] Step 8: 6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-methoxynicotinamide (31-h, 33 mg, 0.1 mmol), cyclopropaneformamide (9.4 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added to anhydrous dioxane (5 ml), purged with nitrogen three times, heated to 120 °C and stirred for 8 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropaneformamido)-N-methoxynicotinamide (31, 8 mg, 0.021 mmol, 21% yield). MS Calcd:381;MS Found:382([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),10.88(s,1H),10.19(s,1H),8.40(s,1H),7.96(s,1H),7.75(dd,J=8.0,1.6Hz,1 H),7.54(dd,J=7.8,1.6Hz,1H),7.33(t,J=8.0Hz,1H),3.91(s,3H),3.73(s,3H),2.05–1.91(m,1H),0.81–0.73(m,4H).

[0734] Example 32

[0735] 6-(cyclopropylcarbamoyl)-4-((3-fluoro-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide

[0736]

[0737] Step 1: Dissolve 1,2-difluoro-3-nitrobenzene (32-a, 0.48 g, 3 mmol) in acetonitrile (10 ml), then add cesium carbonate (2.98 g, 9 mmol) and N-methylmethanesulfonamide (0.36 g, 3.3 mmol) sequentially to a reaction flask. Stir the reaction overnight at room temperature. TLC was used to confirm the reaction was complete. The mother liquor was washed with water (30 ml x 3) and saturated sodium chloride (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) yielded N-(2-fluoro-6-nitrophenyl)-N-methylmethanesulfonamide (32-b, 0.42 g, 1.69 mmol, 56.6% yield). MS Calcd: 248; MS Found: 249 ([M+H) + ).

[0738] Step 2: N-(2-fluoro-6-nitrophenyl)-N-methylmethanesulfonamide (32-b, 420 mg, 1.69 mmol) and palladium on carbon (15 mg) were added to methanol (5 ml). After purging with hydrogen three times, the mixture was stirred overnight at room temperature. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain N-(2-amino-6-fluorophenyl)-N-methylmethanesulfonamide (32-c, 288 mg, 1.32 mmol, 78% yield). MS Calcd: 218; MS Found: 219 ([M+H) + ).

[0739] Step 3: N-(2-amino-6-fluorophenyl)-N-methylmethanesulfonamide (32-c, 218 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (218 mg, 1 mmol) were added to anhydrous tetrahydrofuran (5 ml). A tetrahydrofuran solution of LiHMDS (3 ml, 3 mmol) was slowly added at room temperature, and the mixture was stirred for 2 h at room temperature. The reaction was monitored by TLC until complete. The pH was adjusted to 5 with hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate (30 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography to obtain 6-chloro-4-((3-fluoro-2-(N-methylmethanesulfonamido)phenyl)amino)-N-methoxynicotinamide (32-d, 185 mg, 0.46 mmol, 46% yield). MS Calcd: 402; MS Found: 403 ([M+H) + ).

[0740] Step 4: 6-chloro-4-((3-fluoro-2-(N-methylmethylsulfonamido)phenyl)amino)-N-methoxynicotinamide (32-d, 40 mg, 0.1 mmol), cyclopropylformamide (9.4 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added to anhydrous dioxane (5 ml), purged with nitrogen three times, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography to obtain the title compound: (cyclopropylformamido)-4-((3-fluoro-2-(N-methylmethylsulfonamido)phenyl)amino)-N-methoxynicotinamide (32, 16 mg, 0.36 mmol, 36% yield). MS Calcd:451; MS Found:452([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.87(s,1H),10.17(s,1H),8.40(s,1H),8.38(s,1H),8.24–8.23(m,1H),8 .05–8.03(m,1H),7.36–7.31(m,1H),3.72(s,3H),3.16(s,3H),3.14(s,3H),2.06–1.90(m,1H),0.82–0.73(m,4H).

[0741] Example 33

[0742] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((3-methyl-2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide

[0743]

[0744] Step 1: Dissolve 2-fluoro-1-methyl-3-nitrobenzene (33-a, 0.46 mg, 3 mmol) in acetonitrile (10 ml), then add cesium carbonate (2.97 g, 9 mmol) and N-methylmethanesulfonamide (0.36 g, 3.3 mmol) sequentially to a reaction flask. Stir the reaction overnight at room temperature. TLC was used to confirm the reaction was complete. The mother liquor was washed with water (30 ml x 3) and saturated sodium chloride (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) yielded N-methyl-N-(2-methyl-6-nitrophenyl)methanesulfonamide (33-b, 399 mg, 1.63 mmol, 54% yield). MS Calcd: 244; MS Found: 245 ([M+H) +).

[0745] Step 2: N-methyl-N-(2-methyl-6-nitrophenyl)methanesulfonamide (33-b, 399 mg, 1.63 mmol) and palladium on carbon (15 mg) were added to methanol (5 ml). After purging with hydrogen three times, the mixture was stirred overnight at room temperature. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain N-(2-amino-6-methylphenyl)-N-methylmethanesulfonamide (33-c, 280 mg, 1.30 mmol, 80% yield). MS Calcd: 214; MS Found: 215 ([M+H] + ).

[0746] Step 3: N-(2-amino-6-methylphenyl)-N-methylmethanesulfonamide (33-c, 214 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (218 mg, 1 mmol) were added to anhydrous tetrahydrofuran (5 ml). A tetrahydrofuran solution of LiHMDS (3 ml, 1 mol / L) was slowly added at room temperature, and the mixture was stirred for 2 h at room temperature. The reaction was monitored by TLC until complete. The pH was adjusted to 5 with hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate (30 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography to obtain 6-chloro-N-methoxy-4-((3-methyl-2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide (33-d, 128 mg, 0.32 mmol, 32% yield). MS Calcd: 398; S Found: 399 ([M+H) + ).

[0747] Step 4: 6-chloro-N-methoxy-4-((3-methyl-2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide (33-d, 40 mg, 0.1 mmol), cyclopropaneformamide (9.4 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added to anhydrous dioxane (5 ml), purged with nitrogen three times, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography to obtain 6-(cyclopropaneformamido)-N-methoxy-4-((3-methyl-2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide (33, 6 mg, 0.013 mmol, 13% yield). MS Calcd:447;MS Found:448([M+H] + ). 1H NMR(400MHz,DMSO-d6)δ11.89(s,1H),10.80(s,1H),9.97(s,1H),8.36(s,1H),7.90(s,1H),7.32–7.27(m,2H) ,7.15–7.09(m,1H),3.73(s,3H),3.13(s,3H),3.07(s,3H),2.35(s,3H),2.06–1.90(m,1H),0.78–0.72(m,4H).

[0748] Example 34

[0749] 6-(cyclopropylcarbamoyl)-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-N-methoxynicotinamide

[0750]

[0751] Step 1: 2-Amino-N,N-dimethylbenzenesulfonamide (34-a, 200 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 218 mg, 1 mmol) were added to 5 mL of anhydrous tetrahydrofuran. A tetrahydrofuran solution of LiHMDS (3 mL, 1 mol / L) was slowly added at room temperature, and the mixture was stirred for 2 h at room temperature. The reaction was monitored by TLC until complete. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography to obtain 6-chloro-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-N-methoxynicotinamide (34-b, 178 mg, 0.46 mmol, 46% yield). MS Calcd: 384; MS Found: 385 ([M+H) + ).

[0752] Step 2: 6-chloro-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-N-methoxynicotinamide (34-b, 38 mg, 0.1 mmol), cyclopropylformamide (9.4 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added to anhydrous dioxane (5 ml), purged with nitrogen three times, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography to obtain the title compound: (cyclopropylformamide)-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-N-methoxynicotinamide (34-b, 7 mg, 0.016 mmol, 16% yield). MS Calcd:433;MS Found:434([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),10.87(s,1H),10.27(s,1H),8.38(s,1H),7.97(s,1H),7.84(dd,J=8.0,1. 6Hz,1H),7.70–7.60(m,2H),7.37–7.30(m,1H),3.72(s,3H),2.62(s,6H),2.00–1.92(m,1H),0.79–0.73(m,4H).

[0753] Example 35

[0754] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide

[0755]

[0756] Step 1: Dissolve 2-chloro-3-nitropyridine (35-a, 0.474 g, 3 mmol) in acetonitrile (10 ml), then add cesium carbonate (2.97 g, 9 mmol) and N-methylmethanesulfonamide (0.36 g, 3.3 mmol) sequentially to a reaction flask. Stir the reaction overnight at room temperature. TLC was used to confirm the reaction was complete. The mother liquor was washed with water (30 ml x 3) and saturated sodium chloride (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) yielded N-methyl-N-(3-nitropyridine-2-yl)methanesulfonamide (35-b, 366 mg, 1.58 mmol, 53% yield). MS Calcd: 231; MS Found: 232 ([M+H) + ).

[0757] Step 2: N-methyl-N-(3-nitropyridin-2-yl)methanesulfonamide (35-b, 366 mg, 1.58 mmol) and palladium on carbon (15 mg) were added to methanol (5 ml). After purging with hydrogen three times, the mixture was stirred overnight at room temperature. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain N-(3-aminopyridin-2-yl)-N-methylmethanesulfonamide (35-c, 274 mg, 1.37 mmol, 86% yield). MS Calcd: 201; MS Found: 202 ([M+H) + ).

[0758] Step 3: N-(3-aminopyridin-2-yl)-N-methylmethanesulfonamide (35-c, 201 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (218 mg, 1 mmol) were added to anhydrous tetrahydrofuran (5 ml). A tetrahydrofuran solution of LiHMDS (3 ml, 1 mol / L) was slowly added at room temperature, and the mixture was stirred for 2 h at room temperature. The reaction was monitored by TLC until complete. The pH was adjusted to 5 with hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate (30 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography to obtain 6-chloro-N-methoxy-4-((2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (35-d, 172 mg, 0.45 mmol, 45% yield). MS Calcd: 385; MS Found: 386 ([M+H) + ).

[0759] Step 4: 6-chloro-N-methoxy-4-((2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (35-d, 39 mg, 0.1 mmol), cyclopropylformamide (9.4 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added to anhydrous dioxane (5 ml), purged with nitrogen three times, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography to obtain the title compound: 6-(cyclopropylformamido)-N-methoxy-4-((2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (35, 13 mg, 0.029 mmol, 29% yield). MS Calcd:434;MS Found:435([M+H] + ). 1H NMR (400MHz, DMSO-d6) δ11.85(s,1H),10.86(s,1H),10.15(s,1H),8.39(s,1H),8.26(dd,J=4.8,1.6Hz,1H),7.98–7.95(m, 1H),7.95(s,1H),7.48(dd,J=8.0,1.6Hz,1H),3.73(s,3H),3.18(s,3H),3.14(s,3H),2.01–1.92(m,1H),0.82–0.74(m,4H).

[0760] Example 36

[0761] 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide

[0762]

[0763] Step 1: 6-Chloro-N-methoxy-4-((2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (35-d, 39 mg, 0.1 mmol), 6-fluoropyridin-2-amine (13.2 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.0 mmol) were added. 1 mmol) was added to anhydrous dioxane (5 ml), purged three times with nitrogen, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (HPLC) to obtain the title compound: 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (36, 15 mg, 0.032 mmol, 32% yield). MS Calcd: 461; MS Found: 462 ([M+H) + ). 1 HNMR (400MHz, DMSO-d6) δ11.79(s,1H),10.23(s,1H),10.09(s,1H),8.37(s,1H),8.25(dd,J=4.6,1.6Hz,1H),8.13(d,J= 8.4Hz,1H),7.86–7.77(m,1H),7.70(s,1H),7.49–7.44(m,2H),6.61–6.56(m,1H),3.73(s,3H),3.21(s,3H),3.16(s,3H).

[0764] Example 37

[0765] 4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0766]

[0767] Step 1: 6-chloro-4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-N-methoxynicotinamide (34-b, 39 mg, 0.1 mmol), 6-fluoropyridine-2-amine (13.2 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.02 mmol) were added. 0.01 mmol) was added to anhydrous dioxane (5 ml), purged with nitrogen three times, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography to obtain the title compound: 4-((2-(N,N-dimethylaminosulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (37, 13 mg, 0.028 mmol, 28% yield). MS Calcd: 460; MS Found: 461 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.75(s,1H),10.24(s,1H),10.03(s,1H),8.35(s,1H),7.88–7.84(m,1H),7.84–7.78(m,1H),7.78–7.73(m,1 H),7.73–7.65(m,1H),7.63(s,1H),7.47–7.43(m,1H),7.39–7.31(m,1H),6.55(dd,J=7.8,2.4Hz,1H),3.72(s,3H),2.65–2.61(s,6H).

[0768] Example 38

[0769] 4-((3-fluoro-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0770]

[0771] Step 1: 6-chloro-4-((3-fluoro-2-(N-methylmethylsulfonamido)phenyl)amino)-N-methoxynicotinamide (32-d, 40 mg, 0.1 mmol), 6-fluoropyridine-2-amine (13.2 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.1 mmol) were added. 0.01 mmol) was added to anhydrous dioxane (5 ml), purged with nitrogen three times, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography to obtain the title compound: 4-((3-fluoro-2-(N-methylmethylsulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (38, 18 mg, 0.037 mmol, 37% yield). MS Calcd: 478; MS Found: 479 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),10.25(s,1H),10.11(s,1H),8.37(s,1H),7.86–7.78(m,1H),7.77(s,1H),7.52(d,J =8.4Hz,1H),7.49–7.41(m,2H),7.09(t,J=9.2Hz,1H),6.59(dd,J=8.0,2.4Hz,1H),3.73(s,3H),3.19(s,3H),3.16(s,3H).

[0772] Example 39

[0773] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((2-(oxecyclobut-3-yloxy)phenyl)amino)nicotinamide

[0774]

[0775] Step 1: Dissolve 1-fluoro-2-nitrobenzene (39-a, 0.42 g, 3 mmol) in acetonitrile (10 ml), then add cesium carbonate (2.97 g, 9 mmol) and oxetane-3-ylmethanol (0.3 g, 3.3 mmol) sequentially to a reaction flask. Stir the reaction overnight at room temperature. TLC was used to confirm the reaction was complete. The mother liquor was washed with water (30 ml x 3) and saturated sodium chloride (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) yielded 3-(2-nitrophenoxy)oxetane (39-b, 341 mg, 1.74 mmol, 58% yield). MS Calcd: 195; MS Found: 196 ([M+H) + ).

[0776] Step 2: 3-(2-nitrophenoxy)oxetane (39-b, 341 mg, 1.74 mmol) and palladium on carbon (15 mg) were added to methanol (5 ml). After purging with hydrogen three times, the mixture was stirred overnight at room temperature. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(oxetanebut-3-yloxy)aniline (39-c, 247 mg, 1.49 mmol, 50% yield). MS Calcd: 165; MS Found: 166 ([M+H]) + ).

[0777] Step 3: 2-(oxetane-3-yloxy)aniline (39-c, 165 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (218 mg, 1 mmol) were added to anhydrous tetrahydrofuran (5 ml). A tetrahydrofuran solution of LiHMDS (3 ml, 1 mol / L) was slowly added at room temperature, and the mixture was stirred for 2 h at room temperature. The reaction was monitored by TLC until complete. The pH was adjusted to 5 with hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate (30 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography to obtain 6-chloro-N-methoxy-4-((2-(oxetane-3-yloxy)phenyl)amino)nicotinamide (39-d, 135 mg, 0.39 mmol, 39% yield). MS Calcd: 349; MS Found: 350 ([M+H) + ).

[0778] Step 4: 6-chloro-N-methoxy-4-((2-(oxecyclobut-3-yloxy)phenyl)amino)nicotinamide (39-d, 35 mg, 0.1 mmol), cyclopropylformamide (9.4 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added to anhydrous dioxane (5 ml), purged with nitrogen three times, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography to obtain the title compound: 6-(cyclopropylformamido)-N-methoxy-4-((2-(oxecyclobut-3-yloxy)phenyl)amino)nicotinamide (39, 13 mg, 0.032 mmol, 32% yield). MS Calcd:398;MS Found:399([M+H] + ). 1 H NMR(400MHz,Chloroform-d)δ10.00(s,1H),8.84(s,1H),8.31(s,1H),7.98(s,1H),7.48–7.42(m,1H),7.10–7.02(m,2H),6. 52–6.44(m,1H),5.26–5.17(m,1H),4.98–4.89(m,2H),4.84–4.75(m,2H),3.92(s,3H),1.46–1.38(m,1H),0.92–0.72(m,4H).

[0779] Example 40

[0780] 6-(((6-Fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(oxecyclobut-3-yloxy)phenyl)amino)nicotinamide

[0781]

[0782] Step 1: 6-Chloro-N-methoxy-4-((2-(oxecyclobut-3-yloxy)phenyl)amino)nicotinamide (39-d, 35 mg, 0.1 mmol), 6-fluoropyridine-2-amine (13.2 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added. mmol) was added to anhydrous dioxane (5 ml), purged three times with nitrogen, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography to obtain the title compound: 6-(((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-(oxecyclobut-3-yloxy)phenyl)amino)nicotinamide (40, 12 mg, 0.028 mmol, 28% yield). MS Calcd: 425; MS Found: 426 ([M+H) + ). 1 H NMR(400MHz,Chloroform-d)δ10.07(s,1H),8.36(s,1H),7.84–7.71(m,1H),7.71–7.62(m,1H),7.62–7.51(m,1H),7.17–7.09(m,2H),7 .09–6.99(m,1H),6.56–6.47(m,1H),6.44(dd,J=8.0,2.4Hz,1H),5.28–5.20(m,1H),5.00–4.90(m,2H),4.87–4.74(m,2H),3.93(s,3H).

[0783] Example 41

[0784] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide

[0785]

[0786] Step 1: 2-Bromo-6-nitrophenol (41-a, 1.09 g, 5 mmol), pyrazole (0.68 g, 10 mmol), cuprous iodide (0.095 g, 0.5 mmol), L-proline (0.115 g, 1 mmol), anhydrous potassium carbonate (1.38 g, 10 mmol), and DMSO (10 mL) were placed in a 50 mL single-necked flask. The mixture was heated to 100 °C and stirred for approximately 20 h. TLC analysis showed the reaction was nearly complete. The mother liquor was filtered through diatomaceous earth. The filtrate was adjusted to pH 4 with 1 N hydrochloric acid, resulting in the precipitation of a large amount of solid. Filtering yielded 2-nitro-6-(1H-pyrazole-1-yl)phenol (41-b, 460 mg, 2.24 mmol, 49% yield). MS Calcd: 205; MS Found: 206 ([M+H) + ).

[0787] Step 2: In a 100 mL single-necked flask, 2-nitro-6-(1H-pyrazol-1-yl)phenol (41-b, 460 mg, 2.24 mmol), iodomethane (0.416 g, 3 mmol), anhydrous potassium carbonate (0.618 g, 4.448 mmol), and N,N-dimethylformamide (5 mL) were added sequentially and stirred at room temperature. After the reaction was complete as determined by TLC, the mother liquor was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined and washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give 1-(2-methoxy-3-nitrophenyl)-1H-pyrazol (41-c, 455 mg, 2.07 mmol, 93% yield). MS Calcd: 219; MS Found: 220 ([M+H) + ).

[0788] Step 3: Take 1-(2-methoxy-3-nitrophenyl)-1H-pyrazole (41-c, 455 mg, 2.07 mmol), add iron powder (0.56 g, 10 mmol), saturated ammonium chloride aqueous solution (6 mL), and methanol (6 mL). After the reaction is complete, heat to 100°C and stir. After the reaction is complete, filter the mother liquor with diatomaceous earth. Extract the filtrate with ethyl acetate (20 mL x 3). Combine the organic phases, wash with saturated sodium chloride (20 mL x 3), dry with anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain 2-methoxy-3-(1H-pyrazole-1-yl)aniline (41-d, 204 mg, 1.08 mmol, 52% yield). MS Calcd: 189; MS Found: 190 ([M+H] + ).

[0789] Step 4: Add 2-methoxy-3-(1H-pyrazol-1-yl)aniline (41-d, 0.189 g, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (218 mg, 1 mmol) sequentially to a two-necked flask. Add 5 mL of anhydrous tetrahydrofuran as solvent, and add a tetrahydrofuran solution of LiHMDS (3 mL, 1 mol / L) at room temperature. Continue stirring at room temperature for 2 h. The reaction was checked by TLC until complete. Adjust the pH to 5 with hydrochloric acid (1N) and extract with ethyl acetate (30 mL x 3). Combine the organic layers, dry and concentrate, and purify by silica gel column chromatography to obtain 6-chloro-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide (41-e, 198 mg, 0.53 mmol, 53% yield). MS Calcd: 373; MS Found: 374 ([M+H) + ).

[0790] Step 5: Add 6-chloro-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide (41-e, 37.3 mg, 0.1 mmol), cyclopropylformamide (9.4 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) to the solution. mol) was added to anhydrous dioxane (5 ml), purged three times with nitrogen, heated to 120 °C and stirred for 8 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give 6-(cyclopropaneformamido)-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide (41, 12 mg, 0.028 mmol, 28% yield). MS Calcd: 422; MS Found: 423 ([M+H) + ). 1 H NMR(400MHz,Chloroform-d)δ10.28(s,1H),8.97(s,1H),8.37(s,1H),8.16(s,1H),8.08(d,J=2.4Hz,1H),7.73(d,J=1.6Hz,1 H),7.53–7.43(m,2H),7.35–7.26(m,1H),6.48–6.46(m,1H),3.92(s,3H),3.51(s,3H),1.46–1.37(m,1H),0.95–0.83(m,4H).

[0791] Example 42

[0792] 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide

[0793]

[0794] Step 1: Dissolve 6-chloro-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide (41-e, 37 mg, 0.1 mmol), 6-fluoropyridine-2-amine (13.2 mg, 0.11 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (15 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) in [the following solution]. Added to anhydrous dioxane (5 ml), purged three times with nitrogen, heated to 120 °C and stirred for 8 h, filtered, the filtrate was concentrated, and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)nicotinamide (42, 13 mg, 0.029 mmol, 29% yield). MS Calcd: 449; MS Found: 450 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),10.34(s,1H),10.11(s,1H),8.38(s,1H),8.23(d,J=2.4Hz,1H),7.87–7.79(m,2H),7.78–7.77(m,1 H),7.68–7.62(m,1H),7.54–7.47(m,1H),7.38(dd,J=8.0,1.6Hz,1H),7.29(t,J=8.0Hz,1H),6.62–6.54(m,2H),3.74(s,3H),3.47(s,3H).

[0795] Example 43

[0796] 6-((5-cyanopyridin-2-yl)amino)-N-methoxy-4-((2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide

[0797]

[0798] Step 1: Add 6-chloro-N-methoxy-4-((2-(N-methylmethanesulfonamido)phenyl)amino)nicotinamide (2-d, 117 mg, 0.3 mmol), 6-aminonicotinonitrile (42 mg, 0.35 mmol), cesium carbonate (390 mg, 3.6 mmol), XantPhos (29 mg, 0.06 mmol), and Pd2(dba)3 (54 mg, 0.06 mmol) to anhydrous dioxane. The solution was placed in a ring (5 ml) and evacuated, purged three times with nitrogen, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-((5-cyanopyridin-2-yl)amino)-N-methoxy-4-((2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide (43, 32 mg, 0.068 mmol, 20.5% yield). MS Calcd: 467; MS Found: 468 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),10.37(s,1H),10.09(s,1H),8.63–8.58(m,1H),8.35(s,1H),8.04(d,J=7.2Hz,1H),7.76(d,J=8.8Hz,1H) ,7.73(s,1H),7.62(d,J=8.0Hz,1H),7.57(d,J=8.0Hz,1H),7.50(t,J=7 .8Hz,1H),7.22(t,J=7.8Hz,1H),3.72(s,3H),3.16(s,3H),3.13(s,3H).

[0799] Example 44

[0800] 6-((5-fluoro-4-methylpyridin-2-yl)amino)-N-methoxy-4-((2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide

[0801]

[0802] Step 1: Add 6-chloro-N-methoxy-4-((2-(N-methylmethanesulfonamido)phenyl)amino)nicotinamide (2-d, 117 mg, 0.3 mmol), 5-fluoro-4-methylpyridin-2-amine (44 mg, 0.35 mmol), cesium carbonate (390 mg, 3.6 mmol), XantPhos (29 mg, 0.06 mmol), and Pd2(dba)3 (54 mg, 0.06 mmol) to anhydrous... The solution was placed in dioxane (5 ml) and evacuated, purged three times with nitrogen, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-((5-fluoro-4-methylpyridin-2-yl)amino)-N-methoxy-4-((2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide (44, 26 mg, 0.055 mmol, 16.5% yield). MS Calcd: 474; MS Found: 475 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),10.07(s,1H),9.71(s,1H),8.30(s,1H),8.03(s,1H),7.66–7.57(m,2H),7. 56–7.51(m,2H),7.46(t,J=7.8Hz,1H),7.18(t,J=7.8Hz,1H),3.71(s,3H),3.15(s,3H),3.13(s,3H),2.23(s,3H).

[0803] Example 45

[0804] 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-methoxy-4-((2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide

[0805]

[0806] Step 1: Add 6-chloro-N-methoxy-4-((2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide (2-d, 117 mg, 0.3 mmol), 2,6-dimethylpyrimidin-4-amine (43 mg, 0.35 mmol), cesium carbonate (390 mg, 1.2 mmol), XantPhos (29 mg, 0.06 mmol), and Pd2(dba)3 (54 mg, 0.06 mmol) to anhydrous dioxane. The solution was placed in a ring (5 ml) and evacuated, purged three times with nitrogen, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(((2,6-dimethylpyrimidin-4-yl)amino)-N-methoxy-4-((2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide (45, 20 mg, 0.042 mmol, 12.7% yield). MS Calcd: 471; MS Found: 472 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.75(s,1H),10.11(s,1H),10.05(s,1H),8.34(s,1H),8.00(s,1H),7.65(d,J=8.0Hz,1H),7.58(d,J=8.0H z,1H),7.45(t,J=7.8Hz,1H),7.23(t,J=7.8Hz,1H),7.06(s,1H),3.72(s,3H),3.16(s,3H),3.13(s,3H),2.35(s,3H),2.27(s,3H).

[0807] Example 46

[0808] 4-((4-chloro-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0809] Step 1: Dissolve 4-chloro-2-fluoro-1-nitrobenzene (46-a, 0.53 g, 3.00 mmol) in acetonitrile (30 ml) and add it to a 100 ml reaction flask. Then add cesium carbonate (2 g, 6.1 mmol) and N-methylmethanesulfonamide (0.56 g, 4 mmol) to the reaction flask. Stir the mixture overnight at room temperature. The reaction was monitored by TLC until complete. The reaction solution was washed with water (30 ml x 3) and saturated sodium chloride (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purification was achieved by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give the product N-(5-chloro-2-nitrophenyl)-N-methylmethanesulfonamide (46-b, 0.63 g, 81.1% yield). MS Calcd: 264; MS Found: 265 ([M+H) + Step 2: N-(5-chloro-2-nitrophenyl)-N-methylmethanesulfonamide (46-b, 600 mg, 2.3 mmol) and iron powder (672 mg, 12 mmol) were added to methanol (3 ml) and saturated ammonium chloride aqueous solution (3 ml). The mixture was refluxed at 100 °C and stirred for 8 h. After filtration, the filtrate was extracted with ethyl acetate (30 ml x 3). The organic layers were combined, dried, and concentrated under reduced pressure to obtain N-(2-amino-5-chlorophenyl)-N-methylmethanesulfonamide (46-c, 328 mg, 1.4 mmol, 60.9% yield). No purification was required; the reaction proceeded directly to the next step. MS Calcd: 234; MS Found: 235 ([M+H] + ).

[0810] Step 3: N-(2-amino-5-chlorophenyl)-N-methylmethanesulfonamide (46-c, 234 mg, 1 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 218 mg, 1 mmol) were added to 5 mL of tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (3 mL, 1 mol / L) was added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was confirmed to be complete by TLC. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography of 6-chloro-4-((4-chloro-2-((N-methylmethanesulfonamido)phenyl)amino)-N-methoxynicotinamide (46-d, 156 mg, 0.37 mmol, 37% yield). MS Calcd: 418; MS Found: 419 ([M+H) + ).

[0811] Step 4: Add 6-chloro-4-((4-chloro-2-((N-methylmethylsulfonamido)phenyl)amino)-N-methoxynicotinamide (46-d, 75 mg, 0.18 mmol), 5-fluoropyridine-2-amine (28 mg, 0.25 mmol), cesium carbonate (195 mg, 0.6 mmol), XantPhos (20 mg, 0.04 mmol), and Pd2(dba)3 (37 mg, 0.04 mmol) to anhydrous... The solution was placed in dioxane (5 ml) and evacuated, purged three times with nitrogen, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-chloro-2-(N-methylmethylsulfonamido)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (46, 20 mg, 0.04 mmol, 22.4% yield). MS Calcd: 494; MS Found: 495 ([M+H) + ). 1 H NMR(400MHz,DMSO-d6)δ11.75(s,1H),10.15(s,1H),9.85(s,1H),8.32(s,1H),8.24–8.19(m,1H),8.00(s,1H),7.88– 7.85(m,1H),7.83–7.79(m,1H),7.21(s,1H),7.12–7.08(m,1H),7.02(s,1H),3.71(s,3H),3.17(s,3H),3.13(s,3H).

[0812] Example 47

[0813] 4-((4-chloro-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0814]

[0815] Step 4: Add 6-chloro-4-((4-chloro-2-((N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (46-d, 75 mg, 0.18 mmol), 6-fluoropyridine-2-amine (28 mg, 0.25 mmol), cesium carbonate (195 mg, 0.6 mmol), XantPhos (20 mg, 0.04 mmol), and Pd2(dba)3 (37 mg, 0.04 mmol) to anhydrous dioxins. The solution was placed in an oxane ring (5 ml) under vacuum, purged three times with nitrogen, heated to 125 °C, stirred for 5 h, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-chloro-2-(N-methylmethylsulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (47, 13 mg, 0.026 mmol, 14.6% yield). MS Calcd: 494; MS Found: 495 ([M+H) + ). 1 H NMR(400MHz,DMSO-d6)δ11.80(s,1H),10.24(s,1H),10.09(s,1H),8.36(s,1H),7.85–7.74(m,2H),7.53 –7.36(m,3H),7.09(t,J=9.2Hz,1H),6.58(dd,J=9.2,2.4Hz,1H),3.73(s,3H),3.16(s,3H),3.13(s,3H).

[0816] Example 48

[0817] 4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-(cyclopropylcarbamoyl)-N-methoxynicotinamide

[0818]

[0819] Step 1: Dissolve 2-bromo-6-nitrobenzyl nitrile (48-a, 500 mg, 2.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (458 mg, 2.20 mmol), Pd(dppf)Cl2 (36 mg, 0.044 mmol), and sodium carbonate (700 mg, 6.60 mmol) in a mixed solvent of water and dioxane (2 mL / 8 mL), heat to 100 °C, and react for 3 h. The reaction solution was concentrated, 10 ml of water was added, and the mixture was extracted with ethyl acetate (10 ml ethyl acetate extraction). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 4:1) to give a yellow solid 2-(1-methyl-1H-pyrazol-4-yl)-6-nitrobenzyl nitrile (48-b, 421 mg, 1.85 mmol, 84% yield). MS Calcd: 228; MS Found: 229 ([M+H) + ).

[0820] Step 2: 2-(1-methyl-1H-pyrazol-4-yl)-6-nitrobenzyl nitrile (48-b, 400 mg, 1.75 mmol) and 40 mg palladium on carbon were added to methanol (20 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a gray oily product, 2-amino-6-(1-methyl-1H-pyrazol-4-yl)benzyl nitrile (48-c, 330 mg, 1.67 mmol, 90% yield). No purification was required; the product was directly used in the next reaction. MS Calcd: 198; MS Found: 199 ([M+H]) + ).

[0821] Step 3: 2-Amino-6-(1-methyl-1H-pyrazol-4-yl)benzyl nitrile (48-c, 200 mg, 1.01 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 223.2 mg, 1.01 mmol) were added to 5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (2 mL, 2.02 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL ethyl ester extract, the organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain a white solid 6-chloro-4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxynicotinamide (48-d, 120 °C g, 0.31 mmol, 30% yield). MS Calcd:382;MS Found:383([M+H] + ).

[0822] Step 4: Add 6-chloro-4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxynicotinamide (48-d, 50 mg, 0.13 mmol), cyclopropylformamide (22 mg, 0.26 mmol), cesium carbonate (127 mg, 0.39 mmol), XantPhos (30 mg, 0.04 mmol), and Pd2(dba)3 (24 mg, 0.026 mmol) to... The solution was added to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give a yellow solid 4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-(cyclopropanecarbamate)-N-methoxynicotinamide (48, 10 mg, 0.023 mmol, 18% yield). MS Calcd: 431; MS Found: 432 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.87(s,1H),10.89(s,1H),10.46(s,1H),8.44(s,1H),8.26(s,1H),7.95-7.95(m,2H),7.67( t,J=8.0Hz,1H),7.45-7.42(m,2H),3.92(s,3H),3.73(s,3H),1.98-1.95(m,1H),0.78-0.75(m,2H),0.65-0.62(m,2H).

[0823] Example 49

[0824] 4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0825]

[0826] Step 1: Add 6-chloro-4-((2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxynicotinamide (48-d, 50 mg, 0.13 mmol), 5-fluoropyridine-2-amine (29 mg, 0.26 mmol), cesium carbonate (127 mg, 0.39 mmol), XantPhos (30 mg, 0.04 mmol), and Pd2(dba)3 (24 mg, 0.026 mmol) to... The solution was placed in anhydrous dioxane (2 ml) under vacuum, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((2-cyano-3-(1-methyl-1H-pyrazole-4-yl)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (49, 13 mg, 0.028 mmol, 22% yield). MS Calcd: 458; MS Found: 459 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.85(s,1H),10.51(s,1H),9.94(s,1H),8.40(s,1H),8.28(s,1H),8.11(s,1H),7.96 (s,1H),7.75-7.64(m,4H),7.53-7.55(d,J=8.0Hz,1H),7.42-7.41(d,J=7.8Hz,1H),3.93(s,3H),3.73(s,3H).

[0827] Example 50

[0828] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide

[0829]

[0830] Step 1: 1-(2-hydroxy-3-nitrophenyl)ethyl-1-one (50-a, 2 g, 11 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (2.7 g, 11 mmol), and potassium carbonate (4.6 g, 33 mmol) were added to DMF (50 ml). The temperature was raised to 80 °C, and the mixture was stirred for 2 hours. After the reaction was complete as shown by TLC, the mixture was poured into 250 ml of water and extracted with ethyl acetate (100 ml of ethyl acetate was used to extract the organic layer). The extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown oily substance (50-b, 2.9 g, 10.4 mmol). 94% yield). Step 2: 1-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)ethyl-1-one (50-b, 2.9 g, 10.4 mmol) was added to DMF-DMA (20 ml), and the temperature was raised to 80 °C. After stirring for 30 minutes, TLC showed that the starting material had completely reacted. The mixture was then concentrated, and excess solvent was removed with toluene to obtain a brown oily substance, 2-(dimethylamino)-1-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)ethyl-1-one (50-c, 2.8 g, 8.7 mmol), which was used directly in the next step of the reaction.

[0831] Step 3: 2-(dimethylamino)-1-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)ethyl-1-one (50-c, 2.8 g, 8.7 mmol) was added to ethanol and cooled to 0°C. Then, hydrazine hydrate was added dropwise. After the addition was complete, the temperature was raised to 80°C and stirred for 1 hour. TLC showed that the reaction was complete. The mixture was then concentrated under reduced pressure and poured into DCM (50 ml). A solid precipitated. The mixture was filtered, and the filtrate was concentrated and purified by column chromatography (EA:PE = 2:1) to give a yellow oily product 3-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole (50-d, 700 mg, 2.32 mmol, 27% yield). MS Calcd: 301; MS Found: 302 ([M+H] + ).

[0832] Step 4: 3-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole (50-a, 700 mg, 2.32 mmol) and potassium carbonate (0.97 g, 6.96 mmol) were added to DMF (20 ml). Iodomethane (329 mg, 2.32 mmol) was added at room temperature and the mixture was stirred overnight. After the reaction was complete as shown by TLC, the mixture was poured into 30 ml of water and extracted with ethyl acetate (15 ml ethyl acetate). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (EA:PE = 1:2) to obtain 1-methyl-3-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole (50-e, 620 mg, 2.05 mmol, 88% yield). MS Calcd: 301; MS Found: 302 ([M+H] + ).

[0833] Step 5: Add 1-methyl-3-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole (50-e, 620 mg, 2.05 mmol) and 100 mg palladium on carbon to methanol (20 ml). After purging with hydrogen three times, maintain the system under hydrogen atmosphere at room temperature and stir overnight. Filter, and concentrate the filtrate under reduced pressure to obtain 3-(1-methyl-1H-pyrazole-3-yl)-2-(2,2,2-trifluoroethoxy)aniline (50-f, 530 mg, 1.96 mmol, 95% yield). No purification is required; proceed directly to the next reaction. MS Calcd: 271; MS Found: 272 ([M+H] + Step 6: Add 3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)aniline (50-f, 200 mg, 0.74 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 149 mg, 0.74 mmol) to 2 ml of anhydrous tetrahydrofuran, and add a tetrahydrofuran solution of LiHMDS (1.5 ml, 1.48 mmol) at room temperature. Stir for 2 hours at room temperature, and then add hydrochloric acid (…). Adjust the pH to 5 and extract with ethyl acetate (10 ml ethyl acetate extract, combine the organic layers, dry, concentrate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to give 6-chloro-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide (50 g, 120 °C, 0.26 mmol, 35% yield). MS Calcd: 455; MS Found: 456 ([M+H) + ).

[0834] Step 7: Add 6-chloro-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide (50-g, 50 mg, 0.11 mmol), cyclopropylformamide (19 mg, 0.22 mmol), cesium carbonate (107 mg, 0.33 mmol), XantPhos (20 mg, 0.03 mmol), and Pd2(dba)3 (25 mg, 0.027 mmol) to... The solution was added to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(cyclopropylcarbamoyl)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide (50, 15 mg, 0.03 mmol, 27% yield). MS Calcd: 504; MS Found: 505 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.81(s,1H),10.78(s,1H),9.97(s,1H),8.36(s,1H),7.88(s,1H),7.79(s,1H),7.61-7.58(m, 1H),7.39-7.24(m,2H),6.64(s,1H),4.29-4.25(m,2H),3.91(s,3H),3.71(s,3H),1.97-1.94(m,1H),0.77-0.74(m,4H).

[0835] Example 51

[0836] 6-((5-Fluoropyridin-2-yl)amino)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide

[0837]

[0838] Step 1: Add 6-chloro-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide (50-g, 50 mg, 0.11 mmol), 5-fluoropyridine-2-amine (25 mg, 0.22 mmol), cesium carbonate (107 mg, 0.33 mmol), XantPhos (20 mg, 0.03 mmol), and Pd2(dba)3 (25 mg, 0.027 mmol) to... The solution was transferred to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((3-(1-methyl-1H-pyrazol-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinamide (51, 12 mg, 0.02 mmol, 21% yield). MS Calcd: 531; MS Found: 532 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.70(s,1H),9.97(s,1H),9.84(s,1H),8.34(s,1H),8.09(d,J=3.2, 1H),7.80(s,1H),7.67-7.48(m,6H),6.65(s,1H),4.30-4.28(m,2H),3.91(s,3H),3.71(s,3H).

[0839] Example 52

[0840] 6-(cyclopropylcarbamate)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide

[0841]

[0842] Step 1: Diethyl 3-oxaglutarate (52-a, 7.6 g, 37.6 mmol), 4-acetaminobenzenesulfonyl azide (9 g, 37.6 mmol), and triethylamine (3.8 g, 37.6 mmol) were added to acetonitrile (100 ml). After stirring at room temperature for 1 hour, the mixture was filtered. The filter cake was washed with ether, and the filtrate was concentrated. The residue was slurried with ether:petroleum ether (1:1), filtered, and the filtrate was concentrated to obtain diethyl 2-diazo-3-oxaglutarate (52-b, 9.2 g). No purification was required, and the mixture was directly used for the next reaction.

[0843] Step 2: Diethyl 2-diazo-3-oxopranosate (52-b, 7.2 g, 32 mmol) and triphenylphosphine (8.4 g, 32 mmol) were added to diethyl ether (100 ml). After stirring at room temperature for 48 hours, the mixture was concentrated and then added to a mixed solvent of acetic acid and water (100 ml: 10 ml). The mixture was heated to 120 °C and stirred for 9 hours. The mixture was then directly concentrated, and the residue was added to an aqueous solution of sodium bicarbonate (2 N, 200 ml). The residue was washed with ethyl acetate (100 ml). The pH of the aqueous layer was adjusted to 3, and the residue was extracted with ethyl acetate (200 ml). The remaining organic layer was dried, filtered, and concentrated to obtain ethyl 4,6-dihydroxypyridazine-3-carboxylic acid. No purification was required, and the mixture was directly used in the next reaction step. (52-c, 3.6 g, 19.5 mmol, 61% yield). MS Calcd: 184; MS Found: 183 ([MH]) - ).

[0844] Step 3: Add ethyl 4,6-dihydroxypyridazine-3-carboxylate (52-c, 3.6 g, 19.5 mmol) to phosphorus oxychloride (50 ml), heat to 100 °C, stir for 3 hours, concentrate under reduced pressure, pour the residue into 50 ml of water, and extract with ethyl acetate (20 ml ethyl acetate). Dry the organic layer, filter, and concentrate. Purify the residue by column chromatography (ethyl acetate: petroleum ether = 1:4) to obtain ethyl 4,6-dichloropyridazine-3-carboxylate (52-d, 2.8 g, 12.7 mmol, 65% yield). No purification is required; proceed directly to the next reaction.

[0845] Step 4: Ethyl 4,6-dichloropyridazine-3-carboxylic acid (52-d, 2.8 g, 12.7 mmol) was added to a mixed solvent of tetrahydrofuran and water (40 ml: 10 ml), and lithium hydroxide (914 mg, 38.1 mmol) was added. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1 N), and the mixture was concentrated under reduced pressure. The residue was washed with a mixed solution of methanol and dichloromethane, filtered, and the filtrate was concentrated under reduced pressure to obtain 4,6-dichloropyridazine-3-carboxylic acid (52-e, 1.8 g, 9.3 mmol, 73% yield).

[0846] Step 5: 4,6-Dichloropyridazine-3-carboxylic acid (52-e, 1.8 g, 9.3 mmol) was added to dichloromethane (20 mL), and a catalytic amount of DMF was added. The mixture was cooled to 0 °C, and oxaloyl chloride was slowly added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in 5 mL of ethyl acetate. This residue was then slowly added to a mixed solvent of methoxyamine (900 mg, 18 mmol) and potassium carbonate (3.7 g, 27 mmol) in water and ethyl acetate, and stirred overnight at room temperature. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was dried, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to give 4,6-dichloro-N-methoxypyridazine-3-carboxamide (52-f, 1.3 g, 5.8 mmol, 62% yield). MS Calcd: 221; MS Found: 220 ([MH]) - ).

[0847] Step 6: Add 4,6-dichloro-N-methoxypyridazine-3-carboxamide (52-f, 300 mg, 1.35 mmol) and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (275.2 mg, 1.35 mmol) to 5 ml of anhydrous tetrahydrofuran, and add a tetrahydrofuran solution of LiHMDS (2.7 ml, 2.7 mmol) at room temperature. Stir at room temperature for 2 hours. The pH was adjusted to 5 with hydrochloric acid (1N), and the sample was extracted with ethyl acetate (10 ml ethyl acetate extract, the organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:2) to give 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (52 g, 150 mg, 0.39 mmol, 29% yield). MS Calcd: 389; MS Found: 390 ([MH) - ).

[0848] Step 7: Add 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (52-g, 50 mg, 0.13 mmol), cyclopropaneformamide (22 mg, 0.26 mmol), cesium carbonate (127 mg, 0.39 mmol), XantPhos (30 mg, 0.04 mmol), and Pd2(dba)3 (24 mg, 0.026 mmol) to the following solutions: The solution was added to anhydrous dioxane (2 ml) and the mixture was evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (52, 13 mg, 0.03 mmol, 23% yield). MS Calcd: 438; MS Found: 439 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),11.34(s,1H),10.53(s,1H),8.57(s,1H),8.56(s,1H),7.63(ddd,J=1 2.8,8.0,1.6Hz,2H),7.33(t,J=8.0Hz,1H),3.95(s,6H),3.94(s,3H),2.06–1.93(m,1H),0.78-0.74(m,4H).

[0849] Example 53

[0850] 6-(cyclopropylcarbamate)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide

[0851]

[0852] Step 1: 4,6-Dichloro-N-methoxypyridazine-3-carboxamide (52-f, 260 mg, 1.18 mmol) and 2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)aniline (252 mg, 1.18 mmol) were added to 5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (2.5 mL, 2.4 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL ethyl ester extract, the organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain a white solid 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (53-a, 124 mg, 0.32 mmol, 27% yield). MS Calcd:388;MS Found:389([M+H] + ).

[0853] Step 2: Add 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (53-a, 50 mg, 0.13 mmol), cyclopropaneformamide (22 mg, 0.26 mmol), cesium carbonate (127 mg, 0.39 mmol), XantPhos (30 mg, 0.04 mmol), and Pd2(dba)3 (24 mg, 0.026 mmol) to... The solution was added to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(cyclopropylcarbamate)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (53.8 mg, 0.018 mmol, 14% yield). MS Calcd: 437; MS Found: 438 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),10.65(s,1H),10.52(s,1H),8.19(s,1H),7.93(d,J=4.5Hz,1H),7.52(d,J=7.2Hz,1 H),7.37(d,J=7.2Hz,1H),7.30–7.16(m,2H),3.90(s,3H),3.76(s,3H),3.60(s,3H),2.06–1.93(m,1H),0.78-0.74(m,4H)

[0854] Example 54

[0855] 6-(cyclopropylcarbamoyl)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxynicotinamide

[0856]

[0857] Step 1: 2-Bromo-6-nitrophenol (54-a, 900 mg, 4.17 mmol), 2-chloro-2,2-difluoroacetic acid (812 mg, 6.25 mmol), and potassium carbonate (2.3 g, 16.7 mmol) were added to DMF (15 ml) and the temperature was raised to 100 °C. The mixture was stirred for 3 hours. After the reaction was complete as shown by TLC, the mixture was cooled to room temperature, poured into 50 ml of water, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:60) to obtain the target compound 1-bromo-2-(difluoromethoxy)-3-nitrobenzene (54-b, 530 mg, 1.98 mmol, 47% yield).

[0858] Step 2: Dissolve 1-bromo-2-(difluoromethoxy)-3-nitrobenzene (54-b, 500 mg, 1.87 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (389 mg, 1.87 mmol), Pd(dppf)Cl2 (20 mg, 0.02 mmol), and sodium carbonate (594 mg, 5.61 mmol) in a mixed solvent of water and dioxane (2 mL / 8 mL), heat to 100 °C, and react for 3 h. The reaction solution was concentrated, 10 ml of water was added, and the mixture was extracted with ethyl acetate (10 ml ethyl acetate extraction). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to give a yellow solid 4-(2-(difluoromethoxy)-3-nitrophenyl)-1-methyl-1H-pyrazole (54-c, 420 mg, 1.56 mmol, 83% yield). MS Calcd: 269; MS Found: 270 ([M+H) + ).

[0859] Step 3: 4-(2-(difluoromethoxy)-3-nitrophenyl)-1-methyl-1H-pyrazole (54-c, 420 mg, 1.56 mmol) and 40 mg palladium on carbon were added to methanol (20 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a gray oily product, 2-(difluoromethoxy)-3-(1-methyl-1H-pyrazole-4-yl)aniline (54-d, 360 mg, 1.50 mmol, 95% yield). No purification was required; the product was directly used in the next reaction. MS Calcd: 239; MS Found: 240 ([M+H) + ).

[0860] Step 4: 4,6-Dichloro-N-methoxynicotinamide (int-1, 332 mg, 1.50 mmol) and 2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)aniline (54-d, 360 mg, 1.50 mmol) were added to 5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (3 mL, 3 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL ethyl ester extract, the organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to give a white solid 6-chloro-4-((2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxynicotinamide (54-e, 210 mg, 0.49 mmol, 33% yield). MS Calcd:423;MS Found:424([M+H] + ).

[0861] Step 5: Add 6-chloro-4-((2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxynicotinamide (54-e, 50 mg, 0.12 mmol), cyclopropylformamide (22 mg, 0.26 mmol), cesium carbonate (127 mg, 0.36 mmol), XantPhos (30 mg, 0.04 mmol), and Pd2(dba)3 (24 mg, 0.024 mmol) to... The solution was added to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(cyclopropylcarbamoyl)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methoxynicotinamide (54.9 mg, 0.02 mmol, 16.7% yield). MS Calcd: 472; MS Found: 473 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.83(s,1H),10.79(s,1H),10.01(s,1H),8.36(s,1H),8.10(s,1H),7.88(s,1H),7.85(s,1H), 7.45-7.43(m,1H),7.34-7.32(m,2H),6.95-6.59(m,1H),3.89(s,3H),3.72(s,3H),1.98-1.95(m,1H),0.76-0.74(m,4H).

[0862] Example 55

[0863] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((2-methoxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)amino)nicotinamide

[0864]

[0865] Step 1: 2-Hydroxy-3-nitrobenzenenitrile (55-a, 1.2 g, 7.3 mmol), iodomethane (3.1 g, 22 mmol) and potassium carbonate (5.9 g, 43 mmol) were added to DMF and stirred overnight at room temperature. The mixture was then poured into 150 ml of water, filtered, and the solid was washed with water and dried to obtain 2-methoxy-3-nitrobenzenenitrile (55-b, 800 mg, 4.5 mmol, 62% yield).

[0866] Step 2: 2-Methoxy-3-nitrobenzyl nitrile (55-b, 800 mg, 4.5 mmol) and 40 mg palladium on carbon were added to methanol (20 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the product 3-amino-2-methoxybenzyl nitrile (55-c, 630 mg, 4.2 mmol, 93% yield). No purification was required; it was directly used in the next reaction. MS Calcd: 148; MS Found: 149 ([M+H)) + ).

[0867] Step 3: 4,6-Dichloro-N-methoxynicotinamide (int-1, 332 mg, 1.50 mmol) and 3-amino-2-methoxybenzyl nitrile (55-c, 230 mg, 1.55 mmol) were added to 5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (3 mL, 3 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL ethyl ester extract; the organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain 6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-methoxynicotinamide (55-d, 152 mg, 0.46 mmol, 29% yield). MS Calcd: 332; MS Found: 333 ([M+H) + ).

[0868] Step 4: 6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-methoxynicotinamide (55-d, 52 mg, 0.16 mmol), cyclopropylformamide (27 mg, 0.32 mmol), cesium carbonate (156 mg, 0.48 mmol), XantPhos (30 mg, 0.04 mmol), and Pd2(dba)3 (24 mg, 0.024 mmol) were added to anhydrous dioxane (2 ml) and the mixture was evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain 4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropylformamido)-N-methoxynicotinamide (55-e, 15 mg, 0.04 mmol, 25% yield). MS Calcd:381;MS Found:382([M+H] + ).

[0869] Step 5: 4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropylcarbamoyl)-N-methoxynicotinamide (55-e, 30 mg, 0.08 mmol) and free hydroxylamine (11 mg, 0.32 mmol) were added to a mixed solvent of ethanol and water (1 ml: 2 ml), heated to 90 °C, stirred for 6 hours, concentrated under reduced pressure, and the residue was purified by high performance thin-layer chromatography (methanol: dichloromethane = 1:10) to obtain 6-(cyclopropylcarbamoyl)-4-((3-(N-hydroxyaminocarbamoyl)-2-methoxyphenyl)amino)-N-methoxynicotinamide (55-f, 9 mg, 0.02 mmol, 13% yield). MS Calcd: 414; MS Found: 413 ([MH]) - ). 1 H NMR (400MHz, DMSO-d6): δ11.86(s,1H),10.82(s,1H),10.12(s,1H),9.53(s,1H),8.36(s,1H),8.07(s,1H),7.44( dd,J=4,5.6,1H),7.15-7.12(m,2H),5.76(s,2H),3.73(s,3H),3.70(s,3H),1.99-1.96(m,1H),0.78-0.77(m,4H).

[0870] Step 6: 6-(cyclopropaneformamido)-4-((3-(N-hydroxyaminoformamido)-2-methoxyphenyl)amino)-N-methoxynicotinamide (55-f, 20 mg, 0.05 mmol) and acetic anhydride (5 mg, 0.05 mmol) were added to 1,4-dioxane. The mixture was heated to 90 °C, stirred for 5 hours, concentrated under reduced pressure, and the residue was purified by high performance thin-layer chromatography (methanol: dichloromethane = 1:30) to obtain a white solid 6-(cyclopropaneformamido)-N-methoxy-4-((2-methoxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)amino)nicotinamide (55, 9 mg, 0.02 mmol, 40% yield). MS Calcd: 438; MS Found: 439 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.86(s,1H),10.83(s,1H),10.30(s,1H),8.40(s,1H),8.07(s,1H),7.65-7.60(m,2 H), 7.33 (dd, J=8.0, 4.0Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 2.68 (s, 3H), 2.00-1.96 (m, 1H), 0.78-0.74 (m, 4H).

[0871] Example 56

[0872] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((4-(N-methylsulfonamido)pyridin-3-yl)amino)nicotinamide

[0873]

[0874] Step 1: 4-Chloro-3-nitropyridine (56-a, 1 g, 6.3 mmol), N-methylmethanesulfonamide (680 mg, 6.3 mmol), and potassium carbonate (2.6 g, 19 mmol) were added to DMF. The temperature was raised to 80 °C, and the mixture was stirred for 2 hours. After the reaction was observed by TLC, the mixture was cooled to room temperature and poured into 100 mL of water. A solid precipitated out. The solid was filtered to obtain N-methyl-N-(3-nitropyridine-4-yl)methanesulfonamide (56-b, 920 mg, 3.98 mmol, 63% yield). MS Calcd: 231; MS Found: 232 ([MH]) - ).

[0875] Step 2: N-methyl-N-(3-nitropyridin-4-yl)methanesulfonamide (56-b, 920 mg, 3.98 mmol) and 100 mg palladium on carbon were added to methanol (20 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-(3-aminopyridin-4-yl)-N-methylmethanesulfonamide (56-c, 730 mg, 3.6 mmol, 90% yield). No purification was required; the mixture was directly used in the next reaction. MS Calcd: 201; MS Found: 202 ([M+H]) + ).

[0876] Step 3: 4,6-Dichloro-N-methoxynicotinamide (int-1, 230 mg, 1.14 mmol) and N-(3-aminopyridin-4-yl)-N-methylmethanesulfonamide (56-c, 230 mg, 1.14 mmol) were added to 2.5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (2.5 mL, 2.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL ethyl ester extract, the organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain 6-chloro-N-methoxy-4-((4-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (56-d, 125 mg, 0.32 mmol, 28% yield). MS Calcd: 385; MS Found: 386 ([M+H]) + ).

[0877] Step 4: Add 6-chloro-N-methoxy-4-((4-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (56-d, 50 mg, 0.13 mmol), cyclopropylformamide (22 mg, 0.26 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (20 mg, 0.03 mmol), and Pd2(dba)3 (19 mg, 0.02 mmol) to... The solution was added to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(cyclopropylcarbamoyl)-N-methoxy-4-((4-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (56, 12 mg, 0.03 mmol, 23% yield). MS Calcd: 434; MS Found: 435 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.86(s,1H),10.84(s,1H),9.99(s,1H),8.72(s,1H),8.43(d,J=5.2,1H),8.36 (s,1H),7.84(s,1H),7.63(d,J=5.2,1H),3.72(s,3H),3.16(s,6H),1.99-1.94(m,1H),0.77-0.6(m,4H).

[0878] Example 57

[0879] 4-((3-carbamoyl-2-methoxyphenyl)amino)-6-(cyclopropylcarbamoyl)-N-methoxynicotinamide

[0880]

[0881] Step 1: 4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-methoxynicotinamide (55-e, 20 mg, 0.05 mmol) and potassium carbonate (14 mg, 0.1 mmol) were added to a mixed solvent of water and ethanol. The temperature was raised to 80 °C, stirred for 2 hours, concentrated under reduced pressure, and purified by high performance thin-layer chromatography (methanol: dichloromethane = 1:20) to obtain the title compound: 4-((3-carbamoyl-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-methoxynicotinamide (57, 8 mg, 0.02 mmol, 40% yield). MS Calcd: 399; MS Found: 400 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6): δ11.84(s,1H),10.82(s,1H),10.13(s,1H),8.37(s,1H),8.03(s,1H),7.74(s,1H),7.52-7.4 9(m,2H),7.32-7.30(dd,J=8.0,1.6Hz,1H),7.20(t,J=8.0Hz,1H),3.70(s,6H),1.99-1.94(m,1H),0.78-0.76(m,4H).

[0882] Example 58

[0883] 6-((5-Fluoropyridin-2-yl)amino)-N-methoxy-4-((4-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide

[0884]

[0885] Step 1: Add 6-chloro-N-methoxy-4-((4-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (56-d, 50 mg, 0.13 mmol), 5-fluoropyridin-2-amine (30 mg, 0.26 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (20 mg, 0.03 mmol), and Pd2(dba)3 (19 mg, 0.02 mmol) to The solution was transferred to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((4-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (58, 9 mg, 0.02 mmol, 15% yield). MS Calcd: 461; MS Found: 462 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.86(s,1H),9.98(s,1H),9.86(s,1H),8.83(s,1H),8.44(d,J=5.2Hz,1H),8.33(s,1H) ,8.08(d,J=3.2Hz,1H),7.78-7.77(m,1H),7.64-7.61(m,2H),7.39(s,1H),3.72(s,3H),3.20(s,3H),3.19(s,3H).

[0886] Example 59

[0887] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((6-methyl-2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide

[0888]

[0889] Step 1: 2-Chloro-6-methyl-3-nitropyridine (59-a, 1 g, 5.8 mmol), N-methylmethanesulfonamide (630 mg, 5.8 mmol), and potassium carbonate (2.4 g, 17.4 mmol) were added to DMF. The temperature was raised to 80 °C and stirred for 2 hours. After the reaction was observed by TLC, the mixture was cooled to room temperature and poured into 100 mL of water. A solid precipitated out. The solid was filtered to obtain N-methyl-N-(6-methyl-3-nitropyridine-2-yl)methanesulfonamide (59-b, 965 mg, 3.9 mmol, 67% yield). MS Calcd: 245; MS Found: 246 ([MH]) - ).

[0890] Step 2: N-methyl-N-(6-methyl-3-nitropyridin-2-yl)methanesulfonamide (59-b, 965 mg, 3.9 mmol) and 100 mg palladium on carbon were added to methanol (20 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-(3-amino-6-methylpyridin-2-yl)-N-methylmethanesulfonamide (59-c, 753 mg, 3.5 mmol, 89% yield). No purification was required; the mixture was directly used in the next reaction. MS Calcd: 215; MS Found: 216 ([M+H) + Step 4: N-(3-amino-6-methylpyridin-2-yl)-N-methylmethanesulfonamide (59-c, 253 mg, 1.17 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 230 mg, 1.14 mmol) were added to 2.5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (2.5 mL, 2.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL ethyl ester extract, the organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to give 6-chloro-N-methoxy-4-((6-methyl-2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (59-d, 138 mg, 0.36 mmol, 29% yield). MS Calcd: 399; MS Found: 400 ([M+H]) + ).

[0891] Step 5: Add 6-chloro-N-methoxy-4-((6-methyl-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (59-d, 50 mg, 0.13 mmol), cyclopropylformamide (22 mg, 0.26 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (20 mg, 0.03 mmol), and Pd2(dba)3 (19 mg, 0.02 mmol) to... The solution was added to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(cyclopropylcarbamoyl)-N-methoxy-4-((6-methyl-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (59, 18 mg, 0.04 mmol, 31% yield). MS Calcd: 448; MS Found: 449 ([M+H) +). 1HNMR (400MHz, DMSO-d6): δ11.81(s,1H),10.82(s,1H),10.01(s,1H),8.35(s,1H),7.84-7.82(m,2H),7.34-7. 32(d,J=8.4Hz,1H),3.71(s,3H),3.17(s,3H),3.10(s,3H),2.47(s,3H),1.97-1.95(m,1H),0.78-0.76(m,4H).

[0892] Example 60

[0893] 6-(((5-Fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methyl-2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide

[0894]

[0895] Step 1: Add 6-chloro-N-methoxy-4-((6-methyl-2-(N-methylmethylsulfonamido)pyridin-3-yl)amino)nicotinamide (59-d, 50 mg, 0.13 mmol), 5-fluoropyridin-2-amine (30 mg, 0.26 mmol), cesium carbonate (130 mg, 0.4 mmol), XantPhos (20 mg, 0.03 mmol), and Pd2(dba)3 (19 mg, 0.02 mmol) to anhydrous dioxane. (2 ml) and evacuate under vacuum, replace with nitrogen, heat to 120 °C, stir for 2 hours, filter, concentrate the filtrate, and purify by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 6-(((5-fluoropyridin-2-yl)amino)-N-methoxy-4-((6-methyl-2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (60, 13 mg, 0.03 mmol, 23% yield). MS Calcd: 475; MS Found: 476 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.72(s,1H),10.06(s,1H),9.86(s,1H),8.32(s,1H),8.18(s,1H),7.96-7.94(d,J=8.4Hz ,1H),7.66(d,J=5.2Hz,2H),7.55(s,1H),7.42(d,J=8.4Hz,1H),3.71(s,3H),3.21(s,3H),3.12(s,3H),2.49(s,3H).

[0896] Example 61

[0897] 4-((4-(cyclopropylmethoxy)-2-(N-methylmethanesulfonamide)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0898]

[0899] Step 1: 3-Fluoro-4-nitrophenol (61-a, 1 g, 6.3 mmol), (bromomethyl)cyclopropane (850 mg, 6.3 mmol), and potassium carbonate (2.6 g, 18.9 mmol) were added to DMF. The temperature was raised to 90 °C and stirred for 5 hours. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (30 mL) to room temperature and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give 4-(cyclopropylmethoxy)-2-fluoro-1-nitrobenzene (61-b, 1.1 g, 5.2 mmol, 83% yield). MS Calcd: 211; MS Found: 212 ([M+H] + ).

[0900] Step 2: 4-(cyclopropylmethoxy)-2-fluoro-1-nitrobenzene (61-b, 1.1 g, 5.2 mmol), N-methylmethanesulfonamide (630 mg, 5.8 mmol), and potassium carbonate (2.2 g, 15.6 mmol) were added to DMF. The temperature was raised to 80 °C and stirred for 2 hours. After the reaction of the starting material was observed by TLC, the mixture was cooled to room temperature, poured into 100 mL of water, and extracted with ethyl acetate (100 mL ethyl acetate extract). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:4) to give N-(5-(cyclopropylmethoxy)-2-nitrophenyl)-N-methylmethanesulfonamide (61-c, 862 mg, 2.9 mmol, 56% yield). MS Calcd: 300; MS Found: 301 ([MH]) - ).

[0901] Step 3: N-(5-(cyclopropylmethoxy)-2-nitrophenyl)-N-methylmethanesulfonamide (61-c, 862 mg, 2.9 mmol) and 100 mg palladium on carbon were added to methanol (20 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-(2-amino-5-(cyclopropylmethoxy)phenyl)-N-methylmethanesulfonamide (61-d, 731 mg, 2.7 mmol, 93% yield). No purification was required; the mixture was directly used in the next reaction. MS Calcd: 270; MS Found: 271 ([M+H) + ).

[0902] Step 4: N-(2-amino-5-(cyclopropylmethoxy)phenyl)-N-methylmethanesulfonamide (61-d, 261 mg, 0.96 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 200 mg, 1 mmol) were added to 2.5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (2 mL, 2 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL ethyl ester extract, the organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:2) to give 6-chloro-4-((4-(cyclopropylmethoxy)-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (61-e, 185 mg, 0.41 mmol, 43% yield). MS Calcd: 454; MS Found: 455([M+H]) + ).

[0903] Step 5: Add 6-chloro-4-((4-(cyclopropylmethoxy)-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (61-e, 50 mg, 0.11 mmol), 5-fluoropyridine-2-amine (19 mg, 0.22 mmol), cesium carbonate (107 mg, 0.33 mmol), XantPhos (20 mg, 0.03 mmol), and Pd2(dba)3 (19 mg, 0.02 mmol) to The solution was transferred to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give a white solid 4-((4-(cyclopropylmethoxy)-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (61, 16 mg, 0.03 mmol, 27% yield). MS Calcd: 530; MS Found: 531 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.62(s,1H),9.72(s,1H),9.71(s,1H),8.26(s,1H),8. 12(d,J=2.8Hz,1H),7.66-7.60(m,2H),7.43(d,J=8.8Hz,1H),7.29(s,1H),7.13(d ,J=2.4Hz,1H),7.08(dd,J=8.8,2.8Hz,1H),3.88(d,J=7.2Hz,2H),3.70(s,3H),3 .12(s,3H),3.08(s,3H),1.24-1.23(m,1H),0.61-0.57(m,2H),0.37-0.33(m,2H).

[0904] Example 62

[0905] 4-((4-(cyclopropylmethoxy)-2-(N-methylmethanesulfonamide)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0906]

[0907] Step 1: Add 6-chloro-4-((4-(cyclopropylmethoxy)-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (61-e, 50 mg, 0.11 mmol), 6-fluoropyridine-2-amine (19 mg, 0.22 mmol), cesium carbonate (107 mg, 0.33 mmol), XantPhos (20 mg, 0.03 mmol), and Pd2(dba)3 (19 mg, 0.02 mmol) to... The solution was transferred to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-(cyclopropylmethoxy)-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (62, 13 mg, 0.024 mmol, 22% yield). MS Calcd: 530; MS Found: 531 ([M+H) + ). 1H NMR (400MHz, DMSO-d6): δ11.66(s,1H),9.90(s,1H),9.71(s,1H),8.27(s,1H),7.7 9-7.76(m,1H),7.44(d,J=8.8Hz,2H),7.29(s,1H),7.15(d,J=2.8Hz,1H),7.00(dd, J=8.8,2.8Hz,1H),6.54(dd,J=8.0,2.8Hz,1H),3.865(d,J=7.2,2H),3.72(s,3H), 3.14(s,3H),3.07(s,3H),1.26-1.23(m,1H),0.61-0.57(m,2H),0.37-0.33(m,2H).

[0908] Example 63

[0909] 6-(cyclopropylcarbamoyl)-4-((4-(cyclopropylmethoxy)-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide

[0910]

[0911] Step 1: Add 6-chloro-4-((4-(cyclopropylmethoxy)-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (61-e, 50 mg, 0.11 mmol), cyclopropylformamide (19 mg, 0.22 mmol), cesium carbonate (107 mg, 0.33 mmol), XantPhos (20 mg, 0.03 mmol), and Pd2(dba)3 (19 mg, 0.02 mmol) to... The solution was added to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give a white solid 6-(cyclopropylcarbamoyl)-4-((4-(cyclopropylmethoxy)-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (63, 15 mg, 0.029 mmol, 26% yield). MS Calcd: 503; MS Found: 504 ([M+H) +). 1H NMR (400MHz, DMSO-d6): δ11.71(s,1H),10.69(s,1H),9.68(s,1H),8.28(s,1H), 7.59(s,1H),7.319(d,J=8.8Hz,1H),7.15(d,J=2.8,1H),6.98(dd,J=8.8,2.8Hz, 1H),3.86(d,J=7.2Hz,2H),3.70(s,3H),3.09(s,3H),3.05(s,3H),1.97-1.96(m, 1H),1.23-1.17(m,1H),0.75-0.72(m,4H),0.35-0.34(m,2H),0.28-0.27(m,2H).

[0912] Example 64

[0913] 6-((4-fluorophenyl)amino)-N-methoxy-4-((6-methyl-2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide

[0914]

[0915] Step 1: Add 6-chloro-N-methoxy-4-((6-methyl-2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (59-d, 50 mg, 0.13 mmol), 4-fluoroaniline (30 mg, 0.26 mmol), cesium carbonate (130 mg, 0.4 mmol), Xantphos (20 mg, 0.03 mmol), and Pd2(dba)3 (19 mg, 0.02 mmol) to... The solution was placed in anhydrous dioxane (2 ml) under vacuum, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-((4-fluorophenyl)amino)-N-methoxy-4-((6-methyl-2-(N-methylmethanesulfonyl)pyridin-3-yl)amino)nicotinamide (64, 16 mg, 0.03 mmol, 23% yield). MS Calcd: 474; MS Found: 475 ([M+H) + ). 1HNMR (400MHz, DMSO-d6): δ11.65(s,1H),9.82(s,1H),9.08(s,1H),8.26(s,1H),7.90-7.88(d,J=8.0,1H),7.59(d,J1=4.0,J2= 8.0,2H),7.36-7.34(d,J=8.0,1H),7.11-7.07(t,J=8.0,2H),6.29(m,1H),3.71(s,3H),3.20(s,3H),3.12(s,3H),2.48(s,3H)

[0916] Example 65

[0917] 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-N-methyl-4-((2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide

[0918]

[0919] Step 1: 4,6-Dichloronicotinic acid (65-a, 1 g, 5.2 mmol) was added to dichloromethane (20 ml), along with a catalytic amount of DMF. The mixture was cooled to 0°C, and oxaloyl chloride (0.7 ml, 7.8 mmol) was slowly added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 2 hours. The solution was concentrated under reduced pressure, and the residue was dissolved in 5 ml of ethyl acetate. This residue was then slowly added to a mixture of dimethylhydroxylamine hydrochloride (1.5 g, 16 mmol) and potassium carbonate (3.7 g, 27 mmol) in water and ethyl acetate. The mixture was stirred overnight at room temperature. 50 ml of ethyl acetate was added, and the mixture was separated. The organic layer was dried, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to give 4,6-dichloro-N-methoxy-N-methylnicotinamide (65-b, 800 mg, 3.4 mmol, 65% yield). MS Calcd: 234; MS Found: 235 ([M+H) + ).

[0920] Step 2: 4,6-Dichloro-N-methoxy-N-methylnicotinamide (65-b, 200 mg, 0.9 mmol) and N-(2-aminophenyl)-N-methylmethanesulfonamide (220 mg, 1.1 mmol) were added to 5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (1.8 mL, 1.8 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to give 6-chloro-N-methoxy-N-methyl-4-((2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide (65-c, 160 mg, 0.4 mmol, 44% yield). MS Calcd: 398; MS Found: 399 ([M+H) + ).

[0921] Step 3: Add 6-chloro-N-methoxy-N-methyl-4-((2-(N-methylmethylsulfonamido)phenyl)amino)nicotinamide (65-c, 100 mg, 0.25 mmol), 6-fluoropyridine-2-amine (56 mg, 0.5 mmol), cesium carbonate (240 mg, 0.75 mmol), Xantphos (60 mg, 0.08 mmol), and Pd2(dba)3 (50 mg, 0.05 mmol) to The solution was transferred to anhydrous dioxane (3 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-((6-fluoropyridin-2-yl)amino)-N-methoxy-N-methyl-4-((2-(N-methylmethanesulfonyl)phenyl)amino)nicotinamide 65, 30 mg, 0.06 mmol, 24% yield. MS Calcd: 474; MS Found: 475 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ10.01(brs,1H),8.86(s,1H),8.30(s,1H),7.80-7.78(d,J=8.0,1H),7.78-7.51(m,4H),7 .41-7.37(m,1H),7.20-7.18(m,1H),6.56-6.54(d,J=8.0,1H),3.61(s,3H),3.29(s,3H),3.14(s,3H),3.10(s,3H)

[0922] Example 66

[0923] 6-((4,6-dimethylpyrimidin-2-yl)amino)-N-ethoxy-4-((4-methyl-2-(N-methylcyclopropanesulfonyl)phenyl)amino)nicotinamide

[0924]

[0925] Step 1: Dissolve 2-fluoro-4-methyl-1-nitrobenzene (66-a, 465 g, 3 mmol) in N,N-dimethylformamide (30 ml) and add it to a 100 ml reaction flask. Then add potassium carbonate (1.24 g, 9 mmol) and cyclopropanesulfonamide (400 mg, 3.3 mmol) to the reaction flask. Heat the reaction to 90 °C and stir for 3 h. The reaction was confirmed to be complete by TLC. The reaction solution was washed with water (30 ml x 1) and brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification was achieved by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the product N-(5-methyl-2-nitrophenyl)cyclopropanesulfonamide (66-b, 695 mg, 90% yield). MS Calcd: 256.05; MS Found: 257.10 ([M+H] + )

[0926] Step 2: N-(5-methyl-2-nitrophenyl)cyclopropanesulfonamide (66-b, 690 mg, 2.72 mmol) was dissolved in N,N-dimethylformamide (30 ml) and added to a 100 ml reaction flask. Then, sodium hydroxide (163.2 mg, 60%, 4.08 mmol) and methyl iodoforme (463 mg, 3.26 mmol) were added to the reaction flask. The reaction mixture was stirred at room temperature for 3 h. TLC was used to confirm the reaction was complete. The reaction mixture was then added to water and ethyl acetate, extracted with ethyl acetate (30 ml x 2), washed with brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated to give N-(5-methyl-2-nitrophenyl)-N-methylcyclopropanesulfonamide (66-c, 761 mg, 2.72 mmol, 100% yield). MS Calcd: 270.09; MS Found: 271.22 ([M+H] + ).

[0927] Step 3: N-(5-methyl-2-nitrophenyl)-N-methylcyclopropanesulfonamide (66-c, 761 mg, 2.72 mmol), ammonium chloride (1.46 g, 27.2 mmol), and iron powder (0.76 g, 13.6 mmol) were added sequentially to 10 mL of a mixed solvent of water and ethanol (1:4), and stirred under reflux for 3 hours. The reaction was monitored by TLC until completion. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain N-(2-amino-5-methylphenyl)-N-methylcyclopropanesulfonamide (66-d, 0.47 g, 1.96 mmol, 72% yield). MS Calcd: 240.09; MS Found: 241.22 ([M+H] + ).

[0928] Step 4: N-(2-amino-5-methylphenyl)-N-methylcyclopropanesulfonamide (66-d, 125 mg, 0.5 mmol) and 4,6-dichloro-N-ethoxynicotinamide (int-2, 117 mg, 0.5 mmol) were added to 10 mL of anhydrous N,N-dimethylacetamide, and a tetrahydrofuran solution of LiHMDS (1.5 mL, 1.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC until completion. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain 6-chloro-N-ethoxy-4-((4-methyl-2-(N-methylcyclopropanesulfonamide)phenyl)amino)nicotinamide (66-e, 187 mg, 0.43 mmol, 85.2% yield). MS Calcd:438.10;MSFound:439.29([M+H] + ).

[0929] Step 5: 6-Chloro-N-ethoxy-4-((4-methyl-2-(N-methylcyclopropanesulfonyl)phenyl)amino)nicotinamide (66-e, 132 mg, 0.3 mmol), 4,6-dimethylpyrimidin-2-amine (40.6 mg, 0.33 mmol), cesium carbonate (292.5 mg, 0.9 mmol), Xant-Phos (34.68 mg, 0.06 mmol), and Pd2(dba)3 (27.5 mg, 0.03 mmol) were added. l) Add to anhydrous dioxane (5 ml) and evacuate under vacuum. Replace with nitrogen, heat to 120 °C, stir for 6 hours, filter, concentrate the filtrate, and purify by preparative TLC (MeOH:DCM = 1:20) to obtain the title compound: 6-((4,6-dimethylpyrimidin-2-yl)amino)-N-ethoxy-4-((4-methyl-2-(N-methylcyclopropanesulfonyl)phenyl)amino)nicotinamide (66, 30 mg, 0.057 mmol, 19.2% yield). MS Calcd: 525.21; MS Found: 526.20 ([M+H) + ). 1 H NMR(400MHz,DMSO-d6)δ11.60(s,1H),9.97(s,1H),9.60(s,1H),8.32(s,1H),8. 21(s,1H),7.51(d,J=8.0Hz,1H),7.44(d,J=2.0Hz,1H),7.26(dd,J=8.0,2.0Hz, 1H),6.72(s,1H),3.93(q,J=7.2Hz,2H),3.14(s,3H),2.81-2.77(m,1H),2.34(s ,3H),2.25(s,6H),1.22(t,J=7.2Hz,3H),1.02-0.98(m,2H),0.88–0.82(m,2H).

[0930] Example 67

[0931] 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy-2-methylnicotinamide

[0932]

[0933] Step 1: 4,6-Dichloro-2-methylnicotinic acid (67-a, 1 g, 4.8 mmol) was added to dichloromethane (20 ml), and a catalytic amount of DMF was added. The mixture was cooled to 0°C, and oxaloyl chloride (0.7 ml, 7.8 mmol) was slowly added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in 5 ml of ethyl acetate. This residue was then slowly added to a mixed solvent of methoxyamine hydrochloride (1.2 g, 16 mmol) and potassium carbonate (3.7 g, 27 mmol) in water and ethyl acetate. The mixture was stirred overnight at room temperature. 50 ml of ethyl acetate was added, and the mixture was separated. The organic layer was dried, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain the title compound: 4,6-dichloro-N-methoxy-2-methylnicotinamide (67-b, 750 mg, 3.2 mmol, 66% yield).

[0934] MS Calcd:234;MS Found:235([M+H] + ).

[0935] Step 2: 4,6-Dichloro-N-methoxy-2-methylnicotinamide (67-b, 200 mg, 0.9 mmol) and N-(2-amino-5-cyclopropylphenyl)-N-methylmethanesulfonamide (264 mg, 1.1 mmol) were added to 5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (1.8 mL, 1.8 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to give 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxy-2-methylnicotinamide (67-c, 187 mg, 0.43 mmol, 48% yield), MS Calcd: 438; MS Found: 439 ([M+H]) + ).

[0936] Step 3: Add 6-chloro-4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-methoxy-2-methylnicotinamide (67-c, 60 mg, 0.14 mmol), 6-fluoropyridine-2-amine (31 mg, 0.28 mmol), cesium carbonate (137 mg, 0.42 mmol), XantPhos (30 mg, 0.04 mmol), and Pd2(dba)3 (30 mg, 0.03 mmol) to The solution was transferred to anhydrous dioxane (2 ml) and evacuated under vacuum. The mixture was then purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxy-2-methylnicotinamide (67, 25 mg, 0.05 mmol, 36% yield). MS Calcd: 514; MS Found: 515 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.60 (s, 1H), 9.79 (s, 1H), 7.76 (d, J = 8.0, 1H), 7.74(s,1H),7.48(d,J=8.0,1H),7.44-7.40(m,2H),7.28(d,J=4.0,1H),7 .08(d,J=8.0,1H),6.50(d,J=8.0,1H),3.73(s,3H),3.13(s,3H),3.10(s, 3H),2.35(s,3H),1.96-1.93(m,1H),0.98-0.96(m,2H),0.70-0.68(m,2H)

[0937] Example 68

[0938] 4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-(methoxy-d3)nicotinamide

[0939]

[0940] Step 1: 4,6-Dichloronicotinic acid (68-a, 1 g, 5.2 mmol) was added to dichloromethane (20 ml), along with a catalytic amount of DMF. The mixture was cooled to 0 °C, and oxaloyl chloride (0.7 ml, 7.8 mmol) was slowly added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in 5 ml of ethyl acetate. This residue was then slowly added to a mixed solvent of hydroxylamine hydrochloride (1 g, 16 mmol) and potassium carbonate (3.7 g, 27 mmol) in water and ethyl acetate. The mixture was stirred overnight at room temperature. 50 ml of ethyl acetate was added, and the mixture was separated. The pH was adjusted to 5 with hydrochloric acid. The organic layer was dried, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain 4,6-dichloro-N-hydroxynicotinamide (68-b, 455 mg, 2.2 mmol, 42% yield). MS Calcd: 206; MS Found: 205 ([MH]) - ).

[0941] Step 2: 4,6-Dichloro-N-hydroxynicotinamide (68-b, 455 mg, 2.2 mmol) and sodium hydroxide (264 mg, 6.6 mmol) were added to a mixed solvent of water and ethanol (1 ml / 5 ml), and deuterated iodomethane (319 mg, 2.2 mmol) was added at room temperature. The mixture was stirred at room temperature for 4 hours, the pH was adjusted to 5 with hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate (10 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to give 4,6-dichloro-N-(methoxy-d3)nicotinamide (68-c, 160 mg, 0.72 mmol, 33% yield). MS Calcd: 223; MS Found: 224 ([M+H) + ).

[0942] Step 2: 4,6-Dichloro-N-(methoxy-d3)nicotinamide (68-c, 160 mg, 0.72 mmol) and N-(2-amino-5-cyclopropylphenyl)-N-methylmethanesulfonamide (180 mg, 0.72 mmol) were added to 5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (1.5 mL, 1.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to give 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonyl)phenyl)amino)-N-(methoxy-d3)nicotinamide (68-d, 110 mg, 0.26 mmol, 36% yield) MS Calcd: 427; MS Found: 428 ([M+H])+ ).

[0943] Step 3: Add 6-chloro-4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-N-(methoxy-d3)nicotinamide (68-d, 110 mg, 0.26 mmol), 6-fluoropyridine-2-amine (58 mg, 0.52 mmol), cesium carbonate (254 mg, 0.78 mmol), XantPhos (60 mg, 0.08 mmol), and Pd2(dba)3 (60 mg, 0.06 mmol) to... The solution was transferred to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((4-cyclopropyl-2-(N-methylmethylsulfonamido)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-(methoxy-d3)nicotinamide (68, 30 mg, 0.06 mmol, 23% yield). MS Calcd: 503; MS Found: 504 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.69(s,1H),9.97(s,1H),9.93(s,1H),8.30(s,1H),7.82-7.76(m,1H),7.54(s,1H),7.49(d,J=8.0,1H),7.45(d,J=4. 0,1H),6.55(d,J=4.0,1H)7.28(s,1H),7.09-7.07(d,J=8,1H)3.13(s,3 H),3.10(s,3H),2.00-1.96(m,1H),1.01-0.97(m,2H),0.70-0.68(m,2H)

[0944] Example 69

[0945] 6-(cyclopropylcarbamoyl)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-nicotinamide

[0946]

[0947] Step 1: 3-Nitrosalicylic acid (69-a, 5.0 g, 27 mmol) and potassium carbonate (10.0 g, 36 mmol) were added sequentially to 50 mL of N,N-dimethylformamide solution, followed by the addition of iodomethane (5.0 mL, 80 mmol). The mixture was heated to 60 °C and stirred overnight. The reaction was monitored by TLC until completion. 60 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4) to obtain methyl 2-methoxy-3-nitrobenzoate (69-b, 4.2 g, 19.9 mmol, 74% yield).

[0948] Step 2: Methyl 2-methoxy-3-nitrobenzene (69-b, 3.7 g, 17.3 mmol) was dissolved in ammonia methanol solution (7N, 83 mL), and then concentrated ammonia solution (35 mL) was added. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until completion. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain 2-methoxy-3-nitrobenzeneamide (69-c, 3.0 g, 15.3 mmol, 88% yield). MS Calcd: 196.16; MS Found: 196.74 ([M+H]) + ).

[0949] Step 3: 2-Methoxy-3-nitrobenzamide (69-c, 3.0 g, 15.3 mmol) was suspended in DMF-DMA (20 mL), heated to 95 °C, and stirred for 30 minutes until the reaction solution was clear. The solution was concentrated under reduced pressure to remove volatiles, and 20 mL of ethanol was added to dissolve it for later use. Under ice-water bath conditions, 63 mL of ethanol, 15 mL of acetic acid, and 7.4 mL of hydrazine hydrate (152 mmol) were added sequentially to the reaction flask, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until completion. The organic solvent was removed, water (100 mL) was added, and a solid precipitated. The solid was filtered to obtain 3-(2-methoxy-3-nitrobenzamide)-1-H-1,2,4-triazole (69-d, 2.31 g, 10.5 mmol, 68% yield). MS Calcd: 220.19; MS Found: 243.09 ([M+Na) + ] + ).

[0950] Step 4: 3-(2-methoxy-3-nitrobenzene)-1-H-1,2,4-triazole (69-d, 2.2 g, 10.1 mmol) and potassium carbonate (4.2 g, 30 mmol) were added sequentially to 20 mL of N,N-dimethylformamide solution, followed by the addition of iodomethane (0.86 mL, 13.6 mmol). The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until completion. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1) to obtain 3-(2-methoxy-3-nitrobenzene)-1-methyl-1-H-1,2,4-triazole (69-e, 1.5 g, 6.4 mmol, 63% yield).

[0951] Step 5: 3-(2-methoxy-3-nitrobenzene)-1-methyl-1-H-1,2,4-triazole (69-e, 0.53 g, 2.2 mmol) and 100 mg palladium on carbon were added to methanol (20 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The reaction was detected by TLC and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)aniline (69-f, 330 mg, 1.6 mmol, 74% yield).

[0952] MS Calcd:204.23;MS Found:205.23([M+H] + )

[0953] Step 6: Add 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (69-f, 150 mg, 0.7 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 140 mg, 0.63 mmol) to 5 ml of anhydrous tetrahydrofuran, and add a tetrahydrofuran solution of LiHMDS (2.5 ml, 2.5 mmol) at room temperature. Stir at room temperature for 2 hours. The pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 1:10) to give 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinamide (69 g, 100 mg, 0.25 mmol, 37% yield).

[0954] MS Calcd:388.11;MS Found:389.23([M+H]+ ).

[0955] Step 7: Add 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)nicotinamide (69-g, 100mg, 0.25mmol), cyclopropylformamide (22mg, 0.26mmol), cesium carbonate (127mg, 0.39mmol), XantPhos (30mg, 0.04mmol), and Pd2(dba)3 (24mg, 0.026mmol) The solution was added to anhydrous dioxane (2 ml) and evacuated. The solution was then replaced with nitrogen, heated to 120 °C, stirred for 3 hours, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 6-(cyclopropylcarbamoyl)-N-methoxy4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-nicotinamide (69, 30 mg, 0.068 mmol, 27% yield).

[0956] MS Calcd:437.18; MS Found:438.1([M+H] + ).

[0957] 1 H NMR (400MHz, DMSO-d6) δ11.91(s,1H),10.75(s,1H),10.45(s,1H),8.55(s,1H),8.43(s,1H),8.07(s,1H),7.55(dd,J=8.0,1.2Hz,1 H),7.49(dd,J=8.0,1.2Hz,1H),7.22(t,J=8.0Hz,1H),3.95(s,3H),3.73(s,3H),3.71(s,3H),2.01-1.94(m,1H),0.79-0.75(m,4H).

[0958] Example 70

[0959] 6-(cyclopropylcarbamoyl)-4-((4-fluoro-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide

[0960]

[0961] Step 1: 2,4-Difluoro-1-nitrobenzene (70-a, 1 g, 6.3 mmol), N-methylmethanesulfonamide (690 mg, 6.3 mmol), and potassium carbonate (1.7 g, 12.6 mmol) were added to DMF. The temperature was raised to 80 L, and the mixture was stirred for 2 hours. After the reaction was observed by TLC, the mixture was cooled to room temperature and poured into 100 mL of water. A solid precipitated out. The solid was filtered and purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain N-(5-fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (70-b, 823 mg, 3.3 mmol, 52% yield). MS Calcd: 248; MS Found: 249 ([MH]) - ).

[0962] Step 2: N-(5-fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (70-b, 823 mg, 3.3 mmol) and 100 mg palladium on carbon were added to methanol (20 ml). After purging with hydrogen three times, the system was stirred overnight at room temperature under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-(2-amino-5-fluorophenyl)-N-methylmethanesulfonamide (70-c, 642 mg, 2.9 mmol, 87% yield). No purification was required; the mixture was directly used in the next reaction. MS Calcd: 218; MS Found: 219 ([M+H]) + ).

[0963] Step 3: N-(2-amino-5-fluorophenyl)-N-methylmethanesulfonamide (70-c, 242 mg, 1.1 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 230 mg, 1.1 mmol) were added to 2.5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (2.5 mL, 2.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 mL ethyl ester extract, the organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain 6-chloro-4-((4-fluoro-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (70-d, 147 mg, 0.37 mmol, 34% yield). MS Calcd: 402; MS Found: 403 ([M+H) + ).

[0964] Step 4: Add 6-chloro-4-((4-fluoro-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (70-d, 147 mg, 0.37 mmol), cyclopropylformamide (63 mg, 0.74 mmol), cesium carbonate (400 mg, 1.2 mmol), XantPhos (60 mg, 0.09 mmol), and Pd2(dba)3 (57 mg, 0.06 mmol) to... The solution was added to anhydrous dioxane (6 ml) and evacuated, purged with nitrogen, heated to 120 °C, stirred for 2 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 6-(cyclopropylcarbamoyl)-4-((4-fluoro-2-(N-methylmethanesulfonyl)phenyl)amino)-N-methoxynicotinamide (70, 32 mg, 0.07 mmol, 20% yield). MS Calcd: 451; MS Found: 452 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6): δ11.77(s,1H),10.76(s,1H),9.87(s,1H),8.32(s,1H),7.73(s,1H),7.56(dd,J=9.6,2.8Hz,1 H),7.50-7.46(m,1H),7.33-7.28(m,1H),3.71(s,3H),3.15(s,3H),3.12(s,3H),1.96-1.93(m,1H),0.77-0.74(m,4H).

[0965] Example 71

[0966] 6-(cyclopropylcarbamoyl)-N-ethyl-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide

[0967]

[0968] Step 1: 1-Bromo-2-methoxy-3-nitrobenzene (71-a, 500 mg, 2.16 mmol) and iron powder (900 mg, 16.07 mmol) were added sequentially to a mixture of acetic acid / water (1:1, 15 mL). The reaction mixture was heated to 80 °C and stirred for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (20 mL) and water (20 mL) to separate the organic phase. The organic phase was washed sequentially with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE = 10:1) to obtain 3-bromo-2-methoxyaniline (71-b, 380 mg, 1.48 mmol, 69% yield). MS Calcd: 200.98; MS Found: 202.07 ([M+H) + ).

[0969] Step 3: Dissolve 3-bromo-2-methoxyaniline (71-b, 380 mg, 1.48 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (458 mg, 2.20 mmol), Pd(dppf)Cl2 (60 mg, 0.06 mmol), and sodium phosphate (738 mg, 4.44 mmol) in a mixed solvent of water and dioxane (2 ml / 8 mL), heat to 110 °C, and react for 3 h. Concentrate the reaction solution, add 10 ml of water, and extract with ethyl acetate (10 ml x 10 ml). 3) Combine the ethyl acetate layers, dry with anhydrous sodium sulfate, filter, concentrate to obtain the crude product, and purify by silica gel column chromatography (PE:EA = 10:1) to give 2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline (71-c, 220 mg, 1.08 mmol, 73% yield). MS Calcd: 203.25; MS Found: 204.1 ([M+H] + ).

[0970] Step 3: 2-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline (71-c, 110 mg, 0.54 mmol) and 4,6-dichloro-N-ethylnicotinamide (112 mg, 0.54 mmol) were added to 5 ml of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (3 ml, 3.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain a white solid 6-chloro-N-ethyl-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (71-d, 70 mg, 0.18 mmol, 34% yield).

[0971] Step 4: Add 6-chloro-N-ethyl-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (71-d, 70 mg, 0.18 mmol), cyclopropylformamide (22 mg, 0.26 mmol), cesium carbonate (127 mg, 0.39 mmol), XantPhos (30 mg, 0.04 mmol), and Pd2(dba)3 (24 mg, 0.026 mmol) to The solution was transferred to anhydrous dioxane (2 ml) and evacuated, purged with nitrogen, heated to 125 °C, stirred for 3 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:10) to give the title compound: 6-(cyclopropylcarbamoyl)-N-ethyl-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (71, 10 mg, 0.023 mmol, 12.8% yield). MS Calcd: 434.21; MS Found: 433.26 ([MH] - ). 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),10.63(s,1H),8.66(t,J=5.6Hz,1H) ,8.52(s,1H),8.16(s,1H),8.05(s,1H),7.91(s,1H),7.34(d,J=7.8Hz,1H) ,7.26(d,J=7.8Hz,1H),7.14(dd,J=7.8Hz,1H),3.89(s,3H),3.57(s,3H), 3.29(t,J=7.2,2H),2.00–1.96(m,1H),1.15(t,J=7.2Hz,3H),0.77(m,4H).

[0972] Example 72

[0973] N-Methoxy-4-((2-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-((4-(methanesulfonyl)phenyl)amino)nicotinamide

[0974]

[0975] Step 1: 2-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline (71-c, 110 mg, 0.54 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 112 mg, 0.54 mmol) were added to 5 ml of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (3 ml, 3.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to 5 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (10 ml x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain a white solid 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (72-a, 140 mg, 0.36 mmol, 69% yield). MS Calcd:387.82;MS Found:386.19([MH] - ).

[0976] Step 2: Add 6-chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide (32061-d, 140 mg, 0.36 mmol), cyclopropylformamide (44 mg, 0.52 mmol), cesium carbonate (256 mg, 0.8 mmol), XantPhos (60 mg, 0.08 mmol), and Pd2(dba)3 (48 mg, 0.052 mmol) to anhydrous... The solution was placed in dioxane (2 ml) under vacuum, purged with nitrogen, heated to 125 °C, stirred for 3 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:10) to give the title compound: N-methoxy-4-((2-methoxy-3-(1-methyl-1H-pyrazolyl-4-yl)phenyl)amino)-6-((4-(methanesulfonyl)phenyl)amino)nicotinamide (72, 30 mg, 0.057 mmol, 15.9% yield). MS Calcd: 522.17; MS Found: 523.33 ([M+H) + ). 1H NMR (400MHz, DMSO-d6) δ11.83(s,1H),10.06(s,1H),9.69(s,1H),8.37(s,1H),8.18(s,1H),7.93(s,1H),7.88(d,J=8.8Hz,2H),7.76(d,J=8.8 Hz,2H),7.40(d,J=7.8Hz,1H),7.32(d,J=7.8Hz,1H),7.19(t,J=7.8Hz,1H),6.64(s,1H),3.90(s,3H),3.74(s,3H),3.62(s,3H),3.12(s,3H).

[0977] Example 73

[0978] 6-(cyclopropylcarbamoyl)-4-((2-(dimethylphospho)phenyl)amino)-N-methoxynicotinamide

[0979]

[0980] Step 1: 2-Iodoaniline (73-a, 0.3 g, 1.36 mmol), dimethylphosphorus oxide (128 mg, 1.63 mmol), potassium phosphate (318 mg, 1.50 mmol), palladium acetate (30 mg, 0.14 mmol), and XantPhos (90 mg, 0.16 mmol) were sequentially added to anhydrous dioxane (3 mL). The mixture was purged with nitrogen three times under vacuum and stirred at 130 °C for 16 hours. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 2-(dimethylphosphoro)aniline (32117-b, 200 mg, 1.17 mmol, 87% yield). MS Calcd: 169.16; MS Found: 170.12 ([M+H] + ).

[0981] Step 2: 2-(dimethylphospho)aniline (73-b, 200 mg, 1.17 mmol) and 4,6-dichloro-N-methoxynicotinamide (int-1, 257 mg, 1.17 mmol) were added to 5 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (2.3 mL, 2.3 mmol) was added at room temperature. The mixture was stirred at 50 °C for 3 hours, the pH was adjusted to 5 with hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 6-chloro-4-((2-(dimethylphospho)phenyl)amino)-N-methoxynicotinamide (73-c, 200 mg, 0.56 mmol, 48% yield). MS Calcd: 353.74; MS Found: 354.23 ([M+H] + ).

[0982] Step 3: 6-chloro-4-((2-(dimethylphospho)phenyl)amino)-N-methoxynicotinamide (73-c, 100 mg, 0.28 mmol), cyclopropylformamide (48 mg, 0.52 mmol), cesium carbonate (170 mg, 0.052 mmol), XantPhos (23 mg, 0.04 mmol), and Pd2(dba)3 (27 mg, 0.03 mmol) were added to anhydrous dioxane (2 ml) and the mixture was evacuated, purged with nitrogen, heated to 125 °C, stirred for 3 hours, filtered, and the filtrate was concentrated and purified by high performance thin-layer chromatography (MeOH:DCM = 1:20) to obtain the title compound: 6-(cyclopropylformamido)-4-((2-(dimethylphospho)phenyl)amino)-N-methoxynicotinamide (73, 15 mg, 0.037 mmol, 13% yield). MS Calcd:402.39; MS Found:403.33([M+H] + ). 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),10.59(s,1H),8.45(s,1H),7.85(d,J=7.6Hz,1H),7.69(d,J=12.8Hz,1H),7.62–7.53(m, 2H),7.39(d,J=7.6Hz,1H),7.33(t,J=7.6Hz,1H),3.63(s,3H),1.95–1.87(m,1H),1.68(s,3H),1.65(s,3H),0.75–0.65(m,4H).

[0983] Example 74

[0984] 4-((2-(dimethylphosphono)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide

[0985]

[0986] Step 1: Add 6-chloro-4-((2-(dimethylphospho)phenyl)amino)-N-methoxynicotinamide (73-c, 100 mg, 0.28 mmol), 2-amino-6-fluoropyridine (62 mg, 0.56 mmol), cesium carbonate (170 mg, 0.52 mmol), XantPhos (23 mg, 0.04 mmol), and Pd2(dba)3 (27 mg, 0.03 mmol) to... The solution was placed in anhydrous dioxane (2 ml) under vacuum, purged with nitrogen, heated to 125 °C, stirred for 3 hours, filtered, and the filtrate was concentrated and purified by high-performance thin-layer chromatography (MeOH:DCM = 1:20) to give the title compound: 4-((2-(dimethylphosphono)phenyl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-methoxynicotinamide (74, 15 mg, 0.035 mmol, 12.5% ​​yield). MS Calcd: 429.14; MS Found: 430.31 ([M+H) + ). 1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),10.55(s,1H),9.73(s,1H),8.43(s,1H),7.90–7.81(m,1H),7.77-7.71(m,1H),7.60(t,J=7 .6Hz,1H),7.52-7.49(m,2H),7.37-7.32(m,1H),7.16(s,1H),6.47(dd,J=8.0,6.4Hz,1H),3.63(s,3H),1.70(s,3H),1.67(s,3H).

[0987] Example 75

[0988] 4-((3-chloro-2-(N-methylmethanesulfonyl)phenyl)amino)-6-(cyclopropylformamid...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: (I) in: R 0 It is hydrogen; R 1 Selected from ethyl; R 2 Selected from , , , , , , , , , , , , , ; R 3 Selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from: , , , , .

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from: , .

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 3 Selected from: , , , , , , .

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 3 Selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 6. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

7. A pharmaceutical composition comprising the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

8. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating and / or preventing TYK2-mediated related diseases.

9. The use according to claim 8, wherein, The diseases mentioned are inflammatory diseases, autoimmune diseases, or cancer.

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