TW202043209A - MEK inhibitor and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to a novel MEK inhibitor (as shown in formula I) and a pharmaceutical salt thereof, capable of being used to treat MEK-mediated diseases. The present invention further relates to a preparation method for the compounds and a pharmaceutical composition comprising the compounds.

Description

MEK inhibitor and its application in medicine

The present invention relates to a new type of MEK inhibitor compound and its preparation method and pharmaceutical composition. The present invention also relates to the use of the above-mentioned compound or its pharmaceutical composition in the treatment of MEK-mediated diseases.

According to China’s cancer incidence and mortality data published by the National Central Cancer Registry of China (NCCRC) in 2014, 3.8 million new cancer cases were diagnosed in China that year, with an incidence rate of 278 per 100,000. Among them, 301 per 100,000 men and 253 per 100,000 women; 2.29 million cancer deaths, with a mortality rate of 167 per 100,000, of which 207 per 100,000 men and 126 per 100,000 women. Cancer is a type of disease that seriously endangers the health of the population. It brings a huge burden to families and society, and has become one of the most important public health problems in my country.

Mitogen-activated protein kinases (MAPK) are a group of serine-threonine that can be activated by different extracellular stimulus signals, such as cytokines, neurotransmitters, hormones, cell stress, or cell adhesion. Protein kinase. It mainly includes three sub-families: c-Jun N-terminal kinase (JNK), p38 MAPK and extracellular signal-regulated kinases (ERK). In 30% of tumors, the MAPK/ERK signaling pathway is upregulated. The MAPK/ERK signaling pathway is widely involved in cell growth, proliferation, differentiation, apoptosis, and metastasis, and is also called the Ras-Raf-MEK-ERK signaling pathway. The MAPK/ERK signaling pathway has a conserved three-level kinase mode. Upstream cell signal transduction or Ras oncogene initiation mutations first lead to the initiation of Ras; Ras is a small GTPase, which causes Raf phosphorylation and initiation After activation, Raf phosphorylates and activates MEK (Mitogen-activated and Extracellular signal-regulated Kinase); activated MEK phosphorylates ERK to activate it. Activated ERK1/2 is translocated from the cytoplasm to the nucleus, and then mediates the activation and transcription of various transcription factors and genes such as Elk-1, ATF, NF-1, AP-1, c-fos and c-Jun, and participates in Various biological reactions such as cell proliferation and differentiation, cell morphology maintenance, cytoskeleton construction, cell apoptosis and cell carcinogenesis. Tumors with constitutive initiation of Ras or MEK include colon cancer, pancreatic cancer, breast cancer, brain cancer, ovarian cancer, lung cancer, and skin cancer.

Because MEK is in the middle of the MAPK/ERK signaling pathway, it has a key regulatory role. MEK inhibitors have become one of the current hot spots for tumor drug research and development, and new drugs have been launched, such as Trametinib under the trade name Mekinist. The present invention provides a MEK inhibitor with a novel structure, which has good anti-tumor activity. The MEK inhibitor of the present invention should be understood to inhibit MEK1 and/or MEK2.

(I) 其中， R¹ 選自H、C_1-6 烷基、C_1-6 烷氧基或C_1-6 鹵代烷基； R² 選自C_6-10 芳基、鹵素取代的C_6-10 芳基、C_6-10 雜芳環基或鹵素取代的C_6-10 雜芳環基，所述C_6-10 雜芳環基任意地含有1、2或3個分別獨立地選自N、O或S的雜原子； R³ 或R⁴ 各自獨立地選自H、羥基、C_1-6 烷基、取代的C_1-6 烷基、C_1-6 烷氧基、取代的C_1-6 烷氧基、C_3-6 環烷基或取代的C_3-6 環烷基； R⁵ 選自C_3-10 環烷基、取代的C_3-10 環烷基、C_3-10 雜環基、取代的C_3-10 雜環基、C_6-10 芳基、取代的C_6-10 芳基、C_6-10 雜芳環基或取代的C_6-10 雜芳環基；所述雜環基或雜芳環基任意地含有1、2或3個分別獨立地選自N、O或S的雜原子； R⁶ 選自H、鹵素、C_1-6 烷基、C_1-6 烷氧基或C_1-6 鹵代烷基； X選自NH、O或S；且當X為O時，R⁵ 為稠環或取代的稠環。The present invention relates to a compound represented by general formula (I), or a tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof:

(I) wherein R ^{1 is} selected from H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ^{2 is} selected from C _6-10 aryl, halogen-substituted C _{6- 10} aryl, C _6-10 heteroaromatic ring group or halogen-substituted C _6-10 heteroaromatic ring group, the C _6-10 heteroaromatic ring group optionally contains 1, 2 or 3 independently selected from N , O or S heteroatom; R ³ or R ⁴ are each independently selected from H, hydroxyl, C _1-6 alkyl, substituted C _1-6 alkyl, C _1-6 alkoxy, substituted C _{1 -6} alkoxy, C _3-6 cycloalkyl or substituted C _3-6 cycloalkyl; R ^{5 is} selected from C _3-10 cycloalkyl, substituted C _3-10 cycloalkyl, C _3-10 Heterocyclic group, substituted C _3-10 heterocyclic group, C _6-10 aryl group, substituted C _6-10 aryl group, C _6-10 heteroaryl ring group or substituted C _6-10 heteroaryl ring group; The heterocyclic group or heteroaromatic ring group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O or S; R ^{6 is} selected from H, halogen, C _1-6 alkyl, C _{1 -6} alkoxy or C _1-6 haloalkyl; X is selected from NH, O or S; and when X is O, R ⁵ is a fused ring or a substituted fused ring.

In some embodiments, R ¹ in formula (I) is C _1-3 alkyl.

In some embodiments, R ¹ in formula (I) is methyl.

In some embodiments, R ² in formula (I) is selected from halogen-substituted phenyl groups.

或

。In some embodiments, R ² in formula (I) is

or

.

In some embodiments, R ³ or R ⁴ in formula (I) are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, hydroxy, hydroxy substituted C _1-6 alkyl or hydroxy Substituted C _1-6 alkoxy.

In some embodiments, R ³ or R ⁴ in formula (I) are each independently selected from H, C _1-3 alkyl, C _3-6 cycloalkyl, hydroxy, hydroxy substituted C _1-3 alkyl or hydroxy Substituted C _1-3 alkoxy.

In some embodiments, in formula (I), R ³ is H.

或

。In some embodiments, R ⁴ in formula (I) is selected from H, methyl, cyclopropyl, hydroxyl,

or

.

The compound according to any one of claims 1 to 9, wherein when X is NH or S, R ⁵ is a phenyl group, and the phenyl group is unsubstituted or is selected from C _1-6 alkyl , -NHC (O) R ^a substituents, wherein, R ^a is selected from H, C _1-6 alkyl or C _3-6 cycloalkyl.

。In some embodiments, when X in formula (I) is NH or S, R ⁵ is

.

、

、

或

，其中所述的

、

、

或

未被取代或任意地被選自鹵素、C_1-6 烷基、C_1-6 鹵代烷基、-OR^b 、-OC(O)R^b 、-O(CH₂ )_m C(O)OR^b 、-C(O)R^b 、-C(O)OR^b 、-C(O)NHR^b 、-NHC(O)R^b 、-NO、-CN、-NHC(O)OR^b 或-S(O)₂ R^b 的取代基取代，其中R^b 選自C_1-6 烷基或者C_3-6 環烷基，m選自0、1或2。In some embodiments, when X in formula (I) is O, R ^{5 is} selected from

,

,

or

, Where the

,

,

or

Unsubstituted or randomly selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ^b , -OC(O)R ^b , -O(CH ₂ ) _m C(O)OR ^b , -C(O)R ^b , -C(O)OR ^b , -C(O)NHR ^b , -NHC(O)R ^b , -NO, -CN, -NHC(O)OR ^b or -S( O) ₂ R ^b is substituted by substituents, wherein R ^{b is} selected from C _1-6 alkyl or C _3-6 cycloalkyl, and m is selected from 0, 1, or 2.

、

、

或

，其中所述的

、

、

或

未被取代或任意地被選自C_1-6 烷基、-S(O)₂ R^b 、-NO或-C(O)R^b 的取代基所取代，其中R^b 選自C_1-3 烷基。In some embodiments, when X in formula (I) is O, R ^{5 is} selected from

,

,

or

, Where the

,

,

or

Unsubstituted or optionally substituted with a substituent selected from C _1-6 alkyl, -S(O) ₂ R ^b , -NO or -C(O)R ^b , wherein R ^{b is} selected from C _1-3 alkyl.

、

、

或

，其中所述未被取代或取代的

、

、

或

為

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。In some embodiments, when X in formula (I) is O, R ^{5 is} selected from

,

,

or

, Where the unsubstituted or substituted

,

,

or

for

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

.

In some embodiments, R ⁶ in formula (I) is H or C _1-3 alkyl.

In some embodiments, R ⁶ in formula (I) is H or methyl.

(I-1) 其中， R¹ 選自H、C_1-6 烷基、C_1-6 烷氧基或C_1-6 鹵代烷基； R³ 或R⁴ 各自獨立地選自H、羥基、C_1-6 烷基、羥基取代的C_1-6 烷基、C_1-6 烷氧基、羥基取代的C_1-6 烷氧基或C_3-6 環烷基； R⁶ 選自H、鹵素、C_1-6 烷基、C_1-6 烷氧基或C_1-6 鹵代烷基； R⁷ 選自鹵素； R⁸ 選自H、鹵素、C_1-6 烷基、C_1-6 鹵代烷基、-OR^b 、-OC(O)R^b 、-O(CH₂ )_m C(O)OR^b 、-C(O)R^b 、-C(O)OR^b 、-C(O)NHR^b 、-NHC(O)R^b 、-NO、-CN、-NHC(O)OR^b 或-S(O)₂ R^b ，其中R^b 選自C_1-6 烷基或者C_3-6 環烷基，m選自0、1或2； p1選自0、1、2或3； q1選自0、1、2或3。In some embodiments, the compound represented by general formula (I), or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, is of general formula (I- 1) The compound shown, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug:

(I-1) wherein R ^{1 is} selected from H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ³ or R ⁴ are each independently selected from H, hydroxyl, C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkoxy or C _3-6 cycloalkyl; R ^{6 is} selected from H, halogen , C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ^{7 is} selected from halogen; R ^{8 is} selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl , -OR ^b , -OC(O)R ^b , -O(CH ₂ ) _m C(O)OR ^b , -C(O)R ^b , -C(O)OR ^b , -C(O)NHR ^b , -NHC(O)R ^b , -NO, -CN, -NHC(O)OR ^b or -S(O) ₂ R ^b , wherein R ^{b is} selected from C _1-6 alkyl or C _3-6 cycloalkane Base, m is selected from 0, 1 or 2; p1 is selected from 0, 1, 2 or 3; q1 is selected from 0, 1, 2 or 3.

(I-2) 其中， R¹ 選自H、C_1-6 烷基、C_1-6 烷氧基或C_1-6 鹵代烷基； R³ 或R⁴ 各自獨立地選自H、羥基、C_1-6 烷基、羥基取代的C_1-6 烷基、C_1-6 烷氧基、羥基取代的C_1-6 烷氧基或C_3-6 環烷基； R⁶ 選自H、鹵素、C_1-6 烷基、C_1-6 烷氧基或C_1-6 鹵代烷基； R⁹ 選自鹵素； R¹⁰ 選自H、鹵素、氧代基、C_1-6 烷基、C_1-6 鹵代烷基、-OR^b 、-OC(O)R^b 、-O(CH₂ )_m C(O)OR^b 、-C(O)R^b 、-C(O)OR^b 、-C(O)NHR^b 、-NHC(O)R^b 、-NO、-CN、-NHC(O)OR^b 或-S(O)₂ R^b ，其中R^b 選自C_1-6 烷基或者C_3-6 環烷基，m選自0、1或2； p2選自0、1、2或3； q2選自0、1、2或3。In some embodiments, the compound represented by general formula (I), or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, is of general formula (I- 2) The compound shown, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug:

(I-2) wherein R ^{1 is} selected from H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ³ or R ⁴ are each independently selected from H, hydroxyl, C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkoxy or C _3-6 cycloalkyl; R ^{6 is} selected from H, halogen , C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ^{9 is} selected from halogen; R ^{10 is} selected from H, halogen, oxo, C _1-6 alkyl, C _{1 -6haloalkyl} , -OR ^b , -OC(O)R ^b , -O(CH ₂ ) _m C(O)OR ^b , -C(O)R ^b , -C(O)OR ^b , -C( O)NHR ^b , -NHC(O)R ^b , -NO, -CN, -NHC(O)OR ^b or -S(O) ₂ R ^b , wherein R ^{b is} selected from C _1-6 alkyl or C _{3 -6} cycloalkyl, m is selected from 0, 1 or 2; p2 is selected from 0, 1, 2 or 3; q2 is selected from 0, 1, 2 or 3.

(I-3) 其中， R¹ 選自H、C_1-6 烷基、C_1-6 烷氧基或C_1-6 鹵代烷基； R³ 或R⁴ 各自獨立地選自H、羥基、C_1-6 烷基、羥基取代的C_1-6 烷基、C_1-6 烷氧基、羥基取代的C_1-6 烷氧基或C_3-6 環烷基； R⁶ 選自H、鹵素、C_1-6 烷基、C_1-6 烷氧基或C_1-6 鹵代烷基； R¹¹ 選自鹵素； R¹² 選自H、鹵素、C_1-6 烷基、C_1-6 鹵代烷基、-OR^b 、-OC(O)R^b 、-O(CH₂ )_m C(O)OR^b 、-C(O)R^b 、-C(O)OR^b 、-C(O)NHR^b 、-NHC(O)R^b 、-NO、-CN、-NHC(O)OR^b 或-S(O)₂ R^b ，其中R^b 選自C_1-6 烷基或者C_3-6 環烷基，m選自0、1或2； p3選自0、1、2或3； q3選自0、1、2或3。In some embodiments, the compound represented by general formula (I), or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, is of general formula (I- 3) The compound shown, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug:

(I-3) wherein R ^{1 is} selected from H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ³ or R ⁴ are each independently selected from H, hydroxyl, C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkoxy or C _3-6 cycloalkyl; R ^{6 is} selected from H, halogen , C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ^{11 is} selected from halogen; R ^{12 is} selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl , -OR ^b , -OC(O)R ^b , -O(CH ₂ ) _m C(O)OR ^b , -C(O)R ^b , -C(O)OR ^b , -C(O)NHR ^b , -NHC(O)R ^b , -NO, -CN, -NHC(O)OR ^b or -S(O) ₂ R ^b , wherein R ^{b is} selected from C _1-6 alkyl or C _3-6 cycloalkane Base, m is selected from 0, 1 or 2; p3 is selected from 0, 1, 2 or 3; q3 is selected from 0, 1, 2 or 3.

The present invention further provides a compound, a tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 1) 4-((3-Acetylaminophenyl)thio)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydro Pyridine-3-carboxamide; 2) 4-((3-Acetylaminophenyl)amino)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydro Pyridine-3-carboxamide; 3) 4 -(1-Acetyl- 1,2,3,4-tetrahydroquinolin-5-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1 -Methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 4) 4-(1-Ethylsulfonyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1 -Methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 5) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((2-oxo-1,2,3,4-tetrahydroquinoline -6-yl)oxy)-1,6-dihydropyridine-3-carboxamide; 6) 2-((2-Fluoro-4-iodophenyl)amino)-4-(indol-5-yl)oxy-1-methyl-6-oxo-1,6-dihydropyridine- 3-formamide; 7) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((1,2,3,4-tetrahydroquinolin-6-yl) (Oxy)-1,6-dihydropyridine-3-carboxamide; 8) 4 -(1-Acetyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl Base-6-oxo-1,6-dihydropyridine-3-carboxamide; 9) 4-((1-acetindol-5-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1, 6-Dihydropyridine-3-methanamide; 10) 4 -(1-Ethylindol-5-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1, 6-Dihydropyridine-3-methanamide; 11) 4 -(1-Ethylindol-4-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1, 6-Dihydropyridine-3-methanamide; 12) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((1-nitroso-1,2,3,4-tetrahydroquinolin-5-yl )Oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide; 13) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((2-oxo-1,2,3,4-tetrahydroquinoline -5-yl)oxy)-1,6-dihydropyridine-3-carboxamide; 14) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((1-nitrosoindol-4-yl)oxy)-6-oxo-1 ,6-Dihydropyridine-3-methanamide; 15) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((1,2,3,4-tetrahydroquinolin-5-yl) (Oxy)-1,6-dihydropyridine-3-carboxamide; 16) 2-((2-Fluoro-4-iodophenyl)amino)-4-(indol-4-yl)oxy-1-methyl-6-oxo-1,6-dihydropyridine- 3-formamide; 17) 4-((1-acetindol-4-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1, 6-Dihydropyridine-3-methanamide; 18) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((1-(methylsulfonyl)indol-4-yl)oxy)-6-oxy Substitution-1,6-dihydropyridine-3-carboxamide; 19) 2-((2-Fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-4-((2-oxo-1,2,3,4-tetra (Hydroquinolin-5-yl)oxy)-1,6-dihydropyridine-3-carboxamide; 20) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((3-oxo-3,4-dihydro-2H-benzo[ b][1,4]oxazine-8-yl)oxy)-1,6-dihydropyridine-3-carboxamide; or 21) 2-((4-Bromo-2-fluorophenyl)amino)-1-methyl-4-((1-methylsulfonyl)indol-4-yl)oxy)-6-oxo -1,6-Dihydropyridine-3-methanamide; 22) 2-((2-Fluoro-4-iodophenyl)amino)-N,1-dimethyl-4-((1-(methylsulfonyl)indol-4-yl)oxy)- 6-oxo-1,6-dihydropyridine-3-carboxamide; 23) N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((1-(methylsulfonyl)indol-4-yl)oxy Base)-6-oxo-1,6-dihydropyridine-3-carboxamide; 24) 2-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1-methyl-4-((1-(methylsulfonyl)indole-4 -Yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide; 25) 2-((2-Fluoro-4-iodophenyl)amino)-N-hydroxy-1-methyl-4-((1-(methylsulfonyl)indol-4-yl)oxy) -6-oxo-1,6-dihydropyridine-3-carboxamide; 26) 2-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethyl)-1-methyl-4-((1-(methylsulfonyl)indole-4 -Yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide; 27) 2-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-4-((2-oxo-1 ,2,3,4-tetrahydroquinolin-5-yl)oxy)-1,6-dihydropyridine-3-carboxamide; 28) 2-((2-Fluoro-4-iodophenyl)amino)-N-hydroxy-1-methyl-6-oxo-4-((2-oxo-1,2,3,4-tetrahydro Quinolin-5-yl)oxy)-1,6-dihydropyridine-3-carboxamide; 29) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((7-methyl-2-oxo-1,2,3,4-tetrahydroquinoline -5-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide; 30) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylindol-4-yl)oxy)-6-oxo-1, 6-dihydropyridine-3-methanamide; 31) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((7-methyl-1,2,3,4-tetrahydroquinolin-5-yl) (Oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide; or 32) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methyl-3-oxo-3,4-dihydro-2H-benzo[ b] [1,4]oxazine-8-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide.

(II) 其中，R¹ 、R³ 、R⁴ 、R⁵ 和R⁶ 如權利要求1所述; R¹³ 為鹵素。The present invention also provides a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof,

(II) wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 are} as described in claim 1; R ¹³ is halogen.

(Ⅲ) 其中，R¹ 、R³ 、R⁴ 、R⁵ 和R⁶ 如權利要求1所述。The present invention also provides an intermediate for synthesizing the compound of general formula (II) or a pharmaceutically acceptable salt thereof, which has a structure as shown in general formula (III),

(III) Wherein, R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 are} as claimed in claim 1.

(Ⅲ)                                               (II) 通式(Ⅲ)化合物在酸性條件下發生鹵代反應，得到通式(II)化合物， 其中，R¹ 、R³ 、R⁴ 、R⁵ 和R⁶ 如請求項1所述，R¹³ 為鹵素。The present invention also provides a method for preparing the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

(III) (II) The compound of general formula (III) undergoes halogenation reaction under acidic conditions to obtain the compound of general formula (II), wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 are} as specified in claim 1 As mentioned, R ¹³ is halogen.

The present invention also provides a pharmaceutical composition, which comprises an effective therapeutic dose of at least any one compound represented by the structural formula (I) of the present invention and at least one pharmaceutically acceptable excipient.

The present invention further provides a pharmaceutical composition in which the mass ratio of the compound represented by the structural formula (I) to the excipient is 0.0001:1-10.

The invention provides the application of the compound or pharmaceutical composition represented by the structural formula (I) in the preparation of medicines.

The present invention further provides a preferred technical solution for the application.

Preferably, the application is an application in the preparation of a medicine for treating and/or preventing cancer.

Preferably, the application is an application in the preparation of drugs for treating diseases mediated by MEK. Preferably, the disease is cancer.

Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Xuwang's cell tumor, lung squamous cell carcinoma, lichen Keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

Preferably, the application is as a MEK inhibitor.

Preferably, the application is as a MEK1 and/or MEK2 inhibitor.

The present invention also provides a method for treating and/or preventing diseases mediated by MEK, which comprises administering a therapeutically effective amount of at least any one of the compounds represented by structural formula (I) or pharmaceutical composition to the treatment object.

Preferably, in the above method, the MEK-mediated disease is cancer.

The present invention also provides a method for treating cancer, which comprises administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula (I) to the treatment object.

Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocytoma, head and neck cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lung Squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

Unless otherwise specified, the general chemical terms used in the general structural formula have their usual meanings.

For example, unless otherwise specified, the term "halogen" used in the present invention refers to fluorine, chlorine, bromine or iodine.

In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -Pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, the "1-8" in the "1-8-like alkyl group" refers to a linear or branched arrangement containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms Group.

"Alkoxy" refers to the oxyether form of the aforementioned linear or branched alkyl group, that is, -O-alkyl.

In the present invention, "a", "an", "the", "at least one" and "one or more" can be used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

The term "aryl" in the present invention, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or condensed ring aromatic group including carbon ring atoms. Preferably, the aryl group is a 6 to 10 membered monocyclic or bicyclic aromatic ring group. Preferably it is phenyl and naphthyl. Most preferred is phenyl.

The term "heterocyclic group", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 3-8 membered stable monomer consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S A ring system in which nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom to form a stable structure. Examples of these heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, pyridinyl, oxazinyl, oxopazizinyl, oxopyridinyl, tetrahydrofuranyl, dioxolane, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfonylene, thiomorpholinyl sulfonyl and tetrahydro Oxadiazolyl.

The term "heteroaryl" in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- or 10-membered benzo A fused heteroaromatic ring system or a bicyclic heteroaromatic ring system, which consists of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms can be selectively Upon oxidation, the nitrogen heteroatoms can be selectively quaternized. The heteroaryl group can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene And thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl.

The term "cycloalkyl" refers to a cyclic saturated alkyl chain having 3-10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

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。The term "fused ring" refers to a polycyclic ring composed of two or more aromatic rings, carbocyclic rings, heteroaromatic rings or heterocyclic rings with common ring edges. The "fused ring" can be a fused aromatic ring (consisting of two One or more benzene rings or aromatic rings are fused together, such as naphthalene, anthracene, phenanthrene), aromatic fused rings (condensed by two or more benzene rings or aromatic rings and carbon rings), aromatic fused Heterocycle (condensed by two or more benzene rings or aromatic rings and heteroaromatic or heterocyclic rings, such as indole, quinoline), carbocyclic condensed ring (condensed by two or more carbocyclic rings And together), carbon-fused heterocyclic ring (condensed by two or more carbocyclic and heteroaromatic rings or heterocyclic rings), condensed heteroaromatic ring (condensed by two or more heteroaromatic rings Together) or condensed heterocycles (condensed by two or more heterocycles or condensed together by two or more heterocycles and heteroaromatic rings, such as purines). The fused ring does not include

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The term "substituted" means that one or more hydrogen atoms in the group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C _1-8 alkyl, C _3-12 cycloalkyl, -OR ₁ , -SR ₁ , =0, =S, -C (O)R ₁ , -C(S)R ₁ , =NR ₁ , -C(O)OR ₁ , -C(S)OR ₁ , -NR ₁ R ₁ , -C(O)NR ₁ R ₁ , Cyano, nitro, -S(O) ₂ R ₁ , -OS(O ₂ )OR ₁ , -OS(O) ₂ R ₁ , -OP(O)(OR ₁ )(OR ₂ ); where R ₁ And R _{2 are} independently selected from -H, C _1-6 alkyl or C _1-6 haloalkyl. In some embodiments, the substituents are independently selected from the group comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy Group, isobutoxy, tert-butoxy, -SCH ₃ , -SC ₂ H ₅ , formaldehyde, -C(OCH ₃ ), cyano, nitro, -CF ₃ , -OCF ₃ , amino, dimethyl A group of amino group, methylthio group, sulfonyl group or acetyl group.

Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , Phenylmethyl, Dioxocenylmethyl or Pazizinylmethyl.

Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-Dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy or 3- Hydroxypropoxy.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Pharmaceutically acceptable non-toxic organic bases capable of being derivatized into salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2- Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine, Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

When the compound provided by the present invention is a base, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, Hydroiodic acid, perchloric acid, hydrochloric acid, isethionic acid, propionic acid, glycolic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pantothenic acid, phosphoric acid , Succinic acid, sulfuric acid, 2-naphthalenesulfonic acid, cyclohexylamine sulfonic acid, salicylic acid, saccharic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% purity, a more suitable purity of at least 75%, and a particularly suitable purity of at least 98% (% is weight ratio).

The prodrug of the compound of the present invention is included in the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into a desired compound in the body. For example, any pharmaceutically acceptable salt, ester, salt of ester or other derivative of the compound of the present invention can directly or indirectly provide the compound of the present invention or its pharmaceutically active metabolite or Residues. Particularly preferred derivatives or prodrugs are those compounds that can increase the bioavailability of the compounds of the present invention when administered to patients (for example, can make oral compounds more easily absorbed into the blood), or promote the transfer of parent compounds to biological organs or Those compounds delivered at the site of action (for example, the brain or lymphatic system). Therefore, the term "administration" in the treatment method provided by the present invention refers to the administration of the compound disclosed in the present invention that can treat different diseases, or although it is not clearly disclosed but can be transformed into the present disclosure in vivo after administration to a subject Compound compound. The conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).

Obviously, the definition of any substituent or variable at a specific position in a molecule is independent of other positions in the molecule. It is easy to understand that those skilled in the art can select the substituents or substituted forms of the compounds of the present invention through the existing technical means and the methods described in the present invention to obtain chemically stable and easy-to-synthesize compounds.

The compounds of the present invention may contain one or more asymmetric centers, and may produce diastereomers and optical isomers from this. The present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

The above formula (I) does not exactly define the three-dimensional structure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or in the process of racemization or epimerization known to those skilled in the art, the product obtained may be a mixture of stereoisomers.

When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

When the compound represented by formula (I) and its pharmaceutically acceptable salt have a solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.

The term "composition", in the present invention, refers to a product including a specified amount of each specified ingredient, and any product produced directly or indirectly from a combination of specified amounts of each specified ingredient. Therefore, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods for preparing the compounds of the present invention are also part of the present invention. In addition, some crystalline forms of the compound may exist in polymorphs, and this polymorph is included in the present invention. In addition, some compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.

The pharmaceutical composition provided by the present invention includes a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient, and other optional therapeutic components or adjuvants . Although in any given case, the most suitable way of administering the active ingredient depends on the particular subject to be administered, the nature of the subject and the severity of the disease, the pharmaceutical composition of the present invention includes oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.

In fact, according to conventional drug mixing technology, the compound represented by formula (I) of the present invention, or prodrug, or metabolite, or pharmaceutically acceptable salt, can be used as an active component and mixed with a drug carrier to form a drug combination Things. The pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may adopt a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of bringing into association the active ingredient and the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. In addition, the product can be easily prepared into the desired appearance.

Therefore, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or its stereoisomers, tautomers, polymorphs, solvates, and pharmaceutically acceptable salts thereof , Its prodrug. The combination of the compound represented by formula (I) or its pharmaceutically acceptable salt, and one or more other compounds with therapeutic activity is also included in the pharmaceutical composition of the present invention.

The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include, but are not limited to, lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include but are not limited to syrup, peanut oil, olive oil and water. Gas carriers include but are not limited to carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any pharmacologically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, micro Crystal cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used in oral solid preparations such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here. Alternatively, standard aqueous or non-aqueous formulation techniques can be used for tablet coating.

The tablet containing the compound or pharmaceutical composition of the present invention can be compressed or molded, and optionally, can be made into a tablet together with one or more auxiliary components or adjuvants. The active ingredient is in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to make compressed tablets. The powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to make a molded tablet. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, a formulation intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, compounded with suitable and convenient metering auxiliary materials, which make up about 5% to 95% of the total pharmaceutical composition. The unit dosage form generally contains about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water. A suitable surfactant such as hydroxypropyl cellulose may be included. In glycerin, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared. Further, a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems. Further, the above-mentioned pharmaceutical composition can be prepared into a sterile powder form for immediate preparation of sterile injection or dispersion. In any case, the final injection form must be sterile, and for easy injection, it must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, it is preferable that the pharmaceutical composition be stored under conditions of anti-microbial contamination such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device. Using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, these preparations can be prepared by conventional processing methods. As an example, a cream or ointment is prepared by adding about 5 wt% to 10 wt% of a hydrophilic material and water to produce a cream or ointment with the desired consistency.

The pharmaceutical composition provided by the present invention may take a solid as a carrier and is suitable for rectal administration. A unit dose suppository is the most typical dosage form. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by mixing the pharmaceutical composition with softened or melted auxiliary materials, then cooling and molding.

In addition to the above-mentioned adjuvant components, the above formulations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, thickening agents, Lubricants and preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood. The pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can be prepared in the form of a powder or a concentrated solution.

In general, to treat the conditions or discomfort shown above, the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day. For example, for inflammation, cancer, psoriasis, allergies/asthma, diseases and discomforts of the immune system, diseases and discomforts of the central nervous system (CNS), the effective treatment drug dosage level is 0.01 mg/kg body weight to 50 mg/kg body weight per day, or 0.5mg to 3.5g per patient per day.

However, it is understood that lower or higher dosages than those mentioned above may be required. The specific dosage level and treatment plan for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, gender, diet, time of administration, route of administration, excretion rate, and combination of drugs. The severity of the condition and the specific disease being treated.

Typical compounds of the present invention include, but are not limited to the compounds shown in Table 1.

4-((3-乙醯氨基苯)硫基)-2-((2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 2

4-((3-乙醯氨基苯基)氨基)-2-((2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 3

4 -(1 -乙醯基- 1,2,3,4 -四氫喹啉-5-基)氧基)-2-((2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 4

4 -(1 -乙磺醯基- 1,2,3,4 -四氫喹啉-5-基)氧基)-2-(2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 5

2-((2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-4-((2-氧代-1,2,3,4-四氫喹啉-6-基)氧基)-1,6-二氫吡啶-3-甲醯胺 6

2-((2-氟-4-碘苯基)氨基)-4-(吲哚-5-基)氧基-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 7

2-((2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-4-((1,2,3,4-四氫喹啉-6-基)氧基)-1,6-二氫吡啶-3-甲醯胺 8

4 -(1-乙醯-1,2,3,4 -四氫喹啉-6-基)氧基)-2-(2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 9

4-((1-乙醯吲哚-5-基)氧基)-2-((2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 10

4 -(1 -乙磺醯基吲哚-5-基)氧基)-2-(2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 11

4 -(1 -乙磺醯基吲哚-4-基)氧基)-2-(2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 12

2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((1-亞硝基-1,2,3,4-四氫喹啉-5-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 13

2-((2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-4-((2-氧代-1,2,3,4-四氫喹啉-5-基)氧基)-1,6-二氫吡啶-3-甲醯胺 14

2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((1-亞硝基吲哚-4-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 15

2-((2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-4-((1,2,3,4-四氫喹啉-5-基)氧基)-1,6-二氫吡啶-3-甲醯胺 16

2-((2-氟-4-碘苯基)氨基)-4-(吲哚-4-基)氧基-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 17

4-((1-乙醯吲哚-4-基)氧基)-2-((2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-1,6-二氫吡啶-3-甲醯胺 18

2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((1-(甲基磺醯)吲哚-4-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 19

2-((2-氟-4-碘苯基)氨基)-1,5-二甲基-6-氧代-4-((2-氧代-1,2,3,4-四氫喹啉-5-基)氧基)-1,6-二氫吡啶-3-甲醯胺 20

2-((2-氟-4-碘苯基)氨基)-1-甲基-6-氧代-4-((3-氧代-3,4-二氫-2H-苯并[b][1,4]噁嗪-8-基)氧基)-1,6-二氫吡啶-3-甲醯胺 21

2-((4-溴-2-氟苯基)氨基)-1-甲基-4-((1-甲基磺醯)吲哚-4-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 22

2-((2-氟-4-碘苯基)氨基)-N，1-二甲基-4-((1-(甲磺醯基)吲哚-4-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 23

N-環丙基-2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((1-(甲磺醯基)吲哚-4-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 24

2-((2-氟-4-碘苯基)氨基)-N-(2-羥基乙氧基)-1-甲基-4-((1-(甲磺基)吲哚-4-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 25

2-((2-氟-4-碘苯基)氨基)-N-羥基-1-甲基-4-((1-(甲磺醯基)吲哚-4-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 26

2-((2-氟-4-碘苯基)氨基)-N-(2-羥乙基)-1-甲基-4-((1-(甲磺醯基)吲哚-4-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 27

2-((2-氟-4-碘苯基)氨基)-N-(2-羥基乙氧基)-1-甲基-6-氧代-4-((2-氧代-1,2,3,4-四氫喹啉-5-基)氧基)-1,6-二氫吡啶-3-甲醯胺 28

2-((2-氟-4-碘苯基)氨基)-N-羥基-1-甲基-6-氧-4-((2-氧-1,2,3,4-四氫喹啉-5-基)氧基)-1,6-二氫吡啶-3-甲醯胺 29

2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((7-甲基-2-氧代-1,2,3,4-四氫喹啉-5-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 30

2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吲哚-4-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺    31

2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((7-甲基-1,2,3,4-四氫喹啉-5-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺    32

2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基-3-氧代-3,4-二氫-2H-苯并[b][1,4]噁嗪-8-基)氧基)-6-氧代-1,6-二氫吡啶-3-甲醯胺 [Table 1] Example number Structure and naming 1

4-((3-Acetylaminophenyl)thio)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine- 3-methanamide 2

4-((3-Acetylaminophenyl)amino)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine- 3-methanamide 3

4-(1-Acetyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl 6-oxo-1,6-dihydropyridine-3-carboxamide 4

4-(1-Ethylsulfonyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl 6-oxo-1,6-dihydropyridine-3-carboxamide 5

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((2-oxo-1,2,3,4-tetrahydroquinoline-6 -Yl)oxy)-1,6-dihydropyridine-3-carboxamide 6

2-((2-Fluoro-4-iodophenyl)amino)-4-(indol-5-yl)oxy-1-methyl-6-oxo-1,6-dihydropyridine-3- Formamide 7

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((1,2,3,4-tetrahydroquinolin-6-yl)oxy )-1,6-Dihydropyridine-3-carboxamide 8

4 -(1-Acetyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl- 6-oxo-1,6-dihydropyridine-3-carboxamide 9

4-((1-acetindol-5-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6- Dihydropyridine-3-carboxamide 10

4 -(1-Ethylindol-5-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6- Dihydropyridine-3-carboxamide 11

4 -(1-Ethyl indol-4-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6- Dihydropyridine-3-carboxamide 12

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((1-nitroso-1,2,3,4-tetrahydroquinolin-5-yl)oxy Yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 13

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((2-oxo-1,2,3,4-tetrahydroquinoline-5 -Yl)oxy)-1,6-dihydropyridine-3-carboxamide 14

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((1-nitrosoindol-4-yl)oxy)-6-oxo-1,6 -Dihydropyridine-3-methanamide 15

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((1,2,3,4-tetrahydroquinolin-5-yl)oxy )-1,6-Dihydropyridine-3-carboxamide 16

2-((2-Fluoro-4-iodophenyl)amino)-4-(indol-4-yl)oxy-1-methyl-6-oxo-1,6-dihydropyridine-3- Formamide 17

4-((1-acetindol-4-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6- Dihydropyridine-3-carboxamide 18

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((1-(methylsulfonyl)indol-4-yl)oxy)-6-oxo- 1,6-Dihydropyridine-3-carboxamide 19

2-((2-Fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-4-((2-oxo-1,2,3,4-tetrahydroquine (Alkolin-5-yl)oxy)-1,6-dihydropyridine-3-carboxamide 20

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((3-oxo-3,4-dihydro-2H-benzo[b] [1,4]oxazine-8-yl)oxy)-1,6-dihydropyridine-3-carboxamide twenty one

2-((4-Bromo-2-fluorophenyl)amino)-1-methyl-4-((1-methylsulfonyl)indol-4-yl)oxy)-6-oxo-1 ,6-Dihydropyridine-3-methanamide twenty two

2-((2-Fluoro-4-iodophenyl)amino)-N,1-dimethyl-4-((1-(methylsulfonyl)indol-4-yl)oxy)-6- Oxo-1,6-dihydropyridine-3-carboxamide twenty three

N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((1-(methylsulfonyl)indol-4-yl)oxy) -6-oxo-1,6-dihydropyridine-3-carboxamide twenty four

2-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1-methyl-4-((1-(methylsulfonyl)indol-4-yl )Oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide 25

2-((2-Fluoro-4-iodophenyl)amino)-N-hydroxy-1-methyl-4-((1-(methylsulfonyl)indol-4-yl)oxy)-6 -Oxo-1,6-dihydropyridine-3-carboxamide 26

2-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethyl)-1-methyl-4-((1-(methylsulfonyl)indol-4-yl )Oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide 27

2-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-4-((2-oxo-1,2 ,3,4-Tetrahydroquinolin-5-yl)oxy)-1,6-dihydropyridine-3-carboxamide 28

2-((2-Fluoro-4-iodophenyl)amino)-N-hydroxy-1-methyl-6-oxo-4-((2-oxo-1,2,3,4-tetrahydroquinoline -5-yl)oxy)-1,6-dihydropyridine-3-carboxamide 29

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((7-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-5 -Yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide 30

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylindol-4-yl)oxy)-6-oxo-1,6- Dihydropyridine-3-carboxamide 31

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((7-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy )-6-oxo-1,6-dihydropyridine-3-carboxamide 32

2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methyl-3-oxo-3,4-dihydro-2H-benzo[b] [1,4]oxazine-8-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide

In order to make the above content clearer and clearer, the present invention will use the following embodiments to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific implementations of the present invention, so that those skilled in the art can understand the present invention, but are not used to limit the protection scope of the present invention. In the specific embodiments of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.

Unless otherwise specified, all parts and percentages in the present invention are calculated by weight, and all temperatures refer to degrees Celsius.

The following abbreviations are used in the examples: ACN or MeCN: acetonitrile; AcOH: acetic acid; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; BH ₃ -THF: tetrahydrofuran borane; Con. HCl: concentrated hydrochloric acid; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM: dichloromethane; DMA: N,N-dimethylacetamide; DMF: N ,N-Dimethylformamide; EA: ethyl acetate; EtOAc: ethyl acetate; EtOH: ethanol; h or hrs: hour HPLC: high performance liquid chromatography; HS 15: polyethylene glycol dodecahydroxystearic acid Lithium oxide; IPA: isopropanol; LCMS: liquid chromatography-mass spectrometry; MeOH: methanol; min: minutes; NaOt-Bu: sodium tert-butoxide Pd/C: palladium-carbon catalyst; PE: petroleum ether; Py.: pyridine ; TEA: triethylamine; TFA: trifluoroacetic acid.

Preparation of compound M1

Step 1: Synthesis of compound M1-1

Dissolve dimethyl malonate (39.60g) and malononitrile (19.80g) in anhydrous tetrahydrofuran (200mL), cool to -25 ^o C, slowly add DBU (91.34g) dropwise under the protection of nitrogen. Stir at room temperature for 18h. 30% methylamine aqueous solution (200mL) was added dropwise and stirred at room temperature for 24h. 10N aqueous sodium hydroxide solution (45 mL) was added dropwise, and the mixture was stirred at room temperature for 6 h. After the reaction was completed, acetone (300 mL) was added under ice bath and stirred for 30 min, filtered with suction, the filter cake was rinsed with acetone, and dried under reduced pressure to obtain 50.00 g of white solid, namely compound M1-1.

Step 2: Synthesis of compound M1-2

Compound M1-1 (50.00g) was dissolved in acetonitrile (500 mL), cooled to 0 ^o C was slowly added dropwise phosphorus oxychloride (120 mL), dropwise, after stirring for 30min the reaction was raised to 70 ^o C 12h. After the reaction was completed, the reaction solution was quenched in saturated potassium carbonate solution (1L), a yellow solid precipitated, filtered with suction, the filter cake was washed with water, and dried under reduced pressure to obtain 26.00 g of a yellow solid, namely compound M1-2.

Step 3: Synthesis of compound M1

Compound M1-2 (26.00g) and 3,4-difluoronitrobenzene (22.60 g) was dissolved in DMA (300mL) was added cesium carbonate (69.30g), 100 ^o C the reaction 2h. After the reaction is completed, after cooling to room temperature, the reaction solution is quenched into ice water (1.5L), adjusted by 3N HCl to pH=5-6, a yellow solid is precipitated, filtered with suction, and the filter cake is washed with ethyl acetate to make a slurry to obtain 25.00g yellow Solid, compound M1 .

LCMS: [M+H] ⁺ = 322.88

Example 1: Compound 1 (4-((3-acetamidophenyl)thio)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1 ,6-Dihydropyridine-3-methanamide) synthesis

Step 1: Synthesis of compound 1-1

Add compound M1 (1.12g) and 3-acetaminothiophenol (0.64g) to a 100mL single-neck flask, dissolve in DMA (15mL), add cesium carbonate (2.28g) as a base under N ₂ protection, and react at 150 ^o C 4h. After cooling to room temperature, the reaction solution was quenched in ice water (50 mL), the pH was adjusted to neutral with HCl (3N), a yellow solid precipitated out, filtered with suction, the filter cake was washed with water, and dried to obtain 1.20 g of yellow solid, namely compound 1- 1.

Step 2: Synthesis of compound 1-2

50mL single-neck flask was added compound 1-1 (1.20g), was dissolved in concentrated sulfuric acid (12mL), 100 ^o C the reaction 0.5h. After cooling to room temperature, the reaction solution was quenched in ice water (120 mL), and the pH of the ammonia water was adjusted to 8. The system changed from yellow to red, and the solid precipitated. The filter cake was washed with water and dried to obtain 1.00 g of red-brown solid. Compound 1-2.

Step 3: Synthesis of compound 1-3

50mL single-neck flask was added compound 1-2 (1.00g), dissolved in acetic acid (20mL), was added 10% Pd / C (300mg) , after three permutation N _2, H ₂ three times replacement, 50 ^o C the reaction 1h. It was filtered while hot, the filtrate was spin-dried, ethyl acetate and methanol were added to make a slurry, and then filtered with suction to obtain 723 mg of yellow solid, namely compound 1-3.

Step 4: Synthesis of compound 1

25mL single-neck flask was added compound 1-3 (441mg), dissolved 6mol / L hydrochloric acid (6 mL), cooled to 0-5 ^o C, dissolved NaNO ₂ (83mg) 3mL of water was slowly added dropwise to the reaction solution, After dripping, the reaction is kept for 30 minutes. Potassium iodide (332 mg) was dissolved in 3 mL of water and dropped into the above reaction solution. After the dropping was completed, the mixture was raised to room temperature and reacted overnight. After the reaction was completed, suction filtration, the filter cake was beaten with saturated Na ₂ S ₂ O ₃ , washed with water, and the product was separated by column chromatography (DCM:MeOH=95:5) to obtain 54 mg of white solid, namely compound 1 (purity 94.65%).

LCMS: [M+H] ⁺ = 553.00

Example 2: Compound 2 (4-((3-Acetylaminophenyl)amino)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1 , 6-Dihydropyridine-3-methanamide synthesis)

Step 1: Synthesis of compound 2-1

Add compound M1 (1.23g) and 3-acetaminoaniline (0.66g) to a 100mL single-mouth bottle, dissolve in anhydrous 1,4-dioxane (30mL), add BINAP (200mg) and NaOt-Bu (538mg) , Pd ₂ (dba) ₃ (73mg) was added under the protection of N _{2 and} reacted overnight at 100 ^o C. Cool to room temperature, filter with suction, add water (100mL) to the filtrate, extract with EtOAc (50mL*3), combine the organic phases and wash with saturated brine, dry with anhydrous Na ₂ SO ₄ , spin dry, and separate the product by column chromatography (DCM: MeOH = 95:5) to obtain 0.70 g of yellow solid, namely compound 2-1.

Step 2: Synthesis of compound 2-2

50mL single-neck flask was added compound 2-1 (0.70g), was dissolved in 80% sulfuric acid (7mL), 90 ^o C the reaction 0.5h. After cooling to room temperature, the reaction solution was quenched in ice water (100 mL), and the pH of the ammonia water was adjusted to 8. The system changed from yellow to red, and solids separated out. The product was separated by suction filtration and cake column chromatography (DCM:MeOH=96: 4) to obtain 216 mg of reddish brown solid, namely compound 2-2.

Step 3: Synthesis of compound 2-3

50mL single-neck flask was added compound 2-2 (216mg), dissolved in acetic acid (5mL), was added 10% Pd / C (40mg) , after three permutation N _2, H ₂ three times replacement, 50 ^o C the reaction 1h. Suction and filter while hot, spin-dry the filtrate, add saturated sodium bicarbonate to make a slurry, filter with suction, wash the filter cake with water, and dry to obtain 146 mg of off-white solid, namely compound 2-3.

Step 4: Synthesis of compound 2

Add compound 2-3 (146mg) into a 25mL single-mouth bottle, dissolve it in 6mol/L hydrochloric acid (3mL), cool to 0-5 ^o C, dissolve NaNO ₂ (28mg) in 1.5mL water, and slowly drop into the above reaction solution , After dripping, the reaction is kept for 30min. Potassium iodide (113 mg) was dissolved in 1.5 mL of water and dropped into the above reaction solution. After the dropping, the mixture was raised to room temperature and reacted overnight. After the reaction is completed, suction filtration, the filter cake is slurried with saturated Na ₂ S ₂ O ₃ , washed with water, and the product is separated by column chromatography (DCM:MeOH=96:4) to obtain 7.0 mg of a white solid, which is compound 2 (purity 96.38%).

LCMS: [M+H] ⁺ = 536.03

Example 3: Compound 3(4-(1-acetyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-2-((2-fluoro-4-iodophenyl )Amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbamide) synthesis

Step 1: Synthesis of compound 3-1

500mL three-neck flask was added 5-hydroxy-dihydro-quinolinone (5.00g), dissolved in anhydrous tetrahydrofuran (20mL), cooled to 0 ^o C, under nitrogen was slowly added dropwise _{BH 3 -THF (1mol / L,} 245mL) , After dropping, warm to room temperature and stir overnight. After the reaction is complete, MeOH is slowly added dropwise under ice bath, and 20% sodium hydroxide aqueous solution is added to pH 12 when no bubbles emerge. Stir at room temperature for 2 hours, add 100 mL of water, 3N HCl to adjust the pH to acidity, then neutralize with saturated sodium bicarbonate, extract with EtOAc (100 mL*3), combine the organic phases and wash with saturated brine, anhydrous Na ₂ SO ₄ Dry and spin dry to obtain 5.00 g of the crude product, namely compound 3-1, which is directly used in the next reaction without further purification.

Step 2: Synthesis of compound 3-2

Compound M1 (1.93g) and compound 3-1 (2.70g) was dissolved in DMA (20mL), was added cesium carbonate (9.80 g) as a base, 155 ^o C the reaction 1.5h. After cooling to room temperature, the reaction solution was quenched in ice water (200 mL), the pH was adjusted to neutral with HCl (3N), a yellow solid precipitated out, filtered off with suction, the filter cake was washed with water, and dried to obtain 2.20 g of yellow solid, namely compound 3- 2.

Step 3: Synthesis of compound 3-3

100mL single-neck flask was added compound 3-2 (2.20g), was dissolved in concentrated sulfuric acid (20mL), 100 ^o C the reaction 0.5h. After cooling to room temperature, the reaction solution was quenched in ice water (200 mL), and the pH of the ammonia water was adjusted to 8. The system changed from yellow to red. The solid precipitated out. The filter cake was washed with water and dried to obtain 2.20 g of red-brown solid. Compound 3-3.

Step 4: Synthesis of compound 3-4

50mL single-neck flask was added compound 3-3 (2.20g), dissolved in acetic anhydride (20mL), 30 ^o C reaction 3h. After the reaction is completed, add water and stir, then add saturated sodium bicarbonate and stir. The yellow solid is separated out, filtered with suction, the filter cake is watered, filtered while hot, the filtrate is spin-dried, saturated sodium bicarbonate is added to make a slurry, then filtered with suction, the filter cake is washed with water to obtain a crude product 2.00 g, compound 3-4, was directly used in the next reaction without further purification.

Step 5: Synthesis of compound 3-5

Compound 3-4 (1.20 g) was added to a 100 mL single-necked flask, dissolved in a mixed solvent of ethanol (15 mL) and water (15 mL), reduced iron powder (542 mg) and NH ₄ Cl (385 mg) were added, and the reaction was refluxed for 2 h. After the reaction is complete, the filtrate is filtered while hot, the filtrate is spin-dried, and then water is added to make a slurry, filtered with suction, and the filter cake is beaten with ethyl acetate to obtain 1.00 g of brown solid, namely compound 3-5.

Step 6: Synthesis of compound 3

Add compound 3-5 (1.00g) into a 100mL single-mouth bottle, dissolve it in 6mol/L hydrochloric acid (30mL), cool to 0-5 ^o C, dissolve NaNO ₂ (177mg) in 9mL water, and slowly drop into the above reaction solution , After dripping, the reaction is kept for 30min. Potassium iodide (1.00 g) was dissolved in 6 mL of water and dropped into the above reaction solution. After the dropping was completed, it was raised to room temperature and reacted overnight. After the reaction was completed, filtered with suction, the filter cake was slurried with saturated Na ₂ S ₂ O ₃ , washed with water, and the brown solid was separated from the product by reverse phase column chromatography (H ₂ O:MeOH=40:60) to obtain 470 mg of white solid, namely compound 3 ( Purity 99.47%).

LCMS: [M+H] ⁺ =577.00

Example 4: Compound 4(4-(1-ethanesulfonyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-2-(2-fluoro-4-iodophenyl )Amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbamide) synthesis

Step 1: Synthesis of compound 4-1

Compound 3 (390 mg) was added to a 100 mL single-mouth flask, dissolved in methanol (10 mL), 3N hydrochloric acid (5 mL) was added, and the reaction was refluxed for 5 hours. After the reaction was completed, after the solvent was rotated, the pH of the NaOH aqueous solution was adjusted to neutral, and a light yellow solid was precipitated, filtered with suction, washed with water, and dried to obtain 360 mg of a light yellow solid, namely compound 4-1.

Step 2: Synthesis of compound 4

After the compound 4-1 (200mg) was dissolved in ethyl sulfonic acyl chloride (2 mL), cooled to 0 ^o C, slowly added dropwise pyridine (296 mg of), dropwise, warmed to room temperature the reaction 6h. After the reaction was completed, methanol (5mL) was added dropwise under an ice bath. After sodium bicarbonate adjusted the pH to neutral, ethyl acetate (20mL*3) was added for extraction, the organic phases were combined, washed with saturated sodium bicarbonate, washed with water, and washed with saturated brine After spin-drying, the product was separated by column chromatography (DCM:MeOH=96:4) to obtain 125 mg of off-white solid, namely compound 4 (purity 95.03%).

LCMS: [M+H] ⁺ = 627.12

Example 5: Compound 5 (2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((2-oxo-1,2,3,4 -Tetrahydroquinolin-6-yl)oxy)-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 5-1

Compound M1 (3.00g) and 3-hydroxy-3,4-dihydroquinolinone (3.10g) were added to a 100mL single-mouth flask, dissolved in DMA (30mL), and cesium carbonate (15.20g) was added under N ₂ protection, 150 ^o C for 6h. Cool to room temperature, dilute with water (150mL), adjust the pH to 5 ~ 7 with 3N HCl, precipitate solids, filter with suction and wash the filter cake with water, dry to obtain 5.11g brown solids (purity 92.0%), namely compound 5-1 .

Step 2: Synthesis of compound 5-2

100mL single-neck flask was added compound 5-1 (5.11g) and concentrated sulfuric acid (50mL), 100 ^o C the reaction 0.5h. Cool to room temperature, drip into ice water (100mL), adjust the pH to 7-8 with ammonia water, precipitate solids, filter with suction and wash the filter cake with water, and dry to obtain 2.40g yellow solids, namely compound 5-2, no further Purified and used directly in the next step.

Step 3: Synthesis of compound 5-3

100mL single-neck flask was added compound 5-2 (2.40g), EtOH (24mL ) and H ₂ O (24mL), was added Fe powder _{(1.15g), NH 4 Cl (} 0.81g), 80 o C reaction 4h. Filter while hot, wash the filter cake with hot ethanol, spin off the ethanol to precipitate a solid, filter and wash the filter cake with water, then beat the filter cake with EA, and filter to obtain 1.10 g (purity: 92.5%) of a yellow solid, namely compound 5-3.

Step 4: Synthesis of compound 5

Add compound 5-3 (1.00g) into a 50mL single-neck bottle, dissolve it in concentrated hydrochloric acid (7mL), cool to 0 ~ 5 ^o C in an ice bath, dissolve NaNO ₂ (0.21g) in 4mL water, and slowly drip into the above reaction In the solution, after dripping, the reaction is kept for 30min. Dissolve potassium iodide (0.83g) in 3mL of water, drop it into the above reaction solution, after dripping, stir for 15min, remove the ice bath, react overnight at room temperature, suction filtration, the filter cake is slurried with saturated sodium thiosulfate solution for 30min, filtered, After washing with water, the product was separated by column chromatography (DCM:MeOH=20:1) to obtain 75.4 mg of a yellow solid with a purity (95.28%).

LCMS: [M+H] ⁺ = 549.09

Example 6: Compound 6(2-((2-Fluoro-4-iodophenyl)amino)-4-(indol-5-yl)oxy-1-methyl-6-oxo-1,6 -Dihydropyridine-3-methanamide) synthesis

Step 1: Synthesis of compound 6-1

Add indoline-5-ol (1.00g) and acetic anhydride (1.13g) to a 50mL single-necked flask, dissolve in DCM (10mL), ice bath, drip TEA (1.50g), after dripping, stir for 15min, remove In an ice bath, react at room temperature for 2h. Rotate to dry directly, add the residue to 20% NaOH solution (20mL), stir for 30min, adjust the pH to 5 ~ 7 with 3 N HCl, precipitate solid, filter with suction and wash the filter cake with water, dry to obtain 1.02g light yellow solid, that is Compound 6-1.

Step 2: Synthesis of compound 6-2

50mL single-neck flask was added compound 6-1 (1.02g) and Compound M1 (1.44g), was dissolved in DMA (16mL), was added cesium carbonate (4.66 g of) under N _2, 150 ^o C the reaction 6h. Cooled to room temperature, dropped into water (100 mL), adjusted pH to 5-7 with 3N HCl, precipitated solid, filtered with suction and washed the filter cake with clear water, dried to obtain 1.50 g of brown solid, namely compound 6-2.

Step 3: Synthesis of compound 6-3

50mL single-neck flask was added compound 6-2 (1.50g) and concentrated sulfuric acid (16mL), 100 ^o C the reaction 0.5h. Cooled to room temperature, dropped into ice water (40 mL), adjusted pH to 7-8 with ammonia water, precipitated solid, filtered with suction and washed the filter cake with clear water, dried to obtain 0.90 g of brown solid, namely compound 6-3.

Step 4: Synthesis of compound 6-4

50mL single-neck flask was added compound 6-3 (450mg), EtOH (5mL ) and 3N HCl (5 mL), 80 o C the reaction 6h. It was cooled to room temperature, adjusted to pH 6 with ammonia water under ice bath, and directly spin-dried to obtain 410 mg of crude product, namely compound 6-4.

Step 5: Synthesis of compound 6-5

50mL single-neck flask was added compound 6-4 (410mg), EtOH (5mL ) and H ₂ O (5 mL), was added Fe powder (210mg) and _{NH 4 Cl (147mg), 80} o C reaction 4h. Filter while hot, wash the filter cake with hot ethanol, spin off the ethanol to precipitate a solid, filter and wash the filter cake with water, and filter to obtain 190 mg of a brown solid, namely compound 6-5.

Step 6: Synthesis of compound 6

Add compound 6-5 (190mg) to an 8mL sample bottle, dissolve it in concentrated hydrochloric acid (1.4mL), in an ice bath, dissolve NaNO ₂ (40mg) in 0.5mL water, slowly drop it into the above reaction solution, after dripping, keep the reaction warm 30min. Dissolve potassium iodide (154mg) in 0.9mL water, drop it into the above reaction solution, after dripping, stir for 15min, remove the ice bath, react overnight at room temperature, filter with suction, beat the filter cake with saturated sodium thiosulfate solution for 30min, filter, After washing with water, the product was separated by column chromatography (DCM:MeOH=20:1) to obtain 32.3 mg of yellow solid, namely compound 6, purity (95.24%).

LCMS: [M+H] ⁺ = 521.07

Example 7: Compound 7(2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((1,2,3,4-tetrahydroquinoline -6-yl)oxy)-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 7-1

Add 1,2,3,4-tetrahydroquinoline-6-ol (1.00g) and acetic anhydride (1.02g) into a 50mL single-necked flask, dissolve in DCM (10mL), ice bath, drop TEA (1.36g) After dripping, stir for 15min, remove the ice bath, and react at room temperature for 2h. Rotate to dry directly, add the residue to 20% NaOH solution (20mL), stir for 30min, adjust the pH to 5 ~ 7 with 3N HCl, precipitate solid, filter with suction and wash the filter cake with water, dry to obtain 1.04g of light yellow solid, which is the compound 7-1.

Step 2: Synthesis of compound 7-2

50mL single-neck flask was added compound 7-1 (1.04g) and Compound M1 (1.46g), was dissolved in DMA (15mL), was added cesium carbonate (4.40 g of) under N _2, 150 ^o C the reaction 6h. Cooled to room temperature, dropped into water (100 mL), adjusted pH to 5-7 with 3N HCl, precipitated solid, filtered with suction and washed the filter cake with clear water, dried to obtain 1.34 g of brown solid, namely compound 7-2.

Step 3: Synthesis of compound 7-3

50mL single-neck flask was added compound 7-2 (1.34g), concentrated sulfuric acid (14mL), 100 ^o C the reaction 0.5h. Cooled to room temperature, dripped into ice water (40 mL), adjusted pH to 7-8 with ammonia water, precipitated solids, filtered with suction and washed the filter cake with water, dried to obtain 0.92 g of brown solids, namely compound 7-3.

Step 4: Synthesis of compound 7-4

50mL single-neck flask was added compound 7-3 (460mg), EtOH (5mL ) and ^{3N HCl (5mL), 80 o} C the reaction 6h. It was cooled to room temperature, adjusted to pH 6 with ammonia water under ice bath, and directly spin-dried to obtain 430 mg of crude product, namely compound 7-4.

Step 5: Synthesis of compound 7-5

50mL single-neck flask was added compound 7-4 (430mg), EtOH (5mL ) and H ₂ O (5mL), was added Fe powder (212mg) and _{NH 4 Cl (150mg), 80} o C reaction 4h. Filter while hot, wash the filter cake with hot ethanol, spin off the ethanol to precipitate a solid, filter and wash the filter cake with water, and filter to obtain 203 mg of brown solid, which is compound 7-5.

Step 6: Synthesis of compound 7

Add compound 7-5 (203mg) to an 8mL sample bottle, dissolve it in concentrated hydrochloric acid (1.4mL) in an ice bath, dissolve NaNO ₂ (40mg) in 0.5mL water, slowly drop it into the above reaction solution, after dripping, keep the reaction warm 30min. Potassium iodide (159mg) was dissolved in 0.9mL water, dropped into the above reaction solution, dripped, stirred for 15min, removed the ice bath, reacted overnight at room temperature, suction filtered, the filter cake was slurried with saturated sodium thiosulfate solution for 30min, filtered, After washing with water, the product was separated by column chromatography (DCM:MeOH=20:1) to obtain 65.5 mg of yellow solid, namely compound 7, purity (95.47%).

LCMS: [M+H] ⁺ = 535.04

Example 8: Compound 8 (4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino )-1-Methyl-6-oxo-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 8-1

Add 1,2,3,4-tetrahydroquinoline-6-ol (1.00g) and acetic anhydride (1.02g) into a 50mL single-necked flask, dissolve in DCM (10mL), ice bath, drop TEA (1.36g) After dripping, stir for 15min, remove the ice bath, and react at room temperature for 2h. Rotate to dry directly, add the residue to 20% NaOH solution (20mL), stir for 30min, adjust the pH to 5 ~ 7 with 3N HCl, precipitate solid, filter with suction and wash the filter cake with water, dry to obtain 1.04g of light yellow solid, which is the compound 8-1.

Step 2: Synthesis of compound 8-2

50mL single-neck flask was added compound 8-1 (1.04g) and Compound M1 (1.46g), was dissolved in DMA (15mL), was added cesium carbonate (4.40 g of) under N _2, 150 ^o C the reaction 6h. Cooled to room temperature, dropped into water (100 mL), adjusted pH to 5-7 with 3N HCl, precipitated solid, filtered with suction and washed the filter cake with water, dried to obtain 1.34 g of brown solid, namely compound 8-2.

Step 3: Synthesis of compound 8-3

50mL single-neck flask was added compound 8-2 (1.34g), concentrated sulfuric acid (14mL), 100 ^o C the reaction 0.5h. Cooled to room temperature, dropped into ice water (40 mL), adjusted pH to 7-8 with ammonia water, precipitated solid, filtered with suction and washed the filter cake with clear water, dried to obtain 0.92 g of brown solid, namely compound 8-3.

Step 4: Synthesis of compound 8-4

50mL single-neck flask was added compound 8-3 (460mg), EtOH (5mL ) and H ₂ O (5mL), was added Fe powder (208 mg) and _{NH 4 Cl (146mg), 80} o C reaction 4h. Filter while hot, wash the filter cake with hot ethanol, spin off the ethanol to precipitate a solid, filter and wash the filter cake with water, and filter to obtain 216 mg of brown solid, namely compound 8-4.

Step 5: Synthesis of compound 8

Add compound 8-4 (216mg) to an 8mL sample vial, dissolve it in concentrated hydrochloric acid (1.6mL), in an ice bath, dissolve NaNO ₂ (39mg) in 0.6mL water, slowly drop it into the above reaction solution, finish the drip, keep the reaction warm 30min. Dissolve potassium iodide (154 mg) in 1 mL of water, drop it into the above reaction solution, after dripping, stir for 15 min, remove the ice bath, react overnight at room temperature, suction filtration, the filter cake is slurried with saturated sodium thiosulfate solution for 30 min, filtered, and washed with water The product was separated by column chromatography (DCM:MeOH=20:1) to obtain 8.4 mg of yellow solid, namely compound 8, purity (98.31%).

LCMS: [M+H] ⁺ = 577.08

Example 9: Compound 9 (4-((1-acetindol-5-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6- Synthesis of oxo-1,6-dihydropyridine-3-carboxamide)

Step 1: Synthesis of compound 9-1

50mL single-neck flask was added compound 6-3 (450mg), EtOH (5mL ) and H ₂ O (5mL), was added Fe powder (209 mg) and _{NH 4 Cl (147mg), 80} o C reaction 4h. Filter while hot, wash the filter cake with hot ethanol, spin off the ethanol to precipitate a solid, filter and wash the filter cake with water, and filter to obtain 195 mg of a brown solid, namely compound 9-1.

Step 2: Synthesis of compound 9

Add compound 9-1 (195mg) to an 8mL sample vial, dissolve it in concentrated hydrochloric acid (1.4mL), in an ice bath, dissolve NaNO ₂ (36mg) in 0.5mL water, slowly drop it into the above reaction solution, after dripping, keep the reaction warm 30min. Dissolve potassium iodide (144mg) in 0.9mL water, drop it into the above reaction solution, drip it, stir for 15min, remove the ice bath, react overnight at room temperature, suction and filter, the filter cake is slurried with saturated sodium thiosulfate solution for 30min, filtered, After washing with water, the product was separated by column chromatography (DCM:MeOH=20:1) to obtain 6.6 mg of yellow solid, namely compound 9, purity (94.13%).

LCMS: [M+H] ⁺ = 563.07

Example 10: Compound 10 (4-(1-ethanesulfonylindol-5-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl-6- Synthesis of oxo-1,6-dihydropyridine-3-carboxamide)

Add compound 6 (28mg) to an 8mL sample bottle, dissolve in ethylsulfonyl chloride (1mL), and slowly drip into the above reaction solution of pyridine (0.1mL) in an ice bath. After the dripping is completed, the reaction is kept warm for 35min, and the ice bath is removed. Warm reaction for 2h. The product was separated by direct column chromatography (DCM:MeOH=30:1) to obtain 4.3 mg of yellow solid, namely compound 10, purity (95.04%).

LCMS: [M+H] ⁺ = 613.16

Example 11: Compound 11 (4-(1-ethanesulfonylindol-4-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl-6- Synthesis of oxo-1,6-dihydropyridine-3-carboxamide)

Step 1: Synthesis of compound 11-2

Add compound 11-1 (10.00g) and HAc (80.0mL) into a 250mL single-neck bottle at room temperature. The system is a clear green solution. After being fully cooled in an ice water bath, NaBH ₃ CN (11.84g) is added in batches, and the reaction solution becomes Yellow and vent gas, return to room temperature and react for 5h. In an ice bath, adjust the pH to 12 with a 20wt% NaOH aqueous solution and stir for 1 hour. Adjust the pH to 3 with 1N HCl, and stir for 1 h. Adjust the pH to 8.0 with saturated aqueous NaHCO ₃ solution, and extract three times with 60 mL EA. The organic phase was spin-dried, and the crude product was dissolved in 10 mL methanol and added dropwise to 100 mL DCM. The insoluble matter was filtered out, the filter cake was washed with 50 mL DCM, and dried to obtain 4.232 g of gray-green powder (purity 96.0%), namely compound 11-2.

LCMS: [M+H] ⁺ = 136.1.

Step 2: Synthesis of compound 11-3

Single-neck flask was added 50mL Compound M1 (1.336g) and compound 11-2 (1.678g), was dissolved in DMA (6mL), was added cesium carbonate (6.75 g of) under N ₂ as a base, 150 ^o C the reaction 6h. After cooling to room temperature, the reaction solution was quenched in ice water (50 mL), and the pH was adjusted to neutral with 3N HCl. A yellow solid precipitated out, filtered off with suction, the filter cake was washed with water, and dried to obtain 1.66 g of a crude yellow solid, namely compound 11-3 .

LCMS: [M+H] ⁺ = 422.1.

Step 3: Synthesis of compound 11-4

50mL single-neck flask was added compound 11-3 (1.66g), was dissolved in concentrated sulfuric acid (40mL), 100 ^o C the reaction 35min. After cooling to room temperature, the reaction solution was quenched in ice water (120 mL), the pH of the ammonia water was adjusted to 8, the system changed from yellow to red, solids separated out, filtered with suction, the filter cake was washed with water, and dried to obtain 1.216 g of brown powder (purity 95.6) %), namely compound 11-4.

LCMS: [M+H] ⁺ =440.0

Step 4: Synthesis of compound 11-5

Compound 11-4 (1.2 g) was added to a 100 mL single-neck flask, dissolved with DCM (25.0 mL), ethyl sulfonate chloride (3.512 g) and NaHCO ₃ (2.296 g) were slowly added under ice bath. The temperature was raised to 30°C for 12 hours. The inorganic salt was filtered off, the yellow reaction solution was dropped into 100 mL of stirring anhydrous ether, a yellow sandy solid was precipitated out, filtered, and the filter cake was slurried twice with 100 mL of n-hexane. Drying to obtain 1.715 g of yellow solid (purity 92.0%), namely compound 11-5.

LCMS: [M+H] ⁺ = 532.1.

Step 5: Synthesis of compound 11-6

Add compound 11-5 (1.715g) to a 250mL single-neck flask, dissolve it with a mixed solvent of EtOH (30mL) and H ₂ O (30mL), add ammonium chloride (0.518g) and iron powder (0.722g), and heat to React at 70°C for 12hrs. Filter while hot, spin dry the filtrate, beat with 150 mL of deionized water 3 times, filter and dry the filter cake to obtain 0.789 g of light yellow powder solid, namely compound 11-6.

LCMS: [M+H] ⁺ = 502.0.

Step 6: Synthesis of compound 11

Compound 11-6 (0.789 g) was added to a 25 mL single-neck flask, dissolved in concentrated hydrochloric acid (6 mL), cooled in an ice bath, NaNO ₂ (130 mg) was dissolved in 3 mL of water, and slowly dropped into the above reaction solution for 30 min. Potassium iodide (523 mg) was dissolved in 3 mL of water, dropped into the above reaction solution, and returned to room temperature to react overnight. After suction filtration, the filter cake was dissolved in 10 mL of methanol, dropped into 50 mL of 20wt% sodium thiosulfate aqueous solution and beaten for 1 h, filtered to obtain the filter cake, and the product was separated by column chromatography (DCM:MeOH=95:5) to obtain 63.2 mg of white solid. Purity 96.9%), namely compound 11.

LCMS: [M+H] ⁺ = 613.0.

Example 12: Compound 12 (2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((1-nitroso-1,2,3,4-tetrahydroquine (Alkolin-5-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 12-2

Compound 12-1 (2.0 g) and THF (10.0 mL) were added to a 250 mL dry three-neck flask under N ₂ protection. After being fully cooled in an ice-water bath, 1M BH ₃ -THF (96 mL) was added dropwise, and the reaction solution gassed. After the addition, return to room temperature and react for 12 hours. Slowly add 50 mL methanol to quench under ice bath, adjust the pH to 3 with 1N HCl, and stir for 1 h. Adjust the pH to 8.0 with saturated aqueous NaHCO ₃ solution, and extract three times with 60 mL EA. The organic phase was spin-dried, and EA:PE=1:2 was used as a developing solvent for column chromatography separation, and dried to obtain 1.12 g of gray-green powder (purity 98.3%), namely compound 12-2.

LCMS: [M+H] ⁺ = 150.0.

Step 2: Synthesis of compound 12-3

Single-neck flask was added 50mL Compound M1 (0.700g) and compound 12-2 (0.491g), was dissolved in DMA (2.5mL), was added cesium carbonate (2.11 g) under N ₂ as a base, 150 ^o C the reaction 6h. After cooling to room temperature, the reaction solution was quenched in ice water (50 mL), and the pH was adjusted to neutral with 3N HCl. A yellow solid precipitated out, filtered off with suction, the filter cake was washed with water, and dried to obtain 0.83 g of a crude yellow solid, namely compound 12-3 .

LCMS: [M+H] ⁺ = 436.1.

Step 3: Synthesis of compound 12-4

100mL single-neck flask was added Compound 12-3 (0.83g), was dissolved in concentrated sulfuric acid (40mL), 100 ^o C the reaction 35min. After cooling to room temperature, the reaction solution was quenched in ice water (120 mL), and the pH of the ammonia water was adjusted to 8. The system changed from yellow to red. The solid precipitated out. The filter cake was washed with water and dried to obtain 0.763 g of brown powder (purity 96 %), which is compound 12-4.

LCMS: [M+H] ⁺ = 454.1.

Step 4: Synthesis of compound 12-5

Add compound 12-4 (0.763g) to a 250mL single-neck flask, dissolve it with a mixed solvent of EtOH (30mL) and H ₂ O (30mL), add ammonium chloride (0.442g) and iron powder (0.618g), and heat to React at 70°C for 12hrs. Filter while hot, spin dry the filtrate, beat with 150 mL of deionized water 3 times, filter and dry the filter cake to obtain 0.440 g of crude light yellow powder solid, namely compound 12-5.

LCMS: [M+H] ⁺ = 424.1.

Step 5: Synthesis of compound 12

Compound 12-5 (100 mg) was added to a 25 mL single-necked flask, dissolved in concentrated hydrochloric acid (1.5 mL), cooled in an ice bath, NaNO ₂ (20 mg) was dissolved in 3 mL of water, slowly dropped into the above reaction solution, and reacted for 30 min. Potassium iodide (78 mg) was dissolved in 3 mL of water, dropped into the above reaction solution, and returned to room temperature to react overnight. After suction filtration, the filter cake was dissolved in 2 mL of methanol, dropped into 20 mL of 20wt% sodium thiosulfate aqueous solution to be slurried for 1 h, filtered to obtain the filter cake, and the product was separated by column chromatography (DCM:MeOH=95:5) to obtain 11.1 mg of white solid. Purity 95.1%), namely compound 12.

LCMS: [M-NO+H] ⁺ = 534.0, [M+H] ⁺ = 564.0.

Example 13: Compound 13 (2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((2-oxo-1,2,3,4 -Tetrahydroquinolin-5-yl)oxy)-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 13-2

Single-neck flask was added 50mL Compound M1 (1.0g) and compound 13-1 (0.9g), was dissolved in DMA (4mL), was added cesium carbonate (2.44 g) under N ₂ as a base, 150 ^o C the reaction 6h. After cooling to room temperature, the reaction solution was quenched in ice water (50 mL), the pH was adjusted to neutral with 3N HCl, a yellow solid precipitated, filtered off with suction, the filter cake was washed with water, and dried to obtain 1.35 g of crude yellow solid, namely compound 13-2 .

LCMS: [M+H] ⁺ =450.1.

Step 3: Synthesis of compound 13-3

50mL single-neck flask was added compound 13-2 (1.35g), was dissolved in concentrated sulfuric acid (40mL), 100 ^o C the reaction 35min. After cooling to room temperature, the reaction solution was quenched in ice water (120 mL), the pH of the ammonia water was adjusted to 8, the system changed from yellow to red, and solids separated out, filtered with suction, washed with the filter cake, and dried to obtain a brown powder 1.43g (purity 92.7 %), which is compound 13-3.

LCMS: [M+H] ⁺ = 468.0.

Step 4: Synthesis of compound 13-4

Add compound 13-3 (1.2g) to a 250mL single-neck flask, dissolve it with a mixed solvent of EtOH (40mL) and H ₂ O (40mL), add ammonium chloride (0.491g) and iron powder (0.684g), and heat to React at 70°C for 5hrs. Filter while hot, spin dry the filtrate, beat with 150 mL of deionized water 3 times, filter and dry the filter cake to obtain 0.76 g of crude light yellow powder solid, namely compound 13-4.

LCMS: [M+H] ⁺ = 438.1.

Step 5: Synthesis of compound 13

Compound 13-4 (0.760 g) was added to a 25 mL single-neck flask, dissolved in concentrated hydrochloric acid (6 mL), cooled in an ice bath, NaNO ₂ (144 mg) was dissolved in 3 mL of water, and slowly dropped into the above reaction solution for 30 min. Potassium iodide (577 mg) was dissolved in 3 mL of water, dropped into the above reaction solution, and returned to room temperature to react overnight. After suction filtration, the filter cake was dissolved in 10 mL of methanol, dropped into 50 mL of 20wt% sodium thiosulfate aqueous solution and beaten for 1 h, filtered to obtain the filter cake, and the product was separated by column chromatography (DCM:MeOH=95:5) to obtain 75.5 mg of white solid. Purity 96.5%), which is compound 13.

LCMS: [M+H] ⁺ = 549.1.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ = 10.31 (s, 1H), 9.81 (s, 1H), 7.6-7.60 (m, 3H), 7.42 (dd, J = 8.4, 1.2 Hz, 1H) , 7.26 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 8.1 Hz, 2H), 6.66 (t, J = 8.7 Hz, 1H), 5.08 (s, 1H), 3.15 (s, 3H) , 2.73 (t, J = 7.6 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H).

步驟1

[M+H]⁺ = 563.1 30

步驟1

[M+H]⁺ = 535.1 31

步驟1

[M+H]⁺ = 549.1 32

步驟1

[M+H]⁺ = 565.0 Using commercially available reagents, compounds 29-32 were prepared according to the above method. Numbering Structural formula step Reagent Mass spectrometry 29

step 1

[M+H] ⁺ = 563.1 30

step 1

[M+H] ⁺ = 535.1 31

step 1

[M+H] ⁺ = 549.1 32

step 1

[M+H] ⁺ = 565.0

Example 14: compound 14 (2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((1-nitrosoindol-4-yl)oxy)-6 -Oxo-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 14-2

Add compound 14-1 (10.00g) and HAc (80.0mL) into a 250mL single-neck bottle at room temperature. The system is a clear green solution. After being fully cooled in an ice water bath, NaBH ₃ CN (11.84g) is added in batches, and the reaction solution becomes Yellow and vent gas, return to room temperature and react for 5h. In an ice bath, adjust the pH to 12 with a 20wt% NaOH aqueous solution and stir for 1 hour. Adjust the pH to 3 with 1N HCl, and stir for 1h. Adjust the pH to 8.0 with saturated aqueous NaHCO ₃ solution, and extract three times with 60 mL EA. The organic phase was spin-dried, and the crude product was dissolved in 10 mL methanol and added dropwise to 100 mL DCM. The insoluble matter was filtered off, the filter cake was washed with 50 mL DCM, and dried to obtain 4.232 g of gray-green powder (purity 96.0%), namely compound 14-2.

LCMS: [M+H] ⁺ = 136.1.

Step 2: Synthesis of compound 14-3

Single-neck flask was added 50mL Compound M1 (1.336g) and compound 14-2 (1.678g), was dissolved in DMA (6mL), was added cesium carbonate (6.75 g of) under N ₂ as a base, 150 ^o C the reaction 6h. After cooling to room temperature, the reaction solution was quenched in ice water (50 mL), the pH was adjusted to neutral with 3N HCl, a yellow solid precipitated out, filtered with suction, the filter cake was washed with water, and dried to obtain 1.66 g of crude yellow solid, namely compound 14-3 .

LCMS: [M+H] ⁺ = 422.1.

Step 3: Synthesis of compound 14-4

50mL single-neck flask was added compound 14-3 (1.66g), was dissolved in concentrated sulfuric acid (40mL), 100 ^o C the reaction 35min. After cooling to room temperature, the reaction solution was quenched in ice water (120 mL), the pH of the ammonia water was adjusted to 8, the system changed from yellow to red, solids separated out, filtered with suction, the filter cake was washed with water, and dried to obtain 1.216 g of brown powder (purity 95.6) %), which is compound 14-4.

LCMS: [M+H] ⁺ =440.0

Step 4: Synthesis of compound 14-5

Add compound 14-4 (1.2g) into a 250mL single-necked flask, dissolve it with a mixed solvent of EtOH (30mL) and H ₂ O (30mL), add ammonium chloride (0.439g) and iron powder (0.610g), and heat to React at 70°C for 12hrs. Filter while hot, spin dry the filtrate, beat with 150 mL of deionized water 3 times, filter and dry the filter cake to obtain 0.780 g of crude light yellow powder solid, namely compound 14-5.

LCMS: [M+H] ⁺ = 410.1.

Step 5: Synthesis of compound 14

Compound 14-5 (100 mg) was added to a 25 mL single-mouth bottle, dissolved in 6 mol/L hydrochloric acid (1.5 mL), and cooled in an ice bath. Dissolve NaNO ₂ (20 mg) in 3 mL of water, slowly drip into the above reaction solution, and react for 30 minutes. Potassium iodide (81 mg) was dissolved in 3 mL of water, dropped into the above reaction solution, and returned to room temperature to react overnight. After suction filtration, the filter cake was dissolved in 2 mL of methanol, and the product was separated by column chromatography (DCM:MeOH=95:5) to obtain 6.9 mg (purity 94.3%) of a pale yellow solid, namely compound 14.

LCMS: [M+H] ⁺ = 550.0.

Example 15: compound 15 (2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((1,2,3,4-tetrahydroquinoline -5-yl)oxy)-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 15-2

Compound 15-1 (2.0 g) and THF (10.0 mL) were added to a 250 mL dry three-neck flask under N ₂ protection. After being fully cooled in an ice-water bath, 1M BH ₃ -THF (96 mL) was added dropwise, and the reaction solution gassed. After the addition, return to room temperature and react for 12 hours. Slowly add 50 mL methanol to quench under ice bath, adjust the pH to 3 with 1N HCl, and stir for 1 h. Adjust the pH to 8.0 with saturated aqueous NaHCO ₃ solution, and extract three times with 60 mL EA. The organic phase was spin-dried, EA:PE=1:2 was used as a developing solvent for column chromatography, and dried to obtain 1.12 g of gray-green powder (purity 98.3%), namely compound 15-2.

LCMS: [M+H] ⁺ = 150.0.

Step 2: Synthesis of compound 15-3

Single-neck flask was added 50mL Compound M1 (0.700g) and compound 15-2 (0.491g), was dissolved in DMA (2.5mL), was added cesium carbonate (2.11 g) under N ₂ as a base, 150 ^o C the reaction 6h. After cooling to room temperature, the reaction solution was quenched in ice water (50 mL), and the pH was adjusted to neutral with 3N HCl. A yellow solid precipitated, filtered off with suction, the filter cake was washed with water, and dried to obtain 0.83 g of a crude yellow solid, namely compound 15-3 .

LCMS: [M+H] ⁺ = 436.1.

Step 3: Synthesis of compound 15-4

100mL single-neck flask was added Compound 15-3 (0.83g), was dissolved in concentrated sulfuric acid (40mL), 100 ^o C the reaction 35min. After cooling to room temperature, the reaction solution was quenched in ice water (120 mL), and the pH of the ammonia water was adjusted to 8. The system changed from yellow to red. The solid precipitated out. The filter cake was washed with water and dried to obtain 0.763 g of brown powder (purity 96 %), which is compound 15-4.

LCMS: [M+H] ⁺ = 454.1.

Step 4: Synthesis of compound 15-5

Add compound 15-4 (0.763g) into a 250mL single-neck flask, dissolve it with a mixed solvent of EtOH (30mL) and H ₂ O (30mL), add ammonium chloride (0.442g) and iron powder (0.618g), and heat to React at 70°C for 12hrs. Filter while hot, spin dry the filtrate, beat it with 150 mL of deionized water 3 times, filter and dry the filter cake to obtain 0.440 g of crude light yellow powder solid, namely compound 15-5.

LCMS: [M+H] ⁺ = 424.1.

Step 5: Synthesis of compound 15

Compound 15-5 (100 mg) was added to a 25 mL single-necked flask, dissolved in concentrated hydrochloric acid (3 mL), cooled in an ice bath, NaNO ₂ (20 mg) was dissolved in 1.5 mL of water, and slowly dropped into the above reaction solution for 30 min. Potassium iodide (78 mg) was dissolved in 1.5 mL of water, dropped into the above reaction solution, and returned to room temperature to react overnight. After suction filtration, the filter cake was dissolved in 2 mL of methanol, and dropped into 20 mL of 20wt% sodium thiosulfate aqueous solution to make a slurry for 1 hour. The filter cake was obtained by filtration. The product was separated by column chromatography (DCM:MeOH=95:5) to obtain a white solid 5.6 mg ( Purity 98.94%), namely compound 15.

LCMS: [M+H] ⁺ = 534.9.

Example 16: Compound 16 (2-((2-fluoro-4-iodophenyl)amino)-4-(indol-4-yl)oxy-1-methyl-6-oxo-1,6 -Dihydropyridine-3-methanamide) synthesis

Step 1: Synthesis of compound 16-2

Add compound 16-1 (10.00g) and HAc (80.0mL) to a 250mL single-mouth bottle at room temperature. The system is a clear green solution. After fully cooling in an ice-water bath, NaBH ₃ CN (11.84g) is added in batches, and the reaction solution becomes Yellow and vent gas, return to room temperature and react for 5h. In an ice bath, adjust the pH to 12 with a 20wt% NaOH aqueous solution and stir for 1 hour. Adjust the pH to 3 with 1N HCl, and stir for 1 h. Adjust the pH to 8.0 with saturated aqueous NaHCO ₃ solution, and extract three times with 60 mL EA. The organic phase was spin-dried, and the crude product was dissolved in 10 mL methanol and added dropwise to 100 mL DCM. The insoluble matter was filtered off, the filter cake was washed with 50 mL of DCM, and dried to obtain 4.232 g of gray-green powder (purity 96.0%), namely compound 16-2.

LCMS: [M+H] ⁺ = 136.1.

Step 2: Synthesis of compound 16-3

Single-neck flask was added 50mL Compound M1 (1.336g) and compound 16-2 (1.678g), was dissolved in DMA (6mL), was added cesium carbonate (6.75 g of) under N ₂ as a base, 150 ^o C the reaction 6h. After cooling to room temperature, the reaction solution was quenched in ice water (50 mL), and the pH was adjusted to neutral with 3N HCl. A yellow solid was precipitated, filtered off with suction, the filter cake was washed with water, and dried to obtain 1.66 g of crude yellow solid, namely compound 16-3 .

LCMS: [M+H] ⁺ = 422.1.

Step 3: Synthesis of compound 16-4

50mL single-neck flask was added compound 16-3 (1.66g), was dissolved in concentrated sulfuric acid (40mL), 100 ^o C the reaction 35min. After cooling to room temperature, the reaction solution was quenched in ice water (120 mL), the pH of the ammonia water was adjusted to 8, the system changed from yellow to red, solids separated out, filtered with suction, the filter cake was washed with water, and dried to obtain 1.216 g of brown powder (purity 95.6) %), namely compound 16-4.

LCMS: [M+H] ⁺ =440.0

Step 4: Synthesis of compound 16-5

Add compound 16-4 (1.2g) to a 250mL single-neck flask, dissolve it with a mixed solvent of EtOH (30mL) and H ₂ O (30mL), add ammonium chloride (0.439g) and iron powder (0.610g), and heat to React at 70°C for 12hrs. Filter while hot, spin dry the filtrate, beat with 150 mL of deionized water 3 times, filter and dry the filter cake to obtain 0.780 g of crude light yellow powder solid, namely compound 16-5.

LCMS: [M+H] ⁺ = 410.1.

Step 5: Synthesis of compound 16

Compound 16-5 (0.780 g) was added to a 25 mL single-neck flask, dissolved in concentrated hydrochloric acid (6 mL), and cooled in an ice bath. NaNO ₂ (158 mg) was dissolved in 3 mL of water and slowly dropped into the above reaction solution for 30 min. Potassium iodide (633 mg) was dissolved in 3 mL of water, dropped into the above reaction solution, and returned to room temperature to react overnight. After suction filtration, the filter cake was dissolved in 10 mL of methanol, and dropped into 50 mL of 20wt% sodium thiosulfate aqueous solution to make a slurry for 1 hour. The filter cake was obtained by filtration. The product was separated by column chromatography (DCM:MeOH=95:5) to obtain a white solid of 55.0 mg ( Purity 96.1%), namely compound 16.

LCMS: [M+H] ⁺ = 521.1.

Example 17: Compound 17 (4-((1-acetindol-4-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6- Synthesis of oxo-1,6-dihydropyridine-3-carboxamide)

Step 1: Synthesis of compound 17-2

Compound 17-1 (10.00g) and HAc (80.0mL) were added to a 250mL single-necked flask at room temperature. The system was a clear green solution. After being fully cooled in an ice-water bath, NaBH ₃ CN (11.84g) was added in batches, and the reaction solution became Yellow and vent gas, return to room temperature and react for 5h. In an ice bath, adjust the pH to 12 with a 20wt% NaOH aqueous solution and stir for 1 hour. Adjust the pH to 3 with 1N HCl, and stir for 1 h. Adjust the pH to 8.0 with saturated aqueous NaHCO ₃ solution, and extract three times with 60 mL EA. The organic phase was spin-dried, and the crude product was dissolved in 10 mL methanol and added dropwise to 100 mL DCM. The insoluble matter was filtered out, the filter cake was washed with 50 mL DCM, and dried to obtain 4.232 g of gray-green powder (purity 96.0%), namely compound 17-2.

LCMS: [M+H] ⁺ = 136.1.

Step 2: Synthesis of compound 17-3

Single-neck flask was added 50mL Compound M1 (1.336g) and compound 17-2 (1.678g), was dissolved in DMA (6mL), was added cesium carbonate (6.75 g of) under N ₂ as a base, 150 ^o C the reaction 6h. After cooling to room temperature, the reaction solution was quenched in ice water (50 mL), the pH was adjusted to neutral with 3N HCl, a yellow solid precipitated, filtered off with suction, the filter cake was washed with water, and dried to obtain a crude yellow solid 1.66 g, namely compound 17-3 .

LCMS: [M+H] ⁺ = 422.1.

Step 3: Synthesis of compound 17-4

50mL single-neck flask was added compound 17-3 (1.66g), was dissolved in concentrated sulfuric acid (40mL), 100 ^o C the reaction 35min. After cooling to room temperature, the reaction solution was quenched in ice water (120 mL), the pH of the ammonia water was adjusted to 8, the system changed from yellow to red, solids separated out, filtered with suction, the filter cake was washed with water, and dried to obtain 1.216 g of brown powder (purity 95.6) %), which is compound 17-4.

LCMS: [M+H] ⁺ =440.0

Step 4: Synthesis of compound 17-5

Compound 17-4 (2.688 g) was added to a 100 mL single-neck flask, dissolved in DCM (7.0 mL), and acetic anhydride (6.245 g) was slowly added under ice bath. The temperature was raised to 30°C for 12 hours. The reaction solution was dropped into 100 mL of stirring anhydrous ethyl ether, a yellow powdery solid was precipitated, filtered, and the filter cake was slurried twice with 100 mL of n-hexane. After drying, 2.36 g of a brown solid (purity 91.8%) was obtained, which was compound 17-5.

LCMS: [M+H] ⁺ = 482.1.

Step 5: Synthesis of compound 17-6

Add compound 17-5 (2.36g) to a 250mL single-neck flask, dissolve it with a mixed solvent of EtOH (50mL) and H ₂ O (50mL), add ammonium chloride (0.787g) and iron powder (1.116g), and heat to React at 70°C for 12hrs. Filter while hot, spin dry the filtrate, beat it with 150 mL of deionized water 3 times, filter and dry the filter cake to obtain 1.936 g of crude light yellow powder solid, namely compound 17-6.

LCMS: [M+H] ⁺ = 452.1.

Step 6: Synthesis of compound 17

25mL single-neck flask was added compound 17-6 (1.015g), was dissolved in concentrated hydrochloric acid (12 mL), ice-cooled sufficiently, the NaNO ₂ (180mg) was dissolved in 6mL of water, the reaction solution was slowly added dropwise, the reaction 30min. Potassium iodide (762 mg) was dissolved in 6 mL of water, dropped into the above reaction solution, and returned to room temperature to react overnight. After suction filtration, the filter cake was dissolved in 20 mL of methanol, dropped into 100 mL of 20wt% sodium thiosulfate aqueous solution and beaten for 1 h, filtered to obtain the filter cake, and the product was separated by column chromatography (DCM:MeOH=95:5) to obtain 115.3 mg of light yellow solid (Purity 97.22%), namely compound 17.

LCMS: [M+H] ⁺ = 563.1.

Example 18: compound 18 (2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((1-(methylsulfonyl)indol-4-yl)oxy )-6-oxo-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 18-1

Compound 11-4 (1g) was dissolved in pyridine (5mL), the temperature was lowered to 0°C, and methylsulfonyl chloride (391mg) was added dropwise. After dripping, the temperature was raised to room temperature and reacted for 4h. After the reaction was completed, water (50 mL) and 3N hydrochloric acid were added to adjust the pH to neutral. A yellow solid was precipitated, filtered with suction, the filter cake was washed with water, and dried to obtain 600 mg of a yellow solid, namely compound 18-1.

Step 2: Synthesis of compound 18-2

Compound 18-1 (600 mg) was added to a 100 mL single-neck flask, dissolved in a mixed solvent of ethanol (10 mL) and water (10 mL), reduced iron powder (259 mg) and NH ₄ Cl (186 mg) were added, and the reaction was refluxed for 1 h. After the reaction is completed, the filtrate is filtered while it is hot, the filtrate is spin-dried and then water (30 mL) is added to make a slurry, filtered with suction, and dried to obtain 500 mg of a brown solid, namely compound 18-2.

Step 3: Synthesis of compound 18

Add compound 18-2 (500mg) into a 50mL single-neck bottle, dissolve it in 6mol/L hydrochloric acid (5mL), cool to 0-5°C, dissolve NaNO ₂ (80mg) in 2mL water, and slowly drop it into the above reaction solution. After completion, the reaction is incubated for 30 minutes. Potassium iodide (522 mg) was dissolved in 3 mL of water, dropped into the above reaction solution, after dripping, warmed to room temperature and reacted overnight. After the reaction is completed, the filter cake is saturated with Na ₂ S ₂ O ₃ and washed with water. The brown solid is separated from the product by reverse phase column chromatography (H ₂ O:MeOH=40:60), and 96 mg of off-white solid is obtained, namely compound 18. (Purity 99.85%).

LCMS: [M+H]+=599.04.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ = 9.87 (s, 1H), 7.68-7.54 (m, 3H), 7.43 (d, J = 8.2 Hz, 1H), 7.34 (t, J = 8.1 Hz , 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.66 (t, J = 8.7 Hz, 1H), 5.19 (s, 1H), 3.99 (t , J = 8.4 Hz, 2H), 3.15 (s, 3H), 3.06 (s, 3H), 3.01 (t, J = 8.4 Hz, 2H).

Example 19: Compound 19 (2-((2-fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-4-((2-oxo-1,2, 3,4-Tetrahydroquinolin-5-yl)oxy)-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 19-1

Add dimethyl 2-methylmalonate (10g) and malononitrile (4.52g) to a 25mL single-neck bottle, dissolve in THF (50mL), protect with nitrogen, cool to -25℃ in an ice bath, and add DBU (20.83). g) After 30 minutes of dripping, the mixture was stirred at room temperature for 18 h, and 30% methylamine aqueous solution (50 mL) was added dropwise to react at room temperature. In an ice bath, add acetone, stir for 30 min, a large amount of solids are precipitated out, filtered, and the filter cake is washed with acetone, the solids are slurried with MTBE/MeOH (3:1), filtered and the filter cake is washed with MTBE. The filter cake was collected and dried to obtain 3.66 g of light yellow solid, namely compound 19-1.

Step 2: Synthesis of compound 19-2

Compound 19-1 (2.0g) was added to a 100mL single-necked flask, dissolved in acetonitrile (20mL), POCl ₃ (6.85g) was added under N ₂ protection, and reacted at 70°C overnight. Cool down to room temperature, add the reaction system dropwise to ice water, adjust the pH to 7~8 with saturated potassium hydroxide solution, extract three times with EA, combine the organic phases, backwash three times with 5% formic acid aqueous solution, and use anhydrous organic phase It was dried over sodium sulfate, filtered, and the filtrate was spin-dried to obtain 550 mg of crude yellow solid, compound 19-2, without further purification.

Step 3: Synthesis of compound 19-3

Compound 19-2 (540 mg), 3,4-difluoronitrobenzene (521.66 mg), Cs ₂ CO ₃ (1.78 g), DMA (5 mL) were added to a 10 mL single-necked flask, and the reaction was carried out at 100°C in an oil bath for 4.5 hours. It was cooled to room temperature, added to ice water, extracted three times with EA, combined the organic phases, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The product was separated and purified by silica gel column (DCM:MeOH=30:1) to obtain 360 mg of light yellow solid, namely compound 19-3.

Step 4: Synthesis of compound 19-4

Compound 19-3 (300 mg), 5-hydroxydihydroquinolinone (174 mg), Cs ₂ CO ₃ (871 mg), DMA (5 mL) were added to a 50 mL single-necked flask and reacted in an oil bath at 150°C. Cooled to room temperature, added to ice water (50mL), extracted three times with EA, combined the organic phases, washed twice with saturated brine, dried the organic phase with anhydrous sodium sulfate, filtered, spin-dried, and purified by silica gel column (DCM: MeOH = 30:1) to obtain 160 mg of yellow solid, namely compound 19-4.

Step 5: Synthesis of compound 19-5

8mL sample bottle, add compound 19-4 (160mg), 80% H ₂ SO ₄ (5mL), react at 90 ℃ for 30 min, cool to room temperature, add dropwise to ice water, adjust pH to 7 with ammonia water, precipitate solid, filter , And washed with water, and then dried with ethanol to obtain 200 mg of crude red solid, compound 19-5.

Step 6: Synthesis of compound 19-6

A 100 mL single-mouth flask was added with compound 19-5 (200 mg), iron powder (93 mg), NH ₄ Cl (65 mg), EtOH (10 mL), H ₂ O (10 mL), and reacted at 80° C. for 2 h. Filter while hot, wash the filter cake with hot ethanol, wash with 1N HCl, combine the filtrates, and spin-dry to obtain 220 mg of crude yellow solid, compound 19-6, without further purification.

Step 7: Synthesis of compound 19

Add compound 19-6 (200mg) into a 100mL single-necked flask, dissolve it in concentrated hydrochloric acid (1.4mL), in an ice bath, dissolve NaNO ₂ (37mg) in 0.7mL water, slowly drop it into the above reaction solution, and keep the reaction warm after dripping. 30min. Dissolve potassium iodide (147mg) in 0.7mL water, drop it into the above reaction solution, drop it, stir for 15min, remove the ice bath, react overnight at room temperature, suction and filter, the filter cake is slurried with saturated sodium thiosulfate solution for 30min, filtered, After washing with water, the product was separated by column chromatography (DCM:MeOH=20:1) to obtain 7.4 mg of yellow solid, namely compound 19, purity (90.0%).

LCMS: [M+H]+=563.02.

Example 20: Compound 20 (2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((3-oxo-3,4-dihydro- Synthesis of 2H-benzo[b][1,4]oxazine-8-yl)oxy)-1,6-dihydropyridine-3-carbamide)

Step 1: Synthesis of compound 20-1

Dissolve 2,3-Dimethoxyaniline (2g) and chloroacetic anhydride (2.52g) in THF (10mL), and stir at room temperature for 2h. After the reaction was completed, after the solvent was removed under reduced pressure, saturated sodium bicarbonate solution (50 mL) was added, extracted with ethyl acetate (30 mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was spin-dried to obtain 2.8 g of light yellow solid, namely compound 20-1, which was directly used in the next reaction.

Step 2: Synthesis of compound 20-2

Compound 20-1 (2.8g) was dissolved in DCM (25mL), the temperature was lowered to -78°C, boron tribromide (9.16g) was slowly added dropwise, and the temperature was raised to 0°C for 2 hours. After the reaction, the reactant was quenched into a mixture of ice and water (100 mL), the pH was adjusted to neutral with saturated potassium carbonate solution, extracted with EA/THF (1:1, 50 mL*4), the organic phases were combined and spin-dried to obtain 1.6 g Gray-green solid, compound 20-2.

Step 3: Synthesis of compound 20-3

Compound 20-2 was dissolved in a mixed solvent of MeCN (20 mL) and H ₂ O (2 mL), potassium carbonate (1.9 g) was added, and the mixture was stirred at room temperature overnight. After spin-drying, the product was separated by column chromatography (DCM:MeOH=93:7) to obtain 280 mg of off-white solid, namely compound 20-3.

Step 4: Synthesis of compound 20-4

Compound M1 (50 mg) and compound 20-3 (51 mg) were dissolved in DMA (1 mL), cesium carbonate (175 mg) was added as a base, and the reaction was performed in microwave at 155°C for 3 hours. After the reaction was completed, the reaction solution was quenched in water (30 mL), the pH was adjusted to neutral with 3N HCl, the solid was separated out, filtered with suction, and the filter cake was washed with water to obtain 80 mg of dark brown crude product, namely compound 20-4.

Step 5: Synthesis of compound 20-5

Compound 20-4 (80 mg) was dissolved in concentrated H ₂ SO ₄ (2 mL) and reacted at 100° C. for 0.5 h. After the reaction was completed, it was quenched in 20 mL of ice water, the pH was adjusted to neutral with ammonia water, filtered with suction, and the filter cake was washed with water to obtain 80 mg of dark brown crude product, namely compound 20-5.

Step 6: Synthesis of compound 20-6

A mixed solvent of compound 20-5 (80mg), iron powder (38 mg) and ammonium chloride (27 mg of) was dissolved in H ₂ O (2mL) and EtOH (2mL) in, 80 ℃ reaction 2h. After the reaction is completed, the filter cake is filtered while it is hot, and the filter cake is heated to reflux by adding 20 mL of ethanol, and the filtration is repeated twice while the filter is hot, and the filtrate is combined and spin-dried to obtain 80 mg of dark brown crude product, namely compound 20-6.

Step 7: Synthesis of compound 20

Dissolve compound 20-6 (80mg) in concentrated HCl (3mL) and reduce to 0℃, slowly add 1mL aqueous solution of sodium nitrite (14mg) dropwise. After stirring for 0.5h, add potassium iodide (91mg) 1mL aqueous solution dropwise, After dripping, warm to room temperature overnight. After the reaction was completed, filtered with suction, the filter cake was slurried with saturated sodium thiosulfate solution for 30 min, filtered, washed with water, and the product was separated by climbing a large plate (DCM:MeOH=25:1) to obtain a light yellow solid 7.3mg, namely compound 20, purity ( 94.7%).

LCMS: [M+H]+=551.05.

Example 21: Compound 21 (2-((4-bromo-2-fluorophenyl)amino)-1-methyl-4-((1-methylsulfonyl)indol-4-yl)oxy) -6-oxo-1,6-dihydropyridine-3-carboxamide) synthesis

Dissolve compound 18-2 (200mg) in 48% HBr (2mL), cool to 0°C, add sodium nitrite (31mg) (dissolved in 1mL water), incubate the reaction for 10 minutes, add cuprous bromide (59mg), liter The reaction was stirred at room temperature for 4h. After the reaction is complete, the water phase is decanted, the viscous organic substance at the bottom of the bottle is dissolved in EA (50 mL), washed with saturated sodium thiosulfate, saturated sodium bicarbonate, and finally with saturated brine, and the organic phase is dried with anhydrous sodium sulfate. 19.6 mg of white solid product, compound 21, was obtained through liquid phase separation.

LCMS: [M+H]+=551.11.

Example 22: Compound 22 (2-((2-fluoro-4-iodophenyl)amino)-N,1-dimethyl-4-((1-(methylsulfonyl)indol-4-yl )Oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Preparation of compound 22-2

Compound 22-1 (15 g) and compound SM3 (34.85 g) were dissolved in DMAC (150 mL), and cesium carbonate (79.86 g) was added. Replace with nitrogen for three times. Under the protection of nitrogen, the reaction was raised to 150 ^o C and stirred for 16 hours. TLC detected that the reaction was complete, the reaction solution was cooled, poured into ice water (600 mL), and the solid precipitated out and stirred for 30 minutes. After filtration, the filter cake was washed with water, and the solid was beaten and dried with ethanol to obtain compound 22-2 (23.4 g).

Step 2: Preparation of compound 22-3

Compound 22-2 (22.4 g) was dissolved in acetonitrile (230 mL), and CuCl (18.46 g) and isoamyl nitrite (14.56 g) were added. Nitrogen thrice, the reaction under nitrogen was raised to 60 ^o C the reaction was stirred for 2h. TLC detected that the reaction was complete, the reaction solution was filtered, the filter cake was washed with DCM (50 mL×2), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 22-3 (10 g).

Step 3: Preparation of compound 22-4

Compound SM4 (14.51 g) was dissolved in anhydrous THF (180 mL). Replace with nitrogen three times, under nitrogen protection. Was added dropwise LiHMDS (51.01mL, 1M) at -78 ^o C, stirred for 0.5h. The solution of compound 381172-3 (7.75g) in THF (150 mL) was added dropwise again, and the temperature was slowly heated and stirred for 0.5 h. TLC detected that the reaction was complete. The reaction was quenched by adding water, and then adjusted to pH=5 with 3N HCl. It was extracted twice with ethyl acetate (60 mL), and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was beaten and dried with ethanol to obtain compound 22-4 (10.6 g).

Step 4: Preparation of compound 22-5

Compound 22-4 (10.6 g) was dissolved in anhydrous DCM (400 mL), and replaced with nitrogen three times under nitrogen protection. Was added dropwise DIBAL-H (73.06mL, 1M) at -50 ^o C, stirred for 1.5h. TLC detected that the reaction was complete. The reaction was quenched by adding H ₂ O (3ml) at low temperature, adding NaOH (3ml, 15%) and then adding H ₂ O (7ml), stirring for 0.5h. Add anhydrous sodium sulfate and stir for 20 minutes. Filter and rinse the filter cake with DCM. The filter cake was poured into DCM/MeOH=(10/1), then adjusted to pH=4-5 with 3N HCl, stirred for 15 minutes, filtered, and the filter cake was washed with DCM/MeOH=(10/1). The filtrates were combined and concentrated under reduced pressure. Compound 22-5 (9g) was obtained.

Step 5: Preparation of compound 22-6

Compound 22-5 (9 g) was dissolved in THF (150 mL), and 3N HCl (10 mL) was added. The reaction was raised to 60 ^o C the reaction was stirred for 3h. TLC detected that the reaction was complete, diluted with water, and extracted twice with EA (60 mL). The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain compound 22-6 (8.1 g).

Step 6: Preparation of compound 22-7

Compound 22-6 (1 g) was dissolved in THF (50 mL), and NH ₂ SO ₃ H (333 mg), 2-methyl-2-butene (2.4 g) were added. Dropwise NaCIO ₂ (310mg) at 0 ^o C water (5mL) was added. The reaction was stirred for 4h. The reaction was completed by TLC detection, concentrated under reduced pressure, PE/EA=1/1 (30 mL) was added for beating, filtered, the filter cake was washed with a small amount of ethanol, and dried to obtain compound 22-7 (580 mg).

Step 7: Preparation of compound 22

Compound 22-7 (20 mg) was dissolved in anhydrous DMF (1 mL), methylamine hydrochloride (4.5 mg), HATU (24 mg) were added, and DIEA (10 mg) was added dropwise. Replace with nitrogen three times, and react with stirring at RT for 1 h under nitrogen protection. TLC detected that the reaction was complete, diluted with water, and extracted twice with ethyl acetate (5 mL). The organic layer was washed three times with saturated brine, and then dried with anhydrous sodium sulfate. The residue was separated and purified by TLC plate to obtain compound 22 (8.4 mg, purity 95.5%).

LCMS: [M+H] ⁺ =613.15.

1H NMR (500 MHz, DMSO- d ₆ ) δ = 9.19 (s, 1H), 8.02 (s, 1H), 7.61 (d, J = 10.2 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H) , 7.33 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 6.69 (t, J = 8.3 Hz, 1H), 5.17 (s, 1H), 3.98 (t, J = 7.7 Hz, 2H), 3.23 (s, 3H), 3.05 (s, 3H), 2.98 (t, J = 7.5 Hz, 2H), 2.48 (s, 3H) .

Example 23: Compound 23 (N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((1-(methylsulfonyl)indole- 4-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide) synthesis

Compound 22-7 (20 mg) was dissolved in anhydrous DMF (1 mL), cyclopropylamine (4 mg), HATU (25 mg) were added, and DIEA (10 mg) was added dropwise. Replace with nitrogen three times, and react with stirring at RT for 1 h under nitrogen protection. TLC detected that the reaction was complete, diluted with water, and extracted twice with ethyl acetate (5 mL). The organic layer was washed three times with saturated brine, and then dried with anhydrous sodium sulfate. The residue was separated and purified by TLC plate to obtain compound 23 (19.5 mg, purity 99.8%).

LCMS: [M+H] ⁺ =639.16.

Example 24: Compound 24 (2-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1-methyl-4-((1-(methylsulfonyl) )Indol-4-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Preparation of compound 24-1

Compound 22-7 (20 mg) was dissolved in anhydrous DMF (1 mL), compound M1 (7 mg), HATU (25 mg) were added, and DIEA (10 mg) was added dropwise. Replace with nitrogen three times, and react with stirring at RT for 2h under nitrogen protection. TLC detected that the reaction was complete, diluted with water, and extracted twice with ethyl acetate (5 mL). The organic layer was washed three times with saturated brine, and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain compound 24-1 (20 mg).

Step 2: Preparation of compound 24

Compound 24-1 (20 mg) was dissolved in methanol (2 mL), and HCl (25 uL, 4M) was added. The reaction was stirred at RT for 2h. TLC detected that the reaction was complete, concentrated under reduced pressure, and the residue was separated and purified by TLC plate to obtain compound 24 (13.1 mg, purity 94%).

LCMS: [M+H] ⁺ = 659.15.

¹ H NMR (500 MHz, MeOD) δ = 7.52 (dd, J = 10.3, 1.5 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 4.1 Hz, 2H), 6.88 -6.84 (m, 1H), 6.76 (t, J = 8.6 Hz, 1H), 5.38 (s, 1H), 4.01 (t, J = 8.5 Hz, 2H), 3.72-3.65 (m, 2H), 3.64- 3.56 (m, 2H), 3.43 (s, 3H), 3.04 (t, J = 8.5 Hz, 2H), 2.96 (s, 3H).

步驟1

[M+H]⁺ = 609.1 M2

步驟1

[M+H]⁺ = 550.0 Using commercially available reagents, compound 27 was prepared according to the above method. Numbering Structural formula step Reagent Mass spectrometry 27

step 1

[M+H] ⁺ = 609.1 M2

step 1

[M+H] ⁺ = 550.0

Example 25: Compound 25 (2-((2-fluoro-4-iodophenyl)amino)-N-hydroxy-1-methyl-4-((1-(methylsulfonyl)indole-4- (Yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 25-1

Compound 22-7 (600mg), THP-protected hydroxylamine (235mg) and HATU (1.13g) were added to a 100mL double-necked flask, dissolved in anhydrous DMF (20mL), protected by N ₂ and DIEA (0.7mL) was added with stirring in an ice bath , Reaction for 1h under ice bath. Water (100 mL) was added to the reaction solution to precipitate a yellow solid, which was filtered with suction, and the filter cake was washed with water to obtain a yellow solid, namely compound 25-1.

Step 2: Synthesis of compound 25

Compound 25-1 (200 mg) was added to a 25 mL single-mouth flask, dissolved in 4M methanolic hydrogen chloride solution, and reacted at room temperature for 0.5 h. The reaction solution was directly evaporated to dryness, and separated and purified by preparative TLC (DCM:MeOH=15:1) to obtain 100 mg of white solid, namely compound 25 (purity 97%).

LCMS: [M+H] ⁺ = 615.15

¹ H NMR (500 MHz, DMSO- d ₆ ) δ = 10.75 (s, 1H), 9.07 (s, 1H), 8.58 (s, 1H), 7.60 (d, J = 10.7 Hz, 1H), 7.39 (d , J = 8.3 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.57 (t, J = 8.7 Hz, 1H), 5.24 (s, 1H), 3.99 (t, J = 8.5 Hz, 2H), 3.18 (s, 3H), 3.06 (s, 3H), 2.98 (t, J = 8.3 Hz, 2H ).

步驟1

[M+H]⁺ = 565.0 Using commercially available reagents, compound 28 was prepared according to the above method. Numbering Structural formula step Reagent Mass spectrometry 28

step 1

[M+H] ⁺ = 565.0

Example 26: Compound 26 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethyl)-1-methyl-4-((1-(methylsulfonyl) )Indol-4-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide) synthesis

Step 1: Synthesis of compound 26

Dual port 25 mL flask was added compound 22-7 (20mg), ethanolamine (4mg) and HATU (38mg), was dissolved in anhydrous DMF (2mL), N ₂ protection, was added with stirring DIEA (25μL), rt 1h. Add water (10 mL) to the reaction solution, extract with DCM (5 mL*3), wash the organic phase with water (5 mL*3), wash with saturated brine (5 mL*3), dry with anhydrous sodium sulfate, filter with suction, and evaporate the filtrate to dryness. Preparative TLC separation and purification (DCM:MeOH=15:1) gave a white solid, namely compound 26 (purity 97%).

LCMS: [M+H] ⁺ = 643.24

¹ H NMR (500 MHz, DMSO- d ₆ ) δ = 9.14 (s, 1H), 8.05 (t, J = 5.6 Hz, 1H), 7.61 (dd, J = 10.5, 1.9 Hz, 1H), 7.40 (dd , J = 8.4, 1.4 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.67 (t , J = 8.7 Hz, 1H), 5.22 (s, 1H), 4.63 (t, J = 5.4 Hz, 1H), 3.98 (t, J = 8.5 Hz, 2H), 3.25 (dd, J = 12.1, 6.4 Hz , 2H), 3.22 (s, 3H), 3.06 (s, 3H), 3.08-3.02 (m, 5H), 2.99 (t, J = 8.5 Hz, 2H).

Comparative compound 1: 2-(2fluoro-4-iodophenylamino)-1-methyl-4-(6-methylpyridin-3-yloxy)-6-carbonyl-1,6-dihydropyridine- 3-methanamide

對比化合物1The following comparative compound 1 was prepared as described in Example 31 in WO2015058589.

Comparative compound 1

Comparative compound 2 (D2): 2((2-fluoro4-iodophenyl)amino)-(4-imidazo[1,2-a]pyridine-8-oxy)-1-methyl-6-oxy -1,6-dihydropyridine-3-carboxamide

Step 1: Synthesis of compound D2-1

Add compound M1 (1.50g) and imidazo[1,2-a]pyridine-8-ol (0.69g) into a 20mL microwave tube, dissolve in DMA (15mL), add cesium carbonate (4.54g) under N ₂ protection, Reaction at 150 ^o C for 1h. It was directly spin-dried, and the product was separated by silica gel column (DCM:MeOH = 20:1 ~ 10:1) to obtain 170 mg of yellow solid, namely compound D2-1.

Step 2: Synthesis of compound D2-2

Compound D2-1 (170 mg) and concentrated sulfuric acid (2 mL) were added to a 25 mL single-neck flask and reacted at 100°C for 0.5 h. Cooled to room temperature, dropped into ice water (10 mL), adjusted pH to 7-8 with ammonia water, precipitated solid, filtered with suction and washed the filter cake with clear water, and dried to obtain 240 mg of crude yellow solid product, namely compound D2-2.

Step 3: Synthesis of compound D2-3

Compound D2-2 (240 mg), EtOH (6 mL), H ₂ O (6 mL) were added to a 50 mL single-mouth flask, Fe powder (122 mg), NH ₄ Cl (87 mg) were added, and the reaction was carried out at 80° C. for 4 h. Filter while hot, wash the filter cake with hot ethanol, spin off the ethanol to precipitate a solid, filter and wash the filter cake with water, and filter to obtain 360 mg of crude brown solid product, namely compound D2-3.

Step 4: Synthesis of compound D2

Add compound D2-3 (180mg) to an 8mL sample bottle, dissolve it in concentrated hydrochloric acid (1.3mL), in an ice bath, dissolve NaNO ₂ (36mg) in 0.5mL water, slowly drop it into the above reaction solution, after dripping, keep the reaction warm 30min. Dissolve potassium iodide (146mg) in 0.8mL water, drop it into the above reaction solution, drop it, stir for 15min, remove the ice bath, react at room temperature overnight, suction filtration, and filter the cake with saturated sodium thiosulfate solution for 30min, filter, After washing with water, the product was separated by HPLC (H ₂ O:MeOH=1:1) to obtain 59.1 mg of yellow solid, namely compound D2, purity (95.64%).

LCMS: [M+H]+=519.99.

Pharmacological experiment

Example A: Kinase test

Step 1: Compound preparation

The compound is dissolved in 100% DMSO solution.

Step 2: Kinase reaction process

(1) Prepare 1× kinase buffer solution.

(2) Preparation of compound concentration gradient: the test compound test concentration is 300 nM, diluted into 100% DMSO solution of 100 times final concentration in 384 source plate, and the compound is diluted 3 times with Presision, 10 concentrations. Use a dispenser Echo 550 to transfer 250 nL 100 times the final concentration of the compound to the target plate OptiPlate-384F.

(3) Prepare a 2.5-fold concentration kinase solution with 1× kinase buffer solution.

(4) Add 10 μL of 2.5 times the final concentration of kinase solution to the compound well and the positive control well respectively, and add 10 μL of 1× kinase buffer solution to the negative control well.

(5) Centrifuge at 1000 rpm for 30 seconds, shake and mix the reaction plate and incubate at room temperature for 10 minutes.

(6) Prepare a mixed solution of 5/3 times the final concentration of ATP and kinase substrate with 1× kinase buffer solution.

(7) Add 15 μL of a mixed solution of 5/3 times the final concentration of ATP and substrate to initiate the reaction.

(8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for the corresponding time.

(9) Add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, shake and mix.

(10) Use Caliper EZ Reader to read the conversion rate.

Step 3: Data processing Inhibition percentage%=(Conversion%_max- Conversion%_sample)/(Conversion%_max-Conversion%_min)×100. Among them: "Conversion%_sample" represents the conversion rate reading of the sample; "Conversion%_min" represents the average value of the negative control wells, representing the conversion rate reading of the wells without enzyme activity; "Conversion%_max" represents the average ratio of the positive control wells, representing no compound Suppress the conversion reading of the well.

Fitting the dose-response curve: take the log value of the concentration as the X-axis, and the percentage inhibition rate on the Y-axis. The log(inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism 5 is used to fit the dose-response curve to obtain each compound IC ₅₀ value for enzyme activity. The calculation formula is as follows: Y=bottom + (high-bottom) / (1+10^ ((LogIC ₅₀ -X)*slope))

All Example compounds have good inhibition of MEK1, most of the compounds of MEK1 inhibition IC ₅₀ <100nM, information embodiments IC ₅₀ and Comparative Examples of the compound of Compound MEK1 inhibition in Table 2.

[Table 2] Compound number Compound inhibits the IC ₅₀ (nM) of MEK1 Trametinib 4.7 Compound 3 7.7 Compound 11 1.6 Compound 13 56 Compound 16 33 Compound 17 10 Compound 18 3.6 Compound 19 42 Compound 24 4.3

Example B: COLO205 cell proliferation test

Spread the COLO205 cells in a 96-well plate with 2000 cells and 135 μL/well. After incubating overnight, compound solutions of gradient concentrations were prepared, and 15 were added to the cells in each well. Incubate the DMSO solution of the test compound of each concentration, the final concentration of the compound is 30000, 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 0 nM (the final concentration of DMSO is 0.5%). Incubate at 37°C, 5% CO _{2 for} 72 hours. Add 50μL of Cell-titer Glo working solution to each well, shake and mix and incubate at room temperature for 10 minutes. The multifunctional microplate reader reads the Luminescence luminescence value, and converts the luminescence value reading into inhibition percentage:

Inhibition percentage = (maximum-reading) / (maximum-minimum) * 100.

The "maximum value" is the DMSO control; the "minimum value" indicates the cell-free control group.

Curve were fitted using Graphpad Prism software to obtain a value ₅₀ IC.

All the example compounds have good inhibition on COLO205 cells, most of the compounds inhibit COLO205 cells with IC ₅₀ <100 nM, and the IC ₅₀ information of some of the example compounds and comparative compounds on COLO205 cells is shown in Table 3.

[table 3] Compound number The IC ₅₀ (nM) of the compound against COLO205 cells Trametinib 1.5 Compound 3 0.93 Compound 4 0.77 Compound 9 8.38 Compound 10 5.75 Compound 11 0.98 Compound 12 5.02 Compound 13 3.73 Compound 14 3.84 Compound 16 4.23 Compound 17 1.32 Compound 18 0.21 Compound 19 5.2 Compound 20 18.8 Compound 21 5.3 Compound 22 15 Compound 23 twenty two Compound 24 3.0 Compound 25 0.93 Compound 26 twenty two Comparative compound 1 25.31 Comparative compound 2 170.1

Example C: HCT116 cell proliferation test

Pave the HCT116 cells in a 96-well plate with 2000 cells and 135 μL/well. After incubating overnight, compound solutions of gradient concentrations were prepared, and 15 were added to the cells in each well. Incubate the DMSO solution of the test compound of each concentration, the final concentration of the compound is 30000, 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 0 nM (the final concentration of DMSO is 0.5%). Incubate at 37°C, 5% CO _{2 for} 72 hours. Add 50μL of Cell-titer Glo working solution to each well, shake and mix and incubate at room temperature for 10 minutes. The multifunctional microplate reader reads the Luminescence luminescence value, and converts the luminescence value reading into inhibition percentage:

Inhibition percentage = (maximum-reading) / (maximum-minimum) * 100.

The "maximum value" is the DMSO control; the "minimum value" indicates the cell-free control group.

Curve were fitted using Graphpad Prism software to obtain a value ₅₀ IC.

All the compounds in the examples have a good inhibitory effect on HCT116 cells, and most of the compounds inhibit HCT116 cells with IC ₅₀ <100 nM. See Table 4 for the IC ₅₀ information of some compounds in the examples and comparative compounds on HCT116 cells.

[Table 4] Compound number IC ₅₀ (nM) of compound inhibition of HCT116 cells Trametinib 12.32 Compound 3 3.40 Compound 4 3.07 Compound 5 12.37 Compound 11 17.26 Compound 13 12.96 Compound 16 9.03 Compound 17 10.07 Compound 18 0.87 Compound 21 13.3 Compound 24 7.4 Compound 25 10.4 Comparative compound 1 169.1 Comparative compound 2 393

Example C: Single intravenous and oral administration pharmacokinetic experiment in SD rats

Reagents: DMSO, HS15 and physiological saline.

Animals: SD rats, 6 females, provided by Weitong Lihua Laboratory Animal Technology Co., Ltd.

Drug preparation: All preparations need to be prepared as a clear solution one hour before administration, the preparation ratio is DMSO: HS15: physiological saline = 1:1:8, and the preparation concentration is 1 mg/mL.

Administration and blood collection: Male rats were divided into 2 groups according to their body weights, each with 3 rats. All rats were fasted overnight.

Intravenous administration is by tail vein, the intravenous dose is 2mg/kg, the administration volume is 2mL/kg, and the blood is collected from the fundus venous plexus;

Oral administration adopts gavage, the oral administration dose is 10 mg/kg, the administration volume is 10 mL/kg, and the blood is collected from the fundus venous plexus.

Blood collection time: Intravenous blood collection time point: 5min, 15min, 30min, 1h, 2h, 4h, 7h, 24h. Oral blood collection time point: 15min, 30min, 1h, 2h, 4h, 7h, 24h. The blood was collected in a volume of 300 μL, after anticoagulation with 2.0% EDTA, the blood was centrifuged at 4000 rpm for 10 minutes, and about 100 μL of the supernatant was taken and placed in a -80 degree refrigerator for inspection.

The experimental results are shown in Table 5.

[table 5] Compound number Half-life T1/2(h) Residence time MRT(h) Clearance rate CL/F (mL/min/kg) Apparent volume of distribution Vd (mL/kg) Blood concentration Cmax(ng/mL) Curve area AUC(ng/mL*h) 13 3.48 5.24 7.31 1.80 3347 32134

Although the present invention has been fully described through its embodiments, it is worth noting that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included in the scope of the attached patent application of the present invention.

no.

no.

no.

Claims (30)

A compound represented by general formula (I), or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug:

(I) wherein R ^{1 is} selected from H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ^{2 is} selected from C _6-10 aryl, halogen-substituted C _{6- 10} aryl, C _6-10 heteroaromatic ring group or halogen-substituted C _6-10 heteroaromatic ring group, the C _6-10 heteroaromatic ring group optionally contains 1, 2 or 3 independently selected from N , O or S heteroatom; R ³ or R ⁴ are each independently selected from H, hydroxyl, C _1-6 alkyl, substituted C _1-6 alkyl, C _1-6 alkoxy, substituted C _{1 -6} alkoxy, C _3-6 cycloalkyl or substituted C _3-6 cycloalkyl; R ^{5 is} selected from C _3-10 cycloalkyl, substituted C _3-10 cycloalkyl, C _3-10 Heterocyclic group, substituted C _3-10 heterocyclic group, C _6-10 aryl group, substituted C _6-10 aryl group, C _6-10 heteroaryl ring group or substituted C _6-10 heteroaryl ring group; The heterocyclic group or heteroaromatic ring group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O or S; R ^{6 is} selected from H, halogen, C _1-6 alkyl, C _{1 -6} alkoxy or C _1-6 haloalkyl; X is selected from NH, O or S; and when X is O, R ⁵ is a fused ring or a substituted fused ring. The compound according to claim 1, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein R ¹ is a C _1-3 alkyl group. The compound according to claim 1 or 2, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein R ¹ is a methyl group. The compound according to any one of claims 1 to 3, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein R ^{2 is} selected from halogen Substituted phenyl. The compound according to any one of claims 1 to 4, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein R ² is

or

. The compound according to any one of claims 1 to 5, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein R ³ or R ⁴ Each is independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, hydroxy, hydroxy substituted C _1-6 alkyl, or hydroxy substituted C _1-6 alkoxy. The compound according to any one of claims 1 to 6, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein R ³ or R ⁴ Each is independently selected from H, C _1-3 alkyl, C _3-6 cycloalkyl, hydroxy, hydroxy substituted C _1-3 alkyl, or hydroxy substituted C _1-3 alkoxy. The compound according to any one of claims 1 to 7, or a tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, wherein R ³ is H. The compound according to any one of claims 1 to 8, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein R ^{4 is} selected from H , Methyl, cyclopropyl, hydroxyl,

or

. The compound according to any one of claims 1 to 9, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein when X is NH or when the S, R ⁵ is phenyl, said phenyl is unsubstituted or is selected from C _1-6 alkyl, -NHC (O) R ^a substituents, wherein, R ^a is selected from H, C _{1- 6} alkyl or C _3-6 cycloalkyl. The compound according to any one of claims 1 to 10, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein when X is NH or When S, R ⁵ is

. The compound according to any one of claims 1 to 9, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, wherein when X is O , R ^{5 is} selected from

,

,

or

, Which said

,

,

or

Unsubstituted or randomly selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ^b , -OC(O)R ^b , -O(CH ₂ ) _m C(O)OR ^b , -C(O)R ^b , -C(O)OR ^b , -C(O)NHR ^b , -NHC(O)R ^b , -NO, -CN, -NHC(O)OR ^b or -S( O) ₂ R ^b is substituted by substituents, wherein R ^{b is} selected from C _1-6 alkyl or C _3-6 cycloalkyl, and m is selected from 0, 1, or 2. The compound according to any one of claims 1 to 9 or 12, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein, when X is When O, R ^{5 is} selected from

,

,

or

, Which said

,

,

or

Unsubstituted or optionally substituted with a substituent selected from C _1-6 alkyl, -S(O) ₂ R ^b , -NO or -C(O)R ^b , wherein R ^{b is} selected from C _1-3 alkyl. The compound according to any one of claims 1 to 9 or 12 to 13, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein When X is O, R ^{5 is} selected from

,

,

or

, Where said unsubstituted or substituted

,

,

or

for

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

. The compound according to any one of claims 1 to 14, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein R ⁶ is H or C _1-3 alkyl. The compound according to any one of claims 1 to 15, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, wherein R ⁶ is H or methyl. The compound according to claim 1, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, which is a compound represented by general formula (I-1) , Or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug:

(I-1) wherein R ^{1 is} selected from H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ³ or R ⁴ are each independently selected from H, hydroxyl, C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkoxy or C _3-6 cycloalkyl; R ^{6 is} selected from H, halogen , C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ^{7 is} selected from halogen; R ^{8 is} selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl , -OR ^b , -OC(O)R ^b , -O(CH ₂ ) _m C(O)OR ^b , -C(O)R ^b , -C(O)OR ^b , -C(O)NHR ^b , -NHC(O)R ^b , -NO, -CN, -NHC(O)OR ^b or -S(O) ₂ R ^b , wherein R ^{b is} selected from C _1-6 alkyl or C _3-6 cycloalkane Base, m is selected from 0, 1 or 2; p1 is selected from 0, 1, 2 or 3; q1 is selected from 0, 1, 2 or 3. The compound according to claim 1, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, which is a compound represented by general formula (I-2) , Or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug:

(I-2) wherein R ^{1 is} selected from H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ³ or R ⁴ are each independently selected from H, hydroxyl, C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkoxy or C _3-6 cycloalkyl; R ^{6 is} selected from H, halogen , C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ^{9 is} selected from halogen; R ^{10 is} selected from H, halogen, oxo, C _1-6 alkyl, C _{1 -6haloalkyl} , -OR ^b , -OC(O)R ^b , -O(CH ₂ ) _m C(O)OR ^b , -C(O)R ^b , -C(O)OR ^b , -C( O)NHR ^b , -NHC(O)R ^b , -NO, -CN, -NHC(O)OR ^b or -S(O) ₂ R ^b , wherein R ^{b is} selected from C _1-6 alkyl or C _{3 -6} cycloalkyl, m is selected from 0, 1 or 2; p2 is selected from 0, 1, 2 or 3; q2 is selected from 0, 1, 2 or 3. The compound according to claim 1, or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug, which is a compound represented by general formula (I-3) , Or its tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug:

(I-3) wherein R ^{1 is} selected from H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ³ or R ⁴ are each independently selected from H, hydroxyl, C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkoxy or C _3-6 cycloalkyl; R ^{6 is} selected from H, halogen , C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ^{11 is} selected from halogen; R ^{12 is} selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl , -OR ^b , -OC(O)R ^b , -O(CH ₂ ) _m C(O)OR ^b , -C(O)R ^b , -C(O)OR ^b , -C(O)NHR ^b , -NHC(O)R ^b , -NO, -CN, -NHC(O)OR ^b or -S(O) ₂ R ^b , wherein R ^{b is} selected from C _1-6 alkyl or C _3-6 cycloalkane Base, m is selected from 0, 1 or 2; p3 is selected from 0, 1, 2 or 3; q3 is selected from 0, 1, 2 or 3. A compound, or a tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, wherein the compound is selected from: 1) 4-((3-Acetylaminophenyl)thio)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydro Pyridine-3-carboxamide; 2) 4-((3-Acetylaminophenyl)amino)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydro Pyridine-3-carboxamide; 3) 4-(1-Acetyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1 -Methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 4) 4-(1-Ethylsulfonyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1 -Methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; 5) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((2-oxo-1,2,3,4-tetrahydroquinoline -6-yl)oxy)-1,6-dihydropyridine-3-carboxamide; 6) 2-((2-Fluoro-4-iodophenyl)amino)-4-(indol-5-yl)oxy-1-methyl-6-oxo-1,6-dihydropyridine- 3-formamide; 7) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((1,2,3,4-tetrahydroquinolin-6-yl) (Oxy)-1,6-dihydropyridine-3-carboxamide; 8) 4 -(1-Acetyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl Base-6-oxo-1,6-dihydropyridine-3-carboxamide; 9) 4-((1-acetindol-5-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1, 6-Dihydropyridine-3-methanamide; 10) 4 -(1-ethylsulfonylindol-5-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1, 6-Dihydropyridine-3-methanamide; 11) 4-(1-ethylsulfonylindol-4-yl)oxy)-2-(2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1, 6-Dihydropyridine-3-methanamide; 12) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((1-nitroso-1,2,3,4-tetrahydroquinolin-5-yl )Oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide; 13) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((2-oxo-1,2,3,4-tetrahydroquinoline -5-yl)oxy)-1,6-dihydropyridine-3-carboxamide; 14) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((1-nitrosoindol-4-yl)oxy)-6-oxo-1 ,6-Dihydropyridine-3-methanamide; 15) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((1,2,3,4-tetrahydroquinolin-5-yl) (Oxy)-1,6-dihydropyridine-3-carboxamide; 16) 2-((2-Fluoro-4-iodophenyl)amino)-4-(indol-4-yl)oxy-1-methyl-6-oxo-1,6-dihydropyridine- 3-formamide; 17) 4-((1-acetindol-4-yl)oxy)-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1, 6-Dihydropyridine-3-methanamide; 18) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((1-(methylsulfonyl)indol-4-yl)oxy)-6-oxy Substitution-1,6-dihydropyridine-3-carboxamide; 19) 2-((2-Fluoro-4-iodophenyl)amino)-1,5-dimethyl-6-oxo-4-((2-oxo-1,2,3,4-tetra (Hydroquinolin-5-yl)oxy)-1,6-dihydropyridine-3-carboxamide; 20) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-4-((3-oxo-3,4-dihydro-2H-benzo[ b][1,4]oxazine-8-yl)oxy)-1,6-dihydropyridine-3-carboxamide; or 21) 2-((4-Bromo-2-fluorophenyl)amino)-1-methyl-4-((1-methylsulfonyl)indol-4-yl)oxy)-6-oxo -1,6-Dihydropyridine-3-methanamide; 22) 2-((2-Fluoro-4-iodophenyl)amino)-N,1-dimethyl-4-((1-(methylsulfonyl)indol-4-yl)oxy)- 6-oxo-1,6-dihydropyridine-3-carboxamide; 23) N-cyclopropyl-2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((1-(methylsulfonyl)indol-4-yl)oxy Base)-6-oxo-1,6-dihydropyridine-3-carboxamide; 24) 2-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1-methyl-4-((1-(methylsulfonyl)indole-4 -Yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide; 25) 2-((2-Fluoro-4-iodophenyl)amino)-N-hydroxy-1-methyl-4-((1-(methylsulfonyl)indol-4-yl)oxy) -6-oxo-1,6-dihydropyridine-3-carboxamide; 26) 2-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethyl)-1-methyl-4-((1-(methylsulfonyl)indole-4 -Yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide; 27) 2-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-4-((2-oxo-1 ,2,3,4-tetrahydroquinolin-5-yl)oxy)-1,6-dihydropyridine-3-carboxamide; 28) 2-((2-Fluoro-4-iodophenyl)amino)-N-hydroxy-1-methyl-6-oxo-4-((2-oxo-1,2,3,4-tetrahydro Quinolin-5-yl)oxy)-1,6-dihydropyridine-3-carboxamide; 29) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((7-methyl-2-oxo-1,2,3,4-tetrahydroquinoline -5-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide; 30) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylindol-4-yl)oxy)-6-oxo-1, 6-dihydropyridine-3-methanamide; 31) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((7-methyl-1,2,3,4-tetrahydroquinolin-5-yl) (Oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide; or 32) 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methyl-3-oxo-3,4-dihydro-2H-benzo[ b] [1,4]oxazine-8-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide. A compound represented by general formula (II), or a pharmaceutically acceptable salt thereof,

(II) Wherein, R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 are} as described in claim 1, and R ¹³ is halogen. An intermediate for synthesizing the compound described in claim 21 or a pharmaceutically acceptable salt thereof, having the structure shown in general formula (III),

(III) Among them, R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 are} as described in claim 1. A method for preparing the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof as described in claim 21, the method comprising the following steps:

(III) (II) The compound of general formula (III) undergoes a halogenation reaction under acidic conditions to obtain a compound of general formula (II), wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 are} as in claim 1 As mentioned, R ¹³ is halogen. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1 to 20, or a tautomer, pharmaceutically acceptable salt, solvate, chelate, or non-co- Valence complex or prodrug; and at least one pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 24, wherein the mass ratio of the compound and the pharmaceutically acceptable excipient is 0.0001:1-10. A compound according to any one of claims 1 to 20, or a tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, or a compound described in claim 24 or 25 The application of the pharmaceutical composition in the preparation of medicines. The use according to claim 26, wherein the medicament is used to treat diseases mediated by MEK. The application according to claim 27, wherein the disease is cancer. A compound according to any one of claims 1 to 20, or a tautomer, pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, or a compound described in claim 24 or 25 Application of the pharmaceutical composition in the preparation of drugs for the treatment and/or prevention of cancer. The use according to claim 28 or 29, wherein the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, Polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocytoma, head and neck cancer, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Xuwang's cell Tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.