CN112521336B - Indazole and pyrrolopyridine compounds and application thereof - Google Patents

Indazole and pyrrolopyridine compounds and application thereof Download PDF

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CN112521336B
CN112521336B CN202010108170.7A CN202010108170A CN112521336B CN 112521336 B CN112521336 B CN 112521336B CN 202010108170 A CN202010108170 A CN 202010108170A CN 112521336 B CN112521336 B CN 112521336B
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蔡跃飘
陈小陆
刘亚男
吴建章
夏钦钦
郑小辉
刘志国
梁广
李校堃
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Abstract

The invention discloses indazole and pyrrolopyridine compounds and application thereof, wherein the compounds are compounds with a structure shown in a formula (I) or medicinal salts, prodrugs, hydrates or solvates thereof. The compounds have high selective inhibition effect on FGFR4, can be used as a potential antitumor drug, and particularly as an anti-liver cancer drug with good prospect.

Description

Indazole and pyrrolopyridine compounds and application thereof
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to indazole and pyrrolopyridine compounds and a preparation method and application thereof.
Background
Fibroblast Growth Factor Receptors (FGFR) belong to receptor type protein tyrosine kinases, and the FGFR overexpression and activation of tumor tissues are accompanied in the occurrence of various cancers in clinic discovery, and the FGFR can promote the formation of tumor blood vessels, the division and the proliferation of tumor cells and the like. Therefore, fibroblast growth factor receptors are widely considered as an important anti-tumor drug target, and have attracted extensive attention of various pharmacologists.
The FGFR known so far mainly includes 4 types, i.e., FGFR1, FGFR2, FGFR3, and FGFR4. Chinese patent application with publication number CN 106317023A discloses a preparation method and application of indazole compounds, wherein the indazole compounds have excellent tyrosine kinase inhibition activity and are mainly used as FGFR1-3 inhibitors.
Of the 4 FGFR members, FGFR4 is greatly different from FGFR1 to FGFR3 in structure and function. Structurally, FGFR4 has the least homology with the other three, and the difference in protein domains is large, and the D3 domain structure of the extracellular portion of FGFR4 is also different from FGFR1 to FGFR 3. Functionally, the high expression of FGFR4 is closely related to liver cancer, the knockout of FGFR4 can not cause early embryo death, and the FGFR4 does not participate in the regulation of the development of bones like FGFR 1-3. Therefore, a small molecule inhibitor that selectively targets FGFR4 to treat tumors would not have significant side effects and would be relatively more advantageous.
Disclosure of Invention
The invention discloses indazole and pyrrolopyridine compounds and application thereof, wherein the compounds can inhibit FGFR4 expression with high selectivity and can be used as high-efficiency antitumor drugs.
An indazole and pyrrolopyridine compound is a compound shown as a structural formula (I) or a medicinal salt, a prodrug, a hydrate or a solvate thereof:
Figure BDA0002389089600000021
in the formula (I), R 1 One selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, said aryl orThe substituents on the heteroaryl group are selected from halogen, C l ～C 6 Alkyl radical, C l ～C 6 Alkoxy radical, C l ～C 6 Alkylthio, halo C l ～C 6 Alkyl, halo C l ～C 6 Alkoxy, amino, C l ～C 6 Alkanoyl, NH-CO-C l ～C 6 Alkyl, amino, -NH (C) l ～C 6 Alkyl), -N (C) l ～C 6 Alkyl) (C) l ～C 6 Alkyl) and hydroxyl;
R 2 selected from hydrogen, C l ～C 6 Alkyl radical, C l ～C 6 Alkanoyl, COOC l ～C 6 Alkyl, OCOC l ～C 6 One of the alkyl groups;
A. b, C is each independently selected from: n or CH;
ring Z is a non-substituted or unsubstituted 5-to 8-membered arylene, or a substituted or unsubstituted 5-to 8-membered heteroarylene, wherein the heteroarylene comprises at least one heteroatom selected from the group consisting of: nitrogen, oxygen or sulfur; a substituted or unsubstituted 3-to 12-membered saturated heterocycle or carbocycle, wherein said heterocycle comprises at least one heteroatom selected from the group consisting of: nitrogen, oxygen or sulfur;
the warhead is selected from
Figure BDA0002389089600000022
R 3 Is C 1 ～C 4 Alkyl, halogen substituted C 1 ～C 4 Alkyl radical, C 2 ～C 4 Alkenyl, halogen substituted C 2 ～C 4 Alkenyl, dimethylamino substituted C 2 ～C 4 Alkenyl radical, C 2 ～C 4 An alkynyl group;
R 4 is C 1 ～C 4 Alkyl or C 2 ～C 4 Alkenyl, halogen (F, cl, br).
Preferably, R 1 Selected from substituted or unsubstituted 6-to 10-membered aryl, substituted or unsubstituted 5-to 10-membered containing 1 to 3 heteroatoms selected from N, O and SOne of heteroaryl, wherein the substituent on the aryl or heteroaryl is selected from halogen and C l ～C 4 Alkyl radical, C l ～C 4 Alkoxy radical, C l ～C 4 Alkylthio, halo C l ～C 4 Alkyl, halo C l ～C 4 Alkoxy, amino, C l ～C 4 Alkanoyl, NH-CO-C l ～C 4 Alkyl, amino, -NH (C) l ～C 4 Alkyl), -N (C) l ～C 4 Alkyl) (C) l ～C 4 Alkyl) and hydroxyl.
Preferably, said 6-10 membered aryl is selected from phenyl or naphthyl;
the 5-to 10-membered heteroaryl group is selected from pyridyl, pyrazinyl, furyl, thienyl, pyrazolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, benzofuryl, benzothienyl, benzimidazolyl or benzothiazolyl, or tetrahydrobenzofuryl, tetrahydrobenzothienyl, tetrahydrobenzimidazolyl or tetrahydrobenzothiazolyl.
Preferably, ring Z is a substituted or unsubstituted arylene or heteroarylene group as follows: phenylene, naphthylene, pyridylene, pyrazinylene, thienylene, furylene, pyrrolylene, oxazolylene, thiazolyl, pyrazolyl, indolyl, imidazolyl, benzofuranylene, benzothiazolyl, and benzimidazolylene;
the substituent is 1 or more selected from halogen and C l ～C 4 Alkyl radical, C l ～C 4 Alkoxy and-N (C) l ～C 4 Alkyl) (C l ～C 4 Alkyl) and optionally substituted by 1 or more groups selected from C l ～C 4 Alkyl radical, C l ～C 4 Alkoxy radical, C 3 ～C 8 Cycloalkyl, C 2 ～C 4 Base, C 2 ～C 4 Alkynyl, C l ～C 4 Alkanoyl radical, C l ～C 4 Alkoxy-substituted C l ～C 4 Alkyl, hydroxy substituted C l ～C 4 Alkyl, -CO (O) -C l ～C 4 Alkyl and-SO 2 -C l ～C 4 The substituents in the alkyl group are further substituted.
Preferably, the warhead is selected from the group consisting of:
Figure BDA0002389089600000031
wherein X is selected from halogen (F, cl, br, I).
Preferably, the indazole and pyrrolopyridine compound is one of the following specific compounds or a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvate thereof:
Figure BDA0002389089600000041
Figure BDA0002389089600000051
Figure BDA0002389089600000061
Figure BDA0002389089600000071
the invention also provides a pharmaceutical composition which comprises the indazole and pyrrolopyridine compounds as active ingredients.
The invention also provides application of the indazole and pyrrolopyridine compounds in preparation of medicaments, which is characterized in that the medicaments are used for treating tumors.
The experimental result shows that the compound has a high selective inhibition effect on FGFR4, and preferably, the medicine is used for treating diseases related to abnormal expression of FGF19/FGFR4 signaling pathway.
As a further preference, the medicament is for the treatment of breast cancer, lung cancer, bladder cancer, gastric cancer, membrane adenocarcinoma, prostate cancer, colon cancer, multiple myeloma AML, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, rhabdomyosarcoma, and testicular cancer: preferably breast cancer, non-small cell lung cancer, bladder cancer, gastric cancer, membrane adenocarcinoma, prostate cancer, colon cancer, multiple myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, rhabdomyosarcoma: more preferably liver cancer, breast cancer, colon cancer, rhabdomyosarcoma, gastric cancer and osteosarcoma.
Compared with the prior art, the invention has the beneficial effects that:
the compound has a high selective inhibition effect on FGFR4, can be used as a potential antitumor drug, and particularly as an anti-liver cancer drug which possibly has a good prospect. Has less side effect due to higher selectivity on FGFR4.
Drawings
FIG. 1 is a graph showing the results of the verification of covalent binding of the compound of example 3.
Detailed Description
Preparation and characterization of the Compound of example 1
Synthesis scheme 1
Figure BDA0002389089600000081
Taking compound 1 (1eq, 5g) in a 100mL round bottom flask, adding 50mL tetrahydrofuran, adding DMAP (0.2eq, 435mg), adding (Boc) 2O (1.2eq, 6.175g) with stirring, stirring at normal temperature for 2 hours, after the reaction is completed, spinning off THF, adding each 20mL dichloromethane and water, extracting, collecting the organic phase, extracting with a saturated aqueous ammonium chloride solution, collecting the organic phase, drying with anhydrous sodium sulfate, spinning off, stirring, passing through a thin layer chromatography silica gel column (PE: EA: DCM = 4.
Figure BDA0002389089600000082
Compound 2 (1eq, 100mg) was placed in a 25mL round bottom flask, 10mL of 1,4-dioxane was added, it was dissolved by sonication, DIPEA (3eq, 124mg) was added, 3 (2.5eq, 149mg) was added dropwise at 0 ℃, after completion of the reaction, 10mL of water was added and quenched, 1,4-dioxane was dried, 10mL of each of water and dichloromethane was added, the organic phase was extracted, collected, three times extracted with a saturated sodium bicarbonate solution, three times extracted with a saturated aqueous ammonium chloride solution, the organic phase was collected, dried over anhydrous sodium sulfate, dried, stirred, and subjected to thin layer chromatography silica gel column (PE: EA: DCM = 31, V/V) to obtain compound 4 (126mg, 85%).
Figure BDA0002389089600000083
A50 mL round bottom flask was charged with 4 (1eq, 400mg), 1,4-dioxane 20mL, sonicated to dissolve, 5 (2eq, 316mg), cesium carbonate (2eq, 566mg), tetratriphenylphosphadiumpalladium (0.1eq, 100mg), displaced with nitrogen 3 times, placed at 110 ℃ under reflux for 1 hour, after the reaction was completed, 1,4-dioxane was spin dried, extracted three times with 15mL each of water and dichloromethane, the organic phase was collected, extracted 3 times with a saturated sodium bicarbonate solution, the organic phase was collected, dried over anhydrous sodium sulfate, spin dried, sample stirred, and purified by thin layer chromatography silica gel column (PE: DCM: 1, EA = 2.
Figure BDA0002389089600000091
Compound 6 (1eq, 400mg) was charged in a 100mL round-bottom flask, 30mL of methanol was added, and after dissolution, H 2 After the reaction was completed, the black residue in the system was filtered off through celite, and the filtrate was collected, dried over anhydrous sodium sulfate, spun-dried, sample-mixed and purified by thin layer chromatography silica gel chromatography (PE: EA: DCM = 51, V/V) to obtain compound 7 (343mg, 91%).
Figure BDA0002389089600000092
Taking compound 7 (1eq, 100mg), adding the compound into a 25mL round-bottom flask, adding 1,4-dioxane into 10mL, ultrasonically dissolving, adding DIPEA (3eq, 96mg), dropwise adding 8 (2.5eq, 62mg) under ice bath, reacting overnight, after the reaction is finished, adding 5mL water, stirring, extracting for 3 times by ethyl acetate, collecting an organic phase, extracting by a saturated ammonium chloride solution, collecting the organic phase, drying by anhydrous sodium sulfate, and spin-drying to obtain compound 9.
Figure BDA0002389089600000101
Taking the compound 9, putting the compound in a 25mL round-bottom flask, adding 6mL dichloromethane, stirring by a magnetic stirrer, adding 2mL trifluoroacetic acid, stirring at room temperature for 2 hours, after the reaction is finished, spinning off the trifluoroacetic acid, adding a saturated ammonium chloride solution and a large amount of DCM, extracting for three times, collecting an organic phase, drying by anhydrous sodium sulfate, spinning off, transferring a solid compound into the 25mL round-bottom flask by the dichloromethane, adding 5mL dichloromethane, pulping, filtering, collecting the solid in the 25mL round-bottom flask, collecting the solid, and drying to obtain a compound F-1 (43mg, 47%), wherein the structure and the characterization data are as follows:
Figure BDA0002389089600000102
1 H NMR(400MHz,DMSO-d 6 )δ12.91(s,1H),11.11(s,1H),11.02(s,1H),8.34(d,J＝8.3Hz,1H),8.01(d,J＝7.7Hz,1H),7.84(d,J＝8.5Hz,1H),7.70(s,1H),7.60(t,J＝7.8Hz,1H),7.41(dd,J＝8.6,1.2Hz,1H),7.28(t,J＝7.6Hz,1H),6.86(d,J＝2.2Hz,2H),6.54(t,J＝2.1Hz,1H),6.39(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.5Hz,1H),5.78(dd,J＝10.2,1.5Hz,1H),3.83(s,6H).
using a similar procedure the following compounds were obtained:
2-acrylamido-N- (6- (3-methoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000103
1 H NMR(400MHz,DMSO-d 6 )δ12.93(s,1H),11.10(s,1H),11.03(s,1H),8.32(d,J＝8.0Hz,1H),8.01(d,J＝7.3Hz,1H),7.85(d,J＝8.4Hz,1H),7.69(s,1H),7.59(t,J＝8.0Hz,1H),7.48–7.36(m,2H),7.23-7.34(m 3H),6.97(d,J＝8.0Hz,1H),6.39(dd,J＝16.9,10.1Hz,1H),6.23(d,J＝16.9Hz,1H),5.77(d,J＝10.8Hz,1H),3.85(s,3H).
2-acrylamido-N- (6- (3,5-dimethylphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000111
1 H NMR(400MHz,DMSO-d 6 )δ12.93(s,1H),11.10(s,1H),11.03(s,1H),8.32(d,J＝8.0Hz,1H),8.01(d,J＝7.3Hz,1H),7.85(d,J＝8.4Hz,1H),7.69(s,1H),7.59(t,J＝8.0Hz,1H),7.48–7.36(m,2H),7.23-7.34(m 3H),6.97(d,J＝8.0Hz,1H),6.39(dd,J＝16.9,10.1Hz,1H),6.23(d,J＝16.9Hz,1H),5.77(d,J＝10.8Hz,1H),3.85(s,3H).
2-acrylamido-N- (6- (4-methoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000112
1 H NMR(400MHz,DMSO-d 6 )δ12.93(s,1H),11.10(s,1H),11.03(s,1H),8.32(d,J＝8.0Hz,1H),8.01(d,J＝7.3Hz,1H),7.85(d,J＝8.4Hz,1H),7.69(s,1H),7.59(t,J＝8.0Hz,1H),7.48–7.36(m,2H),7.23-7.34(m 3H),6.97(d,J＝8.0Hz,1H),6.39(dd,J＝16.9,10.1Hz,1H),6.23(d,J＝16.9Hz,1H),5.77(d,J＝10.8Hz,1H),3.85(s,3H).
2-acrylamido-N- (6- (4-fluoro-3-methoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000121
1 H NMR(500MHz,DMSO-d 6 )δ12.93(s,1H),11.11(s,1H),11.03(s,1H),8.34(d,J＝6.9Hz,1H),8.02(d,J＝5.5Hz,1H),7.86(dd,J＝8.4,2.4Hz,1H),7.71(s,1H),7.59(t,J＝7.7Hz,1H),7.48(d,J＝7.8Hz,1H),7.42(d,J＝8.5Hz,1H),7.36–7.08(m,3H),6.39(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.3Hz,1H),5.78(dd,J＝10.2,1.3Hz,1H),3.97(s,3H).
2-acrylamido-N- (6- (3-fluoro-5-methoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000122
1 H NMR(400MHz,DMSO-d 6 )δ12.99(s,1H),11.10(s,1H),11.06(s,1H),8.33(d,J＝8.2Hz,1H),8.01(d,J＝7.7Hz,1H),7.87(d,J＝8.5Hz,1H),7.75(s,1H),7.60(t,J＝7.7Hz,1H),7.43(d,J＝9.1Hz,1H),7.28(t,J＝7.5Hz,1H),7.18(d,J＝9.8Hz,1H),7.15(s,1H),6.87(dd,J＝10.9,1.9Hz,1H),6.40(dd,J＝17.0,10.1Hz,1H),6.24(dd,J＝17.0,1.1Hz,1H),5.78(dd,J＝10.3,1.1Hz,1H),3.87(s,3H).
2-acrylamido-N- (6- (2-methoxypyridin-4-yl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000123
1 H NMR(500MHz,DMSO-d 6 )δ13.07(s,1H),11.10(s,1H),11.06(s,1H),8.33(d,J＝8.2Hz,1H),8.25(d,J＝5.3Hz,1H),8.02(d,J＝7.4Hz,1H),7.91(d,J＝8.5Hz,1H),7.85(s,1H),7.59(t,J＝7.7Hz,1H),7.49(d,J＝8.5Hz,1H),7.39(d,J＝5.2Hz,1H),7.28(t,J＝7.5Hz,1H),7.19(s,1H),6.40(dd,J＝17.0,10.2Hz,1H),6.24(d,J＝16.9Hz,1H),5.77(d,J＝10.3Hz,1H).
2-acrylamido-N- (6- (thien-2-yl) -1H-indol-3-yl) benzamide
Figure BDA0002389089600000131
1 H NMR(400MHz,DMSO-d 6 )δ12.90(s,1H),11.07(s,1H),11.02(s,1H),8.31(d,J＝8.3Hz,1H),7.99(d,J＝7.5Hz,1H),7.82(d,J＝8.5Hz,1H),7.69(s,1H),7.65–7.54(m,3H),7.43(dd,J＝8.6,1.2Hz,1H),7.27(t,J＝7.5Hz,1H),7.17(dd,J＝5.0,3.7Hz,1H),6.39(dd,J＝17.0,10.2Hz,1H),6.23(dd,J＝17.0,1.5Hz,1H),5.77(dd,J＝10.2,1.4Hz,1H).
2-acrylamido-N- (6- (thiophen-3-yl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000132
1 H NMR(500MHz,DMSO-d 6 )δ12.88(s,1H),11.09(s,1H),10.99(s,1H),8.33(d,J＝8.1Hz,1H),8.00(d,J＝7.1Hz,1H),7.97(s,1H),7.80(d,J＝8.5Hz,1H),7.75(s,1H),7.71–7.63(m,2H),7.59(t,J＝7.6Hz,1H),7.49(d,J＝8.5Hz,1H),7.28(t,J＝7.4Hz,1H),6.39(dd,J＝17.0,10.2Hz,1H),6.23(d,J＝17.0Hz,1H),5.78(d,J＝10.3Hz,1H).
2-acrylamido-N- (6- (2,3-dihydrobenzofuran-5-yl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000141
1 H NMR(400MHz,DMSO-d 6 )δ13.02(s,1H),11.09(s,2H),8.32(d,J＝8.1Hz,1H),8.03(d,J＝7.3Hz,1H),7.80(d,J＝8.5Hz,1H),7.66–7.51(m,3H),7.45(d,J＝8.3Hz,1H),7.32(d,J＝8.4Hz,1H),7.26(t,J＝7.2Hz,1H),6.86(d,J＝8.3Hz,1H),6.41(dd,J＝17.0,10.0Hz,1H),6.23(d,J＝16.6Hz,1H),5.77(d,J＝6.1Hz,1H),4.58(t,J＝8.7Hz,2H),3.25(t,J＝8.6Hz,2H).
N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) -2-propionamide benzamide
Figure BDA0002389089600000142
1 H NMR(400MHz,DMSO-d 6 )δ12.93(s,1H),11.01(s,1H),10.88(s,1H),8.33(d,J＝8.4Hz,1H),7.99(d,J＝8.0Hz,1H),7.83(d,J＝8.5Hz,1H),7.70(s,1H),7.56(t,J＝7.5Hz,1H),7.41(dd,J＝8.6,0.6Hz,1H),7.23(t,J＝7.7Hz,1H),6.86(d,J＝2.1Hz,2H),6.54(t,J＝1.9Hz,1H),3.83(s,6H),2.36(q,J＝7.5Hz,2H),1.08(t,J＝7.5Hz,3H).
2-acetamido-N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000143
1 H NMR(400MHz,DMSO-d 6 )δ12.92(s,1H),11.00(s,1H),10.79(s,1H),8.25(d,J＝7.6Hz,1H),7.97(d,J＝8.2Hz,1H),7.84(d,J＝8.5Hz,1H),7.70(s,1H),7.56(t,J＝7.7Hz,1H),7.42(d,J＝8.7Hz,1H),7.23(t,J＝7.4Hz,1H),6.87(s,2H),6.54(s,1H),3.83(s,6H),2.07(s,3H).
2- (2-chloroacetamide) -N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000151
1 H NMR(400MHz,DMSO-d 6 )δ12.97(s,1H),11.54(s,1H),11.13(s,1H),8.40(d,J＝8.3Hz,1H),8.05(d,J＝7.3Hz,1H),7.83(d,J＝8.5Hz,1H),7.72(s,1H),7.62(t,J＝7.7Hz,1H),7.42(d,J＝8.6Hz,1H),7.31(t,J＝7.5Hz,1H),6.87(d,J＝2.0Hz,2H),6.54(s,1H),4.42(s,2H),3.83(s,6H).
2- (2-Bromoacetamide) -N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000152
1 H NMR(400MHz,DMSO-d 6 )δ12.96(s,1H),11.53(s,1H),11.12(s,1H),8.39(d,J＝8.3Hz,1H),8.05(d,J＝7.6Hz,1H),7.83(d,J＝8.5Hz,1H),7.71(s,1H),7.62(t,J＝7.7Hz,1H),7.41(d,J＝8.5Hz,1H),7.31(t,J＝7.6Hz,1H),6.86(d,J＝1.9Hz,2H),6.54(s,1H),4.41(s,2H),3.83(s,6H).
N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) -2- (2-crotonamide) benzamide
Figure BDA0002389089600000153
1 H NMR(400MHz,DMSO-d 6 )δ12.93(s,1H),11.01(s,1H),10.90(s,1H),8.40(d,J＝8.3Hz,1H),8.01(d,J＝7.7Hz,1H),7.82(d,J＝8.5Hz,1H),7.71(s,1H),7.56(t,J＝7.8Hz,1H),7.41(dd,J＝8.6,1.1Hz,1H),7.22(t,J＝7.5Hz,1H),6.86(d,J＝2.2Hz,2H),6.54(t,J＝2.1Hz,1H),5.79(s,1H),3.83(s,6H),2.14(s,3H),1.84(s,3H).
N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) -2-methylacrylamide
Figure BDA0002389089600000161
1 H NMR(400MHz,DMSO-d 6 )δ12.98(s,1H),11.67(s,1H),11.13(s,1H),8.56(d,J＝8.3Hz,1H),8.11(d,J＝7.7Hz,1H),7.79(d,J＝8.5Hz,1H),7.72(s,1H),7.62(t,J＝7.8Hz,1H),7.42(d,J＝9.2Hz,1H),7.26(t,J＝7.7Hz,1H),6.87(d,J＝2.0Hz,2H),6.54(s,1H),5.86(s,1H),5.54(s,1H),3.83(s,7H),1.98(s,3H).
N- (6- (3,5-dimethoxyphenyl) -1H-indol-3-yl) -2-isobutyramide
Figure BDA0002389089600000162
1 H NMR(400MHz,DMSO-d 6 )δ12.95(s,1H),11.02(s,2H),8.36(d,J＝8.3Hz,1H),8.02(d,J＝7.7Hz,1H),7.83(d,J＝8.5Hz,1H),7.72(s,1H),7.57(t,J＝7.7Hz,1H),7.42(d,J＝8.5Hz,1H),7.23(t,J＝7.5Hz,1H),6.87(d,J＝1.6Hz,2H),6.54(s,1H),3.83(s,6H),2.55(dd,J＝13.8,6.9Hz,1H),1.13(d,J＝6.9Hz,6H).
N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) -2-pivaloylamide benzamide
Figure BDA0002389089600000171
1 H NMR(400MHz,DMSO-d 6 )δ12.98(s,1H),11.38(s,1H),11.08(s,1H),8.52(d,J＝8.3Hz,1H),8.07(d,J＝7.6Hz,1H),7.77(d,J＝8.5Hz,1H),7.72(s,1H),7.58(t,J＝7.5Hz,1H),7.42(d,J＝8.5Hz,1H),7.22(t,J＝7.5Hz,1H),6.86(d,J＝2.1Hz,2H),6.54(t,J＝2.0Hz,1H),3.83(s,6H),1.21(s,9H).
2- (2-Chloropropionamide) -N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000172
1 H NMR(400MHz,DMSO-d 6 )δ12.96(s,1H),11.51(s,1H),11.11(s,1H),8.34(d,J＝8.4Hz,1H),8.05(d,J＝7.5Hz,1H),7.84(d,J＝8.5Hz,1H),7.71(s,1H),7.62(t,J＝7.8Hz,1H),7.41(d,J＝8.6Hz,1H),7.31(t,J＝7.5Hz,1H),6.87(d,J＝1.5Hz,2H),6.54(d,J＝1.5Hz,1H),4.82(q,J＝6.7Hz,1H),3.83(s,7H),1.65(d,J＝6.8Hz,3H).
2- (cyclopropylamide) -N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000173
1 H NMR(500MHz,DMSO-d 6 )δ12.91(s,1H),11.10(s,1H),10.99(s,1H),8.26(d,J＝8.2Hz,1H),7.99(d,J＝7.5Hz,1H),7.85(d,J＝8.5Hz,1H),7.71(s,1H),7.55(t,J＝7.8Hz,1H),7.42(dd,J＝8.5,1.0Hz,1H),7.23(t,J＝7.5Hz,1H),6.87(d,J＝2.1Hz,2H),6.54(t,J＝2.0Hz,1H),3.83(s,6H),1.79–1.58(m,1H),0.94–0.67(m,4H).
3-acrylamido-N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000181
1 H NMR(400MHz,DMSO-d 6 )δ12.95(s,1H),10.85(s,1H),10.61(s,1H),8.34(s,1H),7.97(d,J＝7.9Hz,1H),7.80(t,J＝8.0Hz,2H),7.70(s,1H),7.49(t,J＝7.9Hz,1H),7.39(d,J＝8.6Hz,1H),6.85(d,J＝1.8Hz,2H),6.63–6.53(m,1H),6.53(d,J＝1.9Hz,1H),6.29(d,J＝17.0Hz,1H),5.78(d,J＝10.4Hz,1H),3.83(s,6H).
N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) -3-propionamide benzamide
Figure BDA0002389089600000182
1 H NMR(500MHz,DMSO-d 6 )δ12.86(s,1H),10.80(s,1H),10.07(s,1H),8.22(s,1H),7.87(d,J＝7.9Hz,1H),7.78(t,J＝8.0Hz,2H),7.69(s,1H),7.46(t,J＝7.9Hz,1H),7.40(d,J＝8.6Hz,1H),6.86(d,J＝1.9Hz,2H),6.54(s,1H),3.83(s,6H),2.36(q,J＝7.5Hz,2H),1.11(t,J＝7.5Hz,3H).
N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) -3- (3-methyl-2-enamino) benzamide
Figure BDA0002389089600000191
1 H NMR(500MHz,DMSO-d 6 )δ12.87(s,1H),10.81(s,1H),10.06(s,1H),8.28(s,1H),7.88(d,J＝8.0Hz,1H),7.79(d,J＝8.5Hz,1H),7.76(d,J＝7.7Hz,1H),7.69(s,1H),7.45(t,J＝7.9Hz,1H),7.40(d,J＝8.6Hz,1H),6.86(d,J＝2.1Hz,2H),6.54(t,J＝1.9Hz,1H),5.91(s,1H),3.83(s,6H),2.18(s,3H),1.88(s,3H).
N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) -3-methanamide
Figure BDA0002389089600000192
1 H NMR(400MHz,DMSO-d 6 )δ12.89(s,1H),10.86(d,J＝9.1Hz,1H),10.01(s,1H),8.34(s,1H),7.97(dd,J＝8.1,1.3Hz,1H),7.81(dd,J＝11.9,8.3Hz,2H),7.70(s,1H),7.49(t,J＝7.9Hz,1H),7.41(dd,J＝8.6,1.1Hz,1H),6.87(d,J＝2.2Hz,2H),6.55(t,J＝2.1Hz,1H),5.88(s,1H),5.56(s,1H),3.84(s,6H),1.98(s,3H).
3- (2-chloroacetamide) -N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000193
1 H NMR(400MHz,DMSO-d 6 )δ12.88(s,1H),10.88(s,1H),10.53(s,1H),8.24(s,1H),7.92–7.82(m,2H),7.79(d,J＝8.5Hz,1H),7.70(s,1H),7.51(t,J＝7.9Hz,1H),7.40(d,J＝8.6Hz,1H),6.86(d,J＝2.1Hz,2H),6.54(d,J＝2.0Hz,1H),4.30(s,2H),3.83(s,6H).
3- (2-Chloropropionamide) -N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000201
1 H NMR(400MHz,DMSO-d 6 )δ12.89(s,1H),10.89(s,1H),10.56(s,1H),8.27(s,1H),7.86(t,J＝9.6Hz,2H),7.79(d,J＝8.5Hz,1H),7.70(s,1H),7.52(t,J＝7.9Hz,1H),7.40(d,J＝8.6Hz,1H),6.86(d,J＝2.1Hz,2H),6.54(t,J＝2.0Hz,1H),4.71(q,J＝6.6Hz,1H),3.83(s,6H),1.64(d,J＝6.6Hz,3H).
3- (2-Bromoacetamide) -N- (6- (3,5-dimethoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000202
1 H NMR(400MHz,DMSO-d 6 )δ12.87(s,1H),10.86(s,1H),10.52(s,1H),8.23(s,1H),7.84(s,2H),7.79(d,J＝7.5Hz,1H),7.69(s,1H),7.51(t,J＝6.5Hz,1H),7.40(d,J＝8.2Hz,1H),6.86(s,2H),6.54(s,1H),4.30(s,2H),3.83(s,6H).
3- (2-chloroacetamide) -N- (6- (2-fluoro-3-methoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000211
1 H NMR(400MHz,DMSO-d 6 )δ12.93(s,1H),10.90(s,1H),10.53(s,1H),8.24(s,1H),7.85(d,J＝7.8Hz,2H),7.81(d,J＝8.5Hz,1H),7.60(s,1H),7.52(t,J＝7.9Hz,1H),7.28–7.22(m,2H),7.22–7.17(m,1H),7.14(dd,J＝9.6,4.5Hz,1H),4.30(s,2H),3.89(s,3H).
2-acrylamido-N- (6- (2-fluoro-5-methoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000212
1 H NMR(400MHz,DMSO-d 6 )δ12.96(s,1H),11.10(s,1H),11.03(s,1H),8.33(d,J＝8.2Hz,1H),8.02(d,J＝7.8Hz,1H),7.86(d,J＝8.5Hz,1H),7.64(s,1H),7.59(t,J＝7.8Hz,1H),7.27(dd,J＝11.1,8.3Hz,3H),7.12(dd,J＝6.4,3.1Hz,1H),6.94-7.02(m,1H),6.39(dd,J＝17.0,10.2Hz,1H),6.23(dd,J＝17.0,1.5Hz,1H),5.77(dd,J＝10.2,1.5Hz,1H),3.81(s,3H).
2-acrylamido-N- (6- (2-fluoro-3-methoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000213
1 H NMR(400MHz,DMSO-d 6 )δ12.98(s,1H),11.10(s,1H),11.06(s,1H),8.33(d,J＝8.3Hz,1H),8.01(d,J＝7.6Hz,1H),7.86(d,J＝8.5Hz,1H),7.67–7.54(m,2H),7.35–7.17(m,4H),7.14(dd,J＝9.6,4.5Hz,1H),6.40(dd,J＝17.0,10.1Hz,1H),6.24(d,J＝15.9Hz,1H),5.77(d,J＝11.2Hz,1H),3.89(s,3H).
2-acrylamido-N- (6- (3- (trifluoromethoxy) phenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000221
1 H NMR(400MHz,DMSO-d 6 )δ13.03(s,1H),11.11(s,1H),11.07(s,1H),8.33(d,J＝8.2Hz,1H),8.02(d,J＝7.6Hz,1H),7.90(d,J＝8.5Hz,1H),7.81(d,J＝7.8Hz,1H),7.77(s,1H),7.74(s,1H),7.68–7.55(m,2H),7.45(d,J＝8.5Hz,1H),7.40(d,J＝8.1Hz,1H),7.28(t,J＝7.5Hz,1H),6.40(dd,J＝17.0,10.2Hz,1H),6.24(d,J＝16.8Hz,1H),5.77(d,J＝11.9Hz,1H).
2-acrylamido-N- (6- (2-fluoro-5- (trifluoromethoxy) phenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000222
1 H NMR(500MHz,DMSO-d 6 )δ13.05(s,1H),11.11(s,1H),11.07(s,1H),8.34(d,J＝8.2Hz,1H),8.03(d,J＝7.6Hz,1H),7.91(d,J＝8.5Hz,1H),7.70(s,1H),7.66(dd,J＝6.0,2.3Hz,1H),7.59(t,J＝7.8Hz,1H),7.55–7.40(m,2H),7.35–7.20(m,2H),6.40(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.2Hz,1H),5.77(dd,J＝10.3,1.1Hz,1H).
3- (2-bromoacetamide) -N- (6- (2-fluoro-3-methoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000231
1 H NMR(500MHz,DMSO-d 6 )δ12.93(s,1H),10.91(d,J＝15.6Hz,1H),10.53(s,1H),8.24(s,1H),7.85(t,J＝9.2Hz,2H),7.81(d,J＝8.5Hz,1H),7.60(s,1H),7.52(t,J＝7.9Hz,1H),7.25(t,J＝7.7Hz,2H),7.20(t,J＝7.4Hz,1H),7.13(t,J＝6.5Hz,1H),4.30(s,2H),3.90(s,3H).
3- (2-chloroacetamide) -N- (6- (2-fluoro-5-methoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000232
1 H NMR(500MHz,DMSO-d 6 )δ12.94(s,1H),10.91(s,1H),10.54(s,1H),8.25(s,1H),7.86(d,J＝6.1Hz,2H),7.82(d,J＝8.4Hz,1H),7.64(s,1H),7.52(t,J＝7.7Hz,1H),7.27(t,J＝9.4Hz,2H),7.12(d,J＝2.5Hz,1H),6.98(d,J＝8.6Hz,1H),4.31(s,2H),3.82(s,3H).
3- (2-bromoacetamide) -N- (6- (2-fluoro-5-methoxyphenyl) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000233
1 H NMR(500MHz,DMSO-d 6 )δ12.92(s,1H),10.89(s,1H),10.52(s,1H),8.24(s,1H),7.91–7.83(m,2H),7.81(d,J＝8.5Hz,1H),7.64(s,1H),7.52(t,J＝7.9Hz,1H),7.28(dd,J＝13.0,6.0Hz,2H),7.12(dd,J＝6.3,3.1Hz,1H),6.98(dt,J＝8.9,3.4Hz,1H),4.30(s,2H),3.82(s,3H).
Tert-butyl 3- (3- (2-chloroacetyl chloride) benzamide) -6- (3,5-dimethoxyphenyl) -1H-indazole-1-carboxylic acid
Figure BDA0002389089600000241
3- (2-chloroacetamide) -N- (6- (3,5-dimethoxyphenyl) -1-methyl-1H-indazol-3-yl) benzamide
Figure BDA0002389089600000242
Synthesis scheme 2
Figure BDA0002389089600000243
Weighing compound 10 (1eq, 1000mg) in a 100mL round bottom flask, adding 1,4-dioxane 20mL, dissolving with ultrasound, adding 6 (1eq, 1051mg), cesium carbonate (3eq, 5492mg), adding water 4mL, adding tetrakistriphenylphosphine palladium (0.01eq, 63mg), replacing air three times, condensing reflux under nitrogen protection at 110 ℃ for 3h, after completing, spin-drying 1,4-dioxane, adding dichloromethane and water, extracting three times, adding saturated sodium bicarbonate solution and extracting three times, collecting organic phase, drying with anhydrous sodium sulfate, spin-drying, sample-mixing, purifying by thin layer chromatography silica gel column (PE: EA: DCM = 15.
Figure BDA0002389089600000251
Taking compound 11 (1eq, 1000mg) to a 100mL round-bottom flask, adding 30mL of ethanol, heating to 70 ℃, dropwise adding hydrazine hydrate (5eq, 910mg), condensing and refluxing for 3h, after the reaction is finished, spin-drying the ethanol, extracting a saturated ammonium chloride solution, collecting an organic phase, drying the organic phase by anhydrous sodium sulfate, spin-drying, stirring the sample, and purifying by a thin-layer chromatography silica gel chromatographic column (DCM: meOH =70, 1, V/V) to obtain compound 12 (600mg, 61%).
Figure BDA0002389089600000252
Compound 12 (1eq, 600mg) was charged into a 100mL reaction flask, tetrahydrofuran was added to 30mL, DMAP (0.2eq, 55mg) was weighed, added to the reaction flask, di-tert-butyl dicarbonate (1.1eq, 534mg) was added dropwise with stirring, the reaction was stirred at room temperature overnight, after completion of the reaction, THF was spin-dried, water and dichloromethane were added each to 20mL, extracted three times, the organic phase was collected, a saturated aqueous sodium bicarbonate solution was added, extracted three times, the organic phase was collected, dried over anhydrous sodium sulfate, spin-dried, silica gel-stirred, and purified by a thin layer chromatography silica gel column (PE: EA: DCM = 51, V/V).
Figure BDA0002389089600000253
After dissolving 13 (1eq, 600mg) and 40mL of 1,4-dioxane in a 100mL reaction flask, DIPEA (3eq, 627mg) were added, and stirred for 5 minutes in ice bath, 3 (2.5eq, 752mg) was added dropwise with stirring, and after completion of the reaction, 20mL of water was added and stirred, 1,4-dioxane was spin-dried, DCM and water were added and extracted, the organic phase was collected, extracted 3 times with a saturated aqueous sodium bicarbonate solution, the organic phase was collected, dried over anhydrous sodium sulfate, spin-dried, sample-stirred, and purified by a thin layer chromatography silica gel column (PE: EA: DCM = 6.
Figure BDA0002389089600000261
Taking compound 14 (1eq, 500mg), adding into 100mL round-bottom flask, adding into methanol 30mL, dissolving with ultrasound, H 2 The displacement was performed 3 times, and the reaction was performed overnight under a hydrogen atmosphere, after the completion of the reaction, a black residue in the system was filtered off with celite, and the filtrate was collected, dried over anhydrous sodium sulfate, spun-dried, and sample-stirred and purified by thin layer chromatography silica gel chromatography (PE: EA: DCM = 31, V/V) to obtain compound 15 (354 mg, 75%).
Figure BDA0002389089600000262
Adding 15 (1eq, 120mg) into a 25mL reaction flask, adding 1,4-dioxane 10mL, dissolving, adding DIPEA (3eq, 95mg), stirring for 5 minutes in ice bath, dropwise adding 8 (2eq, 45mg) while stirring, reacting overnight, adding 20mL water after the reaction is finished, stirring, spin-drying 1,4-dioxane, adding DCM and water for extraction, collecting an organic phase, extracting 3 times with a saturated sodium bicarbonate aqueous solution, collecting the organic phase, drying with anhydrous sodium sulfate, and spin-drying to obtain compound 16.
Figure BDA0002389089600000271
Adding the compound 16 into a 25mL reaction bottle, adding 6mL dichloromethane, stirring by a magnetic stirrer, adding 2mL trifluoroacetic acid, stirring at room temperature for 2 hours, after the reaction is finished, spinning off the trifluoroacetic acid, adding a saturated ammonium chloride solution and a large amount of DCM, extracting for three times, collecting an organic phase, drying by anhydrous sodium sulfate, spinning off, transferring a solid compound by the dichloromethane into the 25mL round-bottom flask, adding 5mL dichloromethane, pulping, filtering, collecting the solid in the 25mL round-bottom flask, adding 5mL dichloromethane, pulping, filtering, collecting the solid, and drying to obtain the compound F-38 (42mg, 48%).
Figure BDA0002389089600000272
1 H NMR(400MHz,DMSO-d 6 )δ13.17(d,J＝232.3Hz,1H),10.81(d,J＝310.5Hz,1H),8.42(d,J＝8.5Hz,1H),8.20(d,J＝8.1Hz,1H),7.96(d,J＝7.5Hz,1H),7.79(d,J＝8.6Hz,1H),7.57(t,J＝7.6Hz,1H),7.32(d,J＝2.0Hz,2H),7.31–7.16(m,1H),6.62(s,1H),6.44(dd,J＝17.0,10.2Hz,1H),6.23(d,J＝16.9Hz,1H),5.76(d,J＝11.2Hz,1H),3.84(s,6H).
Using a similar procedure the following compounds were obtained:
2-acrylamido-N- (6- (3-methoxyphenyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl) benzamide
Figure BDA0002389089600000281
1 H NMR(400MHz,DMSO-d 6 )δ13.46(s,1H),11.24(s,1H),10.94(s,1H),8.45(d,J＝8.5Hz,1H),8.25(d,J＝8.2Hz,1H),7.97(d,J＝7.6Hz,1H),7.80(d,J＝8.6Hz,1H),7.75(d,J＝7.4Hz,2H),7.59(t,J＝7.7Hz,1H),7.45(t,J＝7.9Hz,1H),7.28(t,J＝7.6Hz,1H),7.13–7.01(m,1H),6.43(dd,J＝17.0,10.2Hz,1H),6.25(d,J＝16.1Hz,1H),5.84–5.71(m,1H),3.86(s,3H).
2-acrylamido-N- (6- (4-fluoro-3-methoxyphenyl) -1H-pyrrole [3,4-b ] pyridin-3-yl) benzamide
Figure BDA0002389089600000282
1 H NMR(400MHz,DMSO-d 6 )δ13.45(s,1H),11.22(s,1H),10.93(s,1H),8.44(d,J＝8.5Hz,1H),8.24(d,J＝8.2Hz,1H),7.95(dd,J＝11.5,4.7Hz,2H),7.83(d,J＝8.6Hz,1H),7.79–7.72(m,1H),7.58(t,J＝7.8Hz,1H),7.36(dd,J＝11.1,8.6Hz,1H),7.28(t,J＝7.5Hz,1H),6.43(dd,J＝17.0,10.2Hz,1H),6.24(dd,J＝17.0,1.1Hz,1H),5.77(d,J＝11.4Hz,1H),3.98(s,3H).
2-acrylamido-N- (6- (3-fluoro-5-methoxyphenyl) -1H-pyrrole [3,4-b ] pyridin-3-yl) benzamide
Figure BDA0002389089600000291
1 H NMR(500MHz,DMSO-d 6 )δ13.44(s,1H),11.17(s,2H),8.47(d,J＝8.5Hz,1H),8.25(d,J＝8.2Hz,1H),7.97(d,J＝7.6Hz,1H),7.83(d,J＝8.6Hz,1H),7.65–7.52(m,3H),7.27(t,J＝7.5Hz,1H),6.95(d,J＝10.7Hz,1H),6.43(dd,J＝17.0,10.2Hz,1H),6.25(d,J＝17.0Hz,1H),5.84–5.71(m,1H),3.88(s,3H).
2-acrylamido-N- (6- (2-fluoro-5-methoxyphenyl) -1H-pyrrole [3,4-b ] pyridin-3-yl) benzamide
Figure BDA0002389089600000292
1 H NMR(400MHz,DMSO-d 6 )δ13.54(s,1H),11.26(s,1H),10.92(s,1H),8.46(d,J＝8.5Hz,1H),8.23(d,J＝8.0Hz,1H),7.96(d,J＝7.6Hz,1H),7.59(dd,J＝10.1,4.0Hz,2H),7.46(dd,J＝6.1,3.2Hz,1H),7.36–7.23(m,2H),7.13–7.03(m,1H),6.43(dd,J＝17.0,10.2Hz,1H),6.24(d,J＝15.8Hz,1H),5.77(d,J＝11.0Hz,1H),3.83(s,3H).
Synthetic scheme 3
Figure BDA0002389089600000293
Weighing 17 (1eq, 1000mg) and dissolving in 20mL DMF, adding NCS (2.3eq, 1163mg), heating and stirring at 100 ℃ for 4 hours, after the reaction is finished, carrying out DCM extraction, washing with saturated saline solution, drying with anhydrous sodium sulfate, collecting an organic phase, spinning, stirring, and carrying out thin-layer silica gel chromatography (PE: EA = 15. The product is a white powdery solid 18.
Figure BDA0002389089600000301
Weighing 18 (1eq, 100mg) and dissolving in 10mL of 1, 4-dioxane, adding 17 (1.5eq, 109mg), tetratriphenylphosphine palladium (0.2eq, 36mg), cesium carbonate (2eq, 142mg), water (2.5 ml), nitrogen protection, condensing and refluxing for 1 hour at 110 ℃, after the reaction is finished, carrying out spin-drying, DCM extraction, saturated brine washing, drying by anhydrous sodium sulfate, collecting an organic phase, carrying out spin-drying, sample stirring, loading on a column, and carrying out thin-layer silica gel chromatography (PE: EA: DCM =6, 1, V/V/V) to obtain a compound, namely tert-butyl 6- (2,6-dichloro-3,5-dimethoxyphenyl) -3- (3-nitrobenzamide) -1H-indazole-1-carboxylic acid (81mg, 63%) and obtaining a white solid 19.
Figure BDA0002389089600000302
Compound 19 (1eq, 81mg) was weighed and dissolved in 4mL of DCM, stirred at room temperature, 1.2mL of TFA was added dropwise, stirred and reacted for 3 hours, after the reaction was completed, spin-dried, extracted with DCM, and the organic phase was collected and spin-dried to obtain compound 20 (59mg, 89%).
Figure BDA0002389089600000311
Iron powder (1eq, 115mg) and ammonium chloride (4eq, 45mg) were weighed into a reaction flask, 2mL of water were added, stirred at 70 ℃ for 30 minutes, compound 20 (1eq, 100mg) was dissolved in 6mL of methanol solution and added dropwise to the reaction flask, stirred at 70 ℃ for 2 hours, after the reaction was completed, filtered while hot, the filter cake was washed with ethyl acetate, spun dry, DCM extracted, washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was collected, spun dry, sample stirred, thin layer silica gel chromatography column (DCM: meOH =300, 6, V/V) gave compound 21 (84mg, 89%).
Figure BDA0002389089600000312
Compound 21 (1eq, 300mg) was weighed and dissolved in 5mL of tetrahydrofuran solution, DMAP (0.1eq, 18mg) was added and stirred uniformly, boc anhydride (0.9eq, 132mg) was added dropwise, and the reaction was stirred at room temperature for 1 hour, and after completion of the reaction, the mixture was dried by spin-drying, DCM-extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was collected, spin-dried, and sample-stirred, and then subjected to thin layer silica gel chromatography (PE: EA: DCM =1, V/V) to obtain compound 22 (245 mg, yield: 67%).
Figure BDA0002389089600000321
Weighing compound 22 (1eq, 110mg) and dissolving in 6mL 1, 4-dioxane, adding DIPEA (2.5eq, 64mg) under ice bath, stirring for five minutes, dropwise adding chloroacetyl chloride (2.5eq, 56mg), stirring at room temperature for reaction for 2 hours, after the reaction is finished, spin-drying, DCM extracting, washing with saturated saline, drying with anhydrous sodium sulfate, collecting the organic phase, spin-drying, mixing with a sample, and carrying out thin-layer silica gel chromatography to obtain compound 23 (102mg, 78%).
Figure BDA0002389089600000322
Compound 23 (1eq, 102mg) was dissolved in 3mL of dichloromethane and 1mL of trifluoroacetic acid was added dropwise with stirring. Reacting at room temperature for 2h, after the reaction is finished, spin-drying, extracting and pulping to obtain the compound F-43 (56mg, 67%).
3- (2-chloroacetamide) -N- (6- (2,6-dichloro-3,5-dimethoxybenzene) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000323
1 H NMR(400MHz,DMSO-d 6 )δ12.91(s,1H),10.88(s,1H),10.53(s,1H),8.22(s,1H),7.84(dd,J＝18.6,10.7Hz,2H),7.78(d,J＝8.4Hz,1H),7.52(t,J＝8.1Hz,1H),7.30(s,1H),7.00(s,1H),6.87(d,J＝8.4Hz,1H),4.30(s,2H),3.97(s,6H).
Using a similar procedure the following compounds were obtained:
3- (2-Bromoacetamide) -N- (6- (2,6-dichloro-3,5-dimethoxybenzene) -1H-indazol-3-yl) benzamide
Figure BDA0002389089600000331
1 H NMR(500MHz,DMSO-d 6 )δ12.92(s,1H),10.89(s,1H),10.59(d,J＝43.0Hz,1H),8.25(s,1H),7.85(dd,J＝17.4,10.0Hz,2H),7.80(d,J＝8.3Hz,1H),7.52(t,J＝7.9Hz,1H),7.32(s,1H),7.00(s,1H),6.88(d,J＝8.3Hz,1H),4.31(s,2H),3.97(s,6H).
Synthesis scheme 4
Figure BDA0002389089600000332
Putting compound 24 (1eq, 600mg) into a 100mL double-neck flask, adding 1,4-dioxane 30mL, ultrasonically dissolving, adding 3,5-dimethoxyphenylboronic acid (2eq, 1413mg), cesium carbonate (3eq, 3795mg), tetratriphenylphosphorated palladium (0.01eq, 45mg), replacing air for 3 times, condensing and refluxing for 2 hours under the protection of nitrogen, after the reaction is finished, adding water and dichloromethane for extraction, collecting an organic phase, drying and spin-drying anhydrous sodium sulfate, and purifying by passing through a column to obtain white solid compound 25 (627mg, 63%).
Figure BDA0002389089600000333
Figure BDA0002389089600000341
Taking compound 25 (1eq, 400mg), adding into 100mL round bottom flask, adding DMF10mL, NIS (1eq, 351mg), reacting overnight at 80 ℃, adding saturated ammonium chloride aqueous solution to quench after the reaction is finished, extracting, collecting organic phase, drying with anhydrous sodium sulfate, spinning, mixing sample, purifying by silica gel column to obtain compound 26 (399mg, 67%).
Figure BDA0002389089600000342
Compound 26 (1eq, 500mg) was charged in a 50mL round-bottomed flask, THF (20 mL) and DMAP (0.2eq, 32mg) were added thereto, and dropwise addition was made under stirring (Boc) 2 O (1.1eq, 314mg), stirring at room temperature for 30 minutes, after completion of the reaction, adding 20mL each of saturated aqueous ammonium chloride and methylene chloride, extracting, collecting the organic phase, drying over anhydrous sodium sulfate, spin-drying, and passing through a column to obtain Compound 27 (492mg, 78%).
Figure BDA0002389089600000343
Taking compound 27 (1eq, 400mg) in a 100mL round-bottom flask, adding DMF (20 mL) to dissolve, adding CuI (0.05eq, 8mg), potassium phosphate (3eq, 528mg), 2-nitrobenzamide (2eq, 138mg), reacting under nitrogen protection, condensing, refluxing overnight, spin-drying, passing through a column, and purifying to obtain compound 29 (203mg, 47%).
Figure BDA0002389089600000351
Compound 29 (1eq, 203mg) was placed in a 100mL two-necked flask, 30mL of methanol solution and a catalytic amount of palladium on carbon were added, and the mixture was reacted overnight under hydrogen protection, filtered through silica gel, the filtrate was collected, spun dry, and sample-mixed, and purified by silica gel column to give compound 30 (168mg, 88%).
Figure BDA0002389089600000352
Placing compound 30 (1eq, 168mg) in a 25mL round-bottomed flask, adding 1,4-dioxane (10 mL), DIPEA (3eq, 133mg), adding chloroacetyl chloride (2eq, 78mg) dropwise at 0 ℃, reacting overnight, adding water for quenching, extracting with saturated ammonium chloride aqueous solution, collecting organic phase, drying with anhydrous sodium sulfate, and spin-drying to obtain compound 31 (138mg, 71%)
Figure BDA0002389089600000353
Adding the compound 31 into a 25mL round-bottom flask, adding 6mL of dichloromethane, dropwise adding 3mL of trifluoroacetic acid while stirring, reacting at room temperature for 3 hours, after the reaction is finished, spin-drying the trifluoroacetic acid, extracting dichloromethane and water, collecting an organic phase, drying by anhydrous sodium sulfate, spin-drying, adding 2mL of dichloromethane, pulping, and filtering to obtain a compound F-45 (49mg, 43%).
Using a similar procedure the following compounds were obtained:
3- (2-chloroacetamide) -N- (6- (3,5-dimethoxyphenyl) -1H-pyrrole [4,3-c ] pyridin-3-yl) benzamide
Figure BDA0002389089600000361
3- (2-chloroacetamide) -N- (6- (3,5-dimethoxyphenyl) -1H-pyrrole [4,3-b ] pyridin-3-yl) benzamide
Figure BDA0002389089600000362
Kinase Activity of the Compounds of example 2
1. Test method
1) Preparing liquid: 1 Xkinase reaction buffer (50mM HEPES, pH 7.5,0.0015% Brij-35) and kinase reaction terminating solution (100mM HEPES, pH 7.5.0.015% Brij-35,0.2% coating reagent #3,50mM EDTA) were prepared.
2) Preparation of compound: the compounds were diluted with 100% dmso to 50X of the desired final maximum inhibitor concentration. Compounds were transferred to 96-well plates and diluted with 100% dmso to the desired 6 concentrations. 100% DMSO solution 100ml was added to two empty wells as a control, and the plate was used as a source plate. 10 μ L of compound DMSO solution was transferred from the source plate to a new 96-well plate, 90 μ L of 1X kinase buffer was added, and the compound was mixed on a shaker screen on an intermediate plate for 10 minutes, which served as the intermediate plate. Transfer 96 well plate intermediate plate complexes 5 μ Ι _ to 384 well plates and repeat 2 wells.
3) Kinase reaction: the kinase was added to 1 Xkinase reaction buffer to prepare a 2.5 Xenzyme solution, and FAM-labeled peptide and ATP were added to 1 Xkinase buffer to prepare a 2.5 Xpeptide solution. mu.L of 2.5 Xenzyme solution was added to a 384-well plate, incubated at room temperature for 10 minutes, 10. Mu.L of 2.5 Xpeptide solution was added, incubated at 28 ℃ for a prescribed time, and 25. Mu.L of reaction stop solution was added to terminate the reaction.
4) And (3) curve fitting: data of Caliper program conversion were collected, and inhibition rate = (max-conversion)/(max-min) × 100."max" is buffer control without compound added, and "min" is negative control in which a stop solution was directly added after kinase was added to terminate the reaction. The data were fitted with XLFit excel (version 5.4.0.8) to obtain IC 50 。
2. Results
Figure BDA0002389089600000371
Figure BDA0002389089600000381
Figure BDA0002389089600000391
Figure BDA0002389089600000401
Figure BDA0002389089600000411
Figure BDA0002389089600000421
Figure BDA0002389089600000431
Figure BDA0002389089600000441
Figure BDA0002389089600000451
Figure BDA0002389089600000461
E, the kinase activity is more than or equal to 1500nM; d, representing that the kinase activity is between 500nM and 1500nM; c, representing a kinase activity between 500nM and 200 nM; b, the kinase activity is between 20nM and 200 nM; a represents a kinase activity of 20nM or less.
Experimental results show that most of the compounds have certain inhibitory activity on FGFR4, and part of the compounds have very high inhibitory activity and selectivity on FGFR4, wherein the kinase activity of F-25 and F-27 is less than or equal to 20nM.
Example 3 verification of covalent binding of Compounds
To demonstrate whether compound F-27 binds covalently irreversibly to the FGFR4 protein, the protein was incubated with an excess of compound for 24 hours at 4 ℃ using pure protein as a control, and the results are shown in FIG. 1. MAL-DI/TOF-MS experiments demonstrate that the molecular weight of the protein is 51654Da, whereas the molecular weight of the protein incubated with compound is 52096Da, with a difference of 442, which demonstrates that compound F-27 binds covalently irreversibly to the FGFR4 protein, within the tolerance range.

Claims (7)

1. An indazole and pyrrolopyridine compound, which is characterized in that the indazole and pyrrolopyridine compound is one of the following specific compounds or medicinal salts thereof:
Figure DEST_PATH_IMAGE002
Figure DEST_PATH_IMAGE004
Figure DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE008
Figure DEST_PATH_IMAGE010
。
2. a pharmaceutical composition comprising the indazole-or pyrrolopyridine-based compound according to claim 1 as an active ingredient.
3. Use of indazoles, pyrrolopyridines according to claim 1 for the preparation of a medicament for the treatment of tumors.
4. The use according to claim 3, wherein the medicament is for the treatment of a disease associated with aberrant expression of the FGF19/FGFR4 signaling pathway.
5. The use according to claim 3, wherein the medicament is for the treatment of breast, lung, bladder, stomach, membrane, prostate, colon, multiple myeloma, liver, melanoma, head and neck, thyroid, renal cell, rhabdomyosarcoma and testicular cancer.
6. The use according to claim 5, wherein the medicament is for the treatment of breast cancer, non-small cell lung cancer, bladder cancer, gastric cancer, membranous adenocarcinoma, prostate cancer, colon cancer, multiple myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, rhabdomyosarcoma.
7. The use according to claim 5, wherein the medicament is for the treatment of liver cancer, breast cancer, colon cancer, rhabdomyosarcoma and gastric cancer.
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