CN114539223B - Aryl-containing aza-seven-membered ring compound and preparation method and application thereof - Google Patents

Aryl-containing aza-seven-membered ring compound and preparation method and application thereof Download PDF

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CN114539223B
CN114539223B CN202210194719.8A CN202210194719A CN114539223B CN 114539223 B CN114539223 B CN 114539223B CN 202210194719 A CN202210194719 A CN 202210194719A CN 114539223 B CN114539223 B CN 114539223B
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CN114539223A (en
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吴筱星
华德翔
陈晓禹
舒成霞
李文强
罗光美
杨可欣
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China Pharmaceutical University
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an aryl-containing aza-seven-membered ring compound, and a preparation method and application thereof. An aryl-containing aza-seven-membered ring compound of formula I and pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, polymorphs, or prodrugs thereof; the invention prepares a new compound of aryl and aza seven-membered ring based on SHP099 as a lead compound to solve the problems of single structure skeleton and the like of the existing SHP2 inhibitor; the invention has the important significance of providing a plurality of modification sites and providing a foundation for the later structural transformation. Meanwhile, the examples of the invention prove that the compound has allosteric inhibition effect on SHP2 phosphatase, and provides skeleton support for the subsequent development of SHP2 phosphatase inhibitors.

Description

Aryl-containing aza-seven-membered ring compound and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an aryl-containing aza-seven-membered ring compound, and a preparation method and application thereof.
Background
Src homology 2 domain-containing protein tyrosine phosphatase (SHP 2) belongs to the protein family of PTPs and plays a key role in regulating the processes of cell growth, proliferation, differentiation, apoptosis and the like. In human cells, SHP2 serves as an important hinge connecting multiple oncogenic signaling pathways, and its mutation and abnormal expression can cause a variety of diseases including developmental disorders, leukemia, solid tumors, and the like. In recent years, SHP2 phosphatase has attracted considerable attention because targeting SHP2 is considered an effective anticancer strategy. On the one hand, SHP2 is used as an upstream core regulatory factor of an RAS/Raf/MAPK signal path, and the inhibition of SHP2 can block the activation of the RAS/Raf/MAPK signal path, so that the growth of tumor cells is inhibited; on the other hand, SHP2 is an important cofactor for regulating tumor immunity, and inhibiting SHP2 can activate T cell immune function and kill tumor cells specifically.
Research on SHP2 inhibitors is mainly focused on developing inhibitors targeting SHP2 catalytic domains, but the inhibitors generally have the problems of low bioavailability, poor selectivity and the like, and subsequent clinical researches are difficult to carry out. In view of this, researchers have begun to shift their eyes toward the development of SHP2 allosteric inhibitors. In 2016, the first SHP2 allosteric inhibitor SHP099 was originally reported by nowa, and this finding has greatly driven the progress in the development of SHP2 inhibitors. Compared with the SHP2 inhibitor targeting the catalytic domain, the SHP099 has better activity, higher selectivity and better drug-forming property. Currently, ten SHP2 allosteric inhibitors have entered the clinical trial phase. However, there is no small molecule inhibitor of SHP2 in the market so far. Therefore, the development of a novel SHP2 small molecule inhibitor with good anti-tumor activity has great significance.
Disclosure of Invention
One of the technical problems to be solved by the invention is to provide a series of aryl-containing aza-seven-membered ring compounds for treating various related tumor diseases by inhibiting SHP2 protein and thus regulating KRAS-MEK-ERK signal paths.
The scheme for solving the technical problems is as follows:
an aromatic aza-seven-membered ring compound shown in formula I, and pharmaceutically acceptable salt, enantiomer, non-isomer, tautomer, solvate, polymorph or prodrug thereof
Ring A is
X is N or CR 4 ；
R 1 、R 2 And R is 4 Independently hydrogen, halogen, amino;
l is a bond, C 1 -C 2 Carbon chain of (2), O or S;
when n=1, m=1;
when n=2, m=0;
R 3 is hydrogen, deuterium, halogen, amino, hydroxy, nitro, cyano, amido, carboxyl, sulfonyl, -C (O) NR 5 R 6 、-C(O)R 5 、-C(O)OR 5 、-NR 5 C(O)R 6 、-NR 5 C(O)NR 6 R 7 、-NR 5 C(O)OR 6 、-NR 5 R 6 、-OC(O)R 5 、-OC(O)NR 5 R 6 、-SR 5 、-S(O) 2 R 5 、-S(O)R 5 、-S(O) 2 NR 5 R 6 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 7 Epoxy group, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 6 -C 10 Aromatic heterocyclic ring, C 6 -C 10 Heteroaryl rings, mono-heterocycles, spiro rings, bridged rings, and fused rings; wherein R is 5 、R 6 And R is 7 Independently hydrogen, deuterium, halogen, C 1 -C 7 Alkyl, C 1 -C 7 Haloalkyl, C 1 -C 7 Alkoxy, C 1 -C 7 Haloalkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 6 -C 10 Aromatic heterocyclic ring, C 6 -C 10 A heteroaromatic ring;
an aromatic aza-seven-membered ring compound shown in formula I, and pharmaceutically acceptable salt, enantiomer, non-isomer, tautomer, solvate, polymorph or prodrug thereof
Ring A is
X is N or CR 4 ；
R 1 、R 2 And R is 4 Independently hydrogen, halogen, amino;
l is a bond, C 1 -C 2 Carbon chain of (2), O or S;
when n=1, m=1;
when n=2, m=0;
R 3 is hydrogen, deuterium, halogen, amino, hydroxy, nitro, cyano, amido, carboxyl, sulfonyl, -C (O) NR 5 R 6 、-C(O)R 5 、-C(O)OR 5 、-NR 5 C(O)R 6 、-NR 5 R 6 、-OC(O)R 5 、-SR 5 、C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 6 -C 10 Aromatic heterocyclic ring, C 6 -C 10 A heteroaromatic ring; wherein R is 5 And R is 6 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl;
the aromatic and aza seven-membered ring compound is any one of the following structural formulas:
a pharmaceutical composition is characterized by comprising the aryl-aza-seven-membered ring compound and pharmaceutically acceptable auxiliary materials.
The pharmaceutical composition is characterized in that the pharmaceutical composition is prepared into tablets, capsules, injection or freeze-dried powder.
The aryl-aza seven-membered ring compound and the pharmaceutical composition are applied to the preparation of anti-tumor drugs, as prodrugs of the anti-tumor drugs or as intermediates of the anti-tumor drugs.
Advantageous effects
The invention prepares the aromatic nitrogen-containing seven-membered ring compound with a brand new skeleton based on SHP099 as a lead compound, has novel structure, has remarkably better enzyme activity than SHP099, and provides support for the subsequent development of anti-tumor drugs.
Detailed Description
Intermediate products(A) Is synthesized by the following steps:
step one: synthesis of 2-fluoro-3-chloro-4-iodopyridine (A-2):
n-butyllithium (76 mL,1.25 eq.) was slowly added dropwise to a solution of A-1 (20.00 g,152.6 mmol) in THF (150 mL) at-78deg.C. Slowly dropwise adding I after reacting for 1h 2 THF (60 mL) solution of (E). The reaction was monitored after 30 min. After monitoring the reaction, saturated Na is added dropwise 2 SO 3 The aqueous solution was quenched, concentrated to remove THF, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give compound a-2 (12.21 g, yield 32%). 1 H NMR(300MHz,CDCl 3 ):δ7.77(dd,J＝5.2,0.9Hz,1H),7.67(d,J＝5.2Hz,1H).
Step two: synthesis of 3-chloro-4-iodo-2-pyridinamine (A-3)
NH is added to 3 ·H 2 O (30 mL) was slowly added dropwise to a solution of A-2 (12.2 g,48.6 mmol) in DMSO (40 mL). After the addition, the tube is sealed at 60 ℃ for 48 hours. After monitoring the reaction, pouring the reaction system into water (200 mL), stirring for 30min, and suction-filtering and drying to obtain a compound A-3 (1)1.0g, 91% yield). 1 H NMR(300MHz,CDCl 3 ):δ7.57(d,J＝5.2Hz,1H),7.12(d,J＝5.2Hz,1H),5.05(s,2H).
Step three: synthesis of ethyl 3- ((2-amino-3-chloropyridin-4-yl) thio) propionate (A-4)
Compound A-3 (5.50 g,22.1mmol,1.0 eq.) Pd (OAc) 2 (248.0 mg,5 mol%) and XantPhos (767.2 mg,6 mol%) were placed in a 250mL single-necked flask, the system was evacuated to displace nitrogen, ethyl mercaptopropionate (3.26 g,24.3mmol,1.1 eq.) 1, 4-dioxane (45 mL) and DIPEA (7.7 mL,44.2mmol,2.0 eq.) were added and reacted overnight in an oil bath at 100deg.C, monitored to complete conversion of the starting material. The mixture was filtered through celite, the filtrate was concentrated, 30mL of ethyl acetate and 10mL of water were added to extract the layer, the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give Compound A-4 (4.10 g, yield 81%). 1 H NMR(300MHz,CDCl 3 ):δ7.87(d,J＝5.5Hz,1H),6.53(d,J＝5.5Hz,1H),4.89(s,2H),4.19(q,J＝7.2Hz,2H),3.23(t,J＝7.5Hz,2H),2.72(t,J＝7.5Hz,2H),1.28(t,J＝7.2Hz,3H).
Step four: synthesis of sodium 3-amino-2-chlorobenzenesulfide (A-5)
Sodium ethoxide in ethanol (5.88 g,17.3mmol,1.1eq., ω=20%) was slowly added dropwise to a solution of a-4 (4.10 g,15.7 mmol) in THF (20 mL). The reaction was carried out at room temperature for 2 hours. After monitoring the reaction, n-hexane (100 mL) was added for beating and suction filtration, and the solid was dried to obtain compound A-5 (3.20 g, crude product).
Step five: synthesis of 3-amino-2-chlorobenzenethiol (A)
Compound a-5 (1.60 g, crude) was dissolved in water (10 mL), and hydrochloric acid (3M) was added dropwise to ph=6. The reaction solution was extracted with ethyl acetate, separated, and the organic phase was washed 3 times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give intermediate a (1.05 g, 75% yield in two steps). 1 H NMR(300MHz,DMSO-d 6 ):δ11.46(s,1H),7.09(d,J＝6.9Hz,1H),6.76(s,2H),6.67(d,J＝6.9Hz,1H).
Intermediate products(B) Is synthesized by the following steps:
step one: synthesis of ethyl 3- ((5-chloropyrazin-2-yl) thio) propionate (B-2) Ethyl 3-mercaptopropionate (4.45 mL,1.05 eq.) was slowly added dropwise to 2, 5-dichloropyrazine (5.00 g,33.6 mmol) and K 2 CO 3 (4.64 g,1.0 eq.) in DMF (42 mL). The reaction was carried out at room temperature for 4 hours. After completion of the reaction was monitored, 200mL of ethyl acetate was added to dilute the mixture, the mixture was washed with saturated brine for 5 times, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give Compound B-2 (7.78 g, yield 94%). 1 H NMR(300MHz,CDCl 3 ):δ8.39(d,J＝1.5Hz,1H),8.22(d,J＝1.5Hz,1H),5.17(q,J＝7.2Hz,2H),3.42(t,J＝7.0Hz,2H),2.75(t,J＝7.0Hz,2H),1.27(t,J＝7.2Hz,3H).
Step two: synthesis of sodium 5-chloropyrazine-2-thiolate (B-3)
Sodium ethoxide in ethanol (11.22 g,33.0mmol,1.1eq.,. Omega. = 20%) was slowly added dropwise to a solution of B-3 (7.38 g,30.0 mmol) in THF (100 mL). The reaction was carried out at room temperature for 2 hours. After monitoring the reaction, n-hexane (100 mL) was added for beating and suction filtration, and the solid was dried to obtain compound B-3 (5.13 g, crude product).
Step three: synthesis of 3-chloro-4- ((5-chloropyrazin-2-yl) thio) pyridin-2-amine (B)
Compounds A-3 (5.50 g,22.1mmol,1.0 eq.) B-3 (4.47 g,26.5mmol,1.2 eq.) Pd 2 dba 3 (303.5 mg,1.5 mol%) and Xantphos (383.6 mg,3 mol%) were placed in a 100mL single-necked flask, the system was evacuated to displace nitrogen, 1, 4-dioxane (45 mL) and DIPEA (7.7 mL,44.2mmol,2.0 eq.) were added and reacted overnight in an oil bath at 100℃until complete conversion of the starting material was monitored. The resulting mixture was filtered through celite, the filtrate was concentrated, 50mL of ethyl acetate and 10mL of water were added to extract the layer, the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give intermediate compound B (4.4 g, yield 73%). 1 H NMR(300MHz,CDCl 3 ):δ8.52(d,J＝1.5Hz,1H),8.36(d,J＝1.5Hz,1H),7.90(d,J＝5.2Hz,1H),6.58(d,J＝5.2Hz,1H),5.04(brs,2H).
Example 1:(1) Is synthesized by the following steps:
step one: synthesis of 3- (benzyl (t-butoxycarbonyl) amino) propionic acid (1-2):
ethyl acrylate (5.34 mL,50.0mmol,1.0 eq.) was slowly added dropwise to a solution of 1-1 (6.05 g,50.0 mmol) in ethanol (100 mL). After the reaction was completed, the mixture was concentrated, and DCM (100 mL), triethylamine (13.8 mL,100.0mmol,2.0 eq.) and Boc were sequentially added to the mixture 2 O (12.01 g,55.0mmol,1.1 eq.). After the reaction was completed at room temperature for half an hour, the reaction was monitored, concentrated, and THF/H was added to the mixture in this order 2 A mixed solution of O/EtOH (25/25/25 mL) and lithium hydroxide (3.62 g,150.0mmol,3.0 eq.). After the reaction was completed, the reaction was concentrated, 30mL of water and 30mL of ethyl acetate were added, the mixture was extracted, the mixture was separated, the aqueous phase was adjusted to ph=3 with hydrochloric acid (3M), and then an appropriate amount of ethyl acetate was added to extract twice. The organic phase was washed 3 times with an appropriate amount of saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 1-2 (13.60 g, crude).
Step two: synthesis of tert-butyl 5-oxo-1, 3,4, 5-tetrahydro-2H-benzo [ c ] aza-2-carboxylate (1-3):
thionyl chloride (10.8 mL,150.0mmol,3.0 eq.) was slowly added dropwise to a solution of 1-2 in anhydrous DCM (100 mL) at 0deg.C, reacted for 2h at room temperature, after monitoring the reaction was complete, concentrated and the oil was pumped for half an hour. The mixture was dissolved in anhydrous DCM (100 mL), aluminum trichloride (19.85 g,150.0 mL,3.0 eq.) was added at 0 ℃ and reacted overnight at room temperature. The reaction solution was poured into an ice aqueous sodium hydroxide solution (6 m,100 mL), filtered, the residue was washed twice with DCM (20 mL), the solution was separated, and the organic phase was washed 3 times with saturated brine. Triethylamine (7.6 mL,55.0mmol,1.1 eq.) and Boc were added sequentially to the organic phase 2 O (10.92 g,50.0mmol,1.0 eq.). Reacting at room temperature for half an hour, washing the reaction solution with a proper amount of saturated sodium chloride solution for 3 times, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain the compound 1-3 (3.10 g, 23% yield in six steps). 1 H NMR(300MHz,CDCl 3 ):δ7.89(dd,J＝7.8,1.5Hz,1H),7.49-7.44(m,1H),7.42-7.29(m,2H),4.70(d,J＝16.0Hz,2H),3.79-3.66(m,2H),3.08-2.98(m,2H),1.39(s,9H).
Step three: synthesis of tert-butyl (S) -5- (((R) -tert-butylsulfinyl) amino) -1,3,4, 5-tetrahydro-2H-benzo [ c ] aza-2-carboxylate (1-4)
(R) -2-methylpropane-2-sulfinamide (2.86 g,23.6mmol,2.0 eq.) and tetraethyltitanate (5.38 g,23.6mmol,2.0 eq.) were added to a solution of 1-3 (3.10 g,11.8 mmol) in THF (20 mL) and reacted overnight at 75 ℃. After monitoring the completion of the reaction, liBH (iBu) was slowly added dropwise at-50 ℃ 3 Is reacted at room temperature for 2 hours. After completion of the reaction, water (1 mL) was slowly added dropwise to the reaction system. The mixture was filtered, the cake was washed with ethyl acetate (10 mL), the solution was separated, the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and the compound 1-4 was isolated by column chromatography (2.85 g, yield 66%). 1 H NMR(300MHz,CDCl 3 ):δ7.42-7.36(m,1H),7.30-7.17(m,3H),4.76(dd,J＝6.0,1.4Hz,2H),4.52(d,J＝15.1Hz,1H),4.38(d,J＝15.1Hz,1H),3.79-3.63(m,2H),2.32-2.19(m,1H),2.06-1.93(m,1H),1.39(s,9H),1.23(s,9H).
Step four: synthesis of (R) -N- ((S) -2- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropylamine-2-sulfinamide (1-5)
Trifluoroacetic acid (0.5 mL) was slowly added dropwise to a solution of 1-4 (118.6 mg,0.33mmol,1.3 eq.) in DCM (2 mL) and reacted at room temperature for 2h. After monitoring the reaction was complete, it was concentrated. DMSO (1 mL), DIPEA (1 mL) and Compound B (68.3 mg,0.25 mmol) were added sequentially. The reaction was carried out at 100℃for 2 hours. After monitoring the reaction was complete, 25mL ethyl acetate and 10mL water were added. The organic phase was washed with saturated brine 5 times, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give compounds 1 to 6 (42.0 mg, yield 33%). 1 H NMR(300MHz,CDCl 3 ):δ8.23(d,J＝1.3Hz,1H),8.21(d,J＝1.3Hz,1H),7.65(d,J＝5.5Hz,1H),7.46-7.34(m,2H),7.33-7.23(m,2H),5.98(d,J＝5.5Hz,1H),5.06(s,2H),4.87(d,J＝15.5Hz,1H),4.76(d,J＝15.5Hz,1H),4.38-4.23(m,1H),4.08-3.93(m,1H),3.73(d,J＝4.1Hz,1H),2.46-2.35(m,1H),2.17-2.02(m,1H),1.23(s,9H).
Step five: synthesis of (S) -2- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-amine (1)
A2M solution of ethyl hydrogen chloride (1.0 mL) was slowly added dropwise to a solution of 1-5 (42.0 mg,0.08 mmol) in ethyl acetate (2 mL) and reacted overnight at room temperature. After monitoring the reaction was complete, 20mL of purified water and 10mL of ethyl acetate were added, extracted, the aqueous phase was adjusted to ph=6 with saturated sodium carbonate, and the aqueous phase was washed with ethyl acetate until all impurities were washed off. The aqueous phase was then adjusted to ph=8, extracted twice with 15mL ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and lyophilized to give compound 1 (21.1 mg, yield 63%). 1 H NMR(300MHz,CDCl 3 ):δ8.24(d,J＝1.4Hz,1H),8.20(d,J＝1.4Hz,1H),7.67(d,J＝5.5Hz,1H),7.44-7.33(m,2H),7.32-7.28(m,1H),7.26-7.18(m,1H),6.00(d,J＝5.5Hz,1H),5.03(d,J＝15.1Hz,1H),4.89(s,2H),4.73(d,J＝15.1Hz,1H),4.43(dd,J＝5.6,2.3Hz,1H),4.25-4.02(m,2H),2.23-2.09(m,1H),1.92-1.81(m,1H)。
Example 2:(2) Is synthesized by the following steps:
detailed procedure referring to the synthesis of compound 1, 3-methoxybenzylamine was used as starting material to replace 1-1, and compound 2 was finally obtained by five steps of reaction. 1 H NMR(300MHz,CDCl 3 ):δ8.24(d,J＝1.4Hz,1H),8.20(d,J＝1.4Hz,1H),7.68(d,J＝5.5Hz,1H),7.29(d,J＝8.4Hz,1H),6.92(d,J＝2.7Hz,1H),6.77(dd,J＝8.4,2.7Hz,1H),6.01(d,J＝5.5Hz,1H),5.00(d,J＝15.1Hz,1H),4.87(s,2H),4.69(d,J＝15.1Hz,1H),4.38(dd,J＝7.8,2.7Hz,1H),4.20-4.09(m,2H),3.81(s,3H),2.19-2.05(m,1H),1.96-1.77(m,1H)。
Example 3:(3) Is synthesized by the following steps:
detailed procedure referring to the synthesis of compound 1, 1-1 was replaced with 3-methylbenzylamine as starting material, the best by five steps of reactionCompound 3 is finally obtained. 1 H NMR(300MHz,CDCl 3 ):δ8.24(d,J＝1.4Hz,1H),8.21(d,J＝1.5Hz,1H),7.68(d,J＝5.4Hz,1H),7.27(d,J＝8.0Hz,1H),7.16(d,J＝1.2Hz,1H),7.08(dd,J＝8.0,1.2Hz,1H),6.02(d,J＝5.4Hz,1H),4.99(d,J＝15.2Hz,1H),4.86(s,2H),4.68(d,J＝15.2Hz,1H),4.39(dd,J＝7.8,2.6Hz,1H),4.19-4.11(m,2H),2.33(s,3H),2.21-2.05(m,1H),1.92-1.79(m,1H)。
Example 4:(4) Is synthesized by the following steps:
detailed procedure referring to the synthesis of compound 1, 3-fluorobenzylamine was used as starting material in place of 1-1 to finally give compound 4 by five steps of reaction. 1 H NMR(300MHz,CDCl 3 ):δ8.25(d,J＝1.4Hz,1H),8.18(d,J＝1.4Hz,1H),7.68(d,J＝5.5Hz,1H),7.35(dd,J＝8.5,5.6Hz,1H),7.10(dd,J＝8.9,2.7Hz,1H),6.94(ddd,J＝8.5,8.2,2.7Hz,1H),6.01(d,J＝5.5Hz,1H),5.03(d,J＝15.1Hz,1H),4.87(s,2H),4.71(d,J＝15.1Hz,1H),4.42(dd,J＝7.8,2.6Hz,1H),4.23-4.08(m,2H),2.24-2.09(m,1H),1.92-1.80(m,1H)。
Example 5:(5) Is synthesized by the following steps:
detailed procedure referring to the synthesis of compound 1, 3-chlorobenzylamine was used as starting material in place of 1-1 to finally give compound 5 by five steps of reaction. 1 H NMR(300MHz,CDCl 3 ):δ8.26(d,J＝1.4Hz,1H),8.18(d,J＝1.4Hz,1H),7.68(d,J＝5.5Hz,1H),7.38-7.31(m,2H),7.24(dd,J＝8.2,2.2Hz,1H),6.02(d,J＝5.5Hz,1H),5.02(d,J＝15.1Hz,1H),4.96(s,2H),4.69(d,J＝15.1Hz,1H),4.41(d,J＝7.7Hz,1H),4.22-4.01(m,2H),2.22-2.08(m,1H),1.92-1.78(m,1H)。
Example 6:(6) Is synthesized by the following steps:
detailed procedure referring to the synthesis of Compound 1, 1-1 was replaced with 3-bromobenzylamine as starting material, followed byThe compound 6 is finally obtained after five steps of reaction. 1 H NMR(300MHz,CDCl 3 ):δ8.26(d,J＝1.4Hz,1H),8.18(d,J＝1.4Hz,1H),7.68(d,J＝5.5Hz,1H),7.51(d,J＝2.1Hz,1H),7.40(dd,J＝8.1,2.1Hz,1H),7.28(d,J＝8.1Hz,1H),6.02(d,J＝5.5Hz,1H),5.01(d,J＝15.1Hz,1H),4.93(s,2H),4.69(d,J＝15.1Hz,1H),4.39(dd,J＝8.1,2.7Hz,1H),4.23-4.01(m,2H),2.21-2.08(m,1H),1.93-1.79(m,1H)。
Example 7:(7) Is synthesized by the following steps:
detailed procedure referring to the synthesis of compound 1, 3-cyanobenzylamine was used as starting material in place of 1-1 to finally obtain compound 7 by five steps of reaction. 1 H NMR(300MHz,DMSO-d 6 ):δ8.50(d,J＝1.4Hz,1H),8.28(d,J＝1.4Hz,1H),7.99(d,J＝1.7Hz,1H),7.75(dd,J＝8.0,1.7Hz,1H),7.64(d,J＝8.0Hz,1H),7.62(d,J＝5.4Hz,1H),6.35(s,2H),5.75(d,J＝5.4Hz,1H),5.08(d,J＝15.3Hz,1H),4.81(d,J＝15.3Hz,1H),4.45(dd,J＝8.7,2.0Hz,1H),4.30-4.14(m,1H),4.04-3.85(m,1H),2.07-1.93(m,1H),1.77-1.61(m,1H)。
Example 8:(8) Is synthesized by the following steps:
detailed procedure referring to the synthesis of compound 1, 3-aminobenzylamine was used as starting material in place of 1-1 to finally give compound 8 by five steps of reaction. 1 H NMR(300MHz,CDCl 3 ):δ8.23(d,J＝1.4Hz,1H),8.19(d,J＝1.4Hz,1H),7.68(d,J＝5.5Hz,1H),7.14(d,J＝8.1Hz,1H),6.69(d,J＝2.5Hz,1H),6.56(dd,J＝8.1,2.5Hz,1H),6.02(d,J＝5.4Hz,1H),4.93(d,J＝15.1Hz,1H),4.87(s,1H)4.62(d,J＝15.1Hz,1H),4.32(dd,J＝7.5,2.5Hz,1H),4.20-4.06(m,2H),3.67(s,2H),2.18-2.04(m,1H),1.91-1.77(m,1H)。
Example 9:(9) Is synthesized by the following steps:
detailed procedure reference compounds1, 3- (pyrrolidine-1-yl) benzylamine is used as a starting material to replace 1-1, and the compound 9 is finally obtained through five steps of reactions. 1 H NMR(300MHz,CDCl 3 ):δ8.25(d,J＝1.4Hz,1H),8.22(d,J＝1.4Hz,1H),7.68(d,J＝5.5Hz,1H),7.19(d,J＝8.2Hz,1H),6.56(d,J＝2.5Hz,1H),6.41(dd,J＝8.2,2.5Hz,1H),6.02(d,J＝5.5Hz,1H),5.00(d,J＝15.1Hz,1H),4.86(s,2H),4.66(d,J＝15.1Hz,1H),4.34(dd,J＝7.6,2.4Hz,1H),4.27-4.10(m,2H),3.36-3.22(m,4H),2.18-2.05(m,1H),2.02-1.92(m,4H),1.93-1.81(m,1H)。
Example 10:(10) Is synthesized by the following steps:
detailed procedure referring to the synthesis of compound 1, 1-1 was replaced with 3-dimethylaminobenzylamine as starting material, and compound 10 was finally obtained by five steps of reaction. 1 H NMR(300MHz,CDCl 3 ):δ8.23(s,2H),7.68(d,J＝5.5Hz,1H),7.22(d,J＝8.4Hz,1H),6.73(d,J＝2.7Hz,1H),6.58(dd,J＝8.4,2.7Hz,1H),6.02(d,J＝5.5Hz,1H),5.00(d,J＝15.1Hz,1H),4.86(s,2H),4.68(d,J＝15.1Hz,1H),4.34(dd,J＝7.4,2.5Hz,1H),4.22-4.09(m,2H),2.95(s,6H),2.19-2.05(m,1H),1.90-1.81(m,1H)。
Example 11:(11) Is synthesized by the following steps:
detailed procedure referring to the synthesis of compound 1, 3- (4-fluorophenyl) benzylamine was used as starting material in place of 1-1 to finally give compound 11 by five steps of reaction. 1 H NMR(400MHz,CDCl 3 ):δ8.25(d,J＝1.4Hz,1H),8.23(d,J＝1.4Hz,1H),7.65(d,J＝5.4Hz,1H),7.58-7.50(m,3H),7.49-7.39(m,2H),7.18-7.07(m,2H),6.01(d,J＝5.4Hz,1H),5.10(d,J＝15.1Hz,1H),4.87(s,2H),4.79(d,J＝15.1Hz,1H),4.76(brs,1H),4.47(dd,J＝7.8,2.6Hz,1H),4.27-4.10(m,2H),2.25-2.14(m,1H),1.96-1.85(m,1H)。
Example 12:(12) Is synthesized by the following steps:
step one: synthesis of N- (tert-Butoxycarbonyl) -N-phenethylglycine (12-2):
ethyl bromopropionate (1.18 mL,10.0mmol,1.0 eq.) and triethylamine (2.78 mL,20.0mmol,2.0 eq.) were added dropwise in sequence to a solution of 12-1 (1.21 g,10.0 mmol) in THF (20 mL). After completion of the reaction, the reaction mixture was concentrated, and DCM (20 mL), triethylamine (2.78 mL,20.0mmol,2.0 eq.) and Boc were added in this order 2 O (2.40 g,11.0mmol,1.1 eq.). After the reaction was completed at room temperature for half an hour, the reaction was monitored, concentrated, and THF/H was added to the mixture in this order 2 A mixed solution of O/EtOH (5/5/5 mL) and lithium hydroxide (0.72 g,30.0mmol,3.0 eq.). After the reaction was completed, the reaction was concentrated, 20mL of water and 20mL of ethyl acetate were added, the mixture was extracted, the mixture was separated, the aqueous phase was adjusted to ph=3 with hydrochloric acid (3M), and then an appropriate amount of ethyl acetate was added to extract twice. The organic phase was washed 3 times with an appropriate amount of saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 12-2 (2.01 g, crude).
Step two: synthesis of 1-oxo-1, 2,4, 5-tetrahydro-3H-benzo [ d ] aza-3-carboxylic acid tert-butyl ester (12-3):
referring to step two of the synthetic route of example 1, 1-2 was replaced with 12-2 to give compound 12-3 (0.31 g, 16% in six steps). 1 H NMR(300MHz,CDCl 3 ):δ7.77(d,J＝7.6,1.2Hz,1H),7.43(ddd,J＝7.5,7.4,1.2Hz,1H),7.36(ddd,J＝7.6,7.4,1.0Hz,1H),7.23(dd,J＝7.5,1.0Hz,1H),4.17(d,J＝17.7Hz,2H),3.79-3.68(m,2H),3.08-2.97(m,2H),1.22(s,9H).
Step three: synthesis of tert-butyl (R) -1- (((R) -tert-butylsulfinyl) amino) -1,2,4, 5-tetrahydro-3H-benzo [ d ] aza-3-carboxylate (12-4):
referring to step three in the synthetic route of example 1, 1-3 was replaced with 12-3 to give compound 12-4 (0.14 g, yield 32%). LC-MS (ESI): 367.2 (M+H) + .
Step four: synthesis of (R) -N- ((R) -3- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropylamine-2-sulfinamide (12-5):
referring to step four in the synthetic route of example 1, substituting 12-4 for 1-4 gave compound 12-5 (98.2 mg, yield 66%). 1 H NMR(300MHz,CDCl 3 ):δ8.36(d,J＝1.4Hz,1H),8.30(d,J＝1.4Hz,1H),7.70(d,J＝5.4Hz,1H),7.46-7.39(m,1H),7.35-7.29(m,1H),7.25-7.19(m,1H),7.14-7.09(m,1H),5.98(d,J＝5.4Hz,1H),5.14(dd,J＝14.6,5.6Hz,1H),4.96(s,2H),4.83-4.78(m,1H),4.36(dd,J＝14.6,5.3Hz,1H),4.26(d,J＝2.2Hz,1H),3.61-3.20(m,3H),2.97-2.85(m,1H),0.98(s,9H).
Step five: synthesis of (R) -3- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ d ] azepin-1-amine (12):
referring to step five of the synthetic route of example 1, substituting 12-5 for 1-5 gave compound 12 (45.2 mg, yield 58%). 1 H NMR(300MHz,CDCl 3 ):δ8.28(d,J＝1.3Hz,1H),8.26(d,J＝1.3Hz,1H),7.69(d,J＝5.5Hz,1H),7.36-7.29(m,1H),7.26-7.19(m,2H),7.19-7.14(m,1H),6.00(d,J＝5.5Hz,1H),4.92(s,2H),4.36(dd,J＝7.2,2.9Hz,1H),4.20(dd,J＝14.3,7.2Hz,1H),4.05(ddd,J＝13.3,6.4,2.8Hz,1H),3.92(dd,J＝14.3,2.9Hz,1H),3.69(ddd,J＝13.3,9.7,2.5Hz,1H),3.37(ddd,J＝15.2,9.7,2.8Hz,1H),2.99(ddd,J＝15.2,6.4,2.5Hz,1H)。
Example 13:(13) Is synthesized by the following steps:
detailed procedure referring to the synthesis of compound 12, the 3-fluorophenylethylamine was used as starting material in place of 12-1 to finally give compound 13 by five steps of reaction. 1 H NMR(300MHz,CDCl 3 )δ8.28(d,J＝1.2Hz,1H),8.26(d,J＝1.2Hz,1H),7.70(d,J＝5.4Hz,1H),7.30(dd,J＝8.2,7.0Hz,1H),6.98-6.82(m,2H),6.00(d,J＝5.4Hz,1H),4.89(s,2H),4.35(dd,J＝7.1,2.7Hz,1H),4.20(dd,J＝14.3,7.1Hz,1H),4.08(ddd,J＝14.5,6.5,2.6Hz,1H),3.88(dd,J＝14.3,2.7Hz,1H),3.68(ddd,J＝14.5,9.8,2.1Hz,1H),3.36(ddd,J＝15.2,9.8,2.6Hz,1H),3.94(ddd,J＝15.2,6.5,2.1Hz,1H)。
Example 14:(14) Is synthesized by the following steps:
detailed procedure referring to the synthesis of compound 12, the 3-methoxyphenylethylamine was used as starting material for the replacement of 12-1, and compound 14 was finally obtained by five steps of reaction. 1 H NMR(300MHz,CDCl 3 ):δ8.28(d,J＝1.4Hz,1H),8.26(d,J＝1.4Hz,1H),7.70(d,J＝5.5Hz,1H),7.24(d,J＝8.1Hz,1H),6.78-6.69(m,2H),6.01(d,J＝5.5Hz,1H),4.87(s,2H),4.32(dd,J＝6.9,2.6Hz,1H),4.22(dd,J＝14.1,6.9Hz,1H),4.10(ddd,J＝14.5,7.1,2.8Hz,1H),3.85(dd,J＝14.1,2.6Hz,1H),3.80(s,3H),3.65(ddd,J＝14.5,10.2,2.0Hz,1H),3.35(ddd,J＝15.4,10.2,2.8Hz,1H),2.91(ddd,J＝15.4,7.1,2.0Hz,1H)。
Example 15:(15) Is synthesized by the following steps:
step one: synthesis of 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amino (15-2):
compound 15-1 (208.4 mg,1.0 mmol), A (192.7 mg,1.2mmol,1.2 eq.) copper iodide (38.9 mg,0.2mmol,0.2 eq.), 1, 10-phenanthroline (54.2 mg,0.3mmol,0.3 eq.) and potassium phosphate (424.5 mg,2.0mmol,2.0 eq.) were placed in a 15mL tube, the system was evacuated to displace nitrogen, and 1, 4-dioxane (4 mL) was added to an oil bath at 85℃to react overnight, and the complete conversion of the starting material was monitored. The resulting mixture was filtered through celite, the filtrate was concentrated, 20mL of ethyl acetate and 10mL of water were added to extract the layer, the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give compound 15-2 (216.2 mg, yield 75%). 1 H NMR(300MHz,CDCl 3 ):δ8.01(s,1H),7.77(d,J＝5.4Hz,1H),6.09(d,J＝5.4Hz,1H),5.23(s,2H),4.96(s,2H).
Step two: synthesis of (R) -N- ((S) -2- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropan-2-sulfinamide (15-3):
trifluoroacetic acid (0.5 mL) was slowly added dropwise to a solution of 1-4 (186.0 mg,0.52mmol,1.3 eq.) in DCM (2 mL) and reacted at room temperature for 2h. After monitoring the reaction was complete, it was concentrated. NMP (1 mL), potassium carbonate (220.8 mg,1.6mmol,4.0 eq.) and compound 15-3 (115.3 mg,0.4 mmol) were added sequentially. The reaction was carried out at 100℃for 10 hours. After monitoring the reaction was complete, 25mL ethyl acetate and 10mL water were added. The mixture was separated, and the organic phase was washed with saturated brine for 5 times, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give compound 15-3 (95.2 mg, yield 46%). 1 H NMR(300MHz,CDCl 3 ):δ8.24(d,J＝1.3Hz,1H),8.20(d,J＝1.3Hz,1H),7.67(d,J＝5.5Hz,1H),7.45-7.34(m,2H),7.33-7.27(m,2H),5.99(d,J＝5.5Hz,1H),5.02-4.72(m,6H),4.40-4.23(m,1H),4.05-3.93(t,J＝11.5Hz,1H),3.46(d,J＝4.0Hz,1H),2.37-2.31(m,1H),2.18-2.03(m,1H),1.22(s,9H).
Step three: synthesis of (S) -2- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-amine (15):
referring to step five in the synthetic route of example 1, replacement of 1-5 with 15-3 (80.9 mg,0.16 mmol) afforded compound 15 (44.2 mg, 67% yield). 1 H NMR(300MHz,CDCl 3 ):δ7.67(d,J＝5.4Hz,1H),7.64(s,1H),7.41(d,J＝7.8Hz,1H),7.36-7.28(m,2H),7.25-7.18(m,1H),6.01(d,J＝5.4Hz,1H),4.92(d,J＝15.2Hz,1H),4.87(s,2H),4.79(s,2H),4.68(d,J＝15.2Hz,1H),4.40(dd,J＝8.2,2.5Hz,1H),4.17-3.88(m,2H),2.23-2.10(m,1H),1.88-1.76(m,1H)。
Example 16:(16) Is synthesized by the following steps:
step one: synthesis of 6-chloro-3- (2, 3-dichlorophenyl) pyrazin-2-amine (16-2):
compound 16-1 (0.21 g,1.0 mmol), 2, 3-dichlorobenzoboric acid (0.21 g,1.1mmol,1.1 eq.) Pd (dppf) Cl2 (14.6 mg,2 mol%) and potassium phosphate (0.42 g,2.0mmol,2.0 eq.) were placed in a 15mL sealed tube, the system was evacuated to displace nitrogen, 1, 4-dioxane (2 mL) and water (0.2 mL) were added to react overnight in an oil bath at 120℃and TLC monitored until complete conversion of the starting material. The resulting mixture was filtered through celite, the filtrate was concentrated, 20mL of ethyl acetate was added to the concentrated solution, the mixture was washed with a proper amount of saturated brine for 3 times, dried over anhydrous sodium sulfate, and concentrated, and the compound 16-2 (0.25 g, yield 91%) was isolated by column chromatography. 1 H NMR(300MHz,CDCl 3 ):δ8.03(s,1H),7.60(dd,J＝7.6,2.0Hz,1H),7.36(dd,J＝7.7,7.6Hz,1H),7.32(dd,J＝7.6,2.0Hz,1H),4.65(s,2H).
Step two: synthesis of 6-chloro-3- (2, 3-dichlorophenyl) pyrazin-2-amino tert-butyl ester (16-3):
compound 17-2 (0.25 g,0.91mmol,1.0 eq.) and DMAP (5.6 mg,0.05mmol,0.05 eq.) were placed in a 10mL single-port flask, DCM (5 mL) and di-tert-butyl dicarbonate (0.44 g,1.91mmol,2.1 eq.) were added sequentially, and the reaction was completed at room temperature for 2h, with TLC monitoring for complete conversion of starting material. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give Compound 16-3 (0.35 g, yield 80%). 1 H NMR(300MHz,CDCl 3 ):δ8.68(s,1H),7.57(d,J＝7.5Hz,1H),7.46-7.24(m,2H),1.37(s,18H).
Step three: synthesis of tert-butyl (6- ((S) -5- (((R) -tert-butylsulfinyl) amino) -1,3,4, 5-tetrahydro-2H-benzo [ c ] azepin-2-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-yl) carbamate (16-4)
Referring to step four in the synthetic route of example 1, substituting 16-3 (0.19 g,0.4 mmol) for B gave compound 16-4 (0.15 g, yield 55%). 1 H NMR(300MHz,CDCl 3 ):δ8.18(s,1H),7.46(dd,J＝7.9,1.7Hz,1H),7.43-7.35(m,2H),7.34-7.23(m,3H),7.20(t,J＝7.8Hz,1H),4.91(d,J＝15.4Hz,1H)4.85-4.78(m,1H),4.74(d,J＝15.4Hz,1H),4.44-4.23(m,1H),4.07-3.93(m,1H),3.47(d,J＝3.8Hz,1H),2.47-2.30(m,1H),2.19-2.10(m,1H),1.34(s,18H),1.24(s,9H).
Step four: synthesis of (S) -2- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-amine (16):
referring to step five of the synthetic route of example 1, 1-5 was replaced with 16-4 to give compound 16 (46.5 mg, yield 52%). 1 H NMR(300MHz,CDCl 3 ):δ7.58(s,1H),7.47(dd,J＝7.0,2.6Hz,1H),7.41(d,J＝7.4Hz,1H),7.36(dd,J＝7.1,1.7Hz,1H),7.32-7.19(m,4H),4.89(d,J＝15.6Hz,1H),4.67(d,J＝15.6Hz,1H),4.40(dd,J＝8.3,2.8Hz,1H),4.20(s,2H),4.10-3.90(m,2H),2.26-2.21(m,1H),1.91-1.83(m,1H)。
Example 17:(17) Is synthesized by the following steps:
step one: synthesis of 2-chloro-N- (2, 2-dimethoxyethyl) -5-iodopyrimidin-4-amine (17-2): triethylamine (2.77 mL,20.0mmol,2.0 eq.) was added dropwise to a solution of 17-1 (2.74 g,10.0 mmol) and 2, 2-dimethoxyethan-1-amine (2.10 g,20.0mmol,2.0 eq.) in ethanol (40 mL) at 0deg.C. The reaction was carried out overnight at room temperature and TLC monitored until complete conversion of starting material. Concentrated, 30mL of ethyl acetate and 10mL of water were added, the solution was separated, and the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 17-2 (3.64 g, crude product).
Step two: synthesis of 8-iodoimidazo [1,2-c ] pyrimidin-5-ol (17-3):
17-2 (3.64 g, crude) was added to concentrated sulfuric acid (40 mL). The reaction was carried out overnight at room temperature and TLC monitored until complete conversion of starting material. The reaction solution was poured into ice water, ph=6 was adjusted with sodium hydroxide, and compound 17-3 (2.55 g, crude product) was obtained by filtration.
Step three: synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine (17-4):
DIPEA (1 mL) was added dropwise to a solution of 17-3 (0.52 g,2.0 mmol) in phosphorus oxychloride (8 mL). The reaction was carried out at 120℃for 5h, and TLC was monitored until complete conversion of starting material was reached. Concentrating, adding 20mL of dichloromethane, pouring the mixture into 10mL of ice water, separating, washing the organic phase with saturated saline for 3 times, drying with anhydrous sodium sulfate, concentratingThe condensation, column chromatography gave compound 17-4 (0.34 g, 63%). 1 H NMR(300MHz,CDCl 3 ):δ8.21(s,1H),7.89(d,J＝1.5Hz,1H),7.82(d,J＝1.5Hz,1H).
Step four: synthesis of (R) -N- ((S) -2- (8-iodoimidazo [1,2-c ] pyrimidin-5-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropan-2-sulfinamide (17-5):
trifluoroacetic acid (0.5 mL) was slowly added dropwise to a solution of 1-4 (0.44 g,1.2mmol,1.2 eq.) in DCM (2 mL) and reacted at room temperature for 2h. After monitoring the reaction was complete, it was concentrated. Acetonitrile (2 mL), DIPEA (0.35 mL,2.0mmol,2.0 eq.) and compound 17-5 (279.5 mg,1.0 mmol) were added sequentially. The reaction was carried out at room temperature for 4 hours. After monitoring the reaction was complete, 25mL ethyl acetate and 10mL water were added. The mixture was separated, and the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give compound 17-5 (0.35 g, yield 69%). 1 H NMR(300MHz,CDCl 3 ):δ8.01(s,1H),7.66(d,J＝1.5Hz,1H),7.58(d,J＝1.5Hz,1H),7.47(dd,J＝7.4,1.4Hz,1H),7.38(ddd,J＝7.5,7.4,1.4Hz,1H),7.31(ddd,J＝7.5,7.4,1.4Hz,1H),7.14(dd,J＝7.4,1.4Hz,1H),4.90-4.83(m,1H),4.78(d,J＝15.8Hz,1H),4.62(d,J＝15.8Hz,1H),4.08-3.84(m,2H),3.72(d,J＝5.9Hz,1H),2.64-2.51(m,1H),2.50-2.35(m,1H),1.17(s,9H).
Step five: synthesis of (R) -N- ((S) -2- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropan-2-sulfinamide (17-6)
Compound 17-5 (127.3 mg,0.25 mmol), A-5 (54.5 mg,0.30mmol,1.2 eq.) Pd 2 dba 3 (23.0 mg,10 mol%) and Xanthos (29.0 mg,20 mol%) were placed in 15mL lock tubes, the system was evacuated to displace nitrogen, 1, 4-dioxane (2 mL) and DIPEA (87. Mu.L, 0.5mmol,2.0 eq.) were added and reacted overnight in an oil bath at 100℃until complete conversion of the starting material was monitored. 10mL of ethyl acetate was diluted, celite was filtered, the filtrate was concentrated, 15mL of ethyl acetate and 5mL of water were added to extract the layer, the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give compound 17-6 (42.1 mg, yield 31%). 1 H NMR(300MHz,CDCl 3 ):δ7.98(s,1H),7.63(d,J＝1.3Hz,1H),7.60(d,J＝5.4Hz,1H),7.57(d,J＝1.3Hz,1H),7.50(dd,J＝7.7,1.4Hz,1H),7.38(ddd,J＝7.7,7.6,1.4Hz,1H),7.32(ddd,J＝7.6,7.5,1.4Hz,1H),7.17(dd,J＝7.5,1.4Hz,1H),5.84(d,J＝5.4Hz,1H),4.94(d,J＝15.4Hz,1H),4.91(s,2H),4.79(d,J＝15.4Hz,1H),4.16-4.03(m,2H),3.66(d,J＝5.4Hz,1H),2.71-2.58(m,1H),2.53-2.38(m,1H),1.19(s,9H).
Step six: synthesis of (S) -2- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-amine (17):
referring to step five of the synthetic route of example 1, 1-5 was replaced with 17-6 to give compound 17 (25.0 mg, yield 72%). 1 H NMR(300MHz,CDCl 3 ):δ7.97(s,1H),7.64-7.54(m,3H),7.48(dd,J＝7.5,1.1Hz,1H),7.36(ddd,J＝7.8,7.5,1.3Hz,1H),7.25(ddd,J＝7.8,7.4,1.1Hz,1H),7.16(ddd,J＝7.4,1.3Hz,1H),5.86(d,J＝5.4Hz,1H),5.05(d,J＝15.6Hz,1H),4.89(s,2H),4.73(d,J＝15.6Hz,1H),4.48(dd,J＝7.8,1.4Hz,1H),4.20-4.09(m,1H),4.01-3.89(m,1H),2.43-2.32(m,1H),2.28-2.15(m,1H)。
Example 18:(18) Is synthesized by the following steps: />
Step one: synthesis of 6-amino-3-methylpyrimidine-2, 4 (1H, 3H) -dione (18-2)
Concentrated sulfuric acid (0.05 mL) was slowly added dropwise to a solution of 4-amino-2, 6-dihydroxypyrimidine (0.52 g,4.1 mmol) in HMDS (2.5 mL). After reaction at 130℃for 6h, the mixture was concentrated to remove HMDS. DMF (2.5 mL) and methyl iodide (0.85 mL,14.4mmol,3.5 eq.) were added sequentially and reacted overnight at room temperature. After the completion of the reaction, a saturated solution of sodium hydrogencarbonate was added dropwise until no bubbles were generated, and the mixture was suction-filtered, and the cake was washed with water and dried to give Compound 18-2 (0.36 g, yield 63%). 1 H NMR(300MHz,DMSO-d6):δ10.43(s,1H),6.23(brs,2H),4.59(s,1H),3.00(s,3H).
Step two: synthesis of 6-amino-5-iodo-3-methylpyrimidine-2, 4 (1H, 3H) -dione (18-3)
Compound 18-2 (0.19 g,1.4 mmol) was dissolved in DMF (2 mL) and AcOH (4 mL) and NIS (0.37 g,1.68mmol,1.2 eq.) was added. After the reaction is monitored to be complete, the reaction is filtered by suction, and a filter cake is washed with water and dried to obtain a compound 18-3 (0.30 g, crude product).
Step three: synthesis of (R) -2-methyl-N- ((S) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) propane-2-sulfinamide (18-4)
Trifluoroacetic acid (0.5 mL) was added to a solution of 1-5 (0.36 g,1.0 mmol) in DCM (2 mL) and reacted at room temperature for 2h. The reaction was monitored for completion, concentrated, 5mL of water was added and ph=9 was adjusted with saturated aqueous sodium carbonate. Ethyl acetate (10 mL) was extracted twice and concentrated to give 18-4 which was directly subjected to the next reaction.
Step four: synthesis of (R) -N- ((S) -2- (4-amino-5-iodo-1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropan-2-sulfinamide (18-5)
DBU (0.8 mL,5.25mmol,7.0 eq.) was added dropwise to a solution of 18-3 (0.2 g,0.75 mmol), 18-4 (step three) and Bop (0.66 g,1.5mmol,2.0 eq.) in DMF (2 mL) and reacted at room temperature for 8h. After completion of the reaction was monitored, 20mL of ethyl acetate and 5mL of water were added, the mixture was separated, and the organic phase was washed with an appropriate amount of saturated brine 5 times, dried over anhydrous sodium sulfate, and concentrated, and column chromatography gave compound 18-5 (0.11 g, yield 28%). LC-MS (ESI): 516.2 (M+H) + .
Step five: synthesis of (R) -N- ((S) -2- (4-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) -1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropan-2-sulfinamide (18-6):
compound 18-5 (0.1 g,0.19 mmol), A (62.6 mg,0.39mmol,2.0 eq.) copper iodide (7.4 mg,0.04mmol,0.2 eq.), TMEDA (12. Mu.L, 0.08mmol,0.4 eq.) and potassium phosphate (120.9 mg,0.57mmol,3.0 eq.) were placed in a 15mL tube enclosure, the system was evacuated to displace nitrogen, and 1, 4-dioxane (1 mL) was added to react overnight in an oil bath at 100℃until complete conversion of the starting material was monitored. Diluting with 10mL of ethyl acetate, filtering with diatomite, concentrating the filtrate, adding 10mL of ethyl acetate and 10mL of water, extracting and layering, washing the organic phase with saturated salt water for 3 times,dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give compound 18-6 (46.7 mg, yield 40%). 1 H NMR(300MHz,CDCl 3 ):δ7.70(d,J＝5.4Hz,1H),7.45(dd,J＝7.5,1.4Hz,1H),7.39-7.31(m,2H),7.20(dd,J＝8.0,1.5Hz,1H),6.15(d,J＝5.4Hz,1H),4.86(s,2H),4.84-4.74(m,1H),4.63(d,J＝15.7Hz,1H),4.50(d,J＝15.7Hz,1H),3.87-3.73(m,2H),3.57(d,J＝5.9Hz,1H),3.42(s,3H),2.60-2.44(m,1H),2.41-2.27(m,1H),1.23(s,9H).
Step six: synthesis of (S) -6-amino-2- (5-amino-1, 3,4, 5-tetrahydro-2H-benzo [ c ] azepin-2-yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyrimidin-4 (3H) -one (18):
referring to step five of the synthetic route of example 1, substituting 18-6 for 1-5 gave compound 18 (17.6 mg, yield 46%). 1 H NMR(300MHz,CDCl 3 ):δ7.67(d,J＝5.4Hz,1H),7.43(dd,J＝7.6,1.4Hz,1H),7.33(ddd,J＝7.6,7.4,1.4Hz,1H),7.23(ddd,J＝7.6,7.4,1.0Hz,1H),7.16(dd,J＝7.6,1.0Hz,1H)6.14(d,J＝5.4Hz,1H),5.23(s,2H),4.93(s,2H),4.72(d,J＝15.5Hz,1H),4.46(d,J＝15.5Hz,1H),4.41(dd,J＝8.1,2.0Hz,1H),3.91-3.77(m,1H),3.70-3.57(m,1H),3.41(s,3H),2.31-3.16(m,1H),2.16-2.06(m,1H)。
Example 19:(19) Is synthesized by the following steps:
step one: synthesis of 5-bromothiazolo [5,4-b ] pyridin-2-amine (19-2)
19-1 (1.0 g,5.78 mmol) was slowly added to a solution of KSCN (2.2 g,22.8mmol,4.0 eq.) in acetic acid (10 mL). After stirring for fifteen minutes at room temperature, a solution of bromine (0.38 mL,7.51mmol,1.3 eq.) in acetic acid (10 mL) was slowly added dropwise. The reaction was carried out at room temperature for 3 hours, and the completion of the reaction was monitored. The reaction was quenched by dropwise addition of water, suction filtration, concentration of the filtrate, adjustment of ph=7 with saturated aqueous sodium carbonate solution, extraction twice with ethyl acetate (20 mL), washing of the organic phase with saturated brine, drying over anhydrous sodium sulfate, and concentration to give compound 19-2 (1.33 g, crude product).
Step two: synthesis of 5-bromo-2-chlorothiazolo [5,4-b ] pyridine (19-3)
To a solution of 19-2 (0.75 g,3.2 mmol) in acetonitrile (10 mL) was added chloroketon (0.65 g,4.9mmol,1.5 eq.) at 0deg.C. After stirring for fifteen minutes at this temperature, a solution of tBuONO (0.57 mL,4.9mmol,1.5 eq.) in acetonitrile (2 mL) was slowly added dropwise. The reaction was allowed to proceed overnight at room temperature, and monitored for completion. Concentrated, ethyl acetate (20 mL) and water (5 mL) were added, the mixture was separated, and the organic phase was washed with saturated sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated, and subjected to column chromatography to give compound 19-3 (0.63 g, two-step yield 44%). 1 H NMR(300MHz,CDCl 3 ):δ8.06(d,J＝8.5Hz,1H),7.63(d,J＝8.5Hz,1H).
Step three: synthesis of 3-chloro-4- ((2-chlorothiazolo [5,4-b ] pyridin-5-yl) thio) pyridin-2-amine (19-4)
Compounds 19-3 (0.63 g,2.5 mmol), A-5 (0.59 g,3.25mmol,1.3 eq.) Pd 2 dba 3 (0.23 g,10 mol%) and Xanthos (0.29 g,20 mol%) were placed in a 15mL tube lock, the system was evacuated to displace nitrogen, 1, 4-dioxane (2 mL) and DIPEA (0.85 mL,5.0mmol,2.0 eq.) were added and reacted overnight in an oil bath at 100℃until complete conversion of the starting material was monitored. 10mL of ethyl acetate was diluted, celite was filtered, the filtrate was concentrated, 15mL of ethyl acetate and 5mL of water were added to extract the layer, the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give compound 19-4 (0.15 g, yield 18%). LC-MS (ESI): 329.0 (M+H) + .
Step four: synthesis of (R) -N- ((S) -2- (5- ((2-amino-3-chloropyridin-4-yl) thio) thiazol [5,4-b ] pyridin-2-yl-2, 3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-yl) -2-methylpropan-2-sulfinamide (19-5):
trifluoroacetic acid (0.5 mL) was slowly added dropwise to a solution of 1-4 (0.22 g,0.59mmol,1.3 eq.) in DCM (2 mL) and reacted at room temperature for 2h. After monitoring the reaction was complete, it was concentrated. DMF (2 mL), cesium carbonate (0.24 g,0.9mmol,2.0 eq.) and compound 19-4 (0.15 g,0.45 mmol) were added sequentially. The reaction was carried out at room temperature for 4 hours. After monitoring the reaction was complete, 25mL ethyl acetate and 10mL water were added. Separating, washing the organic phase with saturated salt water for 3 times, and drying with anhydrous sodium sulfateConcentration and column chromatography gave compound 19-5 (56.2 mg, yield 27%). 1 H NMR(300MHz,CDCl 3 ):δ7.70(d,J＝8.3Hz,1H),7.59(d,J＝5.6Hz,1H),7.50(d,J＝8.3Hz,1H),7.46-7.39(m,2H),7.38-7.30(m,2H),6.04(d,J＝5.6Hz,1H),5.54(s,2H),4.93(d,J＝15.4Hz,1H),4.87-4.79(s,1H),4.71(d,J＝15.4Hz,1H),4.36-4.19(m,2H),3.77(d,J＝4.0Hz,1H),2.54-2.40(m,2H),1.25(s,9H).
Step five: synthesis of (S) -2- (5- ((2-amino-3-chloropyridin-4-yl) thio) thiazolo [5,4-b ] pyridin-2-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c ] azepin-5-amine (19):
referring to step five in the synthetic route of example 1, 1-5 was replaced with 19-5 to give compound 19 (33.0 mg, yield 72%). 1 H NMR(300MHz,CDCl 3 ):δ7.68(d,J＝8.2Hz,1H),7.66(d,J＝5.4Hz,1H),7.46(d,J＝8.2Hz,1H),7.40(dd,J＝7.3,1.3Hz,2H),7.30(ddd,J＝7.6,7.3,1.3Hz,1H),7.25(ddd,J＝7.6,7.3,1.6Hz,1H),6.04(d,J＝5.4Hz,1H),5.10(d,J＝15.1Hz,1H),4.90(s,2H),4.68(d,J＝15.1Hz,1H),4.45(dd,J＝7.9,2.6Hz,1H),4.29-4.16(m,1H),4.15-3.99(m,1H),2.31-2.15(m,1H),1.99-1.84(m,1H)。
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
EXAMPLE 21 in vitro SHP2 enzyme level Activity assay
The compounds of the above examples were tested for SHP2 enzyme level activity as follows:
1 preparation of Compounds
The compound was dissolved in DMSO to prepare a 30mM stock solution, which was stored in-20 ℃ refrigerator in the dark.
2SHP2 reaction Process
(1) 1 XReactionBuffer was prepared.
(2) Preparing a compound concentration gradient: the test compounds were tested at an initial concentration of 30 μm, 3-fold dilution, 10 concentrations, single well test. 100% DMSO solutions at 100-fold final concentrations were diluted in 384source plates and the compound was diluted 3-fold with Precision, 10 concentrations. 250nL of 100-fold final concentration of compound was transferred to the destination plate 384 plates using a dispenser Echo 550. Positive control was added with 250nL DMSO and negative control was added with 250nL of 1mm shp099.
(3) A5-fold final concentration of the activation peptide solution was prepared with 1 XReactionBuffer, and 5. Mu.L of the activation peptide solution was added to the reaction plates, respectively, and centrifuged at 1000rpm for 1min.
(4) An enzyme solution of 2.5 times the final concentration was prepared by 1 XReactionBuffer, and 10. Mu.L of the enzyme solution was added to the reaction plates, and the plates were centrifuged at 1000rpm for 1min and incubated at room temperature for 60 min.
(5) Substrate solutions were prepared with a final concentration of 2.5 times using 1 XReactionBuffer, 10. Mu.L each was added to the reaction plate, centrifuged at 1000rpm for 1min, and incubated at room temperature for 20 min.
(6) Ex355/Em460 fluorescence values were read using EnSight
3 data analysis
Calculation formula
Wherein: RFU: fluorescence value of the sample; mean (NC): control Kong Yingguang mean containing 10 μm SHP 099;
mean (PC): positive control Kong Yingguang value mean.
Fitting dose-response curve
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and a log (inhibitor) vs. response-Variable slope fit quantitative effect curve of analysis software GraphPad Prism 5 is adopted, so that the IC of each compound on the enzyme activity is obtained 50 Values.
The calculation formula is Y=bottom+ (Top-Bottom)/(1+10 ((LogIC) 50 -X)*HillSlope))
4. Experimental results
The specific results are shown in the table:
numbering of compounds SHP2IC 50 (nM) Numbering of compounds SHP2IC 50 (nM)
1 A 10 A
2 A 11 A
3 A 12 C
4 B 13 C
5 B 14 C
6 A 15 C
7 B 16 A
8 B 17 C
9 A 18 C
SHP099 107 19 C
A<50nM，50nM≤B≤100nM，C>100nM。
Conclusion of experiment: the above data show that the inventive examples have allosteric inhibition on SHP2 phosphatase and that several of the examples are significantly superior to the positive control SHP099.
Example 22 in vitro antiproliferative Activity of Compounds
1. Experimental procedure
(1) The PBS solution was autoclaved and stored in a refrigerator at 4 ℃.
(2) Weighing trypsin and pancreatin digestion solution, adding ultrapure water for dissolving, filtering with microporous filter to obtain liquid, and storing at-20deg.C.
(3) Respectively weighing culture medium powder and NaHCO 3 Adding ultrapure water for full dissolution, adding 10% diabody, filtering with microporous membrane to obtain culture solution, storing at 4deg.C in refrigerator, and adding 10% foetus calf serum before use.
(4) NCI-H358 cells or KYSE520 cells are taken out from a liquid nitrogen tank, immediately placed in a constant temperature water bath kettle at 37 ℃ and are shaken to melt, then the cells are poured into a culture flask, and a culture solution (containing 10% fetal bovine blood) is addedClear) and diluting. Transferring the diluted culture medium into a centrifuge tube, centrifuging at 1000r/min for 5 min, discarding supernatant, adding fresh culture medium, blowing, mixing, transferring into a culture bottle, and culturing in 5% CO 2 Culturing in an incubator at 37 ℃. When the cell is adhered to the wall and is fully paved at the bottom of the bottle, a small amount of fresh culture medium (containing 10% of fetal calf serum) is added to stop digestion, liquid in the culture bottle is poured out, PBS is used for washing twice, fresh culture medium is added to blow and uniformly mix, and the culture is continued in the two culture bottles.
(5) Taking cells in the logarithmic phase, pouring out the old culture medium, adding a trypsin solution for digestion for 3 minutes, adding a fresh culture medium containing 10% of fetal bovine serum for stopping digestion, transferring the solution into a centrifuge tube, centrifuging at 1000r/min for 5 minutes, and discarding the supernatant. The cells were counted by adding a medium to prepare a cell suspension. After counting, cells were seeded in 96-well plates at a cell concentration of 5000-10000 cells per well. The 96-well plate with the cells spread is placed at 37 ℃ and 5% CO 2 Culturing in an incubator is continued for 24 hours. The drugs were diluted in gradient to 90. Mu. Mol/L, 30. Mu. Mol/L, 10. Mu. Mol/L, 3.3. Mu. Mol/L, 1.1. Mu. Mol/L, 0.37. Mu. Mol/L with medium and then added to 96-well plates at 100. Mu.L per well, with three multiplex wells per concentration. Adding medium containing solvent in corresponding concentration into control group, adding blank medium with the same volume into zeroing hole, and placing in 5% CO 2 Incubate for 48h at 37 ℃. Adding 20 μl of CCK8 reagent into each well, mixing, adding 5% CO 2 Culturing in a 37 ℃ incubator for 1h in dark. The 96-well plate was then placed in a microplate reader and absorbance was measured at 450 nm.
2. Data processing
Drawing curve and calculating inhibition rate of drug to cell and IC 50 。
Inhibition ratio = [ (control mean OD value-experimental mean OD value)/(control mean OD value-blank mean OD value) ]x100%.
3. Experimental results
The inhibitory activity of the compound on non-small cell lung cancer cell strain NCI-H358 cells and esophagus cancer cell strain KYSE520 cells is as follows:
numbering of compounds NCI-H358(IC 50 ,μM) KYSE520(IC 50 ,μM)
1 8.3 9.7
3 8.6 6.3
9 11.5 6.3
11 3.2 1.2
SHP099 33.4 38.1
Conclusion of experiment: the data show that the compound of the embodiment of the invention has good inhibition effect on proliferation of NCI-H358 and KYSE520 cells. The various embodiments of the present invention have novel structures and superior in vitro antiproliferative activity compared to SHP099.

Claims (6)

1. An aromatic aza seven-membered ring compound shown in a general formula I and pharmaceutically acceptable salt thereof,
wherein ring A is
X is N;
R 1 、R 2 independently hydrogen, halogen, amino;
l is a bond or S;
when n=1, m=1;
R 3 is hydrogen, deuterium, halogen, hydroxy, nitro, cyano, amido, carboxyl, sulfonyl, -NR 5 R 6 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 7 Epoxy group, C 6 -C 10 Aromatic rings; wherein R is 5 、R 6 Independently hydrogen, deuterium, halogen, C 1 -C 7 Alkyl, C 1 -C 7 Haloalkyl, C 1 -C 7 Alkoxy, C 1 -C 7 Haloalkoxy groups.
2. The aromatic azaseven-membered ring compound according to claim 1, wherein the aromatic azaseven-membered ring compound is any one of the following structural formulas:
3. an aromatic and aza seven-membered ring compound and pharmaceutically acceptable salts thereof, wherein the aromatic and aza seven-membered ring compound is shown as formula 10 or 11:
4. a pharmaceutical composition comprising an aryl-aza seven-membered ring compound according to any one of claims 1 to 3 and a pharmaceutically acceptable adjuvant.
5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is formulated as a tablet, capsule, injection or lyophilized powder.
6. Use of an aryl-aza seven-membered ring compound according to any one of claims 1 to 3 and a pharmaceutical composition according to claim 4 or 5 for the preparation of an anti-tumour agent by inhibition of SHP2 protein.
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