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CN111303118A - Compounds and their use in the treatment of hepatitis B - Google Patents

Compounds and their use in the treatment of hepatitis B Download PDF

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CN111303118A
CN111303118A CN202010097534.6A CN202010097534A CN111303118A CN 111303118 A CN111303118 A CN 111303118A CN 202010097534 A CN202010097534 A CN 202010097534A CN 111303118 A CN111303118 A CN 111303118A
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CN111303118B (en
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刘刚
王春廷
裴亚蒙
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Tsinghua University
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Abstract

本发明提出了化合物及含有其的药物组合物和用途，所述化合物为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药。本发明的化合物能够干扰乙肝病毒的壳组装过程，从而抑制乙肝病毒复制。并且，该化合物具有良好的吸收、较高的生物活性和利用度，低毒，尤其是在体内具有较强的稳定性，不易分解，药效时间长，从而起到治疗乙型肝炎的效果，应用前景好。

Figure DDA0002385652180000011
The present invention proposes a compound, a pharmaceutical composition containing the same, and use, wherein the compound is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide of the compound represented by formula (I) , hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug. The compounds of the present invention can interfere with the capsid assembly process of hepatitis B virus, thereby inhibiting the replication of hepatitis B virus. In addition, the compound has good absorption, high biological activity and availability, low toxicity, especially strong stability in the body, is not easy to decompose, and has a long drug effect time, thereby achieving the effect of treating hepatitis B, The application prospect is good.
Figure DDA0002385652180000011

Description

化合物及其在治疗乙型肝炎中的用途Compound and use thereof in the treatment of hepatitis B

技术领域technical field

本发明涉及医药领域。具体地，本发明涉及化合物及其在治疗乙型肝炎中的用途。The present invention relates to the field of medicine. In particular, the present invention relates to compounds and their use in the treatment of hepatitis B.

背景技术Background technique

乙型肝炎是由乙肝病毒引起的一类感染性疾病。虽然乙肝疫苗的普及极大地降低了乙肝的发病率，但是目前世界上仍然有约2.5亿人携带有乙肝病毒，2015年约有88万人死于乙肝导致的肝硬化或肝癌，因此乙肝仍是威胁人类健康的重大疾病。目前，临床上治疗乙肝的药物包括干扰素和核苷类似物(拉米夫定、阿德福韦、恩替卡韦、替比夫定或替诺福韦酯)。干扰素对乙肝的治愈率较低，而且会引起较大的副作用；口服核苷类似物安全性高，但是并不能完全清楚乙肝病毒，需要终身用药。为了改善乙肝的治疗效果，缩短治疗周期，很多公司或机构都致力于开发新的抗乙肝药物。Hepatitis B is an infectious disease caused by the hepatitis B virus. Although the popularization of hepatitis B vaccine has greatly reduced the incidence of hepatitis B, there are still about 250 million people in the world with hepatitis B virus, and about 880,000 people died of liver cirrhosis or liver cancer caused by hepatitis B in 2015. Serious diseases that threaten human health. Currently, the clinical drugs for the treatment of hepatitis B include interferon and nucleoside analogs (lamivudine, adefovir, entecavir, telbivudine or tenofovir dipivoxil). Interferon has a low cure rate for hepatitis B, and it can cause greater side effects; oral nucleoside analogs are highly safe, but they cannot completely clear the hepatitis B virus and require lifelong medication. In order to improve the treatment effect of hepatitis B and shorten the treatment period, many companies or institutions are committed to developing new anti-hepatitis B drugs.

乙肝病毒感染肝细胞后，首先会将基因组转运到宿主细胞的细胞核内，利用宿主细胞中修复DNA的酶，将自身的基因组修复，并形成cccDNA。cccDNA非常稳定，能够在宿主细胞核内长期存在，这是乙肝病毒难以清除的主要原因。以cccDNA为模板，表达出病毒复制所需要的中间体，其中壳蛋白会组装成衣壳，并将前基因组RNA包裹进衣壳，在衣壳内完成逆转录，合成病毒基因组。然后，经过包裹，将病毒颗粒分泌到细胞外。After hepatitis B virus infects liver cells, it first transfers the genome into the nucleus of the host cell, and uses the enzymes that repair DNA in the host cell to repair its own genome and form cccDNA. cccDNA is very stable and can exist in the host cell nucleus for a long time, which is the main reason why hepatitis B virus is difficult to clear. Using cccDNA as a template, the intermediates required for virus replication are expressed, in which the capsid protein is assembled into a capsid, and the pre-genomic RNA is wrapped into the capsid, and reverse transcription is completed in the capsid to synthesize the viral genome. Then, after encapsulation, the viral particles are secreted outside the cell.

壳蛋白的组装在病毒的复制周期内起着重要的作用，通过干扰这一过程，能够抑制病毒的复制。目前，已有多个靶向壳组装的候选药物进入到临床研究(GLS4、JNJ-6379等)，证实了这类药物的疗效。研究发现，壳组装调节剂不仅能够直接地抑制病毒复制，还能够抑制cccDNA的形成，而且对e抗原也有直接地抑制作用。开发不同结构类型的壳组装调节剂，提供更多的候选化合物供临床研究，能够早日实现这类药物在临床上的应用，造福广大患者。The assembly of capsid proteins plays an important role in the viral replication cycle, and by interfering with this process, viral replication can be inhibited. At present, a number of candidate drugs targeting shell assembly have entered into clinical research (GLS4, JNJ-6379, etc.), confirming the efficacy of such drugs. The study found that the capsid assembly regulator can not only directly inhibit virus replication, but also inhibit the formation of cccDNA, and also have a direct inhibitory effect on e-antigen. The development of shell assembly regulators with different structural types and the provision of more candidate compounds for clinical research will enable early clinical application of such drugs and benefit the vast number of patients.

因此，目前乙型肝炎病毒抑制剂仍有待研究。Therefore, the current hepatitis B virus inhibitors still need to be studied.

发明内容SUMMARY OF THE INVENTION

本发明旨在至少在一定程度上解决现有技术中存在的技术问题至少之一。为此，本发明提出了化合物及含有其的药物组合物和用途，该化合物能够干扰乙肝病毒的壳组装过程，从而抑制乙肝病毒复制。并且，该化合物具有良好的吸收、较高的生物活性和利用度，低毒，尤其是在体内具有较强的稳定性，不易分解，药效时间长，从而起到治疗乙型肝炎的效果，应用前景好。The present invention aims to solve at least one of the technical problems existing in the prior art at least to a certain extent. To this end, the present invention proposes a compound, a pharmaceutical composition containing the same, and an application, which can interfere with the capsid assembly process of the hepatitis B virus, thereby inhibiting the replication of the hepatitis B virus. In addition, the compound has good absorption, high biological activity and availability, low toxicity, especially strong stability in the body, is not easy to decompose, and has a long drug effect time, thereby achieving the effect of treating hepatitis B, The application prospect is good.

为此，在本发明的一个方面，本发明提出了一种化合物。根据本发明的实施例，所述化合物为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：To this end, in one aspect of the present invention, the present invention proposes a compound. According to an embodiment of the present invention, the compound is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of the compound represented by formula (I) Product, pharmaceutically acceptable salt or prodrug:

Figure BDA0002385652160000011
Figure BDA0002385652160000011

G、Q、T、Y和X各自独立地选自C或N；Z和V各自独立地选自C、N、S或O；R1选自氢、C1～6烷基、C1～6环烷基、C1～6杂环基、氨基、C1～6烷氨基、羟基、卤代C1～6烷基、C2～6烯基、C3～6炔基、芳基或C1～5杂芳基；R2、R3和R4各自独立地选自氢、氟、氯、溴、碘、羟基、氨基、C1～6烷基、硝基、C1～6烷氧基、C1～6烷氨基、C3～6环烷基或C1～6杂环烷基；R5和R6各自独立地选自氢、C1～6烷基、C1～6烷基芳基、C1～6环烷基、C1～5杂环基、芳基、C1～5杂芳基；L选自-C(＝O)-、-S(＝O)2-、-S(＝O)-、-C(＝O)NH-；W选自C或N；R7和R8各自独立地选自氢、C1～6烷基、卤代C1～6烷基、C2～6烯基、C3～6炔基、C3～6环烷基、C1～6杂环烷基、芳基或C1～5杂芳基；或者R7、W和R8成环，所述环选自C1～6环烷基、C1～6杂环基、C4～8稠环、C4～8稠杂环、C4～8螺环、C4～8螺杂环、C4～8桥环或C4～8桥杂环；其中，所述氨基、烷基、羟基、羧基、环烷基、杂环基、芳基、杂芳基、卤代烷基、烯基、炔基、稠环、稠杂环、螺环、螺杂环、桥环和桥杂环可任选地被一个或多个氟、氯、溴、碘、羟基、氨基、羧基、硝基、氰基、氧代、C1～6烷基、卤代C1～6烷基、C1～6烷氧基、C1～6烷基羟基、C1～6烷氨基、C1～6环烷基、C1～6杂环基、芳基、C1～5杂芳基、-C(＝O)Ra、-C(＝O)ORa、-OC(＝O)Ra、-OC(＝O)RaN(Rb)Rc、-C(＝O)N(Ra)Rb、-N(Ra)C(＝O)ORb、-N(Ra)C(＝O)NRb、-C(＝O)NRa取代，Ra、Rb、Rc选自氢、C1～6烷基或C1～6烷氨基。G, Q, T, Y and X are each independently selected from C or N; Z and V are each independently selected from C, N, S or O; R 1 is selected from hydrogen, C 1-6 alkyl, C 1- 6 cycloalkyl, C 1-6 heterocyclyl, amino, C 1-6 alkylamino, hydroxyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, aryl or C 1-5 heteroaryl; R 2 , R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, C 1-6 alkyl, nitro, C 1-6 alkane oxy, C 1-6 alkylamino, C 3-6 cycloalkyl or C 1-6 heterocycloalkyl; R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 Alkylaryl, C 1-6 cycloalkyl, C 1-5 heterocyclyl, aryl, C 1-5 heteroaryl; L is selected from -C(=O)-, -S(=O) 2 -, -S(=O)-, -C(=O)NH-; W is selected from C or N; R 7 and R 8 are each independently selected from hydrogen, C 1-6 alkyl, halogenated C 1- 6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 heterocycloalkyl, aryl or C 1-5 heteroaryl; or R 7 , W and R 8 form a ring, and the ring is selected from C 1-6 cycloalkyl, C 1-6 heterocyclic group, C 4-8 fused ring, C 4-8 fused heterocyclic ring, C 4-8 spiro ring, C 4-8 spiro heterocycle, C 4-8 bridged ring or C 4-8 bridged heterocycle; wherein, the amino group, alkyl group, hydroxyl group, carboxyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group , haloalkyl, alkenyl, alkynyl, fused rings, fused heterocycles, spirocycles, spiroheterocycles, bridged rings, and bridged heterocycles may be optionally replaced by one or more of fluorine, chlorine, bromine, iodine, hydroxyl, amino , carboxyl, nitro, cyano, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl hydroxyl, C 1-6 alkylamino , C 1-6 cycloalkyl, C 1-6 heterocyclyl, aryl, C 1-5 heteroaryl, -C(=O)R a , -C(=O)OR a , -OC(= O)R a , -OC(=O)R a N(R b )R c , -C(=O)N(R a )R b , -N(R a )C(=O)OR b , - N(R a )C(=O)NR b , -C(=O)NR a substituted, R a , R b , and Rc are selected from hydrogen, C 1-6 alkyl or C 1-6 alkylamino.

根据本发明实施例的化合物能够干扰乙肝病毒的壳组装过程，从而抑制乙肝病毒复制。在动物体内的药代动力学试验中显示出良好的吸收、较高的生物活性和利用度，低毒，尤其是在体内具有较强的稳定性，不易分解，药效时间长，从而起到治疗乙型肝炎的效果，具有很好的应用前景。The compounds according to the embodiments of the present invention can interfere with the capsid assembly process of hepatitis B virus, thereby inhibiting the replication of hepatitis B virus. In the pharmacokinetic test in animals, it shows good absorption, high biological activity and availability, low toxicity, especially strong stability in the body, not easy to decompose, and has a long drug effect, thus playing a role in The effect of treating hepatitis B has a good application prospect.

根据本发明的实施例，上述化合物还可以具有下列附加技术特征：According to the embodiments of the present invention, the above-mentioned compounds may also have the following additional technical features:

根据本发明的实施例，G、Q和T中的至少一个为N，X为C，Z和Y中至少一个为N，V为N或O；R1选自C1～4环烷基或C1～4杂环基；R2、R3和R4各自独立地选自氢、氟、氯、溴、碘、羟基或氨基；R5选自芳基、C3～6环烷基、C3～5杂环基或C3～5杂芳基，所述芳基、环烷基、杂环基和杂芳基可任选地被一个或多个氟、氯、溴、碘、卤代C1～4烷基、C1～4环烷基或C1～4杂环基所取代；R6选自氢或C1～3烷基；L选自-C(＝O)-、-S(＝O)2-、-S(＝O)-、-C(＝O)NH-；W选自C或N；R7、W和R8成环，所述环选自C3～6杂环基或C3～6环烷基，所述环烷基或杂环基可任选地被一个或多个羟基、氟、氯、溴、碘、C1～3烷基、C1～3烷基羟基、-C(＝O)Ra、-C(＝O)ORa、-OC(＝O)Ra、-OC(＝O)RaN(Rb)Rc、-C(＝O)N(Ra)Rb、-N(Ra)C(＝O)ORb、-N(Ra)C(＝O)NRb、-C(＝O)NRa取代，Ra、Rb、Rc选自氢、C1～4烷基或C1～4烷氨基。According to an embodiment of the present invention, at least one of G, Q and T is N, X is C, at least one of Z and Y is N, and V is N or O; R 1 is selected from C 1-4 cycloalkyl or C 1-4 heterocyclic group; R 2 , R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl or amino; R 5 is selected from aryl, C 3-6 cycloalkyl, C 3-5 heterocyclyl or C 3-5 heteroaryl, the aryl, cycloalkyl, heterocyclyl and heteroaryl may be optionally replaced by one or more of fluorine, chlorine, bromine, iodine, halogen substituted C 1-4 alkyl, C 1-4 cycloalkyl or C 1-4 heterocyclic group; R 6 is selected from hydrogen or C 1-3 alkyl; L is selected from -C(=O)-, -S(=O) 2 -, -S(=O)-, -C(=O)NH-; W is selected from C or N; R 7 , W and R 8 form a ring, and the ring is selected from C 3 ~6 heterocyclyl or C 3-6 cycloalkyl, said cycloalkyl or heterocyclyl may be optionally replaced by one or more hydroxyl, fluorine, chlorine, bromine, iodine, C 1-3 alkyl, C 1-3 alkyl hydroxyl groups, -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -OC(=O)R a N(R b )R c , -C(=O)N(R a )R b , -N(R a )C(=O)OR b , -N(R a )C(=O)NR b , -C(=O)NR a For substitution, R a , R b and Rc are selected from hydrogen, C 1-4 alkyl or C 1-4 alkylamino.

根据本发明的实施例，G、Q和T均为C，X为C，Z和Y中至少一个为N，V为N或O；R1为氢、C1～4烷基、C1～4环烷基、C1～4杂环基、卤代C1～4烷基；R2、R3和R4各自独立地选自氢、氟、氯、溴、碘、羟基、氨基、C1～4烷基；R5和R6各自独立地选自氢、C1～4烷基、氰基、芳基、C1～4烷基芳基、C3～5杂芳基、C3～6环烷基、C1～4杂环基，其中，所述烷基、芳基、杂芳基、烷基芳基、环烷基或杂环基可任选地被一个或多个氟、氯、溴、碘、卤代C1～4烷基、C1～4环烷基或C1～4杂环基；L选自-C(＝O)-、-S(＝O)2-、-S(＝O)-、-C(＝O)NH-；W选自C或N；R7和R8各自独立地选自氢、C3～6杂环基、C1～4烷基或卤代C1～4烷基，或者R7、W和R8成环，所述环选自C1～6环烷基、C1～6杂环基、C4～8稠环、C4～8稠杂环、C4～8螺环、C4～8螺杂环、C4～8桥环或C4～8桥杂环，其中，所述环烷基、杂环基、烷基、卤代烷基、稠环、稠杂环、螺环、螺杂环、桥环或桥杂环可任选地被一个或多个羟基、氟、氯、溴、碘、氧代、C1～4烷基、C1～4烷基羟基、-C(＝O)ORa、-C(＝O)NRa，Ra选自氢或C1～4烷基。According to the embodiment of the present invention, G, Q and T are all C, X is C, at least one of Z and Y is N, and V is N or O; R 1 is hydrogen, C 1-4 alkyl, C 1- 4 cycloalkyl, C 1-4 heterocyclyl, halogenated C 1-4 alkyl; R 2 , R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, C 1-4 alkyl; R 5 and R 6 are each independently selected from hydrogen, C 1-4 alkyl, cyano, aryl, C 1-4 alkylaryl, C 3-5 heteroaryl, C 3 ~6 cycloalkyl, C 1-4 heterocyclyl, wherein the alkyl, aryl, heteroaryl, alkylaryl, cycloalkyl or heterocyclyl may be optionally replaced by one or more fluorine , chlorine, bromine, iodine, halogenated C 1-4 alkyl, C 1-4 cycloalkyl or C 1-4 heterocyclyl; L is selected from -C(=O)-, -S(=O) 2 -, -S(=O)-, -C(=O)NH-; W is selected from C or N; R 7 and R 8 are each independently selected from hydrogen, C 3-6 heterocyclyl, C 1-4 Alkyl or halogenated C 1-4 alkyl, or R 7 , W and R 8 form a ring, and the ring is selected from C 1-6 cycloalkyl, C 1-6 heterocyclic group, and C 4-8 fused ring , C 4-8 fused heterocycle, C 4-8 spirocycle, C 4-8 spiro heterocycle, C 4-8 bridged ring or C 4-8 bridged heterocycle, wherein the cycloalkyl, heterocyclyl , alkyl, haloalkyl, fused ring, fused heterocycle, spirocycle, spiroheterocycle, bridged ring, or bridged heterocycle may be optionally replaced by one or more of hydroxy, fluoro, chloro, bromo, iodo, oxo, C 1-4 alkyl, C 1-4 alkyl hydroxyl, -C(=O)OR a , -C(=O)NR a , R a is selected from hydrogen or C 1-4 alkyl.

根据本发明的实施例，当G、Q和T均为C，Z、Y和X至少有一个N，R7、W和R8不成环时，满足下列至少之一的条件：(1)R1为C3～6环烷基；(2)当R7为氢、R8为C3～6环烷基时，所述环烷基被羟基所取代。According to an embodiment of the present invention, when G, Q and T are all C, Z, Y and X have at least one N, and R 7 , W and R 8 do not form a ring, at least one of the following conditions is satisfied: (1) R 1 is C 3-6 cycloalkyl; (2) When R 7 is hydrogen and R 8 is C 3-6 cycloalkyl, the cycloalkyl is substituted by hydroxyl.

根据本发明的实施例，所述化合物具有如下之一所示的结构或其立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药；According to an embodiment of the present invention, the compound has one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt thereof or prodrugs;

Figure BDA0002385652160000021
Figure BDA0002385652160000021

Figure BDA0002385652160000031
Figure BDA0002385652160000031

Figure BDA0002385652160000041
Figure BDA0002385652160000041

Figure BDA0002385652160000051
Figure BDA0002385652160000051

Figure BDA0002385652160000061
Figure BDA0002385652160000061

Figure BDA0002385652160000071
Figure BDA0002385652160000071

在本发明的另一方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药物组合物包括：前面所述的化合物及药学上可接受的辅料、载体、赋形剂、溶媒或它们的组合。由此，根据本发明实施例的药物组合物能够干扰乙肝病毒的壳组装过程，从而抑制乙肝病毒复制。并且，该药物组合物具有良好的吸收、较高的生物活性和利用度，低毒，尤其是在体内具有较强的稳定性，不易分解，药效时间长，从而起到治疗乙型肝炎的效果，应用前景好。In another aspect of the present invention, the present invention proposes a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises: the aforementioned compound and a pharmaceutically acceptable adjuvant, carrier, excipient, vehicle or a combination thereof. Thus, the pharmaceutical composition according to the embodiment of the present invention can interfere with the capsid assembly process of the hepatitis B virus, thereby inhibiting the replication of the hepatitis B virus. In addition, the pharmaceutical composition has good absorption, high biological activity and availability, low toxicity, especially strong stability in the body, is not easy to decompose, and has a long drug effect time, thereby playing a role in the treatment of hepatitis B. The effect is good, and the application prospect is good.

根据本发明的实施例，所述药物组合物进一步包含治疗剂，所述治疗剂选自下列的至少之一：拉米夫定、阿德福韦、恩替卡韦、替比夫定、替诺福韦酯和干扰素。According to an embodiment of the present invention, the pharmaceutical composition further comprises a therapeutic agent selected from at least one of the following: lamivudine, adefovir, entecavir, telbivudine, tenofovir esters and interferons.

在本发明的又一方面，本发明提出了前面所述化合物在制备药物中的用途。根据本发明的实施例，所述药物用于治疗感染性疾病。如前所述，根据本发明实施例的化合物能够干扰乙肝病毒的壳组装过程，从而抑制乙肝病毒复制。并且，该化合物具有良好的吸收、较高的生物活性和利用度，低毒，尤其是在体内具有较强的稳定性，不易分解，药效时间长，从而起到治疗感染性疾病的效果，应用前景好。In yet another aspect of the present invention, the present invention proposes the use of the aforementioned compounds in the preparation of medicaments. According to an embodiment of the present invention, the medicament is used for treating infectious diseases. As mentioned above, the compounds according to the embodiments of the present invention can interfere with the capsid assembly process of hepatitis B virus, thereby inhibiting the replication of hepatitis B virus. In addition, the compound has good absorption, high biological activity and availability, low toxicity, especially strong stability in the body, is not easy to decompose, and has a long drug effect time, thereby achieving the effect of treating infectious diseases, The application prospect is good.

根据本发明的实施例，所述感染性疾病为乙型肝炎。According to an embodiment of the present invention, the infectious disease is hepatitis B.

在本发明的又一方面，本发明提出了一种药物联合。根据本发明的实施例，所述药物联合包括：前面所述化合物；以及至少一种用于治疗乙型肝炎的药物。由此，根据本发明实施例的药物联合能够干扰乙肝病毒的壳组装过程，从而抑制乙肝病毒复制。并且，该化合物具有良好的吸收、较高的生物活性和利用度，低毒，尤其是在体内具有较强的稳定性，不易分解，药效时间长，从而起到治疗乙型肝炎的效果，应用前景好。In yet another aspect of the present invention, the present invention provides a drug combination. According to an embodiment of the present invention, the drug combination comprises: the aforementioned compound; and at least one drug for treating hepatitis B. Thus, the combination of drugs according to the embodiments of the present invention can interfere with the capsid assembly process of the hepatitis B virus, thereby inhibiting the replication of the hepatitis B virus. In addition, the compound has good absorption, high biological activity and availability, low toxicity, especially strong stability in the body, is not easy to decompose, and has a long drug effect time, thereby achieving the effect of treating hepatitis B, The application prospect is good.

根据本发明的实施例，所述药物选自下列的至少之一：拉米夫定、阿德福韦、恩替卡韦、替比夫定、替诺福韦酯和干扰素。According to an embodiment of the present invention, the drug is selected from at least one of the following: lamivudine, adefovir, entecavir, telbivudine, tenofovir disoproxil and interferon.

本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the present invention will be set forth, in part, from the following description, and in part will be apparent from the following description, or may be learned by practice of the invention.

附图说明Description of drawings

本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：The above and/or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of embodiments taken in conjunction with the accompanying drawings, wherein:

图1显示了根据本发明实施例的化合物59和101影响衣壳组装的电镜图；Fig. 1 shows the electron micrograph of compound 59 and 101 according to the embodiment of the present invention affecting capsid assembly;

图2显示了根据本发明实施例的化合物59和101对乙肝病毒复制的影响；Figure 2 shows the effects of compounds 59 and 101 on hepatitis B virus replication according to an embodiment of the present invention;

图3显示了根据本发明实施例的化合物59和109在水动力注射HBV小鼠模型上的抗病毒活性。Figure 3 shows the antiviral activity of compounds 59 and 109 according to an embodiment of the present invention in a mouse model of hydrodynamic injection of HBV.

具体实施方式Detailed ways

现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.

应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

定义或一般术语Definition or General Terms

术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.

“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .

“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。"Chiral" is a molecule that has the property of being non-superimposable with its mirror image; while "achiral" refers to a molecule that is superimposable with its mirror image.

“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。"Enantiomer" refers to two nonsuperimposable, but mirror-image isomers of a compound.

“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。"Diastereomer" refers to a stereoisomer having two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；andEliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。Stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and 1 or (+) and (-) are symbols used to designate the rotation of plane polarized light by the compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。Any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。Depending on the choice of starting materials and process, the compounds of the present invention may be present as one of the possible isomers or as mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have the cis or trans configuration.

所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。The resulting mixtures of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racematesand Resolutions(Wiley Interscience,New York,1981)；Principles of AsymmetricSynthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。Any resulting racemate of the final product or intermediate can be resolved into the optical enantiomers by known methods by methods familiar to those skilled in the art, eg, by performing diastereomeric salts thereof obtained. separation. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of NotreDame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1～6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups .

在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group.

像本发明所描述的，本发明的化合物可以独立任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“独立任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子可以被具体取代基1所取代或未取代。除非其他方面表明，一个任选的取代基团可以有一个取代基1在基团的各个可取代的位置进行取代或未取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基1所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基1可以是，但并不限于：氧代(＝O)，氟，氯，溴，碘，羟基，氨基，羧基，烷基，卤代烷基，羟基烷基，氨基烷基，醛基，氨基酰基，烷氧基，氨基烷基，烷硫基，卤代烷氧基，氰基，芳基，杂芳基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基烷氧基，苄基，环丙基，苯基，或烷氧基烷基等。在合理的情况下，取代基1能进一步被取代基2单取代或相同或不同的多取代。其中所述的取代基2可以是，但不限于：氧代(＝O)，氟，氯，溴，碘，羟基，氨基，羧基，烷基，卤代烷基，羟基烷基，氨基烷基，醛基，氨基酰基，烷氧基，氨基烷基，烷硫基，卤代烷氧基，氰基，芳基，杂芳基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基烷氧基，苄基，环丙基，苯基，或烷氧基烷基等。As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds. It is to be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "independently optionally" whether or not preceded by the term "substituted" means that one or more hydrogen atoms in a given structure may or may not be substituted with a particular substituent. Unless otherwise indicated, an optionally substituted group may have a substituent 1 substituted or unsubstituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents 1 selected from a particular group, the substituents can be substituted at each position identically or differently. The substituent 1 can be, but is not limited to: oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, Aldehyde, aminoacyl, alkoxy, aminoalkyl, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy , hydroxyalkoxy, benzyl, cyclopropyl, phenyl, or alkoxyalkyl, etc. Substituent 1 can be further mono-substituted or polysubstituted by the same or different with Substituent 2, where reasonable. Wherein the substituent 2 can be, but not limited to: oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde base, aminoacyl, alkoxy, aminoalkyl, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, Hydroxyalkoxy, benzyl, cyclopropyl, phenyl, or alkoxyalkyl, etc.

本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-10个碳原子；另外一些实施例是，烷基基团含有1-8个碳原子；另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子；另外一些实施例是，烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(-CH3)，乙基(-CH2CH3)，正丙基(-CH2CH2CH3)，异丙基(-CH(CH3)2)，正丁基(-CH2CH2CH2CH3)，2-甲基丙基或异丁基(-CH2CH(CH3)2)，1-甲基丙基或仲丁基(-CH(CH3)CH2CH3)，叔丁基(-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。烷基可以被本发明所述的取代基所取代。The term "alkyl" as used herein includes saturated straight or branched monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-10 carbon atoms; in other embodiments, the alkyl group contains 1-8 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms In other embodiments, the alkyl group contains 1-4 carbon atoms; in other embodiments, the alkyl group contains 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl ( -CH3 ), ethyl (-CH2CH3), n - propyl ( -CH2CH2CH3 ) , isopropyl ( - -CH( CH3 ) 2 ), n-butyl ( -CH2CH2CH2CH3 ), 2 -methylpropyl or isobutyl (-CH2CH ( CH3 ) 2 ), 1 -methyl Propyl or sec-butyl (-CH( CH3 ) CH2CH3 ), tert-butyl ( -C ( CH3 )3 ) , n - pentyl ( -CH2CH2CH2CH2CH3 ) , 2 -Pentyl (-CH( CH3 ) CH2CH2CH3 ), 3 -pentyl (-CH( CH2CH3 ) 2 ), 2-methyl- 2 -butyl (-C( CH3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl ( -CH( CH3 ) CH2CH2CH2CH3 ), 3 -hexyl (-CH( CH2CH3 ) ( CH2CH2CH3 ) ), 2 -methyl- 2 -pentyl (-C (CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl ( -CH( CH3 )CH2CH( CH3 ) 2 ), 3-methyl-3-pentyl (-C( CH3 )( CH2CH3 ) 2 ), 2 -methyl- 3 -pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethy Methyl-2-butyl (-CH( CH3 )C( CH3 ) 3) , n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alk", as used herein, both encompass straight and branched saturated carbon chains. Alkyl groups may be substituted with the substituents described in the present invention.

术语“卤代烷基”表示烷基可以被一个或多个相同或不同卤素原子所取代的情况。其中烷基基团具有如本发明所述的含义，这样的实例包括，但并不限于三氟甲基，2,2-二氟乙基，3,3,3-三氟丙基等。卤代烷基可以被本发明所述的取代基所取代。The term "haloalkyl" refers to instances where the alkyl group may be substituted with one or more halogen atoms, which may be the same or different. Where the alkyl group has the meaning as described herein, such examples include, but are not limited to, trifluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, and the like. Haloalkyl groups may be substituted with the substituents described in the present invention.

术语“氨基烷基”是指烷基可以被一个或多个相同或不同的氨基取代或者氨基分别独立地被一个或两个烷基基团所取代，其中烷基具有如本发明所述的含义。The term "aminoalkyl" means that an alkyl group may be substituted with one or more identical or different amino groups or the amino groups may be independently substituted with one or two alkyl groups, wherein the alkyl group has the meaning as described herein .

本发明中所使用的术语“烷氧基”，涉及到烷基，像本发明所定义的，通过氧原子连接到主要的碳链上。这样的实施例包括，但并不限于，甲氧基，乙氧基，丙氧基等等。烷氧基可以被本发明所述的取代基所取代。The term "alkoxy," as used herein, relates to an alkyl group, as defined herein, attached to the primary carbon chain through an oxygen atom. Such examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like. The alkoxy group may be substituted with the substituents described in the present invention.

术语“环烷基”是指一价或多价、非芳香族、饱和或部分不饱和环，且不包含杂原子，其中包括3-12个碳原子的单环或7-12个碳原子的二环或三环。具有7-12个原子的双碳环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，同时具有9或10个原子的双碳环可以是二环[5,6]或[6,6]体系。合适的环烷基基团包括，但并不限于，环烷基，环烯基和环炔基。环烷基基团的实例进一步包括，但绝不限于，环丙基，环丁基，环戊基，1-环戊基-1-烯基，1-环戊基-2-烯基，1-环戊基-3-烯基，环己基，1-环己基-1-烯基，1-环己基-2-烯基，1-环己基-3-烯基，环己二烯基，环庚基，环辛基，环壬基，环癸基，环十一烷基，环十二烷基，金刚烷基等等。视结构而定，环烷基可为单价基团或二价基团，即亚环烷基。C4环烷基是指环丁基，C5环烷基是指环戊基，C7环烷基是指环庚基。环烷基可以被本发明所述的取代基所取代。The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring containing no heteroatoms, including monocyclic rings of 3-12 carbon atoms or monocyclic rings of 7-12 carbon atoms Bicyclic or tricyclic. Bicarbocycles with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicarbocycles with 9 or 10 atoms Can be a bicyclic [5,6] or [6,6] system. Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of cycloalkyl groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1 -Cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cyclo Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl and the like. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical, ie, a cycloalkylene. C4cycloalkyl means cyclobutyl, C5cycloalkyl means cyclopentyl, and C7cycloalkyl means cycloheptyl. Cycloalkyl groups may be substituted with substituents described herein.

术语“芳基”可以是单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子，且只有一个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用，如芳香环可以包括苯基，萘基和蒽。视结构而定，芳基可为单价基团或二价基团，即亚芳基。芳基可以被本发明所述的取代基所取代。The term "aryl" can be monocyclic, bicyclic, and tricyclic carbocyclic ring systems, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 atoms, and has only one point of attachment to the molecule connected to the rest of the . The term "aryl" may be used interchangeably with the term "aromatic ring," eg, aromatic rings may include phenyl, naphthyl, and anthracene. Depending on the structure, an aryl group can be a monoradical or a diradical, ie, an arylene group. Aryl groups may be substituted with the substituents described in the present invention.

术语“杂芳基”，“杂芳环”在此处可交换使用，都是指单环，双环，三环或者四环体系，其中，双环杂芳环，三环杂芳环或者四环杂芳环体系以稠合的形式成环。其中，杂芳环体系至少一个环体系是芳香族的，环上一个或多个原子独立任选地被杂原子所取代(杂原子选自N，O，P，S，在此S或P独立任选地被一个或多个氧原子所取代得到像SO，SO2，PO，PO2的基团)。杂芳体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。杂芳体系基团可以是3-7个原子组成的单环，或7-10个原子组成的双环，或10-15个原子组成的三环。具有7-10个原子的双环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，具有10-15个原子的三环可以是三环[5,5,6]，[5,7,6]或[6,5,6]体系。The terms "heteroaryl" and "heteroaromatic" are used interchangeably herein and refer to a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the bicyclic heteroaromatic, tricyclic heteroaromatic or tetracyclic heterocyclic Aromatic ring systems form rings in fused form. wherein, at least one ring system of the heteroaromatic ring system is aromatic, and one or more atoms on the ring are independently optionally substituted by heteroatoms (heteroatoms are selected from N, O, P, S, where S or P are independently Optionally substituted with one or more oxygen atoms to give groups like SO, SO2, PO, PO2 ) . Heteroaromatic systems can be attached to the main structure at any heteroatom or carbon atom to form stable compounds. The heteroaromatic system group may be a monocyclic ring of 3-7 atoms, a bicyclic ring of 7-10 atoms, or a tricyclic ring of 10-15 atoms. Bicyclic rings with 7-10 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, tricyclic rings with 10-15 atoms can be tricyclic [5,5,6], [5,7,6] or [6,5,6] system.

术语“杂环基”，“杂环”，“杂脂环族”或“杂环的”在此处可交换使用，都是指单环，双环，三环或者四环体系，其中环上一个或多个原子独立任选地被杂原子所取代，环可以是完全饱和的或包含一个或多个不饱和度，但绝不是芳香族类。杂环体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。一个或多个环上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，“杂环基”，“杂环”，“杂脂环族”或“杂环的”基团是3-7元环的单环(1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P独立任选地被一个或多个氧原子所取代得到像SO，SO2，PO，PO2的基团，同时，-CH2-基团可以独立任选地被-C(＝O)-替代；当所述的环为三元环时，其中只有一个杂原子)，或7-10个原子组成的双环(4-9个碳原子和选自N，O，P，S的1-3个杂原子，在此N，S或P独立任选地被一个或多个氧原子所取代得到像NO，NO2，SO，SO2，PO，PO2的基团，同时，-CH2-基团可以独立任选地被-C(＝O)-替代；)。The terms "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and all refer to a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which one of the rings The atoms or atoms are independently optionally substituted with heteroatoms, and the ring may be fully saturated or contain one or more degrees of unsaturation, but is never aromatic. The heterocyclic ring system can be attached to the main structure at any heteroatom or carbon atom to form stable compounds. One or more ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. Some examples of which are "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic" groups are 3-7 membered monocyclic rings (1-6 carbon atoms and selected from 1-3 heteroatoms of N, O, P, S, where S or P is independently optionally substituted by one or more oxygen atoms to give groups like SO, SO 2 , PO, PO 2 , and at the same time, The -CH 2 - group can be independently and optionally replaced by -C(=O)-; when the ring is a three-membered ring, there is only one heteroatom in it), or a bicyclic ring consisting of 7-10 atoms (4 - 9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where N, S or P are independently optionally substituted with one or more oxygen atoms to give like NO, NO 2 , Groups of SO, SO2, PO, PO2 , while -CH2- groups can be independently optionally replaced by -C (=O)-;).

“杂环基”可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和碳环或杂环并合所形成的基团。杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，噻噁烷基，氮杂环丁基，氧杂环丁基，硫杂环丁基，哌啶基，高哌啶基，环氧丙基，N-吗啉基，N-哌嗪基，2-哌嗪基，3-哌嗪基，高哌嗪基，氧氮杂卓基，二氮杂卓基，硫氮杂卓基，吡咯啉-1-基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，二氢苯并异噻嗪基，二氢苯并异噁嗪基，二氧戊环基，二氢吡嗪基，二氢吡啶基，二氢吡唑基，二氢嘧啶基，二氢吡咯基，呋喃酮基，呋喃基，咪唑烷基，咪唑啉基，咪唑基，咪唑并吡啶基，咪唑并噻唑基，吲唑基，，吲哚嗪基，吲哚基，吗啉基，噁唑烷二酮基，噁唑烷基，环氧乙烷基，哌嗪基，哌啶基，吡唑烷基，喹宁环基，四氢异喹啉基，四氢噻嗯基，硫吗啉基，噻唑烷基。"Heterocyclyl" may be carbon or heteroatom. "Heterocyclyl" also includes a heterocyclic group in combination with a saturated or partially unsaturated carbocyclic or heterocyclic ring. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Thioxanyl, Azacyclobutyl, Oxetanyl, Thietanyl, Piperidinyl, Homopiperidinyl, Glycidol, N-Morpholinyl, N-Piperazinyl, 2 -piperazinyl, 3-piperazinyl, homopiperazinyl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrole olinyl, indoline, dihydrobenzisothiazinyl, dihydrobenzoisoxazinyl, dioxolane, dihydropyrazinyl, dihydropyridyl, dihydropyrazolyl, Dihydropyrimidinyl, dihydropyrrolyl, furanonyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazopyridyl, imidazothiazolyl, indazolyl, indolazinyl, indole base, morpholinyl, oxazolidinedione, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, pyrazolidine, quinuclidine, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl Hydrothienyl, thiomorpholinyl, thiazolidinyl.

另外，需要说明的是，除非以其他方式明确指出，在本文中通篇采用的描述方式“各…和…独立地为”、“…和…各自独立地为”和“…和…分别独立地为”可以互换，应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，“H-(C(R3)2)n-O-(C(R3)2)n1-C(＝O)-(C(R3)2)n-”中“R3”表示相同或不同的基团，且相互之间不影响；“n”表示相同或不同的取值，且相互之间不影响。In addition, it should be noted that, unless expressly stated otherwise, the descriptions used throughout this document "each ... and ... are independently", "... and ... are each independently" and "... and ... are each independently "" can be interchanged and should be understood in a broad sense. It can either mean that in different groups, the specific options expressed by the same symbol do not affect each other, or it can mean that in the same group, the same symbol is the same. The specific options expressed between them do not affect each other. For example, "R 3 " in "H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(=O)-(C( R 3 ) 2 ) n -" means The same or different groups, and do not affect each other; "n" represents the same or different values, and do not affect each other.

术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, and the like. Preferably, the term "pharmaceutically acceptable" as used herein means approved by a federal regulatory agency or a national government or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, more particularly in humans.

术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体，例如水和油类，包括石油、动物、植物或合成来源的，例如花生油、大豆油、矿物油、芝麻油等。水和水性溶液盐水溶液和水性葡萄糖与甘油溶液优选用作载体、特别是可注射溶液。适宜的药物载体描述于E.W.Martin的“Remington′s PharmaceuticalSciences”中。The term "carrier" refers to a diluent, adjuvant, excipient or base with which the compound is administered. These pharmaceutical carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water and Aqueous Solutions Saline solutions and aqueous dextrose and glycerol solutions are preferred for use as carriers, especially for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

本发明中立体化学的定义和惯例的使用通常参考以下文献：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,NewYork；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",JohnWiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50:50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。Definitions and conventions of stereochemistry in the present invention are generally used by reference to the following references: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. , "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory. The chemical structures of these stereoisomers are the same, but their steric structures are not the same. A specific stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

“异构体”为具有相同分子式的不同化合物。“立体异构体”为仅仅原子的空间排列方式不同的异构体。如本文使用的术语“异构体”包括任何和所有的几何异构体和立体异构体。例如，“异构体”包括顺式和反式异构体、E-和Z-异构体、R-和S-对映异构体、非对映异构体、(d)异构体、(l)-异构体、其外消旋混合物、及落入本说明书范围的其它其混合物。"Isomers" are different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the arrangement of the atoms in space. The term "isomer" as used herein includes any and all geometric and stereoisomers. For example, "isomers" include cis and trans isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (d) isomers , (l)-isomers, racemic mixtures thereof, and other mixtures thereof falling within the scope of this specification.

本发明的“水合物”是指本发明所提供的化合物或其盐，其还包括化学量或非化学当量通过非共价分子间力结合的水，也可说是溶剂分子是水所形成的缔合物。The "hydrate" of the present invention refers to the compound or its salt provided by the present invention, and it also includes water bound by non-covalent intermolecular force in a stoichiometric or non-stoichiometric amount, and it can also be said that the solvent molecule is formed by water associates.

本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂例如二氯甲烷中，使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。"Nitrogen oxide" in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (eg, peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514) in which, for example, in an inert solvent such as dichloromethane, an amine compound is combined with m-chloroperoxybenzoic acid (MCPBA) reaction.

化合物可存在多种不同几何异构体和互变异构体，所述式(I)-式(III)化合物包括所有此类形式。为避免疑惑，当化合物以几种几何异构体或互变异构体之一存在并且只具体描述或显示一种时，显然所有其它形式包括在式(I)-式(III)中。Compounds may exist in a number of different geometric isomers and tautomers, and the compounds of formula (I)-(III) include all such forms. For the avoidance of doubt, when a compound exists as one of several geometric isomers or tautomers and only one is specifically described or shown, it is clear that all other forms are included in formula (I)-(III).

本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)-式(III)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel DeliverySystems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,BioreversibleCarriers in Drug Design,American Pharmaceutical Association and PergamonPress,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,NatureReview Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs ofPhosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。The term "prodrug" as used in the present invention represents the conversion of a compound into a compound of formula (I)-(III) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345 .

除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention.

“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

本发明化合物的各种药学上可接受的盐形式都是有用的。术语“药学上可接受的盐”是指那些盐形式对于制药化学家而言是显而易见的，即它们基本上无毒并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄。其他因素，在性质上更加实用，对于选择也很重要，这些是：原材料的成本、结晶的容易、产率、稳定性、吸湿性和结果原料药的流动性。简单地讲，药物组合物可以通过有效成分与药学上可接受的载体制备得到。Various pharmaceutically acceptable salt forms of the compounds of the present invention are useful. The term "pharmaceutically acceptable salts" refers to those salt forms that are obvious to the pharmaceutical chemist, ie they are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, are also important for selection, these are: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and resulting drug substance flowability. Briefly, pharmaceutical compositions can be prepared by using active ingredients and pharmaceutically acceptable carriers.

本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describepharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，硝酸盐等，和有机酸盐如乙酸盐，丙酸盐，乙醇酸盐，草酸盐，马来酸盐，丙二酸盐，琥珀酸盐，富马酸盐，酒石酸盐，枸橼酸盐，苯甲酸盐，扁桃酸盐，甲磺酸盐，乙磺酸盐，甲苯磺酸盐，磺基水杨酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, Nitrates, etc., and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citric acid Salts, benzoates, mandelates, methanesulfonates, ethanesulfonates, toluenesulfonates, sulfosalicylates, etc., or obtained by other methods such as ion exchange methods described in books and literature these salts.

其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐、等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N+(C1-4烷基)4的盐。Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, Borate, Butyrate, Camphorate, Camphorsulfonate, Cyclopentylpropionate, Digluconate, Lauryl Sulfate, Ethanesulfonate, Formate, Fumaric Acid Salt, Glucoheptonate, Glycerophosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate , laurate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, Pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate , valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.

本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。胺盐，例如但不限于N,N’-二苄基乙二胺，氯普鲁卡因，胆碱，氨，二乙醇胺和其它羟烷基胺，乙二胺，N-甲基还原葡糖胺，普鲁卡因，N-苄基苯乙胺，1-对-氯苄基-2-吡咯烷-1’-基甲基-苯并咪唑，二乙胺和其它烷基胺，哌嗪和三(羟甲基)氨基甲烷；碱土金属盐，例如但不限于钡，钙和镁；过渡金属盐，例如但不限于锌。The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates. Amine salts such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylreduced glucose Amine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkaline earth metal salts such as but not limited to barium, calcium and magnesium; transition metal salts such as but not limited to zinc.

在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。In this specification, if there is any difference between chemical name and chemical structure, the structure will prevail.

本发明所使用的任何保护基团、氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、公认的缩写为准，或参照IUPAC-IUB Commission on BiochemicalNomenclature(参见Biochem.1972，11：942-944)。Any abbreviations for protecting groups, amino acids and other compounds used in the present invention, unless otherwise stated, are based on their commonly used, recognized abbreviations, or refer to the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11 : 942-944).

本发明提供药物组合物，包含治疗有效量的式(I)所示化合物或其药学上可接受的盐和药学上可接受的辅料、载体、赋形剂、溶媒或它们的组合。当本发明的化合物以药物的形式施用于哺乳动物例如人时，其可以以化合物本身的形式被给予或者可以以含有例如0.1至99.5％(更优选0.5至90％)活性成分以及药学可接受的载体的药物组合物的形式被给予。The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, carrier, excipient, vehicle or a combination thereof. When the compound of the present invention is administered in the form of a medicament to a mammal such as a human, it may be administered in the form of the compound itself or may contain, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient together with a pharmaceutically acceptable The carrier is administered in the form of a pharmaceutical composition.

“联合”表示在单个剂量单位形式中的固定组合或用于组合施用的部分的药盒，其中本发明公开化合物和组合伴侣(治疗肿瘤疾病、艾滋病、炎症反应以及免疫缺陷疾病的药物)可以在同一时间独立施用或者可以在一定的时间间隔内分别施用，特别是使联合合伴侣表现出合作、例如协同作用。如本文所用的术语“药物组合物”表示将一种以上活性成分混合或组合所得到的产品，并且既包括活性成分的固定组合也包括非固定组合。术语“固定联合”表示活性成分如本发明公开化合物和组合伙伴以单一实体或剂量的形式同时施用于患者。术语“非固定联合”表示活性成分如本发明公开化合物和组合伙伴均作为单独实体同时、共同或无特定时间限制地先后施用于患者。"Combination" means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein a compound of the present invention and a combination partner (a drug for the treatment of neoplastic diseases, AIDS, inflammatory responses and immunodeficiency diseases) may be The administration is administered independently at the same time or may be administered separately at a time interval, in particular to allow the joint partners to exhibit a cooperative, eg synergistic, effect. The term "pharmaceutical composition" as used herein refers to a product resulting from mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the disclosed compound and the combination partner, are administered to a patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that the active ingredients, such as the disclosed compound and the combination partner, are administered to a patient simultaneously, jointly or sequentially without a specific time limit, as separate entities.

措辞“药学可接受的载体”在本领域中是公认的，包括适于将本发明的化合物施用于哺乳动物的药学可接受的材料、组合物或载体。所述载体包括参与携带主题物质或将其从一个器官或机体的一部分转移到另一个器官或机体的另一部分的液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。各载体在与制剂中的其它成分相容和对患者无害的意义上必须是“可接受的”。可用作药学可接受的载体的材料的一些实例包括：糖类，如乳糖、葡萄糖和蔗糖；淀粉类，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；粉状西黄蓍胶；麦芽；明胶；滑石粉；赋形剂，如可可脂和栓剂蜡类；油类，如花生油、棉子油、红花油、芝麻油、橄榄油、玉米油和豆油；二醇类，如丙二醇；多元醇类，如甘油、山梨醇、甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等张盐水；林格氏溶液；乙醇；磷酸盐缓冲液；和药物制剂中所用的其它无毒的可相容的物质。The phrase "pharmaceutically acceptable carrier" is art-recognized and includes pharmaceutically acceptable materials, compositions or carriers suitable for administering the compounds of the present invention to mammals. Such carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that participate in carrying or transferring the subject substance from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: carbohydrates such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, Ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil , olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycols; esters, such as ethyl oleate and ethyl laurate; agar; buffers alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic compatible substance.

在组合物中也可以存在润湿剂、乳化剂和润滑剂如十二烷基硫酸钠和硬脂酸镁，以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂。Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring, releasing, coating, sweetening, flavoring and perfuming agents can also be present in the compositions , preservatives and antioxidants.

药学可接受的抗氧化剂的实例包括：水溶性抗氧化剂，如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等；油溶性抗氧化剂，如棕榈酸抗坏血酸酯、丁基化羟基苯甲醚(BHA)、丁化羟基甲苯(BHT)、卵磷脂、棓酸丙酯、α-生育酚等；和金属螯合剂，如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxybenzene Methyl ether (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid , phosphoric acid, etc.

本发明的药物组合物包括适于口服、鼻、局部、口含、舌下、直肠和/或胃肠外施用的那些。制剂可以方便地以单位剂型形式存在并且可以通过药学领域公知的任何方法来制备。可以与载体物质组合来制备单剂量形式的活性成分的量一般是产生治疗作用的化合物的量。一般而言，以百分之一为单位，该量为约1％至约99％活性成分，优选约5％至约70％，最优选约10至约30％。Pharmaceutical compositions of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to prepare a unit dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, in one percent units, this amount will be from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

术语“治疗”用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病，包括：(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生；(b)抑制疾病，例如阻滞疾病发展；或(c)缓解疾病，例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述化合物的药物给予有需要的个体。The term "treating" is used to refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or symptoms thereof, and/or therapeutic in terms of partial or complete cure of the disease and/or adverse effects caused by the disease. "Treatment" as used herein encompasses diseases in mammals, particularly humans, including: (a) preventing the development of a disease or disorder in individuals susceptible to but not yet diagnosed with the disease; (b) inhibiting the disease, eg, retarding the progression of the disease; or (c) alleviating the disease, eg reducing symptoms associated with the disease. "Treatment" as used herein encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, alleviate or inhibit a disease in the individual, including but not limited to administration of a drug containing a compound described herein to an individual in need thereof.

一般合成方法General synthetic methods

一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义前面所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。In general, the compounds of the present invention can be prepared by the methods described herein, unless otherwise indicated, wherein the definitions of the substituents are indicated above. The following reaction schemes and examples serve to further illustrate the content of the present invention.

所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的除了本发明所描述的试剂，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.

下面所描述的实施例，除非其他说明，所有的温度定为摄氏度(℃)。实验所用试剂如无特别说明，均购自北京偶合科技有限公司、北京百灵威科技有限公司、AcrosOrganics,Alfa Aesar,Sigma-Aldrich和TCI，未经纯化直接使用。实验所用溶剂主要购自北京化工厂和西陇化工股份有限公司，除THF和DMF经美国VAC公司(Vacuum atmospherescompany)溶剂纯化系统进一步处理外，其余均未经处理直接使用。GF254薄层层析硅胶板，GF254硅胶厚制备板以及柱层析用硅胶粉(60-100目、160-200目、200-300目)均购自青岛海洋化工厂。In the examples described below, unless otherwise stated, all temperatures are in degrees Celsius (°C). Unless otherwise specified, the reagents used in the experiment were purchased from Beijing Coupling Technology Co., Ltd., Beijing Bailingwei Technology Co., Ltd., AcrosOrganics, Alfa Aesar, Sigma-Aldrich and TCI, and were used directly without purification. The solvents used in the experiment were mainly purchased from Beijing Chemical Factory and Xilong Chemical Co., Ltd., except for THF and DMF, which were further processed by the solvent purification system of VAC Company (Vacuum atmospheres company), the rest were used directly without treatment. GF254 thin-layer chromatography silica gel plate, GF254 silica gel thick preparation plate and silica gel powder for column chromatography (60-100 mesh, 160-200 mesh, 200-300 mesh) were purchased from Qingdao Ocean Chemical Factory.

UPLC-MS分析仪：Waters公司的Acquity UPLC-MS系统，包括二元溶剂管理器、样品管理器、色谱柱管理器、PDA检测器以及SQ质谱检测器。色谱柱为Waters公司的Acquity

Figure BDA0002385652160000141
BEH C18柱(1.7μm,2.1mm×50mm)。流动相为含有0.05％HCOOH的乙腈和水。线性梯度洗脱5:95(v:v)acetonitrile-H2O到95:5(v:v)acetonitrile-H2O，时间3minutes，流速0.3mL/min。UV检测波长254nm。SQ质谱检测仪采用正离子或者负离子扫描方式，电喷雾离子源(ESI)。主要用于反应监测和化合物纯度的初步测定。UPLC-MS analyzer: Acquity UPLC-MS system from Waters, including binary solvent manager, sample manager, column manager, PDA detector, and SQ mass spectrometer. The column is Acquity from Waters
Figure BDA0002385652160000141
BEH C18 column (1.7 μm, 2.1 mm×50 mm). The mobile phase was acetonitrile and water containing 0.05% HCOOH. Linear gradient elution 5:95 (v:v) acetonitrile-H2O to 95:5 (v:v) acetonitrile-H2O, time 3 minutes, flow rate 0.3 mL/min. UV detection wavelength 254nm. The SQ mass spectrometer adopts positive or negative ion scanning mode and electrospray ionization (ESI). Mainly used for reaction monitoring and preliminary determination of compound purity.

核磁共振仪：Bruker Avance 400MHz，溶剂为CDCl3,DMSO-d6,Acetone-d6orMethanol-d4。Nuclear magnetic resonance apparatus: Bruker Avance 400MHz, the solvent is CDCl3, DMSO-d6, Acetone-d6 or Methanol-d4.

实施例1 1-(5-(3-((3-氯-4-氟苯基)胺基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成Example 1 Synthesis of 1-(5-(3-((3-chloro-4-fluorophenyl)amino)-1H-indazolyl)sulfonyl)piperidin-4-ol

Figure BDA0002385652160000151
Figure BDA0002385652160000151

5-(苄硫基)-1H-吲唑(1-2)的合成：在100ml的圆底烧瓶里依次加入1-1(390mg,2mmol),Pd2(dba)3(91mg,0.1mmol),Xantphos(117mg,0.2mmol),20mL 1,4-二氧六环，DIPEA(660μL,4mmol),苄硫醇(372mg,3mmol)，用氩气将瓶内的气体置换三次，加热到90℃，反应4小时。LC-MS检测反应液，反应完成后，冷却，过滤，滤液减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯2/1),得440mg橙色油状物，收率92％。Synthesis of 5-(benzylthio)-1H-indazole (1-2): 1-1 (390 mg, 2 mmol), Pd 2 (dba) 3 (91 mg, 0.1 mmol) were sequentially added to a 100 ml round-bottomed flask , Xantphos (117mg, 0.2mmol), 20mL 1,4-dioxane, DIPEA (660μL, 4mmol), benzyl mercaptan (372mg, 3mmol), replace the gas in the bottle with argon three times, heat to 90°C , and react for 4 hours. The reaction solution was detected by LC-MS. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain 440 mg of orange oil with a yield of 92%.

1-((5-1H-吲唑基)磺酰基)哌啶-4-醇(1-3)的合成：将420mg(1.75mmol)1-2溶解于10ml乙腈，依次加入100μL水和乙酸，将混合液冷却到-30℃，分批加入1,3-二氯-5,5-二甲基海因(520mg,2.62mmol)，将反应液升至-15℃，反应1小时。反应液转移到分液漏斗，加入乙酸乙酯稀释和饱和食盐水洗，分取乙酸乙酯层，用无水硫酸钠干燥30min。过滤，减压蒸除乙酸乙酯。加二氯甲烷复溶，加入4-羟基哌啶(520mg,5.2mmol)和三乙胺(1.0ml,7.86mmol),室温反应30分钟，加二氯甲烷稀释，1N盐酸洗，无水硫酸钠干燥，C18分离，得200mg，收率41％。Synthesis of 1-((5-1H-indazolyl)sulfonyl)piperidin-4-ol (1-3): 420 mg (1.75 mmol) 1-2 was dissolved in 10 ml of acetonitrile, 100 μL of water and acetic acid were added successively, The mixture was cooled to -30°C, 1,3-dichloro-5,5-dimethylhydantoin (520 mg, 2.62 mmol) was added in batches, the reaction solution was raised to -15°C and reacted for 1 hour. The reaction solution was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filter and evaporate the ethyl acetate under reduced pressure. Add dichloromethane to redissolve, add 4-hydroxypiperidine (520mg, 5.2mmol) and triethylamine (1.0ml, 7.86mmol), react at room temperature for 30 minutes, add dichloromethane to dilute, wash with 1N hydrochloric acid, anhydrous sodium sulfate After drying, C18 was separated to obtain 200 mg with a yield of 41%.

乙酸-4-(1-(5-(3-溴-1-(2-四氢-2H-吡喃基)-1H-吲唑基)磺酰基)哌啶)酯(1-5)的合成：将1-2(93mg,0.33mmol)溶于氯仿，加65mg(0.37mmol)NBS，60℃反应，LC-MS监测，反应完成后，反应液用二氯甲烷稀释，依次用饱和Na2S2O3溶液、饱和食盐水洗，二氯甲烷层用无水硫酸钠干燥，过滤，减压蒸除二氯甲烷，得中间体1-4。用乙酸乙酯复溶，加入3,4-二氢-2H-吡喃(55mg,0.66mmol)和对甲苯磺酸一水合物(19mg,0.1mmol)，回流反应16小时，LC-MS监测反应液，待完全转化后，向反应液中加入67μL(0.66mmol)醋酸酐，继续反应，LC-MS监测，反应完成后，冷却，加乙酸乙酯稀释，水洗，用无水硫酸钠干燥，过滤，柱层析分离，得138mg，收率86％。Synthesis of Acetate-4-(1-(5-(3-bromo-1-(2-tetrahydro-2H-pyranyl)-1H-indazolyl)sulfonyl)piperidine)ester (1-5) : Dissolve 1-2 (93 mg, 0.33 mmol) in chloroform, add 65 mg (0.37 mmol) of NBS, react at 60°C, and monitor by LC-MS. After the reaction is completed, the reaction solution is diluted with dichloromethane, followed by saturated Na 2 S 2 O 3 solution, washed with saturated brine, the dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated under reduced pressure to obtain intermediate 1-4. Reconstituted with ethyl acetate, added 3,4-dihydro-2H-pyran (55mg, 0.66mmol) and p-toluenesulfonic acid monohydrate (19mg, 0.1mmol), refluxed for 16 hours, and monitored the reaction by LC-MS After complete conversion, add 67 μL (0.66 mmol) of acetic anhydride to the reaction solution, continue the reaction, monitor by LC-MS, after the reaction is completed, cool, add ethyl acetate to dilute, wash with water, dry with anhydrous sodium sulfate, filter , column chromatography to obtain 138mg, yield 86%.

1-(5-(3-((3-氯-4-氟苯基)胺基)-1-(2-四氢-2H-吡喃基)-1H-吲唑基)磺酰基)哌啶-4-醇(1-6)的合成：在反应瓶中依次加入1-5(131mg,0.27mol)、3-氯-4-氟苯胺(58mg,0.4mmol)、Pd(OAc)2(3mg,0.014mmol)、Xantphos(15mg,0.027mmol)、Cs2CO3(176mg,0.54mmol)和1,4-二氧六环(3ml)，用氩气将反应瓶内的气体置换三次，110℃反应12小时。反应完成后，冷却，过滤，滤液减压浓缩。加THF和水溶解，加入LiOH(20mg,0.84mmol)，室温反应1小时，反应液加入乙酸乙酯和水，分离乙酸乙酯相，硅胶柱层析分离，得122mg，收率89％。1-(5-(3-((3-Chloro-4-fluorophenyl)amino)-1-(2-tetrahydro-2H-pyranyl)-1H-indazolyl)sulfonyl)piperidine Synthesis of -4-ol (1-6): 1-5 (131mg, 0.27mol), 3-chloro-4-fluoroaniline (58mg, 0.4mmol), Pd(OAc) 2 (3mg) were added to the reaction flask in turn , 0.014mmol), Xantphos (15mg, 0.027mmol), Cs 2 CO 3 (176mg, 0.54mmol) and 1,4-dioxane (3ml), the gas in the reaction flask was replaced three times with argon, 110 ℃ The reaction was carried out for 12 hours. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure. Add THF and water to dissolve, add LiOH (20 mg, 0.84 mmol), react at room temperature for 1 hour, add ethyl acetate and water to the reaction solution, separate the ethyl acetate phase, and separate by silica gel column chromatography to obtain 122 mg with a yield of 89%.

标题化合物的合成：将1-6溶于无水乙醇(5ml)，加入1ml盐酸，室温反应，待反应完成后，用1N的NaOH溶液调pH8-9，有固体析出，过滤，依次用水和少量甲醇洗，可得目标化合物。1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),9.53(s,1H),8.56(s,1H),8.11(s,1H),7.92–7.45(m,3H),7.35(t,J＝9.3Hz,1H),4.65(s,1H),3.49(s,1H),3.16(s,2H),2.71(s,2H),1.74(s,2H),1.44(s,2H).13C NMR(101MHz,DMSO-d6)δ151.27(d,J＝237.9Hz),146.25,141.74,140.03,126.01,125.69,122.46,119.53(d,J＝18.1Hz),117.43(d,J＝21.6Hz),117.08,116.53(d,J＝6.1Hz),113.89,110.83,64.29,43.75,33.38.Synthesis of the title compound: Dissolve 1-6 in absolute ethanol (5 ml), add 1 ml of hydrochloric acid, and react at room temperature. After the reaction is completed, adjust the pH to 8-9 with 1N NaOH solution, a solid is precipitated, filtered, followed by water and a small amount of The target compound can be obtained by washing with methanol. 1 H NMR (400MHz, DMSO-d 6 )δ12.63(s,1H), 9.53(s,1H), 8.56(s,1H), 8.11(s,1H), 7.92-7.45(m,3H), 7.35(t, J＝9.3Hz, 1H), 4.65(s, 1H), 3.49(s, 1H), 3.16(s, 2H), 2.71(s, 2H), 1.74(s, 2H), 1.44(s , 2H). 13 C NMR (101MHz, DMSO-d 6 )δ151.27(d, J=237.9Hz), 146.25, 141.74, 140.03, 126.01, 125.69, 122.46, 119.53(d, J=18.1Hz), 117.43 (d, J=21.6Hz), 117.08, 116.53 (d, J=6.1Hz), 113.89, 110.83, 64.29, 43.75, 33.38.

实施例2 1-(5-(3-((3-氯-4-氟苯基)胺基))-(1-甲基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：Example 2 1-(5-(3-((3-Chloro-4-fluorophenyl)amino))-(1-methyl)-1H-indazolyl)sulfonyl)piperidin-4-ol Synthesis:

Figure BDA0002385652160000161
Figure BDA0002385652160000161

5-溴-1-甲基-1H-吲唑(2-1)的合成：5-溴-1H-吲唑(394mg,2mmol)溶于15mL丙酮，依次加入碘甲烷(6mmol)，K2CO3(552mg,4mmol)，80℃反应12小时。将反应液过滤，减压浓缩，用硅胶柱层析分离(石油醚/乙酸乙酯2/1)得250mg白色固体，收率59％。1H NMR(400MHz,Chloroform-d)δ7.95(d,J＝1.0Hz,1H),7.89(dd,J＝1.8,0.7Hz,1H),7.49(dd,J＝8.9,1.8Hz,1H),7.31(dt,J＝8.9,0.9Hz,1H),4.09(s,3H).Synthesis of 5-bromo-1-methyl-1H-indazole (2-1): 5-bromo-1H-indazole (394 mg, 2 mmol) was dissolved in 15 mL of acetone, followed by addition of methyl iodide (6 mmol), K 2 CO 3 (552 mg, 4 mmol) was reacted at 80°C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain 250 mg of white solid with a yield of 59%. 1 H NMR (400MHz, Chloroform-d) δ 7.95 (d, J=1.0Hz, 1H), 7.89 (dd, J=1.8, 0.7Hz, 1H), 7.49 (dd, J=8.9, 1.8Hz, 1H) ),7.31(dt,J=8.9,0.9Hz,1H),4.09(s,3H).

5-(苄硫基)-1-甲基-1H-吲唑(2-2)的合成：按化合物1-2的合成方法。Synthesis of 5-(benzylthio)-1-methyl-1H-indazole (2-2): According to the synthetic method of compound 1-2.

1-((5-(1-甲基)1H-吲唑基)磺酰基)哌啶-4-醇(2-3)的合成：按化合物1-3的合成方法，收率66％。Synthesis of 1-((5-(1-methyl)1H-indazolyl)sulfonyl)piperidin-4-ol (2-3): According to the synthesis method of compound 1-3, the yield is 66%.

1-((5-(3-溴-1-甲基)-1H-吲唑基)磺酰基)哌啶-4-醇(2-4)的合成：按化合物1-4的合成方法。Synthesis of 1-((5-(3-bromo-1-methyl)-1H-indazolyl)sulfonyl)piperidin-4-ol (2-4): According to the synthetic method of compound 1-4.

标题化合物的合成：按化合物1-6的合成方法，1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.56(d,J＝1.5Hz,1H),8.04(dd,J＝6.6,2.7Hz,1H),7.76–7.65(m,2H),7.60(ddd,J＝9.1,4.1,2.7Hz,1H),7.37(t,J＝9.1Hz,1H),4.65(s,1H),3.99(s,3H),3.51(dt,J＝7.9,4.0Hz,1H),3.23–3.10(m,2H),2.72(ddd,J＝11.8,8.5,3.4Hz,2H),1.76(ddd,J＝13.1,6.9,3.5Hz,2H),1.44(dtd,J＝12.2,8.0,3.5Hz,2H).Synthesis of the title compound: according to the synthesis method of compound 1-6, 1 H NMR (400MHz, DMSO-d 6 ) δ 9.56(s, 1H), 8.56(d, J=1.5Hz, 1H), 8.04(dd, J=6.6, 2.7Hz, 1H), 7.76–7.65(m, 2H), 7.60(ddd, J=9.1, 4.1, 2.7Hz, 1H), 7.37(t, J=9.1Hz, 1H), 4.65(s ,1H),3.99(s,3H),3.51(dt,J=7.9,4.0Hz,1H),3.23–3.10(m,2H),2.72(ddd,J=11.8,8.5,3.4Hz,2H), 1.76(ddd,J=13.1,6.9,3.5Hz,2H),1.44(dtd,J=12.2,8.0,3.5Hz,2H).

实施例3 1-((5-(3-(3-氯-4-氟苯基)(甲基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：Example 3 1-((5-(3-(3-Chloro-4-fluorophenyl)(methyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine- Synthesis of 4-alcohols:

Figure BDA0002385652160000162
Figure BDA0002385652160000162

1-环丙基-5-溴-1H-吲唑(3-1)的合成：在圆底烧瓶中加入5-溴-1H-吲唑(985mg,5mmol)、环丙基硼酸(859mg,10mmol)、无水醋酸铜(900mg,5mmol)、2,2’-联吡啶(780mg,5mmol)、碳酸钠(1.0g,10mmol)、1,2-二氯乙烷(30ml)，70℃反应2小时。反应液过滤，减压浓缩，然后加乙酸乙酯溶解，用饱和硫酸铜溶液洗2次，有机层用无水硫酸钠干燥，过滤，减压蒸干乙酸乙酯，不经进一步纯化，进行下一步。Synthesis of 1-cyclopropyl-5-bromo-1H-indazole (3-1): 5-bromo-1H-indazole (985mg, 5mmol), cyclopropylboronic acid (859mg, 10mmol) were added to a round bottom flask ), anhydrous copper acetate (900mg, 5mmol), 2,2'-bipyridine (780mg, 5mmol), sodium carbonate (1.0g, 10mmol), 1,2-dichloroethane (30ml), 70 ℃ reaction 2 Hour. The reaction solution was filtered, concentrated under reduced pressure, then dissolved in ethyl acetate, washed twice with saturated copper sulfate solution, the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure with ethyl acetate. step.

5-(苄硫基)-1-环丙基-1H-吲唑(3-2)的合成：将上述产物溶于20mL 1,4-二氧六环，加入Pd2(dba)3(229mg,0.025mmol)、Xantphos(289mg,0.5mmol)、DIPEA(1650μL,10mmol)、苄硫醇(930mg,7.5mmol)，用氩气将瓶内的气体置换三次，加热到90℃，反应4小时。LC-MS检测反应液，反应完成后，冷却，过滤，滤液减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯8/1),得854mg黄色固体，收率61％。1H NMR(400MHz,Chloroform-d)δ7.84(d,J＝0.9Hz,1H),7.66(dd,J＝1.7,0.8Hz,1H),7.48(dt,J＝8.7,0.9Hz,1H),7.35(dd,J＝8.7,1.6Hz,1H),7.28–7.16(m,5H),4.06(s,2H),3.56(tt,J＝7.1,3.7Hz,1H),1.24–1.18(m,2H),1.18–1.10(m,2H).Synthesis of 5-(benzylthio)-1-cyclopropyl-1H-indazole (3-2): The above product was dissolved in 20 mL of 1,4-dioxane, and Pd 2 (dba) 3 (229 mg) was added. , 0.025 mmol), Xantphos (289 mg, 0.5 mmol), DIPEA (1650 μL, 10 mmol), benzyl mercaptan (930 mg, 7.5 mmol), the gas in the bottle was replaced three times with argon, heated to 90 ° C, and reacted for 4 hours. The reaction solution was detected by LC-MS. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 8/1) to obtain 854 mg of yellow solid with a yield of 61%. 1 H NMR (400MHz, Chloroform-d) δ 7.84 (d, J=0.9Hz, 1H), 7.66 (dd, J=1.7, 0.8Hz, 1H), 7.48 (dt, J=8.7, 0.9Hz, 1H) ), 7.35 (dd, J=8.7, 1.6Hz, 1H), 7.28–7.16 (m, 5H), 4.06 (s, 2H), 3.56 (tt, J=7.1, 3.7Hz, 1H), 1.24–1.18 ( m,2H),1.18–1.10(m,2H).

1-((5-(1-环丙基)1H-吲唑基)磺酰基)哌啶-4-醇(3-3)的合成：按化合物1-3的合成方法，不经纯化，进行下一步反应。Synthesis of 1-((5-(1-cyclopropyl)1H-indazolyl)sulfonyl)piperidin-4-ol (3-3): According to the synthetic method of compound 1-3, without purification, proceed next reaction.

乙酸-4-(1-(5-(3-溴-1-环丙基-1H-吲唑基)磺酰基)哌啶)酯(3-4)的合成：上述产物(0.5mmol)溶于CH3CN/AcOH(4/2mL)，加入NBS(133mg,0.75mmol)，室温反应过夜。反应液用乙酸乙酯稀释，用饱和NaHCO3溶液洗，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物溶于10mL乙酸乙酯，加入乙酸酐(510μL,5mmol)、吡啶(160μL,2mmol),回流反应过夜。反应液依次用饱和硫酸铜溶液、饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯4/1)，得140mg白色固体，收率64％。Synthesis of acetate-4-(1-(5-(3-bromo-1-cyclopropyl-1H-indazolyl)sulfonyl)piperidine)ester (3-4): The above product (0.5 mmol) was dissolved in CH 3 CN/AcOH (4/2 mL), NBS (133 mg, 0.75 mmol) was added, and the reaction was carried out at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with saturated NaHCO3 solution, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 mL of ethyl acetate, acetic anhydride (510 μL, 5 mmol) and pyridine (160 μL, 2 mmol) were added, and the reaction was refluxed overnight. The reaction solution was washed successively with saturated copper sulfate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 4/1) to obtain 140 mg of white solid in a yield of 140 mg. 64%.

标题化合物的合成：在反应瓶中依次加入3-4(44mg,0.1mol)、3-氯-4-氟-N-甲基苯胺(24mg,0.15mmol)、Pd(OAc)2(2.2mg,0.01mmol)、Xantphos(5.7mg,0.01mmol)、Cs2CO3(65mg,0.2mmol)和1,4-二氧六环(2ml)，用氩气将反应瓶内的气体置换三次，130℃反应3小时。反应完成后，冷却，过滤，滤液减压浓缩。加THF和水溶解，加入LiOH(12mg,0.5mmol)，室温反应1小时，反应液加入乙酸乙酯和水，分离乙酸乙酯相，硅胶柱层析分离，得目标物。Synthesis of the title compound: 3-4 (44 mg, 0.1 mol), 3-chloro-4-fluoro-N-methylaniline (24 mg, 0.15 mmol), and Pd(OAc) 2 (2.2 mg, 0.15 mmol) were sequentially added to the reaction flask. 0.01 mmol), Xantphos (5.7 mg, 0.01 mmol), Cs 2 CO 3 (65 mg, 0.2 mmol) and 1,4-dioxane (2 ml), replace the gas in the reaction flask with argon three times, 130 ° C The reaction was carried out for 3 hours. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure. Add THF and water to dissolve, add LiOH (12 mg, 0.5 mmol), react at room temperature for 1 hour, add ethyl acetate and water to the reaction solution, separate the ethyl acetate phase, and separate by silica gel column chromatography to obtain the target compound.

实施例4 1-((5-(3-(3-氯-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：Example 4 1-((5-(3-(3-chloro-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin-4-ol synthesis:

Figure BDA0002385652160000171
Figure BDA0002385652160000171

按实施例3的合成方法。1H NMR(400MHz,DMSO-d6)δ9.57(d,J＝1.9Hz,1H),8.55(s,1H),8.01(dd,J＝5.8,3.0Hz,1H),7.72(s,2H),7.62(ddt,J＝9.0,4.5,2.3Hz,1H),7.37(td,J＝9.1,1.9Hz,1H),4.66(t,J＝2.7Hz,1H),3.76–3.61(m,1H),3.52(dt,J＝9.1,4.5Hz,1H),3.23–3.07(m,2H),2.73(t,J＝9.8Hz,2H),1.83–1.68(m,2H),1.53–1.37(m,3H),1.18–1.09(m,4H).According to the synthetic method of Example 3. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.57 (d, J=1.9Hz, 1H), 8.55 (s, 1H), 8.01 (dd, J=5.8, 3.0Hz, 1H), 7.72 (s, 2H), 7.62 (ddt, J=9.0, 4.5, 2.3Hz, 1H), 7.37 (td, J=9.1, 1.9Hz, 1H), 4.66 (t, J=2.7Hz, 1H), 3.76–3.61 (m ,1H),3.52(dt,J=9.1,4.5Hz,1H),3.23–3.07(m,2H),2.73(t,J=9.8Hz,2H),1.83–1.68(m,2H),1.53– 1.37(m,3H),1.18–1.09(m,4H).

实施例5 1-((5-(3-(3,4,5-三氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：Example 5 1-((5-(3-(3,4,5-trifluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin-4-ol Synthesis:

Figure BDA0002385652160000172
Figure BDA0002385652160000172

按实施例3的合成方法。1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.52(s,1H),7.74(d,J＝1.8Hz,2H),7.57(dt,J＝10.9,5.0Hz,2H),4.66(d,J＝3.9Hz,1H),3.69(ddd,J＝10.6,6.9,4.3Hz,1H),3.51(tq,J＝7.5,3.7Hz,1H),3.29–3.09(m,2H),2.73(ddd,J＝11.6,8.4,3.4Hz,2H),1.76(ddt,J＝13.9,7.2,3.6Hz,2H),1.45(dtd,J＝12.0,8.0,3.6Hz,2H),1.24–1.09(m,4H).13C NMR(101MHz,DMSO-d6)δ150.84(ddd,J＝242.6,9.9,6.1Hz),144.71,141.92,139.39–138.31(m),132.73(dt,J＝239.8,16.1Hz),126.51,126.38,122.40,114.83,110.57,100.41(d,J＝24.7Hz),64.20,43.69,33.35,29.67,6.85.According to the synthetic method of Example 3. 1 H NMR (400MHz, DMSO-d 6 )δ9.77(s,1H),8.52(s,1H),7.74(d,J=1.8Hz,2H),7.57(dt,J=10.9,5.0Hz, 2H), 4.66 (d, J=3.9Hz, 1H), 3.69 (ddd, J=10.6, 6.9, 4.3Hz, 1H), 3.51 (tq, J=7.5, 3.7Hz, 1H), 3.29–3.09 (m ,2H),2.73(ddd,J＝11.6,8.4,3.4Hz,2H),1.76(ddt,J＝13.9,7.2,3.6Hz,2H),1.45(dtd,J＝12.0,8.0,3.6Hz,2H ), 1.24–1.09 (m, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ150.84 (ddd, J=242.6, 9.9, 6.1Hz), 144.71, 141.92, 139.39–138.31 (m), 132.73 (dt, J=239.8, 16.1Hz), 126.51, 126.38, 122.40, 114.83, 110.57, 100.41 (d, J=24.7Hz), 64.20, 43.69, 33.35, 29.67, 6.85.

实施例6 1-((5-(3-(3,4,5-三氟苯基)氨基)-(1-环丙基)-(7-氟)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：Example 6 1-((5-(3-(3,4,5-trifluorophenyl)amino)-(1-cyclopropyl)-(7-fluoro)-1H-indazolyl)sulfonyl) Synthesis of piperidin-4-ol:

Figure BDA0002385652160000181
Figure BDA0002385652160000181

中间体6-1的合成：将底物(5.1g,36mmol)溶于25mL浓硫酸，分批加入NBS(7.7g,43.2mmol)，60℃反应过夜。将反应液倒入冰水中，用正己烷提取4次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯40/1)，得1.82g，收率23％。1HNMR(400MHz,Chloroform-d)δ10.32(s,1H),7.80(dtd,J＝5.1,2.4,1.5Hz,1H),7.62(ddd,J＝9.2,6.9,2.5Hz,1H).Synthesis of intermediate 6-1: The substrate (5.1 g, 36 mmol) was dissolved in 25 mL of concentrated sulfuric acid, NBS (7.7 g, 43.2 mmol) was added in batches, and the reaction was carried out at 60° C. overnight. The reaction solution was poured into ice water, extracted four times with n-hexane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 40/1) to obtain 1.82 g, yield 23%. 1 HNMR (400MHz, Chloroform-d) δ 10.32 (s, 1H), 7.80 (dtd, J=5.1, 2.4, 1.5Hz, 1H), 7.62 (ddd, J=9.2, 6.9, 2.5Hz, 1H).

中间体6-2的合成：将中间体6-1(1.79g,8.1mmol)溶于20mL乙二醇二甲醚，加入甲氧胺盐酸盐(1.33g,16mmol)、碳酸钾(3.3g,24mmol)，45℃反应，反应完成后，过滤，滤液减压浓缩，加乙酸乙酯溶解，依次用水、饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸干。Synthesis of intermediate 6-2: Intermediate 6-1 (1.79 g, 8.1 mmol) was dissolved in 20 mL of ethylene glycol dimethyl ether, and methoxyamine hydrochloride (1.33 g, 16 mmol), potassium carbonate (3.3 g) were added. , 24mmol), reacted at 45°C, after completion of the reaction, filtered, the filtrate was concentrated under reduced pressure, dissolved in ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.

中间体6-3的合成：将6-2(160mg,0.64mmol)溶于1.5mL水合肼和四氢呋喃，微波反应仪中150℃反应10分钟，反应液加乙酸乙酯稀释，水洗，干燥，减压蒸干。加少量二氯甲烷，搅拌，过滤，收集固体，79mg，收率57％。Synthesis of intermediate 6-3: Dissolve 6-2 (160 mg, 0.64 mmol) in 1.5 mL of hydrazine hydrate and tetrahydrofuran, react in a microwave reactor at 150°C for 10 minutes, dilute the reaction solution with ethyl acetate, wash with water, dry, reduce Autoclaved dry. Add a small amount of dichloromethane, stir, filter, collect the solid, 79 mg, yield 57%.

中间体6-4的合成：按中间体3-1的合成方法，收率42％。Synthesis of intermediate 6-4: According to the synthesis method of intermediate 3-1, the yield is 42%.

中间体6-5的合成：按中间体3-2的合成方法，收率93％。Synthesis of intermediate 6-5: According to the synthesis method of intermediate 3-2, the yield is 93%.

中间体6-6的合成：按中间体1-3的合成方法。Synthesis of intermediate 6-6: According to the synthesis method of intermediate 1-3.

中间体6-7的合成：将中间体6-6(119mg，0.35mmol)溶于50mL乙酸乙酯，加入乙酰氯(82μL,1.05mmol)、吡啶(112μL,1.4mmol)，回流反应，完成后，反应液用饱和硫酸铜溶液、饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压蒸干。加5mL醋酸溶解，加入NBS(187mg,1.05mmol)，40℃反应过夜，再次补加等量的NBS，继续反应8小时，减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯4/1)，得45mg,收率29％。Synthesis of intermediate 6-7: Intermediate 6-6 (119 mg, 0.35 mmol) was dissolved in 50 mL of ethyl acetate, acetyl chloride (82 μL, 1.05 mmol) and pyridine (112 μL, 1.4 mmol) were added, and the reaction was refluxed. After completion , the reaction solution was washed with saturated copper sulfate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. Add 5 mL of acetic acid to dissolve, add NBS (187 mg, 1.05 mmol), react at 40 ° C overnight, add an equal amount of NBS again, continue to react for 8 hours, concentrate under reduced pressure, and separate by silica gel column chromatography (petroleum ether/ethyl acetate 4/ 1), 45mg was obtained, the yield was 29%.

标题化合物的合成：按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.34(s,1H),7.58–7.44(m,3H),4.68(d,J＝3.9Hz,1H),3.83(tt,J＝7.2,3.7Hz,1H),3.51(tq,J＝7.6,3.6Hz,1H),3.19(ddd,J＝10.6,6.2,3.4Hz,2H),2.75(ddd,J＝11.8,8.3,3.4Hz,2H),1.76(ddt,J＝13.8,7.3,3.6Hz,2H),1.45(dtd,J＝12.3,8.3,3.7Hz,2H),1.25–1.19(m,2H),1.15–1.09(m,2H).13C NMR(101MHz,DMSO-d6)δ150.80(ddd,J＝242.8,10.0,6.0Hz),147.46(d,J＝252.4Hz),144.92(d,J＝2.2Hz),138.64–138.17(m),134.35–131.49(m),131.39(d,J＝13.6Hz),126.93(d,J＝4.4Hz),118.62(d,J＝6.0Hz),118.45(d,J＝3.7Hz),111.37(d,J＝20.7Hz),100.53(d,J＝24.9Hz),64.24,43.75,33.38,31.97(d,J＝2.6Hz),7.81(d,J＝3.0Hz).Synthesis of the title compound: according to the synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 8.34 (s, 1H), 7.58-7.44 (m, 3H), 4.68 (d, J=3.9Hz, 1H), 3.83 (tt, J=7.2, 3.7Hz, 1H), 3.51 (tq, J=7.6, 3.6Hz, 1H), 3.19 (ddd, J=10.6, 6.2, 3.4 Hz,2H),2.75(ddd,J=11.8,8.3,3.4Hz,2H),1.76(ddt,J=13.8,7.3,3.6Hz,2H),1.45(dtd,J=12.3,8.3,3.7Hz, 2H), 1.25–1.19 (m, 2H), 1.15–1.09 (m, 2H). 13 C NMR (101MHz, DMSO-d 6 ) δ 150.80 (ddd, J=242.8, 10.0, 6.0Hz), 147.46 ( d, J＝252.4Hz), 144.92(d, J＝2.2Hz), 138.64-138.17(m), 134.35-131.49(m), 131.39(d, J＝13.6Hz), 126.93(d, J＝4.4Hz ), 118.62(d, J＝6.0Hz), 118.45(d, J＝3.7Hz), 111.37(d, J＝20.7Hz), 100.53(d, J＝24.9Hz), 64.24, 43.75, 33.38, 31.97( d,J=2.6Hz),7.81(d,J=3.0Hz).

实施例7 1-((5-(3-(3,4,5-三氟苯基)氨基)-(1-环丙基)-(6-氟)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：Example 7 1-((5-(3-(3,4,5-trifluorophenyl)amino)-(1-cyclopropyl)-(6-fluoro)-1H-indazolyl)sulfonyl) Synthesis of piperidin-4-ol:

Figure BDA0002385652160000191
Figure BDA0002385652160000191

中间体7-1的合成：将底物(1.25g,10mmol)溶于氯仿，加入NBS(1.96g,11mmol)，室温反应12小时，反应完成后，减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯6/1)，得1.2g，收率60％。Synthesis of intermediate 7-1: The substrate (1.25 g, 10 mmol) was dissolved in chloroform, NBS (1.96 g, 11 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 6/1) to give 1.2 g, yield 60%.

中间体7-2的合成：将中间体7-1(1.2g,6mmol)与10mL水混合，至于冰水浴中冷却，加入亚硝酸钠(621mg,9mmol)、浓盐酸(2.5mL,30mml)，LC/MS监测，待反应完成后，减压蒸干。加氯仿混合，加入乙酸钾(1.17g,12mmol)，室温反应。完成后，减压蒸干，加入水和乙酸乙酯，分取有机相，无水硫酸钠干燥，过滤，减压蒸干。不经进一步纯化，进行下一步Synthesis of intermediate 7-2: Intermediate 7-1 (1.2 g, 6 mmol) was mixed with 10 mL of water, cooled in an ice-water bath, and sodium nitrite (621 mg, 9 mmol) and concentrated hydrochloric acid (2.5 mL, 30 mml) were added, LC/MS monitoring, after the reaction was completed, evaporated to dryness under reduced pressure. Chloroform was added and mixed, potassium acetate (1.17 g, 12 mmol) was added, and the mixture was reacted at room temperature. After completion, it was evaporated to dryness under reduced pressure, water and ethyl acetate were added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Proceed to the next step without further purification

中间体7-3的合成：按中间体3-1的合成方法，两步收率为29％。Synthesis of intermediate 7-3: According to the synthesis method of intermediate 3-1, the two-step yield is 29%.

中间体7-4的合成：按中间体3-2的合成方法，收率70％。Synthesis of intermediate 7-4: According to the synthesis method of intermediate 3-2, the yield is 70%.

中间体7-5的合成：按中间体3-3的合成方法。Synthesis of intermediate 7-5: According to the synthesis method of intermediate 3-3.

中间体7-6的合成：按中间体6-7的合成方法，两步总收率为31％。Synthesis of intermediate 7-6: According to the synthesis method of intermediate 6-7, the total yield of two steps was 31%.

标题化合物的合成：按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.59(d,J＝6.6Hz,1H),7.60(d,J＝11.2Hz,1H),7.53(dd,J＝11.0,6.2Hz,2H),4.71(d,J＝4.0Hz,1H),3.66(p,J＝5.3Hz,1H),3.62–3.51(m,1H),2.89(ddd,J＝12.0,8.3,3.2Hz,2H),1.76(ddt,J＝13.4,7.1,3.5Hz,2H),1.43(dtd,J＝12.5,8.3,3.7Hz,2H),1.13(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ158.3(d,J＝251.3Hz),150.8(ddd,J＝243.0,10.1,6.4Hz),144.9,142.4(d,J＝12.5Hz),138.5(t,J＝12.6Hz),132.8(d,J＝240.9Hz),125.6(d,J＝3.1Hz),117.5(d,J＝19.1Hz),111.5,100.5(d,J＝24.4Hz),97.5(d,J＝27.7Hz),64.5,43.3,33.7,29.8,6.8.Synthesis of the title compound: according to the synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.81 (s, 1H), 8.59 (d, J=6.6 Hz, 1H), 7.60 (d, J =11.2Hz,1H),7.53(dd,J=11.0,6.2Hz,2H),4.71(d,J=4.0Hz,1H),3.66(p,J=5.3Hz,1H),3.62–3.51(m ,1H),2.89(ddd,J＝12.0,8.3,3.2Hz,2H),1.76(ddt,J＝13.4,7.1,3.5Hz,2H),1.43(dtd,J＝12.5,8.3,3.7Hz,2H ), 1.13 (d, J=5.3Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ158.3 (d, J=251.3Hz), 150.8 (ddd, J=243.0, 10.1, 6.4Hz) ,144.9,142.4(d,J＝12.5Hz),138.5(t,J＝12.6Hz),132.8(d,J＝240.9Hz),125.6(d,J＝3.1Hz),117.5(d,J＝19.1 Hz), 111.5, 100.5 (d, J=24.4Hz), 97.5 (d, J=27.7Hz), 64.5, 43.3, 33.7, 29.8, 6.8.

实施例8 1-((5-(3-(3,4,5-三氟苯基)氨基)-(1-环丙基)-(4-氟)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：Example 8 1-((5-(3-(3,4,5-trifluorophenyl)amino)-(1-cyclopropyl)-(4-fluoro)-1H-indazolyl)sulfonyl) Synthesis of piperidin-4-ol:

Figure BDA0002385652160000192
Figure BDA0002385652160000192

中间体8-1的合成：将底物(1.25g,10mmol)溶于乙腈，加入NBS(1.96g,11mmol)，室温反应12小时，反应完成后，减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯4/1)，得1.68g，收率82％。1H NMR(400MHz,Chloroform-d)δ7.13(t,J＝8.1Hz,1H),6.37(dt,J＝8.7,1.2Hz,1H),3.71(s,2H),2.09(t,J＝1.4Hz,3H).Synthesis of intermediate 8-1: The substrate (1.25 g, 10 mmol) was dissolved in acetonitrile, NBS (1.96 g, 11 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, it was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 4/1) to give 1.68 g, 82% yield. 1 H NMR(400MHz, Chloroform-d)δ7.13(t,J=8.1Hz,1H),6.37(dt,J=8.7,1.2Hz,1H),3.71(s,2H),2.09(t,J =1.4Hz,3H).

中间体8-2的合成：按中间体7-2的合成方法，收率86％。Synthesis of intermediate 8-2: According to the synthesis method of intermediate 7-2, the yield is 86%.

中间体8-3的合成：按中间体3-1的合成方法，收率为80％。Synthesis of intermediate 8-3: According to the synthesis method of intermediate 3-1, the yield is 80%.

中间体8-4的合成：按中间体3-2的合成方法，收率45％。Synthesis of intermediate 8-4: According to the synthesis method of intermediate 3-2, the yield is 45%.

中间体8-5的合成：将215mg(0.72mmol)8-4溶解于5ml乙腈，依次加入100μL水和乙酸，将混合液冷却到-15℃，分批加入1,3-二氯-5,5-二甲基海因(284mg,1.44mmol)，-15℃反应1小时。反应液转移到分液漏斗，加入乙酸乙酯稀释和饱和食盐水洗，分取乙酸乙酯层，用无水硫酸钠干燥30min。过滤，减压蒸除乙酸乙酯。加二氯甲烷复溶，加入4-羟基哌啶(144mg,1.4mmol)和三乙胺(0.39ml,2.8mmol),室温反应30分钟，加二氯甲烷稀释，1N盐酸洗，无水硫酸钠干燥，过滤，减压蒸干。加乙酸乙酯复溶，加入乙酰氯(411μL,5.76mmol)、三乙胺(511μL,2.88mmol)，50℃反应，完成，水洗，无水硫酸钠干燥，过滤，减压蒸干，硅胶柱层析分离(石油醚/乙酸乙酯2/1)，得150mg，收率55％。Synthesis of intermediate 8-5: 215 mg (0.72 mmol) of 8-4 was dissolved in 5 ml of acetonitrile, 100 μL of water and acetic acid were added successively, the mixture was cooled to -15°C, and 1,3-dichloro-5 was added in batches, 5-Dimethyl hydantoin (284 mg, 1.44 mmol) was reacted at -15°C for 1 hour. The reaction solution was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filter and evaporate the ethyl acetate under reduced pressure. Add dichloromethane to redissolve, add 4-hydroxypiperidine (144mg, 1.4mmol) and triethylamine (0.39ml, 2.8mmol), react at room temperature for 30 minutes, add dichloromethane to dilute, wash with 1N hydrochloric acid, anhydrous sodium sulfate Dry, filter and evaporate to dryness under reduced pressure. Add ethyl acetate to reconstitute, add acetyl chloride (411 μL, 5.76 mmol), triethylamine (511 μL, 2.88 mmol), react at 50 ° C, complete, wash with water, dry over anhydrous sodium sulfate, filter, evaporate to dryness under reduced pressure, and use a silica gel column Chromatographic separation (petroleum ether/ethyl acetate 2/1) gave 150 mg, yield 55%.

中间体8-6的合成：将中间体8-5(76mg,0.2mmol)溶解于醋酸，加入1,3-二溴-5,5-二甲基海因(86mg,0.3mmol)，40℃反应过夜，减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯2/1)，得64mg,收率70％。Synthesis of Intermediate 8-6: Intermediate 8-5 (76 mg, 0.2 mmol) was dissolved in acetic acid, 1,3-dibromo-5,5-dimethylhydantoin (86 mg, 0.3 mmol) was added, 40°C The reaction was carried out overnight, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain 64 mg with a yield of 70%.

标题化合物的合成：按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),7.68(dd,J＝8.9,6.2Hz,1H),7.59(dd,J＝11.2,6.3Hz,2H),7.55(d,J＝8.9Hz,1H),4.71(d,J＝4.0Hz,1H),3.73(tt,J＝7.0,4.0Hz,1H),3.56(dq,J＝8.1,4.1Hz,1H),3.28(dt,J＝11.3,4.7Hz,2H),2.88(ddd,J＝11.9,8.8,3.2Hz,2H),1.82–1.71(m,2H),1.45(dtd,J＝12.3,8.1,3.7Hz,2H),1.20–1.11(m,4H).13C NMR(101MHz,DMSO-d6)δ153.3(d,J＝263.6Hz),152.0–149.0(m),145.4(d,J＝8.7Hz),142.5(d,J＝2.2Hz),139.0,129.3,113.4(d,J＝11.3Hz),106.8(d,J＝3.9Hz),105.1(d,J＝20.1Hz),101.1(d,J＝24.9Hz),64.3,43.5,33.5,29.9,6.9.Synthesis of the title compound: according to the synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.06 (s, 1H), 7.68 (dd, J=8.9, 6.2 Hz, 1H), 7.59 (dd , J=11.2, 6.3Hz, 2H), 7.55 (d, J=8.9Hz, 1H), 4.71 (d, J=4.0Hz, 1H), 3.73 (tt, J=7.0, 4.0Hz, 1H), 3.56 (dq, J=8.1, 4.1Hz, 1H), 3.28 (dt, J=11.3, 4.7Hz, 2H), 2.88 (ddd, J=11.9, 8.8, 3.2Hz, 2H), 1.82–1.71 (m, 2H) ), 1.45 (dtd, J=12.3, 8.1, 3.7Hz, 2H), 1.20–1.11 (m, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ153.3 (d, J=263.6Hz), 152.0–149.0(m), 145.4(d, J=8.7Hz), 142.5(d, J=2.2Hz), 139.0, 129.3, 113.4(d, J=11.3Hz), 106.8(d, J=3.9Hz) ,105.1(d,J＝20.1Hz),101.1(d,J＝24.9Hz),64.3,43.5,33.5,29.9,6.9.

实施例9 1-((5-(3-(3,4,5-三氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-b]吡啶基)磺酰基)哌啶-4-醇的合成：Example 9 1-((5-(3-(3,4,5-trifluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo[3,4-b]pyridinyl) Synthesis of sulfonyl)piperidin-4-ol:

Figure BDA0002385652160000201
Figure BDA0002385652160000201

中间体9-1的合成：按中间体3-1的合成方法，收率42％。Synthesis of intermediate 9-1: According to the synthesis method of intermediate 3-1, the yield is 42%.

中间体9-2的合成：按中间体3-2的合成方法。Synthesis of intermediate 9-2: According to the synthesis method of intermediate 3-2.

中间体9-3的合成：按中间体8-5的合成方法，两步总收率为73％。Synthesis of intermediate 9-3: According to the synthesis method of intermediate 8-5, the total yield of two steps was 73%.

中间体9-4的合成：按中间体8-6的合成方法，收率41％。Synthesis of intermediate 9-4: According to the synthesis method of intermediate 8-6, the yield is 41%.

标题化合物的合成：按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.82(d,J＝2.1Hz,1H),8.80(d,J＝2.1Hz,1H),7.49(dd,J＝10.8,6.2Hz,2H),4.68(d,J＝4.0Hz,1H),3.82(tt,J＝7.3,3.7Hz,1H),3.51(tq,J＝7.5,3.6Hz,1H),3.20(ddd,J＝13.1,6.1,3.0Hz,2H),2.76(ddd,J＝11.8,8.6,3.3Hz,2H),1.77(ddt,J＝13.5,6.6,3.5Hz,2H),1.45(dtd,J＝12.3,8.0,3.5Hz,2H),1.25–1.18(m,2H),1.18–1.10(m,2H).13C NMR(101MHz,DMSO-d6)δ151.11,150.84(ddd,J＝243.0,10.0,5.8Hz),148.62,143.57,138.15(td,J＝12.3,2.8Hz),133.02(dt,J＝240.5,15.9Hz),131.49,123.75,107.26,100.66(d,J＝24.3Hz),64.24,43.69,33.37,29.17,6.61.Synthesis of the title compound: according to the synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.82 (d, J=2.1 Hz, 1H), 8.80 (d, J =2.1Hz,1H),7.49(dd,J=10.8,6.2Hz,2H),4.68(d,J=4.0Hz,1H),3.82(tt,J=7.3,3.7Hz,1H),3.51(tq , J=7.5, 3.6Hz, 1H), 3.20 (ddd, J=13.1, 6.1, 3.0Hz, 2H), 2.76 (ddd, J=11.8, 8.6, 3.3Hz, 2H), 1.77 (ddt, J=13.5 , 6.6, 3.5Hz, 2H), 1.45 (dtd, J=12.3, 8.0, 3.5Hz, 2H), 1.25–1.18 (m, 2H), 1.18–1.10 (m, 2H). 13 C NMR (101MHz, DMSO) -d 6 )δ151.11,150.84(ddd,J=243.0,10.0,5.8Hz),148.62,143.57,138.15(td,J=12.3,2.8Hz),133.02(dt,J=240.5,15.9Hz),131.49, 123.75, 107.26, 100.66 (d, J=24.3Hz), 64.24, 43.69, 33.37, 29.17, 6.61.

实施例10 1-((5-(3-(3,4,5-三氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶-4-醇的合成：Example 10 1-((5-(3-(3,4,5-trifluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo[3,4-c]pyridyl) Synthesis of sulfonyl)piperidin-4-ol:

Figure BDA0002385652160000211
Figure BDA0002385652160000211

中间体10-1的合成：1.36g(6.3mmol)底物溶于四氢呋喃，加入Raney Ni，在氢气环境下，室温反应过夜。过滤，减压蒸干。Synthesis of intermediate 10-1: 1.36 g (6.3 mmol) of the substrate was dissolved in tetrahydrofuran, Raney Ni was added, and the reaction was carried out at room temperature overnight under a hydrogen atmosphere. Filter and evaporate to dryness under reduced pressure.

中间体10-2的合成：上述产物溶于四氢呋喃，加入乙酸酐(964μL,9.45mmol)，回流反应过夜，反应完成后，减压蒸干。Synthesis of intermediate 10-2: The above product was dissolved in tetrahydrofuran, acetic anhydride (964 μL, 9.45 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, evaporated to dryness under reduced pressure.

中间体10-3的合成：上述产物溶于甲苯，依次加入乙酸酐(2.55mL,25mmol)、亚硝酸异戊酯(1.47g,12.6mmol)、乙酸钾(1.86g,19mmol)、18-冠-6(166mg,0.63mmol)，80℃反应，完成后，加乙酸乙酯稀释，水洗，无水硫酸钠干燥，过滤，减压蒸干。加10mL四氢呋喃和水溶解，加入氢氧化钠(1.2g,30mmol)，室温反应，完成后，减压蒸除四氢呋喃，2N盐酸调pH到5-6，有固体析出，过滤，干燥。549mg，三步总收率44％。Synthesis of intermediate 10-3: The above product was dissolved in toluene, followed by adding acetic anhydride (2.55mL, 25mmol), isoamyl nitrite (1.47g, 12.6mmol), potassium acetate (1.86g, 19mmol), 18-crown -6 (166 mg, 0.63 mmol), reacted at 80 °C, after completion, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Add 10 mL of tetrahydrofuran and water to dissolve, add sodium hydroxide (1.2 g, 30 mmol), and react at room temperature. After completion, the tetrahydrofuran is evaporated under reduced pressure, and the pH is adjusted to 5-6 with 2N hydrochloric acid. 549mg, the three-step total yield is 44%.

中间体10-4的合成：按中间体3-1的合成方法。Synthesis of intermediate 10-4: According to the synthesis method of intermediate 3-1.

中间体10-5的合成：按中间体3-2的合成方法。Synthesis of intermediate 10-5: According to the synthesis method of intermediate 3-2.

中间体10-6的合成：按中间体8-5的合成方法，收率60％。Synthesis of intermediate 10-6: According to the synthesis method of intermediate 8-5, the yield is 60%.

中间体10-7的合成：按中间体8-6的合成方法，收率49％。Synthesis of intermediate 10-7: According to the synthesis method of intermediate 8-6, the yield is 49%.

标题化合物的合成：按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),9.15(s,1H),8.62(s,1H),7.48(dd,J＝10.9,6.1Hz,2H),4.69(d,J＝3.9Hz,1H),3.84(dq,J＝6.9,3.5,3.0Hz,1H),3.63–3.48(m,2H),3.41(dt,J＝11.4,4.5Hz,2H),2.94(ddd,J＝12.2,8.8,3.4Hz,2H),1.83–1.67(m,2H),1.52–1.33(m,2H),1.23–1.16(m,4H).13C NMR(101MHz,DMSO-d6)δ150.83(ddd,J＝242.6,10.0,5.8Hz),144.60,143.90,138.94–137.93(m),137.46,134.84,132.90(d,J＝240.7Hz),118.74,116.43,100.48(d,J＝24.7Hz),64.77,44.16,33.76,30.30,6.94.Synthesis of the title compound: according to the synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.86 (s, 1H), 9.15 (s, 1H), 8.62 (s, 1H), 7.48 (dd , J＝10.9, 6.1Hz, 2H), 4.69(d, J＝3.9Hz, 1H), 3.84(dq, J＝6.9, 3.5, 3.0Hz, 1H), 3.63–3.48(m, 2H), 3.41( dt, J=11.4, 4.5Hz, 2H), 2.94 (ddd, J=12.2, 8.8, 3.4Hz, 2H), 1.83–1.67 (m, 2H), 1.52–1.33 (m, 2H), 1.23–1.16 ( m, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 150.83 (ddd, J=242.6, 10.0, 5.8Hz), 144.60, 143.90, 138.94-137.93 (m), 137.46, 134.84, 132.90 (d , J=240.7Hz), 118.74, 116.43, 100.48 (d, J=24.7Hz), 64.77, 44.16, 33.76, 30.30, 6.94.

实施例11 1-((5-(3-(3,4,5-三氟苯基)氨基)-(1-环丙基)-1H-吲唑并[4,3-b]吡啶基)磺酰基)哌啶-4-醇的合成：Example 11 1-((5-(3-(3,4,5-trifluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo[4,3-b]pyridyl) Synthesis of sulfonyl)piperidin-4-ol:

Figure BDA0002385652160000212
Figure BDA0002385652160000212

中间体11-1的合成：按中间体10-3的合成方法，三步总收率为67％。Synthesis of intermediate 11-1: According to the synthesis method of intermediate 10-3, the total yield of three steps is 67%.

中间体11-3的合成：按3-2的合成方法，两步总收率为66％。Synthesis of intermediate 11-3: According to the synthesis method of 3-2, the total yield of two steps is 66%.

中间体11-4的合成：按中间体8-5的合成方法，收率60％。Synthesis of intermediate 11-4: According to the synthesis method of intermediate 8-5, the yield is 60%.

中间体11-5的合成：按中间体8-6的合成方法，收率63％。Synthesis of intermediate 11-5: According to the synthesis method of intermediate 8-6, the yield is 63%.

标题化合物的合成：按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.25(d,J＝8.8Hz,1H),7.94(d,J＝8.8Hz,1H),7.72(dd,J＝11.2,6.2Hz,2H),4.69(d,J＝4.0Hz,1H),3.81–3.67(m,1H),3.59–3.46(m,1H),3.41(dd,J＝12.4,5.6Hz,2H),2.95(ddd,J＝12.2,8.8,3.3Hz,2H),1.73(ddt,J＝13.6,7.0,3.6Hz,2H),1.40(dtd,J＝12.6,8.6,3.8Hz,2H),1.15(d,J＝5.2Hz,4H).Synthesis of the title compound: according to the synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.67 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.94 (d, J = 8.8Hz, 1H), 7.72 (dd, J = 11.2, 6.2Hz, 2H), 4.69 (d, J = 4.0Hz, 1H), 3.81–3.67 (m, 1H), 3.59–3.46 (m, 1H) ,3.41(dd,J＝12.4,5.6Hz,2H),2.95(ddd,J＝12.2,8.8,3.3Hz,2H),1.73(ddt,J＝13.6,7.0,3.6Hz,2H),1.40(dtd , J=12.6, 8.6, 3.8Hz, 2H), 1.15(d, J=5.2Hz, 4H).

实施例12 1-((5-(3-(3,4,5-三氟苯基)氨基)-(1-(3-氧杂环丁基))-1H-吲唑基)磺酰基)哌啶-4-醇的合成：Example 12 1-((5-(3-(3,4,5-trifluorophenyl)amino)-(1-(3-oxetanyl))-1H-indazolyl)sulfonyl) Synthesis of piperidin-4-ol:

Figure BDA0002385652160000221
Figure BDA0002385652160000221

4-甲基苯磺酸(3-氧杂环丁)酯(12-1)的合成：3-氧杂环丁醇(222mg,3mmol)溶于二氯甲烷中，加入对甲苯磺酰氯(860mg,4.5mmol)、三乙胺(832μL,6mmol)、DMAP(36mg,0.3mmol)，室温反应2小时。反应液减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯4/1)，得648mg，收率95％。Synthesis of (3-oxetane) 4-methylbenzenesulfonate (12-1): 3-oxetanol (222mg, 3mmol) was dissolved in dichloromethane, p-toluenesulfonyl chloride (860mg) was added , 4.5 mmol), triethylamine (832 μL, 6 mmol), DMAP (36 mg, 0.3 mmol), and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 4/1) to obtain 648 mg with a yield of 95%.

1-(3-氧杂环丁基)-5-溴-1H-吲唑(12-2)的合成：5-溴-1H-吲唑(329mg,1.67mmol)溶于15mL DMF，依次加入12-1(570mg,2.5mmol)，K2CO3(691mg,5mmol)，110℃反应12小时，过滤，减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯4/1)。Synthesis of 1-(3-oxetanyl)-5-bromo-1H-indazole (12-2): 5-bromo-1H-indazole (329 mg, 1.67 mmol) was dissolved in 15 mL of DMF, followed by the addition of 12 -1 (570 mg, 2.5 mmol), K 2 CO 3 (691 mg, 5 mmol), reacted at 110° C. for 12 hours, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 4/1).

5-(苄硫基)-1-(3-氧杂环丁基)-1H-吲唑(12-3)的合成：将上述产物溶于10mL 1,4-二氧六环，加入Pd2(dba)3(76mg,0.083mmol)、Xantphos(96mg,0.17mmol)、DIPEA(550μL,3.34mmol)、苄硫醇(310mg,2.5mmol)，用氩气将瓶内的气体置换三次，加热到90℃，反应4小时。LC-MS检测反应液，反应完成后，冷却，过滤，滤液减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯10/1)，得453mg黄色油状物，两步收率为92％。Synthesis of 5-(benzylthio)-1-(3-oxetanyl)-1H-indazole (12-3): The above product was dissolved in 10 mL of 1,4 - dioxane, Pd was added (dba) 3 (76 mg, 0.083 mmol), Xantphos (96 mg, 0.17 mmol), DIPEA (550 μL, 3.34 mmol), benzyl mercaptan (310 mg, 2.5 mmol), replace the gas in the bottle three times with argon, and heat to 90°C, the reaction was carried out for 4 hours. The reaction solution was detected by LC-MS. After the reaction was completed, it was cooled, filtered, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to obtain 453 mg of yellow oil with a two-step yield of 92% .

1-((5-(3-氧杂环丁基)-1H-吲唑基)磺酰基)哌啶-4-醇(12-4)的合成：将296mg(1.0mmol)12-3溶解于10ml乙腈，依次加入100μL水和乙酸，将混合液冷却到-15℃，分批加入1,3-二氯-5,5-二甲基海因(394mg,2.0mmol)，反应1小时。反应液转移到分液漏斗中，加入乙酸乙酯稀释和饱和食盐水洗，分取乙酸乙酯层，用无水硫酸钠干燥30min。过滤，减压蒸除乙酸乙酯。加二氯甲烷溶解，加入4-羟基哌啶(200mg,2.0mmol)和三乙胺(0.41ml,3mmol),室温反应30分钟，加二氯甲烷稀释，1N盐酸洗，无水硫酸钠干燥，硅胶柱层析分离(二氯甲烷/甲醇30/1)，得310mg，收率92％。Synthesis of 1-((5-(3-oxetanyl)-1H-indazolyl)sulfonyl)piperidin-4-ol (12-4): 296 mg (1.0 mmol) of 12-3 were dissolved in 10 ml of acetonitrile, 100 μL of water and acetic acid were added successively, the mixture was cooled to -15° C., 1,3-dichloro-5,5-dimethylhydantoin (394 mg, 2.0 mmol) was added in batches, and the reaction was carried out for 1 hour. The reaction solution was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filter and evaporate the ethyl acetate under reduced pressure. Add dichloromethane to dissolve, add 4-hydroxypiperidine (200mg, 2.0mmol) and triethylamine (0.41ml, 3mmol), react at room temperature for 30 minutes, add dichloromethane to dilute, wash with 1N hydrochloric acid, dry over anhydrous sodium sulfate, It was separated by silica gel column chromatography (dichloromethane/methanol 30/1) to obtain 310 mg with a yield of 92%.

乙酸-4-(1-(5-(3-溴-1-(3-氧杂环丁基)-1H-吲唑基)磺酰基)哌啶)酯(12-6)的合成：将12-6(232mg,0.69mmol)溶于10mL乙酸乙酯，加入乙酰氯(217mg,2.76mmol)、三乙胺(379μL,2.76mmol)，50℃反应，反应完成后，减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯2/3)，的中间体12-5 71mg。将12-5(71mg,0.19mmol)溶于2mL乙腈和2mL冰醋酸的混合溶液，加入NBS(64mg,0.36mmol)，50℃反应，LC-MS监测反应，完成后，减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯1/1)，得46mg，两步收率为14％。Synthesis of acetate-4-(1-(5-(3-bromo-1-(3-oxetanyl)-1H-indazolyl)sulfonyl)piperidine)ester (12-6): 12 -6 (232 mg, 0.69 mmol) was dissolved in 10 mL of ethyl acetate, added with acetyl chloride (217 mg, 2.76 mmol), triethylamine (379 μL, 2.76 mmol), and reacted at 50 ° C. After the reaction was completed, concentrated under reduced pressure, silica gel column layer Isolated (petroleum ether/ethyl acetate 2/3), 71 mg of intermediate 12-5. 12-5 (71 mg, 0.19 mmol) was dissolved in a mixed solution of 2 mL of acetonitrile and 2 mL of glacial acetic acid, NBS (64 mg, 0.36 mmol) was added, the reaction was carried out at 50 °C, and the reaction was monitored by LC-MS. Chromatographic separation (petroleum ether/ethyl acetate 1/1) gave 46 mg with a two-step yield of 14%.

标题化合物的合成：按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.54(s,1H),7.79(d,J＝8.9Hz,1H),7.71(d,J＝9.0Hz,1H),7.65(dd,J＝11.0,6.2Hz,2H),6.06(p,J＝7.0Hz,1H),5.09(t,J＝6.4Hz,2H),4.99(t,J＝7.1Hz,2H),4.63(d,J＝3.8Hz,1H),3.49(dq,J＝7.9,4.2Hz,1H),3.23–3.04(m,2H),2.83–2.61(m,2H),1.73(s,2H),1.43(dtd,J＝12.3,8.2,3.6Hz,2H).Synthesis of the title compound: according to the synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.54 (s, 1H), 7.79 (d, J=8.9 Hz, 1H ),7.71(d,J＝9.0Hz,1H),7.65(dd,J＝11.0,6.2Hz,2H),6.06(p,J＝7.0Hz,1H),5.09(t,J＝6.4Hz,2H ),4.99(t,J=7.1Hz,2H),4.63(d,J=3.8Hz,1H),3.49(dq,J=7.9,4.2Hz,1H),3.23–3.04(m,2H),2.83 –2.61(m,2H),1.73(s,2H),1.43(dtd,J=12.3,8.2,3.6Hz,2H).

实施例13N-仲丁基-5-(1-环丙基-3-((3,4,5-三氟苯基)氨基)-1H-吲唑)磺酰胺的合成：Example 13 Synthesis of N-sec-butyl-5-(1-cyclopropyl-3-((3,4,5-trifluorophenyl)amino)-1H-indazole)sulfonamide:

Figure BDA0002385652160000231
Figure BDA0002385652160000231

N-仲丁基-5-(1-环丙基-1H-吲唑)磺酰胺(13-1)的合成：将140mg(0.5mmol)3-2溶解于10ml乙腈，依次加入100μL水和乙酸，将混合液冷却到-15℃，分批加入1,3-二氯-5,5-二甲基海因(197,1mmol)，将反-15℃下反应1小时。反应液转移到分液漏斗，加入乙酸乙酯稀释和饱和食盐水洗，分取乙酸乙酯层，用无水硫酸钠干燥30min。过滤，减压蒸除乙酸乙酯。加二氯甲烷复溶，异丁胺(100μL,1mmol)和三乙胺(277μL,2mmol),室温反应30分钟，加二氯甲烷稀释，1N盐酸洗，无水硫酸钠干燥，硅胶柱层析分离，得116mg，收率80％。Synthesis of N-sec-butyl-5-(1-cyclopropyl-1H-indazole)sulfonamide (13-1): 140 mg (0.5 mmol) of 3-2 was dissolved in 10 ml of acetonitrile, followed by adding 100 μL of water and acetic acid , the mixture was cooled to -15°C, 1,3-dichloro-5,5-dimethylhydantoin (197,1 mmol) was added in batches, and the reaction was conducted at -15°C for 1 hour. The reaction solution was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filter and evaporate the ethyl acetate under reduced pressure. Add dichloromethane to redissolve, isobutylamine (100 μL, 1 mmol) and triethylamine (277 μL, 2 mmol), react at room temperature for 30 minutes, add dichloromethane to dilute, wash with 1N hydrochloric acid, dry with anhydrous sodium sulfate, and perform silica gel column chromatography After separation, 116 mg was obtained, and the yield was 80%.

N-仲丁基-5-(1-环丙基-3-溴-1H-吲唑)磺酰胺(13-2)的合成：将13-1(117mg,0.4mmol)溶于4mL乙腈和2mL乙酸的混合溶液，加入NBS(142mg,0.8mmol)，室温反应，完成后，加乙酸乙酯稀释，依次用水、饱和食盐水洗，硅胶柱层析分离(石油醚/乙酸乙酯2/1)，得110mg，收率74％。Synthesis of N-sec-butyl-5-(1-cyclopropyl-3-bromo-1H-indazole)sulfonamide (13-2): 13-1 (117 mg, 0.4 mmol) was dissolved in 4 mL acetonitrile and 2 mL The mixed solution of acetic acid was added with NBS (142 mg, 0.8 mmol), reacted at room temperature, after completion, diluted with ethyl acetate, washed with water and saturated brine in turn, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1), 110 mg was obtained, the yield was 74%.

标题化合物的合成：在反应瓶中依次加入13-2(37mg,0.1mol)、3,4,5-三氟苯胺(22mg,0.15mmol)、Pd(OAc)2(2.2mg,0.01mmol)、Xantphos(5.7mg,0.01mmol)、Cs2CO3(65mg,0.2mmol)和1,4-二氧六环(2ml)，用氩气将反应瓶内的气体置换三次，130℃反应3小时。反应完成后，冷却，过滤，滤液减压浓缩。加1mL甲醇，有白色固体析出，过滤，得30mg目标物，收率68％。1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.55(d,J＝1.6Hz,1H),7.81(dd,J＝8.9,1.7Hz,1H),7.74(d,J＝8.9Hz,1H),7.56(dd,J＝11.1,6.2Hz,2H),7.44(d,J＝7.7Hz,1H),3.68(ddd,J＝10.6,7.2,4.5Hz,1H),3.02(p,J＝6.7Hz,1H),1.30(p,J＝7.2Hz,2H),1.14(dd,J＝7.2,2.5Hz,4H),0.85(d,J＝6.6Hz,3H),0.70(t,J＝7.4Hz,3H).Synthesis of the title compound: 13-2 (37 mg, 0.1 mol), 3,4,5-trifluoroaniline (22 mg, 0.15 mmol), Pd(OAc) 2 (2.2 mg, 0.01 mmol), Pd(OAc) 2 (2.2 mg, 0.01 mmol), Xantphos (5.7 mg, 0.01 mmol), Cs 2 CO 3 (65 mg, 0.2 mmol) and 1,4-dioxane (2 ml), replaced the gas in the reaction flask with argon three times, and reacted at 130° C. for 3 hours. After the reaction was completed, it was cooled, filtered, and the filtrate was concentrated under reduced pressure. 1 mL of methanol was added, and a white solid was precipitated, which was filtered to obtain 30 mg of the target compound with a yield of 68%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.55 (d, J=1.6 Hz, 1H), 7.81 (dd, J=8.9, 1.7 Hz, 1H), 7.74 (d, J=8.9Hz, 1H), 7.56 (dd, J=11.1, 6.2Hz, 2H), 7.44 (d, J=7.7Hz, 1H), 3.68 (ddd, J=10.6, 7.2, 4.5Hz, 1H), 3.02(p,J＝6.7Hz,1H),1.30(p,J＝7.2Hz,2H),1.14(dd,J＝7.2,2.5Hz,4H),0.85(d,J＝6.6Hz,3H), 0.70(t,J=7.4Hz,3H).

实施例14N-(2-羟基乙基)-5-(1-环丙基-3-((3,4,5-三氟苯基)氨基)-1H-吲唑)磺酰胺的合成：Example 14 Synthesis of N-(2-hydroxyethyl)-5-(1-cyclopropyl-3-((3,4,5-trifluorophenyl)amino)-1H-indazole)sulfonamide:

Figure BDA0002385652160000232
Figure BDA0002385652160000232

乙酸-2-(5-(3-溴-1-环丙基-1H-吲唑基)磺酰胺基)乙酯(14-2)的合成：按照化合物3-4的合成方法，三步收率42％。Synthesis of acetate-2-(5-(3-bromo-1-cyclopropyl-1H-indazolyl)sulfonamido)ethyl ester (14-2): According to the synthetic method of compound 3-4, three steps rate 42%.

标题化合物的合成：按照实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.55(s,1H),7.80(d,J＝9.0Hz,1H),7.74(d,J＝8.9Hz,1H),7.56(dd,J＝11.1,6.2Hz,2H),7.49(t,J＝6.0Hz,1H),4.65(t,J＝5.6Hz,1H),3.67(tt,J＝6.9,4.1Hz,1H),3.40–3.34(m,2H),2.77(q,J＝6.3Hz,2H),1.14(t,J＝5.3Hz,4H).Synthesis of the title compound: according to the synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 8.55 (s, 1H), 7.80 (d, J=9.0 Hz, 1H ),7.74(d,J＝8.9Hz,1H),7.56(dd,J＝11.1,6.2Hz,2H),7.49(t,J＝6.0Hz,1H),4.65(t,J＝5.6Hz,1H) ), 3.67 (tt, J=6.9, 4.1Hz, 1H), 3.40–3.34 (m, 2H), 2.77 (q, J=6.3Hz, 2H), 1.14 (t, J=5.3Hz, 4H).

实施例15N,N-二甲基-5-(1-环丙基-3-((3,4,5-三氟苯基)氨基)-1H-吲唑)磺酰胺的合成：Example 15 Synthesis of N,N-dimethyl-5-(1-cyclopropyl-3-((3,4,5-trifluorophenyl)amino)-1H-indazole)sulfonamide:

Figure BDA0002385652160000241
Figure BDA0002385652160000241

中间体15-2的合成：按照13-2的合成方法，两步总收率为67％。Synthesis of intermediate 15-2: According to the synthesis method of 13-2, the total yield of two steps was 67%.

标题化合物的合成：按照实施例3的合成方法。Synthesis of the title compound: The synthesis method of Example 3 was followed.

实施例16N-(4-羟基环己基)-5-(1-环丙基-3-((3,4,5-三氟苯基)氨基)-1H-吲唑)磺酰胺的合成：Example 16 Synthesis of N-(4-hydroxycyclohexyl)-5-(1-cyclopropyl-3-((3,4,5-trifluorophenyl)amino)-1H-indazole)sulfonamide:

Figure BDA0002385652160000242
Figure BDA0002385652160000242

N-(4-羟基环己基)-5-(1-环丙基-1H-吲唑)磺酰胺(16-1)的合成：将140mg(0.5mmol)3-2溶解于5ml乙腈，依次加入100μL水和乙酸，将混合液冷却到-15℃，分批加入1,3-二氯-5,5-二甲基海因(197mg,1mmol)，反应1小时。将4-氨基环己醇(115mg,1mmol)和三乙胺(206μL,1.5mmol)溶于2mL乙腈，加入到上述反应液中，室温反应。待反应完成后，加二氯甲烷稀释，依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸除二氯甲烷，不经进一步纯化，进行下一步反应。Synthesis of N-(4-hydroxycyclohexyl)-5-(1-cyclopropyl-1H-indazole)sulfonamide (16-1): 140 mg (0.5 mmol) of 3-2 was dissolved in 5 ml of acetonitrile, followed by adding 100 μL of water and acetic acid, the mixture was cooled to -15° C., 1,3-dichloro-5,5-dimethylhydantoin (197 mg, 1 mmol) was added in batches, and the reaction was carried out for 1 hour. 4-Aminocyclohexanol (115 mg, 1 mmol) and triethylamine (206 μL, 1.5 mmol) were dissolved in 2 mL of acetonitrile, added to the above reaction solution, and reacted at room temperature. After the reaction was completed, dichloromethane was added to dilute, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and dichloromethane was evaporated under reduced pressure, and the next step was carried out without further purification.

乙酸-4-((5-(1-环丙基-3-溴-1H-吲唑))磺酰胺)环己酯(16-2)的合成：将上述产物溶于10mL乙酸乙酯，加入乙酸酐(200μL,2mmol)、吡啶(200μL,2.5mmol)，回流反应过夜。反应完成后，依次用饱和硫酸铜溶液、饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸除乙酸乙酯。向上述产物中加入6mL乙腈、3mL醋酸、178mg NBS，50℃反应1小时。反应液用饱和碳酸氢钠溶液洗，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析分离，得60mg，三步总收率为26％。Synthesis of acetic acid-4-((5-(1-cyclopropyl-3-bromo-1H-indazole))sulfonamide)cyclohexyl ester (16-2): The above product was dissolved in 10 mL of ethyl acetate, added Acetic anhydride (200 μL, 2 mmol), pyridine (200 μL, 2.5 mmol), refluxed overnight. After the reaction was completed, it was washed with saturated copper sulfate solution and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and the ethyl acetate was evaporated under reduced pressure. To the above product were added 6 mL of acetonitrile, 3 mL of acetic acid, and 178 mg of NBS, and reacted at 50°C for 1 hour. The reaction solution was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 60 mg, with a total yield of 26% in three steps.

标题化合物的合成：按化合物3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.55(s,1H),7.81(d,J＝8.8Hz,1H),7.73(d,J＝9.0Hz,1H),7.55(dd,J＝10.1,5.7Hz,3H),4.46(d,J＝4.3Hz,1H),3.67(p,J＝5.0Hz,1H),3.26(q,J＝8.8Hz,1H),2.97–2.76(m,1H),1.80–1.63(m,2H),1.57(d,J＝12.5Hz,2H),1.26–1.08(m,6H),1.09–0.91(m,2H).13CNMR(101MHz,DMSO-d6)δ150.85(ddd,J＝242.2,9.6,5.6Hz),144.65,141.63,138.86(t,J＝12.3Hz),133.18,132.66(dt,J＝240.0,15.6Hz),125.54,120.98,114.20,110.92,100.34(d,J＝24.6Hz),68.03,52.13,34.09,31.44,29.67,6.84.Synthesis of the title compound: according to the synthesis method of compound 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.55 (s, 1H), 7.81 (d, J=8.8 Hz, 1H) ,7.73(d,J＝9.0Hz,1H),7.55(dd,J＝10.1,5.7Hz,3H),4.46(d,J＝4.3Hz,1H),3.67(p,J＝5.0Hz,1H) ,3.26(q,J＝8.8Hz,1H),2.97-2.76(m,1H),1.80-1.63(m,2H),1.57(d,J＝12.5Hz,2H),1.26-1.08(m,6H) ), 1.09–0.91 (m, 2H). 13 CNMR (101MHz, DMSO-d 6 ) δ150.85 (ddd, J=242.2, 9.6, 5.6Hz), 144.65, 141.63, 138.86 (t, J=12.3Hz) ,133.18,132.66(dt,J＝240.0,15.6Hz),125.54,120.98,114.20,110.92,100.34(d,J＝24.6Hz),68.03,52.13,34.09,31.44,29.67,6.84.

实施例17N-(3,4,5-三氟苯基)-3-(1-环丙基-5-(吗啉磺酰基)-1H-吲唑)胺的合成：Example 17 Synthesis of N-(3,4,5-trifluorophenyl)-3-(1-cyclopropyl-5-(morpholinesulfonyl)-1H-indazol)amine:

按照实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.53(s,1H),7.78(d,J＝8.9Hz,1H),7.73(dd,J＝8.9,1.6Hz,1H),7.57(dd,J＝11.1,6.2Hz,2H),3.71(td,J＝6.5,3.3Hz,1H),3.65(t,J＝4.7Hz,4H),2.89(q,J＝5.5,4.6Hz,4H),1.16(t,J＝4.8Hz,4H).According to the synthesis method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.80 (s, 1H), 8.53 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.73 (dd , J=8.9, 1.6Hz, 1H), 7.57 (dd, J=11.1, 6.2Hz, 2H), 3.71 (td, J=6.5, 3.3Hz, 1H), 3.65 (t, J=4.7Hz, 4H) ,2.89(q,J＝5.5,4.6Hz,4H),1.16(t,J＝4.8Hz,4H).

Figure BDA0002385652160000243
Figure BDA0002385652160000243

实施例18N-(4-(四氢-2H-吡喃))-5-(1-环丙基-3-((3,4,5-三氟苯基)氨基)-1H-吲唑)磺酰胺的合成：Example 18 N-(4-(tetrahydro-2H-pyran))-5-(1-cyclopropyl-3-((3,4,5-trifluorophenyl)amino)-1H-indazole) Synthesis of Sulfonamides:

按照实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.57(s,1H),7.88–7.79(m,1H),7.73(dd,J＝8.1,3.5Hz,2H),7.55(dd,J＝11.1,6.1Hz,2H),3.78–3.62(m,3H),3.26–3.06(m,3H),1.57–1.43(m,2H),1.43–1.27(m,2H),1.19–1.04(m,4H).13C NMR(101MHz,DMSO-d6)δ150.89(dd,J＝240.7,7.6Hz),144.66,141.65,138.82(t,J＝11.4Hz),133.11,135.14–130.82(m),125.53,121.09,114.21,111.02,100.34(d,J＝24.5Hz),66.00,49.69,33.72,29.67,6.86.According to the synthetic method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.57 (s, 1H), 7.88-7.79 (m, 1H), 7.73 (dd, J= 8.1, 3.5Hz, 2H), 7.55 (dd, J=11.1, 6.1Hz, 2H), 3.78–3.62 (m, 3H), 3.26–3.06 (m, 3H), 1.57–1.43 (m, 2H), 1.43 -1.27(m, 2H), 1.19-1.04(m, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 150.89 (dd, J=240.7, 7.6Hz), 144.66, 141.65, 138.82 (t, J=11.4Hz), 133.11, 135.14–130.82 (m), 125.53, 121.09, 114.21, 111.02, 100.34 (d, J=24.5Hz), 66.00, 49.69, 33.72, 29.67, 6.86.

Figure BDA0002385652160000251
Figure BDA0002385652160000251

实施例19N-(3,4,5-三氟苯基)-3-(1-环丙基-5-((1-哌啶基)磺酰基)-1H-吲唑)胺的合成：Example 19 Synthesis of N-(3,4,5-trifluorophenyl)-3-(1-cyclopropyl-5-((1-piperidinyl)sulfonyl)-1H-indazol)amine:

中间体19-2的合成：按13-2的合成方法，两步总收率为68％。Synthesis of intermediate 19-2: According to the synthesis method of 13-2, the total yield of two steps is 68%.

标题化合物的合成：按实施例13的合成方法。Synthesis of the title compound: as in Example 13.

实施例20-37的合成：按实施例3的合成方法Synthesis of Examples 20-37: According to the synthetic method of Example 3

Figure BDA0002385652160000253
Figure BDA0002385652160000253

实施例20 4-(1-((5-(3-(4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇的合成：按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.58(d,J＝1.3Hz,1H),7.79–7.72(m,2H),7.70(d,J＝1.2Hz,2H),7.21–7.13(m,2H),4.69(s,1H),3.65(p,J＝5.3Hz,1H),3.51(tt,J＝7.6,3.6Hz,1H),3.18–3.11(m,2H),2.72(ddd,J＝11.8,8.4,3.4Hz,2H),1.76(ddt,J＝13.5,6.8,2.9Hz,2H),1.45(dtd,J＝12.0,7.8,3.6Hz,2H),1.13(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.48(d,J＝235.7Hz),145.65,142.08,138.99(d,J＝2.1Hz),126.06(d,J＝26.0Hz),122.77,117.78(d,J＝7.4Hz),115.84,115.63,115.14,110.22,64.25,43.72,33.37,29.57,6.87.Example 20 Synthesis of 4-(1-((5-(3-(4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)ol: press Synthesis method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.39 (s, 1H), 8.58 (d, J=1.3 Hz, 1H), 7.79-7.72 (m, 2H), 7.70 ( d, J=1.2Hz, 2H), 7.21–7.13 (m, 2H), 4.69 (s, 1H), 3.65 (p, J=5.3Hz, 1H), 3.51 (tt, J=7.6, 3.6Hz, 1H) ), 3.18–3.11 (m, 2H), 2.72 (ddd, J=11.8, 8.4, 3.4Hz, 2H), 1.76 (ddt, J=13.5, 6.8, 2.9Hz, 2H), 1.45 (dtd, J=12.0 , 7.8, 3.6Hz, 2H), 1.13 (d, J=5.2Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 156.48 (d, J=235.7Hz), 145.65, 142.08, 138.99 ( d, J＝2.1Hz), 126.06 (d, J＝26.0Hz), 122.77, 117.78 (d, J＝7.4Hz), 115.84, 115.63, 115.14, 110.22, 64.25, 43.72, 33.37, 29.57, 6.87.

Figure BDA0002385652160000254
Figure BDA0002385652160000254

实施例21 4-(1-((5-(3-(3,4-二氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇的合成：按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.56(d,J＝1.2Hz,1H),7.96–7.82(m,1H),7.71(s,2H),7.48–7.31(m,2H),4.66(s,1H),3.76–3.60(m,1H),3.50(s,1H),3.14(dt,J＝11.2,4.0Hz,2H),2.72(ddd,J＝11.7,8.4,3.4Hz,2H),1.82–1.67(m,2H),1.44(dtd,J＝12.1,8.1,3.7Hz,2H),1.18–1.05(m,4H).13C NMR(101MHz,DMSO-d6)δ151.40–146.76(m),145.17,143.45(dd,J＝237.0,12.4Hz),142.01,139.63(dd,J＝9.7,2.2Hz),126.30,126.23,122.65,117.96(d,J＝17.7Hz),114.97,112.62(dd,J＝5.3,2.8Hz),110.40,105.05(d,J＝22.3Hz),64.22,43.71,33.36,29.62,6.86.Example 21 4-(1-((5-(3-(3,4-difluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)ol Synthesis: According to the synthetic method of Example 3, 1 H NMR (400MHz, DMSO-d 6 )δ9.63(s, 1H), 8.56(d, J=1.2Hz, 1H), 7.96-7.82(m, 1H) ,7.71(s,2H),7.48-7.31(m,2H),4.66(s,1H),3.76-3.60(m,1H),3.50(s,1H),3.14(dt,J=11.2,4.0Hz , 2H), 2.72 (ddd, J=11.7, 8.4, 3.4Hz, 2H), 1.82–1.67 (m, 2H), 1.44 (dtd, J=12.1, 8.1, 3.7Hz, 2H), 1.18–1.05 (m , 4H). 13 C NMR (101MHz, DMSO-d 6 )δ151.40-146.76(m), 145.17, 143.45(dd, J=237.0, 12.4Hz), 142.01, 139.63(dd, J=9.7, 2.2Hz) ),126.30,126.23,122.65,117.96(d,J＝17.7Hz),114.97,112.62(dd,J＝5.3,2.8Hz),110.40,105.05(d,J＝22.3Hz),64.22,43.71,33.36, 29.62, 6.86.

Figure BDA0002385652160000261
Figure BDA0002385652160000261

实施例22 4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇的合成，1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.56(s,1H),7.68(s,2H),7.63(dt,J＝8.2,3.6Hz,1H),7.53(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),4.66(s,1H),3.64(p,J＝5.3Hz,1H),3.50(tt,J＝7.9,3.6Hz,1H),3.22–3.07(m,2H),2.71(ddd,J＝11.9,8.6,3.5Hz,2H),2.24(s,3H),1.74(ddd,J＝13.9,7.3,3.6Hz,2H),1.44(dtd,J＝12.3,8.2,3.6Hz,2H),1.12(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.16(d,J＝234.8Hz),145.67,142.06,138.67(d,J＝2.2Hz),126.01(d,J＝29.0Hz),124.46(d,J＝18.0Hz),122.78,119.17(d,J＝4.0Hz),115.49,115.24(d,J＝4.1Hz),115.19,115.15,110.18,64.24,43.71,33.37,29.57,15.13(d,J＝2.9Hz),6.84.Example 22 4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine) Synthesis of alcohol, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.27 (s, 1H), 8.56 (s, 1H), 7.68 (s, 2H), 7.63 (dt, J=8.2, 3.6 Hz, 1H ), 7.53(dd, J=6.9, 2.8Hz, 1H), 7.09(t, J=9.2Hz, 1H), 4.66(s, 1H), 3.64(p, J=5.3Hz, 1H), 3.50(tt , J=7.9, 3.6Hz, 1H), 3.22–3.07 (m, 2H), 2.71 (ddd, J=11.9, 8.6, 3.5Hz, 2H), 2.24 (s, 3H), 1.74 (ddd, J=13.9 , 7.3, 3.6Hz, 2H), 1.44 (dtd, J=12.3, 8.2, 3.6Hz, 2H), 1.12 (d, J=5.2Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ155. 16(d, J＝234.8Hz), 145.67, 142.06, 138.67(d, J＝2.2Hz), 126.01(d, J＝29.0Hz), 124.46(d, J＝18.0Hz), 122.78, 119.17(d, J=4.0Hz), 115.49, 115.24(d, J=4.1Hz), 115.19, 115.15, 110.18, 64.24, 43.71, 33.37, 29.57, 15.13(d, J=2.9Hz), 6.84.

Figure BDA0002385652160000262
Figure BDA0002385652160000262

实施例23 4-(1-((5-(3-(3-氰基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇的合成，1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.54(s,1H),8.18(dd,J＝5.5,2.9Hz,1H),8.02–7.87(m,1H),7.72(s,2H),7.48(t,J＝9.1Hz,1H),4.64(d,J＝3.8Hz,1H),3.68(p,J＝5.4Hz,1H),3.51(tt,J＝7.7,3.6Hz,1H),3.15(tt,J＝7.0,3.2Hz,2H),2.73(ddd,J＝11.8,8.5,3.5Hz,2H),1.84–1.66(m,2H),1.45(dtd,J＝12.3,8.2,3.7Hz,2H),1.15(d,J＝6.4Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.53(d,J＝248.2Hz),144.85,142.02,139.58(d,J＝2.2Hz),126.46,126.35,123.49(d,J＝7.5Hz),122.53,119.07,117.58(d,J＝20.5Hz),115.00,114.89,110.50,100.15(d,J＝16.0Hz),64.22,43.69,33.37,29.67,6.87.Example 23 4-(1-((5-(3-(3-cyano-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine) Synthesis of alcohols, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 8.54 (s, 1H), 8.18 (dd, J=5.5, 2.9 Hz, 1H), 8.02-7.87 (m ,1H),7.72(s,2H),7.48(t,J＝9.1Hz,1H),4.64(d,J＝3.8Hz,1H),3.68(p,J＝5.4Hz,1H),3.51(tt , J=7.7, 3.6Hz, 1H), 3.15 (tt, J=7.0, 3.2Hz, 2H), 2.73 (ddd, J=11.8, 8.5, 3.5Hz, 2H), 1.84–1.66 (m, 2H), 1.45 (dtd, J=12.3, 8.2, 3.7 Hz, 2H), 1.15 (d, J=6.4 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 156.53 (d, J=248.2 Hz) ,144.85,142.02,139.58(d,J＝2.2Hz),126.46,126.35,123.49(d,J＝7.5Hz),122.53,119.07,117.58(d,J＝20.5Hz),115.00,114.89,110.50,100.15 (d, J＝16.0Hz), 64.22, 43.69, 33.37, 29.67, 6.87.

Figure BDA0002385652160000263
Figure BDA0002385652160000263

实施例24 4-(1-((5-(3-(4-(2-甲基吡啶基))氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO)δ9.82(s,1H),8.59(s,1H),8.23(d,J＝5.7Hz,1H),7.74(q,J＝8.9Hz,2H),7.50(d,J＝4.3Hz,1H),7.44(s,1H),4.71(s,1H),3.72(dt,J＝10.2,5.2Hz,1H),3.51(s,1H),3.15(s,2H),2.72(t,J＝8.4Hz,2H),2.42(s,3H),1.83–1.68(m,2H),1.45(d,J＝8.4Hz,2H),1.16(d,J＝4.8Hz,4H).13C NMR(101MHz,DMSO-d6)δ158.43,149.88,148.61,144.41,141.96,126.53,126.23,122.66,115.22,110.56,109.93,108.70,64.20,43.72,33.35,29.74,24.95,6.90.Example 24 4-(1-((5-(3-(4-(2-methylpyridyl))amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine) Alcohol, 1 H NMR (400MHz, DMSO) δ 9.82 (s, 1H), 8.59 (s, 1H), 8.23 (d, J=5.7Hz, 1H), 7.74 (q, J=8.9Hz, 2H), 7.50(d, J=4.3Hz, 1H), 7.44(s, 1H), 4.71(s, 1H), 3.72(dt, J=10.2, 5.2Hz, 1H), 3.51(s, 1H), 3.15(s ,2H),2.72(t,J＝8.4Hz,2H),2.42(s,3H),1.83–1.68(m,2H),1.45(d,J＝8.4Hz,2H),1.16(d,J＝ 4.8Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ158.43,149.88,148.61,144.41,141.96,126.53,126.23,122.66,115.22,110.56,109.93,108.70,64.20,2.7,4.5 ,6.90.

Figure BDA0002385652160000264
Figure BDA0002385652160000264

实施例25 4-(1-((5-(3-(4-氯苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO)δ9.51(s,1H),8.58(s,1H),7.74(dd,J＝14.7,10.6Hz,4H),7.45–7.30(m,2H),4.66(d,J＝3.6Hz,1H),3.72–3.59(m,1H),3.51(s,1H),3.15(s,2H),2.71(d,J＝8.1Hz,2H),1.75(s,2H),1.53–1.38(m,2H),1.13(d,J＝4.6Hz,4H).13C NMR(101MHz,DMSO-d6)δ145.27,142.03,141.34,129.10,126.23,126.02,123.40,122.74,118.01,115.15,110.32,64.23,43.73,33.36,29.61,6.93.Example 25 4-(1-((5-(3-(4-chlorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)ol, 1 H NMR (400MHz,DMSO)δ9.51(s,1H),8.58(s,1H),7.74(dd,J=14.7,10.6Hz,4H),7.45-7.30(m,2H),4.66(d,J= 3.6Hz, 1H), 3.72–3.59 (m, 1H), 3.51 (s, 1H), 3.15 (s, 2H), 2.71 (d, J=8.1Hz, 2H), 1.75 (s, 2H), 1.53– 1.38(m, 2H), 1.13(d, J=4.6Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ145.27, 142.03, 141.34, 129.10, 126.23, 126.02, 123.40, 122.74, 118.01, 115.15, 110.32, 64.23, 43.73, 33.36, 29.61, 6.93.

Figure BDA0002385652160000271
Figure BDA0002385652160000271

实施例26 4-(1-((5-(3-(4-氟-2-甲基苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.16(s,1H),7.81–7.61(m,3H),7.07(dd,J＝9.7,2.9Hz,1H),7.02–6.93(m,1H),4.65(d,J＝3.8Hz,1H),3.65–3.54(m,1H),3.54–3.45(m,1H),3.14(td,J＝11.1,10.7,5.0Hz,2H),2.78–2.64(m,2H),2.32(s,3H),1.85–1.66(m,2H),1.54–1.36(m,2H),1.14–0.97(m,4H).13C NMR(101MHz,DMSO-d6)δ157.83(d,J＝237.9Hz),146.71,142.63,137.02(d,J＝2.5Hz),131.57(d,J＝7.7Hz),125.90,123.11,122.05(d,J＝8.3Hz),117.16(d,J＝22.0Hz),115.14,112.86(d,J＝21.6Hz),110.29,64.25,43.68,33.38,29.45,18.71,6.83.Example 26 4-(1-((5-(3-(4-Fluoro-2-methylphenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine) Alcohol, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (s, 1H), 8.16 (s, 1H), 7.81-7.61 (m, 3H), 7.07 (dd, J=9.7, 2.9 Hz, 1H ), 7.02–6.93 (m, 1H), 4.65 (d, J=3.8Hz, 1H), 3.65–3.54 (m, 1H), 3.54–3.45 (m, 1H), 3.14 (td, J=11.1, 10.7 ,5.0Hz,2H),2.78–2.64(m,2H),2.32(s,3H),1.85–1.66(m,2H),1.54–1.36(m,2H),1.14–0.97(m,4H). 13 C NMR(101MHz, DMSO-d 6 )δ157.83(d,J=237.9Hz),146.71,142.63,137.02(d,J=2.5Hz),131.57(d,J=7.7Hz),125.90,123.11 ,122.05(d,J＝8.3Hz),117.16(d,J＝22.0Hz),115.14,112.86(d,J＝21.6Hz),110.29,64.25,43.68,33.38,29.45,18.71,6.83.

Figure BDA0002385652160000272
Figure BDA0002385652160000272

实施例27 4-(1-((5-(3-(5-氟-2-甲基苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.26(s,1H),7.83–7.63(m,3H),7.17(t,J＝7.6Hz,1H),6.66(td,J＝8.3,2.6Hz,1H),4.67(d,J＝3.8Hz,1H),3.74–3.63(m,1H),3.51(dd,J＝7.1,3.5Hz,1H),3.15(d,J＝7.0Hz,2H),2.72(t,J＝8.4Hz,2H),2.34(s,3H),1.75(dd,J＝12.4,3.4Hz,2H),1.45(dt,J＝16.7,6.4Hz,2H),1.15–1.04(m,4H).13C NMR(101MHz,DMSO-d6)δ161.33(d,J＝238.1Hz),145.34,142.41,142.12(d,J＝11.0Hz),131.72(d,J＝9.5Hz),126.23,125.99,123.30,122.49(d,J＝2.7Hz),115.48,110.49,107.16(d,J＝21.1Hz),104.87(d,J＝26.4Hz),64.25,43.72,33.38,29.61,18.10,6.86.Example 27 4-(1-((5-(3-(5-Fluoro-2-methylphenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine) Alcohol, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (s, 1H), 8.26 (s, 1H), 7.83-7.63 (m, 3H), 7.17 (t, J=7.6 Hz, 1H), 6.66 (td, J=8.3, 2.6Hz, 1H), 4.67 (d, J=3.8Hz, 1H), 3.74–3.63 (m, 1H), 3.51 (dd, J=7.1, 3.5Hz, 1H), 3.15 (d, J=7.0Hz, 2H), 2.72 (t, J=8.4Hz, 2H), 2.34 (s, 3H), 1.75 (dd, J=12.4, 3.4Hz, 2H), 1.45 (dt, J= 16.7, 6.4Hz, 2H), 1.15–1.04 (m, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 161.33 (d, J=238.1 Hz), 145.34, 142.41, 142.12 (d, J= 11.0Hz), 131.72(d, J=9.5Hz), 126.23, 125.99, 123.30, 122.49(d, J=2.7Hz), 115.48, 110.49, 107.16(d, J=21.1Hz), 104.87(d, J= 26.4Hz), 64.25, 43.72, 33.38, 29.61, 18.10, 6.86.

Figure BDA0002385652160000273
Figure BDA0002385652160000273

实施例28 4-(1-((5-(3-(2-氯-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.54(d,J＝1.5Hz,1H),8.03(dd,J＝9.2,5.6Hz,1H),7.80–7.64(m,2H),7.47(dd,J＝8.5,3.0Hz,1H),7.22(td,J＝8.6,3.0Hz,1H),4.66(d,J＝3.8Hz,1H),3.71–3.60(m,1H),3.53(tq,J＝7.6,3.7Hz,1H),3.16(ddt,J＝11.2,7.3,4.5Hz,2H),2.74(ddd,J＝11.8,8.5,3.4Hz,2H),1.86–1.68(m,2H),1.46(dtd,J＝12.1,8.0,3.6Hz,2H),1.15–1.05(m,4H).13C NMR(101MHz,DMSO-d6)δ156.71(d,J＝240.9Hz),145.40,142.51,135.99(d,J＝3.0Hz),126.35,126.01,123.44(d,J＝10.5Hz),123.33,121.77(d,J＝8.2Hz),117.01(d,J＝25.7Hz),115.32,114.95(d,J＝21.8Hz),110.45,64.23,43.69,33.37,29.59,6.87.Example 28 4-(1-((5-(3-(2-Chloro-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)ol , 1 H NMR (400MHz, DMSO-d 6 )δ8.57(s,1H),8.54(d,J=1.5Hz,1H),8.03(dd,J=9.2,5.6Hz,1H),7.80-7.64 (m, 2H), 7.47 (dd, J=8.5, 3.0Hz, 1H), 7.22 (td, J=8.6, 3.0Hz, 1H), 4.66 (d, J=3.8Hz, 1H), 3.71–3.60 ( m, 1H), 3.53 (tq, J=7.6, 3.7Hz, 1H), 3.16 (ddt, J=11.2, 7.3, 4.5Hz, 2H), 2.74 (ddd, J=11.8, 8.5, 3.4Hz, 2H) , 1.86–1.68(m, 2H), 1.46(dtd, J=12.1, 8.0, 3.6Hz, 2H), 1.15–1.05(m, 4H). 13 C NMR(101MHz, DMSO-d 6 )δ156.71( d, J＝240.9Hz), 145.40, 142.51, 135.99(d, J＝3.0Hz), 126.35, 126.01, 123.44(d, J＝10.5Hz), 123.33, 121.77(d, J＝8.2Hz), 117.01( d, J＝25.7Hz), 115.32, 114.95 (d, J＝21.8Hz), 110.45, 64.23, 43.69, 33.37, 29.59, 6.87.

Figure BDA0002385652160000281
Figure BDA0002385652160000281

实施例29 4-(1-((5-(3-(4-甲基苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.60(t,J＝1.3Hz,1H),7.72–7.67(m,2H),7.67–7.61(m,2H),7.12(d,J＝8.3Hz,2H),4.68(d,J＝3.3Hz,1H),3.64(p,J＝5.3Hz,1H),3.52(d,J＝8.6Hz,1H),3.16(ddd,J＝11.1,6.9,3.7Hz,2H),2.72(ddd,J＝11.8,8.4,3.4Hz,2H),2.26(s,3H),1.76(ddt,J＝13.5,6.8,2.9Hz,2H),1.46(dtd,J＝12.0,7.9,3.5Hz,2H),1.13(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ145.84,142.08,140.06,129.66,128.66,126.10,125.76,122.86,116.64,115.31,110.08,64.27,43.74,33.38,29.55,20.81,6.86.Example 29 4-(1-((5-(3-(4-methylphenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)ol, 1H NMR(400MHz, DMSO-d 6 )δ9.24(s,1H),8.60(t,J=1.3Hz,1H),7.72-7.67(m,2H),7.67-7.61(m,2H),7.12( d,J＝8.3Hz,2H),4.68(d,J＝3.3Hz,1H),3.64(p,J＝5.3Hz,1H),3.52(d,J＝8.6Hz,1H),3.16(ddd, J=11.1, 6.9, 3.7Hz, 2H), 2.72 (ddd, J=11.8, 8.4, 3.4Hz, 2H), 2.26 (s, 3H), 1.76 (ddt, J=13.5, 6.8, 2.9Hz, 2H) , 1.46 (dtd, J=12.0, 7.9, 3.5Hz, 2H), 1.13 (d, J=5.2Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ145.84, 142.08, 140.06, 129.66, 128.66, 126.10,125.76,122.86,116.64,115.31,110.08,64.27,43.74,33.38,29.55,20.81,6.86.

Figure BDA0002385652160000282
Figure BDA0002385652160000282

实施例30 4-(1-((5-(3-(4-氟苄基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.64–7.57(m,1H),7.55(d,J＝8.9Hz,1H),7.45(dd,J＝8.4,5.6Hz,2H),7.16(t,J＝8.7Hz,2H),7.07(t,J＝5.9Hz,1H),4.64(d,J＝3.8Hz,1H),4.42(d,J＝5.7Hz,2H),3.61–3.42(m,2H),3.10(t,J＝8.8Hz,2H),2.75–2.59(m,2H),1.84–1.64(m,2H),1.53–1.32(m,2H),1.02(t,J＝6.4Hz,4H).13C NMR(100MHz,DMSO-d6)δ161.6(d,J＝242.0Hz),150.3,143.2,136.6(d,J＝2.9Hz),130.2(d,J＝8.0Hz),125.9,124.9,123.0,115.3(d,J＝21.2Hz),114.5,109.8,64.3,46.3,43.7,33.4,29.2,6.7.Example 30 4-(1-((5-(3-(4-fluorobenzyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)ol, 1 H NMR (400MHz,DMSO-d 6 )δ8.31(s,1H),7.64-7.57(m,1H),7.55(d,J=8.9Hz,1H),7.45(dd,J=8.4,5.6Hz,2H ), 7.16(t, J＝8.7Hz, 2H), 7.07(t, J＝5.9Hz, 1H), 4.64(d, J＝3.8Hz, 1H), 4.42(d, J＝5.7Hz, 2H), 3.61–3.42 (m, 2H), 3.10 (t, J=8.8Hz, 2H), 2.75–2.59 (m, 2H), 1.84–1.64 (m, 2H), 1.53–1.32 (m, 2H), 1.02 ( t, J=6.4Hz, 4H). 13 C NMR (100MHz, DMSO-d 6 )δ161.6(d, J=242.0Hz), 150.3, 143.2, 136.6(d, J=2.9Hz), 130.2(d , J＝8.0Hz), 125.9, 124.9, 123.0, 115.3(d, J＝21.2Hz), 114.5, 109.8, 64.3, 46.3, 43.7, 33.4, 29.2, 6.7.

Figure BDA0002385652160000283
Figure BDA0002385652160000283

实施例31 4-(1-((5-(3-苯氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1HNMR(400MHz,DMSO)δ9.34(s,1H),8.61(s,1H),7.83–7.64(m,4H),7.32(t,J＝7.9Hz,2H),6.87(t,J＝7.3Hz,1H),4.66(d,J＝3.8Hz,1H),3.66(dt,J＝10.4,5.3Hz,1H),3.59–3.45(m,1H),3.16(s,2H),2.72(t,J＝8.3Hz,2H),1.76(dd,J＝12.3,3.4Hz,2H),1.46(dd,J＝8.2,3.8Hz,2H),1.14(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ145.61,142.46,142.04,129.28,126.14,125.85,122.85,120.08,116.54,115.30,110.19,64.25,43.74,33.37,29.58,6.88.Example 31 4-(1-((5-(3-phenylamino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)ol, 1 HNMR (400 MHz, DMSO) δ 9. 34(s, 1H), 8.61(s, 1H), 7.83–7.64(m, 4H), 7.32(t, J=7.9Hz, 2H), 6.87(t, J=7.3Hz, 1H), 4.66(d , J=3.8Hz, 1H), 3.66 (dt, J=10.4, 5.3Hz, 1H), 3.59–3.45 (m, 1H), 3.16 (s, 2H), 2.72 (t, J=8.3Hz, 2H) , 1.76(dd, J＝12.3, 3.4Hz, 2H), 1.46(dd, J＝8.2, 3.8Hz, 2H), 1.14(d, J＝5.2Hz, 4H). 13 C NMR(101MHz, DMSO-d 6 ) δ145.61, 142.46, 142.04, 129.28, 126.14, 125.85, 122.85, 120.08, 116.54, 115.30, 110.19, 64.25, 43.74, 33.37, 29.58, 6.88.

Figure BDA0002385652160000284
Figure BDA0002385652160000284

实施例32 4-(1-((5-(3-(3-氟-4-甲基苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.58(s,1H),7.80–7.62(m,3H),7.32(dd,J＝8.3,2.2Hz,1H),7.19(t,J＝8.7Hz,1H),4.67(s,1H),3.74–3.61(m,1H),3.50(dq,J＝7.5,4.0,3.5Hz,1H),3.24–3.09(m,2H),2.72(ddd,J＝12.0,8.6,3.4Hz,2H),2.18(d,J＝1.6Hz,3H),1.76(ddt,J＝13.5,6.9,3.4Hz,2H),1.45(dtd,J＝12.4,8.1,3.6Hz,2H),1.18–1.05(m,4H).13C NMR(101MHz,DMSO-d6)δ161.21(d,J＝239.6Hz),145.38,142.03,141.92(d,J＝11.4Hz),131.89(d,J＝7.0Hz),126.21,126.09,122.71,115.11,114.72(d,J＝17.6Hz),112.54(d,J＝2.7Hz),110.28,103.26(d,J＝27.6Hz),64.25,43.72,33.38,29.60,6.86.Example 32 4-(1-((5-(3-(3-Fluoro-4-methylphenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine) Alcohol, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.49 (s, 1H), 8.58 (s, 1H), 7.80-7.62 (m, 3H), 7.32 (dd, J=8.3, 2.2 Hz, 1H ),7.19(t,J＝8.7Hz,1H),4.67(s,1H),3.74-3.61(m,1H),3.50(dq,J＝7.5,4.0,3.5Hz,1H),3.24-3.09( m, 2H), 2.72 (ddd, J=12.0, 8.6, 3.4Hz, 2H), 2.18 (d, J=1.6Hz, 3H), 1.76 (ddt, J=13.5, 6.9, 3.4Hz, 2H), 1.45 (dtd, J=12.4, 8.1, 3.6 Hz, 2H), 1.18–1.05 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 161.21 (d, J=239.6 Hz), 145.38, 142.03 ,141.92(d,J＝11.4Hz),131.89(d,J＝7.0Hz),126.21,126.09,122.71,115.11,114.72(d,J＝17.6Hz),112.54(d,J＝2.7Hz),110.28 ,103.26(d,J＝27.6Hz),64.25,43.72,33.38,29.60,6.86.

Figure BDA0002385652160000291
Figure BDA0002385652160000291

实施例33 4-(1-((5-(3-苄氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1HNMR(400MHz,DMSO-d6)δ8.34(d,J＝1.6Hz,1H),7.65–7.50(m,2H),7.42(d,J＝7.2Hz,2H),7.34(t,J＝7.4Hz,2H),7.25(t,J＝7.3Hz,1H),7.07(t,J＝5.8Hz,1H),4.66(s,1H),4.45(d,J＝5.8Hz,2H),3.48(qt,J＝6.8,3.8Hz,2H),3.11(ddd,J＝11.2,6.9,3.7Hz,2H),2.66(ddd,J＝11.8,8.5,3.4Hz,2H),1.73(ddt,J＝13.9,7.2,3.5Hz,2H),1.43(dtd,J＝12.2,8.2,3.7Hz,2H),1.03(dt,J＝8.3,2.8Hz,4H).13C NMR(101MHz,DMSO-d6)δ150.40,143.17,140.44,128.63,128.28,127.21,125.84,124.86,123.09,114.50,109.72,64.28,47.04,43.70,33.37,29.23.Example 33 4-(1-((5-(3-benzylamino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin) alcohol, 1 HNMR (400 MHz, DMSO-d 6 )δ8.34(d,J＝1.6Hz,1H),7.65–7.50(m,2H),7.42(d,J＝7.2Hz,2H),7.34(t,J＝7.4Hz,2H),7.25( t,J＝7.3Hz,1H),7.07(t,J＝5.8Hz,1H),4.66(s,1H),4.45(d,J＝5.8Hz,2H),3.48(qt,J＝6.8,3.8 Hz, 2H), 3.11 (ddd, J=11.2, 6.9, 3.7Hz, 2H), 2.66 (ddd, J=11.8, 8.5, 3.4Hz, 2H), 1.73 (ddt, J=13.9, 7.2, 3.5Hz, 2H), 1.43 (dtd, J=12.2, 8.2, 3.7Hz, 2H), 1.03 (dt, J=8.3, 2.8Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ150.40, 143.17, 140.44, 128.63,128.28,127.21,125.84,124.86,123.09,114.50,109.72,64.28,47.04,43.70,33.37,29.23.

Figure BDA0002385652160000292
Figure BDA0002385652160000292

实施例34 4-(1-((5-(3-(2-(5-氟吡啶基))氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.71(d,J＝1.2Hz,1H),8.23(d,J＝3.0Hz,1H),8.05(dd,J＝9.2,3.9Hz,1H),7.78–7.66(m,3H),4.65(d,J＝3.8Hz,1H),3.69(tt,J＝6.6,4.5Hz,1H),3.52(tq,J＝7.4,3.6Hz,1H),3.18–3.10(m,2H),2.73(ddd,J＝11.8,8.4,3.4Hz,2H),1.76(ddt,J＝14.0,7.2,3.5Hz,2H),1.46(dtd,J＝11.9,7.9,3.6Hz,2H),1.19–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ154.47(d,J＝243.3Hz),151.52,144.20,142.24,135.23(d,J＝24.7Hz),126.50,126.09,125.85(d,J＝19.9Hz),123.72,115.41,111.14(d,J＝4.0Hz),110.26,64.26,43.71,33.38,29.64,6.84.Example 34 4-(1-((5-(3-(2-(5-fluoropyridyl))amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)ol , 1 H NMR (400MHz, DMSO-d 6 )δ10.19(s,1H),8.71(d,J=1.2Hz,1H),8.23(d,J=3.0Hz,1H),8.05(dd,J =9.2,3.9Hz,1H),7.78–7.66(m,3H),4.65(d,J=3.8Hz,1H),3.69(tt,J=6.6,4.5Hz,1H),3.52(tq,J= 7.4, 3.6Hz, 1H), 3.18–3.10 (m, 2H), 2.73 (ddd, J=11.8, 8.4, 3.4Hz, 2H), 1.76 (ddt, J=14.0, 7.2, 3.5Hz, 2H), 1.46 (dtd, J=11.9, 7.9, 3.6 Hz, 2H), 1.19–1.07 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 154.47 (d, J=243.3 Hz), 151.52, 144.20 ,142.24,135.23(d,J＝24.7Hz),126.50,126.09,125.85(d,J＝19.9Hz),123.72,115.41,111.14(d,J＝4.0Hz),110.26,64.26,43.71,33.38,29.64 ,6.84.

Figure BDA0002385652160000293
Figure BDA0002385652160000293

实施例35 4-(1-((5-(3-(2-(5-氟-4-甲基吡啶基))氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.66(s,1H),8.10(s,1H),7.86(d,J＝5.6Hz,1H),7.78–7.66(m,2H),4.64(d,J＝3.8Hz,1H),3.71(td,J＝6.3,3.2Hz,1H),3.52(tq,J＝7.6,3.7Hz,1H),3.16(ddt,J＝11.2,7.2,4.2Hz,2H),2.73(ddd,J＝11.7,8.2,3.3Hz,2H),2.31(s,3H),1.76(ddt,J＝14.0,7.2,3.5Hz,2H),1.46(dtd,J＝12.1,8.1,3.6Hz,2H),1.19–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ153.91(d,J＝242.1Hz),151.36(d,J＝1.9Hz),144.20,142.27,135.85(d,J＝16.1Hz),134.46(d,J＝25.7Hz),126.46,126.01,123.78,115.54,112.12,110.25,64.26,43.70,33.38,29.66,15.05(d,J＝2.8Hz),6.80.Example 35 4-(1-((5-(3-(2-(5-fluoro-4-methylpyridyl))amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl ) piperidinol, 1 H NMR (400MHz, DMSO-d 6 ) δ 10.02(s, 1H), 8.66(s, 1H), 8.10(s, 1H), 7.86(d, J=5.6Hz, 1H ), 7.78–7.66 (m, 2H), 4.64 (d, J=3.8Hz, 1H), 3.71 (td, J=6.3, 3.2Hz, 1H), 3.52 (tq, J=7.6, 3.7Hz, 1H) ,3.16(ddt,J=11.2,7.2,4.2Hz,2H),2.73(ddd,J=11.7,8.2,3.3Hz,2H),2.31(s,3H),1.76(ddt,J=14.0,7.2, 3.5Hz, 2H), 1.46 (dtd, J=12.1, 8.1, 3.6Hz, 2H), 1.19–1.07 (m, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 153.91 (d, J= 242.1Hz), 151.36 (d, J=1.9Hz), 144.20, 142.27, 135.85 (d, J=16.1Hz), 134.46 (d, J=25.7Hz), 126.46, 126.01, 123.78, 115.54, 112.12, 110.25, 64.26, 43.70, 33.38, 29.66, 15.05 (d, J=2.8Hz), 6.80.

Figure BDA0002385652160000301
Figure BDA0002385652160000301

实施例36 4-(1-((5-(3-(4-氟-3-三氟甲基苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.56(s,1H),8.17(dd,J＝6.3,2.8Hz,1H),8.01(dt,J＝9.1,3.6Hz,1H),7.81–7.69(m,2H),7.49(t,J＝9.8Hz,1H),4.65(d,J＝3.9Hz,1H),3.72(p,J＝5.3Hz,1H),3.51(dh,J＝7.8,3.7Hz,1H),3.25–3.07(m,2H),2.74(ddd,J＝11.8,8.5,3.4Hz,2H),1.76(ddt,J＝10.6,6.9,3.5Hz,2H),1.45(dtd,J＝11.9,7.9,3.5Hz,2H),1.15(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ154.28–150.91(m),145.01,142.00,139.20(d,J＝2.2Hz),126.33(d,J＝3.3Hz),123.29(q,J＝271.8Hz),122.56,121.74(d,J＝7.5Hz),118.20,117.99,116.88(qd,J＝32.0,13.0Hz),114.96,113.81(q,J＝5.3,4.8Hz),110.41,64.21,43.69,33.36,29.66,6.71.Example 36 4-(1-((5-(3-(4-Fluoro-3-trifluoromethylphenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine Iridinol, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.56 (s, 1H), 8.17 (dd, J=6.3, 2.8 Hz, 1H), 8.01 (dt, J =9.1,3.6Hz,1H),7.81–7.69(m,2H),7.49(t,J=9.8Hz,1H),4.65(d,J=3.9Hz,1H),3.72(p,J=5.3Hz ,1H),3.51(dh,J＝7.8,3.7Hz,1H),3.25–3.07(m,2H),2.74(ddd,J＝11.8,8.5,3.4Hz,2H),1.76(ddt,J＝10.6 , 6.9, 3.5Hz, 2H), 1.45 (dtd, J=11.9, 7.9, 3.5Hz, 2H), 1.15 (d, J=5.3Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ154. 28–150.91(m), 145.01, 142.00, 139.20(d, J=2.2Hz), 126.33(d, J=3.3Hz), 123.29(q, J=271.8Hz), 122.56, 121.74(d, J=7.5 Hz), 118.20, 117.99, 116.88 (qd, J=32.0, 13.0Hz), 114.96, 113.81 (q, J=5.3, 4.8Hz), 110.41, 64.21, 43.69, 33.36, 29.66, 6.71.

Figure BDA0002385652160000302
Figure BDA0002385652160000302

实施例37 4-(1-((5-(3-(4-氟-3-环丙基苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇，1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.55(s,1H),7.70(s,2H),7.62–7.52(m,1H),7.31(dd,J＝6.8,2.8Hz,1H),7.09(t,J＝9.5Hz,1H),4.65(d,J＝3.8Hz,1H),3.75–3.61(m,1H),3.51(tt,J＝7.6,3.9Hz,1H),3.15(ddd,J＝11.2,6.7,3.5Hz,2H),2.72(dd,J＝20.2,3.4Hz,2H),2.07(dp,J＝8.5,5.1Hz,1H),1.75(ddd,J＝11.3,7.4,3.6Hz,2H),1.45(dtd,J＝12.3,8.2,3.6Hz,2H),1.12(d,J＝2.3Hz,4H),1.03(dt,J＝8.7,3.2Hz,2H),0.78–0.66(m,2H).13C NMR(101MHz,DMSO-d6)δ155.58(d,J＝235.3Hz),145.61,142.00,138.95(d,J＝2.0Hz),130.42(d,J＝15.3Hz),126.16,125.85,122.70,115.35(d,J＝23.1Hz),115.14,114.54(d,J＝7.5Hz),113.41(d,J＝3.4Hz),110.14,64.24,43.71,33.36,29.59,8.94(d,J＝4.7Hz),8.53,6.67.Example 37 4-(1-((5-(3-(4-Fluoro-3-cyclopropylphenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine ) alcohol, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (s, 1H), 8.55 (s, 1H), 7.70 (s, 2H), 7.62–7.52 (m, 1H), 7.31 (dd, J=6.8, 2.8Hz, 1H), 7.09 (t, J=9.5Hz, 1H), 4.65 (d, J=3.8Hz, 1H), 3.75–3.61 (m, 1H), 3.51 (tt, J=7.6 ,3.9Hz,1H),3.15(ddd,J＝11.2,6.7,3.5Hz,2H),2.72(dd,J＝20.2,3.4Hz,2H),2.07(dp,J＝8.5,5.1Hz,1H) ,1.75(ddd,J＝11.3,7.4,3.6Hz,2H),1.45(dtd,J＝12.3,8.2,3.6Hz,2H),1.12(d,J＝2.3Hz,4H),1.03(dt,J =8.7,3.2Hz,2H),0.78-0.66(m,2H). 13C NMR(101MHz,DMSO-d 6 )δ155.58(d,J=235.3Hz),145.61,142.00,138.95(d,J = 2.0Hz), 130.42 (d, J = 15.3 Hz), 126.16, 125.85, 122.70, 115.35 (d, J = 23.1 Hz), 115.14, 114.54 (d, J = 7.5 Hz), 113.41 (d, J = 3.4 Hz), 110.14, 64.24, 43.71, 33.36, 29.59, 8.94(d, J=4.7Hz), 8.53, 6.67.

Figure BDA0002385652160000303
Figure BDA0002385652160000303

实施例38 4-(1-((5-(3-(环己基氨基))-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇的合成：Example 38 Synthesis of 4-(1-((5-(3-(cyclohexylamino))-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)ol:

Figure BDA0002385652160000304
Figure BDA0002385652160000304

乙酸-4-(1-(5-(3-碘-1-环丙基-1H-吲唑基)磺酰基)哌啶)酯(38-2)的合成：将38-1(363mg,1mmol)溶于乙腈(8mL)和硫酸(2mL)，加入NIS(562mg,2.5mmol)，室温反应48小时。反应液加乙酸乙酯稀释，依次用饱和碳酸氢钠溶液，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析分离(石油醚/乙酸乙酯2/1)，得180mg，收率37％。Synthesis of acetate-4-(1-(5-(3-iodo-1-cyclopropyl-1H-indazolyl)sulfonyl)piperidine)ester (38-2): 38-1 (363 mg, 1 mmol) ) was dissolved in acetonitrile (8 mL) and sulfuric acid (2 mL), NIS (562 mg, 2.5 mmol) was added, and the reaction was carried out at room temperature for 48 hours. The reaction solution was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain 180 mg, Yield 37%.

标题化合物的合成：将化合物38-2(49mg,0.1mmol)、环己基胺(20mg,0.2mmol)、碘化亚铜(3.8mg,0.02mmol)、D-脯氨酸(4.6mg,0.04mmol)、无水磷酸钾(63mg,0.3mmol)溶于2mL DMSO，氩气置换三次，90℃反应3小时，反应完成后，加乙酸乙酯稀释，用饱和食盐水洗3次，无水硫酸钠干燥，过滤，浓缩。加THF和水溶解，加入LiOH(12mg,0.5mmol)，室温反应1小时，反应液加入乙酸乙酯和水，分离乙酸乙酯相，硅胶柱层析分离(石油醚/乙酸乙酯2/1)，得目标物。1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝1.6Hz,1H),7.58(dd,J＝8.8,1.7Hz,1H),7.51(d,J＝8.8Hz,1H),6.40(d,J＝7.3Hz,1H),4.64(d,J＝3.8Hz,1H),3.51(qt,J＝7.3,4.2Hz,2H),3.44(tt,J＝6.9,3.8Hz,1H),3.12(ddd,J＝11.1,7.1,3.8Hz,2H),2.68(ddd,J＝11.7,8.4,3.4Hz,2H),2.11–2.01(m,2H),1.80–1.70(m,4H),1.61(dt,J＝12.7,3.8Hz,1H),1.45(ddt,J＝12.7,8.3,4.0Hz,2H),1.37–1.22(m,5H),1.09–0.98(m,4H).13C NMR(101MHz,DMSO-d6)δ149.75,142.97,125.77,124.51,123.14,114.83,109.52,64.27,51.55,43.70,33.38,32.99,29.15,26.15,25.14,6.82.Synthesis of the title compound: compound 38-2 (49 mg, 0.1 mmol), cyclohexylamine (20 mg, 0.2 mmol), cuprous iodide (3.8 mg, 0.02 mmol), D-proline (4.6 mg, 0.04 mmol) ), anhydrous potassium phosphate (63 mg, 0.3 mmol) was dissolved in 2 mL of DMSO, replaced with argon three times, and reacted at 90 ° C for 3 hours. After the reaction was completed, diluted with ethyl acetate, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. , filtered and concentrated. Add THF and water to dissolve, add LiOH (12 mg, 0.5 mmol), react at room temperature for 1 hour, add ethyl acetate and water to the reaction solution, separate the ethyl acetate phase, and separate by silica gel column chromatography (petroleum ether/ethyl acetate 2/1 ) to get the target. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.34 (d, J=1.6Hz, 1H), 7.58 (dd, J=8.8, 1.7Hz, 1H), 7.51 (d, J=8.8Hz, 1H) ,6.40(d,J＝7.3Hz,1H),4.64(d,J＝3.8Hz,1H),3.51(qt,J＝7.3,4.2Hz,2H),3.44(tt,J＝6.9,3.8Hz, 1H), 3.12 (ddd, J=11.1, 7.1, 3.8Hz, 2H), 2.68 (ddd, J=11.7, 8.4, 3.4Hz, 2H), 2.11–2.01 (m, 2H), 1.80–1.70 (m, 4H), 1.61 (dt, J=12.7, 3.8Hz, 1H), 1.45 (ddt, J=12.7, 8.3, 4.0Hz, 2H), 1.37–1.22 (m, 5H), 1.09–0.98 (m, 4H) . 13 C NMR (101MHz, DMSO-d 6 )δ149.75, 142.97, 125.77, 124.51, 123.14, 114.83, 109.52, 64.27, 51.55, 43.70, 33.38, 32.99, 29.15, 26.15, 25.14, 6.82.

实施例39 4-(1-((5-(3-(环戊基氨基))-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)醇的合成：按实施例38的合成方法，1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝1.5Hz,1H),7.58(dd,J＝8.9,1.7Hz,1H),7.52(d,J＝8.8Hz,1H),6.51(d,J＝6.4Hz,1H),4.64(d,J＝3.6Hz,1H),3.97(p,J＝6.3Hz,1H),3.49(dtt,J＝16.8,6.8,3.8Hz,2H),3.12(ddd,J＝11.1,7.1,3.7Hz,2H),2.68(ddd,J＝11.7,8.4,3.4Hz,2H),2.05–1.90(m,2H),1.80–1.65(m,4H),1.63–1.50(m,4H),1.44(dtd,J＝12.1,8.0,3.5Hz,2H),1.03(t,J＝5.1Hz,4H).13C NMR(101MHz,DMSO-d6)δ150.26,142.97,125.74,124.55,123.09,114.75,109.53,64.28,54.54,43.70,33.38,32.90,29.17,23.97,6.77.Example 39 Synthesis of 4-(1-((5-(3-(cyclopentylamino))-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)ol: as per example Synthesis of 38, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.32 (d, J=1.5 Hz, 1H), 7.58 (dd, J=8.9, 1.7 Hz, 1H), 7.52 (d, J= 8.8Hz, 1H), 6.51 (d, J=6.4Hz, 1H), 4.64 (d, J=3.6Hz, 1H), 3.97 (p, J=6.3Hz, 1H), 3.49 (dtt, J=16.8, 6.8, 3.8Hz, 2H), 3.12 (ddd, J=11.1, 7.1, 3.7Hz, 2H), 2.68 (ddd, J=11.7, 8.4, 3.4Hz, 2H), 2.05–1.90 (m, 2H), 1.80 -1.65(m,4H),1.63-1.50(m,4H),1.44(dtd,J=12.1,8.0,3.5Hz,2H),1.03(t,J=5.1Hz,4H) .13C NMR(101MHz) ,DMSO-d 6 )δ150.26,142.97,125.74,124.55,123.09,114.75,109.53,64.28,54.54,43.70,33.38,32.90,29.17,23.97,6.77.

Figure BDA0002385652160000311
Figure BDA0002385652160000311

实施例40N-(4-氟苯基)-3-(1-环丙基-5-(吗啉磺酰基)-1H-吲唑)胺的合成：按照实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.60(d,J＝1.4Hz,1H),7.75(dd,J＝9.1,4.7Hz,2H),7.73–7.67(m,2H),7.17(t,J＝8.9Hz,2H),3.74–3.59(m,5H),2.97–2.80(m,4H),1.14(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.50(d,J＝235.7Hz),145.70,142.18,138.94(d,J＝2.0Hz),126.23,124.75,123.17,117.79(d,J＝7.4Hz),115.75(d,J＝22.0Hz),115.17,110.36,65.74,46.42,29.59,6.87.Example 40 Synthesis of N-(4-fluorophenyl)-3-(1-cyclopropyl-5-(morpholinesulfonyl)-1H-indazol)amine: according to the synthesis method of Example 13, 1 H NMR (400MHz,DMSO-d 6 )δ9.39(s,1H),8.60(d,J=1.4Hz,1H),7.75(dd,J=9.1,4.7Hz,2H),7.73-7.67(m,2H) ), 7.17(t, J=8.9Hz, 2H), 3.74–3.59 (m, 5H), 2.97–2.80 (m, 4H), 1.14 (d, J=5.3Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ156.50(d,J=235.7Hz),145.70,142.18,138.94(d,J=2.0Hz),126.23,124.75,123.17,117.79(d,J=7.4Hz),115.75(d , J＝22.0Hz), 115.17, 110.36, 65.74, 46.42, 29.59, 6.87.

Figure BDA0002385652160000312
Figure BDA0002385652160000312

实施例41 4-(1-((5-(3-(3-氯4-氟苯基)(甲基)氨基)-(1-甲基)-1H-吲唑基)磺酰基)哌啶)醇的合成：按照实施例2的合成方法，1H NMR(400MHz,DMSO-d6)δ7.79(dd,J＝8.9,2.0Hz,1H),7.63(dt,J＝9.0,2.0Hz,1H),7.38(td,J＝9.0,2.2Hz,1H),7.30(dq,J＝6.9,4.3,3.3Hz,1H),7.19(d,J＝1.8Hz,1H),7.14(ddt,J＝9.1,4.1,2.6Hz,1H),4.69(d,J＝3.6Hz,1H),4.02(d,J＝2.1Hz,3H),3.48(s,1H),3.36(d,J＝2.1Hz,2H),3.09–2.92(m,2H),2.59–2.52(m,2H),1.82–1.62(m,2H),1.51–1.33(m,2H).Example 41 4-(1-((5-(3-(3-Chloro-4-fluorophenyl)(methyl)amino)-(1-methyl)-1H-indazolyl)sulfonyl)piperidine ) Synthesis of alcohol: according to the synthesis method of Example 2, 1 H NMR (400MHz, DMSO-d 6 ) δ 7.79 (dd, J=8.9, 2.0 Hz, 1H), 7.63 (dt, J=9.0, 2.0 Hz) ,1H),7.38(td,J＝9.0,2.2Hz,1H),7.30(dq,J＝6.9,4.3,3.3Hz,1H),7.19(d,J＝1.8Hz,1H),7.14(ddt, J=9.1,4.1,2.6Hz,1H),4.69(d,J=3.6Hz,1H),4.02(d,J=2.1Hz,3H),3.48(s,1H),3.36(d,J=2.1 Hz, 2H), 3.09–2.92 (m, 2H), 2.59–2.52 (m, 2H), 1.82–1.62 (m, 2H), 1.51–1.33 (m, 2H).

Figure BDA0002385652160000313
Figure BDA0002385652160000313

实施例42 1-((5-(3-(4-氟苯基)氨基)-(1-环丙基)-(6-氟)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：以中间体7-6为原料，按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.66(d,J＝6.8Hz,1H),7.80–7.67(m,2H),7.54(d,J＝11.3Hz,1H),7.17(t,J＝8.9Hz,2H),4.72(d,J＝4.0Hz,1H),3.70–3.53(m,2H),3.36–3.28(m,2H),2.89(ddd,J＝12.0,8.5,3.2Hz,2H),1.77(ddt,J＝13.5,7.1,3.5Hz,2H),1.44(dtd,J＝12.4,8.3,3.6Hz,2H),1.12(dq,J＝6.1,2.4Hz,4H).13C NMR(101MHz,DMSO-d6)δ158.61(d,J＝173.9Hz),156.19(d,J＝159.3Hz),145.83,142.58(d,J＝12.4Hz),138.77(d,J＝2.2Hz),125.97(d,J＝3.2Hz),117.88(d,J＝7.4Hz),116.71(d,J＝19.0Hz),115.75(d,J＝22.2Hz),111.82,97.18(d,J＝27.5Hz),64.53,43.36,33.66,29.70,6.83.Example 42 1-((5-(3-(4-Fluorophenyl)amino)-(1-cyclopropyl)-(6-fluoro)-1H-indazolyl)sulfonyl)piperidine-4- Synthesis of alcohol: using intermediate 7-6 as raw material, according to the synthesis method of Example 3, 1 H NMR (400MHz, DMSO-d 6 )δ9.44(s, 1H), 8.66(d, J=6.8Hz, 1H), 7.80–7.67 (m, 2H), 7.54 (d, J=11.3Hz, 1H), 7.17 (t, J=8.9Hz, 2H), 4.72 (d, J=4.0Hz, 1H), 3.70– 3.53(m,2H),3.36–3.28(m,2H),2.89(ddd,J=12.0,8.5,3.2Hz,2H),1.77(ddt,J=13.5,7.1,3.5Hz,2H),1.44( dtd, J=12.4, 8.3, 3.6Hz, 2H), 1.12 (dq, J=6.1, 2.4Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 158.61 (d, J=173.9Hz) , 156.19(d, J＝159.3Hz), 145.83, 142.58(d, J＝12.4Hz), 138.77(d, J＝2.2Hz), 125.97(d, J＝3.2Hz), 117.88(d, J＝7.4 Hz), 116.71(d, J＝19.0Hz), 115.75(d, J＝22.2Hz), 111.82, 97.18(d, J＝27.5Hz), 64.53, 43.36, 33.66, 29.70, 6.83.

Figure BDA0002385652160000321
Figure BDA0002385652160000321

实施例43 1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-(6-氟)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：以中间体7-6为原料，按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.65(d,J＝6.3Hz,1H),7.68–7.57(m,1H),7.53(t,J＝8.2Hz,2H),7.09(t,J＝9.2Hz,1H),4.73(s,1H),3.60(dtd,J＝18.7,8.1,7.6,4.2Hz,2H),3.31(dd,J＝11.9,6.1Hz,2H),2.88(ddd,J＝12.3,8.4,3.5Hz,2H),2.24(d,J＝4.1Hz,3H),1.85–1.69(m,2H),1.44(dt,J＝8.4,4.1Hz,2H),1.15–1.02(m,4H).13C NMR(101MHz,DMSO-d6)δ158.22(d,J＝250.5Hz),155.25(d,J＝235.4Hz),145.87,142.56(d,J＝12.4Hz),138.46(d,J＝2.2Hz),125.97(d,J＝3.1Hz),124.49(d,J＝18.0Hz),119.29(d,J＝4.1Hz),116.66(d,J＝19.0Hz),115.42(d,J＝14.3Hz),115.27,111.87,97.14(d,J＝27.5Hz),64.53,43.35,33.66,29.71,15.10(d,J＝2.9Hz),6.79.Example 43 1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-(6-fluoro)-1H-indazolyl)sulfonyl) Synthesis of piperidin-4-ol: using intermediate 7-6 as raw material, according to the synthetic method of Example 3, 1 H NMR (400MHz, DMSO-d 6 )δ9.35(s, 1H), 8.65(d, J=6.3Hz, 1H), 7.68–7.57(m, 1H), 7.53(t, J=8.2Hz, 2H), 7.09(t, J=9.2Hz, 1H), 4.73(s, 1H), 3.60( dtd, J=18.7, 8.1, 7.6, 4.2Hz, 2H), 3.31 (dd, J=11.9, 6.1Hz, 2H), 2.88 (ddd, J=12.3, 8.4, 3.5Hz, 2H), 2.24 (d, J=4.1 Hz, 3H), 1.85–1.69 (m, 2H), 1.44 (dt, J=8.4, 4.1 Hz, 2H), 1.15–1.02 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 )δ158.22(d,J＝250.5Hz),155.25(d,J＝235.4Hz),145.87,142.56(d,J＝12.4Hz),138.46(d,J＝2.2Hz),125.97(d,J =3.1Hz),124.49(d,J=18.0Hz),119.29(d,J=4.1Hz),116.66(d,J=19.0Hz),115.42(d,J=14.3Hz),115.27,111.87,97.14 (d, J=27.5Hz), 64.53, 43.35, 33.66, 29.71, 15.10 (d, J=2.9Hz), 6.79.

Figure BDA0002385652160000322
Figure BDA0002385652160000322

实施例44N-(4-氟-3-甲基苯基)-3-(1-环丙基-5-(吗啉磺酰基)-1H-吲唑)胺的合成：Example 44 Synthesis of N-(4-fluoro-3-methylphenyl)-3-(1-cyclopropyl-5-(morpholinesulfonyl)-1H-indazol)amine:

Figure BDA0002385652160000323
Figure BDA0002385652160000323

中间体44-2的合成：两步总收率为62％。Synthesis of intermediate 44-2: The overall yield for two steps was 62%.

标题化合物的合成：按照实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.59(d,J＝1.5Hz,1H),7.78–7.67(m,2H),7.67–7.60(m,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),3.75–3.59(m,5H),2.87(dd,J＝5.6,3.4Hz,4H),2.25(s,3H),1.14(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.18(d,J＝235.1Hz),145.74,142.16,138.63(d,J＝2.2Hz),126.19,124.70,124.48(d,J＝18.1Hz),123.20,119.19(d,J＝4.0Hz),110.30,65.74,46.41,29.58,15.12(d,J＝3.0Hz),6.83.Synthesis of the title compound: according to the synthetic method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.29 (s, 1H), 8.59 (d, J=1.5 Hz, 1H), 7.78-7.67 (m ,2H),7.67–7.60(m,1H),7.54(dd,J=6.9,2.8Hz,1H),7.10(t,J=9.2Hz,1H),3.75–3.59(m,5H),2.87( dd, J=5.6, 3.4Hz, 4H), 2.25(s, 3H), 1.14(d, J=5.3Hz, 4H). 13 C NMR(101MHz, DMSO-d 6 )δ155.18(d,J= 235.1Hz), 145.74, 142.16, 138.63 (d, J=2.2Hz), 126.19, 124.70, 124.48 (d, J=18.1Hz), 123.20, 119.19 (d, J=4.0Hz), 110.30, 65.74, 46.41, 29.58, 15.12 (d, J=3.0Hz), 6.83.

实施例45N-(4-氟-苯基)-3-(1-环丙基-5-(吗啉磺酰基)-6-氟-1H-吲唑)胺的合成：Example 45 Synthesis of N-(4-fluoro-phenyl)-3-(1-cyclopropyl-5-(morpholinesulfonyl)-6-fluoro-1H-indazol)amine:

Figure BDA0002385652160000331
Figure BDA0002385652160000331

中间体45-1的合成：用0.6mmol底物，按照中间体1-3的合成方法。Synthesis of Intermediate 45-1: Using 0.6 mmol of substrate, following the synthesis method of Intermediate 1-3.

中间体45-2的合成：将上述产物溶于5mL乙酸，加入NBS(214mg,1.2mmol)，40℃反应24小时，减压蒸干，硅胶柱层析分离(石油醚/乙酸乙酯2/1)，得81mg，两步总收率为34％。Synthesis of intermediate 45-2: The above product was dissolved in 5 mL of acetic acid, NBS (214 mg, 1.2 mmol) was added, the reaction was carried out at 40° C. for 24 hours, evaporated to dryness under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/ 1), 81 mg was obtained, and the two-step total yield was 34%.

标题化合物的合成：按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.67(d,J＝6.6Hz,1H),7.80–7.68(m,2H),7.56(d,J＝11.3Hz,1H),7.16(t,J＝8.9Hz,2H),3.64(t,J＝10.5Hz,5H),3.04(t,J＝4.5Hz,4H),1.16–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ158.60(d,J＝172.4Hz),156.18(d,J＝157.5Hz),145.87,142.68(d,J＝12.4Hz),138.73(d,J＝2.0Hz),126.32(d,J＝3.2Hz),117.88(d,J＝7.3Hz),115.78(d,J＝22.2Hz),115.50(d,J＝19.0Hz),111.88,97.31(d,J＝27.5Hz),66.00,46.05,29.71,6.86.Synthesis of the title compound: according to the synthetic method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.67 (d, J=6.6 Hz, 1H), 7.80-7.68 (m ,2H),7.56(d,J＝11.3Hz,1H),7.16(t,J＝8.9Hz,2H),3.64(t,J＝10.5Hz,5H),3.04(t,J＝4.5Hz,4H The _ J=12.4Hz), 138.73(d, J=2.0Hz), 126.32(d, J=3.2Hz), 117.88(d, J=7.3Hz), 115.78(d, J=22.2Hz), 115.50(d, J=19.0Hz), 111.88, 97.31(d, J=27.5Hz), 66.00, 46.05, 29.71, 6.86.

实施例46N-(3-四氢呋喃基)-5-(1-环丙基-3-((4-氟苯基)氨基)-1H-吲唑)磺酰胺的合成：Example 46 Synthesis of N-(3-tetrahydrofuranyl)-5-(1-cyclopropyl-3-((4-fluorophenyl)amino)-1H-indazole)sulfonamide:

Figure BDA0002385652160000332
Figure BDA0002385652160000332

中间体46-2的合成：按照13-2的合成方法，两步总收率为66％。Synthesis of intermediate 46-2: According to the synthesis method of 13-2, the total yield of two steps was 66%.

标题化合物的合成：按照实施例13的合成方法Synthesis of the title compound: following the synthetic method of Example 13

实施例47 3-(1-((5-(3-(4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)吡咯烷)醇的合成：按照实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.64(s,1H),7.85–7.71(m,3H),7.67(d,J＝8.8Hz,1H),7.17(t,J＝8.7Hz,2H),4.91(s,1H),4.14(s,1H),3.64(p,J＝5.2Hz,1H),3.25(ddd,J＝15.8,9.8,6.2Hz,3H),3.01(dd,J＝10.4,2.4Hz,1H),1.72(dtd,J＝13.3,8.6,4.9Hz,1H),1.61(ddt,J＝13.3,7.0,3.6Hz,1H),1.13(d,J＝5.4Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.47(d,J＝235.5Hz),145.69,142.08,139.02(d,J＝2.2Hz),126.71,126.17,122.65,117.75(d,J＝7.4Hz),115.72(d,J＝22.2Hz),115.07,110.16,69.42,56.28,46.62,34.09,29.56,6.85.Example 47 Synthesis of 3-(1-((5-(3-(4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)pyrrolidin)ol: according to Synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.41 (s, 1H), 8.64 (s, 1H), 7.85-7.71 (m, 3H), 7.67 (d, J=8.8 Hz, 1H), 7.17(t, J＝8.7Hz, 2H), 4.91(s, 1H), 4.14(s, 1H), 3.64(p, J＝5.2Hz, 1H), 3.25(ddd, J＝15.8 ,9.8,6.2Hz,3H),3.01(dd,J＝10.4,2.4Hz,1H),1.72(dtd,J＝13.3,8.6,4.9Hz,1H),1.61(ddt,J＝13.3,7.0,3.6 Hz, 1H), 1.13 (d, J=5.4 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 156.47 (d, J=235.5 Hz), 145.69, 142.08, 139.02 (d, J= 2.2Hz), 126.71, 126.17, 122.65, 117.75 (d, J=7.4Hz), 115.72 (d, J=22.2Hz), 115.07, 110.16, 69.42, 56.28, 46.62, 34.09, 29.56, 6.85.

Figure BDA0002385652160000333
Figure BDA0002385652160000333

实施例48 4-(1-((5-(3-(4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)酮的合成：Example 48 Synthesis of 4-(1-((5-(3-(4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidin)one:

Figure BDA0002385652160000334
Figure BDA0002385652160000334

中间体48-2的合成：按照13-2的合成方法。Synthesis of Intermediate 48-2: Follow the synthetic method of 13-2.

中间体48-3的合成：按照实施例13的合成方法。Synthesis of Intermediate 48-3: The synthetic method of Example 13 was followed.

标题化合物的合成：将48-3(23mg,0.05mmol)溶于2mL丙酮，加入1mL浓盐酸，室温反应。反应完成后，减压蒸除丙酮，调pH到中性，有固体析出，过滤，干燥。1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.67(s,1H),7.82–7.66(m,4H),7.16(t,J＝8.7Hz,2H),3.66(p,J＝5.4Hz,1H),3.33(d,J＝6.6Hz,4H),2.44(t,J＝6.1Hz,4H),1.19–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ205.96,156.50(d,J＝235.6Hz),145.73,142.15,138.96(d,J＝2.1Hz),126.29,125.98,122.94,117.79(d,J＝7.4Hz),115.73(d,J＝22.2Hz),115.21,110.45,45.63,29.58,6.86.Synthesis of the title compound: Dissolve 48-3 (23 mg, 0.05 mmol) in 2 mL of acetone, add 1 mL of concentrated hydrochloric acid, and react at room temperature. After the completion of the reaction, the acetone was evaporated under reduced pressure, and the pH was adjusted to neutral, and a solid was precipitated, which was filtered and dried. 1 H NMR (400MHz, DMSO-d 6 )δ9.40(s,1H),8.67(s,1H),7.82-7.66(m,4H),7.16(t,J=8.7Hz,2H),3.66( p, J=5.4Hz, 1H), 3.33 (d, J=6.6Hz, 4H), 2.44 (t, J=6.1Hz, 4H), 1.19–1.07 (m, 4H). 13 C NMR (101MHz, DMSO) -d 6 )δ205.96,156.50(d,J=235.6Hz),145.73,142.15,138.96(d,J=2.1Hz),126.29,125.98,122.94,117.79(d,J=7.4Hz),115.73(d, J=22.2Hz), 115.21, 110.45, 45.63, 29.58, 6.86.

实施例491-((5-(1-环丙基)-(3-(3-甲基-4-氟苯基)氨基)-1H-吲唑基)磺酰基)-1,4-二氮杂卓-5-酮的合成Example 491-((5-(1-cyclopropyl)-(3-(3-methyl-4-fluorophenyl)amino)-1H-indazolyl)sulfonyl)-1,4-diazepine Synthesis of heterozo-5-one

Figure BDA0002385652160000341
Figure BDA0002385652160000341

中间体49-2的合成：按照13-2的合成方法。两步收率为44％。Synthesis of intermediate 49-2: Follow the synthetic method of 13-2. The two-step yield was 44%.

标题化合物的合成：按照实施例13的合成方法。1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.58(t,J＝1.2Hz,1H),7.75–7.57(m,4H),7.53(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),3.65(p,J＝5.3Hz,1H),3.24(dt,J＝5.8,3.6Hz,2H),3.16(ddd,J＝9.0,5.0,2.2Hz,4H),2.62–2.53(m,2H),2.25(d,J＝1.8Hz,3H),1.13(d,J＝5.3Hz,4H).Synthesis of the title compound: The synthesis method of Example 13 was followed. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (s, 1H), 8.58 (t, J=1.2 Hz, 1H), 7.75-7.57 (m, 4H), 7.53 (dd, J=6.9, 2.8 Hz, 1H), 7.10 (t, J=9.2Hz, 1H), 3.65 (p, J=5.3Hz, 1H), 3.24 (dt, J=5.8, 3.6Hz, 2H), 3.16 (ddd, J=9.0 ,5.0,2.2Hz,4H),2.62–2.53(m,2H),2.25(d,J=1.8Hz,3H),1.13(d,J=5.3Hz,4H).

实施例501-((5-(1-环丙基)-(3-(3,4-二氟苯基)氨基)-1H-吲唑基)磺酰基)-1,4-二氮杂卓-5-酮的合成：按照实施例49的合成方法。1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.58(s,1H),7.97–7.83(m,1H),7.72(s,2H),7.66(t,J＝5.4Hz,1H),7.48–7.32(m,2H),3.67(td,J＝6.8,6.3,3.3Hz,1H),3.24(q,J＝5.7Example 501-((5-(1-cyclopropyl)-(3-(3,4-difluorophenyl)amino)-1H-indazolyl)sulfonyl)-1,4-diazepine Synthesis of -5-keto: The synthetic method of Example 49 was followed. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.61(s, 1H), 8.58(s, 1H), 7.97-7.83(m, 1H), 7.72(s, 2H), 7.66(t, J=5.4 Hz, 1H), 7.48–7.32 (m, 2H), 3.67 (td, J=6.8, 6.3, 3.3Hz, 1H), 3.24 (q, J=5.7

Hz,2H),3.17(q,J＝7.4,6.2Hz,4H),2.59–2.53(m,2H),1.19–1.09(m,4H).Hz, 2H), 3.17 (q, J=7.4, 6.2 Hz, 4H), 2.59–2.53 (m, 2H), 1.19–1.09 (m, 4H).

Figure BDA0002385652160000342
Figure BDA0002385652160000342

实施例51N-(2，3-二羟基丙基)-N-甲基-5-(1-环丙基-3-((3-甲基4-氟苯基)氨基)-1H-吲唑)磺酰胺的合成：Example 51N-(2,3-Dihydroxypropyl)-N-methyl-5-(1-cyclopropyl-3-((3-methyl4-fluorophenyl)amino)-1H-indazole ) Synthesis of sulfonamide:

Figure BDA0002385652160000343
Figure BDA0002385652160000343

中间体51-2的合成：按照3-4的合成方法。三步总收率为49％。Synthesis of Intermediate 51-2: Follow the synthetic method of 3-4. The three-step overall yield was 49%.

标题化合物的合成：按照实施例3的合成方法。1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.61(d,J＝1.5Hz,1H),7.76–7.67(m,2H),7.67–7.61(m,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),4.86(d,J＝5.2Hz,1H),4.62(t,J＝5.6Hz,1H),3.72–3.58(m,2H),3.37–3.34(m,2H),3.08(dd,J＝13.4,4.4Hz,1H),2.85–2.71(m,4H),2.25(d,J＝1.8Hz,3H),1.13(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.14(d,J＝235.0Hz),145.66,141.96,138.68(d,J＝2.2Hz),127.33,125.85,124.47(d,J＝18.1Hz),122.47,119.16(d,J＝4.2Hz),115.38(d,J＝23.0Hz),115.16(d,J＝7.3Hz),115.09,110.33,70.63,64.27,53.51,36.87,29.55,15.15(d,J＝2.9Hz),6.85.Synthesis of the title compound: The synthesis method of Example 3 was followed. 1 H NMR (400MHz, DMSO-d 6 )δ9.28(s,1H),8.61(d,J=1.5Hz,1H),7.76-7.67(m,2H),7.67-7.61(m,1H), 7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),4.86(d,J＝5.2Hz,1H),4.62(t,J＝5.6Hz,1H), 3.72–3.58 (m, 2H), 3.37–3.34 (m, 2H), 3.08 (dd, J=13.4, 4.4Hz, 1H), 2.85–2.71 (m, 4H), 2.25 (d, J=1.8Hz, 3H), 1.13(d, J=5.2Hz, 4H). 13 C NMR(101MHz, DMSO-d 6 )δ155.14(d, J=235.0Hz), 145.66, 141.96, 138.68(d, J=2.2Hz ),127.33,125.85,124.47(d,J＝18.1Hz),122.47,119.16(d,J＝4.2Hz),115.38(d,J＝23.0Hz),115.16(d,J＝7.3Hz),115.09, 110.33, 70.63, 64.27, 53.51, 36.87, 29.55, 15.15 (d, J=2.9Hz), 6.85.

实施例521-(5-(1-环丙基-3-((3-甲基4-氟苯基)氨基)-1H-吲唑)磺酰胺)-4-羟甲基哌啶-4-醇的合成：Example 521-(5-(1-Cyclopropyl-3-((3-methyl4-fluorophenyl)amino)-1H-indazole)sulfonamide)-4-hydroxymethylpiperidine-4- Synthesis of alcohols:

Figure BDA0002385652160000351
Figure BDA0002385652160000351

中间体52-2的合成：按照13-2的合成方法。收率11％。Synthesis of Intermediate 52-2: Follow the synthetic method of 13-2. Yield 11%.

标题化合物的合成：按照实施例13的合成方法。1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.56(s,1H),7.69(s,2H),7.63(dt,J＝8.3,3.6Hz,1H),7.53(dd,J＝6.9,2.7Hz,1H),7.09(t,J＝9.2Hz,1H),4.62(t,J＝5.7Hz,1H),4.08(s,1H),3.64(dq,J＝6.8,4.3,3.4Hz,1H),3.44(d,J＝11.1Hz,2H),3.13(d,J＝5.7Hz,2H),2.49–2.37(m,2H),2.24(s,3H),1.62(td,J＝13.1,4.6Hz,2H),1.41(d,J＝13.4Hz,2H),1.18–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ155.16(d,J＝235.1Hz),145.64,142.06,138.69,126.21,125.75,124.46(d,J＝18.1Hz),122.78,119.19(d,J＝4.0Hz),115.49,115.25(d,J＝2.9Hz),115.18,110.18,69.87,68.21,42.36,32.74,29.58,15.12(d,J＝3.0Hz),6.84.Synthesis of the title compound: The synthesis method of Example 13 was followed. 1 H NMR (400MHz, DMSO-d 6 )δ9.26(s,1H),8.56(s,1H),7.69(s,2H),7.63(dt,J=8.3,3.6Hz,1H),7.53( dd,J=6.9,2.7Hz,1H),7.09(t,J=9.2Hz,1H),4.62(t,J=5.7Hz,1H),4.08(s,1H),3.64(dq,J=6.8 ,4.3,3.4Hz,1H),3.44(d,J=11.1Hz,2H),3.13(d,J=5.7Hz,2H),2.49–2.37(m,2H),2.24(s,3H),1.62 (td, J=13.1, 4.6 Hz, 2H), 1.41 (d, J=13.4 Hz, 2H), 1.18–1.07 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 155.16 (d , J=235.1Hz), 145.64, 142.06, 138.69, 126.21, 125.75, 124.46 (d, J=18.1Hz), 122.78, 119.19 (d, J=4.0Hz), 115.49, 115.25 (d, J=2.9Hz) ,115.18,110.18,69.87,68.21,42.36,32.74,29.58,15.12(d,J＝3.0Hz),6.84.

实施例53 4-(1-(5-(1-环丙基-3-((4-氟苯基)氨基)-1H-吲唑)磺酰胺)哌啶)醇的合成：Example 53 Synthesis of 4-(1-(5-(1-cyclopropyl-3-((4-fluorophenyl)amino)-1H-indazole)sulfonamide)piperidin)ol:

Figure BDA0002385652160000352
Figure BDA0002385652160000352

中间体53-2的合成：按照化合物3-4的合成方法。Synthesis of intermediate 53-2: Follow the synthetic method of compound 3-4.

标题化合物的合成：按照实施例3的合成方法。1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.58(d,J＝1.2Hz,1H),7.80–7.72(m,2H),7.70(d,J＝1.7Hz,2H),7.24–7.10(m,2H),4.98(d,J＝4.8Hz,1H),3.65(p,J＝5.3Hz,1H),3.55(tq,J＝8.8,4.1Hz,1H),3.46(dd,J＝10.9,4.2Hz,1H),3.30(s,1H),2.31(td,J＝11.1,2.5Hz,1H),2.18–2.07(m,1H),1.81–1.65(m,2H),1.47(qd,J＝11.7,10.6,3.7Hz,1H),1.13(d,J＝5.3Hz,4H),1.11–1.00(m,1H).13CNMR(101MHz,DMSO-d6)δ156.49(d,J＝235.5Hz),145.65,142.08,138.97(d,J＝2.0Hz),126.11,125.95,122.71,117.78(d,J＝7.3Hz),115.74(d,J＝22.1Hz),115.13,110.26,65.50,53.14,46.33,32.43,29.57,22.72,6.86.Synthesis of the title compound: The synthesis method of Example 3 was followed. 1 H NMR (400MHz, DMSO-d 6 )δ9.38(s,1H),8.58(d,J=1.2Hz,1H),7.80-7.72(m,2H),7.70(d,J=1.7Hz, 2H), 7.24–7.10 (m, 2H), 4.98 (d, J=4.8Hz, 1H), 3.65 (p, J=5.3Hz, 1H), 3.55 (tq, J=8.8, 4.1Hz, 1H), 3.46 (dd, J=10.9, 4.2Hz, 1H), 3.30 (s, 1H), 2.31 (td, J=11.1, 2.5Hz, 1H), 2.18–2.07 (m, 1H), 1.81–1.65 (m, 2H), 1.47 (qd, J=11.7, 10.6, 3.7Hz, 1H), 1.13 (d, J=5.3Hz, 4H), 1.11-1.00 (m, 1H). 13 CNMR (101MHz, DMSO-d 6 ) δ156.49(d,J＝235.5Hz),145.65,142.08,138.97(d,J＝2.0Hz),126.11,125.95,122.71,117.78(d,J＝7.3Hz),115.74(d,J＝22.1Hz) ),115.13,110.26,65.50,53.14,46.33,32.43,29.57,22.72,6.86.

实施例54(3-(1-(5-(1-环丙基-3-((3-甲基4-氟苯基)氨基)-1H-吲唑)磺酰胺)吡咯基)甲醇的合成：Example 54 (Synthesis of 3-(1-(5-(1-cyclopropyl-3-((3-methyl4-fluorophenyl)amino)-1H-indazole)sulfonamide)pyrrolyl)methanol :

Figure BDA0002385652160000353
Figure BDA0002385652160000353

中间体54-2的合成：按照13-2的合成方法。两步收率为32％。Synthesis of intermediate 54-2: Follow the synthetic method of 13-2. The two-step yield was 32%.

标题化合物的合成：按照实施例13的合成方法。1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.64(d,J＝1.6Hz,1H),7.77(dd,J＝8.9,1.7Hz,1H),7.69(d,J＝8.9Hz,1H),7.64(ddd,J＝8.8,4.3,2.8Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),4.62(t,J＝5.2Hz,1H),3.66(p,J＝5.3Hz,1H),3.29–3.06(m,5H),2.93(dd,J＝10.0,6.6Hz,1H),2.25(d,J＝1.8Hz,3H),2.13(dq,J＝14.1,7.5Hz,1H),1.75(dtd,J＝12.5,7.5,5.1Hz,1H),1.45(dq,J＝12.4,7.6Hz,1H),1.13(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.14(d,J＝235.0Hz),145.70,142.05,138.67(d,J＝2.2Hz),126.20,126.13,124.47(d,J＝18.0Hz),122.73,119.15(d,J＝4.1Hz),115.39(d,J＝22.8Hz),115.19,115.11,110.22,62.55,50.87,47.83,29.56,27.55,15.15(d,J＝3.0Hz),6.85.Synthesis of the title compound: The synthesis method of Example 13 was followed. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.29 (s, 1H), 8.64 (d, J=1.6 Hz, 1H), 7.77 (dd, J=8.9, 1.7 Hz, 1H), 7.69 (d, J=8.9Hz, 1H), 7.64(ddd, J=8.8, 4.3, 2.8Hz, 1H), 7.54(dd, J=6.9, 2.8Hz, 1H), 7.10(t, J=9.2Hz, 1H), 4.62(t, J=5.2Hz, 1H), 3.66(p, J=5.3Hz, 1H), 3.29–3.06(m, 5H), 2.93(dd, J=10.0, 6.6Hz, 1H), 2.25(d , J=1.8Hz, 3H), 2.13 (dq, J=14.1, 7.5Hz, 1H), 1.75 (dtd, J=12.5, 7.5, 5.1Hz, 1H), 1.45 (dq, J=12.4, 7.6Hz, 1H), 1.13(d, J=5.3Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ155.14(d, J=235.0Hz), 145.70, 142.05, 138.67(d, J=2.2Hz) ),126.20,126.13,124.47(d,J＝18.0Hz),122.73,119.15(d,J＝4.1Hz),115.39(d,J＝22.8Hz),115.19,115.11,110.22,62.55,50.87,47.83, 29.56, 27.55, 15.15 (d, J=3.0Hz), 6.85.

实施例55(2-(4-(5-(1-环丙基)-3-((3-甲基4-氟苯基)氨基)-1H-吲唑)磺酰基)吗啉基)甲醇的合成：Example 55 (2-(4-(5-(1-cyclopropyl)-3-((3-methyl4-fluorophenyl)amino)-1H-indazole)sulfonyl)morpholinyl)methanol Synthesis:

Figure BDA0002385652160000361
Figure BDA0002385652160000361

中间体55-1的合成：按照13-1的合成方法。收率32％。Synthesis of Intermediate 55-1: Follow the synthetic method of 13-1. Yield 32%.

中间体55-2的合成：按照13-2的合成方法。收率69％。Synthesis of intermediate 55-2: Follow the synthetic method of 13-2. Yield 69%.

标题化合物的合成：按照实施例13的合成方法。1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.60(d,J＝1.5Hz,1H),7.72(d,J＝8.8Hz,1H),7.68(dd,J＝8.9,1.6Hz,1H),7.67–7.61(m,1H),7.55(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),4.81(t,J＝5.7Hz,1H),3.91–3.84(m,1H),3.66(dq,J＝7.2,4.6Hz,1H),3.62–3.52(m,2H),3.52–3.38(m,3H),3.29(dt,J＝11.6,6.0Hz,1H),2.33–2.21(m,4H),2.02(t,J＝10.7Hz,1H),1.24–1.04(m,4H).13CNMR(101MHz,DMSO-d6)δ155.18(d,J＝235.1Hz),145.72,142.16,138.62(d,J＝2.2Hz),126.16,124.76,124.48(d,J＝18.0Hz),123.16,119.21(d,J＝4.1Hz),115.38(d,J＝23.5Hz),115.22,115.22(d,J＝7.6Hz),110.36,75.90,65.49,62.24,48.32,46.10,29.58,15.13(d,J＝2.9Hz),6.84.Synthesis of the title compound: The synthesis method of Example 13 was followed. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.31 (s, 1H), 8.60 (d, J=1.5 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.68 (dd, J= 8.9, 1.6Hz, 1H), 7.67–7.61 (m, 1H), 7.55 (dd, J=6.9, 2.8Hz, 1H), 7.10 (t, J=9.2Hz, 1H), 4.81 (t, J=5.7 Hz, 1H), 3.91–3.84 (m, 1H), 3.66 (dq, J=7.2, 4.6Hz, 1H), 3.62–3.52 (m, 2H), 3.52–3.38 (m, 3H), 3.29 (dt, J=11.6, 6.0Hz, 1H), 2.33-2.21 (m, 4H), 2.02 (t, J=10.7Hz, 1H), 1.24-1.04 (m, 4H). 13 CNMR (101MHz, DMSO-d 6 ) δ155.18(d,J＝235.1Hz),145.72,142.16,138.62(d,J＝2.2Hz),126.16,124.76,124.48(d,J＝18.0Hz),123.16,119.21(d,J＝4.1Hz ),115.38(d,J＝23.5Hz),115.22,115.22(d,J＝7.6Hz),110.36,75.90,65.49,62.24,48.32,46.10,29.58,15.13(d,J＝2.9Hz),6.84.

实施例56 4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶)酮的合成：按照实施例48的合成方法。1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.65(d,J＝1.6Hz,1H),7.75(dd,J＝8.9,1.7Hz,1H),7.69(d,J＝8.8Hz,1H),7.64(ddd,J＝8.9,4.4,2.9Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),3.65(tt,J＝5.7,4.6Hz,1H),3.31(t,J＝6.2Hz,4H),2.44(t,J＝6.2Hz,4H),2.25(d,J＝1.8Hz,3H),1.18–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ205.94,155.18(d,J＝235.1Hz),145.74,142.13,138.62(d,J＝2.2Hz),126.19,125.94,124.49(d,J＝18.0Hz),122.91,119.17(d,J＝4.0Hz),115.39(d,J＝22.7Hz),115.25,115.20(d,J＝7.3Hz),110.41,45.63,29.58,15.12(d,J＝3.0Hz),6.83.Example 56 4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine) Synthesis of ketones: The synthesis method of Example 48 was followed. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.28 (s, 1H), 8.65 (d, J=1.6 Hz, 1H), 7.75 (dd, J=8.9, 1.7 Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 7.64(ddd, J=8.9, 4.4, 2.9Hz, 1H), 7.54(dd, J=6.9, 2.8Hz, 1H), 7.09(t, J=9.2Hz, 1H), 3.65(tt,J＝5.7,4.6Hz,1H),3.31(t,J＝6.2Hz,4H),2.44(t,J＝6.2Hz,4H),2.25(d,J＝1.8Hz,3H), 1.18–1.07(m, 4H). 13 C NMR(101MHz, DMSO-d 6 )δ205.94,155.18(d,J=235.1Hz),145.74,142.13,138.62(d,J=2.2Hz),126.19,125.94, 124.49(d,J＝18.0Hz),122.91,119.17(d,J＝4.0Hz),115.39(d,J＝22.7Hz),115.25,115.20(d,J＝7.3Hz),110.41,45.63,29.58, 15.12(d, J=3.0Hz), 6.83.

Figure BDA0002385652160000362
Figure BDA0002385652160000362

实施例57 5-(((1S,4S)-2-氧代-5-氮杂二环[2.2.1]己-5-基)磺酰基)-1-环丙基-N-(4-氟-3-甲基苯基)-1H-吲唑-3-胺Example 57 5-(((1S,4S)-2-oxo-5-azabicyclo[2.2.1]hex-5-yl)sulfonyl)-1-cyclopropyl-N-(4- Fluoro-3-methylphenyl)-1H-indazol-3-amine

Figure BDA0002385652160000363
Figure BDA0002385652160000363

中间体57-1的合成：按13-1的合成方法，不经纯化。Synthesis of intermediate 57-1: According to the synthetic method of 13-1 without purification.

中间体57-2的合成：按13-2的合成方法，收率70％。Synthesis of intermediate 57-2: According to the synthetic method of 13-2, the yield is 70%.

标题化合物的合成：按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.67(d,J＝1.6Hz,1H),7.82(dd,J＝8.8,1.7Hz,1H),7.69(d,J＝8.8Hz,1H),7.64(ddd,J＝8.9,4.5,3.0Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),4.46(d,J＝3.0Hz,2H),3.72–3.63(m,2H),3.60(dd,J＝7.6,1.8Hz,1H),3.23(d,J＝10.0Hz,1H),3.12(dd,J＝10.0,1.6Hz,1H),2.25(d,J＝1.9Hz,3H),1.62–1.49(m,1H),1.19–1.07(m,4H),0.96(dd,J＝10.1,2.3Hz,1H).Synthesis of the title compound: according to the synthesis method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.28 (s, 1H), 8.67 (d, J=1.6 Hz, 1H), 7.82 (dd, J ＝8.8,1.7Hz,1H),7.69(d,J＝8.8Hz,1H),7.64(ddd,J＝8.9,4.5,3.0Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H) ,7.10(t,J＝9.2Hz,1H),4.46(d,J＝3.0Hz,2H),3.72–3.63(m,2H),3.60(dd,J＝7.6,1.8Hz,1H),3.23( d, J=10.0Hz, 1H), 3.12 (dd, J=10.0, 1.6Hz, 1H), 2.25 (d, J=1.9Hz, 3H), 1.62–1.49 (m, 1H), 1.19–1.07 (m ,4H),0.96(dd,J＝10.1,2.3Hz,1H).

实施例58N-(3,4,5-三氟苯基)-3-(1-环丙基-5-(吗啉磺酰基)-1H-吲唑并[3,4-c]吡啶)胺的合成：Example 58 N-(3,4,5-Trifluorophenyl)-3-(1-cyclopropyl-5-(morpholinesulfonyl)-1H-indazolo[3,4-c]pyridin)amine Synthesis:

Figure BDA0002385652160000371
Figure BDA0002385652160000371

中间体58-1的合成：按1-3的合成方法，收率97％。Synthesis of intermediate 58-1: According to the synthetic method of 1-3, the yield is 97%.

中间体58-2的合成：将中间体58-1(92mg,0.3mmol)溶于3mL乙腈和乙酸，加入1,3-二溴-5,5-二甲基海因(129mg,0.45mmol)，50℃反应48小时，反应完成后，减压蒸干，硅胶柱层析分离，得68mg，收率59％。Synthesis of Intermediate 58-2: Intermediate 58-1 (92 mg, 0.3 mmol) was dissolved in 3 mL of acetonitrile and acetic acid, and 1,3-dibromo-5,5-dimethylhydantoin (129 mg, 0.45 mmol) was added , and reacted at 50° C. for 48 hours. After the reaction was completed, evaporated to dryness under reduced pressure and separated by silica gel column chromatography to obtain 68 mg with a yield of 59%.

标题化合物的合成：按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),9.13(s,1H),8.73(s,1H),7.61(dt,J＝8.4,3.6Hz,1H),7.52(dd,J＝6.8,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),3.83(tt,J＝7.0,3.8Hz,1H),3.64(t,J＝4.7Hz,4H),3.13(t,J＝4.7Hz,4H),2.26(d,J＝1.8Hz,3H),1.31–1.12(m,4H).13C NMR(101MHz,DMSO-d6)δ155.36(d,J＝235.5Hz),145.64,142.65,138.26(d,J＝2.2Hz),137.71,134.66,124.64(d,J＝18.0Hz),119.27(d,J＝4.2Hz),119.00,117.38,115.66–115.35(m),115.29,66.07,46.85,30.20,15.11(d,J＝2.9Hz),6.95.Synthesis of the title compound: according to the synthetic method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.44 (s, 1H), 9.13 (s, 1H), 8.73 (s, 1H), 7.61 (dt , J=8.4, 3.6Hz, 1H), 7.52 (dd, J=6.8, 2.8Hz, 1H), 7.11 (t, J=9.2Hz, 1H), 3.83 (tt, J=7.0, 3.8Hz, 1H) , 3.64(t, J=4.7Hz, 4H), 3.13(t, J=4.7Hz, 4H), 2.26(d, J=1.8Hz, 3H), 1.31–1.12(m, 4H). 13 C NMR( 101MHz, DMSO-d 6 )δ155.36(d,J=235.5Hz),145.64,142.65,138.26(d,J=2.2Hz),137.71,134.66,124.64(d,J=18.0Hz),119.27(d , J＝4.2Hz), 119.00, 117.38, 115.66–115.35(m), 115.29, 66.07, 46.85, 30.20, 15.11(d, J＝2.9Hz), 6.95.

实施例59 1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶-4-醇的合成：以中间体10-7为原料，按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),9.12(s,1H),8.71(s,1H),7.61(dt,J＝8.3,3.6Hz,1H),7.51(dd,J＝6.8,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),4.70(d,J＝3.9Hz,1H),3.82(dq,J＝7.1,3.5Hz,1H),3.55(tt,J＝8.1,4.6Hz,1H),3.48–3.37(m,2H),2.94(ddd,J＝12.2,8.9,3.4Hz,2H),2.38–2.16(m,3H),1.83–1.68(m,2H),1.42(dtd,J＝12.6,8.6,3.7Hz,2H),1.28–1.13(m,4H).13C NMR(101MHz,DMSO-d6)δ155.34(d,J＝235.5Hz),145.59,143.45,138.29(d,J＝2.3Hz),137.64,134.47,124.62(d,J＝18.2Hz),119.26(d,J＝4.3Hz),119.05,116.87,115.59,115.36,115.30(d,J＝7.2Hz),64.79,44.18,33.77,30.19,15.11(d,J＝3.0Hz),6.94.Example 59 1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo[3,4-c]pyridyl) Synthesis of sulfonyl)piperidin-4-ol: using intermediate 10-7 as raw material, according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.43(s,1H), 9.12 (s,1H),8.71(s,1H),7.61(dt,J=8.3,3.6Hz,1H),7.51(dd,J=6.8,2.8Hz,1H),7.11(t,J=9.2Hz, 1H), 4.70 (d, J=3.9Hz, 1H), 3.82 (dq, J=7.1, 3.5Hz, 1H), 3.55 (tt, J=8.1, 4.6Hz, 1H), 3.48–3.37 (m, 2H) ), 2.94 (ddd, J=12.2, 8.9, 3.4Hz, 2H), 2.38–2.16 (m, 3H), 1.83–1.68 (m, 2H), 1.42 (dtd, J=12.6, 8.6, 3.7Hz, 2H The _ 134.47,124.62(d,J=18.2Hz),119.26(d,J=4.3Hz),119.05,116.87,115.59,115.36,115.30(d,J=7.2Hz),64.79,44.18,33.77,30.19,15.11( d, J=3.0Hz), 6.94.

Figure BDA0002385652160000372
Figure BDA0002385652160000372

实施例60 1-((5-(3-(3,4-二氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶-4-醇的合成：以中间体10-7为原料，按实施例13的合成方法，1H NMR(400MHz,DMSO)δ9.73(s,1H),9.15(s,1H),8.68(s,1H),7.92–7.76(m,1H),7.40(dd,J＝16.9,7.9Hz,2H),4.69(d,J＝3.9Hz,1H),3.92–3.77(m,1H),3.55(dd,J＝7.4,3.7Hz,1H),3.49–3.36(m,2H),2.95(t,J＝9.0Hz,2H),1.84–1.66(m,2H),1.52–1.32(m,2H),1.31–1.12(m,4H).13C NMR(101MHz,DMSO-d6)δ149.72(dd,J＝242.1,13.2Hz),145.07,143.71,143.66(dd,J＝237.6,12.8Hz),139.23(dd,J＝9.3,2.2Hz),137.58,134.69,118.87,118.06(d,J＝18.0Hz),116.66,112.71(dd,J＝5.2,2.7Hz),105.14(d,J＝22.0Hz),64.78,44.17,33.77,30.25,6.95.Example 60 1-((5-(3-(3,4-difluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo[3,4-c]pyridyl)sulfonyl ) Synthesis of piperidin-4-ol: using intermediate 10-7 as raw material, according to the synthesis method of Example 13, 1 H NMR (400 MHz, DMSO) δ 9.73 (s, 1H), 9.15 (s, 1H) , 8.68 (s, 1H), 7.92–7.76 (m, 1H), 7.40 (dd, J=16.9, 7.9Hz, 2H), 4.69 (d, J=3.9Hz, 1H), 3.92–3.77 (m, 1H) ),3.55(dd,J=7.4,3.7Hz,1H),3.49-3.36(m,2H),2.95(t,J=9.0Hz,2H),1.84-1.66(m,2H),1.52-1.32( m, 2H), 1.31–1.12 (m, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 149.72 (dd, J=242.1, 13.2Hz), 145.07, 143.71, 143.66 (dd, J=237.6 ,12.8Hz),139.23(dd,J=9.3,2.2Hz),137.58,134.69,118.87,118.06(d,J=18.0Hz),116.66,112.71(dd,J=5.2,2.7Hz),105.14(d , J＝22.0Hz), 64.78, 44.17, 33.77, 30.25, 6.95.

Figure BDA0002385652160000373
Figure BDA0002385652160000373

实施例61-62的合成：Synthesis of Examples 61-62:

Figure BDA0002385652160000381
Figure BDA0002385652160000381

中间体61-1的合成：按照13-1的合成方法，收率69％。Synthesis of intermediate 61-1: According to the synthetic method of 13-1, the yield is 69%.

中间体61-2的合成：按照13-2的合成方法。Synthesis of Intermediate 61-2: Follow the synthetic method of 13-2.

实施例61(1-(5-(3-(4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)吡咯烷-3-甲酸甲酯的合成：按照实施例13的合成方法，收率71％。1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.66(s,1H),7.83–7.72(m,3H),7.70(d,J＝8.8Hz,1H),7.17(t,J＝8.7Hz,2H),3.66(p,J＝5.2Hz,1H),3.45–3.29(m,2H),3.30–3.13(m,2H),3.04(p,J＝7.3Hz,1H),1.98(dq,J＝13.8,7.2Hz,1H),1.88(dq,J＝13.6,7.1Hz,1H),1.13(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ173.12,156.49(d,J＝235.8Hz),145.72,142.14,138.97(d,J＝2.0Hz),126.14,125.97,122.89,117.76(d,J＝7.4Hz),115.75(d,J＝22.1Hz),115.14,110.32,52.28,50.12,47.84,42.26,29.57,28.26,6.86.Example 61 Synthesis of (1-(5-(3-(4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)pyrrolidine-3-carboxylic acid methyl ester: According to the synthetic method of Example 13, the yield was 71%. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.38(s, 1H), 8.66(s, 1H), 7.83-7.72(m, 3H), 7.70(d, J=8.8Hz, 1H), 7.17( t, J=8.7Hz, 2H), 3.66 (p, J=5.2Hz, 1H), 3.45–3.29 (m, 2H), 3.30–3.13 (m, 2H), 3.04 (p, J=7.3Hz, 1H) ), 1.98(dq, J=13.8, 7.2Hz, 1H), 1.88(dq, J=13.6, 7.1Hz, 1H), 1.13(d, J=5.2Hz, 4H). 13 C NMR (101MHz, DMSO- d 6 )δ173.12,156.49(d,J=235.8Hz),145.72,142.14,138.97(d,J=2.0Hz),126.14,125.97,122.89,117.76(d,J=7.4Hz),115.75(d,J = 22.1Hz), 115.14, 110.32, 52.28, 50.12, 47.84, 42.26, 29.57, 28.26, 6.86.

实施例62(1-(5-(3-(4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)吡咯烷-3-甲酸的合成：30mg(0.065mmol)化合物61溶于1mL THF和1mL水中，加入12mg(0.3mmol)氢氧化锂一水合物，室温反应。完成后，减压蒸除THF，用1N盐酸调节pH到2，过滤，干燥。1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),9.37(s,1H),8.66(s,1H),7.77(dt,J＝8.9,5.7Hz,3H),7.69(d,J＝8.9Hz,1H),7.17(t,J＝8.8Hz,2H),3.65(p,J＝5.3Hz,1H),3.43–3.28(m,2H),3.28–3.12(m,2H),2.94(p,J＝7.3Hz,1H),1.97(dd,J＝13.0,7.1Hz,1H),1.88(td,J＝14.6,12.8,7.9Hz,1H),1.14(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ174.26,156.48(d,J＝235.7Hz),145.71,142.14,138.99(d,J＝2.1Hz),126.16,126.04,122.86,117.77(d,J＝7.5Hz),115.74(d,J＝22.0Hz),115.13,110.30,50.21,47.89,42.52,29.57,28.37,6.86.Example 62 Synthesis of (1-(5-(3-(4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)pyrrolidine-3-carboxylic acid: 30 mg ( 0.065 mmol) compound 61 was dissolved in 1 mL of THF and 1 mL of water, 12 mg (0.3 mmol) of lithium hydroxide monohydrate was added, and the reaction was carried out at room temperature. After completion, the THF was evaporated under reduced pressure, the pH was adjusted to 2 with 1N hydrochloric acid, filtered and dried. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.52 (s, 1H), 9.37 (s, 1H), 8.66 (s, 1H), 7.77 (dt, J=8.9, 5.7Hz, 3H), 7.69 ( d, J=8.9Hz, 1H), 7.17 (t, J=8.8Hz, 2H), 3.65 (p, J=5.3Hz, 1H), 3.43–3.28 (m, 2H), 3.28–3.12 (m, 2H) ),2.94(p,J=7.3Hz,1H),1.97(dd,J=13.0,7.1Hz,1H),1.88(td,J=14.6,12.8,7.9Hz,1H),1.14(d,J= 5.3Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ174.26, 156.48 (d, J=235.7Hz), 145.71, 142.14, 138.99 (d, J=2.1Hz), 126.16, 126.04, 122.86, 117.77 (d, J=7.5Hz), 115.74 (d, J=22.0Hz), 115.13, 110.30, 50.21, 47.89, 42.52, 29.57, 28.37, 6.86.

实施例63 1-环丙基-5-(((2R,6S)-2,6-二甲基吗啉)磺酰基)-N-(4-氟-3-甲基苯基)-1H-吲唑-3-胺的合成：Example 63 1-Cyclopropyl-5-(((2R,6S)-2,6-dimethylmorpholine)sulfonyl)-N-(4-fluoro-3-methylphenyl)-1H- Synthesis of indazol-3-amine:

Figure BDA0002385652160000382
Figure BDA0002385652160000382

中间体63-2的合成：按照13-2的合成方法，收率70％。Synthesis of intermediate 63-2: According to the synthetic method of 13-2, the yield is 70%.

标题化合物的合成：按照实施例13的合成方法。1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.59(s,1H),7.83–7.59(m,3H),7.55(d,J＝6.8Hz,1H),7.10(t,J＝9.2Hz,1H),3.78–3.58(m,3H),3.53(d,J＝11.2Hz,2H),2.26(s,3H),1.86(t,J＝10.8Hz,2H),1.33–0.86(m,10H).13C NMR(101MHz,DMSO-d6)δ155.17(d,J＝235.1Hz),145.73,142.14,138.61(d,J＝2.3Hz),126.18,124.91,124.48(d,J＝18.0Hz),123.03,119.22(d,J＝4.0Hz),115.37(d,J＝23.3Hz),115.21,115.18,110.35,71.11,51.09,29.57,18.96,15.13(d,J＝3.2Hz),6.84.Synthesis of the title compound: The synthesis method of Example 13 was followed. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.29(s, 1H), 8.59(s, 1H), 7.83-7.59(m, 3H), 7.55(d, J=6.8Hz, 1H), 7.10( t, J=9.2Hz, 1H), 3.78–3.58 (m, 3H), 3.53 (d, J=11.2Hz, 2H), 2.26 (s, 3H), 1.86 (t, J=10.8Hz, 2H), 1.33-0.86 (m, 10H). 13 C NMR (101MHz, DMSO-d 6 ) δ155.17 (d, J=235.1Hz), 145.73, 142.14, 138.61 (d, J=2.3Hz), 126.18, 124.91, 124.48(d, J＝18.0Hz), 123.03, 119.22(d, J＝4.0Hz), 115.37(d, J＝23.3Hz), 115.21, 115.18, 110.35, 71.11, 51.09, 29.57, 18.96, 15.13(d, J=3.2Hz), 6.84.

实施例64(4-(1-(5-(1-环丙基)-3-((3-甲基-4-氟苯基)氨基)-1H-吲唑)磺酰基)哌啶)甲醇的合成：Example 64 (4-(1-(5-(1-cyclopropyl)-3-((3-methyl-4-fluorophenyl)amino)-1H-indazole)sulfonyl)piperidine)methanol Synthesis:

Figure BDA0002385652160000383
Figure BDA0002385652160000383

中间体64-2的合成：按3-4的合成方法，两步收率为76％。Synthesis of intermediate 64-2: According to the synthesis method of 3-4, the two-step yield was 76%.

标题化合物的合成：按实施例3的合成方法。1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.57(d,J＝1.4Hz,1H),7.84–7.70(m,3H),7.68(d,J＝1.2Hz,2H),7.16(t,J＝8.9Hz,2H),4.49(t,J＝5.1Hz,1H),3.75–3.58(m,3H),3.27–3.10(m,2H),2.17(td,J＝11.7,2.4Hz,2H),1.70(dd,J＝12.9,3.3Hz,2H),1.20–1.07(m,6H).13C NMR(101MHz,DMSO-d6)δ156.48(d,J＝235.9Hz),145.66,142.07,138.99(d,J＝2.2Hz),126.11(d,J＝8.7Hz),122.75,117.77(d,J＝7.3Hz),115.84,115.62,115.14,110.21,65.67,46.39,37.66,29.57,28.31,6.86.Synthesis of the title compound: follow the synthetic method of Example 3. 1 H NMR (400MHz, DMSO-d 6 )δ9.39(s,1H),8.57(d,J=1.4Hz,1H),7.84-7.70(m,3H),7.68(d,J=1.2Hz, 2H), 7.16(t, J=8.9Hz, 2H), 4.49(t, J=5.1Hz, 1H), 3.75-3.58(m, 3H), 3.27-3.10(m, 2H), 2.17(td, J =11.7,2.4Hz,2H),1.70(dd,J=12.9,3.3Hz,2H),1.20-1.07(m,6H). 13C NMR(101MHz,DMSO-d 6 )δ156.48(d,J = 235.9Hz), 145.66, 142.07, 138.99 (d, J=2.2Hz), 126.11 (d, J=8.7Hz), 122.75, 117.77 (d, J=7.3Hz), 115.84, 115.62, 115.14, 110.21, 65.67 ,46.39,37.66,29.57,28.31,6.86.

实施例65 1-环丙基-5-((1,4-噁氮杂环庚烷-4-基)磺酰基)-N-(4-氟-3-甲基苯基)-1H-吲唑-3-胺的合成：Example 65 1-Cyclopropyl-5-((1,4-oxazepan-4-yl)sulfonyl)-N-(4-fluoro-3-methylphenyl)-1H-indone Synthesis of azol-3-amine:

Figure BDA0002385652160000391
Figure BDA0002385652160000391

中间体65-2的合成：按照13-2的合成方法，两步收率为30％。Synthesis of intermediate 65-2: According to the synthetic method of 13-2, the two-step yield was 30%.

标题化合物的合成：按照实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.64(d,J＝1.7Hz,1H),7.74(dd,J＝8.9,1.7Hz,1H),7.70–7.59(m,2H),7.55(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),3.64(dt,J＝13.0,5.2Hz,5H),3.37–3.27(m,4H),2.25(d,J＝1.9Hz,3H),1.79(p,J＝5.7Hz,2H),1.12(d,J＝4.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.16(d,J＝235.0Hz),145.69,141.95,138.68(d,J＝2.3Hz),128.91,125.45,124.47(d,J＝18.1Hz),122.16,119.16(d,J＝4.0Hz),115.36(d,J＝23.0Hz),115.17(d,J＝7.3Hz),115.09,110.43,69.89,69.09,50.97,47.00,30.49,29.56,15.11(d,J＝3.0Hz),6.81.Synthesis of the title compound: according to the synthetic method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.25 (s, 1H), 8.64 (d, J=1.7 Hz, 1H), 7.74 (dd, J =8.9,1.7Hz,1H),7.70–7.59(m,2H),7.55(dd,J=6.9,2.8Hz,1H),7.09(t,J=9.2Hz,1H),3.64(dt,J= 13.0, 5.2Hz, 5H), 3.37–3.27 (m, 4H), 2.25 (d, J=1.9Hz, 3H), 1.79 (p, J=5.7Hz, 2H), 1.12 (d, J=4.3Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ155.16(d,J=235.0Hz),145.69,141.95,138.68(d,J=2.3Hz),128.91,125.45,124.47(d,J= 18.1Hz), 122.16, 119.16 (d, J=4.0Hz), 115.36 (d, J=23.0Hz), 115.17 (d, J=7.3Hz), 115.09, 110.43, 69.89, 69.09, 50.97, 47.00, 30.49, 29.56, 15.11 (d, J=3.0Hz), 6.81.

实施例66 N-(3,4-二氟苯基)-3-(1-环丙基-5-(吗啉磺酰基)-1H-吲唑)胺的合成：以中间体44-2为原料，按照实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.57(s,1H),7.89(dd,J＝13.8,7.1Hz,1H),7.72(q,J＝8.9Hz,2H),7.45–7.33(m,2H),3.66(dt,J＝15.6,5.0Hz,5H),2.87(t,J＝4.5Hz,4H),1.15(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ149.71(dd,J＝241.7,12.9Hz),145.22,143.48(dd,J＝237.1,12.9Hz),142.11,139.58(dd,J＝9.6,2.2Hz),126.32,125.06,123.03,117.97(d,J＝17.8Hz),115.00,112.62(dd,J＝5.6,2.9Hz),110.53,105.06(d,J＝22.1Hz),65.74,46.40,29.64,6.86.Example 66 Synthesis of N-(3,4-difluorophenyl)-3-(1-cyclopropyl-5-(morpholinesulfonyl)-1H-indazole)amine: using intermediate 44-2 as Raw material, according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 ) δ 9.63 (s, 1H), 8.57 (s, 1H), 7.89 (dd, J=13.8, 7.1 Hz, 1H) ,7.72(q,J＝8.9Hz,2H),7.45–7.33(m,2H),3.66(dt,J＝15.6,5.0Hz,5H),2.87(t,J＝4.5Hz,4H),1.15( d, J=5.3Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 149.71 (dd, J=241.7, 12.9Hz), 145.22, 143.48 (dd, J=237.1, 12.9Hz), 142.11 ,139.58(dd,J＝9.6,2.2Hz),126.32,125.06,123.03,117.97(d,J＝17.8Hz),115.00,112.62(dd,J＝5.6,2.9Hz),110.53,105.06(d,J = 22.1Hz), 65.74, 46.40, 29.64, 6.86.

Figure BDA0002385652160000392
Figure BDA0002385652160000392

实施例67 N-(3,4-二氟苯基)-3-(1-环丙基-5-(吗啉磺酰基)-1H-吲唑)胺的合成：以中间体44-2为原料，按照实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.58(d,J＝1.5Hz,1H),8.18(dd,J＝6.3,2.8Hz,1H),8.01(dt,J＝8.9,3.6Hz,1H),7.77(d,J＝8.9Hz,1H),7.72(dd,J＝8.8,1.7Hz,1H),7.49(t,J＝9.8Hz,1H),3.73(p,J＝5.3Hz,1H),3.65(dd,J＝5.8,3.6Hz,4H),2.97–2.80(m,4H),1.15(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ152.61(dd,J＝244.9,2.6Hz),145.09,142.09,139.16(d,J＝2.3Hz),126.33,125.16,123.28(q,J＝271.8Hz),123.00,121.75(d,J＝7.7Hz),118.07(d,J＝21.5Hz),116.89(qd，J＝31.8，13.1Hz)，115.01，113.81(q，J＝5.0Hz)，110.50，65.74，46.40，29.66，6.70.Example 67 Synthesis of N-(3,4-difluorophenyl)-3-(1-cyclopropyl-5-(morpholinesulfonyl)-1H-indazole)amine: using intermediate 44-2 as Raw material, according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.77(s, 1H), 8.58(d, J=1.5Hz, 1H), 8.18(dd, J=6.3, 2.8Hz, 1H), 8.01(dt, J=8.9, 3.6Hz, 1H), 7.77(d, J=8.9Hz, 1H), 7.72(dd, J=8.8, 1.7Hz, 1H), 7.49(t, J=9.8Hz, 1H), 3.73 (p, J=5.3Hz, 1H), 3.65 (dd, J=5.8, 3.6Hz, 4H), 2.97–2.80 (m, 4H), 1.15 (d, J=5.3 Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ152.61(dd, J=244.9, 2.6Hz), 145.09, 142.09, 139.16(d, J=2.3Hz), 126.33, 125.16, 123.28( q, J=271.8Hz), 123.00, 121.75 (d, J=7.7Hz), 118.07 (d, J=21.5Hz), 116.89 (qd, J=31.8, 13.1Hz), 115.01, 113.81 (q, J= 5.0Hz), 110.50, 65.74, 46.40, 29.66, 6.70.

Figure BDA0002385652160000393
Figure BDA0002385652160000393

实施例68 N-(2-羟基乙基)-5-(1-环丙基-3-((3-甲基-4-氟苯基)氨基)-1H-吲唑)磺酰胺的合成：以中间体14-2为原料，按照实施例3的合成方法。Example 68 Synthesis of N-(2-hydroxyethyl)-5-(1-cyclopropyl-3-((3-methyl-4-fluorophenyl)amino)-1H-indazole)sulfonamide: Using intermediate 14-2 as raw material, follow the synthetic method of Example 3.

Figure BDA0002385652160000401
Figure BDA0002385652160000401

实施例69 N-(3,4,5-三氟苯基)-3-(1-环丙基-5-((1-(4-氟哌啶基))磺酰基)-1H-吲唑)胺的合成：Example 69 N-(3,4,5-Trifluorophenyl)-3-(1-cyclopropyl-5-((1-(4-fluoropiperidinyl))sulfonyl)-1H-indazole ) amine synthesis:

Figure BDA0002385652160000402
Figure BDA0002385652160000402

中间体69-2的合成：按照13-2的合成方法，两步总收率为67％。Synthesis of intermediate 69-2: According to the synthesis method of 13-2, the total yield of two steps was 67%.

标题化合物的合成：按照实施例13的合成方法，Synthesis of the title compound: following the synthetic method of Example 13,

实施例70 N-仲丁基-5-(1-环丙基-3-((3-甲基-4-氟苯基)氨基)-1H-吲唑)磺酰胺的合成：以中间体13-2为原料，按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.60(d,J＝1.6Hz,1H),7.77(dd,J＝8.9,1.7Hz,1H),7.68(d,J＝8.9Hz,1H),7.62(ddd,J＝8.8,4.4,2.9Hz,1H),7.52(dd,J＝6.9,2.8Hz,1H),7.39(d,J＝7.8Hz,1H),7.07(t,J＝9.2Hz,1H),3.63(p,J＝5.3Hz,1H),3.02(hept,J＝6.6Hz,1H),2.23(d,J＝1.9Hz,3H),1.30(p,J＝7.2Hz,2H),1.11(d,J＝5.3Hz,4H),0.85(d,J＝6.6Hz,3H),0.70(t,J＝7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ155.09(d,J＝234.9Hz),145.62,141.75,138.83(d,J＝2.2Hz),132.54,125.42,124.40(d,J＝18.0Hz),121.46,119.09(d,J＝4.0Hz),115.33(d,J＝23.0Hz),115.12(d,J＝7.3Hz),114.55,110.42,51.06,30.03,29.56,21.08,15.13(d,J＝3.0Hz),10.57,6.81.Example 70 Synthesis of N-sec-butyl-5-(1-cyclopropyl-3-((3-methyl-4-fluorophenyl)amino)-1H-indazole)sulfonamide: with intermediate 13 -2 is the raw material, according to the synthesis method of Example 13, 1 H NMR (400MHz, DMSO-d 6 ) δ 9.23 (s, 1H), 8.60 (d, J=1.6 Hz, 1H), 7.77 (dd, J ＝8.9,1.7Hz,1H),7.68(d,J＝8.9Hz,1H),7.62(ddd,J＝8.8,4.4,2.9Hz,1H),7.52(dd,J＝6.9,2.8Hz,1H) ,7.39(d,J＝7.8Hz,1H),7.07(t,J＝9.2Hz,1H),3.63(p,J＝5.3Hz,1H),3.02(hept,J＝6.6Hz,1H),2.23 (d,J=1.9Hz,3H),1.30(p,J=7.2Hz,2H),1.11(d,J=5.3Hz,4H),0.85(d,J=6.6Hz,3H),0.70(t , J=7.4Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 )δ155.09(d, J=234.9Hz), 145.62, 141.75, 138.83(d, J=2.2Hz), 132.54, 125.42, 124.40(d,J＝18.0Hz),121.46,119.09(d,J＝4.0Hz),115.33(d,J＝23.0Hz),115.12(d,J＝7.3Hz),114.55,110.42,51.06,30.03, 29.56, 21.08, 15.13 (d, J=3.0Hz), 10.57, 6.81.

Figure BDA0002385652160000403
Figure BDA0002385652160000403

实施例71 N-(3-四氢呋喃基)-5-(1-环丙基-3-((3-甲基-4-氟苯基)氨基)-1H-吲唑)磺酰胺的合成：以中间体46-2为原料，按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.63(d,J＝1.6Hz,1H),7.87–7.75(m,2H),7.71(d,J＝8.9Hz,1H),7.63(dt,J＝8.4,3.5Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),3.73–3.52(m,5H),3.37(dd,J＝8.4,4.0Hz,1H),1.96–1.79(m,1H),1.72–1.54(m,1H),1.13(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.12(d,J＝235.1Hz),145.66,141.89,138.78(d,J＝2.2Hz),131.25,125.35,124.43(d,J＝18.0Hz),121.99,119.12(d,J＝4.2Hz),115.34(d,J＝22.9Hz),115.16(d,J＝7.1Hz),114.70,110.61,72.50,66.59,53.56,32.60,29.57,15.13(d,J＝2.9Hz),6.83.Example 71 Synthesis of N-(3-tetrahydrofuranyl)-5-(1-cyclopropyl-3-((3-methyl-4-fluorophenyl)amino)-1H-indazole)sulfonamide: with Intermediate 46-2 is the raw material, according to the synthesis method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.26(s, 1H), 8.63(d, J=1.6Hz, 1H), 7.87- 7.75(m, 2H), 7.71(d, J=8.9Hz, 1H), 7.63(dt, J=8.4, 3.5Hz, 1H), 7.54(dd, J=6.9, 2.8Hz, 1H), 7.09(t , J=9.2Hz, 1H), 3.73–3.52 (m, 5H), 3.37 (dd, J=8.4, 4.0Hz, 1H), 1.96–1.79 (m, 1H), 1.72–1.54 (m, 1H), 1.13 (d, J=5.3Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ155.12 (d, J=235.1Hz), 145.66, 141.89, 138.78 (d, J=2.2Hz), 131.25 ,125.35,124.43(d,J＝18.0Hz),121.99,119.12(d,J＝4.2Hz),115.34(d,J＝22.9Hz),115.16(d,J＝7.1Hz),114.70,110.61,72.50 ,66.59,53.56,32.60,29.57,15.13(d,J=2.9Hz),6.83.

Figure BDA0002385652160000404
Figure BDA0002385652160000404

实施例72 N-(3-四氢呋喃基)-5-(1-环丙基-3-((3-三氟甲基-4-氟苯基)氨基)-1H-吲唑)磺酰胺的合成：以中间体46-2为原料，按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.62(d,J＝1.6Hz,1H),8.19(dd,J＝6.3,2.8Hz,1H),8.00(dt,J＝8.9,3.5Hz,1H),7.85(d,J＝6.1Hz,1H),7.82(dd,J＝8.9,1.7Hz,1H),7.76(d,J＝8.9Hz,1H),7.48(t,J＝9.8Hz,1H),3.77–3.51(m,5H),3.37(dd,J＝8.5,4.1Hz,1H),1.87(dq,J＝12.6,7.3Hz,1H),1.69–1.52(m,1H),1.14(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ154.25–150.53(m),144.99,141.82,139.30(d,J＝2.2Hz),131.69,125.53,123.29(q,J＝272.0Hz),121.76,121.68,118.06(d,J＝21.3Hz),116.70(td,J＝31.8,13.0Hz),114.45,113.74(q,J＝5.0Hz),110.85,72.49,66.59,53.57,32.60,29.66,6.71.Example 72 Synthesis of N-(3-tetrahydrofuranyl)-5-(1-cyclopropyl-3-((3-trifluoromethyl-4-fluorophenyl)amino)-1H-indazole)sulfonamide : Using intermediate 46-2 as raw material, according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.74(s, 1H), 8.62(d, J=1.6Hz, 1H), 8.19(dd,J＝6.3,2.8Hz,1H),8.00(dt,J＝8.9,3.5Hz,1H),7.85(d,J＝6.1Hz,1H),7.82(dd,J＝8.9,1.7Hz ,1H),7.76(d,J＝8.9Hz,1H),7.48(t,J＝9.8Hz,1H),3.77–3.51(m,5H),3.37(dd,J＝8.5,4.1Hz,1H) , 1.87(dq, J=12.6, 7.3Hz, 1H), 1.69-1.52(m, 1H), 1.14(d, J=5.3Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ154.25 –150.53(m),144.99,141.82,139.30(d,J=2.2Hz),131.69,125.53,123.29(q,J=272.0Hz),121.76,121.68,118.06(d,J=21.3Hz),116.70( td, J=31.8, 13.0Hz), 114.45, 113.74 (q, J=5.0Hz), 110.85, 72.49, 66.59, 53.57, 32.60, 29.66, 6.71.

Figure BDA0002385652160000411
Figure BDA0002385652160000411

实施例73 N-(3-氧杂环丁基)-5-(1-环丙基-3-((3-三氟甲基-4-氟苯基)氨基)-1H-吲唑)磺酰胺的合成：Example 73 N-(3-oxetanyl)-5-(1-cyclopropyl-3-((3-trifluoromethyl-4-fluorophenyl)amino)-1H-indazole)sulfone Synthesis of Amides:

Figure BDA0002385652160000412
Figure BDA0002385652160000412

中间体73-2的合成：按13-2的合成方法。Synthesis of intermediate 73-2: According to the synthetic method of 13-2.

标题化合物的合成：按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.60(d,J＝1.6Hz,1H),8.41(d,J＝8.0Hz,1H),7.75(dd,J＝8.9,1.7Hz,1H),7.69(d,J＝8.9Hz,1H),7.66–7.58(m,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),4.50(t,J＝6.6Hz,2H),4.35(h,J＝7.0Hz,1H),4.26(t,J＝6.2Hz,2H),3.64(q,J＝5.2Hz,1H),2.25(d,J＝1.8Hz,3H),1.12(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.14(d,J＝235.1Hz),145.69,141.93,138.75(d,J＝2.2Hz),131.03,125.11,124.44(d,J＝18.0Hz),121.79,119.15(d,J＝4.1Hz),115.35(d,J＝23.1Hz),115.18(d,J＝7.4Hz),114.82,110.60,77.52,47.53,29.57,15.12(d,J＝3.0Hz),6.82.Synthesis of the title compound: according to the synthetic method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (s, 1H), 8.60 (d, J=1.6 Hz, 1H), 8.41 (d, J =8.0Hz,1H),7.75(dd,J=8.9,1.7Hz,1H),7.69(d,J=8.9Hz,1H),7.66–7.58(m,1H),7.54(dd,J=6.9, 2.8Hz, 1H), 7.09(t, J＝9.2Hz, 1H), 4.50(t, J＝6.6Hz, 2H), 4.35(h, J＝7.0Hz, 1H), 4.26(t, J＝6.2Hz) , 2H), 3.64 (q, J=5.2Hz, 1H), 2.25 (d, J=1.8Hz, 3H), 1.12 (d, J=5.3Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ155.14(d,J＝235.1Hz),145.69,141.93,138.75(d,J＝2.2Hz),131.03,125.11,124.44(d,J＝18.0Hz),121.79,119.15(d,J＝4.1 Hz), 115.35(d, J＝23.1Hz), 115.18(d, J＝7.4Hz), 114.82, 110.60, 77.52, 47.53, 29.57, 15.12(d, J＝3.0Hz), 6.82.

实施例74 N-(3-甲基-4-氟苯基)-3-(1-环丙基-5-((1-哌啶基)磺酰基)-1H-吲唑)胺的合成：以中间体19-2为原料，按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.57(s,1H),7.69(s,2H),7.64(dt,J＝8.4,3.6Hz,1H),7.54(dd,J＝6.9,2.7Hz,1H),7.09(t,J＝9.2Hz,1H),3.70–3.61(m,1H),2.88(t,J＝5.3Hz,4H),2.25(d,J＝1.8Hz,3H),1.56(t,J＝5.8Hz,4H),1.34(qd,J＝6.8,4.3,3.1Hz,2H),1.13(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.15(d,J＝235.0Hz),145.68,142.05,138.67(d,J＝2.1Hz),124.46(d,J＝18.2Hz),122.77,119.16(d,J＝4.0Hz),115.37(d,J＝23.0Hz),115.19,115.18(d,J＝7.3Hz),110.14,47.11,29.56,25.15,23.28,15.12(d,J＝3.0Hz),6.83.Example 74 Synthesis of N-(3-methyl-4-fluorophenyl)-3-(1-cyclopropyl-5-((1-piperidinyl)sulfonyl)-1H-indazol)amine: Using intermediate 19-2 as raw material, according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.28(s, 1H), 8.57(s, 1H), 7.69(s, 2H) ,7.64(dt,J＝8.4,3.6Hz,1H),7.54(dd,J＝6.9,2.7Hz,1H),7.09(t,J＝9.2Hz,1H),3.70–3.61(m,1H), 2.88(t,J＝5.3Hz,4H),2.25(d,J＝1.8Hz,3H),1.56(t,J＝5.8Hz,4H),1.34(qd,J＝6.8,4.3,3.1Hz,2H ), 1.13 (d, J=5.3 Hz, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ155.15 (d, J=235.0 Hz), 145.68, 142.05, 138.67 (d, J=2.1 Hz) ,124.46(d,J＝18.2Hz),122.77,119.16(d,J＝4.0Hz),115.37(d,J＝23.0Hz),115.19,115.18(d,J＝7.3Hz),110.14,47.11,29.56 ,25.15,23.28,15.12(d,J=3.0Hz),6.83.

Figure BDA0002385652160000413
Figure BDA0002385652160000413

实施例75 N,N-二甲基-5-(1-环丙基-3-((3-甲基-4-氟苯基)氨基)-1H-吲唑)磺酰胺的合成：以中间体15-2为原料，按照实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.60(s,1H),7.75–7.67(m,2H),7.68–7.59(m,1H),7.54(dd,J＝7.0,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),3.65(p,J＝5.3Hz,1H),2.61(s,6H),2.25(d,J＝1.9Hz,3H),1.13(d,J＝5.3Hz,4H).Example 75 Synthesis of N,N-dimethyl-5-(1-cyclopropyl-3-((3-methyl-4-fluorophenyl)amino)-1H-indazole)sulfonamide: with intermediate Body 15-2 is the raw material, according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.29(s,1H),8.60(s,1H),7.75-7.67(m,2H) ,7.68–7.59(m,1H),7.54(dd,J=7.0,2.8Hz,1H),7.09(t,J=9.2Hz,1H),3.65(p,J=5.3Hz,1H),2.61( s, 6H), 2.25 (d, J=1.9Hz, 3H), 1.13 (d, J=5.3Hz, 4H).

Figure BDA0002385652160000421
Figure BDA0002385652160000421

实施例76以中间体57-2为原料，按实施例13的合成方法，1H NMR(400MHz,DMSO)δ9.59(s,1H),8.64(s,1H),7.97–7.81(m,2H),7.74(d,J＝8.9Hz,1H),7.46–7.31(m,2H),4.47(s,2H),3.76–3.63(m,2H),3.61(d,J＝7.5Hz,1H),3.23(d,J＝10.0Hz,1H),3.12(d,J＝9.9Hz,1H),1.57(d,J＝9.8Hz,1H),1.15(d,J＝6.3Hz,4H),0.97(d,J＝10.0Hz,1H).13CNMR(101MHz,DMSO-d6)δ149.72(dd,J＝241.8,13.0Hz),145.25,143.48(dd,J＝237.1,12.8Hz),142.00,139.58(dd,J＝9.5,2.2Hz),128.27,126.02,122.56,117.94(d,J＝17.6Hz),114.90,112.60(dd,J＝5.6,3.0Hz),110.72,105.05(d,J＝22.1Hz),76.10,73.62，60.31，56.24，35.37，29.65，6.83.Example 76 Using intermediate 57-2 as raw material, according to the synthesis method of Example 13, 1 H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 8.64 (s, 1H), 7.97-7.81 (m, 2H), 7.74(d, J=8.9Hz, 1H), 7.46-7.31(m, 2H), 4.47(s, 2H), 3.76-3.63(m, 2H), 3.61(d, J=7.5Hz, 1H) ),3.23(d,J=10.0Hz,1H),3.12(d,J=9.9Hz,1H),1.57(d,J=9.8Hz,1H),1.15(d,J=6.3Hz,4H), 0.97(d, J=10.0Hz, 1H). 13 CNMR(101MHz, DMSO-d 6 ) δ149.72(dd, J=241.8, 13.0Hz), 145.25, 143.48(dd, J=237.1, 12.8Hz), 142.00, 139.58 (dd, J=9.5, 2.2Hz), 128.27, 126.02, 122.56, 117.94 (d, J=17.6Hz), 114.90, 112.60 (dd, J=5.6, 3.0Hz), 110.72, 105.05 (d, J=22.1Hz), 76.10, 73.62, 60.31, 56.24, 35.37, 29.65, 6.83.

Figure BDA0002385652160000422
Figure BDA0002385652160000422

实施例77-78的合成：Synthesis of Examples 77-78:

Figure BDA0002385652160000423
Figure BDA0002385652160000423

中间体77-2的合成：按13-2的合成方法，两步总收率为66％。Synthesis of intermediate 77-2: According to the synthesis method of 13-2, the total yield of two steps is 66%.

实施例77(1-(5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶-4-甲酸甲酯的合成：按照实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.56(d,J＝1.2Hz,1H),7.68(d,J＝1.1Hz,2H),7.62(ddd,J＝8.9,4.4,2.9Hz,1H),7.53(dd,J＝6.9,2.8Hz,1H),7.08(t,J＝9.2Hz,1H),3.65(tt,J＝5.7,4.5Hz,1H),3.56(s,5H),2.36(tt,J＝11.7,3.3Hz,3H),2.24(d,J＝1.8Hz,3H),1.91(dt,J＝13.6,3.5Hz,2H),1.58(qd,J＝11.4,3.9Hz,2H),1.17–1.07(m,4H).13C NMR(101MHz,DMSO-d6)δ174.50,155.17(d,J＝235.1Hz),145.69,142.09,138.64(d,J＝2.2Hz),126.12,125.77,124.47(d,J＝18.0Hz),122.84,119.17(d,J＝4.1Hz),115.38(d,J＝23.0Hz),115.23,115.15,110.25,51.99,45.65,39.15,29.58,27.62,15.12(d,J＝3.0Hz),6.83.Example 77 (1-(5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl)piperidine-4-carboxylic acid Synthesis of methyl ester: according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.26(s, 1H), 8.56(d, J=1.2Hz, 1H), 7.68(d, J ＝1.1Hz, 2H), 7.62(ddd, J＝8.9, 4.4, 2.9Hz, 1H), 7.53(dd, J＝6.9, 2.8Hz, 1H), 7.08(t, J＝9.2Hz, 1H), 3.65 (tt, J=5.7, 4.5Hz, 1H), 3.56(s, 5H), 2.36(tt, J=11.7, 3.3Hz, 3H), 2.24(d, J=1.8Hz, 3H), 1.91(dt, J=13.6, 3.5Hz, 2H), 1.58 (qd, J=11.4, 3.9Hz, 2H), 1.17–1.07 (m, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 174.50, 155.17 (d, J=235.1Hz), 145.69, 142.09, 138.64(d, J=2.2Hz), 126.12, 125.77, 124.47(d, J=18.0Hz), 122.84, 119.17(d, J=4.1Hz), 115.38(d, J=23.0Hz), 115.23, 115.15, 110.25, 51.99, 45.65, 39.15, 29.58, 27.62, 15.12 (d, J=3.0Hz), 6.83.

中间体78-1的合成：将化合物77(340mg,0.7mmol)溶于5mL四氢呋喃和5mL水，加入氢氧化钠(280mg,7mmol)，加热回流，反应完成后，减压蒸除四氢呋喃，用1N盐酸调pH到5，过滤，干燥。Synthesis of intermediate 78-1: Compound 77 (340 mg, 0.7 mmol) was dissolved in 5 mL of tetrahydrofuran and 5 mL of water, sodium hydroxide (280 mg, 7 mmol) was added, heated to reflux, after the reaction was completed, tetrahydrofuran was evaporated under reduced pressure, and 1N The pH was adjusted to 5 with hydrochloric acid, filtered and dried.

实施例78N-正丁基-4-(1-(5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑基)磺酰基)哌啶甲酰胺的合成：将中间体78-1(47mg,0.1mmol)溶于1mL DMF，加入EDCI(38mg,0.2mmol)和HOSu(23mg,0.2mmol)，室温下反应12小时。向反应液中加入正丁胺(0.4mL,0.4mmol)，室温反应1小时，反应液用乙酸乙酯稀释，依次用1N盐酸和饱和食盐水洗，干燥，过滤，减压浓缩，硅胶柱层析分离。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.57(s,1H),7.70(s,2H),7.63(dt,J＝6.7,4.5Hz,2H),7.54(dd,J＝6.9,2.8Hz,1H),7.10(t,J＝9.2Hz,1H),3.66(p,J＝5.3Hz,1H),3.59(dt,J＝11.8,4.0Hz,2H),2.98(q,J＝6.6Hz,2H),2.35–2.20(m,5H),1.79–1.69(m,2H),1.67–1.51(m,2H),1.39–1.26(m,2H),1.21(dq,J＝14.1,7.1Hz,2H),1.13(d,J＝5.3Hz,4H),0.82(t,J＝7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ173.67,155.17(d,J＝235.1Hz),145.70,142.07,138.66(d,J＝2.4Hz),126.11,125.85,124.46(d,J＝18.0Hz),122.82,119.18(d,J＝4.0Hz),115.36(d,J＝23.4Hz),115.20,115.16,110.16,45.90,40.82,38.45,31.66,29.57,28.26,19.94,15.11(d,J＝3.0Hz),14.06,6.82.Example 78 N-n-Butyl-4-(1-(5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolyl)sulfonyl ) Synthesis of piperidinecarboxamide: Intermediate 78-1 (47 mg, 0.1 mmol) was dissolved in 1 mL of DMF, EDCI (38 mg, 0.2 mmol) and HOSu (23 mg, 0.2 mmol) were added, and the reaction was carried out at room temperature for 12 hours. n-Butylamine (0.4 mL, 0.4 mmol) was added to the reaction solution and reacted at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine successively, dried, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography. separation. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.27(s, 1H), 8.57(s, 1H), 7.70(s, 2H), 7.63(dt, J=6.7, 4.5Hz, 2H), 7.54( dd, J=6.9, 2.8Hz, 1H), 7.10 (t, J=9.2Hz, 1H), 3.66 (p, J=5.3Hz, 1H), 3.59 (dt, J=11.8, 4.0Hz, 2H), 2.98(q,J＝6.6Hz,2H),2.35-2.20(m,5H),1.79-1.69(m,2H),1.67-1.51(m,2H),1.39-1.26(m,2H),1.21( dq, J=14.1, 7.1 Hz, 2H), 1.13 (d, J=5.3 Hz, 4H), 0.82 (t, J=7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6 )δ173.67, 155.17 (d, J=235.1Hz), 145.70, 142.07, 138.66 (d, J=2.4Hz), 126.11, 125.85, 124.46 (d, J=18.0Hz), 122.82, 119.18 (d, J=4.0Hz), 115.36 (d, J=23.4Hz), 115.20, 115.16, 110.16, 45.90, 40.82, 38.45, 31.66, 29.57, 28.26, 19.94, 15.11 (d, J=3.0Hz), 14.06, 6.82.

实施例79 1-((5-(3-(3,4,5-三氟苯基)氨基)-(1-乙基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成Example 79 1-((5-(3-(3,4,5-trifluorophenyl)amino)-(1-ethyl)-1H-indazolyl)sulfonyl)piperidin-4-ol synthesis

Figure BDA0002385652160000431
Figure BDA0002385652160000431

中间体79-1的合成：5-溴吲唑(591mg,3mmol)溶于10mL DMF，依次加入碘乙烷(936mg,6mmol)和碳酸钾(1.24g,9mmol)，40℃反应12小时，减压蒸干，硅胶柱层析分离(石油醚/乙酸乙酯8/1)，得125mg，收率19％。1H NMR(400MHz,Chloroform-d)δ7.94(d,J＝1.1Hz,1H),7.88(d,J＝1.8Hz,1H),7.46(dd,J＝8.9,1.8Hz,1H),7.31(d,J＝8.9Hz,1H),4.43(q,J＝7.3Hz,2H),1.52(t,J＝7.3Hz,3H).Synthesis of intermediate 79-1: 5-bromoindazole (591 mg, 3 mmol) was dissolved in 10 mL of DMF, iodoethane (936 mg, 6 mmol) and potassium carbonate (1.24 g, 9 mmol) were added successively, and the reaction was carried out at 40° C. for 12 hours. It was evaporated to dryness under pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 8/1) to obtain 125 mg with a yield of 19%. 1 H NMR (400MHz, Chloroform-d) δ7.94 (d, J=1.1Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 7.46 (dd, J=8.9, 1.8Hz, 1H), 7.31(d,J=8.9Hz,1H),4.43(q,J=7.3Hz,2H),1.52(t,J=7.3Hz,3H).

中间体79-2的合成：按3-2的合成方法。Synthesis of intermediate 79-2: According to the synthetic method of 3-2.

中间体79-4的合成：按3-4的合成方法，三步总收率为79％。Synthesis of intermediate 79-4: According to the synthetic method of 3-4, the total yield of three steps is 79%.

标题化合物的合成：按照实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.52(s,1H),7.77(d,J＝8.9Hz,1H),7.69(dd,J＝9.0,1.7Hz,1H),7.59(dd,J＝11.1,6.2Hz,2H),4.65(d,J＝3.8Hz,1H),4.40(q,J＝7.1Hz,2H),3.57–3.46(m,1H),3.16(t,J＝8.5Hz,2H),2.73(t,J＝9.6Hz,2H),1.82–1.67(m,2H),1.52–1.34(m,5H).Synthesis of the title compound: according to the synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 8.52 (s, 1H), 7.77 (d, J=8.9 Hz, 1H ),7.69(dd,J=9.0,1.7Hz,1H),7.59(dd,J=11.1,6.2Hz,2H),4.65(d,J=3.8Hz,1H),4.40(q,J=7.1Hz ,2H),3.57–3.46(m,1H),3.16(t,J=8.5Hz,2H),2.73(t,J=9.6Hz,2H),1.82–1.67(m,2H),1.52–1.34( m,5H).

实施例80 1-((5-(3-(4-氟苯基)氨基)-(1-乙基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：以中间体79-4为原料，按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.59(d,J＝1.6Hz,1H),7.81–7.73(m,2H),7.72–7.62(m,2H),7.16(t,J＝8.9Hz,2H),4.66(d,J＝3.9Hz,1H),4.36(q,J＝7.1Hz,2H),3.52(tt,J＝7.8,3.9Hz,1H),3.18(ddd,J＝11.1,7.0,3.7Hz,2H),2.73(ddd,J＝11.8,8.6,3.4Hz,2H),1.76(ddt,J＝14.0,7.3,3.6Hz,2H),1.52–1.36(m,5H).13C NMR(101MHz,DMSO-d6)δ156.44(d,J＝235.7Hz),145.96,140.47,139.10(d,J＝2.2Hz),125.86,125.29,122.85,117.69(d,J＝7.3Hz),115.72(d,J＝22.0Hz),114.43,109.83,64.30,43.75,43.33,33.40,15.09.Example 80 Synthesis of 1-((5-(3-(4-fluorophenyl)amino)-(1-ethyl)-1H-indazolyl)sulfonyl)piperidin-4-ol: as intermediate 79-4 is the raw material, according to the synthetic method of Example 3, 1 H NMR (400MHz, DMSO-d 6 )δ9.38(s, 1H), 8.59(d, J=1.6Hz, 1H), 7.81-7.73( m, 2H), 7.72–7.62 (m, 2H), 7.16 (t, J=8.9Hz, 2H), 4.66 (d, J=3.9Hz, 1H), 4.36 (q, J=7.1Hz, 2H), 3.52 (tt, J=7.8, 3.9Hz, 1H), 3.18 (ddd, J=11.1, 7.0, 3.7Hz, 2H), 2.73 (ddd, J=11.8, 8.6, 3.4Hz, 2H), 1.76 (ddt, J=14.0, 7.3, 3.6Hz, 2H), 1.52–1.36 (m, 5H). 13 C NMR (101MHz, DMSO-d 6 ) δ 156.44 (d, J=235.7Hz), 145.96, 140.47, 139.10 ( d, J＝2.2Hz), 125.86, 125.29, 122.85, 117.69 (d, J＝7.3Hz), 115.72 (d, J＝22.0Hz), 114.43, 109.83, 64.30, 43.75, 43.33, 33.40, 15.09.

Figure BDA0002385652160000432
Figure BDA0002385652160000432

实施例81 1-((5-(3-(4-氟苯基)氨基)-(1-异丙基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：Example 81 Synthesis of 1-((5-(3-(4-fluorophenyl)amino)-(1-isopropyl)-1H-indazolyl)sulfonyl)piperidin-4-ol:

Figure BDA0002385652160000441
Figure BDA0002385652160000441

中间体81-1的合成：5-溴吲唑(296mg,1.5mmol)溶于10mL DMF，依次加入2-碘异丙烷(510mg,3mmol)和DBU(456mg,3mmol)，室温反应48小时，减压蒸干，硅胶柱层析分离(石油醚/乙酸乙酯10/1)，得160mg，收率45％。Synthesis of intermediate 81-1: 5-Bromoindazole (296 mg, 1.5 mmol) was dissolved in 10 mL of DMF, 2-iodoisopropane (510 mg, 3 mmol) and DBU (456 mg, 3 mmol) were added successively, and the reaction was carried out at room temperature for 48 hours. It was evaporated to dryness under pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to obtain 160 mg with a yield of 45%.

中间体81-2的合成：按3-2的合成方法。Synthesis of intermediate 81-2: According to the synthetic method of 3-2.

中间体81-4的合成：按3-4的合成方法，三步总收率为68％。Synthesis of intermediate 81-4: According to the synthetic method of 3-4, the total yield of three steps is 68%.

标题化合物的合成：按照实施例3的合成方法。1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.58(d,J＝1.6Hz,1H),7.82–7.74(m,2H),7.72(d,J＝9.0Hz,1H),7.64(dd,J＝8.9,1.7Hz,1H),7.17(t,J＝8.9Hz,2H),4.92(p,J＝6.5Hz,1H),4.66(d,J＝3.9Hz,1H),3.52(tt,J＝7.6,3.7Hz,1H),3.17(ddd,J＝11.1,7.0,3.8Hz,2H),2.73(ddd,J＝11.7,8.5,3.4Hz,2H),1.77(ddt,J＝13.7,7.1,3.2Hz,2H),1.54–1.41(m,8H).13C NMR(101MHz,DMSO-d6)δ156.38(d,J＝235.4Hz),145.74,139.96,139.20(d,J＝1.9Hz),125.70,125.21,122.84,117.57(d,J＝7.4Hz),115.74(d,J＝22.2Hz),114.36,109.82,64.27,49.62,43.75,33.39,22.26.Synthesis of the title compound: The synthesis method of Example 3 was followed. 1 H NMR (400MHz, DMSO-d 6 )δ9.38(s,1H),8.58(d,J=1.6Hz,1H),7.82-7.74(m,2H),7.72(d,J=9.0Hz, 1H), 7.64(dd, J＝8.9, 1.7Hz, 1H), 7.17(t, J＝8.9Hz, 2H), 4.92(p, J＝6.5Hz, 1H), 4.66(d, J＝3.9Hz, 1H), 3.52 (tt, J=7.6, 3.7Hz, 1H), 3.17 (ddd, J=11.1, 7.0, 3.8Hz, 2H), 2.73 (ddd, J=11.7, 8.5, 3.4Hz, 2H), 1.77 (ddt, J=13.7, 7.1, 3.2 Hz, 2H), 1.54–1.41 (m, 8H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 156.38 (d, J=235.4 Hz), 145.74, 139.96 ,139.20(d,J＝1.9Hz),125.70,125.21,122.84,117.57(d,J＝7.4Hz),115.74(d,J＝22.2Hz),114.36,109.82,64.27,49.62,43.75,33.39,22.26 .

实施例82 1-((5-(3-(4-氟苯基)氨基)-(1-(3-氧杂环丁基))-1H-吲唑基)磺酰基)哌啶-4-醇的合成：以中间体12-6为原料，按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.61(s,1H),7.84(dd,J＝8.9,4.8Hz,2H),7.75(d,J＝8.9Hz,1H),7.69(d,J＝9.0Hz,1H),7.21(t,J＝8.7Hz,2H),6.04(p,J＝7.2Hz,1H),5.12(t,J＝6.4Hz,2H),4.97(t,J＝7.0Hz,2H),4.63(d,J＝3.8Hz,1H),3.50(dt,J＝8.2,3.9Hz,1H),3.16(dt,J＝11.2,4.6Hz,2H),2.72(ddd,J＝12.0,8.9,3.3Hz,2H),1.83–1.67(m,2H),1.44(dtd,J＝12.5,8.4,3.7Hz,2H).13C NMR(101MHz,DMSO-d6)δ156.62(d,J＝236.2Hz),146.57,141.06,138.91,126.23,126.09,122.81,117.93(d,J＝7.3Hz),115.85(d,J＝22.1Hz),114.98,110.11,76.91,64.24,51.42,43.72,33.35.Example 82 1-((5-(3-(4-Fluorophenyl)amino)-(1-(3-oxetanyl))-1H-indazolyl)sulfonyl)piperidine-4- Synthesis of alcohol: using intermediate 12-6 as raw material, according to the synthesis method of Example 3, 1 H NMR (400MHz, DMSO-d 6 )δ9.49(s,1H), 8.61(s,1H), 7.84( dd,J＝8.9,4.8Hz,2H),7.75(d,J＝8.9Hz,1H),7.69(d,J＝9.0Hz,1H),7.21(t,J＝8.7Hz,2H),6.04( p, J=7.2Hz, 1H), 5.12 (t, J=6.4Hz, 2H), 4.97 (t, J=7.0Hz, 2H), 4.63 (d, J=3.8Hz, 1H), 3.50 (dt, J=8.2, 3.9Hz, 1H), 3.16 (dt, J=11.2, 4.6Hz, 2H), 2.72 (ddd, J=12.0, 8.9, 3.3Hz, 2H), 1.83–1.67 (m, 2H), 1.44 (dtd, J=12.5, 8.4, 3.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 156.62 (d, J=236.2 Hz), 146.57, 141.06, 138.91, 126.23, 126.09, 122.81, 117.93(d, J＝7.3Hz), 115.85(d, J＝22.1Hz), 114.98, 110.11, 76.91, 64.24, 51.42, 43.72, 33.35.

Figure BDA0002385652160000442
Figure BDA0002385652160000442

实施例83 1-((5-(3-(4-氟苯基)氨基)-(1-环丁基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：Example 83 Synthesis of 1-((5-(3-(4-fluorophenyl)amino)-(1-cyclobutyl)-1H-indazolyl)sulfonyl)piperidin-4-ol:

Figure BDA0002385652160000451
Figure BDA0002385652160000451

中间体83-1的合成：5-溴吲唑(296mg,1.5mmol)溶于10mL DMF，依次加入溴代环丁烷(405mg,3mmol)和NaH(180mg(60％),4.5mmol)，加热到50℃反应12小时，减压蒸干，硅胶柱层析分离(石油醚/乙酸乙酯10/1)，得170mg，收率45％。Synthesis of intermediate 83-1: 5-Bromoindazole (296 mg, 1.5 mmol) was dissolved in 10 mL of DMF, and bromocyclobutane (405 mg, 3 mmol) and NaH (180 mg (60%), 4.5 mmol) were added successively, and heated The reaction was carried out at 50° C. for 12 hours, evaporated to dryness under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to obtain 170 mg with a yield of 45%.

中间体83-4的合成：按3-4的合成方法。Synthesis of intermediate 83-4: According to the synthetic method of 3-4.

标题化合物的合成：按照实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.42(d,J＝2.6Hz,1H),8.57(s,1H),7.81(dt,J＝8.0,3.6Hz,2H),7.72(dd,J＝9.0,2.6Hz,1H),7.64(d,J＝8.5Hz,1H),7.19(td,J＝9.0,2.7Hz,2H),5.22(p,J＝9.0Hz,1H),4.66(t,J＝3.3Hz,1H),3.49(tt,J＝7.4,3.8Hz,1H),3.24–3.08(m,2H),2.69(q,J＝9.5,8.6Hz,4H),2.47–2.34(m,2H),1.95–1.80(m,2H),1.75(ddd,J＝13.6,7.0,3.5Hz,2H),1.45(ddt,J＝16.7,11.9,5.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ156.47(d,J＝235.6Hz),145.98,140.24,139.11(d,J＝1.9Hz),125.88,125.55,122.81,117.69(d,J＝7.4Hz),115.79(d,J＝22.1Hz),114.61,109.95,64.31,51.71,43.76,33.40,29.85,14.94.Synthesis of the title compound: according to the synthesis method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.42 (d, J=2.6 Hz, 1H), 8.57 (s, 1H), 7.81 (dt, J =8.0,3.6Hz,2H),7.72(dd,J=9.0,2.6Hz,1H),7.64(d,J=8.5Hz,1H),7.19(td,J=9.0,2.7Hz,2H),5.22 (p, J=9.0Hz, 1H), 4.66(t, J=3.3Hz, 1H), 3.49(tt, J=7.4, 3.8Hz, 1H), 3.24–3.08(m, 2H), 2.69(q, J=9.5, 8.6Hz, 4H), 2.47–2.34 (m, 2H), 1.95–1.80 (m, 2H), 1.75 (ddd, J=13.6, 7.0, 3.5Hz, 2H), 1.45 (ddt, J= 16.7, 11.9, 5.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 156.47 (d, J=235.6 Hz), 145.98, 140.24, 139.11 (d, J=1.9 Hz), 125.88, 125.55 ,122.81,117.69(d,J＝7.4Hz),115.79(d,J＝22.1Hz),114.61,109.95,64.31,51.71,43.76,33.40,29.85,14.94.

实施例84 N-仲丁基-5-(1-环丙基-3-((3,4-二氟苯基)氨基)-1H-吲唑)磺酰胺的合成：以中间体13-2原料，按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.58(d,J＝9.6Hz,1H),8.62(d,J＝8.9Hz,1H),7.89(ddt,J＝13.8,7.3,4.2Hz,1H),7.80(d,J＝9.0Hz,1H),7.70(d,J＝9.1Hz,1H),7.51–7.27(m,3H),3.64(p,J＝5.3Hz,1H),3.02(p,J＝6.7Hz,1H),1.29(p,J＝7.2Hz,2H),1.12(d,J＝5.3Hz,4H),0.85(d,J＝6.5Hz,3H),0.69(t,J＝7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ149.71(dd,J＝241.6,13.1Hz),145.11,143.38(dd,J＝237.0,12.8Hz),141.68,139.76(dd,J＝9.8,2.1Hz),132.86,125.57,121.29,117.89(d,J＝17.7Hz),114.32,112.52(dd,J＝5.4,2.8Hz),110.61,104.95(d,J＝22.2Hz),51.08,30.02,29.59,21.07,10.55,6.84.Example 84 Synthesis of N-sec-butyl-5-(1-cyclopropyl-3-((3,4-difluorophenyl)amino)-1H-indazole)sulfonamide: with intermediate 13-2 Raw material, according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 ) δ 9.58 (d, J=9.6Hz, 1H), 8.62 (d, J=8.9Hz, 1H), 7.89 (ddt , J=13.8, 7.3, 4.2Hz, 1H), 7.80 (d, J=9.0Hz, 1H), 7.70 (d, J=9.1Hz, 1H), 7.51–7.27 (m, 3H), 3.64 (p, J=5.3Hz, 1H), 3.02 (p, J=6.7Hz, 1H), 1.29 (p, J=7.2Hz, 2H), 1.12 (d, J=5.3Hz, 4H), 0.85 (d, J= 6.5Hz, 3H), 0.69 (t, J=7.2Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ 149.71 (dd, J=241.6, 13.1Hz), 145.11, 143.38 (dd, J ＝237.0, 12.8Hz), 141.68, 139.76 (dd, J＝9.8, 2.1Hz), 132.86, 125.57, 121.29, 117.89 (d, J＝17.7Hz), 114.32, 112.52 (dd, J＝5.4, 2.8Hz) ,110.61,104.95(d,J＝22.2Hz),51.08,30.02,29.59,21.07,10.55,6.84.

Figure BDA0002385652160000452
Figure BDA0002385652160000452

实施例85 N-(2-(1,1,1-三氟丙基))-5-(1-环丙基-3-((3,4-二氟苯基)氨基)-1H-吲唑)磺酰胺的合成：Example 85 N-(2-(1,1,1-trifluoropropyl))-5-(1-cyclopropyl-3-((3,4-difluorophenyl)amino)-1H-indium azole) sulfonamide synthesis:

Figure BDA0002385652160000453
Figure BDA0002385652160000453

中间体85-1的合成：将140mg(0.5mmol)底物溶解于5ml乙腈，依次加入100μL水和乙酸，将混合液冷却到-15℃，分批加入1,3-二氯-5,5-二甲基海因(197mg,1.0mmol)，反应1小时。反应液转移到分液漏斗中，加入乙酸乙酯稀释和饱和食盐水洗，分取乙酸乙酯层，用无水硫酸钠干燥30min。过滤，减压蒸除乙酸乙酯。加乙腈溶解，加入1,1,1-三氟-2-丙胺盐酸盐(112mg,0.75mmol)、DIPEA(0.25ml,1.5mmol),80℃反应12小时，加二氯甲烷稀释，1N盐酸洗，无水硫酸钠干燥，过滤，减压蒸干，不经纯化。Synthesis of Intermediate 85-1: Dissolve 140 mg (0.5 mmol) of the substrate in 5 ml of acetonitrile, add 100 μL of water and acetic acid in turn, cool the mixture to -15°C, and add 1,3-dichloro-5,5 in batches - Dimethyl hydantoin (197 mg, 1.0 mmol), reacted for 1 hour. The reaction solution was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filter and evaporate the ethyl acetate under reduced pressure. Add acetonitrile to dissolve, add 1,1,1-trifluoro-2-propylamine hydrochloride (112mg, 0.75mmol), DIPEA (0.25ml, 1.5mmol), react at 80°C for 12 hours, add dichloromethane to dilute, 1N hydrochloric acid Washed, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, without purification.

中间体85-2的合成：按13-2的合成方法，两步总收率为35％。Synthesis of intermediate 85-2: According to the synthesis method of 13-2, the total yield of two steps is 35%.

标题化合物的合成：按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.65(d,J＝1.7Hz,1H),8.42(d,J＝8.0Hz,1H),7.94–7.80(m,2H),7.75(d,J＝8.9Hz,1H),7.47–7.27(m,2H),3.96(dt,J＝14.9,7.2Hz,1H),3.77–3.60(m,1H),1.22–1.08(m,4H),0.98(d,J＝7.0Hz,3H).Synthesis of the title compound: according to the synthetic method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.58 (s, 1H), 8.65 (d, J=1.7 Hz, 1H), 8.42 (d, J = 8.0Hz, 1H), 7.94–7.80 (m, 2H), 7.75 (d, J=8.9Hz, 1H), 7.47–7.27 (m, 2H), 3.96 (dt, J=14.9, 7.2Hz, 1H) ,3.77–3.60(m,1H),1.22–1.08(m,4H),0.98(d,J=7.0Hz,3H).

实施例86 N-(2-(1,1,1-三氟丙基))-5-(1-环丙基-3-((3-甲基-4-氟苯基)氨基)-1H-吲唑)磺酰胺的合成：以中间体85-2为原料，按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.67(d,J＝1.7Hz,1H),8.39(d,J＝8.7Hz,1H),7.82(dd,J＝8.9,1.8Hz,1H),7.72(d,J＝8.9Hz,1H),7.63(dt,J＝8.5,3.5Hz,1H),7.54(dd,J＝6.9,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),3.94(h,J＝7.4Hz,1H),3.66(p,J＝5.3Hz,1H),2.25(d,J＝1.8Hz,3H),1.13(d,J＝5.3Hz,4H),0.98(d,J＝6.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ155.12(d,J＝235.0Hz),145.73,141.86,138.72(d,J＝2.3Hz),131.36,130.36–121.91(m),125.21,124.46(d,J＝18.0Hz),121.87,119.09(d,J＝4.1Hz),115.38(d,J＝22.8Hz),115.14(d,J＝7.3Hz),114.59,110.70,50.74(q,J＝31.1Hz),29.58,15.15(d,J＝2.9Hz),14.26,6.86.Example 86 N-(2-(1,1,1-trifluoropropyl))-5-(1-cyclopropyl-3-((3-methyl-4-fluorophenyl)amino)-1H -Synthesis of indazole)sulfonamide: using intermediate 85-2 as raw material, according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.26(s,1H),8.67(d, J=1.7Hz, 1H), 8.39 (d, J=8.7Hz, 1H), 7.82 (dd, J=8.9, 1.8Hz, 1H), 7.72 (d, J=8.9Hz, 1H), 7.63 (dt, J=8.5, 3.5Hz, 1H), 7.54(dd, J=6.9, 2.8Hz, 1H), 7.09(t, J=9.2Hz, 1H), 3.94(h, J=7.4Hz, 1H), 3.66( p, J=5.3Hz, 1H), 2.25 (d, J=1.8Hz, 3H), 1.13 (d, J=5.3Hz, 4H), 0.98 (d, J=6.9Hz, 3H). 13 C NMR( 101MHz, DMSO-d 6 )δ155.12(d,J=235.0Hz),145.73,141.86,138.72(d,J=2.3Hz),131.36,130.36–121.91(m),125.21,124.46(d,J= 18.0Hz), 121.87, 119.09 (d, J=4.1Hz), 115.38 (d, J=22.8Hz), 115.14 (d, J=7.3Hz), 114.59, 110.70, 50.74 (q, J=31.1Hz), 29.58, 15.15 (d, J=2.9Hz), 14.26, 6.86.

Figure BDA0002385652160000461
Figure BDA0002385652160000461

实施例87 5-(1-环丙基-3-((3-甲基-4-氟苯基)氨基)-1H-吲唑)磺酰胺的合成：Example 87 Synthesis of 5-(1-cyclopropyl-3-((3-methyl-4-fluorophenyl)amino)-1H-indazole)sulfonamide:

Figure BDA0002385652160000462
Figure BDA0002385652160000462

中间体87-1的合成：将140mg(0.5mmol)底物溶解于5ml乙腈，依次加入100μL水和乙酸，将混合液冷却到-15℃，分批加入1,3-二氯-5,5-二甲基海因(197mg,1.0mmol)，反应1小时。反应液转移到分液漏斗中，加入乙酸乙酯稀释和饱和食盐水洗，分取乙酸乙酯层，用无水硫酸钠干燥30min。过滤，减压蒸除乙酸乙酯。加二氯甲烷溶解，加入7M氨甲醇溶液(1mL)，室温反应，加二氯甲烷稀释，1N盐酸洗，无水硫酸钠干燥，过滤，减压蒸干，不经纯化。Synthesis of Intermediate 87-1: Dissolve 140 mg (0.5 mmol) of the substrate in 5 ml of acetonitrile, add 100 μL of water and acetic acid in turn, cool the mixture to -15°C, and add 1,3-dichloro-5,5 in batches - Dimethyl hydantoin (197 mg, 1.0 mmol), reacted for 1 hour. The reaction solution was transferred to a separatory funnel, diluted with ethyl acetate and washed with saturated brine. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate for 30 min. Filter and evaporate the ethyl acetate under reduced pressure. Add dichloromethane to dissolve, add 7M ammonia methanol solution (1 mL), react at room temperature, add dichloromethane to dilute, wash with 1N hydrochloric acid, dry over anhydrous sodium sulfate, filter, evaporate to dryness under reduced pressure, without purification.

中间体87-2的合成：按13-2的合成方法，两步总收率为28％。Synthesis of intermediate 87-2: According to the synthesis method of 13-2, the total yield of two steps is 28%.

中间体87-3的合成：将中间体87-2(40mg,0.125mmol)溶于2mL二氯甲烷，加入DMAP(15mg,0.125mmol)、Boc2O(51μL,0.23mmol)，室温反应，TLC监测，完成后，加二氯甲烷稀释，依次用pH为3的水溶液、饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸干，得45mg，收率87％。Synthesis of intermediate 87-3: Intermediate 87-2 (40 mg, 0.125 mmol) was dissolved in 2 mL of dichloromethane, DMAP (15 mg, 0.125 mmol), Boc 2 O (51 μL, 0.23 mmol) were added, and the reaction was carried out at room temperature, TLC After monitoring, dichloromethane was added to dilute, washed with pH 3 aqueous solution and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain 45 mg with a yield of 87%.

中间体87-4的合成：按实施例13的合成方法。Synthesis of Intermediate 87-4: Follow the synthetic method of Example 13.

标题化合物的合成：将30mg中间体87-4溶于1mL二氯甲烷和三氟乙酸，室温搅拌。反应完成后，减压蒸干，加水，调pH到8，过滤，收集固体，薄层色谱板分离(二氯甲烷/甲醇20/1)。1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.62(d,J＝1.6Hz,1H),7.84(dd,J＝8.9,1.7Hz,1H),7.68(d,J＝8.9Hz,1H),7.63(dt,J＝8.3,3.5Hz,1H),7.54(dd,J＝7.0,2.7Hz,1H),7.25(s,2H),7.08(t,J＝9.2Hz,1H),3.68–3.59(m,1H),2.24(d,J＝1.8Hz,3H),1.17–1.07(m,4H).Synthesis of the title compound: 30 mg of intermediate 87-4 were dissolved in 1 mL of dichloromethane and trifluoroacetic acid and stirred at room temperature. After the reaction is completed, evaporate to dryness under reduced pressure, add water, adjust the pH to 8, filter, collect the solid, and separate by thin layer chromatography (dichloromethane/methanol 20/1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (s, 1H), 8.62 (d, J=1.6 Hz, 1H), 7.84 (dd, J=8.9, 1.7 Hz, 1H), 7.68 (d, J=8.9Hz, 1H), 7.63(dt, J=8.3, 3.5Hz, 1H), 7.54(dd, J=7.0, 2.7Hz, 1H), 7.25(s, 2H), 7.08(t, J=9.2 Hz, 1H), 3.68–3.59 (m, 1H), 2.24 (d, J=1.8Hz, 3H), 1.17–1.07 (m, 4H).

实施例88 N-(3-三氟甲基-4-氟苯基)-3-(1-环丙基-5-(吗啉磺酰基)-1H-吲唑并[3,4-c]吡啶)胺的合成：以中间体58-2为原料，按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.19(d,J＝1.1Hz,1H),8.70(d,J＝1.1Hz,1H),8.15(dd,J＝6.2,2.9Hz,1H),7.96(dt,J＝9.0,3.6Hz,1H),7.51(t,J＝9.8Hz,1H),3.94–3.83(m,1H),3.64(dd,J＝5.9,3.5Hz,4H),3.25–3.00(m,4H),1.21(ddt,J＝12.7,9.3,5.0Hz,4H).13C NMR(101MHz,DMSO-d6)δ152.79(d,J＝245.9Hz),144.96,142.94,138.82(d,J＝2.5Hz),137.64,134.95,128.87–123.58(m),121.92(d,J＝8.5Hz),118.79,118.26(d,J＝21.3Hz),117.13,117.25–116.64(m),113.83(d,J＝5.2Hz),66.06,46.84,30.31,6.85.Example 88 N-(3-Trifluoromethyl-4-fluorophenyl)-3-(1-cyclopropyl-5-(morpholinesulfonyl)-1H-indazolo[3,4-c] Synthesis of pyridyl)amine: using intermediate 58-2 as raw material, according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.91(s,1H),9.19(d,J=1.1 Hz,1H),8.70(d,J＝1.1Hz,1H),8.15(dd,J＝6.2,2.9Hz,1H),7.96(dt,J＝9.0,3.6Hz,1H),7.51(t,J = 9.8Hz, 1H), 3.94–3.83 (m, 1H), 3.64 (dd, J=5.9, 3.5Hz, 4H), 3.25–3.00 (m, 4H), 1.21 (ddt, J=12.7, 9.3, 5.0 Hz, 4H). 13 C NMR(101MHz, DMSO-d 6 )δ152.79(d,J=245.9Hz),144.96,142.94,138.82(d,J=2.5Hz),137.64,134.95,128.87-123.58( m), 121.92 (d, J=8.5Hz), 118.79, 118.26 (d, J=21.3Hz), 117.13, 117.25–116.64 (m), 113.83 (d, J=5.2Hz), 66.06, 46.84, 30.31, 6.85.

Figure BDA0002385652160000471
Figure BDA0002385652160000471

实施例89 N-(3,4-二氟苯基)-3-(1-环丙基-5-(吗啉磺酰基)-1H-吲唑并[3,4-c]吡啶)胺的合成：以中间体58-2为原料，按实施例13的合成方法，1H NMR(400MHz,DMSO)δ9.75(s,1H),9.17(s,1H),8.71(s,1H),7.85(dd,J＝12.8,6.6Hz,1H),7.41(dd,J＝17.8,7.7Hz,2H),3.85(d,J＝3.7Hz,1H),3.64(s,4H),3.13(s,4H),1.34–1.08(m,4H).13C NMR(101MHz,DMSO-d6)δ149.71(dd,J＝242.0,13.3Hz),145.11,143.66(dd,J＝237.7,12.8Hz),142.84,139.19(dd,J＝9.5,2.1Hz),137.63,134.88,118.81,118.09(d,J＝17.8Hz),117.21,112.72(dd,J＝5.7,3.0Hz),105.14(d,J＝22.2Hz),66.06,46.84,30.26,6.98.Example 89 N-(3,4-difluorophenyl)-3-(1-cyclopropyl-5-(morpholinesulfonyl)-1H-indazolo[3,4-c]pyridin)amine Synthesis: using intermediate 58-2 as raw material, according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO) δ9.75(s, 1H), 9.17(s, 1H), 8.71(s, 1H), 7.85(dd, J＝12.8, 6.6Hz, 1H), 7.41(dd, J＝17.8, 7.7Hz, 2H), 3.85(d, J＝3.7Hz, 1H), 3.64(s, 4H), 3.13(s , 4H), 1.34–1.08 (m, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 149.71 (dd, J=242.0, 13.3Hz), 145.11, 143.66 (dd, J=237.7, 12.8Hz) ),142.84,139.19(dd,J=9.5,2.1Hz),137.63,134.88,118.81,118.09(d,J=17.8Hz),117.21,112.72(dd,J=5.7,3.0Hz),105.14(d, J=22.2Hz), 66.06, 46.84, 30.26, 6.98.

Figure BDA0002385652160000472
Figure BDA0002385652160000472

实施例90 N-(3-甲基-4-氟苯基)-3-(5-(吗啉磺酰基)-1H-吲唑)胺的合成：Example 90 Synthesis of N-(3-methyl-4-fluorophenyl)-3-(5-(morpholinesulfonyl)-1H-indazol)amine:

Figure BDA0002385652160000473
Figure BDA0002385652160000473

中间体90-2的合成：以0.5mmol中间体1-2为原料，按中间体1-4的合成方法，不经纯化，进行下一步反应。Synthesis of intermediate 90-2: Using 0.5 mmol of intermediate 1-2 as raw material, according to the synthesis method of intermediate 1-4, without purification, the next step was carried out.

中间体90-3的合成：将上述产物溶于10mL乙酸乙酯，加入3,4-2H-二氢吡喃(1.5mmol)、对甲苯磺酸一水合物(19mg,0.1mmol)，回流反应24小时，反应完成后，水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯5/2)，得150mg，三步反应总收率为70％。Synthesis of Intermediate 90-3: The above product was dissolved in 10 mL of ethyl acetate, 3,4-2H-dihydropyran (1.5 mmol) and p-toluenesulfonic acid monohydrate (19 mg, 0.1 mmol) were added, and the reaction was carried out under reflux. After 24 hours, the reaction was completed, washed with water, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 5/2) to obtain 150 mg, the total yield of the three-step reaction was 70 %.

标题化合物的合成：按实施例1的合成方法，1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),9.25(s,1H),8.61(s,1H),7.78–7.40(m,4H),7.07(t,J＝9.3Hz,1H),3.65(s,5H),2.88(s,4H),2.25(s,3H).13C NMR(101MHz,DMSO-d6)δ155.04(d,J＝234.5Hz),146.88,141.92,138.95,125.90,124.40(d,J＝17.8Hz),124.19,123.09,119.00(d,J＝3.9Hz),115.36(d,J＝22.2Hz),115.18,114.14,110.73,65.76,46.45,15.09(d,J＝3.1Hz).Synthesis of the title compound: according to the synthetic method of Example 1, 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.54 (s, 1H), 9.25 (s, 1H), 8.61 (s, 1H), 7.78-7.40 (m, 4H), 7.07(t, J=9.3Hz, 1H), 3.65(s, 5H), 2.88(s, 4H), 2.25(s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ155.04(d,J＝234.5Hz),146.88,141.92,138.95,125.90,124.40(d,J＝17.8Hz),124.19,123.09,119.00(d,J＝3.9Hz),115.36(d,J＝ 22.2Hz), 115.18, 114.14, 110.73, 65.76, 46.45, 15.09 (d, J=3.1Hz).

实施例91 1-(5-(3-((3-甲基-4-氟苯基)胺基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：以中间体1-5为原料，按实施例1的合成方法，1H NMR(400MHz,DMSO-d6)δ12.49(s,1H),9.22(s,1H),8.59(d,J＝1.6Hz,1H),7.64(ddd,J＝8.8,5.9,2.2Hz,2H),7.60–7.52(m,2H),7.07(t,J＝9.2Hz,1H),4.65(d,J＝3.8Hz,1H),3.51(dq,J＝7.8,3.8Hz,1H),3.17(ddd,J＝11.1,6.9,3.7Hz,2H),2.71(ddd,J＝11.8,8.5,3.4Hz,2H),2.25(d,J＝1.8Hz,3H),1.76(ddt,J＝13.9,6.9,3.6Hz,2H),1.45(dtd,J＝12.2,8.2,3.7Hz,2H).13C NMR(101MHz,DMSO-d6)δ155.01(d,J＝234.7Hz),146.80,141.81,138.97(d,J＝2.1Hz),125.85,125.37,124.38(d,J＝17.8Hz),122.63,118.97(d,J＝4.0Hz),115.34(d,J＝23.1Hz),115.15,114.09,110.60,64.32,43.75,33.39,15.09(d,J＝3.0Hz).Example 91 Synthesis of 1-(5-(3-((3-methyl-4-fluorophenyl)amino)-1H-indazolyl)sulfonyl)piperidin-4-ol: with Intermediate 1 -5 is the raw material, according to the synthesis method of Example 1, 1 H NMR (400MHz, DMSO-d 6 )δ12.49(s, 1H), 9.22(s, 1H), 8.59(d, J=1.6Hz, 1H ), 7.64 (ddd, J=8.8, 5.9, 2.2Hz, 2H), 7.60–7.52 (m, 2H), 7.07 (t, J=9.2Hz, 1H), 4.65 (d, J=3.8Hz, 1H) ,3.51(dq,J＝7.8,3.8Hz,1H),3.17(ddd,J＝11.1,6.9,3.7Hz,2H),2.71(ddd,J＝11.8,8.5,3.4Hz,2H),2.25(d , J=1.8Hz, 3H), 1.76 (ddt, J=13.9, 6.9, 3.6Hz, 2H), 1.45 (dtd, J=12.2, 8.2, 3.7Hz, 2H). 13 C NMR (101MHz, DMSO-d 6 ) δ155.01(d, J=234.7Hz), 146.80, 141.81, 138.97(d, J=2.1Hz), 125.85, 125.37, 124.38(d, J=17.8Hz), 122.63, 118.97(d, J= 4.0Hz), 115.34(d, J=23.1Hz), 115.15, 114.09, 110.60, 64.32, 43.75, 33.39, 15.09(d, J=3.0Hz).

Figure BDA0002385652160000481
Figure BDA0002385652160000481

实施例92 N-(3-甲基-4-氟苯基)-3-(5-(吗啉磺酰基)-1-(2-氟乙基)-1H-吲唑)胺的合成：Example 92 Synthesis of N-(3-methyl-4-fluorophenyl)-3-(5-(morpholinesulfonyl)-1-(2-fluoroethyl)-1H-indazol)amine:

Figure BDA0002385652160000482
Figure BDA0002385652160000482

中间体92-1的合成：将中间体1-2(240mg,1mmol)溶于10mL DMF，依次加入2-碘-1-氟乙烷(2mmol)，K2CO3(276mg,2mmol)，80℃反应12小时。将反应液过滤，减压浓缩，用硅胶薄层色谱板分离(石油醚/乙酸乙酯2/1)得186mg白色固体，收率66％。Synthesis of intermediate 92-1: Intermediate 1-2 (240 mg, 1 mmol) was dissolved in 10 mL of DMF, followed by addition of 2-iodo-1-fluoroethane (2 mmol), K 2 CO 3 (276 mg, 2 mmol), 80 °C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and separated by silica gel thin-layer chromatography (petroleum ether/ethyl acetate 2/1) to obtain 186 mg of white solid, with a yield of 66%.

中间体92-2的合成：按中间体13-2的合成方法，收率73％。Synthesis of intermediate 92-2: According to the synthesis method of intermediate 13-2, the yield is 73%.

标题化合物的合成：按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.63(s,1H),7.74(d,J＝8.9Hz,1H),7.66(dd,J＝14.4,6.3Hz,2H),7.59(dd,J＝6.9,2.7Hz,1H),7.09(t,J＝9.2Hz,1H),4.86(dt,J＝47.3,4.7Hz,2H),4.68(dt,J＝27.7,4.8Hz,2H),3.64(d,J＝4.6Hz,4H),2.89(d,J＝4.6Hz,4H),2.26(s,3H).13C NMR(101MHz,DMSO-d6)δ155.23(d,J＝235.1Hz),146.52,142.00,138.61(d,J＝2.2Hz),126.13,124.53(d,J＝18.1Hz),124.49,123.20,119.25(d,J＝4.2Hz),115.41(d,J＝13.0Hz),115.26(d,J＝2.5Hz),114.75,110.24,82.65(d,J＝167.7Hz),65.75,49.04(d,J＝19.9Hz),46.44,15.10(d,J＝2.9Hz).Synthesis of the title compound: according to the synthetic method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.36 (s, 1H), 8.63 (s, 1H), 7.74 (d, J=8.9 Hz, 1H ),7.66(dd,J＝14.4,6.3Hz,2H),7.59(dd,J＝6.9,2.7Hz,1H),7.09(t,J＝9.2Hz,1H),4.86(dt,J＝47.3, 4.7Hz, 2H), 4.68 (dt, J=27.7, 4.8Hz, 2H), 3.64 (d, J=4.6Hz, 4H), 2.89 (d, J=4.6Hz, 4H), 2.26 (s, 3H) . 13 C NMR(101MHz, DMSO-d 6 )δ155.23(d,J=235.1Hz),146.52,142.00,138.61(d,J=2.2Hz),126.13,124.53(d,J=18.1Hz), 124.49, 123.20, 119.25 (d, J=4.2Hz), 115.41 (d, J=13.0Hz), 115.26 (d, J=2.5Hz), 114.75, 110.24, 82.65 (d, J=167.7Hz), 65.75, 49.04(d, J=19.9Hz), 46.44, 15.10(d, J=2.9Hz).

实施例93 N-(3-甲基-4-氟苯基)-3-(5-(吗啉磺酰基)-1-(2,2,2-三氟乙基)-1H-吲唑)胺的合成：Example 93 N-(3-Methyl-4-fluorophenyl)-3-(5-(morpholinesulfonyl)-1-(2,2,2-trifluoroethyl)-1H-indazole) Synthesis of Amines:

Figure BDA0002385652160000491
Figure BDA0002385652160000491

中间体93-1的合成：90-2(69mg,0.2mmol)溶于2mL DMF，依次加入2-碘-1,1,1-三氟乙烷(0.4mmol)，K2CO3(52mg,0.44mmol)，80℃反应12小时。将反应液过滤，减压浓缩，用硅胶薄层色谱板分离(石油醚/乙酸乙酯2/1)得39mg白色固体，收率45％。Synthesis of intermediate 93-1: 90-2 (69 mg, 0.2 mmol) was dissolved in 2 mL of DMF, followed by the addition of 2-iodo-1,1,1-trifluoroethane (0.4 mmol), K 2 CO 3 (52 mg, 0.44 mmol), and reacted at 80°C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and separated by silica gel thin-layer chromatography (petroleum ether/ethyl acetate 2/1) to obtain 39 mg of white solid with a yield of 45%.

标题化合物的合成：按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.68(s,1H),7.89(d,J＝8.8Hz,1H),7.78(d,J＝9.0Hz,1H),7.65(dt,J＝8.2,3.6Hz,1H),7.59(d,J＝6.9Hz,1H),7.11(t,J＝9.2Hz,1H),5.39(q,J＝9.0Hz,2H),3.66(t,J＝4.6Hz,4H),2.90(t,J＝4.6Hz,4H),2.26(s,3H).13C NMR(101MHz,DMSO-d6)δ155.40(d,J＝235.5Hz),147.17,142.58,138.31(d,J＝2.2Hz),126.90,129.54–120.93(m),125.74,124.57(d,J＝18.0Hz),123.15,119.46(d,J＝4.0Hz),115.60,115.52,115.37(d,J＝16.7Hz),110.44,65.75,49.24(q,J＝32.8Hz),46.43,15.09(d,J＝3.0Hz).Synthesis of the title compound: according to the synthetic method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.44 (s, 1H), 8.68 (s, 1H), 7.89 (d, J=8.8 Hz, 1H ),7.78(d,J＝9.0Hz,1H),7.65(dt,J＝8.2,3.6Hz,1H),7.59(d,J＝6.9Hz,1H),7.11(t,J＝9.2Hz,1H) ), 5.39(q, J=9.0Hz, 2H), 3.66(t, J=4.6Hz, 4H), 2.90(t, J=4.6Hz, 4H), 2.26(s, 3H). 13 C NMR(101MHz) ,DMSO-d 6 )δ155.40(d,J=235.5Hz),147.17,142.58,138.31(d,J=2.2Hz),126.90,129.54–120.93(m),125.74,124.57(d,J=18.0 Hz), 123.15, 119.46(d, J＝4.0Hz), 115.60, 115.52, 115.37(d, J＝16.7Hz), 110.44, 65.75, 49.24(q, J＝32.8Hz), 46.43, 15.09(d, J =3.0Hz).

实施例94 N-(3-甲基-4-氟苯基)-3-(5-(吗啉磺酰基)-1-(2,2-二氟乙基)-1H-吲唑)胺的合成：Example 94 N-(3-methyl-4-fluorophenyl)-3-(5-(morpholinesulfonyl)-1-(2,2-difluoroethyl)-1H-indazol)amine synthesis:

Figure BDA0002385652160000492
Figure BDA0002385652160000492

中间体94-1的合成：按93-1的合成方法，收率55％。Synthesis of intermediate 94-1: According to the synthetic method of 93-1, the yield is 55%.

标题化合物的合成方法：按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.64(s,1H),7.80(d,J＝8.9Hz,1H),7.71(d,J＝9.0Hz,1H),7.68–7.61(m,1H),7.58(d,J＝6.6Hz,1H),7.09(t,J＝9.2Hz,1H),6.48(t,J＝54.9Hz,1H),4.86(t,J＝14.8Hz,2H),3.64(t,J＝4.4Hz,4H),2.87(s,4H),2.25(s,3H).The synthetic method of the title compound: according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.39(s,1H),8.64(s,1H),7.80(d,J=8.9Hz, 1H), 7.71(d, J=9.0Hz, 1H), 7.68–7.61(m, 1H), 7.58(d, J=6.6Hz, 1H), 7.09(t, J=9.2Hz, 1H), 6.48( t, J＝54.9Hz, 1H), 4.86(t, J＝14.8Hz, 2H), 3.64(t, J＝4.4Hz, 4H), 2.87(s, 4H), 2.25(s, 3H).

实施例95 N-(3-甲基-4-氟苯基)-3-(5-(吗啉磺酰基)-1-(二氟甲基)-1H-吲唑)胺的合成：Example 95 Synthesis of N-(3-methyl-4-fluorophenyl)-3-(5-(morpholinesulfonyl)-1-(difluoromethyl)-1H-indazol)amine:

Figure BDA0002385652160000493
Figure BDA0002385652160000493

中间体95-1的合成：将中间体1-2(240mg,1mmol)溶于5mL乙腈，加入溴氟甲基磷酸二乙酯(534mg,2mmol)和氟化钾(115mg,2mmol)，40℃反应48小时，反应完成后，减压浓缩，硅胶柱层析分离(石油醚/乙酸乙酯2/1)，得245mg，收率84％。Synthesis of intermediate 95-1: Intermediate 1-2 (240 mg, 1 mmol) was dissolved in 5 mL of acetonitrile, added with diethyl bromofluoromethyl phosphate (534 mg, 2 mmol) and potassium fluoride (115 mg, 2 mmol), at 40°C The reaction was carried out for 48 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain 245 mg with a yield of 84%.

中间体95-2的合成：按中间体1-3的合成方法，收率80％。Synthesis of intermediate 95-2: According to the synthesis method of intermediate 1-3, the yield is 80%.

中间体95-3的合成：将中间体95-2(90mg,0.31mmol)溶于4mL乙腈和2mL三氟乙酸，加入NBS(83mg,0.465mmol)，80℃反应，LC-MS监测，反应完成后，减压浓缩，加乙酸乙酯溶解，依次用饱和碳酸氢钠溶液、饱和食盐水洗，硅胶柱层析分离(石油醚/乙酸乙酯2/1)，得61mg，收率54％。Synthesis of Intermediate 95-3: Intermediate 95-2 (90 mg, 0.31 mmol) was dissolved in 4 mL of acetonitrile and 2 mL of trifluoroacetic acid, NBS (83 mg, 0.465 mmol) was added, and the reaction was carried out at 80 °C, monitored by LC-MS, and the reaction was completed After that, it was concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and saturated brine successively, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to obtain 61 mg with a yield of 54%.

标题化合物的合成：按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.76(s,1H),8.23(t,J＝58.7Hz,1H),7.68(d,J＝1.4Hz,1H),7.29(dd,J＝7.0,2.5Hz,1H),7.25–7.12(m,2H),6.87(d,J＝1.4Hz,1H),3.76–3.53(m,4H),2.92(t,J＝4.7Hz,4H),2.23(d,J＝1.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ157.09(d,J＝238.8Hz),144.07,137.37(d,J＝2.8Hz),136.81,131.30,127.44,125.31(d,J＝18.2Hz),124.93(d,J＝4.8Hz),121.20,121.10(d,J＝7.8Hz),116.00(d,J＝23.1Hz),113.17,111.18(t,J＝252.6Hz),100.66,65.92,46.36,14.83(d,J＝2.9Hz).Synthesis of the title compound: according to the synthetic method of Example 13, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.11 (s, 1H), 8.76 (s, 1H), 8.23 (t, J=58.7 Hz, 1H ), 7.68(d, J＝1.4Hz, 1H), 7.29(dd, J＝7.0, 2.5Hz, 1H), 7.25–7.12(m, 2H), 6.87(d, J＝1.4Hz, 1H), 3.76 -3.53(m, 4H), 2.92(t, J=4.7Hz, 4H), 2.23(d, J=1.9Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 )δ157.09(d, J = 238.8Hz), 144.07, 137.37 (d, J = 2.8 Hz), 136.81, 131.30, 127.44, 125.31 (d, J = 18.2 Hz), 124.93 (d, J = 4.8 Hz), 121.20, 121.10 (d, J = 7.8Hz), 116.00 (d, J = 23.1 Hz), 113.17, 111.18 (t, J = 252.6 Hz), 100.66, 65.92, 46.36, 14.83 (d, J = 2.9 Hz).

实施例96 1-(5-(3-((3-甲基-4-氟苯基)胺基)-1-(2,2-二氟乙基)-1H-吲唑基)磺酰基)哌啶-4-醇的合成：按实施例2的合成方法1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.61(d,J＝1.6Hz,1H),7.78(d,J＝8.9Hz,1H),7.72(dd,J＝8.9,1.6Hz,1H),7.64(dt,J＝8.7,3.6Hz,1H),7.58(dd,J＝7.0,2.8Hz,1H),7.09(t,J＝9.2Hz,1H),6.48(tt,J＝54.9,3.7Hz,1H),4.85(td,J＝15.1,3.7Hz,2H),4.66(d,J＝3.8Hz,1H),3.52(dd,J＝7.5,3.9Hz,1H),3.18(td,J＝7.5,4.3Hz,2H),2.82–2.66(m,2H),2.26(d,J＝1.7Hz,3H),1.85–1.70(m,2H),1.46(qd,J＝8.9,8.4,4.0Hz,2H).Example 96 1-(5-(3-((3-methyl-4-fluorophenyl)amino)-1-(2,2-difluoroethyl)-1H-indazolyl)sulfonyl) Synthesis of piperidin-4-ol: according to the synthetic method of Example 2 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.35 (s, 1H), 8.61 (d, J=1.6 Hz, 1H), 7.78 ( d, J=8.9Hz, 1H), 7.72 (dd, J=8.9, 1.6Hz, 1H), 7.64 (dt, J=8.7, 3.6Hz, 1H), 7.58 (dd, J=7.0, 2.8Hz, 1H) ),7.09(t,J＝9.2Hz,1H),6.48(tt,J＝54.9,3.7Hz,1H),4.85(td,J＝15.1,3.7Hz,2H),4.66(d,J＝3.8Hz ,1H),3.52(dd,J＝7.5,3.9Hz,1H),3.18(td,J＝7.5,4.3Hz,2H),2.82–2.66(m,2H),2.26(d,J＝1.7Hz, 3H), 1.85–1.70 (m, 2H), 1.46 (qd, J=8.9, 8.4, 4.0Hz, 2H).

Figure BDA0002385652160000501
Figure BDA0002385652160000501

实施例97 1-(5-(3-(3,4,5-三氟苯酚基)-1-环丙基-1H-吲唑基)磺酰基)哌啶-4-醇的合成：将中间体3-4(44mg,0.1mmol)、3,4,5-三氟苯酚(29mg,0.2mmol)、碘化亚铜(1.9mg,0.01mmol)、N,N-二甲基甘氨酸(2mg,0.02mmol)和碳酸铯(65mg,0.2mmol)混合，加入2mL 1,4-二氧六环，将反应瓶中的气体置换成氩气，120℃反应过夜。反应液过滤，减压浓缩，加乙醇溶解，加入氢氧化钠(20mg,0.5mmol)，60℃反应。反应完成后，加乙酸乙酯稀释，水洗，无水硫酸钠干燥，过滤，减压浓缩，硅胶薄层色谱板分离(二氯甲烷/甲醇20/1)。1HNMR(400MHz,DMSO-d6)δ7.91(dd,J＝5.3,3.6Hz,2H),7.79(dd,J＝9.1,1.5Hz,1H),7.44(dd,J＝9.3,6.0Hz,2H),4.66(d,J＝3.8Hz,1H),3.75(p,J＝5.4Hz,1H),3.51(dq,J＝7.7,3.9Hz,1H),3.13(ddd,J＝11.3,7.1,3.7Hz,2H),2.73(ddd,J＝11.7,8.4,3.4Hz,2H),1.74(ddt,J＝11.3,7.1,3.5Hz,2H),1.44(ddd,J＝12.7,8.1,3.8Hz,2H),1.14(d,J＝5.3Hz,4H).Example 97 Synthesis of 1-(5-(3-(3,4,5-trifluorophenolyl)-1-cyclopropyl-1H-indazolyl)sulfonyl)piperidin-4-ol: the intermediate Form 3-4 (44mg, 0.1mmol), 3,4,5-trifluorophenol (29mg, 0.2mmol), cuprous iodide (1.9mg, 0.01mmol), N,N-dimethylglycine (2mg, 0.02 mmol) and cesium carbonate (65 mg, 0.2 mmol) were mixed, 2 mL of 1,4-dioxane was added, the gas in the reaction flask was replaced with argon, and the reaction was performed at 120° C. overnight. The reaction solution was filtered, concentrated under reduced pressure, dissolved in ethanol, added with sodium hydroxide (20 mg, 0.5 mmol), and reacted at 60°C. After the completion of the reaction, add ethyl acetate to dilute, wash with water, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by silica gel thin layer chromatography (dichloromethane/methanol 20/1). 1 HNMR (400MHz, DMSO-d 6 ) δ 7.91 (dd, J=5.3, 3.6Hz, 2H), 7.79 (dd, J=9.1, 1.5Hz, 1H), 7.44 (dd, J=9.3, 6.0Hz) ,2H),4.66(d,J＝3.8Hz,1H),3.75(p,J＝5.4Hz,1H),3.51(dq,J＝7.7,3.9Hz,1H),3.13(ddd,J＝11.3, 7.1, 3.7Hz, 2H), 2.73 (ddd, J=11.7, 8.4, 3.4Hz, 2H), 1.74 (ddt, J=11.3, 7.1, 3.5Hz, 2H), 1.44 (ddd, J=12.7, 8.1, 3.8Hz, 2H), 1.14 (d, J=5.3Hz, 4H).

Figure BDA0002385652160000502
Figure BDA0002385652160000502

实施例98 1-(5-(3-(3-氯-4-氟苯酚基)-1-环丙基-1H-吲唑基)磺酰基)哌啶-4-醇的合成：以中间体3-4为原料，按实施例97的合成方法，1H NMR(400MHz,DMSO-d6)δ7.88(d,J＝8.9Hz,1H),7.83(d,J＝1.5Hz,1H),7.77(dd,J＝8.9,1.7Hz,1H),7.64(dd,J＝6.2,3.0Hz,1H),7.49(t,J＝9.0Hz,1H),7.36(dt,J＝9.1,3.5Hz,1H),4.65(s,1H),3.72(tt,J＝6.8,4.1Hz,1H),3.49(dq,J＝7.7,4.0Hz,1H),3.11(ddd,J＝11.2,7.1,3.7Hz,2H),2.69(ddd,J＝11.7,8.3,3.4Hz,2H),1.73(ddt,J＝13.9,7.2,3.5Hz,2H),1.42(dtd,J＝12.2,8.1,3.7Hz,2H),1.11(dq,J＝7.7,2.5Hz,4H).13C NMR(101MHz,DMSO-d6)δ154.54(d,J＝243.2Hz),153.04,152.17(d,J＝2.9Hz),143.23,128.42,126.33,121.27,120.97,120.55(d,J＝19.6Hz),119.72(d,J＝7.3Hz),118.10(d,J＝23.1Hz),112.40,111.87,64.19,43.64,33.35,29.97,6.91.Example 98 Synthesis of 1-(5-(3-(3-chloro-4-fluorophenolyl)-1-cyclopropyl-1H-indazolyl)sulfonyl)piperidin-4-ol: as intermediate 3-4 is the raw material, according to the synthesis method of Example 97, 1 H NMR (400MHz, DMSO-d 6 )δ7.88 (d, J=8.9Hz, 1H), 7.83 (d, J=1.5Hz, 1H) ,7.77(dd,J＝8.9,1.7Hz,1H),7.64(dd,J＝6.2,3.0Hz,1H),7.49(t,J＝9.0Hz,1H),7.36(dt,J＝9.1,3.5 Hz, 1H), 4.65 (s, 1H), 3.72 (tt, J=6.8, 4.1Hz, 1H), 3.49 (dq, J=7.7, 4.0Hz, 1H), 3.11 (ddd, J=11.2, 7.1, 3.7Hz, 2H), 2.69 (ddd, J=11.7, 8.3, 3.4Hz, 2H), 1.73 (ddt, J=13.9, 7.2, 3.5Hz, 2H), 1.42 (dtd, J=12.2, 8.1, 3.7Hz) , 2H), 1.11 (dq, J=7.7, 2.5Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ154.54 (d, J=243.2Hz), 153.04, 152.17 (d, J=2.9 Hz), 143.23, 128.42, 126.33, 121.27, 120.97, 120.55 (d, J=19.6 Hz), 119.72 (d, J=7.3 Hz), 118.10 (d, J=23.1 Hz), 112.40, 111.87, 64.19, 43.64 ,33.35,29.97,6.91.

Figure BDA0002385652160000503
Figure BDA0002385652160000503

实施例99 1-((1-环丙基-3-((3-(二氟甲基)-4-氟苯基)氨基)-1H-吲唑-5-基)磺酰基)哌啶-4-醇的合成：按实施例3的合成方法，收率61％，1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.57(s,1H),7.96(td,J＝8.3,3.7Hz,2H),7.72(s,1H),7.37(d,J＝10.3Hz,1H),7.23(t,1H),4.67(d,J＝4.0Hz,1H),3.69(q,J＝5.3Hz,1H),3.51(dt,J＝7.9,3.8Hz,1H),3.16(p,J＝4.7Hz,2H),2.72(ddd,J＝11.8,8.3,3.8Hz,2H),1.86–1.61(m,2H),1.45(dp,J＝12.5,4.2Hz,2H),1.14(d,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ153.7(dt,J＝242.3,5.6Hz),145.2,142.0,139.2(d,J＝2.2Hz),126.3,126.2,122.6,121.6(td,J＝22.7,13.5Hz),120.1(d,J＝7.3Hz),117.0(d,J＝21.1Hz),115.1,114.0(dt,J＝6.4,3.5Hz),112.3(td,J＝236.0,3.8Hz),110.3,64.2,43.7,33.4,29.6,6.8.Example 99 1-((1-Cyclopropyl-3-((3-(difluoromethyl)-4-fluorophenyl)amino)-1H-indazol-5-yl)sulfonyl)piperidine- Synthesis of 4-alcohol: according to the synthetic method of Example 3, yield 61%, 1 H NMR (400MHz, DMSO-d 6 )δ9.61(s,1H), 8.57(s,1H), 7.96(td, J=8.3, 3.7Hz, 2H), 7.72(s, 1H), 7.37(d, J=10.3Hz, 1H), 7.23(t, 1H), 4.67(d, J=4.0Hz, 1H), 3.69( q, J=5.3Hz, 1H), 3.51 (dt, J=7.9, 3.8Hz, 1H), 3.16 (p, J=4.7Hz, 2H), 2.72 (ddd, J=11.8, 8.3, 3.8Hz, 2H) ), 1.86–1.61 (m, 2H), 1.45 (dp, J=12.5, 4.2Hz, 2H), 1.14 (d, J=5.2Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 )δ153. 7 (dt, J=242.3, 5.6Hz), 145.2, 142.0, 139.2 (d, J=2.2Hz), 126.3, 126.2, 122.6, 121.6 (td, J=22.7, 13.5Hz), 120.1 (d, J= 7.3Hz), 117.0 (d, J=21.1Hz), 115.1, 114.0 (dt, J=6.4, 3.5Hz), 112.3 (td, J=236.0, 3.8Hz), 110.3, 64.2, 43.7, 33.4, 29.6, 6.8.

Figure BDA0002385652160000511
Figure BDA0002385652160000511

实施例100 N-(3-二氟甲基-4-氟苯基)-3-(1-环丙基-5-(吗啉磺酰基)-1H-吲唑并[3,4-c]吡啶)胺的合成：按实施例13的合成方法，1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),9.17(s,1H),8.71(s,1H),7.95(d,J＝5.7Hz,1H),7.93–7.84(m,1H),7.38(d,J＝8.2Hz,1H),7.36–7.09(m,1H),3.86(q,J＝4.7,3.5Hz,1H),3.63(t,J＝4.4Hz,4H),3.13(t,J＝4.5Hz,4H),1.34–1.09(m,4H).13C NMR(101MHz,DMSO-d6)δ152.6(td),145.2,142.8,138.8(d,J＝2.2Hz),137.7,134.8,121.7(td,J＝22.6,13.2Hz),120.3(d,J＝7.5Hz),118.9,117.2,117.0,114.1(d,J＝4.3Hz),112.2(td,J＝236.1,3.9Hz),66.1,46.8,30.3,6.9.Example 100 N-(3-Difluoromethyl-4-fluorophenyl)-3-(1-cyclopropyl-5-(morpholinesulfonyl)-1H-indazolo[3,4-c] Synthesis of pyridyl)amine: according to the synthetic method of Example 13, 1 H NMR (400MHz, DMSO-d 6 )δ9.78(s,1H), 9.17(s,1H), 8.71(s,1H), 7.95( d, J=5.7Hz, 1H), 7.93–7.84 (m, 1H), 7.38 (d, J=8.2Hz, 1H), 7.36–7.09 (m, 1H), 3.86 (q, J=4.7, 3.5Hz) ,1H),3.63(t,J＝4.4Hz,4H),3.13(t,J＝4.5Hz,4H),1.34–1.09(m,4H). 13C NMR(101MHz,DMSO-d 6 )δ152. 6(td), 145.2, 142.8, 138.8 (d, J=2.2Hz), 137.7, 134.8, 121.7 (td, J=22.6, 13.2Hz), 120.3 (d, J=7.5Hz), 118.9, 117.2, 117.0 ,114.1(d,J=4.3Hz),112.2(td,J=236.1,3.9Hz),66.1,46.8,30.3,6.9.

Figure BDA0002385652160000512
Figure BDA0002385652160000512

实施例101 1-((5-(3-(3-二氟甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶-4-醇的合成，按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),9.15(d,J＝1.1Hz,1H),8.68(d,J＝1.1Hz,1H),7.94(dd,J＝6.2,2.8Hz,1H),7.89(dt,J＝8.0,3.7Hz,1H),7.42–7.35(m,1H),7.34(s,1H),4.68(d,J＝3.9Hz,1H),3.92–3.81(m,1H),3.54(tt,J＝8.0,4.0Hz,1H),3.46–3.36(m,2H),2.93(ddd,J＝12.3,8.9,3.4Hz,2H),1.74(dp,J＝13.3,3.4Hz,2H),1.41(dtd,J＝12.4,8.1,3.5Hz,2H),1.28–1.16(m,4H).13C NMR(101MHz,DMSO-d6)δ153.8(d,J＝243.0Hz),145.2,143.6,138.8(d,J＝2.3Hz),137.6,134.7,122.3–121.2(m),120.3(d,J＝7.5Hz),118.9,117.2(d,J＝21.3Hz),116.7,114.1(d,J＝5.6Hz),114.9–109.5(m),64.8,44.2,33.8,30.3,6.9.Example 101 1-((5-(3-(3-difluoromethyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo[3,4-c]pyridine Synthesis of yl)sulfonyl)piperidin-4-ol, according to the synthetic method of Example 3, 1 H NMR (400MHz, DMSO-d 6 )δ9.74(s, 1H), 9.15(d, J=1.1Hz ,1H),8.68(d,J＝1.1Hz,1H),7.94(dd,J＝6.2,2.8Hz,1H),7.89(dt,J＝8.0,3.7Hz,1H),7.42–7.35(m, 1H), 7.34 (s, 1H), 4.68 (d, J=3.9Hz, 1H), 3.92–3.81 (m, 1H), 3.54 (tt, J=8.0, 4.0Hz, 1H), 3.46–3.36 (m ,2H),2.93(ddd,J＝12.3,8.9,3.4Hz,2H),1.74(dp,J＝13.3,3.4Hz,2H),1.41(dtd,J＝12.4,8.1,3.5Hz,2H), 1.28-1.16 (m, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 153.8 (d, J=243.0Hz), 145.2, 143.6, 138.8 (d, J=2.3Hz), 137.6, 134.7, 122.3–121.2 (m), 120.3 (d, J=7.5Hz), 118.9, 117.2 (d, J=21.3Hz), 116.7, 114.1 (d, J=5.6Hz), 114.9–109.5 (m), 64.8, 44.2, 33.8, 30.3, 6.9.

Figure BDA0002385652160000513
Figure BDA0002385652160000513

实施例102 N-(3-二氟甲基-4-氟苯基)-3-(5-(吗啉磺酰基)-1-环丙基-1H-吲唑)胺的合成，按实施例13的合成方法，收率58％，1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.58(d,J＝1.7Hz,1H),8.04–7.88(m,2H),7.81–7.66(m,2H),7.40–7.09(m,2H),3.71(p,J＝5.4Hz,1H),3.68–3.58(m,4H),2.91–2.82(m,4H),1.20–1.08(m,4H).13C NMR(101MHz,DMSO-d6)δ153.7(dt,J＝242.3,5.7Hz),145.3,142.1,139.2(d,J＝2.3Hz),126.3,125.0,123.1,121.6(td,J＝22.7,13.5Hz),120.2(d,J＝7.6Hz),117.0(d,J＝21.3Hz),115.1,114.0(t,J＝5.7Hz),112.2(td,J＝235.9,3.8Hz),110.5,65.75,46.4,29.7,6.8.Example 102 Synthesis of N-(3-difluoromethyl-4-fluorophenyl)-3-(5-(morpholinesulfonyl)-1-cyclopropyl-1H-indazol)amine, according to Example Synthesis of 13, yield 58%, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.63 (s, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.04-7.88 (m, 2H) , 7.81–7.66 (m, 2H), 7.40–7.09 (m, 2H), 3.71 (p, J=5.4Hz, 1H), 3.68–3.58 (m, 4H), 2.91–2.82 (m, 4H), 1.20 -1.08 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 153.7 (dt, J=242.3, 5.7 Hz), 145.3, 142.1, 139.2 (d, J=2.3 Hz), 126.3, 125.0 ,123.1,121.6(td,J=22.7,13.5Hz),120.2(d,J=7.6Hz),117.0(d,J=21.3Hz),115.1,114.0(t,J=5.7Hz),112.2(td , J=235.9, 3.8Hz), 110.5, 65.75, 46.4, 29.7, 6.8.

Figure BDA0002385652160000521
Figure BDA0002385652160000521

实施例103 1-((5-(3-(3-甲基-4-氟苯基)氨基)-1-甲基-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶-4-醇的合成，按实施例3的合成方法，1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.57(s,1H),7.65(s,2H),7.60(dd,J＝8.6,4.1Hz,1H),7.56(dd,J＝6.9,2.7Hz,1H),7.08(t,J＝9.2Hz,1H),3.96(s,3H),3.49(dq,J＝7.7,3.9Hz,1H),3.16(q,J＝6.8,5.6Hz,2H),2.70(ddd,J＝11.8,8.5,3.4Hz,2H),2.24(d,J＝1.8Hz,3H),1.74(ddd,J＝10.8,6.8,3.3Hz,2H),1.44(dtd,J＝12.3,8.3,3.5Hz,2H).Example 103 1-((5-(3-(3-methyl-4-fluorophenyl)amino)-1-methyl-1H-indazolo[3,4-c]pyridyl)sulfonyl) Synthesis of piperidin-4-ol, according to the synthetic method of Example 3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26(s, 1H), 8.57(s, 1H), 7.65(s, 2H) ,7.60(dd,J＝8.6,4.1Hz,1H),7.56(dd,J＝6.9,2.7Hz,1H),7.08(t,J＝9.2Hz,1H),3.96(s,3H),3.49( dq,J＝7.7,3.9Hz,1H),3.16(q,J＝6.8,5.6Hz,2H),2.70(ddd,J＝11.8,8.5,3.4Hz,2H),2.24(d,J＝1.8Hz ,3H),1.74(ddd,J=10.8,6.8,3.3Hz,2H),1.44(dtd,J=12.3,8.3,3.5Hz,2H).

Figure BDA0002385652160000522
Figure BDA0002385652160000522

实施例104 N-(3-甲基-4-氟苯基)-3-(5-(吗啉磺酰基)-1-环丙基-6-氟-1H-吲唑)胺的合成，按实施例13的合成方法，收率56％，1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.66(d,J＝6.7Hz,1H),7.61(ddd,J＝8.9,4.4,2.9Hz,1H),7.55(d,J＝11.3Hz,1H),7.52(dd,J＝6.8,2.8Hz,1H),7.08(t,J＝9.2Hz,1H),3.77–3.55(m,5H),3.03(dd,J＝5.7,3.5Hz,4H),2.24(d,J＝1.8Hz,3H),1.11(td,J＝5.2,4.6,3.1Hz,4H).13C NMR(101MHz,DMSO-d6)δ157.7(d,J＝250.6Hz),154.8(d,J＝235.3Hz),145.5,142.2(d,J＝12.5Hz),138.0(d,J＝2.2Hz),125.9(d,J＝3.2Hz),124.0(d,J＝18.1Hz),118.8(d,J＝4.0Hz),115.1(d,J＝11.7Hz),114.9(d,J＝6.2Hz),114.8(d,J＝2.1Hz),111.6,96.8(d,J＝27.7Hz),65.6,45.6,29.2,14.6(d,J＝3.0Hz),6.3.Example 104 Synthesis of N-(3-methyl-4-fluorophenyl)-3-(5-(morpholinesulfonyl)-1-cyclopropyl-6-fluoro-1H-indazole)amine, press Synthetic method of Example 13, yield 56%, 1 H NMR (400MHz, DMSO-d 6 )δ9.36(s, 1H), 8.66(d, J=6.7Hz, 1H), 7.61(ddd, J= 8.9,4.4,2.9Hz,1H),7.55(d,J＝11.3Hz,1H),7.52(dd,J＝6.8,2.8Hz,1H),7.08(t,J＝9.2Hz,1H),3.77– 3.55 (m, 5H), 3.03 (dd, J=5.7, 3.5Hz, 4H), 2.24 (d, J=1.8Hz, 3H), 1.11 (td, J=5.2, 4.6, 3.1Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ 157.7 (d, J=250.6 Hz), 154.8 (d, J=235.3 Hz), 145.5, 142.2 (d, J=12.5 Hz), 138.0 (d, J= 2.2Hz), 125.9(d, J=3.2Hz), 124.0(d, J=18.1Hz), 118.8(d, J=4.0Hz), 115.1(d, J=11.7Hz), 114.9(d, J= 6.2Hz), 114.8 (d, J=2.1Hz), 111.6, 96.8 (d, J=27.7Hz), 65.6, 45.6, 29.2, 14.6 (d, J=3.0Hz), 6.3.

Figure BDA0002385652160000523
Figure BDA0002385652160000523

实施例105 N,N-二甲基甘氨酸-4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶)酯的合成：将44mg(0.1mmol)化合物59溶于2ml二氯甲烷，向溶液中加入DCC(0.3mmol,62mg)、DMAP(0.12mmol,15mg)和N,N-二甲基甘氨酸(0.3mmol,30mg)。40℃下反应3小时，反应完成后，冷却到室温。反应液过滤，滤液减压蒸干，C18柱层析分离，得黄色固体，收率90％。1H NMR(400MHz,Chloroform-d)δ8.43(dd,J＝4.0,1.1Hz,1H),7.45(dt,J＝8.9,3.6Hz,1H),7.39(dd,J＝6.6,3.0Hz,1H),6.98(t,J＝9.0Hz,1H),6.95(s,1H),4.86(tt,J＝7.9,3.8Hz,1H),3.63(tq,J＝11.6,3.5Hz,3H),3.18(ddd,J＝12.4,8.6,3.5Hz,2H),3.12(s,2H),2.37–2.25(m,9H),1.97–1.86(m,2H),1.77–1.68(m,2H),1.33–1.21(m,4H).13C NMR(101MHz,Chloroform-d)δ169.75,156.32(d,J＝238.4Hz),145.63,143.61,137.82,136.93(d,J＝2.5Hz),133.72,125.19(d,J＝18.4Hz),119.96(d,J＝4.4Hz),119.41,116.19,115.69(d,J＝7.4Hz),115.15(d,J＝23.4Hz),68.95,60.21,45.17,44.07,30.23,29.79,14.89(d,J＝3.3Hz),6.95.HRMS(ESI)calculated for C26H31O4N5F3S[M+H]+531.2184,found 531.2169.Example 105 N,N-Dimethylglycine-4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indium Synthesis of azolo[3,4-c]pyridinyl)sulfonyl)piperidine)ester: 44 mg (0.1 mmol) of compound 59 was dissolved in 2 ml of dichloromethane, to the solution was added DCC (0.3 mmol, 62 mg), DMAP (0.12 mmol, 15 mg) and N,N-dimethylglycine (0.3 mmol, 30 mg). The reaction was carried out at 40°C for 3 hours, and after completion of the reaction, it was cooled to room temperature. The reaction solution was filtered, the filtrate was evaporated to dryness under reduced pressure, and separated by C18 column chromatography to obtain a yellow solid with a yield of 90%. 1 H NMR (400MHz, Chloroform-d) δ 8.43 (dd, J=4.0, 1.1 Hz, 1H), 7.45 (dt, J=8.9, 3.6 Hz, 1H), 7.39 (dd, J=6.6, 3.0 Hz) ,1H),6.98(t,J＝9.0Hz,1H),6.95(s,1H),4.86(tt,J＝7.9,3.8Hz,1H),3.63(tq,J＝11.6,3.5Hz,3H) ,3.18(ddd,J=12.4,8.6,3.5Hz,2H),3.12(s,2H),2.37–2.25(m,9H),1.97–1.86(m,2H),1.77–1.68(m,2H) ,1.33–1.21(m,4H). 13 C NMR(101MHz,Chloroform-d)δ169.75,156.32(d,J＝238.4Hz),145.63,143.61,137.82,136.93(d,J＝2.5Hz),133.72, 125.19(d,J＝18.4Hz),119.96(d,J＝4.4Hz),119.41,116.19,115.69(d,J＝7.4Hz),115.15(d,J＝23.4Hz),68.95,60.21,45.17, 44.07,30.23,29.79,14.89(d,J=3.3Hz),6.95.HRMS(ESI) calculated for C26H31O4N5F3S[M+H] + 531.2184,found 531.2169.

Figure BDA0002385652160000531
Figure BDA0002385652160000531

实施例106 L-缬氨酸-4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶)酯三氟乙酸盐的合成：将44mg(0.1mmol)化合物5溶于2ml二氯甲烷，向溶液中加入DCC(0.3mmol,62mg)、DMAP(0.12mmol,15mg)和N-Boc-L-缬氨酸(0.3mmol,65mg)。40℃下反应3小时，反应完成后，冷却到室温。反应液过滤，滤液减压蒸干，硅胶柱层析分离，得黄色固体。溶于2ml二氯甲烷，加1mL三氟乙酸，反应完成后，减压蒸除溶剂，加入乙醚，有黄色固体析出，过滤，固体用乙醚洗，减压干燥，得黄色固体，收率83％。1HNMR(400MHz,DMSO-d6)δ9.45(s,1H),9.10(d,J＝1.1Hz,1H),8.73(d,J＝1.1Hz,1H),8.30(s,3H),7.60(dt,J＝8.7,3.6Hz,1H),7.50(dd,J＝6.9,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),4.93(tt,J＝7.3,3.6Hz,1H),3.92–3.86(m,1H),3.82(dq,J＝7.0,4.2,3.5Hz,1H),3.37(ddt,J＝14.0,6.9,3.8Hz,2H),3.28–3.12(m,2H),2.25(d,J＝1.8Hz,3H),2.14–1.98(m,1H),1.91(s,2H),1.75–1.57(m,2H),1.29–1.13(m,4H),0.89(t,J＝6.4Hz,6H).13C NMR(101MHz,DMSO-d6)δ168.50,158.82(q,J＝32.5Hz),155.35(d,J＝235.7Hz),145.67,143.33,138.28,137.65,134.45,124.63(d,J＝18.1Hz),119.27(d,J＝4.1Hz),119.06,117.25(d,J＝297.5Hz),117.03,115.47(d,J＝23.4Hz),115.28,70.68,57.70,43.55,40.42,30.18,29.93,29.86,29.80,18.65,17.81,15.09(d,J＝3.0Hz),6.93.Example 106 L-valine-4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo[ Synthesis of 3,4-c]pyridyl)sulfonyl)piperidine)ester trifluoroacetate: 44 mg (0.1 mmol) of compound 5 was dissolved in 2 ml of dichloromethane, to the solution was added DCC (0.3 mmol, 62 mg) , DMAP (0.12 mmol, 15 mg) and N-Boc-L-valine (0.3 mmol, 65 mg). The reaction was carried out at 40°C for 3 hours, and after completion of the reaction, it was cooled to room temperature. The reaction solution was filtered, the filtrate was evaporated to dryness under reduced pressure, and separated by silica gel column chromatography to obtain a yellow solid. Dissolve in 2 ml of dichloromethane, add 1 ml of trifluoroacetic acid, after the reaction is completed, evaporate the solvent under reduced pressure, add diethyl ether, a yellow solid is precipitated, filter, wash the solid with diethyl ether, and dry under reduced pressure to obtain a yellow solid with a yield of 83% . 1 HNMR (400MHz, DMSO-d 6 )δ9.45(s, 1H), 9.10(d, J=1.1Hz, 1H), 8.73(d, J=1.1Hz, 1H), 8.30(s, 3H), 7.60(dt,J＝8.7,3.6Hz,1H),7.50(dd,J＝6.9,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),4.93(tt,J＝7.3,3.6Hz ,1H),3.92–3.86(m,1H),3.82(dq,J=7.0,4.2,3.5Hz,1H),3.37(ddt,J=14.0,6.9,3.8Hz,2H),3.28–3.12(m ,2H),2.25(d,J＝1.8Hz,3H),2.14-1.98(m,1H),1.91(s,2H),1.75-1.57(m,2H),1.29-1.13(m,4H), 0.89 (t, J=6.4Hz, 6H). 13 C NMR (101MHz, DMSO-d 6 ) δ 168.50, 158.82 (q, J=32.5Hz), 155.35 (d, J=235.7Hz), 145.67, 143.33, 138.28 ,137.65,134.45,124.63(d,J＝18.1Hz),119.27(d,J＝4.1Hz),119.06,117.25(d,J＝297.5Hz),117.03,115.47(d,J＝23.4Hz),115.28 ,70.68,57.70,43.55,40.42,30.18,29.93,29.86,29.80,18.65,17.81,15.09(d,J＝3.0Hz),6.93.

Figure BDA0002385652160000532
Figure BDA0002385652160000532

实施例107 L-丙氨酸-4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶)酯三氟乙酸盐的合成：同实施例106。1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.11(s,1H),8.73(s,1H),8.28(s,3H),7.60(dt,J＝7.7,3.4Hz,1H),7.50(dd,J＝6.9,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),4.88(tt,J＝6.8,3.4Hz,1H),4.06(q,J＝7.0Hz,1H),3.82(tt,J＝6.9,4.0Hz,1H),3.53–3.25(m,2H),3.28–3.08(m,2H),2.25(s,3H),1.89(td,J＝8.8,4.6Hz,2H),1.67(p,J＝7.5,6.7Hz,2H),1.32(d,J＝7.2Hz,3H),1.27–1.13(m,4H).13C NMR(101MHz,DMSO-d6)δ169.65,158.76(q,J＝31.6Hz),155.35(d,J＝235.6Hz),145.66,143.47,138.29,137.66,134.52,124.63(d,J＝18.1Hz),119.27(d,J＝4.1Hz),119.05,116.95,115.48(d,J＝23.6Hz),115.28,70.55,48.37,43.49,30.19,29.87,29.82,16.12,15.10(d,J＝3.0Hz),6.94.Example 107 L-alanine-4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo[ Synthesis of 3,4-c]pyridyl)sulfonyl)piperidine)ester trifluoroacetate: same as Example 106. 1 H NMR (400MHz, DMSO-d 6 )δ9.45(s,1H), 9.11(s,1H), 8.73(s,1H), 8.28(s,3H), 7.60(dt, J=7.7,3.4 Hz, 1H), 7.50(dd, J＝6.9, 2.8Hz, 1H), 7.11(t, J＝9.2Hz, 1H), 4.88(tt, J＝6.8, 3.4Hz, 1H), 4.06(q, J =7.0Hz,1H),3.82(tt,J=6.9,4.0Hz,1H),3.53-3.25(m,2H),3.28-3.08(m,2H),2.25(s,3H),1.89(td, J=8.8, 4.6Hz, 2H), 1.67 (p, J=7.5, 6.7Hz, 2H), 1.32 (d, J=7.2Hz, 3H), 1.27–1.13 (m, 4H). 13 C NMR (101MHz) ,DMSO-d 6 )δ169.65,158.76(q,J=31.6Hz),155.35(d,J=235.6Hz),145.66,143.47,138.29,137.66,134.52,124.63(d,J=18.1Hz),119.27( d, J＝4.1Hz), 119.05, 116.95, 115.48(d, J＝23.6Hz), 115.28, 70.55, 48.37, 43.49, 30.19, 29.87, 29.82, 16.12, 15.10(d, J＝3.0Hz), 6.94.

Figure BDA0002385652160000533
Figure BDA0002385652160000533

实施例108甘氨酸-4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶)酯三氟乙酸盐的合成：同实施例106。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.12(d,J＝1.1Hz,1H),8.73(d,J＝1.1Hz,1H),8.17(s,3H),7.61(dt,J＝8.7,3.6Hz,1H),7.51(dd,J＝6.9,2.8Hz,1H),7.12(t,J＝9.2Hz,1H),4.90(td,J＝7.7,3.9Hz,1H),3.84(dq,J＝6.7,3.4,3.0Hz,1H),3.79(s,2H),3.48–3.39(m,2H),3.15(ddd,J＝12.3,8.3,3.7Hz,2H),2.25(d,J＝1.9Hz,3H),1.98–1.85(m,2H),1.65(dtd,J＝12.1,7.7,3.6Hz,2H),1.21(dddd,J＝12.0,9.5,6.7,3.0Hz,4H).Example 108 Glycine-4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo[3,4- c] Synthesis of pyridyl)sulfonyl)piperidine)ester trifluoroacetate: same as Example 106. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.46 (s, 1H), 9.12 (d, J=1.1 Hz, 1H), 8.73 (d, J=1.1 Hz, 1H), 8.17 (s, 3H) ,7.61(dt,J＝8.7,3.6Hz,1H),7.51(dd,J＝6.9,2.8Hz,1H),7.12(t,J＝9.2Hz,1H),4.90(td,J＝7.7,3.9 Hz, 1H), 3.84 (dq, J=6.7, 3.4, 3.0Hz, 1H), 3.79 (s, 2H), 3.48–3.39 (m, 2H), 3.15 (ddd, J=12.3, 8.3, 3.7Hz, 2H), 2.25 (d, J=1.9Hz, 3H), 1.98–1.85 (m, 2H), 1.65 (dtd, J=12.1, 7.7, 3.6Hz, 2H), 1.21 (dddd, J=12.0, 9.5, 6.7,3.0Hz,4H).

Figure BDA0002385652160000541
Figure BDA0002385652160000541

实施例109 N,N-二甲基甘氨酸-4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶)酯乙酸盐的合成：将化合物105(25mg)溶于二氯甲烷，加入1ml乙酸，搅拌混匀。减压蒸除溶剂，加入乙醚，有黄色固体析出，过滤，固体用乙醚洗，减压干燥，得黄色固体，定量转化。1H NMR(400MHz,DMSO-d6)δ11.93(s,2H),9.44(d,J＝3.2Hz,1H),9.12(d,J＝3.2Hz,1H),8.71(d,J＝3.2Hz,1H),7.60(dd,J＝8.6,4.3Hz,1H),7.55–7.44(m,1H),7.11(td,J＝9.3,3.3Hz,1H),4.78(s,1H),3.82(dq,J＝7.5,3.8Hz,1H),3.21–3.00(m,4H),2.25(s,3H),2.20(d,J＝3.2Hz,6H),1.98–1.78(m,5H),1.60(s,2H),1.19(t,J＝7.6Hz,4H).Example 109 N,N-Dimethylglycine-4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indium Synthesis of azolo[3,4-c]pyridyl)sulfonyl)piperidine)ester acetate: Compound 105 (25 mg) was dissolved in dichloromethane, 1 ml of acetic acid was added, and the mixture was stirred and mixed. The solvent was evaporated under reduced pressure, ether was added, a yellow solid was precipitated, filtered, the solid was washed with ether, and dried under reduced pressure to obtain a yellow solid, which was quantitatively converted. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.93 (s, 2H), 9.44 (d, J=3.2 Hz, 1H), 9.12 (d, J=3.2 Hz, 1H), 8.71 (d, J= 3.2Hz, 1H), 7.60(dd, J=8.6, 4.3Hz, 1H), 7.55-7.44(m, 1H), 7.11(td, J=9.3, 3.3Hz, 1H), 4.78(s, 1H), 3.82(dq,J＝7.5,3.8Hz,1H),3.21-3.00(m,4H),2.25(s,3H),2.20(d,J＝3.2Hz,6H),1.98-1.78(m,5H) ,1.60(s,2H),1.19(t,J=7.6Hz,4H).

Figure BDA0002385652160000542
Figure BDA0002385652160000542

实施例110 N,N-二甲基甘氨酸-4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶)酯柠檬酸盐的合成：将化合物105(530mg,1mmol)溶于乙酸乙酯，搅拌下，向溶液中滴加柠檬酸溶液(230mg,1.2mmol,溶于乙酸乙酯和甲醇)。在室温下搅拌过夜，有黄色固体析出，过滤，固体用乙酸乙酯和甲醇的混合液(10/1)洗，减压干燥，得黄色固体，收率91％。1H NMR(400MHz,DMSO-d6)δ10.99(s,2H),9.43(s,1H),9.12(s,1H),8.71(s,1H),7.60(dd,J＝8.3,4.1Hz,1H),7.50(dd,J＝6.8,2.8Hz,1H),7.11(t,J＝9.2Hz,1H),4.82(dt,J＝8.0,4.4Hz,1H),3.82(tt,J＝6.9,3.8Hz,1H),3.46–3.31(m,4H),3.13(ddd,J＝12.3,8.5,3.6Hz,2H),2.70(d,J＝15.3Hz,2H),2.60(d,J＝15.3Hz,2H),2.34(s,6H)，2.25(s，3H)，1.94–1.82(m，2H)，1.70–1.54(m，2H)，1.24–1.09(m，4H).Example 110 N,N-Dimethylglycine-4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indium Synthesis of azolo[3,4-c]pyridyl)sulfonyl)piperidine)ester citrate: Compound 105 (530 mg, 1 mmol) was dissolved in ethyl acetate, and citric acid solution was added dropwise to the solution with stirring (230 mg, 1.2 mmol, dissolved in ethyl acetate and methanol). After stirring at room temperature overnight, a yellow solid was precipitated, filtered, and the solid was washed with a mixture of ethyl acetate and methanol (10/1), and dried under reduced pressure to obtain a yellow solid with a yield of 91%. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.99(s, 2H), 9.43(s, 1H), 9.12(s, 1H), 8.71(s, 1H), 7.60(dd, J=8.3, 4.1 Hz,1H),7.50(dd,J=6.8,2.8Hz,1H),7.11(t,J=9.2Hz,1H),4.82(dt,J=8.0,4.4Hz,1H),3.82(tt,J =6.9,3.8Hz,1H),3.46–3.31(m,4H),3.13(ddd,J=12.3,8.5,3.6Hz,2H),2.70(d,J=15.3Hz,2H),2.60(d, J=15.3Hz, 2H), 2.34 (s, 6H), 2.25 (s, 3H), 1.94–1.82 (m, 2H), 1.70–1.54 (m, 2H), 1.24–1.09 (m, 4H).

Figure BDA0002385652160000543
Figure BDA0002385652160000543

实施例111 N,N-二甲基甘氨酸-4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶)酯二甲磺酸盐的合成：将化合物105(26mg,0.05mmol)溶于乙酸乙酯，向溶液中滴加甲磺酸的乙醚溶液(0.1mmol,6.5μL)，有橙红色固体析出，过滤，固体用乙醚洗，减压干燥，得橙红色固体，定量转化。1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.45(s,1H),9.12(s,1H),8.73(s,1H),7.68–7.24(m,3H),7.11(t,J＝9.2Hz,1H),5.01–4.84(m,1H),4.15(d,J＝3.8Hz,2H),3.83(tt,J＝7.0,4.0Hz,1H),3.38(q,J＝7.2,6.8Hz,2H),3.17(t,J＝9.2Hz,2H),2.80(d,J＝3.3Hz,6H),2.35(s,6H),2.25(s,3H),1.92(t,J＝9.9Hz,2H),1.69(s,2H),1.27–1.13(m,4H).Example 111 N,N-Dimethylglycine-4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indium Synthesis of azolo[3,4-c]pyridinyl)sulfonyl)piperidine)ester dimethanesulfonate: Compound 105 (26 mg, 0.05 mmol) was dissolved in ethyl acetate and methanesulfonic acid was added dropwise to the solution ether solution (0.1 mmol, 6.5 μL), an orange-red solid was precipitated, filtered, the solid was washed with ether, and dried under reduced pressure to obtain an orange-red solid, which was quantitatively converted. 1 H NMR (400MHz, DMSO-d 6 )δ9.84(s,1H), 9.45(s,1H), 9.12(s,1H), 8.73(s,1H), 7.68-7.24(m,3H), 7.11 (t, J=9.2Hz, 1H), 5.01–4.84 (m, 1H), 4.15 (d, J=3.8Hz, 2H), 3.83 (tt, J=7.0, 4.0Hz, 1H), 3.38 (q ,J=7.2,6.8Hz,2H),3.17(t,J=9.2Hz,2H),2.80(d,J=3.3Hz,6H),2.35(s,6H),2.25(s,3H),1.92 (t, J=9.9Hz, 2H), 1.69(s, 2H), 1.27–1.13(m, 4H).

Figure BDA0002385652160000544
Figure BDA0002385652160000544

实施例112 N,N-二甲基甘氨酸-4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶)酯盐酸盐的合成：向化合物05的乙酸乙酯溶液中通入氯化氢气体，有橙红色固体析出，过滤，固体用乙酸乙酯洗，减压干燥，收率49％。1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.59(s,1H),9.12(d,J＝3.3Hz,1H),8.79(d,J＝3.4Hz,1H),7.69–7.58(m,1H),7.58–7.49(m,1H),7.11(td,J＝9.4,3.4Hz,1H),4.93(s,1H),4.15(s,2H),3.90–3.77(m,1H),3.39(t,J＝9.6Hz,2H),3.19(t,J＝9.6Hz,2H),2.79(s,6H),2.25(s,3H),1.93(d,J＝12.8Hz,2H),1.68(d,J＝11.3Hz,2H),1.27–1.13(m,4H).Example 112 N,N-Dimethylglycine-4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indium Synthesis of azolo[3,4-c]pyridinyl)sulfonyl)piperidine)ester hydrochloride: hydrogen chloride gas was passed into the ethyl acetate solution of compound 05, an orange-red solid was precipitated, filtered, and the solid was washed with acetic acid Washed with ethyl ester and dried under reduced pressure, the yield was 49%. 1 H NMR (400MHz, DMSO-d 6 )δ10.55(s,1H),9.59(s,1H),9.12(d,J=3.3Hz,1H),8.79(d,J=3.4Hz,1H) ,7.69–7.58(m,1H),7.58–7.49(m,1H),7.11(td,J=9.4,3.4Hz,1H),4.93(s,1H),4.15(s,2H),3.90–3.77 (m, 1H), 3.39(t, J=9.6Hz, 2H), 3.19(t, J=9.6Hz, 2H), 2.79(s, 6H), 2.25(s, 3H), 1.93(d, J= 12.8Hz, 2H), 1.68 (d, J=11.3Hz, 2H), 1.27–1.13 (m, 4H).

Figure BDA0002385652160000551
Figure BDA0002385652160000551

实施例113 NN-二甲基甘氨酸-4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3，4-c]吡啶基)磺酰基)哌啶)酯马来酸盐的合成：同实施例110，收率71％。1HNMR(400MHz,DMSO-d6)δ9.46(s,1H),9.13(s,1H),8.73(s,1H),7.60(dt,J＝8.4,3.6Hz,1H),7.51(dd,J＝6.9,2.9Hz,1H),7.12(t,J＝9.2Hz,1H),6.06(s,2H),4.92(tt,J＝7.7,3.8Hz,1H),4.00(s,2H),3.84(tt,J＝6.9,3.9Hz,1H),3.64–3.23(m,2H),3.17(ddd,J＝12.3,8.2,3.8Hz,2H),2.71(s,6H),2.32–2.18(m,3H),1.93(ddt,J＝11.8,7.6,3.7Hz,2H),1.67(dtd,J＝12.3,7.9,3.8Hz,2H),1.20(t,J＝6.6Hz,4H).Example 113 NN-Dimethylglycine-4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo Synthesis of [3,4-c]pyridyl)sulfonyl)piperidine)ester maleate: same as Example 110, yield 71%. 1 HNMR (400MHz, DMSO-d 6 ) δ 9.46(s, 1H), 9.13(s, 1H), 8.73(s, 1H), 7.60(dt, J=8.4, 3.6Hz, 1H), 7.51(dd ,J=6.9,2.9Hz,1H),7.12(t,J=9.2Hz,1H),6.06(s,2H),4.92(tt,J=7.7,3.8Hz,1H),4.00(s,2H) , 3.84 (tt, J=6.9, 3.9Hz, 1H), 3.64–3.23 (m, 2H), 3.17 (ddd, J=12.3, 8.2, 3.8Hz, 2H), 2.71 (s, 6H), 2.32–2.18 (m, 3H), 1.93 (ddt, J=11.8, 7.6, 3.7Hz, 2H), 1.67 (dtd, J=12.3, 7.9, 3.8Hz, 2H), 1.20 (t, J=6.6Hz, 4H).

Figure BDA0002385652160000552
Figure BDA0002385652160000552

实施例114 NN-二甲基甘氨酸-4-(1-((5-(3-(3-甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3，4-c]吡啶基)磺酰基)哌啶)酯三氟乙酸盐的合成：同实施例109。1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.46(s,1H),9.13(s,1H),8.74(s,1H),7.61(dt,J＝8.7,3.5Hz,1H),7.52(dd,J＝6.9,2.8Hz,1H),7.12(t,J＝9.2Hz,1H),4.94(dq,J＝7.9,4.0Hz,1H),4.12(s,2H),3.84(tt,J＝7.0,3.9Hz,1H),3.45–3.36(m,2H),3.18(ddd,J＝12.1,8.2,3.6Hz,2H),2.79(s,6H),2.26(d,J＝1.8Hz,3H),2.01–1.85(m,2H),1.68(q,J＝9.4Hz,2H),1.26–1.13(m,4H).Example 114 NN-Dimethylglycine-4-(1-((5-(3-(3-methyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H-indazolo Synthesis of [3,4-c]pyridyl)sulfonyl)piperidine)ester trifluoroacetate: same as Example 109. 1 H NMR (400MHz, DMSO-d 6 )δ10.06(s,1H), 9.46(s,1H), 9.13(s,1H), 8.74(s,1H), 7.61(dt, J=8.7,3.5 Hz,1H),7.52(dd,J＝6.9,2.8Hz,1H),7.12(t,J＝9.2Hz,1H),4.94(dq,J＝7.9,4.0Hz,1H),4.12(s,2H) ), 3.84(tt, J=7.0, 3.9Hz, 1H), 3.45–3.36(m, 2H), 3.18(ddd, J=12.1, 8.2, 3.6Hz, 2H), 2.79(s, 6H), 2.26( d, J=1.8Hz, 3H), 2.01–1.85 (m, 2H), 1.68 (q, J=9.4Hz, 2H), 1.26–1.13 (m, 4H).

Figure BDA0002385652160000553
Figure BDA0002385652160000553

实施例115 N,N-二甲基甘氨酸-4-(1-((5-(3-(3-二氟甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶)酯的合成：同实施例11，收率91％。1HNMR(400MHz,DMSO-d6)δ9.75(s,1H),9.16(d,J＝1.2Hz,1H),8.70(d,J＝1.2Hz,1H),7.94(dd,J＝6.2,2.8Hz,1H),7.92–7.84(m,1H),7.40–7.35(m,1H),7.34(t,1H),4.78(tt,J＝7.8,3.7Hz,1H),3.96–3.79(m,1H),3.44–3.34(m,2H),3.18–3.06(m,4H),2.17(s,6H),1.94–1.82(m,2H),1.61(qd,J＝8.2,3.9Hz,2H),1.26–1.16(m,4H).Example 115 N,N-Dimethylglycine-4-(1-((5-(3-(3-difluoromethyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H -Synthesis of indazolo[3,4-c]pyridyl)sulfonyl)piperidine)ester: same as Example 11, yield 91%. 1 HNMR (400MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 9.16 (d, J=1.2 Hz, 1H), 8.70 (d, J=1.2 Hz, 1H), 7.94 (dd, J=6.2 ,2.8Hz,1H),7.92–7.84(m,1H),7.40–7.35(m,1H),7.34(t,1H),4.78(tt,J=7.8,3.7Hz,1H),3.96–3.79( m, 1H), 3.44–3.34 (m, 2H), 3.18–3.06 (m, 4H), 2.17 (s, 6H), 1.94–1.82 (m, 2H), 1.61 (qd, J=8.2, 3.9Hz, 2H),1.26–1.16(m,4H).

Figure BDA0002385652160000554
Figure BDA0002385652160000554

实施例116 N,N-二甲基甘氨酸-4-(1-((5-(3-(3-二氟甲基-4-氟苯基)氨基)-(1-环丙基)-1H-吲唑并[3,4-c]吡啶基)磺酰基)哌啶)酯柠檬酸盐的合成：同实施例110。1HNMR(400MHz,DMSO-d6)δ9.77(s,1H),9.17(s,1H),8.71(s,1H),7.96(dd,J＝6.1,2.8Hz,1H),7.90(dt,J＝7.7,3.6Hz,1H),7.42–7.36(m,1H),7.35(t,1H),4.84(dq,J＝8.1,3.9Hz,1H),3.88(tt,J＝7.0,3.9Hz,1H),3.52–3.28(m,4H),3.15(ddd,J＝12.2,8.4,3.6Hz,2H),2.71(d,J＝15.3Hz,2H),2.61(d,J＝15.3Hz,2H),2.35(s,6H),1.96–1.81(m,2H),1.65(ddd,J＝13.2,8.5,4.1Hz,2H),1.28–1.17(m,4H).Example 116 N,N-Dimethylglycine-4-(1-((5-(3-(3-difluoromethyl-4-fluorophenyl)amino)-(1-cyclopropyl)-1H - Synthesis of indazolo[3,4-c]pyridyl)sulfonyl)piperidine)ester citrate: same as Example 110. 1 HNMR (400MHz, DMSO-d 6 ) δ 9.77(s, 1H), 9.17(s, 1H), 8.71(s, 1H), 7.96(dd, J=6.1, 2.8Hz, 1H), 7.90(dt , J=7.7, 3.6Hz, 1H), 7.42–7.36 (m, 1H), 7.35 (t, 1H), 4.84 (dq, J=8.1, 3.9Hz, 1H), 3.88 (tt, J=7.0, 3.9 Hz, 1H), 3.52–3.28 (m, 4H), 3.15 (ddd, J=12.2, 8.4, 3.6Hz, 2H), 2.71 (d, J=15.3Hz, 2H), 2.61 (d, J=15.3Hz) ,2H),2.35(s,6H),1.96–1.81(m,2H),1.65(ddd,J=13.2,8.5,4.1Hz,2H),1.28–1.17(m,4H).

Figure BDA0002385652160000561
Figure BDA0002385652160000561

化合物在HepAD38细胞系上的抗乙肝病毒活性Anti-HBV Activity of Compounds on HepAD38 Cell Line

1.受试化合物的配制1. Preparation of Test Compounds

化合物筛选时所用的细胞培养基(筛选培养基)由1％的青霉素/链霉素、5％FBS和94％的DMEM构成。The cell culture medium (screening medium) used for compound selection consisted of 1% penicillin/streptomycin, 5% FBS and 94% DMEM.

将100mM储备液用筛选培养基稀释100倍，配成1mM的受试溶液，之后根据需要按照依次5倍或依次10倍的浓度梯度，稀释6个梯度，每个梯度的体积不少于400μL，每个浓度3个副孔，每个副孔100μL培养液。Dilute the 100 mM stock solution 100 times with the screening medium to prepare a 1 mM test solution, and then dilute 6 gradients in 5-fold or 10-fold concentration gradients as needed, and the volume of each gradient is not less than 400 μL, There are 3 sub-wells for each concentration, and each sub-well contains 100 μL of culture medium.

2.细胞培养2. Cell Culture

100μL 1×104HepAD38细胞接种于96孔版中，16-20小时后弃掉原有培养液，加入受试化合物作用6天后，每孔吸取60μL细胞上清于PCR八连管中，4℃保存。其中，在作用3天时更换成新鲜的含有受试化合物的培养基100 μL of 1×10 4 HepAD38 cells were seeded in a 96-well plate. After 16-20 hours, the original culture medium was discarded. After adding the test compound for 6 days, 60 μL of the cell supernatant was aspirated from each well into a PCR eight-connected tube and stored at 4°C. . Among them, the medium containing the test compound was replaced with a fresh medium after 3 days of action.

3.病毒DNA的提取3. Extraction of viral DNA

将收集的60μL细胞上清放在PCR仪上95℃热变性5分钟、10分钟、15分钟和20分钟，4000转离心10分钟后，4℃保存。The collected 60 μL of cell supernatant was heat-denatured at 95°C for 5 minutes, 10 minutes, 15 minutes and 20 minutes on a PCR machine, centrifuged at 4000 rpm for 10 minutes, and stored at 4°C.

4.病毒DNA的定量测定4. Quantitative Determination of Viral DNA

(1)标准曲线的配置：将pZAC1.2HBV质粒用无核酶水稀释成80ng/μL的储备液,此时的质粒浓度相当于1013HBV拷贝数，取2μL储备液加入18μL无核酶水配成1012HBV拷贝数的溶液，再取10μL上述溶液加入到90μL无核酶水中配成1011HBV拷贝数的溶液，之后按此稀释方法10倍梯度稀释8个浓度(即1011拷贝数～104拷贝数)，4℃保存备用，且现配现用。(1) Configuration of standard curve: Dilute pZAC1.2HBV plasmid with nuclease-free water to a stock solution of 80ng/μL, the plasmid concentration at this time is equivalent to 1013 HBV copies, take 2μL of stock solution and add 18μL of ribozyme-free water to make up 1012 HBV copy number solution, then add 10 μL of the above solution to 90 μL nuclease-free water to make 1011 HBV copy number solution, and then dilute 8 concentrations (i.e. 1011 copy number ~ 104 copy number) according to this dilution method 10-fold gradient. Store at ℃ for later use, and use it now.

(2)荧光定量PCR反应体系的配置：细胞上清病毒含量的测定使用Taqman荧光定量PCR的方法，引物和探针设计为：HBV正向引物：5’-CCAAATGCCCCTATCCTATCA-3’，HBV反向引物：5’-GAGGCGAGGGAGTTCTTCTTCTA-3’，HBV探针：5’-FAM-CGGAAACTACTGTTGTTAGACGACGAGGCAG-TAM-3’。20μL荧光定量PCR反应体系的配制方法为：Taqman Mix：10μL，Rox：0.4μL,HBV正向引物(10nM)：1μL,HBV反向引物(10nM)：1μL,HBV探针：0.25μL,H2O：5.35μL。每个反应管中加入18μL反应体系与2μL已处理的细胞上清(模板)或不同浓度的质粒标准品，每个样品三个副孔，混匀，盖上盖子离心,将配好的体系放入荧光定量PCR仪器中，95℃ 10分钟，95℃ 15秒、60℃ 1分钟40个循环进行扩增检测反应。程序完成后，收集数据进行分析处理。(2) Configuration of real-time quantitative PCR reaction system: The determination of virus content in cell supernatant was carried out by using Taqman real-time quantitative PCR method. The primers and probes were designed as: HBV forward primer: 5'-CCAAATGCCCCTATCCTATCA-3', HBV reverse primer : 5'-GAGGCGAGGGAGTTCTTCTTCTA-3', HBV probe: 5'-FAM-CGGAAACTACTGTTGTTAGACGACGAGGCAG-TAM-3'. The preparation method of 20 μL fluorescence quantitative PCR reaction system is: Taqman Mix: 10 μL, Rox: 0.4 μL, HBV forward primer (10 nM): 1 μL, HBV reverse primer (10 nM): 1 μL, HBV probe: 0.25 μL, H2O: 5.35 μL. Add 18 μL of reaction system and 2 μL of treated cell supernatant (template) or plasmid standards of different concentrations to each reaction tube, three sub-wells for each sample, mix well, cover with lid and centrifuge, and put the prepared system in Into the fluorescence quantitative PCR instrument, 95°C for 10 minutes, 95°C for 15 seconds, and 60°C for 1 minute for 40 cycles to perform the amplification detection reaction. After the program is completed, the data is collected for analysis and processing.

5.细胞毒性测定5. Cytotoxicity Assay

用药物筛选培养基将CCK-8配置成含20％CCK-8试剂的培养基，混匀后每孔加入50μL培养基即可。在37℃、5％CO2的恒温培养箱中孵育20～30分钟后用酶标仪检测。在450nm波长处测定吸光度，参比波长为600nm，DMSO对照组OD值在1.5左右时即可读数，保存，收集数据。实施例对乙肝病毒的抑制活性和对HepAD38细胞的细胞毒作用结果见表1。由此，可以看出，本发明的化合物对乙肝病毒的EC50低，且对细胞的毒性低。CCK-8 was prepared into a medium containing 20% CCK-8 reagent with drug screening medium, and 50 μL of medium was added to each well after mixing. Incubate in a constant temperature incubator at 37°C and 5% CO 2 for 20-30 minutes and detect with a microplate reader. The absorbance was measured at a wavelength of 450 nm, and the reference wavelength was 600 nm. When the OD value of the DMSO control group was around 1.5, the reading could be read, saved, and the data collected. Table 1 shows the results of the inhibitory activity on hepatitis B virus and the cytotoxic effect on HepAD38 cells of the examples. From this, it can be seen that the compounds of the present invention have low EC 50 against hepatitis B virus and low toxicity to cells.

表1：实施例在AD38细胞系上的抗病毒活性及细胞毒性。Table 1: Antiviral activity and cytotoxicity of the examples on AD38 cell line.

Figure BDA0002385652160000562
Figure BDA0002385652160000562

Figure BDA0002385652160000571
Figure BDA0002385652160000571

EC50:降低细胞上清中50％的HBV DNA的化合物浓度；CC50:抑制50％的细胞生长时的化合物浓度。 EC50 : Compound concentration that reduced HBV DNA by 50% in the cell supernatant; CC50: Compound concentration that inhibited cell growth by 50 %.

人或鼠的肝微粒体中的稳定性实验Stability assay in human or murine liver microsomes

待测化合物溶液：DMSO溶液，浓度100μM。Test compound solution: DMSO solution, concentration 100 μM.

肝微粒体溶液：磷酸盐缓冲液(50mM K2HPO4,pH 7.4)溶液，浓度1.27mg/mL。Liver microsome solution: phosphate buffered saline (50 mM K 2 HPO 4 , pH 7.4) solution, concentration 1.27 mg/mL.

NADPH溶液：磷酸盐缓冲液(50mM K2HPO4,pH 7.4)溶液，浓度5mM。NADPH solution: Phosphate buffer ( 50 mM K2HPO4 , pH 7.4) solution, concentration 5mM.

将2.5μL待测化合物溶液加入到197.5μL肝微粒体溶液中，混合均匀，37℃下孵育5min，加入50μLNADPH溶液，反应开始，分别于0min、5min、15min、30min和60min从反应体系里取出30μL溶液，加入300μL内标液，震荡混匀，4℃下4000转每分钟离心15min，取100μL上清液，用100μL蒸馏水稀释后用LC/MS/MS检测。Add 2.5 μL of the test compound solution to 197.5 μL of liver microsome solution, mix well, incubate at 37°C for 5 min, add 50 μL of NADPH solution, the reaction starts, and take out 30 μL from the reaction system at 0 min, 5 min, 15 min, 30 min and 60 min respectively. solution, add 300 μL of internal standard solution, shake and mix well, centrifuge at 4000 rpm for 15 min at 4°C, take 100 μL of supernatant, dilute with 100 μL of distilled water, and use LC/MS/MS for detection.

从表2可以看到，实施例17在人和小鼠的肝微粒体中的半衰期均大于60分钟，具有较好的稳定性，化合物101和59在小鼠肝微粒体中半衰期也大于60分钟，同样具有较好的稳定性。It can be seen from Table 2 that the half-lives of Example 17 in human and mouse liver microsomes are both greater than 60 minutes and have good stability, and the half-lives of Compounds 101 and 59 in mouse liver microsomes are also greater than 60 minutes , also has better stability.

表2.部分优选实施例在人和鼠的肝微粒体中半衰期和清除率Table 2. Half-life and clearance in human and murine liver microsomes of some preferred examples

Figure BDA0002385652160000581
Figure BDA0002385652160000581

乙肝病毒的壳组装及复制HBV capsid assembly and replication

将10μM化合物59或化合物101与5μM HBV衣壳蛋白在含有150mM氯化钠和50mMHEPES的pH7.4的缓冲液中共孵育过夜，在电镜下观察衣壳组装的情况。如图1所示，与DMSO对照组相比，乙肝病毒衣壳蛋白经化合物59和101处理，衣壳形成的数量明显增加，而且形成的衣壳大小、形态与对照组相同。10 μM compound 59 or compound 101 was incubated overnight with 5 μM HBV capsid protein in buffer containing 150 mM sodium chloride and 50 mM HEPES pH 7.4, and the capsid assembly was observed under electron microscope. As shown in Figure 1, compared with the DMSO control group, HBV capsid protein was treated with compounds 59 and 101, and the number of capsids formed was significantly increased, and the size and shape of the capsids formed were the same as those in the control group.

HepAD38细胞和HepG2.2.15细胞用2μM化合物59或101处理4天，每两天更换培养基。采用q-PCR和qRT-PCR检测DNA和RNA的含量，用ELISA检测e抗原和s抗原的含量，实验数据表示为平均值±标准差(n＝3)。实验结果用双尾t检验进行统计学分析，*P<0.05；**P<0.01；***P<0.001。结果如图2所示，化合物59或101处理均会阻碍乙肝病毒复制。HepAD38 cells and HepG2.2.15 cells were treated with 2 μM compound 59 or 101 for 4 days with medium changes every two days. The contents of DNA and RNA were detected by q-PCR and qRT-PCR, and the contents of e-antigen and s-antigen were detected by ELISA. The experimental data were expressed as mean±standard deviation (n=3). The experimental results were statistically analyzed by two-tailed t-test, *P<0.05; **P<0.01; ***P<0.001. The results are shown in Fig. 2, treatment with compound 59 or 101 inhibited the replication of hepatitis B virus.

化合物在拉米夫定耐药细胞系HepG2.A64和多药耐药细胞系HepG2.1403F中的抗乙肝病毒活性Anti-HBV Activity of Compounds in Lamivudine Resistant Cell Line HepG2.A64 and Multidrug Resistant Cell Line HepG2.1403F

参照前面关于“化合物在HepAD38细胞系上的抗乙肝病毒活性”方法研究化合物59和101在拉米夫定耐药细胞系HepG2.A64和多药耐药细胞系HepG2.1403F中的抗乙肝病毒活性。从表3中可以看到，化合物59和101能够抑制对核酸类药物耐药的病毒株，相比于TDF和ETV，化合物59和101具有较低的细胞毒性。The anti-HBV activity of compounds 59 and 101 in the lamivudine-resistant cell line HepG2.A64 and the multidrug-resistant cell line HepG2.1403F was studied with reference to the previous method "Anti-HBV Activity of Compounds on HepAD38 Cell Line" . As can be seen from Table 3, compounds 59 and 101 can inhibit the virus strains resistant to nucleic acid drugs, and compared with TDF and ETV, compounds 59 and 101 have lower cytotoxicity.

表3化合物59和101对拉米夫定耐药(HepG2.A64)和多药耐药(HepG2.1403F)病毒株的活性Table 3 Activity of compounds 59 and 101 against lamivudine-resistant (HepG2.A64) and multidrug-resistant (HepG2.1403F) virus strains

Figure BDA0002385652160000582
Figure BDA0002385652160000582

氨基酸前药在血浆中的释放以及在不同pH的缓冲液中的稳定性Release of amino acid prodrugs in plasma and stability in buffers of different pH

摘除小鼠眼球取血，13000转每分钟离心10min制得血浆，取98μL血浆，加2μL待测化合物的DMSO储备液(50mM)，37℃下孵育，分别在0min、5min、15min、30min和60min向反应体系内加入300μL乙腈淬灭，10000转每分钟离心10min。取上清液进行HPLC检测。从表4可以看出，N,N-二甲基甘氨酸前药113(化合物113)在血浆中能较快水解，释放出原型药，而且在pH1-7.4的缓冲液内均能稳定存在；缬氨酸前药116(化合物116)在血浆和缓冲液内的水解速度均很慢；丙氨酸前药106(化合物106)和甘氨酸前药107(化合物107)在血浆中水解速度略快，在缓冲液中的稳定性偏低。The eyeballs of the mice were removed and the blood was collected, centrifuged at 13,000 rpm for 10 min to obtain plasma, 98 μL of plasma was taken, 2 μL of the DMSO stock solution (50 mM) of the compound to be tested was added, and incubated at 37°C for 0 min, 5 min, 15 min, 30 min and 60 min, respectively. The reaction system was quenched by adding 300 μL of acetonitrile, and centrifuged at 10,000 rpm for 10 min. The supernatant was taken for HPLC detection. As can be seen from Table 4, N,N-dimethylglycine prodrug 113 (compound 113) can be hydrolyzed quickly in plasma to release the prototype drug, and can exist stably in buffers of pH 1-7.4; The hydrolysis rate of amino acid prodrug 116 (compound 116) was slow in both plasma and buffer; the hydrolysis rate of alanine prodrug 106 (compound 106) and glycine prodrug 107 (compound 107) was slightly faster in plasma, and the Stability in buffer is low.

Figure BDA0002385652160000591
Figure BDA0002385652160000591

表4.氨基酸前药在血浆以及不同pH的溶液里的稳定性Table 4. Stability of amino acid prodrugs in plasma and solutions at different pH

Figure BDA0002385652160000592
Figure BDA0002385652160000592

a三个小时内，HPLC检测不到水解产物的产生；b没有检测。a Within three hours, no hydrolysis product was detected by HPLC; b was not detected.

不同盐的溶解度Solubility of different salts

将化合物做成盐后能增加溶解度，柠檬酸盐109(化合物109)和甲磺酸盐110(化合物110)在较大pH范围内均具有较好的溶解度。Compounds can be made into salts to increase solubility, and both citrate 109 (compound 109) and mesylate 110 (compound 110) have better solubility in a wide pH range.

表5不同盐的溶解度Table 5 Solubility of different salts

Figure BDA0002385652160000593
Figure BDA0002385652160000593

a0.067M磷酸缓冲液；b0.01M磷酸盐缓冲液。 a 0.067M phosphate buffer; b 0.01M phosphate buffer.

水动力注射HBV小鼠模型上的抗病毒活性Antiviral activity on a hydrodynamically injected HBV mouse model

造模后第二天开始给药，化合物59和109通过尾静脉注射给药，ETV通过灌胃给药，一天一次，分别在给药第1天、第3天、第5天和第7天取血，检测血清中HBV DNA的含量，结果表示为平均值±SEM。给药的第8天处死小鼠，提取肝脏中的DNA，以GAPDH为内参，检测HBVDNA的相对含量。ETV：恩替卡韦，阳性对照。N＝9，结果用双尾t检验进行统计学分析，*P<0.05,**P<0.01,***P<0.001,NS没有统计学差异。如图3所示，结果表明化合物59和109均能抑制体内乙肝病毒的复制。The administration started on the second day after modeling. Compounds 59 and 109 were administered by tail vein injection, and ETV was administered by gavage, once a day, on the 1st, 3rd, 5th and 7th days of administration, respectively. Blood was collected to detect the content of HBV DNA in serum, and the results were expressed as mean ± SEM. The mice were sacrificed on the 8th day of administration, and the DNA in the liver was extracted. GAPDH was used as the internal reference to detect the relative content of HBV DNA. ETV: Entecavir, positive control. N=9, the results were statistically analyzed by two-tailed t-test, *P<0.05, **P<0.01, ***P<0.001, NS had no statistical difference. As shown in Figure 3, the results showed that both compounds 59 and 109 could inhibit the replication of hepatitis B virus in vivo.

在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, description with reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., mean specific features described in connection with the embodiment or example , structure, material or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.

尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (10)

1.一种化合物，其特征在于，为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：1. a compound, it is characterized in that, be the compound shown in formula (I) or the stereoisomer of compound shown in formula (I), tautomer, nitrogen oxide, hydrate, solvate, metabolism Product, pharmaceutically acceptable salt or prodrug:
Figure FDA0002385652150000011
Figure FDA0002385652150000011
 G、Q、T、Y和X各自独立地选自C或N；G, Q, T, Y and X are each independently selected from C or N; Z和V各自独立地选自C、N、S或O；Z and V are each independently selected from C, N, S or O; R1选自氢、C1～6烷基、C1～6环烷基、C1～6杂环基、氨基、C1～6烷氨基、羟基、卤代C1～6烷基、C2～6烯基、C3～6炔基、芳基或C1～5杂芳基；R 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl, C 1-6 heterocyclyl, amino, C 1-6 alkylamino, hydroxyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, aryl or C 1-5 heteroaryl; R2、R3和R4各自独立地选自氢、氟、氯、溴、碘、羟基、氨基、C1～6烷基、硝基、C1～6烷氧基、C1～6烷氨基、C3～6环烷基或C1～6杂环烷基；R 2 , R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, C 1-6 alkyl, nitro, C 1-6 alkoxy, C 1-6 alkane Amino, C 3-6 cycloalkyl or C 1-6 heterocycloalkyl; R5和R6各自独立地选自氢、C1～6烷基、C1～6烷基芳基、C1～6环烷基、C1～5杂环基、芳基、C1～5杂芳基；R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkylaryl, C 1-6 cycloalkyl, C 1-5 heterocyclyl, aryl, C 1-6 5 heteroaryl; L选自-C(＝O)-、-S(＝O)2-、-S(＝O)-、-C(＝O)NH-；L is selected from -C(=O)-, -S(=O) 2- , -S(=O)-, -C(=O)NH-; W选自C或N；W is selected from C or N; R7和R8各自独立地选自氢、C1～6烷基、卤代C1～6烷基、C2～6烯基、C3～6炔基、C3～6环烷基、C1～6杂环烷基、芳基或C1～5杂芳基；或者R7、W和R8成环，所述环选自C1～6环烷基、C1～6杂环基、C4～8稠环、C4～8稠杂环、C4～8螺环、C4～8螺杂环、C4～8桥环或C4～8桥杂环；R 7 and R 8 are each independently selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 heterocycloalkyl, aryl or C 1-5 heteroaryl; or R 7 , W and R 8 form a ring, and the ring is selected from C 1-6 cycloalkyl, C 1-6 heterocycle base, C 4-8 fused ring, C 4-8 fused heterocycle, C 4-8 spirocycle, C 4-8 spiro heterocycle, C 4-8 bridged ring or C 4-8 bridged heterocycle; 其中，所述氨基、烷基、羟基、羧基、环烷基、杂环基、芳基、杂芳基、卤代烷基、烯基、炔基、稠环、稠杂环、螺环、螺杂环、桥环和桥杂环可任选地被一个或多个氟、氯、溴、碘、羟基、氨基、羧基、硝基、氰基、氧代、C1～6烷基、卤代C1～6烷基、C1～6烷氧基、C1～6烷基羟基、C1～6烷氨基、C1～6环烷基、C1～6杂环基、芳基、C1～5杂芳基、-C(＝O)Ra、-C(＝O)ORa、-OC(＝O)Ra、-OC(＝O)RaN(Rb)Rc、-C(＝O)N(Ra)Rb、-N(Ra)C(＝O)ORb、-N(Ra)C(＝O)NRb、-C(＝O)NRa取代，Ra、Rb、Rc选自氢、C1～6烷基或C1～6烷氨基。Wherein, the amino group, alkyl group, hydroxyl group, carboxyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, haloalkyl group, alkenyl group, alkynyl group, fused ring, fused heterocycle, spirocycle, spiroheterocycle , bridged rings and bridged heterocycles can be optionally replaced by one or more fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, nitro, cyano, oxo, C 1-6 alkyl, halogenated C 1 ~6 alkyl, C 1-6 alkoxy, C 1-6 alkyl hydroxyl, C 1-6 alkylamino, C 1-6 cycloalkyl, C 1-6 heterocyclyl, aryl, C 1-6 5 -heteroaryl, -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -OC(=O)R a N(R b )R c , -C (=O)N(R a )R b , -N(R a )C(=O)OR b , -N(R a )C(=O)NR b , -C(=O)NR a substituted, R a , R b and Rc are selected from hydrogen, C 1-6 alkyl or C 1-6 alkylamino. 2.根据权利要求1所述的化合物，其特征在于，G、Q和T中的至少一个为N，X为C，Z和Y中至少一个为N，V为N或O；2. The compound according to claim 1, wherein at least one of G, Q and T is N, X is C, at least one of Z and Y is N, and V is N or O; R1选自C1～4环烷基或C1～4杂环基；R 1 is selected from C 1-4 cycloalkyl or C 1-4 heterocyclyl; R2、R3和R4各自独立地选自氢、氟、氯、溴、碘、羟基或氨基；R 2 , R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy or amino; R5选自芳基、C3～6环烷基、C3～5杂环基或C3～5杂芳基，所述芳基、环烷基、杂环基和杂芳基可任选地被一个或多个氟、氯、溴、碘、卤代C1～4烷基、C1～4环烷基或C1～4杂环基所取代；R 5 is selected from aryl, C 3-6 cycloalkyl, C 3-5 heterocyclyl or C 3-5 heteroaryl, and the aryl, cycloalkyl, heterocyclyl and heteroaryl may be optional is substituted by one or more fluorine, chlorine, bromine, iodine, halogenated C 1-4 alkyl, C 1-4 cycloalkyl or C 1-4 heterocyclyl; R6选自氢或C1～3烷基；R 6 is selected from hydrogen or C 1-3 alkyl; L选自-C(＝O)-、-S(＝O)2-、-S(＝O)-、-C(＝O)NH-；L is selected from -C(=O)-, -S(=O) 2- , -S(=O)-, -C(=O)NH-; W选自C或N；W is selected from C or N; R7、W和R8成环，所述环选自C3～6杂环基或C3～6环烷基，所述环烷基或杂环基可任选地被一个或多个羟基、氟、氯、溴、碘、C1～3烷基、C1～3烷基羟基、-C(＝O)Ra、-C(＝O)ORa、-OC(＝O)Ra、-OC(＝O)RaN(Rb)Rc、-C(＝O)N(Ra)Rb、-N(Ra)C(＝O)ORb、-N(Ra)C(＝O)NRb、-C(＝O)NRa取代，Ra、Rb、Rc选自氢、C1～4烷基或C1～4烷氨基。R 7 , W and R 8 form a ring, and the ring is selected from C 3-6 heterocyclyl or C 3-6 cycloalkyl, and the cycloalkyl or heterocyclyl may be optionally replaced by one or more hydroxyl groups , fluorine, chlorine, bromine, iodine, C 1-3 alkyl, C 1-3 alkyl hydroxyl, -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -OC(=O)R a N(R b )R c , -C(=O)N(R a )R b , -N(R a )C(=O)OR b , -N(R a ) C(=O)NR b and -C(=O)NR a are substituted, and R a , R b and Rc are selected from hydrogen, C 1-4 alkyl or C 1-4 alkylamino. 3.根据权利要求1所述的化合物，其特征在于，G、Q和T均为C，X为C，Z和Y中至少一个为N，V为N或O；3. compound according to claim 1 is characterized in that, G, Q and T are all C, X is C, at least one in Z and Y is N, and V is N or O; R1为氢、C1～4烷基、C1～4环烷基、C1～4杂环基、卤代C1～4烷基；R 1 is hydrogen, C 1-4 alkyl, C 1-4 cycloalkyl, C 1-4 heterocyclic, halogenated C 1-4 alkyl; R2、R3和R4各自独立地选自氢、氟、氯、溴、碘、羟基、氨基、C1～4烷基；R 2 , R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, C 1-4 alkyl; R5和R6各自独立地选自氢、C1～4烷基、氰基、芳基、C1～4烷基芳基、C3～5杂芳基、C3～6环烷基、C1～4杂环基，其中，所述烷基、芳基、杂芳基、烷基芳基、环烷基或杂环基可任选地被一个或多个氟、氯、溴、碘、卤代C1～4烷基、C1～4环烷基或C1～4杂环基；R 5 and R 6 are each independently selected from hydrogen, C 1-4 alkyl, cyano, aryl, C 1-4 alkylaryl, C 3-5 heteroaryl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, wherein the alkyl, aryl, heteroaryl, alkylaryl, cycloalkyl or heterocyclyl may be optionally replaced by one or more fluorine, chlorine, bromine, iodine , halogenated C 1-4 alkyl, C 1-4 cycloalkyl or C 1-4 heterocyclic group; L选自-C(＝O)-、-S(＝O)2-、-S(＝O)-、-C(＝O)NH-；L is selected from -C(=O)-, -S(=O) 2- , -S(=O)-, -C(=O)NH-; W选自C或N；W is selected from C or N; R7和R8各自独立地选自氢、C3～6杂环基、C1～4烷基或卤代C1～4烷基，或者R7、W和R8成环，所述环选自C1～6环烷基、C1～6杂环基、C4～8稠环、C4～8稠杂环、C4～8螺环、C4～8螺杂环、C4～8桥环或C4～8桥杂环，其中，所述环烷基、杂环基、烷基、卤代烷基、稠环、稠杂环、螺环、螺杂环、桥环或桥杂环可任选地被一个或多个羟基、氟、氯、溴、碘、氧代、C1～4烷基、C1～4烷基羟基、-C(＝O)ORa、-C(＝O)NRa，Ra选自氢或C1～4烷基。R 7 and R 8 are each independently selected from hydrogen, C 3-6 heterocyclyl, C 1-4 alkyl or halogenated C 1-4 alkyl, or R 7 , W and R 8 form a ring, and the ring Selected from C 1-6 cycloalkyl, C 1-6 heterocyclyl, C 4-8 fused ring, C 4-8 fused heterocycle, C 4-8 spirocycle, C 4-8 spiro heterocycle, C 4 ~8 bridged ring or C 4-8 bridged heterocycle, wherein said cycloalkyl, heterocyclyl, alkyl, haloalkyl, fused ring, fused heterocycle, spirocycle, spiroheterocycle, bridged ring or bridged heterocycle The ring can be optionally replaced by one or more of hydroxyl, fluorine, chlorine, bromine, iodine, oxo, C 1-4 alkyl, C 1-4 alkyl hydroxyl, -C(=O)OR a , -C( =O)NR a , R a is selected from hydrogen or C 1-4 alkyl. 4.根据权利要求1所述的化合物，其特征在于，当G、Q和T均为C，Z、Y和X至少有一个N，R7、W和R8不成环时，满足下列至少之一的条件：4. compound according to claim 1 is characterized in that, when G, Q and T are all C, Z, Y and X have at least one N, when R 7 , W and R 8 are not cyclic, satisfy at least one of the following One condition: (1)R1为C3～6环烷基；(1) R 1 is C 3-6 cycloalkyl; (2)当R7为氢、R8为C3～6环烷基时，所述环烷基被羟基所取代。(2) When R 7 is hydrogen and R 8 is a C 3-6 cycloalkyl group, the cycloalkyl group is substituted with a hydroxyl group. 5.根据权利要求1所述的化合物，其特征在于，具有如下之一所示的结构或其立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药；5. The compound according to claim 1, characterized in that it has one of the following structures or its stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceuticals an acceptable salt or prodrug;
Figure FDA0002385652150000021
Figure FDA0002385652150000021
Figure FDA0002385652150000031
Figure FDA0002385652150000031
Figure FDA0002385652150000041
Figure FDA0002385652150000041
Figure FDA0002385652150000051
Figure FDA0002385652150000051
Figure FDA0002385652150000061
Figure FDA0002385652150000061
Figure FDA0002385652150000071
Figure FDA0002385652150000071
 6.一种药物组合物，其特征在于，包括：6. a pharmaceutical composition, is characterized in that, comprises: 权利要求1～5任一项所述化合物；以及The compound of any one of claims 1 to 5; and 药学上可接受的辅料、载体、赋形剂、溶媒或它们的组合。Pharmaceutically acceptable adjuvants, carriers, excipients, vehicles or combinations thereof. 7.根据权利要求6所述的药物组合物，其特征在于，所述药物组合物进一步包含治疗剂，所述治疗剂选自下列的至少之一：拉米夫定、阿德福韦、恩替卡韦、替比夫定、替诺福韦酯和干扰素。7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition further comprises a therapeutic agent selected from at least one of the following: lamivudine, adefovir, entecavir , telbivudine, tenofovir disoproxil, and interferon. 8.权利要求1～5任一项所述化合物在制备药物中的用途，其特征在于，所述药物用于治疗感染性疾病。8. Use of the compound according to any one of claims 1 to 5 in the preparation of a medicament, wherein the medicament is used for the treatment of infectious diseases. 9.根据权利要求8所述的用途，其特征在于，所述感染性疾病为乙型肝炎。9. The use according to claim 8, wherein the infectious disease is hepatitis B. 10.一种药物联合，其特征在于，包括：10. A drug combination, characterized in that, comprising: 权利要求1～5任一项所述化合物；以及The compound of any one of claims 1 to 5; and 至少一种用于治疗乙型肝炎的药物，at least one medicine used to treat hepatitis B, 任选地，所述药物选自下列的至少之一：拉米夫定、阿德福韦、恩替卡韦、替比夫定、替诺福韦酯和干扰素。Optionally, the drug is selected from at least one of the following: lamivudine, adefovir, entecavir, telbivudine, tenofovir disoproxil, and interferon.
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