TW202128686A

TW202128686A - A fused heteroaryl derivative, a preparation method and medical use thereof

Info

Publication number: TW202128686A
Application number: TW109136899A
Authority: TW
Inventors: 張曉敏; 胡偉民; 賀峰; 白昌; 陶維康
Original assignee: 大陸商江蘇恆瑞醫藥股份有限公司; 大陸商上海恆瑞醫藥有限公司
Priority date: 2019-10-25
Filing date: 2020-10-23
Publication date: 2021-08-01
Also published as: CN114423759B; WO2021078227A1; CN114423759A

Abstract

The present disclosure relates a fused heteroaryl derivative, a preparation method and medical use thereof. Specifically, the present disclosure relates to a fused heteroaryl derivative represented by general formula (I), a preparation method thereof, and a pharmaceutical composition containing the same, as well as its use as a ATX inhibitor, and its use as a medicament for the treatment of cancers or fibrotic diseases or disorders. The substituents of general formula (I) are the same as those defined in the description.

Description

稠合雜芳基類衍生物、其製備方法及其在醫藥上的應用 Condensed heteroaryl derivatives, preparation method thereof and application in medicine

本公開屬於醫藥領域，涉及一種稠合雜芳基類衍生物、其製備方法及其在醫藥上的應用。特別地，本公開涉及通式(I)所示的稠合雜芳基類衍生物、其製備方法及含有該衍生物的醫藥組成物，以及其作為ATX抑制劑治療癌症或纖維變性疾病或病症的用途。 The present disclosure belongs to the field of medicine, and relates to a fused heteroaryl derivative, a preparation method thereof, and application in medicine. In particular, the present disclosure relates to a fused heteroaryl derivative represented by the general formula (I), its preparation method and a pharmaceutical composition containing the derivative, and its use as an ATX inhibitor to treat cancer or fibrotic diseases or disorders the use of.

自分泌運動因子(Autotaxin，ATX)又稱ENPP2，是一種分泌性的酶，主要是在癌細胞、肺部的支氣管上皮細胞和肺泡巨噬細胞中高表達。ATX於1992年首次從黑色素瘤細胞中分離出來(Stracke,M.L.等人J.Biol.Chem.1992,267,2524-2529)，屬於ENPP家族七名成員之一，其中ENPP1和ENPP3最接近ATX(Albers,H.M.H.G.等人Chem.Rev.2012,112,2593-2603)。ATX是ENPP酶中唯一具有溶血磷脂酶D(lysoPLD)活性，並且主要將LPC轉化為具有生物活性的脂質溶血磷脂酸(LPA)。LPA是一種脂類，在血漿中主要是LPA 16：0、LPA 18：1、LPA 18：2、LPA 20：4(Bandoh,K.等人FEBS Lett.2000,478,159-165)。LPA藉由細胞表面的六個受體蛋白(LPA1-6)，也就是蛋白偶聯受體(GPCR)發揮作用(Lin,M.E.等人Prostaglandins Other Lipid Mediators 2010,91,130-138)。LPA受體家族可以進一步分為兩大類：(1)EDG受體家族，包括LPA1-3；(2) 非EDG受體家族LPA4-6。二者相似度低於40%(Zhao,Y.等人Cell Signalling 2009,21,367-377)。每個LPA受體藉由特定的G體蛋白介導一系列的細胞信號級聯作用。主要的信號通路包括蛋白激酶(MAPK)活化，抑制腺苷酸環化酶通路、花生四烯酸釋放，激活PI3K-AKT通路，調控細胞凋亡和存活，活化Rho、Rock、Rac和Ras信號通路(Mills,G.B.等人Nat.Rev.Cancer 2003,3,582-591)。ATX-LPA信號通路涉及到很多生理和病理過程，導致其與很多嚴重疾病有著重要聯繫，主要包括癌症、纖維化疾病、疼痛、免疫性疾病、炎症神經***及心血管疾病(Nicolas,D.等人US8993590B2)。實驗證明ATX與腫瘤細胞的侵襲及轉移過程有關，如在卵巢癌(Vidot,S.,等人Cell Signal,2010,22,926-935)、乳腺癌(Panupinthu,N.等人British Journal of Cancer 2010,102,941-946)、***癌(Nouh,M.A.等人Cancer Sci.2009,100,1631-1638)、肝細胞癌(Wu,J.等人Mol Cancer；2010,9,71)及肺癌(Xu,X.等人Cancer,2010,116,1739-1750)的腫瘤組織都可以觀察到ATX的過表達。而由其產生的LPA藉由增加細胞運動性和侵襲性促進腫瘤形成。因此，ATX抑制劑可以阻止LPA的產生，有治療多種疾病的潛力。 Autotaxin (ATX), also known as ENPP2, is a secreted enzyme, which is mainly expressed in cancer cells, bronchial epithelial cells of the lung, and alveolar macrophages. ATX was first isolated from melanoma cells in 1992 (Stracke, ML et al . J. Biol. Chem. 1992, 267, 2524-2529), and belongs to one of the seven members of the ENPP family, of which ENPP1 and ENPP3 are closest to ATX ( Albers, HMHG et al . Chem. Rev. 2012, 112, 2593-2603). ATX is the only ENPP enzyme that has lysophospholipase D (lysoPLD) activity, and mainly converts LPC into lipid lysophosphatidic acid (LPA) with biological activity. LPA is a kind of lipid, mainly LPA 16:0, LPA 18:1, LPA 18:2, LPA 20:4 in plasma (Bandoh, K. et al. FEBS Lett. 2000, 478, 159-165). LPA uses six receptor proteins (LPA1-6) on the cell surface, which are protein-coupled receptors (GPCRs) to function (Lin, ME et al. Prostaglandins Other Lipid Mediators 2010, 91, 130-138). The LPA receptor family can be further divided into two categories: (1) the EDG receptor family, including LPA1-3; (2) the non-EDG receptor family LPA4-6. The similarity between the two is less than 40% (Zhao, Y. et al. Cell Signalling 2009, 21, 367-377). Each LPA receptor mediates a series of cell signaling cascades through a specific G body protein. The main signaling pathways include protein kinase (MAPK) activation, inhibition of adenylate cyclase pathway, arachidonic acid release, activation of PI3K-AKT pathway, regulation of cell apoptosis and survival, activation of Rho, Rock, Rac and Ras signaling pathways (Mills, GB et al . Nat. Rev. Cancer 2003, 3, 582-591). The ATX-LPA signaling pathway involves many physiological and pathological processes, leading to important connections with many serious diseases, including cancer, fibrotic diseases, pain, immune diseases, inflammatory nervous system, and cardiovascular diseases (Nicolas, D., etc.) US8993590B2). Experiments have shown that ATX is related to the invasion and metastasis of tumor cells, such as in ovarian cancer (Vidot, S., et al. Cell Signal , 2010, 22, 926-935), breast cancer (Panupinthu, N. et al., British Journal of Cancer 2010, 102,941-946), prostate cancer (Nouh, MA et al. Cancer Sci. 2009, 100, 1631-1638), hepatocellular carcinoma (Wu, J. et al. Mol Cancer ; 2010, 9, 71) and lung cancer (Xu, X . Et al. Cancer , 2010, 116, 1739-1750) overexpression of ATX can be observed in tumor tissues. The LPA produced by it promotes tumor formation by increasing cell motility and aggressiveness. Therefore, ATX inhibitors can prevent the production of LPA and have the potential to treat a variety of diseases.

IPF(特發性肺纖維化)是ATX-LPA信號通路中一個很重要的研究領域，其是肺部的一種進行性、慢性的、纖維化性疾病。IPF的發病機制普遍認為是藉由反復的刺激肺泡細胞，導致肺泡上皮細胞被激活，從而分泌一些促纖維化生長因子(TGFβ、PDGF、FGF等)和促纖維化的細胞因子，這些因子會將成纖維細胞募集到肺泡表面沉積和激活，進一步導致膠原的沉積和細胞外基質的沉澱，膠原的產生和基質的改變也會反過來促進這些因子的產生，而這些因子也會反過來進一步促進肺泡上皮細胞的激活，從而惡性循環，最終導致肺纖維化。與IPF相關的研究表明患者的支氣管肺泡灌洗(BAL)液中ATX和LPA水平顯著增加(Tager,A.M.等人Nat.Med.2008,14,45-54)。藉由對LPA1剔除和抑制劑研究，證明了LPA在肺纖維變性過程中的重要作用。進一步對剔除ATX的支氣管上皮細胞和巨噬細胞的小鼠研究，顯示這些小鼠對肺纖維變性模型敏感度降低(Oikonomo,N.等人Am.J.Repir.Cell Mol.Biol.2012,47,566-574)。LPA在肺重塑中的作用與LPA對肺纖維母細胞(藉由LPA1)和上皮細胞(藉由LPA2)兩者的作用有關，顯示LPA2對上皮細胞TGFβ的活化與纖維變性病症有直接的關係(Xu,M.等人Am.J.pathol.2009,174,1264-1279)。LPA在重塑和纖維變性中的作用與COPD、IPF和哮喘有關。 IPF (Idiopathic Pulmonary Fibrosis) is a very important research field in the ATX-LPA signaling pathway, which is a progressive, chronic, and fibrotic disease of the lung. The pathogenesis of IPF is generally believed to be that by repeatedly stimulating alveolar cells, alveolar epithelial cells are activated, thereby secreting some pro-fibrotic growth factors (TGFβ, PDGF, FGF, etc.) and pro-fibrotic cytokines. These factors will Fibroblasts are recruited to the alveolar surface to deposit and activate, which further leads to the deposition of collagen and the precipitation of extracellular matrix. Collagen production and matrix changes will in turn promote the production of these factors, and these factors will in turn further promote the alveoli The activation of epithelial cells leads to a vicious circle and ultimately leads to pulmonary fibrosis. Studies related to IPF have shown that the levels of ATX and LPA in patients’ bronchoalveolar lavage (BAL) fluid are significantly increased (Tager, AM et al. Nat. Med. 2008, 14, 45-54). Through the study of LPA1 elimination and inhibitors, the important role of LPA in the process of pulmonary fibrosis has been proved. Further studies on mice depleted of ATX bronchial epithelial cells and macrophages showed that these mice were less sensitive to lung fibrosis models (Oikonomo, N. et al. Am.J.Repir.Cell Mol.Biol. 2012,47,566 -574). The role of LPA in lung remodeling is related to the effects of LPA on both lung fibroblasts (through LPA1) and epithelial cells (through LPA2), showing that the activation of TGFβ on epithelial cells by LPA2 is directly related to fibrotic disorders (Xu, M. et al . Am. J. pathol. 2009, 174, 1264-1279). The role of LPA in remodeling and fibrosis is related to COPD, IPF and asthma.

IPF主要症狀是呼吸困難、乾咳，急性期會有發熱、類似流感狀的症狀。該病癒後很差，中位生存期為2-4年，5年存活率為20-30%，比許多惡性腫瘤還低，針對該病，目前沒有好的治療手段，主要是藉由控制症狀穩定病情。 The main symptoms of IPF are dyspnea, dry cough, and fever and flu-like symptoms in the acute phase. The disease is very poor after recovery. The median survival period is 2-4 years, and the 5-year survival rate is 20-30%, which is lower than many malignant tumors. There is currently no good treatment for this disease, mainly by control The symptoms are stable.

目前在市場上針對IPF，僅有吡非尼酮(Pirfenidone)和尼達尼布(Nintedanib)2個藥物被批准上市，吡非尼酮的作用機理尚不明確，而尼達尼布是酪胺酸激酶抑制劑，主要針對PDGFR、FGFR、VEGFR受體。這兩個藥物均不能提高肺功能，只能延緩病情進展，而且有一定的副作用，所以人們一直致力於尋找IPF治療的有效藥物。目前ATX抑制劑藥物進展比較靠前的是GLGP-1690(臨床三期)，用於特發性肺纖維化的治療，其二期臨床已顯示良好的療效。 Currently in the market for IPF, only two drugs, Pirfenidone and Nintedanib, have been approved for marketing. The mechanism of action of pirfenidone is still unclear, while nintedanib is tyramine. Acid kinase inhibitors, mainly targeting PDGFR, FGFR, and VEGFR receptors. Neither of these two drugs can improve lung function, but can only delay the progression of the disease, and have certain side effects. Therefore, people have been working hard to find effective drugs for IPF treatment. At present, the most advanced ATX inhibitor drug is GLGP-1690 (phase III clinical), which is used for the treatment of idiopathic pulmonary fibrosis, and its phase II clinical has shown good efficacy.

與傳統的激酶抑制劑相比，ATX抑制劑藉由抑制LPA的形成，調控了細胞增殖、存活、凋亡和遷移相關的信號通路，可潛在用於對多種癌症的治療，而且由於LPA的信號通路與多個器官的纖維化緊密相關，是研究新型纖維化疾病的一個重要靶點。 Compared with traditional kinase inhibitors, ATX inhibitors regulate the signal pathways related to cell proliferation, survival, apoptosis and migration by inhibiting the formation of LPA, and can potentially be used in the treatment of a variety of cancers, and due to the signal of LPA The pathway is closely related to the fibrosis of multiple organs and is an important target for the study of new types of fibrotic diseases.

目前公開了ATX抑制劑相關的專利有WO2018212534、WO2012024620、WO2014018891、WO2014110000、WO2015008229、WO2016031987和WO2017050732。 Currently, patents related to ATX inhibitors are WO2018212534, WO2012024620, WO2014018891, WO2014110000, WO2015008229, WO2016031987 and WO2017050732.

本公開的目的在於提供一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， The purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof , Or its pharmaceutically acceptable salt,

其中： in:

環A選自環烷基或雜環基； Ring A is selected from cycloalkyl or heterocyclic group;

環B選自環烷基、雜環基、芳基和雜芳基，其中該環烷基、雜環基、芳基和雜芳基各自獨立地任選被選自鹵素、烷基、鹵烷基、烷氧基、氰基、胺基、硝基、羥基、羥烷基、羧基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkane Substituted by one or more substituents in the group, alkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, carboxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

環C選自雜芳基或雜環基； Ring C is selected from heteroaryl or heterocyclyl;

環D選自雜芳基或雜環基； Ring D is selected from heteroaryl or heterocyclic group;

G¹、G²相同或不同，且各自獨立地為CR⁶或N原子； G ¹ and G ^{2 are the} same or different, and each independently is a CR ⁶ or N atom;

G³選自CR⁶、N原子、O原子或S原子； G ^{3 is} selected from CR ⁶ , N atom, O atom or S atom;

L¹不存在，或選自-C(O)-(CH₂)_r-、O原子和S原子； L ¹ does not exist, or is selected from -C(O)-(CH ₂ ) _r -, O atom and S atom;

R¹各自相同或不同，且各自獨立地選自氫原子、鹵素、烷基、鹵烷基、烷氧基、羥基、羥烷基、氰基、胺基、硝基、羧基、醛基、環烷基、雜環基、芳基和雜芳基； R ¹ are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, and a ring Alkyl, heterocyclyl, aryl and heteroaryl;

R²選自氫原子、烷基和環烷基，其中該烷基和環烷基各自獨立地任選被選自鹵素、烷基、烷氧基、氰基、胺基、硝基、羥基、羥烷基、羧基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ^{2 is} selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally selected from halogen, alkyl, alkoxy, cyano, amine, nitro, hydroxyl, Substituted by one or more substituents of hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R³選自氫原子、烷基和環烷基，其中該烷基和環烷基各自獨立地任選被選自鹵素、烷基、烷氧基、氰基、胺基、硝基、羥基、羥烷基、羧基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ^{3 is} selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally selected from halogen, alkyl, alkoxy, cyano, amine, nitro, hydroxyl, Substituted by one or more substituents of hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁴各自相同或不同，且各自獨立地選自氫原子、鹵素、烷基、鹵烷基、烷氧基、氰基、胺基、硝基、羧基、醛基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基； R ⁴ are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, a hydroxyl group, a hydroxyalkyl group, a ring Alkyl, heterocyclyl, aryl and heteroaryl;

R⁵各自相同或不同，且各自獨立地選自氫原子、鹵素、烷基、鹵烷基、烷氧基、氰基、胺基、硝基、羧基、醛基、羥基、羥烷基、側氧基、環烷基、雜環基、芳基和雜芳基，其中該烷基、烷氧基、環烷基、雜環基、芳基和雜芳基各自獨立地任選被選自鹵素、烷基、烷氧基、氰基、胺基、硝基、羧基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ⁵ are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, a hydroxyl group, a hydroxyalkyl group, a side Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen , Alkyl, alkoxy, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;

R⁶選自氫原子、烷基、鹵烷基、羥烷基和環烷基； R ^{6 is} selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group and cycloalkyl group;

n為0、1、2、3、4、5或6； n is 0, 1, 2, 3, 4, 5 or 6;

s為0、1、2或3； s is 0, 1, 2 or 3;

t為0、1、2、3或4；且 t is 0, 1, 2, 3 or 4; and

r為0、1、2或3。 r is 0, 1, 2 or 3.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環B為環烷基或雜環基。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, the ring B is a cycloalkyl group or a heterocyclic group.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環B選自苯基、3員至12員環烷基或3員至8員雜環基，其中該雜環基含有1~3個選自N原子、O原子或S原子的雜原子；較佳地環B為3員至8員環烷基。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from a phenyl group, a 3-membered to 12-membered cycloalkyl group or a 3-membered to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 members selected from Heteroatoms of N atom, O atom or S atom; preferably ring B is a 3-membered to 8-membered cycloalkyl group.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環B為3員至8員雜環基，其中該雜環基含有1~3個選自N原子、O原子或S原子的雜原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3-membered to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N atoms, O atoms or S atoms.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環B為5員或6員雜環基，其中該雜環基含有1~5個選自N原子、O原子或S原子的雜原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered or 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 5 heteroatoms selected from N atoms, O atoms or S atoms.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中

選自

、

和

； In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein

Selected from

,

with

；

R^c各自相同或不同，且各自獨立地選自氫原子、鹵素、烷基、鹵烷基、烷氧基、氰基、胺基、硝基、羥基、羥烷基、羧基、環烷基、雜環基、芳基和雜芳基； R ^c are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a carboxyl group, a cycloalkyl group, Heterocyclic group, aryl group and heteroaryl group;

g為0、1、2或3； g is 0, 1, 2 or 3;

h為0、1、2或3； h is 0, 1, 2 or 3;

p為0、1、2或3； p is 0, 1, 2 or 3;

q為0、1、2或3； q is 0, 1, 2 or 3;

y為0、1、2、3或4； y is 0, 1, 2, 3 or 4;

G¹、G²和R³如通式(I)中所定義。 G ¹ , G ² and R ³ are as defined in the general formula (I).

選自

、

和

Selected from

,

with

；

g為0、1、2或3； g is 0, 1, 2 or 3;

h為0、1、2或3； h is 0, 1, 2 or 3;

p為0、1、2或3； p is 0, 1, 2 or 3;

q為0、1、2或3； q is 0, 1, 2 or 3;

y為0、1、2、3或4； y is 0, 1, 2, 3 or 4;

R³如通式(I)中所定義。 R ^{3 is} as defined in the general formula (I).

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R^c為氫原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ^c is a hydrogen atom.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中G³為N原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, G ³ is a N atom.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is a compound represented by the general formula (II) or a tautomer, meso, racemate, enantiomer, or diastereomer Structure or its mixture form, or its pharmaceutically acceptable salt:

其中： in:

p為0、1、2或3； p is 0, 1, 2 or 3;

q為0、1、2或3； q is 0, 1, 2 or 3;

環A、環C、環D、G¹、G²、L¹、R¹~R⁵、n、s和t如通式(I)中所定義。 Ring A, ring C, ring D, G ¹ , G ² , L ¹ , R ¹ to R ⁵ , n, s, and t are as defined in the general formula (I).

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中G¹和G²為N原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, G ¹ and G ² are N atoms.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(IIIG)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is a compound represented by the general formula (IIIG) or a tautomer, meso, racemate, enantiomer, or diastereomer Structure or its mixture form, or its pharmaceutically acceptable salt:

其中： in:

g為0、1、2或3； g is 0, 1, 2 or 3;

h為0、1、2或3； h is 0, 1, 2 or 3;

環A、環C、環D、L¹、R¹~R⁵、n、s和t如通式(I)中所定義。 Ring A, ring C, ring D, L ¹ , R ¹ to R ⁵ , n, s, and t are as defined in the general formula (I).

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中L¹為-C(O)-(CH₂)_r-；r選自1、2或3，較佳1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, L ¹ is -C(O)-(CH ₂ ) _r -; r is selected from 1, 2 or 3, preferably 1.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環D為7至11員雙環稠雜環基，其中該雙環稠雜環基含有1~5個選自N原子、O原子或S原子的雜原子，更佳6員/5員、5員/5員或5員/6員雙環稠雜環基，最佳6員/5員雙環稠雜環基，更佳5員雜芳基/6員雜環基雙環稠雜環基。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein ring D is a 7 to 11-membered bicyclic fused heterocyclic group, wherein the bicyclic fused heterocyclic group contains 1 to 5 heterocycles selected from N atoms, O atoms or S atoms Atom, more preferably 6-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group, best 6-membered/5-membered bicyclic fused heterocyclic group, more preferably 5-membered heteroaryl/6-membered Heterocyclyl bicyclic fused heterocyclic group.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環A為茚滿基；較佳為如下結構： In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, ring A is indanyl; preferably, the structure is as follows:

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環D為***并吡啶基或***并哌啶基；較佳為如下結構：

或

；更佳為如下結構：

或

。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring D is triazolopyridyl or triazolopiperidinyl; preferably, it has the following structure:

or

; It is better to have the following structure:

or

.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環D為***并吡啶基；較佳為如下結構：

。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, the ring D is a triazolopyridyl group; preferably the following structure:

.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中s為0。在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環C為5員雜芳基，其含有1~3個選自N原子、O原子或S原子的雜原子，較佳噁二唑基；更佳為如下結構：

。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, s is zero. In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein ring C is a 5-membered heteroaryl group, which contains 1 to 3 heteroatoms selected from N atoms, O atoms or S atoms, preferably oxadiazolyl; Preferably, the structure is as follows:

.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R¹為氫原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R²為氫原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R³為氫原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁴為氫原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽，其為通式(IIIM)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIM) or a tautomer, meso, racemate, enantiomer, or diastereomer Body or its mixture form, or its pharmaceutically acceptable salt:

其中： in:

R^1a、R^1b各自相同或不同，且各自獨立地選自氫原子、鹵素、烷基、鹵烷基、烷氧基、羥基、羥烷基、氰基、胺基、硝基、羧基、醛基、環烷基、雜環基、芳基和雜芳基；較佳為氫原子； R ^1a and R ^1b are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxyl group, and an aldehyde Group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; preferably a hydrogen atom;

e為0、1、2、3或4； e is 0, 1, 2, 3 or 4;

f為0、1或2； f is 0, 1 or 2;

環B、R³、R⁵、t如通式(I)中所定義。 Ring B, R ³ , R ⁵ , and t are as defined in the general formula (I).

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽，其為通式(III)、(IIIa)或(IIIb)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III), (IIIa) or (IIIb) or its tautomer, meso, racemate, enantiomer Conformer, diastereomer or its mixture form, or its pharmaceutically acceptable salt:

其中： in:

g為0、1、2或3； g is 0, 1, 2 or 3;

h為0、1、2或3； h is 0, 1, 2 or 3;

p為0、1、2或3； p is 0, 1, 2 or 3;

q為0、1、2或3； q is 0, 1, 2 or 3;

e為0、1、2、3或4； e is 0, 1, 2, 3 or 4;

f為0、1或2； f is 0, 1 or 2;

R⁵、t如通式(I)中所定義。 R ⁵ and t are as defined in the general formula (I).

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中p為1；q為1或2。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, p is 1; q is 1 or 2.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽，其為通式(IIIb-1)或(IIIb-2)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIb-1) or (IIIb-2) or its tautomer, meso, racemate, enantiomer Conformer, diastereomer or its mixture form, or its pharmaceutically acceptable salt:

其中，R^1a、R^1b、R⁵、t、e、f、g和h如通式(IIIb)中所定義。 Wherein, R ^1a , R ^1b , R ⁵ , t, e, f, g, and h are as defined in the general formula (IIIb).

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中g為0、1、2或3，h為0、1、2或3；條件是當g為0時，h為2或3；g為1時，h為1或2；g為2時，h為1或0；g為3時，h為0。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, where g is 0, 1, 2 or 3 and h is 0, 1, 2 or 3; the condition is that when g is 0, h is 2 or 3; g is 1 When, h is 1 or 2; when g is 2, h is 1 or 0; when g is 3, h is 0.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R^1a、R^1b為氫原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, R ^1a and R ^1b are hydrogen atoms.

在本公開的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁵為氫原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom.

本公開的典型化合物包括但不限於： Typical compounds of the present disclosure include but are not limited to:

或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽。 Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

本公開另外提供一種通式(IIIMA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其可藥用的鹽： The present disclosure additionally provides a compound represented by general formula (IIIMA) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof or Medicinal salt:

其中： in:

R^d為氫原子或烷基；較佳為氫原子； R ^d is a hydrogen atom or an alkyl group; preferably a hydrogen atom;

e為0、1、2、3或4；且 e is 0, 1, 2, 3 or 4; and

f為0、1或2。 f is 0, 1, or 2.

本公開另外提供一種通式(IIIA)、(IIIaA)或(IIIbA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其可藥用的鹽： The present disclosure additionally provides a compound represented by the general formula (IIIA), (IIIaA) or (IIIbA) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or its mixture form or its pharmaceutically acceptable salt:

其中： in:

g為0、1、2或3； g is 0, 1, 2 or 3;

h為0、1、2或3； h is 0, 1, 2 or 3;

p為0、1、2或3； p is 0, 1, 2 or 3;

q為0、1、2或3； q is 0, 1, 2 or 3;

e為0、1、2、3或4：且 e is 0, 1, 2, 3, or 4: and

f為0、1或2。 f is 0, 1, or 2.

本公開的典型中間體化合物包括但不限於： Typical intermediate compounds of the present disclosure include but are not limited to:

本公開另外提供一種製備通式(IIIM)所示化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： The present disclosure additionally provides a method for preparing a compound represented by general formula (IIIM) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof, or The method of its pharmaceutically acceptable salt, the method includes:

通式(IIIMA)化合物和通式(IIIB)化合物或其可藥用的鹽(較佳為鹽酸鹽)，在鹼性條件下發生反應得到通式(IIIM)化合物； A compound of general formula (IIIMA) and a compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) react under basic conditions to obtain a compound of general formula (IIIM);

其中，R^d為氫原子或烷基；較佳為氫原子； Among them, R ^d is a hydrogen atom or an alkyl group; preferably a hydrogen atom;

環B、R^1a、R^1b、R³、R⁵、t、e、f如通式(IIIM)中所定義。 Ring B, R ^1a , R ^1b , R ³ , R ⁵ , t, e, and f are as defined in the general formula (IIIM).

本公開另外提供一種製備通式(III)所示化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： The present disclosure additionally provides a method for preparing a compound represented by general formula (III) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof, or The method of its pharmaceutically acceptable salt, the method includes:

通式(IIIA)化合物和通式(IIIB)化合物或其可藥用的鹽(較佳為鹽酸鹽)，在鹼性條件下發生反應得到通式(III)化合物； The compound of general formula (IIIA) and the compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) react under basic conditions to obtain a compound of general formula (III);

其中，R^1a、R^1b、R⁵、t、p、q、e、f如通式(III)中所定義。 Wherein, R ^1a , R ^1b , R ⁵ , t, p, q, e, and f are as defined in the general formula (III).

本公開另外提供一種製備通式(IIIa)所示化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： The present disclosure additionally provides a method for preparing a compound represented by the general formula (IIIa) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof, or The method of its pharmaceutically acceptable salt, the method includes:

通式(IIIaA)化合物和通式(IIIB)化合物或其可藥用的鹽(較佳為鹽酸鹽)，在鹼性條件下發生反應得到通式(IIIa)化合物； The compound of general formula (IIIaA) and the compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) react under basic conditions to obtain a compound of general formula (IIIa);

其中，R^1a、R^1b、R⁵、t、e、f如通式(IIIa)中所定義。 Wherein, R ^1a , R ^1b , R ⁵ , t, e, and f are as defined in the general formula (IIIa).

本公開另外提供一種製備通式(IIIb)所示化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： The present disclosure additionally provides a method for preparing a compound represented by general formula (IIIb) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof, or The method of its pharmaceutically acceptable salt, the method includes:

通式(IIIbA)化合物和通式(IIIB)化合物或其可藥用的鹽(較佳為鹽酸鹽)，在鹼性條件下發生反應得到通式(IIIb)化合物； A compound of general formula (IIIbA) and a compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) react under basic conditions to obtain a compound of general formula (IIIb);

本公開另外提供一種製備通式(IIIb-1)或(IIIb-2)所示化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： The present disclosure additionally provides a method for preparing compounds represented by general formula (IIIb-1) or (IIIb-2) or tautomers, mesosomes, racemates, enantiomers, and diastereomers thereof In the form of a body, a mixture thereof, or a pharmaceutically acceptable salt thereof, the method includes:

通式(IIIb)化合物進行手性製備，得到通式(IIIb-1)和通式(IIIb-2)化合物； The compounds of general formula (IIIb) are prepared by chiral preparation to obtain compounds of general formula (IIIb-1) and general formula (IIIb-2);

本公開的另一方面涉及一種醫藥組成物，其含有通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。本公開還涉及一種製備上述醫藥組成物的方法，其包括將各通式所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽與藥學上可接受的載體、稀釋劑或賦形劑相混合。 Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The present disclosure also relates to a method for preparing the above-mentioned pharmaceutical composition, which comprises combining the compounds represented by the general formulas or their tautomers, mesoisomers, racemates, enantiomers, and diastereomers. The construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier, diluent or excipient.

本公開另一方面涉及一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、其混合物形式、或其可藥用鹽、或保護其的醫藥組成物在製備ATX抑制劑中的用途。 Another aspect of the present disclosure relates to a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, and mixtures thereof, The use of the pharmaceutically acceptable salt or the pharmaceutical composition protecting the same in the preparation of an ATX inhibitor.

本公開另一方面涉及一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、其混合物形式、或其可藥用鹽、或包含其的醫藥組成物在製備預防和/或治療纖維變性疾病、癌症、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系統疾病、心血管疾病、神經變性疾病、皮膚學疾病、代謝疾病、骨髓增生異常綜合症、異常血管生成相關疾病和疼痛的藥物中的用途；較佳為在製備預防和/或治療纖維變性疾病和癌症的藥物中的用途；更佳為在製備預防和/或治療肺纖維化、特發性肺纖維化、肝纖維化和硬皮病的藥物中的用途。 Another aspect of the present disclosure relates to a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, and mixtures thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it in the preparation of the prevention and/or treatment of fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegeneration Use in drugs for diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases and pain; preferably, use in the preparation of drugs for the prevention and/or treatment of fibrotic diseases and cancer; more It is preferably used in the preparation of medicines for preventing and/or treating pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma.

本公開另一方面涉及一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、其混合物形式、或其可藥用鹽、或包含其的醫藥組成物在製備預防和/或治療具有ATX表達增加的病理學特徵的疾病的藥物中的用途；其中該具有ATX表達增加的病理學特徵的疾病選自：纖維變性疾病、癌症、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系統疾病、心血管疾病、神經變性疾病、皮膚學疾病、代謝疾病、骨髓增生異常綜合症、異常血管生成相關疾病和疼痛；較佳為纖維變性疾病和癌症；更佳為肺纖維化、特發性肺纖維化、肝纖維化和硬皮病，該癌症選自腎癌和胰腺癌。 Another aspect of the present disclosure relates to a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, and mixtures thereof, Or the use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a medicine for preventing and/or treating diseases with pathological characteristics of increased ATX expression; wherein the disease with pathological characteristics of increased ATX expression is selected From: fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis related Disease and pain; preferably fibrotic diseases and cancer; more preferably pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma, and the cancer is selected from kidney cancer and pancreatic cancer.

本公開另一方面涉及一種抑制ATX的方法，該方法包括向需要其的患者施用有效量的本公開的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽、或包含其的醫藥組成物。 Another aspect of the present disclosure relates to a method for inhibiting ATX, the method comprising administering to a patient in need thereof an effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomers, mesosomes, and exogenous compounds. Rotates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

本公開另一方面涉及一種預防和/或治療纖維變性疾病、癌症、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系統疾病、心血管疾病、神經變性疾病、皮膚學疾病、代謝疾病、骨髓增生異常綜合症、異常血管生成相關疾病和疼痛的方法，該方法包括向需要其的患者施用預防或治療有效量的本公開的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽、或包含其的醫藥組成物。 Another aspect of the present disclosure relates to a prevention and/or treatment of fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, A method for myelodysplastic syndrome, abnormal angiogenesis-related diseases and pain, the method comprising administering to a patient in need thereof a preventive or therapeutically effective amount of a compound represented by the general formula (I) of the present disclosure or its tautomer, Meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

本公開另一方面涉及一種預防和/或治療具有ATX表達增加的病理學特徵的疾病的方法，該方法包括向需要其的患者施用預防和/或治療有效劑量的本公開的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽、或包含其的醫藥組成物。具有ATX表達增加的病理學特徵的疾病可以為纖維變性疾病、癌症、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系統疾病、心血管疾病、神經變性疾病、皮膚學疾病、代謝疾病、骨髓增生異常綜合症、異常血管生成相關疾病或疼痛；較佳為纖維變性疾病和癌症；更佳為肺纖維化、特發性肺纖維化、肝纖維化和硬皮病，所述的癌症選自腎癌和胰腺癌。 Another aspect of the present disclosure relates to a method for preventing and/or treating a disease with the pathological characteristics of increased expression of ATX, the method comprising administering to a patient in need thereof a preventive and/or therapeutically effective dose of the general formula (I) of the present disclosure The compound shown or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or containing them Pharmaceutical composition. Diseases with pathological characteristics of increased ATX expression can be fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, Myelodysplastic syndrome, abnormal angiogenesis-related diseases or pain; preferably fibrotic diseases and cancer; more preferably pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma, the cancer is selected Since kidney cancer and pancreatic cancer.

本公開另一方面涉及一種本公開的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用鹽、或包含其的醫藥組成物，其作為藥物。 Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, it is used as a medicine.

本公開另一方面涉及一種本公開的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用鹽、或包含其的醫藥組成物，其作為ATX抑制劑。 Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, it is used as an ATX inhibitor.

本公開另一方面涉及一種本公開的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用鹽、或包含其的醫藥組成物，其作為預防和/或治療纖維變性疾病、癌症、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系統疾病、心血管疾病、神經變性疾病、皮膚學疾病、代謝疾病、骨髓增生異常綜合症、異常血管生成相關疾病和疼痛的藥物；較佳為預防和/或治療纖維變性疾病和癌症的藥物；更佳為預防和/或治療肺纖維化、特發性肺纖維化、肝纖維化和硬皮病的藥物。 Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, it is used as the prevention and/or treatment of fibrotic diseases, Drugs for cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases and pain; Preferably, they are drugs for preventing and/or treating fibrotic diseases and cancer; more preferably, they are drugs for preventing and/or treating pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma.

本公開另一方面涉及一種本公開的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用鹽、或包含其的醫藥組成物，其作為預防和/或具有治療ATX表達增加的病理學特徵的疾病的藥物，其中所述的具有ATX表達增加的病理學特徵的疾病選自：纖維變性疾病、癌症、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系統疾病、心血管疾病、神經變性疾病、皮膚學疾病、代謝疾病、骨髓增生異常綜合症、異常血管生成相關疾病和疼痛；較佳為纖維變性疾病和癌症；更佳為肺纖維化、特發性肺纖維化、肝纖維化和硬皮病，所述的癌症選自腎癌和胰腺癌。 Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, it is used as a medicine for preventing and/or treating diseases with the pathological characteristics of increased ATX expression, wherein the said having the pathological characteristics of increased ATX expression The disease is selected from: fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormalities Angiogenesis-related diseases and pain; preferably fibrotic diseases and cancer; more preferably pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma, and the cancer is selected from kidney cancer and pancreatic cancer.

可將活性化合物製成適合於藉由任何適當途徑給藥的形式，活性化合物較佳是以單位劑量的方式，或者是以患者可以以單劑自我給藥的方式。本公開化合物或組合物的單位劑量的表達方式可以是片劑、膠囊、扁囊劑、瓶裝藥水、藥粉、顆粒劑、錠劑、栓劑、再生藥粉或液體製劑。 The active compound can be prepared in a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or in a form in which the patient can self-administer in a single dose. The unit dose of the compound or composition of the present disclosure can be expressed in the form of a tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, rejuvenated powder or liquid preparation.

本公開治療方法中所用化合物或組成物的劑量通常將隨疾病的嚴重性、患者的體重和化合物的相對功效而改變。不過，作為一般性指導，合適的單位劑量可以是0.1~1000mg。 The dosage of the compound or composition used in the treatment method of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose can be 0.1 to 1000 mg.

本公開的醫藥組成物除活性化合物外，可含有一種或多種輔料，所述輔料選自以下成分：填充劑(稀釋劑)、黏合劑、潤濕劑、崩解劑或賦形劑等。根據給藥方法的不同，組合物可含有0.1至99重量%的活性化合物。 In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

含活性成分的醫藥組成物可以是適用於口服的形式，例如片劑、糖錠劑、錠劑、水或油混懸液、可分散粉末或顆粒、乳液、硬或軟膠囊，或糖漿劑或酏劑。可按照本領域任何已知製備藥用組合物的方法製備口服組成物，此類組成物可含有一種或多種選自以下的成分：甜味劑、矯味劑、著色劑和防腐劑，以提供悅目和可口的藥用製劑。片劑含有活性成分和用於混合的適宜製備片劑的無毒的可藥用的賦形劑。這些賦形劑可以是惰性賦形劑、造粒劑、崩解劑、黏合劑和潤滑劑。這些片劑可以不包衣或可藉由掩蓋藥物的味道或在胃腸道中延遲崩解和吸收，因而在較長時間內提供緩釋作用的已知技術將其包衣。 The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. The oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such composition may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing to the eye And delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

也可用其中活性成分與惰性固體稀釋劑或其中活性成分與水溶性載體或油溶媒混合的軟明膠膠囊提供口服製劑。 Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.

水懸浮液含有活性物質和用於混合的適宜製備水懸浮液的賦形劑。此類賦形劑是懸浮劑、分散劑或濕潤劑。水混懸液也可以含有一種或多種防腐劑、一種或多種著色劑、一種或多種矯味劑和一種或多種甜味劑。 Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

油混懸液可藉由使活性成分懸浮於植物油，或礦物油配製而成。油懸浮液可含有增稠劑。可加入上述的甜味劑和矯味劑，以提供可口的製劑。可藉由加入抗氧化劑保存這些組合物。 Oil suspensions can be prepared by suspending the active ingredients in vegetable oil or mineral oil. The oil suspension may contain thickeners. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

藉由加入水可使適用於製備水混懸的可分散粉末和顆粒提供活性成分和用於混合的分散劑或濕潤劑、懸浮劑或一種或多種防腐劑。適宜的分散劑或濕潤劑和懸浮劑可說明上述的例子。也可加入其他賦形劑例如甜味劑、矯味劑和著色劑。藉由加入抗氧化劑例如抗壞血酸保存這些組成物。 By adding water, dispersible powders and granules suitable for preparing water suspensions can be provided with active ingredients and dispersing or wetting agents for mixing, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

本公開的醫藥組成物也可以是水包油乳劑的形式。油相可以是植物油，或礦物油或其混合物。適宜的乳化劑可以是天然產生的磷脂，乳劑也可以含有甜味劑、矯味劑、防腐劑和抗氧劑。此類製劑也可含有緩和劑、防腐劑、著色劑和抗氧劑。 The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, and emulsions can also be It contains sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

本公開的醫藥組成物可以是無菌注射水溶液形式。可以使用的可接受的溶媒或溶劑有水、林格氏液和等滲氯化鈉溶液溶液。無菌注射製劑可以是其中活性成分溶於油相的無菌注射水包油微乳可藉由局部大量注射，將注射液或微乳注入患者的血流中。或者，最好按可保持本公開化合物恆定循環濃度的方式給予溶液和微乳。為保持這種恒定濃度，可使用連續靜脈內遞藥裝置。這種裝置的實例是Deltec CADD-PLUS.TM.5400型靜脈注射泵。 The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. A sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

本公開的醫藥組成物可以是用於肌內和皮下給藥的無菌注射水或油混懸液的形式。可按已知技術，用上述那些適宜的分散劑或濕潤劑和懸浮劑配製該混懸液。無菌注射製劑也可以是在腸胃外可接受的無毒稀釋劑或溶劑中製備的無菌注射溶液或混懸液。此外，可方便地用無菌固定油作為溶劑或懸浮介質。為此目的，可使用任何調和固定油。此外，脂肪酸也可以製備注射劑。 The pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

可按用於直腸給藥的栓劑形式給予本公開化合物。可藉由將藥物與在普通溫度下為固體但在直腸中為液體，因而在直腸中會溶化而釋放藥物的適宜的無刺激性賦形劑混合來製備這些醫藥組成物。 The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum, and thus will melt in the rectum to release the drug.

如本領域技術人員所熟知的，藥物的給藥劑量依賴於多種因素，包括但並非限定於以下因素：所用具體化合物的活性、患者的年齡、患者的體重、患者的健康狀況、患者的行為、患者的飲食、給藥時間、給藥方式、***的速率、藥物的組合等；另外，最佳的治療方式如治療的模式、通式化合物(I)的日用量或可藥用的鹽的種類可以根據傳統的治療方案來驗證。 As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best treatment mode, such as the mode of treatment, the daily dosage of compound (I), or the type of pharmaceutically acceptable salt It can be verified according to the traditional treatment plan.

本公開提供的ATX抑制劑活性高，並且具有較低的心臟毒性，以及高溶解度等良好性能。 The ATX inhibitor provided by the present disclosure has high activity, low cardiotoxicity, and good properties such as high solubility.

發明的詳細說明 Detailed description of the invention

除非有相反陳述，在說明書和申請專利範圍中使用的術語具有下述含義。 Unless stated to the contrary, the terms used in the specification and the scope of the patent application have the following meanings.

術語“烷基”指飽和脂肪族烴基團，其為包含1至20個碳原子的直鏈或支鏈基團，較佳含有1至12個(例如1、2、3、4、5、6、7、8、9、10、11和12個)碳原子的烷基，更佳含有1至6個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各種支鏈異構體等。更佳的是含有1至6個碳原子的低級烷基，非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，該取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基和側氧基中的一個或多個取代基所取代。 The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, and Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Group, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Benzylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro Group, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and pendant oxy group or one of Multiple substituents are substituted.

術語“伸烷基”指飽和的直鏈或支鏈脂肪族烴基，其具有2個從母體烷的相同碳原子或兩個不同的碳原子上除去兩個氫原子所衍生的殘基，其為包含1至20個碳原子的直鏈或支鏈基團，較佳含有1至12個(例如1、2、3、4、5、6、7、8、9、10、11和12個)碳原子，更較佳含有1至6個碳原子的亞烷基。亞烷基的非限制性實例包括但不限於亞甲基(-CH₂-)、1,1-伸乙基(-CH(CH₃)-)、1,2-伸乙基(-CH₂CH₂-)、1,1-伸丙基(-CH(CH₂CH₃)-)、1,2-伸丙基(-CH₂CH(CH₃)-)、1,3-伸丙基(-CH₂CH₂CH₂-)、1,4-伸丁基(-CH₂CH₂CH2CH₂-)等。伸烷基可以是取代的或非取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，該取代基較佳獨立地任選選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、硫醇、羥基、硝基、氰基、環烷基、雜環基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基和側氧基中的一個或多個取代基所取代。 The term "alkylene" refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) The carbon atom is more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH _{2 -)} CH ₂ -), 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH2CH ₂ -), etc. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkane One or more substituents among oxy, cycloalkylthio, heterocycloalkylthio and pendant oxy groups are substituted.

術語“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，環烷基環包含3至20個碳原子，較佳包含3至12個碳原子(可以是具體的點，也可以是任選兩點組成的區間，例如3、4、5、6個環原子、4至11個環原子、6至12個環原子等)，更佳包含3至8個碳原子，最佳包含3至6個(例如3、4、5或6)碳原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等；多環環烷基包括螺環、稠環和橋環的環烷基。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (which may be a specific point). , It can also be a range consisting of two optional points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), and preferably contains 3 to 8 carbon atoms, It preferably contains 3 to 6 (e.g. 3, 4, 5 or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

術語“螺環烷基”指5至20員的單環之間共用一個碳原子(稱螺原子)的多環基團，其可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至10員。根據環與環之間共用螺原子的數目將螺環烷基分為單螺環烷基、雙螺環烷基或多螺環烷基，較佳為單螺環烷基和雙螺環烷基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺環烷基。螺環烷基的非限制性實例包括： The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings of 5 to 20 members, which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between the ring and the ring, the spiro cycloalkyl is divided into single spiro cycloalkyl and double spiro ring. The alkyl group or polyspirocycloalkyl group is preferably a monospirocycloalkyl group and a dispirocycloalkyl group. More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

術語“稠環烷基”指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環稠環烷基，較佳為雙環或三環，更佳3員/4員、3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/4員、5員/5員、5員/6員、6員/3員、6員/4員、6員/5員和6員/6員，最佳為6員/5員、5員/5員或5員/6員雙環烷基。稠環烷基的非限制性實例包括： The term "fused cycloalkyl" refers to an all-carbon polycyclic group consisting of 5 to 20 members. Each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or Multiple double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 members/4 members, 3 members/5 members, 3 members/6 members , 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/4 members, 5 members/5 members, 5 members/6 members, 6 members/3 members, 6 members/4 members, 6 Members/5 members and 6 members/6 members, preferably 6 members/5 members, 5 members/5 members or 5 members/6 members bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

術語“橋環烷基”指5至20員，任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，其可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，較佳為雙環、三環或四環，更有選為雙環或三環。橋環烷基的非限制性實例包括： The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly connected, and which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

該環烷基環包括上述環烷基(例如單環、稠環、螺環和橋環環烷基)稠合於芳基、雜芳基或雜環烷基環上，其中與母體結構連接在一起的環為環烷基，非限制性實例包括茚滿基、四氫萘基、苯并環庚烷基等；較佳茚滿基、四氫萘基。 The cycloalkyl ring includes the above-mentioned cycloalkyl (such as monocyclic, fused ring, spiro ring and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is connected to The ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably indanyl, tetrahydronaphthyl.

環烷基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基和側氧基中的一個或多個取代基所取代。 Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane One or more substituents in the thio group, heterocycloalkylthio group and pendant oxy group are substituted.

術語“烷氧基”指-O-(烷基)和-O-(環烷基)，其中烷基和環烷基的定義如上所述。烷氧基的非限制性實例包括：甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基。烷氧基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代。 The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), where alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, and a halogen. Alkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents.

術語“雜環基”指飽和或部分不飽和單環或多環環狀烴取代基，其包含3至20個環原子，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包含3至12個環原子(可以是具體的點，也可以是任選兩點組成的區間，例如3、4、5、6個環原子、4至11個環原子、6至12個環原子等)，其中1~5個(例如1、2、3、4和5個)是雜原子；較佳包含3至8個環原子，其中1~3個是雜原子；更佳包含3至6個環原子，其中1~3個是雜原子。單環雜環基的非限制性實例包括氮雜環丁基、吡咯烷基、咪唑烷基、四氫呋喃基、四氫吡喃基、四氫噻吩基、二氫咪唑基、二氫呋喃基、二氫吡唑基、二氫吡咯基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基等，較佳四氫吡喃基、哌啶基、吡咯烷基。多環雜環基包括螺環、稠環和橋環的雜環基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms (which can be a specific point or a range composed of two optional points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 Ring atoms, etc.), of which 1 to 5 (such as 1, 2, 3, 4 and 5) are heteroatoms; preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably 3 Up to 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydrofuranyl, Hydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

術語“螺雜環基”指5至20員的單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳，其可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至11員。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基、雙螺雜環基或多螺雜環基，較佳為單螺雜環基和雙螺雜環基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺雜環基。螺雜環基的非限制性實例包括： The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon, which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 11 members. According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is divided into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospiro heterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

術語“稠雜環基”指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。較佳為6至14員，更佳為7至11員。根據組成環的數目可以分為雙環、三環、四環或多環稠雜環基，較佳為雙環或三環，更佳為更較佳3員/4員、3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/4員、5員/5員、5員/6員、6員/3員、6員/4員、6員/5員和6員/6員，最佳為6員/5員、5員/5員或5員/6員雙環稠雜環基。稠雜環基的非限制性實例包括： The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members. Each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bonds, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 11 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3 members/4 members, 3 members/5 members, 3 Members/6 members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/4 members, 5 members/5 members, 5 members/6 members, 6 members/3 members, 6 members/ 4-members, 6-members/5-members and 6-members/6-members, preferably 6-members/5-members, 5-members/5-members or 5-members/6-members bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

術語“橋雜環基”指5至14員，任意兩個環共用兩個不直接連接的原子的多環雜環基團，其可以含有一個或多個雙鍵，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。較佳為6至14員，更佳為7至11員。根據組成環的數目可以分為雙環、三環、四環或多環橋雜環基，較佳為雙環、三環或四環，更有選為雙環或三環。橋雜環基的非限制性實例包括： The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, one or more of the ring atoms It is a heteroatom selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 11 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

該雜環基環包括上述雜環基(例如單環、稠環、螺環和橋環雜環基)稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基，其非限制性實例包括： The heterocyclyl ring includes the above heterocyclic groups (such as monocyclic, fused ring, spiro ring and bridged heterocyclic group) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the parent structure is connected together The ring of is a heterocyclic group, non-limiting examples of which include:

和

等。

with

Wait.

雜環基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基和側氧基中的一個或多個取代基所取代。 The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl Substituted by one or more substituents in the group, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and pendant oxy groups.

術語“芳基”指具有共軛的π電子體系的6至20員全碳單環或稠合多環(也就是共享毗鄰碳原子對的環)基團，較佳為6至10員，更佳6員，例如苯基和萘基。該芳基環包括上述芳基稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環，其非限制性實例包括： The term "aryl" refers to a 6 to 20 member all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 10 members, more Preferred 6 members, such as phenyl and naphthyl. The aryl ring includes the above-mentioned aryl group fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

芳基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基和雜環烷硫基中的一個或多個取代基所取代。 The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and The heterocycloalkylthio group is substituted by one or more substituents.

術語“雜芳基”指包含1至4個(例如1、2、3和4個)雜原子、5至20個環原子的雜芳族體系，其中雜原子選自氧、硫和氮。雜芳基較佳為5至10員，含1至3個雜原子；更佳為5員或6員，含1至3個雜原子；非限制性實例如吡唑基、咪唑基、呋喃基、噻吩基、噻唑基、噁唑基、噁二唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等。該雜芳基環包括上述雜芳基稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，其非限制性實例包括： The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 20 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 3 heteroatoms; non-limiting examples are pyrazolyl, imidazolyl, furanyl , Thienyl, thiazolyl, oxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. The heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

雜芳基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基和雜環烷硫基中的一個或多個取代基所取代。 Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane The thio group and the heterocycloalkylthio group are substituted by one or more substituents.

上述環烷基、雜環基、芳基和雜芳基具有1個從母體碳原子上除去一個氫原子所衍生的殘基，或2個從母體的相同碳原子或兩個不同的碳原子上除去兩個氫原子所衍生的殘基，2個殘基即“二價環烷基”、“二價雜環基”、“伸芳基”、“伸雜芳基”。 The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups have one residue derived from the removal of one hydrogen atom from the parent carbon atom, or two residues derived from the same carbon atom or two different carbon atoms of the parent Excluding the residues derived from two hydrogen atoms, the two residues are "divalent cycloalkyl", "divalent heterocyclic group", "arylene" and "heteroaryl".

術語“烷硫基”指-S-(烷基)和-S-(非取代的環烷基)，其中烷基的定義如上所述。烷硫基的非限制性實例包括：甲硫基、乙硫基、丙硫基、丁硫基、環丙硫基、環丁硫基、環戊硫基、環己硫基。烷硫基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基和雜環烷硫基中的一個或多個取代基所取代。 The term "alkylthio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), where the definition of alkyl is as described above. Non-limiting examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. The alkylthio group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane The thio group and the heterocycloalkylthio group are substituted by one or more substituents.

術語“胺基保護基”是為了使分子其它部位進行反應時胺基保持不變，用易於脫去的基團對胺基進行保護。非限制性實施例包含第三丁氧羰基、乙醯基、苄基、烯丙基和對甲氧苄基等。這些基團可任選地被選自鹵素、烷氧基或硝基中的1-3個取代基所取代。該胺基保護基較佳為第三丁氧羰基。 The term "amino group protecting group" is to keep the amine group unchanged when other parts of the molecule react, and to protect the amine group with a group that is easy to remove. Non-limiting examples include tertiary butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The amine protecting group is preferably tertiary butoxycarbonyl.

術語“環烷基氧基”指-O-環烷基，其中環烷基如上所定義。 The term "cycloalkyloxy" refers to -O-cycloalkyl, where cycloalkyl is as defined above.

術語“鹵烷基”指被鹵素取代的烷基，其中烷基如上所定義。 The term "haloalkyl" refers to an alkyl substituted by halogen, where alkyl is as defined above.

術語“鹵烷氧基”指被鹵素取代的烷氧基，其中烷氧基如上所定義。 The term "haloalkoxy" refers to an alkoxy substituted by halogen, wherein alkoxy is as defined above.

術語“羥烷基”指被羥基取代的烷基，其中烷基如上所定義。 The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

術語“羥基”指-OH基團。 The term "hydroxy" refers to the -OH group.

術語“鹵素”指氟、氯、溴或碘。 The term "halogen" refers to fluorine, chlorine, bromine or iodine.

術語“胺基”指-NH₂。 The term "amino" refers to -NH ₂ .

術語“氰基”指-CN。 The term "cyano" refers to -CN.

術語“硝基”指-NO₂。 The term "nitro" refers to -NO ₂ .

術語“醛基”指-C(O)H。 The term "aldehyde group" refers to -C(O)H.

術語“羧基”指-C(O)OH。 The term "carboxy" refers to -C(O)OH.

術語“羧酸酯基”指-C(O)O(烷基)或-C(O)O(環烷基)，其中烷基、環烷基如上所定義。 The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

術語“互變異構體”是指在質子位置和/或電子分佈彼此不同的化合物的異構體。互變異構體的實例包括但不限於烯醇-酮互變異構體、亞胺-烯胺互變異構體、醯胺-亞胺酸互變異構體、胺-亞胺互變異構體和雜芳基的互變異構形式，該雜芳基包含與環的-NH-部分和環的=N-部分連接的環原子，如吡唑、咪唑、苯并咪唑、***、吡啶并***、哌啶并***和四唑。本公開通式(I) 中，當環D為

時，環D可以以互變異構形式存在：

。例如，本公開通式(IIIM)所示的化合物可以以至少以下互變異構形式存在：

；其中，環B、R^1a、R^1b、R³、R⁵、t、e、f如通式(IIIIM)中所定義。除非另有明確定義，否則本公開包括本文詳細描述的化合物的所有互變異構體，即使僅明確示出一種互變異構體(例如，兩種互變異構形式都是想要的並且藉由呈現一種互變異構形式來描述的，其中可能存在一對兩個互變異構體)。當存在多於兩個互變異構體時，即使僅藉由化學名稱和/或結構描述了單一的互變異構形式，本公開也包括所有這樣的互變異構體。 The term "tautomer" refers to isomers of compounds that differ from each other in proton position and/or electron distribution. Examples of tautomers include, but are not limited to, enol-ketone tautomers, imine-enamine tautomers, amide-imine tautomers, amine-imine tautomers, and hetero The tautomeric form of an aryl group, the heteroaryl group contains ring atoms connected to the -NH- part of the ring and the =N- part of the ring, such as pyrazole, imidazole, benzimidazole, triazole, pyridotriazole, Piperidinotriazole and tetrazole. In the general formula (I) of the present disclosure, when ring D is

When, ring D can exist in tautomeric form:

. For example, the compound represented by the general formula (IIIM) of the present disclosure may exist in at least the following tautomeric forms:

; Wherein, ring B, R ^1a , R ^1b , R ³ , R ⁵ , t, e, f are as defined in the general formula (IIIIM). Unless clearly defined otherwise, the present disclosure includes all tautomers of the compounds described in detail herein, even if only one tautomer is explicitly shown (e.g., both tautomeric forms are desired and by presenting It is described in a tautomeric form, in which there may be a pair of two tautomers). When there are more than two tautomers, even if only a single tautomeric form is described by chemical name and/or structure, the present disclosure includes all such tautomers.

術語“纖維變性疾病”指的是特徵在於因細胞外基質的過度產生、沉積和收縮所致的過度結癲的疾病，並且其與異常累積的細胞和/或纖連蛋白和/或膠原和/或增加的纖維母細胞募集相關，並且包括但不限於個別器官或組織(例如心臟、腎、肝關節、肺、胸膜組織、腹膜組織、皮膚、角膜、視網膜、肌肉骨髓和消化道)的纖維變性。較佳選自特發性肺纖維變性(IPF，特發性肺纖維化)、囊性纖維變性、硬皮病、輻射誘導的纖維變性、慢性阻塞性肺病(COPD)、博來黴素誘導的肺纖維變性(bleomycin induced pulmonary fibrosis)、慢性哮喘、砂肺、石棉誘導的肺纖維變性、急性呼吸窘迫綜合征(ARDS)和不同病因學的其它彌漫性實質性肺疾病(包括醫原性藥物誘導的纖維變性、職業和/或環境誘導的纖維變性)、肉芽腫疾病(結節病、過敏性肺炎)、膠原血管病、肺泡蛋白沉積、朗格漢斯細胞肉芽腫(langerhans cell granulomatosis)、***平滑肌增多症、遺傳疾病(赫曼斯基普德拉克綜合征(Hermansky-Pudlak Syndrome)、結節性硬化症、神經纖維瘤、代謝蓄積障礙、家族性的間質性肺病)；腎纖維變性、肝纖維變性、肝硬化、腸纖維變性、皮膚纖維變性、皮膚硬皮病、骨髓纖維變性、全身性硬化症、血管再狹窄和動脈粥樣硬化；更佳選自特發性肺纖維變性(IPF)。 The term "fibrotic disease" refers to a disease characterized by excessive seizures caused by excessive production, deposition and contraction of extracellular matrix, and which is associated with abnormal accumulation of cells and/or fibronectin and/or collagen and/ Or increased fibroblast recruitment is related, and includes, but is not limited to, fibrosis of individual organs or tissues (such as heart, kidney, liver joint, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, muscle bone marrow, and digestive tract) . Preferably selected from the group consisting of idiopathic pulmonary fibrosis (IPF, idiopathic pulmonary fibrosis), cystic fibrosis, scleroderma, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), bleomycin-induced Pulmonary fibrosis (bleomycin induced pulmonary fibrosis), chronic asthma, sand lung, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS) and other diffuse parenchymal lung diseases of different etiology (including iatrogenic drug-induced Fibrosis, occupational and/or environmentally induced fibrosis), granulomatous disease (sarcoidosis, allergic pneumonia), collagen angiopathy, alveolar protein deposition, Langerhans cell granulomatosis, lymphatic vessels Leiomyosarcosis, genetic diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromas, metabolic accumulation disorders, familial interstitial lung disease); renal fibrosis, liver Fibrosis, liver cirrhosis, intestinal fibrosis, skin fibrosis, skin scleroderma, bone marrow fibrosis, systemic sclerosis, vascular restenosis and atherosclerosis; more preferably selected from idiopathic pulmonary fibrosis (IPF) .

“任選”或“任選地”意味著隨後所描述的事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生的場合。例如，“任選被烷基取代的雜環基團”意味著烷基可以但不必須存在，該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。 "Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

“取代的”指基團中的一個或多個氫原子，較佳為最多5個，更佳為1~3個氫原子彼此獨立地被相應數目的取代基取代，其中每個取代基都有獨立的選項(即取代基可以相同，也可以不同)。不言而喻，取代基僅處在它們的可能的化學位置，本領域技術人員能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 "Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted by a corresponding number of substituents, wherein each substituent has Independent options (that is, the substituents can be the same or different). It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the medicinal composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

“可藥用鹽”是指本公開化合物的鹽，這類鹽用於哺乳動物體內時具有安全性和有效性，且具有應有的生物活性。 "Pharmaceutically acceptable salt" refers to the salt of the compound of the present disclosure, which is safe and effective when used in mammals, and has due biological activity.

本公開的化合物還可包含其同位素衍生物。術語“同位素衍生物”指結構不同僅在於存在一種或多種同位素富集原子的化合物。例如，具有本公開的結構，除了用“氘”或“氚”代替氫，或者用¹⁸F-氟標記(¹⁸F同位素)代替氟，或者用¹¹C-、¹³C-或者¹⁴C-富集的碳(¹¹C-、¹³C-、或者¹⁴C-碳標記；¹¹C-、¹³C-或者¹⁴C-同位素)代替碳原子的化合物處於本公開的範圍內。這樣的化合物可用作例如生物學測定中的分析工具或探針，或者可以用作疾病的體內診斷成像示蹤劑，或者作為藥效學、藥動學或受體研究的示蹤劑。氘代物通常可以保留與未氘代的化合物相當的活性，並且當氘代在某些特定位點時可以取得更好的代謝穩定性，從而獲得某些治療優勢(如體內半衰期增加或劑量需求減少)。 The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, except for replacing hydrogen with "deuterium" or "tritium", or replacing ^{fluorine with 18} F-fluorine label ( ¹⁸ F isotope), or enriching ^{with 11} C-, ¹³ C- or ^{14 C-} Compounds in which carbon atoms ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C- or ¹⁴ C- isotopes) replace carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. Deuterated compounds can generally retain the same activity as non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ).

針對藥物或藥理學活性劑而言，術語“治療有效量”是指無毒的但能達到預期效果的藥物或藥劑的足夠用量。有效量的確定因人而異，取決於受體的年齡和一般情況，也取決於具體的活性物質，個案中合適的有效量可以由本領域技術人員根據常規試驗確定。 For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person and depends on The age and general condition of the recipient also depend on the specific active substance, and the appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

本公開化合物的合成方法 Synthetic method of the compound of the present disclosure

為了完成本公開的目的，本公開採用如下技術方案： In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

方案一 Option One

本公開通式(IIIM)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽製備方法，包括以下步驟： The compound represented by the general formula (IIIM) of the present disclosure or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture form thereof, or pharmacologically thereof The salt preparation method used includes the following steps:

通式(IIIMA)化合物和通式(IIIB)化合物或其可藥用的鹽(較佳為鹽酸鹽)，在鹼性條件下，在縮合劑存在下發生縮合反應得到通式(IIIM)化合物； The compound of general formula (IIIMA) and compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) undergo condensation reaction under alkaline conditions in the presence of a condensing agent to obtain a compound of general formula (IIIM) ；

方案二 Option II

本公開通式(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽製備方法，包括以下步驟： The compound represented by the general formula (III) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form thereof, or pharmacologically The salt preparation method used includes the following steps:

通式(IIIA)化合物和通式(IIIB)化合物或其可藥用的鹽(較佳為鹽酸鹽)，在鹼性條件下，在縮合劑存在下發生縮合反應得到通式(III)化合物； The compound of general formula (IIIA) and the compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) undergo condensation reaction under alkaline conditions in the presence of a condensing agent to obtain a compound of general formula (III) ；

方案三 third solution

本公開通式(IIIa)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽製備方法，包括以下步驟： The compound represented by the general formula (IIIa) of the present disclosure or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture form thereof, or pharmacologically thereof The salt preparation method used includes the following steps:

通式(IIIaA)化合物和通式(IIIB)化合物或其可藥用的鹽(較佳為鹽酸鹽)，在鹼性條件下，在縮合劑存在下發生縮合反應得到通式(IIIa)化合物； The compound of general formula (IIIaA) and the compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) undergo condensation reaction under alkaline conditions in the presence of a condensing agent to obtain a compound of general formula (IIIa) ；

方案四 Option Four

本公開通式(IIIb)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽製備方法，包括以下步驟： The compound represented by the general formula (IIIb) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a medicine thereof The salt preparation method used includes the following steps:

通式(IIIbA)化合物和通式(IIIB)化合物或其可藥用的鹽(較佳為鹽酸鹽)，在鹼性條件下，在縮合劑存在下發生縮合反應得到通式(IIIb)化合物； The compound of general formula (IIIbA) and the compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) undergo condensation reaction under alkaline conditions in the presence of a condensing agent to obtain a compound of general formula (IIIb) ；

方案五 Option Five

本公開通式(IIIb-1)或(IIIb-2)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽製備方法，包括以下步驟： The compound represented by the general formula (IIIb-1) or (IIIb-2) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or The preparation method of its mixture form or its pharmaceutically acceptable salt includes the following steps:

方案一至方案四中提供鹼性條件的試劑包括有機鹼和無機鹼類，該有機鹼類包括但不限於三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、醋酸鉀、第三丁醇鈉或第三丁醇鉀，該無機鹼類包括但不限於氫化鈉、磷酸鉀、碳酸鈉、醋酸鈉、醋酸鉀、碳酸鉀或碳酸銫、氫氧化鈉、氫氧化鋰和氫氧化鉀；較佳N,N-二異丙基乙胺。 The reagents that provide basic conditions in Scheme 1 to Scheme 4 include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine. Lithium base amide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, hydrogen Sodium oxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.

上述方案一至方案四反應較佳在溶劑中進行，所用溶劑包括但不限於：醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氫呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亞碸、1,4-二噁烷、乙二醇二甲醚、水或N,N-二甲基甲醯胺及其混合物，較佳N,N-二甲基甲醯胺。 The above-mentioned Scheme 1 to Scheme 4 reactions are preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof, preferably N,N-dimethylformamide.

方案一至方案四反應中所用的縮合劑包括但不限於1-(3-二甲胺基丙基)-3-乙基碳二亞胺鹽酸鹽、N,N'-二環己基碳化二亞胺、N,N'-二異丙基碳二醯亞胺、O-苯并***-N,N,N',N'-四甲基脲四氟硼酸鹽、1-羥基苯并***、1-羥基-7-偶氮苯并***、O-苯并***-N,N,N',N'-四甲脲六氟磷酸鹽、2-(7-偶氮苯并***)-N,N,N',N'-四甲基脲六氟磷酸鹽、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽、苯并***-1-基氧基三(二甲基胺基)磷鎓六氟磷酸鹽或六氟磷酸苯并***-1-基-氧基三吡咯烷基磷，較佳為六氟磷酸苯并***-1-基-氧基三吡咯烷基磷。 The condensing agent used in the reaction of Scheme 1 to Scheme 4 includes but not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide Amine, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole , 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole ) -N, N, N ', N'- tetramethyluronium hexafluorophosphate, 2- (7-benzotriazol-oxide) - N, N, N' , N '- tetramethyluronium hexafluorophosphate Phosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate, preferably It is hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidinyl phosphorus.

以下結合實施例進一步描述本公開，但這些實施例並非限制著本公開的範圍。 The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

實施例 Example

化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(δ)以10^-6(ppm)的單位給出。NMR的測定是用Bruker AVANCE-400核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d ₆)、氘代氯仿(CDCl₃)、氘代甲醇(CD₃OD)，內標為四甲基矽烷(TMS)。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methyl Silane (TMS).

MS的測定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液質聯用儀(生產商：Agilent，MS型號：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生產商：waters，MS型號：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生產商：THERMO，MS型號：THERMO Q Exactive)。 The measurement of MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

高效液相色譜法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高壓液相色譜儀。 High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

手性HPLC分析測定使用Agilent 1260 DAD高效液相色譜儀。 The chiral HPLC analysis and determination used Agilent 1260 DAD high performance liquid chromatograph.

高效液相製備使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281製備型色譜儀。 Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs were used for HPLC preparation.

手性製備使用Shimadzu LC-20AP製備型色譜儀。 For chiral preparation, Shimadzu LC-20AP preparative chromatograph was used.

CombiFlash快速製備儀使用Combiflash Rf200(TELEDYNE ISCO)。 CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.15mm~0.2mm，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。 The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm. ~0.5mm.

矽膠管柱色譜法一般使用煙臺黃海矽膠200~300目矽膠為載體。 The silica gel column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

激酶平均抑制率及IC₅₀值的測定用NovoStar酶標儀(德國BMG公司)。 The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

本公開的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自ABCR GmbH & Co.KG、Acros Organics、Aldrich Chemical Company、韶遠化學科技(Accela ChemBio Inc)、達瑞化學品等公司。 The known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Darui Chemicals.

實施例中無特殊說明，反應能夠均在氬氣氛或氮氣氛下進行。 There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.

氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。 The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

加壓氫化反應使用Parr 3916EKX型氫化儀和清藍QL-500型氫氣發生器或HC2-SS型氫化儀。 The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

氫化反應通常抽真空，充入氫氣，重複操作3次。 The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

微波反應使用CEM Discover-S 908860型微波反應器。 The microwave reaction uses a CEM Discover-S 908860 microwave reactor.

實施例中無特殊說明，溶液是指水溶液。 There is no special description in the examples, and the solution refers to an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫，為20℃~30℃。 There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑，純化化合物採用的管柱層析的沖提劑的體系和薄層色譜法的展開劑體系包括：A：正己烷/乙酸乙酯體系，B：二氯甲烷/甲醇體系，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和醋酸等鹼性或酸性試劑進行調節。 The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC), the developing reagent used in the reaction, the eluent system of column chromatography used to purify the compound, and the development of thin-layer chromatography The reagent system includes: A: n-hexane/ethyl acetate system, B: dichloromethane/methanol system. The volume ratio of the solvent is adjusted according to the polarity of the compound. A small amount of basic or acetic acid such as triethylamine and acetic acid can also be added. Acidic reagents are adjusted.

實施例1 Example 1

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-7,8-二氫吡啶并[4,3-d]嘧啶-6(5H)-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮1 2-(5-(2-((2,3-Dihydro-1 H -inden-2-yl)amino)-7,8-dihydropyrido[4,3- d ]pyrimidine-6(5 H )-yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4 ,5- c ]pyridin-5-yl)ethan-1-one 1

第一步 first step

N-(2,3-二氫-1H-茚-2-基)-5,6,7,8-四氫吡啶并[4,3-d]嘧啶-2-胺三氟乙酸鹽1b N -(2,3-dihydro-1 H -inden-2-yl)-5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidin-2-amine trifluoroacetate 1b

將2-((2,3-二氫-1H-茚-2-基)胺基)-7,8-二氫吡啶并[4,3-d]嘧啶-6(5H)-羧酸第三丁酯1a(5.5g，15.0mmol，採用專利申請“WO 2014168824，第10頁中間體2公開方法”製備而得)溶於二氯甲烷(50mL)，加入三氟乙酸(10.0mL，adamas)，攪拌反應1小時。減壓濃縮，得到標題產物粗品1b(5.7g，產率：99.8%)。 The 2-((2,3-dihydro- 1H -inden-2-yl)amino)-7,8-dihydropyrido[4,3- d ]pyrimidine-6( 5H )-carboxylic acid Tertiary butyl ester 1a (5.5g, 15.0mmol, prepared by the patent application "WO 2014168824, page 10 Intermediate 2 published method") was dissolved in dichloromethane (50mL), and trifluoroacetic acid (10.0mL, adamas ), the reaction was stirred for 1 hour. Concentrate under reduced pressure to obtain the title product crude product 1b (5.7g, yield: 99.8%).

MS m/z(ESI)：267.2[M+1]。 MS m/z (ESI): 267.2 [M+1].

第二步 Second step

2-(5-側氧-4,5-二氫-1,3,4-噁二唑-2-基)乙酸乙酯1e 2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) ethyl acetate 1e

將3-側氧-3-肼基丙酸乙酯1c(2.0g，13.7mmol，adamas)和三乙胺(1.5g，14.9mmol，國藥)溶於四氫呋喃(50mL)，加入N,N-羰基二咪唑1d(2.4g，4.8mmol，adamas)，攪拌反應16小時。減壓濃縮，殘餘物用矽膠管柱色譜法以沖提劑體系B純化所得殘餘物，得到標題產物1e(1.6g，產率：67.9%)。 Ethyl 3-oxo-3-hydrazinopropionate 1c (2.0g, 13.7mmol, adamas) and triethylamine (1.5g, 14.9mmol, Sinopharm) were dissolved in tetrahydrofuran (50mL), and N , N -carbonyl was added Diimidazole 1d (2.4g, 4.8mmol, adamas) was stirred and reacted for 16 hours. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1e (1.6 g, yield: 67.9%).

MS m/z(ESI)：173.2[M+1]。 MS m/z (ESI): 173.2 [M+1].

第三步 third step

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-7,8-二氫吡啶并[4,3-d]嘧啶-6(5H)-基)-1,3,4-噁二唑-2-基)乙酸乙酯1f 2-(5-(2-((2,3-Dihydro-1 H -inden-2-yl)amino)-7,8-dihydropyrido[4,3- d ]pyrimidine-6(5 H )-yl)-1,3,4-oxadiazol-2-yl)ethyl acetate 1f

將化合物1b(1.0g，2.6mmol)和化合物1e(500mg，2.9mmol)溶於N,N-二甲基甲醯胺(10mL)，加入N,N-二異丙基乙胺(2.0g，15.5mmol，adamas)和卡特縮合劑(3.5g，7.9mmol，畢得)，攪拌反應16小時。向反應液中加水(100mL)，用乙酸乙酯萃取(30mL×2)，合併有機相，減壓濃縮，殘餘物用矽膠管柱色譜法以沖提劑體系B純化所得殘餘物，得到標題產物1f(600mg，產率：54.3%)。 Compound 1b (1.0g, 2.6mmol) and compound 1e (500mg, 2.9mmol) were dissolved in N , N -dimethylformamide (10mL), and N , N -diisopropylethylamine (2.0g, 15.5mmol, adamas) and Carter condensing agent (3.5g, 7.9mmol, complete), stirred and reacted for 16 hours. Water (100mL) was added to the reaction solution, extracted with ethyl acetate (30mL×2), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1f (600mg, yield: 54.3%).

MS m/z(ESI)：421.2[M+1]。 MS m/z (ESI): 421.2 [M+1].

第四步 the fourth step

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-7,8-二氫吡啶并[4,3-d]嘧啶-6(5H)-基)-1,3,4-噁二唑-2-基)乙酸1g 2-(5-(2-((2,3-Dihydro-1 H -inden-2-yl)amino)-7,8-dihydropyrido[4,3- d ]pyrimidine-6(5 H )-yl)-1,3,4-oxadiazol-2-yl)acetic acid 1g

將化合物1f(600mg，1.43mmol)溶於THF(10mL)和水(5.0mL)中，於0℃，加入一水氫氧化鋰(300mg，7.14mmol，國藥)，攪拌反應1小時。減壓濃縮除去有機溶劑，用1N稀鹽酸調pH到3~4，固體析出，過濾乾燥，得到標題產物1g(280mg，產率：50.0%)。 Compound 1f (600mg, 1.43mmol) was dissolved in THF (10mL) and water (5.0mL), at 0°C, lithium hydroxide monohydrate (300mg, 7.14mmol, Sinopharm) was added, and the reaction was stirred for 1 hour. The organic solvent was removed by concentration under reduced pressure, and the pH was adjusted to 3~4 with 1 N dilute hydrochloric acid. The solid precipitated out and was filtered and dried to obtain 1 g (280 mg, yield: 50.0%) of the title product.

MS m/z(ESI)：393.2[M+1]。 MS m/z (ESI): 393.2 [M+1].

第五步 the fifth step

將化合物1g(160mg，0.41mmol)和4,5,6,7-四氫-3H-[1,2,3]***并[4,5-c]吡啶鹽酸鹽1h(90mg，0.56mmol，採用專利申請“WO 2018212534A1，第53頁中間體im-7公開方法”製備而得)溶於N,N-二甲基甲醯胺(2.0mL)，加入N,N-二異丙基乙胺(150mg，1.16mmol，adamas)和六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(600mg，1.15mmol，adamas)，攪拌反應1小時。向反應液中加水(10mL)，用乙酸乙酯(10mL)萃取，減壓濃縮，殘餘物用高效液相色譜法純化(Sharpsil-T C18 Column 21.2*150mm 5um，沖提體系：水(10mmoL/L醋酸銨)、乙腈)，得到標題產物1(70mg，產率：34.4%)。 Compound 1g (160mg, 0.41mmol) and 4,5,6,7-tetrahydro -3 H - [1,2,3] triazolo [4,5- c] pyridine hydrochloride 1h (90mg, 0.56 mmol, prepared by the patent application "WO 2018212534A1, p.53 intermediate im-7 published method") was dissolved in N , N -dimethylformamide (2.0 mL), and N , N -diisopropyl was added Ethylamine (150 mg, 1.16 mmol, adamas) and benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate (600 mg, 1.15 mmol, adamas) were stirred and reacted for 1 hour. Water (10mL) was added to the reaction solution, extracted with ethyl acetate (10mL), concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Sharpsil-T C18 Column 21.2*150mm 5um, extraction system: water (10mmoL/ L ammonium acetate), acetonitrile) to obtain the title product 1 (70 mg, yield: 34.4%).

MS m/z(ESI)：499.2[M+1]。 MS m/z (ESI): 499.2 [M+1].

¹H NMR(400MHz,DMSO-d ₆)δ 8.20(s,1H),7.38(d,1H),7.21-7.19(m,2H),7.14-7.12(m,2H),4.77-4.67(m,2H),4.60-4.57(m,1H),4.44-4.40(m,2H),4.20-4.15(m,2H),3.81(s,2H),3.74-3.67(m,2H),3.33-3.31(m,1H),3.25-3.19(m,2H),2.88-2.83(m,4H),2.27-2.23(m,2H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.20 (s, 1H), 7.38 (d, 1H), 7.21-7.19 (m, 2H), 7.14-7.12 (m, 2H), 4.77-4.67 (m, 2H), 4.60-4.57(m, 1H), 4.44-4.40(m, 2H), 4.20-4.15(m, 2H), 3.81(s, 2H), 3.74-3.67(m, 2H), 3.33-3.31( m, 1H), 3.25-3.19 (m, 2H), 2.88-2.83 (m, 4H), 2.27-2.23 (m, 2H).

實施例2 Example 2

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,7-二氫-6H-吡咯并[3,4-d]嘧啶-6-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮2 2- (5- (2 - ((2,3-dihydro -1 H - inden-2-yl) amino) -5,7-dihydro -6 H - pyrrolo [3,4- d] pyrimidine -6-yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4 ,5- c ]pyridin-5-yl)ethan-1-one 2

第一步 first step

2-((2,3-二氫-1H-茚-2-基)胺基)-5,7-二氫-6H-吡咯并[3,4-d]嘧啶-6-羧酸第三丁酯2c 2 - ((2,3-dihydro -1 H - inden-2-yl) amino) -5,7-dihydro -6 H - pyrrolo [3,4- d] pyrimidine-6-carboxylic acid of Tributyl 2c

將2-氯-5,7-二氫-6H-吡咯并[3,4-d]嘧啶-6-羧酸第三丁酯2a(900mg，3.52mmol，藥石)和N,N-二異丙基乙胺(1.4g，10.8mmol，adamas)溶於乙醇(10mL)，加入2,3-二氫-1H-茚-2-胺鹽酸鹽2b(1.2g，7.07mmol，韶遠)，80℃攪拌24小時。減壓濃縮，殘餘物用矽膠管柱色譜法以沖提劑體系A純化所得殘餘物，得到標題產物2c(1.1g，產率：88.7%)。 2-Chloro-5,7-dihydro -6 H - pyrrolo [3,4- d] pyrimidine-6-carboxylic acid tert-butyl ester 2a (900mg, 3.52mmol, desperate) and N, N - diisopropyl Propylethylamine (1.4g, 10.8mmol, adamas) was dissolved in ethanol (10mL), and 2,3-dihydro-1 H -indene-2-amine hydrochloride 2b (1.2g, 7.07mmol, Shaoyuan) was added , Stir at 80°C for 24 hours. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 2c (1.1 g, yield: 88.7%).

MS m/z(ESI)：353.2[M+1]。 MS m/z (ESI): 353.2 [M+1].

第二步 Second step

N-(2,3-二氫-1H-茚-2-基)-6,7-二氫-5H-吡咯并[3,4-d]嘧啶-2-胺三氟乙酸鹽2d N -(2,3-dihydro-1 H -inden-2-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d ]pyrimidin-2-amine trifluoroacetate 2d

將化合物2c(1.1g，3.12mmol)溶於二氯甲烷(10mL)，加入三氟乙酸(3.0mL，adamas)，攪拌反應1小時。減壓濃縮，得到標題產物粗品2d(1.2g，產率：104.9%)。 Compound 2c (1.1 g, 3.12 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3.0 mL, adamas) was added, and the reaction was stirred for 1 hour. Concentrate under reduced pressure to obtain the title product crude product 2d (1.2 g, yield: 104.9%).

MS m/z(ESI)：253.2[M+1]。 MS m/z (ESI): 253.2 [M+1].

第三步 third step

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,7-二氫-6H-吡咯并[3,4-d]嘧啶-6-基)-1,3,4-噁二唑-2-基)乙酸乙酯2e 2- (5- (2 - ((2,3-dihydro -1 H - inden-2-yl) amino) -5,7-dihydro -6 H - pyrrolo [3,4- d] pyrimidine -6-yl)-1,3,4-oxadiazol-2-yl)ethyl acetate 2e

將化合物2d(500mg，1.36mmol)和化合物1e(240mg，1.39mmol)溶於N,N-二甲基甲醯胺(10mL)，加入N,N-二異丙基乙胺(1.1g，10.1mmol，adamas)和卡特縮合劑(1.82g，4.11mmol，畢得)，攪拌反應16小時。向反應液中加水(10mL)，用乙酸乙酯(10mL×2)萃取，合併有機相，減壓濃縮，殘餘物用矽膠管柱色譜法以沖提劑體系B純化所得殘餘物，得到標題產物2e(500mg，產率：90.1%)。 Compound 2d (500mg, 1.36mmol) and compound 1e (240mg, 1.39mmol) were dissolved in N , N -dimethylformamide (10mL), and N , N -diisopropylethylamine (1.1g, 10.1 mmol, adamas) and Carter condensing agent (1.82 g, 4.11 mmol, complete), and the reaction was stirred for 16 hours. Water (10mL) was added to the reaction solution, extracted with ethyl acetate (10mL×2), the organic phases were combined, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 2e (500mg, yield: 90.1%).

MS m/z(ESI)：407.2[M+1]。 MS m/z (ESI): 407.2 [M+1].

第四步 the fourth step

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,7-二氫-6H-吡咯并[3,4-d]嘧啶-6-基)-1,3,4-噁二唑-2-基)乙酸2f 2- (5- (2 - ((2,3-dihydro -1 H - inden-2-yl) amino) -5,7-dihydro -6 H - pyrrolo [3,4- d] pyrimidine -6-yl)-1,3,4-oxadiazol-2-yl)acetic acid 2f

將化合物2e(500mg，1.23mmol)溶於THF(10mL)和水(5.0mL)中，於0℃，加入一水氫氧化鋰(250mg，5.95mmol，國藥)，攪拌反應1小時。減壓濃縮除去有機溶劑，用1N稀鹽酸調pH到3~4，固體析出，過濾乾燥，得到標題產物2f(400mg，產率：85.9%)。 Compound 2e (500mg, 1.23mmol) was dissolved in THF (10mL) and water (5.0mL), at 0°C, lithium hydroxide monohydrate (250mg, 5.95mmol, Sinopharm) was added, and the reaction was stirred for 1 hour. The organic solvent was removed by concentration under reduced pressure, and the pH was adjusted to 3~4 with 1 N dilute hydrochloric acid. The solid precipitated out and was filtered and dried to obtain the title product 2f (400 mg, yield: 85.9%).

MS m/z(ESI)：379.1[M+1]。 MS m/z (ESI): 379.1 [M+1].

第五步 the fifth step

將化合物2f(150mg，0.40mmol)和化合物1h(90mg，0.56mmol)溶於N,N-二甲基甲醯胺(2.0mL)，加入N,N-二異丙基乙胺(160mg，1.24mmol，adamas)和六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(600mg，1.15mmol，adamas)，攪拌反應1小時。向反應液中加水(10mL)，用乙酸乙酯(10mL)萃取，減壓濃縮，殘餘物用高效液相色譜法純化(Sharpsil-T C18 Column 21.2×150mm 5um，沖提體系：水(10mmoL/L醋酸銨)、乙腈)，得到標題產物2(60mg，產率：31.2%)。 Compound 2f (150mg, 0.40mmol) and compound 1h (90mg, 0.56mmol) were dissolved in N , N -dimethylformamide (2.0mL), and N , N -diisopropylethylamine (160mg, 1.24 mmol, adamas) and benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate (600 mg, 1.15 mmol, adamas), stirred for 1 hour. Water (10mL) was added to the reaction solution, extracted with ethyl acetate (10mL), concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Sharpsil-T C18 Column 21.2×150mm 5um, extraction system: water (10mmoL/ L ammonium acetate), acetonitrile) to obtain the title product 2 (60 mg, yield: 31.2%).

MS m/z(ESI)：485.2[M+1]。 MS m/z (ESI): 485.2 [M+1].

¹H NMR(400MHz,DMSO-d ₆)δ 8.35(s,1H),7.64(d,1H),7.23-7.20(m,2H),7.15-7.13(m,2H),4.78(s,1H)4.68-4.62(m,4H),4.55-4.51(m,2H),4.22-4.18(m,2H),3.82(s,2H),3.27-3.23(m,4H),2.92-2.88(m,3H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.35 (s, 1H), 7.64 (d, 1H), 7.23-7.20 (m, 2H), 7.15-7.13 (m, 2H), 4.78 (s, 1H) 4.68-4.62(m,4H),4.55-4.51(m,2H),4.22-4.18(m,2H),3.82(s,2H),3.27-3.23(m,4H),2.92-2.88(m,3H) ).

實施例3 Example 3

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)喹唑啉-6-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮3 2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)quinazolin-6-yl)-1,3,4-oxadiazole-2- Yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridin-5-yl) ethan-1-one 3

第一步 first step

6-溴-N-(2,3-二氫-1H-茚-2-基)喹唑啉-2-胺3b 6-Bromo- N -(2,3-dihydro-1 H -inden-2-yl)quinazolin-2-amine 3b

將6-溴-2-氯喹唑啉3a(1.0g，4.1mmol，韶遠)和碳酸鉀(1.7g，12.3mmol)溶於乙腈(50mL)，加入化合物2b(1.0g，5.9mmol，adamas)，反應在60℃攪拌16小時。過濾，濾液減壓濃縮，殘餘物用矽膠管柱色譜法以沖提劑體系B純化，得到標題產物3b(1.2g，產率：85.9%)。 6-Bromo-2-chloroquinazoline 3a (1.0g, 4.1mmol, Shaoyuan) and potassium carbonate (1.7g, 12.3mmol) were dissolved in acetonitrile (50mL), and compound 2b (1.0g, 5.9mmol, adamas) was added The reaction was stirred at 60°C for 16 hours. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3b (1.2 g, yield: 85.9%).

MS m/z(ESI)：339.9[M+1]。 MS m/z (ESI): 339.9 [M+1].

第二步 Second step

2-((2,3-二氫-1H-茚-2-基)胺基)喹唑啉-6-羧酸乙酯3c 2-((2,3-Dihydro-1 H -inden-2-yl)amino)quinazolin-6-carboxylic acid ethyl ester 3c

將化合物3b(1.0g，2.9mmol)溶於50mLN,N-二甲基甲醯胺和乙醇(V/V=4/1)的混合溶劑，加入N,N-二異丙基乙胺(900mg，8.9mmol，adamas)、醋酸鈀(130mg，0.58mmol，韶遠)和1,1'-雙(二苯基膦)二茂鐵(550mg，0.94mmol，adamas)，在一氧化碳氣氛下，於80℃攪拌反應16小時。過濾，濾液減壓濃縮，殘餘物用矽膠管柱色譜法以沖提劑體系B純化，得到標題產物3c(510mg，產率：52.0%)。 Compound 3b (1.0g, 2.9mmol) was dissolved in 50 mL N, N - dimethylformamide and ethanol (V / V = 4/1 ) mixed solvent was added N, N - diisopropylethylamine ( 900mg, 8.9mmol, adamas), palladium acetate (130mg, 0.58mmol, Shaoyuan) and 1,1'-bis(diphenylphosphine) ferrocene (550mg, 0.94mmol, adamas), under carbon monoxide atmosphere, The reaction was stirred at 80°C for 16 hours. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3c (510 mg, yield: 52.0%).

MS m/z(ESI)：334.1[M+1]。 MS m/z (ESI): 334.1 [M+1].

第三步 third step

2-((2,3-二氫-1H-茚-2-基)胺基)喹唑啉-6-羧酸3d 2-((2,3-Dihydro-1 H -inden-2-yl)amino)quinazolin-6-carboxylic acid 3d

將化合物3c(500mg，1.5mmol)溶於四氫呋喃(10mL)，加入水(10mL)和一水氫氧化鋰(300mg，7.1mmol)，攪拌反應16小時。減壓濃縮除去有機溶劑，緩慢滴加1M稀鹽酸調pH為3~4，固體析出，過濾乾燥，得到標題產物3d(410mg，產率：89.5%)。 Compound 3c (500 mg, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL), water (10 mL) and lithium hydroxide monohydrate (300 mg, 7.1 mmol) were added, and the reaction was stirred for 16 hours. The organic solvent was removed by concentration under reduced pressure, 1M dilute hydrochloric acid was slowly added dropwise to adjust the pH to 3~4, the solid was precipitated out, filtered and dried to obtain the title product 3d (410mg, yield: 89.5%).

MS m/z(ESI)：306.2[M+1]。 MS m/z (ESI): 306.2 [M+1].

第四步 the fourth step

3-(2-(2-((2,3-二氫-1H-茚-2-基)胺基)喹唑啉-6-羰基)肼基)-3-側氧丙酸乙酯3e 3-(2-(2-((2,3-dihydro- 1H -inden-2-yl)amino)quinazolin-6-carbonyl)hydrazino)-3-oxopropionate ethyl 3e

將化合物3d(400mg，1.3mmol)和化合物1c(290mg，2.0mmol)溶於N,N-二甲基甲醯胺(20mL)，加入N,N-二異丙基乙胺(550mg，4.3mmol)和六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(820mg，1.6mmol，韶遠)，攪拌反應1小時。向反應液中加水(20mL)，用乙酸乙酯(20mL)萃取，減壓濃縮，殘餘物用矽膠管柱色譜法以沖提劑體系B純化，得到標題產物3e(140mg，產率：24.7%)。 Compound 3d (400mg, 1.3mmol) and compound 1c (290mg, 2.0mmol) were dissolved in N , N -dimethylformamide (20mL), and N , N -diisopropylethylamine (550mg, 4.3mmol) was added ) And benzotriazol-1-yl-oxytripyrrolidinyl phosphorous hexafluorophosphate (820mg, 1.6mmol, Shaoyuan), and the reaction was stirred for 1 hour. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3e (140 mg, yield: 24.7%) ).

MS m/z(ESI)：434.2[M+1]。 MS m/z (ESI): 434.2 [M+1].

第五步 the fifth step

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)喹唑啉-6-基)-1,3,4-噁二唑-2-基)乙酸乙酯3f 2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)quinazolin-6-yl)-1,3,4-oxadiazole-2- Base) ethyl acetate 3f

將化合物3e(100mg，0.23mmol)溶於無水四氫呋喃(10mL)，加入N,N-二異丙基乙胺(35mg，0.35mmo)和4-甲苯磺醯氯(53mg，0.28mmol)，攪拌反應4小時。向反應液中加水(10mL)，用乙酸乙酯(10mL)萃取，減壓濃縮，殘餘物用矽膠管柱色譜法以沖提劑體系B純化，得到標題產物3f(85mg，產率：88.7%)。 Compound 3e (100mg, 0.23mmol) was dissolved in anhydrous tetrahydrofuran (10mL), N , N -diisopropylethylamine (35mg, 0.35mmo) and 4-toluenesulfonyl chloride (53mg, 0.28mmol) were added, and the reaction was stirred 4 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3f (85 mg, yield: 88.7%) ).

MS m/z(ESI)：416.2[M+1]。 MS m/z (ESI): 416.2 [M+1].

第六步 Sixth step

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)喹唑啉-6-基)-1,3,4-噁二唑-2-基)乙酸3g 2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)quinazolin-6-yl)-1,3,4-oxadiazole-2- Base) acetic acid 3g

將化合物3f(85mg，0.2mmol)溶於四氫呋喃(5mL)，加入水(5mL)和一水氫氧化鋰(50mg，1.2mmol)，攪拌反應2小時。減壓濃縮除去有機溶劑，緩慢滴加1M稀鹽酸調pH為3~4，固體析出，過濾乾燥，得到標題產物3g(65mg，產率：82.0%)。 Compound 3f (85 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), water (5 mL) and lithium hydroxide monohydrate (50 mg, 1.2 mmol) were added, and the reaction was stirred for 2 hours. The organic solvent was removed by concentration under reduced pressure, 1M dilute hydrochloric acid was slowly added dropwise to adjust the pH to 3~4, the solid was precipitated out, filtered and dried to obtain the title product 3g (65mg, yield: 82.0%).

MS m/z(ESI)：387.9[M+1]。 MS m/z (ESI): 387.9 [M+1].

第七步 Seventh step

將化合物3g(65mg，0.17mmol)和化合物1h(40mg，0.25mmol)溶於N,N-二甲基甲醯胺(5.0mL)，加入N,N-二異丙基乙胺(65mg，0.5mmol)和六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(131mg，0.25mmol，韶遠)，攪拌反應1小時。向反應液中加水(10mL)，用乙酸乙酯(10mL)萃取，減壓濃縮，殘餘物用高效液相色譜法純化(Sharpsil-T C18 Column 21.2×150mm 5um，沖提體系：水(10mmoL/L醋酸銨)、乙腈)，得到標題產物3(17mg，產率：20.5%)。 Compound 3g (65mg, 0.17mmol) and compound 1h (40mg, 0.25mmol) were dissolved in N , N -dimethylformamide (5.0mL), and N , N -diisopropylethylamine (65mg, 0.5 mmol) and benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate (131 mg, 0.25 mmol, Shaoyuan), and the reaction was stirred for 1 hour. Water (10mL) was added to the reaction solution, extracted with ethyl acetate (10mL), concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Sharpsil-T C18 Column 21.2×150mm 5um, extraction system: water (10mmoL/ L ammonium acetate), acetonitrile) to obtain the title product 3 (17 mg, yield: 20.5%).

MS m/z(ESI)：494.1[M+1]。 MS m/z (ESI): 494.1 [M+1].

¹H NMR(400MHz,DMSO-d ₆)δ 9.30(brs,1H),8.44-8.40(m,1H),8.22-8.19(m,2H),7.64-7.62(m,1H),7.23-7.14(m,4H),4.84-4.70(m,3H),4.50-4.46(m,2H),3.87-3.83(m,2H),3.75-3.50(m，2H),3.00-2.92(m,4H),2.77-2.74(m,1H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.30 (brs, 1H), 8.44-8.40 (m, 1H), 8.22-8.19 (m, 2H), 7.64-7.62 (m, 1H), 7.23-7.14 ( m,4H),4.84-4.70(m,3H),4.50-4.46(m,2H),3.87-3.83(m,2H),3.75-3.50(m,2H),3.00-2.92(m,4H), 2.77-2.74 (m, 1H).

實施例4 Example 4

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮4 2-(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ]pyrimidine-5- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridin-5-yl)ethan-1-one 4

第一步 first step

2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-5-羧酸4b 2-((2,3-Dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ]pyrimidine-5-carboxylic acid 4b

將2-((二甲胺基)亞甲基)-3-側氧環戊烷-1-甲酸甲酯4a(2.2g，11.2mmol，採用專利申請“WO 2013028474A1中說明書第96頁的中間體63”公開的方法製備而得)和1-(2,3-二氫-1H-茚-2-基)胍鹽酸鹽(2.35g，13.4mmol，採用專利申請“US20140200231A1中說明書第6頁的中間體1”公開的方法製備而得)溶於無水甲醇(50mL)，加入甲醇鈉(1.0g，40.7mmol，adamas)，80℃攪拌16小時。加入水(10mL)淬滅，然後用1N稀鹽酸調pH到3~4，然後用正丁醇萃取，乾燥，減壓濃縮，殘餘物用矽膠管柱色譜法以沖提劑體系B純化，得到標題產物4b(2.0g，產率：60.7%)。 The 2 - ((dimethylamino) methylene) -3-oxo-1-carboxylate side 4 a (2.2g, 11.2mmol, using patent application "WO 2013028474A1 intermediate in the description on page 96 Body 63" prepared by the method disclosed) and 1-(2,3-dihydro- 1H -inden-2-yl)guanidine hydrochloride (2.35g, 13.4mmol, using patent application "US20140200231A1 Specification No. 6 Intermediate 1" on page "prepared by the method disclosed) was dissolved in anhydrous methanol (50 mL), sodium methoxide (1.0 g, 40.7 mmol, adamas) was added, and the mixture was stirred at 80°C for 16 hours. Add water (10mL) to quench, then adjust the pH to 3~4 with 1 N dilute hydrochloric acid, then extract with n-butanol, dry, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography with eluent system B. The title product 4b (2.0 g, yield: 60.7%) was obtained.

MS m/z(ESI)：296.0[M+1]。 MS m/z (ESI): 296.0 [M+1].

第二步 Second step

3-(2-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-5-羰基)肼基)-3-側氧丙酸乙酯4c 3-(2-(2-((2,3-dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ]pyrimidine-5- Carbonyl) hydrazino) ethyl-3-oxopropionate 4c

將化合物4b(500mg，1.69mmol)和化合物3-肼基-3-側氧丙酸乙酯(371mg,2.53)溶於N,N-二甲基甲醯胺(10mL)，然後加入1H-苯并***-1-基氧三吡咯烷基六氟磷酸鹽(1.06g，2.04mmol，韶遠)和N,N-二異丙基乙胺(657mg，5.08mmol，adamas)，於室溫攪拌反應3小時。加入水淬滅，然後乙酸乙酯萃取，乾燥，減壓濃縮，殘餘物用矽膠管柱色譜法以沖提劑體系B純化所得殘餘物，得到標題產物4c(365mg，產率：50.9%)。 Compound 4b (500mg, 1.69mmol) and compound 3-hydrazino-3-oxopropionic acid ethyl ester (371mg, 2.53) were dissolved in N , N -dimethylformamide (10mL), and then 1 H- Benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (1.06g, 2.04mmol, Shaoyuan) and N,N -diisopropylethylamine (657mg, 5.08mmol, adamas) at room temperature The reaction was stirred for 3 hours. It was quenched by adding water, then extracted with ethyl acetate, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4c (365 mg, yield: 50.9%).

MS m/z(ESI)：424.0[M+1]。 MS m/z (ESI): 424.0 [M+1].

第三步 third step

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸乙酯4d 2-(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ]pyrimidine-5- Yl)-1,3,4-oxadiazol-2-yl)ethyl acetate 4d

將化合物4c(360mg，0.85mmol)溶於四氫呋喃(10mL)，加入伯吉斯試劑(608mg，2.55mmol，adamas)，封管80℃攪拌4小時。減壓濃縮除去有機溶劑，殘餘物用矽膠管柱色譜法以沖提劑體系B純化，得到標題產物4d(167mg，產率：48.5%)。 Compound 4c (360mg, 0.85mmol) was dissolved in tetrahydrofuran (10mL), Burgess reagent (608mg, 2.55mmol, adamas) was added, and the tube was sealed at 80°C and stirred for 4 hours. The organic solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4d (167 mg, yield: 48.5%).

MS m/z(ESI)：406.0[M+1]。 MS m/z (ESI): 406.0 [M+1].

第四步 the fourth step

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-5-基)-1,3,4-噁二唑-2-基)乙酸4e 2-(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ]pyrimidine-5- Yl)-1,3,4-oxadiazol-2-yl)acetic acid 4e

採用實施例1中的化合物1g的合成路線，將原料化合物1f替換為原料化合物4d，製得標題化合物4e(151mg，產率：97.0%)。 Using the synthetic route of compound 1g in Example 1, the starting compound 1f was replaced with the starting compound 4d to obtain the title compound 4e (151 mg, yield: 97.0%).

MS m/z(ESI)：378.0[M+1]。 MS m/z (ESI): 378.0 [M+1].

第五步 the fifth step

採用實施例1中的化合物1的合成路線，將原料化合物1g替換為原料化合物4e，製得標題化合物4(88mg，產率：45.0%)。 Using the synthetic route of compound 1 in Example 1, the starting compound 1g was replaced with the starting compound 4e to obtain the title compound 4 (88 mg, yield: 45.0%).

MS m/z(ESI)：484.0[M+1]。 MS m/z (ESI): 484.0 [M+1].

¹H NMR(400MHz,DMSO-d ₆)δ 14.70(brs,1H),8.17(s,1H),7.54-7.52(m,1H),7.21-7.12(m,4H),4.76-4.60(m,4H),4.37-4.33(m,2H),3.81-3.79(m,2H),3.26-3.20(m,2H),2.89-2.84(m,4H),2.73-2.67(m,3H),2.28-2.21(m,1H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ 14.70 (brs, 1H), 8.17 (s, 1H), 7.54-7.52 (m, 1H), 7.21-7.12 (m, 4H), 4.76-4.60 (m, 4H), 4.37-4.33 (m, 2H), 3.81-3.79 (m, 2H), 3.26-3.20 (m, 2H), 2.89-2.84 (m, 4H), 2.73-2.67 (m, 3H), 2.28- 2.21(m,1H).

實施例4-1和實施例4-2 Example 4-1 and Example 4-2

(S)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮4-1 ( S )-2-(5-(2-((2,3-Dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ] Pyrimidine-5-yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[ 4,5- c )pyridin-5-yl)ethan-1-one 4-1

(R)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-5-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮4-2 ( R )-2-(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ] Pyrimidine-5-yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[ 4,5- c )pyridin-5-yl)ethan-1-one 4-2

將化合物4(88mg，0.16mmol)進行手性製備(分離條件：手性製備管柱CHIRALPAK AS,5.0cm I.D.×25cm,10μm；流動相：甲醇(100%)，流速：60mL/min)，收集其相應組分，減壓濃縮，得到標題化合物(26mg,24mg)。 Compound 4 (88mg, 0.16mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALPAK AS, 5.0cm ID×25cm, 10μm; mobile phase: methanol (100%), flow rate: 60mL/min), and collected The corresponding components were concentrated under reduced pressure to obtain the title compound (26 mg, 24 mg).

單一構型化合物(較短保留時間)： Single configuration compound (shorter retention time):

MS m/z(ESI)：484.0[M+1]。 MS m/z (ESI): 484.0 [M+1].

手性HPLC分析：保留時間5.84分鐘，手性純度：100%(色譜管柱：CHIRALPAK AS-H，0.46cm I.D.×15cm；流動相：甲醇(100%))。 Chiral HPLC analysis: retention time 5.84 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK AS-H, 0.46 cm I.D.×15 cm; mobile phase: methanol (100%)).

單一構型化合物(較長保留時間)： Single configuration compound (longer retention time):

MS m/z(ESI)：484.0[M+1]。 MS m/z (ESI): 484.0 [M+1].

手性HPLC分析：保留時間11.83分鐘，手性純度：99.7%(色譜管柱：CHIRALPAK AS-H，0.46cm I.D.×15cm；流動相：甲醇(100%))。 Chiral HPLC analysis: retention time 11.83 minutes, chiral purity: 99.7% (chromatographic column: CHIRALPAK AS-H, 0.46cm I.D.×15cm; mobile phase: methanol (100%)).

實施例5 Example 5

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-6-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮5 2-(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ]pyrimidine-6- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridin-5-yl)ethan-1-one 5

採用實施例4的合成路線，將原料化合物4a替換為原料化合物5a，製得標題化合物5(54mg，產率：13.4%)。 Using the synthetic route of Example 4, the raw material compound 4a was replaced with the raw material compound 5a to obtain the title compound 5 (54 mg, yield: 13.4%).

MS m/z(ESI)：484.0[M+1]。 MS m/z (ESI): 484.0 [M+1].

¹H NMR(400MHz,CD₃OD)δ 8.15(s,1H),7.23-7.13(m,4H),4.85-4.69(m,3H),4.05-3.92(m,3H),3.39-3.36(m,4H),3.33-3.14(m,4H),2.98-2.85(m,4H)。 ¹ H NMR (400MHz, CD ₃ OD) δ 8.15 (s, 1H), 7.23-7.13 (m, 4H), 4.85-4.69 (m, 3H), 4.05-3.92 (m, 3H), 3.39-3.36 (m , 4H), 3.33-3.14 (m, 4H), 2.98-2.85 (m, 4H).

實施例5-1和實施例5-2 Example 5-1 and Example 5-2

(S)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-6-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮5-1 ( S )-2-(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ] Pyrimidine-6-yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[ 4,5- c )pyridin-5-yl)ethan-1-one 5-1

(R)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-6-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮5-2 ( R )-2-(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ] Pyrimidine-6-yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[ 4,5- c )pyridin-5-yl)ethan-1-one 5-2

將化合物5(54mg，0.11mmol)進行手性製備(分離條件：手性製備管柱CHIRALPAK OJ,5.0cm I.D.×25cm,10μm；流動相：甲醇(100%)，流速：50mL/min)，收集其相應組分，減壓濃縮，得到標題化合物(12mg,13mg)。 Compound 5 (54mg, 0.11mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALPAK OJ, 5.0cm ID×25cm, 10μm; mobile phase: methanol (100%), flow rate: 50mL/min), and collected The corresponding components were concentrated under reduced pressure to obtain the title compound (12mg, 13mg).

MS m/z(ESI)：484.0[M+1]。 MS m/z (ESI): 484.0 [M+1].

手性HPLC分析：保留時間7.04分鐘，手性純度：100%(色譜管柱：CHIRALPAK OJ-H，0.46cm I.D.×15cm；流動相：甲醇(100%))。 Chiral HPLC analysis: retention time 7.04 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK OJ-H, 0.46 cm I.D.×15 cm; mobile phase: methanol (100%)).

MS m/z(ESI)：484.0[M+1]。 MS m/z (ESI): 484.0 [M+1].

手性HPLC分析：保留時間9.84分鐘，手性純度：99.4%(色譜管柱：CHIRALPAK OJ-H，0.46cm I.D.×15cm；流動相：甲醇(100%))。 Chiral HPLC analysis: retention time 9.84 minutes, chiral purity: 99.4% (chromatographic column: CHIRALPAK OJ-H, 0.46 cm I.D.×15 cm; mobile phase: methanol (100%)).

實施例6 Example 6

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-7-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮6 2-(5-(2-((2,3-Dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ]pyrimidine-7- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c )pyridin-5-yl)ethan-1-one 6

採用實施例5的合成路線，，將化合物5a換成3-((二甲胺基)亞甲基)-2-側氧環戊烷-1-甲酸甲酯，得到標題化合物6。 Using the synthetic route of Example 5, the compound 5a was replaced with 3-((dimethylamino)methylene)-2-oxocyclopentane-1-carboxylic acid methyl ester to obtain the title compound 6 .

實施例6-1和實施例6-2 Example 6-1 and Example 6-2

(S)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-7-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮6-1 ( S )-2-(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ] Pyrimidine-7-yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[ 4,5- c )pyridin-5-yl)ethan-1-one 6-1

(R)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-6,7-二氫-5H-環戊并[d]嘧啶-7-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮6-2 ( R )-2-(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)-6,7-dihydro-5 H -cyclopenta[ d ] Pyrimidine-7-yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[ 4,5- c )pyridin-5-yl)ethan-1-one 6-2

將化合物6進行手性製備，可以得到目標化合物6-1，6-2。 By chiral preparation of compound 6 , the target compounds 6-1 and 6-2 can be obtained.

實施例7 Example 7

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-8-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮7 2-(5-(2-((2,3-Dihydro-1 H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-8-yl)-1 ,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridine- 5-yl)ethan-1-one 7

採用實施例5的合成路線，將化合物5a換成3-((二甲胺基)亞甲基)-2-側氧環己烷-1-甲酸甲酯，得到標題化合物7。 Using the synthetic route of Example 5, the compound 5a was replaced with 3-((dimethylamino)methylene)-2-oxocyclohexane-1-carboxylic acid methyl ester to obtain the title compound 7 .

實施例7-1和實施例7-2 Example 7-1 and Example 7-2

(S)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-8-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮7-1 ( S )-2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazoline-8- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c )pyridin-5-yl)ethan-1-one 7-1

(R)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-8-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮7-2 ( R )-2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazoline-8- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c )pyridin-5-yl)ethan-1-one 7-2

將化合物7進行手性製備，可以得到目標化合物7-1，7-2。 The compound 7 is prepared by chiral preparation, and the target compounds 7-1 and 7-2 can be obtained.

實施例8 Example 8

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-7-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮8 2-(5-(2-((2,3-Dihydro-1 H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-7-yl)-1 ,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridine- 5-yl)ethan-1-one 8

採用實施例5的合成路線，將化合物5a換成4-((二甲胺基)亞甲基)-3-側氧環己烷-1-甲酸甲酯，得到標題化合物8。 Using the synthetic route of Example 5, the compound 5a was replaced with 4-((dimethylamino)methylene)-3-oxocyclohexane-1-carboxylic acid methyl ester to obtain the title compound 8 .

實施例8-1和實施例8-2 Example 8-1 and Example 8-2

(S)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-7-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮8-1 ( S) -2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazoline-7- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c)pyridin-5-yl)ethan-1-one 8-1

(R)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-7-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮8-2 ( R) -2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazoline-7- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c)pyridin-5-yl)ethan-1-one 8-2

將化合物8進行手性製備，可以得到目標化合物8-1，8-2。 The compound 8 is prepared by chiral preparation, and the target compounds 8-1 and 8-2 can be obtained.

實施例9 Example 9

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-6-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮9 2-(5-(2-((2,3-Dihydro-1 H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-1 ,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridine- 5-yl)ethan-1-one 9

採用實施例5的合成路線，將化合物5a換成3-((二甲胺基)亞甲基)-4-側氧環己烷-1-甲酸甲酯，得到標題化合物9。 Using the synthetic route of Example 5, the compound 5a was replaced with 3-((dimethylamino)methylene)-4-oxocyclohexane-1-carboxylic acid methyl ester to obtain the title compound 9 .

實施例9-1和實施例9-2 Example 9-1 and Example 9-2

(R)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-6-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮9-1 ( R )-2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazoline-6- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c )pyridin-5-yl)ethan-1-one 9-1

(S)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-6-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮9-2 ( S )-2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazoline-6- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c )pyridin-5-yl)ethan-1-one 9-2

將化合物9進行手性製備，可以得到目標化合物9-1，9-2。 Chiral preparation of compound 9 can obtain target compounds 9-1 and 9-2 .

實施例10 Example 10

2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-5-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮10 2-(5-(2-((2,3-Dihydro-1 H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-5-yl)-1 ,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridine- 5-yl)ethan-1-one 10

採用實施例5的合成路線，將化合物5a換成2-((二甲胺基)亞甲基)-3-側氧環己烷-1-甲酸甲酯，得到標題化合物10。 Using the synthetic route of Example 5, the compound 5a was replaced with 2-((dimethylamino)methylene)-3-oxocyclohexane-1-methyl carboxylate to obtain the title compound 10 .

實施例10-1和實施例10-2 Example 10-1 and Example 10-2

(R)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-5-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮10-1 ( R )-2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazoline-5- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c )pyridin-5-yl)ethan-1-one 10-1

(S)-2-(5-(2-((2,3-二氫-1H-茚-2-基)胺基)-5,6,7,8-四氫喹唑啉-5-基)-1,3,4-噁二唑-2-基)-1-(3,4,6,7-四氫-5H-[1,2,3]***并[4,5-c]吡啶-5-基)乙-1-酮10-2 ( S )-2-(5-(2-((2,3-Dihydro- 1H -inden-2-yl)amino)-5,6,7,8-tetrahydroquinazoline-5- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c )pyridin-5-yl)ethan-1-one 10-2

將化合物10進行手性製備，可以得到目標化合物10-1，10-2。 The compound 10 is chirally prepared to obtain the target compounds 10-1 and 10-2 .

生物學評價 Biological evaluation

以下結合測試例進一步描述解釋本公開，但這些實施例並非意味著限制本公開的範圍。 The following further describes and explains the present disclosure in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

測試例1本公開化合物的酶學實驗 Test Example 1 Enzymology experiment of the compound of the present disclosure

ATX(自分泌運動因子)催化底受質溶血磷脂醯膽鹼(LPC)產生膽鹼，膽鹼被膽鹼氧化酶氧化後生成甜菜鹼和過氧化氫，過氧化物酶在過氧化氫存在的條件下，催化底物2-羥基-3-間甲苯胺丙磺酸鈉(TOOS)和4-胺基安替比林反應顯色，在555nm有吸收。測定的吸光值與第一步酶催化反應釋放的膽鹼量正相關，從而反映化合物對ATX酶活性的抑制作用。 ATX (autocrine motility factor) catalyzes the production of choline from the substrate lysophospholipid choline (LPC). Choline is oxidized by choline oxidase to generate betaine and hydrogen peroxide. Peroxidase is present in hydrogen peroxide. Under the conditions, the catalytic substrate 2-hydroxy-3-m-toluidine propanesulfonate sodium (TOOS) and 4-aminoantipyrine react to develop color, with absorption at 555nm. The measured absorbance is positively correlated with the amount of choline released by the enzyme-catalyzed reaction in the first step, thereby reflecting the inhibitory effect of the compound on the ATX enzyme activity.

1)實驗目的 1) Experimental purpose

利用本公開化合物能抑制ATX酶活性的特點，對化合物進行體外篩選。 Using the characteristics of the compounds of the present disclosure that can inhibit ATX enzyme activity, the compounds are screened in vitro.

2)實驗方法 2) Experimental method

緩衝液A：50mM三羥甲基胺基甲烷-鹽酸pH8.5(北京天恩澤生物，#101207-250)、500mM氯化鈉(國藥集團，#10019318)、5mM氯化鉀(國藥集團，#10016318)、10mM氯化鈣(國藥集團，#10005861)和0.1%牛血清白蛋白(Sigma，#B2064)。 Buffer A: 50mM Tris-Hydrochloride pH8.5 (Beijing Tianenze Biological, #101207-250), 500mM Sodium Chloride (Sinopharm Group, #10019318), 5mM Potassium Chloride (Sinopharm Group, # 10016318), 10mM calcium chloride (China National Pharmaceutical Group, #10005861) and 0.1% bovine serum albumin (Sigma, #B2064).

緩衝液B：50mM三羥甲基胺基甲烷-鹽酸pH8.5、500mM氯化鈉、5mM氯化鉀、10mM氯化鈣、0.1%牛血清白蛋白和20mM EGTA(乙二醇雙(2-胺基乙基醚)四乙酸，Sigma，#E3889)。 Buffer B: 50mM tris-hydrochloric acid pH8.5, 500mM sodium chloride, 5mM potassium chloride, 10mM calcium chloride, 0.1% bovine serum albumin and 20mM EGTA (ethylene glycol bis(2- Amino ethyl ether) tetraacetic acid, Sigma, #E3889).

用二甲基亞碸(Sigma，#D2650)配製化合物，初始濃度為500μM，7倍稀釋，共8個劑量。用緩衝液A將ATX(R&D，#5255-EN)配製成終濃度 0.5ng/μl，將LPC 16：0(Sigma，#855675P)配製成終濃度150uM。按每孔20μlATX、1ul化合物及30μl LPC依次加入96孔板(Corning，#3799)中，37℃孵育3小時。 The compound was prepared with dimethyl sulfoxide (Sigma, #D2650), with an initial concentration of 500 μM, diluted 7 times, and a total of 8 doses. Prepare ATX (R&D, #5255-EN) to the final concentration with buffer A 0.5ng/μl, LPC 16:0 (Sigma, #855675P) was formulated to a final concentration of 150uM. Add 20 μl ATX, 1 ul compound and 30 μl LPC to each well in a 96-well plate (Corning, #3799), and incubate at 37° C. for 3 hours.

用緩衝液B配製含有0.6U/ml膽鹼氧化酶(Sigma，#C5896)、0.6U/ml過氧化物酶(Sigma，#P8375)、1.8mM TOOS(Sigma，#04340)及1.2mM 4-胺基安替比林(Sigma，#A4382)的檢測液。將檢測液以50μl/孔加到孵育3小時後的96孔板中，室溫振盪15分鐘後，用酶標儀(Molecular Devices，Flexstation 3)讀取555nm的OD值。 Prepare buffer B containing 0.6U/ml choline oxidase (Sigma, #C5896), 0.6U/ml peroxidase (Sigma, #P8375), 1.8mM TOOS (Sigma, #04340) and 1.2mM 4- A detection solution for aminoantipyrine (Sigma, #A4382). The detection solution was added to the 96-well plate after 3 hours of incubation at 50 μl/well, and after shaking at room temperature for 15 minutes, the OD value of 555 nm was read with a microplate reader (Molecular Devices, Flexstation 3).

3)測試結果 3) Test results

結論：本公開化合物對ATX酶活性有明顯的抑制作用。 Conclusion: The compound of the present disclosure has a significant inhibitory effect on ATX enzyme activity.

測試例2本公開化合物對TGF-β(轉化生長因子β)誘導分泌IL-6的作用 Test Example 2 The effect of the compound of the present disclosure on the secretion of IL-6 induced by TGF-β (transforming growth factor β)

1)實驗目的 1) Experimental purpose

測試本公開化合物對TGF-β(轉化生長因子β)誘導人皮膚成纖維細胞分泌IL-6(白細胞介素6)的抑制作用。 The compound of the present disclosure was tested for its inhibitory effect on TGF-β (transforming growth factor β) induced human skin fibroblasts to secrete IL-6 (interleukin 6).

2)實驗方法 2) Experimental method

將原代人皮膚成纖維細胞(NHDF，PromoCell，#C-12303)用FGM培養基(Fibroblast Growth Medium2，PromoCell，#C-23020)重新懸浮為8000細胞/孔鋪於96孔板(Corning，#3799)內，37℃，5% CO₂培養箱(thermo scientific，#STERI-CYCLEi160)中培養48小時。用FGM培養基(Fibroblast Growth Medium2,PromoCell，#C-23020)將重組人TGF-β(Cell Signaling Technology，#8915LC)配置成10ng/ml。用FGM培養基將待測化合物配製成初始濃度為100μM，10倍稀釋，共8個劑量。去除細胞板中的培養基，分別加入80μl新鮮FGM培養基及10μl不同濃度的待測化合物溶液，置於37℃，5% CO₂培養箱中孵育1.5小時。再加入10ul TGF-β溶液，置於37℃，5% CO₂培養箱中繼續孵育。24小時後收集細胞上清，用ELISA(欣博盛生物，#EHC007.96)檢測上清中IL-6含量並計算其IC₅₀值。 The primary human skin fibroblasts (NHDF, PromoCell, #C-12303) were resuspended in FGM medium (Fibroblast Growth Medium2, PromoCell, #C-23020) to 8000 cells/well and spread on a 96-well plate (Corning, #3799) ), incubate in a 37°C, 5% CO ₂ incubator (thermo scientific, #STERI-CYCLEi160) for 48 hours. Recombinant human TGF-β (Cell Signaling Technology, #8915LC) was configured to 10ng/ml with FGM medium (Fibroblast Growth Medium2, PromoCell, #C-23020). The compound to be tested was prepared with FGM medium to an initial concentration of 100 μM, diluted 10 times, and a total of 8 doses. The medium in the cell plate was removed, and 80 μl of fresh FGM medium and 10 μl of test compound solutions of different concentrations were added, respectively, and incubated in a 37°C, 5% CO ₂ incubator for 1.5 hours. Then add 10ul TGF-β solution and place it in a 37°C, 5% CO ₂ incubator to continue incubating. After 24 hours, the cell supernatant was collected, and the IL-6 content in the supernatant was detected by ELISA (Xinbosheng Bio, #EHC007.96) and its IC ₅₀ value was calculated.

3)數據分析 3) Data analysis

結論：本公開化合物對TGF-β誘導產生IL-6有明顯的抑制作用。 Conclusion: The compound of the present disclosure has a significant inhibitory effect on the production of IL-6 induced by TGF-β.

測試例3本公開化合物的體外人血漿LPA抑制作用 Test Example 3 Inhibition of human plasma LPA in vitro by the compound of the present disclosure

1)實驗目的 1) Experimental purpose

測試本公開化合物藉由抑制ATX酶活性對健康人血漿中LPA 18：2水平的抑制作用。 The compound of the present disclosure was tested for its inhibitory effect on the 18:2 level of LPA in the plasma of healthy people by inhibiting the activity of ATX enzyme.

2)實驗方法 2) Experimental method

收集健康志願者血液至肝素採血管(BD，#367886)中，4℃，3000rpm離心15分鐘，取上清。將血漿按99μl/孔分配至96孔板(Corning，#3788)中。用二甲基亞碸(Sigma，#D2650)將化合物配製成初始濃度為100μM，10倍稀釋，共7個劑量。取1μl分別加入血漿板中，37℃孵育2小時。用Xevo TQ-S三重四極杆串聯質譜儀及ACQUITY UPLC超高效液相色譜系統(Waters)檢測血漿中LPA 18：2含量。以LPA 17：0(Sigma，#857127P)作為內標，基於LPA 18：2的峰面積評價相對量。 The blood of healthy volunteers was collected into heparin blood collection tube (BD, #367886), centrifuged at 3000 rpm at 4°C for 15 minutes, and the supernatant was taken. The plasma was dispensed into 96-well plates (Corning, #3788) at 99 μl/well. The compound was formulated with dimethyl sulfoxide (Sigma, #D2650) to an initial concentration of 100 μM, diluted 10 times, and a total of 7 doses. Add 1 μl to the plasma plate and incubate at 37°C for 2 hours. Detected with Xevo TQ-S triple quadrupole tandem mass spectrometer and ACQUITY UPLC ultra-high performance liquid chromatography system (Waters) The content of LPA 18:2 in plasma. Using LPA 17:0 (Sigma, #857127P) as an internal standard, the relative amount was evaluated based on the peak area of LPA 18:2.

3)測試結果 3) Test results

結論：本公開化合物對健康人血漿中LPA 18：2水平有明顯的抑制作用。 Conclusion: The compound of the present disclosure has a significant inhibitory effect on the level of LPA 18:2 in the plasma of healthy people.

測試例4本公開化合物對hERG鉀電流的阻斷作用 Test Example 4 The blocking effect of the compound of the present disclosure on hERG potassium current

1)實驗目的 1) Experimental purpose

應用全自動膜片鉗在轉染hERG鉀通道的穩定細胞株上測試本公開化合物對hERG鉀電流的阻斷作用。 Fully automatic patch clamp was used to test the blocking effect of the compounds of the present disclosure on hERG potassium currents on stable cell lines transfected with hERG potassium channels.

2)實驗方法 2) Experimental method

2.1)實驗材料與儀器 2.1) Experimental materials and instruments

實驗材料： Experimental Materials:

實驗儀器： laboratory apparatus:

2.2)全自動膜片鉗實驗步驟 2.2) Fully automatic patch clamp experiment procedure

HEK293-hERG穩定細胞株(根據公知技術內部構建)按照1：4的密度在DMEM/HIGH葡萄糖培養基(10%FBS，1.5μg/ml嘌呤黴素二鹽酸鹽)中進行傳代培養，培養48-72小時之內進行全自動膜片鉗實驗。實驗當天將細胞用0.25%胰酶消化後，離心收集細胞，用細胞外液重新懸浮細胞製成細胞懸液。將細胞懸液放置在Patchliner儀器的細胞庫上，Patchliner儀器利用負壓控制器將細胞加到芯片(NPC-16)上，負壓將單個細胞吸引在芯片的小孔上。當形成全細胞模式後，儀器將按照設定的hERG電流電壓程序得到hERG電流，然後儀器自動的由低濃度到高濃度，進行化合物灌流。藉由HEAK Patchmaster，HEAK EPC10膜片鉗放大器(Nanion)和Pathlinersoftware以及Pathcontrol HT軟件提供的數據分析軟件，對化合物各濃度下的電流以及空白對照電流進行分析。 The HEK293-hERG stable cell line (built in-house according to known techniques) was subcultured in DMEM/HIGH glucose medium (10% FBS, 1.5μg/ml puromycin dihydrochloride) at a density of 1:4, and cultured 48 -Perform fully automatic patch clamp experiments within 72 hours. After the cells were digested with 0.25% trypsin on the day of the experiment, the cells were collected by centrifugation, and the cells were resuspended in extracellular fluid to make a cell suspension. will The cell suspension is placed on the cell bank of the Patchliner instrument. The Patchliner instrument uses a negative pressure controller to add cells to the chip (NPC-16), and the negative pressure attracts individual cells to the small holes of the chip. When the whole-cell mode is formed, the instrument will obtain the hERG current according to the set hERG current and voltage program, and then the instrument will automatically change from low concentration to high concentration for compound perfusion. With the data analysis software provided by HEAK Patchmaster, HEAK EPC10 Patch Clamp Amplifier (Nanion), Pathlinersoftware and Pathcontrol HT software, the current at each concentration of the compound and the blank control current are analyzed.

2.3)測試結果 2.3) Test results

本公開化合物對hERG鉀電流的阻斷作用藉由以上的試驗進行測定，測得的IC₅₀值見下表3。 The blocking effect of the compounds of the present disclosure on hERG potassium current was determined by the above test, and the measured IC ₅₀ values are shown in Table 3 below.

結論：本公開化合物對hERG的抑制作用弱，可降低由hERG通路引起的副作用。 Conclusion: The compound of the present disclosure has a weak inhibitory effect on hERG and can reduce the side effects caused by the hERG pathway.

測試例5本公開化合物的溶解度 Test Example 5 The solubility of the compound of the present disclosure

1)實驗材料 1) Experimental materials

試劑：二甲亞碸(分析純)、乙醇(分析純)、乙腈(色譜純)、NaH₂PO₄‧2H₂O(分析純)、乙酸銨(分析純)、牛膽磺酸鈉、卵磷脂、氫氧化鈉、氯化鈉(分析純) Reagents: dimethyl sulfoxide (analytical grade), ethanol (analytical grade), acetonitrile (chromatographic grade), NaH ₂ PO ₄ ‧2H ₂ O (analytical grade), ammonium acetate (analytical grade), sodium taurosulfonate, egg Phospholipids, sodium hydroxide, sodium chloride (analytical grade)

儀器：液相色譜儀(Agilent 1200，美國安捷倫公司)) Instrument: Liquid Chromatograph (Agilent 1200, Agilent Company, USA))

2)實驗步驟 2) Experimental steps

2.1)在FassIF溶液和FesSIF溶液中的溶解測試 2.1) Dissolution test in FassIF solution and FesSIF solution

a.稱取適量待測化合物用DMSO作為溶劑，配製10mM儲備液。精密量取10μL儲備液(濃度10mM，溶解在DMSO中)與990μL有機混合溶劑(通常為DMSO：乙腈：乙醇=1：1：1)於2mL樣品瓶中，混勻，得到澄清的100μM樣品溶液，作為參比溶液。 a. Weigh an appropriate amount of the compound to be tested and use DMSO as a solvent to prepare a 10 mM stock solution. Precisely measure 10μL of stock solution (concentration 10mM, dissolved in DMSO) and 990μL of organic mixed solvent (usually DMSO: acetonitrile: ethanol = 1:1:1) in a 2mL sample bottle and mix well to obtain a clear 100μM sample solution , As a reference solution.

FassIF溶液配製方法如下：在900mL超純水中加入4.441g NaH₂PO₄‧2H₂O、0.348g NaOH顆粒和6.186g NaCl，混合均勻，並加入1M NaOH調節溶液pH至6.5±0.05，用水定容至1000mL，作為溶液(A)。取溶液(A)20mL，溶解0.161g牛膽磺酸鈉(NaTC)和59mg卵磷脂，強力攪拌過夜，形成澄清的膠束溶液，加入溶液(A)至體積為100mL，4℃冷藏備用。 The preparation method of FassIF solution is as follows: Add 4.441g NaH ₂ PO ₄ ‧2H ₂ O, 0.348g NaOH particles and 6.186g NaCl to 900mL ultrapure water, mix well, and add 1M NaOH to adjust the pH of the solution to 6.5±0.05, set with water Volume up to 1000mL, as the solution (A). Take 20 mL of solution (A), dissolve 0.161 g sodium taurosulfonate (NaTC) and 59 mg lecithin, stir vigorously overnight to form a clear micellar solution, add solution (A) to a volume of 100 mL, and refrigerate at 4°C for use.

FesSIF溶液配製方法如下：20.2g NaOH顆粒、43.25g冰醋酸與59.37g氯化鈉用適量超純水溶解並定容至5L，用1M NaOH或1M HCl調節pH至5.0,作為溶液(A)。取溶液(A)25mL溶解0.80652g牛膽磺酸鈉(NaTC)和295.5mg卵磷脂，強力攪拌過夜，形成澄清的膠束溶液，加入溶液(A)至體積為100mL，4℃冷藏備用。 The preparation method of FesSIF solution is as follows: 20.2g NaOH particles, 43.25g glacial acetic acid and 59.37g sodium chloride are dissolved in an appropriate amount of ultrapure water and the volume is adjusted to 5L, and the pH is adjusted to 5.0 with 1M NaOH or 1M HCl as the solution (A). Take 25mL of solution (A) to dissolve 0.80652g sodium taurosulfonate (NaTC) and 295.5mg lecithin, stir vigorously overnight to form a clear micellar solution, add solution (A) to a volume of 100mL, and refrigerate at 4°C for later use.

b.溶解1mg待測樣品至900μL FassIF溶液(或FesSIF溶液),強力混合，平行配製溶液兩份；在37℃水浴中振搖24小時後，在4000rpm離心30min，上清液作為樣品溶液，轉移至液相色譜分析。 b. Dissolve 1mg of the sample to be tested into 900μL FassIF solution (or FesSIF solution), mix vigorously, and prepare two solutions in parallel; shake in a 37°C water bath for 24 hours, centrifuge at 4000rpm for 30min, and use the supernatant as the sample solution. Transfer To liquid chromatography analysis.

2.2)在pH 7.4 PBS緩衝溶液中的溶解測試 2.2) Dissolution test in pH 7.4 PBS buffer solution

a. pH 7.4 PBS溶液的配製：稱取0.57g NaH₂PO₄‧2H₂O、5.55g Na₂HPO₄‧12H₂O和6.48g NaCl，加入超純水，用1M NaOH或1M HCl調節pH至7.4±0.05，加水定容至1L。放置4℃冰箱保存。 a. Preparation of pH 7.4 PBS solution: Weigh 0.57g NaH ₂ PO ₄ ‧2H ₂ O, _{5.55g Na 2} HPO ₄ ‧12H ₂ O and 6.48g NaCl, add ultrapure water, adjust the pH with 1M NaOH or 1M HCl To 7.4±0.05, add water and make the volume to 1L. Store in a refrigerator at 4°C.

b.化合物PBS 7.4溶液的配製：稱取適量待測化合物用DMSO或DMSO：乙腈：乙醇=1：1：1溶解，配製10mM待測化合物儲備液。精密量取10μL 待測化合物儲備液與990μL pH7.4 PBS溶液於2mL樣品瓶中，混勻，最終溶液DMSO濃度為1%(v/v)。該溶液平行配製兩份，在平板床上室溫振搖24小時，在5000rpm離心20min，上清液轉移至液相色譜儀分析。 b. Preparation of compound PBS 7.4 solution: Weigh an appropriate amount of the compound to be tested and dissolve it with DMSO or DMSO: acetonitrile: ethanol=1:1:1 to prepare a 10mM stock solution of the compound to be tested. Precisely measure 10μL The stock solution of the test compound and 990 μL pH7.4 PBS solution were mixed in a 2 mL sample bottle, and the final solution DMSO concentration was 1% (v/v). Two copies of the solution were prepared in parallel, shaken on a flat bed at room temperature for 24 hours, centrifuged at 5000 rpm for 20 minutes, and the supernatant was transferred to a liquid chromatograph for analysis.

c.對照溶液的配製：精密量取10μL待測樣品儲備液(濃度10mM，溶解在DMSO中)與990μL有機混合溶劑(通常為DMSO：乙腈：乙醇=1：1：1)於2mL樣品瓶中，混勻，得到澄清的100μM樣品溶液。用0.45μm的有機相微孔濾膜(浙江歐爾賽斯科技有限公司)過濾，續濾液進液相色譜儀分析。 c. Preparation of control solution: Precisely measure 10μL of the sample stock solution to be tested (concentration 10mM, dissolved in DMSO) and 990μL of organic mixed solvent (usually DMSO: acetonitrile: ethanol = 1:1:1) in a 2mL sample bottle , And mix well to obtain a clear 100μM sample solution. Filter with a 0.45μm organic phase microporous membrane (Zhejiang Oersaisi Technology Co., Ltd.), and then enter the filtrate into the liquid chromatograph for analysis.

3)實驗結果 3) Experimental results

溶解度(μM)=樣品的峰面積/對照的峰面積×對照溶液濃度(μM)×樣品溶液稀釋倍數。 Solubility (μM)=peak area of the sample/peak area of the control×concentration of the control solution (μM)×the dilution factor of the sample solution.

取兩次測量值得平均值作為最終在FassIF溶液、PBS溶液7.4、FesSIF溶液中的溶解度。 Take the average of the two measurements as the final solubility in FassIF solution, PBS solution 7.4, and FesSIF solution.

結論：本公開化合物在FassIF、pH 7.4 PBS和FesSIF溶液中均具有好的溶解度。 Conclusion: The compound of the present disclosure has good solubility in FassIF, pH 7.4 PBS and FesSIF solutions.

藥物代謝動力學評價 Pharmacokinetic evaluation

測試例6、本公開化合物的藥物代謝動力學測試 Test Example 6. Pharmacokinetic test of the compound of the present disclosure

1、摘要 1. Summary

以大鼠為受試動物，應用LC/MS/MS法測定了大鼠灌胃給予實施例3化合物後不同時刻血漿中的藥物濃度。研究本公開化合物在大鼠體內的藥物代謝動力學行為，評價其藥動學特徵。 Using rats as the test animals, the LC/MS/MS method was used to determine the drug concentration in plasma at different times after the rats were given the compound of Example 3 by intragastric administration. To study the pharmacokinetic behavior of the compound of the present disclosure in rats and evaluate its pharmacokinetic characteristics.

2、試驗方案 2. Test plan

2.1 試驗藥品 2.1 Test drug

實施例3化合物。 Example 3 compound.

2.2 試驗動物 2.2 Experimental animals

健康成年SD大鼠4隻，雌雄各半，購自維通利華實驗動物有限公司。 4 healthy adult SD rats, half male and half male, were purchased from Weitong Lihua Experimental Animal Co., Ltd.

2.3 藥物配製 2.3 Drug preparation

稱取一定量實施例3化合物，加入5%DMSO、5%吐溫80和90%生理鹽水配置成無色澄明溶液。 Weigh a certain amount of the compound of Example 3, add 5% DMSO, 5% Tween 80 and 90% normal saline to prepare a colorless and clear solution.

2.4 給藥 2.4 Administration

SD大鼠禁食過夜後灌胃給藥，給藥劑量均為2mg/kg，給藥體積均為10.0mL/kg。 SD rats were fasted overnight and then given by gavage. The dose was 2 mg/kg and the volume was 10.0 mL/kg.

3.操作 3. Operation

大鼠灌胃給藥實施例3化合物，於給藥前及給藥後0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小時由眼眶採血0.2mL，置於EDTA-K2kk抗凝試管中，4℃、10000轉/分鐘離心1分鐘，1小時內分離血漿，於-20℃保存，給藥後2小時進食。 Rats were intragastrically administered the compound of Example 3, and 0.2 mL of blood was collected from the orbit at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after the administration, and placed in EDTA-K2kk for anticoagulation In the test tube, centrifuge at 4°C at 10,000 rpm for 1 minute, separate plasma within 1 hour, store at -20°C, and eat 2 hours after administration.

測定不同濃度的藥物灌胃給藥後大鼠血漿中的待測化合物含量：取給藥後各時刻的大鼠血漿25μL，加入內標溶液喜樹鹼50μL，乙腈200μL，渦旋混合5分鐘，離心15分鐘(3600轉/分鐘)，血漿樣品取上清液3.0μL進行LC/MS/MS分析。 To determine the content of the test compound in rat plasma after gavage of different concentrations of drugs: Take 25μL of rat plasma at each time after administration, add 50μL of internal standard solution camptothecin, 200μL of acetonitrile, vortex and mix for 5 minutes, Centrifuge for 15 minutes (3600 rpm), and take 3.0 μL of the supernatant from the plasma sample for LC/MS/MS analysis.

4、藥物代謝動力學參數結果 4. Results of pharmacokinetic parameters

結論：本公開化合物的藥物代謝吸收良好，具有明顯的藥物代謝動力學優勢。 Conclusion: The compound of the present disclosure has good drug metabolism and absorption, and has obvious pharmacokinetic advantages.

Claims

一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， A compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable Of salt,

其中： in:

n為0、1、2、3、4、5或6； n is 0, 1, 2, 3, 4, 5 or 6;

s為0、1、2或3； s is 0, 1, 2 or 3;

t為0、1、2、3或4；且 t is 0, 1, 2, 3 or 4; and

r為0、1、2或3。 r is 0, 1, 2 or 3.

如請求項1所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環B選自苯基、3員至12員環烷基或3員至8員雜環基，其中該雜環基含有1~3個選自N原子、O原子或S原子的雜原子。 The compound represented by the general formula (I) as described in claim 1 or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, wherein ring B is selected from a phenyl group, a 3-membered to 12-membered cycloalkyl group or a 3-membered to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 atoms selected from N, Heteroatoms of O atoms or S atoms.

如請求項1所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， The compound represented by the general formula (I) as described in claim 1 or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or its pharmaceutically acceptable salt,

其中

選自

、

和

； in

Selected from

,

with

；

g為0、1、2或3； g is 0, 1, 2 or 3;

h為0、1、2或3； h is 0, 1, 2 or 3;

p為0、1、2或3； p is 0, 1, 2 or 3;

q為0、1、2或3；y為0、1、2、3或4； q is 0, 1, 2 or 3; y is 0, 1, 2, 3 or 4;

G¹、G²和R³如請求項1中所定義。 G ¹ , G ² and R ³ are as defined in claim 1.

如請求項1所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽： The compound represented by the general formula (I) as described in claim 1 or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer or Its mixture form, or its pharmaceutically acceptable salt:

其中： in:

p為0、1、2或3； p is 0, 1, 2 or 3;

q為0、1、2或3； q is 0, 1, 2 or 3;

環A、環C、環D、G¹、G²、L¹、R¹~R⁵、n、s和t如請求項1中所定義。 Ring A, ring C, ring D, G ¹ , G ² , L ¹ , R ¹ to R ⁵ , n, s, and t are as defined in claim 1.

如請求項1至4中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中G¹和G²為N原子。 The compound represented by the general formula (I) as described in any one of claims 1 to 4 or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G ¹ and G ² are N atoms.

如請求項1至3和5中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(IIIG)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽： The compound represented by the general formula (I) as described in any one of claims 1 to 3 and 5 or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIIG) or tautomers, mesoisomers, racemates, enantiomers thereof , Diastereoisomers or their mixtures, or their pharmaceutically acceptable salts:

其中： in:

g為0、1、2或3； g is 0, 1, 2 or 3;

h為0、1、2或3； h is 0, 1, 2 or 3;

環A、環C、環D、L¹、R¹~R⁵、n、s和t如請求項1中所定義。 Ring A, ring C, ring D, L ¹ , R ¹ to R ⁵ , n, s, and t are as defined in claim 1.

如請求項1至6中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中L¹為-C(O)-(CH₂)_r-；r選自1、2或3，較佳1。 The compound represented by the general formula (I) as described in any one of claims 1 to 6 or its tautomer, meso, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L ¹ is _{-C (O) - (CH 2} ) r -; r is selected from 1, 2 or 3, preferably 1.

如請求項1至7中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環D為7至11員雙環稠雜環基，其中該雙環稠雜環基含有1~5個選自N原子、O原子或S原子的雜原子，更佳6員/5員、5員/5員或5員/6員雙環稠雜環基，最較佳6員/5員雙環稠雜環基，更佳5員雜芳基/6員雜環基雙環稠雜環基。 The compound represented by the general formula (I) as described in any one of claims 1 to 7 or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring D is a 7 to 11-membered bicyclic fused heterocyclic group, wherein the bicyclic fused heterocyclic group contains 1 to 5 selected from N atoms, O atoms or S Atomic heteroatoms, better 6 members/5 members, 5 members/5 members Or 5-membered/6-membered bicyclic fused heterocyclic group, most preferably 6-membered/5-membered bicyclic fused heterocyclic group, more preferably 5-membered heteroaryl/6-membered heterocyclyl bicyclic fused heterocyclic group.

如請求項1至8中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環A為茚滿基。 The compound represented by the general formula (I) as described in any one of claims 1 to 8 or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a mixture, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is indanyl.

如請求項1至9中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環D為***并吡啶基或***并哌啶基，較佳為如下結構：

或

。 The compound represented by the general formula (I) as described in any one of claims 1 to 9 or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring D is triazolopyridyl or triazolopiperidinyl, preferably the following structure:

or

.

如請求項1至10中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環C為5員雜芳基，其含有1~3個選自N原子、O原子或S原子的雜原子，較佳噁二唑基。 The compound represented by the general formula (I) as described in any one of claims 1 to 10 or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is a 5-membered heteroaryl group, which contains 1 to 3 heteroatoms selected from N atoms, O atoms or S atoms, preferably oxadiazole base.

如請求項1至11中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R¹為氫原子。 The compound represented by the general formula (I) as described in any one of claims 1 to 11 or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom.

如請求項1至12中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R²為氫原子。 The compound represented by the general formula (I) as described in any one of claims 1 to 12 or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom.

如請求項1至13中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁴為氫原子。 The compound represented by the general formula (I) as described in any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom.

如請求項1至14中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(IIIM)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽： The compound represented by the general formula (I) as described in any one of claims 1 to 14 or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIM) or a tautomer, meso, racemate, enantiomer, or non- Enantiomers or their mixture forms, or their pharmaceutically acceptable salts:

其中： in:

R^1a、R^1b各自相同或不同，且各自獨立地選自氫原子、鹵素、烷基、鹵烷基、烷氧基、羥基、羥烷基、氰基、胺基、硝基、羧基、醛基、環烷基、雜環基、芳基和雜芳基； R ^1a and R ^1b are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxyl group, and an aldehyde Group, cycloalkyl, heterocyclyl, aryl and heteroaryl;

e為0、1、2、3或4； e is 0, 1, 2, 3 or 4;

f為0、1或2； f is 0, 1 or 2;

環B、R³、R⁵、t如請求項1中所定義。 Rings B, R ³ , R ⁵ , and t are as defined in claim 1.

如請求項1至15中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R³為氫原子。 The compound represented by the general formula (I) as described in any one of claims 1 to 15 or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom.

如請求項1至16中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽，其為通式(III)、(IIIa)或(IIIb)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、或其可藥用的鹽： The compound represented by the general formula (I) as described in any one of claims 1 to 16 or its tautomer, meso, racemate, enantiomer, diastereomer Form or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III), (IIIa) or (IIIb) or a tautomer, a meso form, a racemate, Enantiomers, diastereomers or their mixture forms, or their pharmaceutically acceptable salts:

其中： in:

g為0、1、2或3； g is 0, 1, 2 or 3;

h為0、1、2或3； h is 0, 1, 2 or 3;

p為0、1、2或3； p is 0, 1, 2 or 3;

q為0、1、2或3； q is 0, 1, 2 or 3;

e為0、1、2、3或4； e is 0, 1, 2, 3 or 4;

f為0、1或2； f is 0, 1 or 2;

R⁵、t如請求項1中所定義。 R ⁵ , t are as defined in claim 1.

如請求項17所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中p為1；q為1或2。 The compound represented by the general formula (I) as described in claim 17 or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, wherein p is 1; q is 1 or 2.

如請求項17所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中g為0、1、2或3，h為0、1、2或3；條件是當g為0時，h為2或3；g為1時，h為1或2；g為2時，h為1或0；g為3時，h為0。 The compound represented by the general formula (I) as described in claim 17 or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, wherein g is 0, 1, 2 or 3, and h is 0, 1, 2 or 3; provided that when g is 0, h is 2 or 3; when g is 1, h When g is 2, h is 1 or 0; when g is 3, h is 0.

如請求項15至19中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R^1a和R^1b為氫原子。 The compound represented by the general formula (I) as described in any one of claims 15 to 19 or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ^1b are hydrogen atoms.

如請求項1至20中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁵為氫原子。 The compound represented by the general formula (I) as described in any one of claims 1 to 20 or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom.

如請求項1至21中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其選自以下任一化合物： The compound represented by the general formula (I) as described in any one of claims 1 to 21 or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds:

一種通式(IIIMA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其可藥用的鹽： A compound represented by the general formula (IIIMA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable Salt:

其中： in:

e為0、1、2、3或4；且 e is 0, 1, 2, 3 or 4; and

f為0、1或2。 f is 0, 1, or 2.

一種通式(IIIA)、(IIIaA)或(IIIbA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其可藥用的鹽： A compound represented by general formula (IIIA), (IIIaA) or (IIIbA) or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:

其中： in:

g為0、1、2或3； g is 0, 1, 2 or 3;

h為0、1、2或3； h is 0, 1, 2 or 3;

p為0、1、2或3； p is 0, 1, 2 or 3;

q為0、1、2或3； q is 0, 1, 2 or 3;

e為0、1、2、3或4；且f為0、1或2。 e is 0, 1, 2, 3, or 4; and f is 0, 1, or 2.

一種如請求項23所述的通式(IIIMA)所示化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其選自以下任一化合物： A compound represented by the general formula (IIIMA) as described in claim 23 or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds:

一種製備通式(IIIM)所示化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： A kind of compound represented by general formula (IIIM) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The method of salt, the method includes:

通式(IIIMA)化合物和通式(IIIB)化合物或其可藥用的鹽，在鹼性條件下發生反應得到通式(IIIM)化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽； The compound of the general formula (IIIMA) and the compound of the general formula (IIIB) or a pharmaceutically acceptable salt thereof react under basic conditions to obtain the compound of the general formula (IIIM) or its tautomer, meso, racemate Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

環B、R^1a、R^1b、R³、R⁵、t、e、f如請求項15中所定義。 Ring B, R ^1a , R ^1b , R ³ , R ⁵ , t, e, and f are as defined in claim 15.

一種製備通式(III)所示化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： A preparation of a compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable The method of salt, the method includes:

通式(IIIA)化合物和通式(IIIB)化合物或其可藥用的鹽，在鹼性條件下發生反應得到通式(III)化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽； Compounds of general formula (IIIA) and compounds of general formula (IIIB) or their pharmaceutically acceptable salts react under basic conditions to obtain compounds of general formula (III) or their tautomers, mesosomes, racemates Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

其中，R^1a、R^1b、R⁵、t、p、q、e、f如請求項17中所定義。 Among them, R ^1a , R ^1b , R ⁵ , t, p, q, e, and f are as defined in claim 17.

一種醫藥組成物，其含有如請求項1至22中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 A pharmaceutical composition containing the compound represented by the general formula (I) as described in any one of claims 1 to 22 or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

一種如請求項1至22中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽、或如請求項28所述的醫藥組成物在製備ATX抑制劑中的用途。 A compound represented by the general formula (I) as described in any one of claims 1 to 22 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28 in the preparation of an ATX inhibitor.

一種如請求項1至22中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽、或如請求項28所述的醫藥組成物在製備預防和/或治療纖維變性疾病、癌症、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系統疾病、心血管疾病、神經變性疾病、皮膚學疾病、代謝疾病、骨髓增生異常綜合症、異常血管生成相關疾病和疼痛的藥物中的用途。 A compound represented by the general formula (I) as described in any one of claims 1 to 22 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 28 is used in the preparation of the prevention and/or treatment of fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, and autoimmune diseases. Use in medicines for diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases, and pain.

一種如請求項1至22中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽、或如請求項28所述的醫藥組成物在製備預防和/或治療具有ATX表達增加的病理學特徵的疾病的藥物中的用途。 A compound represented by the general formula (I) as described in any one of claims 1 to 22 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28 in the preparation of a medicine for preventing and/or treating diseases with the pathological characteristics of increased ATX expression.

如請求項31所述的用途，其中該具有ATX表達增加的病理學特徵的疾病選自：纖維變性疾病、癌症、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系統疾病、心血管疾病、神經變性疾病、皮膚學疾病、代謝疾病、骨髓增生異常綜合症、異常血管生成相關疾病和疼痛；較佳為纖維變性疾病和癌症。 The use according to claim 31, wherein the disease with the pathological characteristics of increased ATX expression is selected from: fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases , Neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases and pain; preferably fibrotic diseases and cancer.

如請求項30或32所述的用途，其中該纖維變性疾病選自肺纖維化、特發性肺纖維化、肝纖維化和硬皮病，該癌症選自腎癌和胰腺癌。 The use according to claim 30 or 32, wherein the fibrotic disease is selected from pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma, and the cancer is selected from renal cancer and pancreatic cancer.