TW201835079A - 6-pyrazol-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide derivatives, a preparation method thereof and pharmaceutical use thereof - Google Patents

Abstract

The present invention belongs to field of medicine, which relates to 6--pyrazol-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide derivatives, a preparation method thereof and pharmaceutical use thereof. Specifically, The present invention relates to 6--pyrazol-[1,2,4]triazolo[4,3-a] pyridine-3-carboxamide derivatives shown by general formula (I), a preparation method thereof, pharmaceutical compositions containing the derivatives and use of treatment diseases. Particularly, the use of a TGF-[beta] receptor kinase inhibitor and the use in the manufacture of a medicament for treating, preventing or reducing over expression of TGF-[beta] mediated tumour. The definition of each substituent group in general formula (I) is the same as the definition in the description.

Description

6-吡唑-[1,2,4]***並[4,3- a ]吡啶-3-醯胺類衍生物、其製備方法及其在醫藥上的應用6-pyrazole- [1,2,4] triazolo [4,3-a] pyridine-3-amidine derivatives, preparation method and application thereof in medicine

本發明屬於醫藥領域，涉及一種新的6-吡唑-[1,2,4]***並[4,3-a]吡啶-3-醯胺類衍生物、其製備方法及含有該衍生物的醫藥組成物及其作為治療劑特別是作為TGF-β受體激酶的抑制劑的用途和在製備治療、預防或減少由TGF-β過度表達介導的腫瘤的藥物中的用途。 The invention belongs to the field of medicine, and relates to a novel 6-pyrazole- [1,2,4] triazolo [4,3- a ] pyridine-3-amidine derivative, a preparation method thereof, and a derivative containing the same. Pharmaceutical composition and its use as a therapeutic agent, especially as an inhibitor of TGF-β receptor kinase, and its use in the manufacture of a medicament for treating, preventing or reducing tumors mediated by TGF-β overexpression.

轉化生長因子TGF-β(Transforming Growth Factor β)是二聚多肽生長因子超家族中的一員，其包括例如活化素、抑制素、骨形成蛋白(Bone morphogenetic proteins，BMPs)、生長和分化因子(Growth differentiation factors，GDFs)和繆勒氏管抑制物(Müllerian-inhibiting substance，MIS)。 Transforming Growth Factor TGF-β (Transforming Growth Factor β) is a member of the dimeric polypeptide growth factor superfamily, which includes, for example, activin, inhibin, Bone morphogenetic proteins (BMPs), growth and differentiation factors (Growth differentiation factors (GDFs) and Müllerian-inhibiting substance (MIS).

TGF-β有TGF-β1、TGF-β2和TGF-β3三種亞型，它們參與細胞增殖與分化、傷口癒合、細胞外基質產生和免疫 抑制的調控。參見如Massague,J.Ann.Rev,Cell.Biol.6：594-641(1990)；Roberts,A.B.Peptide Growth Factor and Their receptors,95：419-472 Berlin：Springer-Verlag(1990)；Roberts,A.B.和Sporn M.B.Growth Factor 8：1-9(1993)；以及Alexandrow,M.G.,Moses,H.L.Cancer Res.55：1452-1457(1995)。TGF-β的三種亞型與其受體一起存在於大多數的細胞中。每種TGF-β亞型被合成作為前體蛋白，該前體蛋白在細胞內裂解成C-端區域(潛伏相關肽latency associated peptide，LAP)和N-端部分，被稱為成熟或活性TGF-β。從細胞中分泌前，LAP一般與成熟TGF-β以非共價的方式連接。LAP-TGF-β複合體不能與TGF-β受體結合且不具有生物學活性。TGF-β通常藉由多種機制包括例如，與血小板反應蛋白-1或纖溶酶相互作用，從複合體中釋放出來(並具有活性)。TGF-β1藉由兩種高保守性單跨膜絲胺酸/蘇胺酸激酶轉導信號，即I型(ALK5)和II型TGF-β受體。一旦配體誘發低聚化，II型受體過度磷酸化ALK5GS區中的絲胺酸/蘇胺酸殘基，藉由創建Smad蛋白的結合位點引起ALK5的活化。活化的ALK5繼而磷酸化C-末端SSXS-基序處的Smad2和Smad3蛋白，從而導致它們從受體中離解，並且與Smad4生成異質複合體(heteromeric complex)。Smad複合體易位於核，與特異性DNA-結合性輔因子和輔調控劑裝配，最終活化細胞外基質組分和基質-降解性蛋白酶抑制劑的轉錄。 TGF-β has three subtypes of TGF-β1, TGF-β2 and TGF-β3, and they are involved in the regulation of cell proliferation and differentiation, wound healing, extracellular matrix production, and immunosuppression. See, e.g., Massague, J. Ann. Rev, Cell. Biol. 6: 594-641 (1990); Roberts, ABPeptide Growth Factor and Their receptors, 95: 419-472 Berlin: Springer-Verlag (1990); Roberts, AB And Sporn MBGrowth Factor 8: 1-9 (1993); and Alexandrow, MG, Moses, HLCancer Res. 55: 1452-1457 (1995). The three isoforms of TGF-β are present in most cells with their receptors. Each TGF-β isoform is synthesized as a precursor protein, which is cleaved into the C-terminal region (latency associated peptide (LAP)) and N-terminal part in the cell, which is called mature or active TGF -β. Before secretion from cells, LAP is generally linked to mature TGF-β in a non-covalent manner. LAP-TGF-β complex cannot bind TGF-β receptor and has no biological activity. TGF-β is typically released (and active) from the complex by a variety of mechanisms including, for example, interaction with thrombospondin-1 or plasmin. TGF-β1 transduces signals through two highly conserved single-transmembrane serine / threonine kinases, namely type I (ALK5) and type II TGF-β receptors. Once the ligand induces oligomerization, type II receptors overphosphorylate serine / threonine residues in the ALK5GS region, causing activation of ALK5 by creating a binding site for the Smad protein. Activated ALK5 in turn phosphorylates the Smad2 and Smad3 proteins at the C-terminal SSXS-motif, causing them to dissociate from the receptor and generate a heteromeric complex with Smad4. The Smad complex is easily located in the nucleus and assembles with specific DNA-binding cofactors and co-regulators, ultimately activating the transcription of extracellular matrix components and matrix-degrading protease inhibitors.

TGF-β信號通路的極度活躍是許多人類疾病(如細胞 外基質的過量沉積、炎症應答的異常高水準、纖維變性病症以及進行性癌)的原因。在各種腫瘤的晚期，腫瘤細胞和腫瘤內基質細胞一般過度表達TGF-β。這引起血管生成與細胞運動的刺激、免疫系統的抑制和腫瘤細胞與細胞外基質的相互作用增加(例如，Hojo,M.等人，Nature 397：530-534(1999))。所以，腫瘤細胞變得更有侵襲性，轉移至遠側器官例如，Maehara,Y.等人，J.Clin.Oncol.17：607-614(1999)；Picon,A.等人，Cancer Epidemiol.Biomarkers Prev.7：497-504(1998))。 The extreme activity of the TGF-β signaling pathway is responsible for many human diseases such as excessive deposition of extracellular matrix, abnormally high levels of inflammatory response, fibrotic conditions, and progressive cancer. In the advanced stages of various tumors, tumor cells and intrastromal stromal cells generally overexpress TGF-β. This causes stimulation of angiogenesis and cell movement, suppression of the immune system, and increased interaction of tumor cells with the extracellular matrix (eg, Hojo, M. et al., Nature 397: 530-534 (1999)). Therefore, tumor cells become more aggressive and metastasize to distant organs. For example, Maehara, Y. et al., J. Clin. Oncol. 17: 607-614 (1999); Picon, A. et al., Cancer Epidemiol. Biomarkers Prev. 7: 497-504 (1998)).

大量實驗性動物研究證明了TGF-β的腎小球表達與纖維化之間的關聯，包括增殖性腎小球性腎炎的Thy-1大鼠模型、兔抗-GBM腎小球性腎炎和局灶性節段性腎小球硬化的5/6腎切除大鼠模型，最近已有評述(例如，Bitzer,M.等，Kidney Blood Press.Res.21：1-12(1998))。TGF-β的中和抗體改進Thy-1腎炎模型中的腎小球組織學(如，Border,W.A.等人，Nature 346：371-374(1990))。 A large number of experimental animal studies have demonstrated the correlation between glomerular expression of TGF-β and fibrosis, including Thy-1 rat model of proliferative glomerulonephritis, rabbit anti-GBM glomerulonephritis and local A 5/6 nephrectomy rat model of focal segmental glomerulosclerosis has been recently reviewed (eg, Bitzer, M. et al., Kidney Blood Press. Res. 21: 1-12 (1998)). TGF-β neutralizing antibodies improve glomerular histology in a Thy-1 nephritis model (eg, Border, W.A. et al., Nature 346: 371-374 (1990)).

TGF-β1及其受體在受損血管和纖維增殖性血管損傷中被過度表達，引起細胞外基質的過度產生(例如，Saltis,J.等人，Clin.Exp.Pharmacol.Physiol.23：193-200(1996)；McCaffrey,T.A.等人，J.Clin.Invest.96：2667-2675(1995))。 TGF-β1 and its receptors are overexpressed in damaged blood vessels and fibroproliferative vascular injuries, causing excessive production of extracellular matrix (eg, Saltis, J. et al., Clin. Exp. Pharmacol. Physiol. 23: 193 -200 (1996); McCaffrey, TA et al., J. Clin. Invest. 96: 2667-2675 (1995)).

TGF-β2水準在大多數患有少年青光眼的眼房水腫瘤眼中和幾乎一半患有原發性開放角度青光眼(POAG)的眼中都有增加(例如，Picht,G.等人，Graefes Arch.Clin.Exp. Ophthalmol.239：199-207(2001))。 TGF-β2 levels are increased in most eyes with aqueous humor tumors in juvenile glaucoma and almost half with primary open-angle glaucoma (POAG) (for example, Picht, G. et al., Graefes Arch. Clin Exp. Ophthalmol. 239: 199-207 (2001)).

因此希望開發出對TGF-β家族成員的抑制劑來預防和/或治療包括這種信號通路的疾病。公開的TGF-β家族成員受體的調節劑(如拮抗劑)專利申請包括WO2004111046、WO2012000595、WO2012002680、WO2013009140、WO2016106266。 It is therefore desirable to develop inhibitors of members of the TGF-β family to prevent and / or treat diseases including this signaling pathway. Published patent applications for modulators (such as antagonists) of TGF-β family member receptors include WO2004111046, WO2012000595, WO2012002680, WO2013009140, WO2016106266.

為了達到更好的治療效果的目的，更好的滿足市場需求，本發明將提供一種新型結構的高效低毒的TGF-β受體激酶抑制劑，並發現藉由引入醯胺基，可使得此類結構的化合物具有藥物代謝性質良好的特點。 In order to achieve the goal of better therapeutic effect and better meet market demand, the present invention will provide a novel structure of a highly efficient and low toxicity TGF-β receptor kinase inhibitor. Compounds with a similar structure have the characteristics of good drug metabolism.

本發明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醫藥上可接受之鹽， An object of the present invention is to provide a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof. Or a pharmaceutically acceptable salt thereof,

其中：環A為芳基或雜芳基；R¹選自氫原子、烷基、鹵烷基、羥基、羥烷基、胺基、 環烷基、雜環基、芳基、雜芳基、-C(O)OR⁶、-C(O)R⁶、-S(O)_mR⁶、-NR⁷R⁸、-S(O)_mNR⁷R⁸和-C(O)NR⁷R⁸，其中該烷基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、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、雜芳基、-C(O)OR⁶、-C(O)R⁶、-S(O)_mR⁶、-NR⁷R⁸、-S(O)_mNR⁷R⁸和-C(O)NR⁷R⁸中的一個或多個取代基所取代；R²相同或不同，且各自獨立地選自氫原子、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、雜芳基、-C(O)OR⁶、-C(O)R⁶、-S(O)_mR⁶、-NR⁷R⁸、-S(O)_mNR⁷R⁸和-C(O)NR⁷R⁸；R³相同或不同，且各自獨立地選自氫原子、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；R⁴和R⁵各自獨立地選自氫原子、烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基，其中該烷基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自烷基、烷氧基、鹵素、胺基、氰基、硝基、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；或者，該R⁴和R⁵與相連接的氮原子一起形成雜環基，其中該雜環基內含有1~2個相同或不同選自N、O和S的雜原子，並且該雜環基視需要被選自烷基、烷氧基、鹵素、胺基、氰基、硝基、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； R⁶選自氫原子、烷基、胺基、鹵烷基、環烷基、雜環基、芳基和雜芳基；R⁷和R⁸各自獨立地選自氫原子、烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基，其中該烷基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自烷基、烷氧基、鹵素、胺基、氰基、硝基、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；或者，該R⁷和R⁸與相連接的氮原子一起形成雜環基，其中該雜環基內含有1~2個相同或不同選自N、O和S的雜原子，並且該雜環基視需要被選自烷基、烷氧基、鹵素、胺基、氰基、硝基、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；n為0、1、2、3或4；s為0、1、2或3；且m為0、1或2。 Wherein: ring A is aryl or heteroaryl; R ^{1 is} selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyl group, hydroxyalkyl group, amino group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ , wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano , Amine, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ are substituted by one or more substituents; R ^{2 is the} same or different, and each is independently selected from a hydrogen atom, a halogen , Alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ ; R ^{3 is the} same or different, And each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, Cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl; each of R ⁴ and R ^{5 is} independently selected from a hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclic Group, aryl group, and heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently selected from alkyl, alkoxy, halogen, amine, and cyano , Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted with one or more substituents; or, R ⁴ and R ⁵ together with the nitrogen atom to which they are attached A heterocyclic group is formed, wherein the heterocyclic group contains 1 to 2 heteroatoms which are the same or different and are selected from N, O and S, and the heterocyclic group is optionally selected from alkyl, alkoxy, halogen, and amine Group, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted with one or more substituents; R ^{6 is} selected from a hydrogen atom, an alkyl group, and an amine Group, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R ⁷ and R ⁸ are each independently selected from a hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aromatic And heteroaryl, where the alkyl , Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, and cycloalkyl , Heterocyclyl, aryl, and heteroaryl are substituted with one or more substituents; or, R ⁷ and R ⁸ together with the nitrogen atom to form a heterocyclic group, wherein the heterocyclic group contains 1 ~ 2 same or different heteroatoms selected from N, O, and S, and the heterocyclic group is optionally selected from alkyl, alkoxy, halogen, amine, cyano, nitro, hydroxyl, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted with one or more substituents; n is 0, 1, 2, 3, or 4; s is 0, 1, 2, or 3; and m Is 0, 1, or 2.

在本發明的一個較佳的實施方案中，該通式(I)所示的化合物，其中環A為雜芳基，較佳為5員或6員雜芳基，更佳為吡啶基。 In a preferred embodiment of the present invention, the compound represented by the general formula (I), wherein ring A is a heteroaryl group, preferably a 5-membered or 6-membered heteroaryl group, and more preferably a pyridyl group.

在本發明的一個較佳的實施方案中，該通式(I)所示的化合物，其為通式(II)所示的化合物： In a preferred embodiment of the present invention, the compound represented by the general formula (I) is a compound represented by the general formula (II):

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醫藥上可接受之鹽，其中：R¹~R⁵、n和s如通式(I)中所定義。 Or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R ¹ to R ⁵ , N and s are as defined in general formula (I).

在本發明的一個較佳的實施方案中，該通式(I)所示的化合物，其中R⁴和R⁵均為氫原子。 In a preferred embodiment of the present invention, the compound represented by the general formula (I), wherein R ⁴ and R ⁵ are both hydrogen atoms.

在本發明的一個較佳的實施方案中，該通式(I)所示的化合物，其為通式(III)所示的化合物： In a preferred embodiment of the present invention, the compound represented by the general formula (I) is a compound represented by the general formula (III):

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醫藥上可接受之鹽，其中：R¹和R²如通式(I)中所定義。 Or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ² As defined in general formula (I).

在本發明的一個較佳的實施方案中，該通式(I)所示的化合物，其中R¹選自氫原子、烷基、環烷基和雜環基，較佳為氫原子、C_1-6烷基、3至6員環烷基、3至6員雜環基，更佳為氫原子、甲基、乙基、異丙基、環丙基、環丁基、環戊基、環己基、四氫呋喃基或四氫吡喃基。 In a preferred embodiment of the present invention, the compound represented by the general formula (I), wherein R ^{1 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group, and is preferably a hydrogen atom, C _{1 -6} alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclic group, more preferably hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, tetrahydrofuryl or tetrahydropyranyl.

在本發明的一個較佳的實施方案中，該通式(I)所示的化合物，其中R²為氫原子或烷基，較佳為氫原子、甲基、乙基、丙基、異丙基或丁基。 In a preferred embodiment of the present invention, the compound represented by the general formula (I), wherein R ² is a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group. Or butyl.

在本發明的一個較佳的實施方案中，該通式(I)所示的化合物，其中R³為氫原子。 In a preferred embodiment of the present invention, the compound represented by the general formula (I), wherein R ³ is a hydrogen atom.

本發明的化合物包括其所有構象異構體，例如順式和反式異構體；以及其所有旋光異構體和立體異構體及其混合物。本發明的化合物具有不對稱中心，因此存在不同的對映異構體與非對映異構體。本發明涉及本發明化合物的用途，和可以採用和含有它們的所有醫藥組成物和治療方法。本發明涉及所有這類異構體及其混合物的用途。 The compounds of the present invention include all their conformational isomers, such as the cis and trans isomers; and all their optical isomers and stereoisomers, and mixtures thereof. The compounds of the present invention have asymmetric centers and therefore exist in different enantiomers and diastereomers. The present invention relates to the use of the compounds of the present invention, and to all pharmaceutical compositions and methods of treatment which can be employed and contain them. The invention relates to the use of all such isomers and mixtures thereof.

本發明的典型化合物包括但不限於： Typical compounds of the invention 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醫藥上可接受之鹽。 Or a tautomer, a meso, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof.

本發明的另一方面涉及一種製備通式(I)所示的化合物的方法，該方法包括： Another aspect of the present invention relates to a method for preparing a compound represented by the general formula (I), the method comprising:

通式(I-A)的化合物和通式(I-B)的化合物反應，得到通式(I)的化合物，其中：W為硼酸基或4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基；X為鹵素，較佳為溴； 環A、R¹~R⁵、n和s如通式(I)中所定義。 A compound of the general formula (IA) and a compound of the general formula (IB) are reacted to obtain a compound of the general formula (I), wherein: W is a boric acid group or 4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl; X is halogen, preferably bromine; rings A, R ¹ to R ⁵ , n and s are as defined in general formula (I).

本發明的另一方面涉及一種製備通式(I)所示的化合物的方法，該方法包括： Another aspect of the present invention relates to a method for preparing a compound represented by the general formula (I), the method comprising:

通式(I-Aa)的化合物和通式(I-Bb)的化合物反應，得到通式(I)的化合物，其中：W為硼酸基或4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基；X為鹵素，較佳為溴；環A、R¹~R⁵、n和s如通式(I)中所定義。 A compound of the general formula (I-Aa) and a compound of the general formula (I-Bb) are reacted to obtain a compound of the general formula (I), wherein: W is a boric acid group or 4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl; X is halogen, preferably bromine; rings A, R ¹ to R ⁵ , n and s are as defined in general formula (I).

本發明的另一方面涉及一種醫藥組成物，該醫藥組成物含有治療有效劑量的通式(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、或其混合物形式或醫藥上可接受之鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。本發明還涉及一種製備上述組合物的方法，其包括將通式(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、或其醫藥上可接受之鹽與一 種或多種藥學上可接受的載體、稀釋劑或賦形劑相混合。 Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective dose of a compound represented by the general formula (I) or a tautomer, a meso, a racemate, an enantiomer thereof. Conformers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The present invention also relates to a method for preparing the above composition, which comprises converting a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer The isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is mixed with one or more pharmaceutically acceptable carriers, diluents, or excipients.

本發明進一步涉及通式(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，在製備用於抑制TGF-β(特別是人類TGF-β)信號傳導途徑的藥物中的用途。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a medicinal composition containing the same for the preparation of a medicament for inhibiting the TGF-β (especially human TGF-β) signaling pathway.

本發明進一步涉及通式(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，在製備用於治療、預防或減少腫瘤細胞(特別是人類腫瘤細胞)轉移的藥物中的用途。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a medicinal composition comprising the same for the preparation of a medicament for treating, preventing or reducing metastasis of tumor cells (especially human tumor cells).

本發明進一步涉及通式(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在製備用於治療、預防或減少由TGF-β過度表達介導的腫瘤的藥物中的用途，特別是藉由抑制人類TGF-β信號傳導途徑來治療、預防或減少由TGF-β過度表達介導的腫瘤的藥物中的用途。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a medicinal composition comprising the same in the manufacture of a medicament for treating, preventing or reducing a tumor mediated by TGF-β overexpression, in particular by treating it by inhibiting the human TGF-β signaling pathway Use of a medicament for preventing or reducing tumors mediated by TGF-β overexpression.

在本發明文中，該治療、預防或減輕(特別是人類的)的疾病選自：心血管疾病、各類炎症、腫瘤、各種病因的纖維化、血管損傷、腎病、肝功能障礙、肺病、成人呼吸窘迫綜合症、內膜增厚、眼部疾病、發生在由創傷或手術傷口所致傷口癒合期間的過度性或肥厚性真皮瘢痕或瘢痕疙瘩形成、腹膜與皮下粘連、硬皮病、纖維硬化、進行性 系統性硬化病、骨質疏鬆、潰瘍、神經系統功能減低、男性***功能障礙、佩羅尼氏病、杜普伊特倫氏攣縮、阿爾茨海默氏病和雷諾氏綜合症。 In the present invention, the disease to be treated, prevented or reduced (especially for humans) is selected from the group consisting of: cardiovascular disease, various inflammations, tumors, fibrosis of various etiologies, vascular injury, kidney disease, liver dysfunction, lung disease, adults Respiratory Distress Syndrome, Endometrial Thickening, Eye Diseases, Excessive or Hypertrophic Dermal Scars or Keloids Occuring During Wound Healing Caused by Trauma or Surgical Wounds, Peritoneal and Subcutaneous Adhesion, Scleroderma, Fibrosis , Progressive systemic sclerosis, osteoporosis, ulcers, decreased nervous system function, male erectile dysfunction, Peyronie's disease, Dupuytren's contracture, Alzheimer's disease and Raynaud's syndrome.

本發明進一步涉及通式(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，在製備用於治療、預防或減輕(特別是人類的)的上述疾病的藥物中的用途。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a medicinal composition comprising the same for the preparation of a medicament for treating, preventing or alleviating the above-mentioned diseases (especially for humans).

本發明進一步涉及一種治療、預防或減少人類腫瘤細胞轉移的方法，其包括給予所需患者治療有效量的通式(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。 The invention further relates to a method for treating, preventing or reducing human tumor cell metastasis, which comprises administering a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, meso, racemic Rotates, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same.

本發明進一步涉及一種治療、預防或減少由TGF-β過度表達介導的腫瘤的方法，特別是藉由抑制TGF-β信號傳導途徑來治療、預防或減少由TGF-β過度表達介導的腫瘤的方法，其包括給予所需患者治療有效量的通式(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。 The invention further relates to a method for treating, preventing or reducing tumors mediated by TGF-β overexpression, in particular by treating, preventing or reducing tumors mediated by TGF-β overexpression by inhibiting TGF-β signaling pathway Method comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

本發明進一步涉及一種治療、預防或減輕(特別是人類的)選自上述疾病的方法，其包括給予所需患者治療有效量的通式(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。 The present invention further relates to a method for treating, preventing or alleviating (especially human) diseases selected from the above, which comprises administering to a desired patient a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, Racemates, racemates, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same.

本發明進一步涉及一種抑制TGF-β(特別是人類TGF-β)信號傳導途徑的方法，其包括給予所需患者治療有效量的通式(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。 The invention further relates to a method for inhibiting the TGF-β (especially human TGF-β) signaling pathway, which comprises administering a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, Racemates, racemates, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same.

本發明進一步涉及一種通式(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、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物，其作用藥物。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salt or medicinal composition containing it, and its action medicine.

本發明進一步涉及一種通式(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、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物，其作用TGF-β受體激酶抑制劑，特別是TGF-β受體I(TGF-βRI)激酶抑制劑。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition containing the same acts as a TGF-β receptor kinase inhibitor, especially a TGF-β receptor I (TGF-βRI) kinase inhibitor.

本發明進一步涉及一種通式(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、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物，其用於治療、預防或減少腫瘤細胞(特別是人類腫瘤細胞)轉移。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salt or pharmaceutical composition containing it is used for treating, preventing or reducing metastasis of tumor cells, especially human tumor cells.

本發明進一步涉及一種通式(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、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物，其用於治療、預防或減少由TGF-β過度表達介導的 腫瘤，特別是藉由抑制TGF-β信號傳導途徑來治療、預防或減少由TGF-β過度表達介導的腫瘤。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Its pharmacologically acceptable salt or pharmaceutical composition containing the same is used for treating, preventing or reducing tumors mediated by TGF-β overexpression, especially by inhibiting TGF-β signaling pathway to treat, prevent or reduce TGF-β overexpression mediates tumors.

本發明進一步涉及一種通式(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、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物，其用於治療、預防或減輕(特別是人類的)的上述的疾病。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salt or a pharmaceutical composition containing the same is used for treating, preventing or alleviating the above-mentioned diseases (especially human).

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合物，此類組合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，粘合劑，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 active ingredient-containing pharmaceutical composition 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 Tincture. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide pleasing looks And delicious medicinal preparations. Tablets contain the active ingredients 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 can be uncoated or they can 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 over a longer period.

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 formulations may also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an 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 the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension 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 formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. The sweeteners and flavoring agents described above can be added to provide a palatable formulation. These compositions can be preserved by the addition of antioxidants.

本發明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 invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

本發明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。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，最好按可保持本發明化合物恒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 invention may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection solution or microemulsion may be injected into the bloodstream of the patient by local large-volume injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of a compound of the invention. To maintain this constant concentration, continuous intravenous drug delivery devices can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

本發明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 invention may be in the form of a sterile injectable water or oil suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, a sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blending fixing oil can be used. In addition, fatty acids can also be prepared for injection.

可按用於直腸給藥的栓劑形式給予本發明化合物。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 invention may 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 therefore will dissolve 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)的日用量或醫藥上可接受之鹽的種類可以根據傳統的治療方案來驗證。 As known to those skilled in the art, the dosage of a drug depends on a number of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the patient's health, the patient's behavior, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc .; In addition, the optimal treatment such as the mode of treatment, the daily dosage of the general compound (I) or the pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan.

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, terms used in the specification and the scope of patent applications 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，該取代基較佳獨立地視需要選自烷基、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、雜環基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、C(O)OR⁶、-C(O)R⁶、-S(O)_mR⁶、-NR⁷R⁸、-S(O)_mNR⁷R⁸和-C(O)NR⁷R⁸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 an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 Carbon atom alkyl. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third 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-diethyl-pentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl group, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third butyl, Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Methyl, 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 Pentyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently selected from alkyl, alkenyl, alkynyl, Alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , Cycloalkylthio, heterocycloalkylthio, C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ are substituted with one or more substituents.

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，更佳包含3至10個碳原子，最佳包含3至6個碳原子。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，較佳為環丙基、環丁基、環戊基和環己基；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 contains 3 to 12 carbon atoms, and more preferably contains 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Group, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl.

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，但沒有一個環具有完全共軛的π電子系統。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 with 5 to 20 members of a single ring sharing a carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated Π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Spirocycloalkyl is divided into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings, preferably monospirocycloalkyl and bispirocycloalkyl . More preferably, it is 4/4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members, or 5 members / 6 members monospirocycloalkyl. Non-limiting examples of spirocycloalkyl 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用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，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更較佳為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，更較佳為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 a 5 to 20 member, each ring in the system and the other rings in the system share a pair of full carbon polycyclic groups adjacent to each other, where one or more rings may contain one or Multiple double bonds, but none of the rings have a completely conjugated π-electron system. It is preferably 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl 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，但沒有一個環具有完全共軛的π電子系統。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 a full-carbon polycyclic group of 5 to 20 members in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete Conjugate π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

該環烷基環可以稠合於芳基、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、苯並環庚烷基等。環烷基可以是視需要取代的或非取代的，當被取代時，取代基較佳為獨立地視需要選自烷基、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、C(O)OR⁶、-C(O)R⁶、-S(O)_mR⁶、-NR⁷R⁸、-S(O)_mNR⁷R⁸和-C(O)NR⁷R⁸中的一個或多個取代基所取代。 The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, and alkylamine. Group, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclothio Base, C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ is substituted with 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，其中1~4個是雜原子；更佳雜環基包含3至10個環原子，最佳為雜環基包含3至6個環原子。單環雜環基的非限制性實例包括氧雜環丁基、氮雜環丁基、四氫呋喃基、四氫吡喃基、吡咯基、哌啶基、哌嗪基、嗎啉基、硫代嗎啉基、高哌嗪基和等，較佳為氮雜環丁基、氧雜環丁基、吡咯基和哌啶基；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 / partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O ) heteroatoms of _m (where m is an integer from 0 to 2), excluding ring parts of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably a heterocyclic group contains 3 to 10 ring atoms, and most preferably a heterocyclic group contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl include oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, thio? Phosphono, homopiperazinyl and Etc., azacyclobutyl, oxetanyl, pyrrolyl and piperidinyl are preferred; 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，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更較佳為7至10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，較佳為單螺環烷基和雙螺環烷基。更較佳為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 "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which 5 to 20 members of a single ring share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O ) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a completely conjugated π-electron system. It is preferably 6 to 14 members, and more preferably 7 to 10 members. Spiro heterocyclyl is divided into monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings, preferably monospirocycloalkyl and bispirocycloalkyl . More preferred are 4-membered / 4-membered, 4-membered 5-membered, 4-membered-6-membered, 5-membered 5-membered, or 5-membered / 6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl 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用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，但沒有一個環具有完全共軛的π電子系統，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10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 heterocyclyl" refers to a polycyclic heterocyclic group of 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, but none of the rings have a completely conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) _m (where m is an integer from 0 to 2), and the remaining rings Atoms are carbon. 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 fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5 member / 5 member or 5 member / 6 member bicyclic fused heterocyclic group . Non-limiting examples of fused heterocyclyl 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，但沒有一個環具有完全共軛的π電子系統，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10員。7至10員。根據組成環的數目可以分為雙環、三環、四環或多環橋雜環基，較佳為雙環、三環或四環，更佳為雙環或三環。橋雜環基的非限制性實例包括： The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete A y-electron system of a yoke in which one or more ring atoms are heteroatoms 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 10 members. 7 to 10 members. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridge heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyls include:

該雜環基環可以稠合於芳基、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 may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:

雜環基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地視需要選自烷基、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、C(O)OR⁶、-C(O)R⁶、-S(O)_mR⁶、-NR⁷R⁸、-S(O)_mNR⁷R⁸和-C(O)NR⁷R⁸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 the group consisting of alkyl, alkenyl, alkynyl, and alkoxy Alkyl, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Cycloalkylthio, heterocycloalkylthio, C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ are substituted with one or more substituents.

術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團，較佳為6至10員，例如苯基和萘基。該芳基環可以稠合於雜 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 14 membered all-carbon monocyclic or fused polycyclic (i.e., ring sharing a pair of adjacent carbon atom pairs) group, preferably 6 to 10 members, having a conjugated pi-electron system, such as Phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples 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，其獨立地視需要選自烷基、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、C(O)OR⁶、-C(O)R⁶、-S(O)_mR⁶、-NR⁷R⁸、-S(O)_mNR⁷R⁸和-C(O)NR⁷R⁸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 the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkanethio Group, heterocycloalkylthio, C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and- C (O) NR ⁷ R ⁸ is substituted with one or more substituents.

術語“雜芳基”指包含1至4個雜原子、5至14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，更佳為5員或6員，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、吡唑基、四唑基等。該雜芳基環可以稠合於芳基、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 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, Pyrazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

雜芳基可以是視需要取代的或非取代的，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、C(O)OR⁶、-C(O)R⁶、-S(O)_mR⁶、-NR⁷R⁸、-S(O)_mNR⁷R⁸和-C(O)NR⁷R⁸中的一個或多個取代基所取代。 Heteroaryl 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 Thio, heterocycloalkylthio, C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ is substituted with one or more substituents.

術語“烷氧基”指-O-(烷基)和-O-(非取代的環烷基)，其中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。烷氧基可以是視需要取代的或非取代的，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、胺基、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、C(O)OR⁶、-C(O)R⁶、-S(O)_mR⁶、-NR⁷R⁸、-S(O)_mNR⁷R⁸和-C(O)NR⁷R⁸中的一個或多個取代基所取代。 The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy 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 alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, amine, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , Cycloalkylthio, heterocycloalkylthio, C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ are substituted with one or more substituents.

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, wherein the alkyl group is as defined above.

術語“鹵代烷基”指烷基被一個或多個鹵素取代，其中烷基如上所定義。 The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

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

術語“巰基”指-SH基團。 The term "mercapto" refers to the -SH 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“氧代基”指=O。 The term "oxo" refers to = O.

“視需要”或“視需要地”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地場合。例如，“視需要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。 "As needed" or "as needed" means that the event or environment described later can, but does not have to occur, and the description includes situations where the event or environment occurs or does not occur. For example, "heterocyclic group substituted with an alkyl group as necessary" means that the alkyl group may but need not exist, and the description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with 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，更較佳為1~3個氫原子彼此獨立地被相應數目的取代基取代。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 a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms independently of one another by a corresponding number of substituents. 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 undue effort. For example, an amine or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, 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/醫藥上可接受之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 a physiological / pharmaceutically acceptable salt or prodrug thereof with other chemical components, as well as other components such as physiological / pharmaceutically acceptable Carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to the living body, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.

“可藥用鹽”是指本發明化合物的鹽，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 a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.

m和R⁶~R⁸如通式(I)中所定義。 m and R ⁶ to R ⁸ are as defined in the general formula (I).

本發明化合物的合成方法     Method for synthesizing compounds of the present invention    

為了完成本發明的目的，本發明採用如下技術方案： In order to achieve the object of the present invention, the present invention adopts the following technical solutions:

方案一     Option One    

本發明通式(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，或其醫藥上可接受之鹽的製備方法，包括以下步驟： The compound represented by the general formula (I) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a medicament thereof A method for preparing an acceptable salt includes the following steps:

第一步，通式(I-1)的化合物和鹵代試劑反應，得到通式(I-A)的化合物；第二步，通式(I-2)的化合物和通式(I-3)的化合物反應，得到通式(I-4)的化合物；第三步，通式(1-4)的化合物和NHR⁴R⁵的化合物反應，得到通式(I-Bb)的化合物；第四步，通式(I-Bb)的化合物和硼烷類化合物在鹼性條件下，在催化劑存在下，反應得到通式(I-B)的化合物；第五步，通式(I-A)的化合物和通式(I-B)的化合物在鹼性條件下，在催化劑存在下經Suzuki反應，得到通式(I)的化合物；R¹為四氫吡喃基時，可在酸性條件下脫去；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、雙三甲基矽基胺基鋰、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、碳酸鉀、醋酸鉀、碳酸銫、氫氧化鈉和氫氧化鋰；提供酸性條件的試劑包括但不限於氯化氫、氯化氫的1,4-二噁烷溶液、三氟乙酸、甲酸、乙酸、鹽酸、硫酸、甲磺酸、硝酸、磷酸、對苯甲磺酸、Me₃SiCl和TMSOT_f；鹵試劑包括但不限於液溴、溴化氫、N-溴丁二醯亞胺(NBS)、PBr₃、POBr₃、過溴化吡啶氫溴酸鹽(PHP)、四溴環酮(TBCO)、溴丙二酸二乙酯、四丁基溴化銨，N-氯琥珀醯亞胺，PCl₃和POCl₃； 催化劑包括但不限於鈀/碳、雷尼鎳、四-三苯基膦鈀、二氯化鈀、醋酸鈀、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀、1,1’-雙(二苄基磷)二氯二戊鐵鈀、三(二亞苄基丙酮)二鈀或2-雙環己基膦-2’,6’-二甲氧基聯苯，較佳為[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀或2-雙環己基膦-2’,6’-二甲氧基聯苯；硼烷類化合物包括但不限於4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷、4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-二(1,3,2-二氧雜硼雜環戊烷)、聯硼酸新戊二醇酯、B(OB_u-n)₃或B(OP_r-i)₃；上述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、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、水、N,N-二甲基甲醯胺及其混合物；其中：W為或；X為鹵素，較佳為溴；R⁹為烷基；較佳為C_1-6烷基；環A、R¹~R⁵、n和s如通式(I)中所定義。 In the first step, a compound of the general formula (I-1) and a halogenating reagent are reacted to obtain a compound of the general formula (IA); in a second step, a compound of the general formula (I-2) and a compound of the general formula (I-3) Compound reaction to obtain compound of general formula (I-4); third step, compound of general formula (1-4) and compound of NHR ⁴ R ⁵ react to obtain compound of general formula (I-Bb); fourth step The compound of general formula (I-Bb) and borane compounds are reacted under basic conditions in the presence of a catalyst to obtain a compound of general formula (IB); in a fifth step, the compound of general formula (IA) and general formula The compound of (IB) is subjected to a Suzuki reaction in the presence of a catalyst under basic conditions to obtain a compound of general formula (I); when R ¹ is a tetrahydropyranyl group, it can be removed under acidic conditions; basic conditions are provided The reagents include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N , N -diisopropylethylamine, n-butyllithium, diisopropylaminolithium, and bistrimethyl Lithium silylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, hydroxide Sodium chloride and lithium hydroxide; reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, Benzenesulfonic acid, Me ₃ SiCl and TMSOT _f ; halogen reagents include, but are not limited to, liquid bromine, hydrogen bromide, N-bromosuccinimide (NBS), PBr ₃ , POBr ₃ , perbrominated pyridine hydrobromic acid Salt (PHP), tetrabromocyclic ketone (TBCO), diethyl bromomalonate, tetrabutylammonium bromide, N -chlorosuccinimide, PCl ₃ and POCl ₃ ; catalysts include, but are not limited to, palladium / carbon , Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, 1,1'-bis (Dibenzyl phosphorus) dichlorodipentylpalladium, tris (dibenzylideneacetone) dipalladium or 2-dicyclohexylphosphine-2 ', 6'-dimethoxybiphenyl, preferably [1,1 '-Bis (diphenylphosphino) ferrocene] palladium dichloride or 2-biscyclohexylphosphine-2', 6'-dimethoxybiphenyl; borane compounds include, but are not limited to 4,4, 5,5-tetramethyl-1,3,2-dioxaborolane, 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2 '-Di (1,3,2-dioxaboraza Pentane), biphenyl boronic acid neopentyl glycol ester, B (OB _u -n) ₃ or B (OP _r -i) _3; the above reaction is preferably carried out in a solvent, the solvent used include but are not limited to: acetic acid, methanol, Ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfinium, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof; Where: W is or X is halogen, preferably bromine; R ⁹ is alkyl; preferably C _1-6 alkyl; ring A, R ¹ to R ⁵ , n and s are as defined in general formula (I).

方案二     Option II    

本發明通式(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，或其醫藥上可接受之鹽的製備方法，包括以下步驟： The compound represented by the general formula (I) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a medicament thereof A method for preparing an acceptable salt includes the following steps:

第一步，通式(I-1)的化合物和鹵代試劑反應，得到通式(I-A)的化合物；第二步，通式(I-A)的化合物和硼烷類化合物在鹼性條件下，在催化劑存在下，反應得到通式(I-Aa)的化合物；第三步，通式(I-2)的化合物和通式(I-3)的化合物反應，得到通式(I-4)的化合物；第四步，通式(I-4)的化合物和NHR⁴R⁵的化合物反 應，得到通式(I-Bb)的化合物；第五步，通式(I-Bb)的化合物和通式(I-Aa)的化合物在鹼性條件下，在催化劑存在下經Suzuki反應，得到通式(I)的化合物；R¹為四氫吡喃基時，可在酸性條件下脫去；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、雙三甲基矽基胺基鋰、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、碳酸鉀、醋酸鉀、碳酸銫、氫氧化鈉和氫氧化鋰；提供酸性條件的試劑包括但不限於氯化氫、氯化氫的1,4-二噁烷溶液、三氟乙酸、甲酸、乙酸、鹽酸、硫酸、甲磺酸、硝酸、磷酸、對苯甲磺酸、Me₃SiCl和TMSOT_f；鹵試劑包括但不限於液溴、溴化氫、N-溴丁二醯亞胺(NBS)、PBr₃、POBr₃、過溴化吡啶氫溴酸鹽(PHP)、四溴環酮(TBCO)、溴丙二酸二乙酯、四丁基溴化銨，N-氯琥珀醯亞胺，PCl₃和POCl₃；硼烷類化合物包括但不限於4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷、4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-二(1,3,2-二氧雜硼雜環戊烷)、聯硼酸新戊二醇酯、B(OB_u-n)₃或B(OP_r-i)₃；催化劑包括但不限於鈀/碳、雷尼鎳、四-三苯基膦鈀、二氯化鈀、醋酸鈀、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀、1,1’-雙(二苄基磷)二氯二戊鐵鈀或三(二亞苄基丙酮) 二鈀，較佳為[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀；上述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、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、水、N,N-二甲基甲醯胺及其混合物；其中：W為或；X為鹵素，較佳為溴；R⁹為烷基；較佳為C_1-6烷基；環A、R¹~R⁵、n和s如通式(I)中所定義。 In the first step, a compound of the general formula (I-1) and a halogenating reagent are reacted to obtain a compound of the general formula (IA); in a second step, the compound of the general formula (IA) and a borane compound are under basic conditions, In the presence of a catalyst, a compound of the general formula (I-Aa) is obtained by reaction; in the third step, a compound of the general formula (I-2) and a compound of the general formula (I-3) are reacted to obtain a general formula (I-4) In the fourth step, a compound of the general formula (I-4) and a compound of NHR ⁴ R ⁵ are reacted to obtain a compound of the general formula (I-Bb); in a fifth step, the compound of the general formula (I-Bb) The compound of the general formula (I-Aa) is subjected to a Suzuki reaction in the presence of a catalyst under basic conditions to obtain a compound of the general formula (I); when R ¹ is a tetrahydropyranyl group, it can be removed under acidic conditions; Reagents that provide basic conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N , N -diisopropylethylamine, n-butyllithium, diisopropylaminolithium, Lithium bistrimethylsilylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate , Sodium oxide and lithium hydroxide; reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, Benzenesulfonic acid, Me ₃ SiCl and TMSOT _f ; halogen reagents include, but are not limited to, liquid bromine, hydrogen bromide, N -bromosuccinimide (NBS), PBr ₃ , POBr ₃ , perbrominated pyridine hydrobromic acid Salt (PHP), tetrabromocyclic ketone (TBCO), diethyl bromomalonate, tetrabutylammonium bromide, N -chlorosuccinimide, PCl ₃ and POCl ₃ ; borane compounds include, but are not limited to 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl -2,2'-bis (1,3,2-dioxaborolane), neopentyl glycol diborate, B (OB _u -n) ₃ or B (OP _r -i) ₃ ; Catalysts include, but are not limited to, palladium / carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis (diphenylphosphino) ferrocene] dichloride Palladium, 1,1'-bis (dibenzylphosphine) dichlorodipentylpalladium or tris (dibenzylideneacetone) dipalladium, preferably [1,1'-bis (diphenylphosphino) di Ferrocene] palladium dichloride; It is preferably carried out in a solvent. The solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfine, and 1,4-dioxane. , Water, N , N -dimethylformamide and mixtures thereof; wherein: W is or X is halogen, preferably bromine; R ⁹ is alkyl; preferably C _1-6 alkyl; ring A, R ¹ to R ⁵ , n and s are as defined in general formula (I).

實施例     Examples    

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). The NMR measurement was performed using Bruker AVANCE-400 nuclear magnetometer. The measurement solvents were deuterated dimethylsulfinium (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). Methylsilane (TMS).

MS的測定用FINNIGAN LCQAd(ESI)質譜儀(生產商：Thermo，型號：Finnigan LCQ advantage MAX)。 MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

HPLC的測定使用安捷倫1200DAD高壓液相色譜儀 (Sunfire C18 150×4.6mm色譜管柱)和Waters 2695-2996高壓液相色譜儀(Gimini C18 150×4.6mm色譜管柱)。 HPLC was measured using an Agilent 1200DAD high-pressure liquid chromatography (Sunfire C18 150 × 4.6mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 × 4.6mm column).

手性HPLC分析測定使用LC-10A vp(Shimadzu)或者SFC-analytical(Berger Instruments Inc.)；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。 Chiral HPLC analysis was performed using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.); thin-layer chromatography silica gel plates used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, and thin-layer chromatography (TLC) silica gel The specifications of the plate are 0.15mm ~ 0.2mm, and the specifications of thin-layer chromatography purification products are 0.4mm ~ 0.5mm.

管柱層析一般使用煙臺黃海矽膠200~300目矽膠為載體。 Column chromatography generally uses Yantai Huanghai Silicone 200 ~ 300 mesh silica gel as the carrier.

手性製備管柱層析使用Prep Star SD-1(Varian Instruments Inc.)或SFC-multigram(Berger Instruments Inc.)。 Chiral preparative column chromatography used Prep Star SD-1 (Varian Instruments Inc.) or SFC-multigram (Berger Instruments Inc.).

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

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 inhibition rate of the kinase and the IC ₅₀ value were measured using a NovoStar microplate reader (BMG, Germany).

本發明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 invention can be synthesized by or in accordance with methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Chemicals and other companies.

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 be performed 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。 An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

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 a reaction balloon is connected to a hydrogen gas balloon with a volume of about 1 L.

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。 Pressurized hydrogenation reaction uses Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

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。 For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

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 means an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫，為20℃~30℃。 There is no special description 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洗脫劑的體系和薄層色譜法的展開劑體系包括：A：二氯甲烷/甲醇體系，B：正己烷/乙酸乙酯體系，C：石油醚/乙酸乙酯體系，D：石油醚/乙酸乙酯/甲醇，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 uses thin layer chromatography (TLC), a developing agent used in the reaction, a column chromatography eluent system for purifying compounds, and a thin layer chromatography developing system including: A : Dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, D: petroleum ether / ethyl acetate / methanol, and the volume ratio of the solvent is performed according to the polarity of the compound. It can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

實施例1     Example 1     6-(1-環丙基-3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 1 6- (1-cyclopropyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] Pyridine-3-carboxamide 1

第一步     First step     2-(1-環丙基-1 H-吡唑-3-基)-6-甲基吡啶 1c 2- (1-cyclopropyl-1 H -pyrazol-3-yl) -6-methylpyridine 1c

將2-甲基-6-(1H-吡唑-3-基)吡啶1a(700mg，4.40mmol，採用公知的方法“Bioorganic and Medicinal Chemistry,2015,23(6),1260-1275”製備而得)，環丙基硼酸1b(756mg，8.80mmol)，一水合乙酸銅(1.76g，8.80mmol)，碳酸鈉(933mg，8.80mmol)和2,2-聯吡啶(1.37g，8.80mmol)溶於25mL 1,2-二氯乙烷中，升溫至50℃攪拌反應16小時。反應結束後，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到標題化合物1c(440mg，產率：50.2%)。 2-methyl-6- (1 H -pyrazol-3-yl) pyridine 1a (700 mg, 4.40 mmol, prepared by a known method " Bioorganic and Medicinal Chemistry , 2015, 23 (6), 1260-1275" and Obtained), cyclopropylboronic acid 1b (756mg, 8.80mmol), copper acetate monohydrate (1.76g, 8.80mmol), sodium carbonate (933mg, 8.80mmol) and 2,2-bipyridine (1.37g, 8.80mmol) were dissolved. In 25 mL of 1,2-dichloroethane, the temperature was raised to 50 ° C and the reaction was stirred for 16 hours. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1c (440 mg, yield: 50.2%).

MS m/z(ESI)：200.2[M+1] MS m / z (ESI): 200.2 [M + 1]

第二步     Second step     2-(4-溴-1-環丙基-1 H-吡唑-3-基)-6-甲基吡啶 1d 2- (4-bromo-1-cyclopropyl-1 H -pyrazol-3-yl) -6-methylpyridine 1d

將化合物1c(330mg，1.66mmol)溶於8mL二氯甲烷中，加入N-溴丁二醯亞胺(295mg，1.66mmol)，室溫攪拌1小時。反應結束後，反應液中加入水，二氯甲烷萃取(10 mL×3)，合併有機相，減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到標題化合物1d(335mg，產率：72.6%)。 Compound 1c (330 mg, 1.66 mmol) was dissolved in 8 mL of dichloromethane, N -bromosuccinimide (295 mg, 1.66 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, water was added to the reaction solution, and extracted with dichloromethane (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1d. (335 mg, yield: 72.6%).

第三步     third step     2-(1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1 H-吡唑-3-基)-6-甲基吡啶 1f 2- (1-cyclopropyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H -pyrazole- 3-yl) -6-methylpyridine 1f

將化合物1d(400mg，1.44mmol)、4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷1e(1.84g，14.4mmol)、2-雙環己基膦-2’,6’-二甲氧基聯苯(89mg，0.216mmol)、三乙胺(364mg，3.6mmol)和二(氰基苯)二氯化鈀(18.6mg，0.072mmol)溶於甲苯中，90℃條件下，微波反應1小時。反應液中加水，用乙酸乙酯萃取(30mL×2)，合併有機相，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系A純化，得標題化合物1f(300mg，產率：64.1%)。 Compound 1d (400mg, 1.44mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1e (1.84g, 14.4mmol), 2-dicyclohexylphosphine -2 ', 6'-dimethoxybiphenyl (89mg, 0.216mmol), triethylamine (364mg, 3.6mmol) and bis (cyanobenzene) palladium dichloride (18.6mg, 0.072mmol) were dissolved in toluene At 90 ° C, microwave reaction was performed for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A. To give the title compound 1f (300 mg, yield: 64.1%).

MS m/z(ESI)：244.4[M-82+1] MS m / z (ESI): 244.4 [M-82 + 1]

第四步     the fourth step     6-溴-[1,2,4]***並[4,3- a]吡啶-3-羧酸乙酯 1h 6-Bromo- [1,2,4] triazolo [4,3- a ] pyridine-3-carboxylic acid ethyl ester 1h

氬氣氛下，將5-溴-2-肼基吡啶1g(4g，21.27mmol，採用專利申請“US20140134133”公開的方法製備而得)、2-側氧基乙酸乙酯(2.17g，21.27mmol)溶於60mL甲醇中，60℃下，反應1h，反應液溫度降至室溫，減壓濃縮，向濃縮液中加入60mL 1,4-二噁烷，加入碘苯二乙酯(8.22g，25.53mmol)，反應18小時。減壓濃縮，拌樣過管柱，殘 餘物用矽膠色譜法以洗脫劑體系D純化，得標題化合物1h(4.5g，產率：70.49%)。 Under an argon atmosphere, 1 g of 5-bromo-2-hydrazinopyridine (4 g, 21.27 mmol, prepared by the method disclosed in the patent application "US20140134133"), ethyl 2-lanthoxyacetate (2.17 g, 21.27 mmol) Dissolved in 60mL of methanol and reacted at 60 ° C for 1h. The temperature of the reaction solution was reduced to room temperature, and concentrated under reduced pressure. 60mL of 1,4-dioxane was added to the concentrated solution, and iodophenylenediethyl ester (8.22g, 25.53) was added. mmol), reaction for 18 hours. The solution was concentrated under reduced pressure, and the sample was passed through a column. The residue was purified by silica gel chromatography using eluent system D to obtain the title compound for 1 h (4.5 g, yield: 70.49%).

MS m/z(ESI)：270.3[M+1] MS m / z (ESI): 270.3 [M + 1]

第五步     the fifth step     6-溴-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 1i 6-bromo- [1,2,4] triazolo [4,3- a ] pyridine-3-carboxamide 1i

將化合物1h(500mg，1.85mmol)溶於7N胺甲醇溶液(8.37mL，58.58mmol)，攪拌反應1小時。反應液減壓濃縮，殘餘物用矽膠色譜法以洗脫劑體系A純化，得標題化合物1i(450mg，產率：99%)。 Compound 1 h (500 mg, 1.85 mmol) was dissolved in a 7 N amine methanol solution (8.37 mL, 58.58 mmol), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using eluent system A to obtain the title compound 1i (450 mg, yield: 99%).

MS m/z(ESI)：241.3[M+1] MS m / z (ESI): 241.3 [M + 1]

第六步     Step Six     6-(1-環丙基-3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 1 6- (1-cyclopropyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] Pyridine-3-carboxamide 1

氬氣氛下，依次將化合物1f(75mg，0.23mmol)、化合物1i(55.59mg，0.23mmol)、雙二苯基膦二茂鐵(12.79mg，0.02mmol)、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(16.87mg，0.02mmol)和碳酸鉀(63.75mg，0.46mmol)溶於12mL 1,4-二噁烷和水的混合溶液(V/V=5：1)。80℃條件下，攪拌反應18小時。反應液冷卻至室溫，過濾，濾液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系I純化，得標題化合物1(35mg，產率：40%)。 Under an argon atmosphere, compound 1f (75 mg, 0.23 mmol), compound 1i (55.59 mg, 0.23 mmol), bisdiphenylphosphine ferrocene (12.79 mg, 0.02 mmol), and [1,1'-bis (di Phenylphosphino) ferrocene] palladium dichloride (16.87 mg, 0.02 mmol) and potassium carbonate (63.75 mg, 0.46 mmol) in 12 mL of a mixed solution of 1,4-dioxane and water (V / V = 5: 1). The reaction was stirred at 80 ° C for 18 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system I to obtain the title compound 1 (35 mg, yield: 40%).

MS m/z(ESI)：360.4[M+1] MS m / z (ESI): 360.4 [M + 1]

¹H NMR(400MHz,CD₃OD)δ 9.32(s,1H),8.13(s,1H),7.79-7.72(m,2H),7.61-7.56(m,2H),7.24-7.22(d,1H), 3.83-3.79(m,1H),2.40(s,3H),1.28-1.23(m,2H),1.15-1.10(m,2H). ¹ H NMR (400MHz, CD ₃ OD) δ 9.32 (s, 1H), 8.13 (s, 1H), 7.79-7.72 (m, 2H), 7.61-7.56 (m, 2H), 7.24-7.22 (d, 1H ), 3.83-3.79 (m, 1H), 2.40 (s, 3H), 1.28-1.23 (m, 2H), 1.15-1.10 (m, 2H).

實施例2     Example 2     6-(1-環丁基-3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 2 6- (1-cyclobutyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] Pyridine-3-carboxamide 2

第一步     First step     (3-胺基甲醯基-[1,2,4]***並[4,3- a]吡啶-6-基)硼酸 2a (3-Aminomethylamidino- [1,2,4] triazolo [4,3- a ] pyridin-6-yl) boronic acid 2a

在氬氣氛下依次加入化合物1i(4.2g，17.42mmol)、4,4,4’,4’,5,5,5’,5’-八甲基-2,2'-二(1,3,2-二氧雜硼雜環戊烷)(6.64g，26.14mmol，採用公知的方法“Journal of the American Chemical Society,2009,131(5),1656-1657”製備而得)、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(1.29g，1.74mmol)和乙酸鉀(4.28g，43.56mmol)溶解於80mL 1,4-二噁烷溶液中，加熱至80℃，攪拌反應3小時。停止反應， 反應液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系A純化，得到標題化合物2a(2.6g，產率：36.2%)。 Under argon atmosphere, compound 1i (4.2g, 17.42mmol), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bis (1,3 , 2-dioxaborolane) (6.64 g, 26.14 mmol, prepared by a known method " Journal of the American Chemical Society , 2009, 131 (5), 1656-1657"), [1, 1'-bis (diphenylphosphino) ferrocene] palladium dichloride (1.29 g, 1.74 mmol) and potassium acetate (4.28 g, 43.56 mmol) were dissolved in 80 mL of a 1,4-dioxane solution and heated The temperature was stirred at 80 ° C for 3 hours. The reaction was stopped, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 2a (2.6 g, yield: 36.2%).

MS m/z(ESI)：207.4[M+1] MS m / z (ESI): 207.4 [M + 1]

第二步     Second step     2-(1-環丁基-1 H-吡唑-3-基)-6-甲基吡啶 2c 2- (1-cyclobutyl-1 H -pyrazol-3-yl) -6-methylpyridine 2c

依次將化合物1a(2.01g，12.6mmol)、4-甲基苯磺酸環丁酯2b(4.29g，18.9mmol，採用公知的方法“Journal of the American Chemical Society,1980,102(11),3863-3870”製備而得)和碳酸銫(8.23g，25.3mmol)加入100mL N,N-二甲基甲醯胺中，加畢，60℃條件下，攪拌反應12小時。反應液冷卻至室溫，加入水，用乙酸乙酯萃取(20mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(10mL×2)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系B純化，得標題化合物2c(1.81g，產率：67.3%)。 Compound 1a (2.01 g, 12.6 mmol) and cyclobutyl 4-methylbenzenesulfonate 2b (4.29 g, 18.9 mmol) were sequentially used in accordance with a well-known method " Journal of the American Chemical Society , 1980, 102 (11), 3863. -3870 ") and cesium carbonate (8.23 g, 25.3 mmol) were added to 100 mL of N, N -dimethylformamide, and the reaction was stirred at 60 ° C for 12 hours. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 2c (1.81 g, yield: 67.3%).

MS m/z(ESI)：214.4[M+1] MS m / z (ESI): 214.4 [M + 1]

第三步     third step     2-(4-溴-1-環丁基-1 H-吡唑-3-基)-6-甲基吡啶 2d 2- (4-bromo-1-cyclobutyl-1 H -pyrazol-3-yl) -6-methylpyridine 2d

將化合物2c(1.81g，8.49mmol)溶於18mL二氯甲烷中，加入N-溴代丁二醯亞胺(1.51g，8.49mmol)，室溫攪拌1小時。反應結束後，反應液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到標題化合物2d(2.13g，產率：85.9%)。 Compound 2c (1.81 g, 8.49 mmol) was dissolved in 18 mL of dichloromethane, N -bromosuccinimide (1.51 g, 8.49 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 2d (2.13 g, yield: 85.9%).

MS m/z(ESI)：292.3[M+1] MS m / z (ESI): 292.3 [M + 1]

第四步     the fourth step     6-(1-環丁基-3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 2 6- (1-cyclobutyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] Pyridine-3-carboxamide 2

氬氣氛下，依次將化合物2a(78.25mg，0.38mmol)、化合物2d(74mg，0.25mmol)、碳酸鉀(70.01mg，0.51mmol)、雙二苯基膦二茂鐵(14.04mg，0.03mmol)和[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(18.53mg，0.03mmol)溶於11mL 1,4-二噁烷和水的混合溶液(V/V=10：1)。80℃條件下，攪拌反應12小時。反應液冷卻至室溫，反應液中加入20mL水，再用乙酸乙酯萃取(10mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(10mL×2)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系A純化，所得粗品用高效液相色譜法純化，得標題化合物2(4mg，產率：4.2%)。 Under argon atmosphere, compound 2a (78.25mg, 0.38mmol), compound 2d (74mg, 0.25mmol), potassium carbonate (70.01mg, 0.51mmol), bisdiphenylphosphineferrocene (14.04mg, 0.03mmol) And [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (18.53mg, 0.03mmol) in 11mL of a mixed solution of 1,4-dioxane and water (V / V = 10: 1). The reaction was stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with a saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was collected, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A, and the obtained crude product was purified by high performance liquid chromatography to obtain the title compound 2 (4 mg, yield: 4.2%).

MS m/z(ESI)：374.5[M+1] MS m / z (ESI): 374.5 [M + 1]

¹H NMR(400MHz,CDCl₃)δ 9.34(s,1H),7.76(d,1H),7.72(s,1H),7.64-7.62(m,2H),7.54(d,1H),7.42(brs,1H),7.11(d,1H),5.76(brs,1H),4.93-4.84(m,1H),2.66-2.56(m,4H),2.46(s,3H),1.96-1.88(m,2H). ¹ H NMR (400MHz, CDCl ₃ ) δ 9.34 (s, 1H), 7.76 (d, 1H), 7.72 (s, 1H), 7.64-7.62 (m, 2H), 7.54 (d, 1H), 7.42 (brs , 1H), 7.11 (d, 1H), 5.76 (brs, 1H), 4.93-4.84 (m, 1H), 2.66-2.56 (m, 4H), 2.46 (s, 3H), 1.96-1.88 (m, 2H ).

實施例3     Example 3     6-(1-甲基-3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 3 6- (1-methyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] Pyridine-3-formamidine 3

第一步     First step     2-甲基-6-(1-甲基-1 H-吡唑-3-基)吡啶 3a 2-methyl-6- (1-methyl-1 H -pyrazol-3-yl) pyridine 3a

將化合物1a(1g，6.28mmol)、碘甲烷(1.07g，7.54mmol)和碳酸鉀(1.74g，12.56mmol)加入到10mL N,N-二甲基甲醯胺中，反應12小時。反應結束後，反應液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系A純化，得標題化合物3a(320mg，產率：29.4%)。 Compound 1a (1 g, 6.28 mmol), methyl iodide (1.07 g, 7.54 mmol), and potassium carbonate (1.74 g, 12.56 mmol) were added to 10 mL of N , N -dimethylformamide, and reacted for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 3a (320 mg, yield: 29.4%).

MS m/z(ESI)：174.4[M+1] MS m / z (ESI): 174.4 [M + 1]

第二步     Second step     2-(4-溴-1-甲基-1 H-吡唑-3-基)-6-甲基吡啶 3b 2- (4-bromo-1-methyl-1 H -pyrazol-3-yl) -6-methylpyridine 3b

將化合物3a(240mg，1.39mmol)和N-溴丁二醯亞胺(294.29mg，1.66mmol)加入到10mL二氯甲烷中，攪拌反應12小時。反應結束後，向反應液中加入10mL飽和碳酸氫鈉溶液，再用乙酸乙酯萃取，收集有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得粗品標題化合物3b(349mg)，產物不經純化直接用於下一步反應。 Compound 3a (240 mg, 1.39 mmol) and N -bromosuccinimide (294.29 mg, 1.66 mmol) were added to 10 mL of dichloromethane, and the reaction was stirred for 12 hours. After the reaction, 10 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3b (349 mg). Purified and used directly in the next reaction.

MS m/z(ESI)：253.1[M+1] MS m / z (ESI): 253.1 [M + 1]

第三步     third step     6-(1-甲基-3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 3 6- (1-methyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] Pyridine-3-formamidine 3

氬氣氛下，依次將粗品3b(300mg，1.19mmol)、化合物2a(294.11mg，1.43mmol)、碳酸鉀(328.92mg，2.38mmol)和[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(88.27mg，0.119mmol)溶於10.2mL 1,4-二噁烷和水的混合溶液(V/V=50：1)。90℃條件下，攪拌反應12小時。矽藻土過濾，濾液減壓濃縮，殘餘物用高效液相色譜法純化，得標題化合物3(120mg，產率：30.3%)。 Under an argon atmosphere, crude 3b (300 mg, 1.19 mmol), compound 2a (294.11 mg, 1.43 mmol), potassium carbonate (328.92 mg, 2.38 mmol), and [1,1'-bis (diphenylphosphino) di Ferrocene] palladium dichloride (88.27 mg, 0.119 mmol) was dissolved in 10.2 mL of a mixed solution of 1,4-dioxane and water (V / V = 50: 1). The reaction was stirred at 90 ° C for 12 hours. The celite was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 3 (120 mg, yield: 30.3%).

MS m/z(ESI)：334.4[M+1] MS m / z (ESI): 334.4 [M + 1]

¹H NMR(400MHz,CDCl₃)δ 9.39(s,1H),7.80(d,1H),7.67(s,1H),7.63(t,1H),7.58-7.56(dd,2H),7.40(s,1H),7.12(d,1H),5.71(s,1H),4.08(s,3H),2.47(s,3H). ¹ H NMR (400MHz, CDCl ₃ ) δ 9.39 (s, 1H), 7.80 (d, 1H), 7.67 (s, 1H), 7.63 (t, 1H), 7.58-7.56 (dd, 2H), 7.40 (s , 1H), 7.12 (d, 1H), 5.71 (s, 1H), 4.08 (s, 3H), 2.47 (s, 3H).

實施例4     Example 4     6-(1-乙基-3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 4 6- (1-ethyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] Pyridine-3-formamidine 4

第一步     First step     2-(1-乙基-1 H-吡唑-3-基)-6-甲基吡啶 4a 2- (1-ethyl- 1H -pyrazol-3-yl) -6-methylpyridine 4a

將化合物1a(1.2g，7.54mmol)、碘乙烷(1.18g，7.54mmol)和碳酸鉀(2.08g，15.08mmol)加入到5mL N,N-二甲基甲醯胺中，反應12小時。反應結束後，反應液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系A純化，得標題化合物4a(520mg，產率：36.8%)。 Compound 1a (1.2 g, 7.54 mmol), iodoethane (1.18 g, 7.54 mmol), and potassium carbonate (2.08 g, 15.08 mmol) were added to 5 mL of N, N -dimethylformamide, and reacted for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 4a (520 mg, yield: 36.8%).

MS m/z(ESI)：188.4[M+1] MS m / z (ESI): 188.4 [M + 1]

第二步     Second step     2-(4-溴-1-乙基-1 H-吡唑-3-基)-6-甲基吡啶 4b 2- (4-bromo-1-ethyl-1 H -pyrazol-3-yl) -6-methylpyridine 4b

將化合物4a(460mg，2.46mmol)和N-溴丁二醯亞胺(521.80mg，2.95mmol)加入到10mL二氯甲烷中，攪拌反應12小時。反應結束後，向反應液中加入10mL飽和碳酸氫鈉溶液，再用乙酸乙酯萃取，收集有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得粗品標題化合物4b(650mg)，產物不經純化直接用於下一步反應。 Compound 4a (460 mg, 2.46 mmol) and N -bromosuccinimide (521.80 mg, 2.95 mmol) were added to 10 mL of dichloromethane, and the reaction was stirred for 12 hours. After the reaction, 10 mL of a saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 4b (650 mg). Purified and used directly in the next reaction.

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

第三步     third step     6-(1-乙基-3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 4 6- (1-ethyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] Pyridine-3-formamidine 4

氬氣氛下，依次將粗品4b(300mg，1.13mmol)、化合物2a(278.61mg，1.35mmol)、碳酸鉀(311.58mg，2.25mmol)和[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(83.62mg，0.112mmol))溶於10.2mL 1,4-二噁烷和水(V/V=50：1)的混合溶液。90℃條件下，攪拌反應12小時。矽藻土過濾，濾液減壓濃縮，殘餘物用高效液相色譜法純化，得標題化合物4(125mg，產率：31.9%)。 Under an argon atmosphere, crude 4b (300 mg, 1.13 mmol), compound 2a (278.61 mg, 1.35 mmol), potassium carbonate (311.58 mg, 2.25 mmol), and [1,1'-bis (diphenylphosphino) di Ferrocene] palladium dichloride (83.62 mg, 0.112 mmol)) was dissolved in 10.2 mL of a mixed solution of 1,4-dioxane and water (V / V = 50: 1). The reaction was stirred at 90 ° C for 12 hours. The celite was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 4 (125 mg, yield: 31.9%).

MS m/z(ESI)：348.4[M+1] MS m / z (ESI): 348.4 [M + 1]

¹H NMR(400MHz,CDCl₃)δ 9.39(s,1H),7.79(d,1H),7.70(s,1H),7.63(t,1H),7.59-7.56(dd,2H),7.39(s,1H),7.12(d,1H),5.68(s,1H),4.34(q,2H),2.46(s,3H),1.65(t,3). ¹ H NMR (400MHz, CDCl ₃ ) δ 9.39 (s, 1H), 7.79 (d, 1H), 7.70 (s, 1H), 7.63 (t, 1H), 7.59-7.56 (dd, 2H), 7.39 (s , 1H), 7.12 (d, 1H), 5.68 (s, 1H), 4.34 (q, 2H), 2.46 (s, 3H), 1.65 (t, 3).

實施例5     Example 5     6-(1-異丙基-3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 5 6- (1-isopropyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] Pyridine-3-carboxamide 5

第一步     First step    

2-(1-異丙基-1H-吡唑-3-基)-6-甲基吡啶5a’將化合物1a(1.2g，7.54mmol)、2-溴丙烷(927.14mg，7.54mmol)和碳酸鉀(2.08g，15.08mmol)加入到5mL N,N-二甲基甲醯胺中，反應12小時。反應結束後，反應液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系A純化，得標題化合物5a(520mg，產率：36.8%)。 2- (1-Isopropyl-1 H -pyrazol-3-yl) -6-methylpyridine 5a ′ will compound 1a (1.2 g, 7.54 mmol), 2-bromopropane (927.14 mg, 7.54 mmol) and Potassium carbonate (2.08 g, 15.08 mmol) was added to 5 mL of N, N -dimethylformamide, and reacted for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 5a (520 mg, yield: 36.8%).

MS m/z(ESI)：202.4[M+1] MS m / z (ESI): 202.4 [M + 1]

第二步     Second step     2-(4-溴-1-異丙基-1 H-吡唑-3-基)-6-甲基吡啶 5b 2- (4-bromo-1-isopropyl-1 H -pyrazol-3-yl) -6-methylpyridine 5b

將化合物5a(250mg，1.24mmol)和N-溴丁二醯亞胺(263.82mg，1.49mmol)加入到10mL二氯甲烷中，攪拌反應12小時。反應結束，反應液減壓濃縮，殘餘物用矽膠色譜法以洗脫劑體系A純化，得標題化合物5b(348mg，產率：100%)。 Compound 5a (250 mg, 1.24 mmol) and N -bromosuccinimide (263.82 mg, 1.49 mmol) were added to 10 mL of dichloromethane, and the reaction was stirred for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using eluent system A to obtain the title compound 5b (348 mg, yield: 100%).

MS m/z(ESI)：281.2[M+1] MS m / z (ESI): 281.2 [M + 1]

第三步     third step     6-(1-異丙基-3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 5 6- (1-isopropyl-3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] Pyridine-3-carboxamide 5

氬氣氛下，依次將粗品5b(300mg，1.07mmol)、化合物2a(330.82mg，1.61mmol)、碳酸鉀(295.99mg，2.14mmol)和[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(79.43mg，107.08μmol)溶於10.2mL 1,4-二噁烷和水的混合溶液(V/V=50：1)中。90℃條件下，攪拌反應12小時。矽藻土過濾，濾液減壓濃縮，殘餘物用高效液相色譜法純化，得 標題化合物5(132mg，產率：34.1%)。 Under an argon atmosphere, the crude 5b (300 mg, 1.07 mmol), compound 2a (330.82 mg, 1.61 mmol), potassium carbonate (295.99 mg, 2.14 mmol), and [1,1'-bis (diphenylphosphino) di Ferrocene] palladium dichloride (79.43 mg, 107.08 μmol) was dissolved in 10.2 mL of a mixed solution of 1,4-dioxane and water (V / V = 50: 1). The reaction was stirred at 90 ° C for 12 hours. The celite was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 5 (132 mg, yield: 34.1%).

MS m/z(ESI)：362.5[M+1] MS m / z (ESI): 362.5 [M + 1]

¹H NMR(400MHz,CDCl₃)δ 9.39(t,1H),7.80-7.78(dd,1H),7.71(s,1H),7.64(s,1H),7.63(d,1H),7.59-7.56(d,1H),7.41(s,1H),7.12-7.10(m,1H),5.69(s,1H),4.71-4.64(m,1H),2.45(s,3H),1.64(d,6H). ¹ H NMR (400MHz, CDCl ₃ ) δ 9.39 (t, 1H), 7.80-7.78 (dd, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.63 (d, 1H), 7.59-7.56 (d, 1H), 7.41 (s, 1H), 7.12-7.10 (m, 1H), 5.69 (s, 1H), 4.71-4.64 (m, 1H), 2.45 (s, 3H), 1.64 (d, 6H ).

實施例6     Example 6     6-(3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 6 6- (3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] pyridine-3-methyl Tamine 6

第一步     First step     2-(4-溴-1 H-吡唑-3-基)-6-甲基吡啶 6a 2- (4-bromo-1 H -pyrazol-3-yl) -6-methylpyridine 6a

將化合物1a(1g，6.28mmol)和N-溴丁二醯亞胺(1.12g，6.28mmol)加入到30mL二氯甲烷中，攪拌反應1.5小時。反應結束，向反應液中加入10mL飽和碳酸鉀溶液，再用二氯甲烷萃取(10mL×3)，合併有機相，有機相用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘餘物用矽膠管柱色 譜法以洗脫劑體系A純化，得標題化合物6a(1.45g，產率：87.3%)。 Compound 1a (1 g, 6.28 mmol) and N -bromosuccinimide (1.12 g, 6.28 mmol) were added to 30 mL of dichloromethane, and the reaction was stirred for 1.5 hours. After the reaction was completed, 10 mL of a saturated potassium carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was passed through a silica gel tube. Column chromatography was purified with eluent system A to obtain the title compound 6a (1.45 g, yield: 87.3%).

MS m/z(ESI)：238.5[M+1] MS m / z (ESI): 238.5 [M + 1]

第二步     Second step     2-(4-溴-1-(四氫-2 H-吡喃-2-基)-1 H-吡唑-3-基)-6-甲基吡啶 6b 2- (4-bromo-1- (tetrahydro-2 H -pyran-2-yl) -1 H -pyrazol-3-yl) -6-methylpyridine 6b

氬氣氛下，將化合物6a(1.4g，5.88mmol)和3,4-二氫-2H-吡喃(1.12g，6.28mmol)加入到20mL甲苯中，再將三氟乙酸(0.03g，0.29mmol)加入上述反應液，80℃條件下，攪拌反應48小時。反應結束，向反應液中加入10mL飽和碳酸鈉溶液，再用乙酸乙酯萃取(20mL×3)，合併有機相，有機相用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系C純化，得標題化合物6b(1.45g，產率：87.26%)。 Under an argon atmosphere, compound 6a (1.4 g, 5.88 mmol) and 3,4-dihydro-2 H -pyran (1.12 g, 6.28 mmol) were added to 20 mL of toluene, and trifluoroacetic acid (0.03 g, 0.29 mmol) was added to the above reaction solution, and the reaction was stirred at 80 ° C. for 48 hours. After the reaction was completed, 10 mL of a saturated sodium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was passed through a silica gel tube. Column chromatography was purified with eluent system C to obtain the title compound 6b (1.45 g, yield: 87.26%).

MS m/z(ESI)：322.5[M+1] MS m / z (ESI): 322.5 [M + 1]

第三步     third step     6-(3-(6-甲基吡啶-2-基)-1-(四氫-2 H-吡喃-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 6c 6- (3- (6-methylpyridin-2-yl) -1- (tetrahydro-2 H -pyran-2-yl) -1 H -pyrazol-4-yl)-[1,2, 4] triazolo [4,3- a ] pyridine-3-carboxamide 6c

氬氣氛下，依次將化合物6b(300mg，0.93mmol)、化合物2a(9.59mg，0.05mmol)、碳酸鉀(386.06mg，2.79mmol)和[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(690.67mg，0.93mmol)溶於16.5mL 1,4-二噁烷和水(V/V=10：1)的混合溶液。80℃條件下，攪拌反應18小時。加入乙酸乙酯，水洗，收集有機相，無水硫酸鈉乾燥，過濾，濾液減 壓濃縮，殘餘物用高效液相色譜法純化，得標題化合物6c(150mg，產率：35.94%)。 Under an argon atmosphere, compound 6b (300 mg, 0.93 mmol), compound 2a (9.59 mg, 0.05 mmol), potassium carbonate (386.06 mg, 2.79 mmol), and [1,1'-bis (diphenylphosphino) di Ferrocene] palladium dichloride (690.67 mg, 0.93 mmol) was dissolved in 16.5 mL of a mixed solution of 1,4-dioxane and water (V / V = 10: 1). The reaction was stirred at 80 ° C for 18 hours. Ethyl acetate was added, washed with water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain the title compound 6c (150 mg, yield: 35.94%).

MS m/z(ESI)：404.5[M+1] MS m / z (ESI): 404.5 [M + 1]

第四步     the fourth step     6-(3-(6-甲基吡啶-2-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 6 6- (3- (6-methylpyridin-2-yl) -1 H -pyrazol-4-yl)-[1,2,4] triazolo [4,3- a ] pyridine-3-methyl Tamine 6

氬氣氛下，將化合物6c(20mg，0.05mmol)加入2mL 1,4-二噁烷中，0℃條件下，向上述反應液中滴加4mL 4N氯化氫1,4-二噁烷溶液，加畢，反應2小時。反應液減壓濃縮，殘餘物用高效液相色譜法純化，得標題化合物6(5mg，產率：26.9%)。 In an argon atmosphere, compound 6c (20 mg, 0.05 mmol) was added to 2 mL of 1,4-dioxane. At 0 ° C, 4 mL of a 4 N hydrogen chloride 1,4-dioxane solution was added dropwise. At the end, the reaction takes 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 6 (5 mg, yield: 26.9%).

MS m/z(ESI)：427.2[M+1] MS m / z (ESI): 427.2 [M + 1]

¹H NMR(400MHz,CD₃OD)δ 9.38(s,1H),8.03-8.07(m,1H),7.83-7.85(m,1H),7.74-7.78(m,1H),7.64-7.67(m,1H),7.49-7.54(m,1H),7.27-7.29(m,1H),3.50(m,1H),3.15(m,1H),2.48(s,3H) ¹ H NMR (400MHz, CD ₃ OD) δ 9.38 (s, 1H), 8.03-8.07 (m, 1H), 7.83-7.85 (m, 1H), 7.74-7.78 (m, 1H), 7.64-7.67 (m , 1H), 7.49-7.54 (m, 1H), 7.27-7.29 (m, 1H), 3.50 (m, 1H), 3.15 (m, 1H), 2.48 (s, 3H)

實施例7     Example 7     ( R)-6-(3-(6-甲基吡啶-2-基)-1-(四氫呋喃-3-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 7 (R) -6- (3- (6- methylpyridin-2-yl) -1- (tetrahydrofuran-3-yl) -1 H - pyrazol-4-yl) - [1,2,4] Zolo [4,3- a ] pyridine-3-carboxamide 7

第一步     First step     ( R)-2-甲基-6-(1-(四氫呋喃-3-基)-1 H-吡唑-3-基)吡啶 7b ( R ) -2-methyl-6- (1- (tetrahydrofuran-3-yl) -1 H -pyrazol-3-yl) pyridine 7b

將化合物1a(637mg，4.0mmol)溶於20mL N,N-二甲基甲醯胺中，加入(S)-四氫呋喃-3-基4-甲基苯磺酸酯7a(1.45g，6.0mmol，採用專利申請“WO2014049133”公開的方法製備而得)和碳酸銫(2.61g，8.0mmol)，60℃攪拌反應16小時。反應液減壓濃縮，用CombiFlash快速製備儀以洗脫劑體系B純化所得殘餘物，得到標題化合物7b(610mg，產率：66.5%)。 Compound 1a (637 mg, 4.0 mmol) was dissolved in 20 mL of N , N -dimethylformamide, and ( S ) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate 7a (1.45 g, 6.0 mmol, Prepared by the method disclosed in the patent application "WO2014049133") and cesium carbonate (2.61 g, 8.0 mmol), and stirred at 60 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified with a eluent system B using a CombiFlash rapid preparation instrument to obtain the title compound 7b (610 mg, yield: 66.5%).

MS m/z(ESI)：230.4[M+1] MS m / z (ESI): 230.4 [M + 1]

第二步     Second step     ( R)-2-(4-溴-1-(四氫呋喃-3-基)-1 H-吡唑-3-基)-6-甲基吡啶 7c ( R ) -2- (4-bromo-1- (tetrahydrofuran-3-yl) -1 H -pyrazol-3-yl) -6-methylpyridine 7c

將化合物7b(600mg，2.62mmol)溶於30mL二氯甲烷中，加入N-溴丁二醯亞胺(466mg，2.62mmol)，室溫攪拌16小時。反應結束後，減壓濃縮，用CombiFlash快速製備儀以洗脫劑體系B純化所得殘餘物，得到標題化合物7c(795mg，產率：98.6%)。 Compound 7b (600 mg, 2.62 mmol) was dissolved in 30 mL of dichloromethane, and N -bromosuccinimide (466 mg, 2.62 mmol) was added, followed by stirring at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by using a CombiFlash rapid preparation device as eluent system B to obtain the title compound 7c (795 mg, yield: 98.6%).

MS m/z(ESI)：310.3[M+1] MS m / z (ESI): 310.3 [M + 1]

第三步     third step     ( ^R )-6-(3-(6-甲基吡啶-2-基)-1-(四氫呋喃-3-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 7 ^(R) -6- (3- (6- methylpyridin-2-yl) -1- (tetrahydrofuran-3-yl) -1 H - pyrazol-4-yl) - [1,2,4] Zolo [4,3- a ] pyridine-3-carboxamide 7

氬氣氛下，依次將化合物7c(115mg，0.37mmol)、化合物2a(307.45mg，1.49mmol)、雙二苯基膦二茂鐵(20.69mg，0.04mmol)、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(27.31mg，0.040mmol)和碳酸鉀(103.15mg，0.75mmol)溶於16.5mL 1,4-二噁烷和水(V/V=10：1)的混合溶液。80℃條件下，攪拌反應18小時。反應液冷卻至室溫，反應液中加入30mL水，再用乙酸乙酯萃取(20mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(10mL×2)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘餘物用矽膠色譜法以洗脫劑體系A純化，所得粗品用高效液相色譜法純化，得標題化合物7(8mg，產率：5.5%)。 Under an argon atmosphere, compound 7c (115 mg, 0.37 mmol), compound 2a (307.45 mg, 1.49 mmol), bisdiphenylphosphine ferrocene (20.69 mg, 0.04 mmol), and [1,1'-bis (di Phenylphosphino) ferrocene] palladium dichloride (27.31 mg, 0.040 mmol) and potassium carbonate (103.15 mg, 0.75 mmol) were dissolved in 16.5 mL of 1,4-dioxane and water (V / V = 10: 1) Mixed solution. The reaction was stirred at 80 ° C for 18 hours. The reaction solution was cooled to room temperature, 30 mL of water was added to the reaction solution, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was collected, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using eluent system A, and the resulting crude product was purified by high performance liquid chromatography to obtain the title compound 7 (8 mg, yield: 5.5%).

MS m/z(ESI)：390.4[M+1] MS m / z (ESI): 390.4 [M + 1]

¹H NMR(400MHz,CDCl₃)δ 9.31(s,1H),7.82-7.77(m,3H),7.58(d,1H),7.51(d,1H),7.35(brs,1H),7.26(s,1H),5.64(brs,1H),5.17-5.12(m,1H),4.28-4.22(m,2H),4.14-4.10(m,1H),4.02-3.97(m,1H),2.63(s,3H),2.61-2.54(m,2H). ¹ H NMR (400MHz, CDCl ₃ ) δ 9.31 (s, 1H), 7.82-7.77 (m, 3H), 7.58 (d, 1H), 7.51 (d, 1H), 7.35 (brs, 1H), 7.26 (s , 1H), 5.64 (brs, 1H), 5.17-5.12 (m, 1H), 4.28-4.22 (m, 2H), 4.14-4.10 (m, 1H), 4.02-3.97 (m, 1H), 2.63 (s , 3H), 2.61-2.54 (m, 2H).

實施例8     Example 8     ( S)-6-(3-(6-甲基吡啶-2-基)-1-(四氫呋喃-3-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 8 (S) -6- (3- (6- methylpyridin-2-yl) -1- (tetrahydrofuran-3-yl) -1 H - pyrazol-4-yl) - [1,2,4] Zolo [4,3- a ] pyridine-3-carboxamide 8

第一步     First step     ( S)-2-甲基-6-(1-(四氫呋喃-3-基)-1 H-吡唑-3-基)吡啶 8b ( S ) -2-methyl-6- (1- (tetrahydrofuran-3-yl) -1 H -pyrazol-3-yl) pyridine 8b

將化合物1a(328mg，2.06mmol)溶於10mL N,N-二甲基甲醯胺中，加入(R)-四氫呋喃-3-基4-甲基苯磺酸酯8a(500mg，2.06mmol，採用專利申請“WO2016021192”公開的方法製備而得)和碳酸銫(1.3g，4.12mmol)，60℃攪拌反應2小時。反應液減壓濃縮，殘餘物中加入水，乙酸乙酯萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到標題化合物8b(175mg，產率：37.0%)。 Compound 1a (328 mg, 2.06 mmol) was dissolved in 10 mL of N , N -dimethylformamide, and ( R ) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate 8a (500 mg, 2.06 mmol, was used. It was prepared by the method disclosed in the patent application "WO2016021192") and cesium carbonate (1.3 g, 4.12 mmol), and stirred at 60 ° C for 2 hours. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A. The title compound 8b (175 mg, yield: 37.0%) was obtained.

MS m/z(ESI)：230.4[M+1] MS m / z (ESI): 230.4 [M + 1]

第二步     Second step     ( S)-2-(4-溴-1-(四氫呋喃-3-基)-1 H-吡唑-3-基)-6-甲基吡啶 8c ( S ) -2- (4-bromo-1- (tetrahydrofuran-3-yl) -1 H -pyrazol-3-yl) -6-methylpyridine 8c

將化合物8b(370mg，1.6mmol)溶於18mL二氯甲烷中，加入N-溴丁二醯亞胺(341.76mg，1.92mmol)，室溫 攪拌12小時。反應結束後，反應液中加入水，二氯甲烷萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘餘物用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到標題化合物8c(325.5mg，產率：65.1%)。 Compound 8b (370 mg, 1.6 mmol) was dissolved in 18 mL of dichloromethane, and N -bromosuccinimide (341.76 mg, 1.92 mmol) was added, followed by stirring at room temperature for 12 hours. After the reaction, the reaction solution was added with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A, The title compound 8c (325.5 mg, yield: 65.1%) was obtained.

第三步     third step     ( S)-6-(3-(6-甲基吡啶-2-基)-1-(四氫呋喃-3-基)-1 H-吡唑-4-基)-[1,2,4]***並[4,3- a]吡啶-3-甲醯胺 8 (S) -6- (3- (6- methylpyridin-2-yl) -1- (tetrahydrofuran-3-yl) -1 H - pyrazol-4-yl) - [1,2,4] Zolo [4,3- a ] pyridine-3-carboxamide 8

氬氣氛下，依次將化合物8c(100mg，0.32mmol)、化合物2a(300mg，1.46mmol)、雙二苯基膦二茂鐵((17.99mg，0.0300mmol)、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(23.74mg，0.03mmol)和碳酸鉀(89.7mg，0.65mmol)溶於11mL 1,4-二噁烷和水(V/V=10：1)的混合溶液。85℃條件下，攪拌反應12小時。反應液冷卻至室溫，反應液中加入30mL水，再用乙酸乙酯萃取(10mL×3)，合併有機相，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘餘物用矽膠色譜法以洗脫劑體系A純化，所得粗品用高效液相色譜法純化，得標題化合物8(14mg，產率：11.1%)。 Under an argon atmosphere, compound 8c (100 mg, 0.32 mmol), compound 2a (300 mg, 1.46 mmol), bisdiphenylphosphine ferrocene ((17.99 mg, 0.0300 mmol), [1,1'-bis (di Phenylphosphino) ferrocene] palladium dichloride (23.74mg, 0.03mmol) and potassium carbonate (89.7mg, 0.65mmol) were dissolved in 11mL of 1,4-dioxane and water (V / V = 10: 1 ) Mixed solution. The reaction was stirred at 85 ° C for 12 hours. The reaction solution was cooled to room temperature, 30 mL of water was added to the reaction solution, and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration, the filtrate was collected, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography using eluent system A, and the obtained crude product was purified by high performance liquid chromatography to obtain the title compound 8 (14 mg, yield: 11.1%).

MS m/z(ESI)：390.4[M+1] MS m / z (ESI): 390.4 [M + 1]

¹H NMR(400MHz,CDCl₃)δ 9.39(s,1H),7.81(d,1H),7.78(s,1H),7.62(d,1H),7.57(d,1H),7.42(s,1H),7.14(d,1H),5.75-5.69(m,1H),5.19-5.13(m,1H),4.29-4.23(m,2H),4.18-4.12(m,1H),4.06-4.00(m,1H),2.66-2.55(m,1H),2.48(s,3H). ¹ H NMR (400MHz, CDCl ₃ ) δ 9.39 (s, 1H), 7.81 (d, 1H), 7.78 (s, 1H), 7.62 (d, 1H), 7.57 (d, 1H), 7.42 (s, 1H ), 7.14 (d, 1H), 5.75-5.69 (m, 1H), 5.19-5.13 (m, 1H), 4.29-4.23 (m, 2H), 4.18-4.12 (m, 1H), 4.06-4.00 (m , 1H), 2.66-2.55 (m, 1H), 2.48 (s, 3H).

測試例：Test example:

生物學評價Biological evaluation

測試例1、本發明化合物對TGFβRI(ALK5)激酶活性的抑制作用的測定 Test Example 1. Determination of the inhibitory effect of the compound of the present invention on the activity of TGFβRI (ALK5) kinase

體外TGFβRI(ALK5)激酶活性的抑制作用藉由以下的方法進行測試。 The inhibitory effect of TGFβRI (ALK5) kinase activity in vitro was tested by the following method.

本發明化合物對TGFβRI激酶ALK5活性的抑制作用採用如下實驗方法測定：酶活性檢測使用TGFβRI激酶檢測試劑盒(V4093，Promega)，在384孔板(4514，Corning)中依次加入2μl用反應緩衝液(40mM Tris pH7.5，20mM MgCl₂，0.1mg/ml BSA)昢製的酶溶液(反應體系中酶終濃度為2ng/μL)，1μl溶於5%DMSO的3倍梯度稀釋的化合物，2μl ATP和TGFβRI受質多肽的混合溶液(ATP終濃度為50μM，受質終濃度為0.2μg/μL)，27℃反應2.5小時後，每孔加入5μl試劑盒中的ADP-Glo溶液，27℃放置40分鐘，每孔再加入10μl激酶檢測試劑，27℃放置30分鐘。使用Victor 3(PerkinElmer)多功能酶標儀檢測化學發光信號值。用Graphpad prism軟體根據化合物各濃度與相應的信號值計算化合物對酶抑制作用的IC₅₀值。 The inhibitory effect of the compound of the present invention on the activity of TGFβRI kinase ALK5 was determined by the following experimental method: Enzyme activity was detected using a TGFβRI kinase detection kit (V4093, Promega), and 2 μl of a reaction buffer ( 40mM Tris pH7.5, 20mM MgCl ₂ , 0.1mg / ml BSA) enzyme solution (final enzyme concentration in the reaction system is 2ng / μL), 1μl compound diluted 3 times in 5% DMSO, 2μl ATP Mixed solution with TGFβRI receptor peptide (final ATP concentration: 50 μM, final receptor concentration: 0.2 μg / μL), after reacting at 27 ° C for 2.5 hours, add 5 μl of ADP-Glo solution in the kit to each well, and place at 27 ° C for 40 For 10 minutes, add 10 μl of kinase detection reagent to each well and leave at 27 ° C for 30 minutes. The value of the chemiluminescence signal was detected using a Victor 3 (PerkinElmer) multifunctional microplate reader. Graphpad prism software was used to calculate the IC ₅₀ value of the inhibitory effect of the compound on the enzyme according to the concentration of the compound and the corresponding signal value.

本發明化合物的生物活性藉由以上的試驗進行測定，測得的IC₅₀值見下表1。 The biological activity of the compounds of the present invention was determined by the above tests. The IC ₅₀ values measured are shown in Table 1 below.

結論：本發明實施例化合物對TGFβRI激酶ALK5活性均有明顯地抑制作用。 Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on the activity of TGFβRI kinase ALK5.

測試例2、本發明化合物對VEGFR2激酶活性的的抑制作用的測定 Test Example 2: Determination of the inhibitory effect of the compound of the present invention on the activity of VEGFR2 kinase

體外VEGFR2激酶活性的的抑制作用藉由以下的方法進行測試。 The inhibitory effect of VEGFR2 kinase activity in vitro was tested by the following method.

以下所述實驗方法用來測定本發明化合物對VEGFR2激酶活性的抑制作用：酶活性檢測使用Z’-LYTE® Kinase Assay Kit-Tyrosine 1 Peptide(PV3190，Invitrogen)試劑盒，在384孔板(4513，Corning)中依次加入5μl用反應緩衝液(50mM HEPES pH7.5，10mM MgCl₂，1mM EGTA，0.05%BRIJ-35)配製的重組人VEGFR2酶(PV3660，Invitrogen)和VEGFR2受質多肽(反應體系中酶終濃度為0.14ng/μL，受質終濃度為2μM)，2.5μl溶於5%DMSO的2倍梯度稀釋的化合物，2.5μL ATP溶液(ATP終濃度為50μM)，25℃反應2 小時後，每孔加入5μL檢測試劑，25℃放置1小時後，用NOVOstar(BMG)多功能酶標儀檢測發射波長445nm和520nm的螢光信號值。用Graphpad prism軟體根據化合物各濃度與相應的信號值計算化合物對酶抑制作用的IC₅₀值。 The following experimental methods were used to determine the inhibitory effect of the compounds of the present invention on the activity of VEGFR2 kinase: Enzyme activity was measured using Z'-LYTE® Kinase Assay Kit-Tyrosine 1 Peptide (PV3190, Invitrogen) kit in a 384-well plate (4513, Corning) was sequentially added with 5 μl of a recombinant human VEGFR2 enzyme (PV3660, Invitrogen) and a VEGFR2 receptor peptide (in the reaction system) prepared with a reaction buffer (50mM HEPES pH7.5, 10mM MgCl ₂ , 1mM EGTA, 0.05% BRIJ-35). The final enzyme concentration is 0.14ng / μL, the final substrate concentration is 2μM), 2.5μl of the compound diluted in 5% DMSO with a 2-fold gradient dilution, 2.5μL ATP solution (the final ATP concentration is 50μM), and the reaction at 25 ℃ for 2 hours 5 μL of detection reagent was added to each well, and after being left at 25 ° C. for 1 hour, the fluorescence signal values of the emission wavelengths of 445 nm and 520 nm were detected with a NOVOstar (BMG) multifunctional microplate reader. Graphpad prism software was used to calculate the IC ₅₀ value of the inhibitory effect of the compound on the enzyme according to the concentration of the compound and the corresponding signal value.

本發明化合物的生物活性藉由以上的試驗進行測定，測得的IC₅₀值見下表2。 The biological activity of the compound of the present invention was measured by the above test, and the IC ₅₀ values measured are shown in Table 2 below.

結論：本發明實施例化合物對VEGFR2激酶活性抑制作用弱，說明本發明實施例化合物對TGFβRI激酶具有選擇性抑制作用。 Conclusion: The compounds of the examples of the present invention have a weak inhibitory effect on the activity of VEGFR2 kinase, indicating that the compounds of the examples of the present invention have a selective inhibitory effect on the TGFβRI kinase.

測試例3、本發明化合物對p38α激酶活性的抑制作用的測定 Test Example 3, Determination of the inhibitory effect of the compound of the present invention on p38α kinase activity

體外p38α激酶活性的抑制藉由以下的方法進行測試。 Inhibition of p38α kinase activity in vitro was tested by the following method.

以下所述實驗方法用來測定本發明化合物對p38α激酶活性的抑制作用：酶活性檢測使用p38α激酶檢測試劑盒(V9591，Promega)，在384孔板(4514，Corning)中依次加入2μL用反應緩衝液(40mM Tris pH7.5，20mM MgCl₂，0.1mg/mL BSA)配製的酶溶液(反應體系中酶終濃度為0.5ng/μL)， 1μL溶於5%DMSO的3倍梯度稀釋的化合物，2μL ATP和p38受質多肽的混合溶液(ATP終濃度為50μM，受質終濃度為0.2μg/μL)，27℃反應2.5小時後，每孔加入5μL試劑盒中的ADP-Glo溶液，27℃放置40分鐘，每孔再加入10μL激酶檢測試劑，27℃放置30分鐘。使用Victor 3(PerkinElmer)多功能酶標儀檢測化學發光信號值。用Graphpad prism軟體根據化合物各濃度與相應的信號值計算化合物對酶抑制作用的IC₅₀值。 The following experimental methods are used to determine the inhibitory effect of the compounds of the present invention on p38α kinase activity: Enzyme activity was measured using a p38α kinase detection kit (V9591, Promega). 2 μL of reaction buffer was sequentially added to a 384 well plate (4514, Corning) Enzyme solution (40 mM Tris pH 7.5, 20 mM MgCl ₂ , 0.1 mg / mL BSA) (the final enzyme concentration in the reaction system is 0.5 ng / μL), 1 μL of a compound diluted in a 3-fold gradient in 5% DMSO, 2 μL of a mixed solution of ATP and p38 receptor peptide (final ATP concentration is 50 μM, and the final receptor concentration is 0.2 μg / μL). After reacting at 27 ° C for 2.5 hours, add 5 μL of ADP-Glo solution in the kit to each well, 27 ° C. Leave it for 40 minutes, add 10 μL of kinase detection reagent to each well, and leave it at 27 ° C for 30 minutes. The value of the chemiluminescence signal was detected using a Victor 3 (PerkinElmer) multifunctional microplate reader. Graphpad prism software was used to calculate the IC ₅₀ value of the inhibitory effect of the compound on the enzyme according to the concentration of the compound and the corresponding signal value.

本發明化合物的生物活性藉由以上的試驗進行測定，測得的IC₅₀值見下表3。 The biological activity of the compounds of the present invention was determined by the above tests. The IC ₅₀ values measured are shown in Table 3 below.

結論：本發明實施例化合物對p38α激酶活性的抑制作用弱，說明本發明實施例化合物對TGFβRI激酶具有選擇性抑制作用。 Conclusion: The compounds of the examples of the present invention have weak inhibitory effects on p38α kinase activity, which indicates that the compounds of the examples of the present invention have selective inhibitory effects on TGFβRI kinase.

測試例4、本發明化合物對NIH3T3細胞增殖的抑制測定 Test Example 4. Inhibition of NIH3T3 cell proliferation by the compound of the present invention

下面的體外試驗是用來測定本發明化合物對NIH3T3細胞增殖的抑制活性。 The following in vitro tests are used to determine the inhibitory activity of the compounds of the present invention on the proliferation of NIH3T3 cells.

以下所述實驗方法用來測定本發明化合物對NIH3T3細胞增殖的抑制作用： 在96孔透明底白板(3903，Corning)中用含10%FBS的DMEM培養基(SH30243.01，GE)每孔接種100μL NIH3T3細胞(GNM6，中國科學院典型培養物保藏委員會細胞庫)，接種密度為2000細胞/孔，細胞在37℃，5%CO₂條件下培養過夜。過夜培養後，每孔更換為90μL含0.5%FBS的DMEM培養基，然後加入10μL用含0.5%FBS的DMEM培養基3倍梯度稀釋的化合物，放置37℃，5%CO₂細胞培養箱中培養72小時。最後每孔加入50μL CellTiter-Glo(G7573，Promega)，室溫孵育10分鐘後使用Victor3酶標儀(PerkinElmer)讀取化學發光信號值。用Graphpad Prism軟體根據化合物各濃度與相應的信號值計算化合物的IC₅₀值。 The following experimental methods were used to determine the inhibitory effect of the compounds of the present invention on the proliferation of NIH3T3 cells: In a 96-well transparent bottom white plate (3903, Corning), 100 μL of each well was inoculated with DMEM medium (SH30243.01, GE) containing 10% FBS. NIH3T3 cells (GNM6, Cell Bank of the Chinese Academy of Sciences Type Culture Collection Committee) were seeded at a density of 2000 cells / well, and the cells were cultured overnight at 37 ° C and 5% CO ₂ . After overnight culture, each well was replaced with 90 μL of DMEM medium containing 0.5% FBS, and then 10 μL of the compound diluted 3 times with DMEM medium containing 0.5% FBS was added, and placed in a 5% CO ₂ cell culture incubator at 37 ° C for 72 hours. . Finally, 50 μL of CellTiter-Glo (G7573, Promega) was added to each well, and the chemiluminescence signal value was read using a Victor3 microplate reader (PerkinElmer) after incubating at room temperature for 10 minutes. Compound IC ₅₀ value calculated using Graphpad Prism software corresponding to each concentration of compound according to the signal value.

本發明化合物生物活性由上述分析所得，計算所得的IC₅₀值如下表4： The biological activity of the compound of the present invention is obtained from the above analysis, and the calculated IC ₅₀ value is shown in Table 4 below:

結論：本發明化合物對NIH3T3細胞增殖有明顯的抑制活性。 Conclusion: The compound of the present invention has obvious inhibitory activity on the proliferation of NIH3T3 cells.

測試例5、本發明化合物對TGFβRI的Smad信號通 路的抑制活性的測定 Test Example 5. Determination of the inhibitory activity of the compound of the present invention on the Smad signaling pathway of TGFβRI

下面的體外試驗是用來測定本發明化合物對TGFβRI的Smad信號通路的抑制活性。 The following in vitro tests are used to determine the inhibitory activity of the compounds of the present invention on the Smad signaling pathway of TGFβRI.

以下所述實驗方法用來測定本發明化合物對TGFβRI的Smad信號通路的抑制活性：在96孔板中用含10%FBS的EMEM培養液(42360-099，Gibco)每孔接種100μL HepG2(TCHu 72，中國科學院典型培養物保藏委員會細胞庫)細胞，接種密度為2.5×10⁴細胞/孔，細胞在37℃，5%CO₂條件下培養過夜。更換含10%FBS的EMEM新鮮培養液，每孔轉染0.1μg 3TP-lux質粒(11767，普如汀生物技術(北京)有限公司)，細胞繼續在37℃，5%CO₂條件下培養24小時。每孔更換90μL含0.5%FBS的EMEM培養液，饑餓6小時。將化合物配置成20mM的儲存液，用100%DMSO梯度稀釋成400×的濃度，再用含0.5%FBS的EMEM稀釋40倍。取出細胞培養板，每孔分別加入10μL稀釋後的化合物或對照(0.25%DMSO)，輕輕振盪混勻，放置37℃，5%CO₂培養箱中培養18小時，最後每孔加入100μL檢測試劑ONE-Glo^TM Luciferase Assay(E6110，Promega)，室溫避光放置10分鐘，採用Victor3.0(PerkinElmer)讀取化學發光信號值。用Graphpad Prism軟體根據化合物各濃度與相應的信號值計算化合物的IC₅₀值。 The experimental method described below was used to determine the inhibitory activity of the compound of the present invention on the Smad signaling pathway of TGFβRI: 100 μL HepG2 (TCHu 72) was inoculated in a 96-well plate with 10% FBS-containing EMEM medium (42360-099, Gibco) per well. (Cell Bank of the Typical Culture Collection Committee of the Chinese Academy of Sciences) cells, seeded at a density of 2.5 × 10 ⁴ cells / well, and the cells were cultured overnight at 37 ° C. and 5% CO ₂ . The fresh EMEM containing 10% FBS was replaced, and each well was transfected with 0.1 μg of 3TP-lux plasmid (11767, Puruting Biotechnology (Beijing) Co., Ltd.), and the cells continued to be cultured at 37 ° C and 5% CO ₂ for 24 hours. hour. Each well was replaced with 90 μL of 0.5% FBS EMEM culture medium and starved for 6 hours. The compound was prepared as a 20 mM stock solution, diluted to a concentration of 400 × with 100% DMSO gradient, and then diluted 40-fold with EMEM containing 0.5% FBS. Remove the cell culture plate, add 10 μL of the diluted compound or control (0.25% DMSO) to each well, mix by shaking gently, and incubate at 37 ° C in a 5% CO ₂ incubator for 18 hours. Finally add 100 μL of detection reagent to each well. ONE-Glo ^(TM) Luciferase Assay (E6110, Promega), placed at room temperature and protected from light for 10 minutes, and read the chemiluminescence signal value using Victor 3.0 (PerkinElmer). Compound IC ₅₀ value calculated using Graphpad Prism software corresponding to each concentration of compound according to the signal value.

本發明化合物生物活性由上述分析所得，計算所得的IC₅₀值如下表5： The biological activity of the compound of the present invention is obtained from the above analysis, and the calculated IC ₅₀ value is shown in Table 5 below:

結論：本發明化合物均對TGFβRI的Smad信號通路具有明顯的抑制活性。 Conclusion: The compounds of the present invention all have significant inhibitory activity on the Smad signaling pathway of TGFβRI.

藥物代謝動力學評價Pharmacokinetic evaluation

測試例6、本發明化合物的藥物代謝動力學測試 Test Example 6. Pharmacokinetic test of the compound of the present invention

1、摘要 1.Abstract

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1化合物、後不同時刻血漿中的藥物濃度。研究本發明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 test animals, LC / MS / MS method was used to determine the drug concentration in the plasma of rats after intragastric administration of the compound of Example 1 at different times. The pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.

2、試驗方案 2. Test plan

2.1試驗藥品 2.1 Test drugs

實施例1化合物。 Example 1. Compound.

2.2試驗動物 2.2 Test animals

健康成年SD大鼠4隻，雌雄各半，購自上海傑思捷實驗動物有限公司，動物生產許可證號：SCXK(滬)2013-0006。 Four healthy adult SD rats, male and female, purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.

2.3藥物配製 2.3 Drug Formulation

稱取一定量藥物，加5%體積的DMSO、5%體積的吐溫80和90%體積的生理鹽水配製成0.2mg/mL的無色澄清透明液體。 Weigh a certain amount of drug, add 5% volume of DMSO, 5% volume of Tween 80, and 90% volume of normal saline to prepare a 0.2 mg / mL colorless, clear liquid.

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2.0mg/kg，給藥體積均為10.0mL/kg。 SD rats were fasted orally after fasting overnight. The doses were all 2.0 mg / kg, and the volumes were 10.0 mL / kg.

3.操作 3. operation

大鼠灌胃給藥實施例1化合物，於給藥前及給藥後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，置於肝素化試管中，4℃、3500轉/分鐘離心10分鐘分離血漿，於-20℃保存，給藥後2小時進食。 Rats were administered with the compound of Example 1 by gavage, and 0.2 mL of blood was collected from the orbit before and after 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, and placed in a heparinized test tube at 4 ° C Centrifuge at 3500 rpm for 10 minutes to separate plasma, 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80μL(100ng/mL)，乙腈200μL，渦旋混合5分鐘，離心10分鐘(4000轉/分鐘)，血漿樣品取上清液1.0μL進行LC/MS/MS分析。 Determining the content of test compound in rat plasma after drug administration at different concentrations: Take 25 μL of rat plasma at each time after administration, add 80 μL of internal standard solution camptothecin (100 ng / mL), 200 μL of acetonitrile, vortex Spin-mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 1.0 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

本發明化合物的藥物代謝動力學參數如下： The pharmacokinetic parameters of the compounds of the invention are as follows:

結論：本發明化合物的藥物代謝吸收較好，具有藥物代謝動力學優勢。 Conclusion: The compound of the present invention has good drug metabolism and absorption, and has pharmacokinetic advantages.

Claims (20)

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醫藥上可接受之鹽， 其中：環A為芳基或雜芳基；R ¹選自氫原子、烷基、鹵烷基、羥基、羥烷基、胺基、環烷基、雜環基、芳基、雜芳基、-C(O)OR ⁶、-C(O)R ⁶、-S(O) _mR ⁶、-NR ⁷R ⁸、-S(O) _mNR ⁷R ⁸和-C(O)NR ⁷R ⁸，其中該烷基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、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、雜芳基、-C(O)OR ⁶、-C(O)R ⁶、-S(O) _mR ⁶、-NR ⁷R ⁸、-S(O) _mNR ⁷R ⁸和-C(O)NR ⁷R ⁸中的一個或多個取代基所取代；R ²相同或不同，且各自獨立地選自氫原子、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、雜芳基、-C(O)OR ⁶、-C(O)R ⁶、-S(O) _mR ⁶、-NR ⁷R ⁸、-S(O) _mNR ⁷R ⁸和-C(O)NR ⁷R ⁸；R ³相同或不同，且各自獨立地選自氫原子、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；R ⁴和R ⁵各自獨立地選自氫原子、烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基，其中該烷基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自烷基、烷氧基、鹵素、胺基、氰基、硝基、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；或者，該R ⁴和R ⁵與相連接的氮原子一起形成雜環基，其中該雜環基內含有1~2個相同或不同選自N、O和S的雜原子，並且該雜環基視需要被選自烷基、烷氧基、鹵素、胺基、氰基、硝基、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 ⁶選自氫原子、烷基、胺基、鹵烷基、環烷基、雜環基、芳基和雜芳基；R ⁷和R ⁸各自獨立地選自氫原子、烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基，其中該烷基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自烷基、烷氧基、鹵素、胺基、氰基、硝基、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；或者，該R ⁷和R ⁸與相連接的氮原子一起形成雜環基，其中該雜環基內含有1~2個相同或不同選自N、O和S的雜原子，並且該雜環基視需要被選自烷基、烷氧基、鹵素、胺基、氰基、硝基、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；n為0、1、2、3或4；s為0、1、2或3；且m為0、1或2。 A compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable form thereof Salt, Wherein: ring A is aryl or heteroaryl; R ^{1 is} selected from hydrogen atom, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, amine, cycloalkyl, heterocyclic, aryl, heteroaryl, -C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ , wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano , Amine, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ are substituted by one or more substituents; R ^{2 is the} same or different, and each is independently selected from a hydrogen atom, a halogen , Alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) OR ⁶ , -C (O) R ⁶ , -S (O) _m R ⁶ , -NR ⁷ R ⁸ , -S (O) _m NR ⁷ R ⁸ and -C (O) NR ⁷ R ⁸ ; R ^{3 is the} same or different, And each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, Cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl; each of R ⁴ and R ^{5 is} independently selected from a hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclic Group, aryl group, and heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently selected from alkyl, alkoxy, halogen, amine, and cyano , Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted with one or more substituents; or, R ⁴ and R ⁵ together with the nitrogen atom to which they are attached A heterocyclic group is formed, wherein the heterocyclic group contains 1 to 2 heteroatoms which are the same or different and are selected from N, O and S, and the heterocyclic group is optionally selected from alkyl, alkoxy, halogen, and amine Group, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted with one or more substituents; R ^{6 is} selected from a hydrogen atom, an alkyl group, and an amine Group, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R ⁷ and R ⁸ are each independently selected from a hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aromatic And heteroaryl, where the alkyl Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents; or, R ⁷ and R ⁸ together with the nitrogen atom to form a heterocyclic group, wherein the heterocyclic group contains 1 ~ 2 heteroatoms which are the same or different and are selected from N, O and S, and the heterocyclic group is optionally selected from alkyl, alkoxy, halogen, amine, cyano, nitro, hydroxy, hydroxyalkyl, Substituted with one or more substituents of cycloalkyl, heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2, 3, or 4; s is 0, 1, 2, or 3; and m is 0, 1, or 2. 如申請專利範圍第1項所述之通式(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醫藥上可接受之鹽，其中環A為雜芳基。     The compound represented by the general formula (I) or the tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof or a pharmaceutically acceptable salt thereof, wherein ring A is a heteroaryl group.     如申請專利範圍第2項所述之通式(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醫藥上可接受之鹽，其中環A為5員或6員雜芳基。     The compound represented by the general formula (I) or the tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5-membered or 6-membered heteroaryl group.     如申請專利範圍第3項所述之通式(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醫藥上可接受之鹽，其中環A為吡啶基。     The compound represented by the general formula (I) or the tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof or a pharmaceutically acceptable salt thereof, wherein ring A is pyridyl.     如申請專利範圍第1或2項所述之通式(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醫藥上可接受之鹽，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醫藥上可接受之鹽， 其中：R ¹~R ⁵、n和s如申請專利範圍第1項中所定義。 The compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or a tautomer, meso, racemate, enantiomer, diastereomer Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, Among them: R ¹ ~ R ⁵ , n and s are as defined in the first scope of the patent application. 如申請專利範圍第1至5項中任一項所述之通式(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醫藥上可接受之鹽，其中R ⁴和R ⁵均為氫原子。 The compound represented by the general formula (I) as described in any one of claims 1 to 5 or a tautomer, meso, racemate, enantiomer, diastereomer Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁴ and R ⁵ are both hydrogen atoms. 如申請專利範圍第1至6項中任一項所述之通式(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醫藥上可接受之鹽，其為通式(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醫藥上可接受之鹽， 其中：R ¹和R ²如如申請專利範圍第1項中所定義。 The compound represented by the general formula (I) as described in any one of claims 1 to 6 or a tautomer, meso, racemate, enantiomer, diastereomer Enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or a tautomer, meso, racemate, enantiomer Isomers, diastereomers, or a mixture thereof or a pharmaceutically acceptable salt thereof, Wherein: R ¹ and R ² are as defined in item 1 of the scope of patent application. 如申請專利範圍第1至7項中任一項所述之通式(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醫藥上可接受之鹽，其中R ¹選自氫原子、烷基、環烷基和雜環基。 The compound represented by the general formula (I) as described in any one of claims 1 to 7 or a tautomer, meso, racemate, enantiomer, diastereomer An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group. 如申請專利範圍第1至8項中任一項所述之通式(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醫藥上可接受之鹽，其中R ²為氫原子或烷基。 The compound represented by the general formula (I) as described in any one of claims 1 to 8 or a tautomer, meso, racemate, enantiomer, diastereomer An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom or an alkyl group. 如申請專利範圍第1至6項中任一項所述之通式(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醫藥上可接受之鹽，其中R ³為氫原子。 The compound represented by the general formula (I) as described in any one of claims 1 to 6 or a tautomer, meso, racemate, enantiomer, diastereomer An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom. 如申請專利範圍第1至10項中任一項所述之通式(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醫藥上可接受之鹽，其選自： The compound represented by the general formula (I) as described in any one of claims 1 to 10 or a tautomer, meso, racemate, enantiomer, diastereomer Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, are selected from: 一種製備如申請專利範圍第1項所述之通式(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醫藥上可接受之鹽的方法，該方法包括： 通式(I-A)的化合物和通式(I-B)的化合物反應，得到通式(I)的化合物， 其中：W為硼酸基或4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基；X為鹵素；環A、R ¹~R ⁵、n和s如申請專利範圍第1項中所定義。 Preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer as described in item 1 of the scope of patent application , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: A compound of the general formula (IA) and a compound of the general formula (IB) are reacted to obtain a compound of the general formula (I), wherein: W is a boronic acid group or 4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl; X is halogen; rings A, R ¹ to R ⁵ , n and s are as defined in item 1 of the scope of patent application. 如申請專利範圍第12項所述之方法，其中X為溴。     The method as described in claim 12 in which X is bromine.     一種製備如申請專利範圍第1項所述之通式(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醫藥上可接受之鹽的方法，該方法包括： 通式(I-Aa)的化合物和通式(I-Bb)的化合物反應，得到通式(I)的化合物，其中：W為硼酸基或4,4,5,5-四甲基-1,3,2-二氧雜硼環戊烷-2-基；X為鹵素；環A、R ¹~R ⁵、n和s如申請專利範圍第1項中所 定義。 Preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer as described in item 1 of the scope of patent application , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: A compound of the general formula (I-Aa) and a compound of the general formula (I-Bb) are reacted to obtain a compound of the general formula (I), wherein: W is a boric acid group or 4,4,5,5-tetramethyl-1 , 3,2-dioxaborylcyclopentane-2-yl; X is halogen; rings A, R ¹ to R ⁵ , n and s are as defined in the first item of the scope of patent application. 如申請專利範圍第14項所述的方法，其中X為溴。     The method as described in claim 14 in which X is bromine.     一種醫藥組成物，該醫藥組成物含有治療有效量的如申請專利範圍第1至11項中任一項所述之通式(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、或其醫藥上可接受之鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。     A medicinal composition containing a therapeutically effective amount of a compound represented by the general formula (I) as described in any one of claims 1 to 11 of the scope of application for a patent, or a tautomer or meso , Racemates, enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients .     一種申請專利範圍第1至11項中任一項所述之通式(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、或其醫藥上可接受之鹽或申請專利範圍第16項所述的醫藥組成物的用途，其用在製備用於治療、預防或減少腫瘤細胞轉移的藥物。     A compound represented by the general formula (I) described in any one of claims 1 to 11 or a tautomer, meso, racemate, enantiomer, diastereomer Enantiomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the use of a medicinal composition described in claim 16, which is used to prepare a medicament for treating, preventing or reducing tumor cell metastasis .     一種申請專利範圍第1至11項中任一項所述之通式(I)所示的化合物或其互變異構體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其醫藥上可接受之鹽或申請專利範圍第16項所述的醫藥組成物的用途，其用在製備用於治療、預防或減少由TGF-β過度表達介導的腫瘤的藥物。     A compound represented by the general formula (I) described in any one of claims 1 to 11 or a tautomer, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition described in claim 16 for the preparation of a tumor for the treatment, prevention, or reduction of TGF-β overexpression Drug.     一種申請專利範圍第1至11項中任一項所述之通式(I)所示的化合物或其互變異構體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其醫藥上可接受之鹽或申請專利範圍第16項所述的醫藥組成物的 用途，其用在製備用於治療、預防或減輕疾病的藥物，該疾病選自：心血管疾病、各類炎症、腫瘤、各種病因的纖維化、血管損傷、腎病、肝功能障礙、肺病、成人呼吸窘迫綜合症、內膜增厚、眼部疾病、發生在由創傷或手術傷口所致傷口癒合期間的過度性或肥厚性真皮瘢痕或瘢痕疙瘩形成、腹膜與皮下粘連、硬皮病、纖維硬化、進行性系統性硬化病、骨質疏鬆、潰瘍、神經系統功能減低、男性***功能障礙、佩羅尼氏病、杜普伊特倫氏攣縮、阿爾茨海默氏病和雷諾氏綜合症。     A compound represented by the general formula (I) described in any one of claims 1 to 11 or a tautomer, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition described in item 16 of the scope of patent application, which is used to prepare a medicament for treating, preventing or reducing a disease selected from the group consisting of: heart Vascular diseases, various inflammations, tumors, various causes of fibrosis, vascular injury, kidney disease, liver dysfunction, lung disease, adult respiratory distress syndrome, endometrial thickening, eye diseases, caused by trauma or surgical wounds Excessive or hypertrophic dermal scar or keloid formation during wound healing, peritoneal and subcutaneous adhesions, scleroderma, fibrosis, progressive systemic sclerosis, osteoporosis, ulcers, decreased nervous system function, male erectile dysfunction, Peyronie's disease, Dupuytren's contracture, Alzheimer's disease and Raynaud's syndrome.     一種申請專利範圍第1至11項中任一項所述之通式(I)所示的化合物或其互變異構體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其醫藥上可接受之鹽或申請專利範圍第16項所述的醫藥組成物的用途，其用在製備抑制TGF-β信號傳導途徑的藥物。     A compound represented by the general formula (I) described in any one of claims 1 to 11 or a tautomer, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition described in item 16 of the scope of patent application, which is used for preparing a medicament for inhibiting the TGF-β signaling pathway.