TWI437985B - Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof - Google Patents

Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof Download PDF

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TWI437985B
TWI437985B TW98100578A TW98100578A TWI437985B TW I437985 B TWI437985 B TW I437985B TW 98100578 A TW98100578 A TW 98100578A TW 98100578 A TW98100578 A TW 98100578A TW I437985 B TWI437985 B TW I437985B
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TW201026311A (en
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Peng Cho Tang
Hejun Lu
Hao Zheng
Yiqian Chen
Hongbo Fei
Shenglan Wang
Li Wang
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Shanghai Hengrui Pharm Co Ltd
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雙環取代吡唑酮偶氮類衍生物、其製備方法及其在醫藥上的應用Bicyclic substituted pyrazolone azo derivative, preparation method thereof and application thereof in medicine

本發明涉及通式(I)所示新的雙環取代吡唑酮偶氮類衍生物、其製備方法以及含有該衍生物的醫藥組合物、以及其作為治療劑特別是血小板生成素(TPO)類似物和它們用作血小板生成素受體激動劑的用途。The present invention relates to a novel bicyclic-substituted pyrazolone azo derivative of the formula (I), a process for the preparation thereof, and a pharmaceutical composition containing the same, and a therapeutic agent thereof, particularly thrombopoietin (TPO) And their use as thrombopoietin receptor agonists.

血小板生成素(Thrombopoietin,TPO),又稱為巨核細胞生長發育因數(megakaryocytegrowth and development factor,MGDF),血小板生成刺激因數(thrombocytopoiesis stimulating factor,TSF),c-Mpl配體(c-myeloproliferative feukemia ligand,c-Mpl),mpl配體,megapoietin是一種與產生血小板有關的糖蛋白(Wendling,F.,et. al.,Biotherapy 10(4):269-77(1998);Kuter D. l. et al.,The Oncologist;1:98-106(1996);Metcalf,Nature 369:519-520(1994))。Thrombopoietin (TPO), also known as megakaryocyte growth and development factor (MGDF), thrombocytopoiesis stimulating factor (TSF), c-myeloproliferative feukemia ligand (c-myeloproliferative feukemia ligand, c-Mpl), mpl ligand, megapoietin is a glycoprotein associated with platelet production (Wendling, F., et. al., Biotherapy 10(4): 269-77 (1998); Kuter D. l. et al , The Oncologist; 1: 98-106 (1996); Metcalf, Nature 369: 519-520 (1994)).

在某些情況下,TPO的活性源自TPO與TPO受體(也稱MPL)的結合。TPO受體已經被成功克隆,也進行了氨基酸序列的測序(Vigon et al.,Proc. Nat. Acad. Sci.,89:5640-5644(1992))。In some cases, the activity of TPO is derived from the binding of TPO to the TPO receptor (also known as MPL). The TPO receptor has been successfully cloned and the amino acid sequence has also been sequenced (Vigon et al., Proc. Nat. Acad. Sci., 89: 5640-5644 (1992)).

TPO是一種332-氨基酸糖基化多肽,在調節巨核細胞生成和由骨髓巨核細胞產生血小板的過程中起著關鍵的作用(Kuter et al.,Proc. Nat. Acad. Sci. USA 91:11104-11108(1994);Barley et al.,Cell 77:1117-1124(1994);Kaushansky et al.,Nature 369:568-571(1994);Wendling et al.,Nature 369:571-574(1994);and Sauvage et al.,Nature 369:533-538(1994))。TPO產生於肝臟但主要作用於骨髓,刺激幹細胞分化成為巨核細胞以及巨核細胞的增殖,多倍體化,最重要的是進入血小板身體循環分裂。TPO在血小板減少症和大量關於增加血小板數量、大小、增加實驗動物同位素參入血小板的研究中是一種主要的調節劑(Metcalf Nature 369:519-520(1994))。TPO被認為主要通過幾個途徑影響巨核細胞生成:(1)引起巨核細胞大小和數量的增加;(2)增加DNA內含物,多倍體的形式,巨核細胞;(3)增加巨核細胞的核內有絲分裂;(4)增加成熟的巨核細胞;(5)增加前體細胞的百分比,小乙醯膽鹼酶-陽性形式的細胞,骨髓細胞。TPO is a 332-amino acid glycosylation polypeptide that plays a key role in regulating megakaryocyte production and platelet production by bone marrow megakaryocytes (Kuter et al., Proc. Nat. Acad. Sci. USA 91:11104- 11108 (1994); Barley et al., Cell 77: 1117-1124 (1994); Kaushansky et al., Nature 369: 568-571 (1994); Wendling et al., Nature 369: 571-574 (1994); And Sauvage et al., Nature 369: 533-538 (1994)). TPO is produced in the liver but mainly acts on the bone marrow, stimulating the differentiation of stem cells into megakaryocytes and proliferation of megakaryocytes, polyploidization, and most importantly, into the platelet body cycle. TPO is a major regulator of thrombocytopenia and a large number of studies on increasing the number and size of platelets and increasing the isotope of experimental animals into platelets (Metcalf Nature 369:519-520 (1994)). TPO is thought to affect megakaryocyte production mainly through several pathways: (1) causing an increase in the size and number of megakaryocytes; (2) increasing DNA inclusions, polyploid forms, megakaryocytes; (3) increasing megakaryocytes Mitochondrial mitosis; (4) increase of mature megakaryocytes; (5) increase the percentage of precursor cells, small acetylcholinease-positive forms of cells, bone marrow cells.

血小板是血液凝固必需的,當它的數量非常低時,病人就有出血死亡的危險。因此,TPO已經被用於診斷和治療多種血液疾病,如主要由血小板缺陷引起的疾病。同時,TPO可以用於治療血小板減少症,尤其是為治療癌症和淋巴瘤而進行的化療、放療和骨髓移植。Platelets are essential for blood clotting, and when it is very low, the patient is at risk of bleeding. Therefore, TPO has been used to diagnose and treat a variety of blood diseases, such as those caused primarily by platelet defects. At the same time, TPO can be used to treat thrombocytopenia, especially chemotherapy, radiation and bone marrow transplants for the treatment of cancer and lymphoma.

患者因血小板減少症而導致血小板水準恢復過慢是一個嚴重的問題,因此希望可以找到一種治療血小板減少症的活性TPO類似物。幾年前,多肽類TPO類似物的發展被報導。(WO96/40750,WO98/25965)這些多肽可以結合並活化TPO受體,但是不具備天然TPO的序列同源性。最近幾年,一些小分子的活性TPO類似物被報導。包括1,4-苯並二氮雜卓-2-酮類(JP11001477),由希夫鹼配體得到的金屬絡合物(WO 99/11262),環多胺衍生物(WO00/28987),噻唑-2-基-苯醯胺類(WO01/07423,WO01/53267),偶氮-芳基衍生物(WO00/35446,WO1/17349),2-芳基-萘唑類(WO01/39773,WO01/53267)和縮氨基脲衍生物(WO01/34585)。在基於細胞的體系內,所有這些分子都能活化細胞膜上的TPO受體的信號轉導途徑,一些類型能直接作用於TPO受體本身。據介紹,取代縮氨硫脲居然是非常有效的TPO受體激動劑。這一系列中一些最優先的化合物被發現可以刺激TPO-responsive人類細胞系和低於100nM的人類骨髓培養液中的TPO的增殖和分化。Patients with thrombocytopenia due to thrombocytopenia are a serious problem, so it is hoped that an active TPO analog for thrombocytopenia can be found. A few years ago, the development of peptide TPO analogs was reported. (WO 96/40750, WO 98/25965) These polypeptides bind to and activate the TPO receptor, but do not possess the sequence homology of native TPO. In recent years, some small molecule active TPO analogs have been reported. Including 1,4-benzodiazepine-2-ones (JP11001477), metal complexes obtained from Schiff base ligands (WO 99/11262), cyclic polyamine derivatives (WO 00/28987), thiazole -2-yl-benzoguanamines (WO 01/07423, WO 01/53267), azo-aryl derivatives (WO 00/35446, WO 1/17349), 2-aryl-naphthazoles (WO 01/39773, WO 01) /53267) and a semicarbazone derivative (WO 01/34585). Within a cell-based system, all of these molecules activate the signal transduction pathway of the TPO receptor on the cell membrane, and some types act directly on the TPO receptor itself. According to reports, the replacement of thiourea is actually a very effective TPO receptor agonist. Some of the most preferential compounds in this series have been found to stimulate the proliferation and differentiation of TPO in TPO-responsive human cell lines and human bone marrow broth below 100 nM.

GSK公司在專利(WO-00189457/WO-01089457/WO-2006064957)中報導血小板生成素類似物eltrombopag,並表現出了相當的活性。The thrombopoietin analog eltrombopag is reported by the GSK company in the patent (WO-00189457/WO-01089457/WO-2006064957) and exhibits considerable activity.

本發明公開了一系列化合物且更有效地用作TPO受體激動劑,是有效的TPO類似物。The present invention discloses a series of compounds and is more effective as a TPO receptor agonist and is a potent TPO analog.

為了克服現有技術的不足之處,本發明的目的在於提供一種通式(I)所示的雙環取代吡唑酮偶氮類衍生物,以及它們的互變異構體、對映體、非對映體、消旋體和藥學上可接受的鹽、水合物或溶劑化物,以及代謝產物和代謝前體或前藥。In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a bicyclic substituted pyrazolone azo derivative represented by the general formula (I), and their tautomers, enantiomers and diastereoisomers. Body, racemate and pharmaceutically acceptable salts, hydrates or solvates, as well as metabolites and metabolic precursors or prodrugs.

其中:among them:

A選自碳原子或氧原子;A is selected from a carbon atom or an oxygen atom;

R選自氫原子或烷基;R is selected from a hydrogen atom or an alkyl group;

R1 、R2 、R3 和R4 各自獨立地選自氫原子、烷基、烷氧基、鹵素、芳基或雜芳基,其中芳基或雜芳基可進一步被一個或多個選自烷基、鹵素、羥基、四唑基、咪唑、二氫咪唑、羧酸或羧酸酯的取代基所取代;R 1 , R 2 , R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, an aryl group or a heteroaryl group, wherein the aryl group or the heteroaryl group may be further selected by one or more Substituted from a substituent of an alkyl group, a halogen, a hydroxyl group, a tetrazolyl group, an imidazole, a dihydroimidazole, a carboxylic acid or a carboxylic acid ester;

R5 、R6 和R7 各自獨立地選自氫原子、烷基、烷氧基、鹵素、羥基、氨基、硝基、氰基、羧酸或羧酸酯;R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;

R8 、R9 、R10 和R11 各自獨立地選自氫原子或烷基;且R 8 , R 9 , R 10 and R 11 are each independently selected from a hydrogen atom or an alkyl group;

n是0,1或2。n is 0, 1 or 2.

本發明較佳較佳的實施方案中,In a preferred embodiment of the invention,

A選自碳原子或氧原子;A is selected from a carbon atom or an oxygen atom;

R選自氫原子或烷基;R is selected from a hydrogen atom or an alkyl group;

R1 選自芳基或雜芳基,其中芳基或雜芳基可進一步被一個或多個選自烷基、鹵素、羥基、四唑基、咪唑、二氫咪唑、羧酸或羧酸酯的取代基所取代;R2 、R3 和R4 各自獨立地選自氫原子、烷基、烷氧基或鹵素;R 1 is selected from aryl or heteroaryl, wherein the aryl or heteroaryl group may be further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, tetrazolyl, imidazole, dihydroimidazole, carboxylic acid or carboxylic acid ester. Substituted by a substituent; R 2 , R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group or a halogen;

R5 、R6 和R7 各自獨立地選自氫原子、烷基、烷氧基、鹵素、羥基、氨基、硝基、氰基、羧酸或羧酸酯;R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;

R8 、R9 、R10 和R11 各自獨立地選自氫原子或烷基;且R 8 , R 9 , R 10 and R 11 are each independently selected from a hydrogen atom or an alkyl group;

n是0,1或2。n is 0, 1 or 2.

本發明通式(I)所示的化合物的較佳化合物包括,但不限於下列:Preferred compounds of the compound of the formula (I) of the present invention include, but are not limited to, the following:

或其藥學上可以接受的鹽、水合物或溶劑化物。Or a pharmaceutically acceptable salt, hydrate or solvate thereof.

進一步,本發明包括通式(IA)所示的化合物,其作為通式(I)化合物合成的中間體:Further, the present invention includes a compound represented by the formula (IA) which is an intermediate for the synthesis of the compound of the formula (I):

其中:among them:

A選自碳原子或氧原子;A is selected from a carbon atom or an oxygen atom;

R5 、R6 和R7 各自獨立地選自氫原子、烷基、烷氧基、鹵素、羥基、氨基、硝基、氰基、羧酸或羧酸酯;R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylic acid ester;

R8 、R9 、R10 和R11 各自獨立地選自氫原子或烷基;且R 8 , R 9 , R 10 and R 11 are each independently selected from a hydrogen atom or an alkyl group;

n是0,1或2。n is 0, 1 or 2.

本發明通式(IA)所示的化合物的較佳化合物包括,但不限於下列:Preferred compounds of the compound of the formula (IA) of the present invention include, but are not limited to, the following:

本發明另一方面是製備中間體(IA)所示化合物的方法,包括以下步驟:Another aspect of the invention is a process for the preparation of a compound of the intermediate (IA) comprising the steps of:

氨基取代的苯並多員環與亞硝酸鈉在酸性溶液中發生重氮化反應,再通過氯化亞錫還原得到肼,肼與親電子的羰基化合物如乙醯乙酸乙酯,在適宜的溶劑中(如乙酸、乙醇等)加熱下縮合得到通式(IA)化合物。The amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, hydrazine and an electrophilic carbonyl compound such as ethyl acetate, in a suitable solvent. Condensation under heating (e.g., acetic acid, ethanol, etc.) gives the compound of the formula (IA).

進一步,本發明的另一方面是提供通式(I)化合物的製備方法,該方法包括:Further, another aspect of the present invention provides a process for the preparation of a compound of the formula (I), which comprises:

將取代的苯胺類化合物與亞硝酸鈉在適宜的酸性溶液(如硝酸、硫酸、鹽酸)中進行重氮化反應,再與通式(IA)化合物在鹼性溶液(如碳酸氫鈉、碳酸氫鉀)中發生偶聯反應得到通式(I)化合物。The substituted aniline compound is diazotized with sodium nitrite in a suitable acidic solution (such as nitric acid, sulfuric acid, hydrochloric acid), and then mixed with a compound of the formula (IA) in an alkaline solution (such as sodium hydrogencarbonate or hydrogencarbonate). A coupling reaction occurs in potassium) to give a compound of the formula (I).

本發明涉及通式(I)和(IA)化合物在製備TPO受體激動劑中的用途,The present invention relates to the use of the compounds of the formulae (I) and (IA) for the preparation of TPO receptor agonists,

本發明涉及通式(I)和(IA)化合物在製備治療血小板減少症藥物中的用途。包括合併使用治療有效量的選自下列的藥物:集落刺激因數、細胞因數、趨化因數、白細胞介素或細胞因數受體激動劑或拮抗劑、可溶的受體、受體激動劑或拮抗劑抗體或與一個或多個所述藥物具有相同的機制而起作用的肽或小分子類。The present invention relates to the use of the compounds of the general formulae (I) and (IA) for the preparation of a medicament for the treatment of thrombocytopenia. This includes combining a therapeutically effective amount of a drug selected from the group consisting of colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonist, soluble receptor, receptor agonist or antagonist An antibody or a peptide or small molecule that functions in the same mechanism as one or more of the drugs.

本發明涉及一種藥用組合物,其包括藥物有效劑量的通式(I)和(IA)化合物及其藥學上可以接受的鹽、水合物或溶劑化物及藥學上可接受的鹽。該組合物可以進一步含有合併使用的治療有效量的選自下列的藥物:集落刺激因數、細胞因數、趨化因數、白細胞介素或細胞因數受體激動劑,以及該醫藥組合物在製備治療血小板減少症藥物的用途。The present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula (I) and (IA), and a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable salt thereof. The composition may further comprise a therapeutically effective amount of a drug selected from the group consisting of a colony stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist, and the pharmaceutical composition for preparing a therapeutic platelet The use of a reduction medication.

所述的合併使用包括同時使用或者先後依次使用本發明所述的化合物。The combined use includes the simultaneous or sequential use of the compounds described herein.

本發明涉及一種製備含有藥用載體或稀釋劑和有效量的通式(I)和(IA)化合物及其藥學上可以接受的鹽、水合物或溶劑化物的醫藥組合物的方法,該方法包括將通式(I)和(IA)化合物與藥用載體和稀釋劑相結合。The present invention relates to a process for the preparation of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula (I) and (IA), and a pharmaceutically acceptable salt, hydrate or solvate thereof, comprising The compounds of formula (I) and (IA) are combined with a pharmaceutically acceptable carrier and diluent.

除非有相反陳述,下列用在說明書和申請專利範圍中的術語具有下述含義。Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

“烷基”指飽和的脂族烴基團,包括1至20個碳原子的直鏈和支鏈基團。較佳含有1至10個碳原子的烷基,例如甲基、乙基、丙基、2-丙基、正丁基、異丁基、第三丁基或戊基等。更佳的是含有1至4個碳原子的低級烷基,例如甲基、乙基、丙基、2-丙基、正丁基、異丁基或第三丁基等。烷基可以是取代的或未取代的,當被取代時,取代基較佳為一個或多個,獨立地選自烷基、烷氧基、鹵素、羥基、氨基、硝基、氰基、芳基、雜芳基、羧酸或羧酸酯。"Alkyl" means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl groups and the like. More preferred are lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, aryl. Base, heteroaryl, carboxylic acid or carboxylic acid ester.

“芳基”指具有至少一個芳環結構的基團,即具有共軛的π電子體系的芳環,包括碳環芳基、雜芳基和聯芳基。炔基可以是取代的或未取代的,當被取代時,取代基較佳為一個或多個,獨立地選自烷基、烷氧基、鹵素、羥基、氨基、硝基、氰基、芳基、雜芳基、羧酸或羧酸酯。"Aryl" means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated π-electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, aryl. Base, heteroaryl, carboxylic acid or carboxylic acid ester.

“雜芳基”指具有1至4個雜原子作為環原子,其餘的環原子為碳的芳基,雜原子包括氧、硫和氮。所述環可以是5員或6員環。雜芳基基團的實例包括呋喃基、噻吩基、吡啶基、吡咯、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。雜芳基可以是取代的或未取代的,當被取代時,取代基較佳為一個或多個,獨立地選自烷基、烷氧基、鹵素、羥基、氨基、硝基、氰基、芳基、雜芳基、羧酸或羧酸酯。"Heteroaryl" refers to an aryl group having from 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen. The ring can be a 5 or 6 member ring. Examples of heteroaryl groups include furyl, thienyl, pyridyl, pyrrole, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, Aryl, heteroaryl, carboxylic acid or carboxylic acid ester.

“羥基”指-OH基團。"Hydroxy" refers to an -OH group.

“烷氧基”指-O-(烷基)和-O-(未取代的環烷基)。代表性實例包括但不限於甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基等。烷氧基可以是取代的或未取代的,當被取代時,取代基較佳為一個或多個,獨立地選自烷基、烷氧基、鹵素、羥基、氨基、硝基、氰基、芳基、雜芳基、羧酸或羧酸酯。"Alkoxy" means -O-(alkyl) and -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, Aryl, heteroaryl, carboxylic acid or carboxylic acid ester.

“鹵素”指氟、氯、溴或碘。"Halogen" means fluoro, chloro, bromo or iodo.

“氨基”指-NH2"Amino" means -NH 2 .

“氰基”指-CN。"Cyano" means -CN.

“硝基”指-NO2"Nitro" means -NO 2 .

“烷氧基”指-O-(烷基)。"Alkoxy" means -O-(alkyl).

“羧酸”指(烷基)C(=O)OH。"Carboxylic acid" means (alkyl)C(=O)OH.

“羧酸酯”指(烷基)C(=O)O(烷基)。"Carboxylic acid ester" means (alkyl)C(=O)O(alkyl).

“醫藥組合物”表示一種或多種本文所述化合物或其生理學上/藥學上可接受的鹽或前體藥物與其他化學組分的混合物,其他組分為例如生理學/藥學上可接受的載體和賦形劑。醫藥組合物的目的是促進化合物對生物體的給藥。"Pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable Carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

本發明化合物的合成方法Method for synthesizing the compound 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 accomplish the object of the present invention, the present invention adopts the following technical solutions:

流程圖IFlowchart I

氨基取代的苯並多環與亞硝酸鈉在酸性溶液中進行重氮化反應,再通過氯化亞錫還原得到肼,肼與親電子的羰基化合物如乙醯乙酸乙酯、在適宜的溶劑中(如乙酸、乙醇等)加熱下縮合得到通式(IA)化合物。The amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, hydrazine and an electrophilic carbonyl compound such as ethyl acetate, in a suitable solvent. Condensation under heating (e.g., acetic acid, ethanol, etc.) affords the compound of formula (IA).

流程圖IIFlowchart II

取代的鄰溴苯酚經硝酸鈉硝化得到硝基苯酚,硝基苯酚在適宜的溫度下與鹵代烷基,如碘甲烷發生烷基化反應得到羥基被保護的硝基苯酚;羥基被保護的硝基苯酚與取代的芳基硼酸在四(三苯基膦)鈀催化下發生Suzuki偶聯,或者與硼酸類化合物反應,得到的芳基硼酸類化合物與鹵代化合物R1 X發生Suzuki偶聯,得到R1 取代的芳基化合物;R1 取代的芳基化合物在氫氣氛下,經鈀/碳還原得到芳基苯胺,芳基苯胺在溴化氫中去掉烷基得到去保護的苯胺。或者,取代的芳基化合物在溴化氫中去掉烷基得到去保護的硝基化合物,硝基化合物在氫氣氛下,經鈀/碳還原得到去保護的芳基苯胺。Substituted o-bromophenol is nitrated to obtain nitrophenol, and nitrophenol is alkylated with a haloalkyl group such as methyl iodide at a suitable temperature to obtain a hydroxy-protected nitrophenol; a hydroxy-protected nitrophenol Suzuki coupling with a substituted aryl boronic acid under the catalysis of tetrakis(triphenylphosphine)palladium or a reaction with a boric acid compound, the resulting aryl boronic acid compound is Suzuki coupled with the halogenated compound R 1 X to obtain R A 1- substituted aryl compound; an R 1 -substituted aryl compound is reduced by palladium on carbon under hydrogen atmosphere to give an aryl aniline, and the aryl aniline is removed from the alkyl bromide to give a deprotected aniline. Alternatively, the substituted aryl compound is deprotected from the alkyl group in hydrogen bromide to give the deprotected nitro compound. The nitro compound is reduced under palladium on carbon under hydrogen to give the deprotected aryl aniline.

將取代的苯胺類化合物與亞硝酸鈉在適宜的酸性溶液(如硝酸、硫酸、鹽酸)中重氮化,再與通式(IA)化合物在鹼性溶液(如碳酸氫鈉、碳酸氫鉀)中發生偶聯反應得到通式(I)化合物。Diluting the substituted aniline compound with sodium nitrite in a suitable acidic solution (such as nitric acid, sulfuric acid, hydrochloric acid), and then reacting the compound of the formula (IA) with an alkaline solution (such as sodium hydrogencarbonate or potassium hydrogencarbonate) The coupling reaction takes place to give a compound of the formula (I).

以下結合實施例用於進一步描述本發明,但這些實施例並非限制著本發明的範圍。The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

實施例Example

化合物的結構是通過核磁共振(1 HNMR)或質譜(MS)來確定的。1 HNMR位移(δ)以百萬分之一(ppm)的單位計。1 HNMR的測定是用Bruker AVANCE-400核磁儀,測定溶劑為氘代甲醇(CD3 OD)、氘代氯仿(CDCl3 ),六氘代二甲基亞碸(DMSO-d6)內標為四甲基矽烷(TMS),化學位移是以10-6 (ppm)作為單位計;The structure of the compound is determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS). The 1 H NMR shift (δ) is in parts per million (ppm). The 1 H NMR measurement was performed on a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), and the hexa-deuterated dimethyl hydrazine (DMSO-d6) was internally labeled as four. Methyl decane (TMS), chemical shift in units of 10 -6 (ppm);

MS的測定用FINNIGAN LCQAd(ESI)質譜儀(生產商:Therm,型號:Finnigan LCQ advantage MAX;The measurement of MS was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX;

IC50 值的測定用NovoStar酶標儀(德國BMG公司);The IC 50 value was determined using a NovoStar plate reader (BMG, Germany);

薄層矽膠使用煙臺黃海HSGF254或青島GF254矽膠板;Thin layer of silicone rubber using Yantai Yellow Sea HSGF254 or Qingdao GF254 silicone sheet;

矽膠管柱層析一般使用煙臺黃海矽膠200至300目矽膠為載體;Tannin tube chromatography is generally carried out using Yantai Huanghai Silicone 200 to 300 mesh silicone as a carrier;

HPLC測試使用安捷倫1200DAD高壓液相層析儀(Sunfire C18 150×4.6mm層析柱)和Waters 2695-2996高壓液相層析儀(Gimini C18 150×4.6mm層析柱)The HPLC test was performed using an Agilent 1200 DAD high pressure liquid chromatography (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150 x 4.6 mm column).

加壓氫化反應使用Pau 3916EKX型氫化儀和清藍QL型氫氣發生器;微波反應使用CEM Discover-S 908860型微波反應器;The pressurized hydrogenation reaction uses a Pau 3916EKX type hydrogenation apparatus and a clear blue QL type hydrogen generator; the microwave reaction uses a CEM Discover-S 908860 type microwave reactor;

實施例中無特殊說明,反應均在氮氣氛下進行;Unless otherwise stated in the examples, the reactions were all carried out under a nitrogen atmosphere;

氮氣氛是指反應瓶連接一個約1L容積的氮氣氣球;The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;

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

實施例中無特殊說明,反應中的溶液是指水溶液;Unless otherwise specified in the examples, the solution in the reaction means an aqueous solution;

TLC是指薄層層析。TLC refers to thin layer chromatography.

實施例1Example 1 2’-羥基-3’-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-聯苯基-3-羧酸2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-biphenyl-3-carboxylic acid

第一步first step 2-溴-6-硝基苯酚2-bromo-6-nitrophenol

將60mL濃硫酸稀釋到186mL水中,冷卻至室溫後加入硝酸鈉(79.2g,0.932mol),保持25℃以下,滴加鄰溴苯酚1a(60mL,0.516mol),室溫反應2小時。以TLC追蹤至原料消失,加入320mL乙酸乙酯溶解析出的固體,分別用水和飽和氯化鈉溶液洗滌,用無水硫酸鎂乾燥,過濾,濾液減壓濃縮,用矽膠管柱層析法純化所得殘餘物,得到標題產物2-溴-6-硝基苯酚1b(48.2g,黃色固體)。產率:42.8%。MS m/z(ESI):218[M+1]1 HNMR(400MHz,CDCl3 ):δ6.88-7.02(m,1H),7.89-7.91(d,J=8Hz,1H),8.12-8.15(m,1H),11.18(s,1H)60 mL of concentrated sulfuric acid was diluted into 186 mL of water, and after cooling to room temperature, sodium nitrate (79.2 g, 0.932 mol) was added thereto, and the mixture was kept at 25 ° C or lower, and o-bromophenol 1a (60 mL, 0.516 mol) was added dropwise thereto, and the mixture was reacted at room temperature for 2 hours. The residue was removed by TLC, and the precipitated solid was dissolved by adding ethyl acetate (320 mL), and washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography. The title product 2-bromo-6-nitrophenol 1b (48.2 g, yellow solid) was obtained. Yield: 42.8%. MS m/z (ESI): 218 [M + 1] 1 H NMR (400 MHz, CDCl 3 ): δ 6.88 - 7.02 (m, 1H), 7.89 - 7.91 (d, J = 8 Hz, 1H), 8.12 - 8.15 (m, 1H), 11.18 (s, 1H)

第二步Second step 1-溴-2-甲氧基-3-硝基苯1-bromo-2-methoxy-3-nitrobenzene

將2-溴-6-硝基苯酚1b(46.55g,0.214mol)溶解於500mL丙酮中,加入碳酸鉀(35.36g,0.256mol)和碘甲烷(20.1mL,0.32mol),70℃加熱回流40小時。以TLC追蹤至原料消失,減壓濃縮,加入1300mL乙酸乙酯和500mL水,水相用乙酸乙酯萃取(300mL×2),合併有機相,分別用4N鹽酸和飽和碳酸氫鈉溶液洗滌,用無水硫酸鎂乾燥,過濾,濾液減壓濃縮,用矽膠管柱層析法純化所得殘餘物,得到標題產物1-溴-2-甲氧基-3-硝基苯1c(44.59g,棕色固體)。產率:90.0%。MS m/z(ESI):234[M+1]2-Bromo-6-nitrophenol 1b (46.55 g, 0.214 mol) was dissolved in 500 mL of acetone, potassium carbonate (35.36 g, 0.256 mol) and methyl iodide (20.1 mL, 0.32 mol) were added, and heated at 70 ° C under reflux 40 hour. The residue was evaporated to dryness with EtOAc (EtOAc) (EtOAc) The residue was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ . Yield: 90.0%. MS m/z (ESI): 234 [M+1]

第三步third step 2’-甲氧基-3’-硝基聯苯基-3-羧酸2'-Methoxy-3'-nitrobiphenyl-3-carboxylic acid

將1-溴-2-甲氧基-3-硝基苯1c(23.25g,0.10mol)、3-羧基苯基硼酸(19.5g,0.117mol)和四(三苯基膦)鈀(8.86g,7.7mol)溶解於100mL 2N碳酸鈉溶液和500mLl,4-二氧陸圜的混和溶劑中,105℃加熱回流43小時。以TLC追蹤至原料消失,減壓濃縮,加入300mL 6N鹽酸溶液和400mL乙酸乙酯,水相用乙酸乙酯萃取(200mL×2),合併有機相,用無水硫酸鎂乾燥,過濾,濾液減壓濃縮,得到標題產物2’-甲氧基-3’-硝基聯苯基-3-羧酸1d(53.93g,淺黃色固體)。MS m/z(ESI):272[M-1]1 HNMR(400MHz,CDCl3 ):δ3.44-3.46(d,J=8Hz,3H),7.42-7.46(m,1H),7.63-7.67(m,1H),7.21-7.75(m,1H),7.82-7.84(m,1H),7.90-7.92(m,1H),8.01-8.03(d,J=8Hz,1H),8.11(s,1H)1-Bromo-2-methoxy-3-nitrobenzene 1c (23.25 g, 0.10 mol), 3-carboxyphenylboronic acid (19.5 g, 0.117 mol) and tetrakis(triphenylphosphine)palladium (8.86 g) 7.7 mol) was dissolved in a mixed solvent of 100 mL of 2N sodium carbonate solution and 500 mL of 1,4-dioxane, and heated under reflux at 105 ° C for 43 hours. The residue was evaporated to dryness eluting with EtOAc (EtOAc) (EtOAc) Concentration gave the title product 2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid 1d (53.93 g, pale yellow solid). MS m/z (ESI): 272 [M-1] 1 H NMR (400 MHz, CDCl 3 ): δ 3.44 - 3.46 (d, J = 8 Hz, 3H), 7.42 - 7.46 (m, 1H), 7.63 - 7.67 (m, 1H), 7.21-7.75 (m, 1H), 7.82-7.84 (m, 1H), 7.90-7.92 (m, 1H), 8.01-8.03 (d, J = 8 Hz, 1H), 8.11 (s, 1H)

第四步the fourth step 2’-甲氧基-3’-氨基聯苯基-3-羧酸2'-Methoxy-3'-aminobiphenyl-3-carboxylic acid

將2’-甲氧基-3’-硝基聯苯基-3-羧酸1d(0.48g,1.74mmol)溶解於60mL乙醇中,加入0.5g鈀-碳和甲酸銨(1.1g,17.4mmol),80℃加熱回流20分鐘。以TLC追蹤至原料消失,過濾,濾液減壓濃縮,乾燥,得到標題產物2’-甲氧基-3’-氨基聯苯基-3-羧酸1e(0.42g,白色固體)。產率:93.3%。MS m/z(ESI):242[M-1]2'-Methoxy-3'-nitrobiphenyl-3-carboxylic acid 1d (0.48 g, 1.74 mmol) was dissolved in 60 mL of ethanol, and 0.5 g of palladium-carbon and ammonium formate (1.1 g, 17.4 mmol) were added. The mixture was heated to reflux at 80 ° C for 20 minutes. The residue was evaporated to dryness eluted with EtOAc (EtOAc) elute Yield: 93.3%. MS m/z (ESI): 242 [M-1]

第五步the fifth step 3’-氨基-2’-羥基聯苯基-3-羧酸氫溴酸鹽3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide salt

將2’-甲氧基-3’-氨基聯苯基-3-羧酸1e(2.5g,10.3mmol)溶解於100mL氫溴酸溶液(40%)中,120℃加熱回流過夜。以TLC追蹤至原料消失,減壓濃縮,用矽膠管柱層析法純化所得殘餘物,得到標題產物3’-氨基-2’-羥基聯苯基-3-羧酸氫溴酸鹽1f(2.4g,土黃色固體),產率:88.8%。MS m/z(ESI):230[M+1][注:參考文獻:WO0189457]2'-Methoxy-3'-aminobiphenyl-3-carboxylic acid 1e (2.5 g, 10.3 mmol) was dissolved in 100 mL of a hydrobromic acid solution (40%), and heated to reflux overnight at 120 °C. The residue was purified by TLC, and then evaporated to dryness. g, khaki solid), Yield: 88.8%. MS m/z (ESI): 230 [M + 1] [Note: Reference: WO0189457]

第六步Step 6 5-肼基茚滿5-肼基茚满

冰浴下將5-氨基茚滿1g(3.59g,27.0mmol)溶解於20mL濃鹽酸中,攪拌10分鐘。滴加入10mL亞硝酸鈉溶液(1.86g,27.0mmol),冰浴下繼續攪拌15分鐘備用。5-Aminoindan 1 g (3.59 g, 27.0 mmol) was dissolved in 20 mL of concentrated hydrochloric acid under ice-cooling and stirred for 10 min. 10 mL of sodium nitrite solution (1.86 g, 27.0 mmol) was added dropwise, and stirring was continued for 15 minutes in an ice bath.

冰鹽浴下將二水合氯化亞錫(24.4g,108.0mmol)溶解於10mL濃鹽酸中,將備用中間體溶液加入其中,升至室溫反應1.5小時。冰浴下用40%氫氧化鈉溶液調pH至9,加入400mL乙酸乙酯萃取,減壓濃縮,乾燥,得到標題產物5-肼基茚滿1h(2.05g,紅棕色固體)。產率:51.3%。MS m/z(ESI):149[M+1]Stannous chloride dihydrate (24.4 g, 108.0 mmol) was dissolved in 10 mL of concentrated hydrochloric acid under ice-salt bath, and the intermediate intermediate solution was added thereto, and the mixture was allowed to react at room temperature for 1.5 hours. The mixture was adjusted to pH 9 with a 40% EtOAc EtOAc. EtOAc (EtOAc) Yield: 51.3%. MS m/z (ESI): 149 [M+1]

第七步Seventh step 2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one

將5-肼基茚滿1h(2.05g,13.8mmol)溶解於50mL乙酸中,加入乙醯乙酸乙酯(1.76mL,13.8mmol),加熱至100℃過夜。以TLC追蹤至原料消失,減壓濃縮,用矽膠管柱層析法純化所得殘餘物,得到標題產物2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(1.84g,黃色固體)。產率:62.3%。MS m/z(ESI):215[M+1]1 HNMR(400MHz,CDCl3 ):δ7.69(s,1H),7.60(d,J=8.0Hz,1H),7.24(d,J=8Hz,lH),3.44(s,2H),2.90-2.97(m,4H),3.21(s,3H),2.07-2.14(m,2H)。The 5-mercaptopurpur 1 h (2.05 g, 13.8 mmol) was dissolved in 50 mL of ethyl acetate. ethyl acetate ethyl acetate (1.76 mL, 13.8 mmol) The residue was purified by TLC, evaporated, evaporated, evaporated, evaporated, - Ketone 1i (1.84 g, yellow solid). Yield: 62.3%. MS m/z (ESI): 215 [M+1] 1 H NMR (400 MHz, CDCl 3 ): δ 7.69 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8 Hz, lH), 3.44 (s, 2H), 2.90-2.97 (m, 4H), 3.21 (s, 3H), 2.07-2.14 (m, 2H).

第八步Eighth step 2’-羥基-3’-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-聯苯基-3-羧酸2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基聯苯基-3-羧酸氫溴酸鹽1f(267mg,1.16mmol)溶解於10mL鹽酸(1N)中,滴加入10mL亞硝酸鈉溶液(88mg,1.28mmol),再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮li(249mg,1.16mmol),用飽和碳酸氫鈉溶液將反應液pH調至8,加入10mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾,乾燥,用甲醇再結晶,得到標題產物2’-羥基-3’-[N’-(1-茚滿-5-基-3-甲基-5-羰基-1,5-二氫吡唑-4-亞基)-肼基]-聯苯基-3-羧酸1(60mg,黃色固體)。產率:11.4%。MS m/z(ESI):453[M-1]1 HNMR(400MHz,DMSO-d 6 ):δ2.03-2.10(m,2H),2.34(s,3H),2.86-2.93(m,4H),7.13-7.17(m,2H),7.28-7.30(d,J=8.1Hz,1H),7.60-7.82(m,5H),7.96-7.98(d,J=8.1Hz,1H),8.13(s,1H),9.66(s,1H),13.03(s,1H),13.76(s,1H)。3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (267 mg, 1.16 mmol) was dissolved in 10 mL of hydrochloric acid (1 N) under ice bath, and 10 mL of sodium nitrite solution (88 mg) was added dropwise. , 1.28 mmol), followed by 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (249 mg, 1.16 mmol), using a saturated sodium hydrogen carbonate solution The pH was adjusted to 8, and 10 mL of ethanol was added and allowed to warm to room temperature overnight. The residue was traced by TLC, filtered, dried and recrystallized from methanol to give the title product 2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-carbonyl- 1,5-Dihydropyrazole-4-ylidene)-indenyl]-biphenyl-3-carboxylic acid 1 (60 mg, yellow solid). Yield: 11.4%. MS m/z (ESI): 453 [M-1] 1 H NMR (400 MHz, DMSO- d 6 ): δ 2.03-2.10 (m, 2H), 2.34 (s, 3H), 2.86-2.93 (m, 4H) ), 7.13-7.17 (m, 2H), 7.28-7.30 (d, J = 8.1 Hz, 1H), 7.60-7.82 (m, 5H), 7.96-7.98 (d, J = 8.1 Hz, 1H), 8.13 ( s, 1H), 9.66 (s, 1H), 13.03 (s, 1H), 13.76 (s, 1H).

實施例2Example 2 5’-氟-2’-羥基-3’-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-聯苯基-3-羧酸5'-Fluoro-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-oxy-1,5-dihydropyrazole-4-arylene Base)-fluorenyl]-biphenyl-3-carboxylic acid

第一步first step 2-溴-4-氟-6-硝基苯酚2-bromo-4-fluoro-6-nitrophenol

冰鹽浴下將2-溴-4-氟-苯酚2a(8.0g,41.9mmol)溶解於10mL硫酸溶液(50%)中,滴加入硝酸鈉(7.1g,83.5mmol)的24mL硫酸溶液(25%),室溫反應1.5小時。以TLC追蹤至原料消失,加入50mL水,用乙酸乙酯萃取(50mL×2),合併有機相,乙酸乙酯層分別用水和飽和碳酸氫鈉溶液洗滌,用無水硫酸鎂乾燥,過濾,濾液減壓濃縮,得到標題產物2-溴-4-氟-6-硝基苯酚2b(8.0g,紅色固體),直接用於下一步反應,產率:80.8%。2-Bromo-4-fluoro-phenol 2a (8.0 g, 41.9 mmol) was dissolved in 10 mL of sulfuric acid solution (50%) under ice salt bath, and sodium nitrate (7.1 g, 83.5 mmol) in 24 mL of sulfuric acid solution (25) was added dropwise. %), reacted at room temperature for 1.5 hours. The residue was evaporated to dryness with EtOAc (EtOAc) (EtOAc (EtOAc) Concentration by pressure gave the title product 2-bromo-4-fluoro-6-nitrophenol 2b (8.0 g, red solid).

第二步Second step 1-溴-5-氟-2-甲氧基-3-硝基苯1-bromo-5-fluoro-2-methoxy-3-nitrobenzene

將2-溴-4-氟-6-硝基苯酚2b(24.7g,104.7mmol)和碳酸鉀(17.34g,125.6mmol)溶解於300mL丙酮中,快速加入碘甲烷(9.8mL,157.1mmol),80℃加熱回流22小時。以TLC追蹤至原料消失,減壓濃縮,加入200mL乙酸乙酯和200mL水,水相用乙酸乙酯萃取(100mL×2),合併有機相,分別用4N鹽酸和飽和碳酸氫鈉溶液洗滌,用無水硫酸鎂乾燥,過濾,濾液減壓濃縮,用矽膠管柱層析法純化所得殘餘物,得到標題產物1-溴-5-氟-2-甲氧基-3-硝基苯2c(16.18g,白色固體)。產率:61.8%。MS m/z(ESI):252[M+1]1 H NMR(CDC13 ):δ3.99(s,3H),7.81(d,J=8.0Hz,1H),7.28(q,J=8.0Hz,4.0Hz,1H),7.89(q,J=8.0Hz,4.0Hz,1H)。2-Bromo-4-fluoro-6-nitrophenol 2b (24.7 g, 104.7 mmol) and potassium carbonate (17.34 g, 125.6 mmol) were dissolved in 300 mL of acetone, and methyl iodide (9.8 mL, 157.1 mmol) was quickly added. The mixture was heated to reflux at 80 ° C for 22 hours. The residue was evaporated to dryness with EtOAc (EtOAc) (EtOAc) (EtOAc) Drying over anhydrous magnesium sulfate, EtOAc (EtOAc m. , white solid). Yield: 61.8%. MS m/z (ESI): 252 [M+1] 1 H NMR (CDC1 3 ): δ 3.99 (s, 3H), 7.81 (d, J = 8.0 Hz, 1H), 7.28 (q, J = 8.0) Hz, 4.0 Hz, 1H), 7.89 (q, J = 8.0 Hz, 4.0 Hz, 1H).

第三步third step 5’-氟-2’-甲氧基-3’-硝基聯苯基-3-羧酸5'-Fluoro-2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid

將1-溴-5-氟-2-甲氧基-3-硝基苯2c(16.18g,64.7mmol)、3-羧基苯基硼酸(13.88g,77.7mmol)和四(三苯基膦)鈀(3.73g,3.2mmol)溶解於65mL碳酸鈉溶液(2N)和300mL1,4-二氧陸圜的混和溶劑中,120℃加熱回流24小時。以TLC追蹤至原料消失,減壓濃縮,加入150mL鹽酸溶液(6N)和200mL乙酸乙酯,水相用乙酸乙酯萃取(100mL×2),合併有機相,用無水硫酸鎂乾燥,過濾,濾液減壓濃縮,得到標題產物5’-氟-2’-甲氧基-3’-硝基聯苯基-3-羧酸2d(7.86g,黃色固體)。產率:41.7%。MS m/z(ESI):290[M-1]1-Bromo-5-fluoro-2-methoxy-3-nitrobenzene 2c (16.18 g, 64.7 mmol), 3-carboxyphenylboronic acid (13.88 g, 77.7 mmol) and tetrakis(triphenylphosphine) Palladium (3.73 g, 3.2 mmol) was dissolved in a mixed solvent of 65 mL of sodium carbonate solution (2N) and 300 mL of 1,4-dioxane, and heated under reflux at 120 ° C for 24 hours. The residue was evaporated to dryness eluted with EtOAc (EtOAc) (EtOAc) (EtOAc) Concentration under reduced pressure gave the title product 5'-fluoro-2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid 2d (7.86 g, yellow solid). Yield: 41.7%. MS m/z (ESI): 290 [M-1]

第四步the fourth step 3’-硝基-5’-氟-2’-羥基聯苯基-3-羧酸3'-Nitro-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

將5’-氟-2’-甲氧基-3’-硝基聯苯基-3-羧酸2d(2.91g,10.0mmol)溶解於10mL氫溴酸溶液(40%)中,120℃加熱回流過夜。以TLC追蹤至原料消失,減壓濃縮,用矽膠管柱層析法純化所得殘餘物,得到標題產物3’-硝基-5’-氟-2’-羥基聯苯基-3-羧酸2e(2.38g,黃色固體),直接用於下一步反應。產率:85.7%。MS m/z(ESI):277[M-1]2'-Fluoro-2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid 2d (2.91 g, 10.0 mmol) was dissolved in 10 mL of hydrobromic acid solution (40%), heated at 120 ° C Reflux overnight. The residue was purified by TLC, and the residue was evaporated to purified crystals. (2.38 g, yellow solid) was used directly in the next step. Yield: 85.7%. MS m/z (ESI): 277 [M-1]

第五步the fifth step 3’-氨基-5’-氟-2’-羥基聯苯基-3-羧酸3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

將3’-硝基-5’-氟-2’-羥基聯苯基-3-羧酸氫溴酸鹽2e(417mg,1.5mmol)溶解於60mL乙醇中,加入0.5g鈀-碳和甲酸銨(0.95g,1.5mmol),80℃加熱回流20分鐘。以TLC追蹤至原料消失,過濾,減壓濃縮,乾燥,得到標題產物3’-氨基-5’-氟-2’-羥基聯苯基-3-羧酸2f(339mg,紫紅色固體)。產率:91.5%。MS m/z(ESI):246[M-1]3'-Nitro-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 2e (417 mg, 1.5 mmol) was dissolved in 60 mL of ethanol, and 0.5 g of palladium-carbon and ammonium formate were added. (0.95 g, 1.5 mmol), heated to reflux at 80 ° C for 20 min. The residue was purified by TLC, filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield: 91.5%. MS m/z (ESI): 246 [M-1]

第六步Step 6 5’-氟-2’-羥基-3’-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-聯苯基-3-羧酸5'-Fluoro-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-oxy-1,5-dihydropyrazole-4-arylene Base)-fluorenyl]-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-5’-氟-2’-羥基聯苯基-3-羧酸2f(296mg,1.20mmol)溶解於10mL鹽酸(1N)中,滴加入10mL亞硝酸鈉溶液(91mg,1.32mmol),再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮li(257mg,1.20mmol),用飽和碳酸氫鈉溶液將反應液pH調至8,加入10mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾,乾燥,用甲醇再結晶,得到標題產物5’-氟-2’-羥基-3’-[N’-(1-茚滿-5-基1-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-聯苯基-3-羧酸2(87mg,紅色固體)。產率:14.1%。MS m/z(ESI):471[M-1]l HNMR(400MHz,DMSO-d6):δ 2.02(m,2H),2.34(s,3H),2.87(m,4H),7.03(dd,J1=9.2Hz,J2=2.8Hz,lH),7.28(d,J=8.0Hz,1H),7.48(m,1H),7.61(m,2H),7.76(s,1H),7.83(d,J=7.6Hz,1H),7.98(d,J=8.0Hz,1H),8.17(s,1H),9.59(s,lH),13.03(s,1H),13.62(s,1H)3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid 2f (296 mg, 1.20 mmol) was dissolved in 10 mL of hydrochloric acid (1 N) under ice-cooling, and 10 mL of sodium nitrite solution was added dropwise ( 91 mg, 1.32 mmol), followed by 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (257 mg, 1.20 mmol). The pH of the solution was adjusted to 8, and 10 mL of ethanol was added and allowed to warm to room temperature overnight. The material disappeared by TLC, filtered, dried and recrystallized from methanol to give the title product 5'-fluoro-2'-hydroxy-3'-[N'-(1-indane-5-yl 1-3-A 5-O-oxy-1,5-dihydropyrazole-4-ylidene)-indenyl]-biphenyl-3-carboxylic acid 2 (87 mg, red solid). Yield: 14.1%. MS m / z (ESI): 471 [M-1] l HNMR (400MHz, DMSO-d6): δ 2.02 (m, 2H), 2.34 (s, 3H), 2.87 (m, 4H), 7.03 (dd, J1=9.2 Hz, J2=2.8 Hz, lH), 7.28 (d, J=8.0 Hz, 1H), 7.48 (m, 1H), 7.61 (m, 2H), 7.76 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 9.59 (s, lH), 13.03 (s, 1H), 13.62 (s, 1H)

實施例3Example 3 2’-羥基-3’-{N’-「3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基」-肼基}-聯苯基-3-羧酸2'-Hydroxy-3'-{N'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro Pyrazole-4-ylidene-indenyl}-biphenyl-3-carboxylic acid

第一步first step 2-肼基-5,6,7,8-四氫萘2-mercapto-5,6,7,8-tetrahydronaphthalene

冰浴下將2-氨基-5,6,7,8-四氫萘3g(3.68g,25.0mmol)溶解於20mL濃鹽酸中,攪拌10分鐘。滴加入10mL亞.硝酸鈉溶液(1.72g,25.0mmol),冰浴下繼續攪拌15分鐘備用。2-Amino-5,6,7,8-tetrahydronaphthalene 3 g (3.68 g, 25.0 mmol) was dissolved in 20 mL of concentrated hydrochloric acid and stirred for 10 min. 10 mL of sodium nitrite solution (1.72 g, 25.0 mmol) was added dropwise, and stirring was continued for 15 minutes under ice bath.

冰鹽浴下將二水合氯化亞錫(22.6g,100mmol)溶解於10mL濃鹽酸中,將備用中間體溶液加入其中,升至室溫反應1.5小時。冰浴下用40%氫氧化鈉溶液調pH至9,加入400mL乙酸乙酯萃取,減壓濃縮,乾燥,得到標題產物2-肼基-5,6,7,8-四氫萘3h(2.19g,黃色油狀液體)。產率:53.7%。MSm/z(ESI):163[M+1]Stannous chloride dihydrate (22.6 g, 100 mmol) was dissolved in 10 mL of concentrated hydrochloric acid under ice salt bath, and the intermediate intermediate solution was added thereto, and the mixture was allowed to react at room temperature for 1.5 hours. The pH was adjusted to 9 with 40% sodium hydroxide solution under ice-cooling, extracted with ethyl acetate (400 mL), and concentrated under reduced pressure and dried to give the title product 2-meryl-5,6,7,8-tetrahydronaphthalene 3h (2.19) g, yellow oily liquid). Yield: 53.7%. MSm/z (ESI): 163 [M+1]

第二步Second step 5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one

將2-肼基-5,6,7,8-四氫萘3h(2.0g,12.3mmol)溶解於50mL乙酸中,再加入乙醯乙酸乙酯(1.57mL,12.3mmol),加熱至100℃過夜。以TLC追蹤至原料消失,減壓濃縮,用矽膠管柱層析法純化所得殘餘物,得到標題產物5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(1.58g,無色油狀液體)。產率:56.2%。MS m/z(ESI):457[2M+1]1 H NMR(CDCl3 ):δ7.54-7.58(m,2H),7.08-7.10(d,J=8Hz,1H),3.43(s,2H),δ2.77-2.81(m,4H),2.21(s,3H),1.80-1.83(m,4H).2-Mercapto-5,6,7,8-tetrahydronaphthalene 3h (2.0g, 12.3mmol) was dissolved in 50mL of acetic acid, then ethyl acetate ethyl acetate (1.57mL, 12.3mmol) was added and heated to 100 ° C overnight. The residue was purified by TLC, and the residue was evaporated to dryness. -2,4-Dihydropyrazol-3-one 3i (1.58 g, colorless oily liquid). Yield: 56.2%. MS m/z (ESI): 495 [2M +1] 1 H NMR (CDCl 3 ): δ 7.54 - 7.58 (m, 2H), 7.08-7.10 (d, J = 8 Hz, 1H), 3.43 (s, 2H), δ 2.77-2.81 (m, 4H), 2.21 (s, 3H), 1.80-1.83 (m, 4H).

第三步third step 2’-羥基-3’-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸2'-Hydroxy-3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro Pyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基聯苯基-3-羧酸氫溴酸鹽1f(250mg,1.09mmol)溶解於10mL鹽酸(1N)中,滴加入10mL亞硝酸鈉溶液(82mg,1.2mmol),再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(249mg,1.09mmol),用飽和碳酸氫鈉溶液將反應液pH調至8,加入10mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾,乾燥,用甲醇再結晶,得到標題產物2’-羥基-3’-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸3(59mg,黃色固體)。產率:11.6%。MS m/z(ESI):467[M-1]1 HNMR(400MHz,DMSO-d6):δ 1.75(m,4H),2.33(s,3H),2.70(m,4H),7.13(m,3H),7.36(m,1H),7.60(m,2H),7.71(m,1H),7.75(m,1H),7.97(d,J=7.6Hz,1H),8.14(s,1H),9.66(s,1H),13.03(br,1H),13.76(s,1H)3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (250 mg, 1.09 mmol) was dissolved in 10 mL of hydrochloric acid (1 N) under ice bath, and 10 mL of sodium nitrite solution (82 mg) was added dropwise. , 1.2 mmol), further adding 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 3i (249 mg, 1.09 mmol The pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 10 mL of ethanol was added, and the mixture was allowed to warm to room temperature overnight. It was traced by TLC until the material disappeared, filtered, dried and recrystallized from methanol to give the title product 2'-hydroxy-3'-{N'-[3-methyl-5-sideoxy-1-(5,6, 7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid 3 (59 mg, yellow solid). Yield: 11.6%. MS m/z (ESI): 467 [M-1] 1 H NMR (400 MHz, DMSO-d6): δ 1.75 (m, 4H), 2.33 (s, 3H), 2.70 (m, 4H), 7.13 (m, 3H), 7.36 (m, 1H), 7.60 (m, 2H), 7.71 (m, 1H), 7.75 (m, 1H), 7.97 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 9.66(s,1H), 13.03(br,1H),13.76(s,1H)

實施例4Example 4 5’-氟-2’-羥基-3’-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸5'-Fluoro-2'-hydroxy-3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1 ,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-5’-氟-2’-羥基聯苯基-3-羧酸2f(250mg,1.01mmol)溶解於10mL鹽酸(1N)中,滴加入10mL亞硝酸鈉溶液(77mg,1.12mmol),再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮4i(230mg,1.01mmol),用飽和碳酸氫鈉溶液將反應液pH調至8,加入10mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾,乾燥,用甲醇再結晶,得到標題產物5’-氟- 2’-羥基-3’-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-聯苯基-4-羧酸4(64mg,紅色固體)。產率:13.1%。MS m/z(ESI):485[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.74(m,4H),2.33(s,1H),2.73(m,4H),7.02(dd,J1=9.2Hz,J2=2.0Hz,1H),7.11(d,d=8.0Hz,1H),7.47(m,1H),7.63(m,3H),7.82(d,J=7.6Hz,1H),7.98(d,J=7.6Hz,1H),8.18(s,1H),9.58(s,1H),13.05(s,1H),13.62(s,1H)3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid 2f (250 mg, 1.01 mmol) was dissolved in 10 mL of hydrochloric acid (1 N) under ice-cooling, and 10 mL of sodium nitrite solution was added dropwise. 77 mg, 1.12 mmol), then 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 4i (230 mg, 1.01) (mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and then 10 mL of ethanol was added and the mixture was allowed to warm to room temperature overnight. The residue was traced by TLC, filtered, dried, and then recrystallized from methanol to give the title product 5'-fluoro- 2'-hydroxy-3'-{N'-[3-methyl-5-sideoxy-1- (5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-4-carboxylic acid 4 (64 mg, red solid). Yield: 13.1%. MS m/z (ESI): 495 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.74 (m, 4H), 2.33 (s, 1H), 2.73 (m, 4H), 7.02 (dd , J1=9.2Hz, J2=2.0Hz, 1H), 7.11(d,d=8.0Hz,1H), 7.47(m,1H), 7.63(m,3H),7.82(d,J=7.6Hz,1H ), 7.98 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 9.58 (s, 1H), 13.05 (s, 1H), 13.62 (s, 1H)

實施例5Example 5 3’-「N’-(1-雙環「4.2.0]辛烷-1(6),2,4-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-2’-羥基聯苯基-3-羧酸3'-"N'-(1-bicyclo"4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-sideoxy-1,5- Dihydropyrazol-4-ylidene)-indenyl]-2'-hydroxybiphenyl-3-carboxylic acid

第一步first step 3-溴-雙環[4.2.0]辛烷-1(6),2,4-三烯3-bromo-bicyclo[4.2.0]octane-1(6), 2,4-triene

室溫下,將雙環[4.2.0]辛烷-1(6),2,4-三烯5a(7.9g,76mmol)溶解於80mL水中,冰浴冷卻後緩慢滴加3.9mL溴,加畢撤去冰浴,反應混合物緩慢升至室溫後攪拌過夜。TLC監測反應至原料反應完全,停止反應。向反應液中加入50mL正已烷和Na2 SO3 (3g,23.8mmol),加畢於室溫下攪拌30分鐘。反應混合物分液後取有機層用無水硫酸鈉乾燥,過濾除去乾燥劑,有機相減壓濃縮得到標題產物3-溴-雙環[4.2.0]辛烷-1(6),2,4-三烯5b(13.53g,無色油狀液體),直接投入下步反應。MS m/z(ESI):181.8[M-1]Bicyclo[4.2.0]octane-1(6), 2,4-triene 5a (7.9 g, 76 mmol) was dissolved in 80 mL of water at room temperature, and 3.9 mL of bromine was slowly added dropwise after cooling in an ice bath. The ice bath was removed and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was monitored by TLC until the starting material was completely reacted and the reaction was stopped. 50 mL of n-hexane and Na 2 SO 3 (3 g, 23.8 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was separated, the organic layer was dried (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Alkene 5b (13.53 g, colorless oily liquid) was directly introduced into the next step. MS m/z (ESI): 181.8 [M-1]

第二步Second step (N-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-N’-第三丁氧羰基-肼基)-碳酸第三丁酯(N-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-N'-t-butoxycarbonyl-indenyl)-tert-butyl carbonate

將3-溴-雙環[4.2.0]辛烷-1(6),2,4-三烯5b(13.5g,73.8mmol)溶解於100mL四氫呋喃(乾燥)中,用乾冰-乙醇浴冷卻至-78℃後加入正丁基鋰(66mL,165mmol),加畢繼續低溫攪拌。將偶氮二甲酸二第三丁酯(20.1g,87.4mmol)溶解於80mL四氫呋喃(乾燥)中,緩慢加入到上述反應液中,加畢撤去乾冰-乙醇浴,反應體系溫度緩慢升至室溫後攪拌過夜。TLC監測原料反應完全後停止反應。向反應體系中加入100mL水淬滅反應,反應液分液,水相用乙酸乙酯萃取(100mL×2),合併有機相,有機相用飽和氯化鈉溶液洗滌(150mL×1),無水硫酸鈉乾燥,過濾除去乾燥劑,濾液經管柱層析得到標題產物(N-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-N’-第三丁氧羰基-肼基)-碳酸第三丁酯5c(4.07g,黃色油狀液體),產率:16.5%。3-Bromo-bicyclo[4.2.0]octane-1(6), 2,4-triene 5b (13.5 g, 73.8 mmol) was dissolved in 100 mL of tetrahydrofuran (dry) and cooled with dry ice-ethanol bath - After 78 ° C, n-butyllithium (66 mL, 165 mmol) was added, and the mixture was stirred at low temperature. Ditributyl azodicarboxylate (20.1 g, 87.4 mmol) was dissolved in 80 mL of tetrahydrofuran (dry), slowly added to the above reaction solution, and the dry ice-ethanol bath was removed, and the temperature of the reaction system was slowly raised to room temperature. Stir overnight. The TLC monitors the reaction of the starting material and stops the reaction. The reaction mixture was quenched by adding 100 mL of water, and the reaction mixture was separated. The aqueous phase was extracted with ethyl acetate (100 mL×2), and the organic phase was combined, and the organic phase was washed with saturated sodium chloride solution (150 mL×1), anhydrous sulfuric acid The sodium was dried, filtered to remove the desiccant, and the filtrate was subjected to column chromatography to give the title product (N-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-N'-tributyl Oxycarbonyl-indenyl)-tert-butyl carbonate 5c (4.07 g, yellow oily liquid), yield: 16.5%.

第三步third step 2-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-5-甲基-2,4-二氫吡唑-3-酮2-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-5-methyl-2,4-dihydropyrazol-3-one

將(N-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-N’-第三丁氧羰基-肼基)-碳酸第三丁酯5c(4.0g,12mmol)溶解於30mL乙酸中,加入30mL三氟乙酸,室溫攪拌30分鐘,向反應體系中加入3-側氧基-丁酸甲酯(1.6mL,15mmol)於100℃油浴中攪拌1.5小時,TLC表明原料反應完全,停止反應。反應液減壓蒸除溶劑,分批加入100mL水,60mL乙酸乙酯和碳酸鈉(3g),加畢將反應液分液,水相用乙酸乙酯萃取(40mL×2),合併有機相,有機相用飽和氯化鈉溶液洗滌(100mL×1),無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物2-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-5-甲基-2,4-二氫吡唑-3-酮5d(910mg,黃色固體),產率:37.9%。MS m/z(ESI):201.2[M+1](N-Bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-N'-t-butoxycarbonyl-fluorenyl)-tert-butyl carbonate 5c (4.0 g, 12 mmol) was dissolved in 30 mL of acetic acid, 30 mL of trifluoroacetic acid was added, and stirred at room temperature for 30 minutes. To the reaction system was added 3-oxo-butyric acid methyl ester (1.6 mL, 15 mmol) and stirred in a 100 ° C oil bath. After 1.5 hours, TLC indicated that the starting material was completely reacted and the reaction was stopped. The reaction solution was evaporated under reduced pressure. EtOAc (EtOAc) (EtOAc,EtOAc. The organic phase was washed with a saturated sodium chloride solution (100 mL×1), dried over anhydrous sodium sulfate, and then filtered and evaporated. 6) 2,4-Trien-3-yl-5-methyl-2,4-dihydropyrazol-3-one 5d (910 mg, yellow solid), yield: 37.9%. MS m/z (ESI): 201.2 [M+1]

第四步the fourth step 3’-[N’-(1-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-2’-羥基聯苯基-3-羧酸3'-[N'-(1-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5- Dihydropyrazol-4-ylidene)-indenyl]-2'-hydroxybiphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基聯苯基-3-羧酸1f(258mg,0.83mmol)溶解於10mL鹽酸(1N)中,滴加入10mL亞硝酸鈉溶液(63mg,0.92mmol),再加入2-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-5-甲基-2,4-二氫吡唑-3-酮5d(150mg,0.75mmol),用飽和碳酸氫鈉溶液將反應液pH調至8,加入10mL乙醇,升至室溫攪拌過夜。以TLC追蹤至原料消失,過濾。所得固體溶於30mL水中,用濃鹽酸調節pH至3-4左右,繼之過濾,所得固體用二氯甲烷洗滌(8mL),乾燥後得到標題產物3’-[N’-(1-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-2’-羥基聯苯基-3-羧酸5(198mg,紅色固體),產率:60%。MSm/z(ESI):439.5[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.33(s,3H),3.16(m,4H),7.14(m,3H),7.64(m,2H),7.79(m,2H),7.80(m,1H),7.98(m,1H),8.18(s,1H),9.61(s,1H),12.93(br,1H),13.75(br,1H)3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid 1f (258 mg, 0.83 mmol) was dissolved in 10 mL of hydrochloric acid (1 N), and 10 mL of sodium nitrite solution (63 mg, 0.92 mmol) was added dropwise. , then add 2-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-5-methyl-2,4-dihydropyrazol-3-one 5d (150mg , 0.75 mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 10 mL of ethanol was added thereto, and the mixture was stirred at room temperature overnight. Followed by TLC until the starting material disappeared and filtered. The obtained solid was dissolved in 30 mL of water, and the pH was adjusted to about 3-4 with concentrated hydrochloric acid, followed by filtration, and the obtained solid was washed with methylene chloride (8mL), and dried to give the title product 3'-[N'-(1-bicyclo[ 4.2.0] Octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime Base]-2'-hydroxybiphenyl-3-carboxylic acid 5 (198 mg, red solid), yield: 60%. MS m/z (ESI): 439.5 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.33 (s, 3H), 3.16 (m, 4H), 7.14 (m, 3H), 7.64 (m, 2H), 7.79 (m, 2H), 7.80 (m, 1H), 7.98 (m, 1H), 8.18 (s, 1H), 9.61 (s, 1H), 12.93 (br, 1H), 13.75 (br, 1H) )

實施例6Example 6 5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, Ethyl 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate

第一步first step 2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate

將1-溴-2-甲氧基-3-硝基苯1c(67g,0.289mol)、4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-聯-1,3,2-硼酸乙二醇酯(110g,0.433mol)、四(三苯基膦)鈀(11.80g,14.44mmol)和乙酸鉀(71g,0.724mol)溶解於600mL乙二酸二甲醚中,加熱回流17小時。以TLC追蹤至原料消失,減壓濃縮,用矽膠管柱層析分離純化,得到標題產物2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯6a(50.5g,黃色晶體)。產率:61.9%。1-Bromo-2-methoxy-3-nitrobenzene 1c (67 g, 0.289 mol), 4,4,4',4',5,5,5',5'-octamethyl-2, Ethyl 2'-linked-1,3,2-borate (110 g, 0.433 mol), tetrakis(triphenylphosphine)palladium (11.80 g, 14.44 mmol) and potassium acetate (71 g, 0.724 mol) were dissolved in 600 mL The mixture was heated under reflux for 17 hours in dimethyl oxalate. The residue was traced by TLC to dryness, concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 2-(2-methoxy-3-nitrophenyl)-4,4,5,5-tetra. Base-[1,3,2]ethylene glycol borate 6a (50.5 g, yellow crystals). Yield: 61.9%.

第二步Second step 3,5-二甲基-1H-吡咯-2,4-二羧酸4-乙酯4,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester

冰浴下,將3,5-二甲基-1H-吡咯-2,4-二羧酸2-第三丁酯4-乙酯6b(5.34g,20mmol)溶解於三氟醋酸中(7.4mL,100mmol),攪拌2小時,TLC監測反應至原料反應完全,向反應液中加入40mL水,過濾,濾餅用二氯甲烷洗滌後乾燥,得到標題產物3,5-二甲基-1H-吡咯-2,4-二羧酸4-乙酯6c(3.65g,粉色固體),產率:86.5%。MS m/z(ESI):209.8[M-1]3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-t-butyl ester 4-ethyl ester 6b (5.34 g, 20 mmol) was dissolved in trifluoroacetic acid (7.4 mL). , 100 mmol), stirred for 2 hours, the reaction was monitored by TLC until the starting material was completely reacted, 40 mL of water was added to the reaction mixture, and the filtrate was washed with dichloromethane and dried to give the title product 3,5-dimethyl-1H-pyrrole. 4-Ethyl 4-ethyldicarboxylate 6c (3.65 g, pink solid), yield: 86.5%. MS m/z (ESI): 209.8 [M-1]

第三步third step 5-碘-2,4-二甲基-1H-吡咯-3-羧酸乙酯Ethyl 5-iodo-2,4-dimethyl-1H-pyrrole-3-carboxylate

將3,5-二甲基-1H-吡咯-2,4-二羧酸4-乙酯6c(3.65g,17.3mmol)加入到100mL二氯甲烷和10mL水的混合溶劑中,再加入碘化鉀(11.5g,69.2mmol)和碘(4.39g,17.3mmol),加畢後加熱回流2小時,TLC監測反應至原料反應完全,反應液冷卻至室溫,加入20mL水和10mL硫代硫酸鈉溶液(2M),用二氯甲烷萃取(30mL×3),合併有機相,有機相用飽和食鹽水洗滌,無水硫酸鎂乾燥,過濾除去乾燥劑,濾液減壓濃縮得到標題產物5-碘-2,4-二甲基-1H-吡咯-3-羧酸乙酯6d(4.1g,橙色固體),產率:80.8%。Add 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester 6c (3.65 g, 17.3 mmol) to a mixed solvent of 100 mL of dichloromethane and 10 mL of water, and then add potassium iodide ( 11.5g, 69.2mmol) and iodine (4.39g, 17.3mmol), after heating and refluxing for 2 hours, the reaction was monitored by TLC until the reaction of the starting material was complete, the reaction solution was cooled to room temperature, and 20 mL of water and 10 mL of sodium thiosulfate solution were added. 2M), extracted with methylene chloride (30 mL × 3), EtOAcjjjjjjjjjjjj Ethyl dimethyl-1H-pyrrole-3-carboxylate 6d (4.1 g, orange solid), yield: 80.8%.

第四步the fourth step 5-碘-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯Ethyl 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylate

將5-碘-2,4-二甲基-1H-吡咯-3-羧酸乙酯6d(4.1g,13.99mmol)溶解於80mL四氫呋喃中,加入4-甲基苯磺酸甲酯(2.73g,14.69mmol)和第三丁醇鈉(2.02g,20.99mmol),加畢後室溫攪拌0.5小時,TLC監測反應至原料反應完全,反應液過濾,濾餅用四氫呋喃洗滌,濾液減壓濃縮,得到標題產物5-碘-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯6e(3.8g,灰色固體),產率:88.6%。MS m/z(ESI):308.1[M+1]1 HNMR(400MHz,CDCl3 ):δ4.287~4.340(q,2H),3.561(s,3H),2.618(s,3H),2.888(s,3H),1.369~1.405(t,3H)6-Iodo-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6d (4.1 g, 13.99 mmol) was dissolved in 80 mL of tetrahydrofuran, and methyl 4-methylbenzenesulfonate (2.73 g) was added. , 14.69 mmol) and sodium butoxide sodium (2.02 g, 20.99 mmol), after stirring, the mixture was stirred at room temperature for 0.5 hr, and the reaction was monitored by TLC until the reaction mixture was completed, and the reaction mixture was filtered, and the filtrate was washed with THF. The title product 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6e (3.8 g, m.p.). MS m/z (ESI): 308.1 [M + 1] 1 H NMR (400 MHz, CDCl 3 ): δ 4.287~4.340 (q, 2H), 3.561 (s, 3H), 2.618 (s, 3H), 2.888 ( s,3H), 1.369~1.405(t,3H)

第五步the fifth step 5-(3-硝基-2-甲氧基-苯基)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯Ethyl 5-(3-nitro-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate

將5-碘-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯6e(2.88g,9.38mmol)溶解於25mL1,4-二氧陸圜中,加入2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯6a(3.6g,10.3mmol)、四(三苯基膦)鈀(270mg,0.234mmol)、碳酸鈉(1.99g,18.77mmol)和10mL水,加畢後加熱回流3小時,TLC監測反應至原料反應完全,反應液冷卻至室溫,加入30mL水,用乙酸乙酯萃取(30mL×3),合併有機相,有機相用飽和食鹽水洗滌,無水硫酸鎂乾燥,過濾除去乾燥劑,濾液減壓濃縮得到標題產物5-(3-硝基-2-甲氧基-苯基)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯6f(1.25g,黃色油狀液體),產率:40.4%。MS m/z(ESI):333.2[M+1]1 HNMR(400MHz,CDCl3 ):δ7.817~7.841(m,1H),7.457~7.476(m,IH),7.284~7.324(m,1H),4.322~4.375(q,2H),3.521(s,3H),3.316(s,3H),.2.625(s,3H),2.177(s,3H),1.398~1.434(t,3H)Ethyl 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylate 6e (2.88 g, 9.38 mmol) was dissolved in 25 mL of 1,4-dioxane, and 2-(2) was added. -methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (3.6 g, 10.3 mmol), tetrakis (triphenyl) Palladium (270 mg, 0.234 mmol), sodium carbonate (1.99 g, 18.77 mmol) and 10 mL of water. After the addition, the mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the reaction mixture was completed. The extract was extracted with ethyl acetate (30 mL×3), and the organic layer was evaporated. Ethyl-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate 6f (1.25 g, yellow oily). Yield: 40.4%. MS m/z (ESI): 333.2 [M + 1] 1 H NMR (400 MHz, CDCl 3 ): δ 7.8 s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s ), 4.322~4.375(q,2H), 3.521(s,3H), 3.316(s,3H),.2.625(s,3H), 2.177(s,3H),1.398~1.434(t,3H)

第六步Step 6 5-(3-氨基-2-甲氧基-苯基)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯Ethyl 5-(3-amino-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate

將5-(3-硝基-2-甲氧基-苯基)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯6f(300mg,0.9mmol)溶解於5mL乙酸乙酯中,加入甲醯胺(227mg,1.61mmol)和60mg鈀/碳,加熱回流1小時,TLC監測反應至原料反應完全,反應液過濾,濾餅用乙酸乙酯洗滌,濾液減壓濃縮得到標題產物5-(3-氨基-2-甲氧基-苯基)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯6g(234mg,白色固體),產率:86%。MS m/z(ESI):303.4[M+1]1 HNMR(400MHz,CDCl3 ):δ6.968~7.006(m,1H),6.817~6.840(m,1H),6.595~6.618(m,1H),4.311~4.364(q,2H),3.381(s,3H),3.315(s,3H),2.615(s,3H),2.181(s,3H),1.391~1.426(t,3H)Ethyl 5-(3-nitro-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate 6f (300 mg, 0.9 mmol) was dissolved in 5 mL of acetic acid To the ethyl ester, toluidine (227 mg, 1.61 mmol) and 60 mg of palladium/carbon were added, and the mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the reaction mixture was completed. The reaction mixture was filtered, and the filtrate was washed with ethyl acetate. Product title: 5-(3-Amino-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6 g (234 mg, white solid) 86%. MS m/z (ESI): 303.4 [M + 1] 1 H NMR (400 MHz, CDCl 3 ): δ 6.968~7.006 (m, 1H), 6.818~6.840 (m, 1H), 6.559~6.618 (m, 1H) ), 4.311~4.364(q,2H), 3.381(s,3H),3.315(s,3H),2.615(s,3H),2.181(s,3H),1.391~1.426(t,3H)

第七步Seventh step 5-(3-氨基-2-羥基苯基)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯氫溴酸鹽5-(3-Amino-2-hydroxyphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester hydrobromide

將5-(3-氨基-2-甲氧基-苯基)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯6g(210mg,0.69mmol)溶解於5mL二氯甲烷中,加入溴化硼(1.39mL,2.78mmol),室溫反應0.5小時,TLC監測反應至原料反應完全,用甲醇淬滅反應,反應液減壓濃縮後加入50mL乙酸乙酯和15mL飽和碳酸氫鈉溶液,攪拌均勻後分液,有機相用飽和食鹽水洗滌,無水硫酸鎂乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物5-(3-氨基-2-羥基苯基)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯氫溴酸鹽6h(165mg,白色固體),產率:82.5%。MS m/z(ESI):289.3[M+1]1 HNMR(400MHz,DMSO-d6 ):δ7.313~7.396(m,1H),7.098~7.117(m,1H),6.993~7.032(m,1H),4.173~4.227(q,2H),3.221(s,3H),1.979(s,3H),1.242~1.295(t,3H)Ethyl 5-(3-amino-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate 6 g (210 mg, 0.69 mmol) was dissolved in 5 mL of dichloro To the methane, boron bromide (1.39 mL, 2.78 mmol) was added, and the mixture was reacted at room temperature for 0.5 hour. The reaction was monitored by TLC until the reaction mixture was completed. The reaction was quenched with methanol. The mixture was concentrated under reduced pressure. The sodium hydrogen hydride solution was stirred, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate Phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester hydrobromide 6h (165 mg, white solid), yield: 82.5%. MS m/z (ESI): 289.3 [M+1] 1 H NMR (400 MHz, DMSO- d6 ): δ7.313~7.396 (m, 1H), 7.098~7.117 (m, 1H), 6.993~7.032 (m, 1H), 4.173~4.227(q,2H), 3.221(s,3H), 1.979(s,3H),1.242~1.295(t,3H)

第八步Eighth step 5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, Ethyl 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate

冰浴下將5-(3-氨基-2-羥基苯基)-1,2,4-三甲基-lH-吡咯-3-羧酸乙酯氫溴酸鹽6h(140mg,0.51mmol)溶解於1.76mL鹽酸(1N)中,滴加入1mL亞硝酸鈉溶液(39mg,0.56mmol),攪拌20分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(105mg,0.46mmol),用飽和碳酸氫鈉溶液將反應液pH調至8,加入1mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾,濾餅乾燥後用二氯甲烷溶解,用飽和食鹽水洗滌,有機相減壓濃縮後經管柱層析,得到標題產物5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯6(120mg,紅色固體)。產率:50.8%。MS m/z(ESI):514.1[M+1]1 HNMR(400MHz,DMSO-d6 ):δ1.84(m,4H),2.14(s,3H),2.41(s,3H),2.57(s,3H),2.80(m,4H),3.34(s,3H),3.87(s,3H),6.51(m,1H),7.00(d,J=7,6Hz,1H),7.11(m,2H),7.71(m,2H),13.82(br,1H)Dissolve 5-(3-amino-2-hydroxyphenyl)-1,2,4-trimethyl-lH-pyrrole-3-carboxylic acid ethyl ester hydrobromide 6 h (140 mg, 0.51 mmol) in an ice bath 11.7 mL of sodium nitrite solution (39 mg, 0.56 mmol) was added dropwise to 1.76 mL of hydrochloric acid (1N), stirred for 20 minutes, and then 5-methyl-2-(5,6,7,8-tetrahydronaphthalene-2 was added. -yl)-2,4-dihydropyrazol-3-one 3i (105 mg, 0.46 mmol). The pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 1 The title material was obtained as a title product 5-(2-hydroxy-3-{N). The residue was purified by chromatography. '-[3-Methyl-5-o-oxy-1-(5,6,7,8-tetrahydronaphthalenylene-2-yl)-1,5-dihydropyrazole-4-ylidene ]-Mercapto}-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6 (120 mg, red solid). Yield: 50.8%. MS m/z (ESI): 514.1 [M+1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.84 (m, 4H), 2.14 (s, 3H), 2.41 (s, 3H), 2. , 3H), 2.80 (m, 4H), 3.34 (s, 3H), 3.87 (s, 3H), 6.51 (m, 1H), 7.00 (d, J = 7, 6 Hz, 1H), 7.11 (m, 2H) ), 7.71 (m, 2H), 13.82 (br, 1H)

實施例7Example 7 3’-{N’-[1-(2,3-二氫苯並呋喃-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基聯苯基-3-羧酸3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

第一步first step 1-(2,3-二氫苯並呋喃基)肼基-1,2-二羧酸二(2,2,2-三氯乙酯)1-(2,3-dihydrobenzofuranyl)indolyl-1,2-dicarboxylic acid bis(2,2,2-trichloroethyl ester)

將2,3-二氫苯並呋喃7a(0.6mL,5.32mmol)、二(2,2,2-三氯乙基)偶氮二碳酸酯(1.96g,5.15mmol)和氯化鋅(920mg,6.76mmol)溶解於40mL二氯甲烷中,室溫反應過夜。以TLC追蹤至原料消失,用矽膠管柱層析分離純化,得到標題產物1-(2,3-二氫苯並呋喃基)肼基-1,2-二羧酸二(2,2,2-三氯乙酯)7b(2.5g,白色固體)。產率:96.6%。2,3-Dihydrobenzofuran 7a (0.6 mL, 5.32 mmol), bis(2,2,2-trichloroethyl)azodicarbonate (1.96 g, 5.15 mmol) and zinc chloride (920 mg) , 6.76 mmol) was dissolved in 40 mL of dichloromethane and allowed to react at room temperature overnight. The material disappeared by TLC, and purified by silica gel column chromatography to give the title product 1-(2,3-dihydrobenzofuranyl)indolyl-1,2-dicarboxylic acid (2,2,2). - Trichloroethyl ester) 7b (2.5 g, white solid). Yield: 96.6%.

第二步Second step 2-(2,3-二氫苯並呋喃-5-基)-5-甲基-2,4-二氫吡唑-3-酮2-(2,3-dihydrobenzofuran-5-yl)-5-methyl-2,4-dihydropyrazol-3-one

將1-(2,3-二氫苯並呋喃基)肼基-1,2-二羧酸二(2,2,2-三氯乙酯)7b(2.9g,5.8mmol)溶解於50mL乙醇和5mL甲醇的混合溶劑中,再加入鋅粉(10.8g,166mmol)和乙酸銨溶液(15mL,1mol/L)室溫反應1小時,滴加乙醯乙酸乙酯(0.75mL,5.9mmol),加熱回流2小時。以TLC追蹤至原料消失,將反應液冷卻至室溫,過濾,濾液減壓濃縮後用矽膠管柱層析法純化,得到標題產物2-(2,3-二氫苯並呋喃-5-基)-5-甲基-2,4-二氫吡唑-3-酮7c(706mg,黃色固體)。產率:56.5%。MS m/z (ESI):217[M+1]1 HNMR(400MHz,CDCl3 ):δ7.63(s,1H),7.51(d,J=1.2Hz,1H),6.78(d,J=8.8Hz,1H),4.57(t,J=8.8Hz,2H),3.39(s,2H),3.22(t,J=8.4Hz,2H),2.16(s,3H)。Dissolving 1-(2,3-dihydrobenzofuranyl)indolyl-1,2-dicarboxylic acid bis(2,2,2-trichloroethyl ester) 7b (2.9 g, 5.8 mmol) in 50 mL of ethanol In a mixed solvent of 5 mL of methanol, zinc powder (10.8 g, 166 mmol) and ammonium acetate solution (15 mL, 1 mol/L) were further added to react at room temperature for 1 hour, and ethyl acetate (0.75 mL, 5.9 mmol) was added dropwise. Heat to reflux for 2 hours. The residue was evaporated to dryness by TLC, and the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 2-(2,3-dihydrobenzofuran-5-yl. 5-methyl-2,4-dihydropyrazol-3-one 7c (706 mg, yellow solid). Yield: 56.5%. MS m/z (ESI): 217 [M+1] 1 H NMR (400 MHz, CDCl 3 ): δ 7.63 (s, 1H), 7.51 (d, J = 1.2 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 4.57 (t, J = 8.8 Hz, 2H), 3.39 (s, 2H), 3.22 (t, J = 8.4 Hz, 2H), 2.16 (s, 3H).

第三步third step 3’-{N’-[1-(2,3-二氫苯並呋喃-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基聯苯基-3-羧酸3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基聯苯基-3-羧酸氫溴酸鹽1f(155mg,0.5mmol)溶解於1.7mL鹽酸(1N)中,滴加入0.6mL亞硝酸鈉溶液(36mg,0.53mmol),攪拌10分鐘,再加入2-(2,3-二氫苯並呋喃-5-基)-5-甲基-2,4-二氫吡唑-3-酮7c(97mg,0.45mmol),分批加入飽和碳酸氫鈉溶液(630mg,7.5mmol)將pH調至7,升至室溫過夜。以TLC追蹤至原料消失,用濃鹽酸調pH至<5,過濾,乾燥,得到標題產物3’-{N’-[1-(2,3-二氫苯並呋喃-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基聯苯基-3-羧酸7(131mg,棕色固體)。產率:63.9%。MS m/z(ESI):455[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.33(s,3H),3.24(t,J=8.4Hz,2H),4.56(t,J=8.4Hz,2H),6.82(d,J=8.4Hz,1H),7.16(m,2H),7.61(m,2H),7.72(m,2H),7.80(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,1H),8.13(d,J=1.6Hz,1H),9.64(s,1H),13.01(s,1H),13.75(s,1H)3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (155 mg, 0.5 mmol) was dissolved in 1.7 mL of hydrochloric acid (1 N) under ice bath, and 0.6 mL of sodium nitrite solution was added dropwise. (36 mg, 0.53 mmol), stirred for 10 minutes, then added 2-(2,3-dihydrobenzofuran-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 7c ( 97 mg, 0.45 mmol) was added portionwise with saturated sodium bicarbonate solution (630 mg, 7.5 mmol). The product disappeared by TLC, the pH was adjusted to <5 with concentrated hydrochloric acid, filtered and dried to give the title product 3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3 Methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxybiphenyl-3-carboxylic acid 7 (131 mg, brown solid). Yield: 63.9%. MS m/z (ESI): 455 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.33 (s, 3H), 3.24 (t, J = 8.4 Hz, 2H), 4.56 (t, J) = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 7.16 (m, 2H), 7.61 (m, 2H), 7.72 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H) ), 7.96 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 9.64 (s, 1H), 13.01 (s, 1H), 13.75 (s, 1H)

實施例8Example 8 2-(3,3-二甲基茚滿-5-基)-4-{「2-羥基-3’-(1H-四唑-5-基)-聯苯基-3-基]-肼基}-5-甲基-2,4-二氫吡唑-3-酮2-(3,3-Dimethylindan-5-yl)-4-{"2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-indole -5--5-methyl-2,4-dihydropyrazol-3-one

第一步first step

5-(3-溴-苯基)-1H-四唑5-(3-bromo-phenyl)-1H-tetrazole

氬氣氛下將3-溴-苯甲腈8a(18.2g,0.1mol)和氯化銨(5.9g,0.11mol)溶解於80mLN,N’-二甲基甲醯胺中,再加入疊氮化鈉(7.16g,0.11mol),加熱至100℃反應過夜。冷卻至60℃,減壓濃縮除去N,N’-二甲基甲醯胺,加入100mL水和4mL濃鹽酸,攪拌1小時,過濾,乾燥,得到標題產物5-(3-溴-苯基)-1H-四唑8b(23g,白色固體)。3-Bromo-benzonitrile 8a (18.2 g, 0.1 mol) and ammonium chloride (5.9 g, 0.11 mol) were dissolved in 80 mL of N,N'-dimethylformamide under argon atmosphere, followed by azide Sodium (7.16 g, 0.11 mol) was heated to 100 ° C overnight. After cooling to 60 ° C, N,N'-dimethylformamide was concentrated under reduced pressure, and 100 mL of water and 4 mL of concentrated hydrochloric acid were added and stirred for 1 hour, filtered and dried to give the title product 5-(3-bromo-phenyl) -1H-tetrazole 8b (23 g, white solid).

第二步Second step

5-(2’-甲氧基-聯苯基-3-基)-1H-四唑5-(2'-methoxy-biphenyl-3-yl)-1H-tetrazole

氬氣氛下將5-(3-溴-苯基)-1H-四唑8b(20g,89mmol)和鄰甲氧基苯硼酸(14.2g,93.3mmol)溶解於530mL 1,4-二氧陸圜中,加入四(三苯基膦)鈀(1.84g)和碳酸鈉(18.9g,178mmol),加熱回流過夜。以TLC追蹤至原料消失,減壓濃縮除去1,4-二氧陸圜,加入鹽酸(200mL,6mol/L),冷卻2小時,棄去水層,殘餘物溶解於500mL乙酸乙酯中,用250mL水洗滌,無水硫酸鈉乾燥,減壓濃縮,殘餘物溶解於25mL乙酸乙酯中,靜置過夜,過濾,得到標題產物5-(2’-甲氧基-聯苯基-3-基)-1H-四唑8c(15g,淡黃色固體)。產率:68.2%。5-(3-Bromo-phenyl)-1H-tetrazole 8b (20 g, 89 mmol) and o-methoxyphenylboronic acid (14.2 g, 93.3 mmol) were dissolved in 530 mL of 1,4-dioxane under argon. Tetrakis(triphenylphosphine)palladium (1.84 g) and sodium carbonate (18.9 g, 178 mmol) were added and heated to reflux overnight. The residue was traced by TLC, and 1,4-dioxane was removed under reduced pressure. Hydrochloric acid (200 mL, 6 mol/L) was added, and the mixture was cooled for 2 hours. The aqueous layer was discarded and the residue was dissolved in ethyl acetate (500 mL). The residue was washed with EtOAc (EtOAc m. -1H-tetrazole 8c (15 g, pale yellow solid). Yield: 68.2%.

第三步third step

3’-(1H-四唑-5-基)-聯苯基-2-醇3'-(1H-tetrazol-5-yl)-biphenyl-2-ol

氬氣氛下將5-(2’-甲氧基-聯苯基-3-基)-1H-四唑8c(15.5g,61.5mol)溶解於195mL乙酸中,加入195mL氫溴酸,加熱回流5小時。以TLC追蹤至原料消失,冷卻過夜,過濾,固體溶解於500mL乙酸乙酯中,用水洗滌(500mL×2),無水硫酸鈉乾燥,過濾,減壓濃縮,加入100mL乙酸乙酯再結晶,得到標題產物3’-(1H-四唑-5-基)-聯苯基-2-醇8d(12g,白色固體)。產率:82.8%。5-(2'-Methoxy-biphenyl-3-yl)-1H-tetrazole 8c (15.5 g, 61.5 mol) was dissolved in 195 mL of acetic acid under argon atmosphere, and 195 mL of hydrobromic acid was added and heated to reflux. hour. The residue was evaporated to dryness eluted with EtOAc (EtOAc) eluted eluted eluted eluted eluted eluted eluted Product 3'-(1H-tetrazol-5-yl)-biphenyl-2-ol 8d (12 g, white solid). Yield: 82.8%.

第四步the fourth step

3-硝基-3’-(1H-四唑-5-基)-聯苯基-2-醇3-nitro-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol

氬氣氛下將3’-(1H-四唑-5-基)-聯苯基-2-醇8d(3.5g,14.7mmol)溶解於145mL乙醇中,35℃下滴加發煙硝酸(0.565mL,13.2mmol),室溫反應1小時,加入150mL水,靜置過夜,過濾,固體用100mL水洗滌,溶解於500mL乙酸乙酯和250mL水中,萃取,有機相用飽和氯化鈉溶液洗滌,無水硫酸鎂乾燥,用矽膠管柱層析分離純化,得到標題產物3-硝基-3’-(1H-四唑-5-基)-聯苯基-2-醇8e(1g,黃色固體)。產率:27.0%。MS m/z(ESI):282[M-1]3'-(1H-tetrazol-5-yl)-biphenyl-2-ol 8d (3.5g, 14.7mmol) was dissolved in 145mL of ethanol under argon atmosphere, and fuming nitric acid (0.565mL) was added dropwise at 35 °C. , 13.2 mmol), react at room temperature for 1 hour, add 150 mL of water, stand overnight, filter, solid wash with 100 mL of water, dissolve in 500 mL of ethyl acetate and 250 mL of water, extract, and wash the organic phase with saturated sodium chloride solution, anhydrous Drying over MgSO4, EtOAc (EtOAc) Yield: 27.0%. MS m/z (ESI): 282 [M-1]

第五步the fifth step

3-氨基-3’-(1H-四唑-5-基)-聯苯基-2-醇鹽酸鹽3-amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride

將3-硝基-3’-(1H-四唑-5-基)-聯苯基-2-醇8e(2.5g,8.83mmol)溶解於118mL乙醇和78.6mL水中,再加入氫氧化鈉溶液(2.95mL,3mol/L)和313mg鈀-碳,於氫化儀中在3個大氣壓下用氫氣氫化,室溫反應3小時。以TLC追蹤至原料消失,過濾,濾液中加入鹽酸(60mL,3mol/L),減壓濃縮,向殘餘物中加入少量水,過濾,固體用少量水和正己烷洗滌,乾燥,得到標題產物3-氨基-3’-(1H-四唑-5-基)-聯苯基-2-醇鹽酸鹽8f(2.33g,紅棕色固體)。MS m/z(ESI):252[M+1]3-Nitro-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol 8e (2.5 g, 8.83 mmol) was dissolved in 118 mL of ethanol and 78.6 mL of water, then sodium hydroxide solution was added (2.95 mL, 3 mol/L) and 313 mg of palladium-carbon were hydrogenated with hydrogen in a hydrogenation apparatus at 3 atm. and reacted at room temperature for 3 hours. The residue was removed by TLC, filtered, and then filtered, and then filtered, and then filtered, evaporated, evaporated, evaporated, evaporated, evaporated. -Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (2.33 g, red brown solid). MS m/z (ESI): 252 [M+1]

第六步Step 6

1-(3,3-二甲基茚滿-5-基)肼基-1,2-二羧酸二(第三丁酯)1-(3,3-dimethylindan-5-yl)indolyl-1,2-dicarboxylic acid bis(t-butyl ester)

將6-溴-1,1-二甲基茚滿(WO2005066115)8g(4.32g,19.27mmol)溶解於40mL四氫呋喃中,-78℃下滴加丁基鋰(15.67mL,1.6mol/L,25.05mmol),反應40分鐘,加入偶氮二甲酸二第三丁酯(5.32g,23.12mmol)的30mL四氫呋喃溶液,-78℃下繼續反應3小時。以TLC追蹤至原料消失,加入5mL甲醇,反應液升至室溫,用矽膠過濾,濾液減壓濃縮,用矽膠管柱層析分離純化,得到標題產物1-(3,3-二甲基茚滿-5-基)肼基-1,2-二羧酸二(第三丁酯)8h(2.70g,黃色固體)。產率:37.2%。6-bromo-1,1-dimethylindane (WO2005066115) 8g (4.32g, 19.27mmol) was dissolved in 40mL of tetrahydrofuran, and butyl lithium (15.67mL, 1.6mol/L, 25.05) was added dropwise at -78 °C. Methyl), the reaction was carried out for 40 minutes, and a solution of di-tert-butyl azodicarboxylate (5.32 g, 23.12 mmol) in 30 mL of tetrahydrofuran was added, and the reaction was continued at -78 ° C for 3 hours. After the residue was traced to the disappearance of the starting material, 5 mL of methanol was added, and the reaction mixture was warmed to room temperature, and the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 1-(3,3-dimethylindole). -5-5-yl) decyl-1,2-dicarboxylic acid bis(t-butyl ester) 8 h (2.70 g, yellow solid). Yield: 37.2%.

第七步Seventh step

2-(3,3-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one

將1-(3,3-二甲基茚滿-5-基)肼基-1,2-二羧酸二(第三丁酯)8h(2.70g,7.18mmol)溶解於100mL乙酸中,加入20mL三氟乙酸,室溫反應2小時,加入乙醯乙酸乙酯(0.98g,7.54mmol),加熱至100℃反應2小時。以TLC追蹤至原料消失,冷卻至室溫,減壓濃縮除去乙酸,用飽和碳酸氫鈉溶液中和反應液中的酸,用乙酸乙酯萃取,合併有機相,用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,減壓濃縮,用矽膠管柱層析法純化所得殘餘物,得到標題產物2-(3,3-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮8i(1.0g,淡褐色固體)。產率:47.7%。MSm/z(ESI):243[M+1]Dissolve 1-(3,3-dimethylindol-5-yl)indolyl-1,2-dicarboxylic acid bis(t-butyl ester) 8h (2.70g, 7.18mmol) in 100mL acetic acid, add 20 mL of trifluoroacetic acid was reacted at room temperature for 2 hours, and ethyl acetate (0.98 g, 7.54 mmol) was added, and the mixture was heated to 100 ° C for 2 hours. The mixture was traced by TLC until the material disappeared, cooled to room temperature and concentrated to remove acetic acid under reduced pressure. The acid in the reaction mixture was neutralized with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was combined and washed with saturated sodium chloride solution. Drying over anhydrous sodium sulfate, EtOAc (EtOAc m.) 4-Dihydropyrazol-3-one 8i (1.0 g, light brown solid). Yield: 47.7%. MSm/z (ESI): 243 [M+1]

第八步Eighth step

2-(3,3-二甲基茚滿-5-基)-4-{[2-羥基-3’-(1H-四唑-5-基)-聯苯基-3-基]-肼基}-5-甲基-2,4-二氫吡唑-3-酮2-(3,3-Dimethylindan-5-yl)-4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-indole -5--5-methyl-2,4-dihydropyrazol-3-one

冰浴下將3-氨基-3’-(1H-四唑-5-基)-聯苯基-2-醇鹽酸鹽8f(290mg,1.0mmol)溶解於鹽酸(3.4mL,1mol/L)中,滴加入1.2mL亞硝酸鈉溶液(73mg,1.05mmol),反應10分鐘,再加入2-(3,3-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮8i(218mg,0.9mmol),分批加入碳酸氫鈉(1.26g,15mmol)和4.4mL乙醇,室溫反應10小時。以TLC追蹤至原料消失,過濾,固體用20mL水洗滌,再溶解於20mL水中,冰浴下用濃鹽酸調節至pH<5,過濾,乾燥,得到標題產物2-(3,3-二甲基茚滿-5-基)-4-{[2-羥基-3’-(1H-四唑-5-基)-聯苯基-3-基]-肼基}-5-甲基-2,4-二氫吡唑-3-酮8(336mg,黃色固體)。產率:73.8%。MS m/z(ESI):505[M-1]1 H NMR(400MHz,DMSO-d6 ):δ1.24(m,6H),1.92(t,J=7.2Hz,2H),2.36(s,3H),2.87(t,J=7.2Hz,2H),7.21(m,3H),7.73(m,5H),8.08(d,J=7.6Hz,lH),8.25(s,1H),9.77(s,1H),13.80(s,1H)3-Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (290 mg, 1.0 mmol) was dissolved in hydrochloric acid (3.4 mL, 1 mol/L). Add 1.2 mL of sodium nitrite solution (73 mg, 1.05 mmol) dropwise, and react for 10 minutes, then add 2-(3,3-dimethylindol-5-yl)-5-methyl-2,4- Dihydropyrazol-3-one 8i (218 mg, 0.9 mmol) was added portionwise sodium bicarbonate (1.26 g, 15 mmol) and 4.4 mL of ethyl alcohol. The product disappeared by TLC, filtered, and the solid was washed with 20 mL of water, and then dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 2-(3,3-dimethyl Indole-5-yl)-4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-indenyl}-5-methyl-2, 4-Dihydropyrazol-3-one 8 (336 mg, yellow solid). Yield: 73.8%. MS m/z (ESI): 495 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.24 (m, 6H), 1.92 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 7.21 (m, 3H), 7.73 (m, 5H), 8.08 (d, J = 7.6 Hz, lH), 8.25 (s, 1H), 9.77 ( s, 1H), 13.80 (s, 1H)

實施例9Example 9

5-{2-羥基-3-「N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯基}-呋喃-2-羧酸5-{2-hydroxy-3-"N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime P-phenyl}-furan-2-carboxylic acid

第一步first step

5-(2-甲氧基-3-硝基苯基)-呋喃-2-羧酸5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylic acid

將2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯6a(10g,35.85mmol)、5-溴-呋喃-2-羧酸(5.47g,28.66mmol)、四(三苯基膦)鈀(2.07g,1.79mmol)和碳酸鈉(7.60g,71.66mmol)溶解於200mL 1,4-二氧陸圜和30mL水的混合溶劑中,加熱回流2.5小時。以TLC追蹤至原料消失,過濾,濾液減壓濃縮,向殘餘物中加入150mL水,用1N鹽酸酸化至pH~3,過濾,固體用50mL正己烷和乙酸乙酯的混合溶劑(1/1)洗滌,乾燥,得到標題產物5-(2-甲氧基-3-硝基苯基)-呋喃-2-羧酸9a(4.23g,灰白色固體)。產率:56.1%。MS m/z(ESI):262[M-1]2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (10 g, 35.85 mmol), 5-bromo-furan-2-carboxylic acid (5.47 g, 28.66 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.60 g, 71.66 mmol) dissolved in 200 mL 1,4- In a mixed solvent of dioxane and 30 mL of water, the mixture was heated under reflux for 2.5 hours. The mixture was traced by TLC until the material disappeared, filtered, and the filtrate was concentrated under reduced pressure. 150 mL of water was added to the residue, acidified to pH~3 with 1N hydrochloric acid, and filtered, and the mixture was mixed with 50 mL of n-hexane and ethyl acetate (1/1) Washing and drying gave the title product 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylic acid 9a (4.23 g, m. Yield: 56.1%. MS m/z (ESI): 262 [M-1]

第二步Second step

5-(3-氨基-2-甲氧基-苯基)-呋喃-2-羧酸5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid

將5-(2-甲氧基-3-硝基苯基)-呋喃-2-羧酸9a(4.23g,16.09mmol)溶解於125mL乙酸乙酯中,再加入423mg鈀-碳和甲酸銨(4.054g,64.35mmol),加熱回流3.5小時。以TLC追蹤至原料消失,減壓濃縮,用矽膠管柱層析法純化所得殘餘物,得到標題產物5-(3-氨基-2-甲氧基-苯基)-呋喃-2-羧酸9b(2.79g,淡綠色固體),產率:74.4%。MS m/z(ESI):232[M-1]5-(2-Methoxy-3-nitrophenyl)-furan-2-carboxylic acid 9a (4.23 g, 16.09 mmol) was dissolved in 125 mL of ethyl acetate and then 423 mg of palladium-carbon and ammonium formate ( 4.054 g, 64.35 mmol), heated to reflux for 3.5 hours. The residue was purified by EtOAc (EtOAc) eluting (2.79 g, pale green solid), Yield: 74.4%. MS m/z (ESI): 232 [M-1]

第三步third step

5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽5-(3-amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide

將5-(3-氨基-2-甲氧基-苯基)-呋喃-2-羧酸9b(2.79g,11.97mmol)溶解於25mL二氯甲烷中,滴加入三溴化硼(23.9mL,2.0mol/L),室溫反應1小時。以TLC追蹤至原料消失,加入5mL甲醇,減壓濃縮,向殘餘物中加入100mL乙酸乙酯,攪拌1小時,過濾,收集固體,乾燥,得到標題產物5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽9c(1.24g,黃色固體)。產率:47.2%。MS m/z(ESI):218[M-1]5-(3-Amino-2-methoxy-phenyl)-furan-2-carboxylic acid 9b (2.79 g, 11.97 mmol) was dissolved in 25 mL of dichloromethane, and boron tribromide (23.9 mL, 2.0 mol/L), reacted at room temperature for 1 hour. The title material was obtained as 5-(3-amino-2-hydroxybenzene). The title product was obtained after the residue was evaporated. Base)-furan-2-carboxylic acid hydrobromide 9c (1.24 g, yellow solid). Yield: 47.2%. MS m/z (ESI): 218 [M-1]

第四步the fourth step

冰浴下將5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽9c(300mg,1.0mmol)溶解於鹽酸(3.4mL,1mol/L)中,滴加入1.2mL亞硝酸鈉溶液(73mg,1.05mmol),反應10分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(193mg,0.9mmol),分批加入碳酸氫鈉(1.26g,15mmol)和4.4mL乙醇,室溫反應24小時。以TLC追蹤至原料消失,過濾,固體用20mL水洗滌,再溶解於20mL水中,冰浴下用濃鹽酸調節至pH<5,過濾,乾燥,得到標題產物5-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯基}-呋喃-2-羧酸9(287mg,黃色固體)。產率:71.8%。MS m/z(ESI):443[M-1]1 H NMR(400MHz,DMSO-d6 ):δ2.03(m,2H),2.32(s,3H),2.89)m,4H),7.15(m,1H),7.22(t,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),7.36(d,J=3.6Hz,1H),7.57(m,1H),7.70(m,2H),7.78(s,1H),9.97(s,1H),13.73(s,1H)5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (300 mg, 1.0 mmol) was dissolved in hydrochloric acid (3.4 mL, 1 mol/L) and added dropwise. 1.2 mL of sodium nitrite solution (73 mg, 1.05 mmol), react for 10 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (193 mg, 0.9 (mmol), sodium hydrogencarbonate (1.26 g, 15 mmol) and 4.4 mL of ethanol were added portionwise and allowed to react at room temperature for 24 hours. The material disappeared by TLC, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid under ice-cooling, filtered and dried to give the title product 5-{2-hydroxy-3-[ N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-phenyl}-furan-2 - Carboxylic acid 9 (287 mg, yellow solid). Yield: 71.8%. MS m/z (ESI): 443 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.03 (m, 2H), 2.32 (s, 3H), 2.89) m, 4H), 7.15 ( m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 7.57 (m, 1H), 7.70 ( m, 2H), 7.78 (s, 1H), 9.97 (s, 1H), 13.73 (s, 1H)

實施例10Example 10

4-{「2-羥基-3’-(1H-四唑-5-基)-聯苯基-3-基]-亞肼基}-5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮4-{"2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-arylene]-5-methyl-2-(5,6,7, 8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one

冰浴下將3-氨基-3’-(1H-四唑-5-基)-聯苯基-2-醇鹽酸鹽8f(340mg,1.34mmol)溶解於3mL 1N鹽酸中,滴加入3mL亞硝酸鈉溶液(98mg,1.41mmol),反應10分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(276mg,1.21mmol),分批加入碳酸氫鈉(1.69g,20mmol)和3mL乙醇,室溫反應18小時。以TLC追蹤至原料消失,過濾,固體用20mL水洗滌,再溶解於20mL水中,冰浴下用濃鹽酸調節pH=3至4,過濾,乾燥,得到標題產物4-{[2-羥基-3’-(1H-四唑-5-基)-聯苯基-3-基]-亞肼基}-5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮10(208mg,黃色固體)。產率:31.6%。MS m/z(ESI):491[M-1]1 HNMR(400MHz,DMSO-d 6 ):δ8.19(1H,s),7.99(1H,s),7.69(2H,t,J=8.8),7.49(2H,d,J=7.6),7.I5(3H,m),2.75(4H,m),2.39(3H,s),1.75(4H,m)3-Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (340 mg, 1.34 mmol) was dissolved in 3 mL of 1N hydrochloric acid, and 3 mL Sodium nitrate solution (98 mg, 1.41 mmol), reacted for 10 minutes, and then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole- 3-keto 3i (276 mg, 1.21 mmol), sodium hydrogencarbonate (1.69 g, 20 mmol) and 3 mL of ethanol were added portionwise and reacted at room temperature for 18 hours. The product disappeared by TLC, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 4-{[2-hydroxy-3 '-(1H-tetrazol-5-yl)-biphenyl-3-yl]-arylene}-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl -2,4-Dihydropyrazol-3-one 10 (208 mg, yellow solid). Yield: 31.6%. MS m/z (ESI): 491 [M-1] 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.19 (1H, s), 7.99 (1H, s), 7.69 (2H, t, J = 8.8 ), 7.49 (2H, d, J = 7.6), 7.I5 (3H, m), 2.75 (4H, m), 2.39 (3H, s), 1.75 (4H, m)

實施例11Example 11 2’-羥基-5’-甲基-3’-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-I,5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸2'-Hydroxy-5'-methyl-3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)- I,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

第一步first step

2-溴-4-甲基-6-硝基苯酚2-bromo-4-methyl-6-nitrophenol

-5℃下將硝酸鈉(28g,0.33mmol)溶解於70mL濃硫酸和210mL水的混合溶劑中,緩慢滴加2-溴-4-甲基苯酚11a(30.8g,0.165mol),冰浴反應2小時,升至室溫反應1小時。以TLC追蹤至原料消失,加入200mL乙酸乙酯萃取,有機相用水洗滌(100mL×5),無水硫酸鈉乾燥,過濾,減壓濃縮,用矽膠管柱層析分離純化,得到標題產物2-溴-4-甲基-6-硝基苯酚11b(22.24g,黃色固體)。產率:58.1%。1 HNMR(400MHz,DMSO-d6 ):δ2.29(s,3H),7.81(m,2H),10.76(s,1H)Sodium nitrate (28 g, 0.33 mmol) was dissolved in a mixed solvent of 70 mL of concentrated sulfuric acid and 210 mL of water at -5 ° C, and 2-bromo-4-methylphenol 11a (30.8 g, 0.165 mol) was slowly added dropwise thereto. After 2 hours, the reaction was allowed to rise to room temperature for 1 hour. The residue was purified by TLC. The title compound was obtained from ethyl acetate. EtOAc (EtOAc) 4-methyl-6-nitrophenol 11b (22.24 g, yellow solid). Yield: 58.1%. 1 H NMR (400 MHz, DMSO-d 6 ): δ 2.29 (s, 3H), 7.81 (m, 2H), 10.76 (s, 1H)

第二步Second step

1-溴-2-甲氧基-5-甲基-3-硝基苯1-bromo-2-methoxy-5-methyl-3-nitrobenzene

將2-溴-4-甲基-6-硝基苯酚11b(22.24g,95.9mmol)溶解於150mL丙酮中,加入碳酸鉀(15.9g,115mmol)和碘甲烷(13.7mL,220.6mmol),加熱回流過夜。以TLC追蹤至原料消失,過濾,濾液減壓濃縮,向殘餘物中加入100mL乙酸乙酯,再次過濾,減壓濃縮,得到標題產物1-溴-2-甲氧基-5-甲基-3-硝基苯11c(23.1g,橙色固體)。產率:97.9%。2-Bromo-4-methyl-6-nitrophenol 11b (22.24 g, 95.9 mmol) was dissolved in 150 mL of acetone, and potassium carbonate (15.9 g, 115 mmol) and methyl iodide (13.7 mL, 220.6 mmol) were added and heated. Reflux overnight. The title material was obtained by the residue eluting with EtOAc (EtOAc). - Nitrobenzene 11c (23.1 g, orange solid). Yield: 97.9%.

第三步third step

2’-甲氧基-5’-甲基-3’-硝基聯苯基-3-羧酸2'-Methoxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid

將1-溴-2-甲氧基-5-甲基-3-硝基苯11c(15.0g,61mmol)和間羧基苯硼酸(11.6g,70.1mmol)溶解於200mL1,4-二氧陸圜中,再加入四(三苯基膦)鈀(2.8g,2.44mmol)和61mL碳酸鈉溶液(12.9g,122mmol),加熱回流過夜。以TLC追蹤至原料消失,減壓濃縮,向殘餘物中加入500mL水,用150mL正己烷和150mL乙酸乙酯的混合溶劑洗滌,再用乙酸乙酯洗滌(300mL×2),水相用濃鹽酸調節pH至1~2,過濾,收集固體乾燥,得到標題產物2’-甲氧基-5’-甲基-3’-硝基聯苯基-3-羧酸11d(15.4g,黃色固體),產率:88.1%。1 HNMR(400MHz,DMSO-d 6 ):δ2.40(s,3H),3.42(s,3H),7.58(s,1H),7.58-7.75(m,1H),7.75(d,J=1.6Hz,lH),7.82-7.84(m,1H),8.02(d,J=8Hz,1H),8.11(d,J=1.6Hz,1H),13.12(s,1H)1-Bromo-2-methoxy-5-methyl-3-nitrobenzene 11c (15.0 g, 61 mmol) and m-carboxyphenylboronic acid (11.6 g, 70.1 mmol) were dissolved in 200 mL of 1,4-dioxane. Further, tetrakis(triphenylphosphine)palladium (2.8 g, 2.44 mmol) and 61 mL of sodium carbonate solution (12.9 g, 122 mmol) were added, and the mixture was heated to reflux overnight. The residue was evaporated to dryness with EtOAc (EtOAc) eluted eluted The pH was adjusted to 1-2, filtered, and the solid was dried to give the title product 2'-methoxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid 11d (15.4 g, yellow solid) , Yield: 88.1%. 1 H NMR (400 MHz, DMSO- d 6 ): δ 2.40 (s, 3H), 3.42 (s, 3H), 7.58 (s, 1H), 7.58-7.75 (m, 1H), 7.75 (d, J = 1.6) Hz, lH), 7.82-7.84 (m, 1H), 8.02 (d, J = 8 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 13.12 (s, 1H)

第四步the fourth step 2’-羥基-5’-甲基-3’-硝基聯苯基-3-羧酸2'-Hydroxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid

將2’-甲氧基-5’-甲基-3’-硝基聯苯基-3-羧酸11d(11.2g,39.0mmol)溶解於氫溴酸溶液(250mL,40%)中,加熱回流過夜。以TLC追蹤至原料消失,將反應液冷卻至室溫,過濾,固體用少量水和正己烷洗滌,乾燥,得到標題產物2’-羥基-5’-甲基-3’-硝基聯苯基-3-羧酸11e(9.15g,黃色固體)。產率:85.9%。MS m/z(ESI):272[M-1]1 HNMR(400MHz,DMSO-d 6 ):δ2.36(s,3H),7.60(m,2H),7.78(d,J=8Hz,1H),7.88(d,J=1.2Hz,1H),7.97(d,J=8Hz,1H),8.11(s,1H),10.44(s,1H),13.06(s,1H)2'-Methoxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid 11d (11.2 g, 39.0 mmol) was dissolved in hydrobromic acid solution (250 mL, 40%) and heated Reflux overnight. The title material was washed with a small amount of water and n-hexane and dried to give the title product 2'-hydroxy-5'-methyl-3'-nitrobiphenyl. 3-carboxylic acid 11e (9.15 g, yellow solid). Yield: 85.9%. MS m/z (ESI): 272 [M-1] 1 H NMR (400 MHz, DMSO- d 6 ): δ 2.36 (s, 3H), 7.60 (m, 2H), 7.78 (d, J = 8 Hz, 1H) ), 7.88 (d, J = 1.2 Hz, 1H), 7.97 (d, J = 8 Hz, 1H), 8.11 (s, 1H), 10.44 (s, 1H), 13.06 (s, 1H)

第五步the fifth step 3’-氨基-2’-羥基-5’-甲基聯苯基-3-羧酸鹽酸鹽3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride

將2’-羥基-5’-甲基-3’-硝基聯苯基-3-羧酸11e(9.15g,33.5mmol)溶解於200mL乙酸乙酯,加入2g鈀-碳和甲酸銨(8.45g,134mmol),加熱回流30分鐘。以TLC追蹤至原料消失,將反應液,過濾,濾液用鹽酸酸化,過濾,乾燥,得到標題產物3’-氨基-2’-羥基-5’-甲基聯苯基-3-羧酸鹽酸鹽11f(6.65g,白色固體)。產率:71.0%。MS m/z(ESI):242[M-1]1 HNMR(400MHz,DMSO-d 6 ):δ2.29(s,3H),7.09(d,J=1.6Hz,1H),7.14(d,J=1.6Hz,lH),7.59(t,J=8Hz,1H),7.74(dd,J-1 =6.4Hz,J2 =1.6Hz,1H),7.94(dd,J-1 =6.4Hz,J2 =1.6Hz,1H),8.07(s,1H)2'-Hydroxy-5'-methyl-3'-nitrobiphenyl-3-carboxylic acid 11e (9.15 g, 33.5 mmol) was dissolved in 200 mL of ethyl acetate, and 2 g of palladium-carbon and ammonium formate (8.45) were added. g, 134 mmol), heated to reflux for 30 minutes. The mixture was traced by TLC until the material disappeared, the reaction mixture was filtered, and the filtrate was acidified with hydrochloric acid, filtered and dried to give the title product 3'-amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride. Salt 11f (6.65 g, white solid). Yield: 71.0%. MS m/z (ESI): 242 [M-1] 1 H NMR (400 MHz, DMSO- d 6 ): δ 2.29 (s, 3H), 7.09 (d, J = 1.6 Hz, 1H), 7.14 (d, J=1.6 Hz, lH), 7.59 (t, J=8 Hz, 1H), 7.74 (dd, J- 1 = 6.4 Hz, J 2 = 1.6 Hz, 1H), 7.94 (dd, J- 1 = 6.4 Hz, J 2 =1.6 Hz, 1H), 8.07 (s, 1H)

第六步Step 6 2’-羥基-5’-甲基-3’-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸2'-Hydroxy-5'-methyl-3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)- 1,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基-5’-甲基聯苯基-3-羧酸鹽酸鹽11f(272mg,0.97mmol)溶解於鹽酸(3.3mL,1mol/L)中,滴加入1.3mL亞硝酸鈉溶液(74mg,1.07mmol),反應20分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(200mg,0.88mmol),分批加入碳酸氫鈉(1.22g,14.6mmol)和2.1mL乙醇,室溫反應4小時。以TLC追蹤至原料消失,過濾,固體用20mL水洗滌,再溶解於20mL水中,冰浴下用濃鹽酸調節至pH<5,過濾,乾燥,得到標題產物2’-羥基-5’-甲基-3’-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸11(170mg,紅色固體)。產率:40.2%。MS m/z(ESI):481[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.75(m,4H),2.30(s,3H),2.34(s,3H),2.74(m,4H),7.00(d,J=1.2Hz,1H),7.11(d,J=8.0Hz,1H),7.53(s,1H),7.62(m,3H),7.80(d,J=7.6Hz,1H),7.95(d,J=7.6Hz,1H),8.14(s,1H),9.39(s,1H),13.03(s,1H),13.77(s,1H)3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (272 mg, 0.97 mmol) was dissolved in hydrochloric acid (3.3 mL, 1 mol/L). Add 1.3 mL of sodium nitrite solution (74 mg, 1.07 mmol) dropwise for 20 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4- Dihydropyrazol-3-one 3i (200 mg, 0.88 mmol), sodium hydrogencarbonate (1.22 g, 14.6 mmol) and 2.1 mL of ethanol were added portionwise and allowed to react at room temperature for 4 hours. The material disappeared by TLC, filtered, and the solid was washed with 20 mL of water, and then dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 2'-hydroxy-5'-methyl. -3'-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4 - subunit]-mercapto}-biphenyl-3-carboxylic acid 11 (170 mg, red solid). Yield: 40.2%. MS m/z (ESI): 481 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.75 (m, 4H), 2.30 (s, 3H), 2.34 (s, 3H), 2.74 (m) , 4H), 7.00 (d, J = 1.2 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.62 (m, 3H), 7.80 (d, J = 7.6 Hz) , 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 9.39 (s, 1H), 13.03 (s, 1H), 13.77 (s, 1H)

實施例12Example 12 5-(3-{N’-「1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2-羥基苯基)-噻吩-2-羧酸5-(3-{N'-"1-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit]-mercapto}-2-hydroxyphenyl)-thiophene-2-carboxylic acid

第一步first step 5-(2-甲氧基-3-硝基苯基)-噻吩-2-羧酸5-(2-methoxy-3-nitrophenyl)-thiophene-2-carboxylic acid

將2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯6a(10g,35.85mmol)、5-溴-噻吩-2-羧酸(6.68g,32.2mmol)、四(三苯基膦)鈀(2.07g,1.79mmol)和碳酸鈉(7.59g,71.6mmol)溶解於200mL 1,4-二氧陸圜和30mL水的混合溶劑中,加熱回流1小時。以TLC追蹤至原料消失,過濾,濾液減壓濃縮,向殘餘物中加入150mL水,用1N鹽酸酸化至pH=3,過濾,固體用50mL正己烷和乙酸乙酯的混合溶劑(V:V=1/1)洗滌,乾燥,得到標題產物5-(2-甲氧基-3-硝基苯基)-噻吩-2-羧酸12a(7.7g,淡黃色固體)。產率:77%。MS m/z(ESI):277.9[M-1]2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (10 g, 35.85 mmol), 5-bromo-thiophene-2-carboxylic acid (6.68 g, 32.2 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.59 g, 71.6 mmol) dissolved in 200 mL 1,4- In a mixed solvent of dioxane and 30 mL of water, the mixture was heated under reflux for 1 hour. The mixture was traced by TLC until the material disappeared, filtered, and the filtrate was concentrated under reduced pressure. 150 mL of water was added to the residue, acidified to pH = 3 with 1N hydrochloric acid, filtered, and mixed with 50 mL of n-hexane and ethyl acetate (V:V = 1/1) Washing and drying gave the title product 5-(2-methoxy-3-nitrophenyl)-thiophene-2-carboxylic acid 12a (7.7 g, pale yellow solid). Yield: 77%. MS m/z (ESI): 277.9 [M-1]

第二步Second step 5-(3-氨基-2-甲氧基-苯基)-噻吩-2-羧酸5-(3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid

將5-(2-甲氧基-3-硝基苯基)-噻吩-2-羧酸12a(7.7g,27.6mmol)溶解於300mL乙酸乙酯中,再加入500mg鈀-碳和甲酸銨(6.96g,110mmol),加熱回流4小時。以TLC追蹤至原料消失,減壓濃縮,用矽膠管柱層析法純化所得殘餘物,得到標題產物5-(3-氨基-2-甲氧基-苯基)-噻吩-2-羧酸12b(6.2g,灰色固體),產率:90.1%。MS m/z(ESI):248[M-1]5-(2-Methoxy-3-nitrophenyl)-thiophene-2-carboxylic acid 12a (7.7 g, 27.6 mmol) was dissolved in 300 mL of ethyl acetate, followed by 500 mg of palladium-carbon and ammonium formate ( 6.96 g, 110 mmol), heated to reflux for 4 h. The residue was purified by TLC, EtOAc (EtOAc) eluted (6.2 g, gray solid), Yield: 90.1%. MS m/z (ESI): 248 [M-1]

第三步third step 5-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽5-(3-amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide salt

將5-(3-氨基-2-甲氧基-苯基)-噻吩-2-羧酸12b(2.2g,8.83mmol)溶解於20mL二氯甲烷中,滴加入三溴化硼(35mL,35.32mmol/L),室溫反應1.5小時。以TLC追蹤至原料消失,加入5mL甲醇,減壓濃縮,向殘餘物中加入100mL乙酸乙酯,攪拌1.5小時,過濾,收集固體,乾燥,得到標題產物5-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽12c(1.2g,灰色固體)。產率:57.1%。MS m/z(ESI):234[M-1]Dissolve 5-(3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 12b (2.2 g, 8.83 mmol) in 20 mL of dichloromethane and add boron tribromide (35 mL, 35.32) Mmmol/L), reacted at room temperature for 1.5 hours. The title material was obtained as 5-(3-amino-2-hydroxybenzene). The title product was obtained from the residue. Base)-thiophene-2-carboxylic acid hydrobromide 12c (1.2 g, grey solid). Yield: 57.1%. MS m/z (ESI): 234 [M-1]

第四步the fourth step 5-(3-{N’-[1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2-羥基苯基)-噻吩-2-羧酸5-(3-{N'-[1-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit]-mercapto}-2-hydroxyphenyl)-thiophene-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽12c(171mg,0.62mmol)溶解於3mL鹽酸(1N)中,滴加入1mL亞硝酸鈉溶液(47mg,0.68mmol),攪拌20分鐘,再加入2-(3,3-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮8i(150mg,0.62mmol),分批加入飽和碳酸氫鈉溶液(781mg,9.3mmol)將pH調至8至9,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,固體用20mL水溶解,濃鹽酸調至pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物5-(3-{N’-[1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2-羥基苯基)-噻吩-2-羧酸12(48mg,橙色固體)。產率:15.9%。MS m/z(ESI):487[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.24(t,J=8.6,6H),1.93(t,J=7.0,2H),2.87(t,J=7.0,2H),7.16(m,J=6.0,1H),7.27(d,J=4.2,2H),7.57(d,J=8.0,1H),7.64(d,J=4.0,1H),7.70(t,J=8.4,2H),7.75(d,J=4.0,1H)5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (171 mg, 0.62 mmol) was dissolved in 3 mL of hydrochloric acid (1 N), and 1 mL of sodium nitrite was added dropwise. Solution (47 mg, 0.68 mmol), stirred for 20 minutes, then added 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 8i (150 mg, 0.62 mmol), EtOAc (EtOAc m. The material disappeared by TLC, the solid was filtered, solid was dissolved in 20 mL of water, and concentrated hydrochloric acid was adjusted to pH = 3 to 4, filtered, dried, and the crude product was purified by HPLC to give the title product 5-(3-{N'- [1-(3,3-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2 -Hydroxyphenyl)-thiophene-2-carboxylic acid 12 (48 mg, orange solid). Yield: 15.9%. MS m/z (ESI): 487 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.24 (t, J = 8.6, 6H), 1.93 (t, J = 7.0, 2H), 2.87 ( t, J = 7.0, 2H), 7.16 (m, J = 6.0, 1H), 7.27 (d, J = 4.2, 2H), 7.57 (d, J = 8.0, 1H), 7.64 (d, J = 4.0, 1H), 7.70 (t, J = 8.4, 2H), 7.75 (d, J = 4.0, 1H)

實施例13Example 13 3’-{N’-[1-(2,3-二氫苯並呋喃-5-基)-3-甲基-5-側氧基3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-sideoxy -1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基-5’-甲基聯苯基-3-羧酸-1,5-dihydropyrazol-4-ylidene]-mercapto}-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基-5’-甲基聯苯基-3-羧酸鹽酸鹽11f(287mg,1.03mmol)溶解於3.5mL鹽酸(1N)中,滴加入1.5mL亞硝酸鈉溶液(78mg,1.13mmol),攪拌20分鐘,再加入2-(2,3-二氫苯並呋喃-5-基)-5-甲基-2,4-二氫吡唑-3-酮7c(200mg,0.93mmol),分批加入飽和碳酸氫鈉溶液(1.298g,15.45mmol)將pH調至8至9,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,用20mL水溶解,攪拌均勻,用濃鹽酸調至pH=3至4,過濾,乾燥,固體用10mL二氯甲烷和甲醇混合溶劑(V:V=1:1)洗滌,粗製品用HPLC分離純化,得到標題產物3’-{N’-[1-(2,3-二氫苯並呋喃-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基-5’-甲基聯苯基-3-羧酸13(100mg,紅色固體)。產率:23.0%。MS m/z(ESI):469[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.34(s,3H),2.36(s,3H),3.24(t,J=8.8Hz,2H),4.57(t,J=8.8Hz,2H),6.82(d,J=8.8Hz,1H),7.00(s,1H),7.54(s,1H),7.61(m,2H),7.74(s,1H),7.80(d,J=7.6Hz,1H),7.95(d,J=7.6Hz,1H),8.13(s,1H),9.38(s,1H),13.02(s,1H),13.76(s,1H)3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (287 mg, 1.03 mmol) was dissolved in 3.5 mL of hydrochloric acid (1 N) and added dropwise 1.5 mL sodium nitrite solution (78 mg, 1.13 mmol), stirred for 20 minutes, then added 2-(2,3-dihydrobenzofuran-5-yl)-5-methyl-2,4-dihydropyrazole- 3-keto 7c (200 mg, 0.93 mmol), EtOAc (EtOAc m. The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and mixed with 10 mL of dichloromethane and methanol (V:V=1) :1) Washing, crude product was separated and purified by HPLC to give the title product 3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-side oxygen Base-1,5-dihydropyrazol-4-ylidene]-mercapto}-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid 13 (100 mg, red solid). Yield: 23.0%. MS m/z (ESI): 469 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.34 (s, 3H), 2.36 (s, 3H), 3.24 (t, J = 8.8 Hz, 2H) ), 4.57 (t, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 1H), 7.00 (s, 1H), 7.54 (s, 1H), 7.61 (m, 2H), 7.74 (s) , 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.13 (s, 1H), 9.38 (s, 1H), 13.02 (s, 1H), 13.76 (s, 1H)

實施例14Example 14 3’-{N’-[1-(2,3-二氫苯並呋喃-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-5’-氟-2’-羥基聯苯基-3-羧酸3'-{N'-[1-(2,3-dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

冰浴下將3’-氨基-5’-氟-2’-羥基聯苯基-3-羧酸鹽酸鹽2f(219mg,0.772mmol)溶解於3mL鹽酸(1N)中,滴加入1mL亞硝酸鈉溶液(59mg,0.85mmol),攪拌20分鐘,再加入2-(2,3-二氫苯並呋喃-5-基)-5-甲基-2,4-二氫吡唑-3-酮7c(150mg,0.69mmol),分批加入飽和碳酸氫鈉溶液(1.007g,11.57mmol)將pH調至8至9,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,用15mL水溶解,攪拌均勻,用濃鹽酸調pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物3’-{N’-[1-(2,3-二氫苯並呋喃-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-5’-氟-2’-羥基聯苯基-3-羧酸14(65mg,紅色固體)。產率:20.0%。MS m/z(ESI):473[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.33(s,3H),3.23(t,J=8.8Hz,2H),4.56(t,J=8.8Hz,2H),6.83(d,J=8.4Hz,1H),7.03(m,1H),7.48(m,1H),7.60(m,2H),7.65(s,1H),7.83(d,J=8.0Hz,1H),7.98(d,J=8.0Hz,1H),8.17(s,1H),9.57(s,1H),13.07(s,1H),13.62(s,1H)3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrochloride 2f (219 mg, 0.772 mmol) was dissolved in 3 mL of hydrochloric acid (1N), and 1 mL of nitrous acid was added dropwise. Sodium solution (59 mg, 0.85 mmol), stirred for 20 minutes, then added 2-(2,3-dihydrobenzofuran-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 7c (150 mg, 0.69 mmol), EtOAc (EtOAc: m. The material disappeared by TLC, the solid was filtered, dissolved in 15 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 3'-{N'- [1-(2,3-Dihydrobenzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-5 '-Fluoro-2'-hydroxybiphenyl-3-carboxylic acid 14 (65 mg, red solid). Yield: 20.0%. MS m/z (ESI): 473 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.33 (s, 3H), 3.23 (t, J = 8.8 Hz, 2H), 4.56 (t, J) = 8.8 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 7.03 (m, 1H), 7.48 (m, 1H), 7.60 (m, 2H), 7.65 (s, 1H), 7.83 (d) , J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 8.17 (s, 1H), 9.57 (s, 1H), 13.07 (s, 1H), 13.62 (s, 1H)

實施例15Example 15 5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯基)-呋喃-2-羧酸5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽9c(292mg,0.975mmol)溶解於3.3mL鹽酸(1N)中,滴加入1.3mL亞硝酸鈉溶液(74mg,1.07mmol),攪拌20分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(200mg,0.88mmol),分批加入飽和碳酸氫鈉溶液(1.226g,14.6mmol)將pH調至8至9,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,用20mL水溶解,攪拌均勻,用濃鹽酸調至pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯基)-呋喃-2-羧酸15(160mg,紅色固體)。產率:39.8%。MS m/z(ESI):457[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.76(m,4H),2.33(s,3H),2.75(m,4H),7.13(m,2H),7.22(t,J=8.0Hz,1H),7.37(d,J=3.2Hz,1H),7.56(d,J=7.6Hz,lH),7.63(m,2H),7.71(d,J=8.4Hz,1H)5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (292 mg, 0.975 mmol) was dissolved in 3.3 mL of hydrochloric acid (1N), and then added dropwise Sodium nitrate solution (74 mg, 1.07 mmol), stirred for 20 minutes, then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole- 3-ketone 3i (200 mg, 0.88 mmol) was added portionwise EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 5-(2-hydroxyl -3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4- Subunit]-mercapto}-phenyl)-furan-2-carboxylic acid 15 (160 mg, red solid). Yield: 39.8%. MS m/z (ESI): 457 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.76 (m, 4H), 2.33 (s, 3H), 2.75 (m, 4H), 7.13 (m) , 2H), 7.22 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 7.6 Hz, lH), 7.63 (m, 2H), 7.71 (d) , J=8.4Hz, 1H)

實施例16Example 16 3’-{N’-[1-(3.3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1.5-二氫吡唑-4-亞基]-肼基}-2’-羥基-5’-甲基聯苯基-3-羧酸3'-{N'-[1-(3.3-Dimethylindan-5-yl)-3-methyl-5-oxo-1.5-dihydropyrazole-4-ylidene]-indenyl }-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基-5’-甲基聯苯基-3-羧酸鹽酸鹽11f(257mg,0.92mmol)溶解於3.1mL鹽酸(1N)中,滴加入1.2mL亞硝酸鈉溶液(70mg,1.01mmol),攪拌20分鐘,再加入2-(3,3-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮8i(200mg,0.83mmol),分批加入飽和碳酸氫鈉溶液(1.157g,13.8mmol)將pH調至8至9,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,用30mL水溶解,攪拌均勻,用濃鹽酸調至pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物3’-{N’-[1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基-5’-甲基聯苯基-3-羧酸16(160mg,橙色固體)。產率:39.0%。MS m/z(ESI):495[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.25(s,6H),1.92(t=7.2Hz,2H),2.35(s,3H),2.86(t,J=7.6Hz,2H),7.00(s,1H),7.25(d,J=8.8Hz,1H),7.54(s,lH),7.61(t,J=8.0Hz,1H),7.69(m,2H),7.80(d,J=7.6Hz,1H),7.95(d,J=7.6Hz,1H),8.14(s,1H),9.41(s,1H),13.05(br,1H),13.77(s,1H)3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (257 mg, 0.92 mmol) was dissolved in 3.1 mL of hydrochloric acid (1 N), and then added dropwise. mL sodium nitrite solution (70 mg, 1.01 mmol), stirred for 20 minutes, then added 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole- 3-ketone 8i (200 mg, 0.83 mmol), EtOAc (EtOAc m. The material disappeared by TLC, the solid was filtered, dissolved in 30 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 3'-{N'. -[1-(3,3-dimethylindan-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}- 2'-Hydroxy-5'-methylbiphenyl-3-carboxylic acid 16 (160 mg, orange solid). Yield: 39.0%. MS m/z (ESI): 495 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.25 (s, 6H), 1.92 (t = 7.2 Hz, 2H), 2.35 (s, 3H), 2.86 (t, J = 7.6 Hz, 2H), 7.00 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.54 (s, lH), 7.61 (t, J = 8.0 Hz, 1H), 7.69 (m, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 9.41 (s, 1H), 13.05 (br, 1H) ), 13.77(s,1H)

實施例17Example 17 3’-{N’-「1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-5’-氟-2’-羥基聯苯基-3-羧酸3'-{N'-"1-(3,3-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

冰浴下將3’-氨基-5’-氟-2’-羥基聯苯基-3-羧酸鹽酸鹽2f(200mg,0.71mmol)溶解於2.4mL鹽酸(1N)中,滴加入1mL亞硝酸鈉溶液(54mg,0.78mmol),攪拌20分鐘,再加入2-(3,3-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮8i(153mg,0.64mmol),分批加入飽和碳酸氫鈉溶液(889mg,10.6mmol)將pH調至8至9,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,用20mL水溶解,攪拌均勻,用濃鹽酸調至pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物3’-{N’-[1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-5’-氟-2’-羥基聯苯基-3-羧酸17(120mg,暗紅色固體)。產率:38.0%。MSm/z(ESI):499[M-1]l HNMR(400MHz,DMSO-d6 ):δ1.25(s,6H),1.92(t,J=7.2Hz,2H),2.34(s,3H),2.86(t,J=7.2Hz,2H),7.03(m,1H),7.25(d,J=8.4Hz,1H),7.47(m,1H),7.63(m,3H),7.83(d,J=7.6Hz,1H),7.98(d,J=8.0Hz,1H),8.18(s,1H),9.60(s,lH),13.07(br,1H),13.64(s,1H)3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrochloride 2f (200 mg, 0.71 mmol) was dissolved in 2.4 mL of hydrochloric acid (1 N) and added dropwise to 1 mL. Sodium nitrate solution (54 mg, 0.78 mmol), stirred for 20 minutes, then added 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole-3- Ketone 8i (153 mg, 0.64 mmol) was added portionwise EtOAc EtOAc (EtOAc:EtOAc) The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 3'-{N'. -[1-(3,3-dimethylindan-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}- 5'-Fluoro-2'-hydroxybiphenyl-3-carboxylic acid 17 (120 mg, dark red solid). Yield: 38.0%. MSm / z (ESI): 499 [M-1] l HNMR (400MHz, DMSO- d6): δ1.25 (s, 6H), 1.92 (t, J = 7.2Hz, 2H), 2.34 (s, 3H) , 2.86 (t, J = 7.2 Hz, 2H), 7.03 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.47 (m, 1H), 7.63 (m, 3H), 7.83 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.18 (s, 1H), 9.60 (s, lH), 13.07 (br, 1H), 13.64 (s, 1H)

實施例18Example 18 5-{2-羥基-3-「N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基」-苯基}-噻吩-2-羧酸5-{2-hydroxy-3-"N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime "-phenyl}-thiophene-2-carboxylic acid

冰浴下,將5-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽12c(380mg,1.2mmol)溶解於3.9mL鹽酸(1N)中,滴加入1.5mL亞硝酸鈉溶液(90mg,1.32mmol),攪拌20分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(210mg,1mmol),分批加入飽和碳酸氫鈉溶液(1.51g,18mmol)將pH調至8至9,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,用20mL5%氫氧化鈉溶液溶解,水相用二氯甲烷萃取(50mL×3),水相用濃鹽酸調pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物5-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯基}-噻吩-2-羧酸18(15mg,橙色固體)。產率:3.3%。MSm/Z(ESI):459[M-1]l HNMR(400MHZ,DMS0-d6 ):δ1.36-1.78(m,2H),2.33(s,3H),2.86-2.94(m,4H),7.17(t,J=8Hz,1H),7.30(d,J=8Hz,1H),7.56(dd,J-1=8Hz,J2 =0.8Hz,1H),7.56(d,J=4Hz,1H),7.70(m,2H),7.75(d,J=4Hz,1H),7.79(s,1H)5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (380 mg, 1.2 mmol) was dissolved in 3.9 mL of hydrochloric acid (1 N), and 1.5 mL was added dropwise. Sodium nitrite solution (90 mg, 1.32 mmol), stirred for 20 minutes, then added 2-indane-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (210 mg, 1 mmol). The saturated sodium bicarbonate solution (1.51 g, 18 mmol) was added portionwise to adjust the pH to 8 to 9, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature overnight. Followed by TLC until the disappearance of the starting material, the solid was filtered out, dissolved in 20 mL of 5% sodium hydroxide solution, the aqueous phase was extracted with dichloromethane (50 mL×3), the aqueous phase was adjusted to pH 3 to 4 with concentrated hydrochloric acid, filtered, dried, crude The product was isolated and purified by HPLC to give the title product 5-{2-hydroxy-3-[N'-(1-indane-5-yl-3-methyl-5-oxo-1,5-dihydropyridin. Azole-4-ylidene)-indenyl]-phenyl}-thiophene-2-carboxylic acid 18 (15 mg, orange solid). Yield: 3.3%. MSm / Z (ESI): 459 [M-1] l HNMR (400MHZ, DMS0-d 6): δ1.36-1.78 (m, 2H), 2.33 (s, 3H), 2.86-2.94 (m, 4H) , 7.17 (t, J = 8 Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 7.56 (dd, J-1 = 8 Hz, J 2 = 0.8 Hz, 1H), 7.56 (d, J = 4 Hz, 1H), 7.70 (m, 2H), 7.75 (d, J = 4 Hz, 1H), 7.79 (s, 1H)

實施例19Example 19 2’-羥基-3’-{N’-[3-甲基-5-側氧基-1-(1,1,3,3-四甲基茚滿-5-基)-1.5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸2'-Hydroxy-3'-{N'-[3-methyl-5-o-oxy-1-(1,1,3,3-tetramethylindan-5-yl)-1.5-dihydro Pyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

第一步first step 5-溴-3,3-二甲基茚滿-1-酮5-bromo-3,3-dimethylindan-1-one

將6-溴-1,1-二甲基茚滿8g(4g,17.8mmol)溶解於40mL重蒸的二氯甲烷中,加入氧化鉻(280mg,1.8mmol),緩慢滴加過氧化第三丁醇(19mL,190mmol),反應液呈深紅色,有氣體放出,密閉反應,室溫下攪拌過夜。以TLC追蹤至原料消失,反應液中加入50mL水稀釋,用二氯甲烷萃取(100mL×3),合併的有機相通過無水硫酸鈉乾燥,過濾,減壓下濃縮,得到標題產物5-溴-3,3-二甲基茚滿-1-酮19a(3.5g,白色固體),產率:82.3%。MS m/z(ESI):238[M-1]6-bromo-1,1-dimethylindane 8 g (4 g, 17.8 mmol) was dissolved in 40 mL of re-distilled dichloromethane, chromium oxide (280 mg, 1.8 mmol) was added, and the third peroxide was slowly added dropwise. Alcohol (19 mL, 190 mmol), the reaction mixture was dark red, eluted with a gas, sealed, and stirred at room temperature overnight. The residue was evaporated to dryness eluting with EtOAc (EtOAc) (EtOAc) 3,3-Dimethylindan-1-one 19a (3.5 g, white solid), yield: 82.3%. MS m/z (ESI): 238 [M-1]

第二步Second step 5-溴-1,1,3,3-四甲基茚滿5-bromo-1,1,3,3-tetramethylindan

將40mL二氯甲烷用乙腈-乾冰冷卻至-40℃,以注射器加入四氯化鈦(2.7mL,24.6mmol),冷卻下攪拌20分鐘後加入二甲基鋅(29.3mL,35.1mmol)甲苯溶液,控制反應在-30℃下,滴加完畢後低溫反應30分鐘,加入5-溴-3,3-二甲基茚滿-1-酮19a(2.8g,11.7mmol)的10mL二氯甲烷溶液,反應緩慢升至室溫,反應過夜。以TLC追蹤至原料消失,將反應液在減壓下濃縮,得到的殘留物通過矽膠管柱層析分離純化,得到標題產物5-溴-1,1,3,3-四甲基茚滿19b(1.55g,無色油狀液體),產率:52.3%。MS m/z(ESI):252[M-1]40 mL of dichloromethane was cooled to -40 ° C with acetonitrile-dry ice, titanium tetrachloride (2.7 mL, 24.6 mmol) was added by syringe, and stirred under cooling for 20 minutes, then dimethylzinc (29.3 mL, 35.1 mmol) in toluene was added. Control the reaction at -30 ° C, after the completion of the dropwise addition, react at low temperature for 30 minutes, and add 5-bromo-3,3-dimethylindan-1-one 19a (2.8 g, 11.7 mmol) in 10 mL of dichloromethane. The reaction was slowly warmed to room temperature and allowed to react overnight. The residue was evaporated to dryness under reduced pressure. (1.55 g, colorless oily liquid), yield: 52.3%. MS m/z (ESI): 252 [M-1]

第三步third step 1-(1,1,3,3-四甲基-2,3-二氫-1H-茚滿-5-基)肼基-1,2-二甲酸二第三丁酯1-(1,1,3,3-tetramethyl-2,3-dihydro-1H-indan-5-yl)indenyl-1,2-dicarboxylic acid di-t-butyl ester

將5-溴-1,1,3,3-四甲基茚滿19b(1.4g,5.53mmol)溶於10mL四氫呋喃中,在丙酮-乾冰浴冷卻至-78℃,滴加第三丁基鋰(4.4mL,11.1mmol),攪拌40分鐘,恒壓漏斗滴加偶氮二甲酸二第三丁酯(1.59g,6.92mmol)的10mL四氫呋喃溶液,-78℃下繼續反應3小時。以TLC追蹤至原料消失,加入5mL甲醇,反應液升至室溫,用乙酸乙酯萃取(20mL×3)反應液,合併的有機相用無水硫酸鈉乾燥,過濾,減壓下濃縮,用矽膠管柱層析分離純化,得到標題產物1-(1,1,3,3-四甲基-2,3-二氫-1H-茚滿-5-基)肼基-1,2-二甲酸二第三丁酯19c(1.326g,黃色油狀液體)。產率:59.3%。MS m/z(ESI):403[M+1]5-Bromo-1,1,3,3-tetramethylindan 19b (1.4g, 5.53mmol) was dissolved in 10mL of tetrahydrofuran, cooled to -78 ° C in acetone-dry ice bath, and added tributyllithium (4.4 mL, 11.1 mmol), stirring for 40 minutes, a solution of dibutyl azodicarboxylate (1.59 g, 6.92 mmol) in 10 mL of tetrahydrofuran was added dropwise to a constant pressure funnel, and the reaction was continued at -78 ° C for 3 hours. The mixture was traced by TLC until the disappearance of the material, and 5 mL of methanol was added. The reaction mixture was warmed to room temperature, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate. Purification by column chromatography to give the title product 1-(1,1,3,3-tetramethyl-2,3-dihydro-1H-indan-5-yl)indol-1,2-dicarboxylic acid Di-tert-butyl ester 19c (1.326 g, yellow oily liquid). Yield: 59.3%. MS m/z (ESI): 403 [M+1]

第四步the fourth step 5-甲基-2-(1,1,3,3-四甲基茚滿-5基)-2,4-二氫吡唑-3-酮5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydropyrazol-3-one

將1-(1,1,3,3-四甲基-2,3-二氫-1H-茚滿-5-基)肼基-1,2-二甲酸二第三丁酯19c(2.70g,7.18mmol)溶解於10mL乙酸中,加入13mL三氟乙酸,室溫反應30分鐘,加入乙醯乙酸乙酯(502mg,3.86mmol),加熱至100℃反應2小時。以TLC追蹤至原料消失,冷卻至室溫,減壓濃縮除去乙酸,用飽和碳酸氫鈉溶液中和反應液中的酸,用乙酸乙酯萃取(20mL×3),合併有機相,用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,所得殘餘物用矽膠管柱層析法純化,得到標題產物5-甲基-2-(1,1,3,3-四甲基茚滿-5基)-2,4-二氫吡唑-3-酮19d(130mg,淡黃色油狀液體)。產率:13.6%。MS m/z(ESI):269[M+1]1-(1,1,3,3-Tetramethyl-2,3-dihydro-1H-indan-5-yl)indolyl-1,2-dicarboxylic acid di-t-butyl ester 19c (2.70 g) , 7.18 mmol) was dissolved in 10 mL of acetic acid, and 13 mL of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 30 minutes, and ethyl acetate (502 mg, 3.86 mmol) was added thereto, and the mixture was heated to 100 ° C for 2 hours. The mixture was traced by TLC until the material disappeared, cooled to room temperature, and concentrated to remove acetic acid under reduced pressure. The acid in the reaction mixture was neutralized with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (20 mL×3). The sodium salt solution was washed with anhydrous sodium sulfate and filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjj Base-5-5-dihydropyrazol-3-one 19d (130 mg, pale yellow oily liquid). Yield: 13.6%. MS m/z (ESI): 269 [M+1]

第五步the fifth step

2’-羥基-3’-{N’-[3-甲基-5-側氧基-1-(1,1,3,3-四甲基茚滿-5-基)-1,5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸2'-Hydroxy-3'-{N'-[3-methyl-5-o-oxy-1-(1,1,3,3-tetramethylindan-5-yl)-1,5- Dihydropyrazol-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基聯苯基-3-羧酸氫溴酸鹽1f(172mg,0.56mmol)溶解於1.9mL 1N鹽酸中,滴加入0.7mL亞硝酸鈉溶液(42mg,0.61mmol),再加入5-甲基-2-(1,1,3,3-四甲基茚滿-5基)-2,4-二氫吡唑-3-酮19d(135mg,0.5mmol),分批加入碳酸氫鈉(700mg,8.33mmol),將反應液pH調至8至9,加入2mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾,固體用20mL水溶解,攪拌均勻,用濃鹽酸調至pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物2’-羥基-3’-{N’-[3-甲基-5-側氧基-1-(1,1,3,3-四甲基茚滿-5-基)-1,5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸19(75mg,紅色固體)。產率:29.4%。MSm/z(ESI):509[M-1]1 HNMR(400MHz,DMSO-d6 ):δ 1.30(m,12H),1.92(s,2H),2.35(s,3H),7.14(m,2H),7.23(d,J=8.0Hz,1H),7.62(m,2H),7.72(m,2H),7.80(d,J=7.6Hz,lH),7.96(d,J=8.0Hz,1H),8.14(s,1H),9.68(s,1H),13.10(br,1H),13.78(s,1H)3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (172 mg, 0.56 mmol) was dissolved in 1.9 mL of 1N hydrochloric acid under ice bath, and 0.7 mL of sodium nitrite solution (42 mg) was added dropwise. , 0.61 mmol), further added 5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydropyrazol-3-one 19d (135 mg, 0.5 (mmol), sodium hydrogencarbonate (700 mg, 8.33 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8 to 9 and 2 mL of ethanol was added and the mixture was allowed to warm to room temperature overnight. The material disappeared by TLC, filtered, and the solid was dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 2'-hydroxy-3. -{N'-[3-methyl-5-o-oxy-1-(1,1,3,3-tetramethylindan-5-yl)-1,5-dihydropyrazole-4- Subunit]-mercapto}-biphenyl-3-carboxylic acid 19 (75 mg, red solid). Yield: 29.4%. MS m / z (ESI): 509 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.30 (m, 12H), 1.92 (s, 2H), 2.35 (s, 3H), 7.14 (m, 2H) ), 7.23 (d, J = 8.0 Hz, 1H), 7.62 (m, 2H), 7.72 (m, 2H), 7.80 (d, J = 7.6 Hz, lH), 7.96 (d, J = 8.0 Hz, 1H) ), 8.14 (s, 1H), 9.68 (s, 1H), 13.10 (br, 1H), 13.78 (s, 1H)

實施例20Example 20

2’-羥基-5’-甲基-3’-{N’-[3-甲基-5-側氧基-1-(1,1,3,3-四甲基茚滿-5-基)-1,5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸2'-Hydroxy-5'-methyl-3'-{N'-[3-methyl-5-oxo-l-(1,1,3,3-tetramethylindan-5-yl) )-1,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基-5’-甲基聯苯基-3-羧酸鹽酸鹽11f(155mg,0.56mmol)溶解於1.9mL鹽酸(1N)中,滴加入1.2mL亞硝酸鈉溶液(42mg,0.61mmol),攪拌20分鐘,再加入5-甲基-2-(1,1,3,3-四甲基茚滿-5-基)-2,4-二氫吡唑-3-酮19d(135mg,0.5mmol),分批加入飽和碳酸氫鈉溶液(700mg,8.33mmol)將pH調至8至9,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,用30mL水溶解,攪拌均勻,用濃鹽酸調至pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物2’-羥基-5’-甲基-3’-{N’-[3-甲基-5-側氧基-1-(1,1,3,3-四甲基茚滿-5-基)-1,5-二氫吡唑-4-亞基]-肼基}-聯苯基-3-羧酸20(50mg,紅色固體)。產率:19.1%。MS m/z(ESI):523[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.30(m,12H),1.92(s,2H),2.35(m,6H),7.00(m,lH),7.23(d,J=8.4Hz,1H),7.59(s,1H),7.65(m,2H),7.74(m,1H),7.80(d,J=8.0Hz,1H),7.95(d,J=7.6Hz,1H),8.14(s,1H),9.41(s,1H),13.05(br,1H),13.78(s,1H)3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (155 mg, 0.56 mmol) was dissolved in 1.9 mL of hydrochloric acid (1 N), and then added dropwise. mL sodium nitrite solution (42 mg, 0.61 mmol), stirred for 20 minutes, then added 5-methyl-2-(1,1,3,3-tetramethylindan-5-yl)-2,4-di Hydropyrazol-3-one 19d (135 mg, 0.5 mmol) was added portionwise with saturated sodium bicarbonate solution (700 mg, 8.33 mmol). The pH was adjusted to 8 to 9 and quenched with 2 mL of ethanol. . The material disappeared by TLC, the solid was filtered, dissolved in 30 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 2'-hydroxy-5. '-Methyl-3'-{N'-[3-methyl-5-o-oxy-1-(1,1,3,3-tetramethylindan-5-yl)-1,5- Dihydropyrazol-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid 20 (50 mg, red solid). Yield: 19.1%. MS m/z (ESI): 523 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ1.30 (m, 12H), 1.92 (s, 2H), 2.35 (m, 6H), 7.00 (m) , lH), 7.23 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.65 (m, 2H), 7.74 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 9.41 (s, 1H), 13.05 (br, 1H), 13.78 (s, 1H)

實施例21Example 21

3’-「N’-(1-雙環「4.2.0]辛烷-1,3,5-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-2’-羥基-5’-甲基聯苯基-3-羧酸3'-"N'-(1-bicyclo"4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyridyl Azole-4-ylidene)-indenyl]-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基-5’-甲基聯苯基-3-羧酸鹽酸鹽11f(311mg,1.11mmol)溶解於3.7mL1N鹽酸中,滴加入1.5mL亞硝酸鈉溶液(84mg,1.22mmol),再加入2-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-5-甲基-2,4-二氫吡唑-3-酮5d(200mg,1mmol),分批加入碳酸氫鈉(1.4g,16.7mmol),將反應液pH調至8至9,加入2mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾出固體,用20mL水溶解,攪拌均勻,用濃鹽酸調pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物3’-[N’-(1-雙環[4.2.0]辛烷-1,3,5-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-2’-羥基-5’-甲基聯苯基-3-羧酸21(330mg,橙色固體)。產率:72.7%。MS m/z(ESI):453[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.34(m,6H),3.16(m,4H),7.00(s,1H),7.15(d,J=8.0Hz,1H),7.54(s,1H),7.62(m,2H),7.71(d,J=8.0Hz,1H),7.80(d,J=7.6Hz,1H),7.95(d,J=7.6Hz,1H),8.13(s,1H),9.40(s,1H),13.02(s,1H),13.75(s,1H)3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (311 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and 1.5 mL of nitrous acid was added dropwise. Sodium solution (84 mg, 1.22 mmol) followed by 2-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-5-methyl-2,4-dihydropyr Zyridin-3-one 5d (200 mg, 1 mmol), sodium hydrogencarbonate (1.4 g, 16.7 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8 to 9, and 2 mL of ethanol was added and allowed to warm to room temperature overnight. The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 3'-[N'- (1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) -mercapto]-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid 21 (330 mg, orange solid). Yield: 72.7%. MS m/z (ESI): 453 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.34 (m, 6H), 3.16 (m, 4H), 7.00 (s, 1H), 7.15 (d) , J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.62 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.95 (d , J=7.6Hz, 1H), 8.13(s,1H), 9.40(s,1H), 13.02(s,1H),13.75(s,1H)

實施例22Example 22

5-{3-[N’-(1-雙環[4.2.0]辛烷-1,3,5-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基-胼基-2-呋喃-2-羧酸5-{3-[N'-(1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-di Hydropyrazol-4-ylidene-mercapto-2-furan-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽9c(333mg,1.11mmol)溶解於3.7mLlN鹽酸中,滴加入1.5mL亞硝酸鈉溶液(84mg,1.22mmol),再加入2-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-5-甲基-2,4-二氫吡唑-3-酮5d(200mg,1mmol),分批加入碳酸氫鈉(1.4g,16.7mmol),將反應液pH調至8至9,加入2mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾出固體,用20mL水溶解,攪拌均勻,用濃鹽酸調pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物5-{3-[N’-(1-雙環[4.2.0]辛烷-1,3,5-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-2-羥基苯基}-呋喃-2-羧酸22(275mg,暗紅色固體)。產率:63.9%。MS m/z(ESI):429[M-1]1 HNMR(400MHz,DMSO-d6 ): δ 2.31(s,3H),3.15(m,4H),7.15(m,2H),7.20(t,J=8.0Hz,1H),7.36(d,J=3.6Hz,1H),7.54(m,1H),7.68(m,1H),7.72(m,2H),9.97(z,1H),13.71(z,1H)5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (333 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid, and 1.5 mL of sodium nitrite solution was added dropwise. (84 mg, 1.22 mmol) followed by 2-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-5-methyl-2,4-dihydropyrazole- 3-ketone 5d (200 mg, 1 mmol), sodium bicarbonate (1.4 g, 16.7 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8 to 9 and 2 mL of ethanol was added and the mixture was allowed to warm to room temperature overnight. The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 5-{3-[N '-(1-Bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-oxy-1,5-dihydropyrazole-4-ya Base)-indenyl]-2-hydroxyphenyl}-furan-2-carboxylic acid 22 (275 mg, dark red solid). Yield: 63.9%. MS m/z (ESI): 429 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.31 (s, 3H), 3.15 (m, 4H), 7.15 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 7.54 (m, 1H), 7.68 (m, 1H), 7.72 (m, 2H), 9.97 (z, 1H), 13.71 ( z,1H)

實施例23Example 23

2-雙環{4.2.0]辛烷-1,3,5-三烯-3-基-4-{[2-羥基-3’-(1H-四唑-5-基)-聯苯-3-基]-亞肼基-5-甲基-2,4-二氫吡唑-3-酮2-bicyclo{4.2.0]octane-1,3,5-trien-3-yl-4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3 -yl]-arylene-5-methyl-2,4-dihydropyrazol-3-one

冰浴下將3-氨基-3’-(1H-四唑-5-基)-聯苯基-2-醇鹽酸鹽8f(321mg,1.11mmol)溶解於3.7mL 1N鹽酸中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),反應20分鐘,再加入2-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-5-甲基-2,4-二氫吡唑-3-酮5d(200mg,1mmol),分批加入碳酸氫鈉(1.69g,20mmol)和3mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體用20mL水洗滌,再溶解於20mL水中,冰浴下用濃鹽酸調節至pH=3至4,過濾,乾燥,得到標題產物2-雙環[4.2.0]辛烷-1,3,5-三烯-3-基-4-{[2-羥基-3’-(1H-四唑-5-基)-聯苯-3-基]-亞肼基}-5-甲基-2,4-二氫吡唑-3-酮23(150mg,紅色固體)。產率:32.3%。MS m/z(ESI):463[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.34(s,3H),3.16(m,4H),7.18(m,3H),7.68(s,1H),7.73(m,4H),8.08(d,J=7.6Hz,1H),8.25(d,J=10Hz,1H),9.71(br,1H),13.77(br,1H)3-Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (321 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise 1.5 mL sodium nitrite solution (85 mg, 1.22 mmol), react for 20 minutes, then add 2-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-5-methyl- 2,4-Dihydropyrazol-3-one 5d (200 mg, 1 mmol), sodium bicarbonate (1.69 g, 20 mmol) and 3 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The material disappeared by TLC, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and dried to give the title product 2-bicyclo[4.2.0] Octane-1,3,5-trien-3-yl-4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-anthracene} 5-5-Methyl-2,4-dihydropyrazol-3-one 23 (150 mg, red solid). Yield: 32.3%. MS m/z (ESI): 463 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.34 (s, 3H), 3.16 (m, 4H), 7.18 (m, 3H), 7.68 (s) , 1H), 7.73 (m, 4H), 8.08 (d, J = 7.6 Hz, 1H), 8.25 (d, J = 10 Hz, 1H), 9.71 (br, 1H), 13.77 (br, 1H)

實施例24Example 24

5-{2-羥基-3-「N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5-甲基苯基}-噻吩-2-羧酸5-{2-hydroxy-3-"N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime 5-methylphenyl}-thiophene-2-carboxylic acid

第一步first step

2-(2-甲氧基-5-甲基-3-硝基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊環2-(2-Methoxy-5-methyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

將3-溴-2-甲氧基-5-甲基-硝基苯11c(20g,81.3mmol)和4,4,4’,4’,5,5,5’,5’-八甲基-2,2’聯-1,3,2-硼酸乙二醇酯(30.9g,112mmol)溶解於400mL二甲醚中,加入1,1’-雙(二苯膦基)二茂鐵二氯化鈀(3.3g,4.06mmol)和醋酸鉀(19.9g,203mmol),加畢後加熱回流3小時,反應液過濾除去1,1’-雙(二苯膦基)二茂鐵二氯化鈀,濾液減壓濃縮後經矽膠管柱層析法純化得到標題產物3-(4,5-二甲基-[1,3,2]硼酸頻那醇酯-2-基)-2-甲氧基-5-甲基-硝基苯24a(13.1g,黃色油狀液體),產率57.1%。MS m/z(ESI):293.09[M+1]l HNMR(400MHz,CDCl3 ):δ 1.16(s,12H),2.39(s,3H),3.5(s,3H),7.53(d,J=2Hz,lH),7.83(d,J=2Hz,1H)3-Bromo-2-methoxy-5-methyl-nitrobenzene 11c (20 g, 81.3 mmol) and 4,4,4',4',5,5,5',5'-octamethyl -2,2'-linked -1,3,2-boronic acid ethylene glycol ester (30.9 g, 112 mmol) was dissolved in 400 mL of dimethyl ether, and 1,1'-bis(diphenylphosphino)ferrocene dichloride was added. Palladium (3.3 g, 4.06 mmol) and potassium acetate (19.9 g, 203 mmol) were added and heated under reflux for 3 hours. The reaction solution was filtered to remove 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 3-(4,5-dimethyl-[1,3,2]boronic acid benzoate-2-yl)-2-methoxy 5-methyl-nitrobenzene 24a (13.1 g, yellow oily liquid), yield 57.1%. MS m / z (ESI): 293.09 [M + 1] l HNMR (400MHz, CDCl 3): δ 1.16 (s, 12H), 2.39 (s, 3H), 3.5 (s, 3H), 7.53 (d, J =2Hz, lH), 7.83 (d, J=2Hz, 1H)

第二步Second step

5-(3-硝基-2-甲氧基-5-甲基苯基)-噻吩-2-羧酸5-(3-nitro-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid

將3-(4,5-二甲基-[1,3,2]硼酸頻那醇酯-2-基)-2-甲氧基-5-甲基-硝基苯24a(4.0g,14.5mmol)、5-溴-噻吩-2-羧酸(1.0g,4.8mmol)、四(三苯基膦)鈀(0.276g,0.24mmol)和碳酸鈉(1.01g,9.6mmol)溶解於30mL1,4-二氧陸圜和10mL水中,反應體系加熱回流1小時,以TLC追蹤至原料消失,反應液減壓濃縮後加水溶解,過濾除去四(三苯基膦)鈀,濾液用乙酸乙酯萃取,水相經酸化後有固體析出,固體用乙酸乙酯溶解,經無水硫酸鎂乾燥,過濾除去乾燥劑,濾液濃縮得到標題產物5-(3-硝基-2-甲氧基-5-甲基苯基)-噻吩-2-羧酸24b(1.03g,黃色固體),產率:73.6%。MS m/z(ESI):291.7[M-1]1 HNMR(400MHz,CDCl3 ):δ2.41(s,3H),3.73(s,3H),7.73-7.79(m,3H),8.00(m,1H),13.20(Br,1H)3-(4,5-Dimethyl-[1,3,2]boronic acid pinacol-2-yl)-2-methoxy-5-methyl-nitrobenzene 24a (4.0 g, 14.5 Methyl), 5-bromo-thiophene-2-carboxylic acid (1.0 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium (0.276 g, 0.24 mmol) and sodium carbonate (1.01 g, 9.6 mmol) were dissolved in 30 mL1. 4-Dioxanthracene and 10 mL of water, the reaction system was heated under reflux for 1 hour, and the mixture was traced by TLC until the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure and then dissolved with water, and then filtered to remove tetras(triphenylphosphine)palladium. After the aqueous phase is acidified, a solid precipitates, the solid is dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and filtered to remove the desiccant, and the filtrate is concentrated to give the title product 5-(3-nitro-2-methoxy-5- Phenyl)-thiophene-2-carboxylic acid 24b (1.03 g, yellow solid), yield: 73.6%. MS m/z (ESI): 291.7 [M-1] 1 H NMR (400 MHz, CDCl 3 ): δ 2.41 (s, 3H), 3.73 (s, 3H), 7.73-7.79 (m, 3H), 8.00 ( m, 1H), 13.20 (Br, 1H)

第三步third step

5-(3-氨基-2-甲氧基-5-甲基苯基)-噻吩-2-羧酸5-(3-amino-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid

將5-(3-硝基-2-甲氧基-5-甲基苯基)-噻吩-2-羧酸24b(0.29g,1mmol)溶解於30mL乙酸乙酯中,加入0.06g鈀-碳和甲酸銨(0.25g,4mmol),加畢後加熱回流45分鐘。以TLC追蹤至原料消失,過濾除去鈀-碳,濾液減壓濃縮,乾燥,得到標題產物5-(3-氨基-2-甲氧基-5-甲基苯基)-噻吩-2-羧酸24c(0.26g,綠色固體)。產率:99%。MS m/z(ESI):261.7[M-1]1 HNMR(400MHz,CDCl3 ):δ2.18(s,3H),3.58(s,3H),6.54(d,J=1.6Hz,1H),6.78(d,J=1.6Hz,1H),7.53(d,J=4Hz,1H),7.68(d,J=4Hz,1H)Dissolve 5-(3-nitro-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 24b (0.29 g, 1 mmol) in 30 mL of ethyl acetate and add 0.06 g of palladium-carbon Ammonium formate (0.25 g, 4 mmol) was added and heated and refluxed for 45 minutes. The residue was removed by TLC, and the palladium-carbon was removed by filtration. The filtrate was concentrated under reduced pressure and dried to give the title product 5-(3-amino-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 24c (0.26 g, green solid). Yield: 99%. MS m/z (ESI): 261.7 [M-1] 1 H NMR (400 MHz, CDCl 3 ): δ 2.18 (s, 3H), 3.58 (s, 3H), 6.54 (d, J = 1.6 Hz, 1H) , 6.78 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 4 Hz, 1H), 7.68 (d, J = 4 Hz, 1H)

第四步the fourth step

5-(3-氨基-2-羥基-5-甲基苯基)-噻吩-2-羧酸氫溴酸鹽5-(3-amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide

將5-(3-氨基-2-甲氧基-5-甲基苯基)-噻吩-2-羧酸24c(0.26g,1mmol)溶解於20mL二氯甲烷中,滴加入三溴化硼(5mL,35.32mmol/L),室溫反應1小時。以TLC追蹤至原料消失,減壓濃縮,向殘餘物中加入30mL乙酸乙酯,攪拌0.5小時,過濾,濾餅用乙酸乙酯洗滌後乾燥,得到標題產物5-(3-氨基-2-羥基-5-甲基苯基)-噻吩-2-羧酸氫溴酸鹽24d(0.15g,灰色固體)。產率:45.5%。MS m/z(ESI):247.8[M-1]1 H NMR(400MHz,CDCl3 ):δ2.29(s,3H),7.02(d,J=1.6Hz,1H),7.41(s,1H),7.59(d,J=4Hz,1H),7.73(d,J=4Hz,1H)Dissolve 5-(3-amino-2-methoxy-5-methylphenyl)-thiophene-2-carboxylic acid 24c (0.26 g, 1 mmol) in 20 mL of dichloromethane and add boron tribromide dropwise. 5 mL, 35.32 mmol/L), and reacted at room temperature for 1 hour. The title material was obtained as a title product 5-(3-amino-2-hydroxyl). -5-Methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (0.15 g, m.p.). Yield: 45.5%. MS m/z (ESI): 247.8 [M-1] 1 H NMR (400 MHz, CDCl 3 ): δ 2.29 (s, 3H), 7.02 (d, J = 1.6 Hz, 1H), 7.41 (s, 1H) ), 7.59 (d, J = 4 Hz, 1H), 7.73 (d, J = 4 Hz, 1H)

第五步the fifth step

5-{2-羥基-3-[N’-(1-茚滿-5--基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5-甲基苯基}-噻吩-2-羧酸5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxooxy-1,5-dihydropyrazole-4-ylidene)- Mercapto]-5-methylphenyl}-thiophene-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基-5-甲基苯基)-噻吩-2-羧酸氫溴酸鹽24d(138mg,0.42mmol)溶解於1.5mL 1N鹽酸中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),反應20分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(81mg,0.38mmol),分批加入碳酸氫鈉(527mg,6.27mmol)和2mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體用20mL水洗滌,再溶解於10mL水中,冰浴下用濃鹽酸調節至pH=3至4,過濾,乾燥,得到標題產物5-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5-甲基苯基}-噻吩-2-羧酸24(30mg,紅色固體)。產率:16.7%。MS m/z(ESI):473[M-1]1 HNMR(400MHz,DMS0-d6 ):δ2.03(m,2H),2.32(s,3H),2.36(s,3H),2.89(m,4H),7.29(d,J=8.0Hz,1H),7.38(s,1H),7.50(s,1H),7.63(d,J=4.0Hz,1H),7.68(d,J=8.0Hz,1H),7.74(m,2H),9.78(s,1H),13.72(br,1H)5-(3-Amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (138 mg, 0.42 mmol) was dissolved in 1.5 mL of 1N hydrochloric acid and added dropwise. 1.5mL sodium nitrite solution (85mg, 1.22mmol), reaction for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (81mg, 0.38 Methyl) sodium hydrogencarbonate (527 mg, 6.27 mmol) and 2 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The material disappeared by TLC, filtered, and the solid was washed with 20 mL of water, dissolved in 10 mL of water, adjusted to pH = 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 5-{2-hydroxy-3. -[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indolyl]-5-methylbenzene }--thiophene-2-carboxylic acid 24 (30 mg, red solid). Yield: 16.7%. MS m/z (ESI): 473 [M-1] 1 H NMR (400 MHz, DMS0- d6 ): δ 2.03 (m, 2H), 2.32 (s, 3H), 2.36 (s, 3H), 2.89 (m) , 4H), 7.29 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.50 (s, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.68 (d, J = 8.0 Hz) , 1H), 7.74 (m, 2H), 9.78 (s, 1H), 13.72 (br, 1H)

實施例25Example 25

5-(2-羥基-3-{N’-「3-甲基-5-側氧基-1-(1,1,3,3-四甲基茚滿-5-基)-1,5-二氫吡唑-4-亞基}-肼基}-苯基)-呋喃-2-羧酸5-(2-hydroxy-3-{N'-"3-methyl-5-oxo-l-(1,1,3,3-tetramethylindan-5-yl)-1,5 -dihydropyrazole-4-ylidene}-indenyl}-phenyl)-furan-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽9c(124mg,0.41mmol)溶解於1.4mL鹽酸(1N)中,滴加入0.5mL亞硝酸鈉溶液(32mg,0.45mmol),攪拌20分鐘,再加入5-甲基-2-(1,1,3,3-四甲基茚滿-5基)-2,4-二氫吡唑-3-酮19d(100mg,0.37mmol),用飽和碳酸氫鈉溶液調節pH值至8,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,固體中加入10mL水,用濃鹽酸調pH=3至4,過濾,固體後經管柱層析後乾燥得到標題產物5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(1,1,3,3-四甲基茚滿-5-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯基)-呋喃-2-羧酸25(22mg,紅色固體)。產率:11.9%。1 HNMR(400MHz,DMSO-d6 ):δ1.30(m,12H),1.92(s,2H),2.34(s,3H),7,15(d,J=3.6Hz,1H),7.22(m,2H),7.36(d,J=3.2Hz,1H),7.56(dd,J1=8,0Hz,J2=1.2Hz,1H),7.66(d,J=2.0Hz,1H),7.75(m,2H)5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (124 mg, 0.41 mmol) was dissolved in 1.4 mL of hydrochloric acid (1N), and 0.5 mL Sodium nitrate solution (32 mg, 0.45 mmol), stirred for 20 minutes, then added 5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydropyrazole 3-ketone 19d (100 mg, 0.37 mmol), the pH was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature overnight. The product disappeared by TLC, the solid was filtered, 10 mL of water was added to the solid, pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and the solid was subjected to column chromatography and dried to give the title product 5-(2-hydroxy-3-{ N'-[3-Methyl-5-oxo-l-(1,1,3,3-tetramethylindan-5-yl)-1,5-dihydropyrazole-4-ylidene ]-Mercapto}-phenyl)-furan-2-carboxylic acid 25 (22 mg, red solid). Yield: 11.9%. 1 H NMR (400 MHz, DMSO- d6 ): δ 1.30 (m, 12H), 1.92 (s, 2H), 2.34 (s, 3H), 7, 15 (d, J = 3.6 Hz, 1H), 7.22 (m) , 2H), 7.36 (d, J = 3.2 Hz, 1H), 7.56 (dd, J1 = 8, 0 Hz, J2 = 1.2 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.75 (m, 2H)

實施例26Example 26

3’-[N’-(1-雙環[4.2.0]辛烷-1,3,5-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5’-氟-2’-羥基聯苯-3-羧酸3'-[N'-(1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyridyl Azole-4-ylidene)-indenyl]-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid

第一步first step

3’-氨基-5’-氟-2’-羥基聯苯基-3-羧酸氫溴酸鹽將實施例2第五步所得中間體3’-氨基-5’-氟-2’-羥基聯苯基-3-羧酸2f(500mg’1.92mmol)滴加20mL氫溴酸,有白色渾濁物生成,加熱回流反應過夜,反應澄清,變為黃褐色溶液。以TLC追蹤至原料消失,減壓下濃縮溶液,得到的棕黃色固體用20mL乙酸乙酯溶解,攪拌20分鐘,過濾,得到標題產物3’-氨基-5’-氟-2’-羥基聯苯基-3-羧酸氫溴酸鹽26a(344mg,灰白色固體)。產率:54.8%。MSm/z(ESI):248[M+1]3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide salt The intermediate 3'-amino-5'-fluoro-2'-hydroxy group obtained in the fifth step of Example 2 Biphenyl-3-carboxylic acid 2f (500 mg '1.92 mmol) was added dropwise with 20 mL of hydrobromic acid, and a white turbid substance was formed. The mixture was heated and refluxed overnight, and the reaction was clarified to give a yellow-brown solution. The residue was evaporated to dryness, and the mixture was concentrated under reduced pressure. The solid brown solid was dissolved in ethyl acetate (20 mL), and stirred for 20 min, and filtered to give the title product 3'-amino-5'-fluoro-2'-hydroxybiphenyl. Base-3-carboxylic acid hydrobromide 26a (344 mg, off-white solid). Yield: 54.8%. MSm/z (ESI): 248 [M+1]

第二步Second step

3’-[N’-(1-雙環[4.2.0]辛烷-1,3,5-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5’-氟-2’-羥基-二苯基-3-羧酸3'-[N'-(1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyridyl Azole-4-ylidene)-indenyl]-5'-fluoro-2'-hydroxy-diphenyl-3-carboxylic acid

冰浴下將3’-氨基-5’-氟-2’-羥基聯苯基-3-羧酸氫溴酸鹽26a(328mg,1.11mmol)溶解於3.7mL 1N鹽酸中,滴加入1.5mL亞硝酸鈉溶液(84mg,1.22mmol),再加入2-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-5-甲基-2,4-二氫吡唑-3-酮5d(200mg,1mmol),分批加入碳酸氫鈉(1.4g,16.7mmol),將反應液pH調至8至9,加入2mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾出固體,用20mL水溶解,攪拌均勻,用濃鹽酸調pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物3’-[N’-(1-雙環[4.2.0]辛烷-1,3,5-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5’-氟-2’-羥基聯苯-3-羧酸26(335mg,紅色固體)。產率:73.1%。MS m/z(ESI):457[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.32(s,3H),3.22(m,4H),7.02(m,1H),7.14(d,J=8.0Hz,1H),7.46(m,1H),7.61(m,2H),7.69(m,1H),7.82(d,J=7,6Hz,1H),7.98(d,J=7.6Hz,1H),8.17(s,1H),9.58(s,1H),13.07(s,1H),13.60(s,1H)3'-Amino-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 26a (328 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise 1.5 mL. Sodium nitrate solution (84 mg, 1.22 mmol) followed by 2-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-5-methyl-2,4-dihydrogen Pyrazol-3-one 5d (200 mg, 1 mmol), sodium hydrogencarbonate (1.4 g, 16.7 mmol) was added portionwise, the pH of the reaction mixture was adjusted to 8 to 9 and 2 mL of ethanol was added and allowed to warm to room temperature overnight. The material disappeared by TLC, the solid was filtered, dissolved in 20 mL of water, stirred well, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and the crude product was purified by HPLC to give the title product 3'-[N'- (1-bicyclo[4.2.0]octane-1,3,5-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) - mercapto]-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid 26 (335 mg, red solid). Yield: 73.1%. MS m/z (ESI): 457 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.32 (s, 3H), 3.22 (m, 4H), 7.02 (m, 1H), 7.14 (d) , J = 8.0 Hz, 1H), 7.46 (m, 1H), 7.61 (m, 2H), 7.69 (m, 1H), 7.82 (d, J = 7, 6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 9.58 (s, 1H), 13.07 (s, 1H), 13.60 (s, 1H)

實施例27Example 27

4-{[2-羥基-3’-(1H-四唑-5-基)-聯苯-3-基]-肼叉}-2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-anthracene}-2-indan-5-yl-5-methyl-2, 4-dihydropyrazol-3-one

冰浴下將3-氨基-3’-(1H-四唑-5-基)-聯苯基-2-醇鹽酸鹽8f(188mg,0.74mmol)溶解於4mL 2N鹽酸中,滴加入1mL亞硝酸鈉溶液(57mg,0.82mmol),反應30分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(159mg,0.74mmol),用飽和碳酸氫鈉調節pH值至8,加入0.5mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體用氫氧化鈉溶液(3N)溶解後用二氯甲烷洗滌3次,水相用2N鹽酸調節pH值至3,有大量固體析出,過濾,所得固體經管柱層析得到標題產物4-{[2-羥基-3’-(1H-四唑-5-基)-聯苯-3-基]-肼叉}-2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮27(67mg,橙色固體),產率:18.8%。MS m/z(ESI):477.2[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.03(m,2H),2.33(s,3H),2.89(m,4H),7.17(m,2H),7.28(d,J=8.0Hz,1H),7.71(m,5H),8.08(d,J=8.0Hz,1H),8.25(s,1H),9.73(br,1H),13,77(s,1H)3-Amino-3'-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (188 mg, 0.74 mmol) was dissolved in 4 mL of 2N hydrochloric acid and added dropwise Sodium nitrate solution (57 mg, 0.82 mmol), reacted for 30 minutes, and then added 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (159 mg, 0.74 mmol). The pH was adjusted to 8 with saturated sodium bicarbonate, and 0.5 mL of ethanol was added and allowed to react at room temperature overnight. The material disappeared by TLC, filtered, and the solid was dissolved in sodium hydroxide solution (3N) and then washed three times with dichloromethane. The aqueous phase was adjusted to pH 3 with 2N hydrochloric acid, and a large amount of solid was precipitated and filtered. Chromatography gave the title product 4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)-biphenyl-3-yl]-indole}-2-indan-5-yl-5- Methyl-2,4-dihydropyrazol-3-one 27 (67 mg, orange solid), yield: 18.8%. MS m/z (ESI): 477.2 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.03 (m, 2H), 2.33 (s, 3H), 2.89 (m, 4H), 7.17 (m) , 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.71 (m, 5H), 8.08 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 9.73 (br, 1H), 13 ,77(s,1H)

實施例28Example 28

4-(2-羥基-3-{N’-「3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯基)-呋喃-2-羧酸4-(2-hydroxy-3-{N'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylic acid

第一步first step

4-溴-呋喃-2-羧酸4-bromo-furan-2-carboxylic acid

室溫下,將4,5-二溴-呋喃-2-羧酸28a(5.5g,20.3mmol)和18mL氨水加入到63mL水中,加入鋅粉(1.46g,22.33mmol),加畢後室溫攪拌6小時,TLC監測至原料反應完全,停止反應。用鹽酸(1N)調節反應液pH至3,有大量固體析出,過濾,濾餅用正己烷洗滌(15mL×4)後乾燥,得到標題產物4-溴-呋喃-2-羧酸28b(3.2g,白色固體),產率:83.1%。MS m/z(ESI):188.7[M-1]4,5-dibromo-furan-2-carboxylic acid 28a (5.5 g, 20.3 mmol) and 18 mL of aqueous ammonia were added to 63 mL of water at room temperature, and zinc powder (1.46 g, 22.33 mmol) was added. After stirring for 6 hours, TLC was monitored until the starting material was completely reacted and the reaction was stopped. The pH of the reaction mixture was adjusted to 3 with hydrochloric acid (1N), and a large solid was precipitated, filtered, and the filter cake was washed with n-hexane (15 mL × 4) and dried to give the title product 4-bromo-furan-2-carboxylic acid 28b (3.2 g) , white solid), Yield: 83.1%. MS m/z (ESI): 188.7 [M-1]

第二步Second step

4-(3-硝基-2-甲氧基-苯基)-呋喃-2-羧酸4-(3-nitro-2-methoxy-phenyl)-furan-2-carboxylic acid

將2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯6a(4g,14.34mmol)、4-溴-呋喃-2-羧酸28b(2.18g,11.47mmol)、四(三苯基膦)鈀(829mg,0.717mmol)和碳酸鉀(3.96g,28.68mmol)溶解於80mL 1,4-二氧陸圜和30mL水的混合溶劑中,加熱回流2.5小時。以TLC追蹤至原料消失,反應液用1N鹽酸酸化至pH至3,乙酸乙酯萃取(80mL×3),合併有機相,有機相減壓濃縮後經管柱層析得到標題產物4-(3-硝基-2-甲氧基-苯基)-呋喃-2-羧酸28c(3.42g,棕色油狀液體)。產率:90.7%。MS m/z(ESI):261.8[M-1]2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (4 g, 14.34 mmol), 4-bromo-furan-2-carboxylic acid 28b (2.18 g, 11.47 mmol), tetrakis(triphenylphosphine)palladium (829 mg, 0.717 mmol) and potassium carbonate (3.96 g, 28.68 mmol) dissolved in 80 mL 1,4- In a mixed solvent of dioxane and 30 mL of water, the mixture was heated under reflux for 2.5 hours. After the residue was traced to the disappearance of the starting material, the reaction mixture was acidified to pH 3 with 1N hydrochloric acid and ethyl acetate (EtOAc (EtOAc) Nitro-2-methoxy-phenyl)-furan-2-carboxylic acid 28c (3.42 g, brown oily). Yield: 90.7%. MS m/z (ESI): 261.8 [M-1]

第三步third step

4-(3-氨基-2-甲氧基-苯基)-呋喃-2-羧酸4-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid

將4-(3-硝基-2-甲氧基-苯基)-呋喃-2-羧酸28c(500mg,1.9mmol)溶解於15mL乙酸乙酯中,再加入100mg鈀-碳和甲酸銨(429mg,7.6mmol),加熱回流3小時。以TLC追蹤至原料消失,反應液過濾除去鈀/碳,減壓濃縮得到標題產物4-(3-氨基-2-甲氧基-苯基)-呋喃-2-羧酸28d(325mg,黃色油狀液體),產率:73.4%。MS m/z(ESI):231.8[M-1]4-(3-Nitro-2-methoxy-phenyl)-furan-2-carboxylic acid 28c (500 mg, 1.9 mmol) was dissolved in 15 mL of ethyl acetate, and then 100 mg of palladium-carbon and ammonium formate ( 429 mg, 7.6 mmol), heated to reflux for 3 hours. The residue was removed by TLC, and the reaction mixture was filtered to remove palladium/carbon, and concentrated under reduced pressure to give the title product 4-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid 28d (325 mg, yellow oil Liquid), yield: 73.4%. MS m/z (ESI): 231.8 [M-1]

第四步the fourth step

4-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide

將4-(3-氨基-2-甲氧基-苯基)-呋喃-2-羧酸28d(325mg,1.4mmol)溶解於5mL二氯甲烷中,滴加入三溴化硼(2.8mL,5.6mmol),室溫反應4.5小時。以TLC追蹤至原料消失,加入5mL甲醇,減壓濃縮,向殘餘物中加入10mL乙酸乙酯,攪拌0.5小時,過濾,收集固體,乾燥,得到標題產物4-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽28e(174mg,灰色固體)。產率:57.1%。MS m/z(ESI):217.7[M-1]4-(3-Amino-2-methoxy-phenyl)-furan-2-carboxylic acid 28d (325 mg, 1.4 mmol) was dissolved in 5 mL dichloromethane, and boron tribromide (2.8 mL, 5.6) was added dropwise. Methyl), reacted at room temperature for 4.5 hours. The title material (4-amino-2-hydroxybenzene) was obtained after the residue was purified by chromatography. Base)-furan-2-carboxylic acid hydrobromide 28e (174 mg, gray solid). Yield: 57.1%. MS m/z (ESI): 217.7 [M-1]

第五步the fifth step

4-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯基)-呋喃-2-羧酸4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylic acid

冰浴下將4-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽28e(170mg,0.57mmol)溶解於鹽酸(1.9mL,1mol/L)中,滴加入0.7mL亞硝酸鈉溶液(43mg,0.63mmol),反應20分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(116mg,0.51mmol),用飽和碳酸氫鈉溶液調節pH至8至9,加入2mL乙醇,室溫反應24小時。以TLC追蹤至原料消失,過濾,固體中加入15mL水,冰浴下用濃鹽酸調節pH至2至3,過濾,濾餅用乙酸乙酯洗滌,乾燥,得到標題產物4-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯基)-呋喃-2-羧酸28(13mg,紅色固體)。產率:5.5%。MS m/z(ESI):456.7[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.75(m,4H),2.31(s,3H),2.78(m,4H),3.86(s,3H),7.13(m,2H),7.43(d,J=7.6Hz,1H),7.62(m,2H),7.78(s,1H),8.43(s,1H),9.68(br,1H),13.73(br,1H)4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 28e (170 mg, 0.57 mmol) was dissolved in hydrochloric acid (1.9 mL, 1 mol/L). 0.7 mL of sodium nitrite solution (43 mg, 0.63 mmol), reacted for 20 minutes, and then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydrogen Pyrazol-3-one 3i (116 mg, 0.51 mmol) was adjusted to pH 8 to 9 with a saturated sodium hydrogen carbonate solution, and 2 mL of ethanol was added and allowed to react at room temperature for 24 hours. After the TLC was traced to the disappearance of the starting material, the mixture was filtered, and 15 mL of water was added to the solid. The mixture was adjusted to pH 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was washed with ethyl acetate and dried to give the title product 4-(2-hydroxy- 3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole- 4-Subphenyl]-fluorenyl}-phenyl)-furan-2-carboxylic acid 28 (13 mg, red solid). Yield: 5.5%. MS m/z (ESI): 456.7 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.75 (m, 4H), 2.31 (s, 3H), 2.78 (m, 4H), 3.86 (s) , 3H), 7.13 (m, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.62 (m, 2H), 7.78 (s, 1H), 8.43 (s, 1H), 9.68 (br, 1H) , 13.73 (br, 1H)

實施例29Example 29

2’-羥基-3’-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5’-甲基-聯苯-3-羧酸2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-5'-Methyl-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基-5’-甲基聯苯基-3-羧酸鹽酸鹽11f(346mg,1.07mmol)溶解於鹽酸(5mL,2mol/L)中,滴加入2mL亞硝酸鈉溶液(81mg,1.17mmol),反應30分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(229mg,1.07mmol),用飽和碳酸氫鈉溶液調節pH值至8,加入5mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體用乙醇洗滌,濾液倒入冰水中,用1N鹽酸調節pH值至4,有固體析出,過濾,所得固體用乙酸乙酯洗滌3次,乾燥後得到標題產物2’-羥基-3’-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5’-甲基-聯苯-3-羧酸29(75mg,紅色固體)。產率:15%。MS m/z(ESI):467.2[M-1]1 H NMR(400MHz,DMSO-d6 ):δ2.01(m,2H),2.35(m,6H),2.88(m,4H),6.97(S,1H),7.30(s,1H),7.70(m,5H),8.02(s,1H),8.15(s,1H),9.42(br,1H),13.03(br,1H),13.77(s,1H)3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (346 mg, 1.07 mmol) was dissolved in hydrochloric acid (5 mL, 2 mol/L). Add 2 mL of sodium nitrite solution (81 mg, 1.17 mmol), react for 30 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (229 mg, 1.07) (mmol), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and 5 mL of ethanol was added and allowed to react overnight at room temperature. It was traced to the disappearance of the starting material by TLC, filtered, and the solid was washed with ethanol, and the filtrate was poured into ice water, and the pH was adjusted to 4 with 1N hydrochloric acid, and solids were precipitated, filtered, and the obtained solid was washed three times with ethyl acetate. 2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-5'-Methyl-biphenyl-3-carboxylic acid 29 (75 mg, red solid). Yield: 15%. MS m/z (ESI): 467.2 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.01 (m, 2H), 2.35 (m, 6H), 2.88 (m, 4H), 6.97 ( S, 1H), 7.30 (s, 1H), 7.70 (m, 5H), 8.02 (s, 1H), 8.15 (s, 1H), 9.42 (br, 1H), 13.03 (br, 1H), 13.77 (s , 1H)

實施例30Example 30

3’-{N’-[1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基聯苯-3-羧酸3'-{N'-[1-(3,3-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基聯苯基-3-羧酸氫溴酸鹽1f(310mg,f.0mmol)溶解於鹽酸(3.4mL,1mol/L)中,滴加入1.2mL亞硝酸鈉溶液(73mg,1.05mmol),反應10分鐘,再加入2-(3,3-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮8i(218mg,0.9mmol),分批加入碳酸氫鈉(1.26g,15mmol)和4.4mL乙醇,室溫反應10小時。以TLC追蹤至原料消失,過濾,固體用20mL水洗滌,再溶解於20mL水中,冰浴下用濃鹽酸調節至pH<5,過濾,乾燥,得到標題產物3’-{N’-[1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基聯苯-3-羧酸30(500mg,黃色固體)。產率:94%。MS m/z(ESI):509.1[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.24(m,6H),1.92(t,J=7.2Hz,2H),2.34(s,3H),2.86(t,J=7.2Hz,2H),7.16(m,2H),7.25(d,J=8.8Hz,1H),7.62(t,J=7.6Hz,1H),7.70(m,3H),7.80(d,J=7.6Hz,1H),7.96(d,J=7.2Hz,1H),8.14(s,1H),9.68(s,1H)3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (310 mg, f. 0 mmol) was dissolved in hydrochloric acid (3.4 mL, 1 mol/L) under ice-cooling, and 1.2 mL was added dropwise. Sodium nitrite solution (73 mg, 1.05 mmol), reacted for 10 minutes, and then added 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole-3 - Ketone 8i (218 mg, 0.9 mmol), sodium bicarbonate (1.26 g, 15 mmol) and 4.4 mL of ethanol were added portionwise and reacted at room temperature for 10 hours. The material disappeared by TLC, filtered, and the solid was washed with 20 mL of water, dissolved in 20 mL of water, adjusted to pH <5 with concentrated hydrochloric acid in an ice bath, filtered and dried to give the title product 3'-{N'-[1- (3,3-Dimethylindan-5-yl)-3-methyl-5-oxooxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxyl Biphenyl-3-carboxylic acid 30 (500 mg, yellow solid). Yield: 94%. MS m/z (ESI): 509.1 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.24 (m, 6H), 1.92 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H) ), 2.86 (t, J = 7.2 Hz, 2H), 7.16 (m, 2H), 7.25 (d, J = 8.8 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.70 (m, 3H) ), 7.80 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 8.14 (s, 1H), 9.68 (s, 1H)

實施例31Example 31

4-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-呋喃-2-羧酸4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-anthracene Benzene-furan-2-carboxylic acid

冰浴下將4-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽28e(170mg,0.57mmol)溶解於鹽酸(1.9mL,1mol/L)中,滴加入0.7mL亞硝酸鈉溶液(43mg,0.63mmol),反應20分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮li(109mg,0.51mmol),用飽和碳酸氫鈉溶液調節pH至8至9,加入2mL乙醇,室溫反應24小時。以TLC追蹤至原料消失,過濾,固體中加入15mL水,冰浴下用濃鹽酸調節pH至2至3,過濾,濾餅用乙酸乙酯洗滌,乾燥,得到標題產物4-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-呋喃-2-羧酸31(83mg,黑色固體)。產率:36.7%。MS m/z(ESI):442.8[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.08(m,2H),2.32(s,3H),2.89(m,4H),7.13(t,J=8.0Hz,1H),7.28(d,J=8.4Hz,1H),7.41(d,J=7.6Hz,1H),7.65(m,3H),7.75(m,1H),8.37(s,1H),9.68(s,1H),13.22(br,1H),13.74(s,1H)4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 28e (170 mg, 0.57 mmol) was dissolved in hydrochloric acid (1.9 mL, 1 mol/L). 0.7mL sodium nitrite solution (43mg, 0.63mmol), reaction for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (109mg, 0.51 Methyl), the pH was adjusted to 8 to 9 with a saturated sodium hydrogen carbonate solution, and 2 mL of ethanol was added thereto, and the mixture was reacted at room temperature for 24 hours. After the TLC was traced to the disappearance of the starting material, the mixture was filtered, and 15 mL of water was added to the solid. The mixture was adjusted to pH 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was washed with ethyl acetate and dried to give the title product 4-{2-hydroxy- 3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl]-phenyl}-furan 2-carboxylic acid 31 (83 mg, black solid). Yield: 36.7%. MS m/z (ESI): 442.8 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.08 (m, 2H), 2.32 (s, 3H), 2.89 (m, 4H), 7.13 (t) , J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.65 (m, 3H), 7.75 (m, 1H), 8.37 (s , 1H), 9.68 (s, 1H), 13.22 (br, 1H), 13.74 (s, 1H)

實施例32Example 32

4-{[4’-(4,5-二氫-1H-咪唑-2-基)-2-羥基聯苯-3-基]-肼叉}-2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮4-{[4'-(4,5-Dihydro-1H-imidazol-2-yl)-2-hydroxybiphenyl-3-yl]-anthracene}-2-indan-5-yl-5- Methyl-2,4-dihydropyrazol-3-one

第一步first step

3’-硝基-2’-甲氧基-聯苯-4-甲醛3'-Nitro-2'-methoxy-biphenyl-4-carbaldehyde

室溫下,將4-甲醯基苯硼酸(3.0g,0.02mol)、1-溴-2-甲氧基-3-硝基苯1c(4.64g,0.02mol)、四(三苯基膦)鈀(1.15g,1mmol)和碳酸鈉(4.24g,0.04mol)加入到60mL1,4-二氧陸圜和10mL水中,加畢後加熱回流5小時,TLC監測至原料反應完全,過濾,濾餅用乙酸乙酯洗滌,濾液減壓濃縮後經管柱層析得到標題產物3’-硝基-2’-甲氧基-聯苯-4-甲醛32a(4.1g,黃色固體),產率:80.4%。4-Methylphenylbenzeneboronic acid (3.0 g, 0.02 mol), 1-bromo-2-methoxy-3-nitrobenzene 1c (4.64 g, 0.02 mol), tetrakis(triphenylphosphine) at room temperature Palladium (1.15g, 1mmol) and sodium carbonate (4.24g, 0.04mol) were added to 60mL of 1,4-dioxane and 10mL of water. After the addition, it was heated and refluxed for 5 hours. TLC was monitored until the reaction of the starting material was complete, filtered and filtered. The cake was washed with ethyl acetate, and the filtrate was evaporated. mjjjjjjjjjjjj 80.4%.

第二步Second step

2-(2’-甲氧基-3’-硝基-聯苯-4-基)-4,5-二氫-1H-咪唑2-(2'-methoxy-3'-nitro-biphenyl-4-yl)-4,5-dihydro-1H-imidazole

冰浴下,將3’-硝基-2’-甲氧基-聯苯-4-甲醛32a(4.0g,15.5mmol)加入到40mL二氯甲烷中,攪拌至溶解後加入1,2-二氨基乙烷(981mg,16.3mmol),繼續攪拌0.5小時,加入1-溴-吡咯烷-2,5-二酮(2.91g,16.33mmol),加畢撤去冰浴,室溫攪拌過夜,TLC監測至原料反應完全,反應液減壓濃縮後經管柱層析得到標題產物2-(2’-甲氧基-3’-硝基-聯苯-4-基)-4,5-二氫-1H-咪唑32b(4.0g,黃色固體),產率:86.9%。MS m/z(ESI):298.1[M+1]1 HNMR(400MHz,DMSO-d 6 ):δ 8.11(2H,d,J=8.4),7.89(1H,dd,J1=8.0,J2=1.6),7.87(2H,d,J=8.4),7.79(1H,m),7.49(1H,t,J=8.0),4.04(4H,m),3.47(3H,s)Add 3'-nitro-2'-methoxy-biphenyl-4-carbaldehyde 32a (4.0 g, 15.5 mmol) to 40 mL of dichloromethane under ice-cooling, stir until dissolved, then add 1,2- Aminoethane (981 mg, 16.3 mmol), stirring was continued for 0.5 h, 1-bromo-pyrrolidine-2,5-dione (2.91 g, 16.33 mmol) was added, and the ice bath was removed and stirred at room temperature overnight. The reaction to the starting material was completed, and the reaction mixture was concentrated under reduced pressure and then purified to give the title product 2-(2'-methoxy-3'-nitro-biphenyl-4-yl)-4,5-dihydro-1H. - Imidazole 32b (4.0 g, yellow solid), yield: 86.9%. MS m/z (ESI): 298.1 [M + 1] 1 H NMR (400 MHz, DMSO - d 6 ): δ 8.11 (2H, d, J = 8.4), 7.89 (1H, dd, J1 = 8.0, J2 = 1.6 ), 7.87 (2H, d, J = 8.4), 7.79 (1H, m), 7.49 (1H, t, J = 8.0), 4.04 (4H, m), 3.47 (3H, s)

第三步third step

2-(2’-甲氧基-3’-氨基-聯苯-4-基)-4,5-二氫-1H-咪唑2-(2'-methoxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole

室溫下,將2-(2’-甲氧基-3’-硝基-聯苯-4-基)-4,5-二氫-1H-咪唑32b(1.5g,5.05mmol)加入到30mL甲醇中,攪拌溶解後加入甲酸胺(1.28g,20.2mmol)和鈀-碳(200mg),加畢後加熱回流1小時,TLC監測至原料反應完全,反應液自然冷卻至室溫後過濾,濾液減壓濃縮得到標題產物2-(2’-甲氧基-3’-氨基-聯苯-4-基)-4,5-二氫-1H-咪唑32c(1.1g,黃色固體),產率:81.5%。MSm/z(ESI):268.2[M+1]1 HNMR(400MHZ ,DMSO-d 6 ):δ8.42(2H,s),7.96(2H,d,J=8.0),6.89(1H,t,J=7.6),6.75(1H,m),6.54(1H,dd,J1=8.0,J2=1.6),3.80(4H,m),3.47(3H,s)2-(2'-Methoxy-3'-nitro-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32b (1.5 g, 5.05 mmol) was added to 30 mL at room temperature After stirring in methanol, add formic acid amine (1.28 g, 20.2 mmol) and palladium-carbon (200 mg). After the addition, the mixture was heated to reflux for 1 hour. The reaction was completed by TLC until the reaction mixture was cooled to room temperature and then filtered. The title product 2-(2'-methoxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32c (1.1 g, yellow solid) : 81.5%. MS m/z (ESI): 268.2 [M + 1] 1 H NMR (400 MH Z , DMSO - d 6 ): δ 8.42 (2H, s), 7.96 (2H, d, J = 8.0), 6.89 (1H, t , J=7.6), 6.75 (1H, m), 6.54 (1H, dd, J1=8.0, J2=1.6), 3.80 (4H, m), 3.47 (3H, s)

第四步the fourth step

2-(2’-羥基-3’-氨基-聯苯-4-基)-4,5-二氫-1H-咪唑2-(2'-hydroxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole

室溫下,將2-(2’-甲氧基-3’-氨基-聯苯-4-基)-4,5-二氫-1H-咪唑32c(1.1g,4.1mmol)溶解於50mL二氯甲烷中,加入溴化硼的二氯甲烷溶液(1N,16.5mL),繼續室溫攪拌4小時,TLC監測至原料反應完全,用甲醇淬滅反應,反應液減壓濃縮,所得固體加入10mL乙酸乙酯溶解後攪拌0.5小時,過濾,濾餅用乙酸乙酯洗滌(5mL×2),乾燥後得到標題產物2-(2’-羥基-3’-氨基-聯苯-4-基)-4,5-二氫-1H-咪唑32d(900mg,灰色固體),產率:89.6%。Msm/z(EsI):254.3[M十1]l HNMR(400MHz,DMSO-d 6 ):δ7.23(2H,m),7.01(2H,t,J=6.8),6.65(1H,m),6.62(1H,dd,J=8.0,J2=1.6),6,36(1H,t,J=7.6),4.03(4H,m)2-(2'-Methoxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32c (1.1 g, 4.1 mmol) was dissolved in 50 mL at room temperature To the methyl chloride, a solution of boron bromide in dichloromethane (1N, 16.5 mL) was added, and the mixture was stirred at room temperature for 4 hrs, and the mixture was monitored by TLC until the reaction mixture was completed. The reaction was quenched with methanol. The ethyl acetate was dissolved and stirred for 0.5 hours, filtered, and the filter cake was washed with ethyl acetate (5mL×2), and dried to give the title product 2-(2'-hydroxy-3'-amino-biphenyl-4-yl)- 4,5-Dihydro-1H-imidazole 32d (900 mg, gray solid), yield: 89.6%. Msm/z(EsI): 254.3 [M1 1] l HNMR (400 MHz, DMSO- d 6 ): δ 7.23 (2H, m), 7.01 (2H, t, J = 6.8), 6.65 (1H, m) , 6.62 (1H, dd, J = 8.0, J2 = 1.6), 6, 36 (1H, t, J = 7.6), 4.03 (4H, m)

第五步the fifth step

4-{[4’-(4,5-二氫-1H-咪唑-2-基)-2-羥基聯苯-3-基]-肼叉}-2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮4-{[4'-(4,5-Dihydro-1H-imidazol-2-yl)-2-hydroxybiphenyl-3-yl]-anthracene}-2-indan-5-yl-5- Methyl-2,4-dihydropyrazol-3-one

冰浴下將2-(2’-羥基-3’-氨基-聯苯-4-基)-4,5-二氫-1H-咪唑32d(334mg,1.11mmol)溶解於鹽酸(3.7mL,1mol/L)中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),反應20分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(214mg,1mmol),用飽和碳酸氫鈉溶液調節pH值至8,加入5mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,所得固體加入到30mL水中,攪拌均勻用濃鹽酸調節pH值至4,有固體析出,過濾,所得固體經管柱層析得到標題產物4-{[4’-(4,5-二氫-1H-咪唑-2-基)-2-羥基聯苯-3-基]-肼叉}-2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮32(145mg,紅色固體)。產率:30.3%。MS m/z(ESI):476.9[M-1]1 H NMR(400MHz,DMSO-d 6 ):δ2.02(m,2H),2.34(s,3H),2.87(m,4H),4.00(s,4H),6.88(m,1H),7.18(m,2H),7.49(m,1H),7.90(m,5H),8.18(s,1H)2-(2'-Hydroxy-3'-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazole 32d (334 mg, 1.11 mmol) was dissolved in hydrochloric acid (3.7 mL, 1 mol). In /L), 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol) was added dropwise, and the reaction was carried out for 20 minutes, followed by the addition of 2-indan-5-yl-5-methyl-2,4-dihydropyrazole-3. - Ketone 1i (214 mg, 1 mmol), adjusted to pH 8 with saturated sodium bicarbonate solution, and 5 mL of ethyl alcohol. The material disappeared by TLC, filtered, and the obtained solid was added to 30 mL of water. The mixture was stirred and concentrated with concentrated hydrochloric acid to adjust pH to 4, and solids were precipitated and filtered. The obtained solid was subjected to column chromatography to give the title product 4-{[4'-( 4,5-dihydro-1H-imidazol-2-yl)-2-hydroxybiphenyl-3-yl]-purine}-2-indan-5-yl-5-methyl-2,4-di Hydropyrazol-3-one 32 (145 mg, red solid). Yield: 30.3%. MS m/z (ESI): 476.9 [M-1] 1 H NMR (400 MHz, DMSO - d 6 ): δ 2.02 (m, 2H), 2.34 (s, 3H), 2.87 (m, 4H), 4.00 (s, 4H), 6.88 (m, 1H), 7.18 (m, 2H), 7.49 (m, 1H), 7.90 (m, 5H), 8.18 (s, 1H)

實施例33Example 33

5-(2-羥基-5-甲基-3-{N’-「3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-噻吩-2-羧酸5-(2-hydroxy-5-methyl-3-{N'-"3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)- 1,5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基-5-甲基苯基)-噻吩-2-羧酸氫溴酸鹽24d(366mg,1.11mmol)溶解於3.7mL 1N鹽酸中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),反應20分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(228mg,1mmol),分批加入碳酸氫鈉(1.4g,16.67mmol)和2mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入到30mL水中,再用濃鹽酸調節pH=3至4,過濾,固體乾燥後經管柱層析得到標題產物5-(2-羥基-5-甲基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基)-苯)-噻吩-2-羧酸33(88mg,紅色固體)。產率:18.09%。MS m/z(ESI):486.7[M-1]1 HNMR(400MHz,DMS0-d6 ):δ1.75(m,4H),2.31(s,3H),2.36(s,3H),2.73(m,4H),7.12(d,J=8.4Hz,lH),7.37(s,1H),7.56(s,1H),7.63(m,3H),7.74(d,J=3.6Hz,1H),9.77(s,1H),13.07(br,1H),13.70(s,1H)5-(3-Amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (366 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise. 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), reacted for 20 minutes, and then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydrogen Pyrazol-3-one 3i (228 mg, 1 mmol) was added portionwise sodium bicarbonate (1. 4 g, 16.67 mmol) and 2 mL of ethyl alcohol. The product disappeared by TLC, filtered, and the solid was added to 30 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried and dried to give the title product 5-(2-hydroxy-5-methyl- 3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ya Benzyl)-phenyl)-thiophene-2-carboxylic acid 33 (88 mg, red solid). Yield: 18.09%. MS m/z (ESI): 486.7 [M-1] 1 H NMR (400 MHz, DMS0- d6 ): δ 1.75 (m, 4H), 2.31 (s, 3H), 2.36 (s, 3H), 2.73 (m) , 4H), 7.12 (d, J = 8.4 Hz, lH), 7.37 (s, 1H), 7.56 (s, 1H), 7.63 (m, 3H), 7.74 (d, J = 3.6 Hz, 1H), 9.77 (s, 1H), 13.07 (br, 1H), 13.70 (s, 1H)

實施例34Example 34

5-(3-{N’-「1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1.5-二氫吡唑-4-亞基]-肼基}-2-羥基-5-甲基苯)-噻吩-2-羧酸5-(3-{N'-"1-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1.5-dihydropyrazole-4-subunit ]-mercapto}-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基-5-甲基苯基)-噻吩-2-羧酸氫溴酸鹽24d(366mg,1.11mmol)溶解於3.7mL 1N鹽酸中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),反應20分鐘,再加入2-(3,3-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮8i(242mg,1mmol),用飽和碳酸氫鈉溶液調節pH值至8,加入2mL乙醇,撤去冰浴,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入到30mL水中,再用濃鹽酸調節pH=3至4,過濾,固體乾燥後得到標題產物5-(3-{N’-[1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2-羥基-5-甲基苯)-噻吩-2-羧酸34(308mg,紅色固體)。產率:61.4%。MS m/z(ESI):500.8[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.25(s,6H),1.93(m,2H),2.36(s,3H),2.38(s,3H),2.87(t,J=7.2Hz,2H),7.27(d,1=8.8Hz,1H),7.40(d,J=1.6Hz,1H),7.53(d,J=1.2Hz,1H),7.65(m,1H),7.71(m,2H),7.74(d,J=4.0Hz,1H),9.82(br,1H),13.06(s,1H),13.71(br,1H)5-(3-Amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (366 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise. 1.5mL sodium nitrite solution (85mg, 1.22mmol), reaction for 20 minutes, then add 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole 3-ketone 8i (242 mg, 1 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, 2 mL of ethanol was added, and the ice bath was removed and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, solid was added to 30 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and dried to give the title product 5-(3-{N'-[1-(3,3) -Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2-hydroxy-5-methyl Benzene)-thiophene-2-carboxylic acid 34 (308 mg, red solid). Yield: 61.4%. MS m/z (ESI): 500.8 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.25 (s, 6H), 1.93 (m, 2H), 2.36 (s, 3H), 2.38 (s) , 3H), 2.87 (t, J = 7.2 Hz, 2H), 7.27 (d, 1 = 8.8 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H) ), 7.65 (m, 1H), 7.71 (m, 2H), 7.74 (d, J = 4.0 Hz, 1H), 9.82 (br, 1H), 13.06 (s, 1H), 13.71 (br, 1H)

實施例35Example 35

5-{3-[N’-(1-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-2-羥基-5-甲基苯}-噻吩-2-羧酸5-{3-[N'-(1-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1, 5-dihydropyrazole-4-ylidene)-indenyl]-2-hydroxy-5-methylphenyl}-thiophene-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基-5-甲基苯基)-噻吩-2-羧酸氫溴酸鹽24d(366mg,1.11mmol)溶解於3.7mL 1N鹽酸中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),反應20分鐘,再加入2-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-5-甲基-2,4-二氫吡唑-3-酮5d(200mg,1mmol),用飽和碳酸氫鈉溶液調節pH值至8,加入2mL乙醇,撤去冰浴,室溫反應5小時。以TLC追蹤至原料消失,過濾,固體加入到30mL水中,再用濃鹽酸調節pH=3至4,過濾,濾餅用6mL二氯甲烷洗滌後乾燥得到標題產物5-{3-[N’-(1-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-2-羥基-5-甲基苯}-噻吩-2-羧酸35(306mg,紅色固體)。產率:66.5%。MS m/z(ESI):459.2[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.33(s,3H),2.36(s,3H),3.16(m,4H),7.16(d,J=8.0Hz,1H),7.38(s,1H),7.49(s,1H),7.62(m,2H),7.73(m,2H)5-(3-Amino-2-hydroxy-5-methylphenyl)-thiophene-2-carboxylic acid hydrobromide 24d (366 mg, 1.11 mmol) was dissolved in 3.7 mL of 1N hydrochloric acid and added dropwise. 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), react for 20 minutes, then add 2-bicyclo[4.2.0]octane-1(6), 2,4-trien-3-yl-5-methyl -2,4-Dihydropyrazol-3-one 5d (200 mg, 1 mmol), the pH was adjusted to 8 with a saturated sodium hydrogen carbonate solution, 2 mL of ethanol was added, the ice bath was removed, and the reaction was carried out at room temperature for 5 hours. The material disappeared by TLC, filtered, and the solid was added to 30 mL of water, then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and the filter cake was washed with 6 mL of dichloromethane and dried to give the title product 5-{3-[N'- (1-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit)-indenyl]-2-hydroxy-5-methylphenyl}-thiophene-2-carboxylic acid 35 (306 mg, red solid). Yield: 66.5%. MS m/z (ESI): 459.2 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.33 (s, 3H), 2.36 (s, 3H), 3.16 (m, 4H), 7.16 (d) , J=8.0Hz, 1H), 7.38(s,1H), 7.49(s,1H), 7.62(m,2H),7.73(m,2H)

實施例36Example 36

5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-噻吩-2-羧酸5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽12c(351mg,1.11mmol)溶解於3.7mL鹽酸(1N)中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),攪拌20分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(228mg,lmmol),用飽和碳酸氫鈉溶液調節pH值至8,用2mL乙醇淬滅氣泡,升至室溫反應3小時。以TLC追蹤至原料消失,過濾出固體,固體中加入30mL水,用濃鹽酸調pH=3至4,過濾,固體乾燥後經管柱層析得到標題產物5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-噻吩-2-羧酸36(30mg,紅色固體)。產率:6.3%。MS m/z(ESI):472.8[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.74(m,4H),2.30(s,3H),2.73(m,4H),7.12(d,J=8.0Hz,1H),7.17(m,1H),7.53(d,J=7.6Hz,1H),7.62(m,3H),7.67(d,J=8.0Hz,lH),7.74(d,J=4.0Hz,1H)5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (351 mg, 1.11 mmol) was dissolved in 3.7 mL of hydrochloric acid (1 N) and added dropwise 1.5 mL. Sodium nitrate solution (85 mg, 1.22 mmol), stirred for 20 minutes, then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole- 3-ketone 3i (228 mg, 1 mmol) was adjusted to pH 8 with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react at room temperature for 3 hours. The material disappeared by TLC, the solid was filtered, 30 mL of water was added to the solid, pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and dried, and then subjected to column chromatography to give the title product 5-(2-hydroxy-3-{N '-[3-Methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4-ylidene]-oxime }-Benzene)-thiophene-2-carboxylic acid 36 (30 mg, red solid). Yield: 6.3%. MS m/z (ESI): 472.8 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.74 (m, 4H), 2.30 (s, 3H), 2.73 (m, 4H), 7.12 (d) , J = 8.0 Hz, 1H), 7.17 (m, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.62 (m, 3H), 7.67 (d, J = 8.0 Hz, lH), 7.74 (d , J=4.0Hz, 1H)

實施例37Example 37

5-{3-「N’-(1-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-2-羥基苯}-噻吩-2-羧酸5-{3-"N'-(1-bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-sideoxy-1, 5-dihydropyrazole-4-ylidene)-indolyl]-2-hydroxyphenyl}-thiophene-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽12c(298mg,0.94mmol)溶解於3.1mL鹽酸(1N)中,滴加入1.3mL亞硝酸鈉溶液(72mg,1.04mmol),攪拌20分鐘,再加入2-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-5-甲基-2,4-二氫吡唑-3-酮5d(170mg,0.85mmol),用飽和碳酸氫鈉溶液調節pH值至8,用2mL乙醇淬滅氣泡,升至室溫反應3小時。以TLC追蹤至原料消失,過濾出固體,固體中加入30mL水,用濃鹽酸調pH=3至4,過濾,固體乾燥後經管柱層析得到標題產物5-{3-[N’-(1-雙環[4.2.0]辛烷-1(6),2,4-三烯-3-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-2-羥基苯}-噻吩-2-羧酸37(57mg,紅色固體)。產率:15.01%。MS m/z(ESI):444.5[M-1]1HNMR(400MHz,DMSO-d6 ):δ2.31(s,3H),3.15(m,4H),7.15(m,2H),7.54(d,J=7.6Hz,lH),7.63(m,2H),7.67(d,J=7.6Hz,1H),7.73(m,2H).5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (298 mg, 0.94 mmol) was dissolved in 3.1 mL of hydrochloric acid (1 N) and added dropwise Sodium nitrate solution (72 mg, 1.04 mmol), stirred for 20 minutes, then added 2-bicyclo[4.2.0]octane-1 (6), 2,4-trien-3-yl-5-methyl-2, 4-Dihydropyrazol-3-one 5d (170 mg, 0.85 mmol) was adjusted to pH 8 using a saturated sodium hydrogen carbonate aqueous solution, and the mixture was quenched with 2 mL of ethanol and allowed to react at room temperature for 3 hours. The material disappeared by TLC, the solid was filtered, 30 mL of water was added to the solid, pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and the solid was dried and then subjected to column chromatography to obtain the title product 5-{3-[N'-(1 -bicyclo[4.2.0]octane-1(6),2,4-trien-3-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-subunit )-Mercapto]-2-hydroxyphenyl}-thiophene-2-carboxylic acid 37 (57 mg, red solid). Yield: 15.01%. MS m/z (ESI): 444.5 [M-1] 1H NMR (400 MHz, DMSO- d6 ): δ 2.31 (s, 3H), 3.15 (m, 4H), 7.15 (m, 2H), 7.54 (d, J = 7.6 Hz, lH), 7.63 (m, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.73 (m, 2H).

實施例38Example 38

2’-羥基-3’-{N’-[3-甲基-1-(3-甲基茚滿-5-基)-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-聯苯-3-羧酸2'-Hydroxy-3'-{N'-[3-methyl-1-(3-methylindan-5-yl)-5-o-oxy-1,5-dihydropyrazole-4- Subunit]-mercapto}-biphenyl-3-carboxylic acid

第一步first step

6-溴-茚滿-1-酮6-bromo-indan-1-one

將3-(4-溴苯基)-丙酸38a(20.6g,90mmol,ABCR)加入250mL單口燒瓶中,真空乾燥20分鐘後加入110mL重蒸過的二氯甲烷,於氮氣保護,攪拌下加入氯化亞碸(20mL,276mmol),加熱回流過夜。減壓下除去大部分溶劑,加入100mL二氯甲烷,攪拌下分批加入氯化鋁(24.5g,25.8mmol),有大量氣體放出,升溫回流反應過夜。將反應液倒入200g碎冰中,析出大量固體,用矽膠過濾,分液,水相用30mL二氯甲烷萃取,合併的有機相用無水硫酸鈉乾燥,減壓濃縮,得到標題產物6-溴-茚滿-1-酮38b(18.34g,黃色固體)。產率:96.6%。MS m/z(ESI):210[M-1]Add 3-(4-bromophenyl)-propionic acid 38a (20.6 g, 90 mmol, ABCR) to a 250 mL single-necked flask, dry in vacuo for 20 min, then add 110 mL of re-distilled methylene chloride. Arsenic chloride (20 mL, 276 mmol) was heated to reflux overnight. Most of the solvent was removed under reduced pressure, and 100 mL of dichloromethane was added, and aluminum chloride (24.5 g, 25.8 mmol) was added portionwise with stirring, and a large amount of gas was released, and the reaction was refluxed overnight. The reaction mixture was poured into 200 g of crushed ice, and a large amount of solid was precipitated, which was filtered with EtOAc (EtOAc). - Indan-1-one 38b (18.34 g, yellow solid). Yield: 96.6%. MS m/z (ESI): 210 [M-1]

第二步Second step

6-溴-1-亞甲基-茚滿6-bromo-1-methylene-indane

將甲基三苯基溴化膦(4.56g,12.76mmol)溶解於25mL四氫呋喃中,一次性加入第三丁醇鉀(1.5g,13.4mmol),加入完畢後室溫下攪拌35分鐘備用。Methyltriphenylphosphonium bromide (4.56 g, 12.76 mmol) was dissolved in 25 mL of tetrahydrofuran, and potassium t-butoxide (1.5 g, 13.4 mmol) was added in one portion, and the mixture was stirred at room temperature for 35 minutes.

將6-溴-茚滿-1-酮38b(898mg,4.25mmol)溶解於5mL四氫呋喃中,攪拌下滴加入上述的溶液中,所得溶液在室溫下攪拌1小時,加入25mL水淬滅反應。用二氯甲烷萃取(25mL×4)反應液,合併的有機相用飽和食鹽水(10mL×2)洗滌,無水硫酸鈉乾燥,過濾,減壓下濃縮,得到的殘留物通過矽膠管柱層析進一步分離純化,得到標題產物6-溴-1-亞甲基-茚滿38c(830mg,黃色油狀液體)。產率:93.4%。MS m/z(ESI):208[M-1]6-Bromo-indan-1-one 38b (898 mg, 4.25 mmol) was dissolved in 5 mL of tetrahydrofuran, and the above solution was added dropwise with stirring. The resulting solution was stirred at room temperature for 1 hour, and quenched by adding 25 mL of water. The reaction mixture was extracted with EtOAc (EtOAc) (EtOAc) Further isolation and purification gave the title product 6-bromo-1-methylene-indane 38c (830 mg,yield of yellow oil). Yield: 93.4%. MS m/z (ESI): 208 [M-1]

第三步third step

6-溴-1-甲基茚滿6-bromo-1-methylindole

將6-溴-1-亞甲基茚滿38c(4.91g,23.5mmol)溶解於乙酸乙酯中,加入鈀-碳(0.98g),在氫氣氛下室溫反應4小時,以TLC追蹤至原料消失,反應液過濾,濾液減壓濃縮後經管柱層析得到標題產物6-溴-1-甲基茚滿38d(3.1lg,無色油狀液體),產率:62.7%。MS m/z(ESI):209.8[M-1]6-Bromo-1-methylene indane 38c (4.91 g, 23.5 mmol) was dissolved in ethyl acetate, palladium-carbon (0.98 g) was added, and reacted under a hydrogen atmosphere at room temperature for 4 hours, followed by TLC to The disappearance of the starting material, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and then purified to give the title product 6-bromo-1-methylindane 38d (3.1 g, colorless oily liquid), yield: 62.7%. MS m/z (ESI): 209.8 [M-1]

第四步the fourth step

1-(3-甲基茚滿-5-基)肼-1,2-二甲酸二第三丁酯1-(3-methylindan-5-yl)indole-1,2-dicarboxylic acid di-t-butyl ester

氬氣氛下,將正丁基鋰(8.6mL,13.76mmol)加入到三口燒瓶中,在乾冰-丙酮浴冷卻下加入8mL四氫呋喃,攪拌下加入6-溴-1-甲基茚滿38d(1.32g,6.26mmol),所得溶液在乾冰-丙酮浴下反應2小時,滴加偶氮二甲酸二第三丁酯(1.87g,8.14mmol)的10mL四氫呋喃溶液,繼續攪拌30分鐘,撤去冰浴,升溫至室溫,攪拌20小時反應完畢。於反應液中加入20mL飽和氯化胺淬滅反應,用乙酸乙酯萃取(25mL×3)反應液,合併的有機相用飽和食鹽水(10mL×2)洗滌,無水硫酸鈉乾燥,過濾,濾液減壓下濃縮,殘留物通過矽膠管柱層析得到標題產物1-(3-甲基茚滿-5-基)肼-1,2-二甲酸二第三丁酯38e(1.05g,黃色油狀液體)。產率:46.7%。MS m/z(ESI):362.6[M+1]Under an argon atmosphere, n-butyllithium (8.6 mL, 13.76 mmol) was added to a three-necked flask, and 8 mL of tetrahydrofuran was added under cooling in a dry ice-acetone bath, and 6-bromo-1-methylindane 38d (1.32 g) was added with stirring. , 6.26 mmol), the obtained solution was reacted in a dry ice-acetone bath for 2 hours, and a solution of dibutyl azodicarboxylate (1.87 g, 8.14 mmol) in 10 mL of tetrahydrofuran was added dropwise, stirring was continued for 30 minutes, the ice bath was removed, and the temperature was raised. The reaction was completed by stirring for 20 hours at room temperature. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) Concentration under reduced pressure, the residue was purified mjjjjjjjjjjjjjj Liquid). Yield: 46.7%. MS m/z (ESI): 362.6 [M+1]

第五步the fifth step

5-甲基-2-(3-甲基茚滿-5-基)-2,4-二氫吡唑-3-酮5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one

將1-(3-甲基茚滿-5-基)肼-1,2-二甲酸二第三丁酯38e(1.05g,2.9mmol)溶解於16mL乙醇和水混合溶劑(V:V=5:3)中,攪拌下依次加入乙醯乙酸乙酯(0.377mL,2.9mmol)和1.45mL 6N鹽酸,氮氣保護下,加熱回流反應1.5小時反應完畢。冷卻至室溫,將反應液在減壓下濃縮,除去乙醇,水相用二氯甲烷萃取(15mL×3),合併的有機相通過無水硫酸鈉乾燥,過濾,減壓下濃縮,殘留物通過矽膠管柱層析得到標題產物5-甲基-2-(3-甲基茚滿-5-基)-2,4-二氫吡唑-3-酮38f(103mg,黃色油狀液體)。產率:15.6%。MS m/z(ESI):229.3[M+1]Dissolving 1-(3-methylindan-5-yl)indole-1,2-dicarboxylic acid di-t-butyl ester 38e (1.05 g, 2.9 mmol) in 16 mL of a mixed solvent of ethanol and water (V: V=5) In 3), ethyl acetate (0.377 mL, 2.9 mmol) and 1.45 mL of 6N hydrochloric acid were successively added under stirring, and the reaction was heated under reflux for 1.5 hours under nitrogen. The mixture was cooled to room temperature, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjj Chromatography of the title compound gave 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one 38f (103 mg, m. Yield: 15.6%. MS m/z (ESI): 229.3 [M+1]

第六步Step 6

2’-羥基-3’-{N’-[3-甲基-1-(3-甲基茚滿-5-基)-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-聯苯-3-羧酸2'-Hydroxy-3'-{N'-[3-methyl-1-(3-methylindan-5-yl)-5-o-oxy-1,5-dihydropyrazole-4- Subunit]-mercapto}-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基聯苯基-3-羧酸氫溴酸鹽1f(344mg,1.11mmol)溶解於3.7mL鹽酸(1N)中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),再加入5-甲基-2-(3-甲基茚滿-5-基)-2,4-二氫吡唑-3-酮38f(228mg,1mmol),用飽和碳酸氫鈉溶液將反應液pH調至8,加入2mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾出固體,固體中加入30mL水,用濃鹽酸調節至pH=3至4,過濾,固體乾燥後加入10mL二氯甲烷和甲醇的混合溶液(V:V=50:1),加畢攪拌1小時,過濾,濾餅用二氯甲烷洗滌(2mL×3),乾燥後得到標題產物2’-羥基-3’-{N’-[3-甲基-1-(3-甲基茚滿-5-基)-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-聯苯-3-羧酸38(300mg,黃色固體)。產率:64.1%。MS m/z(ESI):466.9[M-1]1 HNMR(400MHz,DMS0-d6 ):δ1.25(m,3H),1.58(m,1H),2.30(m,1H),2.33(s,3H),2.80(m,2H),3.19(m,1H),7.13(m,2H),7.26(d,J=8.0Hz,1H),7.62(t,J=7.6Hz,1H),7.69(m,3H),7.80(d,J=7.6Hz,1H),7.97(d,J=7.6Hz,1H),8.43(s,1H),9.69(br,1H),13.06(s,1H),13.76(s,1H)3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (344 mg, 1.11 mmol) was dissolved in 3.7 mL of hydrochloric acid (1 N) under ice bath, and 1.5 mL of sodium nitrite solution was added dropwise. (85 mg, 1.22 mmol), followed by addition of 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one 38f (228 mg, 1 mmol). The pH of the reaction solution was adjusted to 8 with sodium bicarbonate solution, 2 mL of ethanol was added, and the mixture was allowed to warm to room temperature overnight. The material disappeared by TLC, the solid was filtered, 30 mL of water was added to the solid, and the mixture was adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and the solid was dried, and then 10 mL of a mixed solution of dichloromethane and methanol (V:V=50: 1), after stirring for 1 hour, filtering, the filter cake was washed with dichloromethane (2 mL×3), and dried to give the title product 2'-hydroxy-3'-{N'-[3-methyl-1-( 3-methylindan-5-yl)-5-sideoxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid 38 (300 mg, yellow solid ). Yield: 64.1%. MS m/z (ESI): 466.9 [M-1] 1 H NMR (400 MHz, DMS0- d6 ): δ 1.25 (m, 3H), 1.58 (m, 1H), 2.30 (m, 1H), 2.33 (s) , 3H), 2.80 (m, 2H), 3.19 (m, 1H), 7.13 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.69 (m, 3H), 7.80 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 8.43 (s, 1H), 9.69 (br, 1H), 13.06 (s, 1H) , 13.76(s,1H)

實施例39Example 39

2’-羥基-5’-甲基-3’-{N’-「3-甲基-1-(3-甲基茚滿-5-基)-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-聯苯-3-羧酸2'-Hydroxy-5'-methyl-3'-{N'-"3-methyl-1-(3-methylindan-5-yl)-5-sideoxy-1,5-di Hydropyrazol-4-ylidene]-mercapto}-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基-5’-甲基聯苯基-3-羧酸鹽酸鹽11f(360mg,1.11mmol)溶解於3.7mL鹽酸(1N)中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol)’攪拌20分鐘,再加入5-甲基-2-(3-甲基茚滿-5-基)-2,4-二氫吡唑-3-酮38f(228mg,1.0mmol),用飽和碳酸氫鈉溶液將反應液pH調至8,加入2mL乙醇’升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,用30mL水溶解,攪拌均勻,用濃鹽酸調節至pH=3至4,過濾,固體乾燥後加入10mL二氯甲烷攪拌1小時,過濾出固體,固體乾燥後得到標題產物2’-羥基-5’-甲基-3’-{N’-[3-甲基-1-(3-甲基茚滿-5-基)-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-聯苯-3-羧酸39(240mg,紅色固體)。產率:49.8%。MS m/z(ESI):480.9[M-1]1 HNMR(400MHz,DMSO-d6 ): δ 1.29(m,3H),1.56(m,1H),2.28(m,1H),2.34(s,3H),2.36(s,3H),2.80(m,2H),3.18(m,1H),7.00(s,1H),7.27(d,J=8.0Hz,1H),7.54(s,1H),7.61(t,J=7.6Hz,1H),7.70(m,2H),7.80(d,J=8.0Hz,1H),7.95(d,J=7.6Hz,1H),8.14(d,J=4.4Hz,1H),9.40(br,1H),13.03(s,1H),13.76(s,1H)3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (360 mg, 1.11 mmol) was dissolved in 3.7 mL of hydrochloric acid (1N) and added dropwise 1.5 mL sodium nitrite solution (85 mg, 1.22 mmol) was stirred for 20 minutes, then 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one was added. 38f (228 mg, 1.0 mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 2 The material disappeared by TLC, the solid was filtered out, dissolved in 30 mL of water, stirred uniformly, adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and then added to 10 mL of dichloromethane and stirred for 1 hour, and the solid was filtered and dried. The title product 2'-hydroxy-5'-methyl-3'-{N'-[3-methyl-1-(3-methylindol-5-yl)-5-sideoxy-1 was obtained. , 5-dihydropyrazole-4-ylidene]-indenyl}-biphenyl-3-carboxylic acid 39 (240 mg, red solid). Yield: 49.8%. MS m/z (ESI): 480.9 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.29 (m, 3H), 1.56 (m, 1H), 2.28 (m, 1H), 2.34 (s, 3H), 2.36 (s, 3H), 2.80 (m, 2H), 3.18 (m, 1H), 7.00 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.70 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 4.4) Hz, 1H), 9.40 (br, 1H), 13.03 (s, 1H), 13.76 (s, 1H)

實施例40Example 40

5-(2-羥基-3-{N’-[3-甲基-1-(3-甲基茚滿-5-基)-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-苯)-噻吩-2-羧酸5-(2-hydroxy-3-{N'-[3-methyl-1-(3-methylindan-5-yl)-5-oxo-1,5-dihydropyrazole-4 -subunit]-mercapto}-phenyl)-thiophene-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽12c(351mg,1.11mmol)溶解於3.7mL鹽酸(1N)中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),攪拌20分鐘,再加入5-甲基-2-(3-甲基茚滿-5-基)-2,4-二氫吡唑-3-酮38f(228mg,1mmol),用飽和碳酸氫鈉溶液調節pH值至8,用2mL乙醇淬滅氣泡,升至室溫反應3小時。以TLC追蹤至原料消失,過濾出固體,固體中加入30mL水,用濃鹽酸調節至pH=3至4,過濾,固體乾燥後經管柱層析得到標題產物5-(2-羥基-3-{N’-[3-甲基-1-(3-甲基茚滿-5-基)-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-苯)-噻吩-2-羧酸40(90mg,紅色固體)。產率:19.0%。MS m/z(ESI):472.8[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.26(m,3H),1.58(m,lH),2.30(m,1H),2.32(s,3H),2.82(m,2H),3.18(m,1H),7.16(t,J=8.0Hz,1H),7.27(d,J=8.0Hz,1H),7.54(d,J=7.6Hz,1H),7.70(m,5H),10.09(br,1H),13.71(br,1H)5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (351 mg, 1.11 mmol) was dissolved in 3.7 mL of hydrochloric acid (1 N) and added dropwise 1.5 mL. Sodium nitrate solution (85 mg, 1.22 mmol), stirred for 20 minutes, then added 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazol-3-one 38f ( 228 mg, 1 mmol), the pH was adjusted to 8 with a saturated sodium bicarbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature for 3 hours. The product disappeared by TLC, the solid was filtered out, 30 mL of water was added to the solid, and the mixture was adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and dried, and then subjected to column chromatography to give the title product 5-(2-hydroxy-3-{ N'-[3-Methyl-1-(3-methylindan-5-yl)-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-benzene )-thiophene-2-carboxylic acid 40 (90 mg, red solid). Yield: 19.0%. MS m/z (ESI): 472.8 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.26 (m, 3H), 1.58 (m, lH), 2.30 (m, 1H), 2.32 (s) , 3H), 2.82 (m, 2H), 3.18 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.6 Hz) , 1H), 7.70 (m, 5H), 10.09 (br, 1H), 13.71 (br, 1H)

實施例41Example 41

3’-{N’-「1-(3-乙基-茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基聯苯-3-羧酸3'-{N'-"1-(3-Ethyl-indan-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]- Mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

第一步first step

6-溴-1-亞乙基-茚滿6-bromo-1-ethylidene-indane

室溫下,將乙基三苯基溴化膦(14.5g,39.1mmol)溶解於75mL四氫呋喃中,加入第三丁醇鉀(5.29g,47.3mmol),加畢後室溫攪拌1小時。將6-溴-茚滿-1-酮38b(3.39g,18.6mmol)溶解於25mL四氫呋喃中,攪拌下滴加入上述的溶液中,加畢繼續於室溫下攪拌1小時。TLC監測至原料反應完全,向反應液中加入150mL水淬滅反應,用二氯甲烷萃取反應液(50mL×4),合併有機相,有機相用飽和食鹽水洗滌(45mL×2),無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物6-溴-1-亞乙基-茚滿41a(3.07g,黃色油狀液體),產率:74%。MS m/z(ESI):221.8[M-1]Ethyltriphenylphosphonium bromide (14.5 g, 39.1 mmol) was dissolved in 75 mL of tetrahydrofuran at room temperature, and potassium butoxide (5.29 g, 47.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 6-Bromo-indan-1-one 38b (3.39 g, 18.6 mmol) was dissolved in 25 mL of tetrahydrofuran, and the above solution was added dropwise with stirring, and the mixture was further stirred at room temperature for 1 hour. TLC was monitored until the reaction of the starting material was complete. The reaction was quenched by the addition of 150 mL of water. The mixture was extracted with dichloromethane (50 mL×4). The organic phase was combined and washed with brine (45 mL×2) The sodium was dried, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and then purified to give the title product 6-bromo-1-ethylidene-yield 41a (3.07 g, yellow oily liquid). MS m/z (ESI): 221.8 [M-1]

第二步Second step

6-溴-1-乙基-茚滿6-bromo-1-ethyl-indane

室溫下,將6-溴-1-亞乙基-.茚滿41a(3.07g,13.7mmol)溶解於80mL乙酸乙酯中,加入鈀-碳(0.61g),於氫化儀中在3個大氣壓下用氫氣氫化,室溫反應5小時後,TLC監測原料反應完全,反應液過濾除去鈀-碳,濾餅用乙酸乙酯洗滌(10mL×3),濾液減壓濃縮後經管柱層析,得到標題產物6-溴-1-乙基-茚滿41b(2.75g,淺黃色液體),產率:88.7%。MSm/z(ESI):224[M-1]6-Bromo-1-ethylidene-indan 41a (3.07 g, 13.7 mmol) was dissolved in 80 mL of ethyl acetate at room temperature, palladium-carbon (0.61 g) was added, in a hydrogenation apparatus in 3 Hydrogenation with hydrogen at atmospheric pressure, reaction at room temperature for 5 hours, the reaction of the starting material was completely monitored by TLC, the reaction mixture was filtered to remove palladium-carbon, and the filter cake was washed with ethyl acetate (10 mL×3), and the filtrate was concentrated under reduced pressure and then subjected to column chromatography. The title product 6-bromo-1-ethyl-indan 41b (2.75 g, pale yellow liquid) was obtained, yield: 88.7%. MSm/z (ESI): 224 [M-1]

第三步third step

1-(3-乙基-2,3-二氫-1H-茚滿-5-基)-1-第三丁氧羰基-2-第三丁氧羰基-肼1-(3-ethyl-2,3-dihydro-1H-indan-5-yl)-1-tert-butoxycarbonyl-2-tert-butoxycarbonyl-indole

氬氣氛下,將6-溴-1-乙基-茚滿41b(2.52g,11.2mmol)溶解於15mL四氫呋喃中,滴加到乾冰-丙酮浴冷卻的第三丁基鋰的環已烷溶液中(18.1mL,1.3N),加畢繼續於乾冰-丙酮浴中攪拌2小時。將偶氮二甲酸二第三丁酯溶解於15mL四氫呋喃中,滴加到上述反應液中,加畢繼續於乾冰-丙酮浴中攪拌0.5小時,撤去乾冰-丙酮浴,反應液自然升至室溫後攪拌18小時,TLC監測原料反應完全,向反應液中加入25mL氯化氨飽和溶液淬滅反應,用乙酸乙酯(30mL×3)萃取反應液,合併有機相,用無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物1-(3-乙基-2,3-二氫-1H-茚滿-5-基)-1-第三丁氧羰基-2-第三丁氧羰基-肼41c(3.43g,棕黃色油狀液體),產率:81.5%。6-Bromo-1-ethyl-indan 41b (2.52 g, 11.2 mmol) was dissolved in 15 mL of tetrahydrofuran under argon, and added dropwise to a solution of dry butyl-acetone-cooled tributyllithium in cyclohexane. (18.1 mL, 1.3 N), stirring was continued for 2 hours in a dry ice-acetone bath. Dissolve ditributyl azodicarboxylate in 15 mL of tetrahydrofuran, add dropwise to the above reaction solution, continue to stir in a dry ice-acetone bath for 0.5 hour, remove the dry ice-acetone bath, and the reaction solution naturally rises to room temperature. After stirring for 18 hours, the reaction of the starting material was completed by TLC. The reaction mixture was quenched by the addition of 25 mL of a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with ethyl acetate (30 mL×3). The desiccant was removed, and the filtrate was concentrated under reduced pressure and then purified by column chromatography to give the title product 1-(3-ethyl-2,3-dihydro-1H-indane-5-yl)-1-t-butoxycarbonyl-2 - Third butoxycarbonyl-oxime 41c (3.43 g, brownish yellow oily liquid), yield: 81.5%.

第四步the fourth step

2-(3-乙基-茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮2-(3-ethyl-indan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one

室溫下,將1-(3-乙基-2,3-二氫-1H-茚滿-5-基)-1-第三丁氧羰基-2-第三丁氧羰基-肼41c(3.43g,9.1mmol)溶解於50mL乙醇和水的混合溶劑中(V:V=3:2),加入3-側氧基-丁酸乙酯(1.18g,9.1mmol)和4.55mL鹽酸(6N),加畢,反應液回流1小時,TLC監測原料反應完全,反應液減壓除去乙醇,再用二氯甲烷萃取(15mL×3),合併有機相,有機相用無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物2-(3-乙基-茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮41d(0.712g,黃色油狀液體),產率:39.8%。MS m/z(ESI):243.2[M+1]1-(3-Ethyl-2,3-dihydro-1H-indan-5-yl)-1-tert-butoxycarbonyl-2-tert-butoxycarbonyl-indole 41c (3.43) at room temperature g, 9.1 mmol) was dissolved in 50 mL of a mixed solvent of ethanol and water (V:V=3:2), and 3-ethyloxy-butyric acid ethyl ester (1.18 g, 9.1 mmol) and 4.55 mL of hydrochloric acid (6N) were added. After the reaction was completed, the reaction solution was refluxed for 1 hour, and the reaction of the reaction mixture was completed by TLC. The reaction mixture was evaporated to remove ethanol, and then extracted with dichloromethane (15mL×3). The organic phase was combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography to give the title product 2-(3-ethyl-indane-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 41d (0.712 g, yellow oily liquid), yield: 39.8%. MS m/z (ESI): 243.2 [M+1]

第五步the fifth step

3’-{N’-[1-(3-乙基-茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基聯苯-3-羧酸3'-{N'-[1-(3-ethyl-indan-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]- Mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基聯苯基-3-羧酸氫溴酸鹽1f(285mg,0.92mmol)溶解於3.1mL鹽酸(1N)中,滴加入1.2mL亞硝酸鈉溶液(70mg,1.01mmol),繼續攪拌20分鐘,加入2-(3-乙基-茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮41d(200mg,0.83mmol),用飽和碳酸氫鈉溶液將反應液pH調至8,加入2mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾,固體加入20mL水,用濃鹽酸調節pH值至3至4,過濾出固體,固體乾燥後得到標題產物3’-{N’-[1-(3-乙基-茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基聯苯-3-羧酸41(145mg,紅色固體),產率:36.4%。MS m/z(ESI):480.9[M-1]1 HNMR(400MHz,DMSO-d6 ):δ0.95(m,3H),1.43(m,1H),1.65(m,1H),1.83(m,1H),2.23(m,1H),2.34(s,3H),2.92(m,2H),3.05(m,1H),7.15(s,2H),7.27(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.72(m,3H),7.80(d,J=7.6Hz,1H),7.97(d,J=8.0Hz,1H),8.14(s,1H),9.66(s,1H),13.04(s,1H),13.76(s,1H)3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (285 mg, 0.92 mmol) was dissolved in 3.1 mL of hydrochloric acid (1 N) under ice bath, and 1.2 mL of sodium nitrite solution was added dropwise. (70 mg, 1.01 mmol), stirring was continued for 20 minutes, and 2-(3-ethyl-indan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 41d (200 mg, 0.83 mmol), the pH of the reaction mixture was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 2 mL of ethanol was added, and the mixture was allowed to warm to room temperature overnight. The product disappeared by TLC, filtered, solid was added to 20 mL of water, and the pH was adjusted to 3 to 4 with concentrated hydrochloric acid. The solid was filtered and dried to give the title product 3'-{N'-[1-(3-ethyl -indol-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxybiphenyl-3-carboxylic acid 41 (145 mg, red solid), Yield: 36.4%. MS m/z (ESI): 480.9 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 0.95 (m, 3H), 1.43 (m, 1H), 1.65 (m, 1H), 1.83 (m) , 1H), 2.23 (m, 1H), 2.34 (s, 3H), 2.92 (m, 2H), 3.05 (m, 1H), 7.15 (s, 2H), 7.27 (d, J = 8.0 Hz, 1H) , 7.62 (t, J = 8.0 Hz, 1H), 7.72 (m, 3H), 7.80 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.14 (s, 1H) , 9.66(s,1H), 13.04(s,1H),13.76(s,1H)

實施例42Example 42

3’-{N’-[1-(3-乙基-茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基-5’-甲基-聯苯-3-羧酸3'-{N'-[1-(3-ethyl-indan-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]- Mercapto}-2'-hydroxy-5'-methyl-biphenyl-3-carboxylic acid

冰浴下將3’-氨基-2’-羥基-5’-甲基聯苯基-3-羧酸鹽酸鹽11f(298mg,0.92mmol)溶解於3.1mL鹽酸(1N)中,滴加入1.2mL亞硝酸鈉溶液(70mg,1.01mmol),繼續攪拌20分鐘,加入2-(3-乙基-茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮41d(200mg,0.83mmol),用飽和碳酸氫鈉溶液將反應液pH調至8,加入2mL乙醇,升至室溫過夜。以TLC追蹤至原料消失,過濾,固體加入20mL水,用濃鹽酸調節pH值至3至4,過濾出固體,固體乾燥後得到標題產物3’-{N’-[1-(3-乙基-茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基-5’-甲基-聯苯-3-羧酸42(290mg,紅色固體),產率:70.7%。MS m/z(ESI):494.9[M-1]1 HNMR(400MHz,DMSO-d6 ):δ0.95(m,3H),1.43(m,1H),1.65(m,1H),1.83(m,1H),2.23(m,1H),2.34(s,3H),2.92(m,2H),3.05(m,1H),6.99(s,1H),7.26(d,J=8.0Hz,1H),7.53(s,1H),7.60(t,J=8.0Hz,1H),7.68(m,1H),7.75(s,1H),7.80(d,J=7.6Hz,1H),7.96(d,J=7.6Hz,1H),8.14(s,1H),9.39(s,1H),13.03(s,1H),13.76(s,1H)3'-Amino-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid hydrochloride 11f (298 mg, 0.92 mmol) was dissolved in 3.1 mL of hydrochloric acid (1 N), and then added dropwise. mL sodium nitrite solution (70 mg, 1.01 mmol), stirring was continued for 20 minutes, and 2-(3-ethyl-indan-5-yl)-5-methyl-2,4-dihydropyrazole-3- The ketone 41d (200 mg, 0.83 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to warm to room temperature overnight. The product disappeared by TLC, filtered, solid was added to 20 mL of water, and the pH was adjusted to 3 to 4 with concentrated hydrochloric acid. The solid was filtered and dried to give the title product 3'-{N'-[1-(3-ethyl -Indolyl-5-yl)-3-methyl-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-2'-hydroxy-5'-methyl- Biphenyl-3-carboxylic acid 42 (290 mg, red solid), yield: 70.7%. MS m/z (ESI): 494.9 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 0.95 (m, 3H), 1.43 (m, 1H), 1.65 (m, 1H), 1.83 (m) , 1H), 2.23 (m, 1H), 2.34 (s, 3H), 2.92 (m, 2H), 3.05 (m, 1H), 6.99 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H) , 7.53 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.68 (m, 1H), 7.75 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 8.14 (s, 1H), 9.39 (s, 1H), 13.03 (s, 1H), 13.76 (s, 1H)

實施例43Example 43

5-(3-{N’-「1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2-羥基苯)-呋喃-2-羧酸5-(3-{N'-"1-(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit]-mercapto}-2-hydroxyphenyl)-furan-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽9c(333mg,1.1mmol)溶解於鹽酸(3.7mL,1mol/L)中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),反應20分鐘,再加入2-(3,3-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮8i(242mg,1.0mmol),分批加入碳酸氫鈉(1.4g,16.67mmol)和3mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入20mL水,用濃鹽酸調節pH值至3至4,過濾出固體,固體乾燥後經管柱層析得到標題產物5-(3-{N’-[1-(3,3-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2-羥基苯)-呋喃-2-羧酸43(190mg,紅色固體),產率:40.3%。MS m/z(ESI):470.9[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.26(s,6H),1.92(t,J=7.2Hz,2H),2.33(s,3H),2.86(t,J=7.2Hz,2H),7.15(m,1H),7.20(m,2H),7.37(d,J=3.6Hz,1H),7.55(d,J=6.8Hz,1H),7.71(m,3H),9.99(br,1H),13.15(br,1H),13.74(br,1H)5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (333 mg, 1.1 mmol) was dissolved in hydrochloric acid (3.7 mL, 1 mol/L) and added dropwise. 1.5mL sodium nitrite solution (85mg, 1.22mmol), reaction for 20 minutes, then add 2-(3,3-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole 3-ketone 8i (242 mg, 1.0 mmol), sodium hydrogencarbonate (1.4 g, 16.67 mmol) and 3 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The material disappeared by TLC, filtered, and the solid was added to 20 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid, and the solid was filtered. The solid was dried and then subjected to column chromatography to give the title product 5-(3-{N'-[1 -(3,3-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}-2-hydroxyl Benzene)-furan-2-carboxylic acid 43 (190 mg, red solid), yield: 40.3%. MS m/z (ESI): 470.9 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.26 (s, 6H), 1.92 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H) ), 2.86 (t, J = 7.2 Hz, 2H), 7.15 (m, 1H), 7.20 (m, 2H), 7.37 (d, J = 3.6 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H) ), 7.71 (m, 3H), 9.99 (br, 1H), 13.15 (br, 1H), 13.74 (br, 1H)

實施例44Example 44

5-(2-羥基-3-{N’-[3-甲基-1-(3-甲基茚滿-5-基)-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-苯)-呋喃-2-羧酸5-(2-hydroxy-3-{N'-[3-methyl-1-(3-methylindan-5-yl)-5-oxo-1,5-dihydropyrazole-4 -subunit]-mercapto}-phenyl)-furan-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽9c(333mg,1.1mmol)溶解於鹽酸(3.7mL,1mol/L)中,滴加入1.5mL亞硝酸鈉溶液(85mg,1.22mmol),反應20分鐘,再加入5-甲基-2-(3-甲基茚滿-5-基)-2,4-二氫吡唑-3-酮38c(228mg,1.0mmol),分批加入碳酸氫鈉(1.4g,16.67mmol)和3mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入20mL水,用濃鹽酸調節pH值至3至4,過濾出固體,固體乾燥後經管柱層析得到標題產物5-(2-羥基-3-{N’-[3-甲基-1-(3-甲基茚滿-5-基)-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-苯)-呋喃-2-羧酸44(110mg,紅色固體),產率:24.0%。MS m/z(ESI):457.0[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.25(m,3H),1.59(m,1H),2.29(m,1H),2.33(s,3H),2.84(m,2H),3.17(m,1H),7.14(d,J=3.2Hz,1H),7.22(t,J=8.0Hz,1H),7.28(d,J=8.0Hz,1H),7.36(d,J=3.2Hz,1H),7.55(d,J=8.0Hz,1H),7.71(m,3H)9.96(br,1H)13.75(br,1H)5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (333 mg, 1.1 mmol) was dissolved in hydrochloric acid (3.7 mL, 1 mol/L) and added dropwise. 1.5 mL of sodium nitrite solution (85 mg, 1.22 mmol), reacted for 20 minutes, and then added 5-methyl-2-(3-methylindan-5-yl)-2,4-dihydropyrazole-3- Ketone 38c (228 mg, 1.0 mmol) was added portionwise sodium bicarbonate (1.4 g, 16.67 mmol) and 3 mL of ethyl alcohol. The product disappeared by TLC, filtered, and the solid was added to 20 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid, and the solid was filtered. The solid was dried and then subjected to column chromatography to give the title product 5-(2-hydroxy-3-{N '-[3-Methyl-1-(3-methylindan-5-yl)-5-o-oxy-1,5-dihydropyrazole-4-ylidene]-indenyl}-benzene) - furan-2-carboxylic acid 44 (110 mg, red solid), yield: 24.0%. MS m/z (ESI): 457.0 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.25 (m, 3H), 1.59 (m, 1H), 2.29 (m, 1H), 2.33 (s) , 3H), 2.84 (m, 2H), 3.17 (m, 1H), 7.14 (d, J = 3.2 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz) , 1H), 7.36 (d, J = 3.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.71 (m, 3H) 9.96 (br, 1H) 13.75 (br, 1H)

實施例45Example 45

5-(3-{N’-[1-(2,2-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2-羥基苯)-呋喃-2-羧酸5-(3-{N'-[1-(2,2-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit]-mercapto}-2-hydroxyphenyl)-furan-2-carboxylic acid

第一步first step

6-溴-2,2-二甲基茚滿-1-酮6-bromo-2,2-dimethylindan-1-one

將6-溴-茚滿-1-酮38b(6.02g,28.5mmol)和碘甲烷(4.4mL,70mmol)溶解於200mL四氫呋喃(乾燥)中,室溫攪拌15分鐘,加入氫化鈉(2.73g,68.2mmol),繼續攪拌2小時,TLC監測至原料反應完全,反應液中加入150mL水,用乙酸乙酯萃取(150mL×2),合併有機相,有機相用飽和食鹽水洗滌,無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物6-溴-2,2-二甲基茚滿-1-酮45a(5.36g,棕色固體),產率:78.6%。1 HNMR(400MHz,CDCl3 ):δ7.918(d,J=l.6Hz,1H),7.725(dd,J1 =8Hz,J2 =2Hz,1H),7.352(d,J=8Hz,1H),2.979(s,2H),1.273(s,6H)6-Bromo-indan-1-one 38b (6.02 g, 28.5 mmol) and iodomethane (4.4 mL, 70 mmol) were dissolved in 200 mL of tetrahydrofuran (dry), stirred at room temperature for 15 min, and sodium hydride (2.73 g, 68.2 mmol), stirring for 2 hours, TLC was carried out until the reaction of the starting material was completed, 150 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL × 2), the organic phase was combined, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure, and then purified to give the title product 6-bromo-2,2-dimethylindan-1-one 45a (5.36 g, brown solid). 1 H NMR (400 MHz, CDCl 3 ): δ 7.918 (d, J = 1. 6 Hz, 1H), 7.725 (dd, J 1 = 8 Hz, J 2 = 2 Hz, 1H), 7.352 (d, J = 8 Hz, 1H) ), 2.979(s, 2H), 1.273(s, 6H)

第二步Second step

5-溴-2,2-二甲基茚滿5-bromo-2,2-dimethylindole

將6-溴-2,2-二甲基茚滿-1-酮45a(7.23g,30.3mmol)溶解於150mL三氟醋酸中,加入三乙基矽烷(12.1mL,75.6mmol),室溫攪拌過夜,TLC監測反應至原料反應完全,加水淬滅反應,反應液減壓濃縮除去三氟醋酸,加入飽和碳酸鈉調節pH值至鹼性,用乙酸乙酯萃取(50mL×3),合併有機相,有機相用飽和食鹽水洗滌,無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物5-溴-2,2-二甲基茚滿45b(14g,無色油狀液體),直接投下一步反應。1 HNMR(400MHz,CDCl3 ):δ7.335(s,1H),7.281(d,J+8Hz,1H),7.063(s,J=8Hz,1H),2.749(s,2H),2.702(s,2H),1.188(s,6H)6-Bromo-2,2-dimethylindan-1-one 45a (7.23 g, 30.3 mmol) was dissolved in 150 mL of trifluoroacetic acid, and triethyl decane (12.1 mL, 75.6 mmol) was added and stirred at room temperature. After overnight, TLC monitored the reaction until the reaction of the starting material was complete, and the reaction was quenched with water. The reaction mixture was concentrated under reduced pressure to remove trifluoroacetic acid. The mixture was adjusted to pH with saturated sodium carbonate and extracted with ethyl acetate (50mL×3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Liquid), directly to the next reaction. 1 H NMR (400 MHz, CDCl 3 ): δ 7.335 (s, 1H), 7.281 (d, J + 8 Hz, 1H), 7.063 (s, J = 8 Hz, 1H), 2.749 (s, 2H), 2.702 (s) , 2H), 1.188 (s, 6H)

第三步third step

1-(2,2-二甲基茚滿-5-基)肼-1,2-二甲酸二第三丁酯1-(2,2-dimethylindan-5-yl)indole-1,2-dicarboxylic acid di-t-butyl ester

將5-溴-2,2-二甲基茚滿45b(2.4g,10.7mmol)溶解於20mL四氫呋喃(乾燥)中,用乾冰/乙醇浴冷卻至-78℃,滴加正丁基鋰(12.1mL,30.2mmol),加畢攪拌2小時,將偶氮二甲酸二第三丁酯(3.27g,14.2mmol)溶解於20mL四氫呋喃(乾燥),加入到上述反應液中,繼續低溫反應3小時,TLC監測至原料反應完全,用50mL水淬滅反應,反應液用乙酸乙酯萃取(50mL×2),合併有機相,有機相用飽和食鹽水洗滌,無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物1-(2,2-二甲基茚滿-5-基)肼-1,2-二甲酸二第三丁酯45c(2.68g,黃色油狀液體),產率:66.8%。Dissolve 5-bromo-2,2-dimethylindane 45b (2.4g, 10.7mmol) in 20mL tetrahydrofuran (dry), cool to -78 ° C with dry ice / ethanol bath, add n-butyl lithium (12.1 mL, 30.2 mmol), stirring for 2 hours, dissolving dibutyl azodicarboxylate (3.27 g, 14.2 mmol) in 20 mL of tetrahydrofuran (dry), adding to the above reaction solution, and continuing the low temperature reaction for 3 hours. TLC was monitored until the reaction of the starting material was completed. The reaction was quenched with 50 mL of water. The mixture was evaporated to ethyl acetate (50 mL×2). The organic phase was combined and washed with brine, dried over anhydrous sodium sulfate After concentration under reduced pressure, the title product was obtained from the title product 1-(2,2-dimethylindan-5-yl)indole-1,2-dicarboxylic acid di-t-butyl ester 45c (2.68 g, yellow oily liquid ), yield: 66.8%.

第四步the fourth step

2-(2,2-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮2-(2,2-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazol-3-one

將1-(2,2-二甲基茚滿-5-基)肼-1,2-二甲酸二第三丁酯45c(3.3g,8.78mmol)溶解於12mL乙酸中,加入6mL三氟乙酸和3-側氧基-丁酸甲酯(1.5mL,13.8mmol),加畢於90℃下攪拌2小時,TLC監測反應至原料反應完全,反應液減壓濃縮,向殘餘物中加入30mL水和30mL乙酸乙酯,攪拌均勻後分液,有機相用飽和食鹽水洗滌,無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物2-(2,2-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮45d(464mg,黃色油狀液體),產率:22.1%。MS m/z(ESI):243.3[M+1]Dissolve 1-(2,2-dimethylindan-5-yl)indole-1,2-dicarboxylic acid di-t-butyl ester 45c (3.3 g, 8.78 mmol) in 12 mL of acetic acid, add 6 mL of trifluoroacetic acid And methyl 3-butoxy-butyrate (1.5 mL, 13.8 mmol), and the mixture was stirred at 90 ° C for 2 hours. The reaction was monitored by TLC until the reaction mixture was completed. The reaction mixture was concentrated under reduced pressure. And 30 mL of ethyl acetate, and the mixture was stirred, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Methyl indane-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 45d (464 mg, yellow oily). Yield: 22.1%. MS m/z (ESI): 243.3 [M+1]

第五步the fifth step

5-(3-{N’-[1-(2,2-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2-羥基苯)-呋喃-2-羧酸5-(3-{N'-[1-(2,2-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4- Subunit]-mercapto}-2-hydroxyphenyl)-furan-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸氫溴酸鹽9c(150mg,0.5mmol)溶解於鹽酸(1.7mL,1mol/L)中,滴加入0.6mL亞硝酸鈉溶液(38mg,0.55mmol),反應20分鐘,再加入2-(2,2-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮45d(109mg,0.45mmol),分批加入碳酸氫鈉(630mg,7.5mmol)和1mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入15mL水,用濃鹽酸調節pH值至3至4,過濾,濾餅用乙酸乙酯洗滌(1mL×3)後乾燥得到標題產物5-(3-{N’-[1-(2,2-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2-羥基苯)-呋喃-2-羧酸45(67mg,黃色固體),產率:31.6%。MS m/z(ESI):470.7[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.13(s,6H),2.32(s,3H),2.70(m,4H),7.14(d,J=3.6Hz,1H),7.21(m,2H),7.36(d,J=3.6Hz,1H),7.54(m,1H),7.62(m,1H),7.69(m,2H)5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 9c (150 mg, 0.5 mmol) was dissolved in hydrochloric acid (1.7 mL, 1 mol/L) and added dropwise. 0.6 mL of sodium nitrite solution (38 mg, 0.55 mmol), react for 20 minutes, then add 2-(2,2-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole 3-ketone 45d (109 mg, 0.45 mmol), sodium bicarbonate (630 mg, 7.5 mmol) and 1 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, and the solid was added to 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and the filter cake was washed with ethyl acetate (1 mL×3) and dried to give the title product 5-(3-{ N'-[1-(2,2-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl "-2-Hydroxybenzene)-furan-2-carboxylic acid 45 (67 mg, yellow solid), yield: 31.6%. MS m/z (ESI): 470.7 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.13 (s, 6H), 2.32 (s, 3H), 2.70 (m, 4H), 7.14 (d) , J = 3.6 Hz, 1H), 7.21 (m, 2H), 7.36 (d, J = 3.6 Hz, 1H), 7.54 (m, 1H), 7.62 (m, 1H), 7.69 (m, 2H)

實施例46Example 46

5-{2-羥基-3-[N’-(1-茚滿-5-基-3甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5-甲基苯}-呋喃-2-羧酸5-{2-hydroxy-3-[N'-(1-indan-5-yl-3methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-5-methylphenyl}-furan-2-carboxylic acid

第一步first step

5-(3-硝基-2-甲氧基-5-甲基苯基)-呋喃-2-羧酸5-(3-nitro-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid

將3-(4,5-二甲基-[1,3,2]硼酸頻那醇酯-2-基)-2-甲氧基-5-甲基-硝基苯24a(3.lg,7.5mmol)、5-溴-呋喃-2-羧酸(1.3g,6.8mmol)、四(三苯基膦)鈀(0.43g,0.4mmol)和碳酸鈉(1.6g,15.1mmol)加入到30mL1,4-二氧陸圜和15mL水的混合溶劑中,反應體系加熱回流1小時,以TLC追蹤至原料消失,反應液冷卻後過濾,濾液用乙酸乙酯洗滌後減壓濃縮,所得固體中加入50mL水,用濃鹽水調節pH值至3,過濾,濾餅用乙酸乙酯洗滌後乾燥得到標題產物5-(3-硝基-2-甲氧基-5-甲基苯基)-呋喃-2-羧酸46a(522mg,黃色固體),產率:29%。MS m/z(ESI):275.7[M-1]1 HNMR(400MHz,DMSO-d6 ):δ13.31(1H,br),7.90(1H,s),7.78(1H,s),7.39(1H,d,J=3.2Hz),7.16(1H,d,J=3.6Hz),3.80(3H,s),2.42(3H,s)3-(4,5-Dimethyl-[1,3,2]boronic acid pinacol-2-yl)-2-methoxy-5-methyl-nitrobenzene 24a (3.lg, 7.5 mmol), 5-bromo-furan-2-carboxylic acid (1.3 g, 6.8 mmol), tetrakis(triphenylphosphine)palladium (0.43 g, 0.4 mmol) and sodium carbonate (1.6 g, 15.1 mmol) were added to 30 mL1 The reaction system was heated under reflux for 1 hour, and the reaction mixture was heated to reflux for 1 hour. The residue was evaporated to dryness eluted with EtOAc. 50 mL of water, adjusted to pH 3 with brine, filtered, washed with ethyl acetate and dried to give the title product 5-(3-nitro-2-methoxy-5-methylphenyl)-furan- 2-carboxylic acid 46a (522 mg, yellow solid), yield: 29%. MS m/z (ESI): 275.7 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 13.31 (1H, br), 7.90 (1H, s), 7.78 (1H, s), 7.39 (1H) , d, J = 3.2 Hz), 7.16 (1H, d, J = 3.6 Hz), 3.80 (3H, s), 2.42 (3H, s)

第二步Second step

5-(3-氨基-2-甲氧基-5-甲基苯基)-呋喃-2-羧酸5-(3-amino-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid

將5-(3-硝基-2-甲氧基-5-甲基苯基)-呋喃-2-羧酸46a(410mg,1.48mmol)溶解於28mL乙酸乙酯中,加入61mg鈀-碳和甲酸銨(658mg,10.44mmo1),加畢後加熱回流3小時。以TLC追蹤至原料消失,過濾除去鈀-碳,濾液減壓濃縮,乾燥,得到標題產物5-(3-氨基-2-甲氧基-5-甲基苯基)-呋喃-2-羧酸46b(356mg,白色固體)。產率:97.3%。Ms m/z(ESI):246.0[M-1]1 HNMR(400MHz,DMSO-d6 ):δ7.18(1H,s),6.98(1H,m),6.80(1H,s),6.56(1H,s),3.62(3H,s),2.20(3H,s)Dissolve 5-(3-nitro-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid 46a (410 mg, 1.48 mmol) in 28 mL of ethyl acetate and add 61 mg of palladium-carbon and Ammonium formate (658 mg, 10.44 mmol) was heated and refluxed for 3 hours. The residue was removed by TLC, and the palladium-carbon was removed by filtration. The filtrate was concentrated under reduced pressure and dried to give the title product 5-(3-amino-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid 46b (356 mg, white solid). Yield: 97.3%. Ms m/z (ESI): 246.0 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 7.18 (1H, s), 6.98 (1H, m), 6.80 (1H, s), 6.56 (1H) , s), 3.62 (3H, s), 2.20 (3H, s)

第三步third step

5-(3-氨基-2-羥基-5-甲基苯基)-呋喃-2-羧酸氫溴酸鹽5-(3-amino-2-hydroxy-5-methylphenyl)-furan-2-carboxylic acid hydrobromide

將5-(3-氨基-2-甲氧基-5-甲基苯基)-呋喃-2-羧酸46b(248mg,1mmol)溶解於20mL二氯甲烷中,滴加入三溴化硼的二氯甲烷溶液(3mL,lmmol/L),室溫反應2小時。以TLC追蹤至原料消失,減壓濃縮,所得固體用乙酸乙酯洗滌(50mL×3),乾燥後得到標題產物5-(3-氨基-2-羥基-5-甲基苯基)-呋喃-2-羧酸氫溴酸鹽46c(172mg,白色固體)。產率:54.7%。MS m/z(ESI):231.8[M-1]1 HNMR(400MHz,DMSO-d6 ):δ 7.46(1H,m),7.34(1H,m),7.10(2H,m),2.31(3H,s)Dissolve 5-(3-amino-2-methoxy-5-methylphenyl)-furan-2-carboxylic acid 46b (248 mg, 1 mmol) in 20 mL of dichloromethane and add dropwise boron tribromide The methyl chloride solution (3 mL, 1 mmol/L) was reacted at room temperature for 2 hours. The residue was purified by EtOAc (EtOAc) eluting 2-carboxylic acid hydrobromide 46c (172 mg, white solid). Yield: 54.7%. MS m/z (ESI): 231.8 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 7.46 (1H, m), 7.34 (1H, m), 7.10 (2H, m), 2.31 (3H, s)

第四步the fourth step

5-{2-羥基-3-[N’-(1-茚滿-5-基-3甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5-甲基苯}-呋喃-2-羧酸5-{2-hydroxy-3-[N'-(1-indan-5-yl-3methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-5-methylphenyl}-furan-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基-5-甲基苯基)-呋喃-2-羧酸氫溴酸鹽46c(219mg,0.70mmol)溶解於2.3mL 1N鹽酸中,滴加入1.0mL亞硝酸鈉溶液(53mg,0.77mmol),反應20分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮li(134mg,0.63mmol),分批加入碳酸氫鈉(878mg,10.45mmol)和2mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入到20mL水中,冰浴下用濃鹽酸調節至pH+3至4,過濾,濾餅用6mL二氯甲烷洗滌後乾燥,得到標題產物5-{2-羥基-3-[N’-(1-茚滿-5-基-3甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-5-甲基苯}-呋喃-2-羧酸46(170mg,紅色固體)。產率:59.2%。Ms m/z(ESI):456.8[M-1]1 HNMR(400MHz,DMSO-d6 ):δ 2.05(m,2H),2.32(s,3H),2.37(s,3H),2.88(m,4H),7.13(d,J=3.6Hz,1H),7.28(d,J=8.0Hz,1H),7.35(m,2H),7.51(s,lH),7.68(d,J+7.6Hz,1H),7.78(s,lH)5-(3-Amino-2-hydroxy-5-methylphenyl)-furan-2-carboxylic acid hydrobromide 46c (219 mg, 0.70 mmol) was dissolved in 2.3 mL of 1N hydrochloric acid and added dropwise. 1.0 mL of sodium nitrite solution (53 mg, 0.77 mmol), reacted for 20 minutes, and then added 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one li (134 mg, 0.63) Methyl) sodium hydrogencarbonate (878 mg, 10.45 mmol) and 2 mL of ethanol were added portionwise and allowed to react overnight at room temperature. The material disappeared by TLC, filtered, and the solid was added to 20 mL of water, adjusted to pH + 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was washed with 6 mL of dichloromethane and dried to give the title product 5-{2- Hydroxy-3-[N'-(1-indan-5-yl-3methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-indenyl]-5-A Benzo}-furan-2-carboxylic acid 46 (170 mg, red solid). Yield: 59.2%. Ms m/z (ESI): 456.8 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.05 (m, 2H), 2.32 (s, 3H), 2.37 (s, 3H), 2.88 (m, 4H), 7.13 (d, J = 3.6 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.35 (m, 2H), 7.51 (s, lH), 7.68 (d, J + 7.6 Hz, 1H), 7.78 (s, lH)

實施例47Example 47

2-{2-羥基-3-「N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-5-甲基-噻唑-4-羧酸2-{2-hydroxy-3-"N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime Base]-benzene}-5-methyl-thiazole-4-carboxylic acid

第一步first step

2-(2-甲氧基-3-硝基苯基)-5-甲基-噻唑-4-羧酸2-(2-methoxy-3-nitrophenyl)-5-methyl-thiazole-4-carboxylic acid

將2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯6a(1.7g,6.08mmol)、2-溴-5-甲基-噻唑-4-羧酸(900mg,4.05mmol)、四(三苯基膦)鈀(233mg,0.2mmol)和碳酸鈉(1.29g,12.16mmol)溶解於30mL 1,4-二氧陸圜中,加熱回流4小時。以TLC追蹤至原料消失,過濾,濾液減壓濃縮,向殘餘物中加入20mL鹽酸(1N)和30mL乙酸乙酯,攪拌後靜置分液,將有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後用乙酸乙酯和正己烷的混合溶劑再結晶,所得固體乾燥後得到標題產物2-(2-甲氧基-3-硝基苯基)-5-甲基-噻唑-4-羧酸47a(310mg,黃色固體)。產率:26%。MS m/z(ESI):292.6[M-1]1 HNMR(400MHz,DMSO-d 6 ):δ13.45(br,1H),8.58(dd,J=8.0,1H),8.14(dd,J=8.0,1H),7.52(t,J=8.0,1H),3.93(s,3H),2.71(s,3H)2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (1.7 g, 6.08 mmol) 2-Bromo-5-methyl-thiazole-4-carboxylic acid (900 mg, 4.05 mmol), tetrakis(triphenylphosphine)palladium (233 mg, 0.2 mmol) and sodium carbonate (1.29 g, 12.16 mmol) dissolved in 30 mL In 1,4-dioxane, the mixture was heated under reflux for 4 hours. After the residue was traced by TLC, the mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added 20 mL of hydrochloric acid (1N) and 30 mL of ethyl acetate. After stirring, the mixture was separated and the organic phase was washed with saturated sodium chloride solution. The sodium salt was dried, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure and then recrystallized from ethyl acetate and n-hexane, and the obtained solid was dried to give the title product 2-(2-methoxy-3-nitrophenyl)- 5-Methyl-thiazole-4-carboxylic acid 47a (310 mg, yellow solid). Yield: 26%. MS m/z (ESI): 292.6 [M-1] 1 H NMR (400 MHz, DMSO - d 6 ): δ 13.45 (br, 1H), 8.58 (dd, J = 8.0, 1H), 8.14 (dd, J =8.0,1H), 7.52 (t, J=8.0, 1H), 3.93 (s, 3H), 2.71 (s, 3H)

第二步Second step

2-(2-甲氧基-3-氨基-苯基)-5-甲基-噻唑-4-羧酸2-(2-methoxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid

將2-(2-甲氧基-3-硝基苯基)-5-甲基-噻唑-4-羧酸47a(300mg,1.02mmol)溶解於15mL甲醇中,加入30mg鈀-碳,於氫氣氛下攪拌24小時。以TLC追蹤至原料消失,反應液過濾除去鈀-碳,濾液減壓濃縮得到標題產物2-(2-甲氧基-3-氨基-苯基)-5-甲基-噻唑-4-羧酸47b(250mg,黃色固體),產率:92%。MS m/z(ESI):262.8[M-1]2-(2-Methoxy-3-nitrophenyl)-5-methyl-thiazole-4-carboxylic acid 47a (300 mg, 1.02 mmol) was dissolved in 15 mL of methanol, and 30 mg of palladium-carbon was added to hydrogen. Stir for 24 hours under the atmosphere. The residue was removed by TLC, the reaction mixture was filtered to remove palladium-carbon, and the filtrate was concentrated under reduced pressure to give the title product 2-(2-methoxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid. 47b (250 mg, yellow solid). Yield: 92%. MS m/z (ESI): 262.8 [M-1]

第三步third step

2-(2-羥基-3-氨基-苯基)-5-甲基-噻唑-4-羧酸氫溴酸鹽2-(2-hydroxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid hydrobromide

將2-(2-甲氧基-3-氨基-苯基)-5-甲基-噻唑-4-羧酸47b(280mg,0.94mmol)溶解於5mL溴化氫中,於80℃下攪拌過夜。以TLC追蹤至原料消失,反應液過濾,濾餅用乙酸乙酯洗滌後乾燥,得到標題產物2-(2-羥基-3-氨基-苯基)-5-甲基-噻唑-4-羧酸氫溴酸鹽47c(200mg,黃色固體)。產率:64%。MS m/z(ESI):262.7[M-1]1 HNMR(400MHz,DMSO-d 6 ):δ7.88(d,J=8.0,1H),7.51(d,J=8.0,1H),7.09(t,J=8.0,1H),2.73(s,3H)2-(2-Methoxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid 47b (280 mg, 0.94 mmol) was dissolved in 5 mL of hydrogen hydrogen chloride and stirred at 80 ° C overnight. . It was traced by TLC until the disappearance of the starting material, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate and dried to give the title product 2-(2-hydroxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid Hydrobromide 47c (200 mg, yellow solid). Yield: 64%. MS m/z (ESI): 262.7 [M-1] 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.78 (d, J = 8.0, 1H), 7.51 (d, J = 8.0, 1H), 7.09 (t, J=8.0, 1H), 2.73 (s, 3H)

第四步the fourth step

2-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-5-甲基-噻唑-4-羧酸2-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-anthracene Base]-benzene}-5-methyl-thiazole-4-carboxylic acid

冰浴下將2-(2-羥基-3-氨基-苯基)-5-甲基-噻唑-4-羧酸氫溴酸鹽47c(200mg,0.60mmol)溶解於2mL鹽酸(1N)中,滴加入0.82mL亞硝酸鈉溶液(46mg,0.66mmol),攪拌20分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(116mg,0.544mmol),分批加入飽和碳酸氫鈉溶液(781mg,9.3mmol)將pH調至8至9,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,固體用20mL水溶解,濃鹽酸調節至pH=3至4,過濾,乾燥,粗製品用HPLC分離純化,得到標題產物2-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-5-甲基-噻唑-4-羧酸47(195mg,紅色固體)。產率:75.9%。MSm/z(ESI):473.7[M-1]1 HNMR(400MHz,D2 O):δ1.97(m,2H),2.31(s,3H),2.53(s,3H),2.80(m,4H),6.52(t,J=8.0Hz,1H),7.23(m,4H),7.84(d,J+8.0Hz,1H)2-(2-Hydroxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid hydrobromide 47c (200 mg, 0.60 mmol) was dissolved in 2 mL hydrochloric acid (1 N). 0.82 mL of sodium nitrite solution (46 mg, 0.66 mmol) was added dropwise, stirred for 20 minutes, and then 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (116 mg) was added. , 0.544 mmol), a saturated sodium hydrogencarbonate solution (781 mg, 9.3 mmol) was added portionwise to adjust the pH to 8 to 9, and the mixture was quenched with 2 mL of ethanol and allowed to react to room temperature overnight. The product disappeared by TLC, the solid was filtered, solid was dissolved in 20 mL of water, and concentrated hydrochloric acid was adjusted to pH = 3 to 4, filtered, dried, and the crude product was purified by HPLC to give the title product 2-{2-hydroxy-3- [N'-(1-indan-5-yl-3-methyl-5-oxooxy-1,5-dihydropyrazol-4-ylidene)-indenyl]-phenyl}-5-A Base-thiazole-4-carboxylic acid 47 (195 mg, red solid). Yield: 75.9%. MS m/z (ESI): 473.7 [M-1] 1 H NMR (400 MHz, D 2 O): δ 1.97 (m, 2H), 2.31 (s, 3H), 2.53 (s, 3H), 2.80 (m, 4H), 6.52 (t, J = 8.0 Hz, 1H), 7.23 (m, 4H), 7.84 (d, J + 8.0 Hz, 1H)

實施例48Example 48

5-{2-羥基-3-「N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯5-{2-hydroxy-3-"N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-oxime Ethyl]-phenyl}-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester

冰浴下,將5-(3-氨基-2-羥基苯基)-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯氫溴酸鹽6h(180mg,0.66mmol)溶解於2.2mL鹽酸(1N)中,滴加入0.8mL亞硝酸鈉溶液(50mg,0.72mmol),攪拌20分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(126mg,0.59mmol),用飽和碳酸氫鈉溶液pH調至8至9,用2mL乙醇淬滅氣泡,升至室溫反應過夜。以TLC追蹤至原料消失,過濾出固體,加入20mL二氯甲烷和20mL水,攪拌均勻後用濃鹽酸調節至pH=3至4,分液,有機相用飽和食鹽水洗滌,無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物5-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-1,2,4-三甲基-1H-吡咯-3-羧酸乙酯48(80mg,紅色固體)。產率:25.8%。MS m/z(ESI):514.0[M+1]1 HNMR(400MHz,DMSO-d 6 ):δ1.30(m,3H),2,01(m,2H),2.23(s,3H),2.50(s,3H),2.95(m,4H),3.32(s,3H),4.33(m,2H),6.63(m,1H),7.00(m,1H),7.12(m,1H),7.28(m,1H),7.73(m,2H),13.91(br,1H)Ethyl 5-(3-amino-2-hydroxyphenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate hydrobromide 6h (180 mg, 0.66 mmol) Dissolved in 2.2 mL of hydrochloric acid (1N), added 0.8 mL of sodium nitrite solution (50 mg, 0.72 mmol), stirred for 20 minutes, and then added 2-indan-5-yl-5-methyl-2,4-di Hydropyrazol-3-one 1i (126 mg, 0.59 mmol) was adjusted to a pH of 8 to 9 using a saturated sodium hydrogen carbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react at room temperature overnight. After the residue was traced to the disappearance of the material, the solid was filtered, and 20 mL of dichloromethane and 20 mL of water were added, and the mixture was stirred and concentrated to pH = 3 to 4 with concentrated hydrochloric acid, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure, and then purified by column chromatography to give the title product 5-{2-hydroxy-3-[N'-(1-indane-5-yl-3-methyl-5-s. -1,5-Dihydropyrazole-4-ylidene)-indolyl]-phenyl}-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 48 (80 mg, red solid) . Yield: 25.8%. MS m/z (ESI): 514.0 [M+1] 1 H NMR (400 MHz, DMSO - d 6 ): δ 1.30 (m, 3H), 2,01 (m, 2H), 2.23 (s, 3H), 2.50 (s, 3H), 2.95 (m, 4H), 3.32 (s, 3H), 4.33 (m, 2H), 6.63 (m, 1H), 7.00 (m, 1H), 7.12 (m, 1H), 7.28 (m, 1H), 7.73 (m, 2H), 13.91 (br, 1H)

實施例49Example 49 5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(1,1,3,3-四甲基茚滿-5-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-噻吩-2-羧酸5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(1,1,3,3-tetramethylindan-5-yl)-1,5 -dihydropyrazole-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽12c(260mg,0.823mmol)溶解於2.7mL鹽酸(1N)中,滴加入1.1mL亞硝酸鈉溶液(62mg,0.91mmol),攪拌20分鐘,再加入5-甲基-2-(1,1,3,3-四甲基茚滿-5基)-2,4-二氫吡唑-3-酮19d(200mg,0.74mmol),用飽和碳酸氫鈉溶液調節pH值至8,用2mL乙醇淬滅氣泡,升至室溫反應3小時。以TLC追蹤至原料消失,過濾出固體,固體中加入20mL水,用濃鹽酸調節至pH=3至4,過濾,固體乾燥後經管柱層析得到標題產物5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(1,1,3,3-四甲基茚滿-5-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-噻吩-2-羧酸49(216mg,紅色固體)。產率:56.5%。1 HNMR(400MHz,DMSO-d6 ):δ1.30(m,12H),1.93(s,2H),2.34(s,3H),7.19(t,J=8.0Hz,1H),7.25(d,J=8.0Hz,1H),7.57(d,J=8.0Hz,1H),7.66(m,2H),7.71(d,J=8.0Hz,1H),7.77(m,2H),10.10(s,fH),13.06(br,1H),13.72(br,1H)5-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 12c (260 mg, 0.823 mmol) was dissolved in 2.7 mL of hydrochloric acid (1 N) and added dropwise to 1.1 mL. Sodium nitrate solution (62 mg, 0.91 mmol), stirred for 20 minutes, then added 5-methyl-2-(1,1,3,3-tetramethylindan-5yl)-2,4-dihydropyrazole 3-ketone 19d (200 mg, 0.74 mmol), the pH was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and the mixture was quenched with 2 mL of ethanol and allowed to react at room temperature for 3 hours. The material disappeared by TLC, the solid was filtered, 20 mL of water was added to the solid, and the mixture was adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and then subjected to column chromatography to give the title product 5-(2-hydroxy-3-{ N'-[3-Methyl-5-oxo-l-(1,1,3,3-tetramethylindan-5-yl)-1,5-dihydropyrazole-4-ylidene ]-Mercapto}-phenyl)-thiophene-2-carboxylic acid 49 (216 mg, red solid). Yield: 56.5%. 1 H NMR (400 MHz, DMSO- d6 ): δ 1.30 (m, 12H), 1.93 (s, 2H), 2.34 (s, 3H), 7.19 (t, J = 8.0 Hz, 1H), 7.25 (d, J) = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.66 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.77 (m, 2H), 10.10 (s, fH ), 13.06 (br, 1H), 13.72 (br, 1H)

實施例50Example 50 5-(2-羥基-5-甲基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-呋喃-2-羧酸5-(2-hydroxy-5-methyl-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)- 1,5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylic acid

冰浴下將5-(3-氨基-2-羥基-5-甲基苯基)-呋喃-2-羧酸氫溴酸鹽46c(120mg,0.38mmol)溶解於1.3mL 1N鹽酸中,滴加入0.5mL亞硝酸鈉溶液(29mg,0.42mmol),反應20分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(78mg,0.34mmol),用飽和碳酸氫鈉溶液調節pH至8,加入2mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入到20mL水中,再用濃鹽酸調節至pH=3至4,過濾,固體乾燥後經管柱層析得到標題產物5-(2-羥基-5-甲基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-呋喃-2-羧酸50(56mg,紅色固體)。產率:34.8%。MS m/z(ESI):470.8[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.75(m,4H),2.31(s,3H),2.37(s,3H),2.73(m,4H),7.13(m,2H),7.35(m,2H),7.50(s,1H),7.62(m,2H)5-(3-Amino-2-hydroxy-5-methylphenyl)-furan-2-carboxylic acid hydrobromide 46c (120 mg, 0.38 mmol) was dissolved in 1.3 mL of 1N hydrochloric acid and added dropwise. 0.5 mL of sodium nitrite solution (29 mg, 0.42 mmol), reacted for 20 minutes, and then added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydrogen Pyrazol-3-one 3i (78 mg, 0.34 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, and the solid was added to 20 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, dried, and then subjected to column chromatography to give the title product 5-(2-hydroxy-5-methyl -3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole-4- Subunit]-mercapto}-phenyl)-furan-2-carboxylic acid 50 (56 mg, red solid). Yield: 34.8%. MS m/z (ESI): 470.8 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.75 (m, 4H), 2.31 (s, 3H), 2.37 (s, 3H), 2.73 (m) , 4H), 7.13 (m, 2H), 7.35 (m, 2H), 7.50 (s, 1H), 7.62 (m, 2H)

實施例51Example 51 4-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-噻吩-2-羧酸4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid

第一步first step 4-(3-硝基-2-甲氧基-苯基)-噻吩-2-羧酸4-(3-nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid

將2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯6a(0.81g,2.9mmol)、4-溴-噻吩-2-羧酸(0.3g,1.45mmol)、四(三苯基膦)鈀(80mg,0.073mmol)和碳酸鈉(0.31g,2.9mmol)溶解於20mL 1,4-二氧陸圜和10mL水的混合溶劑中,加熱回流0.5小時。以TLC追蹤至原料消失,反應液用1N鹽酸酸化至pH3,乙酸乙酯萃取(20mL×3),合併有機相,有機相減壓濃縮後經管柱層析得到標題產物4-(3-硝基-2-甲氧基-苯基)-噻吩-2-羧酸51a(0.54g,棕色油狀液體),直接進行下一步反應。MS m/z(ESI):277.6[M-1]Ethylene 2-(2-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (0.81 g, 2.9 mmol) 4-bromo-thiophene-2-carboxylic acid (0.3 g, 1.45 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.073 mmol) and sodium carbonate (0.31 g, 2.9 mmol) dissolved in 20 mL of 1,4- In a mixed solvent of dioxane and 10 mL of water, the mixture was heated under reflux for 0.5 hour. The title material (4-nitro-nitro) was obtained by the TLC. The residue was evaporated to dryness eluted with 1N hydrochloric acid to pH 3 and ethyl acetate (20 mL×3). 2-methoxy-phenyl)-thiophene-2-carboxylic acid 51a (0.54 g, brown oily liquid) was directly subjected to the next reaction. MS m/z (ESI): 277.6 [M-1]

第二步Second step 4-(3-氨基-2-甲氧基-苯基)-噻吩-2-羧酸4-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid

將4-(3-硝基-2-甲氧基-苯基)-噻吩-2-羧酸51a(400mg,1.45mmol)溶解於30mL乙酸乙酯中,再加入100mg鈀-碳和甲酸胺(360mg,5.8mmol),加熱回流3小時。以TLC追蹤至原料消失,反應液過濾除去鈀/碳,減壓濃縮得到標題產物4-(3-氨基-2-甲氧基-苯基)-噻吩-2-羧酸51b(410mg,棕色油狀液體),直接進行下一步反應。MS m/z(ESI):247.8[M-1]4-(3-Nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51a (400 mg, 1.45 mmol) was dissolved in 30 mL of ethyl acetate, and then 100 mg of palladium-carbon and amine formate ( 360 mg, 5.8 mmol), heated to reflux for 3 hours. The residue was removed by TLC, and the reaction mixture was filtered to remove palladium/carbon, and concentrated under vacuo to give the title product 4-(3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51b (410 mg, brown oil Liquid)) directly to the next reaction. MS m/z (ESI): 247.8 [M-1]

第三步third step 4-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽4-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide salt

將4-(3-氨基-2-甲氧基-苯基)-噻吩-2-羧酸51b(360mg,1.45mmol)溶解於5mL二氯甲烷中,滴加入三溴化硼(2.8mL,5.6mmol),室溫反應4.5小時。以TLC追蹤至原料消失,加入5mL甲醇,減壓濃縮,向殘餘物中加入10mL乙酸乙酯,攪拌0.5小時,過濾,收集固體,乾燥,得到標題產物4-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽51c(80mg,灰色固體)。產率:17.5%。MS m/z(ESI):236.1[M+1]4-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 51b (360 mg, 1.45 mmol) was dissolved in 5 mL of dichloromethane, and boron tribromide (2.8 mL, 5.6) was added dropwise. Methyl), reacted at room temperature for 4.5 hours. The title material (4-amino-2-hydroxybenzene) was obtained after the residue was purified by chromatography. Base)-thiophene-2-carboxylic acid hydrobromide 51c (80 mg, grey solid). Yield: 17.5%. MS m/z (ESI): 236.1 [M+1]

第四步the fourth step 4-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-噻吩-2-羧酸4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid

冰浴下將4-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽51c(80mg,0.25mmol)溶解於1mL 1N鹽酸中,滴加入0.3mL亞硝酸鈉溶液(19mg,0.28mmol),反應20分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(52mg,0.23mmol),用飽和碳酸氫鈉溶液調節pH至8,加入2mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入到20mL水中,再用濃鹽酸調節至pH=3至4,過濾,固體中加入4mL乙酸乙酯攪拌2小時,過濾,所得固體乾燥後得到標題產物4-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-噻吩-2-羧酸51(11mg,黑色固體)。產率:10.2%。MS m/z(ESI):472.8[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.76(m,4H),2.33(s,3H),2.74(m,4H),7.13(m,2H),7.33(m,1H),7.65(m,3H),8.06(d,J=1.6Hz,1H),8.14(d,J=1.6Hz,.1H),9.68(s,1H),13.75(s,1H)4-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 51c (80 mg, 0.25 mmol) was dissolved in 1 mL of 1N hydrochloric acid, and 0.3 mL of sodium nitrite solution was added dropwise. (19 mg, 0.28 mmol), react for 20 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 3i (52 mg, 0.23 mmol), the pH was adjusted to 8 with a saturated sodium hydrogen carbonate solution, and 2 mL of ethanol was added and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, and the solid was added to 20 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and 4 mL of ethyl acetate was added to the solid for 2 hours, filtered, and the obtained solid was dried to give the title product 4 -(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro Pyrazole-4-ylidene]-indenyl}-phenyl)-thiophene-2-carboxylic acid 51 (11 mg, mp. Yield: 10.2%. MS m/z (ESI): 472.8 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.76 (m, 4H), 2.33 (s, 3H), 2.74 (m, 4H), 7.13 (m) , 2H), 7.33 (m, 1H), 7.65 (m, 3H), 8.06 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.6 Hz, .1H), 9.68 (s, 1H), 13.75(s,1H)

實施例52Example 52 4-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-噻吩-2-羧酸4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-anthracene Benzene-thiophene-2-carboxylic acid

冰浴下將4-(3-氨基-2-羥基苯基)-噻吩-2-羧酸氫溴酸鹽51c(120mg,0.38mmol)溶解於2.7mL 1N鹽酸中,滴加入0.45mL亞硝酸鈉溶液(29mg,0.42mmol),反應20分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(73mg,0.34mmol),用飽和碳酸氫鈉溶液調節pH至8,加入2mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入到20mL水中,再用濃鹽酸調節pH=3至4,過濾,固體中加入5mL乙酸乙酯攪拌1小時,過濾,所得固體乾燥後得到標題產物4-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-噻吩-2-羧酸52(45mg,黃色固體)。產率:28.7%。MS m/z(ESI):458.8[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.05(m,2H),2.32(s,3H),2.87(m,4H),7.13(t,J=8.0Hz,1H),7.32(m,2H),7.67(m,2H),7.78(s,1H),8.05(d,J=1.6Hz,1H),8.13(d,J=1.2Hz,1H),9.68(s,1H),13.79(s,1H)4-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 51c (120 mg, 0.38 mmol) was dissolved in 2.7 mL of 1N hydrochloric acid and 0.45 mL of sodium nitrite was added dropwise. Solution (29 mg, 0.42 mmol), react for 20 min, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (73 mg, 0.34 mmol). The sodium hydrogencarbonate solution was adjusted to pH 8, and 2 mL of ethanol was added and allowed to react at room temperature overnight. The product disappeared by TLC, filtered, and the solid was added to 20 mL of water, then adjusted to pH 3 to 4 with concentrated hydrochloric acid, filtered, and 5 mL of ethyl acetate was added to the solid for 1 hour, filtered, and the obtained solid was dried to give the title product 4- {2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-l,5-dihydropyrazole-4-ylidene)-indenyl] -Benzene-thiophene-2-carboxylic acid 52 (45 mg, yellow solid). Yield: 28.7%. MS m/z (ESI): 458.8 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.05 (m, 2H), 2.32 (s, 3H), 2.87 (m, 4H), 7.13 (t) , J = 8.0 Hz, 1H), 7.32 (m, 2H), 7.67 (m, 2H), 7.78 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 8.13 (d, J = 1.2 Hz) , 1H), 9.68 (s, 1H), 13.79 (s, 1H)

實施例53Example 53 5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑1-4-亞基]-肼基}-苯)-2-甲基呋喃-3-羧酸5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol 1-4-ylidene]-mercapto}-phenyl)-2-methylfuran-3-carboxylic acid

第一步first step 5-溴-2-甲基呋喃-3-羧酸甲酯Methyl 5-bromo-2-methylfuran-3-carboxylate

將2-甲基呋喃-3-羧酸甲酯(2.0g,14.3mmol)溶解於苯中,加入偶氮二異丁腈(10mg,0.06mmol),冰浴冷卻至0℃,加入N-溴代琥珀醯亞胺(2.8g,15.7mmol),加畢撤去冰浴,反應液於室溫下攪拌過夜,以TLC追蹤至原料消失,反應液過濾,濾液減壓濃縮後經管柱層析得到標題產物5-溴-2-甲基呋喃-3-羧酸甲酯53a(1.9g,無色油狀液體),產率:61%。Methyl 2-methylfuran-3-carboxylate (2.0 g, 14.3 mmol) was dissolved in benzene, azobisisobutyronitrile (10 mg, 0.06 mmol) was added, cooled to 0 ° C in ice bath, and N-bromine was added. The amber succinimide (2.8 g, 15.7 mmol) was added to the ice bath. The reaction mixture was stirred at room temperature overnight. The product, methyl 5-bromo-2-methylfuran-3-carboxylate, 53a (1.9 g, mp.

第二步Second step 5-(2-甲氧基-3-硝基苯基)-2-甲基呋喃-3-羧酸甲酯Methyl 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylate

將5-溴-2-甲基呋喃-3-羧酸甲酯53a(0.65g,3.0mmol)和2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯6a(1.0g,3.58mmol)溶解於1,4-二氧陸圜(15mL)中,加入四(三苯基膦)鈀(173mg,0.15mmol)和碳酸鈉(636mg,6.0mmol),加畢於100℃下回流3小時,以TLC追蹤至原料消失,反應液冷卻後過濾,濾液減壓濃縮後經管柱層析得到標題產物5-(2-甲氧基-3-硝基苯基)-2-甲基呋喃-3-羧酸甲酯53b(659mg,白色固體)。產率:75%。Methyl 5-bromo-2-methylfuran-3-carboxylate 53a (0.65 g, 3.0 mmol) and 2-(2-methoxy-3-nitrophenyl)-4,4,5,5 Tetramethyl-[1,3,2]ethylene glycolate 6a (1.0 g, 3.58 mmol) was dissolved in 1,4-dioxane (15 mL), and tetrakis(triphenylphosphine)palladium ( 173 mg, 0.15 mmol) and sodium carbonate (636 mg, 6.0 mmol) were added to reflux at 100 ° C for 3 hours, followed by TLC until the disappearance of the starting material, the reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. Methyl 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylate 53b (659 mg, white solid). Yield: 75%.

第三步third step 5-(2-甲氧基-3-硝基苯基)-2-甲基呋喃-3-羧酸5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylic acid

將5-(2-甲氧基-3-硝基苯基)-2-甲基呋喃-3-羧酸甲酯53b(650mg,2.23mmol)溶解於甲醇中,加入氫氧化鈉(268mg,6.7mmol),加畢於50℃下攪拌3小時,以TLC追蹤至原料消失,反應液減壓濃縮後用1N的鹽酸調節pH至3至4,有大量固體析出,過濾,所得固體用正己烷和乙酸乙酯的混合溶劑(V:V=5:1)再結晶,得到標題產物5-(2-甲氧基-3-硝基苯基)-2-甲基呋喃-3-羧酸53c(450mg,白色固體),產率:84%。MS m/z(ESI):275.7[M-1]1 HNMR(400MHz,DMSO-d 6 ):δ12.80(s,1H),8.03(dd,J=8.0,1H),7.87(dd,J=8.0,1H),7.44(t,J=8.0,1H),7.13(s,1H),3.83(s,3H),2.64(s,3H)Methyl 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylate 53b (650 mg, 2.23 mmol) was dissolved in methanol and sodium hydroxide (268 mg, 6.7) After stirring for 3 hours at 50 ° C, the mixture was traced by TLC until the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure. The pH was adjusted to 3 to 4 with 1N hydrochloric acid, and a large amount of solid was precipitated and filtered. The mixed solvent of ethyl acetate (V: V = 5:1) was recrystallized to give the titled product 5-(2-methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylic acid 53c ( 450 mg, white solid), yield: 84%. MS m/z (ESI): 275.7 [M-1] 1 H NMR (400 MHz, DMSO- d 6 ): δ 12.80 (s, 1H), 8.03 (dd, J = 8.0, 1H), 7.87 (dd, J = 8.0, 1H), 7.44 (t, J = 8.0, 1H), 7.13 (s, 1H), 3.83 (s, 3H), 2.64 (s, 3H)

第四步the fourth step 5-(2-甲氧基-3-氨基-苯基)-2-甲基呋喃-3-羧酸5-(2-methoxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid

將5-(2-甲氧基-3-硝基苯基)-2-甲基呋喃-3-羧酸53c(450mg,1.62mmol)溶解於甲醇中,加入45mg鈀/碳,在氫氣氛下回流攪拌4小時,以TLC追蹤至原料消失,反應液過濾,濾液減壓濃縮得到標題產物5-(2-甲氧基-3-氨基-苯基)-2-甲基呋喃-3-羧酸53d(370mg,白色固體),產率:92%。MS m/z(ESI):245.8[M-1]1 HNMR(400MHz,CDCl3 ):δ6.97(s,1H),6.87(m,2H),6.68(m,1H),5.06(br,2H),3.63(s,3H),2.59(s,3H)5-(2-Methoxy-3-nitrophenyl)-2-methylfuran-3-carboxylic acid 53c (450 mg, 1.62 mmol) was dissolved in methanol, and 45 mg of palladium/carbon was added under hydrogen atmosphere. After stirring under reflux for 4 hours, the residue was evaporated to dryness eluted with EtOAc (EtOAc). 53d (370 mg, white solid), yield: 92%. MS m/z (ESI): 245.8 [M-1] 1 H NMR (400 MHz, CDCl 3 ): δ 6.97 (s, 1H), 6.87 (m, 2H), 6.68 (m, 1H), 5.06 (br, 2H), 3.63 (s, 3H), 2.59 (s, 3H)

第五步the fifth step 5-(2-羥基-3-氨基-苯基)-2-甲基呋喃-3-羧酸氫溴酸鹽5-(2-hydroxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid hydrobromide

將5-(2-甲氧基-3-氨基-苯基)-2-甲基呋喃-3-羧酸53d(370mg,1.5mmol)溶解於二氯甲烷中,冰浴冷卻至0℃,滴加三溴化硼的二氯甲烷溶液(1N,3.6mL),加畢後室溫反應2小時,以TLC追蹤至原料消失,反應液中加入0.5mL甲醇淬滅反應,反應液攪拌30分鐘後濃縮,所得固體中加入10mL乙酸乙酯攪拌30分鐘,過濾,所得固體乾燥後得到標題產物5-(2-羥基-3-氨基-苯基)-2-甲基呋喃-3-羧酸氫溴酸鹽53e(240mg,灰色固體),產率:46%。MS m/z(ESI):231.7[M-1]1 HNMR(400MHz,CDCl3 ):δ7.57(dd,J=6.0,1H),7.24(dd,J=8.0,1H),7.05(t,J=8.0,1H),2.61(s,3H)5-(2-Methoxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid 53d (370mg, 1.5mmol) was dissolved in dichloromethane, cooled to 0 ° C in ice bath, drip Add a solution of boron tribromide in dichloromethane (1N, 3.6 mL), and add the reaction at room temperature for 2 hours. The mixture was traced by TLC until the disappearance of the starting material. The reaction mixture was quenched by adding 0.5 mL of methanol. The reaction mixture was stirred for 30 minutes. Concentration, the obtained solid was added with 10 mL of ethyl acetate and stirred for 30 min, filtered, and the obtained solid was dried to give the title product 5-(2-hydroxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid hydrobromide. Acid salt 53e (240 mg, gray solid), yield: 46%. MS m/z (ESI): 231.7 [M-1] 1 H NMR (400 MHz, CDCl 3 ): δ 7.57 (dd, J = 6.0, 1H), 7.24 (dd, J = 8.0, 1H), 7.05 (t) , J=8.0, 1H), 2.61(s, 3H)

第六步Step 6 5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑1-4-亞基]-肼基}-苯)-2-甲基呋喃-3-羧酸5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-di Hydropyrazol 1-4-ylidene]-mercapto}-phenyl)-2-methylfuran-3-carboxylic acid

冰浴下將5-(2-羥基-3-氨基-苯基)-2-甲基呋喃-3-羧酸氫溴酸鹽53e(200mg,0.64mmol)溶解於2.2mL 1N鹽酸中,滴加入0.9mL亞硝酸鈉溶液(48mg,0.7mmol),反應20分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(131mg,0.57mmol),用飽和碳酸氫鈉溶液調節pH至8,加入2mL乙醇,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入到20mL水中,再用濃鹽酸調節至pH=3至4,過濾,固體中加入8mL乙酸乙酯攪拌1小時,過濾,所得固體乾燥後得到標題產物5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘-2-基)-1,5-二氫吡唑1-4-亞基]-肼基}-苯)-2-甲基呋喃-3-羧酸53(200mg,紅色固體)。產率:73.8%。1 HNMR(400MHz,DMSO-d6 ):δ1.75(m,4H),2.31(s,3H),2.62(s,3H),2.77(m,4H),7.14(m,3H),7.47(d,J=7.6Hz,1H),7.65(m,3H),9.79(s,1H),12.73(br,1H),13.76(br,1H)5-(2-Hydroxy-3-amino-phenyl)-2-methylfuran-3-carboxylic acid hydrobromide 53e (200 mg, 0.64 mmol) was dissolved in 2.2 mL of 1N hydrochloric acid and added dropwise. 0.9mL sodium nitrite solution (48mg, 0.7mmol), reaction for 20 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydrogen Pyrazol-3-one 3i (131 mg, 0.57 mmol) was adjusted to pH 8 with saturated sodium bicarbonate solution, and 2 mL of ethanol was added and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, and the solid was added to 20 mL of water, and then adjusted to pH = 3 to 4 with concentrated hydrochloric acid, filtered, and 8 mL of ethyl acetate was added to the solid for 1 hour, filtered, and the obtained solid was dried to give the title product 5 -(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro Pyrazole 1-4-ylidene]-mercapto}-phenyl)-2-methylfuran-3-carboxylic acid 53 (200 mg, red solid). Yield: 73.8%. 1 HNMR (400MHz, DMSO- d6) : δ1.75 (m, 4H), 2.31 (s, 3H), 2.62 (s, 3H), 2.77 (m, 4H), 7.14 (m, 3H), 7.47 (d , J=7.6Hz, 1H), 7.65 (m, 3H), 9.79 (s, 1H), 12.73 (br, 1H), 13.76 (br, 1H)

實施例54Example 54 5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯基)-呋喃-2-羧酸甲酯5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, Methyl 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylate

第一步first step 5-(2-甲氧基-3-硝基苯基)-呋喃-2-羧酸甲酯Methyl 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylate

將2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯6a(3.6g,12mmol)、5-溴-呋喃-2-羧酸甲酯(2.05g,10mmol)、四(三苯基膦)鈀(1.55g,0.5mmol)和碳酸鈉(2.12g,20mmol)溶解於1,4-二氧陸圜中,加熱回流3小時。以TLC追蹤至原料消失,過濾,濾液減壓濃縮,向殘餘物中加入30mL水和50mL乙酸乙酯,攪拌均勻後靜置,有機相濃縮後用乙酸乙酯和正己烷再結晶,得到標題產物5-(2-甲氧基-3-硝基苯基)-呋喃-2-羧酸甲酯54a(500mg,黃色固體)。產率:18%。1 HNMR(400MHz,CDCl3 ):δ8.23(dd,J=7.6,1H),7.83(dd,J=7.6,1H),7.35(m,.2H),7.16(d,J=4.0,1H),3.98(s,3H),3.94(s,3H)2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (3.6 g, 12 mmol), Methyl 5-bromo-furan-2-carboxylate (2.05 g, 10 mmol), tetrakis(triphenylphosphine)palladium (1.55 g, 0.5 mmol) and sodium carbonate (2.12 g, 20 mmol) were dissolved in 1,4-di In the oxygen earth mash, it was heated to reflux for 3 hours. The residue was removed by TLC, filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Methyl 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylate 54a (500 mg, yellow solid). Yield: 18%. 1 H NMR (400 MHz, CDCl 3 ): δ 8.23 (dd, J = 7.6, 1H), 7.83 (dd, J = 7.6, 1H), 7.35 (m, .2H), 7.16 (d, J = 4.0, 1H) ), 3.98 (s, 3H), 3.94 (s, 3H)

第二步Second step 5-(3-氨基-2-甲氧基-苯基)-呋喃-2-羧酸甲酯Methyl 5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylate

將5-(2-甲氧基-3-硝基苯基)-呋喃-2-羧酸甲酯54a(500mg,1.8mmol)溶解於甲醇中,再加入50mg鈀-碳,於氫氣氛下加熱回流4小時。以TLC追蹤至原料消失,減壓濃縮,所得固體用乙酸乙酯和正己烷的混合溶劑再結晶(V:V=1:5)後乾燥,得到標題產物5-(3-氨基-2-甲氧基-苯基)-呋喃-2-羧酸甲酯54b(370mg,白色固體),產率:83%。Methyl 5-(2-methoxy-3-nitrophenyl)-furan-2-carboxylate 54a (500 mg, 1.8 mmol) was dissolved in methanol, then 50 mg palladium-carbon was added and heated under hydrogen atmosphere Reflux for 4 hours. The residue was traced to dryness by EtOAc (EtOAc) eluted eluted Methyloxy-phenyl)-furan-2-carboxylate 54b (370 mg, white solid), yield: 83%.

第三步third step 5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸甲酯Methyl 5-(3-amino-2-hydroxyphenyl)-furan-2-carboxylate

將5-(3-氨基-2-甲氧基-苯基)-呋喃-2-羧酸甲酯54b(350mg,1.42mmol)溶解於二氯甲烷中,滴加入三溴化硼(3.3mL,2.0mol/L),室溫反應2小時。以TLC追蹤至原料消失,用甲醇淬滅反應,反應液用飽和碳酸氫鈉溶液調節pH至5至6,用乙酸乙酯萃取,有機相濃縮後經管柱層析得到標題產物5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸甲酯54c(170mg,灰色固體)。產率:451%。MS m/z(ESI):232.0[M-1]1 HNMR(400MHz,DMSO-d 6 ):δ7.32(d,J=7.6,1H),7.05(d,J=7.6,1H),6.82(m,3H),3.96(s,3H)Methyl 5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylate 54b (350 mg, 1.42 mmol) was dissolved in dichloromethane, and boron tribromide (3.3 mL, 2.0 mol/L), reacted at room temperature for 2 hours. The mixture was traced by TLC until the material disappeared, and the reaction was quenched with methanol. The mixture was adjusted to pH 5 to 6 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to give the title product 5-- 3- Methylamino-2-hydroxyphenyl)-furan-2-carboxylate 54c (170 mg, gray solid). Yield: 451%. MS m / z (ESI): 232.0 [M-1] 1 HNMR (400MHz, DMSO- d 6): δ7.32 (d, J = 7.6,1H), 7.05 (d, J = 7.6,1H), 6.82 (m, 3H), 3.96 (s, 3H)

第四步the fourth step 5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯基)-呋喃-2-羧酸甲酯5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, Methyl 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-furan-2-carboxylate

冰浴下將5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸甲酯54c(110mg,0.47mmol)溶解於鹽酸(1.6mL,1mol/L)中,滴加入0.6mL亞硝酸鈉溶液(36mg,0.52mmol),反應10分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(97mg,0.43mmol),用飽和碳酸氫鈉溶液調節pH至8至9,室溫反應24小時。以TLC追蹤至原料消失,過濾,固體溶解於15mL水中,冰浴下用濃鹽酸調節pH至3至4,過濾,固體經管柱層析後乾燥,得到標題產物5-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯基)-呋喃-2-羧酸甲酯54(48mg,紅色固體)。產率:23.9%。MS m/z(ESI):470.7[M-1]1 HNMR(400MHz,DMSO-d6 ):δ1.76(m,4H),2.31(s,3H),2.73(m,4H),3.86(s,3H),7.12(m,1H),7.17(m,1H),7.22(t,J=8.0Hz,1H),7.46(m,1H),7.56(m,1H),7.65(m,2H),7.72(m,1H),10.02(s,1H),13.72(br,1H)5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid methyl ester 54c (110 mg, 0.47 mmol) was dissolved in hydrochloric acid (1.6 mL, 1 mol/L), and 0.6 mL was added dropwise. Sodium nitrite solution (36 mg, 0.52 mmol), react for 10 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole 3-ketone 3i (97 mg, 0.43 mmol) was adjusted to pH 8 to 9 with saturated sodium bicarbonate solution and allowed to react at room temperature for 24 hours. The title material was obtained by the TLC. {N'-[3-Methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalenylene-2-yl)-1,5-dihydropyrazole-4- Subunit]-mercapto}-phenyl)-furan-2-carboxylic acid methyl ester 54 (48 mg, red solid). Yield: 23.9%. MS m/z (ESI): 470.7 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 1.76 (m, 4H), 2.31 (s, 3H), 2.73 (m, 4H), 3.86 (s) , 3H), 7.12 (m, 1H), 7.17 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.46 (m, 1H), 7.56 (m, 1H), 7.65 (m, 2H) , 7.72 (m, 1H), 10.02 (s, 1H), 13.72 (br, 1H)

實施例55Example 55 5-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯基}-呋喃-2-羧酸甲酯5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-anthracene Methyl]-phenyl}-furan-2-carboxylate

冰浴下將5-(3-氨基-2-羥基苯基)-呋喃-2-羧酸甲酯54c(110mg,0.47mmol)溶解於鹽酸(1.6mL,1mol/L)中,滴加入0.6mL亞硝酸鈉溶液(36mg,0.52mmol),反應20分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(91mg,0.43mmol),用飽和碳酸氫鈉溶液調節pH至8至9,室溫反應24小時。以TLC追蹤至原料消失,用乙醇淬滅反應,過濾,固體溶解於15mL水中,冰浴下用濃鹽酸調節pH至3至4,過濾,固體經管柱層析後乾燥,得到標題產物5-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯基}-呋喃-2-羧酸甲酯55(137mg,紅色固體)。產率:70.3%。MS m/z(ESI):456.7[M-1]1 HNMR(400MHz,DMSO-d6 ):δ2.05(m,2H),2.33(s,3H),2.89(m,4H),3.86(s,3H),7.18(m,2H),7.30(d,J=8.4Hz,1H),7.46(d,J=3.6Hz,1H),7.56(m,1H),7.71(m,2H),7.78(s,1H)5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid methyl ester 54c (110 mg, 0.47 mmol) was dissolved in hydrochloric acid (1.6 mL, 1 mol/L), and 0.6 mL was added dropwise. Sodium nitrite solution (36 mg, 0.52 mmol), react for 20 minutes, then add 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (91 mg, 0.43 mmol) The pH was adjusted to 8 to 9 with a saturated sodium hydrogencarbonate solution and allowed to react at room temperature for 24 hours. The material disappeared by TLC, the reaction was quenched with ethanol, filtered, and the solid was dissolved in 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and the solid was dried by column chromatography to give the title product 5-- 2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-indenyl]- Phenyl}-furan-2-carboxylic acid methyl ester 55 (137 mg, red solid). Yield: 70.3%. MS m/z (ESI): 456.7 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 2.05 (m, 2H), 2.33 (s, 3H), 2.89 (m, 4H), 3.86 (s) , 3H), 7.18 (m, 2H), 7.30 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.56 (m, 1H), 7.71 (m, 2H), 7.78 (s, 1H)

實施例56Example 56 3’-{N’-[1-(2,2-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基聯苯-3-羧酸3'-{N'-[1-(2,2-Dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-mercapto}-2'-hydroxybiphenyl-3-carboxylic acid

冰浴下將2’-羥基-3’-氨基聯苯基-3-羧酸氫溴酸鹽1f(150mg,0.5mmol)溶解於鹽酸(1.7mL,1mol/L)中,滴加入0.6mL亞硝酸鈉溶液(38mg,0.55mmol),反應20分鐘,再加入2-(2,2-二甲基茚滿-5-基)-5-甲基-2,4-二氫吡唑-3-酮45d(109mg,0.45mmol),用飽和碳酸氫鈉溶液調節pH至8至9,用乙醇淬滅氣泡,室溫反應過夜。以TLC追蹤至原料消失,過濾,固體加入15mL水,用濃鹽酸調節pH值至3至4,過濾,濾餅用乙酸乙酯洗滌(1mL×3)後乾燥得到標題產物3’-{N’-[1-(2,2-二甲基茚滿-5-基)-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基]-肼基}-2’-羥基聯苯-3-羧酸56(16mg,黃色固體),產率:7.6%。MS m/z(ESI):480.7[M-1]1 HNMR(400MHz,DMSO-d 6 ):δ1.13(s,6H),2.32(s,3H),2.70(m,4H),7.14(m,2H),7.22(d,J=8.8Hz,1H),.7.61(t,J=8.0Hz,1H),7.66(d,J=7.6Hz,1H),7.70(m,2H),7.80(d,J=7.6Hz,1H),7.95(d,J=8.0Hz,1H),8.13(s,1H)2'-hydroxy-3'-aminobiphenyl-3-carboxylic acid hydrobromide salt 1f (150 mg, 0.5 mmol) was dissolved in hydrochloric acid (1.7 mL, 1 mol/L) under ice bath, and 0.6 mL was added dropwise. Sodium nitrate solution (38 mg, 0.55 mmol), reacted for 20 minutes, and then added 2-(2,2-dimethylindan-5-yl)-5-methyl-2,4-dihydropyrazole-3- Ketone 45d (109 mg, 0.45 mmol), the pH was adjusted to 8 to 9 with saturated sodium bicarbonate solution, and the solvent was quenched with ethanol and allowed to react overnight at room temperature. The product disappeared by TLC, filtered, and the solid was added to 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid, filtered, and the filter cake was washed with ethyl acetate (1mL×3) and dried to give the title product 3'-{N' -[1-(2,2-dimethylindan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-indenyl}- 2'-Hydroxybiphenyl-3-carboxylic acid 56 (16 mg, yellow solid), yield: 7.6%. MS m/z (ESI): 480.7 [M-1] 1 H NMR (400 MHz, DMSO- d 6 ): δ 1.13 (s, 6H), 2.32 (s, 3H), 2.70 (m, 4H), 7.14 m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.70 (m, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H)

實施例57Example 57 4-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-1H-吡咯-2-羧酸4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-1H-pyrrole-2-carboxylic acid

第一步first step 2,2,2-三氯-1-(1H-吡咯-2-基)-乙醯2,2,2-trichloro-1-(1H-pyrrol-2-yl)-acetamidine

將三氯乙醯氯(45g,247mmol)溶解於100mL乙醚中,將吡咯(15.4g,230mmol)溶解於100mL中,滴加到上述溶液中,加入200mL碳酸鉀溶液(20g,145mmol),加畢後室溫攪拌1小時,TLC監測反應至原料反應完全,反應液分液,有機相用無水硫酸鎂乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物2,2,2-三氯-1-(1H-吡咯-2-基)-乙醯57b(38g,白色固體),產率:77.8%。MS m/z(ESI):210.3[M-1]Trichloroethane chloride (45 g, 247 mmol) was dissolved in 100 mL of diethyl ether, and pyrrole (15.4 g, 230 mmol) was dissolved in 100 mL, added dropwise to the above solution, and 200 mL of potassium carbonate solution (20 g, 145 mmol) was added thereto. After stirring at room temperature for 1 hour, the reaction was monitored by TLC until the reaction mixture was completed. The reaction mixture was partitioned, and the organic phase was dried over anhydrous magnesium sulfate and filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to give the title product 2, 2, 2 Trichloro-1-(1H-pyrrol-2-yl)-acetamidine 57b (38 g, white solid), yield: 77.8%. MS m/z (ESI): 210.3 [M-1]

第二步Second step 2,2,2-三氯-1-(4-碘-1H-吡咯-2-基)-乙醯2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)-acetamidine

將2,2,2-三氯-1-(1H-吡咯-2-基)-乙醯57b(32g,151.8mmol)溶解於250mL二氯甲烷中,將氯化碘(25g,153mmol)溶解於125mL二氯甲烷中,滴加到上述溶液中,加畢後室溫攪拌2小時,TLC監測反應至原料反應完全,反應液依次用飽和碳酸鈉溶液、硫代硫酸鈉溶液(2M)和飽和食鹽水洗滌,用無水硫酸鎂乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物2,2,2-三氯-1-(4-碘-1H-吡咯-2-基)-乙醯57c(47g,黃色固體),產率:92%。MS m/z(ESI):336.4[M-1]2,2,2-Trichloro-1-(1H-pyrrol-2-yl)-acetamidine 57b (32 g, 151.8 mmol) was dissolved in dichloromethane (250 mL), and iodine chloride (25 g, 153 mmol) was dissolved in In 125 mL of dichloromethane, it was added dropwise to the above solution, and after stirring, the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until the reaction of the starting material was complete. The reaction mixture was successively saturated sodium carbonate solution, sodium thiosulfate solution (2M) and saturated salt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered, evaporated, evaporated, evaporated. - acetamidine 57c (47 g, yellow solid), yield: 92%. MS m/z (ESI): 336.4 [M-1]

第三步third step 4-碘-1H-吡咯-2-羧酸甲酯Methyl 4-iodo-1H-pyrrole-2-carboxylate

將2,2,2-三氯-1-(4-碘-1H-吡咯-2-基)-乙醯57c(47g,136mmol)溶解於265mL甲醇中,將甲醇鈉(17.23g,163mmol)溶解於200mL甲醇中,滴加到上述溶液中,室溫攪拌1小時,TLC監測反應至原料反應完全,反應液減壓濃縮,殘餘物中加入20mL水,用乙酸乙酯萃取(30mL×3),合併有機相,有機相用飽和食鹽水洗滌,用無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮得到標題產物4-碘-1H-吡咯-2-羧酸甲酯57d(32.2g,灰色固體),產率:92.5%。MS m/z(ESI):250.1[M-1]Dissolve 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)-acetam 57c (47 g, 136 mmol) in 265 mL of methanol and dissolve sodium methoxide (17.23 g, 163 mmol). The mixture was added dropwise to 200 ml of methanol, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until the reaction was completed. The mixture was concentrated under reduced pressure. The organic phase was combined, and the organic layer was evaporated, evaporated, evaporated, evaporated Solid), Yield: 92.5%. MS m/z (ESI): 250.1 [M-1]

第四步the fourth step 4-碘-1-(甲苯-4-磺醯)-1H-吡咯-2-羧酸甲酯Methyl 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylate

將4-碘-1H-吡咯-2-羧酸甲酯57d(25.1g,100mmol)溶解於150mL二氯甲烷中,加入三乙胺(30.6mL,220mmol)、4-二甲氨基吡啶(1.22g,10mmol)和對甲苯磺酸(21g,110mmol),於20℃下反應過夜,TLC監測反應至原料反應完全,加入30mL鹽酸(1N)淬滅反應。反應液用二氯甲烷萃取(50mL×3),有機相依次用飽和碳酸鈉溶液、飽和食鹽水洗滌,用無水硫酸鈉乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物4-碘-1-(甲苯-4-磺醯)-1H-吡咯-2-羧酸甲酯57e(32.5g,白色固體),產率:80.2%。MS m/z(ESI):405.8[M+1]Methyl 4-iodo-1H-pyrrole-2-carboxylate 57d (25.1 g, 100 mmol) was dissolved in 150 mL of dichloromethane, then triethylamine (30.6 mL, 220 mmol), 4-dimethylaminopyridine (1.22 g) , 10 mmol) and p-toluenesulfonic acid (21 g, 110 mmol) were reacted at 20 ° C overnight. The reaction was monitored by TLC until the starting material was completely reacted, and the reaction was quenched by adding 30 mL of hydrochloric acid (1 N). The reaction mixture was extracted with methylene chloride (50 mL×3). The organic phase was washed with saturated sodium carbonate and brine, and dried over anhydrous sodium sulfate. 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57e (32.5 g, white solid), yield: 80.2%. MS m/z (ESI): 405.8 [M+1]

第五步the fifth step 4-(3-硝基-2-甲氧基-苯基)-1-(甲苯-4-磺醯)-1H-吡咯-2-羧酸甲酯Methyl 4-(3-nitro-2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylate

將2-(2-甲氧基-3-硝基苯基)-4,4,5,5-四甲基-[1,3,2]硼酸乙二醇酯6a(2.05g,5.5mmol)、4-碘-1-(甲苯-4-磺醯)-1H-吡咯-2-羧酸甲酯57e(2.03g,5mmol)、碳酸鉀(1.38g,10mmol)和四(苯基膦)鈀(144mg,0.125mmol)加入到15mL1,4-二氧陸圜和5mL水的混合溶劑中,加畢于80℃微波反應30分鐘,TLC監測反應原料反應完全,反應液減壓濃縮,加入20mL水,攪拌均勻後用乙酸乙酯萃取(20mL×3),合併有機相,有機相用飽和食鹽水洗滌,無水硫酸鎂乾燥,過濾除去乾燥劑,濾液減壓濃縮後經管柱層析得到標題產物4-(3-硝基-2-甲氧基-苯基)-1-(甲苯-4-磺醯)-1H-吡咯-2-羧酸甲酯57f(1.04g,灰色固體),產率:48%。MS m/z(ESI):431.0[M+1]1 HNMR(400MHz,CDCl3 ):δ8.225~8.231(m,1H),7.979~8.00(m,2H),7.710~7.765(m,1H),7.452~7.457(m,1H),7.389~7.409(m,2H),7.271~7.311(m,2H),3.839(s,3H),3.829(s,2H),2.488(s,3H)2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]borate 6a (2.05 g, 5.5 mmol) , 4-iodo-1-(toluene-4-sulfonium)-1H-pyrrole-2-carboxylic acid methyl ester 57e (2.03 g, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and tetrakis(phenylphosphine)palladium (144 mg, 0.125 mmol) was added to a mixed solvent of 15 mL of 1,4-dioxane and 5 mL of water, and subjected to microwave reaction at 80 ° C for 30 minutes. The reaction of the reaction was completed by TLC, and the reaction mixture was concentrated under reduced pressure. After stirring, the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was combined and evaporated. Methyl (3-nitro-2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylate 57f (1.04 g, m. 48%. MS m/z (ESI): 431.0 [M + 1] 1 H NMR (400 MHz, CDCl 3 ): δ 8.225~8.231 (m, 1H), 7.79~8.00 (m, 2H), 7.710~7.765 (m, 1H) ), 7.452~7.457(m,1H), 7.389~7.409(m,2H), 7.271~7.311(m,2H),3.839(s,3H),3.829(s,2H),2.488(s,3H)

第六步Step 6 4-(3-硝基-2-甲氧基-苯基)-1H-吡咯-2-羧酸4-(3-nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid

將4-(3-硝基-2-甲氧基-苯基)-1-(甲苯-4-磺醯)-1H-吡咯-2-羧酸甲酯57f(1.04g,2.42mmol)和一水合氫氧化鋰(1.01g,24.19mmol)加入到10mL N,N-二甲基甲醯胺和5mL水的混合溶劑中,於100℃微波反應30分鐘,TLC監測反應原料反應完全,反應液用鹽酸(1N)調節pH至3,有大量固體析出,過濾,濾餅乾燥後得到標題產物4-(3-硝基-2-甲氧基-苯基)-1H-吡咯-2-羧酸57g(350mg,黃色固體),產率:50%。MS m/z(ESI):260.8[M-1]4-(3-Nitro-2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57f (1.04 g, 2.42 mmol) and one Lithium hydroxide hydrate (1.01 g, 24.19 mmol) was added to a mixed solvent of 10 mL of N,N-dimethylformamide and 5 mL of water, and microwave-reacted at 100 ° C for 30 minutes. The reaction of the reaction material was completely monitored by TLC. Hydrochloric acid (1N) was adjusted to pH 3, a large amount of solid was precipitated, filtered, and filtered to give the title product 4-(3-nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57 g. (350 mg, yellow solid), yield: 50%. MS m/z (ESI): 260.8 [M-1]

第七步Seventh step 4-(3-氨基-2-甲氧基-苯基)-1H-吡咯-2-羧酸4-(3-Amino-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid

將4-(3-硝基-2-甲氧基-苯基)-1H-吡咯-2-羧酸57g(633mg,2.41mmol)溶解於15mL乙酸乙酯中,加入127mg鈀/碳和甲酸胺(609mg,9.66mmol),加畢後加熱回流2小時,TLC監測反應至原料反應完全,反應過濾除去鈀/碳,濾液減壓濃縮後經管柱層析得到標題產物4-(3-氨基-2-甲氧基-苯基)-1H-吡咯-2-羧酸57h(130mg,灰色固體),產率:23.2%。MS m/z(ESI):230.8[M-1]1 HNMR(400MHz,DMSO-d6 ):δ11.631(s,1H),7.305(s,1H),7.025(s,1H),6.712~6.798(m,2H),6.524~6.543(m,1H),3.514(s,3H)57 g (633 mg, 2.41 mmol) of 4-(3-nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid was dissolved in 15 mL of ethyl acetate, and 127 mg of palladium/carbon and ammonium formate were added. (609 mg, 9.66 mmol), after heating and refluxing for 2 hours, the reaction was monitored by TLC until the starting material was completely reacted, and the mixture was filtered to remove palladium/carbon. The filtrate was concentrated under reduced pressure and purified by column chromatography to give the title product 4-(3-amino-2). -Methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57 h (130 mg, m.p.). MS m/z (ESI): 230.8 [M-1] 1 H NMR (400 MHz, DMSO- d6 ): δ 11.631 (s, 1H), 7.305 (s, 1H), 7.025 (s, 1H), 6.712~6.798 (m, 2H), 6.524~6.543 (m, 1H), 3.514 (s, 3H)

第八步Eighth step 4-(3-氨基-2-羥基苯基)-1H-吡咯-2-羧酸4-(3-Amino-2-hydroxyphenyl)-1H-pyrrole-2-carboxylic acid

將4-(3-氨基-2-甲氧基-苯基)-1H-吡咯-2-羧酸57h(130mg,0.56mmol)加入2mL二氯甲烷中,加入溴化硼(1.12mL,2.24mmol),室溫攪拌6小時,TLC監測反應至原料反應完全,用甲醇淬滅反應,反應液減壓濃縮後經管柱層析得到標題產物4-(3-氨基-2-羥基苯基)-1H-吡咯-2-羧酸57i(140mg,灰色固體),產率:99%。1 HNMR(400MHz,CD3 OD):δ7.312(s,1H),7.178(s,1H),7.006~7.028(m,1H),6.822~6.837(m,2H)4-(3-Amino-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57h (130mg, 0.56mmol) was added to 2mL of dichloromethane, then boron bromide (1.12mL, 2.24mmol) After stirring at room temperature for 6 hours, the reaction was monitored by TLC until the reaction mixture was completed. The reaction was quenched with methanol, and the mixture was concentrated under reduced pressure to give the title product 4-(3-amino-2-hydroxyphenyl)-1H. Pyrrole-2-carboxylic acid 57i (140 mg, gray solid), yield: 99%. 1 H NMR (400 MHz, CD 3 OD): δ 7.312 (s, 1H), 7.178 (s, 1H), 7.06 to 7.028 (m, 1H), 6.822 to 6.837 (m, 2H)

第九步Step 9 4-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-1H-吡咯-2-羧酸4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1, 5-dihydropyrazole-4-ylidene]-indenyl}-phenyl)-1H-pyrrole-2-carboxylic acid

冰浴下將4-(3-氨基-2-羥基苯基)-1H-吡咯-2-羧酸57i(130mg,0.43mmol)溶解於鹽酸(1.5mL,1mol/L)中,滴加入0.6mL亞硝酸鈉溶液(33mg,0.47mmol),反應10分鐘,再加入5-甲基-2-(5,6,7,8-四氫萘-2-基)-2,4-二氫吡唑-3-酮3i(89mg,0.3mmol),用飽和碳酸氫鈉溶液調節pH至8至9,室溫反應24小時。以TLC追蹤至原料消失,過濾,固體溶解於15mL水中,冰浴下用濃鹽酸調節pH至3至4,過濾,濾餅用乙酸乙酯洗滌後乾燥,得到標題產物4-(2-羥基-3-{N’-[3-甲基-5-側氧基-1-(5,6,7,8-四氫萘亞甲基-2-基)-1,5-二氫吡唑-4-亞基]-肼基}-苯)-1H-吡咯-2-羧酸57(38mg,灰色固體)。產率:21.3%。1 HNMR(400MHz,DMSO-d6 ):δ11.74(1H,br),11.64(1H,br),7.60(1H,d J=8.2),7.49(1H,d J=8.0),7.32(3H,m),7.05(3H,m),2.67(4H,m),1.95(3H,s),1.13(4H,m)4-(3-Amino-2-hydroxyphenyl)-1H-pyrrole-2-carboxylic acid 57i (130 mg, 0.43 mmol) was dissolved in hydrochloric acid (1.5 mL, 1 mol/L), and 0.6 mL was added dropwise. Sodium nitrite solution (33 mg, 0.47 mmol), react for 10 minutes, then add 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazole 3-ketone 3i (89 mg, 0.3 mmol) was adjusted to pH 8 to 9 with a saturated sodium hydrogen carbonate solution and allowed to react at room temperature for 24 hours. The title material (4-hydroxy-) was obtained by the TLC. 3-{N'-[3-methyl-5-oxo-l-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazole- 4-Mercapto]-indenyl}-phenyl)-1H-pyrrole-2-carboxylic acid 57 (38 mg, m.p.). Yield: 21.3%. 1 HNMR (400MHz, DMSO- d6) : δ11.74 (1H, br), 11.64 (1H, br), 7.60 (1H, d J = 8.2), 7.49 (1H, d J = 8.0), 7.32 (3H, m), 7.05 (3H, m), 2.67 (4H, m), 1.95 (3H, s), 1.13 (4H, m)

實施例58Example 58 44 -{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-1H-吡咯-2-羧酸-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-indenyl ]-Benzene}-1H-pyrrole-2-carboxylic acid

冰浴下將4-(3-氨基-2-羥基苯基)-1H-吡咯-2-羧酸57i(240mg,0.8mmol)溶解於鹽酸(3mL,1mol/L)中,滴加入1.1mL亞硝酸鈉溶液(61mg,0.88mmol),反應20分鐘,再加入2-茚滿-5-基-5-甲基-2,4-二氫吡唑-3-酮1i(154mg,0.72mmol),用飽和碳酸氫鈉溶液調節pH至8至9,室溫反應24小時。以TLC追蹤至原料消失,用乙醇淬滅反應,過濾,固體溶解於15mL水中,冰浴下用濃鹽酸調節pH至3至4,過濾,固體經管柱層析後乾燥,得到標題產物4-{2-羥基-3-[N’-(1-茚滿-5-基-3-甲基-5-側氧基-1,5-二氫吡唑-4-亞基)-肼基]-苯}-1H-吡咯-2-羧酸58(101mg,紅色固體),產率:28.4%。1 HNMR(400MHz,DMSO-d6 ):δ11.83(1H,br),11.77(1H,br),7.57(1H,d,J=7.2),7.50(1H,s),7.37(4H,m),7.26(1H,m),7.10(1H,m),2.87(4H,m),2.32(3H,s),2.04(2H,m)4-(3-Amino-2-hydroxyphenyl)-1H-pyrrole-2-carboxylic acid 57i (240 mg, 0.8 mmol) was dissolved in hydrochloric acid (3 mL, 1 mol/L) under ice-cooling, and 1.1 mL was added dropwise. Sodium nitrate solution (61 mg, 0.88 mmol), reacted for 20 minutes, then added 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (154 mg, 0.72 mmol). The pH was adjusted to 8 to 9 with a saturated sodium hydrogencarbonate solution and allowed to react at room temperature for 24 hours. The mixture was traced to disappearance by TLC, quenched with ethanol, filtered, and the solid was dissolved in 15 mL of water. The pH was adjusted to 3 to 4 with concentrated hydrochloric acid in an ice bath, filtered, and the solid was subjected to column chromatography and dried to give the title product 4-{ 2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-indenyl]- Benzene}-1H-pyrrole-2-carboxylic acid 58 (101 mg, red solid), yield: 28.4%. 1 HNMR (400MHz, DMSO- d6) : δ11.83 (1H, br), 11.77 (1H, br), 7.57 (1H, d, J = 7.2), 7.50 (1H, s), 7.37 (4H, m) , 7.26 (1H, m), 7.10 (1H, m), 2.87 (4H, m), 2.32 (3H, s), 2.04 (2H, m)

測試例:Test case: 生物學評價Biological evaluation 測試例1 TPO系列化合物對BAF3-TPOR細胞的增殖作用Test Example 1 Proliferation of BAF3-TPOR cells by TPO series compounds 1.材料和方法:1. Materials and methods:

a.RPM1 Medium 1640,Powder,10*1L,含HEPES(Gibco Catalog no. 23400021)a.RPM1 Medium 1640, Powder, 10*1L, with HEPES (Gibco Catalog no. 23400021)

b.FBS胎牛血清(Gibco Catalog no. 10099-141)b. FBS fetal bovine serum (Gibco Catalog no. 10099-141)

c.PENICILLIN STREPTOMYCIN SOL(Gibco Catalog no. 15140-122)c.PENICILLIN STREPTOMYCIN SOL (Gibco Catalog no. 15140-122)

d.Geneticin(G418)(Gibco Catalog no. 11811-098)d.Geneticin(G418)(Gibco Catalog no. 11811-098)

e.recombinant mouse IL-3(chemicon Catalog no. IL015)E.recombinant mouse IL-3(chemicon Catalog no. IL015)

f.Human Thrombopoietin R Mab(TPO)(R&D Catalog no. MAB1016)f.Human Thrombopoietin R Mab(TPO)(R&D Catalog no. MAB1016)

g.DMSO(AppliChem Catalog no. A3672)g.DMSO (AppliChem Catalog no. A3672)

h.Multi Site Directed Mutagenesis Kit,10 Runs(Stratagene ST200515)h. Multi Site Directed Mutagenesis Kit, 10 Runs (Stratagene ST200515)

i.Cell Counting Kit-8(同仁化學研究所Catalog no. CK04-13)i.Cell Counting Kit-8 (Tongren Chemical Institute Catalog no. CK04-13)

j.Ba/F3細胞(協和細胞庫Catalog no. 0095)j.Ba/F3 cells (Concord Cell Bank Catalog no. 0095)

k.EX-EGFP-M02(FulenGen Catalog no. EX-EGFP-M02 Control)k.EX-EGFP-M02 (FulenGen Catalog no. EX-EGFP-M02 Control)

l.EX-B0010-M02(FulenGen Catalog no. EX-B0010-M02)l.EX-B0010-M02 (FulenGen Catalog no. EX-B0010-M02)

2.操作步驟:2. Operation steps:

(1)質體構建:根據Entrez Gene ID:4325,Refseq:NM_005373提供的TPOR基因序列,對購買的EX-B0010-M02質體(FulenGen)利用Multi Site Directed Mutagenesis Kit(Stratagene)試劑盒進行2點突變。多點突變引物序列分別為:g491a:5’-gggaacttcagatcagctgggaggagccg-3’,g491a_antisense:5’-cggctcctcccagctgatctgaagttccc-3’;c965t:5’-caggaccatgctagctcccaaggcttcttct-3’,c965t_antisense:5’-agaagaagccttgggagctagcatggtcctg-3’。突變後質體轉化大腸桿菌DH5α,經Amp篩選出陽性克隆,測序鑒定突變結果正確。(1) plastid construction: According to the TPOR gene sequence provided by Entrez Gene ID: 4325, Refseq: NM_005373, the purchased EX-B0010-M02 plastid (FulenGen) was utilized. The Multi Site Directed Mutagenesis Kit (Stratagene) kit performs a 2-point mutation. The multi-point mutation primer sequences were: g491a: 5'-gggaacttcagatcagctgggaggagccg-3', g491a_antisense: 5'-cggctcctcccagctgatctgaagttccc-3'; c965t: 5'-caggaccatgctagctcccaaggcttcttct-3', c965t_antisense: 5'-agaagaagccttgggagctagcatggtcctg-3'. After the mutation, the plastid was transformed into E. coli DH5α, and the positive clone was screened by Amp, and the mutation result was confirmed by sequencing.

(2)BAF3-TPOR細胞株構建:構建穩定高表現功能性TPO受體的BaF3細胞株。將經2點突變後的表現人TPO受體和篩選基因neomycin的EX-B0010-M02質體25μg轉染野生型BaF3細胞(1X107 ),轉染所用儀器為Electro Square Porator ECM830(BTX Division of Genetronic,Inc. US),轉染條件為:250V,18ms。通過G418(Gibco,US)篩選獲得BAF3-TPOR穩定細胞株。BAF3-TPOR在RPMI1640(Gibco,US)培養基,10%FB(Gibco,US)S,800ng/ml G418,5ng/ml,rmIL-3(Chemicon,US)中培養。(2) Construction of BAF3-TPOR cell line: A BaF3 cell line stably constructing a highly functional TPO receptor was constructed. 25 μg of the human TPO receptor and the EX-B0010-M02 plastid of the screening gene neomycin were transfected into wild-type BaF3 cells (1× 10 7 ), and the instrument used for transfection was Electro Square Porator ECM830 (BTX Division of Genetronic). , Inc. US), the transfection conditions are: 250V, 18ms. The BAF3-TPOR stable cell line was obtained by G418 (Gibco, US) screening. BAF3-TPOR was cultured in RPMI 1640 (Gibco, US) medium, 10% FB (Gibco, US) S, 800 ng/ml G418, 5 ng/ml, rmIL-3 (Chemicon, US).

3.化合物篩選:3. Compound screening:

(1)離心清洗細胞:取適量細胞懸浮液1000rpm,離心5分鐘,棄去上清液,再用10ml不含IL3的細胞培養液將細胞重新懸浮,1000rpm,離心5分鐘,棄去上清液;(1) Centrifugal washing of cells: take appropriate amount of cell suspension at 1000 rpm, centrifuge for 5 minutes, discard the supernatant, resuspend the cells with 10 ml of cell culture medium without IL3, centrifuge at 1000 rpm for 5 minutes, discard the supernatant. ;

(2)加入1ml不含IL3的細胞培養液將細胞吹打均勻,取適量細胞懸浮液稀釋後計數;(2) Add 1 ml of cell culture medium containing no IL3 to blow the cells evenly, and take appropriate amount of cell suspension to dilute and count;

(3)根據細胞計數結果製備密度為100000個/ml的細胞懸液;(3) preparing a cell suspension having a density of 100,000 / ml according to the cell counting result;

(4)於96-well平板中每孔加入100μl細胞懸液,設置3個複孔,並設置空白對照組(B),陰性對照組(N),TPO陽性對照組(P)和待測化合物組(S);(4) Add 100 μl of cell suspension to each well of 96-well plate, set 3 replicate wells, and set blank control group (B), negative control group (N), TPO positive control group (P) and test compound Group (S);

(5)用DMSO將待測化合物粉末配成10mM的儲存液,再用RPM11640稀釋成不同濃度:30μM,10μM,3μM,1μM,0.3μM,0.1μM,0.03μM,0.01μM,0.003μM,0.001μM;(5) The test compound powder was formulated into 10 mM stock solution in DMSO, and diluted to different concentrations with RPM11640: 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM. ;

(6)每孔加入10μl相應濃度的藥液,陽性對照孔中加入1μl rhTPO(10μg/mL);(6) Add 10 μl of the corresponding concentration of the drug solution to each well, and add 1 μl of rhTPO (10 μg/mL) to the positive control well;

(7)置於5%C02,37℃細胞培養箱中培養24小時;(7) placed in a 5% CO 2, 37 ° C cell culture incubator for 24 hours;

(8)每孔加入10μlCCK-8,于細胞培養箱中培養4小時;(8) 10 μl of CCK-8 was added to each well, and cultured in a cell culture incubator for 4 hours;

(9)利用VICTOR3(Perkin Elmer 1420-120)儀器在450nm檢測OD值。(9) The OD value was measured at 450 nm using a VICTOR 3 (Perkin Elmer 1420-120) instrument.

4.結果分析計算:4. Results analysis and calculation:

(1)增值率定義:[(S-B)/(P-B)]*100%S:樣品;B:空白對照;P:陽性對照(1) Value-added rate definition: [(S-B)/(P-B)]*100%S: sample; B: blank control; P: positive control

(2)通過Origin 7.0計算EC50 .(2) Calculate EC 50 by Origin 7.0.

5.結果:5. Results:

藥物動力學測試Pharmacokinetic test 測試例1 本發明化合的藥代動力學測試Test Example 1 Pharmacokinetic test of the present invention 1、試驗目的1. Purpose of the test

以大鼠為受試動物,應用LC/MS/MS法測定了大鼠分別灌胃給予實施例1、實施例15和實施例29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代動力學行為,評價其藥動學特徵。Rats were used as test animals, and the concentrations of the drugs in plasma at different times after administration of Example 1, Example 15, and Example 29 by intragastric administration were determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2、試驗方案2, the test plan 2.1、試驗藥品2.1, test drugs 實施例1、實施例15和實施例29Example 1, Example 15, and Example 29 2.2、試驗動物2.2, test animals

健康成年SD大鼠24隻,雌雄各半,購自上海西普爾-必凱實驗動物有限公司,動物生產許可證號:SCXK(滬)2003-0002。24 healthy adult SD rats, male and female, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2003-0002.

2.3、儀器設備2.3, equipment

TSQ Quantum Ultra AM三重四極柱質譜儀,美國Thermo Finnigan公司;TSQ Quantum Ultra AM Triple Quadrupole Mass Spectrometer, Thermo Finnigan, USA;

Agilent 1200高效液相層析系統,美國Agilent公司。Agilent 1200 High Performance Liquid Chromatography System, Agilent, USA.

2.4、藥物配製2.4, drug preparation

稱取適量樣品加1%羧甲基纖維素鈉製成0.5mg/ml(以原形計)混懸液,臨用時配製。An appropriate amount of the sample was weighed and added with 1% sodium carboxymethylcellulose to prepare a 0.5 mg/ml (as prototype) suspension, which was prepared immediately.

2.5、給藥2.5, administration

健康成年SD大鼠24隻,雌雄各半,平均分成5組,禁食過夜後分別灌胃給藥,給藥劑量均為5.0mg/kg(以原形計),給藥體積10ml/kg。Twenty-four healthy adult SD rats, half male and half female, were divided into 5 groups on average. After fasting overnight, the rats were intragastrically administered at a dose of 5.0 mg/kg (in original form) at a dose of 10 ml/kg.

2.6、樣品採集2.6, sample collection

SD大鼠24隻,雌雄各半,禁食一夜後灌胃給藥,劑量為5mg/kg。於給藥前及給藥後0.5,1.0,2.0,3.0,4.0,5.0,6.0,8.0,11.0,14.0,24.0,36.0,48.0小時由眼眶採血0.2ml,置於肝素化試管中,3500rpm離心10min分離血漿,於20℃保存。Twenty-four SD rats, half male and half female, were intragastrically administered overnight after fasting for a dose of 5 mg/kg. 0.2 ml of blood was collected from the eyelids before and after administration and 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 11.0, 14.0, 24.0, 36.0, 48.0 hours after administration, placed in heparinized tubes, centrifuged at 3500 rpm for 10 min. Plasma was separated and stored at 20 °C.

2.7、分析方法2.7, analytical methods

取給藥後各時刻的大鼠血漿501,加入內標溶液201,甲醇:水(80:20,v/v)201,混勻後加入甲醇1501沉澱蛋白,渦流混合1min,13000rpm離心10min,取201進行LC/MS/MS分析。Rat plasma 501 at each time after administration, adding internal standard solution 201, methanol: water (80:20, v/v) 201, mixing, adding methanol 1501 precipitation protein, vortex mixing for 1 min, centrifugation at 13000 rpm for 10 min, 201 was subjected to LC/MS/MS analysis.

2.8、標準曲線製備2.8, standard curve preparation

取大鼠空白血漿501,分別加入標準系列溶液,使血藥濃度為1.0,5.0,25.0,50.0,100.0,250.0,500.0ng/ml,加入內標溶液201,依據“血漿樣品預處理”項下進行操作。以血藥濃度為橫坐標,樣品與內標層析峰面積比為縱坐標,以加權最小二乘法(w=1/x2 )進行線性回歸,獲得典型標準曲線方程式。Rat blank plasma 501 was taken and added to the standard series solution to make the plasma concentration of 1.0, 5.0, 25.0, 50.0, 100.0, 250.0, 500.0 ng/ml, and the internal standard solution 201 was added, according to the "pretreatment of plasma samples". Take action. Taking the plasma concentration as the abscissa, the ratio of the peak area of the sample to the internal standard is the ordinate, and the linear regression is performed by the weighted least squares method (w=1/x 2 ) to obtain the typical standard curve equation.

2.9、藥代動力學參數計算2.9, calculation of pharmacokinetic parameters

對受試化合物的藥代動力學行為進行房室模型擬合,並計算主要藥代動力學參數,其中Cmax 、tmax 採用實測值。The pharmacokinetic behavior of the test compound was fitted to the atrioventricular model, and the main pharmacokinetic parameters were calculated, wherein C max and t max were measured.

3、藥代動力學參數結果3, pharmacokinetic parameters results

試驗結果表明,大鼠分別灌胃給予上述本發明化合物後,各化合物均吸收較好。The test results showed that each of the compounds was well absorbed after the rats were intragastrically administered with the above compounds of the present invention.

Claims (12)

一種通式(I)所示的化合物或其藥學上可以接受的鹽: 其中:A選自碳原子或氧原子;R、R2 和R4 是氫原子;R1 選自苯基、呋喃基、吡咯基、噻吩基或噻唑基,其中各基團可進一步被一個或多個含有1至4個碳原子的烷基、鹵素、羥基、四唑基、咪唑、二氫咪唑、羧酸或羧酸酯的取代基所取代;R3 選自氫原子、含有1至4個碳原子的烷基或鹵素;R5 、R6 和R7 各自獨立地選自氫原子、含有1至4個碳原子的烷基、含有1至4個碳原子的烷氧基、鹵素、羥基、氨基、硝基、氰基、羧酸或羧酸酯;R8 、R9 、R10 和R11 各自獨立地選自氫原子或含有1至4個碳原子的烷基;且n是0,1或2。A compound of the formula (I) or a pharmaceutically acceptable salt thereof: Wherein: A is selected from a carbon atom or an oxygen atom; R, R 2 and R 4 are a hydrogen atom; and R 1 is selected from a phenyl group, a furyl group, a pyrrolyl group, a thienyl group or a thiazolyl group, wherein each group may be further one or Substituted with a plurality of substituents of an alkyl group having 1 to 4 carbon atoms, a halogen, a hydroxyl group, a tetrazolyl group, an imidazole, a dihydroimidazole, a carboxylic acid or a carboxylate; R 3 is selected from a hydrogen atom and contains 1 to 4 An alkyl group or a halogen of one carbon atom; R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxylic acid or a carboxylate; R 8 , R 9 , R 10 and R 11 are each independently selected from a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and n is 0, 1 or 2. 如申請專利範圍第1項的化合物或其藥學上可接受的鹽,其中所述的化合物係選自下列者: The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 一種通式(IA)所示的化合物,該化合物為合成申請專利範圍第1項的通式(I)化合物的中間體: 其中:A選自碳原子或氧原子;R5 、R6 和R7 各自獨立地選自氫原子、含有1至4個碳原子的烷基、含有1至4個碳原子的烷氧基、鹵素、羥基、氨基、硝基、氰基、羧酸或羧酸酯;R8 、R9 、R10 和R11 各自獨立地選自氫原子或含有1至4個碳原子的烷基;且n是0或1。A compound of the formula (IA) which is an intermediate for the synthesis of a compound of the formula (I) in claim 1 of the patent application: Wherein: A is selected from a carbon atom or an oxygen atom; and R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, Halogen, hydroxy, amino, nitro, cyano, carboxylic acid or carboxylic acid ester; R 8 , R 9 , R 10 and R 11 are each independently selected from a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; n is 0 or 1. 如申請專利範圍第3項的化合物,其中該化合物係選自下列者: A compound as claimed in claim 3, wherein the compound is selected from the group consisting of: 一種製備申請專利範圍第3項的通式(IA)化合物的方法,該方法包括: 將氨基取代的苯並多員環與亞硝酸鈉在酸性溶液中進行重氮化反應,再經由氯化亞錫還原得到肼,將肼與羰基化合物在溶劑中加熱下縮合而得到通式(IA)化合物,其中:A,n和R5 ~R11 的定義如申請專利範圍1中所述。A method of preparing a compound of the general formula (IA) of claim 3, the method comprising: The amino-substituted benzopolycyclic ring is diazotized with sodium nitrite in an acidic solution, and then reduced by stannous chloride to obtain hydrazine, and hydrazine is condensed with a carbonyl compound in a solvent to obtain a general formula (IA). a compound wherein: A, n and R 5 to R 11 are as defined in Patent Application No. 1. 一種製備申請專利範圍第1項的通式(I)化合物的方法,該方法包括: 將取代的苯胺類化合物與亞硝酸鈉在酸性溶液中進行重氮化反應,再與通式(IA)化合物在鹼性溶液中發生偶聯反應而得到通式(I)化合物。其中:A,n和R5 ~R11 的定義如申請專利範圍1中所述。A method of preparing a compound of the general formula (I) of claim 1 of the patent, the method comprising: The substituted aniline compound is subjected to a diazotization reaction with sodium nitrite in an acidic solution, and a coupling reaction with a compound of the formula (IA) in an alkaline solution is carried out to obtain a compound of the formula (I). Wherein: A, n and R 5 to R 11 are as defined in Patent Application No. 1. 一種申請專利範圍第1至4項中任一項的化合物或其鹽 的用途,其係用於製備血小板生成素(TPO)受體激動劑。 A compound or a salt thereof according to any one of claims 1 to 4 The use thereof is for the preparation of a thrombopoietin (TPO) receptor agonist. 一種申請專利範圍第1至4項中任一項的化合物或其鹽的用途,其係用於製備治療血小板減少症藥物。 Use of a compound of any one of claims 1 to 4, or a salt thereof, for the manufacture of a medicament for treating thrombocytopenia. 如申請專利範圍第8項的用途,其中該藥物係進一步與選自下列的藥物合併使用者:集落刺激因數、細胞因數、趨化因數、白細胞介素或細胞因數受體激動劑或拮抗劑、可溶的受體、受體激動劑或拮抗劑抗體或與一個或多個與該藥物具有相同的作用機制的肽或小分子類物質。 The use of claim 8 wherein the drug is further combined with a drug selected from the group consisting of: colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonist, A soluble receptor, receptor agonist or antagonist antibody or a peptide or small molecule substance having one or more of the same mechanisms of action as the drug. 一種醫藥組合物,該組合物包括有效劑量的申請專利範圍第1至4項中任一項的化合物及其藥學上可以接受的鹽,及藥學上可以接受的載體。 A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 4, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 如申請專利範圍第10項的醫藥組合物,其中該組合物進一步含有合併使用的治療有效量的選自下列的藥物:集落刺激因數、細胞因數、趨化因數、白細胞介素或細胞因數受體激動劑。 The pharmaceutical composition of claim 10, wherein the composition further comprises a therapeutically effective amount of a drug selected from the group consisting of: colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor Agonist. 一種申請專利範圍第10項的醫藥組合物的用途,其係用於製備治療血小板減少症藥物。 A use of a pharmaceutical composition according to claim 10 for the preparation of a medicament for treating thrombocytopenia.
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