CN101003537A - Derivative in pyrrolopyridazine category, preparation method, and application - Google Patents
Derivative in pyrrolopyridazine category, preparation method, and application Download PDFInfo
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Abstract
This invention relates to a kind of pyrropyridazine derivatives shown in general formula (I), their preparation method, drug composition containing the derivatives, and their application as tyrosine kinase inhibitor. The substituents shown in general formula (I) are defined in the description book.
Description
Technical field
The pharmaceutical composition that the present invention relates to a kind of new Pyrrolopyridazine analog derivative, its preparation method and contain this derivative with and as therapeutical agent particularly as the purposes of tyrosine kinase inhibitor.
Background technology
(Protein kinases PKs) has important effect to protein kinase in the signal conductive process.It can be transferred to γ-phosphate of ATP on the particular amino acid residue of functional protein, causes a series of biological respinses.According in the phosphorylation process as the amino acid classification of substrate, protein kinase can be divided into serine-threonine kinase (STKs) and Tyrosylprotein kinase (PTKs).
Nearly 100 kinds of protein tyrosine kinases (protein tyrosine kinases) have been determined aminoacid sequence (Hanks and Hunter, 1995, FASEB J.9:576-596), and appreciable amt may reach 1000 kinds.
Tyrosine phosphorylation mechanism is prevalent in the signal conductive process, is regulating and control such as various kinds of cell function (Hanks and Hunter, 1995, FASEB J. 9:576-596 such as mitotic division, cell cycle progression and differentiation; Cadena and Gill, 1992, FASEB J. 6:2332-2337; Schlessinger and Ullrich, 1992, Neuron 9:383-391; Vandergeer et al., 1994, Annu. Rev. Cell Biol.10:251-337).When protein tyrosine kinase is expressed under variation, situation out of control, or when under abnormal high level, expressing, normal cell can be transformed into tumour phenotype (neoplastic phenotype) (Chiaoet al., 1994, Cancer Metast. Rev. 9:63-80; Hunter, 1991, Cell 64:249-270).
The most cells growth factor receptors contains the peptide chain-ordering of Tyrosylprotein kinase, the overexpression of visible different tyrosine kinase receptors or excessive activation in many tumours, as the overexpression of common EGFR family in the epithelial cell tumour, the overexpression of the growth factor receptors (PDGFR) in common thrombocyte source etc. in the glioma.Similarity and some other structural characteristics according to the peptide chain-ordering, these acceptors are divided into some families: be the receptor family of representative with EGF-R ELISA (EGFR) 1), comprise EGFR, HER2, HER3 and HER4 etc., the high expression level of this receptoroid is common in the epithelial cell tumour; 2) Insulin Receptor Family comprises insulin receptor, IGF-1 (IGF-R) and Regular Insulin associated receptor (IRR) etc., the high expression level of common this receptoroid in leukemia; 3) platelet-derived growth factor receptors (PDGFR) family comprises PDGFR
α, PDGFR
β, clone's stimulating factor (CSF-1R), c-Kit etc., this receptoroid is common high expression level in cerebral tumor and leukemia; 4) bfgf receptor (FGFR) includes FGFR1, FGFR2, and FGFR3, FGFR4 and keratinocyte growth factor acceptor etc., this receptoroid plays an important role aspect vasculogenesis; 5) vascular endothelial growth factor receptor (VEGFR) is the important positivity regulatory factor of vasculogenesis; In addition, also have hepatocyte growth factor receptor (HGFR) class, Fibronectin III receptor class and the tame same clan of nerve growth factor acceptor (NGFR).Tyrosine kinase receptor overexpression in different types of tumors respectively causes the interior abnormal signal of its cell to activate, and causes cell transformation, constantly breeds, and promotes generation, the development of tumour, resists apoptosis, upsets the growth balance of cell.Therefore, target tyrosine kinase signal approach is good antitumor strategy.
(Epidermal Growth Factor Receptor, EGFR) family's (comprising EGFR, HER2, HER3 and HER4 etc.) is the more Tyrosylprotein kinase of a class research to EGF-R ELISA.Become the important target spot direction of anticancer therapy in recent years.Clinical proof, EGFR has high expression level in the various human cancer, and their expression level is relevant with phenomenons such as cancer cell multiplication, transfers.This provides the thinking of the new anticancer means of searching, and promptly seeking with the EGFR Tyrosylprotein kinase is the inhibitor of target spot.
Up to the present, EGFR inhibitor Gefitinib (Gefitinib, US 5770599, WO 0205791) and Erlotinib hydrochlorib (WO 9630347, US 6476040) go on the market, Gefitinib is applicable to treats local late period or the transitivity nonsmall-cell lung cancer (NSCLC) of previously accepting chemotherapy or being unsuitable for chemotherapy, the two wires or the three-way treatment plan of the advanced NSCLC that drugs approved by FDA erlotinib effect standard scheme is failed to respond to any medical treatment.Also have some other micromolecular compound to enter I, II, III phase clinical study stage as tyrosine kinase inhibitor.The information of comprehensive above EGFR inhibitor has designed and synthesized the Pyrrolopyridazine analog derivative shown in the following general formula of a class (I):
In existing technology, 4-amino-pyrroles and pyridazine compound that N-replaces, for example: Margaret Abbott share limited two closes the patent CN-1390220A (WO0119828A1) of department application, discloses main structure and is pyrrolo-[2,3d] pyridazine and at 4 bit strips amino substituent compound has been arranged; The patent CN-1279682A of Hoffman-Laluoai Ltd (WO9920624A), the compound that discloses Pyrrolopyridazine and be agent structure can be as kinase inhibitor; The patent CN-1143964A of Sankyo Co., Ltd (WO9519980A1), CN-1422272A (WO0158901A), CN-1370172A (WO0077003A) have announced the Pyrrolopyridazine compounds with gastric acid secretion inhibiting activity and anti-microbial activity.But all there are deficiency in various degree in the activity, the solvability that relate to this compounds in the prior art.
Summary of the invention
In order to overcome the deficiencies in the prior art part, the object of the present invention is to provide the new Pyrrolopyridazine compounds shown in a kind of general formula (I), and their tautomer, enantiomorph, diastereomer, raceme and pharmacy acceptable salt, and meta-bolites and metabolic precursor thereof or prodrug.
Wherein:
X is selected from W (CH
2), (CH
2) W or W, wherein W is O, S, SO, SO
2Or-NR
8(R wherein
8Be hydrogen atom or alkyl);
When X is-NR
8, R
8Be alkyl, R then
8Can form 4～8 yuan of heterocyclic radicals with R1; Wherein can contain one or more N, O, S atom in 5～8 yuan of heterocycles, and can be further on 4～8 yuan of heterocycles by one or more alkyl, halogen, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR
5R
6Replace;
R
1Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl can be further by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, alkoxyl group, aryloxy, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR
5R
6Replace; Wherein aryl, heteroaryl, aralkyl or heteroaralkyl can and become dicyclo;
R
2Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl can be further by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, alkoxyl group, aryloxy, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR
5R
6Replace;
R
3Be selected from hydrogen atom, alkyl ,-C (=O) R
7,-C (=S) R
7,-NC (=O) R
7,-(CH
2)
nO (C=O) R
7,-(CH
2)
nO (C=S) R
7,-(CH
2)
nR
7,-(CH
2CH
2O)
nR
8
R
4Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl ,-(CH
2CH
2O)
nR
8, alkenyl or alkynyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, alkenyl or alkynyl can further be replaced by one or more alkyl, hydroxyl, alkoxyl group, cyano group, amino, alkylamino, carboxylic acid or carboxylicesters;
R
5And R
6Be selected from respectively and be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or heteroaralkyl respectively, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or heteroaralkyl can further be replaced by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid or carboxylicesters;
Simultaneously, R
5And R
6Can form 4～8 yuan of heterocyclic radicals; Wherein can contain one or more N, O, S atom in 5～8 yuan of heterocycles, and can be further on 4～8 yuan of heterocycles by one or more alkyl, halogen, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, amino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR
5R
6Replace;
R
7Be selected from hydroxyl, alkoxyl group, aryloxy, heterocycle alkoxyl group, aralkoxy ,-N (R
8) (CH
2)
nR
9,-NR
8[CH
2CH
2O]
nR
8,-NR
5R
6Perhaps-NR
8(CH
2)
n[CH (OH) CH
2]
rZ, wherein Z be aryl, heteroaryl, Heterocyclylalkyl ,-NR
5R
6,-COOR
8Or CONR
5R
6
R
8Be selected from hydrogen atom or alkyl;
R
9Be selected from-NR
5R
6, hydroxyl, aryl, heteroaryl, alkoxyl group ,-O[CH
2CH
2O]
rR
8,-N
+(O
-) R
5R
6,-N (OH) R
5,-NHC (O) R
10Or-COR
10(R wherein
10Be alkyl, haloalkyl or aralkyl);
R
10Be alkyl, haloalkyl or aralkyl
N is 1～6;
R is 1～2.
In the described compound or its salt of general formula of the present invention (I), preferably X is W (CH
2), (CH
2) W or W, wherein W is O; In addition, more preferably wherein X be W (CH
2), (CH
2) W or W, wherein W is S, SO or SO
2
In the described compound or its salt of general formula of the present invention (I), more preferably X is NR
8, R wherein
8Be hydrogen atom or C
1～C
8Alkyl,
In the described compound or its salt of general formula of the present invention (I), R preferably
2It is methyl.
In the described compound or its salt of general formula of the present invention (I), R preferably
4Be hydrogen atom or alkyl, more preferably R
4It is methyl.
The synthetic method of The compounds of this invention
In order to finish purpose of the present invention, the present invention adopts following technical scheme:
The preparation method of the described compound or its salt of general formula of the present invention (I) may further comprise the steps:
Wherein, with general formula (I)-a raw material pyrrole derivatives ceric ammonium nitrate oxidation, general formula (I)-c compound that the compound of gained general formula (I)-b obtains with the hydrazine hydrate cyclization again obtains the compound of general formula (I)-d with the phosphorus oxychloride halo;
The compound of general formula (I)-e that the compound of general formula (I)-d is obtained through the amido nucleophilic substitution, the compound hydrolysis of general formula (I)-e is got the compound of general formula (I)-f, the compound of general formula (I)-f is contracted again and becomes the amidated compound, make the compound shown in the general formula (I).
In brief,, use the hydrazine hydrate cyclization again with the ceric ammonium nitrate oxidation of raw material pyrrole derivatives, the phosphorus oxychloride halo, the amido nucleophilic substitution, hydrolysis is contracted and is become these a few step reactions of acid amides, finally makes compound shown in the general formula I.
Showing as with prior art that beneficial effect of the present invention is outstanding compared, the compound that compound of the present invention and prior art relate to and structure be not quite similar, particularly substituent introducing on the R2 position has all had very big improvement to activity, the solvability of this compounds.
The present invention relates to a kind of pharmaceutical composition, its contain the treatment effective dose according to any one described compound or its salt and pharmaceutical carriers in the claim 1～5, general formula compound perhaps of the present invention or its salt purposes in preparation tyrosine kinase inhibitor medicine.In other words, the present invention also provides the above-claimed cpd that contains medicine effective dose composition, and described compound and/or the purposes of pharmaceutical composition in the preparation tyrosine kinase inhibitor that contain this compound.
Embodiment
Be used to further describe the present invention below in conjunction with embodiment, but these embodiment and unrestricted scope of the present invention.
Embodiment
The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.The mensuration of NMR is that measuring solvent is deuterochloroform (CDCl with Bruker AVANCE-400 nuclear magnetic resonance spectrometer
3), deuterated dimethyl sulfoxide (DMSO-D
6), in be designated as trimethyl silane (TMS), chemical shift is with 10
-6(ppm) provide as unit.
The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph.
Average inhibiting rate of kinases and IC
50The mensuration of value is with NovoStar microplate reader (German BMG company)
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate
Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.
DMSO-D
6: deuterated dimethyl sulfoxide;
CDCl
3: deuterochloroform;
Embodiment 1
4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(4-(morphine quinoline-4-yl)-piperidyl) formyl
Amine
The first step
5-formyl radical-3-methyl isophthalic acid H-pyrroles-2, the 4-ethyl dicarboxylate
With 3; 5-dimethyl-1H-pyrroles-2; 4-ethyl dicarboxylate 1a (4.79g; 20mmol) be dissolved in the tetrahydrofuran (THF) (100mL); the mixed solvent that adds acetate (120mL) and water (100mL) again; (44.4g 81mmol), reacts after 1.5 hours stirring at room property adding next time ceric ammonium nitrate; in system, add water (200mL); with dichloromethane extraction reaction solution (100mL * 3), merge organic phase, organic phase with saturated sodium bicarbonate solution clean to the pH value be meta-alkalescence; wash (25mL * 1) with saturated nacl aqueous solution again; the dichloromethane layer anhydrous magnesium sulfate drying filters, and filtrate decompression concentrates; with silica gel column chromatography purifying gained resistates; obtain title product 5-formyl radical-3-methyl isophthalic acid H-pyrroles-2,4-ethyl dicarboxylate 1b (2.544g, off-white color solid).Productive rate: 65.09%.
MS：254.2(M-1)。
1HNMR：(CDCl
3，400MHz)10.269(s，1H，-CHO)，9.915(s，1H，-NH)，4.417～4.356(m，4H，2×-CH
2-)，2.600(s，3H，CH
3)，1.411～1.352(q，6H，2×-CH
3)。
Second step
3-methyl-4-carbonyl-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester
Under the room temperature; with 5-formyl radical-3-methyl isophthalic acid H-pyrroles-2,4-ethyl dicarboxylate 1b (2.544g, 10mmol;) be dissolved in the acetate (43mL); (0.65mL 11mmol), has yellow mercury oxide to generate to the hydrazine hydrate solution of adding 85% under stirring; continue to stir; be heated to 100 ℃ of reactions 2 hours, reaction solution be cooled to room temperature, standing over night.Next day, decompress filter, solid drying obtains title product 3-methyl-4-carbonyl-3a, and 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 1c (1.74g, yellow powder shape solid).Productive rate: 78.73%.
MS：222.2(M+1)。
HNMR：(DMSO-D
6，400MHz)8.091(s，1H，ArH)，4.345(q，2H，J＝7.2Hz，-CH
2-)，2.629(s，3H，CH
3)，1.350(t，3H，J＝7.2Hz，-CH
3)。
The 3rd step
3-methyl-4-chloro-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester
Under the nitrogen atmosphere, in the three-necked bottle of 100mL, with 3-methyl-4-carbonyl-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 1c (553mg, 2.5mmol) be dissolved in anhydrous acetonitrile (15mL), the anhydrous phosphorus oxychloride of slow dropping under the stirring at room (0.465mL, 5mmol), after dropwising, reflux is reacted gradually to yellow solid 1c and is dissolved as yellow solution, continues to reflux 0.5 hour.Reaction solution is moved in the eggplant-shape bottle of 100mL, vacuum rotary steam is removed acetonitrile, adds normal hexane (10mL) again in reaction system, and decompression is spin-dried for, triplicate (removing remaining phosphorus oxychloride).Obtain title product 3-methyl-4-chloro-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 1d (yellow solid), standby, directly do next step.
But this step is purifying also, this solid is placed the eggplant-shape bottle of 50mL, add tetrahydrofuran (THF) (8mL), room temperature condition stirred 30 minutes down, filter, get title product 3-methyl-4-chloro-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester yellow solid 1d (569mg, light yellow solid), productive rate: 94-9%.
MS：240.4(M+1)。
1HNMR：(DMSO-D
6，400MHz)9.506(s，1H，ArH)，4.432(q，2H，J＝7.2Hz，-CH
2-)，2.767(s，3H，CH
3)，1.392(t，3H，J＝7.2Hz，-CH
3)。
The 4th step
4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride
3-methyl-4-chloro-3a, 4,5 have been taken advantage of in the 3rd step, following directly adding Virahol (15mL) of stirring and 3-chloro-4-fluoro-aniline in the eggplant-shape bottle of 7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester yellow solid 1d (546mg, 3.75mmol), reflux, some plate track to raw material and disappear.Reaction solution is cooled to room temperature, continuation is cooled off with ice-water bath and is stirred, there is yellow solid to produce, decompress filter, solid washs with amount of ethyl acetate, and vacuum-drying obtains title product 4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride 1e (440mg, yellow powder shape solid).Productive rate: 50.4%.
MS：349.2(M+1)。
The 5th step
4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid
In the 100mL eggplant-shape bottle, (440mg 1.26mmol) is dissolved in the ethanol (30mL) under stirring with 4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester 1e, add sodium hydroxide solution (5mL again, 1mol/L), reflux, the some plate tracks to raw material and disappears, reaction solution is cooled to ambient temperature overnight, vacuum rotary steam is removed ethanol, stirs and uses 1N hydrochloric acid soln adjust pH to 2 down, has a large amount of solids to separate out.Decompress filter, the solid distilled water wash, drying obtains title product 4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 1f (367mg, yellow solid).Productive rate: 91%.
MS：319.7(M-1)。
The 6th step
4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(4-(morphine quinoline-4-yl)-piperidyl) methane amide
In the eggplant-shape bottle of a 100mL, add 4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 1f (320mg, 1mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (288mg, 1.5mmol), I-hydroxybenzotriazole (203mg, 1.5mmo) and N ' dinethylformamide (30mL), after being stirred to dissolving, add triethylamine (0.35mL, 2.5mmol), stir and add 4-(morphine quinoline-4-yl)-piperidines (255mg after 5 minutes, 1.5mmol), stir under the room temperature and spend the night, the point plate is monitored to raw material and is disappeared, reaction solution is poured in the frozen water (200mL), with ethyl acetate extraction reaction solution (80mL * 4), merge organic phase, organic phase is washed (25mL * 1) with saturated nacl aqueous solution, the ethyl acetate layer anhydrous magnesium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates, obtain title product 4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(4-(morphine quinoline-1-yl)-piperidyl) methane amide 1 (43mg, yellow solid).Productive rate: 9%.
MS：473.4(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.887(s，1H，-ArH)，7.995(d，1H，-ArH)，7.619(t，1H，-ArH)，7.366～7.320(q，1H，-ArH)3.571(s，4H，-OCH
2-)，3.447(s，9H，-NCH
2-，-NCH-)2.468(s，3H，-CH
3)，1.844～1.834(m，2H，-CH
2-)，1.379～1.351(m，2H，-CH
2-)。
Embodiment 2
4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin ethyl) methane amide
Repeat the embodiment of the invention reaction in five steps of 1 the first step to the, use resulting compound 4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2 in above-mentioned the 5th step, 3-d] and pyridazine-2-formic acid 1f make raw material, carry out the reaction of this raw material and diethyl ethylenediamine according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin ethyl) methane amide 2 (239mg, light yellow solid).Productive rate: 38%.
MS：419.3(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.913(s，1H，-ArH)，7.983(d，1H，-ArH)，9.604(d，1H，-ArH)，7.365～7.320(t，1H，-ArH)，3.390(t，2H，-CH
2-)，2.706(s，3H，-CH
3)，2.638(t，2H，-CH
2-)，2.574(m，4H，2×-CH
2-)，1.002(t，6H，2×-CH
3)。
Embodiment 3
4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-morphine quinoline-4 bases-ethyl) methane amide
Repeat the embodiment of the invention reaction in five steps of 1 the first step to the, use resulting compound 4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2 in above-mentioned the 5th step, 3-d] and pyridazine-2-formic acid 1f make raw material, carry out the reaction of this raw material and morphine quinoline-4 bases-quadrol according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-(3-chloro-4-fluoro-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-morphine quinoline-4 bases-ethyl) methane amide 3 (248mg, yellow solid).Productive rate: 38.4%.
MS：433.3(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.917(s，1H，-ArH)，7.989(d，1H，-ArH)，7.624(d，1H，-ArH)，7.368～7.322(t，1H，-ArH)，3.595(t，4H，-CH
2-)，3.425(t，2H，-CH2-)，2.714(s，3H，-CH
3)，2.501(t，2H，-CH2-)，2.435(s，4H，2×-CH
2-)。
Embodiment 4
4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin ethyl) methane amide
The first step
4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride
Third and fourth goes on foot described same procedure according to embodiment 1, under the nitrogen atmosphere, in the three-necked bottle of 100mL, with 3-methyl-4-carbonyl-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 1c (1-549g, 7mmol) be dissolved in the anhydrous acetonitrile (50mL), slowly drip anhydrous phosphorus oxychloride (1.3mL) under the stirring at room, after dropwising, reflux is reacted gradually to yellow solid 1c and is dissolved as orange-red solution, continues to reflux 30 minutes.Reaction solution is moved in the eggplant-shape bottle of 150mL, vacuum rotary steam is removed acetonitrile, adds normal hexane (10mL) again in reaction system, and decompression is spin-dried for, triplicate (removing remaining phosphorus oxychloride).Obtain 3-methyl-4-chloro-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 1d (yellow solid) directly add a Virahol (35mL) and an ethynyl aniline (0.9g in this eggplant-shape bottle, 7.7mmol), reflux 3 hours, the some plate tracks to raw material and disappears.Reaction solution is cooled to room temperature, continuation is cooled off with ice-water bath and is stirred, there is yellow solid to produce, decompress filter, solid is with a spot of ethyl acetate and washing with alcohol, and infrared drying obtains title product 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride 4a (1.194g, yellow solid).Productive rate: 44.22%.
MS(M+1)：321.3。
Second step
4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid
According to described same way as of the 5th step of the embodiment of the invention 1, use 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride 4a make raw material, make this title product 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 4b (970mg, yellow solid).
MS：219.3(M+1)。
The 3rd step
4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin ethyl) methane amide
According to described same way as of the 6th step of the embodiment of the invention 1, use 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 4b make raw material, carry out the reaction of this raw material and diethyl ethylenediamine, then obtain title product 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin ethyl) methane amide 4 (253mg, white solid).Productive rate: 43.2%.
MS：391.5(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.913(s，1H，-ArH)，7.884(s，1H，-ArH)，7.660(d，1H，-ArH)，7.311(t，1H，-ArH)，7.068(d，1H，-ArH)，4.082(s，1H，-C≡H)，3.373(t，2H，-CH
2-)，2.696(s，3H，-CH
3)，2.596(t，2H，-CH
2-)，2.579～2.513(m，4H，2×-CH
2-)，0.987(t，6H，2×-CH
3)。
Embodiment 5
4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(4-(morphine quinoline-4-yl)-piperidyl) methane amide
Repeat the reaction in step of the embodiment of the invention 4 the first steps to the second, use resulting compound 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2 in above-mentioned second step, 3-d] and pyridazine-2-formic acid 4b make raw material, carry out the reaction of this raw material and 4-(morphine quinoline-4-yl)-piperidines according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(4-(morphine quinoline-4-yl)-piperidyl) methane amide 5 (122mg, orange/yellow solid).Productive rate: 20%.
MS：445.5(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.895(s，1H，-ArH)，7.854(s，1H，-ArH)，7.670(d，1H，-ArH)，7.315(t，1H，-ArH)，7.066(d，1H，-ArH)，4.101(s，1H，-C≡H)，3.583(s，4H，-OCH
2-)，3.470(s，9H，-NCH
2-，-NCH-)，2.456(s，3H，-CH
3)，1.902～1.856(m，2H，-CH
2-)，1.384～1.357(m，2H，-CH
2-)。
Embodiment 6
4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-Pyrrolizidine-1-yl)-ethyl) methane amide
Repeat the reaction in step of the embodiment of the invention 4 the first steps to the second, use resulting compound 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2 in above-mentioned second step, 3-d] and pyridazine-2-formic acid 4b make raw material, carry out the reaction of this raw material and 2-(Pyrrolizidine-1-yl)-ethamine according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-Pyrrolizidine-1-yl)-ethyl) methane amide 6 (405mg, light yellow solid).Productive rate: 57.9%.
MS：389.6(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.960(s，1H，-ArH)，7.838(s，1H，-ArH)，7.661(d，1H，-ArH)，7.329(t，1H，-ArH)，7.093(d，1H，-ArH)，4.116(s，1H，-C≡H)，3.651(t，2H，-CH
2-)，3.352(t，2H，-CH
2-)，2.728(s，3H，-CH
3)，2.535～2.505(m，4H，2×-CH
2-)，2.019～1.957(m，4H，2×-CH
2)。
Embodiment 7
4-(3-alkynyl-aniline-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-morphine quinoline-4-yl)-ethyl) methane amide
Repeat the reaction in step of the embodiment of the invention 4 the first steps to the second, use resulting compound 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2 in above-mentioned second step, 3-d] and pyridazine-2-formic acid 4b make raw material, carry out the reaction of this raw material and (2-morphine quinoline-4-yl)-ethamine according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-morphine quinoline-4-yl)-ethyl) methane amide 7 (139mg, yellow solid).Productive rate: 23%.
MS：405.3(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.922(s，1H，-ArH)，7.853(s，1H，-ArH)，7.670(d，1H，-ArH)，7.314(t，1H，-ArH)，7.073(d，1H，-ArH)，4.087(s，1H，-C≡H)，3.604～3.584(t，4H，2×-CH
2-)，3.424(q，2H，-CH
2-)，2.701(s，3H，-CH
3)，2.513(s，2H，-CH
2-)，2.446(q，4H，2×-CH
2-)。
Embodiment 8
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-Pyrrolizidine-1-yl)-ethyl)
Methane amide
The first step
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride
Third and fourth goes on foot described same way as according to embodiment 1, under the nitrogen atmosphere, in the three-necked bottle of a 50mL, with 3-methyl-4-carbonyl-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 1c (443mg 2mmol) is dissolved in the anhydrous acetonitrile (15mL), slowly drips anhydrous phosphorus oxychloride (0.372mL under the stirring at room, 4mmol), after dropwising, reflux is reacted gradually to yellow solid 1c and is dissolved as yellow solution, continues to reflux 30 minutes.Reaction solution is moved in the eggplant-shape bottle of 100mL, vacuum rotary steam is removed acetonitrile, in reaction system, add normal hexane (10mL) again, decompression is spin-dried for, and triplicate (removing remaining phosphorus oxychloride) obtains 3-methyl-4-chloro-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 1d (yellow solid).In this eggplant-shape bottle, directly add Virahol (15mL) and 3-chloro-4-(3-fluorine benzyloxy)-anilinechloride (0.576g, 2.0mmo) and triethylamine (0.3mL, 2.2mmol), reflux 3 hours, the some plate tracks to the raw material disappearance.Reaction solution is cooled to room temperature, continuation is cooled off with ice-water bath and is stirred, there is yellow solid to produce, decompress filter, the a spot of washed with isopropyl alcohol of solid, drying obtains title product 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride 8a (0.445g, yellow solid).Productive rate: 45.4%.This solid is placed the 50mL eggplant-shape bottle, add methyl alcohol (10mL), regulating PH with strong aqua is 9, room temperature condition stirs 5min down, filter, get 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester (light yellow solid).
MS(M+1)：455.3。
Second step
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid
According to described same way as of the 5th step of the embodiment of the invention 1, use 4-(3-alkynyl-aniline)-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride 8a make raw material, make this title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 8b.
MS：427.3(M+1)。
The 3rd step
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-Pyrrolizidine-1-yl)-ethyl) methane amide
According to described same way as of the 6th step of the embodiment of the invention 1, use 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 8b make raw material, carry out the reaction of this raw material and 2-(Pyrrolizidine-1-yl)-ethamine, then obtain title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-Pyrrolizidine-1-yl)-ethyl) methane amide 8 (80mg, khaki color solid).Productive rate: 17.3%.
MS：523.5(M+1)。
LC-MS：98.3％。
1HNMR：(DMSO-D
6，400MHz)8.866(s，1H，-ArH)，7.886(s，1H，-ArH)，7.547(d，1H，-ArH)，7.494～7.439(m，1H，-ArH)，7.337～7.288(m，2H，-ArH)，7.205～7.146(m，2H，-ArH)，5.219(s，2H，-CH
2-)，3.426(t，2H，-CH
2-)
2.698(s，3H，-CH
3)，2.630(t，2H，-CH
2-)，2.522～2.509(m，4H，2×-CH
2-)，1.706(s，4H，2×-CH
2)。
Embodiment 9
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(3-morphine quinoline-4-base-propyl group) first
Acid amides
Repeat the reaction in step of the embodiment of the invention 8 the first steps to the second, use resulting compound 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline in above-mentioned second step]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 8b make raw material, carry out the reaction of this raw material and (3-morphine quinoline-4-yl)-propylamine according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(3-morphine quinoline-4-base-propyl group) methane amide 9 (174mg, light yellow solid).Productive rate: 35%.
MS：553.4(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.864(s，1H，-ArH)，7.896(s，1H，-ArH)，7.549(d，1H，-ArH)，7.494～7.439(m，1H，-ArH)，7.337～7.287(m，2H，-ArH)，7.206～7.152(m，2H，-ArH)，5.220(s，2H，-CH
2-)，3.357(t，4H，2×-CH
2-)，3?333(t，2H，-CH
2-)，2.687(s，3H，-CH
3)，2.368～2.335(m，6H，3×-CH
2-)，1.720(t，2H，-CH
2-)。
Embodiment 10
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin-ethyl) formyl
Amine
Repeat the reaction in step of the embodiment of the invention 8 the first steps to the second, use resulting compound 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline in above-mentioned second step]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 8b make raw material, carry out the reaction of this raw material and diethyl ethylenediamine according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin-ethyl) methane amide 10 (234mg, light yellow solid).Productive rate: 34.9%.
MS：525.3(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.863(s，1H，-ArH)，7.882(s，1H，-ArH)，7.557(d，1H，-ArH)，7.495～7.440(m，1H，-ArH)，7.338～7.288(m，2H，-ArH)，7.205～7.147(m，2H，-ArH)，5.220(s，2H，-CH
2-)，3.377(t，2H，-CH
2-)，2.703(s，3H，-CH
3)，2.615(t，2H，-CH
2-)，2.580～2.514(m，4H，2×-CH
2-)，0.994(t，6H，2×-CH
3)。
Embodiment 11
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-Pyrrolizidine-1 base-methyl-pyrrole
Cough up pyridine-1-yl) methane amide
Repeat the reaction in step of the embodiment of the invention 8 the first steps to the second, use resulting compound 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline in above-mentioned second step]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 8b make raw material, carry out the reaction of this raw material and 2-Pyrrolizidine-1 base-methyl-Pyrrolizidine according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-Pyrrolizidine-1 base-methyl-Pyrrolizidine-1-yl) methane amide 11 (100mg, orange/yellow solid).Productive rate: 18%.
MS：563.5(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.837(s，1H，-ArH)，7.900(s，1H，-ArH)，7.551(d，1H，-ArH)，7.491～7.436(m，1H，-ArH)，7.335～7.285(m，2H，-ArH)，7.200～7.142(m，2H，-ArH)，5.216(s，2H，-CH
2-)，3.460～1.158(m，20H，-CH-)。
Embodiment 12
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(4-(morphine quinoline-4-yl)-piperidines
Base) methane amide
Repeat the reaction in step of the embodiment of the invention 8 the first steps to the second, use resulting compound 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline in above-mentioned second step]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 8b make raw material, carry out the reaction of this raw material and 4-(morphine quinoline-4-yl)-piperidines according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(4-(morphine quinoline-4-yl)-piperidyl) methane amide 12 (31mg, orange/yellow solid).Productive rate: 7%.
MS：579.6(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.837(s，1H，-ArH)，7.885(s，1H，-ArH)，7.543(d，1H，-ArH)，7.491～7.437(m，1H，-ArH)，7.334～7.285(m，2H，-ArH)，7.202～7.143(m，2H，-ArH)，5.215(s，2H，-CH
2-)，3.572(s，4H，-OCH
2-)，3.453(s，9H，4×-NCH
2-，-NCH-)，2.455(s，3H，-CH
3)，1.851(s，2H，-CH
2-)，1.413～1.306(m，2H，-CH
2-)。
Embodiment 13
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-morphine quinoline-4-base-ethyl) first
Acid amides
Repeat the reaction in step of the embodiment of the invention 8 the first steps to the second, use resulting compound 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline in above-mentioned second step]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-formic acid 8b make raw material, carry out the reaction of this raw material and 2-morphine quinoline-4-base-ethamine according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-morphine quinoline-4-base-ethyl) methane amide 13 (176mg, yellow solid).Productive rate: 30.2%.
MS：539.4(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.868(s，1H，-ArH)，7.893(s，1H，-ArH)，7.554(d，1H，-ArH)，7.493～7.438(m，1H，-ArH)，7.338～7.287(m，2H，-ArH)，7.205～7.144(m，2H，-ArH)，5.219(s，2H，-CH
2-)，3.595(t，4H，-CH
2-)，3.437(t，2H，-CH
2-)，2.712(s，3H，-CH
3)，2.496(t，2H，-CH
2-)，2.454～2.445(m，4H，2×-CH
2-)。
Embodiment 14
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-base-diethylin methyl-formiate
The first step
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-methyl alcohol
Under the nitrogen atmosphere, (120mg 3mmol) is dissolved in the tetrahydrofuran (THF) (30mL), stirs, and reaction system is emitted some bubbles, and is standby with tetrahydrochysene lithium aluminium.Then with 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester 8a (700mg, 1.5mmol) miscible in tetrahydrofuran (THF) (70mL), and this suspension slowly is added dropwise in the tetrahydrofuran solution of above-mentioned tetrahydrochysene lithium aluminium, reaction system becomes the muddy suspension of light green at once by the muddy suspension of original grey, continued back flow reaction 3.5 hours, the muddy suspension of visible green slowly becomes the muddy suspension of khaki color, and the some plate tracks to reaction to be finished.Add the shrend reaction of going out, the saturated common salt water washing, the organic layer drying is filtered, filtrate decompression concentrates, title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-methyl alcohol 14a (499mg), productive rate 81%.
MS(M+1)：413.4。
1HNMR：(DMSO-D
6，400MHz)8.795(s，1H，-ArH)，7.883(s，1H，-ArH)，7.521(d，1H，-ArH)，7.470～7.435(m，1H，-ArH)，7.333～7.284(m，2H，-ArH)，7.184～7.161(m，2H，-ArH)，5.205(s，2H，-CH
2-)，4.622s，2H，-CH
2-)，2.417(s，3H，-CH
3)。
Second step
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-base-diethylin methyl-formiate in the eggplant type bottle of a 50mL, with 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-methyl alcohol 14a (206mg, 0.5mmol) be dissolved in the N ' dinethylformamide (5mL) under stirring, take by weighing 55%～65% sodium hydride solid (26mg under the room temperature condition, 0.6mmol), slowly add in the preceding solution of ready-formed stirring at room 5 minutes.Then, slowly drip N ' the dinethylformamide solution (5mL) of diethylamine formyl chloride (82mg, 0.6mmol), solution becomes red-brown by yellow, and the some plate shows most of disappearance of raw material this moment, continues to stir at ambient temperature 3 hours.Stopped reaction is slowly poured reaction solution in the frozen water, has solid to produce, continue to stir 30 minutes, filter, obtain title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-base-diethylin methyl-formiate 14 (195mg, yellow solid).Productive rate 76%.
MS(M+1)：512.7。
1HNMR：(DMSO-D
6，400MHz)8.795(s，1H，-ArH)，7.883(s，1H，-ArH)，7.521(d，1H，-ArH)，7.470～7.435(m，1H，-ArH)，7.333～7.284(m，2H，-ArH)，7.184～7.161(m，2H，-ArH)，5.205(s，2H，-CH
2-)，4.622s，2H，-CH
2-)，2.417(s，3H，-CH
3)。
Embodiment 15
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-(2-diethylin-ethyl)
Methane amide
The first step
1,3,5-trimethylammonium-pyrroles-2,4-ethyl dicarboxylate
Under the nitrogen atmosphere, in 50mL eggplant type bottle, with 55%～65% sodium hydride (240mg, 5.5mmol) be dissolved in N ' dinethylformamide (5mL) under stirring, slowly add raw material 3,5-dimethyl-1H-pyrroles-2,4-ethyl dicarboxylate 1a (1.196g, 5mmol), stirred under the room temperature 10 minutes, then add methyl iodide (2.7mL, 53mmol), stirred overnight at room temperature, some plate are followed the tracks of reaction and are finished.Next day, reaction solution to be poured in the water, the adularescent solid is separated out, and filters, and the infrared oven dry of solid obtains title product 15a (1.086g, white solid).Productive rate 86%.
MS(M-1)：254.1。
Second step
5-formyl radical-3-methyl isophthalic acid-methyl-pyrroles-2, the 4-ethyl dicarboxylate
According to the described same way as of the embodiment of the invention 1 the first step; use resulting compound 1 in the above-mentioned the first step; 3; 5-trimethylammonium-pyrroles-2; 4-ethyl dicarboxylate 15a makes raw material; carry out the reaction of this raw material and ceric ammonium nitrate, then obtain title product 5-formyl radical-3-methyl isophthalic acid-methyl-pyrroles-2,4-ethyl dicarboxylate 15b (5.283g).Productive rate 45%.
MS：268.3(M+1)。
1HNMR：(CDCl
3，400MHz)10.376(s，1H，-CHO)，9.915(s，1H，-NH)，4.417～4.348(m，4H，2×-CH
2-)，4.173(s，3H，-NCH
3)2.493(s，3H，-CH
3)，1.424～1.370(q，6H，2×-CH
3)。
The 3rd step
3-methyl-4-carbonyl-3a, 4,5,7a-tetrahydrochysene-1-methyl-pyrroles [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester
According to described same way as of 1 second step of the embodiment of the invention; use resulting compound 5-formyl radical-3-methyl isophthalic acid-methyl-pyrroles-2 in above-mentioned second step; (3.24g 12mmol) makes raw material to 4-ethyl dicarboxylate 15b, carries out this raw material and hydrazine hydrate (0.72g; reaction 12mmol); then obtain title product 3-methyl-4-carbonyl-3a, 4,5; 7a-tetrahydrochysene-1-methyl-pyrroles [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 15c (2.272g).Productive rate 79.3%.
MS(M+1)：236.3。
1HNMR：(DMSO-D
6，400MHz)8.400(s，1H，ArH)，4.341(q，2H，J＝7.2?Hz，-CH
2-)，3.979(s，3H，-CH
3)，2.620(s，3H，CH
3)，1.351(t，3H，J＝7.2?Hz，-CH
3)
The 4th step
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride
Third and fourth goes on foot described same way as reaction according to the embodiment of the invention 1, use resulting compound 3-methyl-4-carbonyl-3a in above-mentioned the 3rd step, 4,5,7a-tetrahydrochysene-1-methyl-pyrroles [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 15c make raw material, obtain this title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride 15d (1.642g, white solid).Productive rate 79.7%.
MS(M+1)：468.9。
The 5th step
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-carboxylic acid
According to the described same way as reaction of the embodiment of the invention 1 the 5th step, use resulting compound 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline in above-mentioned the 4th step]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride make raw material.Obtain this title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-carboxylic acid 15e (1.410g, yellow solid).
MS：441.4(M+1)。
The 6th step
4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-(2-diethylin-ethyl) methane amide
According to the described same way as reaction of the 6th step of the embodiment of the invention 1, use resulting compound 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline in above-mentioned the 5th step]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-carboxylic acid 15e make raw material, obtain this title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-(2-diethylin-ethyl) methane amide 15 (41mg, beige circle).
MS：539.8(M+1)。
1HNMR：(DMSO-D6，400MHz)9.062(s，1H，-ArH)，7.899(d，1H，-ArH)，7.571～7.5432(dd，1H，-ArH)，7.492～7.438(m，1H，-ArH)，7.336～7.286(m，2H，-ArH)，7.202～7.150(m，2H，-ArH)，5.219(s，2H，-CH
2-)，3.827(s，3H，-CH
3)，3.394(t，2H，-CH
2-)，2.737～2.341(m，9H，-CH
3，3×-CH
2-)，0.990(t，6H，2×-CH
3)。
Embodiment 16
4-[3-chloro-4-(3-benzyl chloride oxygen)-aniline]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-(2-Pyrrolizidine-1-yl)-second
Base) methane amide
Repeat the embodiment of the invention reaction in five steps of 15 the first steps to the, use resulting compound 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline in above-mentioned the 5th step]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-carboxylic acid 15e make raw material, carry out the reaction of this raw material and 2-(Pyrrolizidine-1-yl)-ethamine according to described same way as of the 6th step of the embodiment of the invention 15, then obtain title product 4-[3-chloro-4-(3-fluorine benzyloxy)-aniline]-3-methyl isophthalic acid-methyl-pyrroles [2,3-d] and pyridazine-2-(2-Pyrrolizidine-1-yl)-ethyl) methane amide 16 (24mg, yellow solid).
MS：537.3(M+1)。
1HNMR：(DMSO-D
6，400MHz)9.074(s，1H，-ArH)，7.889(s，1H，-ArH)，7.565～7.545(m，1H，-ArH)，7.492～7.437(m，1H，-ArH)，7.335～7.284(m，2H，-ArH)，7.203～7.142(m，2H，-ArH)，5.218(s，2H，-CH
2-)，3.841(s，3H，-NCH
3)，3.557(t，2H，-CH
2-)，3.102～2.917(m，6H，3×-CH
2-)，2.554(s，3H，-CH
3)，1.181(s，4H，2×-CH
2)。
Embodiment 17
4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-(2-methoxyethyl) formyl
Amine
The first step
4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride
Third and fourth goes on foot described method according to embodiment 1, under the nitrogen atmosphere, in the three-necked bottle of a 50mL, with 3-methyl-4-carbonyl-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 1c (1.264g, 1.2mmol) be dissolved in the anhydrous acetonitrile (15mL), slowly drip under the stirring at room anhydrous phosphorus oxychloride (0.223mL, 2.4mmol) dropwise after, reflux is reacted gradually to yellow solid 1c and is dissolved as yellow solution, continues to reflux 30 minutes.Reaction solution is moved in the eggplant-shape bottle of 100mL, vacuum rotary steam is removed acetonitrile, adds normal hexane (10mL) again in reaction system, and decompression is spin-dried for, triplicate (removing remaining phosphorus oxychloride).Then in this eggplant-shape bottle, add Virahol (15mL) and 1-(3-luorobenzyl)-5-amino-1H-indazole (258mg, 1.07mmol) and triethylamine, reflux 3 hours, the some plate is followed the tracks of to react to raw material and is disappeared.Reaction solution is cooled to room temperature, continuation is cooled off with ice-water bath and is stirred, there is yellow solid to produce, decompress filter, the a spot of washed with isopropyl alcohol of solid, drying obtains title product 4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride 17a (0.329g, light yellow solid).Productive rate 66.5%.
MS(M+1)：445.2。
1HNMR：(DMSO-D
6，400MHz)8.828(s，1H，-ArH)，8.090(s，2H，-ArH)，7.684～7.662(m，1H，-ArH)，7.560～7.539(m，1H，-ArH)，7.393～7.338(m，1H，-ArH)，7.117～7.006(m，3H，-ArH)，5.683(s，2H，-CH
2-)，4.396(q，2H，-CH
2)，2.687(s，3H，-CH
3)，1.372(t，3H，-CH
3)。
Second step
4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid
According to described same way as of the 5th step of the embodiment of the invention 1, use 4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride make raw material, make title product 4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid 17b.MS：517.4(M+1)。
The 3rd step
4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-(2-methoxyethyl) methane amide
According to described same way as of the 6th step of the embodiment of the invention 1, use 4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid make raw material, carry out the reaction of this raw material and 2-methoxyethyl amine, then obtain title product 4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-(2-methoxyethyl) methane amide 17 (45mg, light yellow solid).Productive rate 8%.
MS：474.7(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.842(s，1H，-ArH)，8.080(s，2H，-ArH)，7.673～7.651(m，1H，-ArH)，7.567(m，1H，-ArH)，7.372～7.338(m，1H，-ArH)，7.119～7.007(m，3H，-ArH)，5.680(s，2H，-CH
2-)，3.501(t，2H，-CH
2)，2.723(s，3H，-CH
3)，2.515(t，2H，-CH
2)。
Embodiment 18
4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin-ethyl)
Methane amide
Repeat the reaction in step of the embodiment of the invention 17 the first steps to the second, use resulting compound 4-[1-(3-luorobenzyl)-1H-indazole-5-amino in above-mentioned second step]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid 17b make raw material, carry out the reaction of this raw material and diethyl ethylenediamine according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin-ethyl) methane amide 18 (90mg, light brown solid).Productive rate 13.5%.
MS：515.3(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.837(s，1H，-ArH)，8.092(s，2H，-ArH)，8.071(s，1H，-ArH)，7.660～7.638(m，1H，-ArH)，7.575～7.553(m，1H，-ArH)，7.392～7.336(m，1H，-ArH)，7.117～7.067(m，1H，-ArH)，7.045～7.001(m，2H，-ArH)，5.675(s，2H，-CH
2-)，3.367(t，2H，-CH
2)，2.712(s，3H，-CH
3)，2.610～2.504(m，6H，3×-CH
2-)，0.940(t，6H，2×-CH
3)
Embodiment 19
4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-[(2-Pyrrolizidine-1-yl)-
Ethyl] methane amide
Repeat the reaction in step of the embodiment of the invention 17 the first steps to the second, use resulting compound 4-[1-(3-luorobenzyl)-1H-indazole-5-amino in above-mentioned second step]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid 17b make raw material, carry out the reaction of this raw material and 2-(Pyrrolizidine-1-yl)-ethamine according to described same way as of the 5th step of the embodiment of the invention 1, then obtain title product 4-[1-(3-luorobenzyl)-1H-indazole-5-amino]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-[(2-Pyrrolizidine-1-yl)-ethyl] methane amide 19 (58mg, light yellow solid).Productive rate 9%.
MS：513.4(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.829(s，1H，-ArH)，8.072(s，2H，-ArH)，7.662～7.641(m，1H，-ArH)，7.561(m，1H，-ArH)，7.389～7.337(m，1H，-ArH)，7.113～7.005(m，3H，-ArH)，5.677(s，2H，-CH
2-)，3.937～0.853(m，15H，6×-CH
2-，-CH
3)。
Embodiment 20
4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin-ethyl)
Methane amide
The first step
4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride
Third and fourth goes on foot described method according to embodiment 1, under the nitrogen atmosphere, in the three-necked bottle of 50mL, with 3-methyl-4-carbonyl-3a, 4,5,7a-tetrahydro-1 H-pyrrolo [2,3-d] and pyridazine-2 carboxylic acid, ethyl ester 1c (1.1g 5mmol) is dissolved in anhydrous acetonitrile (35mL), slowly drips anhydrous phosphorus oxychloride (0.92mL under the stirring at room, 10mmol, 2eq) dropwise after, reflux is reacted gradually to yellow solid and is dissolved as yellow solution, continue to reflux 30 minutes.Reaction solution is moved in the eggplant-shape bottle of 100mL, vacuum rotary steam is removed acetonitrile, adds normal hexane (10mL) again in reaction system, and decompression is spin-dried for, triplicate (removing remaining phosphorus oxychloride).Then in this eggplant-shape bottle, add Virahol (30mL) and 3-chloro-4-(pyridine-2-methoxyl group)-aniline (1.056g, 4.5mmol) and triethylamine, reflux 12 hours, the some plate tracks to raw material and disappears.Reaction solution is cooled to room temperature, continuation is cooled off with ice-water bath and is stirred, there is yellow solid to produce, decompress filter, the a spot of washed with isopropyl alcohol of solid, drying obtains title product 4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride 20a (0.939g, yellow solid).Productive rate 42.9%.
MS(M+1)：438.4。
Second step
4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid
According to described same way as of the 5th step of the embodiment of the invention 1, use 4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid, ethyl ester hydrochloride 20a make raw material, make this title product 4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid 20b (0.686g, yellow solid).Productive rate 79.8%.
MS：410.4(M+1)。
The 3rd step
4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin-ethyl) methane amide
According to described same way as of the 6th step of the embodiment of the invention 1, use 4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid 20b make raw material, carry out the reaction of this raw material and diethyl ethylenediamine, then obtain title product 4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-(2-diethylin-ethyl) methane amide 20 (25mg, yellow solid).
MS：508.4(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.889(s，1H，-ArH)，8.593(d，1H，-ArH)，7.907～7.864(m，2H，-ArH)，7.581(d，1H，-ArH)，7.5?17(d，1H，-ArH)，7.391～7.358(m，1H，-ArH)，7.207(d，1H，-ArH)，5.261(s，2H，-CH
2-)，
3.636(t，2H，-CH
2)，2.736(s，3H，-CH
3)，2.518～2.509(m，6H，3×-CH
2-)，1.203(t，6H，2×-CH
3)。
Embodiment 21
4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-[(2-Pyrrolizidine-1-yl)-
Ethyl] methane amide
Repeat the reaction in step of the embodiment of the invention 20 the first steps to the second, use resulting compound 4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline in above-mentioned second step]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-carboxylic acid 20b make raw material, carry out the reaction of this raw material and 2-(Pyrrolizidine-1-yl)-ethamine according to described same way as of the 6th step of the embodiment of the invention 1, then obtain title product 4-[3-chloro-4-(pyridine-2-methoxyl group)-aniline]-3-methyl isophthalic acid H-pyrroles [2,3-d] and pyridazine-2-[(2-Pyrrolizidine-1-yl)-ethyl] methane amide 21 (46mg, yellow solid).
MS：506.7(M+1)。
1HNMR：(DMSO-D
6，400MHz)8.864(s，1H，-ArH)，8.589(d，1H，-ArH)，7.897～7.859(m，2H，-ArH)，7.585(d，1H，-ArH)，7.533(d，1H，-ArH)，7.383～7.352(m，1H，-ArH)，7.190(d，1H，-ArH)，5.253(s，2H，-CH
2-)，3.424(t，2H，-CH
2-)，2.699(s，3H，-CH
3)，2.626(t，2H，-CH
2-)，2.517～2.513(m，4H，2×-CH
2-)，1.704(s，4H，2×-CH
2)
Experimental example 1
The mensuration of kinase inhibiting activity
Use the K-LISA of CALBIOCHEM company
TMPTK Screening Kit (Cat.No.539701) and EGFR/HER-2 effect E
496 hole elisa plates of Y substrate bag quilt, kinases (rat spleenextract) 1 μ g is used in the reaction of every hole, using the inhibition compound concentration simultaneously is the basic parameter of the experiment condition of 50 μ M as the screening platform,, as positive control testing compound is screened with ZD6474.
After this, the working concentration gradient is to ZD6474, SHR114090, the IC of SHR114092
50Investigate.
The present invention records the average kinase inhibition rate of EGFR/HER-2 and the IC of compound
50Value sees Table 1
Average kinase inhibition rate of table 1 EGFR/HER-2 and IC
50Value
Claims (9)
1. one kind by general formula (I) expression Pyrrolopyridazine compounds or its salt:
Wherein:
X is selected from W (CH
2), (CH
2) W or W, wherein W is O, S, SO or SO
2Or-NR
8, R wherein
8Be hydrogen atom or alkyl;
When X is-NR
8, R
8Be alkyl, R then
8Can form 4～8 yuan of heterocyclic radicals with R1; Wherein can contain one or more N, O, S atom in 5～8 yuan of heterocycles, and can be further on 4～8 yuan of heterocycles by one or more alkyl, halogen, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR
5R
6Replace;
R
1Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl can be further by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, alkoxyl group, aryloxy, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR
5R
6Replace; Wherein aryl, heteroaryl, aralkyl or heteroaralkyl can and become dicyclo;
R
2Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl can be further by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, alkoxyl group, aryloxy, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR
5R
6Replace;
R
3Be selected from hydrogen atom, alkyl ,-C (=O) R
7,-C (=S) R
7,-NC (=O) R
7,-(CH
2)
nO (C=O) R
7,-(CH
2)
nO (C=S) R
7,-(CH
2)
nR
7Or-(CH
2CH
2O)
nR
8
R
4Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl ,-(CH
2CH
2O)
nR
8, alkenyl or alkynyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, alkenyl or alkynyl can further be replaced by one or more alkyl, hydroxyl, alkoxyl group, cyano group, amino, alkylamino, carboxylic acid or carboxylicesters;
R
5And R
6Be selected from respectively and be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or heteroaralkyl respectively, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or heteroaralkyl can further be replaced by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid or carboxylicesters;
Simultaneously, R
5And R
6Can form 4～8 yuan of heterocyclic radicals; Wherein can contain one or more N, O, S atom in 5～8 yuan of heterocycles, and can be further on 4～8 yuan of heterocycles by one or more alkyl, halogen, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, amino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR
5R
6Replace;
R
7Be selected from hydroxyl, alkoxyl group, aryloxy, heterocycle alkoxyl group, aralkoxy ,-N (R
8) (CH
2)
nR
9,-NR
8[CH
2CH
2O]
nR
8,-NR
5R
6Perhaps-NR
8(CH
2)
n[CH (OH) CH
2]
rZ, wherein Z be aryl, heteroaryl, Heterocyclylalkyl ,-NR
5R
6,-COOR
8Or CONR
5R
6
R
8Be selected from hydrogen atom or alkyl;
R
9Be selected from-NR
5R
6, hydroxyl, aryl, heteroaryl, alkoxyl group ,-O[CH
2CH
2O]
rR
8,-N
+(O
-) R
5R
6,-N (OH) R
5,-NHC (O) R
10Or-COR
10, R wherein
10Be alkyl, haloalkyl or aralkyl;
R
10Be alkyl, haloalkyl or aralkyl
N is 1～6;
R is 1～2.
2. compound or its salt according to claim 1, wherein X is W (CH
2), (CH
2) W or W, wherein W is O.
3. compound or its salt according to claim 1, wherein X is W (CH
2), (CH
2) W or W, wherein W is S, SO or SO
2
4. compound or its salt according to claim 1, wherein X is NR
8, R wherein
8Be hydrogen atom or C
1～C
8Alkyl.
5. compound or its salt according to claim 1, wherein R
2It is methyl.
6. compound or its salt according to claim 1, wherein R
4Be hydrogen atom or alkyl.
7. method for preparing the described compound or its salt of claim 1 said method comprising the steps of:
Wherein, with general formula (I)-a raw material pyrrole derivatives ceric ammonium nitrate oxidation, general formula (I)-c compound that the compound of gained general formula (I)-b obtains with the hydrazine hydrate cyclization again obtains the compound of general formula (I)-d with the phosphorus oxychloride halo;
The compound of general formula (I)-e that the compound of general formula (I)-d is obtained through the amido nucleophilic substitution, the compound hydrolysis of general formula (I)-e is got the compound of general formula (I)-f, the compound of general formula (I)-f is contracted again and becomes the amidated compound, make the compound shown in the general formula (I).
8. pharmaceutical composition, its contain the treatment effective dose according to any one described compound or its salt and pharmaceutical carriers in the claim 1～6.
9. according to the purposes of any one described compound or its salt in the claim 1～6 in preparation tyrosine kinase inhibitor medicine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100648490A CN101003537A (en) | 2006-01-17 | 2006-03-14 | Derivative in pyrrolopyridazine category, preparation method, and application |
| PCT/CN2007/000176 WO2007082470A1 (en) | 2006-01-17 | 2007-01-17 | Pyrrolo-pyridazine derivatives,their preparation methods and uses |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610001444.2 | 2006-01-17 | ||
| CN200610001444 | 2006-01-17 | ||
| CNA2006100648490A CN101003537A (en) | 2006-01-17 | 2006-03-14 | Derivative in pyrrolopyridazine category, preparation method, and application |
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| Publication Number | Publication Date |
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| CN101003537A true CN101003537A (en) | 2007-07-25 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100648490A Pending CN101003537A (en) | 2006-01-17 | 2006-03-14 | Derivative in pyrrolopyridazine category, preparation method, and application |
Country Status (2)
| Country | Link |
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| CN (1) | CN101003537A (en) |
| WO (1) | WO2007082470A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023041061A1 (en) * | 2021-09-17 | 2023-03-23 | 江苏恒瑞医药股份有限公司 | Fused bicyclic derivative, pharmaceutically acceptable salt, crystal form thereof and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA3160367A1 (en) * | 2019-12-18 | 2021-06-24 | Jose Manuel Bartolome-Nebreda | Oga inhibitor compounds |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU7754691A (en) * | 1990-04-27 | 1991-11-27 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Novel pyridazines |
| WO1995019980A1 (en) * | 1994-01-19 | 1995-07-27 | Sankyo Company, Limited | Pyrrolopyridazine derivative |
| TWI287014B (en) * | 1999-06-15 | 2007-09-21 | Sankyo Co | Optically active pyrrolopyridazine compound |
| DE60128329T2 (en) * | 2000-02-10 | 2008-01-10 | Sankyo Co., Ltd. | Pyrrolopyridazine CONNECTIONS |
| WO2004006836A2 (en) * | 2002-07-11 | 2004-01-22 | Merck & Co., Inc. | Treatment of neuropathic pain with 6h-pyrrolo[3,4-d]pyridazine compounds |
| TW200418479A (en) * | 2002-09-25 | 2004-10-01 | Sankyo Co | Pharmaceutical compositions for the treatment or prevention of visceral pains |
| TW200509936A (en) * | 2003-03-24 | 2005-03-16 | Sankyo Co | Pharmaceutical composition comprising a pyrrolopyridazine compound |
| WO2004089378A1 (en) * | 2003-04-04 | 2004-10-21 | Sankyo Company, Limited | Medicinal composition containing pyrrolopyridazine derivative |
| EP2168968B1 (en) * | 2004-04-02 | 2017-08-23 | OSI Pharmaceuticals, LLC | 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors |
-
2006
- 2006-03-14 CN CNA2006100648490A patent/CN101003537A/en active Pending
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023041061A1 (en) * | 2021-09-17 | 2023-03-23 | 江苏恒瑞医药股份有限公司 | Fused bicyclic derivative, pharmaceutically acceptable salt, crystal form thereof and preparation method therefor |
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| Publication number | Publication date |
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| WO2007082470A1 (en) | 2007-07-26 |
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