CN102617599B - Macrocyclic compound and application thereof - Google Patents
Macrocyclic compound and application thereof Download PDFInfo
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- CN102617599B CN102617599B CN201210104154.6A CN201210104154A CN102617599B CN 102617599 B CN102617599 B CN 102617599B CN 201210104154 A CN201210104154 A CN 201210104154A CN 102617599 B CN102617599 B CN 102617599B
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- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
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- 235000013311 vegetables Nutrition 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of biological medicine, particularly to a macrocyclic compound, namely a compound with a general formula (I), and pharmaceutically acceptable equivalent or salt. The invention further relates to a preparation method of the compound with the general formula (I) and the use of such novel pyrimidine compound, particularly to the use of the compound as Janus kinase restrainer. The macrocyclic compound is used in but not limited to real red erythrocytosis, spontaneous thrombocytosis, chronic and idiopathic myelofibrosis, myelogenic metaplasia with myelofibrosis, chronic myelocytic leukemia, chronic bone marrow mononuclear cell leukemia, tranformation reaction, asthma, and autoimmunization diseases such as transplant rejection restrain, chronic infectious arthritis, muscle shrinkage lateral sclerosis, multiple sclerosis and material solid and blood malignancy such as lymphocytic leukemia, and lymphoma.
Description
Technical field:
The present invention relates to biomedicine field, be specifically related to general formula for macrocyclic compounds and pharmaceutically acceptable Equivalent or the salt of (I), and preparation method thereof and as the purposes of Janus kinase inhibitor.
Background technology:
Feature proliferative diseases such as cancer is the uncontrolled growth of health inner cell, and this is fatal for patient, because continuous several in a part of cell take turns sudden change, conventionally can cause the cancer cells in patient body to occupy advantage.Subsequently, cancer metastasis other body parts to its source part, cause Secondary cases pain, finally cause even death of organ failure.
Research discovery, the signal conduction of the generation of cancer and growth and cell, the adjusting of cell cycle, apoptotic induction and tumor vascular growth etc. are closely related.And protein kinase is mainly responsible for the control of intracellular signal transduction process.The abnormal cells reaction that a lot of diseases all cause with protein kinase mediated event is relevant.
Janus kinases (JAK), comprises JAK1, JAK2, and JAK3 and TYK2 belong to cytoplasm protein kinases, with I type and II cytokines receptor acting, regulate cytokine signaling.The downstream substrate of JAK family comprises signal transduction agent and the activator (STAT) of transcription factor.JAK/STAT signal transduction relates to the reaction of a lot of abnormal immunes, as transformation reactions, and asthma, autoimmune disease is as transplant rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies be as leukemia, lymphoma.
From benefiting from the various symptoms that relate to the treatment that regulates JAK approach, for regulating the compound of jak kinase and using the large method of these compounds to seem to provide substantial result for the treatment of for various patients.
Therefore, in the urgent need to developing the compound that can be used for kinases inhibitor, definite says, needs exploitation to can be used for the compound of JAK family kinase inhibitors.New compound of the present invention can suppress one or more jak kinases, and therefore expection can be used for treating associated disease.
Summary of the invention:
The object of the present invention is to provide the macrocyclic compounds that a class is new.
Object of the present invention can reach by following measures:
One class macrocyclic compounds, as general structure (I) compound and pharmacy acceptable salt thereof:
Wherein: Z be selected from O, S,
r
2be selected from hydrogen, C
1-6alkyl, described C
1-6alkyl is independent alternatively by one or more halogens, nitro, amino, hydroxyl, C
1-6alkoxyl group, C
1-6alkyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
3-6cycloalkyl, halo C
3-6cycloalkyl substituted;
Q is selected from C
3-6cycloalkyl, C
6-12aryl, 5-6 unit heterocyclic radical, 5-6 unit heteroaryl; The first heterocyclic radical of described 5-6,5-6 unit heteroaryl comprise 1-3 independently selected from the heteroatoms in N, O and S, described C
3-6cycloalkyl, C
6-12aryl, 5-6 unit heterocyclic radical, 5-6 unit heteroaryl independent alternatively by one or more halogens, nitro, amino, hydroxyl, C
1-6alkoxyl group, C
1-6alkyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
3-6cycloalkyl, halo C
3-6cycloalkyl substituted;
R
1be selected from hydrogen, C
1-6alkyl, C
3-6cycloalkyl or-(CH
2) mR
3, described C
1-6alkyl, C
3-6cycloalkyl ,-(CH
2) mR
3independent alternatively by one or more halogens, nitro, amino, hydroxyl, C
1-6alkoxyl group, C
1-6alkyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
3-6cycloalkyl, halo C
3-6cycloalkyl substituted; L is-X
1-Y-X
2-, X
1be connected with Q, X
2be connected with phenyl, wherein X
1, X
2make L group in normal chain, there are 7,8,9,10 or 11 atoms with the selection of Y;
X
1and X
2independently of one another for contain the alkylidene group of at least one Sauerstoffatom, described X in normal chain
1, X
2independent alternatively by one or more halogens, nitro, amino, hydroxyl, C
1-6alkoxyl group, C
1-6alkyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
3-6cycloalkyl, halo C
3-6cycloalkyl substituted;
Y is-CR
a=CR
b-, wherein R
aand R
bindependently be selected from hydrogen, C
1-6alkyl, described C
1-6alkyl is independent alternatively by one or more halogens, nitro, amino, hydroxyl, C
1-6alkoxyl group, C
1-6alkyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
3-6cycloalkyl, halo C
3-6cycloalkyl substituted;
M is selected from 1,2,3,4 or 5;
R
3be selected from hydroxyl, halogen, C
1-3the heterocyclic radical of alkoxyl group, 5-6 unit, 5-6 unit heteroaryl, heterocyclic radical, the 5-6 unit heteroaryl of described 5-6 unit comprise 1-3 independently selected from the heteroatoms in N, O and S, described C
1-3heterocyclic radical, the 5-6 unit heteroaryl of alkoxyl group, 5-6 unit are independent alternatively by one or more halogens, nitro, amino, hydroxyl, C
1-6alkoxyl group, C
1-6alkyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
3-6cycloalkyl, halo C
3-6cycloalkyl substituted.
Preferably, Z be selected from O, S,
r
2be selected from hydrogen, C
1-6alkyl;
Q is selected from C
3-6cycloalkyl, C
6-12aryl, 5-6 unit heterocyclic radical, 5-6 unit heteroaryl; The first heterocyclic radical of described 5-6,5-6 unit heteroaryl comprise 1-3 independently selected from the heteroatoms in N, O and S, described C
3-6cycloalkyl, C
6-12aryl, 5-6 unit heterocyclic radical, 5-6 unit heteroaryl independent alternatively by one or more halogens, nitro, amino, hydroxyl, C
1-6alkoxyl group, C
1-6alkyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
3-6cycloalkyl, halo C
3-6cycloalkyl substituted;
R
1be selected from hydrogen, C
1-6alkyl, C
3-6cycloalkyl or-(CH
2) mR
3;
X
1and X
2independently of one another for contain the alkylidene group of at least one Sauerstoffatom in normal chain;
R
aand R
bindependently be selected from hydrogen, C
1-6alkyl;
M is selected from 1,2,3,4 or 5;
R
3be selected from hydroxyl, halogen, C
1-3the heterocyclic radical of alkoxyl group, 5-6 unit, 5-6 unit heteroaryl, heterocyclic radical, the 5-6 unit heteroaryl of described 5-6 unit comprise 1-3 independently selected from the heteroatoms in N, O and S.
Further preferably, Z is
r
2for hydrogen;
Q is independently selected from C
6-12aryl, 5-6 unit heterocyclic radical; The first heterocyclic radical of described 5-6 comprises 1-2 and is selected from the heteroatoms in N, O and S, described C
6-12aryl, 5-6 unit heterocyclic radical independent alternatively by one or more C
1-6alkoxyl group, C
1-6alkyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
3-6cycloalkyl, halo C
3-6cycloalkyl substituted;
X
1and X
2be selected from independently of one another:
(a)-O-C
1-5alkyl-,
(b)-C
1-5alkyl-O-C
1-5alkyl-,
(c)-C
1-5alkyl-O-;
Wherein Ra and R
bindependently be selected from hydrogen;
R
1be selected from C
1-6alkyl ,-(CH
2) mR
3;
M is selected from 2 or 3;
R
3be selected from the heterocyclic radical of hydroxyl, 5-6 unit; The heterocyclic radical of described 5-6 unit comprises 1-2 and is selected from the heteroatoms in N, O and S.
Still more preferably, Q is selected from phenyl, 6 yuan of heterocyclic radicals; Described 6 yuan of heterocyclic radicals comprise 1-2 heteroatoms that is selected from N or O, and described phenyl, 6 yuan of heterocyclic radicals are independently alternatively by one or more C
1-6alkoxyl group, halo C
1-6alkoxyl group replaces;
X
1and X
2be selected from independently of one another:
(a)-OCH
2CH
2-，
(b)-OCH
2CH
2CH
2-，
(c)-CH
2O-，
(d)-CH
2OCH
2-；
R
1be selected from methyl or-(CH
2) mR
3;
R
3be selected from hydroxyl, morpholinyl or pyrrolidyl;
M is 2.
Again still more preferably, Q is selected from following group:
Wherein R
4be selected from hydrogen ,-OCH
3, n is selected from 0,1,2,3 or 4.
Most preferably, the macrocyclic compounds of formula (I) include but not limited to following particular compound example:
The present invention also aims to the purposes of the macrocyclic compounds that provides new, specifically as the purposes of Janus kinase inhibitor.
In the present invention, except special instruction, the implication of term representative used is as described below.
Alkyl represents the straight or branched saturated hydrocarbyl of the carbon atom with described number.Typical alkyl includes, but is not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, 3-methylheptyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.
Cycloalkyl represent be all carbon monocycle, condense, the ring of volution or bridged ring.Typically be cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, spiral shell [3.4] octyl, two ring [3.1.1] hexyls.
Represent-O-of alkoxyl group alkyl, wherein alkyl as defined herein.Typically be C
1-6alkoxyl group, including, but not limited to methoxyl group, oxyethyl group.
Halogen or halogen group are fluorine, chlorine, bromine or iodine.Be preferably fluorine, chlorine, bromine.The C being replaced by halogen
1-6alkyl group represents the alkyl that wherein one or more hydrogen are replaced by halogen, preferably containing one, the group of two or three halogens.
Aryl represents full carbon monocycle or the fused polycycle group of 5 to 12 carbon atoms, has the π-electron system of total conjugated.Typically be phenyl ring base, naphthalene nucleus base and anthracene nucleus base.
Heterocyclic radical is Heterocyclylalkyl, represents containing one or more N, O or the heteroatomic monocycle of S or the ring condensing.Typically be heteroatomic 5-6 first heterocyclic radical, for example Piperazino, morpholino base, piperidino-(1-position only), pyrrolidyl and derivative thereof containing one or more N, O or S.
Piperazino refers to the group with following chemical structure.
Morpholino base refers to the group with following chemical structure.
Piperidino-(1-position only) refers to the group with following chemical structure.
Pyrrolidyl refers to the group with following chemical structure.
Heteroaryl, represents monocycle or fused rings group, contains one, two, three or four ring hetero atoms that are selected from N, O or S, and all the other annular atomses are C, have in addition the π-electron system of total conjugated.Typical heteroaryl (but being not limited to) pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyrimidine, pyridine.
The present invention also provides a kind of medicinal compositions that is used for the treatment of jak kinase relative disease in organism, comprises above-mentioned each compound provided by the invention and pharmaceutically acceptable carrier, vehicle or thinner.
Pharmacy acceptable salt represents those salt of the biological effectiveness and the character that retain parent compound.Wherein refer to sour salify, by the free alkali of parent compound, react and obtain with mineral acid or organic acid.Mineral acid comprises hydrochloric acid, phosphoric acid and sulfuric acid etc.Organic acid comprises acetic acid, trichoroacetic acid(TCA), dichloro acetic acid, propionic acid, butyric acid, toxilic acid and tosic acid etc.
Medicinal compositions refers to one or more the compounds of this invention or their pharmacy acceptable salt and prodrug and other chemical composition, comprises the mixture of pharmaceutically acceptable carrier and vehicle.The object of medicinal compositions is to promote the administration of compound to organism.
Pharmaceutically acceptable carrier refers to organism is not caused obvious pungency and do not disturb the biological activity of given compound and the carrier of character or thinner.
Vehicle refers to and joins in medicinal compositions with the further convenient inert substance that gives compound.The example of vehicle comprises (being not limited to) calcium carbonate, calcium phosphate, various saccharides and polytype starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol.
The present invention also provides the purposes of new large lopps derivative, specifically as the purposes of Janus kinase inhibitor.Comprising but be not limited to polycythemia vera, hemorrhagic thrombocythemia, chronic idiopathic myelofibrosis, with the marrow metaplasia of myelofibrosis, chronic special myelomatosis, chronic myelomonocytic leukemia, transformation reactions, asthma, autoimmune disease is as suppressed transplant rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies be as leukemia, lymphoma etc.
Invention also provides the application of above-mentioned each compound aspect the illness medicine of preparation treatment JAK2, JAK3 mediation, comprise to arbitrary defined compound or its pharmaceutical composition in the system of this type for the treatment of of needs or individual the present invention who uses significant quantity, thereby treat described illness.
In order to check the exposure level of compound provided by the invention for jak kinase, adopt biochemistry level enzymic activity to test and determine activity and the exposure level of various compound of the present invention to one or more PK.The method of knowing in operation, all tests like design class in the same way for any kinases.
In the test of biochemistry level enzymic activity, utilize the activity of HTRF technology for detection Tyrosylprotein kinase, HTRF is a kind of time resolved fluorescence resonance ability transfer techniques.HTRF (homogeneous phase time discrimination fluorescence) is a kind of the most frequently used method for detecting determinand in homogeneous system, this technology combines FRET (fluorescence resonance energy transfer) (FRET) and TIME RESOLVED TECHNIQUE (TR), has been widely used in the different steps of the medicament research and development based on cell experiment and biochemical test.According to the measuring principle of HTRF method, by pure enzyme JAK2 together with biotinylated substrate and ATP after incubation reaction, add the antibody of the XL-665 of avidin mark and the Eu mark of identification substrate phosphorylation, after substrate is by JAK2 phosphorylation, the antibody of Eu mark can identify this phosphorylation product, the FRET (fluorescence resonance energy transfer) (FRET) of differentiating with the XL665 formation time of avidin mark, and the substrate not being phosphorylated is owing to can not being formed FRET signal by antibody recognition, by measure the fluorescent signal difference of 665nm and 620nm measure determinand under different concns to JAK2, the kinase whose inhibition of JAK3 is active.Thereby, adopt this method can measure the active function of the biochemistry level of the compounds of this invention to above-mentioned Tyrosylprotein kinase, utilize method well known in the art simultaneously, can use similar measuring method to other protein kinase.
Structure prepared by the present invention has good restraining effect suc as formula the compound shown in I to multiple kinase activity, and it is to the kinase whose half-inhibition concentration (IC of JAK2, JAK3
50) generally 10
-7mol.L
-1below.Know by inference thus, the compound that the present invention has formula I structure can be applicable to prepare the medicine for the treatment of jak kinase relative disease in organism.
Specific implementation method:
The invention discloses intermediate of a kind of compound and preparation method thereof, this compound and preparation method thereof, and this compound is as the application of jak kinase inhibitor, those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described in content of the present invention, spirit and scope or suitably change and combination not departing from, and realizes and apply the technology of the present invention.
Below in conjunction with embodiment, further set forth the present invention:
Embodiment 1: the preparation of compound 1
The chloro-4-of 2-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] under pyrimidine nitrogen protection; in reaction flask, add 2; the chloro-7-of 4-bis-is to this alkylsulfonyl of first 7H-pyrroles [2; 3-d] pyrimidine (1.0g1.0eq), 3-(3-butenyloxy) phenylo boric acid (674mg, 1.2eq), KF.2H
2(1.1g, 4.0eq) is with Er Openmouthedness alkane (20mL) continues to add Pd (dba) to O
2(167mg, 0.1eq) and 2-(dicyclohexyl phosphino-) biphenyl (203mg, 0.2eq), induction stirring, 80 ℃ of reaction overnight.Stopped reaction, is cooled to room temperature, concentrated except desolventizing, the saturated NH of gained solid
4cl dilution; dichloromethane extraction; dichloromethane layer is washed with saturated common salt; anhydrous sodium sulfate drying; filter, concentrated, crude product silica gel column chromatography obtains the chloro-4-of 2-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine (583mg, 44.8%)
2-(3-(2-propenyloxy group methyl)-4-p-methoxy-phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine
In reaction flask, add the chloro-4-of 2-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine (100mg 1.0eq), 3-(2-propenyloxy group methyl)-4-anisidine (85mg; 2.0eq), HCl (4N; 0.2mL) and propyl carbinol (3mL); induction stirring, 116 ℃ are reacted two days.Stopped reaction; the concentrated propyl carbinol of removing; crude product silica gel column chromatography obtains 2-(4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine (28mg, 20.9%)
ACS806209
Under nitrogen protection; in reaction flask, add 2-(4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine (85mg; 1.0eq), methylene dichloride (300mL, 0.5mmol/L) and Grubbs catalyzer (two generations; 12mg; 0.1eq), induction stirring, 40 ℃ of reactions are spent the night.Stopped reaction, concentrated, ACS806209 (80mg, the 98.7%) .MS:[M+H of crude product column chromatography]
+=583.5.
Compound 1
In reaction flask, add ACS806209 (28mg), MeOH (8mL), DCM (2mL) and 1N NaOH (2mL).Induction stirring, 60 ℃ of reaction 2h.Stopped reaction, concentrated, crude product column chromatography obtains compound 1 (17mg, 85%) .MS:[M+H]
+=429.4.
1HNMR(CDCl
3，500MHz)δ：8.94(s，1H)，8.49(s，1H)，7.96(d，1H)，7.64-7.66(m，1H)，7.41-7.45(m，1H)，7.04-7.06(m，2H)，6.96(s，1H)，6.81-6.82(t，2H)，6.72-6.73(m，1H)，5.76-5.84(m，2H)，4.56(s，2H)，4.25-4.29(m，2H)，4.12-4.15(m，2H)，3.83(s，3H)，2.51-2.55(m，2H)PPm
Embodiment 2: the preparation of compound 2
3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) oil of mirbane
In reaction flask, add 3-(2-propenyloxy group methyl)-4-(2-chloroethoxy) oil of mirbane (271mg, 1eq), morpholine (174.2mg, 2eq) and DMA (10mL), 60 ℃ of reaction 12h.Stopped reaction, add frozen water (40mL), dichloromethane extraction, merge organic layer, anhydrous sodium sulfate drying, suction filtration, concentrated, crude product column chromatography obtains 3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) oil of mirbane (318mg, 98.7%) 3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) aniline
In reaction flask, add 3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) oil of mirbane (322mg, 1eq), SnCl
22H
2o (3.6g, 4eq), methyl alcohol (5mL) and methylene dichloride (5mL), stirring at room 24h.Stopped reaction, adds saturated aqueous sodium carbonate (25mL), dichloromethane extraction, anhydrous sodium sulfate drying, suction filtration, concentrated, crude product column chromatography obtains 3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) aniline (237mg, 81.3%)
ACS806254
2-(3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine
Preparation method is with (4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-of 2-in embodiment 1 (3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine synthetic, difference is to change 3-(2-propenyloxy group methyl)-4-anisidine into 3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) aniline MS:[M+H]
+=710.8.
ACS806255
Preparation method is synthetic with ACS806209's in embodiment 1; difference is 2-(4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine changes 2-(3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine into.MS：[M+H]
+＝682.7.
Compound 2
Preparation method is synthetic with compound 1 in embodiment 1, and difference is to change ACS806209 into ACS806255.MS：[M+H]
+＝528.5.
1HNMR(CDCl
3，300MHz)δ：8.99(s，1H)，8.71(s，1H)，7.96(s，1H)，7.64-7.65(d，1H)，7.42-7.44(t，1H)，7.02-7.04(m，3H)，6.79(s，1H)，6.73(s，1H)，5.78-5.83(m，2H)，4.53(s，2H)，4.08-4.25(m，7H)，3.79(s，4H)，2.87-2.90(t，2H)，2.71(s，4H)，2.52-2.55(d，2H)PPm
Embodiment 3: the preparation of compound 3
2-(3-(2-propenyloxy group methyl)-4-(2-pyrrolidyl oxyethyl group) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine
Preparation method is with (4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-of 2-in embodiment 1 (3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine synthetic, difference is to change 3-(2-propenyloxy group methyl)-4-anisidine into 3-(2-propenyloxy group methyl)-4-(2-pyrrolidyl oxyethyl group) aniline MS:[M+H]
+=694.7.
ACS806243
Preparation method is synthetic with ACS806209's in embodiment 1; difference is 2-(4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine changes 2-(3-(2-propenyloxy group methyl)-4-(2-pyrrolidyl oxyethyl group) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine into.MS：[M+H]
+＝665.7.
Compound 3
Preparation method is synthetic with compound 1 in embodiment 1, and difference is to change ACS806209 into ACS806243.MS：[M+H]
+＝512.3.
1HNMR(CDCl
3，500MHz)δ：8.94(s，1H)，8.32(s，1H)，7.95(s，1H)，7.63-7.65(d，1H)，7.44-7.46(t，1H)，7.04-7.05(m，3H)，6.72-6.83(m，4H)，5.77-5.88(m，2H)，4.53(s，2H)，4.24(s，1H)，4.11-4.14(m，4H)，2.92-2.95(t，2H)，2.66(s，4H)，2.52-2.53(m，2H)，1.81-1.91(m，4H)PPm
Embodiment 4: the preparation of compound 4
3-(3-butenyloxy)-4-methoxyl group-1-bromobenzene
In reaction flask, add 2-methoxyl group-4-bromophenol (203mg, 1eq), the bromo-1-butylene of 4-(148.5mg, 1.1eq), salt of wormwood (207mg, 1.5eq) and DMF (15mL), 90 ℃ of reaction 12h.Stopped reaction, suction filtration, concentrated, crude product silica gel column chromatography obtains 3-(3-butenyloxy)-4-methoxyl group-1-bromobenzene (245mg, 95.7%) 3-(3-butenyloxy)-4-methoxyphenylboronic acid
Under-78 ℃ of conditions, in reaction flask, add 3-(3-butenyloxy)-4-methoxyl group-1-bromobenzene (257mg, 1eq) and anhydrous THF (15mL), slowly add n-Butyl Lithium (76.87mg, 1.2eq), induction stirring 1h.Slowly add subsequently trimethyl borate (124.6mg, 1.2eq), continue to stir 1.5h.Stopped reaction, add saturated aqueous ammonium chloride, reacting liquid temperature returns to room temperature, adds water (100mL), extracted with diethyl ether, saturated sodium bicarbonate aqueous solution is washed, saturated common salt washing, anhydrous sodium sulfate drying, suction filtration, concentrated, crude product silica gel column chromatography obtains 3-(3-butenyloxy)-4-methoxyphenylboronic acid (62.1mg, 28%)
The chloro-4-of 2-(3-(3-butenyloxy-4-methoxyl group) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine
Preparation method is with the chloro-4-of 2-in embodiment 1 (3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine synthetic, difference is to change 3-(3-butenyloxy) phenylo boric acid into 3-(3-butenyloxy-4-methoxyl group) phenylo boric acid.
2-(3-(2-propenyloxy group methyl)-4-p-methoxy-phenyl)-4-(3-(3-butenyloxy-4-methoxyl group) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine
Preparation method is with (4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-of 2-in embodiment 1 (3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] preparation of pyrimidine-2-amine; difference is chloro-2-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine changes the chloro-4-of 2-(3-(3-butenyloxy-4-methoxyl group) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine into
ACS806223
Preparation method is synthetic with ACS806209's in embodiment 1; difference is 2-(4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine changes 2-(3-(2-propenyloxy group methyl)-4-p-methoxy-phenyl)-4-(3-(3-butenyloxy-4-methoxyl group) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine into.MS：[M+H]
+＝613.6.
Compound 4
Preparation method is synthetic with compound 1 in embodiment 1, and difference is to change ACS806209 into ACS806223.MS：[M+H]
+＝459.5.
1HNMR(CDCl
3，500MHz)δ：9.39(s，1H)，8.40(s，1H)，7.92(d，1H)，7.87(d，1H)，6.90-7.05(m，2H)，6.69-6.70(d，1H)，6.81-6.82(t，2H)，6.72-6.73(m，1H)，5.92-5.93(m，1H)，5.78-5.80(m，1H)，4.55-4.62(m，2H)，4.21-4.28(m，2H)，4.11-4.18(m，2H)，3.94-3.96(d，3H)，3.82-3.83(d，3H)，2.46-2.48(m，2H)
Embodiment 5: the preparation of compound 5
2-(3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) phenyl)-4-(3-(3-butenyloxy-4-methoxyl group) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2, 3-d] pyrimidine-2-amine preparation method is with 2-in embodiment 4 (3-(2-propenyloxy group methyl)-4-p-methoxy-phenyl)-4-(3-(3-butenyloxy-4-methoxyl group) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2, 3-d] pyrimidine-2-amine synthetic, difference is to change 3-(2-propenyloxy group methyl)-4-anisidine into 3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) aniline
ACS806249
Preparation method is synthetic with ACS806209's in embodiment 1; difference is 2-(4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine changes 2-(3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) phenyl)-4-(3-(3-butenyloxy-4-methoxyl group) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine into
Compound 5
Preparation method is synthetic with compound 1 in embodiment 1, and difference is to change ACS806209 into ACS806249.MS：[M+H]
+＝558.5.
1HNMR(CDCl
3，300MHz)δ：8.53-8.54(m，2H)，7.95-7.97(m，1H)，7.74-7.77(m，1H)，7.02-7.03(m，2H)，6.98-6.99(d，1H)，6.81-6.87(m，2H)，6.69-6.70(m，1H)，5.93-5.95(m，1H)，5.80-5.82(m，1H)，4.59-4.60(m，2H)，4.27-4.29(m，2H)，4.10-4.18(m，4H)，3.94(s，3H)，3.77-3.79(m，4H)，2.86-2.89(t，2H)，2.69-2.71(m，4H)，2.47-2.49(t，2H)PPm
Embodiment 6: the preparation of compound 6
3-(2-propenyloxy group methyl)-4-nitrophenols
In reaction flask, add 2-methylol-4-nitrophenols (169mg, 1eq), the bromo-1-propylene of 3-(483.9mg, 4eq), TBAB (16mg, 0.05eq) and KOH (112.2mg, 2eq), 50 ℃ are stirred 12h.Stopped reaction, be cooled to room temperature, add water (20mL), ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration, concentrated, crude product column chromatography obtains 3-(2-propenyloxy group methyl)-4-nitrophenols (191.6mg, 91.7%) 3-(2-propenyloxy group methyl)-4-hydroxy ethoxy-1-oil of mirbane
In reaction flask, add 3-(2-propenyloxy group methyl)-4-nitrophenols (209mg, 1eq), ethylene bromohyrin (137.4mg, 1.1eq), salt of wormwood (207mg, 1.5eq) and DMF (10mL), 90 ℃ of reaction 12h.Stopped reaction, suction filtration, concentrated, crude product silica gel column chromatography obtains 3-(2-propenyloxy group methyl)-4-hydroxy ethoxy-1-oil of mirbane (231mg, 91.4%)
3-(2-propenyloxy group methyl)-4-hydroxy ethoxy aniline
Preparation method is synthetic with 3-in embodiment 2 (2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) aniline, and difference is to change 3-(2-propenyloxy group methyl)-4-(2-morpholinyl oxyethyl group) oil of mirbane into 3-(2-propenyloxy group methyl)-4-hydroxy ethoxy-1-oil of mirbane
2-(3-(2-propenyloxy group methyl)-4-(2-hydroxyl-oxethyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine
Preparation method is with (4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-of 2-in embodiment 1 (3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine synthetic, difference is to change 3-(2-propenyloxy group methyl)-4-anisidine into 3-(2-propenyloxy group methyl)-4-(2-hydroxyl-oxethyl) aniline
ACS806216
Preparation method is synthetic with ACS806209's in embodiment 1; difference is 2-(4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine changes 2-(3-(2-propenyloxy group methyl)-4-(2-hydroxyl-oxethyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine MS:[M+H into]
+=613.6.
Compound 6
Preparation method is synthetic with compound 1 in embodiment 1, and difference is to change ACS806209 into ACS806216.MS：[M+H]
+＝459.6.
1HNMR(CDCl
3，400MHz)δ：9.09(s，1H)，8.48-8.50(m，1H)，7.98(s，1H)，7.64-7.66(m，1H)，7.40-7.46(m，1H)，7.03-7.05(m，2H)，6.89(m，2H)，6.82(s，1H)，6.75(s，1H)，5.76-5.86(m，2H)，4.58(s，2H)，4.23-4.25(m，5H)，4.16-4.18(m，2H)，3.81-3.82(m，2H)，2.54-2.58(m，2H)PPm
Embodiment 7: the preparation of compound 7
The chloro-4-of 2-(3-(2-propenyloxy group methyl) piperidyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine adds 3-(2-propenyloxy group methyl) piperidines (232mg in reaction flask; 1.5eq), the chloro-7-p-toluenesulfonyl of 2,4-bis-7H-pyrroles [2; 3-d] pyrimidine (342mg; 1.0eq), triethylamine (215 μ L, 1.5eq) and acetonitrile (15mL); induction stirring, 80 ℃ of reactions are spent the night.Stopped reaction, concentrated except desolventizing, the saturated NH of gained solid
4cl dilution; dichloromethane extraction; dichloromethane layer is washed with saturated common salt; anhydrous sodium sulfate drying; filter, concentrated, crude product silica gel column chromatography obtains the chloro-4-of 2-(3-(2-propenyloxy group methyl) piperidyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine (368mg, 80%)
2-(3-(2-propenyloxy group methyl)-4-(2-pyrrolidyl oxyethyl group) phenyl)-4-(3-(2-propenyloxy group methyl) piperidines)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine
Preparation method is with (3-(2-propenyloxy group methyl)-4-(2-pyrrolidyl oxyethyl group) the phenyl)-4-of 2-in embodiment 3 (3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine synthetic; difference is chloro-2-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine changes the chloro-4-of 2-(3-(2-propenyloxy group methyl) piperidines)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine into.
ACS807536
Preparation method is synthetic with ACS806209's in embodiment 1; difference is 2-(4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine changes 2-(3-(2-propenyloxy group methyl)-4-(2-pyrrolidyl oxyethyl group) phenyl)-4-(3-(2-propenyloxy group methyl) piperidines)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine into
Compound 7
Preparation method is synthetic with compound 1 in embodiment 1, and difference is to change ACS806209 into ACS807536.MS：[M+H]
+＝519.8
1HNMR(CDCl
3，300MHz)δ：8.46(s，1H)，8.31(s，1H)，6.75-6.82(m，3H)，6.61(s，1H)，6.41-6.43(d，1H)，5.74-5.92(m，2H)，4.66-4.78(m，1H)，4.53-4.58(m，2H)，4.34-4.38(m，1H)，4.10-4.34(m，5H)，3.93-3.98(m，1H)，3.51-3.74(m，1H)，3.33-3.48(m，4H)，3.06-3.13(t，1H)，2.91-2.95(t，2H)，2.66(s，4H)，1.37-2.04(m，7H)PPm
Embodiment 8: the preparation of compound 8
The chloro-4-of 2-(4-(4-amylene oxygen base) piperidyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine preparation method is with the chloro-4-of 2-in embodiment 7 (3-(2-propenyloxy group methyl) piperidyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine synthetic, difference is to change 3-(2-propenyloxy group methyl) piperidines into 4-(4-amylene oxygen base) piperidines.
2-(4-(4-amylene oxygen base) piperidyl)-4-(2-pyrrolidyl oxyethyl group) phenyl)-4-(3-(2-propenyloxy group methyl) piperidines)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine
Preparation method is with 2-in embodiment 7 (3-(2-propenyloxy group methyl)-4-(2-pyrrolidyl oxyethyl group) phenyl)-4-(3-(2-propenyloxy group methyl) piperidines)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine synthetic; difference is chloro-2-4-(3-(2-propenyloxy group methyl) piperidyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine changes the chloro-4-of 2-(4-(4-amylene oxygen base) piperidyl)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine into
ACS807548
Preparation method is synthetic with ACS806209's in embodiment 1; difference is 2-(4-methoxyl group-3-(2-propenyloxy group methyl) phenyl)-4-(3-(3-butenyloxy) phenyl)-7-p-toluenesulfonyl-7H-pyrroles [2; 3-d] pyrimidine-2-amine changes 2-(4-(4-amylene oxygen base) piperidyl)-4-(2-pyrrolidyl oxyethyl group) phenyl into)-4-(3-(2-propenyloxy group methyl) piperidines)-7-p-toluenesulfonyl-7H-pyrroles [2,3-d] pyrimidine-2-amine.
Compound 8
Preparation method is synthetic with compound 1 in embodiment 1, and difference is to change ACS806209 into ACS807548.
1HNMR(CDCl
3，300MHz)δ：8.42-8.43(d，1H)，8.31(s，1H)，6.71-6.80(m，3H)，6.62(s，1H)，6.41-6.42(d，1H)，5.79-5.83(m，1H)，5.54-5.56(m，1H)，5.30(s，1H)，4.57(s，2H)，4.14-4.17(m，2H)，4.07-4.09(m，2H)，3.98-4.02(m，2H)，3.28-3.50(m，4H)，2.99(s，2H)，2.76(s，4H)，1.52-1.99(m，12H)PPm
Embodiment 9: external biochemistry level suppresses jak kinase (PK) activity experiment
Materials and methods: JAK2, JAK3 kinases, derives from Invitrogen; 384 orifice plates (Greiner company); HTRF KinEASE; MgCl
2(sigma) company; DTT (Sunshine); The multi-functional microplate reader of PHERAstar FS (BMG company); MH-1 type low speed centrifuge (StaiteXiangyi company); TD25-W5 type thermostat container (Binder company); YG020524/ vibrator (Lindberg Optic Design A/S); ATP (sigma company); The positive drug of choosing is CP-690550, and structure is as follows:
Compound dissolution and preservation: with DMSO, test-compound is configured to the mother liquor of 0.5-10mmol/L ,-20 ℃ of preservations after packing;
The preparation of compound working fluid: except CP-690550, all the other compounds are 10uM and play 10 concentration of 3 times of dilutions, then add a full DMSO of zero-dose.
Enzyme reaction step: to the kinases that adds 4 μ l in each hole of 384 microwell plates, simultaneously add the Enzymatic buffer of 4 μ L as negative control (Negative); To hole, add the compound working fluid of 2 μ l, add damping fluid (being positive control, Positive) in contrast that does not contain compound of 2 μ L simultaneously; In 25 ℃ (or 30 ℃), hatch 5-10min; Xiang Kongzhong adds 2 μ L ATP and TK Substrate-biotin mixed solution, starts enzyme reaction, in 25 ℃ of (or 30 ℃) oscillatory reaction 15-60min; Xiang Kongzhong adds 4uLTK-Ab-cryptate; In 25 ℃ (or 30 ℃), hatch 5-10min; PHERAstar FS instrument reads HTRF signal.
The raw data of reading for every hole, ratio=665nm/620nm;
The calculating of inhibiting rate:
Calculate IC50:
Take log[administration concentration] be X-coordinate, inhibiting rate is ordinate zou, simulates a dose response curve in Graphpad Prism 5, the drug level while drawing its 50% inhibiting rate, for this reason compound at the IC of enzyme level
50value.
Experimental result: the active half-inhibition concentration (IC of jak kinase
50nM)
The invention provides structure suc as formula compound shown in I the half-inhibition concentration (IC to jak kinase activity
50) in Table 1:
Half-inhibition concentration (the IC of table 1 compound to JAK2 kinase activity
50)
| Compound | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | CP-690550 | |
| Active strong | +++ | +++ | +++ | +++ | +++ | +++ | +++ | +++ | +++ |
| Degree |
+++ represent IC
50< 500nM; ++ represent IC
50scope is 500-5000nM; + expression IC
50scope is 5000nM-50 μ M;-represent not test
Half-inhibition concentration (the IC of table 2 compound to JAK3 kinase activity
50)
+++ represent IC
50< 500nM; ++ represent IC
50scope is 500-5000nM; + expression IC
50scope is 5000nM-50 μ M;-represent not test
Experimental result: the compounds of this invention is to JAK2, and the inhibition of JAK3 kinases biochemistry level is active suitable with positive drug CP-690550.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (9)
1. structure is suc as formula the compound shown in I or its pharmacy acceptable salt:
Wherein:
Z is
r
2for hydrogen;
Q is selected from phenyl, 6 yuan of heterocyclic radicals; Described 6 yuan of heterocyclic radicals comprise 1-2 heteroatoms that is selected from N or O, and described phenyl, 6 yuan of heterocyclic radicals are independently alternatively by one or more C
1-6alkoxyl group, halo C
1-6alkoxyl group replaces;
R
1be selected from hydrogen, C
1-6alkyl, C
3-6cycloalkyl or-(CH
2) mR
3;
L is-X
1-Y-X
2-, X
1be connected with Q, X
2be connected with phenyl, wherein X
1, X
2make L group in normal chain, there are 7,8,9,10 or 11 atoms with the selection of Y;
X
1and X
2independently of one another for contain the alkylidene group of at least one Sauerstoffatom in normal chain;
Y is-CR
a=CR
b-,
R
aand R
bindependently be selected from hydrogen, C
1-6alkyl;
M is selected from 1,2,3,4 or 5;
R
3be selected from hydroxyl, halogen, C
1-3the heterocyclic radical of alkoxyl group, 5-6 unit, 5-6 unit heteroaryl, heterocyclic radical, the 5-6 unit heteroaryl of described 5-6 unit comprise 1-3 independently selected from the heteroatoms in N, O and S.
2. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that,
X
1and X
2be selected from independently of one another:
(a)-O-C
1-5alkyl-,
(b)-C
1-5alkyl-O-C
1-5alkyl-,
(c)-C
1-5alkyl-O-;
Wherein Ra and R
bindependently be selected from hydrogen;
R
1be selected from C
1-6alkyl ,-(CH
2) mR
3;
M is selected from 2 or 3;
R
3be selected from the heterocyclic radical of hydroxyl, 5-6 unit; The heterocyclic radical of described 5-6 unit comprises 1-2 and is selected from the heteroatoms in N, O and S.
3. compound according to claim 2 or its pharmacy acceptable salt, is characterized in that,
X
1and X
2be selected from independently of one another:
（a）-OCH
2CH
2-，
（b）-OCH
2CH
2CH
2-，
（c）-CH
2O-，
（d）-CH
2OCH
2-；
R
1be selected from methyl or-(CH
2) mR
3;
R
3be selected from hydroxyl, morpholinyl or pyrrolidyl;
M is 2.
4. compound according to claim 3 or its pharmacy acceptable salt, is characterized in that Q is selected from following group:
Wherein R
4be selected from hydrogen ,-OCH
3, n is selected from 0,1,2,3 or 4.
5. compound or its pharmacy acceptable salt, described compound is selected from:
6. a pharmaceutical composition, it comprises pharmaceutically acceptable carrier, vehicle or thinner, and as the compound described in the claim 1-5 of activeconstituents or its pharmacy acceptable salt.
7. the compound described in any one or its pharmacy acceptable salt application aspect the illness medicine of preparation treatment JAK mediation in claim 1-5.
8. according to application described in claim 7, it is characterized in that described illness is selected from: polycythemia vera, hemorrhagic thrombocythemia, chronic idiopathic myelofibrosis, the marrow metaplasia with myelofibrosis, chronic special myelomatosis, transformation reactions, autoimmune disease, muscle contracting lateral sclerosis or entity or hematologic malignancies.
According to Claim 8 described in application, it is characterized in that described illness is selected from: chronic myelomonocytic leukemia, asthma, inhibition transplant rejection, rheumatoid arthritis or multiple sclerosis.
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| Anthony D. William,等.Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor fo.《Journal of Medicinal Chemistry》.2011,第54卷(第13期),第4638-4658页. |
| Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor fo;Anthony D. William,等;《Journal of Medicinal Chemistry》;20110523;第54卷(第13期);第4638-4658页 * |
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