CN103159736B - Substitutional pyrazol kinase inhibitor - Google Patents
Substitutional pyrazol kinase inhibitor Download PDFInfo
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- CN103159736B CN103159736B CN201210528817.7A CN201210528817A CN103159736B CN 103159736 B CN103159736 B CN 103159736B CN 201210528817 A CN201210528817 A CN 201210528817A CN 103159736 B CN103159736 B CN 103159736B
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- 0 CON=C1c2ccc(*)cc2CC1 Chemical compound CON=C1c2ccc(*)cc2CC1 0.000 description 3
- DOKLOTLZWFDGPE-UHFFFAOYSA-O CC(C)(C(C)(C)OBc(cc1)ccc1OCCN(C)C)[OH2+] Chemical compound CC(C)(C(C)(C)OBc(cc1)ccc1OCCN(C)C)[OH2+] DOKLOTLZWFDGPE-UHFFFAOYSA-O 0.000 description 1
- ZREWDRNQPHFGID-UHFFFAOYSA-N CN(C)CCOc(cc1)ccc1-[n](cc1-c2ccncc2)nc1-c(cc1CC2)ccc1C2=O Chemical compound CN(C)CCOc(cc1)ccc1-[n](cc1-c2ccncc2)nc1-c(cc1CC2)ccc1C2=O ZREWDRNQPHFGID-UHFFFAOYSA-N 0.000 description 1
- IEWSDAIEOYDECL-UHFFFAOYSA-N CN(C)CCOc(cc1)ccc1-c(cc1-c(cc2)cc(CC3)c2C3=N)n[n]1-c1ccncc1 Chemical compound CN(C)CCOc(cc1)ccc1-c(cc1-c(cc2)cc(CC3)c2C3=N)n[n]1-c1ccncc1 IEWSDAIEOYDECL-UHFFFAOYSA-N 0.000 description 1
- PMFPENRCBNVXCW-CCFHIKDMSA-N CN(C)CCOc(cc1)ccc1-c(cc1C2=CC=CCC=C2)n[n]1-c(cc1CC2)ccc1/C2=N/C Chemical compound CN(C)CCOc(cc1)ccc1-c(cc1C2=CC=CCC=C2)n[n]1-c(cc1CC2)ccc1/C2=N/C PMFPENRCBNVXCW-CCFHIKDMSA-N 0.000 description 1
- PUFWUUVZCIUKAS-UHFFFAOYSA-N CN(C)CCOc(cc1)ccc1-c1cc(-c2ccncc2)n[n]1-c(cc1CC2)ccc1C2=N Chemical compound CN(C)CCOc(cc1)ccc1-c1cc(-c2ccncc2)n[n]1-c(cc1CC2)ccc1C2=N PUFWUUVZCIUKAS-UHFFFAOYSA-N 0.000 description 1
- BRZOEMWZCQTWHV-UHFFFAOYSA-N CN(C)CCOc(cc1)ccc1-c1cc(-c2ccncc2)n[n]1-c(cc1CC2)ccc1C2=[U] Chemical compound CN(C)CCOc(cc1)ccc1-c1cc(-c2ccncc2)n[n]1-c(cc1CC2)ccc1C2=[U] BRZOEMWZCQTWHV-UHFFFAOYSA-N 0.000 description 1
- VEQUWNGEOSYDRN-KOVXHEOQSA-N CN(C)CCOc(cc1)ccc1C(/C=C\c(cc1CC2)ccc1/C2=N\OC)=O Chemical compound CN(C)CCOc(cc1)ccc1C(/C=C\c(cc1CC2)ccc1/C2=N\OC)=O VEQUWNGEOSYDRN-KOVXHEOQSA-N 0.000 description 1
- DSZBJMFAWVOJKB-UHFFFAOYSA-N CN(C)CCOc(cc1)ccc1C(CC(c1ccncc1)=O)=O Chemical compound CN(C)CCOc(cc1)ccc1C(CC(c1ccncc1)=O)=O DSZBJMFAWVOJKB-UHFFFAOYSA-N 0.000 description 1
- RDSHAHWXZXWMMU-MECKSWLXSA-N CN(C)CCOc(cc1)ccc1N/C=C\C(c(cc1)cc(CC2)c1C2=N)=N Chemical compound CN(C)CCOc(cc1)ccc1N/C=C\C(c(cc1)cc(CC2)c1C2=N)=N RDSHAHWXZXWMMU-MECKSWLXSA-N 0.000 description 1
- RUHVDRGWCIAFLG-UHFFFAOYSA-N CN(C)CCOc1ccccc1 Chemical compound CN(C)CCOc1ccccc1 RUHVDRGWCIAFLG-UHFFFAOYSA-N 0.000 description 1
- SLCVBIMNKRQIRN-UHFFFAOYSA-O CNN=C1c2ccc(C(CC(c(cc3)ccc3OCCN(C)C)=N)[NH2+]c3ccncc3)cc2CC1 Chemical compound CNN=C1c2ccc(C(CC(c(cc3)ccc3OCCN(C)C)=N)[NH2+]c3ccncc3)cc2CC1 SLCVBIMNKRQIRN-UHFFFAOYSA-O 0.000 description 1
- UVWBADYWXYEXEE-ZRDIBKRKSA-N CO/N=C1/c2ccc(B(O)O)cc2CC1 Chemical compound CO/N=C1/c2ccc(B(O)O)cc2CC1 UVWBADYWXYEXEE-ZRDIBKRKSA-N 0.000 description 1
- SLZILQRRXDNMQE-CPCUFIRASA-N CO/N=C1/c2ccc(C(/C=C\N)N)cc2CC1 Chemical compound CO/N=C1/c2ccc(C(/C=C\N)N)cc2CC1 SLZILQRRXDNMQE-CPCUFIRASA-N 0.000 description 1
- ODJKVXCLYBHWHR-QGLMHHTBSA-N C[C@@H](C(C/C=C\N)NN)I Chemical compound C[C@@H](C(C/C=C\N)NN)I ODJKVXCLYBHWHR-QGLMHHTBSA-N 0.000 description 1
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Abstract
The invention belongs to the field of medical technology, in particular to a substitutional pyrazol kinase inhibitor which is shown by general formulas (I), (II), (III) or (IV), salt or a stereoisomer which are acceptable in pharmacy, wherein R<1>, R<2>, L1and L2 are defined as same as the definitions in an instruction book. The invention further relates to preparation methods of the compounds, application of the compounds, the salt or the stereoisomer which is acceptable in pharmacy in the drugs of preparing, treating and/or preventing diseases which are related to or not related to cancers caused by mutation of b-RAF.
Description
Technical field
The invention belongs to medical art, be specifically related to the pyrazole kinase inhibitors, its pharmacy acceptable salt or its steric isomer that replace, the preparation method of these compounds, pharmaceutical preparation containing these compounds and pharmaceutical composition, and this compound, its pharmacy acceptable salt or its steric isomer treat and/or prevent the application in the medicine of cancer-related diseases or the non-cancer-related diseases being suddenlyd change by b-RAF and cause in preparation.
Background technology
Receptor tyrosine kinase (RTKs) participates in the growth of cell, differentiation, growth, propagation, the process such as division and adhesion, simultaneously also relevant to the process such as transcriptional regulatory, vasculogenesis, endotheli ocytosis of cell, have in process of cell signal transduction and act on widely.For these kinase whose adjustments, cell proliferation and differentiation can be controlled, regulate the cell cycle, especially to the tumour cell that some morph, by the kinase whose activity of adjusted expression, the growth of cancer cell can be suppressed significantly, reach the effect for the treatment of tumour.
The kinases micromolecular inhibitor with targeting has become the focus of field of cancer, the imatinib gone on the market, erlotinib, Gefitinib, Sutent, rope draw for Buddhist nun and lapatinibditosylate, Gospel is brought to global cancer patients, clinical study shows, these small molecules can extend the lifetime of the patients such as nonsmall-cell lung cancer, kidney, liver cancer, cancer of the stomach, colorectal carcinoma and mammary cancer significantly, improve the quality of life of patient, show the unique advantage of small-molecule drug.But also there is problem in various degree in these medicines, wherein selectivity poor, easily occur that resistance is all the subject matter that they face, such as BAY 43-9006 can suppress VEGFR-2/3, b-RAF, c-RAF and PDGF, erlotinib suppresses EGFR and ERBB2, imatinib is except suppressing PDGFR, also suppress c-kt, Bcr-Abl etc.Therefore, improving selectivity is the important content that small molecules suppresses research.
RAF is a Key kinases in Ras/RAF/MEK/ERK path, also be MAPK(mitogen-activated proteinkinase) member important in signal path, RAF plays its intracellular signaling regulating effect by the mode relying on or do not rely on Ras, in cell proliferation, differentiation and apoptosis, have important regulating and controlling effect.The kinase whose 3 kinds of hypotypes of RAF comprise a-RAF, b-RAF and Raf-1 (c-RAF), closely related with the adjustment of cell proliferation, differentiation, existence, attachment and vasculogenesis.A-RAF is mainly distributed in the urogenital organ such as kidney, testis; B-RAF mainly expresses in nervous tissue, and RAF-1 is distributed widely in body Various Tissues, and has the function not by Ras/RAF/MEK/ERK path and adjustable cell.
RAF sudden change can cause kinds cancer clinically, the highest with melanoma sickness rate, takes second place for thyroid carcinoma and colorectal carcinoma, also comprises liver cancer, lung cancer, mammary cancer, ovarian cancer and bladder cancer.In the sudden change of RAF, especially suddenly change at most with b-RAF V599E, therefore, for the research of b-RAF inhibition from mutation agent, above-mentioned cancer patients is had great importance.
The b-RAF inhibitor gone on the market at present includes BAY 43-9006, and it is a Mutiple Targets inhibitor, and other has necessarily optionally b-RAF inhibitor and includes RAF-265, PLX-4032, XL-281, SB-590885, RO-5126766 etc.All there is the problems such as the poor or activity of selectivity is good not in these compounds, is necessary to carry out corresponding research work thus, searches out for b-RAF sudden change and have micromolecular inhibitor active very well.
Summary of the invention
The present invention with exploitation for b-RAF sudden change have excellent activity and optionally micromolecular inhibitor for target, invented the pyrazole kinase inhibitors with the inhibiting replacement of b-RAF.Concrete technical scheme is as follows:
General formula (I), (II), (III) or the compound shown in (IV), its pharmacy acceptable salt or its steric isomer:
Wherein,
L
1represent a key, 6-14 unit aryl, 3-14 unit heterocyclic radical, 5-14 unit heteroaryl, aryl wherein, heterocyclic radical and heteroaryl can be selected from hydrogen, halogen atom, cyano group, amino C by 1-3
1-6alkyl, formamyl, hydroxyl or C
1-6the group of alkoxyl group replaced;
L
2represent hydrogen, C
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, C
1-6alkyl-carbonyl, halogen atom, cyano group, amino C
1-6alkyl, formamyl, hydroxyl, 3-14 unit cycloalkyl, 3-14 unit heterocyclic radical, 5-14 unit heteroaryl, 6-14 unit aryl, above-mentioned C
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, C
1-6alkyl-carbonyl can by 1-3 L
3replaced, L
3be selected from hydrogen, halogen atom, cyano group, amino C
1-6alkyl, formamyl, hydroxyl, C
1-6alkoxyl group, C
1-6alkyl thiol, C
1-6alkylamino, two (C
1-6alkyl) amino, the first heterocyclic radical of 3-14 or C
1-6the 3-14 unit heterocyclic radical that alkyl replaces;
R
1be selected from phenyl, containing 1-3 to be selected from the 3-14 unit heterocyclic radical of O, S, N, 5-14 unit heteroaryl, by the 5-10 of oxo unit heterocyclic radical, by the 5-8 of oxo unit heteroaryl, 6-14 unit fused heterocycle base, phenyl wherein, heterocyclic radical, heteroaryl and fused heterocycle base can replace by 1-3 Y, Y is selected from halogen atom, hydroxyl, C
1-6alkyl, halo C
1-6alkyl, carboxyl C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
1-8alkoxyl group, C
1-6alkyl thiol, C
1-6alkyl amidine, formamyl, halo C
1-8alkoxyl group, amino, C
1-6alkylamino, two (C
1-6alkyl) amino, two (C
1-6alkyl) amino C
1-6alkoxyl group, cyano group, nitro, C
1-6alkyl-carbonyl, sulfonamido or C
1-6alkyl sulfonyl-amino;
R
2be selected from
or by 1-3 R
3the 6-14 unit's aryl replaced or 5-14 unit heteroaryl,
Wherein, A represents phenyl or 5-6 unit heteroaryl, and B represents 5-6 unit heterocyclic radical, 5-6 unit heteroaryl, 5-6 unit cycloalkyl, and n is the integer of 0-3,
Z represents hydrogen, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
1-8alkoxyl group, amino, C
1-6alkylamino, two (C
1-6alkyl) amino, cyano group, nitro, C
1-6alkyl sulfonyl-amino or C
1-6alkyl amino sulfonyl,
R
3represent hydrogen, halogen atom, amino, urea groups, amino C
1-6alkyl, alkylsulfonyl C
1-6alkyl, carboxyl, C
1-6alkyl, halo C
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, formamyl, 3-8 unit cycloalkyl, C
1-6alkyl-carbonyl, 3-14 unit heterocyclic radical, 6-14 unit aryl, cycloalkyl wherein, heterocyclic radical and aryl can by 1-3 R
4replaced, R
4be selected from hydrogen, halogen atom, cyano group, amino C
1-6alkyl, hydroxyl C
1-6alkyl, formamyl, hydroxyl, oxo, C
1-6alkoxyl group, C
1-6alkylamino, C
1-6alkyl sulphonyl, two (C
1-6alkyl) amino, the first heterocyclic radical of 3-14, C
1-6alkyl sulfonyl-amino, C
1-6alkyl amino sulfonyl, C
1-6alkyl sulphonyl, halo C
1-6alkyl sulphonyl, 3-14 unit heterocyclic radical, C
1-63-14 unit's heterocyclic radical that alkyl replaces or C
1-6the 6-14 unit aryl that alkyl replaces.
Be preferably:
Wherein,
L
1represent a key, 6-10 unit aryl, 5-10 unit heterocyclic radical, 5-8 unit heteroaryl, aryl wherein, heterocyclic radical and heteroaryl can be selected from hydrogen, halogen atom, cyano group, amino C by 1-3
1-6alkyl, formamyl, hydroxyl or C
1-6the group of alkoxyl group replaced;
L
2represent hydrogen, C
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, C
1-6alkyl-carbonyl, halogen atom, cyano group, amino C
1-6alkyl, formamyl, hydroxyl, 3-8 unit cycloalkyl, 5-10 unit heterocyclic radical, 5-8 unit heteroaryl, 6-14 unit aryl, above-mentioned C
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl can by 1-3 L
3replaced, L
3be selected from hydrogen, halogen atom, cyano group, amino C
1-6alkyl, formamyl, hydroxyl, C
1-6alkoxyl group, C
1-6alkyl thiol, C
1-6alkylamino, two (C
1-6alkyl) amino, the first heterocyclic radical of 5-10 or C
1-6the 5-10 unit heterocyclic radical that alkyl replaces;
R
1be selected from phenyl, containing 1-3 to be selected from the 5-10 unit heterocyclic radical of O, S, N, 5-8 unit heteroaryl, by 6 yuan of heterocyclic radicals of oxo, by 6 yuan of heteroaryls of oxo, 8-14 unit fused heterocycle base, phenyl wherein, heterocyclic radical, heteroaryl and fused heterocycle base can replace by 1-3 Y, Y is selected from halogen atom, hydroxyl, C
1-6alkyl, halo C
1-6alkyl, carboxyl C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
1-8alkoxyl group, C
1-6alkyl thiol, C
1-6alkyl amidine, formamyl, halo C
1-8alkoxyl group, amino, C
1-6alkylamino, two (C
1-6alkyl) amino, two (C
1-6alkyl) amino C
1-6alkoxyl group, cyano group, nitro, C
1-6alkyl-carbonyl, sulfonamido or C
1-6alkyl sulfonyl-amino;
R
2be selected from
or by 1-3 R
3the phenyl replaced or 5-6 unit heteroaryl,
Wherein, A represents phenyl or 5-6 unit heteroaryl, and B represents 5-6 unit heterocyclic radical, 5-6 unit heteroaryl, 5-6 unit cycloalkyl, and n is the integer of 0-3,
Z represents hydrogen, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
1-8alkoxyl group, amino, cyano group, nitro, C
1-6alkyl sulfonyl-amino or C
1-6alkyl amino sulfonyl,
R
3represent hydrogen, halogen atom, amino, urea groups, amino C
1-6alkyl, alkylsulfonyl C
1-6alkyl, carboxyl, C
1-6alkyl, halo C
1-6alkyl, C
1-6alkoxyl group, formamyl, 3-8 unit cycloalkyl, 5-10 unit heterocyclic radical, phenyl, cycloalkyl wherein, heterocyclic radical and phenyl can by 1-3 R
4replaced, R
4be selected from hydrogen, halogen atom, cyano group, hydroxyl C
1-6alkyl, hydroxyl, oxo, C
1-6alkoxyl group, C
1-6alkylamino, C
1-6alkyl sulphonyl, two (C
1-6alkyl) amino, C
1-6alkyl sulfonyl-amino, C
1-6alkyl amino sulfonyl, C
1-6alkyl sulphonyl, halo C
1-6alkyl sulphonyl, 5-10 unit heterocyclic radical, C
1-65-10 unit's heterocyclic radical that alkyl replaces or C
1-6the 6-10 unit aryl that alkyl replaces.
Be preferably:
Wherein,
L
1represent a key, 6-10 unit aryl, 5-10 unit heterocyclic radical, 5-8 unit heteroaryl;
L
2represent hydrogen, C
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, C
1-6alkyl-carbonyl, halogen atom, cyano group, amino C
1-6alkyl, formamyl, hydroxyl, 3-8 unit cycloalkyl, 5-8 unit heteroaryl, 6-10 unit aryl, above-mentioned C
1-6alkyl, C
1-6alkoxyl group can by 1-3 L
3replaced, L
3be selected from hydrogen, halogen atom, cyano group, amino C
1-6alkyl, formamyl, hydroxyl, C
1-6alkoxyl group, C
1-6alkyl thiol, C
1-6alkylamino, two (C
1-6alkyl) amino, the first heterocyclic radical of 5-10 or C
1-6the 5-10 unit heterocyclic radical that alkyl replaces;
R
1be selected from phenyl, containing 1-3 to be selected from the 5-10 unit heterocyclic radical of O, S, N, 5-8 unit heteroaryl, by 6 yuan of heterocyclic radicals of oxo, by 6 yuan of heteroaryls of oxo, 8-14 unit fused heterocycle base, phenyl wherein, heterocyclic radical, heteroaryl and fused heterocycle base can replace by 1-3 Y, Y is selected from halogen atom, hydroxyl, C
1-6alkyl, halo C
1-6alkyl, carboxyl C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
1-8alkoxyl group, halo C
1-8alkoxyl group, amino, C
1-6alkylamino, two (C
1-6alkyl) amino, two (C
1-6alkyl) amino C
1-6alkoxyl group, cyano group, nitro, C
1-6alkyl-carbonyl, sulfonamido or C
1-6alkyl sulfonyl-amino;
R
2be selected from
or by 1-3 R
3the phenyl replaced or 5-6 unit heteroaryl,
Wherein, A represents phenyl or 5-6 unit heteroaryl, and B represents 5-6 unit heterocyclic radical, 5-6 unit heteroaryl, 5-6 unit cycloalkyl, and n is the integer of 0-3,
Z represents hydrogen, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
1-8alkoxyl group, amino, C
1-6alkyl sulfonyl-amino or C
1-6alkyl amino sulfonyl,
R
3represent hydrogen, halogen atom, amino, urea groups, amino C
1-6alkyl, alkylsulfonyl C
1-6alkyl, carboxyl, C
1-6alkyl, halo C
1-6alkyl, C
1-6alkoxyl group, formamyl, 3-8 unit cycloalkyl, 5-10 unit heterocyclic radical, phenyl, cycloalkyl wherein, heterocyclic radical and phenyl can by 1-3 R
4replaced, R
4be selected from hydrogen, halogen atom, hydroxyl C
1-6alkyl, hydroxyl, oxo, C
1-6alkoxyl group, C
1-6alkylamino, C
1-6alkyl sulfonyl-amino, C
1-6alkyl amino sulfonyl, C
1-6alkyl sulphonyl, halo C
1-6alkyl sulphonyl, 5-6 unit's heterocyclic radical or C
1-6the phenyl that alkyl replaces.
Be preferably:
Wherein,
L
1represent a key, phenyl, 5-6 unit heteroaryl;
L
2represent hydrogen, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkyl-carbonyl, cyano group, amino C
1-6alkyl, formamyl, 5-6 unit heteroaryl, above-mentioned C
1-6alkoxyl group can by 1-3 L
3replaced, L
3be selected from hydrogen, cyano group, amino C
1-6alkyl, formamyl, hydroxyl, C
1-6alkoxyl group, C
1-6alkylamino, two (C
1-6alkyl) amino, the first heterocyclic radical of 5-6;
R
1be selected from phenyl, containing 1-3 to be selected from O, S, N 5-6 unit heteroaryl, by 6 yuan of heteroaryls of oxo, phenyl wherein, heteroaryl can replace by 1-3 Y, Y is selected from halogen atom, hydroxyl, C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
1-6alkoxyl group, C
1-6alkylamino, two (C
1-6alkyl) amino, two (C
1-6alkyl) amino C
1-6alkoxyl group, C
1-6alkyl-carbonyl, sulfonamido or C
1-6alkyl sulfonyl-amino;
R
2be selected from
Wherein, A represents phenyl or 5-6 unit heteroaryl, and B represents 5-6 unit heterocyclic radical, 5-6 unit heteroaryl, 5-6 unit cycloalkyl, and n is 1,
Z represents hydrogen, C
1-6alkyl sulfonyl-amino or C
1-6alkyl amino sulfonyl.
Be preferably:
Wherein,
be selected from
R
1be selected from
R
2be selected from
Be preferably:
Wherein,
be selected from
R
1be selected from
R
2be selected from
Detailed Description Of The Invention
" halogen atom " of the present invention refers to fluorine atom, chlorine atom, bromine atoms, atomic iodine etc.Preferred fluorine atom and chlorine atom.
" halo " of the present invention refer to atom that in described group, any one can be substituted by above-mentioned " halogen atom " replace, can perhalogeno, i.e. all positions that can be substituted in halogen atom substituent group.
" C of the present invention
1-6alkyl " represent straight or branched containing the alkyl of 1-6 carbon atom; as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1; 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1,2-dimethyl propyl etc.Preferred C1-4 alkyl.
" C of the present invention
2-6thiazolinyl " refer to that the carbonatoms containing double bond is the straight or branched of 2-6 or the thiazolinyl of ring-type, as vinyl, 1-propenyl, 2-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-Ethyl-2-Methyl-1-propenyl, 1-Ethyl-2-Methyl-2-propenyl, 1,3-butadiene base, 1,3-pentadiene base, Isosorbide-5-Nitrae-pentadienyl, 2,4-pentadienyl, Isosorbide-5-Nitrae-hexadienyl, 2,4-hexadienyl, cyclopentenyl, 1，3-cyclopentadiene base, cyclohexenyl and 1，4-cyclohexadiene base etc.Double bond is optionally cis and trans.
" C of the present invention
2-6alkynyl " refer to containing triple bond carbonatoms and be the alkynyl of the straight or branched of 2-6, as ethynyl, 1-proyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 4-methyl-valerylene base, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1, 1-dimethyl-2-butyne base, 1, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2, 2-dimethyl-3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl etc.
" C of the present invention
1-8alkoxyl group " refer to term " C
1-8alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, 1-methyl ethoxy, butoxy, 1-methyl propoxy-, 2-methyl propoxy-, 1, 1-dimethylethyloxy, pentyloxy, 1-methylbutoxy group, 2-methylbutoxy group, 3-methylbutoxy group, 1, 1-dimethyl propoxy-, 1, 2-dimethyl propoxy-, 2, 2-dimethyl propoxy-, 1-ethylpropoxy, hexyloxy, 1-methyl pentyloxy, 2-methyl pentyloxy, 3-methyl pentyloxy, 4-methyl pentyloxy, 1, 1-dimethyl butoxy, 1, 2-dimethyl butoxy, 1, 3-dimethyl butoxy, 2, 2-dimethyl butoxy, 2, 3-dimethyl butoxy, 3, 3-dimethyl butoxy, 1-ethyl-butoxy, 2-ethyl-butoxy, 1, 1, 2-trimethylammonium propoxy-, 1, 2, 2-trimethylammonium propoxy-, 1-ethyl-1-methyl propoxy-and 1-Ethyl-2-Methyl propoxy-etc." C of the present invention
1-6alkoxyl group " refer in above-mentioned example containing the specific examples of 1-6 carbon atom.
" C of the present invention
1-6alkyl-carbonyl ", " C
1-6alkylamino ", " C
1-6alkyl amidine ", " C
1-6alkyl thiol ", " C
1-6alkyl sulphonyl ", " C
1-6alkyl sulfonyl-amino ", " C
1-6alkyl amino sulfonyl " refer to " C respectively
1-6alkyl " group that is connected with other structures by carbonyl, amino, amidino groups, sulfydryl, alkylsulfonyl, sulfuryl amino, amino-sulfonyl, wherein " C
1-6alkyl " as defined hereinabove.
" halo C of the present invention
1-6alkyl ", " carboxyl C
1-6alkyl ", " amino C
1-6alkyl ", " hydroxyl C
1-6alkyl ", " alkylsulfonyl C
1-6alkyl " refer to that halogen atom, carboxyl, amino, hydroxyl, alkylsulfonyl replace above-mentioned " C respectively
1-6alkyl " on one or more hydrogen atoms, and by the group that alkyl is connected with other structures, wherein " C
1-6alkyl " as defined hereinabove.
" halo C of the present invention
1-8alkoxyl group " refer to that " halogen atom " replaces above-mentioned " C
1-8alkoxyl group " on one or more hydrogen atoms, and by the group that alkoxyl group is connected with other structures, described " halogen atom " and " C
1-6alkoxyl group " as defined hereinabove.
" halo C of the present invention
1-6alkyl sulphonyl " refer to that " halogen atom " replaces above-mentioned " C
1-6alkyl " on one or more hydrogen atoms, and by group that alkylsulfonyl is connected with other structures.
" two (C of the present invention
1-6alkyl) amino " refer to that in amino, any two atoms that can be substituted are by above-mentioned " C
1-6alkyl " replaced, and by the amino group be connected with other structures.
" two (C of the present invention
1-6alkyl) amino C
1-6alkoxyl group " refer to above-mentioned " two (C
1-6alkyl) amino " pass through " C
1-6alkoxyl group " group that is connected with other structures, described " C
1-6alkoxyl group " as defined hereinabove.
" 3-14 unit cycloalkyl " of the present invention refers to that the paraffin section of 3-14 carbon atom removes the derivative cyclic alkyl of a hydrogen atom, comprises 3-8 unit cycloalkyl, 6-14 unit also ring cycloalkyl.
3-8 unit cycloalkyl, refer to that the paraffin section of 3-8 carbon atom removes the derivative cyclic alkyl of a hydrogen atom, the example includes but not limited to: cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, methylcyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl, cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadiene base, cyclooctene base, 1, 5-cyclooctadiene base etc." 3-8 unit cycloalkyl " of the present invention, " 5-6 unit cycloalkyl " refer to specific examples that is individual containing 3-8 in above-mentioned example, a 5-6 carbon atom.
6-14 unit also ring cycloalkyl, refer to and share by two or more ring texturees the 6-14 cyclic group that two adjacent carbon atoms are formed each other, the example includes but not limited to: two rings [3.1.0] hexyl, two rings [4.1.0] heptane base, two rings [2.2.0] hexyl, two rings [3.2.0] heptane base, two rings [4.2.0] octyl, octahydro pentalene base, octahydro-1H-indenyl, decahydronaphthalene naphthyl, ten tetrahydrochysene phenanthryl, own-2-the thiazolinyl of dicyclo [3.1.0], dicyclo [4.1.0]-3-in heptan thiazolinyl, dicyclo [3.2.0]-3-in heptan thiazolinyl, pungent-3-the thiazolinyl of dicyclo [4.2.0], 1, 2, 3, 3a-tetrahydrochysene pentalene base, 2, 3, 3a, 4, 7, 7a-six hydrogen-1H-indenyl, 1, 2, 3, 4, 4a, 5, 6, the octahydro naphthyl of 8a-, 1, 2, 4a, 5, 6, 8a-hexahydro-naphthyl, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10-decahydro phenanthryl etc.
" 6-14 unit aryl " of the present invention refers to that annular atoms is the monovalent moiety that the cyclic nonaromatics removing hydrogen atom of 6-14 unit carbon atom obtains, and comprises 6-8 unit's aryl and 8-14 unit fused ring aryl.6-8 unit aryl comprises phenyl, cyclooctatetraenyl etc.8-14 unit fused ring aryl refers to and shares by two or more aromatic rings the condensed ring group that two adjacent carbon atoms are formed each other, comprise naphthyl, anthryl and phenanthryl etc., also comprise 8-14 unit fractional saturation fused ring aryl, such as benzo 3-8 unit cycloalkyl, specific examples is as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, Isosorbide-5-Nitrae-dihydro naphthyl etc.Preferred 6-10 unit aryl, refers to that in above-mentioned " 6-14 unit aryl ", annular atoms number is the specific examples of 6-10 unit.
" 5-14 unit heteroaryl " of the present invention, its annular atoms, except carbon atom, also comprises one or more heteroatoms, and described " heteroatoms " is selected from N, S, O, CO, SO and/or SO
2deng.Heteroaryl is by carbon or heterocyclic atom bonding.Comprise the thick heteroaryl of 5-8 unit's heteroaryl and 8-14 unit.
5-8 unit heteroaryl, preferred 5-6 unit heteroaryl, include but not limited to pyrryl, imidazolyl, pyrazolyl, 1,2,3-triazoles base, 1,2,4-triazolyl, pyridyl, furyl, thienyl,
azoles base, different
azoles base, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-
di azoly, 1,2,4-
di azoly, 1,2,5-
di azoly, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrazyl,
triazolyl, 2H-1,2-
piperazine base, 4H-1,2-
piperazine base, 6H-1,2-
piperazine base, 2H-1,3-
piperazine base, 4H-1,3-
piperazine base, 6H-1,3-
piperazine base, 2H-1,4-
piperazine base, 4H-1,4-
piperazine base, different
piperazine base, pyridazinyl, pyrimidyl and pyrazinyl etc.;
The thick heteroaryl of 8-14 unit, refer to that sharing two adjacent atoms containing 8-14 annular atoms (wherein at least containing a heteroatoms) each other by two or more hetero-aromatic rings couples together the condensed cyclic structure formed, and includes but not limited to benzofuryl, isobenzofuran-base, benzothienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl, indolizine base, indazolyl, phthalazinyl, quinoxalinyl, quinazolyl, benzodiazine base, benzisoxa
azoles base, benzo
piperazine base, benzimidazolyl-, pyridopyridine base, pyrazolo [3,4-b] pyridyl, purine radicals, acridyl and xanthenyl etc.
" 3-14 unit heterocyclic radical " of the present invention refers to that described " heteroatoms " is selected from N, S, O, CO, SO and/or SO containing one or more heteroatomic 3-14 cyclic group
2deng.Comprise 3-8 unit's heterocyclic radical and 6-14 unit fused heterocycle base.3-8 unit heterocyclic radical, refers to the heterocyclic radical containing 3-8 annular atoms (wherein at least containing a heteroatoms), preferred 5-6 unit heterocyclic radical.Specific examples includes but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline base, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-4H-1,3-oxazinyl, ethylenimine base, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, imidazolidyl, pyrazolidyl, tetrahydrofuran base, Isosorbide-5-Nitrae-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl etc.
6-14 unit fused heterocycle base, refers to that sharing two adjacent atoms containing 6-14 annular atoms (wherein at least containing a heteroatoms) each other by two or more ring texturees couples together the condensed cyclic structure formed, the first fused heterocycle base of preferred 6-10,
As the structure that benzo 3-8 unit heterocyclic radical is formed, 3-8 unit heterocyclic radical and 3-8 unit heterocyclic radical formed structure etc., specific examples includes but not limited to: 1,3-dihydro benzo furyl, benzo [d] [1.3] dioxa cyclopentenyl, isoindoline base, chromanyl, 1,2,3,4-Pyrrolidine also [3,4-c] pyrroles,
tetramethylene Pyrrolidine base, pentamethylene Pyrrolidine base, azetidine imidazolidyl,
deng
" 5-10 unit heterocyclic radical " of the present invention, " 5-6 unit heterocyclic radical " refer to that in above-mentioned " 3-14 unit heterocyclic radical ", annular atoms number is the specific examples that 5-10 is first, 5-6 is first.
" 8-14 unit fused heterocycle base " of the present invention refers to that in above-mentioned " 6-14 unit fused heterocycle base ", annular atoms number is the specific examples of 8-14 unit.
Of the present invention
refer to two kinds of cis-trans-isomers, Z configuration or E, concrete finger, as compound 1,
representative:
E:
and/or Z configuration:
Its pharmacy acceptable salt of particularly preferred compound or its steric isomer comprise:
The method that above-claimed cpd of the present invention can adopt the present invention to describe and/or other technology known to persons of ordinary skill in the art are synthesized, but are not limited only to following methods.
Work as R
2for
time, synthetic method is as follows:
Reaction equation:
Reactions steps:
(1) preparation of TM1
In there-necked flask, add bromo-2, the 3-dihydro-1H-1-Indanone O-methyloxime SM1(of 5-with reference to US2007/99954A1 (2007) preparation), new steaming tetrahydrofuran (THF), under the dry ice bath-75 DEG C of conditions, add n-Butyl Lithium (1.4 equivalent) with syringe, stirring reaction 0.5 hour.Add boric acid isopropyl ester (1.4 equivalent) again, continue stirring reaction, then remove the dry ice bath, mixed solution slowly rises to room temperature, stirring reaction.Then 2M hydrochloric acid is added, stirring reaction.After reaction terminates, add saturated sodium-chloride water, separatory, organic phase is dry, and concentrating under reduced pressure, silica gel column chromatography separating purification, obtains intermediate TM1.
(2) preparation of TM2
Take iso methyl nicotinate SM3 to join in appropriate tetrahydrofuran (THF), stir, add sodium hydride (1.2 equivalent).Stirring reaction, then uses constant pressure funnel, drips the tetrahydrofuran solution of SM2 (1 equivalent), dropwises.Under room temperature condition, stirring reaction.After completion of the reaction, add suitable quantity of water, separatory, get organic phase concentrating under reduced pressure, obtain intermediate TM2.
(3) preparation of TM3
1.3-dione compounds TM2 is dissolved in dehydrated alcohol, stirs, after dissolving completely, add glacial acetic acid (1 equivalent).Constant pressure funnel, dropwise adds the ethanolic soln containing hydrazine hydrate (1 equivalent), and after dropwising, stirred overnight at room temperature is reacted.After completion of the reaction, add a small amount of saturated sodium bicarbonate solution, add water, extraction into ethyl acetate, separatory, by organic phase rotary evaporation except desolventizing, recrystallization, obtains intermediate TM3.
(4) preparation of TM4 and isomer TM4 ' thereof
In reaction flask, be dissolved in appropriate anhydrous methanol by TM3 and TM1 (1 equivalent), add Red copper oxide (0.075 equivalent), under room temperature condition, uncovered reaction, then reactant TM1 runs out.Suction filtration, by filtrate reduced in volume, silica gel column chromatography, obtains intermediate TM4 or its isomer TM4 ', is directly used in next step without purification.
(5) preparation of TM5 and isomer TM5 ' thereof
The mixing solutions of the 1.4-dioxane of midbody compound TM4 or its isomer TM4 ' and hydrochloric acid (being greater than 15 equivalents), stirs, is heated to 100 DEG C of sustained reactions.Stop heating, add proper amount of acetone, be heated to 100 DEG C of reactions.Room temperature is down to by mixed solution, with the neutralization of 1M sodium hydroxide solution, adds extraction into ethyl acetate, separatory, organic phase washed with water, anhydrous sodium sulfate drying, concentrating under reduced pressure, silica gel column chromatography separating purification, obtains intermediate TM5 or its isomer TM5 '.
(6) Compound I ' preparation
Under 80 DEG C of conditions, in the ethanolic soln of intermediate TM5 or its isomer TM5 ', add oxammonium hydrochloride (3 equivalent) and sodium-acetate (3 equivalent), heating reflux reaction.Solution after reaction terminates is cooled to room temperature, is evaporated to dry, obtains Compound I '.
In reaction equation, R
1, L
1and L
2as defined hereinabove.
Arbitrary compound pharmacy acceptable salt shown in general formula of the present invention (I), (II), (III) or (IV) refers to the salt by pharmaceutically acceptable, non-toxic alkali or acid preparation, comprises organic acid salt, inorganic acid salt, organic alkali salt, inorganic base salts.Organic acid salt comprises the salt of formic acid, acetic acid, Phenylsulfonic acid, phenylformic acid, tosic acid, camphorsulfonic acid, citric acid, methylsulfonic acid, ethyl sulfonic acid, propanesulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, glactaric acid, pamoic acid, pantothenic acid, succsinic acid, tartrate etc.Inorganic acid salt comprises the salt of Hydrogen bromide, spirit of salt, nitric acid, sulfuric acid, phosphoric acid etc.
Organic alkali salt comprises primary, secondary and tertiary amine, be substituted amine and comprise naturally occurring replacement amine, cyclammonium and basic ion-exchange resins, be selected from trimethyl-glycine, caffeine, choline, N, N ' salt of-dibenzyl-ethylenediamin, diethylamine, 2-Diethylaminoethanol, 2-dimethylamino-ethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Hai Baming, isopropylamine, methylglucosamine, morpholine, piperazine, piperidines, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.Native amino hydrochlorate is as the salt of glycine, L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, nor-leucine, tyrosine, Gelucystine, halfcystine, methionine(Met), proline(Pro), oxyproline, Histidine, ornithine, Methionin, arginine, Serine etc.Inorganic base salts comprises the salt of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminium, iron, ketone, ferrous iron, manganese, bivalent manganese etc.
Application claims protection (I), (II), (III) or (IV) compound " steric isomer "; the compounds of this invention contains one or more asymmetric center, thus can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.The compounds of this invention has asymmetric center, and this kind of asymmetric center respectively independently will produce two optical isomers, and scope of the present invention comprises all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all stereoisomeric forms in any ratio of these compounds.Comprise the steric isomer of formula (I) or (II) compound, geometrical isomer and cis-trans-isomer, comprise enantiomer and composition thereof, as racemoid.Different isomeric forms ordinary methods is separable or split out, or any appointment isomeric form can obtain by ordinary method or with three-dimensional special or method of asymmetric synthesis.
General formula of the present invention (I), (II), the arbitrary compound shown in (III) or (IV) have two or more chiral centre.What synthesis obtained is raceme, and the compound of required enantiomer-pure can be obtained by the method for chiral separation: can by having the chromatography (image height compacting standby liquid phase, supercritical fluid chromatography) of chiral stationary phase.Chirality padding includes but not limited to: ChiralcelOJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
The present invention is the claimed pharmaceutical composition comprising general formula recited above (I), (II), (III) or (IV) arbitrary compound, its pharmacy acceptable salt or its steric isomer and other one or more antineoplastic agents and immunosuppressor further.Described antineoplastic agent and immunosuppressor, as anti-metabolism, include but are not limited to methotrexate, capecitabine, gemcitabine, doxifluridine; Growth factor receptor inhibitors class, includes but are not limited to pazopanib, imatinib, Gefitinib; Target class, includes but are not limited to Trastuzumab, rhuMAb-VEGF, Rituximab, Herceptin; Mitotic inhibitor class, includes but are not limited to taxol, vinorelbine, docetaxel, Dx, hydroxycamptothecine, mitomycin, epirubicin, pirarubicin, bleomycin; Antitumor hormones, includes but are not limited to letrozole, tamoxifen, fulvestrant, music score of Chinese operas Rayleigh, flutamide, Leuprolide, Anastrozole; Alkylating agent class, includes but are not limited to ifosfamide, busulfan, endoxan, carmustine, nimustine, semustine; Metal platinum class, includes but are not limited to carboplatin, cis-platinum, oxaliplatin, network platinum; Topoisomerase enzyme inhibitor, includes but are not limited to Topotecan; Immunosuppression class, includes but are not limited to everolimus.
The present invention is the claimed pharmaceutical composition comprising above-mentioned general formula (I), (II), the arbitrary compound shown in (III) or (IV), its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner further, can make pharmaceutically acceptable arbitrary formulation.With oral, parenteral, rectum or be applied to through modes such as lung administrations the patient needing this treatment.During for oral administration, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.When making oral preparations, suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc. can be added.During for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, the ordinary method in existing pharmacy field can be adopted to produce, during preparation injection, can not additives be added, also can add suitable additives according to the character of medicine.During for rectal administration, can be made into suppository etc.For through lung administration time, can be made into inhalation or sprays etc.Formula (I) containing physiology significant quantity in per unit preparation, (II), (III) or the compound 0.01g ~ 10g shown in (IV) can be 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 10g etc.
Invention further provides general formula of the present invention (I), (II), or the compound shown in (IV) (III), its pharmacy acceptable salt or its steric isomer are used for the treatment of the disease relevant to kinases, particularly with Ab1, Bcr-Ab1, Bmx, BTK, b-RAF, c-RAF, CSK, cSRC, Fes, FGFR3, Flt3, IKK α, IKK β, JNK1 α 1, JNK2 α 2, Lck, Met, MKK4, MKK6, p70S6K, PAK2, PDGFR α, PKA, PKC α, PKD α, ROCK-II, Ros, Rsk1, SAPK2 α, SAPK2 β, SAPK3, SAPK4, SGK, Syk, application in the medicine of the disease that the kinases such as Tie2 with TrkB are relevant.
Present invention also offers general formula of the present invention (I), (II), (III) or the compound shown in (IV), its pharmacy acceptable salt or its steric isomer treats and/or prevents by kinases in preparation, specifically refer to a-RAF, application in the medicine of b-RAF, the c-RAF particularly cancer-related diseases that causes of b-RAF kinases abnormal activation or disorder or non-cancer-related diseases.Cancer-related diseases of the present invention includes but are not limited to: brain tumor, lung cancer, lung cancer in non-cellule type, squamous cell, bladder cancer, cancer of the stomach, ovarian cancer, peritoneal cancer, carcinoma of the pancreas, mammary cancer, head and neck cancer, cervical cancer, carcinoma of endometrium, the rectum cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin lymphoma, neurospongioma, glioblastoma multiforme, glioma sarcomatosum, prostate cancer, thyroid carcinoma, female reproductive tract cancer, carcinoma in situ, lymphoma, histocytic lymphoma, neurofibromatosis, thyroid carcinoma, osteocarcinoma, skin carcinoma, the cancer of the brain, colorectal carcinoma, carcinoma of testis, small cell lung cancer, gastrointestinal stromal tumor, tumor of prostate, mast cell tumor, multiple myeloma, melanoma, glioma, glioblastoma multiforme, astrocytoma, neuroblastoma, sarcoma etc.Non-cancer-related diseases includes but are not limited to skin or prostatic hyperplasia of prostate etc.
The compounds of this invention has the following advantages:
(1) formula (I), (II), (III) or (IV) compound, its pharmacy acceptable salt or its steric isomer have excellent b-RAF kinase inhibiting activity and selectivity;
(2) formula (I), (II), (III) or (IV) compound, its pharmacy acceptable salt or its steric isomer demonstrate good biologically stable, and effect is more lasting, and bioavailability is high;
(3) the compounds of this invention preparation technology is simple, and medicine purity is high, steady quality, is easy to carry out large-scale commercial production.
Set forth the beneficial effect of the compounds of this invention below by way of external pharmacology activity experiment further, but this should be interpreted as the compounds of this invention only has following beneficial effect.
the external zymetology activity experiment of experimental example 1 the compounds of this invention
Trial-product: the compound 2 that embodiment 2 prepares
Reference substance: SB-590885, commercial
Experimental technique:
Implication representated by the abbreviation of following test Chinese and English is as follows:
HEPES: hydroxyethyl piperazine second thiosulfonic acid;
Brij-35: Brij-35;
EDTA: ethylenediamine tetraacetic acid (EDTA);
Fluorescein-MAP2K1: fluorescein-labelled MAP2K1;
ATP: Triphosaden;
DMSO: dimethyl sulfoxide (DMSO);
MgCl
2: magnesium chloride.
1. test preparation of reagents
1. 1 times of kinase buffer liquid (50mM HEPES, PH7.5,10mM MgCl
2, 1mM EGTA, 0.01%Brij-35);
2. 2 times of kinase solution (add corresponding kinases and prepare 2 times of kinase solution in 1 times of kinase buffer liquid, final concentration is b-RAF3.5nM, b-RAF V599E0.35nM);
3. 4 times of substrate solutions (add Fluorescein-MAP2K1 and ATP in 1 times of kinase buffer liquid, prepare 4 times of solution, two kinds of kinase substrate Fluorescein-MAP2K1 final concentrations are 0.2 μM, wherein in b-RAF kinases 4 times of substrate solutions, ATP concentration is 0.5 μM, and in b-RAF V599E kinases 4 times of substrate solutions, ATP concentration is 1.5 μMs);
4. 2 times are detected solution (prepare 2 times and detect solution, final concentration is antibody 2nM, EDTA10mM);
5. 4 times of compound solutions (adopt 100%DMSO to prepare the solution of final concentration 100 times, 4 times of gradient dilutions, 10 concentration, then 25 times are diluted with kinase buffer liquid respectively, be mixed with each compound solution of the gradient dilution of final concentration 4 times, final compound concentration maximum concentration is 10000nM);
2. get 2.5 μ L4 times compound solutions and add 384 orifice plates, multiple hole;
3. add 5 μ L2 times enzyme solution and hatch 10 minutes;
4. then add 2.5 μ L4 times substrate and ATP solution, room temperature, hatches 1 hour;
5. finally add 10 μ L and detect solution termination reaction, after 30 minutes, microplate reader reading of data;
6.IC50。
Calculate RFU ratio
Calculate inhibiting rate (%)=(maximum value-sample ratio)/(maximum value-minimum value) × 100
Adopt Xlfit software to carry out curve fitting, draw IC50 value.
Experimental result and conclusion:
The external zymetology inhibit activities of table 1 the compounds of this invention
From table 1, the compounds of this invention 2 is compared with contrast medicine SB-590885, suitable to b-RAF kinases and the kinase whose inhibit activities of b-RAF V599E, can be used for treating illness or the patient's condition that the disease, particularly b-RAF V599E kinases relevant with b-RAF V599E kinases to b-RAF kinases cause.
the pharmacokinetic of experimental example 2 the compounds of this invention in male SD rat body
Trial-product: the compound 2 that embodiment 2 prepares
Contrast medicine: SB-590885, commercial
（SB-590885）
Experimental Animals Male SD rat, 3/route of administration/compound, body weight 220-250g.
Dissolving scheme
The compounds of this invention 2:1%DMSO+15%HP-β-CD solution+84% physiological saline.
Contrast medicine SB-590885:1%DMSO+10%HP-β-CD solution+89% physiological saline;
Experimental technique
Administration trial-product intravenous injection administration (IV), dosage is 1mg/kg, administration volume 1mL/kg; Trial-product gastric infusion (PO), dosage is 2mg/kg, administration volume 2mL/kg.
To take a blood sample quiet pushing away after administration 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours; After gastric infusion 0.17 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, each time point takes 200 μ about L whole bloods, centrifugal 6 minutes separated plasmas in the supercentrifuge of 8000rpm, blood plasma is frozen in-80 DEG C of refrigerators.
SB-590885 and compound 2 Plasma sample analysis: get 20 μ L blood plasma, add mark (PLX-4032, commercial) in 200 μ L, 1500 revs/min of vortex 5min, then 12000 revs/min centrifugal 5 minutes, get supernatant liquor 100 μ L and add 100 μ L water, vortex mixes; LC-MS/MS is to be analyzed.
Experimental result: after male SD rat oral administration, the compounds of this invention bioavailability (F%) is 27.86%, contrast medicine SB-590885 lifeless matter availability.
Conclusion: the compounds of this invention 2 is compared with contrast medicine, and the bioavailability in male rat body is higher, and clinical administration dosage is low, greatly saves treatment cost, has obvious progress.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
embodiment 15-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-5-(pyridin-4-yl)-1H-pyrazol-1-yl)-2,3-dihydro-1H-
the preparation of 1-Indanone oxime (compound 1)
(1) preparation of (1-(methoxyimino)-2,3-dihydro-1H-indenes-5-base) boric acid
To in there-necked flask (100mL), add bromo-2,3-dihydro-1H-1-Indanone O-methyloxime (1.2g, 5mmol) of 5-, newly steam tetrahydrofuran (THF) (40mL).Under the dry ice bath-75 DEG C of conditions, add n-Butyl Lithium (2.8ml, 2.5M), stirring reaction 0.5 hour.Add boric acid isopropyl ester (1.8g, 10mmol) with syringe again, continue stirring after 1 hour, remove the dry ice bath, mixed solution slowly rises to room temperature, stirs 0.5 hour.After completion of the reaction, add the hydrochloric acid (50mL) of 2M, stir 2 hours.After reaction terminates, add saturated sodium-chloride water (50mL), separatory, get organic phase, rotary evaporation is except desolventizing, and residuum obtains product (527mg, productive rate 51%) through silica gel column chromatography (methylene dichloride: methyl alcohol=20:1) separation and purification.
(2) preparation of 1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(pyridin-4-yl)-1,3-propanedione
To in reaction flask (100mL), add iso methyl nicotinate (707mg, 5mmol) and tetrahydrofuran (THF) (20mL), stir, then add sodium hydride (252mg, 6.0mmol).Stir after 0.5 hour, slowly drip with constant pressure funnel and be dissolved with 1-(4-(2-(dimethylamino) oxyethyl group) phenyl) ethyl ketone (1.04g, tetrahydrofuran (THF) (30mL) solution 5mmol), dropwises for 0.5 hour.Under room temperature condition, stirring is spent the night.After completion of the reaction, add water (60mL) and ethyl acetate (40mL), separatory, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains product (1.3g, productive rate 83%).
(3) preparation of N, N-dimethyl-2-(4-(5-(pyridin-4-yl)-1H-pyrazole-3-yl) phenoxy group) ethamine
By 1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(pyridin-4-yl)-1,3-propanedione (1.31g, 4.2mmol) be dissolved in dehydrated alcohol (40mL), add glacial acetic acid (212mg, 3.5mmol), stir.At ambient temperature, with constant pressure funnel, dropwise add the ethanolic soln of hydrazine hydrate (312mg, 5.3mmol) containing 85%, after dropwising, stirred overnight at room temperature.After completion of the reaction, concentrating under reduced pressure, in resistates, add saturated sodium bicarbonate solution (40mL) and ethyl acetate (40mL), separatory, gets organic phase, concentrating under reduced pressure, recrystallization, obtains product (0.9g, productive rate 70%).
(4) preparation of 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-5-(pyridin-4-yl)-1H-pyrazol-1-yl)-2,3-dihydro-1H-1-Indanone O-methyloximes
By N, N-dimethyl-2-(4-(5-(pyridin-4-yl)-1H-pyrazole-3-yl) phenoxy group) ethamine (620mg, 2mmol) with (1-(methoxyimino)-2,3-dihydro-1H-indenes-5-base) boric acid (412mg, 2mmol) be dissolved in anhydrous methanol (15mL), add Red copper oxide (20mg, 0.14mmol) again.Under room temperature condition, uncovered reaction about 72 hours, reactant (1-(methoxyimino)-2,3-dihydro-1H-indenes-5-base) boric acid runs out.Suction filtration, by filtrate reduced in volume, residuum obtains 5-(3-(4-(2-(dimethylin) oxyethyl group) phenyl)-5-(pyridin-4-yl)-1H-pyrazol-1-yl)-2 through silica gel column chromatography (sherwood oil: ethyl acetate=1:3) separation and purification, the mixture (0.34g) of 3-dihydro-1H-1-Indanone O-methyloxime crude product and isomers thereof, not purified be directly used in next step reaction.
(5) preparation of 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-5-(pyridin-4-yl)-1H-pyrazol-1-yl)-2,3-dihydro-1H-1-Indanones
To in reaction flask (50mL), add 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-5-(pyridin-4-yl)-1H-pyrazol-1-yl)-2, the mixture (0.28g) of 3-dihydro-1H-1-Indanone O-methyloxime crude product and isomers thereof, 2M hydrochloric acid (5mL) and 1.4-dioxane (10mL), stir, be heated to 100 DEG C, react 1 hour, stop heating, add acetone (8mL), be heated to 100 DEG C, react 2 hours.Room temperature is down to by mixed solution, being neutralized to pH with 1M sodium hydroxide solution is 7, add ethyl acetate (20mL) extraction, separatory, get organic phase washed with water, dried over sodium sulfate, concentrating under reduced pressure, residuum obtains the mixture (151mg) of 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-5-(pyridin-4-yl)-1H-pyrazol-1-yl)-2,3-dihydro-1H-1-Indanones and isomers thereof through silica gel column chromatography (methylene dichloride: methyl alcohol=20:1) separation and purification.
(6) preparation of 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-5-(pyridin-4-yl)-1H-pyrazol-1-yl)-2,3-dihydro-1H-1-Indanone oximes
To in reaction flask (50mL), add 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-5-(pyridin-4-yl)-1H-pyrazol-1-yl)-2, the mixture (150mg) of 3-dihydro-1H-1-Indanone and isomers thereof, oxammonium hydrochloride (69mg, 1mmol), sodium acetate (82mg, 1.0mmol) with dehydrated alcohol (20mL), be heated to backflow, react about 3 hours.After completion of the reaction, mixed solution is cooled to room temperature, concentrating under reduced pressure, and residuum is prepared liquid phase separation through high pressure and obtained product (15mg).
Molecular formula: C
27h
27n
5o
2molecular weight: 453.54LC-MS (m): 454.3 [M+H]
+
1H-NMR(400MHz,MeOD)δ：2.40(s,6H),2.85(t,2H),2.97(m,2H),3.07(m,2H),4.18(t,2H),7.05(d,2H),7.16(s,1H),7.24(d,1H),7.36(d,2H),7.40(s,1H),7.69(d,1H),7.85(m,2H),8.51(m,2H).
embodiment 25-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1-(pyridin-4-yl)-1H-pyrazoles-5-base)-2,3-dihydro-1H-
the preparation of 1-Indanone oxime (compound 2)
(1) preparation of 1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(1-(methoxyimino)-2,3-dihydro-1H-indenes-5-base)-2-propylene-1-ketone
By 1-(methoxyimino)-2,3-dihydro-1H-indenes-5-formaldehyde (2.5g, 13mmol) with 1-(4-(2-(dimethylamino) oxyethyl group) phenyl) ethyl ketone (2.75g, 13mmol) be dissolved in dehydrated alcohol (50mL), add sodium hydroxide (1.04g, 26mmol), stirred overnight at room temperature.LC-MS instrument monitoring reaction end.After completion of the reaction, suction filtration obtains faint yellow solid (3.73g, productive rate 76%).
(2) preparation of 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1-(pyridin-4-yl)-4,5-dihydro-1 h-pyrazole-5-base)-2,3-dihydro-1H-1-Indanone O-methyloximes
By 1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(1-(methoxyimino)-2,3-dihydro-1H-indenes-5-base)-2-propylene-1-ketone (3.73g, 9.8mmol) be dissolved in dehydrated alcohol (30mL), add 4-hydrazino pyridine hydrochloride (1.43g, 9.8mmol) with sodium hydroxide (1.2g, 30mmol).Mixed solution stirs 8 hours under 80 DEG C of conditions, and thin-layer chromatography (methylene chloride/methanol=10:1) monitors reaction end.After completion of the reaction, concentrating under reduced pressure is except desolventizing, and residuum silica gel column chromatography separating purification obtains product (2.3g, productive rate 50%).
(3) preparation of 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1-(pyridin-4-yl)-1H-pyrazoles-5-base)-2,3-dihydro-1H-1-Indanone O-methyloximes
By compound 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1-(pyridin-4-yl)-4,5-dihydro-1 h-pyrazole-5-base)-2,3-dihydro-1H-1-Indanone O-methyloxime (1g, 2.1mmol) be dissolved in methylene dichloride (50mL), add Manganse Dioxide (3.3g, 38mmol), stir 3 hours under 50 DEG C of conditions.LC-MS instrument monitoring reaction end.After completion of the reaction, by diatomite filtration, removing Manganse Dioxide, rotary evaporation is except desolventizing, and residuum silica gel column chromatography separating purification obtains product (0.69g, productive rate 71%).
(4) preparation of 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1-(pyridin-4-yl)-1H-pyrazoles-5-base)-2,3-dihydro-1H-1-Indanones
By 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1-(pyridin-4-yl)-1H-pyrazoles-5-base)-2,3-dihydro-1H-1-Indanone O-methyloxime (0.4g, 0.86mmol) be dissolved in dioxane (10mL), drip 6N hydrochloric acid (3mL), acetone (1mL), stir under 80 DEG C of conditions and spend the night, LC-MS instrument monitoring reaction end.After completion of the reaction, rotary evaporation is except desolventizing, residuum is placed in ice-water bath, adds saturated sodium bicarbonate solution, adjust ph to 8, dichloromethane extraction, get organic over anhydrous dried over sodium sulfate, filter, concentrating under reduced pressure, residuum obtains product (0.21g, productive rate 56%) through silica gel column chromatography separating purification.
(5) preparation of 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1-(pyridin-4-yl)-1H-pyrazoles-5-base)-2,3-dihydro-1H-1-Indanone oximes
By 5-(3-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1-(pyridin-4-yl)-1H-pyrazoles-5-base)-2,3-dihydro-1H-1-Indanone (0.3g, 0.68mmol) be dissolved in ethanol (10mL), add oxammonium hydrochloride (160mg, 2.3mmol) with sodium acetate (0.34g, 4mmol), room temperature for overnight, LC-MS instrument monitoring reaction end.After completion of the reaction, rotary evaporation is except desolventizing, and residuum obtains product (42mg, productive rate 14%) through preparative high performance liquid chromatography purifying.
Molecular formula: C
27h
27n
5o
2molecular weight: 453.54LC-MS (m/z): 454.2 [M+H]
+
1H-NMR(400MHz,MeOD)δ：2.51(s,6H),2.97(m,4H),3.07(m,2H),4.23(t,2H),7.00(s,1H),7.07(d,2H),7.24(d,1H),7.39(s,1H),7.43(m,2H),7.69(d,1H),7.90(d,2H),8.52(m,2H).
embodiment 35-(1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-4-(pyridin-4-yl)-1H-pyrazole-3-yl)-2,3-dihydro-1H-
the preparation of 1-Indanone oxime (compound 3)
(1) preparation of 5-(1H-pyrazole-3-yl)-2,3-dihydro-1H-1-Indanone O-methyloxime
To in reaction flask (100mL); add 1H-pyrazoles-3-boric acid (1.12g respectively; 10mmol), bromo-2, the 3-dihydro-1H-1-Indanone O-methyloxime (2.4g of 5-; 10mmol), sodium carbonate (3.2g; 30mmol), tetra-triphenylphosphine palladium (1.2g, 1mmol), toluene (20mL), ethanol (10mL) and water (5mL), under nitrogen protection; be heated to 80 DEG C, backflow is spent the night.After completion of the reaction, filter, by filtrate rotary evaporation except desolventizing, residuum obtains product (1.7g, productive rate 75%) through silica gel column chromatography separating purification.
(2) preparation of 5-(1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1H-pyrazole-3-yl)-2,3-dihydro-1H-1-Indanone O-methyloximes
Under room temperature condition, by 5-(1H-pyrazole-3-yl)-2,3-dihydro-1H-1-Indanone O-methyloxime (1.13g, 5mmol), N, N-dimethyl-2-(4-(4,4,5,5-tetramethyl--1,3,2-dioxaborinate-2-base) phenoxy group) second ammonia (2.91g, 10mmol), venus crystals (1.5g, 7.5mmol) and pyridine (0.79g, 10mmol) be dissolved in methylene dichloride (20mL), stir 12 hours.After completion of the reaction, filter, by filtrate rotary evaporation except desolventizing, residuum obtains product (1.1g, productive rate 56%) through silica gel column chromatography separating purification.
(3) preparation of 5-(the bromo-1-of 4-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1H-pyrazole-3-yl)-2,3-dihydro-1H-1-Indanone O-methyloximes
By 5-(1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1H-pyrazole-3-yl)-2,3-dihydro-1H-1-Indanone O-methyloxime (0.98g, 2.5mmol) with N-bromo-succinimide (0.54g, 3mmol) be dissolved in tetracol phenixin (15mL), under 80 DEG C of conditions, react 6 hours.After completion of the reaction, filter, filtrate is used successively water and saturated sodium-chloride water washing, rotary evaporation is except desolventizing, and residuum obtains product (0.7g, productive rate 60%) through silica gel column chromatography separating purification.
(4) preparation of 5-(1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-4-(pyridin-4-yl)-1H-pyrazole-3-yl)-2,3-dihydro-1H-1-Indanone O-methyloximes
To in reaction flask (100mL); add pyridine-4-boric acid (0.16g respectively; 1.3mmol), 5-(the bromo-1-of 4-(4-(2-(dimethylamino) oxyethyl group) phenyl)-1H-pyrazole-3-yl)-2; 3-dihydro-1H-1-Indanone O-methyloxime (0.6g; 1.3mmol), sodium carbonate (0.43g; 4mmol), N-bromo-succinimide (0.15g; 0.13mmol), toluene (5mL), ethanol (2mL) and water (1mL); under nitrogen protection; be heated to 80 DEG C, backflow is spent the night.After completion of the reaction, filter, by filtrate rotary evaporation except desolventizing, residuum obtains product (0.43g, productive rate 71%) through silica gel column chromatography separating purification.
(5) preparation of 5-(1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-4-(pyridin-4-yl)-1H-pyrazole-3-yl)-2,3-dihydro-1H-1-Indanones
By 5-(1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-4-(pyridin-4-yl)-1H-pyrazole-3-yl)-2,3-dihydro-1H-1-Indanone O-methyloxime (0.3g, 0.64mmol) be dissolved in dioxane (10mL), drip 6N hydrochloric acid (3mL), acetone (1mL), stir under 80 DEG C of conditions and spend the night.After completion of the reaction, by organic phase rotary evaporation except desolventizing, saturated sodium carbonate solution is added, adjust ph to 8, dichloromethane extraction, saturated sodium-chloride water washing, anhydrous sodium sulfate drying, filter, obtain product (0.15g, productive rate 53%) through silica gel column chromatography separating purification.
(6) preparation of 5-(1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-4-(pyridin-4-yl)-1H-pyrazole-3-yl)-2,3-dihydro-1H-1-Indanone oximes
By (5-(1-(4-(2-(dimethylamino) oxyethyl group) phenyl)-4-(pyridin-4-yl)-1H-pyrazole-3-yl)-2,3-dihydro-1H-1-Indanone (0.1g, 0.2mmol) be dissolved in ethanol (5mL), add oxammonium hydrochloride (40mg, 0.6mmol) sodium-acetate (0.17g, 2mmol), room temperature for overnight.After completion of the reaction, by organic phase rotary evaporation except desolventizing, saturated sodium carbonate solution is added, adjust ph to 8, dichloromethane extraction, saturated sodium-chloride water washing, anhydrous sodium sulfate drying, filter, obtain product (30mg, productive rate 33%) through high pressure preparative chromatography.
Molecular formula: C
27h
27n
5o
2molecular weight: 453.54LC-MS (m): 454.2 [M+H]
+
1H-NMR(400MHz,CDCl
3)δ：2.42(s,6H),2.84(t,2H),2.98(m,2H),3.05(m,2H),4.18(t,2H),7.03(d,2H),7.24(d,2H),7.38(d,1H),7.55(s,1H),7.61(d,1H),7.66(d,2H),8.03(s,1H),8.53(d,2H),9.32(s,1H).
embodiment 45-(5-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-2,3-dihydro-1H-
the preparation of 1-Indanone oxime (compound 5)
(1) preparation of 5-(5-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-2,3-dihydro-1H-1-Indanone O-methyloximes
By N, N-dimethyl-2-(4-(5-(pyridin-4-yl)-1H-pyrazole-3-yl) phenoxy group) ethamine (620mg, 2mmol) with (1-(methoxyimino)-2,3-dihydro-1H-indenes-5-base) boric acid (412mg, 2mmol) be dissolved in anhydrous methanol (15mL), add Red copper oxide (20mg, 0.14mmol) again.Under room temperature condition, uncovered reaction about 72 hours, reactant (1-(methoxyimino)-2,3-dihydro-1H-indenes-5-base) boric acid runs out.Suction filtration, by filtrate reduced in volume, residuum obtains 5-(5-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-2 through silica gel column chromatography (sherwood oil: ethyl acetate=1:3) separation and purification, the mixture (0.34g) of 3-dihydro-1H-1-Indanone O-methyloxime crude product and isomers thereof, not purified be directly used in next step reaction.
(2) preparation of 5-(5-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-2,3-dihydro-1H-1-Indanones
To in reaction flask (50mL), add 5-(5-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-2, the mixture (0.28g) of 3-dihydro-1H-1-Indanone O-methyloxime crude product and isomers thereof, 2M hydrochloric acid (5mL) and 1.4-dioxane (10mL), stir, be heated to 100 DEG C, react 1 hour, stop heating, add acetone (8mL), be heated to 100 DEG C, react 2 hours.Room temperature is down to by mixed solution, being neutralized to pH with 1M sodium hydroxide solution is 7, add ethyl acetate (20mL) extraction, separatory, get organic phase washed with water, dried over sodium sulfate, concentrating under reduced pressure, residuum obtains the mixture (151mg) of 5-(5-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-2,3-dihydro-1H-1-Indanones and isomers thereof through silica gel column chromatography (methylene dichloride: methyl alcohol=20:1) separation and purification.
(3) preparation of 5-(5-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-2,3-dihydro-1H-1-Indanone oximes
To in reaction flask (50mL), add 5-(5-(4-(2-(dimethylamino) oxyethyl group) phenyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)-2, the mixture (150mg) of 3-dihydro-1H-1-Indanone and isomers thereof, oxammonium hydrochloride (69mg, 1mmol), sodium acetate (82mg, 1.0mmol) with dehydrated alcohol (20mL), be heated to backflow, react about 3 hours.After completion of the reaction, mixed solution is cooled to room temperature, concentrating under reduced pressure, and residuum is prepared liquid phase separation through high pressure and obtained product (23mg).
Molecular formula: C
27h
27n
5o
2molecular weight: 453.54LC-MS (m): 454.3 [M+H]
+
1H-NMR(400MHz,MeOD)δ：2.36(s,6H),2.79(t,2H),2.97(m,2H),3.04(m,2H),4.12(t,2H),6.95(d,2H),7.12(s,1H),7.20(d,1H),7.25(d,2H),7.39(s,1H)7.65(d,1H),7.94(d,2H),8.58(d,2H).
Claims (4)
1. the compound shown in formula (I), its pharmacy acceptable salt or its steric isomer:
2. the pharmaceutical composition of compound as claimed in claim 1, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner, can make pharmaceutically acceptable arbitrary formulation.
3. pharmaceutical composition as claimed in claim 2, also containing one or more antineoplastic agents and immunosuppressor, be selected from anti-metabolism, growth factor receptor inhibitors class, target class, mitotic inhibitor class, antitumor hormones, alkylating agent class, metal platinum class, topoisomerase enzyme inhibitor, immunosuppression class.
4. the compound as described in claim as arbitrary in claim 1, its pharmacy acceptable salt or its steric isomer are preparing the application treated and/or prevented in the medicine of cancer-related diseases or the non-cancer-related diseases caused by kinases abnormal activation or disorder, the disease that described cancer is relevant is selected from lung cancer, squamous cell, bladder cancer, cancer of the stomach, ovarian cancer, peritoneal cancer, carcinoma of the pancreas, mammary cancer, head and neck cancer, cervical cancer, carcinoma of endometrium, the rectum cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, prostate cancer, thyroid carcinoma, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, osteocarcinoma, skin carcinoma, the cancer of the brain, colorectal carcinoma, carcinoma of testis, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, non-cancer-related diseases, is selected from skin or prostatic hyperplasia of prostate.
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| EP3558994A4 (en) * | 2016-12-23 | 2021-05-12 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides |
| WO2022196927A1 (en) * | 2021-03-15 | 2022-09-22 | (주)피알지에스앤텍 | Composition for prevention or treatment of neurofibromatosis type 2 syndrome |
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| SI3689868T1 (en) | 2016-12-01 | 2024-02-29 | Arvinas Operations, Inc. | Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders |
| US11173211B2 (en) | 2016-12-23 | 2021-11-16 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of rapidly accelerated Fibrosarcoma polypeptides |
| WO2020113094A1 (en) | 2018-11-30 | 2020-06-04 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
| KR20220024605A (en) * | 2019-06-17 | 2022-03-03 | 데시페라 파마슈티칼스, 엘엘씨. | Aminopyrimidine amide autophagy inhibitors and methods of use thereof |
| US11957759B1 (en) | 2022-09-07 | 2024-04-16 | Arvinas Operations, Inc. | Rapidly accelerated fibrosarcoma (RAF) degrading compounds and associated methods of use |
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| CN1471523A (en) * | 2000-09-21 | 2004-01-28 | ʷ | Imidazole derivatives as Raf kinase inhibitors |
| CN101815712A (en) * | 2007-08-01 | 2010-08-25 | 辉瑞有限公司 | Pyrazole compound and as the purposes of RAF inhibitor |
| WO2011025927A1 (en) * | 2009-08-28 | 2011-03-03 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
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| CN1471523A (en) * | 2000-09-21 | 2004-01-28 | ʷ | Imidazole derivatives as Raf kinase inhibitors |
| CN101815712A (en) * | 2007-08-01 | 2010-08-25 | 辉瑞有限公司 | Pyrazole compound and as the purposes of RAF inhibitor |
| WO2011025927A1 (en) * | 2009-08-28 | 2011-03-03 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
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| EP3558994A4 (en) * | 2016-12-23 | 2021-05-12 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides |
| WO2022196927A1 (en) * | 2021-03-15 | 2022-09-22 | (주)피알지에스앤텍 | Composition for prevention or treatment of neurofibromatosis type 2 syndrome |
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| C06 | Publication | ||
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| C53 | Correction of patent of invention or patent application | ||
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Address after: 210 room 134000, building 2, Kai Kai Road, Tonghua Economic Development Zone, Jilin, China Applicant after: Tonghua Jida Pharmaceutical Co., Ltd. Address before: 210 room 134000, building 2, Kai Kai Road, Tonghua Economic Development Zone, Jilin, China Applicant before: Tonghua Sihuan Pharm Co., Ltd. |
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Free format text: CORRECT: APPLICANT; FROM: TONGHUA SIHUAN PHARMACEUTICAL CO., LTD. TO: TONGHUA JIDA MEDICINE CO., LTD. |
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Effective date of registration: 20220530 Address after: Room 301, Building 3, East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing Patentee after: Beijing Aohe Pharmaceutical Research Institute Co.,Ltd. Address before: 134000 room 210, service building, No. 2, Jingkai Ring Road, Tonghua Economic Development Zone, Jilin Province Patentee before: TONGHUA JIDA PHARMACEUTICAL Co.,Ltd. |
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