CN103130775A - Indolinone derivatives serving as tyrosine kinase inhibitors - Google Patents
Indolinone derivatives serving as tyrosine kinase inhibitors Download PDFInfo
- Publication number
- CN103130775A CN103130775A CN2012104768923A CN201210476892A CN103130775A CN 103130775 A CN103130775 A CN 103130775A CN 2012104768923 A CN2012104768923 A CN 2012104768923A CN 201210476892 A CN201210476892 A CN 201210476892A CN 103130775 A CN103130775 A CN 103130775A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- mean
- amino
- unit
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CC1C(C*)(CCCl)C1 Chemical compound CC1C(C*)(CCCl)C1 0.000 description 6
- VMMJTOBEOULNLD-UHFFFAOYSA-N CN(C(CC1C2C1CN(C)C2)=O)c(cc1)ccc1N Chemical compound CN(C(CC1C2C1CN(C)C2)=O)c(cc1)ccc1N VMMJTOBEOULNLD-UHFFFAOYSA-N 0.000 description 1
- YPOGESCLINSNND-UHFFFAOYSA-N CN(C(CC1C2C1CN(C)C2)N)C(CC1)=CC=C1N Chemical compound CN(C(CC1C2C1CN(C)C2)N)C(CC1)=CC=C1N YPOGESCLINSNND-UHFFFAOYSA-N 0.000 description 1
- VVYWUQOTMZEJRJ-UHFFFAOYSA-N CNc(cc1)ccc1N Chemical compound CNc(cc1)ccc1N VVYWUQOTMZEJRJ-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to the technical field of medicine, and particularly relates to indolinone derivatives of general formula (I), deuterium of the derivatives, pharmaceutically acceptable salts of the derivatives or stereoisomer of the derivatives, wherein the indolinone derivatives serve as tyrosine kinase inhibitors, and R1, R2, R3, R4, R5, R6, R7, R8, R9, n, X and cycle A are defined as in the description. The invention further relates to preparation methods of the compounds, a pharmaceutical preparation comprising the compounds, and applications of the compounds, wherein the applications of the compounds include prevention or treatment of fibrosis diseases, treatment of excessive hyperplasia diseases, especially breast cancer, colorectal cancer and non-small cell lung cancer, anti-angiogenesis and/or reduction of vascular permeability.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to the dihydroindole ketone derivate as tyrosine kinase inhibitor, its deuterium is for thing, its pharmacy acceptable salt or its steric isomer, the preparation method of these compounds, contain these compounds, its deuterium is for thing, the pharmaceutical preparation of its pharmacy acceptable salt or its steric isomer and pharmaceutical composition, and these compounds, its deuterium is for thing, its pharmacy acceptable salt or its steric isomer are at preparation prevention or treatment fibrotic conditions and overmedication proliferative disease, mammary cancer particularly, colorectal carcinoma, lung cancer in non-cellule type, application in angiogenesis inhibitor and/or reduction vascular permeability.。
2, background technology
Vasculogenesis is the generation of neovascularity in tissue or organ, and under normal physiological condition, humans and animals is only in the situation that very specific, the limited vasculogenesis that carries out.For example, usually in the formation of wound healing, fetus and fetal development and corpus luteum, uterine endometrium and placenta, observe vasculogenesis.
Capillary vessel comprises endotheliocyte and pericyte, and they are surrounded by basement membrane.Vasculogenesis starts from the erosion to basement membrane by the enzyme of endotheliocyte and white corpuscle secretion.Then, liner stretches out by basement membrane at the endotheliocyte of intravascular space.The stimulator inducing endothelial cell migration of angiogenic is by the basement membrane corroded.Migrating cell carries out outside the place of mitotic division and propagation forming " bud " at the parent blood vessel endotheliocyte.The endothelium bud merges mutually, generates capillary loops, thereby produces neovascularity.
Protein tyrosine kinase is that a class is transferred to phosphate group the enzyme of the tyrosine residues that is positioned at protein substrate from ATP catalysis, and it works in normal cell growth.Many growth factor receptor proteins work by Tyrosylprotein kinase, and by this process influence signal, and then regulate Growth of Cells.For example, FGFR(Fibroblast growth factor receptor, fibroblast growth factor acceptor), VEGFR(Vascular endothelial growth factor receptor, vascular endothelial growth factor receptor) and PDGFR(Platelet-derived growth factor receptor, platelet derived growth factor receptor).Yet under certain conditions, these acceptors or sudden change or overexpression, become abnormal, causes that cell proliferation is uncontrolled, causes tumor growth, final disease---the cancer of knowing that causes.The growth factor receptor protein tyrosine kinase inhibitor, by suppressing above-mentioned phosphorylation process, plays the treatment cancer and is characterized as the disease of uncontrolled or abnormal cell growth with other.
Uncontrolled vasculogenesis is the sign of cancer.At Dr.Judah Folkman in 1971, propose, tumor growth depends on vasculogenesis, referring to Folkman, and New England Journal of Medicine, 285:1182-86(1971).According to Dr.Folkman in the situation that the other blood vessel of not growing to nourish tumour, tumour only can grow into certain size.In it is the most simply explained, this proposal is pointed out, once tumour has occurred, " survives ", and each increase of tumor cell group must be undertaken by the increase new capillaceous of assembling on tumour." surviving " of the tumour of understanding at present refers to phase before the blood vessel of tumor growth, and the tumor cell group that wherein accounts for several cubic millimeters of volumes and be no more than millions of cells can survive on existing host's microvascular.
Show, can treat tumour by the propagation that suppresses vasculogenesis rather than inhibition tumor cell itself.Vasculogenesis is relevant to a large amount of dissimilar cancers, and described cancer comprises the tumour of solid tumor and blood delivery.The solid tumor relevant to vasculogenesis includes but not limited to: rhabdosarcoma, retinoblastoma, Ewing sarcoma, neuroblastoma and osteosarcoma.Vasculogenesis is relevant to mammary cancer, prostate cancer, lung cancer and colorectal carcinoma.Vasculogenesis also with the Tumor-assaciated of blood delivery, the tumour of described blood delivery is as leukemia, lymphoma, any in multiple myeloma and various acute or chronic marrow tumor disease, the unrestricted propagation of white cell wherein occurs, and usually is attended by the blood coagulation of anaemia, weakening and the increase of lymphoglandula, liver and spleen.Also think, vasculogenesis plays a part certain in marrow is abnormal, described abnormal leukemogenesis, lymphoma and multiple myeloma.
Vasculogenesis plays a major role in cancer metastasis, if can suppress or eliminate the blood vessel source activity, although the tumour existence will not grown yet so.Under morbid state, prevent that vasculogenesis from can reduce the damage caused by the intrusion of new Microvasculature.Therapy for the control of angiogenic process may cause the removal of these diseases or alleviate.
Wherein, FGFR(Fibroblast growth factor receptor, fibroblast growth factor acceptor), VEGFR(Vascular endothelial growth factor receptor, vascular endothelial growth factor receptor) and PDGFR(Platelet-derived growth factor receptor, platelet derived growth factor receptor) to suppress vasculogenesis research more and more ripe for inhibitor.
In addition; lot of documents research is found; FGF(Fibroblast growth factor; fibroblast growth factor), VEGF(Vascular endothelial growth factor; vascular endothelial growth factor) and PDGF(Platelet-derived growthfactor; Thr6 PDGF BB) with fibrotic inducing and lasting implication (Levitzki, Cytokine & GrowthFactor Rev, 2004,15 (4): 229-35; Strutz et al., Kidney Int, 2000,57:1521-38; Strutz et al., 2003, Springer Semin Immunopathol, 24:459-76; Rice et al., 1999, Amer J Pathol, 155 (1): 213-221; Broekelmann et al., 1991, Proc Nat Acad Sci, 88:6642-6; Wynn, 2004, Nat Rev Immunol, 4 (8): 583-94).
The mouse of FGF1/FGF2 deficiency is at Long Term Contact tetracol phenixin (CCl
4) the remarkable reduction (Yu et al., 2003, Am J Pathol, 163 (4): 1653-62) that show afterwards hepatic fibrosis.Express and increase (Strutz et al. in the sex change of people's kidney interstitial fibers to the strong relevant FGF of interstitial scarring, 2000, Kidney Intl, 57:1521-38), increase equally (Barrios et al., 1997, Am J Physiol in experimental lung fibrosis model, 273 (2 Pt 1): L451-8), this reconfirms that the fibrosis in different tissues has the viewpoint of common base.
The expression increase of VEGF/VEGFR is relevant to a large amount of capillary blood vesseies and pulmonary fibrosis, and (X.-M Ou et al.InternationalImmunopharmacology 9 (2009): 70-79), VEGFR-2 inhibitor SU5416 has alleviated the mouse pulmonary fibrosis fibrous tissue pathology that bleomycin is induced.
In experimental model, the inhibition of PDGF weakens hepatic fibrosis and pnemnofibrosis, and the fibrosis in the hint different tissues can have common cause (Borkham-Kamphorst et al.2004, Biochem Biophys Res Commun; Rice et al., 1999, Amer J Pathol, 155 (1): 213-221).
Pulmonary fibrosis is one of respiratory disease four serious diseases, by Different types of etiopathogenises, is caused, is the final a kind of serious pathological condition due to Pulmonary Diseases, its cause of disease is complicated, poor prognosis, lack clinically effective treatment means, except Pirfenidone, the whole world pasts medical help at present.Wherein the Pirfenidone(structure is shown in following formula) play anti-fibrosis effect by suppressing TGF signal β path.
At present, the inhibitor listing that simultaneously acts on FGFR, VEGFR and PDGFR Tyrosylprotein kinase is not yet arranged, for tumour and pulmonary fibrosis treatment.Develop the fastest Compound I ntedanib in clinical three phases research, structure is shown in following formula:
It is target that the medicine that exploitation has good antitumor action and a pulmonary fibrosis effect is simultaneously take in the present invention, has found to act on the inhibitor of FGFR, VEGFR and PDGFR Tyrosylprotein kinase simultaneously.
3, summary of the invention
The object of the invention is to provide has good antitumor action and pulmonary fibrosis effect, dihydroindole ketone derivate as tyrosine kinase inhibitor that is easy to synthesize and preparation method thereof.
Technical scheme of the present invention is summarized as follows:
Compound shown in logical formula I, its deuterium are for thing, its pharmacy acceptable salt or its steric isomer:
Wherein, X means Sauerstoffatom or sulphur atom;
R
1mean hydrogen atom or prodrug base;
R
2, R
4and R
5independently mean respectively hydrogen atom, hydroxyl, amino, halogen atom, C
1-6alkyl or C
1-6alkoxyl group;
R
3mean sulfonic group, sulfino, cyano group, R
10-S (O)
2-, R
10-S (O)-, be not substituted or by 1 to 3 Q
1the C replaced
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, C
1-6alkylthio, amino, 3-10 unit heterocyclic radical,
Q
1mean halogen atom, hydroxyl, amino, 6-14 unit aryl, 3-14 unit heterocyclic radical, carboxyl, C
1-3alkoxyl group, C
1-3carbalkoxy, C
1-3alkylamino, two (C
1-3alkyl) amino, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl,
R
10mean halogen atom, amino, 6-14 unit aryl, 3-10 unit heterocyclic radical, C
1-3alkyl, C
1-3alkylamino, two (C
1-3alkyl) amino;
R
6mean hydrogen atom, be not substituted or by 1 to 3 Q
2the C replaced
1-6alkyl, 3-14 unit cycloalkyl, 6-14 unit aryl, the bridged ring base C of 7-12 unit
0-3alkyl, the volution C of 7-12 unit
0-3alkyl or the heterocyclic radical C of 3-14 unit
0-3alkyl, 1 ~ 3 carbon atom in described ring can be by 1 ~ 3 identical or different O, S (O) m, N (H) m, NCH of being selected from
3and heteroatoms and/or the group displacement of C (O),
Q
2mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, C
1-3alkyl, C
1-3alkoxyl group, hydroxyl C
1-3alkyl, amino C
1-3alkyl, C
1-3alkoxy C
1-3alkyl, carboxyl C
1-3alkoxyl group, C
1-3alkylamino, two (C
1-3alkyl) amino, C
1-3carbalkoxy, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl, C
1-3alkyl carbonyl is amino, N-(C
1-3alkyl) C
1-3alkyl carbonyl is amino, C
1-3alkane sulfuryl amino, N-(C
1-3alkyl) C
1-3alkane sulfuryl amino, the aryl C of 6-14 unit
1-3alkyl sulfonyl-amino;
R
7mean hydrogen atom, be not substituted or by 1 to 3 Q
3the C replaced
1-3alkyl, 3-14 unit's cycloalkyl or 3-14 unit heterocyclic radical;
Ring A means 3-14 unit cycloalkyl, 6-14 unit aryl, 7-12 unit bridged ring base, 7-12 unit's volution or 3-14 unit heterocyclic radical;
R
8mean hydrogen atom, halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, C
1-3alkyl, trifluoromethyl, C
1-3alkoxyl group, C
1-3carbalkoxy, kharophen, C
1-3alkyl sulfonyl-amino, formamyl, C
1-3alkyl-carbamoyl, two (C
1-3alkyl) formamyl, sulfamyl, C
1-3alkylsulfamoyl group or two (C
1-3alkyl) sulfamyl;
R
9as shown in formula II
formula II
Wherein, ring B means 3-14 unit cycloalkyl, 6-14 unit aryl, 7-12 unit bridged ring base, 7-12 unit's volution or 3-14 unit heterocyclic radical, the first cycloalkyl of described 3-14,6-14 unit aryl, 7-12 unit bridged ring base, the carbon atom on 7-12 unit's volution or 3-14 unit heterocyclic radical can be replaced by C (O);
R
amean hydrogen atom, be not substituted or by 1 to 3 Q
3the C replaced
1-3alkyl, 3-14 unit's cycloalkyl or 3-14 unit heterocyclic radical;
R
band R
dindependently mean respectively hydrogen atom, C
1-3alkyl, C
1-3alkoxyl group, amino, C
1-3alkylamino, two (C
1-3alkyl) amino, anilino, N-(C
1-3alkyl) anilino, benzamido group, N-(C
1-3alkyl) benzamido group or 3-14 unit heterocyclic radical, the first heterocyclic radical of described 3-14 can be by 1-3 Q
3replace;
R
cmean not to be substituted or by 1 to 3 substituting group Q
3the 6-12 unit the cyclic group C that replace
0-3alkyl, the volution base C of 7-12 unit
0-3alkyl or the bridged ring base C of 6-12 unit
0-3alkyl, 1 ~ 3 carbon atom in described and ring, volution or bridged ring can be by 1 ~ 3 identical or different O, S (O) m, N (H) m, NCH of being selected from
3and heteroatoms and/or the group displacement of C (O),
Q
3mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkylamino, two (C
1-3alkyl) amino, C
1-3carbalkoxy, formamyl, C
1-3alkylamino formyl radical, C
1-3alkyl carbonyl amino;
M means 0,1 or 2;
N means 0,1 or 2, when n means 2, and R
8the substituting group meaned can be the same or different;
N
1mean 0 or 1;
N
2mean 0 or 1;
N
3mean 0 or 1;
N
4mean 0,1 or 2.
Be preferably:
Wherein, X means Sauerstoffatom;
R
1mean hydrogen atom;
R
2, R
4and R
5independently mean respectively hydrogen atom;
R
3mean sulfonic group, sulfino, methyl sulphonyl, cyano group, be not substituted or by 1 to 3 Q
1the C replaced
1-4alkyl, C
3-6cycloalkyl, C
1-3alkoxyl group, C
1-3alkylthio, amino, 3-8 unit heterocyclic radical,
Q
1mean halogen atom, hydroxyl, amino, carboxyl, C
1-3alkoxyl group, C
1-3carbalkoxy, C
1-3alkylamino, two (C
1-3alkyl) amino, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl;
R
6mean not to be substituted or by 1 to 3 Q
2the following group replaced:
(1) 3-8 unit monocyclic cycloalkyl, phenyl, on described phenyl, cycloalkyl, carbon atom can be by 1 ~ 3 identical or different N (H) m, N (C
1-3alkyl), O, S (O)
m, C (O) replaces,
P means 0,1,2 or 3,
R means 1,
S means 1,
Q
2mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, C
1-3alkyl, C
1-3alkoxyl group, hydroxyl C
1-3alkyl, amino C
1-3alkyl, C
1-3alkoxy C
1-3alkyl, carboxyl C
1-3alkoxyl group, C
1-3alkylamino, two (C
1-3alkyl) amino, C
1-3carbalkoxy, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl, C
1-3alkyl carbonyl is amino, N-(C
1-3alkyl) C
1-3alkyl carbonyl is amino, C
1-3alkane sulfuryl amino, N-(C
1-3alkyl) C
1-3alkane sulfuryl amino, phenyl C
1-3alkyl sulfonyl-amino;
R
7mean hydrogen atom or 3-6 unit monocyclic cycloalkyl;
Ring A means phenyl or 5-10 unit heterocyclic radical;
R
8mean hydrogen atom, halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, C
1-3alkyl, trifluoromethyl, C
1-3alkoxyl group, C
1-3carbalkoxy, kharophen, C
1-3alkyl sulfonyl-amino, formamyl, C
1-3alkyl-carbamoyl, two (C
1-3alkyl) formamyl, sulfamyl, C
1-3alkylsulfamoyl group or two (C
1-3alkyl) sulfamyl;
R
9as shown in formula II
Wherein, ring B means 5-10 unit heterocyclic radical, and the carbon atom on the first heterocyclic radical of described 5-10 can be replaced by C (O);
R
amean hydrogen atom, be not substituted or by 1 to 3 Q
3the C replaced
1-3alkyl, 3-6 unit monocyclic cycloalkyl;
R
band R
dindependently mean respectively hydrogen atom, C
1-3alkyl, C
1-3alkoxyl group, amino, C
1-3alkylamino, two (C
1-3alkyl) amino, anilino or N-(C
1-3alkyl) anilino;
R
cmean not to be substituted or by 1 to 3 substituting group Q
3the 6-9 unit the cyclic group C that replace
0-3alkyl, the volution base C of 7-10 unit
0-3alkyl or the bridged ring base C of 7-8 unit
0-3alkyl, 1 ~ 3 carbon atom in described ring can be by 1 ~ 3 identical or different O, S (O) m, N (H) m, NCH of being selected from
3and heteroatoms and/or the group displacement of C (O),
Q
3mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkylamino, two (C
1-3alkyl) amino, C
1-3carbalkoxy, formamyl, C
1-3alkylamino formyl radical, C
1-3alkyl carbonyl amino;
M means 0,1 or 2;
N means 0,1 or 2, when n means 2, and R
8the substituting group meaned can be the same or different;
N
1mean 0 or 1;
N
2mean 0 or 1;
N
3mean 0 or 1;
N
4mean 0,1 or 2.
Be preferably:
Wherein, X means Sauerstoffatom;
R
1mean hydrogen atom;
R
2, R
4and R
5independently mean respectively hydrogen atom;
R
3mean methyl sulphonyl, trifluoromethyl, trifluoromethoxy, be not substituted or by 1 to 2 Q
1the 5-6 unit heterocyclic radical replaced,
Q
1mean halogen atom, hydroxyl, amino, carboxyl, C
1-3alkoxyl group, C
1-3carbalkoxy, C
1-3alkylamino, two (C
1-3alkyl) amino, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl;
R
6mean not to be substituted or by 1 to 3 Q
2the following group replaced:
Phenyl, tetrahydrofuran (THF), tetrahydropyrans,
Q
2mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, C
1-3alkyl, C
1-3alkoxyl group, hydroxyl C
1-3alkyl, amino C
1-3alkyl, C
1-3alkoxy C
1-3alkyl, carboxyl C
1-3alkoxyl group, C
1-3alkylamino, two (C
1-3alkyl) amino, C
1-3carbalkoxy, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl, C
1-3alkyl carbonyl is amino, N-(C
1-3alkyl) C
1-3alkyl carbonyl is amino, C
1-3alkane sulfuryl amino, N-(C
1-3alkyl) C
1-3alkane sulfuryl amino, aryl C
1-3alkyl sulfonyl-amino;
R
7mean hydrogen atom or 3-6 unit monocyclic cycloalkyl;
The ring A mean piperidyl, phenyl, pyrryl, pyridyl, pyrimidyl or
R
8mean hydrogen atom, halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, C
1-3alkyl, trifluoromethyl, C
1-3alkoxyl group, C
1-3carbalkoxy, kharophen, C
1-3alkyl sulfonyl-amino, formamyl, C
1-3alkyl-carbamoyl, two (C
1-3alkyl) formamyl, sulfamyl, C
1-3alkylsulfamoyl group or two (C
1-3alkyl) sulfamyl;
R
9as shown in formula II
Wherein, ring B means 5-6 unit heterocyclic radical, and the carbon atom on the first heterocyclic radical of described 5-6 can be replaced by C (O);
R
amean hydrogen atom, be not substituted or by 1 to 3 Q
3the methyl, ethyl, sec.-propyl, the cyclopropyl that replace;
R
band R
dindependently mean respectively hydrogen atom, C
1-3alkyl, C
1-3alkoxyl group, amino, C
1-3alkylamino, two (C
1-3alkyl) amino;
R
cmean not to be substituted or by 1 to 3 substituting group Q
3replace
1 ~ 3 carbon atom in described and ring, volution or bridged ring can be by 1 ~ 3 identical or different O, S (O) m, N (H) m, NCH of being selected from
3and heteroatoms and/or the group displacement of C (O),
Q
3mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, methyl, methoxyl group, methylamino or dimethylamino;
P means 0,1,2 or 3;
M means 0,1 or 2;
N means 0 or 1; n
1mean 0 or 1; n
2mean 0 or 1; n
3mean 0 or 1; n
4mean 0 or 1.
Be preferably:
Wherein, X means Sauerstoffatom;
R
1mean hydrogen atom;
R
2, R
4and R
5independently mean respectively hydrogen atom;
R
3mean azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, tetramethylene sulfide, imidazolidyl, pyrazolidyl, tetrazyl, Isosorbide-5-Nitrae-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl, super morpholinyl, 2,5-dihydro-thiophene base, 4,5-pyrazoline base, 4,5-dihydro-oxazole base, furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl group ， oxazolyl oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl or Isosorbide-5-Nitrae-Dioxin base;
R
6mean phenyl, tetrahydrofuran base, THP trtrahydropyranyl,
R
7mean hydrogen atom or cyclopropyl;
The ring A mean piperidyl, phenyl, pyrryl, pyridyl, pyrimidyl or
R
8mean hydrogen atom or C
1-3alkyl;
R
9as shown in formula II
formula II
Wherein, the ring B Biao Shi oxazolyl or
R
amean hydrogen atom, methyl or cyclopropyl;
R
band R
dindependently mean respectively hydrogen atom or C
1-3alkyl;
R
cmean not to be substituted or replaced by halogen atom, hydroxyl, amino, trifluoromethyl, methyl, methoxyl group or methylamino
N means 0 or 1;
N
1mean 0 or 1;
N
2mean 0 or 1;
N
3mean 0 or 1;
N
4mean 0 or 1.
Be preferably:
Wherein, X means Sauerstoffatom;
R
1mean hydrogen atom;
R
2, R
4and R
5independently mean respectively hydrogen atom;
R
3biao Shi oxazolyl, thiazolyl, imidazolyl or pyrazolyl;
R
6mean phenyl,
R
7mean hydrogen atom or cyclopropyl;
The ring A mean piperidyl, phenyl, pyrryl, pyridyl, pyrimidyl or
R
8mean hydrogen atom or C
1-3alkyl;
R
9as shown in formula II
Wherein, the ring B Biao Shi oxazolyl or
R
amean methyl, cyclopropyl;
R
band R
dindependently mean respectively hydrogen atom;
R
cmean
N means 0 or 1; n
1mean 0 or 1; n
2mean 0 or 1; n
3mean 0 or 1; n
4mean 0 or 1.
Particularly preferred compound is:
Detailed Description Of The Invention
" halogen " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention
1-6alkyl " refer to that the hydrocarbon that contains 1 ~ 6 carbon atom partly removes the alkyl of the derivative straight or branched of hydrogen atom, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, neo-pentyl, the 1-ethyl propyl, n-hexyl, isohexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 2-ethyl-butyl, 1-methyl-2-methyl-propyl etc." C of the present invention
1-4alkyl " refer to the specific examples that contains 1 ~ 4 carbon atom in above-mentioned example.
" C of the present invention
1-6carbalkoxy " refer to " C
1-6alkyl " by connecting the group that carbonyl is connected with other structures again after Sauerstoffatom, as methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, isopropyl oxygen carbonyl, butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, secondary butoxy carbonyl, penta oxygen carbonyl, new penta oxygen carbonyl, own oxygen carbonyl etc.Term " C
1-4carbalkoxy " refer to the specific examples that contains 1 ~ 4 carbon atom in above-mentioned example.
" C of the present invention
1-3alkoxyl group " refer to " C
1-3alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy etc.
" 3-14 unit cycloalkyl " of the present invention refers to that annular atoms is all carbon atom, removes a cyclic alkyl group that hydrogen atom is derivative, comprises 3-8 unit's monocyclic cycloalkyl and 6-14 unit condensed ring cycloalkyl.
3-8 unit monocyclic cycloalkyl, comprise the 3-8 saturated monocyclic cycloalkyl of unit and 3-8 unit fractional saturation monocyclic cycloalkyl.The saturated monocyclic cycloalkyl of 3-8 unit, refer to that this monocycle is for whole saturated carbocyclic rings, 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, dimethyl tetramethylene base, methylcyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyl cyclohexane base etc.3-8 unit fractional saturation monocyclic cycloalkyl, refer to the carbocyclic ring that this monocycle is fractional saturation, the example includes but are not limited to cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadiene base, cyclooctene base, 1,5-cyclooctadiene base etc.
" 3-6 unit monocyclic cycloalkyl " of the present invention, refer to and contain 3-6 carbon atom cycloalkyl.
6-14 unit condensed ring cycloalkyl, refer to that this condensed ring shares two formed cyclic groups of adjacent carbon atom each other by two or more ring texturees, comprises the 6-14 saturated condensed ring cycloalkyl of unit and 6-14 unit fractional saturation condensed ring cycloalkyl.The saturated condensed ring cycloalkyl of 6-14 unit, refer to that this condensed ring is for whole saturated carbocyclic rings, the example includes but not limited to: two ring [3.1.0] hexyls, two ring [4.1.0] heptane bases, two ring [2.2.0] hexyls, two ring [3.2.0] heptane bases, two encircle [4.2.0] octyls, octahydro pentalene base, octahydro-1H-indenyl, naphthane base, ten tetrahydrochysene phenanthryl etc.6-14 unit fractional saturation condensed ring cycloalkyl, refer to that in this and ring, at least one ring is the carbocyclic ring of fractional saturation, and the example includes but not limited to: dicyclo [3.1.0] is own-2-thiazolinyl, dicyclo [4.1.0] heptan-3-thiazolinyl, dicyclo [3.2.0] heptan-3-thiazolinyl, dicyclo [4.2.0] suffering-3-thiazolinyl, 1,2,3,3a-tetrahydrochysene pentalene base, 2,3,3a, 4,7,7a-, six hydrogen-1H-indenyl, 1,2,3,4,4a, 5,6,8a-octalin base, 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 all the ring-type aromatic group of carbon atom, comprises 6-8 unit's monocyclic aryl and 8-14 unit fused ring aryl.
6-8 unit monocyclic aryl refers to whole undersaturated aryl, such as phenyl, cyclooctatetraenyl etc.
8-14 unit fused ring aryl refers to that shared two adjacent carbon atoms are formed each other by two or more ring texturees, has the cyclic group that a ring is whole undersaturated aromatic nucleus at least, comprise the whole unsaturated fused ring aryl of 8-14 unit, such as naphthalene, phenanthrene etc., also comprise 8-14 unit fractional saturation fused ring aryl, the for example saturated monocyclic cycloalkyl of benzo 3-8 unit, benzo 3-8 unit fractional saturation monocyclic cycloalkyl, specific examples is as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, Isosorbide-5-Nitrae-dihydro naphthyl etc." the unsaturated aryl of 6-10 unit " of the present invention refers to that in " 6-14 unit aryl " be all monocyclic aryl and the fused ring aryl of a undersaturated 6-10 carbon atom.
" 7-12 unit bridged ring base " of the present invention refers to that any two rings share neither that directly connected atom forms contains 7-12 carbon atom and/or heteroatomic structure, and described heteroatoms has nitrogen, oxygen and sulphur etc." 7-12 unit bridged ring " comprises the saturated bridged ring of 7-12 unit, 7-12 unit fractional saturation bridged ring.
The saturated bridged ring of 7-12 unit, refer to that all rings in this bridged ring are saturated cyclic group, is preferably the saturated bridged ring of 7-8 unit, and specific examples includes but not limited to:
deng.
7-12 unit fractional saturation bridged ring, referring in this bridged ring has that to have a ring at least be undersaturated cyclic group, is preferably 7-8 unit fractional saturation bridged ring, and specific examples includes but not limited to:
deng.
" 7-12 unit volution " of the present invention refers to that a class has that two rings share that atoms form at least contains 7-12 carbon atom and/or heteroatomic structure, and described heteroatoms has nitrogen, oxygen and sulphur etc.7-12 unit volution comprises the saturated volution of 7-12 unit, 7-12 unit fractional saturation volution.
The saturated volution of 7-12 unit, refer to that all rings in this volution are saturated cyclic group, and specific examples includes but are not limited to:
deng.
7-12 unit fractional saturation volution, refer in this volution that having a ring at least is undersaturated cyclic group, and specific examples includes but are not limited to:
deng.
" 3-14 unit heterocyclic radical " of the present invention, refer to and contain 3-14 the annular atoms cyclic group of (wherein at least containing a heteroatoms), comprises the single heterocyclic radical of 3-8 unit, 6-14 unit fused heterocycle base, and described heteroatoms has nitrogen, oxygen and sulphur etc.
The single heterocyclic radical of 3-8 unit, refer to and contain 3-8 the annular atoms monocyclic heterocycles base of (wherein at least containing a heteroatoms), comprises the unsaturated single heterocyclic radical of 3-8 unit, the single heterocyclic radical of 3-8 unit fractional saturation, 3-8 unit saturated mono heterocyclic radical.The single heterocyclic radical of preferred 5-6 unit.The unsaturated single heterocyclic radical of 3-8 unit, refer to heteroatomic cyclic group of containing of aromaticity, the unsaturated single heterocyclic radical of preferred 5-6 unit, specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl group, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, 1, 4-Dioxin base, 2H-1, the 2-oxazinyl, 4H-1, the 2-oxazinyl, 6H-1, the 2-oxazinyl, 4H-1, the 3-oxazinyl, 6H-1, the 3-oxazinyl, 4H-1, the 4-oxazinyl, pyridazinyl, pyrazinyl, 1, 2, the 3-triazinyl, 1, 2, the 4-triazinyl, 1, 3, the 5-triazinyl, 1, 2, 4, 5-tetrazine base, the oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1, 3-diazacyclo heptantriene base, azepine cyclooctatetraenyl etc.The single heterocyclic radical of 3-8 unit fractional saturation, refer to the heteroatomic cyclic group that contains that contains two keys, the single heterocyclic radical of preferred 5-6 unit's fractional saturation, 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 etc.3-8 unit saturated mono heterocyclic radical, refer to be all heteroatomic cyclic group of containing of saturated bond, the first saturated mono heterocyclic radical of preferred 5-6, specific examples includes but are not limited to: ethylenimine base, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, imidazolidyl, pyrazolidyl, tetrahydrofuran base, 1,4-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl etc.
6-14 unit fused heterocycle base, refer to that containing 6-14 annular atoms (wherein at least containing a heteroatoms) shares each other two adjacent atoms by two or more ring texturees and couple together the condensed ring structure formed, comprises the unsaturated fused heterocycle base of 6-14 unit, 6-14 unit fractional saturation fused heterocycle base, the first saturated fused heterocycle base of 6-14.
The unsaturated fused heterocycle base of 6-14 unit, refer to that whole rings is undersaturated condensed ring structure, the structure that single heterocyclic radical as unsaturated as benzo 3-8 unit forms, the structure that the unsaturated single heterocyclic radical of the 3-8 unsaturated single heterocyclic radical of unit 3-8 unit forms etc., specific examples includes but not limited to: benzofuryl, the benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, the benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, the benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl etc.
6-14 unit fractional saturation fused heterocycle base, refer to the condensed ring structure that at least contains a fractional saturation ring, structure as the single heterocyclic radical formation of benzo 3-8 unit fractional saturation, the structure that the single heterocyclic radical of 3-8 unit fractional saturation the 3-8 unit single heterocyclic radical of fractional saturation form 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 is [3,4-c] pyrroles etc. also.
The saturated fused heterocycle base of 6-14 unit, refer to that whole rings is saturated condensed ring structure, as 3-8 unit's saturated mono heterocyclic radical the formed structure of 3-8 unit's saturated mono heterocyclic radical, specific examples includes but are not limited to: tetramethylene Pyrrolidine base, pentamethylene Pyrrolidine base, azetidine imidazolidyl etc.
" 3-10 unit heterocyclic radical " of the present invention, " 5-10 unit heterocyclic radical ", refer to respectively and contain 3-10, single heterocyclic radical and the fused heterocycle base of a 5-10 annular atoms.
" prodrug base " of the present invention, refer to the protecting group on the lactam group nitrogen-atoms, and specific embodiment includes but are not limited to, ester group, alkylsulfonyl etc.
" 6-12 unit cyclic group C of the present invention
0-3alkyl, the volution base C of 7-12 unit
0-3alkyl or the bridged ring base C of 6-12 unit
0-3alkyl " refer to C
0-3alkyl, by connecting the group be connected with other structures again after " 6-12 unit cyclic group, 7-12 unit volution base, 6-12 unit bridged ring base ", comprises " 6-9 unit cyclic group C
0-3alkyl, the volution base C of 7-10 unit
0-3alkyl or the bridged ring base C of 7-8 unit
0-3alkyl ", specific examples includes but are not limited to:
deng (and 1 ~ 3 carbon atom on described ring can be by 1 ~ 3 identical or different N (H) m, N (C
1-3alkyl), O, S (O)
m, C (O) replaces, p means 0,1,2 or 3).
Above-claimed cpd of the present invention can adopt method and/or other technology known to persons of ordinary skill in the art of describing in following flow process to synthesize, but is not limited only to following methods.
Reaction equation:
Reactions steps:
Intermediate 4 is according to J.Med.Chem.2009, and 52,4466-4480 is synthetic
The preparation of step 1 intermediate 1
Raw material 1 and organic bases are dissolved in DCM, drip raw material 2 under ice-water bath, rise to room temperature reaction half an hour, add water, with DCM extraction, drying, evaporate to dryness, solid vacuum-drying obtains intermediate 1.
The preparation of step 2 intermediate 2
Intermediate 1 and organic bases are dissolved in DCM, drip raw material 3, under room temperature, react 12h, use the DCM(methylene dichloride) extraction, the organic layer anhydrous sodium sulfate drying, evaporate to dryness obtains intermediate 2.
The preparation of step 3 intermediate 3
Intermediate 2 is dissolved in DCM, adds TFA, after under room temperature, reaction finishes, concentrated intermediate 3 or intermediate 2 is dissolved in methyl alcohol, the Pd/C hydrogenation spends the night, and filters, the concentrated intermediate 3 that to obtain, this product is directly used in next step reaction without purification.
The preparation of step 4 formula I compound
Intermediate 4 and intermediate 3 are dissolved in DMF, are heated to 80 degree reaction 5h, after being cooled to room temperature continuation reaction 2h, add water, filter, solid vacuum-drying obtains the formula I compound.
In reaction equation, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
a, R
b, R
c, R
d, X, n, n
1, n
2, n
3, n
4, the ring A and the ring B as defined above.
Above-claimed cpd of the present invention also can adopt method and/or other technology known to persons of ordinary skill in the art of describing in following flow process to synthesize, but is not limited only to following methods:
Reaction equation:
Reactions steps:
The preparation of step 1 intermediate 1
At ambient temperature, the triethylamine of raw material 2 and 2 times of amounts is joined in organic solvent in (as DCM etc.), drip the freshly prepd raw material 2 of equivalent, be heated to 70 ℃ of reaction half an hour.After reacting completely, the mixed solution concentrating under reduced pressure.Residuum separates through silica gel column chromatography, and vacuum-drying obtains intermediate 1.
The preparation of step 2 intermediate 2
Intermediate 1 is dissolved in organic solvent in (as dehydrated alcohol etc.), room temperature condition first, adds the catalyzer (as Raney's nickel etc.) of catalytic amount, and atmosphere of hydrogen, stir reaction overnight.After reaction finishes, mixed solution is through diatomite filtration, and filtrate decompression is concentrated dry.Residuum separates through silica gel column chromatography, and vacuum-drying obtains intermediate 1.
The preparation of step 3 intermediate 3
The alkali of raw material 3 and 0.5 equivalent (as KOH etc.) is joined in organic solvent in (as dehydrated alcohol etc.), be heated to 80 ℃ of reaction half an hour.Add again intermediate 2 reflux reaction overnight.After reacting completely, the mixed solution concentrating under reduced pressure.Residuum separates through silica gel column chromatography, and vacuum-drying obtains intermediate 3.
The preparation of step 4 end product thing
The raw material 4 of intermediate 3 and 3 equivalents is dissolved in the mixed solvent of (as Isosorbide-5-Nitrae-dioxane etc.) and water in appropriate non-polar organic solvent, then adds the Pd (PPh of 3 equivalent mineral alkalis and catalytic amount
3)
4or Pd (dppf)
2cl
2, be heated to 100 and spend the reaction at night.After reaction finishes, mixed solution is cooled to room temperature, concentrating under reduced pressure, and the ethyl acetate extraction, filter, drying, concentrating under reduced pressure is dry, and solid vacuum-drying obtains end product.
In reaction equation, wherein: X means the group as previously described such as nitrogen-atoms; Y means the groups (while being expressed as the 2-oxazolyl, the SUZUKI linked reaction in step 4 is default) such as bromine atoms or 2-oxazolyl; R
1mean the 2-oxazolyl, the groups such as 5-pyrazolyl or 2-furyl; R
2the groups such as expression phenyl or indoline base (while being expressed as the indoline base, radicals X and R
3default); R
3mean the groups such as methyl or cyclopropyl.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention refers to by the salt of pharmaceutically acceptable, non-toxic bases 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 resin, be selected from trimethyl-glycine, caffeine, choline, N, the salt of N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylin ethanol, 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.Natural amino acid salt 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.
The present invention is claimed arbitrary compound recited above, its deuterium pharmaceutical composition for thing, its pharmacy acceptable salt or its steric isomer that contains further, also can comprise the second therapeutical agent that is selected from antineoplastic agent and immunosuppressor, described the second therapeutical agent is selected from metabolic antagonist, includes but are not limited to capecitabine, gemcitabine etc.; Growth factor receptor inhibitors, include but are not limited to Gefitinib, lapatinibditosylate, pazopanib, imatinib etc.; Antibody, include but are not limited to Trastuzumab, rhuMAb-VEGF etc.; Mitotic inhibitor, include but are not limited to taxol, vinorelbine, docetaxel, Dx etc.; Antitumor hormones, include but are not limited to letrozole, tamoxifen, fulvestrant etc.; The alkylating agent class, include but are not limited to endoxan, carmustine etc.; The metal platinum class, include but are not limited to carboplatin, cis-platinum, oxaliplatin etc.; Topoisomerase enzyme inhibitor, include but are not limited to Topotecan etc.; The immunosuppression class, include but are not limited to everolimus etc.
The present invention further protection contains above-mentioned logical formula I compound, its deuterium pharmaceutical preparation for thing, its pharmacy acceptable salt or its steric isomer, comprises one or more pharmaceutical carriers.
The compounds of this invention is mixed with arbitrary pharmaceutical preparation by manner known in the art, is applied to the patient who needs this treatment with oral, parenteral, rectum or through modes such as lung administrations.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.While making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.During for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.While making injection, can adopt the ordinary method production in existing pharmacy field, during the preparation injection, can not add additives, also can add according to the character of medicine suitable additives.During for rectal administration, can be made into suppository etc.For when the lung administration, can be made into inhalation or sprays etc.
The present invention also provides the present invention above-mentioned logical formula I compound, its deuterium is for thing, its pharmacy acceptable salt or its steric isomer are in the application being selected from for the preparation of prevention or treatment aspect the medicine of following fibrotic conditions, wherein said fibrotic conditions, include but are not limited to: the fibrosis of lung tissue and refigure in chronic obstructive pulmonary disease, the fibrosis of lung tissue and refigure in chronic bronchitis, the fibrosis of lung tissue and refigure in pulmonary emphysema, pnemnofibrosis and there is the lung disease of fibrosis composition, fibrosis and refigure in asthma, fibrosis in rheumatoid arthritis, the liver cirrhosis that virus causes, radioactive fibrosis, postangioplasty restenosis, chronic glomerulonephritis, the kidney fibrosis of accepting the patient of ciclosporin reaches the kidney fibrosis caused due to hypertension, dermatosis with fibrosis composition, and excessive cicatrization.
The present invention also provides the present invention above-mentioned logical formula I compound, its deuterium is for thing, its pharmacy acceptable salt or its steric isomer are for the preparation of the overmedication proliferative disease, the application of the medicine aspect of angiogenesis inhibitor and/or reduction vascular permeability effects, wherein said excessively proliferative disease comprises cancer and non-Cancerous disease, 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, central nerve neuroma (neurospongioma, glioblastoma multiforme, glioma sarcomatosum), prostate cancer, thyroid carcinoma, the 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-Cancerous disease includes but are not limited to skin or prostatic hyperplasia of prostate etc.
" deuterium is for the thing " of the claimed formula I compound of the present invention, the hydrogen atom in compound is during by the some or all of replacement of its isotropic substance deuterium (symbol is D), and the material produced also belongs to category of the present invention.
" steric isomer " of the claimed formula I compound of the present invention; the compounds of this invention contains one or more asymmetric centers, thereby 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 each will independently produce two optical isomers this class asymmetric center, 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.
Dihydroindole ketone derivate as tyrosine kinase inhibitor of the present invention has two or more chiral centre.Synthetic what obtain is raceme, and the compound of needed enantiomer-pure can obtain by the method for chiral separation: can be by the chromatography (the standby liquid phase of image height compacting, supercritical fluid chromatography) with chiral stationary phase.Chirality padding includes but not limited to: ChiralcelOJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
The present invention also provides compound shown in formula I, its deuterium preparation method for thing, its pharmacy acceptable salt or its steric isomer, it is characterized in that, compound shown in formula II is reacted and prepares formula I with compound shown in formula III
Shown in the preparation method of compound,
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, n and ring A be as defined above.
The compounds of this invention is compared with immediate prior art, has the following advantages:
(1) the compounds of this invention can act on the inhibitor of FGFR, VEGFR and PDGFR Tyrosylprotein kinase simultaneously, can prevent or treat fibrotic conditions, suppress cell proliferation and vasculogenesis, there is good anti-tumor activity, to being used for the treatment of and/or preventing various Mammalss (comprising the mankind) tumor disease that excellent results is arranged;
(2) the compounds of this invention Side effect is lower;
(3) the compounds of this invention preparation technology is simple, and physico-chemical property is good, and steady quality is easy to carry out large-scale commercial production.
Below further set forth the compounds of this invention beneficial effect by pharmacological evaluation, but this should be interpreted as to the compounds of this invention only has following beneficial effect.
experimental example: 1, the external zymetology of the compounds of this invention suppresses active
Test materials:
The compounds of this invention: self-control, its chemical name and structural formula and preparation method are shown in the Preparation Example of each compound.
Experimental technique:
(1) reagent and compound preparation
1. 1 times does not contain MnCl
2kinase buffer liquid (50mM HEPES, pH=7.5,0.0015% Brij-35,10mMMgCl
2, 2mM DTT);
2. 1 times contains MnCl
2kinase buffer liquid (50mM HEPES, pH=7.5,0.0015% Brij-35,10mMMgCl
2, 10mM MnCl
2, 2mM DTT);
3. stop buffer (100mM HEPES, pH=7.5,0.015% Brij-35,0.2% Coating Reagent#3,50mM EDTA);
4. 2.5 times of kinase solution (adding corresponding kinases preparation 2.5 times of VEGFR2, FGFR1, FGFR3, PDGFR beta kinase solution in 1 times of kinase buffer liquid);
5. 2.5 times of substrate solutions (peptide and the ATP preparation peptide solution that add the FAM mark in 1 times of kinase buffer liquid);
6. 4 times of diluted compounds solution: accurately take compound, add DMSO to dissolve, fully mix, be made into 10mM.Then DMSO is diluted to 500 μ M, then 4 times be diluted to 10 concentration, and peak concentration is 50 μ M, standby.
(2) get 5 times of compound solutions of 5 μ L and add 384 orifice plates;
(3) add 2.5 times of kinase solution of 10 μ L to hatch 10min;
(4) then add 2.5 times of substrate solutions of 10 μ L, 28 ℃, reaction 1h; Contain the PGDFR beta kinase, reaction 5h.
(5) finally add 25 μ L stop buffer termination reactions, Caliper reading of data.
(6) fitting of a curve draws IC
50
Calculate inhibiting rate (%)=(maximum turnover ratio-sample changeover rate)/(maximum turnover ratio-minimum transition rate) * 100 and adopt Xlfit software to carry out curve fitting, draw IC
50value.
Experimental result: the external zymetology of table 1 suppresses active
From table 1, the compounds of this invention all has and suppresses active FGFR1, FGFR3, VEGFR2, PDGFR beta kinase.Wherein, compound 1 and compound 15 hydrochlorides have stronger inhibition activity to FGFR1, FGFR3, VEGFR2, PDGFR beta kinase.
2, the cell in vitro of the compounds of this invention is learned and is suppressed active
Experiment material:
The compounds of this invention: self-control, its chemical name and structural formula and preparation method are shown in the Preparation Example of each compound.
Experimental technique:
(1) cell recovery, growth.
(2) cell bed board: with the resuspended 3T3 cell of substratum containing 10% foetal calf serum, cell concn is: 5x10
4/ ml, add the every hole 100 μ L of 96 orifice plate by cell suspension; Night incubation; With the resuspended HUVEC cell of substratum containing 10% heat-inactivated fetal bovine serum, cell concn is: 7.5x10
4/ ml, add the every hole 100 μ L of 96 orifice plate by cell suspension.
(3) medicine adds: diluted chemical compound is become to different concns, add 60 μ Lh-PDGF-BB(3T3 cells), 40ng/ml h-VEGFa(HUVEC cell), hatch 1h.
(4) will contain compound and h-PDGF-BB(h-VEGFa for HUVEC cell) solution 100 μ L join Tissue Culture Plate, the h-PDGF-BB final concentration is 10ng/ml, the h-VEGFa final concentration is 10ng/ml, and the compound final concentration is 10,3.3333,1.1111,0.3704,0.1235,0.0412,0.0137,0.0046,0.0015 μ M.Hatch 40 hours, the HUVEC cell is hatched 89 hours.Every hole adds 20 μ L Promega Substrate, hatches 7.5 hours for 37 ℃, and the HUVEC cell is hatched 11.5 hours, puts into microplate reader and reads the 490nm extinction.
(5) data processing
Net OD=compound OD-MinOD, draw compound concentration and Net OD curve, according to following formula, calculates ED50:Conc.ED50 (x)=(y-b)/a, y=Calculated Net O.D.for IC
50, a=slope, b=intercept.
Experimental result: table 2 pair cell in vitro is learned and is suppressed active
From table 2, the compounds of this invention has restraining effect to the propagation of HUVEC cell, 3T3 cell.
4, embodiment
The embodiment of form, be described in further detail foregoing of the present invention by the following examples.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following examples.
(Z) preparation of the bromo-3-of-6-(methoxyl group (phenyl) methylene radical) indole-2-ketone (TM)
Referenced patent WO 2010012747A1 is synthetic.
embodiment 1 (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(1H-pyrazoles-5-yl)
indoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide
(1) preparation of the chloro-N-methyl-N-of 2-(4-nitrophenyl) ethanamide
By N-methyl-4-nitrophenylamine (7.6g, 50mmol) and triethylamine (5.5g, 54mmol) be dissolved in 200mL DCM, drip chloroacetyl chloride (11.5g under ice-water bath, 50mmol), rise to room temperature reaction half an hour, add 30mL water, DCM is extracted, dry, evaporate to dryness, solid vacuum-drying obtains the chloro-N-methyl-N-of 2-(4-nitrophenyl) ethanamide 9.69g, productive rate 85%.
(2) preparation of N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-nitrophenyl) ethanamide
By the chloro-N-methyl-N-of 2-(4-nitrophenyl) ethanamide (4.56g, 20mmol) and triethylamine (2.42g, 24mmol) be dissolved in 50mL DCM, drip 3-methyl-3-azabicyclo [3.1.0] hexane (2.13g, 22mmol), under room temperature, react 12h, use dichloromethane extraction, the organic layer anhydrous sodium sulfate drying, evaporate to dryness obtains solid N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-nitrophenyl) ethanamide 3.65g, productive rate 57%.
(3) preparation of N-(4-aminophenyl)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl) ethanamide
N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-nitrophenyl) ethanamide (2.89g, 10mmol) is dissolved in to 50mL methyl alcohol, adds 0.4g 5%Pd/C, hydrogenation 12h under room temperature.Filter, concentrate to obtain solid N-(4-aminophenyl)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl) ethanamide 2.08g, productive rate 80%.
(4) preparation of (Z)-N-(4-((the bromo-2-oxindole quinoline of 6--3-methylene) (phenyl) methyl amido) phenyl)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl) ethanamide
By the bromo-3-of (Z)-6-(methoxyl group (phenyl) methylene radical) indole-2-ketone (3.3g, 10mmol) and N-(4-aminophenyl)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl) ethanamide (2.85g, 11mmol) be dissolved in 50mLDMF, be heated to 80 ℃ of reaction 5h, after being cooled to room temperature continuation reaction 2h, add water, filter, solid vacuum-drying obtains (Z)-N-(4-((the bromo-2-oxindole quinoline of 6--3-methylene) (phenyl) methyl amido) phenyl)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl) ethanamide 2.76g, productive rate 50%.
(5) preparation of (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(1H-pyrazoles-5-yl) indoline-3-methylene) (phenyl) methyl amido) phenyl) ethanamide
By (Z)-N-(4-((the bromo-2-oxindole quinoline of 6--3-methylene) (phenyl) methyl amido) phenyl)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl) ethanamide (800mg, 1.44mmol), 1H-pyrazoles-3-boric acid (168mg, 1.50mmol), cesium carbonate (1.5g, 4.5mmol) and Pd(dppf) Cl
2(100mg, 0.17mmol) is dissolved in 30mL dioxane and 1mL water, is heated to 100 degree reaction 3h.By the solvent evaporate to dryness, solid separates (methylene dichloride: methyl alcohol=50:1) obtain (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(1H-pyrazoles-5-yl) indoline-3-methylene) (phenyl) methyl amido) phenyl) ethanamide 350mg, productive rate 45% through silicagel column.
Molecular formula: C
33h
32n
6o
5molecular weight: 544 mass spectrums (m/e): 545[M+H]
+.
This compound also can adopt following methods synthetic:
(1) preparation of TM 1
SM 1 (14.1g, 100mmol) is joined in the dehydrated alcohol of 150mL, then add methylamine alcohol solution 20g, be heated to 80 ° of C reaction overnight, LC-MS monitoring reaction process.Recrystallization obtains yellow solid compound TM 1 for 16g, productive rate 90%.
(2) preparation of intermediate TM 5-1
Add SM 5-1 (465mg, 3.0mmol) and DMF (0.05mL) stirring reaction in the methylene dichloride of 80mL, then drip under 0 ℃ (COCl)
2(952mg, 7.5mmol), at room temperature stirring reaction 2h, concentrate to obtain colorless oil intermediate TM 5-1 (520mg, 100%).
(3) preparation of TM 2
TM 1 (1.52g, 10mmol) is dissolved in to 1 of 20mL, in the 2-ethylene dichloride, is heated to 70 ° of C, add TM 5-1 (1.73g, 10mmol), the TLC monitoring reaction, reacted completely after 30 minutes.Column chromatography for separation obtains compound TM 2 for yellow solid 2.4g, and productive rate is 83%.
(4) preparation of .TM 3
TM 2 (2g, 6.9mmol) is dissolved in the dehydrated alcohol of 20mL, adds Raney's nickel 0.2 gram, under hydrogen shield, under room temperature condition, reaction is spent the night, LC-MS monitoring reaction process, and column chromatography for separation obtains compound TM 3 for 1.35g, productive rate 76%.
(5) preparation of .TM 4
By TM 3 (0.2g, 0.77mmol), TM (0.29g, 0.78mmol) and KOH (40mg, 0.71mmol) join in reaction flask, then add the 20mL anhydrous methanol, and stirring and dissolving is heated to 80 ° of C reaction overnight.After reaction finishes, mixed solution is cooled to room temperature, add wherein 20mL water and 50mL methylene dichloride, separatory, water is used dichloromethane extraction three times again, merge organic phase, use respectively saturated NaCl solution and washing, drying, concentrating under reduced pressure, obtain 0.3g yellow solid TM 4 through column chromatography for separation, productive rate is 70%.
(6). the preparation of (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(1H-pyrazoles-5-yl) indoline-3-methylene) (phenyl) methyl amido) phenyl) ethanamide
By TM 1 (0.2g, 0.36mmol), SM 3A (80mg, 0.71mmol), the Pb (PPh of catalytic amount
3)
4and K
2cO
3(0.75mmol) be dissolved in the mixed solvent (V of 20ml Isosorbide-5-Nitrae-dioxane and water
isosorbide-5-Nitrae-dioxane: V
water=4:1) in, N
2under protection, be heated to 100 ° of C reactions and spend the night.After reaction finishes, the reaction solution decompression is spin-dried for, obtain 50mg (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(1H-pyrazoles-5-yl) indoline-3-methylene) (phenyl) methyl amido) phenyl) ethanamide, productive rate 26% through column chromatography for separation.
Molecular formula: C
33h
32n
6o
2molecular weight: 544.6 mass spectrums (m/e): 273.2[M/2+H]
+
1H?NMR(400MHz,DMSO-d
6，δppm)δ:1.38(s,3H),1.84(s,2H),2.70(d,3H),3.13(m,5H),3.45(m,2H),5.79(d,1H),6.60(s,1H),6.82(d,2H),7.02(d,1H),7.10(d,2H),7.32(s,1H),7.53(m,3H),7.62(m,3H),7.76(s,1H),10.90(s,1H),12.02(s,1H).
embodiment 2 (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(thiazol-2-yl) Yin
diindyl quinoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide
(1) (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(4,4,5,5-tetramethyl--1,3,2-dioxa boron pentane-3-methylene) (phenyl) methyl amido) phenyl)-ethanamide
By (Z)-N-(4-((the bromo-2-oxindole quinoline of 6--3-methylene) (phenyl) methyl amido) phenyl)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl) ethanamide (11.1g, 20mmol) be dissolved in the 120mL dioxane, add duplex tetramethyl ethylene ketone boric acid ester (7.38g, 29mmol), potassium acetate (2.45g, 25mmol) and Pd (Ph
3p)
2cl
2(0.7g, 0.1mmol).Being heated to 90 degree reactions spends the night.Adding water is extracted with ethyl acetate, dry, concentrate and separate to obtain (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(4 by silicagel column, 4,5,5-tetramethyl--1,3,2-dioxa boron pentane-3-methylene) (phenyl) methyl amido) phenyl)-ethanamide 8.5g, productive rate 70%.
(2) (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(thiazol-2-yl) indoline-3-methylene) (phenyl) methyl amido) phenyl) ethanamide
Operation is with embodiment 1(5), productive rate 50%.
Molecular formula: C
33h
31n
5o
2s molecular weight: 561 mass spectrums (m/e): 562[M+H]
+.
embodiment 3 (Z)-N-methyl-2-(6-methyl-2,6-diaza spiroheptane-2-yl)-N-(4-((2-oxo-6-(thiazol-2-yl)-Yin
diindyl quinoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide (compound 3)
Method is with reference to embodiment 1, productive rate 60%.
Molecular formula: C
33h
32n
6o
2s molecular weight: 576 mass spectrums (m/e): 577[M+H]
+.
embodiment 4 (Z)-N-methyl-2-(6-methyl-2,6-diaza spiroheptane-2-yl)-N-(4-((2-oxo-6-(thiazole
-5-yl)-indoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide (compound 4)
Method is with reference to embodiment 1, productive rate 60%.
Molecular formula: C
33h
32n
6o
2s molecular weight: 576 mass spectrums (m/e): 577[M+H]
+.
embodiment 5 (Z)-N-(4-((6-(1H-imidazoles-2-yl)-2-oxindole quinoline-3-methylene) (phenyl) methyl amido) phenyl-N-first
the preparation of base-2-(6-methyl-2,6-diaza spiroheptane-2-yl) ethanamide (compound 5)
Method is with reference to embodiment 1, productive rate 60%.
Molecular formula: C
33h
33n
7o
2molecular weight: 559 mass spectrums (m/e): 560[M+H]
+.
embodiment 6 (Z)-N-methyl-2-(6-methyl-2,6-diaza spiroheptane-2-yl)-N-(4-((6-(oxazole-2-yl)-2-oxo Yin
diindyl quinoline-3-methylene radical) (phenyl) methylamino) phenyl) preparation of ethanamide (compound 6)
Method is with reference to embodiment 1, productive rate 60%.
Molecular formula: C
33h
32n
6o
3molecular weight: 560 mass spectrums (m/e): 561[M+H]
+.
embodiment 7 (Z)-N-cyclopropyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(thiazol-2-yl)
indoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide (compound 7)
Method is with reference to embodiment 1, productive rate 60%.
Molecular formula: C
35h
33n
5o
2s molecular weight: 587 mass spectrums (m/e): 588[M+H]
+.
embodiment 8 (Z)-N-cyclopropyl-2-(6-methyl-2,6-diaza spiroheptane-2-yl)-N-(4-((2-oxo-6-(thiazol-2-yl)-
indoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide (compound 8)
Method is with reference to embodiment 1, productive rate 60%.
Molecular formula: C
35h
34n
6o
2s molecular weight: 602 mass spectrums (m/e): 603[M+H]
+.
embodiment 9 (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.2.1] octane-8 base)-N-(4-((2-oxo-6-(thiazol-2-yl) indoles
quinoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide (compound 9)
Method is with reference to embodiment 1, productive rate 60%.
Molecular formula: C
35h
35n
5o
2s molecular weight: 589 mass spectrums (m/e): 590[M+H]
+.
embodiment 10 (Z)-N-methyl-2-(2-methyl-2-azabicyclo [2.2.2] octane-5-yl)-N-(4-((6-(oxazole-2-yl)-2-oxo Yin
diindyl quinoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide (compound 10)
Method is with reference to embodiment 1, productive rate 60%.
Molecular formula: C
35h
35n
5o
3molecular weight: 573 mass spectrums (m/e): 574[M+H]
+.
embodiment 11 (Z)-3-((1-(2-((1R, 5S, 6s)-3-methyl-3-azabicyclo [3.1.0] hexane-6-yl) ethanoyl) indoline-5-base ammonia
the preparation of base) (phenyl) methylene radical)-6-(oxazole-2-yl) indole-2-ketone (compound 11)
(1) preparation of TM 11-1
By intermediate TM 5-1 (5.6g, 32.3mmol), compound S M 11 (5.3g, 32.3mmol) and triethylamine (6g, 59.4mmol) join in the reaction flask of 100mL, then add the DCM of 50mL, stir the room temperature condition reaction overnight.After reaction finishes, the mixed solution concentrating under reduced pressure is dry, through column chromatography for separation, obtain 6g yellow solid TM 11-1, productive rate is 62%.
(2) preparation of .TM 11-2
The Raney Ni of midbody compound TM 11-1 (6g, 19.9mmol) and catalytic amount is joined in the reaction flask that fills 100mL methyl alcohol to H
2atmosphere, the stirring at room reaction is spent the night.After reaction finishes, mixed solution is through the diatomite suction filtration, and filtrate decompression is concentrated dry, obtains 45g yellow solid TM 11-2, and thick productive rate is 83%, and intermediate TM 9 is not purified for next step reaction.
(3). the preparation of compound 11
Intermediate SM 3 (180mg, 0.5mmol) is dissolved in 10mL methyl alcohol, adds KOH (14mg, 0.25mmol), reflux half an hour under 80 ° of C, then add TM 11-2 (135mg, 0.5mmol), 80 ° of C reflux 12 hours.React complete, reaction solution is spin-dried for, through column chromatography for separation, obtain 110mg product compound 11, productive rate 40%.
Molecular formula: C
34h
31n
5o
3molecular weight: 557.6 mass spectrums (m/e): 558.4[M+H]
+
1H?NMR(400MHz,DMSO-d
6，δppm)δ:1.54(m,3H),2.38(s,2H),2.72(s,3H),2.95(s,2H),3.19(s,2H),3.51(m,2H),3.98(s,2H),5.85(d,1H),6.64(d,1H),6.79(s,1H),7.18(d,1H),7.28(s,1H),7.45～7.66(m,6H),7.79(d,1H),8.10(s,1H),9.17(s,1H),10.58(s,1H),10.96(s,1H),12.05(s,1H).
embodiment 12 (Z)-6-(furans-2-yl)-3-((1-(2-((1R, 5S, 6s)-3-methyl-3-azabicyclo [3.1.0] hexane-6-yl) ethanoyl)
the preparation of indoline-5-base amino) (phenyl) methylene radical)-6-(oxazole-2-yl) indole-2-ketone (compound 12)
(1) preparation of TM 12-1
TM (0.28g, 0.75mmol) is dissolved in 10mL methyl alcohol, adds KOH (40mg, 0.71mmol), reflux half an hour under 80 ° of C, then add TM 11-2 (0.2g, 0.74mmol), 80 ° of C reflux and spend the night.After completion of the reaction, the reaction solution decompression is spin-dried for, through column chromatography, obtains 0.3g product TM 12-1, productive rate 71%.
(2).
compound 12preparation
TM 12-1 (0.2g, 0.35mmol) is dissolved in to V
toluene: V
ethanolin the mixed solvent system of=1:1, then add salt of wormwood (103mg, 0.7mmol), SM 2A (45mg, 0.4mmol) and tetra-triphenylphosphine palladium 15mg, N
2under protection, rise to 100 ° of C, backflow is spent the night.React complete, concentrating under reduced pressure is dry, dichloromethane extraction, organic phase drying, concentrating under reduced pressure.Residuum separates through efficient preparative chromatography (HPLC), obtains the 50mg solid chemical compound, and productive rate is 26%.
Molecular formula: C
35h
32n
4o
3molecular weight: 556.7 mass spectrums (m/e): 557.6[M+H]
+
1H?NMR(400MHz,DMSO-d
6，δppm)δ:1.58(m,3H),2.38(d,2H),2.74(s,3H),2.95(t,2H),3.20(m,2H),3.51(m,2H),3.95(m,2H),5.78(d,1H),6.51(d,1H),6.63(d,1H),6.71(d,1H),6.76(s,1H),6.91(m,1H),7.13(d,1H),7.46m,2H),7.54(m,3H),7.64(s,1H),7.78(d,1H),9.04(s,1H),10.22(s,1H),10.81(s,1H),11.90(s,1H).
embodiment 13 (Z)-N-methyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((6-(oxazole-2-yl)-2-oxo Yin
diindyl quinoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide (compound 13) and hydrochloride thereof
SM 3 (0.23g, 0.5mmol) is dissolved in 10mL ethanol, adds potassium hydroxide (0.014g, 0.25mmol), 80 ° of C reactions, after 30 minutes, add intermediate TM3 (0.13g, 0.5mmol), the TLC monitoring reaction.After reaction finishes, aftertreatment, column chromatography for separation obtains 0.209g yellow solid compound 13, and productive rate is 77%.
By in the methanol aqueous solution to compound 13 (0.15g, 0.27mmol), dripping hydrochloric acid, obtain the hydrochloride of compound 13 by DCM/ ether mixed solvent recrystallization purifying.
Molecular formula: C
33h
31n
5o
3molecular weight: 545.6 mass spectrums (m/e): 546.2[M+H]
+
1H?NMR(400MHz,DMSO-d
6，δppm)δ:1.48(m,2H),1.96(m,2H),2.74(s,3H),3.05(s,3H),3.16(m,2H),3.49(m,3H),5.88(d,1H),6.85(d,2H),7.10(d,2H),7.19(d,1H),7.29(s,1H),7.45(s,1H),7.54(m,2H),7.62(m,3H),8.11(s,1H),9.61(s,1H),10.98(s,1H),12.14(s,1H).
embodiment 14 (Z)-N-cyclopropyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((6-(oxazole-2-yl)-2-oxo
indoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide (compound 14) and hydrochloride thereof
(1) preparation of .TM 14-1
SM 1 (14.1g, 100mmol) is added in the dehydrated alcohol of 150mL, add cyclopropylamine (5.7g, 100mmol), 80 ° of C reaction overnight, LC-MS monitoring reaction process.It is 16g that recrystallization obtains yellow solid compound TM 14-1, productive rate 90%.
(2) preparation of .TM 14-2
TM 14-1 (1.78g, 10mmol) is dissolved in to 1 of 20mL, in the 2-ethylene dichloride, is heated to 70 ° of C, add SM 2 (1.73g, 10mmol), the TLC monitoring reaction, reacted completely after 30 minutes.It is yellow solid 2.3g that column chromatography for separation obtains compound TM 14-2, and productive rate is 73%.
(3) preparation of .TM 14-3
TM 14-2 (2g, 6.3mmol) is dissolved in the dehydrated alcohol of 20mL, adds Raney's nickel 0.2g, under atmosphere of hydrogen, room temperature reaction spends the night, LC-MS monitoring reaction process.After reaction finishes, obtaining compound TM 14-3 through column chromatography for separation is 1.2g, productive rate 67%.
(4) preparation of ._ compound 14 and hydrochloride thereof
SM 3 (0.23g, 0.5mmol) is dissolved in 10mL ethanol, adds potassium hydroxide (0.014g, 0.25mmol), 80 ° of C reactions added raw material TM 14-33 (0.14g, 0.5mmol), the TLC monitoring reaction after 30 minutes.After reacting completely, through column chromatography for separation, obtain 0.17g yellow solid compound 14, productive rate is 60%.To dripping excessive hydrochloric acid in the methanol aqueous solution of intermediate TM 4, stirring reaction, obtain the hydrochloride of compound 14 with DCM/ ether mixed solvent recrystallization purifying.
Molecular formula: C
35h
33n
5o
3molecular weight: 571.7 mass spectrums [M+H]
+: 572.2
1h NMR (400MHz, its hydrochloride, DMSO-d
6, δ ppm) and δ: 0.46 (s, 2H), 0.72 (s, 2H), (1.44 m, 2H), 1.51 (m, 2H), 2.74 (s, 3H), 3.03 (m, 1H), 3.18 (m, 2H), (3.50 m, 3H), 5.87 (d, 1H), (6.82 d, 2H), 6.97 (d, 2H), (7.19 d, 1H), 7.28 (s, 1H), (7.45 s, 1H), 7.52 (d, 2H), (7.59 m, 3H), 8.11 (s, 1H), (8.86 s, 1H), 9.78 (s, 1H), (10.97 s, 1H), 12.13 (s, 1H).
embodiment 15 (Z)-N-cyclopropyl-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)-N-(4-((2-oxo-6-(1H-pyrazoles-5-
base) indoline-3-methylene) (phenyl) methyl amido) phenyl) preparation of ethanamide (compound 15) and hydrochloride thereof
(1) preparation of .TM 15-1
By TM 14-3 (0.285g, 1.0mmol), TM (0.372g, 1.0mmol) and KOH (0.028g, 0.5mmol) be dissolved in 20mL methyl alcohol, refluxed overnight, react complete, reaction solution is spin-dried for, and through column chromatography for separation, must obtain 0.293g intermediate TM15-1, productive rate 51%.
(2). the preparation of compound 15 and hydrochloride thereof
By TM 15-1 (0.145g, 0.25mmol), SM 3A (0.083g, 0.75mmol), Pb (dppf) Cl
2(15mg) and Cs
2cO
3(0.244g, 0.75mmol) is dissolved in the mixed solvent (V of 20ml Isosorbide-5-Nitrae-dioxane and water
isosorbide-5-Nitrae-dioxane: V
water=4:1) in, N
2under protection, be heated to 100 ° of C reactions and spend the night.After reaction finishes, the reaction solution decompression is spin-dried for, obtains 81mg compound 15 through column chromatography for separation, productive rate 57%.To dripping excessive hydrochloric acid in the methanol aqueous solution of compound 15, stirring reaction, obtain the hydrochloride of compound 15 with DCM/ ether mixed solvent recrystallization purifying.
Molecular formula: C
35h
34n
6o
2molecular weight: 570.7 mass spectrums (m/e): 571.2[M+H]
+
1h NMR (400MHz, its hydrochloride, DMSO-d
t,, δ ppm) δ: 0.34 (s, 2H), 0.74 (s, 2H), (1.04 m, 1H), 1.47 (m, 2H), 2.70 (d, 3H), (3.05 m, 1H), 3.15 (m, 3H), 3.50 (m, 3H), (5.79 d, 1H), 6.55 (d, 1H), 6.78 (d, 2H), (6.95 m, 3H), 7.30 (s, 1H), 7.58 (m, 7H), (10.61 s, 1H), 10.86 (s, 1H), 11.99 (s, 1H).
embodiment 16 (Z)-N-cyclopropyl-N-(4-((6-(furans-2-yl)-2-oxindole quinoline-3-methylene) (phenyl) methyl amido) benzene
the preparation of base)-2-(3-methyl-3-azabicyclo [3.1.0] hexane-6-yl) ethanamide (compound 16) and hydrochloride thereof
TM 15-1 (100mg, 0.17mmol) is dissolved in to V
dioxane: V
waterin the mixed system of=4:1, then add cesium carbonate (167mg, 0.51mmol), SM 2A (57mg, 0.51mmol), Pd (dppf)
2cl
2(10mg), N
2under protection, rise to 100 ° of C, backflow is spent the night, and reacts complete, and organic phase is spin-dried for, and the ethyl acetate extraction, through column chromatography, obtain 43mg compound 16, and productive rate is 41%.To dripping excessive hydrochloric acid in the methanol aqueous solution of compound 16, stirring reaction, obtain the hydrochloride of compound 16 with DCM/ ether mixed solvent recrystallization purifying.
Molecular formula: C
36h
34n
4o
3molecular weight: 570.7 mass spectrums (m/e): 571.3[M+H]
+
1H?NMR(400MHz,DMSO-d
6，δppm)δ:0.43(s,2H),0.70(s,2H),0.84(m,1H),1.51(m,2H),2.63(m,7H),3.02(m,3H),5.79(s,1H),6.55(s,1H),7.14(m,6H),7.51(m,5H),7.80(m,2H),9.87(s,1H),10.86(s,1H),11.99(s,1H).
Also prepared following compounds with reference to the preparation method inventor:
Claims (10)
1. the compound shown in logical formula I, its deuterium are for thing, its pharmacy acceptable salt or its steric isomer:
Wherein, X means Sauerstoffatom or sulphur atom;
R
1mean hydrogen atom or prodrug base;
R
2, R
4and R
5independently mean respectively hydrogen atom, hydroxyl, amino, halogen atom, C
1-6alkyl or C
1-6alkoxyl group;
R
3mean sulfonic group, sulfino, cyano group, R
10-S (O)
2-, R
10-S (O)-, be not substituted or by 1 to 3 Q
1the C replaced
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, C
1-6alkylthio, amino, 3-10 unit heterocyclic radical,
Q
1mean halogen atom, hydroxyl, amino, 6-14 unit aryl, 3-14 unit heterocyclic radical, carboxyl, C
1-3alkoxyl group, C
1-3carbalkoxy, C
1-3alkylamino, two (C
1-3alkyl) amino, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl,
R
10mean halogen atom, amino, 6-14 unit aryl, 3-10 unit heterocyclic radical, C
1-3alkyl, C
1-3alkylamino, two (C
1-3alkyl) amino;
R
6mean hydrogen atom, be not substituted or by 1 to 3 Q
2the C replaced
1-6alkyl, 3-14 unit cycloalkyl, 6-14 unit aryl, the bridged ring base C of 7-12 unit
0-3alkyl, the volution C of 7-12 unit
0-3alkyl or the heterocyclic radical C of 3-14 unit
0-3alkyl, 1 ~ 3 carbon atom in described ring can be by 1 ~ 3 identical or different O, S (O) m, N (H) m, NCH of being selected from
3and heteroatoms and/or the group displacement of C (O),
Q
2mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, C
1-3alkyl, C
1-3alkoxyl group, hydroxyl C
1-3alkyl, amino C
1-3alkyl, C
1-3alkoxy C
1-3alkyl, carboxyl C
1-3alkoxyl group, C
1-3alkylamino, two (C
1-3alkyl) amino, C
1-3carbalkoxy, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl, C
1-3alkyl carbonyl is amino, N-(C
1-3alkyl) C
1-3alkyl carbonyl is amino, C
1-3alkane sulfuryl amino, N-(C
1-3alkyl) C
1-3alkane sulfuryl amino, the aryl C of 6-14 unit
1-3alkyl sulfonyl-amino;
R
7mean hydrogen atom, be not substituted or by 1 to 3 Q
3the C replaced
1-3alkyl, 3-14 unit's cycloalkyl or 3-14 unit heterocyclic radical;
Ring A means 3-14 unit cycloalkyl, 6-14 unit aryl, 7-12 unit bridged ring base, 7-12 unit's volution or 3-14 unit heterocyclic radical;
R
8mean hydrogen atom, halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, C
1-3alkyl, trifluoromethyl, C
1-3alkoxyl group, C
1-3carbalkoxy, kharophen, C
1-3alkyl sulfonyl-amino, formamyl, C
13alkyl-carbamoyl, two (C
1-3alkyl) formamyl, sulfamyl, C
1-3alkylsulfamoyl group or two (C
1-3alkyl) sulfamyl;
R
9as shown in formula II
Wherein, ring B means 3-14 unit cycloalkyl, 6-14 unit aryl, 7-12 unit bridged ring base, 7-12 unit's volution or 3-14 unit heterocyclic radical, the first cycloalkyl of described 3-14,6-14 unit aryl, 7-12 unit bridged ring base, the carbon atom on 7-12 unit's volution or 3-14 unit heterocyclic radical can be replaced by C (O);
R
amean hydrogen atom, be not substituted or by 1 to 3 Q
3the C replaced
1-3alkyl, 3-14 unit's cycloalkyl or 3-14 unit heterocyclic radical;
R
band R
dindependently mean respectively hydrogen atom, C
1-3alkyl, C
1-3alkoxyl group, amino, C
1-3alkylamino, two (C
1-3alkyl) amino, anilino, N-(C
1-3alkyl) anilino, benzamido group, N-(C
1-3alkyl) benzamido group or 3-14 unit heterocyclic radical, the first heterocyclic radical of described 3-14 can be by 1-3 Q
3replace;
R
cmean not to be substituted or by 1 to 3 substituting group Q
3the 6-12 unit the cyclic group C that replace
0-3alkyl, the volution base C of 7-12 unit
0-3alkyl or the bridged ring base C of 6-12 unit
0-3alkyl, 1 ~ 3 carbon atom in described and ring, volution or bridged ring can be by 1 ~ 3 identical or different O, S (O) m, N (H) m, NCH of being selected from
3and heteroatoms and/or the group displacement of C (O),
Q
3mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkylamino, two (C
1-3alkyl) amino, C
1-3carbalkoxy, formamyl, C
1-3alkylamino formyl radical, C
1-3alkyl carbonyl amino;
M means 0,1 or 2;
N means 0,1 or 2, when n means 2, and R
8the substituting group meaned can be the same or different;
N
1mean 0 or 1;
N
2mean 0 or 1;
N
3mean 0 or 1;
N
4mean 0,1 or 2.
2. compound as claimed in claim 1, its deuterium are for thing, its pharmacy acceptable salt or its steric isomer:
Wherein, X means Sauerstoffatom;
R
1mean hydrogen atom;
R
2, R
4and R
5independently mean respectively hydrogen atom;
R
3mean sulfonic group, sulfino, methyl sulphonyl, cyano group, be not substituted or by 1 to 3 Q
1the C replaced
1-4alkyl, C
3-6cycloalkyl, C
1-3alkoxyl group, C
1-3alkylthio, amino, 3-8 unit heterocyclic radical,
Q
1mean halogen atom, hydroxyl, amino, carboxyl, C
1-3alkoxyl group, C
1-3carbalkoxy, C
13alkylamino, two (C
13alkyl) amino, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl;
R
6mean not to be substituted or by 1 to 3 Q
2the following group replaced:
(1) 3-8 unit monocyclic cycloalkyl, phenyl, on described phenyl, cycloalkyl, carbon atom can be by 1 ~ 3 identical or different N (H) m, N (C
1-3alkyl), O, S (O)
m, C (O) replaces,
And 1 ~ 3 carbon atom on described ring can be by 1 ~ 3 identical or different N (H) m, N (C
1-3alkyl), O, S (O)
m, C (O) replaces,
P means 0,1,2 or 3,
R means 1,
S means 1,
Q
2mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, C
1-3alkyl, C
1-3alkoxyl group, hydroxyl C
1-3alkyl, amino C
1-3alkyl, C
1-3alkoxy C
1-3alkyl, carboxyl C
1-3alkoxyl group, C
1-3alkylamino, two (C
1-3alkyl) amino, C
1-3carbalkoxy, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl, C
1-3alkyl carbonyl is amino, N-(C
1-3alkyl) C
1-3alkyl carbonyl is amino, C
1-3alkane sulfuryl amino, N-(C
1-3alkyl) C
1-3alkane sulfuryl amino, phenyl C
1-3alkyl sulfonyl-amino;
R
7mean hydrogen atom or 3-6 unit monocyclic cycloalkyl;
Ring A means phenyl or 5-10 unit heterocyclic radical;
R
8mean hydrogen atom, halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, C
1-3alkyl, trifluoromethyl, C
1-3alkoxyl group, C
1-3carbalkoxy, kharophen, C
1-3alkyl sulfonyl-amino, formamyl, C
1-3alkyl-carbamoyl, two (C
1-3alkyl) formamyl, sulfamyl, C
1-3alkylsulfamoyl group or two (C
1-3alkyl) sulfamyl;
R
9as shown in formula II
Wherein, ring B means 5-10 unit heterocyclic radical, and the carbon atom on the first heterocyclic radical of described 5-10 can be replaced by C (O);
R
amean hydrogen atom, be not substituted or by 1 to 3 Q
3the C replaced
1-3alkyl, 3-6 unit monocyclic cycloalkyl;
R
band R
dindependently mean respectively hydrogen atom, C
1-3alkyl, C
1-3alkoxyl group, amino, C
1-3alkylamino, two (C
1-3alkyl) amino, anilino or N-(C
1-3alkyl) anilino;
R
cmean not to be substituted or by 1 to 3 substituting group Q
3the 6-9 unit the cyclic group C that replace
0-3alkyl, the volution base C of 7-10 unit
0-3alkyl or the bridged ring base C of 7-8 unit
0-3alkyl, 1 ~ 3 carbon atom in described ring can be by 1 ~ 3 identical or different O, S (O) m, N (H) m, NCH of being selected from
3and heteroatoms and/or the group displacement of C (O),
Q
3mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkylamino, two (C
1-3alkyl) amino, C
1-3carbalkoxy, formamyl, C
1-3alkylamino formyl radical, C
1-3alkyl carbonyl amino;
M means 0,1 or 2;
N means 0,1 or 2, when n means 2, and R
8the substituting group meaned can be the same or different;
N
1mean 0 or 1;
N
2mean 0 or 1;
N
3mean 0 or 1;
N
4mean 0,1 or 2.
3. compound as claimed in claim 2, its deuterium are for thing, its pharmacy acceptable salt or its steric isomer:
Wherein, X means Sauerstoffatom;
R
1mean hydrogen atom;
R
2, R
4and R
5independently mean respectively hydrogen atom;
R
3mean methyl sulphonyl, trifluoromethyl, trifluoromethoxy, be not substituted or by 1 to 2 Q
1the 5-6 unit heterocyclic radical replaced,
Q
1mean halogen atom, hydroxyl, amino, carboxyl, C
1-3alkoxyl group, C
1-3carbalkoxy, C
1-3alkylamino, two (C
1-3alkyl) amino, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl;
R
6mean not to be substituted or by 1 to 3 Q
2the following group replaced:
Phenyl, tetrahydrofuran (THF), tetrahydropyrans,
Q
2mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, C
1-3alkyl, C
1-3alkoxyl group, hydroxyl C
1-3alkyl, amino C
1-3alkyl, C
1-3alkoxy C
1-3alkyl, carboxyl C
1-3alkoxyl group, C
1-3alkylamino, two (C
1-3alkyl) amino, C
1-3carbalkoxy, formamyl, C
1-3alkylamino formyl radical, two (C
1-3alkyl) formamyl, C
1-3alkyl carbonyl is amino, N-(C
1-3alkyl) C
1-3alkyl carbonyl is amino, C
1-3alkane sulfuryl amino, N-(C
1-3alkyl) C
1-3alkane sulfuryl amino, aryl C
1-3alkyl sulfonyl-amino;
R
7mean hydrogen atom or 3-6 unit monocyclic cycloalkyl;
The ring A mean piperidyl, phenyl, pyrryl, pyridyl, pyrimidyl or
R
8mean hydrogen atom, halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, C
1-3alkyl, trifluoromethyl, C
1-3alkoxyl group, C
1-3carbalkoxy, kharophen, C
1-3alkyl sulfonyl-amino, formamyl, C
1-3alkyl-carbamoyl, two (C
1-3alkyl) formamyl, sulfamyl, C
1-3alkylsulfamoyl group or two (C
1-3alkyl) sulfamyl;
R
9as shown in formula II
formula II
Wherein, ring B means 5-6 unit heterocyclic radical, and the carbon atom on the first heterocyclic radical of described 5-6 can be replaced by C (O);
R
amean hydrogen atom, be not substituted or by 1 to 3 Q
3the methyl, ethyl, sec.-propyl, the cyclopropyl that replace;
R
band R
dindependently mean respectively hydrogen atom, C
1-3alkyl, C
1-3alkoxyl group, amino, C
1-3alkylamino, two (C
1-3alkyl) amino;
R
cmean not to be substituted or by 1 to 3 substituting group Q
3replace
1 ~ 3 carbon atom in described and ring, volution or bridged ring can be by 1 ~ 3 identical or different O, S (O) m, N (H) m, NCH of being selected from
3and heteroatoms and/or the group displacement of C (O),
Q
3mean halogen atom, hydroxyl, cyano group, carboxyl, amino, nitro, trifluoromethyl, methyl, methoxyl group, methylamino or dimethylamino;
P means 0,1,2 or 3;
M means 0,1 or 2;
N means 0 or 1;
N
1mean 0 or 1;
N
2mean 0 or 1;
N
3mean 0 or 1;
N
4mean 0 or 1.
4. compound as claimed in claim 3, its deuterium are for thing, its pharmacy acceptable salt or its steric isomer:
Wherein, X means Sauerstoffatom;
R
1mean hydrogen atom;
R
2, R
4and R
5independently mean respectively hydrogen atom;
R
3mean azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, tetramethylene sulfide, imidazolidyl, pyrazolidyl, tetrazyl, Isosorbide-5-Nitrae-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl, super morpholinyl, 2,5-dihydro-thiophene base, 4,5-pyrazoline base, 4,5-dihydro-oxazole base, furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl group ， oxazolyl oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl or Isosorbide-5-Nitrae-Dioxin base;
R
6mean phenyl, tetrahydrofuran base, THP trtrahydropyranyl,
R
7mean hydrogen atom or cyclopropyl;
The ring A mean piperidyl, phenyl, pyrryl, pyridyl, pyrimidyl or
R
8mean hydrogen atom or C
1-3alkyl;
R
9as shown in formula II
formula II
Wherein, the ring B Biao Shi oxazolyl or
R
amean hydrogen atom, methyl or cyclopropyl;
R
band R
dindependently mean respectively hydrogen atom or C
1-3alkyl;
R
cmean not to be substituted or replaced by halogen atom, hydroxyl, amino, trifluoromethyl, methyl, methoxyl group or methylamino
N means 0 or 1;
N
1mean 0 or 1;
N
2mean 0 or 1;
N
3mean 0 or 1;
N
4mean 0 or 1.
5. compound as claimed in claim 4, its deuterium are for thing, its pharmacy acceptable salt or its steric isomer:
Wherein, X means Sauerstoffatom;
R
1mean hydrogen atom;
R
2, R
4and R
5independently mean respectively hydrogen atom;
R
3biao Shi oxazolyl, thiazolyl, imidazolyl or pyrazolyl;
R
6mean phenyl,
R
7mean hydrogen atom or cyclopropyl;
The ring A mean piperidyl, phenyl, pyrryl, pyridyl, pyrimidyl or
R
8mean hydrogen atom or C
1-3alkyl;
R
9as shown in formula II
Wherein, the ring B Biao Shi oxazolyl or
R
amean methyl, cyclopropyl;
R
band R
dindependently mean respectively hydrogen atom;
R
cmean
N means 0 or 1;
N
1mean 0 or 1;
N
2mean 0 or 1;
N
3mean 0 or 1;
N
4mean 0 or 1.
6. compound as claimed in claim 5, its deuterium are for thing, its pharmacy acceptable salt or its steric isomer, and wherein compound is selected from:
7. one kind prepares the described compound of claim 1～6 any one, its deuterium method for thing, its pharmacy acceptable salt or its steric isomer, it is characterized in that, compound shown in formula II is reacted to the described compound of claim 1～6 any one for preparing shown in formula I, its deuterium with compound shown in formula III for thing, its pharmacy acceptable salt or its steric isomer
formula II
formula III,
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, n and ring A defined as claim 1.
8. pharmaceutical composition, contain the described compound of claim 1～6 any one, its deuterium for thing, its pharmacy acceptable salt or its steric isomer, also comprise the second therapeutical agent that is selected from antineoplastic agent and immunosuppressor, described the second therapeutical agent is selected from metabolic antagonist, comprises capecitabine, gemcitabine; Growth factor receptor inhibitors, comprise Gefitinib, lapatinibditosylate, pazopanib, imatinib; Antibody, comprise Trastuzumab, rhuMAb-VEGF; Mitotic inhibitor, comprise taxol, vinorelbine, docetaxel, Dx; Antitumor hormones, comprise letrozole, tamoxifen, fulvestrant; The alkylating agent class, comprise endoxan, carmustine; The metal platinum class, comprise carboplatin, cis-platinum, oxaliplatin; Topoisomerase enzyme inhibitor, comprise Topotecan; The immunosuppression class, comprise everolimus.
9. containing the described compound of claim 1～6 any one, its deuterium pharmaceutical preparation for thing, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers, is pharmaceutically acceptable arbitrary formulation.
10. compound as described as claim 1～6 any one, its deuterium is for thing, its pharmacy acceptable salt or its steric isomer are at the application and the overmedication proliferative disease that are selected from for the preparation of prevention or treatment aspect the medicine of following fibrotic conditions, the application of the medicine aspect of angiogenesis inhibitor and/or reduction vascular permeability effects, wherein said fibrotic conditions comprises: the fibrosis of lung tissue and refigure in chronic obstructive pulmonary disease, the fibrosis of lung tissue and refigure in chronic bronchitis, the fibrosis of lung tissue and refigure in pulmonary emphysema, pnemnofibrosis and there is the lung disease of fibrosis composition, fibrosis and refigure in asthma, fibrosis in rheumatoid arthritis, the liver cirrhosis that virus causes, radioactive fibrosis, postangioplasty restenosis, chronic glomerulonephritis, the kidney fibrosis of accepting the patient of ciclosporin reaches the kidney fibrosis caused due to hypertension, dermatosis with fibrosis composition, and excessive cicatrization, wherein said excessively proliferative disease comprises cancer and non-Cancerous disease, and described cancer is selected from: 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, colorectal cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin lymphoma, central nerve neuroma, be selected from neurospongioma, glioblastoma multiforme, glioma sarcomatosum, prostate cancer or thyroid carcinoma, non-Cancerous disease, be selected from skin or prostatic hyperplasia of prostate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210476892.3A CN103130775B (en) | 2011-11-22 | 2012-11-21 | As the dihydroindole ketone derivate of tyrosine kinase inhibitor |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110374352.X | 2011-11-22 | ||
| CN201110374352 | 2011-11-22 | ||
| CN201110374352X | 2011-11-22 | ||
| CN201210476892.3A CN103130775B (en) | 2011-11-22 | 2012-11-21 | As the dihydroindole ketone derivate of tyrosine kinase inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103130775A true CN103130775A (en) | 2013-06-05 |
| CN103130775B CN103130775B (en) | 2015-09-30 |
Family
ID=48491276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210476892.3A Active CN103130775B (en) | 2011-11-22 | 2012-11-21 | As the dihydroindole ketone derivate of tyrosine kinase inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103130775B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014086102A1 (en) * | 2012-12-06 | 2014-06-12 | 山东亨利医药科技有限责任公司 | Indole full ketone derivative used as tyrosine-kinase inhibitor |
| WO2016161160A1 (en) * | 2015-04-03 | 2016-10-06 | Kalyra Pharmaceuticals, Inc. | Spirocyclic compounds |
| US10934304B2 (en) | 2016-10-05 | 2021-03-02 | Recurium Ip Holdings, Llc | Spirocyclic compounds |
| CN115703758A (en) * | 2021-08-12 | 2023-02-17 | 中国医学科学院药物研究所 | Compound used as kinase inhibitor and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1303374A (en) * | 1998-06-04 | 2001-07-11 | 贝林格尔英格海姆法玛公司 | Substituted indolinones, production thereof and their use as medicaments |
| CN101087605A (en) * | 2004-12-24 | 2007-12-12 | 贝林格尔·英格海姆国际有限公司 | Indolidone derivatives for the treatment or prevention of fibrotic diseases |
| WO2010130757A1 (en) * | 2009-05-14 | 2010-11-18 | Boehringer Ingelheim International Gmbh | New combination therapy in treatment of oncological and fibrotic diseases |
| CN102112468A (en) * | 2008-07-29 | 2011-06-29 | 贝林格尔.英格海姆国际有限公司 | New compounds |
-
2012
- 2012-11-21 CN CN201210476892.3A patent/CN103130775B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1303374A (en) * | 1998-06-04 | 2001-07-11 | 贝林格尔英格海姆法玛公司 | Substituted indolinones, production thereof and their use as medicaments |
| CN101087605A (en) * | 2004-12-24 | 2007-12-12 | 贝林格尔·英格海姆国际有限公司 | Indolidone derivatives for the treatment or prevention of fibrotic diseases |
| CN102112468A (en) * | 2008-07-29 | 2011-06-29 | 贝林格尔.英格海姆国际有限公司 | New compounds |
| WO2010130757A1 (en) * | 2009-05-14 | 2010-11-18 | Boehringer Ingelheim International Gmbh | New combination therapy in treatment of oncological and fibrotic diseases |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014086102A1 (en) * | 2012-12-06 | 2014-06-12 | 山东亨利医药科技有限责任公司 | Indole full ketone derivative used as tyrosine-kinase inhibitor |
| EP2930167A4 (en) * | 2012-12-06 | 2016-08-03 | Kbp Biosciences Co Ltd | Indole full ketone derivative used as tyrosine-kinase inhibitor |
| US9642851B2 (en) | 2012-12-06 | 2017-05-09 | Kbp Biosciences Co., Ltd. | Indolinone derivative as tyrosine kinase inhibitor |
| WO2016161160A1 (en) * | 2015-04-03 | 2016-10-06 | Kalyra Pharmaceuticals, Inc. | Spirocyclic compounds |
| CN107849053A (en) * | 2015-04-03 | 2018-03-27 | 卡利拉制药公司 | Spiro-compound |
| US10493060B2 (en) | 2015-04-03 | 2019-12-03 | Recurium Ip Holdings, Llc | Spirocyclic compounds |
| US10525036B2 (en) | 2015-04-03 | 2020-01-07 | Recurium Ip Holdings, Llc | Spirocyclic compounds |
| US10934304B2 (en) | 2016-10-05 | 2021-03-02 | Recurium Ip Holdings, Llc | Spirocyclic compounds |
| CN115703758A (en) * | 2021-08-12 | 2023-02-17 | 中国医学科学院药物研究所 | Compound used as kinase inhibitor and preparation method and application thereof |
| CN115703758B (en) * | 2021-08-12 | 2024-03-26 | 中国医学科学院药物研究所 | Compounds used as kinase inhibitors, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103130775B (en) | 2015-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101759683B (en) | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor | |
| CN102643268B (en) | Quinoline and cinnoline compound and application thereof | |
| CN103987700A (en) | 4-quinazoline amine derivative and application thereof | |
| KR20140040774A (en) | Imidazopyridine compound | |
| CN102471312A (en) | 6-amino quinazoline or 3-cyano quinoline derivatives, preparation methods and pharmaceutical uses thereof | |
| CN102399220A (en) | Tricyclic dual PI3K and mTOR inhibitors | |
| MX2008012820A (en) | 3-SUBSTITUTED N-(ARYL- OR HETEROARYL)-PYRAZO[1,5-a]PYRIMIDINES AS KINASE INHIBITORS. | |
| CN101970424A (en) | Indolylpyridone derivatives with checkpoint kinase 1 inhibitory activity | |
| CA2990564A1 (en) | Bicyclic heterocyclic amide derivative | |
| CN103102352B (en) | Tyrosine kinase inhibitor indolinone derivative | |
| CN104045642A (en) | Fused ring compound containing pyrimidine or pyridine and its application as antitumor drug | |
| CN103130775B (en) | As the dihydroindole ketone derivate of tyrosine kinase inhibitor | |
| JP2003528880A (en) | Tricyclic protein kinase inhibitors | |
| WO2012155339A1 (en) | 4-phenylamino-6-butenamide-7-alkyloxy quinazoline derivatives, preparative method and use thereof | |
| CN102108078B (en) | 1,4-substituted phthalazine compound and preparation method and applications thereof | |
| US20120258957A1 (en) | Heterocyclic derivatives | |
| EP2501233A1 (en) | Quinazoline compounds | |
| CN104936944B (en) | It is used as the dihydroindole ketone derivate of tyrosine kinase inhibitor | |
| CN112521336B (en) | Indazole and pyrrolopyridine compounds and application thereof | |
| CN103848814B (en) | The full ketone derivatives of substituted indole as tyrosine kinase inhibitor | |
| CN103130791A (en) | Novel benzamides compound | |
| CN102421779B (en) | Dihydropteridinone derivatives, preparation method and pharmaceutical use thereof | |
| CN110724137B (en) | Thiophene derivative and preparation method and application thereof | |
| CN103965107A (en) | 2-aryl-substituted quinoline compounds and application thereof | |
| CN103965170A (en) | Benzene sulfonamide pyrazole kinase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: 250101 Shandong city of Ji'nan province high tech Zone Hong Xing three North Road No. 2 building 401 Ji'nan trough Patentee after: Shandong Henry Medical Science and Technology Co., Ltd. Address before: 250101 Shandong city of Ji'nan province high tech Zone Shun Road No. 750 room B302 Patentee before: Shandong Henry Medical Science and Technology Co., Ltd. |