CN101027055A - Tricycles, their manufacture and use as pharmaceutical agents - Google Patents
Tricycles, their manufacture and use as pharmaceutical agents Download PDFInfo
- Publication number
- CN101027055A CN101027055A CNA2005800319711A CN200580031971A CN101027055A CN 101027055 A CN101027055 A CN 101027055A CN A2005800319711 A CNA2005800319711 A CN A2005800319711A CN 200580031971 A CN200580031971 A CN 200580031971A CN 101027055 A CN101027055 A CN 101027055A
- Authority
- CN
- China
- Prior art keywords
- ketone
- pyrazole
- dihydro
- imidazo
- indole
- 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.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Objects of the present invention are the compounds of Formula (I) their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above-mentioned compounds in the control or prevention of illnesses such as cancer.
Description
The present invention relates to new tricyclic compound (tricycles), their preparation method contain their pharmaceutical composition and their preparation, and these chemical compounds is as the application of pharmaceutically active agents.
Protein kinase is regulated many unlike signal conductive processes (Hunter, T., Cell 50 (1987) 823-829) by phosphate group is increased on the protein; Especially serine/threonine kinase on the alcohol moiety of serine or threonine residues with protein phosphorylation.Serine/threonine kinase family comprises the growth of control cell, migration, differentiation, gene expression, muscle contraction, glucose metabolism, cell protein is synthetic and the member of Cycle Regulation.
The Aurora kinases is gang's serine/threonine kinase, is considered to bring into play pivotal role in the protein phosphorylation incident, and this protein phosphorylation incident is essential for finishing basic mitosis incident.Aurora kinases family is made up of three key members: Aurora A, B and C (also being called Aurora-2, Aurora-1 and Aurora-3).Aurora-1 and Aurora-2 for example describe among EP 0868519 and the EP 1051500 in the US 6,207,401 of Sugen and relevant patent and patent application.
For Aurora A, exist cumulative evidence to show that it is new proto-oncogene.In most of human tumour cell lines and constitutional colorectal carcinoma, mammary neoplasms and other tumor Aurora A gene be amplified and transcript/protein by high expressed.Shown that Aurora A overexpression causes genetic instability, this shows by the centrosome of amplification and the remarkable increase of aneuploidy, and vitro conversion Ratl fibroblast and mouse NIH 3T3 cell.The NIH3T3 cell that AuroraA-transforms in nude mice as tumor growth (Bischoff, J.R., and Plowman, G.D., Trends Cell Biol.9 (1999) 454-459; Giet, R., and Prigent, C., J.Cell Sci.112 (1999) 3591-3601; Nigg, E.A., Nat.Rev.Mol.Cell Biol.2 (2001) 21-32; Adams, R.R., etc., TrendsCell Biol.11 (2001) 49-54).In addition, the amplification of Aurora A and aneuploidy and the relevant (Sen of the clinical behavior of invasive, S., Deng, J.Natl.Cancer Inst.94 (2002) 1320-1329) and the amplification of its locus and the relevant (Isola of prognosis for the patient with breast cancer's of lymph node-feminine gender difference, J.J., etc., Am.J.Pathology 147 (1995) 905-911).Owing to these reasons, the someone proposes the AuroraA overexpression by participating in chromosome separation and mitosis checkpoint control promotion cancerous phenotype.
The human tumor cell line of disappearance Aurora A transcript is stuck in the mitosis.Therefore, by selective depressant Aurora kinases specificity is suppressed to be considered to stop uncontrolled propagation, rebuilds the control of mitosis checkpoint and causes the tumor cell programmed cell death.Therefore in heteroplastic transplantation model, the Aurora inhibitor has slowed down tumor growth and has induced degeneration (Harrington, E.A. is etc., Nat.Med.10 (2004) 262-267).
The low-molecular-weight depressor of protein kinase is extensively known in this area.Suppress these inhibitor for Aurora and be based on promptly quinazoline derivant claimed in following patent and patent application: WO 00/44728; WO 00/47212; WO 01/21594; WO 01/21595; WO 01/21596; WO 01/21597; WO 01/77085; WO 01/55116; WO 95/19169; WO 95/23141; WO 97/42187; WO 99/06396; Claimed pyrazoles and triazole derivative in following patent and patent application: WO 02/22601; WO 02/22602; WO 02/22603; WO 02/22604; WO 02/22605; WO 02/22606; WO 02/22607; WO 02/22608; WO 02/50065; WO 02/50066; WO 02/057259; WO 02/059112; WO 02/,059 111; WO 02/062789; WO 02/066461; WO 02/068415; Pyrimidine derivatives: WO 03/077921; WO 03/078423; WO 03/078426; WO 03/078427; WO 04/000833 or imidazoles, uh azoles and thiazole: WO 02/96905; WO 04/005283;
Yet, still needing to have the chemical compound of new construction of the curative properties of improvement, the toxicity of the curative properties of described improvement such as enhanced activity, reduction, the better pharmacokinetics curve of dissolubility and improvement have only been enumerated a few examples here.
The present invention relates to the chemical compound of general formula I and all pharmaceutical salts thereof and be used for the treatment of application in the medicine of cancer in preparation,
Wherein
R
1Be hydrogen, alkyl or-C (O)-alkyl;
R
2Be hydrogen, alkyl, cyano group or halogen;
R
3Be hydrogen, alkyl, (C
3-C
6)-cycloalkyl, alkoxyl or alkylthio group;
X is-C (O)-or-CH
2-;
Y is-NH--CH
2-CR
4R
5-,-CR
4R
5-CH
2-or-CR
4R
5-; Wherein
R
4It is hydrogen or alkyl; And
R
5Be hydrogen or alkyl,
Or alternatively
R
4And R
5The carbon atom that connects with them forms cycloalkyl ring.
Another embodiment of the invention is that the chemical compound of formula I is used for the treatment of application in the medicine of cancer, wherein R in preparation
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl.
Another embodiment of the invention is the application of the chemical compound of formula I as the Aurora family kinase inhibitors, wherein R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl.
From US 4,835,280A, EP 0189103, and US 4,954, and 498 and also from Mertens, A., etc., J.Med.Chem.30 (1987) 1279-1287; Von der Saal, W., etc., J.Med.Chem.32 (1989) 1481-1491; EP 0318902; DE 3417643; Known some tricyclic compounds or related compound among DE 3642315 and the DE 3701277 as the erythrocyte aggregation inhibitor.US 5,212, and 186A has described the relevant tricyclic compound that is used for the treatment of cardiac insufficiency, hypertension and other disease.
WO 03/035065 relates to benzimidizole derivatives, and it is an inhibitors of kinases, and particularly conduct is at containing the inhibitor that kinases inserts domain receptor (KDR) tyrosine kinase, spleen tyrosine kinase (SYK) and derivable T cell kinase (ITK).
According to the activity of compound exhibits of the present invention as kinases inhibitor.Numerous disease is replied relevant with the abnormal cell that is caused by protein kinase mediated incident.These diseases comprise autoimmune disease, inflammatory diseases, neuropathy and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, presenile dementia or hormone relevant disease.Therefore, carried out sizable effort in the medical chemistry field and sought effective kinases inhibitor as therapeutic agent.
Especially show as the Aurora family kinase inhibitors, particularly as the activity of Aurora A inhibitors of kinases according to chemical compound of the present invention, and therefore can be effective to treat by described kinase mediated disease.Aurora A suppresses to cause the G2 phase of cell cycle arrest at cell cycle, and brings into play antiproliferative effect in tumor cell line.This shows that it is hyperplasia disorders such as cancers and particularly colorectal cancer, breast carcinoma, pulmonary carcinoma, carcinoma of prostate, cancer of pancreas, gastric cancer, bladder cancer, ovarian cancer, melanoma, neuroblastoma, cervical cancer, renal cancer or renal carcinoma, leukemia or lymphoma that Aurora A inhibitor can be used for the treatment of.Comprise acute-myelomatosis (AML, the treatment of acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumor (GIST).
The objective of the invention is the chemical compound of formula I and their tautomer, pharmaceutical salts, enantiomeric forms, diastereomer and racemate, they are as the application of Aurora inhibitors of kinases, the preparation of above-claimed cpd, contain they medicine and their preparation and above-claimed cpd in control or prevent disease or the application in the preparation relative medicine, particularly above-mentioned disease of described disease and disease.
As used herein, that term " alkyl " is meant is saturated, straight or branched contain 1 to 6, the alkyl of preferred 1 or 4 carbon atom, as methyl, ethyl, just-propyl group, isopropyl, just-butyl, 2-butyl, the tert-butyl group.Described alkyl is randomly by one or several halogen atoms replacements, described halogen atom preferred fluorine or chlorine, particularly fluorine.Preferred described alkyl is replaced one to five time and more preferably one to three time by this halogen.Example has trifluoromethyl, and 2,2,2-trifluoroethyl, perfluor ethyl etc., preferred trifluoromethyl.In one embodiment of the invention, R only
3In used " alkyl " randomly replaced and R by halogen
1, R
2, R
4And R
5Middle other " alkyl " that uses do not replaced by halogen.In another embodiment of the invention, all " alkyl " groups are not replaced by halogen.
Term used herein " alkoxyl " is meant the alkyl as defined above that connects via oxygen atom (alkyl-O-).
Term used herein " alkylthio group " is meant the alkyl as defined above that connects via sulphur atom (alkyl-S-).
Term used herein " cycloalkyl " is meant and contains 3 to 6, the unsaturated ring system of carbocyclic ring of preferred 3 to 5 carbon atoms.The unsaturated ring system of this carbocyclic ring can be randomly by alkyl replace one to three time, preferably once or twice, particularly once.Example has cyclopropyl, 1-methyl-cyclopropyl-1-base, cyclobutyl, cyclopenta and cyclohexyl, preferred cyclopropyl.In one embodiment of the invention, R
3Middle term " cycloalkyl " the representative ring propyl group that uses.Pass through R
4And R
5And the cycloalkyl ring that their carbon atoms of connecting form together is preferably cyclopenta or cyclohexyl ring, particularly the cyclopenta ring.
Term used herein " halogen " is meant fluorine, chlorine, bromine and iodine, preferred fluorine, chlorine or bromine, and more preferably fluorine and chlorine.
Formula I chemical compound can exist with different tautomeric forms or its variable mixture.All tautomeric forms of formula I chemical compound and composition thereof are purposes of the present invention.For example, the imidazoles of three ring systems of formula I part can exist with two kinds of tautomeric forms as follows:
In addition, for example the pyrazoles ring of formula I can form this paper two kinds of tautomeric forms as follows:
As used herein, (MS) is relevant with mass spectral analysis, and term " API+ " is meant positive air pressure ionization pattern, and term " API-" is meant negative pressure ionization pattern, and term " ESI+ " is meant positive electrospray ionization pattern.
To be formula I chemical compounds be used for the treatment of application in the medicine of cancer in preparation to one embodiment of the invention, and wherein X is-CH
2-.
To be formula I chemical compounds be used for the treatment of application in the medicine of cancer, wherein R in preparation to one embodiment of the invention
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl; And X is-CH
2-.
One embodiment of the invention are the application as the Aurora family kinase inhibitors of formula I chemical compound, and wherein X is-CH
2-.
To be formula I chemical compound be used for the treatment of application in the medicine of cancer in preparation to another embodiment of the invention, and wherein X is-CH
2-; And Y is-CR
4R
5-.
To be formula I chemical compound be used for the treatment of application in the medicine of cancer, wherein R in preparation to another embodiment of the invention
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl; X is-CH
2-; And Y is-CR
4R
5-.
Another embodiment of the invention is the application of formula I chemical compound as the Aurora family kinase inhibitors, and wherein X is-CH
2-; And Y is-CR
4R
5-.
The present invention also has another embodiment, and to be formula I chemical compound be used for the treatment of application in the medicine of cancer in preparation, and wherein X is-CH
2-; And
Y is-NH--CH
2-CR
4R
5-or-CR
4R
5-CH
2-.
The present invention also has another embodiment, and to be formula I chemical compound be used for the treatment of application in the medicine of cancer, wherein R in preparation
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl; X is-CH
2-; And
Y is-NH--CH
2-CR
4R
5-or-CR
4R
5-CH
2-.
It is the application of formula I chemical compound as the Aurora family kinase inhibitors that the present invention also has another embodiment, wherein
X is-CH
2-; And
Y is-NH--CH
2-CR
4R
5-or-CR
4R
5-CH
2-.
The present invention also has another embodiment, and to be formula I chemical compound be used for the treatment of application in the medicine of cancer in preparation, wherein X be-C (O)-.
The present invention also has another embodiment, and to be formula I chemical compound be used for the treatment of application in the medicine of cancer, wherein R in preparation
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl; And X is-C (O)-.
It is the application of formula I chemical compound as the Aurora family kinase inhibitors that the present invention also has another embodiment, wherein X be-C (O)-.
To be formula I chemical compound be used for the treatment of application in the medicine of cancer in preparation to another embodiment of the invention, wherein X be-C (O)-; And Y is-CH
2-CR
4R
5-or-CR
4R
5-CH
2-.
To be formula I chemical compound be used for the treatment of application in the medicine of cancer, wherein R in preparation to another embodiment of the invention
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl; X is-C (O)-; And Y is-CH
2-CR
4R
5-or-CR
4R
5-CH
2-.
Another embodiment of the invention is the application of formula I chemical compound as the Aurora family kinase inhibitors, wherein X be-C (O)-; And Y is-CH
2-CR
4R
5-or-CR
4R
5-CH
2-.
The present invention also has another embodiment, and to be formula I chemical compound be used for the treatment of application in the medicine of cancer in preparation, wherein
X is-C (O)-; And
Y is-NH-or-CR
4R
5-.
The present invention also has another embodiment, and to be formula I chemical compound be used for the treatment of application in the medicine of cancer in preparation, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-NH-or-CR
4R
5-.
It is the application of formula I chemical compound as the Aurora family kinase inhibitors that the present invention also has another embodiment, wherein
X is-C (O)-; And
Y is-NH-or-CR
4R
5-.
The present invention also has another embodiment, and to be formula I chemical compound be used for the treatment of application in the medicine of cancer in preparation, wherein
X is-C (O)-; And
Y is-CR
4R
5-.
The present invention also has another embodiment, and to be formula I chemical compound be used for the treatment of application in the medicine of cancer in preparation, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-CR
4R
5-.
It is the application of formula I chemical compound as the Aurora family kinase inhibitors that the present invention also has another embodiment, wherein
X is-C (O)-; And
Y is-CR
4R
5-.
To be formula I chemical compound be used for the treatment of application in the medicine of cancer in preparation to another embodiment of the invention, wherein
X is-C (O)-; And
Y is-NH-.
To be formula I chemical compound be used for the treatment of application in the medicine of cancer in preparation to another embodiment of the invention, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-NH-.
Another embodiment of the invention is the application of formula I chemical compound as the Aurora family kinase inhibitors, wherein
X is-C (O)-; And
Y is-NH-.
Containing The compounds of this invention or its pharmaceutical salts and treating the medicine of going up inert carrier is purpose of the present invention, their preparation method equally also is, this method comprises that valuable material (if desired) is gone up in one or more chemical compounds of the present invention and/or pharmaceutical salts and one or more other treatment to be gone up inert carrier with one or more treatments and make the galenical form of medication.
According to the present invention, chemical compound of the present invention and their pharmaceutical salts are used for control or prevent disease.Based on their inhibition of Aurora tyrosine kinase and their antiproliferative activity, described chemical compound is used for the treatment of disease such as the mankind or animal cancer or is used to produce corresponding medicine.Dosage depends on various factors such as administering mode, species, age and/or individual health situation.
Another embodiment of the invention is to contain as one or more formulas I chemical compound of active component and the medicine of medicinal adjuvant, and it is used for the treatment of the disease by the inappropriate activation mediation of Aurora family tyrosine kinase, particularly Aurora A tyrosine kinase.
Another embodiment of the invention is to contain as one or more formulas I chemical compound of active component and the medicine that is used for the treatment of cancer of medicinal adjuvant.
Another embodiment of the invention is to contain as one or more formulas I chemical compound of active component and the medicine of medicinal adjuvant, it is used for the treatment of colorectal cancer, breast carcinoma, pulmonary carcinoma, carcinoma of prostate, cancer of pancreas, gastric cancer, bladder cancer, ovarian cancer, melanoma, neuroblastoma, cervical cancer, renal cancer or renal carcinoma, leukemia or lymphoma.
Another embodiment of the invention is to contain as one or more formulas I chemical compound of active component and the medicine of medicinal adjuvant, and it is used for the treatment of acute-myelomatosis (AML, acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumor (GIST).
Another embodiment of the invention is the application of one or more formulas I chemical compound in the preparation medicine, and described medicine is used for the treatment of the disease by the inappropriate activation mediation of Aurora family tyrosine kinase.
Another embodiment of the invention is the application of formula I chemical compound as Aurora A tyrosine kinase inhibitor.
Another embodiment of the invention is the application of formula I chemical compound as antiproliferative.
The application of one or more formulas of another embodiment of the invention I chemical compound in the treatment cancer.
Another embodiment of the invention is the application of one or more formulas I chemical compound in the preparation medicine, and described medicine is used for the treatment of the disease by the inappropriate activation mediation of Aurora family tyrosine kinase.
Another embodiment of the invention is the application of one or more formulas I chemical compound in the medicine of preparation treatment cancer.
Another embodiment of the invention is the application of one or more formulas I chemical compound in the preparation medicine, described medicine is used for the treatment of colorectal cancer, breast carcinoma, pulmonary carcinoma, carcinoma of prostate, cancer of pancreas, gastric cancer, bladder cancer, ovarian cancer, melanoma, neuroblastoma, cervical cancer, renal cancer or renal carcinoma, leukemia or lymphoma.
Another embodiment of the invention is the application of one or more formulas I chemical compound in the preparation medicine, and described medicine is used for the treatment of acute-myelomatosis (AML, acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumor (GIST).Another embodiment of the invention is to contain as one or more formulas I chemical compound of active component and the medicine of medicinal adjuvant, and it is used for the treatment of the disease by the inappropriate activation mediation of Aurora family tyrosine kinase, particularly Aurora A tyrosine kinase.
Another embodiment of the invention is to contain as one or more formulas I chemical compound of active component and the medicine that is used for the treatment of cancer of medicinal adjuvant.
Another embodiment of the invention is to contain as one or more formulas I chemical compound of active component and the medicine of medicinal adjuvant, it is used for the treatment of colorectal cancer, breast carcinoma, pulmonary carcinoma, carcinoma of prostate, cancer of pancreas, gastric cancer, bladder cancer, ovarian cancer, melanoma, neuroblastoma, cervical cancer, renal cancer or renal carcinoma, leukemia or lymphoma.
Another embodiment of the invention is to contain as one or more formulas I chemical compound of active component and the medicine of medicinal adjuvant, and it is used for the treatment of acute-myelomatosis (AML, acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumor (GIST).
Another embodiment of the invention is the chemical compound of formula I, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
Precondition is, if R
1And R
2Be hydrogen, X is-C (O)-and Y be-CR
4R
5-; R wherein
4And R
5It is methyl;
R so
3Be hydrogen, (C
2-C
6) alkyl or (C
3-C
6)-cycloalkyl.
It is the chemical compound of formula I that the present invention also has another embodiment, wherein
R
3Be hydrogen, (C
2-C
6) alkyl or (C
3-C
6)-cycloalkyl.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl; And
X is-CH
2-.
It is the chemical compound of formula I that the present invention also has another embodiment, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-CH
2-; And
Y is-CR
4R
5-.
These chemical compounds for example have:
7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-3,5,6,7-tetrahydrochysene-imidazo [4,5-f] indole; With
1-[7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-6,7-dihydro-3H-imidazo [4,5-f] indole-5-yl]-ethyl ketone.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-CH
2-; And
Y is-NH--CH
2-CR
4R
5-or-CR
4R
5-CH
2-.
It is the chemical compound of formula I that the present invention also has another embodiment, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl; And
X is-C (O)-;
Precondition is, if R
1And R
2Be hydrogen, X is-C (O)-and Y be-CR
4R
5-; R wherein
4And R
5It is methyl;
R so
3Be hydrogen, (C
2-C
6) alkyl or (C
3-C
6)-cycloalkyl.
It is the chemical compound of formula I that the present invention also has another embodiment, wherein
R
3Be hydrogen, (C
2-C
6) alkyl or (C
3-C
6)-cycloalkyl; And
X is-C (O)-.
It is the chemical compound of formula I that the present invention also has another embodiment, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-CH
2-CR
4R
5-or-CR
4R
5-CH
2-.
These chemical compounds for example have:
8,8-dimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone; With
2-(5-isobutyl group-2H-pyrazole-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-NH--CR
4R
5-;
Precondition is, if R
1And R
2Be hydrogen, X is-C (O)-and Y be-CR
4R
5-; R wherein
4And R
5It is methyl;
R so
3Be hydrogen, (C
2-C
6) alkyl or (C
3-C
6)-cycloalkyl.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
3Be hydrogen, (C
2-C
6) alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-NH--CR
4R
5-.
It is the chemical compound of formula I that the present invention also has another embodiment, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-CR
4R
5-;
Precondition is, if R
1And R
2Be hydrogen, X is-C (O)-and Y be-CR
4R
5-; R wherein
4And R
5It is methyl;
R so
3Be hydrogen, (C
2-C
6) alkyl or (C
3-C
6)-cycloalkyl.
It is the chemical compound of formula I that the present invention also has another embodiment, wherein
R
3Be hydrogen, (C
2-C
6) alkyl or (C
3-C
6)-cycloalkyl.
X is-C (O)-; And
Y is-CR
4R
5-.
These chemical compounds for example have:
2-(5-isobutyl group-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-methyl-2H-pyrazole-3-yl)-spiral shell [7,7-Pentamethylene .-5,7-dihydro-3H-imidazo [4,5-f] indole]-6-ketone; Or according to existing IUPAC nomenclature 2-(5-methyl-2H-pyrazole-3-yl)-spiral shell-5, the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-spiral shell [7,7-Pentamethylene .-5,7-dihydro-1H-imidazo [4,5-f] indole]-6-ketone; Or according to existing IUPAC nomenclature 2-(5-isobutyl group-2H-pyrazole-3-yl)-spiral shell-5, the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
5-ethyl-7,7-dimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-2-(5-isobutyl group-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone; And
2-(5-isobutyl group-2H-pyrazole-3-yl)-5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-NH-.
These chemical compounds for example have:
6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone;
3-methyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone; And
3-isopropyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1Be alkyl or-C (O)-alkyl.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl; And
R
2It is hydrogen or alkyl.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl;
R
2It is hydrogen or alkyl; And
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl;
X is-C (O)-; And
Y is-CH
2-CR
4R
5-,-CR
4R
5-CH
2-or-CR
4R
5-.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl;
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-CH
2-CR
4R
5-,-CR
4R
5-CH
2-or-CR
4R
5-.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl;
R
2It is hydrogen or alkyl;
X is-C (O)-; And
Y is-CR
4R
5-.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl;
R
2Be hydrogen;
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-CR
4R
5-.
These chemical compounds for example have:
5-ethyl-7,7-dimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-2-(5-isobutyl group-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone; Chemical compound with acetic acid;
5-isopropyl-7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
5-isopropyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5-propyl group-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-5-propyl group-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl;
R
2It is hydrogen or alkyl;
R
3Replaced once or alkyl for several times by halogen;
X is-C (O)-; And
Y is-CR
4R
5-.
These chemical compounds for example have:
5-ethyl-7,7-dimethyl-2-(5-Trifluoromethyl-1 H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-isopropyl-7,7-dimethyl-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-5-propyl group-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone; And
5,7,7-trimethyl-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl;
R
2It is hydrogen or alkyl;
R
3Be alkoxyl or alkylthio group;
X is-C (O)-; And
Y is-CR
4R
5-.
These chemical compounds for example have:
5-ethyl-2-(5-methoxyl group-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone; And
5-ethyl-7,7-dimethyl-2-(5-methyl mercapto-1H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl;
R
2It is hydrogen or alkyl;
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-CH
2-CR
4R
5-or-CR
4R
5-CH
2-.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is alkyl;
R
2It is hydrogen or alkyl;
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-NH-.
These chemical compounds for example have:
3-methyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone; And
3-isopropyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone.
Another embodiment of the invention is the chemical compound of formula I, wherein
R
1It is-C (O)-alkyl;
R
2It is hydrogen or alkyl;
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-CH
2-; And
Y is-CH
2-CR
4R
5-,-CR
4R
5-CH
2-or-CR
4R
5-.
This chemical compound for example is:
1-[7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-6,7-dihydro-3H-imidazo [4,5-f] indole-5-yl]-ethyl ketone.
Another embodiment of the invention is to contain as the chemical compound of one or more formulas I of active component and the medicine of medicinal adjuvant, and precondition is, if R
1And R
2Be hydrogen, X is-C (O)-and Y be-CR
4R
5-; R wherein
4And R
5It is methyl; R so
3Be hydrogen, (C
2-C
6) alkyl or (C
3-C
6)-cycloalkyl.
Another embodiment of the invention is chemical compound and the medicine of medicinal adjuvant, the wherein R that contains as one or more formulas I of active component
3Be hydrogen, (C
2-C
6) alkyl, (C
3-C
6)-cycloalkyl or fluorine.
Another embodiment of the invention is chemical compound and the medicine of medicinal adjuvant, the wherein R that contains as one or more formulas I of active component
1Be alkyl or-C (O)-alkyl.
Another embodiment of the invention is chemical compound and the medicine of medicinal adjuvant, the wherein R that contains as one or more formulas I of active component
1It is alkyl.
To be one of following compounds be used for the treatment of application in the medicine of cancer in preparation to another embodiment of the invention:
7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-3,5,6,7-tetrahydrochysene-imidazo [4,5-f] indole;
1-[7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-6,7-dihydro-3H-imidazo [4,5-f] indole-5-yl]-ethyl ketone;
8,8-dimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone;
7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-methyl-2H-pyrazole-3-yl)-spiral shell [7,7-Pentamethylene .-5,7-dihydro-3H-imidazo [4,5-f] indole]-6-ketone; Or according to existing IUPAC nomenclature 2-(5-methyl-2H-pyrazole-3-yl)-spiral shell-5, the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-spiral shell [7,7-Pentamethylene .-5,7-dihydro-1H-imidazo [4,5-f] indole]-6-ketone; Or according to existing IUPAC nomenclature 2-(5-isobutyl group-2H-pyrazole-3-yl)-spiral shell-5, the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone;
2-(4,5-dimethyl-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-2-[5-(3-methyl-butyl)-1H-pyrazole-3-yl]-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-ethyl-4-methyl isophthalic acid H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-cyclopropyl-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-isopropyl-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
8,8-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone;
8,8-dimethyl-2-(1H-pyrazole-3-yl)-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone;
2-(5-cyclopropyl-1H-pyrazole-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone
2-(5-isopropyl-2H-pyrazole-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone;
2-(2H-pyrazole-3-yl)-spiral shell-5, and the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
2-(5-isopropyl-2H-pyrazole-3-yl)-spiral shell-5, and the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
2-(5-propyl group-2H-pyrazole-3-yl)-spiral shell-5, and the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
7,7-dimethyl-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone; And
2-(5-cyclopropyl-2H-pyrazole-3-yl)-spiral shell-5, and the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone.
To be one of following compounds be used for the treatment of application in the medicine of cancer in preparation to another embodiment of the invention:
3-methyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone;
3-isopropyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone;
5-ethyl-7,7-dimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-2-(5-isobutyl group-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone; Chemical compound with acetic acid;
5-isopropyl-7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
5-isopropyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5-propyl group-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-5-propyl group-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-Trifluoromethyl-1 H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-isopropyl-7,7-dimethyl-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-are narrowed also [4,5-f] indole-6-ketone of azoles;
7,7-dimethyl-5-propyl group-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-2-(5-methoxyl group-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone; And
5-ethyl-7,7-dimethyl-2-(5-methyl mercapto-1H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
Another embodiment of the invention is preparation R
1Be alkyl or-method of the formula I chemical compound of C (O)-alkyl, wherein
A) chemical compound of formula II,
R wherein
1Be alkyl or-C (O)-alkyl and X and Y have the above implication that provides about formula I;
With the chemical compound reaction of formula III,
Wherein A is-OH ,-Cl ,-H or-OMe and R
2And R
3Has the above implication that provides about formula I;
The chemical compound of acquisition formula I,
R wherein
1Be alkyl or-C (O)-alkyl and R
2, R
3, X and Y have the above implication that provides about formula I;
B) chemical compound of the described formula I of separation from reactant mixture, and
C) if desired, it is converted into pharmaceutical salts.
Chemical compound or its pharmaceutical salts as the formula I of theme of the present invention can be known any method preparation that is suitable for preparing chemical related compound by oneself.These methods, when being used for the compound or pharmaceutically acceptable salt thereof of preparation formula I, by following representative reactions route 1 and 2 and embodiment illustrate, wherein unless otherwise noted, X, Y, R
1, R
2And R
3Has the implication that provides more than this paper.Required raw material can obtain by vitochemical standard step.These preparing raw material are described in the attached embodiment in back.Alternatively, required raw material can obtain by being similar to illustrational those step, and it belongs in organic chemist's the ordinary skill.
The benzimidazole ring system of formula I can by be similar to document (Mertens, A. is etc., J.Med.Chem.30 (1987) 1279-1287; DE 3531678) the different route of synthesis of described method form.
Be used for the diamidogen of a route (reaction scheme 1) of preparation I compound from formula II, the diamidogen of formula II can with carboxylic acid (wherein A is the chemical compound of the formula III of OH), acid chloride (A is Cl), aldehyde (A is H), carboxylate methyl ester (A is OMe) or Acibenzolar (A for example be hydroxybenzotriazole) reaction.About detailed step, referring to document cited above.
Reaction scheme 1
The pyrazoles of formula III commercially available or they can be by vitochemical standard method preparation (referring to for example Stanovnik, B., and Svete, J., Science of Synthesis 12 (2002) 15-225), for example 1,3-dicarbonyl compound and hydrazine condensation are (referring to for example WO 04/032928 or van Herk, T., etc., J.Med.Chem.46 (2003) 3945-3951) or diazo compound and acetylene between 1, the cycloaddition of 3-dipole is (referring to for example Sewald, N., etc., Liebigs Ann.Chem. (1992) 947-952).R wherein
3The pyrazoles that is the formula III of alkoxyl can be via 5-hydroxyl-pyrazoles-3-carboxylate (referring to for example Ochi, H. etc., Chem.Pharm.Bull.31 (1983) 1228-1234), subsequently in the presence of alkali such as cesium carbonate etc., in solvent such as dimethyl formamide (DMF), N-methyl-ketopyrrolidine (NMP) etc. with alkyl halide with 5-hydroxyl O-alkylation (referring to for example WO 03/035065) or according to Martins, M.A.P., etc., the method for Synthesis 15 (2003) 2353-2357 prepares.R wherein
3The pyrazoles that is the formula III of alkylthio group can be according to Mahata, P.K., etc., Tetrahedron 59 (2003) 2631-2639 are via corresponding oxygen-ketenes dithioacetals preparation.As the alternative of reaction scheme 1, wherein R
35-alkoxyl-or the 5-alkylthio group-pyrazoles part that is the formula I chemical compound of alkoxyl or alkylthio group can be introduced by the reactions steps of WO 03/035065 described another sequence.R wherein
2Be hydrogen, R
3Be that trifluoromethyl and A are that the pyrazoles of the formula III of hydroxyl can prepare with three one step process according to reaction scheme la: under acid condition 4,4,4-three fluoro-1-(2-furyl)-1, the condensation of 3-diacetyl and benzyl hydrazine, furan nucleus and potassium permanganate be degraded to carboxylic functionality (referring to for example Djuric, S.W., etc., J.Med.Chem.43 (2000) 2975-2981; Jia, Z.J., etc., Bioorg.Med.Chem.Lett.12 (2002) 1651-1655 or Pruitt, J.R. is etc., J.Med.Chem.46 (2003) 5298-5315) and the cracking of benzyl protecting group required 5-trifluoromethyl-2H-pyrazoles-3-carboxylic acid is provided.
Reaction scheme 1a
This method relate to the N-benzyl or alternatively the p-methoxy-benzyl (Subramanyam, C., Synth.Commun.25 (1995) 761-774 also can be applied to prepare as other required pyrazoles of raw material as the intermediate protecting group.
Wherein X be-C (O)-, R
1Be that hydrogen or alkyl and Y are-CR
4R
5Or-the formula II chemical compound of NH-can prepare to be similar to the described mode of following document: Mertens, and A., etc., J.Med.Chem.30 (1987) 1279-1287; Von der Saal, W., etc., J.Med.Chem.32 (1989) 1481-1491; DE 3417643; EP 0318902, and US 4,666,923A, and US 4,695,567A, US 4,863,945A and US 4,985,448A.Wherein X be-C (O)-or-CH
2-, R
1Be hydrogen or-C (O) alkyl and Y be-CR
4R
5-formula II chemical compound can be according to DE 3642315 preparation.In addition, wherein X be-C (O)-or-CH
2-, R
1Be that hydrogen or alkyl and Y are-CR
4R
5-CH
2-or-CH
2-CR
4R
5-the formula III chemical compound in DE 3701277, describe.
For example, wherein X be-C (O)-, R
1Be that hydrogen or alkyl and Y are-CR
4R
5Formula II diamidogen called after IIa and can be according to US 4,666,923A, DE 3410168 and Mertens, A., etc., J.Med.Chem.30 (1987) 1279-1287, synthetic shown in reaction scheme 1b:
Reaction scheme 1b
In reaction scheme 1b, R
1, R
4And R
5Have the above implication that provides about formula I, and L represents for example iodine of leaving group, bromine, chlorine, triflate etc.
In alternative approach, R wherein
1Be alkyl formula IIa diamidogen can by with the diamidogen of formula IIb (Compound I I, wherein X be-C (O)-, R
1Be that hydrogen and Y are-CR
4R
5) alkylation and obtaining, shown in reaction scheme 1c.
Reaction scheme 1c
The diamidogen of formula IIb can be synthetic under omission step 5 according to reaction scheme 1b.
Another of formula I chemical compound synthetic (reaction scheme 2) is initial from nitro-compound IV or V, and nitro-compound IV or V are hydrogenated and are required benzimidizole derivatives with acetic acid or hydrochloric acid cyclisation subsequently.About detailed step, referring to Mertens, A., etc., J.Med.Chem.30 (1987) 1279-1287; DE 3531678.
Reaction scheme 2
Wherein X is C (O), R
1Be that hydrogen or alkyl and Y are-CR
4R
5, the formula IV of-NH-and the chemical compound of V can be being similar to Mertens, A., etc., J.Med.Chem.30 (1987) 1279-1287; Vonder Saal, W., etc., J.Med.Chem.32 (1989) 1481-1491; DE 3417643; EP 0318902 described mode prepares.Wherein X be C (O) or-CH
2-, R
1Be hydrogen or-C (O) alkyl and Y be-CR
4R
5-formula IV and the chemical compound of V can be according to DE 3642315 preparations.In addition, wherein X be C (O) or-CH
2-, R
1Be that hydrogen or alkyl and Y are-CR
4R
5-CH
2-or-CH
2-CR
4R
5-formula II chemical compound in DE 3701277, describe.
Can exist with their form of pharmaceutical salts according to chemical compound of the present invention.Term " pharmaceutical salts " is meant conventional acid-addition salts, biological effectiveness of their freeze mode I chemical compounds and performance and formed by suitable non-toxicity organic or inorganic acid.The sample acid-addition salts comprise be derived from mineral acid those and be derived from organic acid those, described mineral acid example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, sulfamic acid, phosphoric acid and nitric acid, described organic acid such as p-methyl benzenesulfonic acid, LOMAR PWA EINECS 246-676-2, naphthalenedisulfonic acid, methanesulfonic acid, ethyl sulfonic acid etc.With medical compounds (that is, medicine) chemical modification salify is the well-known technology of Pharmaceutical Chemist, and this technology is used to obtain physics and chemical stability, hygroscopicity, flowability and the dissolubility of the improvement of chemical compound.Referring to for example Stahl, P.H., and Wermuth, G., (editor), Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta (VHCA), Z ü rich, (2002) or Bastin, R.J., etc., Organic Proc.Res.Dev.4 (2000) 427-435.
Formula I chemical compound can contain one or several chiral centre and therefore can exist with raceme or optically-active form.This racemate can be separated into enantiomer according to known method.For example, by with the optically-active acid reaction, form diastereoisomeric salt by racemic mixture, it can separate by crystallization process, described optically-active acid as for example D-or L-camphorsulfonic acid.Alternatively, Separation of Enantiomers also can realize by the chromatography that uses commercially available chirality HPLC-to go up mutually.
Pharmacological activity
Formula I chemical compound and pharmaceutical salts thereof have valuable pharmacological character.Find that described compound exhibits is as the active of Aurora kinases man group inhibitor and show antiproliferative activity.Therefore, the disease that chemical compound of the present invention is used for the treatment of and/or Radix Stephaniae Tetrandrae is known Aurora family, preferred Aurora A kinases overexpression in advance is used in particular for treating and/or preventing above-mentioned disease.As the activity of the The compounds of this invention of Aurora kinases man group inhibitor by measuring proof following biology:
IC for Aurora A inhibitor
50Measure
(96 MTP-ELISA)
Measuring principle
Aurora A is the serine threonine kinases that participates in spindle assembling and chromosome separation.
This mensuration is that typical ELISA-type is measured, and wherein biotinylated substrate (PKB-GSK2) is by phosphorylation.The polyclonal antibody of phosphorylation by peroxidase (POD) labelling (PAK＜M-Ig〉S-IgG-POD) and phosphoeptide monoclonal antibody (Mab) (MAK＜P-GSK〉M-27E5-IgG) detection.Mensuration is proved for IC
50-measure effectively.
Material
Assay plate 96-hole polystyrene flat board, streptavidin-Bao quilt,
Sample 10mM is in dimethyl sulfoxine (DMSO)
The terminal histidine of Aurora A-His-4 C-
4(His
4The Aurora A total length egg of)-labelling
In vain, storage liquid 0,7mg/ml, final concentration: 250ng/ml
PKB-GSK2 is derived from the biotinylation peptide of people GSK3-α sequence
(Biotin-SGRARTSSFAEPGG-CONH
2), storage liquid
600 μ M, final concentration: 200nM
PAK＜M-Ig〉S-IgG-POD is anti--mice IgG, the antibody of horseradish peroxidase (HRP)-connection,
Be diluted in (1: 10000) among the 3%BSA/PBS-T (Cell
Signaling，Cat.No.：7076)
MAK＜P-GSK〉(27E5) monoclonal antibody of M-27E5-IgG phosphoric acid-GSK-3-α (Ser21),
Storage liquid 1,85mg/ml is diluted among the 3%BSA/PBS-T
(1: 6000), final concentration: 0,31 μ g/ml, (Cell Signaling, Cat.
No.：9337B)
ATP adenosine-5 '-triphosphoric acid 1mM is diluted in the kinase buffer liquid,
(Roche Diagnostics GmbH，Cat.No.：127531-001，)，
Final concentration: 4 μ M
TRIS 2-amino-2-hydroxymethyl-1, ammediol (" three-(hydroxymethyl)-
Aminomethane ") (MERCK, Cat.No.:108382.2500)
BSA bovine serum albumin fraction V, not fatty acids
(Roche Diagnostics GmbH，Cat.No.9100221)
EDTA Titriplex III (two-sodium-EDTA two-hydrate), 120mM,
(MERCK，Cat.No.：1.08418.1000)
ABTS buffer A BTS (2,2 '-azine-two (3-ethyl benzo thiazole phenanthrolines-6-sulphur
Acid)) 16,7mg/ml (Roche Diagnostics GmbH, Cat.
No.：1204530)
The ABTS tablet is dissolved in the working solution of 50ml with a slice ABTS, and (ABTS is slow
Towards liquid) (Roche Diagnostics GmbH, Cat.No.:
1112422) in
The polysorbas20 polysorbate 20 (Roche Diagnostics GmbH, Cat.No.:
10006394-001)
DTT 1,4-dithiothreitol, DTT (Roche Diagnostics GmbH, Cat.
No.：197777)
MgCl
2×6H
2O MERCK，Cat.No.：105833.1000
Kinase buffer liquid 50mM TRIS, 10mM MgCl
2, 1mM DTT, 0,1% tells
Temperature 20, pH7,8
PBS-T (=lavation buffer solution) is 10g/l PBS (phosphate-buffered saline) (PBS-T), contains
0,033% polysorbas20
3%BSA/PBS-T 3%BSA is dissolved among the PBS-T
Method
This is determined in the form of 96-hole and carries out IC
50Measure, 5 samples (having 8 concentration separately, dual test) have 100 μ l incubation volume and following tablet arrangement:
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | |
| A | NC | RSa | RSa | S1a | S1a | S2a | S2a | NC | S3a | S3a | S4a | S4a |
| B | NC | RSb | RSb | S1b | S1b | S2b | S2b | NC | S3b | S3b | S4b | S4b |
| C | NC | RSc | RSc | S1c | S1c | S2c | S2c | NC | S3c | S3c | S4c | S4c |
| D | NC | RSd | RSd | S1d | S1d | S2d | S2d | NC | S3d | S3d | S4d | S4d |
| E | PC | RSe | RSe | S1e | S1e | S2e | S2e | PC | S3e | S3e | S4e | S4e |
| F | PC | RSf | RSf | S1f | S1f | S2f | S2f | PC | S3f | S4f | S4f | S4f |
| G | PC | RSg | RSg | S1g | S1g | S2g | S2g | PC | S3g | S4g | S4g | S4g |
| H | PC | RSh | RSh | S1h | S1h | S2h | S2h | PC | S3h | S4h | S4h | S4h |
The NC negative control does not contain ATP, 1%DMSO
The PC positive control contains ATP, 1%DMSO
The S sample contains ATP, 1%DMSO, and final concentration: a=100 μ M, b=20 μ M, c=4 μ M,
d＝0.8μM，e＝0.16μM，f＝0.032μM，g＝0.0064μM，h＝0.00128μM
Steps/actions
1. sample preparation: the sample (order of successively decreasing) that will be diluted in 24 μ l/ holes in the kinase buffer liquid adds assay plate (DMSO final concentration 1%).
2. the 16 μ l Aurora-A-his-4 that directly will be diluted in the kinase buffer liquid add assay plate.
3. directly 40 μ l/ hole PKB-GSK2/ATP mixture are added assay plate, (final concentration: Aurora A=250ng/ml, GSK2=200nM, ATP=4 μ M).Negative control: do not contain ATP.
4. incubation flat board just in time 90 minutes at room temperature.
5. by in institute is porose, adding 20 μ l EDTA cessation reactions.
6. with 200 μ l lavation buffer solutions/hole washing assay plate 3x.
7. will be dissolved in 100 μ l MAK＜P-GSK among the 3%BSA/PBS-T〉M27E5-IgG (1: 10000) and PAK＜M-Ig〉S-IgG-POD (1: 6000) adds in each hole of assay plate.
8. incubation assay plate 60 minutes at room temperature.
9. assay plate 3x is washed with 200 μ l lavation buffer solutions in every hole
10. 100 μ l ABTS solution are added in each hole of assay plate, under the RT on the MTP agitator about 4 minutes of incubation.
Absorb 11. under 405/492nm, measure.
12. calculate the % inhibition be:
(1-(E
sample-E
NC)/(E
PC-E
NC))×100
13. the use non-linear curve fitting (XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK)) calculating IC
50
Result: table 1
| Embodiment | IC50 Aurora A kinase inhibition [nM] |
| 11 | 158 |
| 3 | 212 |
| 2，5，7，10，17，18，19，21，23，25， 27，31，34，35，36，37 | 10-500 |
| 4，6，9，24，28，29，41 | 500-1500 |
Antiproliferative activity
The compounds of this invention proves by measuring following biology as the activity of antiproliferative: the CellTiter-Glo in HCT 116 cells
TMMeasure
CellTiter-Glo
TM(Luminescent Cell Viability Assay Promega) is the even method of measuring the number of survivaling cell in the culture to luminescent cell viability mensuration, and this method is quantitative based on the ATP's that exists, and ATP has represented the existence of metabolic activity cell.
(human colon carcinoma ATCC-No.CCl-247) is cultivated in RPMI 1640 culture medium, wherein contains GlutaMAX with HCT 116 cells
TMI (Invitrogen, Cat-No.61870-010), 2,5% hyclones (FCS, Sigma Cat-No.F4135 (FBS)); 100Units/ml penicillin/100 μ g/ml streptomycins (=Pen/Strep is from Invitrogen Cat.No.15140).Cell is seeded in the 384 hole flat boards 1000 cells in every hole for this mensuration in same medium.The test compounds that adds various concentration next day, concentration is from 30 μ M to 0.00015 μ M (10 concentration, dilution in 1: 3).After 5 days, carry out CellTiter-Glo according to the operation instruction of manufacturer
TMMeasure (CellTiter-Glo
TMLuminescent Cell Viability Assay is from Promega).In brief:, add CellTiter-Glo then with cell-plate balance about 30 minutes to room temperature
TMReagent.With the carefully mixed inducing cell cracking in 15 minutes of content.After 45 minutes,, (scan the porous spectrophotometer, Wallac) the middle luminous signal of measuring at Victor 2.
Details:
The 1st day:
-culture medium: RPMI 1640 contains GlutaMAX
TMI (Invitrogen, Cat-Nr.61870), 5%FCS (Sigma Cat.-No.F4135), Pen/Strep (Invitrogen, Cat No.15140).
-HCT116 (ATCC-No.CCl-247): 384 hole flat boards (Greiner 781098, the dull and stereotyped white of μ Clear-), 1000 cells among every hole 60 μ l
-after inoculation at 37 ℃, 5%CO
2The dull and stereotyped 24h of following incubation
The 2nd day: induce (using compound treatment, 10 concentration):
In order to obtain final concentration is maximum concentration 30 μ M, and 3,5 μ l 10mM chemical compounds storage liquid is directly added 163 μ l culture medium.Follow the step e) of the dilution process of the following stated then.
In order to obtain the inferior least concentration that is up to, follow a series of dilutions of 1: 3 dilution step according to this paper the following stated method (a-e):
A), 10 μ l 10mM chemical compounds storage liquid is added 20 μ l dimethyl sulfoxines (DMSO) for inferior maximum concentration
B) 1: 3 (10 μ l add to 20 μ l DMSO all the time) (obtaining concentration in 9 holes is 3333,3 μ M to 0.51 μ M) of dilution 8x in this DMSO dilution row
C) diluted each concentration 1: 47,6 (3,5 μ l diluted chemical compound liquid add 163 μ l culture medium)
E) each concentration of 10 μ l being added the final concentration that 60 μ l culture medium in cell flat board obtain DMSO in every hole is: 0.3% and obtain 10 times of chemical compound final concentrations, and scope is 30 μ M to 0.0015 μ M.
-each chemical compound is tested in triplicate.
-at 37 ℃, 5%CO
2Following incubation 120h (5 days)
Analyze:
-every hole adds 30 μ l CellTiter-Glo
TMReagent is (from the CellTiter-Glo available from Promega
TMBuffer and CellTiter-Glo
TMSubstrate (lyophilizing) preparation),
Vibration is 15 minutes under the-room temperature
-other 45 minutes of incubation under nonoscillatory at room temperature
Measure:
-Victor 2 scanning porous spectrophotometers (Wallac), (0.5sec/ reads the Luminescence pattern, 477nm)
-use non-linear curve fitting (XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK)) mensuration IC50
Detect all chemical compounds and significantly suppress HCT 116 cell survivals, this illustrates by the chemical compound shown in the table 1.
Result: table 2
| Embodiment | IC50 HCT 116[μM] |
| 42 | 0.98 |
| 14 | 1.20 |
| 2 | 4.67 |
| 4 | 7.65 |
| 5，6，7，8，12，13，15，16，17， 18，20，22，23，24，27，28，30， 31，32，33，34，35，36，37，39， 41，43，44，45 | 0.1-10.0 |
| 3，9，11，38 | 10.0-100 |
Can be used as medicine according to chemical compound of the present invention and pharmaceutical salts thereof, for example with the form of pharmaceutical composition.Pharmaceutical composition can be Orally administered, for example with the form of tablet, coated tablet, dragee, hard and Perle, solution, Emulsion or suspensoid.Yet administration can also for example be undertaken by rectum with the form of suppository, perhaps for example carries out with the form parenteral of injection.
Aforementioned pharmaceutical compositions can obtain by processing chemical compound of the present invention with medicinal inert inorganic or organic carrier.For example lactose, corn starch or derivatives thereof, Talcum, stearic acid or its salt etc. can be used for the carrier of tablet, coated tablet, dragee and hard gelatin capsule as these.The suitable carrier of Perle has, for example, and vegetable oil, wax, fat, semisolid and liquid polyol etc.Yet depending on the character of active substance does not need carrier usually in the situation of Perle.Producing solution and syrupy suitable carrier has, for example, and water, polyhydric alcohol, glycerol, plant wet goods.The suitable carrier of suppository has, for example, and natural or fixed oil, wax, fat, semiliquid or liquid polyol etc.
In addition, pharmaceutical composition can contain antiseptic, solubilizing agent, stabilizing agent, wetting agent, emulsifying agent, sweeting agent, coloring agent, flavoring agent, salt, buffer, screening agent or the antioxidant of change osmotic pressure.They also can also contain other valuable material in treatment.
Pharmaceutical composition for example comprises following:
A) tablet formulation (wet granulation):
| Project | Composition | The mg/ sheet |
| 1. | Formula (I) chemical compound | 5 | 25 | 100 | 500 |
| 2. | Lactis Anhydrous DTG | 125 | 105 | 30 | 150 |
| 3. | Sta-Rx 1500 | 6 | 6 | 6 | 30 |
| 4. | Microcrystalline Cellulose | 30 | 30 | 30 | 150 |
| 5. | Magnesium stearate | 1 | 1 | 1 | 1 |
| Add up to | 167 | 167 | 167 | 831 |
Preparation method:
1, mixes the 1st, 2,3 and 4, and use the pure water pelletize.
2, at 50 ℃ of following dried particles.
3, allow granule pass through suitable milling apparatus.
4, add the 5th and mixed 3 minutes; Tabletting on suitable tablet machine.
B) capsule preparations:
| Project | Composition | The mg/ capsule | |||
| 1. | Formula (I) chemical compound | 5 | 25 | 100 | 500 |
| 2. | Lactose hydrous | 159 | 123 | 148 | --- |
| 3. | Corn starch | 25 | 35 | 40 | 70 |
| 4. | Talcum | 10 | 15 | 10 | 25 |
| 5. | Magnesium stearate | 1 | 2 | 2 | 5 |
| Add up to | 200 | 200 | 300 | 600 | |
Preparation method:
1, in suitable blender, mix the 1st, 2 and 3 30 minutes;
2, add the 4th and 5 and mixed 3 minutes;
3, be filled in the examples of suitable.
C) little suspensoid
1. weighing 4.0g bead in the pipe GL 25 of customization, 4cm (beadlet fill with pipe half).
2. add the 50mg chemical compound, disperse and vortex with spatulum.
Gelatin solution=2: 1) and vortex 3. add 2ml gelatin solution (beadlet weight:.
4. add a cover and be wrapped in lucifuge in the aluminium foil.
5. the balance weight for preparing grater.
6. in the Retsch grater, ground 4 hours 20/s (, under 30/s, can reach 24 hours) for some materials.
7. by under 400g centrifugal 2 minutes, on filter bracket, from beadlet, extract suspension, described filter and receiving tube coupling with two-layer filter (100 μ m).
8. extract is transferred in the graduated cylinder.
9. clarify until reaching final volume or extract with small size (1ml step here) repeated washing.
10. be filled to final volume and homogenize with gelatin.
Provide following embodiment and list of references to help to understand the present invention, true scope of the present invention is illustrated by appended claim.Should be understood that, under the situation that does not depart from essence of the present invention, can improve described method.
Embodiment
A: raw material
Preparation 5,6-diaminostilbene-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one
I) 1-ethyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one
With 3,3-dimethyl-6-nitro-1, the 3-dihydro-indol-2-one (6g, 29.10mmol) at anhydrous N, handle with sodium hydride by the solution of dinethylformamide (DMF) in (35ml).The suspension that obtains was stirred 1 hour down at 60 ℃.Add bromo-ethane (2.17mL, 3.17g, 29.10mmol) solution in DMF (10ml).Make mixture be cooled to room temperature and stirred 1 hour.After removing solvent, water (100ml) quencher mixture is also used ethyl acetate (3 * 100ml) extractions.Pass through Na
2SO
4Dry extract, evaporation is also passed through silica gel column chromatography purification crude product.With ethyl acetate/normal heptane (1: 3) eluting, obtain 5.94g (87%) yellow solid.
MS：M＝235.3(ESI+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.16(t，3H)，1.32(s，6H)，3.81(q，2H)，7.66(d，1H)，7.86(s，1H)，7.97(d，1H)
Ii) 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one
To 1-ethyl-3,3-dimethyl-6-nitro-1, the 3-dihydro-indol-2-one (5.9g, 25.19mmol) methanol/oxolane (THF) (1: 1, the solution in 80ml) add palladium carbon (10%, 1.2g), with mixture hydrogenation at room temperature 4 hours.Behind filtration and evaporating solvent, separate 5.05g (98%) 6-amino-1-ethyl-3,3-dimethyl-1, the 3-dihydro-indol-2-one is white solid.
MS：M＝205.0(API+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.11(t，3H)，1.17(s，6H)，3.58(q，2H)，5.12(br，2H)，6.21(d，1H)，6.25(s，1H)，6.92(d，1H)
Iii) N-(1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-6-yl)-acetamide
With 6-amino-1-ethyl-3,3-dimethyl-1, (5.05g, 24.72mmol) solution in acetic anhydride (80ml) at room temperature stirred 4 hours the 3-dihydro-indol-2-one.Mixture is poured in the frozen water (150ml), made that being warming up to room temperature also stirred 2 hours once more.(after 3 * 100ml) extractions, using saturated NaHCO with ethyl acetate
3-solution (3 * 100ml), the organic layer that merges of saline (100ml) washing, and pass through dried over sodium sulfate.After removing solvent, by silica gel column chromatography (ethyl acetate/normal heptane 1: 1) purification crude product, obtain 5.6g (91%) N-(1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-6-yl)-acetamide, be faint yellow solid.
MS：M＝247.1(API+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.13(t，3H)，1.23(s，6H)，2.04(s，3H)，3.63(q，2H)，7.12(d，1H)，7.23(d，1H)，7.37(s，1H)，9.97(br，1H)
Iv) N-(1-ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-1H-indole-6-yl)-acetamide
Under 0 ℃ to N-(1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-6-yl)-acetamide (5.6g, 22.73mmol) solution in acetic anhydride (70ml) add nitric acid (100%, 1.96g, 1.29ml, 31.2mmol).Stirred the mixture 30 minutes, and be poured on then on the frozen water (150ml).After stirring 4 hours, with ethyl acetate (3 * 100ml) extraction mixture.With sodium hydroxide solution (1M, 100ml) and the organic layer that merges of water (100ml) washing, by dried over sodium sulfate and concentrate.By silica gel column chromatography purification crude product (ethyl acetate/normal heptane 1: 1), obtain 5.2g (78%) N-(1-ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-1H-indole-6-yl)-acetamide, be yellow solid.
MS：M＝292.0(API+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.16(t，3H)，1.31(s，6H)，2.13(s，3H)，3.71(m，2H)，7.54(s，1H)，8.12(s，1H)，10.39(br，1H)
V) 6-amino-1-ethyl-3,3-dimethyl-5-nitro-1,3-dihydro-indol-2-one
(1-ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-1H-indole-6-yl)-(5.2g 17.85mmol) is dissolved in the ethanol (40ml) acetamide with N-.Add hydrochloric acid (25%, 8ml, 81.44mmol) after, under refluxing, stirred the mixture 3 hours.Make reactant mixture be cooled to room temperature, water (80ml) quencher then.By the isolated at suction yellow mercury oxide, with ethanol/water (1: 1) washing.Solid is dissolved in the ethyl acetate,, obtains 4.15g (93%) 6-amino-1-ethyl-3 by dried over sodium sulfate and concentrated, 3-dimethyl-5-nitro-1, the 3-dihydro-indol-2-one is orange solids.
MS：M＝250.0(API+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.15(t，3H)，1.27(s，6H)，3.64(m，2H)，6.54(s，1H)，7.67(br，2H)，7.95(s，1H)
Vi) 5,6-diaminostilbene-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one
To 6-amino-1-ethyl-3,3-dimethyl-5-nitro-1, (4.15g, 16.65mmol) solution in ethanol (80ml) adds PtO to the 3-dihydro-indol-2-one
2(0.4g), with mixture hydrogenation at room temperature 3.5 hours.Behind filtration and evaporating solvent, separate 3.25g (89%) 5,6-diaminostilbene-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one as orange solids.
MS：M＝220.0(API+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.10(t，3H)，1.13(s，6H)，3.53(m，2H)，4.08(br，2H)，4.48(br，2H)，6.27(s，1H)，6.50(s，1H)
Preparation 5,6-diaminostilbene, 3,3-trimethyl-1,3-dihydro-indol-2-one
To be similar to about 5 6-diaminostilbene-ethyl-3,3-dimethyl-1, the described 6-step-synthetic method of 3-dihydro-indol-2-one, preparation 5,6-diaminostilbene, 3,3-trimethyl-1,3-dihydro-indol-2-one.
MS：M＝206.1(API+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.57(s，6H)，3.43(s，3H)，4.94(br，4H)，6.66(s，1H)，6.95(s，1H)
Preparation 5,6-diaminourea-3,3-dimethyl-1-propyl group-1,3-dihydro-indol-2-one
To be similar to about 5 6-diaminostilbene-ethyl-3,3-dimethyl-1, the described 6-step-synthetic method of 3-dihydro-indol-2-one, preparation 5,6-diaminourea-3,3-dimethyl-1-propyl group-1,3-dihydro-indol-2-one.
MS：M＝234.1(API+)
1H-NMR(400MHz，DMSO)：(ppm)＝0.82(t，3H)，1.15(s，6H)，1.58(m，2H)，3.46(q，2H)，4.16(br，2H)，4.45(br，2H)，6.27(s，1H)，6.50(s，1H)
Preparation 5,6-diaminostilbene-isopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one
To be similar to about 5 6-diaminostilbene-ethyl-3,3-dimethyl-1, the described 6-step-synthetic method of 3-dihydro-indol-2-one, preparation 5,6-diaminourea-3,3-dimethyl-1-isopropyl-1,3-dihydro-indol-2-one.
MS：M＝234.1(API+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.12(s，6H)，1.33(d，6H)，4.09(br，2H)，4.40(m，1H)，4.46(br，2H)，6.46(s，1H)，6.48(s，1H)
Preparation 5-trifluoromethyl-2H-pyrazoles-3-carboxylic acid
I) 1-benzyl-5-furan-2-base-3-Trifluoromethyl-1 H-pyrazoles
To 50g (0.240mol) 4,4,4-three fluoro-1-(2-furyl)-1, the 3-diacetyl solution in 24ml (0.024mol) adds the 1M solution of hydrogen chloride in ethanol, and at room temperature other aliquot adds 50g (0.248mol) benzyl hydrazine dihydrochloride.Then reactant mixture was heated 7 hours under refluxing.After being cooled to room temperature, use saturated NaHCO
3The neutralization reaction mixture distills EtOH, with oil/aqueous mixtures of 300ml dichloromethane extraction remnants.With 100ml water washing organic facies twice, pass through Na
2SO
4Dry also vacuum concentration obtains 73.7g 1-benzyl-5-furan-2-base-3-Trifluoromethyl-1 H-pyrazoles, is brown oil, and its rough thing is used for next reaction.
MS：M＝293.0(API+)
Ii) 2-benzyl-5-trifluoromethyl-2H-pyrazoles-3-carboxylic acid
Be added in 27.2g (0.172mol) potassium permanganate in the 450ml water to 9.5g (0.0325mol) 1-benzyl-5-furan-2-base-solution of 3-Trifluoromethyl-1 H-pyrazoles in 350mL acetone.Reactant mixture was heated 4 hours down at 60 ℃.After being cooled to room temperature, add 200ml 2-propanol, stir the mixture and spend the night, it is filtered by Celite pad with 1 l washing with acetone.With the filtrate vacuum concentration to 150mL.Residue is dissolved in 20mL 2M NaOH and the 150mL water.With the water that obtains 70ml ether washed twice, use the acidify of 30ml 5M HCl solution then.With 200 and 50ml ethyl acetate (EtOAc) extraction suspension.The organic extract that merges with 30mL water and the water washing of 5mL salt also concentrates.By silica gel chromatography (CH
2Cl
2, contain 1% acetic acid) and the purification residue, 2-benzyl-5-trifluoromethyl-2H-pyrazoles-3-carboxylic acid of acquisition 6.1g (0.022mol, 67%) is pale solid.
MS：M＝271.1(ESI+)
Iii) 5-trifluoromethyl-2H-pyrazoles-3-carboxylic acid
In ethanol-the dry ice bath, about 50ml ammonia is compressed in the three-neck flask, adds 100mg (3.70mmol) 2-benzyl-5-trifluoromethyl-2H-pyrazoles-3-carboxylic acid.In this solution aliquot add sodium until blueness keep surpassing 5 minutes (about 260mg, 11.3mmol).Vaporized ammonia is spent the night.Add entry and use the acidify of 2N HCl solution.Use the ethyl acetate extraction water, pass through Na
2SO
4The dry organic facies that merges, vacuum evaporating solvent obtains 560mg (3.11mmol, 84%) 5-trifluoromethyl-2H-pyrazoles-3-carboxylic acid, is yellow solid, and it be not further purified use down.MS：M＝179.0(API-)
5-methoxyl group-1H-pyrazoles-3-carboxylic acid, ethyl ester
With 5-hydroxyl-1H-pyrazoles-3-carboxylic acid, ethyl ester (300mg 1.92mmol) is dissolved in anhydrous N, dinethylformamide (DMF) (35ml) in and add cesium carbonate (626mg, 1.92mmol).(120 μ l, 273mg 1.92mmol) handle and at room temperature stirred 12 hours with iodomethane with the suspension that obtains.(3 * 100ml) extract with saturated sodium bisulfate quencher reactant mixture and with ethyl acetate.The organic layer that water (50ml) and saline (50ml) washing merge.By the dried over sodium sulfate extract, evaporation is also passed through silica gel column chromatography purification crude product.With ethyl acetate/normal heptane (1: 3) eluting, obtain 124mg (38%) white solid.
MS：M＝171.2(ESI+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.29(t，3H)，3.79(s，3H)，4.29(q，2H)，6.21(s，1H)，13.10(br，1H)
5-methoxyl group-1H-pyrazoles-3-carboxylic acid
With 5-methoxyl group-1H-pyrazoles-3-carboxylic acid, ethyl ester (120mg, 0.71mmol) be dissolved in oxolane (THF) (2mL) in.Add sodium hydroxide (2M, in water, 1mL) after, with mixture heating 2 hours under refluxing.Reactant mixture is cooled to room temperature and by adding hcl acidifying (pH3), uses ethyl acetate (3 * 20ml) extractions.By the dried over sodium sulfate extract, and evaporation, 86mg (86%) white solid obtained.
Preparation 2-(3,3-couple-methyl mercapto-acryloyl group)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone
(i) 5-ethyl-2-(1-hydroxyl-ethyl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone
With 5,6-diaminostilbene-ethyl-3,3-dimethyl-1, (10g, 46mmol), (9.13g, 91.2mmol) (100mL, 4N) mixture in refluxed 16 hours 2-hydroxyl-propanoic acid the 3-dihydro-indol-2-one at HCl.After cooling, neutralize and stirred 1.5 hours with ammonia (25%), with sedimentation and filtration with at 50 ℃ of following vacuum dryings, obtain 12.29g (95%) gray solid.
MS：M＝274.3(ESI+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.17(t，3H)，1.28(s，6H)，1.48(d，3H)，3.73(q，2H)，4.90(m，1H)，5.68(d，1H，OH)，7.05(s，1H)，7.43(s，1H)，12.2(br，1H)
(ii) 2-acetyl group-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone
With 5-ethyl-2-(1-hydroxyl-ethyl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone (13g, 47.6mmol) and manganese dioxide (IV) (16.54g 190mmol) is suspended in the chloroform (400mL) and stirred 16 hours down at 65 ℃.Cooling mixture by diatomite filtration, with the filtrate vacuum concentration, obtains 11.6g (90%) beige solid.
MS：M＝272.0(ESI+)
1H-NMR (400MHz, DMSO): (ppm)=1.18 (t, 3H), 1.32 (s, 6H), 2.66 (s, 3H), 3.77 (q, 2H), 7.00 and 7.40 (s, 1H, two kinds of tautomeric forms), 7.50 with 7.80 (s, 1H, two kinds of tautomeric forms), 13.3 (br, 1H)
(iii) 2-acetyl group-5-ethyl-7,7-dimethyl-1-(tetrahydrochysene-pyrans-2-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone
With 2-acetyl group-5-ethyl-7,7-dimethyl-5, (11.7g, 43.1mmol) (0.82g 4.3mmol) is dissolved in the dichloromethane (200mL) 7-dihydro-1H-imidazo [4,5-f] indole-6-ketone with the p-methyl benzenesulfonic acid monohydrate.Add 3 in this solution, (4.81g 56mmol), heats mixture 24 hours under refluxing 4-dihydro-2H-pyrans.Filtering mixt, (2 * 100mL) wash filtrates are by dried over sodium sulfate and vacuum concentration for water.By silica gel column chromatography (methylene chloride 93: 3) purification crude product, obtain 6.8g (44%) faint yellow solid.
MS：M＝356.3(ESI+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.21(t，3H)，1.32(s，6H)，1.59-2.23(m，6H)，2.70(s，3H)，3.65(t，1H)，3.80(m，2H)，4.15(d，1H)，6.47(d，1H)，7.30(s，1H)，7.82(s，1H)
(iv) 2-(3,3-is two-methyl mercapto-acryloyl group)-5-ethyl-7,7-dimethyl-1-(tetrahydrochysene-pyrans-2-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone
(0.57g, 22.5mmol) (0.88g 11.8mmol), stirs mixture 2 hours the adding of the suspension in toluene (20mL) tert-butyl alcohol to sodium hydride under 80 ℃.After being cooled to room temperature; aliquot adds 2-acetyl group-5-ethyl-7; 7-dimethyl-1-(tetrahydrochysene-pyrans-2-yl)-5; 7-dihydro-1H-imidazo [4,5-f] indole-6-ketone (2g, 5.63mmol) and Carbon bisulfide (0.43g; 5.63mmol) at N; the suspension of dinethylformamide (DMF) in (12mL) stirred the mixture under the room temperature 30 minutes, stirred 30 minutes down at 80 ℃ at last.After being cooled to room temperature, add entry (20mL) and ethyl acetate (15mL), separate each layer and use ethyl acetate (3 * 10mL) aqueous layer extracted.Water (organic facies and vacuum concentration that 3 * 10mL) washings merge; obtain the 2-(3 of 2.27g (88%); 3-pair-methyl mercapto-acryloyl group)-5-ethyl-7; 7-dimethyl-1-(tetrahydrochysene-pyrans-2-yl)-5; 7-dihydro-1H-imidazo [4; 5-f] indole-6-ketone, it is the part deprotection during reaction.It is used for next step under not being further purified.
MS：M＝460.1(ESI+)
(v) 2-(3,3-is two-methyl mercapto-acryloyl group)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone
With rough 2-(3; 3-pair-methyl mercapto-acryloyl group)-5-ethyl-7; 7-dimethyl-1-(tetrahydrochysene-pyrans-2-yl)-5; 7-dihydro-1H-imidazo [4; 5-f] indole-6-ketone (2.25g; 4.9mmol) and the p-methyl benzenesulfonic acid monohydrate (0.5g 2.6mmol) is dissolved in methanol (25mL) and the water (3mL), stirs 3 hours under refluxing.After being cooled to room temperature, adding entry (50mL) and use ethyl acetate (3 * 50mL) extraction mixture.Wash the organic layer and the vacuum concentration of merging with water.Recrystallize crude product from methanol obtains 2-(3,3-couple-methyl mercapto-acryloyl group)-5-ethyl-7,7-dimethyl-5, and 7-dihydro-1H-imidazo [4,5-f] indole-6-ketone (0.71g, 39%) is yellow solid.
MS：M＝376.3(ESI+)
1H-NMR (400MHz, CDC13): (ppm)=1.31 (t, 3H), 1.42 (s, 6H), 2.63 (s, 3H), 2.72 (s, 3H), 3.83 (m, 2H), 7.13 and 7.25 (s, 1H, two kinds of tautomeric forms), 7.49 (s, 1H), 7.58 and 7.65 (s, 1H, two kinds of tautomeric forms), 11.5 (br, 1H)
B: end-product
Embodiment 1 to 43
Standard method:
Preparation 1-isopropyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone (embodiment 11)
With 5-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (126mg, 1mmol) with 5,6-diaminostilbene-isopropyl-1,3-dihydro-benzimidazolyl-2 radicals-ketone (206mg, 1mmol) (500mg is heated to 160 ℃ and reaches 6 hours in mixture 3.5mmol) at polyphosphoric acid (5g) and phosphorus pentoxide.This mixture is poured on that water (20ml) is gone up and continues to stir until forming precipitation.After filtration, be suspended in crude product in the water and pass through to add ammonia (25%) and neutralize.Collecting precipitation washes with water and vacuum drying.Realize purification by silica gel chromatography (methylene chloride 95: 5), obtain 1-isopropyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone, be faint yellow solid.Productive rate 36mg (12%)
Use the experiment condition of above report and suitable raw material, prepare following derivant 1 to 43:
| Embodiment No. | Systematic naming method | MS (method) | 1H-NMR |
| 1 | 7,7-dimethyl-2-(5-methyl-2H-pyrazoles-3-yl)-3,5,6,7-tetrahydrochysene-imidazo [4,5-f] indole | 268.3(ESI+) | |
| 2 | 1-[7,7-dimethyl-2-(5-methyl-2H-pyrazoles-3-yl)-6,7-dihydro-3H-imidazo [4,5-f] indole-5-yl]-ethyl ketone | 310.3(ESI+) | |
| 3 | 8,8-dimethyl-2-(5-methyl isophthalic acid H-pyrazoles-3-yl)-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone | 296.3(ESI+) | |
| 4 | 2-(5-isobutyl group-2H-pyrazole-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone | 338.0(API+) |
| Embodiment No. | Systematic naming method | MS (method) | 1H-NMR |
| 13 | 5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone | 338.1(API+) | [D6]DMSO，400MHz： d＝12.64(bs，1H)，7.48 (s，1H)，7.09(s，1H)， 6.59(s，1H)，3.76(q， 2H)，2.64(t，2H)，1.72- 1.63(m，2H)，1.31(s， 6H)，1.19(t，3H)，0.95 (t，3H) |
| 14 | 5,7,7-trimethyl-2-(5-propyl group-2H-pyrazoles-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone | 324.1(API+) | |
| 15 | 5-ethyl-2-(5-isobutyl group-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone | 352.1(API+) | |
| 16 | 2-(5-isobutyl group-2H-pyrazole-3-yl)-5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone | 338.1(API+) | |
| 17 | 2-(4,5-dimethyl-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone | 294.0(API-) | |
| 18 | 7,7-dimethyl-2-[5-(3-methyl-butyl)-1H-pyrazole-3-yl]-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone | 336.1(API-) |
| Embodiment No. | Systematic naming method | MS (method) | 1H-NMR |
| 19 | 2-(5-ethyl-4-methyl isophthalic acid H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone | 308.1(API-) | |
| 20 | 7,7-dimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone | 268,0(ESI+) | |
| 21 | 2-(5-cyclopropyl-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone | 308,1(ESI+) | |
| 22 | 2-(5-isopropyl-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone | 310,1(ESI+) | |
| 23 | 8,8-dimethyl-2-(5-propyl group-2H-pyrazoles-3-yl)-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone | 324,2(ESI+) | |
| 24 | 8,8-dimethyl-2-(1H-pyrazole-3-yl)-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone | 282,2(ESI+) |
| Embodiment No. | Systematic naming method | MS (method) | 1H-NMR |
| 31 | 5,7,7-trimethyl-2-(5-methyl isophthalic acid H-pyrazoles-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone | 296.0(API+) | [D6]DMSO，400MHz： d＝12.89(m，1H)， 12.61(m，1H)， 7.56-6.94(m，2H)，6.55 (s，1H)，3.19(s，3H)， 2.32(s，3H)，1.31(s， 6H) |
| 32 | 5-ethyl-7,7-dimethyl-2-(1H-pyrazoles-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone | 296,2(ESI+) | |
| 33 | 5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone; Chemical compound with acetic acid | 338.2(ESI+) | |
| 34 | 5-isopropyl-7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone | 324,1(API+) | [D6] DMSO, 400MHz:1.28 (s, 6H), 1.45 (d, 3H), 2.31 (s, 3H), 4.56 (br, 1H), 6.55 (s, 1H), 6.88 and 7.09 and 7.32 and 7.54 (2H, two kinds of tautomeric forms), 12.61 (NH), 12.87 (NH) |
| 35 | 5-isopropyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone | 352,2(API+) | [D6] DMSO, 400MHz:0.95 (t, 3H), 1.29 (s, 6H), 1.44 (d, 6H), 1.66 (m, 2H), 2.64 (t, 2H), 4.56 (br, 1H), 6.57 (s,! H), 7.71 and 7.31 (1H, two kinds of tautomeric forms), 7.35 and 7.55 (1H, two kinds of tautomeric forms), 12.49 and 12.60 (NH, two kinds of tautomeric forms), 12.90 (NH) |
| Embodiment No. | Systematic naming method | MS (method) | 1H-NMR |
| 36 | 7,7-dimethyl-2-(5-methyl-2H-pyrazoles-3-yl)-5-propyl group-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone | 324,1(API+) | [D6] DMSO, 400MHz:0.88 (t, 3H), 1.31 (s, 6H), 1.66 (m, 2H), 2.31 (s, 3H), 3.69 (t, 2H), 6.55 (s, 1H), 6.95 and 7.22 (1H, two kinds of tautomeric forms), 7.35 and 7.56 (1H, two kinds of tautomeric forms), 12.54 and 12.62 (NH, two kinds of tautomeric forms), 12.88 (NH) |
| 37 | 7,7-dimethyl-5-propyl group-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone | 352.1(API+) | [D6] DMSO, 400MHz:0.88 (t, 3H), 0.95 (t, 3H), 1.31 (s, 6H), 1.67 (m, 4H), 2.64 (t, 2H), 3.69 (t, 2H), 6.58 (s, 1H), 6.95 and 7.23 (s, 1H, two kinds of tautomeric forms), 7.39 and 7.57 (s, 1H, two kinds of tautomeric forms), 12.60 (br, 1H), 12.91 (br, 1H) |
| 38 | 7,7-dimethyl-2-(5-trifluoromethyl-2H-pyrazoles-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone | 336.0(API+) | [D6] DMSO, 400MHz:1.32 (s, 6H), 6.94 and 7.04 (1H, two kinds of tautomeric forms), 7.22 and 7.51 (1H, two kinds of tautomeric forms), 7.28 and 7.60 (1H, two kinds of tautomeric forms), 10.35 (NH), 12.88 and 12,98 (NH, two kinds of tautomeric forms), 14.64 (NH) |
| 39 | 5-ethyl-7,7-dimethyl-2-(5-Trifluoromethyl-1 H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone | 364.1(API+) | [D6]DMSO，400MHz： 1.18(t，3H)，1.32(d， 6H)，3.79(q，2H)，7.20 (s，1H)，7.28(s，1H)， 7.63(s，1H)， |
Embodiment 44:
5-ethyl-2-(5-methoxyl group-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone
With 5-methoxyl group-1H-pyrazoles-3-carboxylic acid (86mg, 0.61mmol), I-hydroxybenzotriazole hydrate (111mg, 0.73mmol) and triethylamine (253 μ l, 184mg 1.82mmol) is dissolved in N, dinethylformamide (DMF) (2ml) in, adding be dissolved in 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) among the DMF (2ml) (139mg, 0.73mmol) after, reactant mixture is at room temperature stirred.After 1 hour, add 5,6-diaminostilbene-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one solution and the stirred reaction mixture 16 hours at room temperature in DMF (2ml).Solvent is removed in decompression, and water (20ml) quencher residue is also used ethyl acetate (3 * 20mL) extractions.Organic layer with saline (15ml) washing merges also evaporates by dried over sodium sulfate.Residue is dissolved in the ethanol (5ml), and (10M stirs them 2 hours under refluxing after 2ml) adding hydrochloric acid.Ethanol evaporation is adjusted to pH9-10 with ammonium hydroxide with residue.Adding entry (20ml) afterwards, with ethyl acetate (3 * 20ml) aqueous phase extracted.Organic layer with saline (10ml) washing merges also evaporates by dried over sodium sulfate.By silica gel column chromatography purification crude product.With ethyl acetate/normal heptane (9: 1) eluting, obtain 56mg (28%) pale solid.
MS：M＝326.1(API+)
1H-NMR(400MHz，DMSO)：(ppm)＝1.19(t，3H)，1.32(s，6H)，3.76(q，2H)，3.84(s，3H)，6.28(s，1H)，7.14(s，1H)，7.56(s，1H)，12.80(br，2H)
Embodiment 45:
5-ethyl-7,7-dimethyl-2-(5-methyl mercapto-1H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone
With hydrazine monohydrate (0.92g; 1.8mmol) adding 2-(3; 3-pair-methyl mercapto-acryloyl group)-5-ethyl-7; 7-dimethyl-1-(tetrahydrochysene-pyrans-2-yl)-5; 7-dihydro-1H-imidazo [4; 5-f] indole-6-ketone (0.68g, 1.81mmol) suspension in acetonitrile (15mL) and stirring 24 hours.After being cooled to room temperature, collecting precipitation with acetonitrile and ether washing, obtains the shallow white powder of 0.5g (81%).
MS：M＝342.1(API+)
1H-NMR (400MHz, DMSO): (ppm)=1.19 (t, 3H), 1.31 (s, 6H), 2.53 (s, 3H), 3.76 (m, 2H), 6.83 (s, 1H), 6.95-7.65 (brm, 2H, tautomeric forms), 12.75 (br, 1H), 13.45 (br, 1H)
The list of references tabulation
Adams, R.R., etc., Trends Cell Biol.11 (2001) 49-54
Bastin, R.J., etc., Organic Proc.Res.Dev.4 (2000) 427-435
Bischoff, J.R., and Plowman, G.D., Trends Cell Biol.9 (1999) 454-459
DE 3417643
DE 3642315
DE 3701277
Djuric, S.W., etc., J.Med.Chem.43 (2000) 2975-2981
EP 0189103
EP 0318902
EP 0868519
EP 1051500
Giet, R., and Prigent, C., J.Cell Sci.112 (1999) 3591-3601
Harrington, E.A., etc., Nat.Med.10 (2004) 262-267
Hunter，T.，Cell 50(1987)823-829
Isola, J.J., etc., Am.J.Pathology 147 (1995) 905-911
Jia, Z.J., etc., Bioorg.Med.Chem.Lett.12 (2002) 1651-1655
Mahata, P.K., etc., Tetrahedron 59 (2003) 2631-2639
Martins, M.A.P., etc., Synthesis 15 (2003) 2353-2357
Mertens, A., etc., J.Med.Chem.30 (1987) 1279-1287
Nigg，E.A.，Nat.Rev.Mol.Cell Biol.2(2001)21-32
Ochi, H., etc., Chem.Pharm.Bull.31 (1983) 1228-1234
Pruitt, J.R., etc., J.Med.Chem.46 (2003) 5298-5315
Sen, S., etc., J.Natl.Cancer Inst.94 (2002) 1320-1329
Sewald, N., etc., Liebigs Ann.Chem. (1992) 947-952
Stahl, P.H., and Wermuth, G., (editors), Handbook of Pharmaceutical Salts,
Verlag Helvetica Chimica Acta(VHCA)，Zürich(2002)
Stan ovnik, B., and Svete, J., Science of Synthesis 12 (2002) 15-225
Subramanyam，C.，Synth.Commun.25(1995)761-774
US 4,835,280A
US 4,954,498
US 5,212,186A
US 6,207,401
Van Herk, T., etc., J.Med.Chem.46 (2003) 3945-3951
Von der Saal, W., etc., J.Med.Chem.32 (1989) 1481-1491
WO 00/44728
WO 00/47212
WO 01/21594
WO 01/21595
WO 01/21596
WO 01/21597
WO 01/55116
WO 01/77085
WO 02/057259
WO 02/059111
WO 02/059112
WO 02/062789
WO 02/066461
WO 02/068415
WO 02/22601
WO 02/22602
WO 02/22603
WO 02/22604
WO 02/22605
WO 02/22606
WO 02/22607
WO 02/22608
WO 02/50065
WO 02/50066
WO 02/96905
WO 03/035065
WO 03/077921
WO 03/078423
WO 03/078426
WO 03/078427
WO 04/000833
WO 04/005283
WO 04/032928
WO 95/19169
WO 95/23141
WO 97/42187
WO 99/06396
Claims (12)
1. the chemical compound of formula I and all pharmaceutical salts thereof are used for the treatment of application in the medicine of cancer in preparation,
Wherein
R
1Be hydrogen, alkyl, or-C (O)-alkyl;
R
2Be hydrogen, alkyl, cyano group or halogen;
R
3Be hydrogen, alkyl, (C
3-C
6)-cycloalkyl, alkoxyl or alkylthio group;
X is-C (O)-or-CH
2-;
Y is-NH--CH
2-CR
4R
5-,-CR
4R
5-CH
2-or-CR
4R
5-; Wherein
R
4It is hydrogen or alkyl; And
R
5Be hydrogen or alkyl,
Or alternatively
R
4And R
5The carbon atom that connects with them forms cycloalkyl ring.
2. be used for the treatment of application in the medicine of cancer, wherein R according to the chemical compound of the formula I of claim 1 in preparation
3Be hydrogen, alkyl, (C
3-C
6)-cycloalkyl.
3. be used for the treatment of application in the medicine of cancer according to the chemical compound of the formula I of claim 1 or 2 in preparation, wherein X is-CH
2-.
4. be used for the treatment of application in the medicine of cancer according to the chemical compound of the formula I of claim 1 or 2 in preparation, wherein X be-C (O)-.
5. be used for the treatment of application in the medicine of cancer according to the chemical compound of the formula I of claim 1 or 2 in preparation, the chemical compound of described formula I is selected from the group of being made up of following:
7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-3,5,6,7-tetrahydrochysene-imidazo [4,5-f] indole;
1-[7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-6,7-dihydro-3H-imidazo [4,5-f] indole-5-yl]-ethyl ketone;
8,8-dimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone;
7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-methyl-2H-pyrazole-3-yl)-spiral shell-5, and the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-spiral shell-5, and the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone;
2-(4,5-dimethyl-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-2-[5-(3-methyl-butyl)-1H-pyrazole-3-yl]-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-ethyl-4-methyl isophthalic acid H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-cyclopropyl-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-isopropyl-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
8,8-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone;
8,8-dimethyl-2-(1H-pyrazole-3-yl)-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone;
2-(5-cyclopropyl-1H-pyrazole-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone
2-(5-isopropyl-2H-pyrazole-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydrochysene-imidazo [4,5-g] quinoline-6-ketone;
2-(2H-pyrazole-3-yl)-spiral shell-5, and the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
2-(5-isopropyl-2H-pyrazole-3-yl)-spiral shell-5, and the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
2-(5-propyl group-2H-pyrazole-3-yl)-spiral shell-5, and the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
7,7-dimethyl-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
2-(5-cyclopropyl-2H-pyrazole-3-yl)-spiral shell-5, and the 7-dihydro [Pentamethylene .-1 ', 7-imidazo [4,5-f] indole]-6 (3H)-ketone;
3-methyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone;
3-isopropyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone;
5-ethyl-7,7-dimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-2-(5-isobutyl group-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone; Chemical compound with acetic acid;
5-isopropyl-7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
5-isopropyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5-propyl group-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-5-propyl group-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-Trifluoromethyl-1 H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-isopropyl-7,7-dimethyl-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-5-propyl group-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-2-(5-methoxyl group-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone; With
5-ethyl-7,7-dimethyl-2-(5-methyl mercapto-1H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone.
6. according to the chemical compound of formula I,
Wherein
R
1Be alkyl or-C (O)-alkyl;
R
2Be hydrogen, alkyl, cyano group or halogen;
R
3Be hydrogen, alkyl, (C
3-C
6)-cycloalkyl, alkoxyl or alkylthio group;
X is-C (O)-or-CH
2-;
Y is-NH--CH
2-CR
4R
5-,-CR
4R
5-CH
2-or-CR
4R
5-; Wherein
R
4It is hydrogen or alkyl; And
R
5Be hydrogen or alkyl,
Or alternatively
R
4And R
5The carbon atom that connects with them forms cycloalkyl ring;
And all pharmaceutical salts.
7. according to the chemical compound of claim 6, it is selected from the group of being made up of following:
5-ethyl-7,7-dimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-2-(5-isobutyl group-2H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
2-(5-isobutyl group-2H-pyrazole-3-yl)-5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-methyl isophthalic acid H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(1H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone; Chemical compound with acetic acid;
5-isopropyl-7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
5-isopropyl-7,7-dimethyl-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-5-propyl group-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-5-propyl group-2-(5-propyl group-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-Trifluoromethyl-1 H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-isopropyl-7,7-dimethyl-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
7,7-dimethyl-5-propyl group-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
5,7,7-trimethyl-2-(5-trifluoromethyl-2H-pyrazole-3-yl)-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-2-(5-methoxyl group-1H-pyrazole-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-ketone;
5-ethyl-7,7-dimethyl-2-(5-methyl mercapto-1H-pyrazole-3-yl)-5,7-dihydro-1H-imidazo [4,5-f] indole-6-ketone;
3-methyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone;
3-isopropyl-6-(5-methyl isophthalic acid H-pyrazole-3-yl)-3, and 5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazole-2-ketone; With
1-[7,7-dimethyl-2-(5-methyl-2H-pyrazole-3-yl)-6,7-dihydro-3H-imidazo [4,5-f] indole-5-yl]-ethyl ketone.
8. according to the chemical compound of claim 6, wherein
R
1It is alkyl;
R
2It is hydrogen or alkyl;
X is-C (O)-; And
Y is-CR
4R
5-.
9. according to the chemical compound of claim 6, wherein
R
1It is alkyl;
R
2It is hydrogen or alkyl;
R
3Be hydrogen, alkyl or (C
3-C
6)-cycloalkyl;
X is-C (O)-; And
Y is-CR
4R
5-.
10. one kind is used to prepare R
1Be alkyl or-method of the chemical compound of the formula I of C (O)-alkyl, wherein
A) chemical compound of formula II,
R wherein
1Be alkyl or-C (O)-alkyl and X and Y have the above implication that provides about formula I;
With the chemical compound reaction of formula III,
Wherein A is-OH ,-Cl ,-H or-OMe and R
2And R
3Has the above implication that provides about formula I;
The chemical compound of acquisition formula I,
R wherein
1Be alkyl or-C (O)-alkyl and R
2, R
3, X and Y have the above implication that provides about formula I;
B) chemical compound of the described formula I of separation from reactant mixture, and
If desired, it is converted into pharmaceutical salts.
11. a medicine, its contain one or more as active component according to any one chemical compound and medicinal adjuvant in the claim 6 to 9.
12. a medicine that is used for the treatment of cancer, its contain one or more as active component according to any one chemical compound and medicinal adjuvant in the claim 6 to 9.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04022753 | 2004-09-24 | ||
| EP04022753.0 | 2004-09-24 | ||
| EP05010528.7 | 2005-05-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101027055A true CN101027055A (en) | 2007-08-29 |
Family
ID=34926694
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800319711A Pending CN101027055A (en) | 2004-09-24 | 2005-09-23 | Tricycles, their manufacture and use as pharmaceutical agents |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101027055A (en) |
| BR (1) | BRPI0516030A (en) |
-
2005
- 2005-09-23 BR BRPI0516030-8A patent/BRPI0516030A/en not_active IP Right Cessation
- 2005-09-23 CN CNA2005800319711A patent/CN101027055A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0516030A (en) | 2008-08-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6963146B1 (en) | Administration of KRAS inhibitors to treat cancer | |
| Chen et al. | Critical molecular pathways in cancer stem cells of chronic myeloid leukemia | |
| Garcia-Echeverria et al. | Drug discovery approaches targeting the PI3K/Akt pathway in cancer | |
| EP2604610B1 (en) | Phthalazinone ketone derivative, preparation method thereof, and pharmaceutical use thereof | |
| CN112402385B (en) | 4-hydroxymethyl-1H-indole compound pharmaceutical preparation and preparation method thereof | |
| JP2018524382A (en) | Chiral diaryl macrocycles and uses thereof | |
| CN102112478A (en) | 5H-pyrr0l0 [2, 3-B] pyrazine derivatives for kinase modulation, and indications therefor | |
| CN105377299B (en) | For treat prostate cancer comprising dihydro pyrazine simultaneously-combination treatments of pyrazine compound and androgen receptor antagonists | |
| CN104066723A (en) | 1-(arylmethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diones and analogs and the use thereof | |
| JP7323896B2 (en) | Casein kinase 1ε inhibitor, pharmaceutical composition and use thereof | |
| CA2897258C (en) | Methods of treatment of fibrosis and cancers | |
| Schäkel et al. | Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39–a promising target for cancer immunotherapy | |
| JP2003535038A (en) | 3-Heteroarylidenyl-2-indolinone compounds for modulating protein kinase activity and for use in cancer chemotherapy | |
| CN101160312A (en) | Tricyclic azole derivatives, their manufacture and use as pharmaceutical agents | |
| Wang et al. | Design, synthesis and biological evaluation of potent epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors against resistance mutation for lung cancer treatment | |
| Hekmat et al. | Protein kinase inhibitors and cancer targeted therapy | |
| CN102020648B (en) | 3-aryl-6-aryl-[1,2,4] triazol [4,3-b] pyridazine taken as cell proliferation inhibitor and application of cell proliferation inhibitor | |
| KR100845749B1 (en) | Tricycles, their manufacture and use as pharmaceutical agents | |
| CN101027055A (en) | Tricycles, their manufacture and use as pharmaceutical agents | |
| CN104066736A (en) | Substituted pyrazolopyrimidines as akt kinase inhibitors | |
| JP2014515026A (en) | Acadesine derivatives, formulations and compositions containing them, their therapeutic use, and their synthesis | |
| CN101381320B (en) | Compounds with mannich base structure and application thereof in preparation of medicament treating and/or preventing leukemia | |
| CN101321762A (en) | Tricyclic lactam derivatives, their manufacture and use as pharmaceutical agents | |
| WO2014106763A1 (en) | Pyridopyrazines as anticancer agents | |
| US7285569B2 (en) | Tricycles, their manufacture and use as pharmaceutical agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20070829 |