WO2009084695A1 - 2-アミノキナゾリン誘導体 - Google Patents
2-アミノキナゾリン誘導体 Download PDFInfo
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- WO2009084695A1 WO2009084695A1 PCT/JP2008/073866 JP2008073866W WO2009084695A1 WO 2009084695 A1 WO2009084695 A1 WO 2009084695A1 JP 2008073866 W JP2008073866 W JP 2008073866W WO 2009084695 A1 WO2009084695 A1 WO 2009084695A1
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- 0 *c1ccc(cnc(Nc2ccc(*CICC*3)c3c2)n2)c2c1* Chemical compound *c1ccc(cnc(Nc2ccc(*CICC*3)c3c2)n2)c2c1* 0.000 description 3
- QOIMHXKTPYUYPA-UHFFFAOYSA-N CCc1cccc(C(N2)=O)c1NC2=O Chemical compound CCc1cccc(C(N2)=O)c1NC2=O QOIMHXKTPYUYPA-UHFFFAOYSA-N 0.000 description 2
- JXRLXRSQNFSYKV-UHFFFAOYSA-N CC(Nc1cccc(Nc2nc3c(C)cccc3cn2)c1)=O Chemical compound CC(Nc1cccc(Nc2nc3c(C)cccc3cn2)c1)=O JXRLXRSQNFSYKV-UHFFFAOYSA-N 0.000 description 1
- KQISJTWUGIEOCQ-UHFFFAOYSA-N CCN(CC)c(cc1)c(C)c2c1cnc(Nc1ccc(cn[nH]3)c3c1)n2 Chemical compound CCN(CC)c(cc1)c(C)c2c1cnc(Nc1ccc(cn[nH]3)c3c1)n2 KQISJTWUGIEOCQ-UHFFFAOYSA-N 0.000 description 1
- QRTZLUCHOLGVCP-UHFFFAOYSA-N CCNC(Nc(cc1)c(C)c2c1cnc(Nc1ccc(cn[nH]3)c3c1)n2)=O Chemical compound CCNC(Nc(cc1)c(C)c2c1cnc(Nc1ccc(cn[nH]3)c3c1)n2)=O QRTZLUCHOLGVCP-UHFFFAOYSA-N 0.000 description 1
- VHBAUWHHLIDLGA-UHFFFAOYSA-N CCOC(NCc1c(cn[nH]2)c2cc(Nc2nc3c(C)cccc3cn2)c1)=O Chemical compound CCOC(NCc1c(cn[nH]2)c2cc(Nc2nc3c(C)cccc3cn2)c1)=O VHBAUWHHLIDLGA-UHFFFAOYSA-N 0.000 description 1
- KFSMDATVDNJYTA-UHFFFAOYSA-N CCOC(Nc1c(cc[nH]2)c2cc(Nc2nc3c(C)cccc3cn2)c1)=O Chemical compound CCOC(Nc1c(cc[nH]2)c2cc(Nc2nc3c(C)cccc3cn2)c1)=O KFSMDATVDNJYTA-UHFFFAOYSA-N 0.000 description 1
- OEGGYXFIGUGLRY-UHFFFAOYSA-N CCOC(Nc1c(cn[nH]2)c2cc(N)c1)=O Chemical compound CCOC(Nc1c(cn[nH]2)c2cc(N)c1)=O OEGGYXFIGUGLRY-UHFFFAOYSA-N 0.000 description 1
- OOIYQEFCLQTDQL-UHFFFAOYSA-N COC(c1cc([N+]([O-])=O)cc2c1nc[nH]2)=O Chemical compound COC(c1cc([N+]([O-])=O)cc2c1nc[nH]2)=O OOIYQEFCLQTDQL-UHFFFAOYSA-N 0.000 description 1
- XBTYGUBMKNKSMK-UHFFFAOYSA-N Cc([nH]c1cc(Nc2nc3c(C)cccc3cn2)c2)nc1c2N Chemical compound Cc([nH]c1cc(Nc2nc3c(C)cccc3cn2)c2)nc1c2N XBTYGUBMKNKSMK-UHFFFAOYSA-N 0.000 description 1
- XPLRFEZPDVQOMJ-UHFFFAOYSA-N Cc(c(N)c1)c(C(F)(F)F)cc1[N+]([O-])=O Chemical compound Cc(c(N)c1)c(C(F)(F)F)cc1[N+]([O-])=O XPLRFEZPDVQOMJ-UHFFFAOYSA-N 0.000 description 1
- XTZNLELDRXUAOX-UHFFFAOYSA-N Cc(c([N+]([O-])=O)cc(Br)c1)c1OC Chemical compound Cc(c([N+]([O-])=O)cc(Br)c1)c1OC XTZNLELDRXUAOX-UHFFFAOYSA-N 0.000 description 1
- QXDOLINPPQNYIL-UHFFFAOYSA-N Cc(c1c(cc2)cnc(Nc3cc(OC)c(cn[nH]4)c4c3)n1)c2N1CCC(CO)CC1 Chemical compound Cc(c1c(cc2)cnc(Nc3cc(OC)c(cn[nH]4)c4c3)n1)c2N1CCC(CO)CC1 QXDOLINPPQNYIL-UHFFFAOYSA-N 0.000 description 1
- QKIXEGCCEQDWBR-UHFFFAOYSA-N Cc1c2nc(Nc(cc3O)ccc3OC)ncc2ccc1 Chemical compound Cc1c2nc(Nc(cc3O)ccc3OC)ncc2ccc1 QKIXEGCCEQDWBR-UHFFFAOYSA-N 0.000 description 1
- MYBPVXIZIBMVPX-UHFFFAOYSA-N Cc1c2nc(Nc3cc(C(F)(F)F)c(cn[nH]4)c4c3)ncc2ccc1 Chemical compound Cc1c2nc(Nc3cc(C(F)(F)F)c(cn[nH]4)c4c3)ncc2ccc1 MYBPVXIZIBMVPX-UHFFFAOYSA-N 0.000 description 1
- GRLDEMCSBCTAGK-UHFFFAOYSA-N Cc1c2nc(Nc3cc(C(N)=O)c(cn[nH]4)c4c3)ncc2ccc1 Chemical compound Cc1c2nc(Nc3cc(C(N)=O)c(cn[nH]4)c4c3)ncc2ccc1 GRLDEMCSBCTAGK-UHFFFAOYSA-N 0.000 description 1
- ZQBIQLBVEHAXBO-UHFFFAOYSA-N Cc1c2nc(Nc3cc(N)c4nc[n](C)c4c3)ncc2ccc1 Chemical compound Cc1c2nc(Nc3cc(N)c4nc[n](C)c4c3)ncc2ccc1 ZQBIQLBVEHAXBO-UHFFFAOYSA-N 0.000 description 1
- ZAOHIFQWKMEDEX-UHFFFAOYSA-N Cc1c2nc(Nc3ccc(cc[nH]4)c4c3)ncc2ccc1 Chemical compound Cc1c2nc(Nc3ccc(cc[nH]4)c4c3)ncc2ccc1 ZAOHIFQWKMEDEX-UHFFFAOYSA-N 0.000 description 1
- FTYGKZNVRUBFFL-UHFFFAOYSA-N Cc1c2nc(Nc3ccc(cn[nH]4)c4c3)ncc2ccc1NCCO Chemical compound Cc1c2nc(Nc3ccc(cn[nH]4)c4c3)ncc2ccc1NCCO FTYGKZNVRUBFFL-UHFFFAOYSA-N 0.000 description 1
- UWMJBFBSQFHRNI-UHFFFAOYSA-N Cc1n[nH]c2cc(NC3=NCC(C=CC=C4C)C4=N3)ccc12 Chemical compound Cc1n[nH]c2cc(NC3=NCC(C=CC=C4C)C4=N3)ccc12 UWMJBFBSQFHRNI-UHFFFAOYSA-N 0.000 description 1
- RAGZRCJYHKGTFT-UHFFFAOYSA-N Cc1n[nH]c2cc(Nc3nc4c(C)c(N)ccc4cn3)ccc12 Chemical compound Cc1n[nH]c2cc(Nc3nc4c(C)c(N)ccc4cn3)ccc12 RAGZRCJYHKGTFT-UHFFFAOYSA-N 0.000 description 1
- DKAZHOYOJGDNTL-UHFFFAOYSA-N Cc1nc(c(CO)cc(N)c2)c2[nH]1 Chemical compound Cc1nc(c(CO)cc(N)c2)c2[nH]1 DKAZHOYOJGDNTL-UHFFFAOYSA-N 0.000 description 1
- XSZZHOALJUVOIG-UHFFFAOYSA-N Clc(cccc1c(Cl)n2)c1nc2Cl Chemical compound Clc(cccc1c(Cl)n2)c1nc2Cl XSZZHOALJUVOIG-UHFFFAOYSA-N 0.000 description 1
- AKXWCWNEEZHWFL-UHFFFAOYSA-N O=C(c(cccc1Cl)c1N1)NC1=O Chemical compound O=C(c(cccc1Cl)c1N1)NC1=O AKXWCWNEEZHWFL-UHFFFAOYSA-N 0.000 description 1
- OQSAMGQYHIMFPN-UHFFFAOYSA-N [O-][N+](c1cc(C(F)(F)F)c(cn[nH]2)c2c1)=O Chemical compound [O-][N+](c1cc(C(F)(F)F)c(cn[nH]2)c2c1)=O OQSAMGQYHIMFPN-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to 2-aminoquinazoline derivatives useful as pharmaceuticals, particularly inhibitors of protein kinases.
- Protein kinases transmit signals involved in proliferation, intercellular communication, survival, etc. by phosphorylating tyrosine, serine or threonine on self or other proteins. These signals play an important role in the growth and survival of normal cells (see, for example, Non-Patent Document 1).
- phosphorylation events are triggered in response to various extracellular and other stimuli.
- stimuli include environmental stress signals and chemical stress signals (eg, osmotic stimuli, heat stimuli, ultraviolet irradiation, bacterial endotoxins, etc.), cytokines (eg, interleukin-1 (IL-1), tumors Necrosis factor ⁇ (TNF- ⁇ ), growth factor (eg, granulocyte macrophage colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF))) and the like.
- environmental stress signals eg, osmotic stimuli, heat stimuli, ultraviolet irradiation, bacterial endotoxins, etc.
- cytokines eg, interleukin-1 (IL-1), tumors Necrosis factor ⁇ (TNF- ⁇ ), growth factor (eg, granulocyte macrophage colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF)
- IL-1 interleukin-1
- TNF- ⁇ tumor
- Extracellular stimulation is one or more cellular responses related to cell proliferation, cell migration, cell differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle control. Can affect.
- diseases are known to be associated with abnormal cellular responses via protein kinases as described above.
- diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Is mentioned.
- the type III receptor tyrosine kinase family (Flt3, c-Kit, PDGF receptor, and c-Fms) is important in the maintenance, proliferation and growth of hematopoietic and non-hematopoietic cells.
- Flt3, c-Kit, PDGF receptor, and c-Fms type III receptor tyrosine kinase family
- Flt3 and c-Kit receptors regulate the maintenance of stem / early progenitor cells and the growth of mature lymphocyte cells and bone marrow cells (see Non-Patent Document 3).
- PLC ⁇ , PI3 kinase, Grb-2, SHIP, and Src-related kinases are known (see Non-Patent Document 2), various hematopoietic cells and non-hematopoietic cells. It has been shown to play an important role in cellular malignancies.
- Aurora kinase family has been discovered as an important regulator of mitosis, involving the G2 and M phases of the cell cycle.
- Aurora kinase is a family of tumor serine / threonine kinases localized in mitotic organs (centrosome, pole of bipolar spindle, or intermediate), complete centrosome separation, bipolar spindle Regulates the construction and segregation of chromosomes.
- Aurora A Three homologs of Aurora kinase have been identified (Aurora A, Aurora B and Aurora C (also referred to in the literature as Aurora 2, Aurora 1 and Aurora 3, respectively) (see Non-Patent Document 4). All share a highly conserved catalytic domain located at the carboxy terminus, but their amino termini have no sequence similarity and extend in various lengths (see Non-Patent Document 5). Human Aurora kinase is expressed during cell proliferation and is overexpressed in many tumor cell lines including breast, ovary, prostate, pancreas and colon.
- Aurora A kinase is involved in the formation of spindles and is thought to localize to the centrosome in the early G2 phase, where they phosphorylate spindle-related proteins.
- Significant overexpression of Aurora A has been detected in human breast cancer, ovarian cancer, and pancreatic cancer (see Non-Patent Document 6, Non-Patent Document 7 and Non-Patent Document 8).
- Aurora B kinase functions as an oncogene and transforms Rat1 fibroblasts and mouse NIH3T3 cells in vitro. Aurora B also transforms NIH3T3 cells that grow as tumors in nude mice. Excessive Aurora B can cause aneuploidy (abnormality) in cells by accelerating the loss of tumor suppressor genes and / or by amplifying events known to contribute to oncogenes, cell transformation. A large number of chromosomes). Cells with excess Aurora B may bypass the mitotic checkpoint, resulting in inappropriate activation of the protooncogene. Aurora B upregulation has been observed in many pancreatic cancer cell lines. Furthermore, it has been observed that Aurora B kinase antisense oligonucleotide treatment causes cell cycle arrest and increased apoptosis.
- a signal is not regulated by gene mutation, overexpression or activation of a molecule having protein kinase activity, and is abnormally enhanced. Therefore, a compound that inhibits protein kinase is considered to be a prophylactic / therapeutic agent for cancer by inhibiting cancer cell proliferation or blocking survival signals.
- JAK Janus kinase
- This JAK plays an important role in cytokine signaling.
- Examples of the downstream substrate of this JAK family kinase include STAT (Signal transducer and activator of transcription) protein.
- JAK / STAT signaling is associated with many abnormal immune responsive diseases (eg allergies, asthma, autoimmune diseases (eg transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis), solid tumors And hematopoietic malignant tumors (eg, leukemia and lymphoma)) (see Non-Patent Document 9 and Non-Patent Document 10).
- abnormal immune responsive diseases eg allergies, asthma, autoimmune diseases (eg transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis), solid tumors And hematopoietic malignant tumors (eg, leukemia and lymphoma)
- IgE immunoglobulin E receptors expressed on mast cells are cross-linked by allergen sensitization, leading to pro-inflammatory mediators (many vessels leading to acute allergic or immediate (type I) hypersensitivity reactions) It is known to release active cytokines (see Non-Patent Document 11 and Non-Patent Document 12).
- Syk is a tyrosine kinase that plays an important role in mast cell degranulation and eosinophil activation via the high affinity IgE receptor. Therefore, Syk kinase is involved in various allergic diseases (such as asthma) (see Non-Patent Document 13).
- protein kinase abnormalities are involved in various diseases besides cancer. Therefore, compounds that inhibit kinases against these proteins are considered to be preventive / therapeutic agents for these diseases.
- the compounds provided by the present invention are also useful for the study of kinases in biological and pathological phenomena, the study of intracellular signaling pathways mediated by such kinases, and the comparative evaluation of novel kinase inhibitors. Useful.
- 2-aminoquinazoline derivatives having a protein kinase inhibitory action are known.
- 2-aminoquinazoline derivatives having a cyclin-dependent kinase (Cdks) inhibitory action see Patent Document 1
- Raf protein kinase inhibitor 2-aminoquinazoline derivatives having an action see Patent Document 2
- 2-aminoquinazoline derivatives having a protein kinase-regulating action see Patent Document 3
- 2-aminoquinazoline derivatives having a p38 MAP kinase inhibitory action see Patent Document 4
- 2-aminoquinazoline derivatives (see Patent Document 5) having a PDK1 kinase inhibitory action are known.
- the present inventors have found that specific 2-aminoquinazoline derivatives or their pharmaceutically acceptable salts are present.
- the present invention has been completed by finding out that it meets the object of the invention, and its object is to provide a novel compound having a protein kinase inhibitory action and useful as a pharmaceutical product.
- the object of the present invention is achieved by the following first to seventeenth inventions.
- R 1 represents a lower alkyl group optionally substituted with a halogen atom or a halogen atom
- R 2 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a halogen atom, a hydroxyl group, substituted or non-substituted.
- ⁇ Second invention> A 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to the first invention, wherein in formula (I), R 1 is a lower alkyl group optionally substituted with a halogen atom.
- R 1 represents a lower alkyl group optionally substituted with a halogen atom
- R 2 represents a hydrogen atom
- X, Y and Z are each independently a hydrogen atom
- a substituted or unsubstituted lower alkyl group, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a carbamoyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted amino group, and a substituted or unsubstituted acylamino group are represented.
- X and Y each independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted acylamino group.
- X and Y each independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted acylamino group.
- a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of the inventions.
- the 2-aminoquinazoline derivatives or pharmaceutically acceptable salts thereof of the present invention are known to be associated with abnormal cellular responses via protein kinases, such as autoimmune diseases, inflammatory It is effective as a preventive or therapeutic drug for diseases, bone diseases, metabolic diseases, neurological diseases and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. It is also useful as a protein kinase inhibitor in laboratory and research reagents.
- the 2-aminoquinazoline derivative of the present invention is a compound represented by the following formula (I) or a compound represented by the following formula (II).
- R 1 represents a lower alkyl group optionally substituted with a halogen atom or a halogen atom
- R 2 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a halogen atom, a hydroxyl group, substituted or non-substituted.
- R 1 represents a lower alkyl group optionally substituted with a halogen atom, a halogen atom
- R 2 represents a hydrogen atom
- X, Y and Z are each independently a hydrogen atom
- a substituted or unsubstituted lower alkyl group, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a carbamoyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted amino group, and a substituted or unsubstituted acylamino group are represented.
- the lower alkyl group which may be substituted with the halogen atom of R 1 may be any of a C1 to C3 linear, branched or cyclic alkyl group. Specifically, a methyl group , An isopropyl group, a cyclopropyl group, and the like, and a methyl group is particularly preferable.
- specific examples of the lower alkyl group substituted with a halogen atom include a trifluoromethyl group.
- the substituted or unsubstituted lower alkyl group for R 2 represents a substituted or unsubstituted C1-C6 linear, branched or cyclic alkyl group.
- the substituted lower alkyl group represents an alkyl group substituted with a substituted or unsubstituted amino group, a substituted or unsubstituted alkoxy group, etc., and these may be substituted with a halogen atom, specifically, a morpholinomethyl group Pyrrolidinoethyl group, methoxyethyl group and the like.
- halogen atom for R 2 examples include a fluorine atom, a chlorine atom, and a bromine atom.
- Examples of the substituted or unsubstituted lower alkoxy group include a substituted or unsubstituted C1-C6 linear, branched or cyclic alkyl group or a linear, branched or cyclic alkyl group.
- the carbon atom represents an alkoxy group which may be substituted with a hetero atom, and these may be substituted with a halogen atom.
- Specific examples include a methoxy group, 2-morpholinoethyloxy group, 2-pyrrolidinoethyloxy group, 2-dimethylaminoethyloxy group, 2-ethoxyethyloxy group and the like.
- the substituted or unsubstituted amino group includes an amino group having a substituted or unsubstituted C1 to C6 linear, branched or cyclic alkyl group, or carbon of a linear, branched or cyclic alkyl group. It represents an amino group in which an atom may be substituted with a hetero atom, and these may be substituted with a halogen atom.
- the substituted or unsubstituted acylamino group represents a C1 to C6 linear or branched alkylcarboxyamino group.
- the lower alkoxycarbonyl group represents a C1-C6 linear, branched or cyclic alkoxycarbonyl group, and specific examples thereof include a methoxycarbonyl group.
- the substituted or unsubstituted lower alkylureido group represents a substituted or unsubstituted C1 to C6 linear, branched or cyclic alkylureido group, and specific examples thereof include an ethylureido group. it can.
- the substituted or unsubstituted lower alkyl group in X, Y and Z represents a substituted or unsubstituted C1 to C6 linear, branched or cyclic alkyl group, and the substituted lower alkyl group includes:
- the alkyl group substituted by the substituted or unsubstituted amino group, the substituted or unsubstituted alkoxy group, etc. is represented, These may be substituted by the halogen atom.
- the halogen atom represents a fluorine atom, a chlorine atom, or a bromine atom.
- the lower alkoxycarbonyl group represents a C1 to C6 linear or branched alkyloxycarbonyl group, and specific examples include a methoxycarbonyl group.
- Examples of the substituted or unsubstituted lower alkoxy group include a substituted or unsubstituted C1-C6 linear, branched or cyclic alkyl group or a linear, branched or cyclic alkyl group.
- the carbon atom represents an alkoxy group which may be substituted with a hetero atom, and these may be substituted with a halogen atom.
- the substituted or unsubstituted amino group includes an amino group having a substituted or unsubstituted C1 to C6 linear, branched or cyclic alkyl group, or carbon of a linear, branched or cyclic alkyl group. It represents an amino group in which an atom may be substituted with a hetero atom, and these may be substituted with a halogen atom.
- the substituted or unsubstituted lower alkoxycarbonylamino group represents a substituted or unsubstituted C1-C6 linear, branched or cyclic alkyloxycarbonylamino group, specifically, an ethoxycarbonylamino group or the like. Can be mentioned.
- the substituted or unsubstituted lower alkylaminocarbonyl group represents a substituted or unsubstituted C1 to C6 linear, branched or cyclic alkylaminocarbonyl group, and these linear, branched or cyclic alkyl groups. Of carbon atoms may be substituted with a heteroatom. Specific examples include 2-dimethylaminoethylaminocarbonyl group and 2-morpholinoethylaminocarbonyl group.
- the lower alkylsulfonylamino group represents a C1 to C6 linear, branched or cyclic alkylsulfonylamino group.
- the substituted or unsubstituted lower alkylureido group represents a substituted or unsubstituted C1 to C6 linear, branched or cyclic alkylureido group, and specific examples thereof include an ethylureido group. it can.
- the substituted or unsubstituted acylamino group represents a substituted or unsubstituted C1 to C6 linear, branched or cyclic alkylcarbonylamino group.
- a 5- or 6-membered ring may be formed, and a bicyclic condensed ring that may have a substituent in the formed ring may be formed.
- X and Y together form a condensed ring, it can form a saturated or unsaturated bicyclic alicyclic or heterocyclic condensed ring, specifically, indazole, benzo
- indazole benzo
- bicyclic condensed rings such as triazole, benzimidazole, dihydroindene, indole, benzodioxole, dihydrobenzodioxin, benzoxazin-3-one, and benzothiazole.
- examples of the bicyclic fused ring include a 1H-indazol-6-yl group, a 1H-indole-6-yl group, a 1H-benzo [d] imidazol-6-yl group, and the like. .
- the 2-aminoquinazoline derivative of the present invention can be converted into a pharmaceutically acceptable salt by a known method.
- Salts include alkali metal salts with sodium, potassium, etc., alkaline earth metal salts with magnesium, calcium, etc., organic amine salts with lower alkyl amines, lower alcohol amines, etc., basicity with lysine, arginine, ornithine, etc.
- amino acid salts ammonium salts and the like can be mentioned.
- inorganic acid salts with hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid, etc. organic acid salts with fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.
- the compound of the present invention can be produced by the method exemplified below.
- a method commonly used in organic synthetic chemistry such as functional group Protection, deprotection [T. W. Greene, Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, Inc. , 1999] can be easily manufactured. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
- NMP N-methylpyrrolidone
- POCl 3 phosphoryl chloride
- CH 2 Cl 2 Dichloromethane
- WSC 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride
- HOBt 1-hydroxy-1H-benzotriazole
- THF Tetrahydrofuran
- DIEA N, N-diisopropylethylamine
- Xantphos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene
- the compound of the present invention represented by the formula (I) can be produced, for example, according to Scheme 1.
- Compound (I) is prepared by heating 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents, of Compound (III) with Compound (III) in a solvent, if necessary in the presence of an acid catalyst such as hydrochloric acid. Can be obtained.
- the solvent is not particularly limited as long as it is inert to the reaction, and for example, a lower alcohol, preferably n-butanol can be used.
- the reaction can be carried out by heating at 100 to 150 ° C. for 3 to 24 hours.
- the reaction can be carried out using a microwave synthesizer at 120 to 130 ° C. for 10 to 25 minutes.
- disassembly other process can also be added as needed.
- Compound (IV) which is one of the raw materials of Scheme 1 can be obtained as a commercial product (for example, a product of SIGMA-ALDRICH) or by a known method or a method analogous thereto.
- Step 2-1 This step can be performed by a known method [for example, refer to WO0121598] or a method analogous thereto. That is, compound (VI) can be obtained by reacting compound (V) and urea in a solvent by heating.
- the solvent is not particularly limited as long as it is inert to the reaction.
- NMP NMP, DMF, 1,4-dioxane and the like can be used, but NMP can be preferably used. .
- the reaction is completed in 3 to 6 hours at 150 to 200 ° C, preferably 175 to 190 ° C.
- Compound (V) which is the starting material of Scheme 2 is a commercially available product (for example, a product of SIGMA-ALDRICH) or a known method [for example, see J. Med. Chem. 1991, 34, 217] or a method analogous thereto Can be obtained.
- Step 2-2 This step can be performed by a known method [for example, see Published Patent Publication No. 2-502462] or a method according thereto.
- compound (VII) can be obtained by reacting compound (VI) with POCl 3 in the presence of dimethylaniline.
- the reaction is completed in 3 to 6 hours at 100 to 150 ° C., preferably 100 to 130 ° C.
- Step 2-3 This step can be performed by a known method [see, for example, US6040488] or a method analogous thereto.
- Compound (III) can be obtained by selectively removing the 4-position chloro group of compound (VII). That is, it can be synthesized by adding zinc powder in a two-layer mixed solution of CH 2 Cl 2 and ammonia-containing saturated saline solution and reacting under reflux conditions for 3 to 6 hours.
- Compound (III) can also be produced, for example, by treating compound (VII) obtained in Step 2-2 of Scheme 2 with ammonia and then reacting with nitrites as shown in Scheme 3. .
- This step can be performed by a known method [see, for example, US20040209904] or a method based thereon, and can be specifically performed as follows.
- Step 3-1 Compound (VIII) can be obtained by regioselectively aminating compound (VII) with ammonia in a solvent.
- the solvent is not particularly limited as long as it is inert to the reaction, and THF can be preferably used.
- ammonia source a commercially available ammonia solution, preferably a 7N methanol solution, can be used, and the reaction is completed in 3 hours to 48 hours at 0 ° C. to room temperature.
- Step 3-2 Compound (III) can be obtained by reacting compound (VIII) with a nitrite in a solvent.
- the solvent is not particularly limited as long as it is inert to the reaction, and THF can be preferably used.
- nitrite tert-butyl nitrite or isoamyl nitrite can be preferably used.
- the reaction is completed at 60-100 ° C. in 4-24 hours.
- the compound of the present invention represented by the formula (I) can also be produced, for example, according to Scheme 4.
- Compound (I) is reacted by heating 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents, of Compound (IX) in a solvent in the presence of a base catalyst and a palladium catalyst as necessary. Can be obtained.
- the solvent is not particularly limited as long as it is inert to the reaction.
- NMP, DMF, 1,4-dioxane and the like can be used, but 1,4-dioxane is preferably used. Can be used.
- sodium carbonate potassium carbonate, cesium carbonate can be used as the base.
- palladium catalyst commonly used palladium sources and phosphine ligands can be used, but tris (dibenzylideneacetone) dipalladium is preferably used as the palladium source, and Xantphos can be used as the ligand.
- the reaction can be carried out by heating at 100 to 150 ° C. for 3 to 24 hours.
- Compound (X) can be obtained as a commercial product (for example, a product of SIGMA-ALDRICH) or by a known method or a method analogous thereto.
- This step can be carried out by a known method [for example, see J. Org. Chem. 2006, 71, 3959] or a method analogous thereto.
- Compound (IX) which is the starting material of Scheme 4 can be obtained by subjecting compound (XI) to a reaction with guanidine in a solvent in the presence of a base catalyst as necessary.
- Compound (XI) can be obtained as a commercial product (for example, a product of SIGMA-ALDRICH) or by a known method or a method analogous thereto.
- the solvent is not particularly limited as long as it is inert to the reaction.
- NMP NMP, DMF, 1,4-dioxane and the like can be used, but NMP can be preferably used. .
- Examples of the base include triethylamine, tributylamine, DIEA and the like.
- the reaction is completed in 1 to 3 hours at 150 to 160 ° C.
- R 1 is a lower alkyl group which may be substituted with a halogen atom
- R 2 is NR 3 R 4 (wherein R 3 and R 4 are each independently a hydrogen atom, A substituted or unsubstituted lower alkyl group, or R 3 and R 4 together form a 5- to 6-membered ring, and form a bicyclic fused ring that may have a substituent in the formed ring.
- R 3 and R 4 together form a condensed ring, a saturated or unsaturated bicyclic alicyclic or heterocyclic condensed ring can be formed.
- a certain compound (Ib) can be obtained, for example, by the production method shown below.
- Compound (Ib) can be obtained by subjecting compound (Ia) to 1 to 5 molar equivalents, preferably 2 to 3 molar equivalents of compound (XII) by heating in a solvent.
- the solvent is not particularly limited as long as it is inert to the reaction.
- NMP NMP, DMF, 1,4-dioxane and the like can be used, but NMP can be preferably used. .
- the reaction can be carried out by heating at 100 to 150 ° C. for 3 to 48 hours.
- the reaction can be carried out using a microwave synthesizer at 120 to 140 ° C. for 10 to 60 minutes. .
- Compound (XII) can be obtained as a commercial product (for example, a product of SIGMA-ALDRICH) or by a known method or a method analogous thereto.
- Compound (Ia) can be obtained by performing the same reaction as in Schemes 1 and 2.
- the compound (Ic) in which R 1 is a lower alkyl group which may be substituted with a halogen atom and R 2 is an unsubstituted amino group is obtained, for example, by the production method shown below. be able to.
- Compound (Ic) is compound (Ia) with 1 to 20 molar equivalents, preferably 5 to 10 molar equivalents of sodium azide in the presence of 1 to 1.5 molar equivalents of 18-crown 6-ether in a solvent. It can be obtained by heating reaction.
- the solvent is not particularly limited as long as it is inert to the reaction.
- NMP, DMF, 1,4-dioxane and the like can be used, but DMF can be preferably used. .
- the reaction can be carried out by heating at 100 to 150 ° C. for 3 to 24 hours.
- R 1 is a lower alkyl group which may be substituted with a halogen atom
- R 2 is OR 5 (wherein R 5 represents a substituted or unsubstituted lower alkyl group).
- (Id) can be obtained, for example, by the following production method.
- Compound (Id) can be obtained by reacting compound (Ia) with 1 to 5 molar equivalents of compound (XIV) in the presence of 5 to 20 molar equivalents of a base in a solvent.
- the solvent is not particularly limited as long as it is inert to the reaction.
- NMP, DMF, 1,4-dioxane and the like can be used, but DMF can be preferably used. .
- the reaction can be carried out by heating at 70 to 150 ° C. for 3 to 24 hours.
- sodium hydride sodium hydroxide, lithium hydroxide, potassium hydroxide and the like can be used, and preferably sodium hydride can be used.
- Compound (XIV) can be obtained as a commercial product (for example, a product of SIGMA-ALDRICH) or by a known method or a method analogous thereto.
- the compound (If) in which R 1 is a lower alkyl group optionally substituted with a halogen atom and R 2 is a hydroxyl group can be obtained, for example, by the production method shown below. .
- Compound (If) is obtained by subjecting compound (Ie) to conditions for demethylation reaction of arylmethyl ether usually used in organic synthetic chemistry [T. W. Greene, Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, Inc. 1999, pp. 249, etc., or a method analogous thereto].
- Test example 1 Measuring biological activity
- test compound solution The test compound was dissolved in DMSO to a concentration of 10 mM and stored in a dark place at ⁇ 20 ° C. until measurement.
- biological activity kinase activity
- the test compound solution is diluted with DMSO to a concentration 100 times higher than that of the test compound solution, and further diluted 25 times with the following assay buffer (DMSO concentration is 4%) Prepared.
- protein kinase (recombinant human kinase) used for the test for measuring the kinase activity
- the following products of Carna Biosciences were used.
- SYK product number 08-176
- JAK3 product number 08-046)
- FLT3 product number 08-154
- PDGFR ⁇ product number 08-154
- TRKA TRKA
- NDRK1 product number 08-186
- KDR product number 08-191
- CDK2 / cycA product number 04-103
- AurA (AURKA) (product number 05-101)
- the kinase activity was measured by a mobility shift assay (MSA) method using QuickScout® Screening® Assist® MSA TM (commercially available kit manufactured by Carna Biosciences).
- MSA mobility shift assay
- test compound solution 4 times the final concentration or 5 ⁇ l of solvent (4% DMSO-assay buffer) dissolved or suspended in assay buffer [20 mM HEPES, 0.01% TritonX-100 TM, 1 mM dithiothreitol, pH 7.5] )
- assay buffer [20 mM HEPES, 0.01% TritonX-100 TM, 1 mM dithiothreitol, pH 7.5]
- assay buffer 20 mM HEPES, 0.01% TritonX-100 TM, 1 mM dithiothreitol, pH 7.5]
- assay buffer 20 mM HEPES, 0.01% TritonX-100 TM, 1 mM dithiothreitol, pH 7.5
- 5 ⁇ l of ATP / substrate / Metal solution of QuickScout Screening Assist MSA was added.
- 10 ⁇ l of a kinase solution diluted with an assay buffer was
- the inhibition rate (%) of the test compound was calculated according to the following formula.
- Inhibition rate (%) (1 ⁇ (C ⁇ A) / (B ⁇ A)) ⁇ 100
- A is a blank
- B is a solvent
- C shows P / (P + S) of a compound well.
- N- (1H-indol-6-yl) -8-methylquinazolin-2-amine shows an inhibitory activity of 50% or more at 0.1 ⁇ M against AurA kinase
- N- (3,4-dimethylphenyl) -8-methylquinazolin-2-amine shows an inhibitory activity of 50% or more at 0.1 ⁇ M against JAK2 and JAK3 kinase.
- N- (1H-indazol-6-yl) -8-methylquinazolin-2-amine (the compound of Example 1)
- N- (1H-benzo [d] [1,2,3] triazol-5-yl ) -8-methylquinazolin-2-amine (compound of Example 2)
- 5- (8-methylquinazolin-2-ylamino) -2-methylphenol (compound of Example 29)
- 8-methyl-N- ( 3-Methyl-1H-indazol-6-yl) -quinazolin-2-amine (compound of Example 34)
- 8-methyl-N- (4-methyl-1H-indazol-6-yl) -quinazoline-2- Amine (the compound of Example 37), 7-hydroxy-N- (1H-indazol-6-yl) -8-methylquinazolin-2-amine (the compound of Example 48), 8-methyl-N- (4- Amino-1H-indazol-6-yl) quinazolin
- Test example 2 Effect on IgE-induced degranulation
- Rat basophil cells, RBL-2H3 were incubated overnight with anti-DNP-IgE antibody (1 ⁇ g / mL, Zymed). The cells were washed twice with HBSS, antigen DNP-BSA (1 ⁇ g / mL, LSL) was added, and the cells were further incubated for 30 minutes. The supernatant was taken and the ⁇ -hexosaminidase activity in the solution released by degranulation was measured using p-nitrophenyl-N- ⁇ -D-glucosaminide as a substrate.
- the absorbance at 405 nm and 570 nm of the solution was measured using an absorptiometer (Spectra MAX Pro, Molecular Devices), and the increased amount was defined as the enzyme activity.
- Test substances and vehicle (0.1% DMSO) were added to the cells 10 minutes before adding the antigen.
- the inhibition rate (%) for degranulation was calculated by the following formula.
- Inhibition rate (%) (1- (AC) / (BC)) x 100
- N- (1H-indazol-6-yl) -8-methyl-7- (4-methylpiperazin-1-yl) quinazolin-2-amine (the compound of Example 63), 4-amino -N-ethyl-6- (8-methylquinazolin-2-ylamino) -1H-indazole-1-carboxamide (compound of Example 79), ethyl [6- (8-methylquinazolin-2-ylamino) -1H- Indazol-4-yl] methyl carbamate (compound of example 80), 8-methyl-N- (4-hydroxy-1H-indazol-6-yl) quinazolin-2-amine (compound of example 82), 8- Methyl-N- (2-methyl-4-amino-1H-benzo [d] imidazol-6-yl) quinazolin-2-amine (the compound of Example 88) and the like show an inhibitory activity of 50% or more at 0.05
- the compound of the present invention since the compound of the present invention has Syk inhibitory action and degranulation inhibitory action, it is useful as a preventive or therapeutic agent for diseases such as allergic diseases, autoimmune diseases, arthritis and the like involving Syk. Conceivable.
- the compound was identified by hydrogen nuclear magnetic resonance spectrum ( 1 H-NMR), mass spectrum (MS) and the like.
- the hydrogen nuclear magnetic resonance spectrum was measured at 600 MHz unless otherwise specified, and exchangeable hydrogen atoms may not be clearly observed depending on the compound and measurement conditions. Note that br means a broad signal (broad).
- Zinc powder (3.25 g) was added to a two-phase solution of the product of the second step (3.25 g, 15.26 mmol) in CH 2 Cl 2 (25 mL) and 9% ammonia-containing saturated brine solution (25 mL). Reflux for hours. The reaction mixture was filtered through celite, and then the CH 2 Cl 2 layer was distilled off under reduced pressure. Ethyl acetate was added to the obtained aqueous layer residue, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate.
- the compound (I) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (Compound (III) -A) (71 mg, 0.4 mmol), 6-aminoindazole (67 mg, 0.5 mmol), one drop of concentrated hydrochloric acid and n of Reference Example 1 -A mixed solution of butanol (1.5 mL) was reacted for 15 minutes using a microwave synthesizer (CEM, 120 ° C, 100W). The reaction solution was allowed to cool to room temperature, and the precipitated solid was collected by filtration and washed with cold 2-propanol.
- CEM microwave synthesizer
- the compound (I) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline of Reference Example 1 (compound (III) -A) (71 mg, 0.4 mmol), 5-aminobenztriazole (67 mg, 0.5 mmol), a drop of concentrated hydrochloric acid and A mixed solution of n-butanol (1.5 mL) was reacted for 15 minutes using a microwave synthesizer (CEM, 120 ° C., 100 W). The reaction mixture was diluted with ethyl acetate, washed with water, and the organic layer was dried over anhydrous magnesium sulfate.
- CEM microwave synthesizer
- Example 2 was performed using 2-chloro-8-methylquinazoline (Compound (III) -A) (71 mg, 0.4 mmol) and 5-aminoindane (67 mg, 0.5 mmol) of Reference Example 1. The product was reacted and treated in the same manner as above to obtain 60 mg of the following compound (I) -D, which is a kind of the compound (I) of the present invention.
- Example 2 was performed using 2-chloro-8-methylquinazoline (compound (III) -A) (71 mg, 0.4 mmol) and 6-aminoindole (66 mg, 0.5 mmol) of Reference Example 1.
- the compound (I) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (compound (III) -A) (71 mg, 0.4 mmol) and 3,4-methylenedioxyaniline (69 mg, 0.5 mmol) of Reference Example 1 were used. The reaction and treatment were conducted in the same manner as in Example 2 to obtain 26 mg of the following compound (I) -F, which is a kind of the compound (I) of the present invention.
- the compound (I) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline of Reference Example 1 (compound (III) -A) (71 mg, 0.4 mmol), 3,4-ethylenedioxyaniline (91 mg, 0.5 mmol), concentrated A mixed solution of one drop of hydrochloric acid and n-butanol (1.5 mL) was reacted for 15 minutes using a microwave synthesizer (CEM, 120 ° C., 100 W).
- CEM microwave synthesizer
- reaction solution was allowed to cool to room temperature, and the precipitated solid was collected by filtration and washed with cold 2-propanol to obtain 119 mg of the following compound (I) -G, which is a kind of the compound (I) of the present invention.
- the compound (I) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline of Reference Example 1 (compound (III) -A) (71 mg, 0.4 mmol) and 6-amino-2H-benzo [b] [1,4] oxazine- Using 3 (4H) -one (82 mg, 0.5 mmol) in the same manner as in Example 1, 61.0 mg of the following compound (I) -H, which is a kind of the compound (I) of the present invention, was colorless. Obtained as a powder.
- the compound (I) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline of Reference Example 1 (compound (III) -A) (71 mg, 0.4 mmol) and 6-amino-2-methyl-2H-benzo [b] [1, 4] Oxazin-3 (4H) -one (71 mg, 0.4 mmol) was used for the reaction and treatment in the same manner as in Example 7 to obtain the following compound (I) -I, which is a kind of the compound (I) of the present invention. 115 mg was obtained.
- the compound (I) of the present invention was produced. Specifically, using 2-chloro-8-methylquinazoline (compound (III) -A) (71 mg, 0.4 mmol) and 6-aminobenzothiazole (75 mg, 0.5 mmol) of Reference Example 1, The reaction and treatment were conducted in the same manner as in 2 to obtain 36 mg of the following compound (I) -J, which is a kind of the compound (I) of the present invention.
- the compound (II) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (Compound (III) -A) (89 mg, 0.5 mmol), 3-aminoacetanilide (90 mg, 0.6 mmol), one drop of concentrated hydrochloric acid and n of Reference Example 1 -A mixed solution of butanol (2.0 mL) was reacted for 15 minutes using a microwave synthesizer (CEM, 120 ° C, 100W).
- CEM microwave synthesizer
- Example 11 Compound 11 (100 mg, 0.34 mmol) of Example 11 was dissolved in ethanol (5.0 mL), concentrated hydrochloric acid (4.0 mL) was added, heated to 100 ° C., and stirred for 3.5 hours. The reaction solution was cooled to room temperature, and the precipitated solid was collected by filtration to obtain 12 mg of the following compound (II) -B, which is a kind of the compound (II) of the present invention.
- the compound (II) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (compound (III) -A) (47 mg, 0.263 mmol), 3-aminophenol (29 mg, 0.263 mmol), one drop of concentrated hydrochloric acid and n of Reference Example 1 -A mixed solution of butanol (2.0 mL) was reacted for 25 minutes using a microwave synthesizer (CEM, 135 ° C, 100W).
- CEM microwave synthesizer
- the compound (II) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (Compound (III) -A) (89 mg, 0.5 mmol), 2-aminoanisole (76 mg, 0.6 mmol), one drop of concentrated hydrochloric acid and n of Reference Example 1 were used. -A mixed solution of butanol (2.0 mL) was reacted for 15 minutes using a microwave synthesizer (CEM, 120 ° C, 100W). The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate.
- CEM microwave synthesizer
- the compound (II) of the present invention was produced. Specifically, Example 7 using 2-chloro-8-methylquinazoline (compound (III) -A) (89 mg, 0.5 mmol) and 4-aminoanisole (76 mg, 0.6 mmol) of Reference Example 1 was used. The product was reacted and treated in the same manner as described above to obtain 74 mg of the following compound (II) -F, which is a kind of the compound (II) of the present invention.
- Example 16 The compound of Example 16 (53 mg, 0.2 mg mmol) was reacted and treated in the same manner as in Example 15 to obtain 11 mg of the following compound (II) -G, which is a kind of the compound (II) of the present invention. .
- the compound (II) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (compound (III) -A) (89 mg, 0.5 mmol) and 3-trifluoromethylaniline (97 mg, 0.6 mmol) of Reference Example 1 were used. The reaction and treatment were conducted in the same manner as in Example 7 to obtain 20 mg of the following compound (II) -H, which is a kind of the compound (II) of the present invention.
- Example 7 was performed using 2-chloro-8-methylquinazoline (Compound (III) -A) (89 mg, 0.5 mmol) and 3-bromoaniline (102 mg, 0.6 mmol) of Reference Example 1.
- 127 mg of the following compound (II) -I which is a kind of the compound (II) of the present invention, was obtained.
- the compound (II) of the present invention was produced. Specifically, in the same manner as in Example 7, using 2-chloro-8-methylquinazoline (71 mg, 0.4 mmol) and 3-chloroaniline (64 mg, 0.5 mmol) of (Compound (III) -A). The reaction and treatment were carried out to obtain 34 mg of the following compound (II) -J, which is a kind of the compound (II) of the present invention.
- Example 7 was performed using 2-chloro-8-methylquinazoline (Compound (III) -A) (71 mg, 0.4 mmol) and 3-fluoroaniline (56 mg, 0.5 mmol) of Reference Example 1. The product was reacted and treated in the same manner as described above to obtain 26 mg of the following compound (II) -K which is a kind of the compound (II) of the present invention.
- the compound (II) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (Compound (III) -A) (89 mg, 0.5 mmol) and methyl 3-aminobenzoate (91 mg, 0.6 mmol) of Reference Example 1 were used. The reaction and treatment were conducted in the same manner as in Example 7 to obtain 111 mg of methyl 3- (8-methylquinazolin-2-ylamino) benzoate.
- WSC 61 mg, 0.32 mmol
- HOBt 49 mg, 0.32 mmol
- the compound (II) of the present invention was produced. Specifically, in Example 1, 2-chloro-8-methylquinazoline (compound (III) -A) (71 mg, 0.5 mmol) and 3-aminobenzonitrile (59 mg, 0.6 mmol) were used. The product was reacted and treated in the same manner as in Example 7 to obtain 71 mg of the following compound (II) -N, which is a kind of the compound (II) of the present invention.
- the compound (II) of the present invention was produced. Specifically, Example 7 using 2-chloro-8-methylquinazoline (Compound (III) -A) (71 mg, 0.4 mmol) and 4-aminoacetanilide (75 mg, 0.5 mmol) of Reference Example 1 was used. The product was reacted and treated in the same manner as described above to obtain 99 mg of the following compound (II) -O, which is a kind of the compound (II) of the present invention.
- the compound (II) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (compound (III) -A) (89 mg, 0.5 mmol) and 5-amino-2-methoxyphenol (83 mg, 0.6 mmol) of Reference Example 1 were used. Then, the reaction and treatment were conducted in the same manner as in Example 2 to obtain 38 mg of the following compound (II) -P which is a kind of the compound (II) of the present invention.
- the compound (II) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (compound (III) -A) (89 mg, 0.5 mmol) and 4-chloro-3-methoxyaniline (95 mg, 0.6 mmol) of Reference Example 1 were used. Then, the reaction and treatment were conducted in the same manner as in Example 7 to obtain 127 mg of the following compound (II) -Q, which is a kind of the compound (II) of the present invention.
- Example 27 The compound of Example 27 (60 mg, 0.2 mg mmol) was reacted and treated in the same manner as in Example 15 to obtain 15 mg of the following compound IV (II) -R, which is a kind of the compound (II) of the present invention. It was.
- the compound (II) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (compound (III) -A) (71 mg, 0.4 mmol) and 5-amino-2-methylphenol (62 mg, 0.5 mmol) of Reference Example 1 were used. Then, the reaction and treatment were conducted in the same manner as in Example 2 to obtain 30 mg of the following compound (II) -S, which is a kind of the compound (II) of the present invention.
- the compound (II) of the present invention was produced. Specifically, 2-chloro-8-methylquinazoline (Compound (III) -A) (89 mg, 0.5 mmol) and 3,4-dimethoxyaniline (92 mg, 0.6 mmol) of Reference Example 1 were used. The reaction and treatment were conducted in the same manner as in Example 7 to obtain 80 mg of the following compound (II) -T, which is a kind of the compound (II) of the present invention.
- Step 3 Step 3-1 in Scheme 3
- the THF solution (2 mL) of the product (VII) -B (151 mg, 0.65 mmol) and 28% aqueous ammonia (1.5 mL) in the second step was stirred overnight at room temperature.
- Water (5 mL) was added to the residue obtained by concentrating the solvent under reduced pressure, and the precipitated solid was collected by filtration, washed with water, and dried to give a compound of compound (VIII) in Scheme 3, 2,8-dichloroquinazoline-4 -122 mg of amine (VIII) -B was obtained.
- the compound (I) of the present invention was produced. Specifically, using 2,8-dichloroquinazoline (compound (III) -B) (47 mg, 0.24 mmol) and 6-aminoindazole (31 mg, 0.24 mmol) of Reference Example 2, The same reaction and treatment were performed to obtain 39 mg of the following compound (I) -K, which is a kind of the compound (I) of the present invention, as a yellow powder.
- Zinc powder (0.215 g) was added to a two-phase solution of the product of the third step (0.20 g, 0.82 mmol) in dichloromethane (10 mL) and 9% ammonia-containing saturated saline solution (10 mL), and the mixture was refluxed for 4 hours. .
- the reaction mixture was filtered through celite, and the filtrate was washed successively with dilute hydrochloric acid (10%) and saturated brine, and dried over anhydrous sodium sulfate.
- 2,3-Dimethyl-5-nitroaniline [for example, synthesized by the method described in WO2005117819] (1.0 g, 6.02 mmol) in glacial acetic acid solution (120 mL), sodium nitrite (0.42 g , 6.14 mmol) was added (3 mL). The mixture was stirred for 1 hour under ice-cooling, and further stirred at room temperature for 2 days. Acetic acid was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was stirred for 30 minutes under ice cooling. The precipitate was collected by filtration to obtain 1.14 g of 6-nitro-4-methylindazole.
- Ammonium chloride (0.12 g, 2.26 mmol) and pig iron (2.56 g, 45.2 mmol) were added to 80% ethanol aqueous solution (75 mL) of the product of the first step (0.80 g, 4.52 mmol) and refluxed for 1 hour.
- the reaction mixture was cooled to room temperature, insolubles were filtered through celite, and washed successively with ethanol and ethyl acetate. Water was added to the residue obtained by concentrating the filtrate under reduced pressure, and the precipitated solid was collected by filtration to obtain 0.43 g of 6-amino-4-methylindazole.
- Methyl 3-amino-2-methyl-5-nitrobenzoate [for example, synthesized by the method described in JP04295441] (3.99 g, 19.0 mm mmol) in a glacial acetic acid solution (450 ml) under ice-cooling sodium nitrite An aqueous solution (8 mL) of (1.35 g, 19.6 mmol) was added. After stirring for 1 hour under ice cooling, the mixture was further stirred at room temperature for 3 days. Acetic acid was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was stirred for 30 minutes under ice cooling. The precipitate was collected by filtration to obtain 3.99 g of methyl 6-nitro-1H-indazole-4-carboxylate.
- Example 44 The same reaction and treatment as in Example 44 were carried out using 2-chloro-7-methoxy-8-methylquinazoline (see Reference Example 4) (100 mg, 0.48 mmol) and 6-aminoindazole (64 mg, 0.48 mmol). As a result, 83 mg of the title compound was obtained.
- N-bromosuccinimide (705 mg, 3.96 mmol) and azobisisobutyronitrile (0.02 mg) are added to a carbon tetrachloride solution (30 mL) of the product of the first step (1.0 kg, 3.6 mL) at 85 ° C. For 6 hours.
- the reaction mixture was cooled to room temperature, filtered through celite, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 3- (bromomethyl) -6-nitro-1H-indazole-1-carboxylic acid. 611 mg of tert-butyl tert was obtained.
- a THF solution (2M, 0.42 mL, 0.84 mmol) of dimethylamine was added to a THF solution (3 mL) of the product of the second step (200 mg, 0.56 mmol), and stirred at room temperature for 3 hours.
- the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain 163 mg of tert-butyl 3-[(dimethylamino) methyl)]-6-nitro-1H-indazole-1-carboxylate. .
- the organic layer was separated, washed successively with 0.5N aqueous sodium hydroxide solution and water, and then dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure, and the resulting solid was collected by filtration and washed with cold ethyl acetate to obtain 53 mg of the title compound.
- Methyl 6-nitro-1H-indazole-4-carboxylate (see Example 41) (3.02 g, 13.65 mmol) was dissolved in a 1: 1 mixture of THF-methanol (200 mL), and 2N aqueous sodium hydroxide solution was dissolved. (35 mL) was added and stirred at 70 ° C. for 1 hour. The reaction mixture was acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.86 g of 6-nitro-1H-indazole-4-carboxylic acid.
- Triethylamine (1.73 g, 17.06 mmol) was added to an anhydrous toluene solution ⁇ ⁇ (250 mL) of this product, followed by diphenyl phosphate azide (4.70 g, 17.06 mmol). After the reaction mixture was refluxed for 1 hour, ethanol (3.14 g, 68.3 mmol) was added, and the mixture was further refluxed for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed successively with 1N aqueous sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3.42 g of ethyl 6-nitro-1H-indazole-4-carbamate.
- Example 51 (18 mg, 0.05 mg mmol) of Example 51 was dissolved in a 1: 1 solution of dioxane and methanol (10 mL), 2N aqueous sodium hydroxide solution (1.5 mL) was added, and 1 using a microwave synthesizer. The reaction was performed for an hour (Biotage, 120 ° C). The reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 15 mg of the title compound.
- 6-nitro-1H-indazole-3-carboxylic acid 100 mg, 0.48 mmol
- DMF solution 2 mL
- 2-dimethylaminoethylamine (0.06 mL, 0.58 mmol
- triethylamine 0.1 mL, -3-0.73 mmol
- PyBOP Trademark
- SIGMA-ALDRICH PyBOP (Trademark)
- the reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain 116 mg of N- [2- (dimethylamino) ethyl] -6-nitro-1H-indazole-3-carboxamide.
- Example 54 The same reaction and treatment as in Example 54 were carried out using 6-nitro-1H-indazole-3-carboxylic acid (100 mg, 0.48 mmol) and N- (2-aminoethyl) morpholine (0.08 mL, 0.58 mmol). To give 4 mg of the title compound.
- Example 44 Using the compound of Example 44 (100 mg, 0.341 mmol) and N- (2-aminoethyl) morpholine (88 mg, 0.682 mmol), the same reaction and treatment as in Example 56 were carried out to obtain 55 mg of the title compound. It was.
- Example 44 Using the compound of Example 44 (40 mg, 0.136 mmol) and N- (3-aminopropyl) morpholine (59 mg, 0.408 mmol), the same reaction and treatment as in Example 56 was performed to obtain 30 mg of the title compound. It was.
- Example 44 Using the compound of Example 44 (40 mg, 0.136 mmol) and N-methylpiperazine (41 mg, 0.408 mmol), the same reaction and treatment as in Example 56 were carried out to obtain 8 mg of the title compound.
- Example 44 Using 1- (2-hydroxyethyl) pyrrolidine (59 mg, 0.512 mmol) and the compound of Example 44 (50 mg, 0.17 mmol), the same reaction and treatment as in Example 62 was carried out to give 12.5 mg of the title compound (12.5 mg). Obtained.
- Example 44 Using N, N-dimethylethanolamine (46 mg, 0.512 mmol) and the compound of Example 44 (50 mg, 0.17 mmol), the same reaction and treatment as in Example 62 was carried out to obtain 15.1 mg of the title compound. .
- Example 44 Using 2-ethoxyethanol (46 mg, 0.512 mmol) and the compound of Example 44 (50 mg, 0.17 mmol), the same reaction and treatment as in Example 62 was performed to obtain 12.2 mg of the title compound.
- Example 44 Using the compound of Example 44 (100 mg, 0.341 mmol) and 2-methoxyethylamine (76 mg, 1.02 mmol), the same reaction and treatment as in Example 56 was performed to obtain 7.7 mg of the title compound.
- Example 44 Using the compound of Example 44 (40 mg, 0.136 mmol) and pyrrolidine (29 mg, 0.409 mmol), the same reaction and treatment as in Example 56 was performed to obtain 45 mg of the title compound.
- 6-Nitrobenzo [d] imidazole-4-carboxylic acid [e.g., synthesized by the method described in J. Org. Chem. 1960, 25, ⁇ 942 etc.] (3.0 g, 14.5 mmol) in a methanol solution (32 mL) Thionyl chloride (1.58 mL) was added while cooling to 0 ° C. under a nitrogen stream, and then the reaction mixture was refluxed for 24 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, water (5 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate.
- Example 44 Using the compound of Example 44 (50 mg, 0.17 mmol) and 2-dimethylaminoethylamine (45 mg, 0.511 mmol), the same reaction and treatment as in Example 56 were carried out to obtain 22 mg of the title compound.
- Example 44 Using the compound of Example 44 (50 mg, 0.17 mmol) and 2-aminoethanol (31 mg, 0.511 mmol), the same reaction and treatment as in Example 56 were carried out to obtain 21 mg of the title compound.
- Example 44 Using the compound of Example 44 (100 mg, 0.34 mmol) and 1- (2-aminoethyl) piperazine (130 mg, 1.02 mmol), the same reaction and treatment as in Example 56 was performed to obtain 14 mg of the title compound. It was.
- Example 44 Using the compound of Example 44 (59 mg, 0.201 mmol), dimethylamine hydrochloride (160 mg, 2.01 mmol) and triethylamine (203 mg, 2.01 mmol), the same reaction and treatment as in Example 56 were carried out to give the title compound 16 mg was obtained.
- 6-nitrobenzo [d] imidazole-4-carboxylic acid [for example, synthesized by the method described in J. Org. Chem. 1960, 25, 942, etc.] (900 mg, 4.34 mmol) and triethylamine (1 mL, 5.2 mmol)
- Diphenylphosphoric acid azide (1.4 mL, 5.0 mL) was added to an anhydrous ethanol solution (150 mL), and the mixture was refluxed for 3 hours.
- reaction mixture was diluted with ethyl acetate (150 mL), washed sequentially with 1N aqueous sodium hydroxide solution (2 mL x 50 mL), water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to remove ethyl 6-nitro- 195 mg of 1H-benzo [d] imidazol-4-ylcarbamate was obtained.
- Example 77 The compound of Example 77 (100 mg, 0.275 mmol) was dissolved in 1,4-dioxane / methanol 1: 1 solution (5 mL), 2N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was refluxed for 12 hr. The reaction mixture was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 65 mg of the title compound.
- the DMF solution (0.5 mL) of the product of the fourth step (119 mg, 0.281 mmol) and hydrazine monohydrate (0.5 ⁇ ⁇ mL, °C 10.3 mmol) was stirred at 60 ° C for 0.5 hour.
- the reaction mixture was diluted with 2-butanol and washed successively with 2N sodium hydroxide and saturated brine.
- the solvent was distilled off under reduced pressure to obtain 82 mg of tert-butyl 4-aminomethyl-6-nitro-1H-indazole-1-carboxylate.
- Acetic anhydride (0.021 mL, 0.219 mmol) was added to a DMF solution (2 mL) of the compound of Example 74 (53 mg, 0.182 mmol) and triethylamine (0.030 mL, 0.219 mmol), and stirred at room temperature for 24 hours.
- the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to obtain 3 mg of the title compound.
- Example 44 Using the compound of Example 44 (50 mg, 0.17 mmol) and morpholine (45 mg, 0.51 mmol), the same reaction and treatment as in Example 56 was performed to obtain 7 mg of the title compound.
- Example 44 Using the compound of Example 44 (60 mg, 0.20 mmol) and 4-piperidinemethanol (71 mg, 0.61 mmol), the same reaction and treatment as in Example 56 were carried out to obtain 7 mg of the title compound.
- Example 44 Using the compound of Example 44 (50 mg, 0.17 mmol) and piperidine (44 mg, 0.51 mmol), the same reaction and treatment as in Example 56 was performed to obtain 7 mg of the title compound.
- Example 87 The compound of Example 87 (13 mg, 0.035 mmol) was dissolved in 1,4-dioxane / methanol 1: 1 solution (1 mL), 2N aqueous sodium hydroxide solution (0.3 mL) was added, and the mixture was refluxed for 12 hr. The reaction mixture was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 8 mg of the title compound.
- Example 56 The title compound was treated in the same manner as in Example 56 using the compound of Example 44 (60 mg, 0.205 mmol), methylamine hydrochloride (138 mg, 2.05 mmol) and triethylamine (0.28 mL, 2.05 mmol). 28 mg was obtained.
- Example 44 Using the compound of Example 44 (70 mg, 0.239 mmol) and 1- (2-hydroxyethyl) piperidine (93 mg, 0.741 mmol), the same reaction and treatment as in Example 56 was carried out to obtain 32 mg of the title compound. It was.
- Lithium aluminum hydride 300 mg, 7.89 mmol was added to a THF solution (15 mL) of 6-aminoindole-4-carboxylic acid methyl ester hydrochloride (0.9 g, 4.66 mmol) while cooling to 0 C. The mixture was stirred at 5 ° C for 2 hours. Saturated aqueous ammonium chloride (1.5 mL) was gradually added to the reaction mixture under ice-cooling, and the solvent was evaporated under reduced pressure. Water (15 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 110 mg of (6-amino-1H-indol-4-yl) methanol.
- Example 44 Using the compound of Example 44 (55 mg, 0.188 mmol) and 1-acetylpiperazine (96 mg, 0.75 mmol), the same reaction and treatment as in Example 56 were carried out to obtain 8 mg of the title compound.
- the NMP solution (0.5 mL) of the compound of Example 93 (21.5 mg, 0.07 mmol) and 4-piperidinemethanol (202 mg, 1.75 mmol) was reacted for 3 hours using a microwave synthesizer (manufactured by Biotage) 220 ° C).
- the reaction solution was diluted with water and the precipitated solid was collected by filtration and washed with ethanol.
- 2-aminoethanol (26 mg, 0.43 mmol) was added to an NMP solution of the compound ⁇ (20 mg, 0.066 mmol) of Example 99 and reacted for 60 minutes using a microwave synthesizer (Biotage, 180 ° C) .
- 2-aminoethanol (20 mg), and the mixture was stirred at 140 ° C. for 3 days.
- the reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
- Example 95 Using the compound of Example 95 (30.7 mg, 0.1 mol) and 4-piperidinemethanol (288 mg, 2.5 mol), the same reaction and treatment as Example 94 was carried out to obtain 10.2 mg of the title compound.
- Example 103 The same reaction and treatment as in Example 103 were carried out using the compound of Example 95 (40 mg, 0.13 mmol), sodium azide (85 mg, 1.3 mmol) and 18-crown 6-ether (34.4 mg, 0.13 mmol). As a result, 15.6 mg of the title compound was obtained.
- Example 44 Using the compound of Example 44 (50 mg, 0.170 mmol) and piperazine (58 mg, 0.682 mmol), the same reaction and treatment as in Example 56 was performed to obtain 8 mg of the title compound.
- Ethyl isocyanate (0.018 mL, 0.20674mmol) was added to a DMF solution (2 mL) of the compound of Example 74 (60 mg, 0.206 mmol), and stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to obtain 6 mg of the title compound.
- Example 94 Using the compound of Example 93 (10 mg, 0.033 mmol) and 2-aminoethanol (40 mg, 0.651 mmol), the same reaction and treatment as in Example 94 was carried out to obtain 7.2 mg of the title compound.
- Example 95 Using the compound of Example 95 (30.7 mg, 0.1 mol) and 2-aminoethanol (611 mg, 10 mmol), the same reaction and treatment as in Example 94 was performed to obtain 23.1 mg of the title compound.
- the product of the first step (5.8 g, 24.57 mmol) was added little by little to methanesulfonic acid (24 mL) previously heated to 80 ° C and stirred at 80 ° C for 2 hours.
- the reaction mixture was added to ice water, extracted with ethyl acetate, and the organic layer was washed with saturated brine.
- the obtained organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 4.5 g of methyl 7-methyl-2,3-dioxoindoline-6-carboxylate.
- the product of the second step (4.5 g, 21 mmol) was suspended in 1.5 N aqueous sodium hydroxide solution (100 mL), 30% hydrogen peroxide (2.46 mL) was added dropwise, and the mixture was stirred at 23 ° C for 12 hours. .
- the reaction solution was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. After drying the organic layer with sodium sulfate, the solvent was distilled off under reduced pressure to obtain 3.23 g of 2-amino-3-methylterephthalic acid.
- Step 6 Add 10% palladium on carbon (60 mg) to ethyl acetate solution (40 kg) of product (0.5 g, 1.85 mmol) and N, N-diisopropylethylamine (0.35 mL, 0.28 mmol) in Step 6 And stirred at room temperature for 2 hours. Water was added to the reaction mixture, the insoluble material was filtered through Celite, and the organic layer was separated from the filtrate.
- Example 44 The same reaction as in Example 44 was carried out using methyl 2-chloro-8-methylquinazoline-7-carboxylate (see Reference Example 7) (150 mg, 0.63 mmol) and 6-aminoindazole (90 mg, 0.66 mmol). Treatment gave 110 mg of the title compound.
- Example 113 The compound of Example 113 (120 mg, 0.36 mmol) was dissolved in a 1: 1 solution of methanol and THF (10 mL), 5N aqueous sodium hydroxide solution (0.1 mL) was added, and the mixture was stirred at room temperature for 30 hr. Water (2 mL) was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 50 mg of the title compound.
- Example 113 The compound of Example 113 (50 mg, 0.15 mmol) was added to a solution of lithium aluminum hydride (18 mg, 0.54 mmol) in THF (8 mL) while cooling to 0 ° C. under a nitrogen stream and stirred for 1 hour.
- the reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered through celite. The filtrate was distilled off under reduced pressure to obtain 6 mg of the title compound.
- Ethyl 6-nitro-1H-benzo [d] imidazol-4-ylcarbamate (see Example 77) (250 mg, 1.0 mmol) in acetone solution (15 mL), potassium carbonate (50 mg, 0.15 mmol) and iodine Methyl chloride (50 mg, 0.15 mmol) was added and stirred at room temperature for 12 hours. Water (2 mL) was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the mixture was extracted with ethyl acetate.
- Example 96 Using the compound of Example 96 (10 mg, 0.031 mmol), the same reaction and treatment as in Example 44 were carried out to obtain 3.5 mg of the title compound.
- 6-aminoindole-4-carboxylic acid methyl ester hydrochloride (1.5 g, 6.62 mmol) was added to a mixed solution of THF solution (20 mL) and 4N aqueous sodium hydroxide solution (4 mL).
- Di-tert-butyl dicarbonate (1.73 g, 7.92 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours.
- the organic layer was separated and washed with saturated aqueous ammonium chloride (2 mL), and the solvent was evaporated under reduced pressure.
- Trifluoroacetic acid (1 mL) was added to a dichloromethane solution (5 mL) of the product of the third step (0.1 g, 0.313 mmol) and stirred at room temperature for 2 hours.
- a saturated aqueous sodium hydrogen carbonate solution (10 mL)
- the mixture was extracted with ethyl acetate.
- the organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 57 mg of ethyl 6-amino-1H-indol-4-ylcarbamate.
- Example 123 Using the compound of Example 123 (75 mg, 0.24 mmol) and 2-aminoethanol (45 mg, 0.73 mmol), the same reaction and treatment as in Example 56 was performed to obtain 8 mg of the title compound.
- Example 122 The compound of Example 122 (35 mg, 0.096 mmol) was dissolved in a 1: 1 solution of dioxane and methanol (3 mL), 2N aqueous sodium hydroxide solution (1.5 mL) was added, and the mixture was refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure, water (15 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 21 mg of the title compound.
- Ethyl 6-amino-1-methyl-1H-benzo [d] imidazol-4-ylcarbamate (see Example 116) (100 mg, 0.427 mmol) and 2-chloro-7-fluoro-8-methylquinazoline (reference example) 3) (84 mg, 0.427 mmol), and the same reaction and treatment as in Example 44 was carried out to obtain ethyl 6- (7-fluoro-8-methylquinazolin-2-ylamino) -1-methyl-1H-benzo [d] 142 mg of imidazol-4-ylcarbamate was obtained.
- a 2N aqueous sodium hydroxide solution (0.4 mL) was added to a methanol solution (1 mL) of the compound of Example 80 (26.2 mg, ⁇ ⁇ 0.070 mmol) and reacted for 3 hours using a microwave synthesizer (manufactured by Biotage, 100-120 ° C).
- the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was extracted with 2N hydrochloric acid.
- 4N Sodium hydroxide was added to the obtained aqueous layer to make it alkaline, and then extracted with 2-butanol.
- the 2-aminoquinazoline derivative of the present invention or a pharmaceutically acceptable salt thereof is used as a medicine as a disease known to be associated with an abnormal cellular response via protein kinase, such as an autoimmune disease. It is useful as a therapeutic agent for inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Further, the 2-aminoquinazoline derivatives of the present invention or their pharmaceutically acceptable salts are useful for studying kinases in biological and pathological phenomena, studies on intracellular signal transduction pathways mediated by kinases, and novel methods. It is also useful for comparative evaluation of other kinase inhibitors.
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Abstract
Description
下式(I)で示される2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
式(I)において、R1がハロゲン原子で置換されていてもよい低級アルキル基である第一の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
式(I)において、R1がメチル基である第一の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
式(I)において、R1がハロゲン原子である第一の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
式(I)において、R1がメチル基、R2が水素原子である第一の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
式(I)において、R1がメチル基、R2が水酸基、置換もしくは非置換のアミノ基である第一の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
式(I)において、XとYとが一緒になって、2環性縮合環を形成している第一の発明ないし第六の発明のいずれかに記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
2環性縮合環が複素環式縮合環である第七の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
複素環式縮合環が1H-インダゾール-6-イル基である第八の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
複素環式縮合環が1H-インドール-6-イル基である第八の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
複素環式縮合環が1H-ベンゾ[d]イミダゾール-6-イル基である第八の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
複素環式縮合環の水素原子が夫々独立してZで置換されていてもよいる第九の発明ないし第十一の発明のいずれかに記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
Zが夫々独立してメチル基、アミノ基、水酸基である第十二の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
下式(II)で示される2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
式(II)において、R1がハロゲン原子で置換されていてもよい低級アルキル基である第十四の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
式(II)において、R1がハロゲン原子である第十四の発明に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
X及びYが夫々独立して、水素原子、水酸基、置換もしくは非置換の低級アルコキシ基、置換もしくは非置換のアミノ基、置換もしくは非置換のアシルアミノ基を表す第十四の発明ないし第十六の発明のいずれかに記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
また、プロテインキナーゼの阻害剤として、実験用,研究用の試薬に有用である。
以下、本発明を詳細に説明する。
本発明の2-アミノキナゾリン誘導体は、下式(I)で示される化合物,又は、下式(II)で示される化合物である。
本発明の2-アミノキナゾリン誘導体は、公知の方法により薬学的に許容される塩に変換することができる。塩としては、ナトリウム,カリウム等とのアルカリ金属塩,マグネシウム,カルシウム等とのアルカリ土類金属塩,低級アルキルアミン,低級アルコールアミン等との有機アミン塩,リジン,アルギニン,オルニチン等との塩基性アミノ酸塩の他、アンモニウム塩等が挙げられる。また、塩酸,硫酸,炭酸,リン酸等との無機酸塩、フマル酸,マレイン酸,メタンスルホン酸,p-トルエンスルホン酸等との有機酸塩等が挙げられる。
本発明化合物は、以下に例示する方法によって製造することができる。なお、以下に示した製造法において、定義した基が実施方法の条件下で変化するか、または方法を実施するのに不適切な場合、有機合成化学で通常用いられる方法、例えば、官能基の保護、脱保護[T.W.Greene,Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, Inc.,1999]等の手段を付すことにより容易に製造することができる。また、必要に応じて置換基導入等の反応工程の順序を変えることもできる。
POCl3 : 塩化ホスホリル
CH2Cl2 : ジクロロメタン
WSC : 1-エチル-3-(ジメチルアミノプロピル)カルボジイミド塩酸塩
HOBt : 1-ヒドロキシ-1H-ベンゾトリアゾール
THF : テトラヒドロフラン
DIEA : N,N-ジイソプロピルエチルアミン
Xantphos : 4,5-ビス(ジフェニルホスフィノ)-9,9-ジメチルキサンテン
尚、この後、必要に応じて、さらにエステル分解その他の工程を加えることもできる。
本工程は公知の方法[例えば、WO0121598参照]またはそれに準じた方法で行なうことができる。
すなわち、化合物(VI)は、化合物(V)と尿素とを溶媒中、加熱反応させることによって得ることができる。
本工程は公知の方法[例えば、公表特許公報平2-502462参照]またはそれに準じた方法で行なうことができる。
本工程は公知の方法[例えば、US6040488参照]またはそれに準じた方法で行なうことができる。
化合物(VIII)は、化合物(VII)を溶媒中、アンモニアで位置選択的にアミノ化することで得ることができる。
化合物(III)は、化合物(VIII)を溶媒中、亜硝酸エステルを反応させることにより得ることができる。
化合物(XI)は、市販品(例えば、SIGMA-ALDRICH社製品)として,または公知の方法もしくはそれに準じた方法によって得ることができる。
溶媒は反応に不活性なものであればいずれでも良く、特に限定されるものではないが、例えばNMP、DMF、1,4-ジオキサン等を用いることができるが、好ましくはDMFを用いることができる。
本発明化合物の生物学的活性は、以下に示す方法に従って測定した。
生物学的活性の測定
被験化合物は10mMになるようにDMSOに溶解し、測定するまで-20℃の暗所に保存した。生物活性(キナーゼ活性)を測定する場合、被験化合物溶液は、当該被験化合物溶液の100倍高濃度になるようにDMSOで希釈し、さらに下記アッセイバッファーで25倍(DMSO濃度は4%)に希釈して調製した。
試験に使用したプロテインキナーゼ(組換えヒトキナーゼ)は、カルナバイオサイエン
ス社(神戸)の以下の製品を用いた。
SYK(製品番号08-176)、JAK3(製品番号08-046)、FLT3(製品番号08-154)、PDGFRα(PDGFRA)(製品番号08-157)、TRKA(NTRK1)(製品番号08-186)、KDR(製品番号08-191)、CDK2/cycA(製品番号04-103)、及びAurA(AURKA)(製品番号05-101)
上記のようにして、種々のプロテインキナーゼに対する本発明化合物の阻害作用を検討したところ、本発明化合物は優れた阻害活性を示した。例えば、N-(ベンゾ[d][1,3]ジオキソール-5-イル)-8-メチルキナゾリン-2-アミン(実施例6の化合物)、N-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)-8-メチルキナゾリン-2-アミン(実施例7の化合物)等はFlt3キナーゼに対して0.1μMで50%以上の阻害活性を示し、6-(8-メチルキナゾリン-2-イルアミノ)-2H-ベンゾ[b][1,4]オキサジン-3(4H)-オン(実施例8の化合物)、N-(3-(8-メチルキナゾリン-2-イルアミノ)フェニル)アセトアミド(実施例11の化合物)、8-クロロ-N-(1H-インダゾール-6-イル)キナゾリン-2-アミン(実施例32の化合物)等は0.01μMで50%以上の阻害活性を示した。
IgE誘発脱顆粒に対する作用
SYKに対する阻害作用をIgEで誘発される好塩基球の脱顆粒に対する阻害作用により評価した。ラット好塩基球細胞であるRBL-2H3を抗DNP-IgE抗体(1μg/mL, Zymed)と一晩インキュベーションした。細胞をHBSSで2回洗浄後、抗原であるDNP-BSA(1μg/mL, LSL)を加えて、さらに30分間インキュベーションした。上清を取り、脱顆粒で遊離した溶液中のβ-hexosaminidaseの活性をp-nitrophenyl-N-β-D-glucosaminideを基質にして測定した。吸光度計(Spectra MAX Pro, Molecular Devices)を用いて、溶液の405nmおよび570nmにおける吸光度を測定し、その増加量を酵素活性とした。被験物質および溶媒(0.1% DMSO)は抗原を加える10分前に細胞に添加した。脱顆粒に対する阻害率(%)は次式で算出した。
A: 被験物質群の吸光度の増加; B: 溶媒群の吸光度の増加; C: 抗原で非刺激の溶媒群の吸光度の増加
2-クロロ-8-メチルキナゾリン(本発明化合物(I),(II)の原料化合物(III))の製造
2-メチル-3-アミノ安息香酸(7.56 g, 50 mmol) (前記スキーム2中の化合物(V)の一種)と 尿素(9.00 g, 150 mmol) のNMP溶液 (30 mL)を180-190 ℃ に加熱し3.5時間攪拌した。室温まで冷却後、水 (100 mL) を加えてさらに0.5時間攪拌し、析出物を濾取、水洗、乾燥し、前記スキーム2中の化合物(VI)の一種である、下記の8-メチル-2,4-キナゾリンジオン(VI)-Aを6.44 g得た。
第1工程の生成物 (3.11 g, 17.65 mmol)とN,N-ジメチルアニリン(1.8 mL)及びPOCl3 (18 mL) の混合物を115 ℃ で3.5時間攪拌した。室温まで冷却後、反応混合物を氷水 (50 mL)に加えて析出した固体を濾取し、水洗、乾燥し前記スキーム2中の化合物(VII)の一種である2,4-ジクロロ-8-メチルキナゾリン(VII)-Aを3.25 g得た。
N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)、 6-アミノインダゾール (67 mg, 0.5 mmol)、濃塩酸一滴及びn-ブタノール (1.5 mL)の混合溶液を、マイクロ波合成装置を用いて15分間反応させた(CEM 社製、120℃、100W)。反応溶液を室温まで放冷し、析出した固体を濾取、冷2-プロパノールで洗浄した。得られた固体をシリカゲルクロマトグラフィー(酢酸エチル:n-ヘキサン= 3:2)で精製し、本発明化合物(I)の一種である、下記化合物(I)-Aの 22 mgを無色粉末として得た。
N-(1H-ベンゾ[d][1,2,3]トリアゾール-5-イル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)、5-アミノベンズトリアゾール(67 mg, 0.5 mmol) 、濃塩酸一滴及びn-ブタノール (1.5 mL)の混合溶液を、マイクロ波合成装置を用いて15分間反応させた(CEM 社製、120℃、100W)。反応混合物を酢酸エチルで希釈後、水洗し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー(酢酸エチル:n-ヘキサン= 2:1)で精製し、本発明化合物(I)の一種である、下記化合物(I)-Bの15 mgを無色粉末として得た。
N-(1H-ベンゾ[d]イミダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)及び5-アミノベンズイミダゾール (67 mg, 0.5 mmol)を用い、実施例2と同様に反応・処理して得られた粗精製物を分取薄層クロマトグラフィー(クロロホルム:メタノール= 10:1)で精製し、本発明化合物(I)の一種である、下記化合物 (I)-Cの20 mgを得た。
N-(2,3-ジヒドロ-1H-インデン-5-イル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)及び5-アミノインダン (67 mg, 0.5 mmol)を用い、実施例2と同様に反応・処理し、本発明化合物(I)の一種である、下記化合物(I)-Dの60 mgを得た。
N-(1H-インドール-6-イル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)及び6-アミノインドール (66 mg, 0.5 mmol)を用い、実施例2と同様に反応・処理して得られた粗精製物を分取薄層クロマトグラフィー(クロロホルム:メタノール= 10:1)で精製し、本発明化合物(I)の一種である、下記化合物(I)-Eの 10 mgを得た。
N-(ベンゾ[d][1,3]ジオキソール-5-イル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)及び3,4-メチレンジオキシアニリン (69 mg, 0.5 mmol)を用い、実施例2と同様に反応・処理し、本発明化合物(I)の一種である、下記化合物 (I)-Fの26 mgを得た。
N-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol), 3,4-エチレンジオキシアニリン (91 mg, 0.5 mmol)、濃塩酸一滴及びn-ブタノール(1.5 mL)の混合溶液を、マイクロ波合成装置を用いて15分間反応させた(CEM 社製、120℃、100W)。反応溶液を室温まで放冷し、析出した固体を濾取、冷2-プロパノールで洗浄し、本発明化合物(I)の一種である、下記化合物(I)-Gの119 mgを得た。
6-(8-メチルキナゾリン-2-イルアミノ)-2H-ベンゾ[b][1,4]オキサジン-3(4H)-オンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)及び6-アミノ-2H-ベンゾ[b][1,4]オキサジン-3(4H)-オン(82 mg, 0.5 mmol)を用い、実施例1と同様に反応・処理し、本発明化合物(I)の一種である、下記化合物(I)-Hの61.0 mgを無色粉末として得た。
6-(8-メチルキナゾリン-2-イルアミノ)-2-メチル-2H-ベンゾ[b][1,4]オキサジン-3(4H)-オンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)及び6-アミノ-2-メチル-2H-ベンゾ[b][1,4]オキサジン-3(4H)-オン(71 mg, 0.4 mmol)を用い、実施例7と同様に反応・処理し、本発明化合物(I)の一種である、下記化合物(I)-Iの115 mgを得た。
N-(ベンゾ[d]チアゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)及び6-アミノベンゾチアゾール (75 mg, 0.5 mmol)を用い、実施例2と同様に反応・処理し、本発明化合物(I)の一種である、下記化合物 (I)-Jの36 mgを得た。
N-(3-(8-メチルキナゾリン-2-イルアミノ)フェニル)アセトアミドの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(89 mg, 0.5 mmol), 3-アミノアセトアニリド (90 mg, 0.6 mmol)、濃塩酸一滴及びn-ブタノール (2.0 mL)の混合溶液をマイクロ波合成装置を用いて15分間反応させた(CEM 社製、120℃、100W)。反応混合物を減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー(酢酸エチル:n-ヘキサン= 2:1)で精製し、本発明化合物(II)の一種である、下記化合物(II)-Aの106 mgを得た。
N1-(8-メチルキナゾリン-2-イル)ベンゼン-1,3-ジアミン塩酸塩の製造
3-(8-メチルキナゾリン-2-イル-アミノ)フェノールの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(47 mg, 0.263 mmol)、 3-アミノフェノール (29 mg, 0.263 mmol)、濃塩酸一滴及びn-ブタノール (2.0 mL)の混合溶液をマイクロ波合成装置を用いて25分間反応させた(CEM 社製、135℃、100W)。析出物を濾過して取り除き、濾液を減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー(クロロホルム:メタノール= 10:1)で精製し、本発明化合物(II)の一種である、下記化合物(II)-Cの 8 mgを得た。
N-(2-メトキシフェニル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(89 mg, 0.5 mmol), 2-アミノアニソール (76 mg, 0.6 mmol)、濃塩酸一滴及びn-ブタノール (2.0 mL)の混合溶液をマイクロ波合成装置を用いて15分間反応させた(CEM 社製、120℃、100W)。反応混合物を酢酸エチルで希釈し、水、飽和食塩水で洗浄し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー(酢酸エチル:n-ヘキサン= 3:7)で精製し、本発明化合物(II)の一種である、下記化合物 (II)-Dの43 mgを得た。
2-(8-メチルキナゾリン-2-イルアミノ)フェノールの製造
N-(4-メトキシフェニル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(89 mg, 0.5 mmol)及び4-アミノアニソール (76 mg, 0.6 mmol)を用い、実施例7と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物 (II)-Fの74 mgを得た。
2-(8-メチルキナゾリン-2-イルアミノ)フェノールの製造
N-(3-(トリフルオロメチル)フェニル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(89 mg, 0.5 mmol)及び3-トリフルオロメチルアニリン (97 mg, 0.6 mmol)を用い、実施例7と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物(II)-Hの 20 mgを得た。
N-(3-ブロモフェニル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(89 mg, 0.5 mmol)及び3-ブロモアニリン (102 mg, 0.6 mmol)を用い、実施例7と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物(II)-Iの127 mgを得た。
N-(3-クロロフェニル)-8-メチルキナゾリン-2-アミンの製造
具体的には、(化合物(III)-A)の2-クロロ-8-メチルキナゾリン(71 mg, 0.4 mmol)及び3-クロロアニリン (64 mg, 0.5 mmol)を用い、実施例7と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物(II)-Jの 34 mgを得た。
N-(3-フルオロフェニル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)及び3-フルオロアニリン (56 mg, 0.5 mmol)を用い、実施例7と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物(II)-Kの 26 mgを得た。
3-(8-メチルキナゾリン-2-イルアミノ)安息香酸の製造
3-(8-メチルキナゾリン-2-イルアミノ)安息香酸メチル
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(89 mg, 0.5 mmol)及び3-アミノ安息香酸メチル (91 mg, 0.6 mmol)を用い、実施例7と同様に反応・処理し、3-(8-メチルキナゾリン-2-イルアミノ)安息香酸メチル 111 mgを得た。
第1工程の生成物(63 mg, 0.21 mmol)のTHF・メタノールの1:1混合液 (4mL)に、1規定水酸化ナトリウム水溶液 (1 mL)を加え、マイクロ波合成装置を用いて30分間反応させた(CEM 社製、50℃、10W)。反応液を氷冷しながら、水 (15 mL)で希釈し、濃塩酸を加え酸性にした。析出した固体を濾取し、水 (15 mL)で2回洗浄し、本発明化合物(II)の一種である、(II)-Lの3-(8-メチルキナゾリン-2-イルアミノ)安息香酸59 mgを得た。
3-(8-メチルキナゾリン-2-イルアミノ)安息香酸アミドの製造
3-(8-メチルキナゾリン-2-イルアミノ)ベンゾニトリルの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.5 mmol)及び3-アミノベンゾニトリル (59 mg, 0.6 mmol)を用い、実施例7と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物(II)-Nの 71 mgを得た。
N-(4-(8-メチルキナゾリン-2-イルアミノ)フェニル)アセトアミドの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン (化合物(III)-A)(71 mg, 0.4 mmol)と4-アミノアセトアニリド (75 mg, 0.5 mmol)を用いて実施例7と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物 (II)-Oの99 mgを得た。
5-(8-メチルキナゾリン-2-イルアミノ)-2-メトキシフェノールの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A) (89 mg, 0.5 mmol)と5-アミノ-2-メトキシフェノール (83 mg, 0.6 mmol)を用いて、実施例2と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物 (II)-Pの38 mgを得た。
N-(4-クロロ-3-メトキシフェニル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A) (89 mg, 0.5 mmol)と4-クロロ-3-メトキシアニリン (95 mg, 0.6 mmol)を用いて、実施例7と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物(II)-Qの 127 mgを得た。
5-(8-メチルキナゾリン-2-イルアミノ)-2-クロロフェノールの製造
5-(8-メチルキナゾリン-2-イルアミノ)-2-メチルフェノールの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(71 mg, 0.4 mmol)と5-アミノ-2-メチルフェノール (62 mg, 0.5 mmol)を用いて、実施例2と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物(II)-Sの30 mgを得た。
N-(3,4-ジメチルフェニル)-8-メチルキナゾリン-2-アミンの製造
具体的には、参考例1の2-クロロ-8-メチルキナゾリン(化合物(III)-A)(89 mg, 0.5 mmol)と3,4-ジメトキシアニリン (92 mg, 0.6 mmol)を用いて実施例7と同様に反応・処理し、本発明化合物(II)の一種である、下記化合物 (II)-Tの80 mgを得た。
2,8-ジクロロキナゾリン(本発明化合物(I),(II)の原料化合物(III))の製造
前記スキーム2及びスキーム3に従って、下記の様に、2,8-ジクロロキナゾリンを製造した。
2-アミノ-3-クロロ安息香酸(1.0 g, 5.83 mmol)と尿素(1.05 mg, 17.5 mmol)のNMP溶液(5 mL)を180-190 ℃に加熱し、4時間攪拌した。室温まで冷却後、水 (15 mL)を加えてさらに0.5時間攪拌し、析出物を濾取、水洗、乾燥し、前記スキーム2中の化合物(VI)の一種である、下記の8-クロロ-2,4-キナゾリンジオン(VI)-Bを819 mg得た。
第1工程の生成物(VI)-B(700 mg, 3.56 mmol)とN,N-ジメチルアニリン(0.1 mL)及びPOCl3 (7 mL)の混合物を115 ℃で4時間攪拌した。室温まで冷却後、反応混合物を氷水(20 mL)に加えて析出した固体を濾取し、水洗、乾燥し、前記スキーム2中の化合物(VII)の一種2,4,8-トリクロロキナゾリン(VII)-Bを414 mg得た。
第2工程の生成物(VII)-B(151 mg, 0.65 mmol)と28%アンモニア水(1.5 mL)のTHF溶液(2 mL)を室温で1晩攪拌した。溶媒を減圧濃縮して得られた残渣に水(5 mL)を加え、析出した固体を濾取、水洗、乾燥し、前記スキーム3中の化合物(VIII)の一種2,8-ジクロロキナゾリン-4-アミン(VIII)-Bを122 mg得た。
第3工程の生成物(VIII)-B(87 mg, 0.41 mmol)と亜硝酸イソアミル(0.11 mL, 0.81 mmol)のTHF溶液(2 mL)を60 ℃に加熱し、4時間攪拌した。室温まで冷却後、水で希釈し、酢酸エチルで抽出した。得られた有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー(酢酸エチル:ヘキサン= 3:1)で精製し、2,8-ジクロロキナゾリン (III)-Bを60 mg得た。
N-(3-(8-クロロキナゾリン-2-イルアミノ)フェニル)アセトアミドの製造
具体的には、参考例2の2,8-ジクロロキナゾリン(化合物(III)-B)(70 mg, 0.35 mmol)と3-アミノアセトアニリド(66 mg, 0.35 mmol)のn-ブタノール(2 mL)溶液を110℃で3時間攪拌した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー(CH2Cl2:酢酸エチル = 1:1)で精製し、本発明化合物(II)の一種である、下記化合物(II)-U の35 mgを黄色粉末として得た。
8-クロロ-N-(1H-インダゾール-6-イル)キナゾリン-2-アミンの製造
具体的には、参考例2の2,8-ジクロロキナゾリン(化合物(III)-B)(47 mg, 0.24 mmol)および6-アミノインダゾール (31 mg, 0.24 mmol)を用いて、実施例31と同様に反応・処理し、本発明化合物(I)の一種である、下記化合物(I)-Kの 39 mgを黄色粉末として得た。
2-クロロ-7-フルオロ-8-メチルキナゾリンの製造
2-アミノ-4-フルオロ-3-メチル安息香酸[例えば、J. Med. Chem. 1991, 34, 217等に記載の方法により合成できる](11.4 g, 67.45 mmol)と尿素(12.14 g, 20.23 mmol)のNMP溶液(24 mL)を180 ℃で4時間撹拌した。室温まで冷却後、反応混合物を水(60 mL)で希釈し、析出した固体を濾取した。固体を水、酢酸エチルで順に洗浄後、乾燥し、7-フルオロ-8-メチル-2,4-キナゾリンジオンを10.0 gを得た。
第1工程の生成物 (1.5 g)とN,N-ジメチルアニリン(5 mL)及び塩化ホスホリル (25 mL) の混合物を12時間還流した。室温まで冷却後、溶媒を減圧留去し、残渣を氷水に加えて酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィー(酢酸エチル:ヘキサン= 1:9)で精製し、2,4-ジクロロ-7-フルオロ-8-メチルキナゾリンを0.55 gを得た。
第2工程の生成物(0.50 g, 2.17 mmol)のジクロロメタン溶液 (21 mL) 及び9 %アンモニア含有飽和食塩水溶液 (14 mL)の二相溶液に亜鉛粉末 (0.92 g)を加え、6時間還流した。反応混合物をセライトでろ過した後、濾液を希塩酸(10%)および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー(酢酸エチル:ヘキサン= 1:4)で精製し、2-クロロ-7-フルオロ-8-メチルキナゾリン0.187 gを無色粉末として得た。
2-クロロ-7-メトキシ-8-メチルキナゾリンの製造
2-アミノ-4-メトキシ-3-メチル安息香酸[例えば、J. Med. Chem. 1991, 34, 217あるいはWO2007014927等に記載の方法により合成できる](2.3 g, 12.70 mmol)のエタノール溶液(50 mL)に塩化チオニル(10 mL)を窒素気流下、0 ℃に冷却しながら加え、その後、反応混合液を24時間還流した。室温まで冷却後、溶媒を減圧留去し、得られた残渣に飽和炭酸水素ナトリウム水溶液(15 mL)を加え、酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィー(酢酸エチル:ヘキサン= 1:9 ~ 3:17)で精製し、2-アミノ-4-メトキシ-3-メチル安息香酸エチルエステル1.01 gを得た。
第1工程の生成物(1.00 g, 4.78 mmol)と尿素(2.29 g, 38.27 mmol) の混合物を封管中、220 ℃ で2時間撹拌した。室温まで冷却後、反応混合物を酢酸エチルに懸濁し、固体を濾取した。水で洗浄、乾燥し、尿素と7-メトキシ-8-メチル-2,4-キナゾリンジオンの混合物を2.01 gを得た。
第2工程の生成物 (2.0 g)とN,N-ジメチルアニリン(5 mL)及び塩化ホスホリル (50 mL) の混合物を7時間還流した。室温まで冷却後、溶媒を減圧留去し、残渣を氷水に加えて酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィー(酢酸エチル:ヘキサン= 1:9)で精製し、2,4-ジクロロ-7-メトキシ-8-メチルキナゾリンを0.95 gを得た。
第3工程の生成物(0.20 g, 0.82 mmol)のジクロロメタン溶液 (10 mL) 及び9 %アンモニア含有飽和食塩水溶液 (10 mL)の二相溶液に亜鉛粉末 (0.215 g)を加え、4時間還流した。反応混合物をセライトでろ過した後、濾液を希塩酸(10%)および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー(酢酸エチル:ヘキサン= 1:4)で精製し、2-クロロ-7-メトキシ-8-メチルキナゾリン0.104 gを無色粉末として得た。
2-クロロ-8-エチルキナゾリンの製造
2-アミノ-3-エチル安息香酸(382 mg, 2.31 mmol)と尿素(417 mg, 6.94 mmol)の混合物のNMP溶液(3 mL)を180 ℃で5時間撹拌した。反応混合物に冷水を加え、析出した固体を濾取し、8-エチル-2,4-キナゾリンジオンの混合物を382 mgを得た。
第1工程の生成物 (313 mg, 1.65 mmol)と塩化ホスホリル (3 mL) の混合物を115 ℃で4時間撹拌した。溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィーで精製し、2,4-ジクロロ-8-エチルキナゾリンを221 mgを得た。
第2工程の生成物(221 mg, 0.97 mmol)と28%アンモニア水(2 mL)のTHF溶液(2 mL)を室温で1晩攪拌した。溶媒を減圧留去後、残渣をシリカゲルクロマトグラフィーで精製し、2-クロロ-8-エチルキナゾリン-4-アミンを183 mg得た。
第3工程の生成物(183 mg, 0.88 mmol)と亜硝酸イソアミル(0.24 mL, 1.76 mmol)のTHF溶液(5 mL)を60 ℃に加熱し、5時間攪拌した。室温まで冷却後、水で希釈し、酢酸エチルで抽出した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィーで精製し、2-クロロ-8-エチルキナゾリンを61 mg得た。
N-(1H-インダゾール-6-イル)-8-エチルキナゾリン-2-アミンの製造
8-メチル-N-(3-メチル-1H-インダゾール-6-イル)-キナゾリン-2-アミンの製造
2-クロロ-8-メチルキナゾリン(参考例1参照)(89 mg, 0.5 mmol)、第2工程の生成物(88 mg, 0.6 mmol)及びn-ブタノール (2.0 mL)の混合溶液をマイクロ波合成装置を用いて120分間反応させた (CEM社製、120 ℃, 100W)。反応液を室温まで放冷し、析出した固体を濾取、冷2-プロパノールで洗浄し、8-メチル-N-(3-メチル-1H-インダゾール-6-イル)-キナゾリン-2-アミン75 mgを黄色固体で得た。
N-(インドリン-6-イル)-8-メチルキナゾリン-2-アミンの製造
8-メチル-N-(7-メチル-1H-インダゾール-6-イル)-キナゾリン-2-アミンの製造
8-メチル-N-(4-メチル-1H-インダゾール-6-イル)-キナゾリン-2-アミンの製造
2-クロロ-8-メチルキナゾリン(参考例1参照) (89 mg, 0.5 mmol)と第2工程の生成物(77 mg, 0.53 mmol) を用いて、実施例34と同様の反応・処理をし、8-メチル-N-(4-メチル-1H-インダゾール-6-イル)-キナゾリン-2-アミン50 mgを黄色固体で得た。
8-メチル-N-(5-メチル-1H-インダゾール-6-イル)-キナゾリン-2-アミンの製造
(6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-3-イル)メタノールの製造
N-[3-(ブトキシメチル)-1H-インダゾール-6-イル]- 8-メチルキナゾリン-2-アミンの製造
2-クロロ-8-メチルキナゾリン(参考例1参照) (179 mg, 1.0 mmol)と(6-アミノインダゾール-3-イル)メタノール[例えば、US2006194801等に記載の方法により合成できる] (269 mg, 1.65 mmol)を用いて実施例1と同様の反応・処理をし、標記化合物 38mgを得た。
[6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-イル]メタノールの製造
1H-NMR (500 MHz, DMSO-d6) d: 3.89 (s, 3H), 5.52 (s, 2H), 6.77 (dd, 1H, J = 1.8, 1.0 Hz), 7.26 (d, 1H, J = 1.8 Hz), 8.07 (s, 1H), 12.59 (s, 1H).
第2工程の生成物(2.28 g, 11.9 mmol)のTHF溶液(200 mL)に、氷冷下で水素化リチウムアルミニウムのTHF溶液(1M, 36 mL)溶液を加え、室温で20時間撹拌した。反応混合物に氷冷下で水 (2 mL)、15% 水酸化ナトリウム水溶液 (2 mL)、水(5 mL)を順に加えて反応を停止させた。不溶物をセライトでろ過後、濾液を減圧濃縮して(6-アミノ-1H-インダゾール-4-イル)メタノール1.34 gを得た。
2-クロロ-8-メチルキナゾリン(参考例1参照) (357 mg, 2.0 mmol)と第3工程の生成物(408 mg, 2.5 mmol)の90%ジオキサン水溶液(17 mL)に濃塩酸 50 μLを加え、マイクロ波合成装置を用いて30分間反応させた (Biotage社製、120°C)。反応混合物を酢酸エチルで希釈し、水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して、[6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-イル]メタノール120 mgを得た。
8-メチル-N-[4-(トリフルオロメチル)-1H-インダゾール-6-イル]-キナゾリン-2-アミンの製造
2-クロロ-8-メチルキナゾリン(参考例1参照) (89 mg, 0.5 mmol)と第3工程の生成物 (106 mg, 0.53 mmol) を用いて、実施例34と同様の反応・処理をし、8-メチル-N-[4-(トリフルオロメチル)-1H-インダゾール-6-イル]-キナゾリン-2-アミン50 mgを得た。
メチル 6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-カルボキシレートの製造
7-フルオロ-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
N-(1H-インダゾール-6-イル)-7-メトキシ-8-メチルキナゾリン-2-アミンの製造
N-{3-[(ジメチルアミノ)メチル]-1H-インダゾール-6-イル}-8-メチルキナゾリン-2-アミンの製造
2-クロロ-8-メチルキナゾリン(参考例1参照)(85 mg, 0.48 mmol)及び第4工程の生成物(138 mg, 0.48 mmol)のn-ブタノール(3 mL)溶液を120℃で3時間撹拌した。反応溶液を室温まで放冷後、溶媒を減圧留去し、残渣を分取HPLCで精製し、N-{3-[(ジメチルアミノ)メチル]-1H-インダゾール-6-イル}-8-メチルキナゾリン-2-アミン 5 mgを得た。
8-メチル-N-(3-アミノ-1H-インダゾール-6-イル)-キナゾリン-2-アミンの製造
第1工程の生成物(47 mg, 0.17 mmol)のn-ブタノール(2 mL)溶液にヒドラジン一水和物(0.5 mL)を加え、110℃で5時間撹拌した。反応溶液を室温まで放冷後、溶媒を減圧留去し、残渣を分取HPLCで精製し、8-メチル-N-(3-アミノ-1H-インダゾール-6-イル)-キナゾリン-2-アミン 18 mgを得た。
7-ハイドロキシ-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-カルボン酸の製造
6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-カルボキサミドの製造
エチル 6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-カーバメートの製造
2-クロロ-8-メチルキナゾリン(参考例1参照) (50 mg, 0.28 mmol)及び第2工程の生成物(62 mg, 0.28 mmol)を用いて、実施例34と同様の反応・処理をし、エチル 6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-カーバメート40 mgを得た。
1H-NMR (400 MHz, DMSO-d6) d: 1.31 (t, 3H, J = 7.1 Hz), 2.70 (s, 3H), 4.20 (q, 2H, J = 7.1 Hz), 7.31 (dd, 1H, J = 8.0, 6.6 Hz), 7.71 (d, 1H, J = 6.8 Hz), 7.76 (d, 1H, J = 8.0 Hz), 7.91 (s, 1H), 8.21 (d, 1H, J = 0.8 Hz), 8.35 (s, 1H), 9.28 (s, 1H), 9.75 (s, 1H), 10.01 (s, 1H), 12.88 (br, 1H); ESI-MS (m/z): 363 [M+H]+.
8-メチル-N-(4-アミノ-1H-インダゾール-6-イル)キナゾリン-2-アミンの製造
6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-3-カルボン酸の製造
2-クロロ-8-メチルキナゾリン(参考例1参照)(113 mg, 0.63 mmol)及び第1工程の生成物(112 mg, 0.63 mmol)のn-ブタノール(3 mL)溶液を120℃で3時間撹拌した。反応溶液を室温まで放冷後、溶媒を減圧留去し、残渣を分取HPLCで精製し、6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-3-カルボン酸6 mgを得た。
N-[2-(ジメチルアミノ)エチル]-6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-3-カルボキサミドの製造
第1工程の生成物(116 mg, 0.42 mmol)のメタノール溶液(5 mL)に10%パラジウム炭素(20 mg)を加え、水素気流下、室温で2時間撹拌した。反応混合物をセライトでろ過し、溶媒を減圧留去後して、6-アミノ-N-[2-(ジメチルアミノ)エチル]-1H-インダゾール-3-カルボキサミド86 mgを得た。(第3工程)
6-(8-メチルキナゾリン-2-イルアミノ)-N-(2-モルホリノエチル)-1H-インダゾール-3-カルボキサミドの製造
N-(1H-インダゾール-6-イル)-7-[2-(ピロリジン-1-イル)エチルアミノ]-8-メチルキナゾリン-2-アミンの製造
N-(1H-インダゾール-6-イル)-7-(2-モルホリノエチルアミノ)-8-メチルキナゾリン-2-アミンの製造
N-(1H-インダゾール-6-イル)-7-(3-モルホリノプロピルアミノ)-8-メチルキナゾリン-2-アミンの製造
6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-3-カルボニトリルの製造
8-メチル-N-{3-[(2-モルホリノエチルアミノ)メチル]-1H-インダゾール-6-イル}-キナゾリン-2-アミンの製造
8-メチル-N-{3-[(2-(ジメチルアミノ)エチルアミノ)メチル]-1H-インダゾール-6-イル}-キナゾリン-2-アミンの製造
N-(1H-インダゾール-6-イル)-8-メチル-7-(2-モルホリノエトキシ)キナゾリン-2-アミンの製造
N-(1H-インダゾール-6-イル)-8-メチル-7-(4-メチルピペラジン-1-イル)キナゾリン-2-アミンの製造
1H-NMR (400 MHz, DMSO-d6) d (ppm): 2.63 (s, 3H), 2.92 (s, 3H), 3.0-3.6 (m, 8H), 7.24 (d, 1H, J = 8.7 Hz), 7.46 (d, 1H, J = 8.6 Hz), 7.64 (d, 1H, J = 8.7 Hz), 7.79 (d, 1H, J = 8.6 Hz), 7.94 (s, 1H), 9.21 (s, 1H), 9.62 (br, 1H), 10.03 (s, 1H); ESI-MS (m/z): 374 [M+H]+.
N-(1H-インダゾール-6-イル)-8-メチル-7-[2-(ピロリジン-1-イル)エトキシ]キナゾリン-2-アミンの製造
7-[2-(ジメチルアミノ)エトキシ]-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
7-(2-エトキシエトキシ)-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
7-(2-メトキシエチルアミノ)-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
N-(1H-インダゾール-6-イル)-8-メチル-7-(ピロリジン-1-イル)キナゾリン-2-アミンの製造
[6-(7-メトキシ-8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イル]メタノールの製造
2-クロロ-7-メトキシ-8-メチルキナゾリン(参考例4参照)(104 mg, 0.5 mmol)と第3工程の生成物(82 mg, 0.5 mmol)のn-ブタノール(1.3 mL)溶液を120℃で3時間撹拌した。反応溶液を室温まで放冷後、アセトンで希釈し析出した固体を濾取し、アセトンで洗浄して、[6-(7-メトキシ-8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イル]メタノール 95 mgを得た。
[6-(8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イル]メタノールの製造
8-メチルキナゾリン-2-アミンの製造
N-(4-メトキシ-1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
5-ブロモ-2-メチル-3-ニトロフェノール[例えば、WO2005084315等に記載の方法により合成できる] (1.52 g, 6.55 mmol)のDMF溶液(22 mL)に、氷冷下で水素化ナトリウム (341 mg, 8.52 mmol)を少しずつ加え、10分間撹拌した。反応溶液にヨウ化メチル (1.40g, 9.83 mmol)を加え、室温で5時間撹拌した。反応混合物に氷水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で順に洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィー(酢酸エチル : n-ヘキサン= 1:9~1:6)で精製し、5-ブロモ-1-メトキシ-2-メチル-3-ニトロベンゼン0.32 gを得た。
第3工程の生成物 (30 mg, 0.074 mmol)をジオキサン(10 mL)に溶解し、氷冷下で4規定塩酸・ジオキサン溶液 (5 mL)を加え、室温で1日撹拌した。反応溶液を減圧濃縮して析出した固体を濾取し、冷酢酸エチルで洗浄した。得られた固体をシリカゲルクロマトグラフィー(クロロホルム : メタノール= 1:0~50:1)で精製し、N-(4-メトキシ-1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミン1 mgを得た。
7-[2-(ジメチルアミノ)エチルアミノ]-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
2-[2-(1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イルアミノ]エタノールの製造
1H-NMR (400 MHz, DMSO-d6) d (ppm): 2.32 (s, 3H), 3.3-3.4 (m, 2H), 3.6-3.7 (m, 2H), 6.98 (d, 1H, J = 9.7 Hz), 7.35 (d, 1H, J = 8.7 Hz), 7.63 (d, 2H, J = 7.9 Hz), 7.93 (s, 1H), 8.62 (br, 1H), 8.89 (s, 1H), 9.75 (bs, 1H), 12.95 (br, 1H); ESI-MS (m/z): 335 [M+H]+.
7-アミノ-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
N-(1H-インダゾール-6-イル)-7-[2-(ピペラジン-1-イル)エチルアミノ]-8-メチルキナゾリン-2-アミンの製造
7-ジメチルアミノ-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
エチル 6-(8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イルカーバメートの製造
2-クロロ-8-メチルキナゾリン(参考例1参照)(145 mg, 0.88 mmol)及び第2工程の生成物(150 mg, 0.68 mmol)のn-ブタノール(1.3 mL)溶液を120℃で10時間撹拌した。反応溶液を室温まで放冷後、酢酸エチルで希釈し析出した固体を濾取し、酢酸エチルで洗浄後、エチル 6-(8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イルカーバメート160 mgを得た。
8-メチル-N-(4-アミノ-1H-ベンゾ[d]イミダゾール-6-イル)キナゾリン-2-アミンの製造
4-アミノ-N-エチル-6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-1-カルボキサミドの製造
エチル [6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-イル]メチルカーバメートの製造
2-クロロ-8-メチルキナゾリン(参考例1参照)(24 mg, 0.135 mmol)と第7工程の生成物(45 mg, 0.135 mmol)のn-ブタノール溶液(1.0 mL)をマイクロ波合成装置を用いて2時間反応させた(バイオタージ社製、120℃)。反応溶液を室温まで放冷後、析出した固体を濾取し、ジイソプロピルエーテルで洗浄してエチル [6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-イル]メチルカーバメート 52.6 mgを得た。
2-(1H-インダゾール-6-イル)-8-メチルキナゾリン-7-アセトアミドの製造
8-メチル-N-(4-ハイドロキシ-1H-インダゾール-6-イル)キナゾリン-2-アミンの製造
N-(1H-インダゾール-6-イル)-8-メチル-7-モルホリノキナゾリン-2-アミンの製造
{1-[2-(1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イル]ピペリジン-4-イル}メタノールの製造
N-(1H-インダゾール-6-イル)-8-メチル-7-(ピペリジン-1-イル)キナゾリン-2-アミンの製造
[2-メチル-6-(8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イル]メタノールの製造
2-クロロ-8-メチルキナゾリン(参考例1参照)(52 mg, 0.294 mmol)と第3工程の生成物(40 mg, 0.226 mmol)のn-ブタノール(1 mL)溶液を120℃で10時間撹拌した。反応溶液を室温まで放冷後、酢酸エチルで希釈し析出した固体を濾取した。得られた固体を分取HPLCで精製し、[2-メチル-6-(8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イル]メタノール 7 mgを得た。
エチル 2-メチル-6-(8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イルカーバメートの製造
2-クロロ-8-メチルキナゾリン(参考例1参照)(22 mg, 0.127 mmol)及び第2工程の生成物(23 mg, 0.098 mmol)のn-ブタノール(1 mL)溶液を120℃で10時間撹拌した。反応溶液を室温まで放冷後、酢酸エチルで希釈し析出した固体を濾取し、酢酸エチルで洗浄して、エチル 2-メチル-6-(8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イルカーバメート20 mgを得た。
8-メチル-N-(2-メチル-4-アミノ-1H-ベンゾ[d]イミダゾール-6-イル)キナゾリン-2-アミンの製造
7-メチルアミノ-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
2-{1-[2-(1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イル]ピペリジン-4-イル}エタノールの製造
[6-(8-メチルキナゾリン-2-イルアミノ)-1H-インドール-4-イル]メタノールの製造
2-クロロ-8-メチルキナゾリン(参考例1参照)(142 mg, 0.797 mmol)、第1工程の化合物(105 mg, 0.648 mmol)及びトリエチルアミン(100 mg, 1.0 mmol)のn-ブタノール(2 mL)溶液を100℃で6時間撹拌した。溶媒を減圧留去し、残渣を分取HPLCで精製し、[6-(8-メチルキナゾリン-2-イルアミノ)-1H-インドール-4-イル]メタノール18 mgを得た。
1-{4-[2-(1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イル]ピペラジン-1-イル}エタノンの製造
N-(3-メチル-1H-インダゾール-6-イル)-7-フルオロ-8-メチルキナゾリン-2-アミンの製造
{1-[2-(3-メチル-1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イル]ピペリジン-4-イル}メタノールの製造
N-(4-メチル-1H-インダゾール-6-イル)-7-フルオロ-8-メチルキナゾリン-2-アミンの製造
1H-NMR (400 MHz, DMSO-d6) d (ppm): 2.53 (s, 3H), 2.59 (d, 3H, J = 2.0 Hz), 7.26 (d, 1H, J = 9.2 Hz), 7.29 (d, 1H, J = 5.2 Hz), 7.87 (dd, 1H, J = 8.8, 6.4 Hz), 7.99 (s, 1H), 8.48 (s, 1H), 9.29 (s, 1H), 10.07 (s, 1H), 12.91 (s, 1H); ESI-MS (m/z): 308 [M+H]+.
N-(3-メチル-1H-インダゾール-6-イル)-7-メトキシ-8-メチルキナゾリン-2-アミンの製造
N-(4-メチル-1H-インダゾール-6-イル)-7-メトキシ-8-メチルキナゾリン-2-アミンの製造
1-(2-ヒドロキシエチル)-3-[6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-イル]ウレアの製造
7-フルオロ-N-(4-アミノ-1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
第1工程の化合物 (120 mg, 0.32 mmol)のジオキサン溶液(15 mL)に2規定水酸化ナトリウム水溶液 (3.0 mL)を加え、マイクロ波合成装置を用いて1時間反応させた (Biotage社製、120℃)。反応溶液に2規定水酸化ナトリウム水溶液 1.5 mLを追加し、さらにマイクロ波合成装置で1.5時間反応させた。反応混合物を酢酸エチルで希釈後、水洗し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して得られた残渣に冷水を加え、析出した固体を濾取し、7-フルオロ-N-(4-アミノ-1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミン90 mgを得た。
2-[2-(4-アミノ-1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イルアミノ]エタノールの製造
{1-[2-(4-アミノ-1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イル]ピペリジン-4-イル}メタノールの製造
N-(4-アミノ-1H-インダゾール-6-イル)-7-メトキシ-8-メチルキナゾリン-2-アミンの製造
第1工程の化合物 (60 mg, 0.15 mmol)のジオキサンとメタノールの1:1溶液(10 mL)に2規定水酸化ナトリウム水溶液(1.5 mL)を加え、マイクロ波合成装置を用いて1時間反応させた (Biotage社製、120℃)。反応混合物を酢酸エチルで希釈し、水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、N-(4-アミノ-1H-インダゾール-6-イル)-7-メトキシ-8-メチルキナゾリン-2-アミン12 mgを得た。
N-(3-メチル-1H-インダゾール-6-イル)-7-アミノ-8-メチルキナゾリン-2-アミンの製造
{1-[2-(4-メチル-1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イル]ピペリジン-4-イル}メタノールの製造
N-(4-メチル-1H-インダゾール-6-イル)-7-アミノ-8-メチルキナゾリン-2-アミンの製造
N-(1H-インダゾール-6-イル)-8-メチル-7-(ピペラジン-1-イル)-キナゾリン-2-アミンの製造
1-(2-(1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イル)-3-エチルウレアの製造
2-[2-(3-メチル-1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イルアミノ]エタノールの製造
2-[2-(4-メチル-1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イルアミノ]エタノールの製造
N-(4-メチル-1H-インダゾール-6-イル)-7-ヒドロキシ-8-メチルキナゾリン-2-アミンの製造
7-ジエチルアミノ-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
7-エチルアミノ-N-(1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
2-クロロ-8-メチルキナゾリン-7-カルボン酸メチルの製造
3-アミノ-2-メチル安息香酸メチル(2 g, 12.12 mmol)の2規定塩酸溶液(4 mL)を、2,2,2-トリクロロ-1,1-エタンジオール(2.39 g, 14.48 mmol)、ヒドロキシルアミン塩酸塩(2.99 g, 43.02 mmol)及び硫酸ナトリウム(48 g, 337.1 mmol)の水溶液(80 mL)に加え、55℃で18時間撹拌した。反応混合物を室温まで冷却し、析出した固体を濾取した。得られた固体を酢酸エチルに溶解し、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィー(酢酸エチル : n-ヘキサン= 2:3)で精製し、3-[2-(ヒドロキシイミノ)アセトアミド]-2-メチル安息香酸メチル 1.25 gを得た。
2-(1H-インダゾール-6-イル)-8-メチルキナゾリン-7-カルボン酸メチルの製造
2-(1H-インダゾール-6-イル)-8-メチルキナゾリン-7-カルボン酸の製造
エチル 1-メチル-6-(8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イルカーバメートの製造
第2工程の生成物(50 mg, 0.21 mmol)及び6-アミノインダゾール(38 mg, 0.21 mmol)を用い、実施例44と同様の反応・処理をし、エチル 1-メチル-6-(8-メチルキナゾリン-2-イルアミノ)-1H-ベンゾ[d]イミダゾール-4-イルカーバメート 60 mgを得た。
N-(3-メチル-1H-インダゾール-6-イル)-7-ヒドロキシ-8-メチルキナゾリン-2-アミンの製造
7-フルオロ-8-メチルキナゾリン-2-アミンの製造
7-フルオロ-N-(4-メトキシ-1H-インダゾール-6-イル)-8-メチルキナゾリン-2-アミンの製造
N-[6-(8-メチルキナゾリン-2-イルアミノ)-1H-インダゾール-4-イル]メタンスルホンアミドの製造
8-メチル-N-(4-アミノ-1-メチル-1H-ベンゾ[d]イミダゾール-6-イル)キナゾリン-2-アミンの製造
2-(1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-カルボキサミドの製造
エチル 6-(8-メチルキナゾリン-2-イルアミノ)-1H-インドール-4-イルカーバメートの製造
7-フルオロ-8-メチル-N-(4-アミノ-1H-ベンゾ[d]イミダゾール-6-イル)キナゾリン-2-アミンの製造
第1工程の生成物(220 mg, 0.5 mmol)のジオキサン溶液(5.5 mL)に2規定水酸化ナトリウム水溶液(2.5 mL)を加え、24時間還流した。反応混合物を酢酸エチルで抽出し、水、飽和食塩水で順に洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、7-フルオロ-8-メチル-N-(4-アミノ-1H-ベンゾ[d]イミダゾール-6-イル)キナゾリン-2-アミン150 mgを得た。
2-[2-(4-アミノ-1H-ベンゾ[d]イミダゾール-6-イル)-8-メチルキナゾリン-7-イルアミノ]エタノールの製造
8-メチル-N-(4-アミノ-1H-インドール-6-イル)キナゾリン-2-アミンの製造
7-フルオロ-8-メチル-N-(4-アミノ-1-メチル-1H-ベンゾ[d]イミダゾール-6-イル)キナゾリン-2-アミンの製造
第1工程の生成物(140 mg, 0.355 mmol)のジオキサン溶液(4 mL)に2規定水酸化ナトリウム水溶液(2 mL)を加え、12時間還流した。反応混合物を減圧濃縮して得られた残渣に水(15 mL)を加え、酢酸エチルで抽出した。得られた有機層を水、飽和食塩水で順に洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、7-フルオロ-8-メチル-N-(4-アミノ-1-メチル-1H-ベンゾ[d]イミダゾール-6-イル)キナゾリン-2-アミン70 mgを得た。
2-[2-(4-メトキシ-1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イルアミノ]エタノールの製造
{1-[2-(4-メトキシ-1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イル]ピペリジン-4-イル}メタノールの製造
{1-[2-(4-ヒドロキシ-1H-インダゾール-6-イルアミノ)-8-メチルキナゾリン-7-イル]ピペリジン-4-イル}メタノールの製造
N-[4-(アミノメチル)-1H-インダゾール-6-イル]-8-メチルキナゾリン-2-アミンの製造
Claims (17)
- 下式(I)で示される2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 式(I)において、R1がハロゲン原子で置換されていてもよい低級アルキル基である請求項1に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 式(I)において、R1がメチル基である請求項1に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 式(I)において、R1がハロゲン原子である請求項1に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 式(I)において、R1がメチル基、R2が水素原子である請求項1に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 式(I)において、R1がメチル基、R2が水酸基、置換もしくは非置換のアミノ基である請求項1に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 式(I)において、XとYとが一緒になって、2環性縮合環を形成している請求項1ないし請求項6のいずれかに記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 2環性縮合環が複素環式縮合環である請求項7に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 複素環式縮合環が1H-インダゾール-6-イル基である請求項8に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 複素環式縮合環が1H-インドール-6-イル基である請求項8に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 複素環式縮合環が1H-ベンゾ[d]イミダゾール-6-イル基である請求項8に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 複素環式縮合環の水素原子が夫々独立してZで置換されていてもよい請求項9ないし請求項11のいずれかに記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- Zが夫々独立してメチル基、アミノ基、水酸基である請求項12に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 式(II)において、R1がハロゲン原子で置換されていてもよい低級アルキル基である請求項14に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- 式(II)において、R1がハロゲン原子である請求項14に記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
- X及びYが夫々独立して、水素原子、水酸基、置換もしくは非置換の低級アルコキシ基、置換もしくは非置換のアミノ基、置換もしくは非置換のアシルアミノ基を表す請求項14ないし請求項16のいずれかに記載の2-アミノキナゾリン誘導体又はその薬学的に許容される塩。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/810,386 US20100311965A1 (en) | 2007-12-28 | 2008-12-26 | 2-aminoquinazoline derivative |
EP08869161A EP2226315A4 (en) | 2007-12-28 | 2008-12-26 | 2-AMINOQUINAZOLINE DERIVATIVE |
JP2009548122A JPWO2009084695A1 (ja) | 2007-12-28 | 2008-12-26 | 2−アミノキナゾリン誘導体 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007341248 | 2007-12-28 | ||
JP2007-341248 | 2007-12-28 |
Publications (1)
Publication Number | Publication Date |
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WO2009084695A1 true WO2009084695A1 (ja) | 2009-07-09 |
Family
ID=40824408
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2008/073866 WO2009084695A1 (ja) | 2007-12-28 | 2008-12-26 | 2-アミノキナゾリン誘導体 |
Country Status (4)
Country | Link |
---|---|
US (1) | US20100311965A1 (ja) |
EP (1) | EP2226315A4 (ja) |
JP (1) | JPWO2009084695A1 (ja) |
WO (1) | WO2009084695A1 (ja) |
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US20100311965A1 (en) | 2010-12-09 |
EP2226315A4 (en) | 2012-01-25 |
EP2226315A1 (en) | 2010-09-08 |
JPWO2009084695A1 (ja) | 2011-05-19 |
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