WO2017035753A1 - 2-芳胺基吡啶、嘧啶或三嗪衍生物及其制备方法和用途 - Google Patents
2-芳胺基吡啶、嘧啶或三嗪衍生物及其制备方法和用途 Download PDFInfo
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- WO2017035753A1 WO2017035753A1 PCT/CN2015/088643 CN2015088643W WO2017035753A1 WO 2017035753 A1 WO2017035753 A1 WO 2017035753A1 CN 2015088643 W CN2015088643 W CN 2015088643W WO 2017035753 A1 WO2017035753 A1 WO 2017035753A1
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- 0 CN(C)C[C@](CCC1)N1c(cc(*)c(Nc1nccc(-c2c[n](C)c3cccnc23)n1)c1)c1NC(C=C)=O Chemical compound CN(C)C[C@](CCC1)N1c(cc(*)c(Nc1nccc(-c2c[n](C)c3cccnc23)n1)c1)c1NC(C=C)=O 0.000 description 4
- QAXZRSICOHKXML-UHFFFAOYSA-N CC1(C)OB(c2c3[nH]ccc3ccc2)OC1(C)C Chemical compound CC1(C)OB(c2c3[nH]ccc3ccc2)OC1(C)C QAXZRSICOHKXML-UHFFFAOYSA-N 0.000 description 1
- GJJAYFUHVKUIQG-VIFPVBQESA-N CN(C)C[C@H](CCC1)N1c(c([N+]([O-])=O)c1)cc(OC(F)F)c1Br Chemical compound CN(C)C[C@H](CCC1)N1c(c([N+]([O-])=O)c1)cc(OC(F)F)c1Br GJJAYFUHVKUIQG-VIFPVBQESA-N 0.000 description 1
- OGBHYBZQYAEYGU-UHFFFAOYSA-N C[n]1c2ncccc2c(-c2cc(N)ncc2)c1 Chemical compound C[n]1c2ncccc2c(-c2cc(N)ncc2)c1 OGBHYBZQYAEYGU-UHFFFAOYSA-N 0.000 description 1
- IWQXLTCAHXEURE-UHFFFAOYSA-N Cc([nH]1)cc2c1[s]c(C)c2 Chemical compound Cc([nH]1)cc2c1[s]c(C)c2 IWQXLTCAHXEURE-UHFFFAOYSA-N 0.000 description 1
- HMWJQUGXAJNSTN-UHFFFAOYSA-N Cc1cc([n](C)cc2-c3ccnc(Nc(cc(c(N(C)CCN(C)C)c4)NC(C=C)=O)c4OC)n3)c2[s]1 Chemical compound Cc1cc([n](C)cc2-c3ccnc(Nc(cc(c(N(C)CCN(C)C)c4)NC(C=C)=O)c4OC)n3)c2[s]1 HMWJQUGXAJNSTN-UHFFFAOYSA-N 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/42—One nitrogen atom
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- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
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- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions
- the invention belongs to the field of new medical technology, in particular to 2-arylaminopyridine, pyrimidine or triazine derivatives or pharmaceutically acceptable salts thereof, or solvates thereof, which can be used for epidermal growth of certain variant forms Treatment or prevention of a disease or condition mediated by a factor receptor (eg, L858R activating mutant, delE746_A750 mutant, Exonl9 deletion activating mutant, and T790M resistant mutant).
- a factor receptor eg, L858R activating mutant, delE746_A750 mutant, Exonl9 deletion activating mutant, and T790M resistant mutant.
- Such compounds or salts thereof, or solvates thereof are useful in the treatment or prevention of many different cancers.
- the invention also relates to a process for the preparation of intermediates useful in the preparation of said compounds.
- NSCLC non-small-cell lung cancer
- the epidermal growth factor receptor is a member of the transmembrane protein tyrosine kinase of the erbB receptor family.
- the receptor can homodimerize with additional EGFR molecules, or with another family member (eg erbB2 (HER2), erbB3 (HER3) , or erbB4 (HER4)) heterodimerization occurs.
- growth factor ligands such as epidermal growth factor (EGF)
- the receptor can homodimerize with additional EGFR molecules, or with another family member (eg erbB2 (HER2), erbB3 (HER3) , or erbB4 (HER4)) heterodimerization occurs.
- HER2 erbB2
- HER3 erbB3
- HER4 erbB4
- erbB receptor Homology dimerization and/or heterodimerization of the erbB receptor leads to phosphorylation of key tyrosine residues in the intracellular domain, which in turn leads to stimulation of many intracellular signaling pathways involved in cell proliferation and survival. .
- Abnormalities in the body's control of erbB family signaling promote proliferation, invasion, metastasis, angiogenesis, and tumor cell production, and have been described in many human cancers, including the lungs, head and neck, and chest. Therefore, the erbB receptor family is a reasonable target for the development of anticancer drugs.
- Non-Patent Documents 1 and 2 provide a detailed discussion of erbB receptor signaling and its involvement in tumorigenesis.
- Non-Patent Documents 3 and 4 report that activating mutations of the epidermal growth factor receptor in non-small cell lung cancer are associated with response to gefitinib treatment.
- the most common epidermal growth factor receptor activating mutation (L858R del E746_A750) results in small molecule tyrosine kinase inhibitors (such as gefitinib and erlotinib relative to the wild-type (WT) epidermal growth factor receptor Increased affinity and decreased affinity for ATP.
- WT wild-type
- resistance to gefitinib and erlotinib treatment was developed, for example due to mutations in the gate residue T790M, which was reported to be detected in 50% of clinically resistant patients.
- This mutation is not considered to sterically hinder the binding of gefitinib or erlotinib to EGFR, and only changes the level of ATP affinity to the level of wild-type (WT) epidermal growth factor receptor.
- EGFR eg, L858R EGFR mutant, or delE746_A750 mutant or Exonl9 deletion EGFR
- resistant mutant forms of EGFR eg, T790M EGFR mutant
- WT EGFR WT EGFR
- some irreversible ATP competitive inhibitors such as PF00299804, CI-1033, HKI-272, AZD9291, etc.
- the irreversible inhibitor contains a Michael-added receptor fragment that is capable of generating a covalent bond with the sulfhydryl group (SH) of a conserved amino acid residue (Cys797) at the binding site.
- Non-Patent Document 5 The ability of such an inhibitor to bind to an EGFR through an irreversible covalent bond is generally stronger than that between a reversible inhibitor and EGFR. Nevertheless, the clinical trial results of these irreversible inhibitors indicate that these inhibitors still have certain limitations, such as toxic effects due to off-target effects, side effects caused by low selectivity, and insufficient drug concentration in patients. Therefore, the development of new irreversible EGFR inhibitors It has great clinical significance and application prospects.
- Non-Patent Document 1 New England Journal of Medicine, 2008, vol. 358, 1160-1174
- Non-Patent Document 2 Biochemical and Biophysical Research Communications, 2004, vol. 319, 1-11
- Non-Patent Document 3 Science, 2004, vol. 304, 1497-1500
- Non-Patent Document 4 New England Journal of Medicine, 2004, vol. 350, 2129-2139
- Non-Patent Document 5 Journal of Medicinal Chemistry, 2009, vol. 52, 1231-1236
- the present inventors designed and synthesized a series of 2-arylaminopyridine, pyrimidine or triazine derivatives which have not been reported in the literature and characterized them.
- this series of compounds was tested for cell-level activity with high EGFR inhibitory activity and showed relatively low inhibitory activity against WT EGFR.
- the 2-arylaminopyridine, pyrimidine or triazine derivative EGFR inhibitor of the present invention can block the phosphorylation process of EGFR, inhibit the growth, proliferation and differentiation of tumor cells, and thus can be developed into a new antitumor drug. .
- the invention is as follows.
- X is selected from carbon, Y is selected from carbon, Z is selected from CR a , R 1 is selected from methoxy; or X is selected from nitrogen, Y is selected from carbon, Z is selected from CR b , and R 1 is selected from methoxy Or difluoromethoxy; or X is selected from nitrogen, Y is selected from nitrogen, Z is selected from CR c , R 1 is selected from methoxy or difluoromethoxy; or X is selected from nitrogen, and Y is selected from nitrogen, Z Selected from CR d , R 1 is selected from the group consisting of difluoromethoxy;
- R a is selected from the group consisting of 3-methyl-1H-carbazol-1-yl, 1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl, 1-methyl-1H-thieno[ 3,2-c]pyrazol-3-yl, 1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl, pyrazolo[1,5-a]pyrimidine-3- Or imidazo[1,2-a]pyridin-3-yl;
- R b is selected from the group consisting of benzo[d]isoxazol-3-yl, 1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl, 2,4-dimethyl-4H-thiophene And [3,2-b]pyrrole-6-yl, 2,5,6-trimethyl-6H-thieno[2,3-b]pyrrol-4-yl or 1-methyl-1H-thiophene [3,2-c]pyrazol-3-yl;
- R c is selected from 1H-benzo[d]imidazol-1-yl, 1H-indol-7-yl or 1-methyl-1H-indol-7-yl;
- R d is selected from the group consisting of 1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl;
- R 2 is selected from (2-(dimethylamino)ethyl)(methyl)amino, 4-methylpiperazin-1-yl, 3-(dimethylamino)azetidin-1-yl, 4- (Dimethylamino)piperidin-1-yl, (S)-2-((dimethylamino)methyl)pyrrolidin-1-yl or 5-methyl-2,5-diazaspiro[3.4] Oct-2-yl.
- R a is selected from the group consisting of 3-methyl-1H-carbazol-1-yl, 1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl, 1-methyl-1H-thiophene And [3,2-c]pyrazol-3-yl, 1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl, pyrazolo[1,5-a]pyrimidine- 3-yl or imidazo[1,2-a]pyridin-3-yl;
- R 2 is selected from (2-(dimethylamino)ethyl)(methyl)amino, 4-methylpiperazin-1-yl, 3-(dimethylamino)azetidin-1-yl, 4- (Dimethylamino)piperidin-1-yl, (S)-2-((dimethylamino)methyl)pyrrolidin-1-yl or 5-methyl-2,5-diazaspiro[3.4] Oct-2-yl.
- R b is selected from the group consisting of benzo[d]isoxazol-3-yl, 1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl, 2,4-dimethyl-4H -thieno[3,2-b]pyrrole-6-yl, 2,5,6-trimethyl-6H-thieno[2,3-b]pyrrol-4-yl or 1-methyl-1H- Thieno[3,2-c]pyrazol-3-yl;
- R 1 is selected from methoxy or difluoromethoxy
- R 2 is selected from (2-(dimethylamino)ethyl)(methyl)amino, 4-methylpiperazin-1-yl, 3-(dimethylamino)azetidin-1-yl, 4- (Dimethylamino)piperidin-1-yl, (S)-2-((dimethylamino)methyl)pyrrolidin-1-yl or 5-methyl-2,5-diazaspiro[3.4] Oct-2-yl.
- R c is selected from 1H-benzo[d]imidazol-1-yl, 1H-indol-7-yl or 1-methyl-1H-indol-7-yl;
- R 1 is selected from methoxy or difluoromethoxy
- R 2 is selected from (2-(dimethylamino)ethyl)(methyl)amino, 4-methylpiperazin-1-yl, 3-(dimethylamino)azetidin-1-yl, 4- (Dimethylamino)piperidin-1-yl, (S)-2-((dimethylamino)methyl)pyrrolidin-1-yl or 5-methyl-2,5-diazaspiro[3.4] Oct-2-yl.
- R d is selected from the group consisting of 1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl;
- R 2 is selected from (2-(dimethylamino)ethyl)(methyl)amino, 4-methylpiperazin-1-yl, 3-(dimethylamino)azetidin-1-yl, 4- (Dimethylamino)piperidin-1-yl, (S)-2-((dimethylamino)methyl)pyrrolidin-1-yl or 5-methyl-2,5-diazaspiro[3.4] Oct-2-yl.
- R b is selected from the group consisting of benzo[d]isoxazol-3-yl, 1-methyl-1H-pyrrole, or a pharmaceutically acceptable salt thereof, or a solvate thereof And [3,2-b]pyridin-3-yl or 1-methyl-1H-thieno[3,2-c]pyrazol-3-yl.
- R c is 1H-indol-7-yl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
- the compound according to the item 10 or a pharmaceutically acceptable salt thereof, or a solvate thereof comprising non-small cell lung cancer, breast cancer, glioma, prostate cancer, ovarian cancer, head and neck Squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, leukemia, lymphoma, gastric cancer, multiple myeloma or solid tumor.
- a pharmaceutical composition comprising the compound according to any one of items 1 to 11, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable diluent and/or carrier.
- the cancer comprises non-small cell lung cancer, breast cancer, glioma, prostate cancer, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, Kidney cancer, pancreatic cancer, colon cancer, skin cancer, leukemia, lymphoma, gastric cancer, multiple myeloma or solid tumor.
- a method of producing an anti-cancer effect in a warm-blooded animal, such as a human, in need of treatment comprising: administering to the animal an effective amount of a compound according to any one of items 1 to 11 or a pharmaceutically acceptable compound thereof Salt, or a solvate thereof.
- the compound represented by the following formula (VI) or a salt thereof is reacted with a carboxylic acid or a carboxylic acid derivative in the presence of an organic solvent.
- organic solvent comprises dichloromethane, tetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide.
- a pharmaceutically acceptable salt of a compound of the formula (I), formula (II), formula (III), formula (IV) or formula (V) may be, for example, an acid addition salt.
- an acid addition salt for example, a mineral acid or an organic acid addition salt can be used.
- An acid addition salt can be formed using an inorganic salt selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
- It may be selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.
- Organic The acid forms an acid addition salt.
- N-(5-((4-(benzo[d]isoxazol-3-yl)pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2 is provided a methanesulfonic acid salt of ((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide.
- N-(2-((2-(dimethylamino)ethyl))(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H) is provided.
- a mesylate salt of pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide is provided.
- N-(5-((4-(1H-indol-7-yl)-1,3,5-triazin-2-yl)amino)-4-(difluoromethoxy) is provided Methanesulfonate of 2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide.
- the compound of formula (I), formula (II), formula (III), formula (IV) or formula (V), or a pharmaceutically acceptable salt thereof may be solvated and unsolvated.
- Form exists.
- the solvated form can be in hydrated form. It should be understood that the present invention encompasses all such solvated and unsolvated forms.
- the compound of the formula (I), the formula (II), the formula (III), the formula (IV) or the formula (V) can be administered in the form of a prodrug which is decomposed in the human or animal body to give a formula ( I), a compound of formula (II), formula (III), formula (IV) or formula (V).
- prodrugs include in vivo hydrolysable esters of the compounds of formula (I), formula (II), formula (III), formula (IV) or formula (V).
- the in vivo hydrolysable ester can be formed by esterifying a hydroxyl group in a compound represented by formula (I), formula (II), formula (III), formula (IV) or formula (V).
- Various forms of prodrugs are known in the art. Examples of such prodrug derivatives can be found in:
- One aspect of the invention provides a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) which inhibits activation or resistance mutation of one or more EGFR,
- EGFR for example, the L858R EGFR mutant, or the delE746_A750 mutant or the Exonl9 deletion EGFR and/or the resistant mutant form of EGFR (such as the T790M EGFR mutant).
- the compounds are useful in the treatment of cancer in patients who have developed or are at risk of developing a degree of resistance to existing therapies based on EGFR inhibitors.
- a compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) which exhibits an EGFR ratio for an activated or resistant mutant form WT EGFR has a higher inhibitory activity. Due to the reduced toxicity associated with WT EGFR inhibition, this compound is expected to be more suitable for use as a therapeutic, especially for cancer therapy. This toxicology is known to manifest as a rash and/or diarrhea in the human body.
- the compound represented by the formula (VI) can be produced by deprotecting the corresponding amino-protected amine compound.
- protecting groups include protecting groups suitable for protecting nitrogen atoms and methods for formation and final deprotection, see TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley & Sons New York, 1991.
- Another aspect of the invention provides these other intermediates.
- Another aspect of the invention provides a compound of formula (VII) or a salt thereof:
- X is selected from carbon, Y is selected from carbon, Z is selected from CR a , R 1 is selected from methoxy; or X is selected from nitrogen, Y is selected from carbon, Z is selected from CR b , and R 1 is selected from methoxy Or difluoromethoxy; or X is selected from nitrogen, Y is selected from nitrogen, Z is selected from CR c , R 1 is selected from methoxy or difluoromethoxy; or X is selected from nitrogen, and Y is selected from nitrogen, Z Selected from CR d , R 1 is selected from the group consisting of difluoromethoxy;
- R a is selected from the group consisting of 3-methyl-1H-carbazol-1-yl, 1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl, 1-methyl-1H-thieno[ 3,2-c]pyrazol-3-yl, 1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl, pyrazolo[1,5-a]pyrimidine-3- Or imidazo[1,2-a]pyridin-3-yl;
- R b is selected from the group consisting of benzo[d]isoxazol-3-yl, 1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl, 2,4-dimethyl-4H-thiophene And [3,2-b]pyrrole-6-yl, 2,5,6-trimethyl-6H-thieno[2,3-b]pyrrol-4-yl or 1-methyl-1H-thiophene [3,2-c]pyrazol-3-yl;
- R c is selected from 1H-benzo[d]imidazol-1-yl, 1H-indol-7-yl or 1-methyl-1H-indol-7-yl;
- R d is selected from the group consisting of 1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl;
- R 2 is selected from (2-(dimethylamino)ethyl)(methyl)amino, 4-methylpiperazin-1-yl, 3-(dimethylamino)azetidin-1-yl, 4- (Dimethylamino)piperidin-1-yl, (S)-2-((dimethylamino)methyl)pyrrolidin-1-yl or 5-methyl-2,5-diazaspiro[3.4] Oct-2-yl.
- the intermediate compound 12a or a salt thereof, is provided.
- N 1 -(4-(benzo[d]isoxazol-3-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl) is provided.
- the intermediate compound 19a or a salt thereof, is provided.
- intermediate compound 29a or a salt thereof, is provided.
- N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methyl-N 4 -(4-(1-methyl-1H-) is provided.
- intermediate compound 37a or a salt thereof, is provided.
- intermediate compound 49a or a salt thereof, is provided.
- N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methyl-N 4 -(4-(1-methyl-1H-) is provided.
- intermediate compound 49b or a salt thereof, is provided.
- intermediate compound 78a or a salt thereof, is provided.
- N 1 -(4-(1H-indol-7-yl)-1,3,5-triazin-2-yl)-N 4 -(2-(dimethylamino) is provided.
- intermediate compound 78b or a salt thereof, is provided.
- N 1 -(4-(1H-indol-7-yl)-1,3,5-triazin-2-yl)-2-(difluoromethoxy)-N is provided.
- intermediate compound 83 or a salt thereof, is provided.
- the pharmaceutically acceptable diluent and/or carrier there is no particular limitation, and conventionally known diluents and/or carriers can be used.
- the pharmaceutical composition of the present invention may be in a form suitable for the following administration modes: for example, a tablet, a lozenge, a hard or soft capsule, an aqueous suspension or an oil suspension, an emulsion, a dispersible powder or a granule, or Syrup, etc.); topical use (eg creams, ointments, gels, aqueous or oil solutions, or suspensions); administration by inhalation (eg fine powder or liquid aerosol); administration by insufflation ( For example, subdivided) or parenteral (for example, sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular administration, or suppositories for rectal administration).
- a tablet, a lozenge, a hard or soft capsule, an aqueous suspension or an oil suspension, an emulsion, a dispersible powder or a granule, or Syrup, etc. topical use (eg creams, ointments
- compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art.
- compositions for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents, and/or preservatives.
- the optimal dose of each active ingredient in the product is orally administered to a mammal daily in an amount of from about 0.0025 to 50 mg/kg body weight. Preferably, however, about 0.01 to 10 mg is administered orally per kilogram of body weight. Depending on the subject being treated, the particular route of administration, and the severity of the condition being treated, it may be necessary to change the daily dose.
- the compounds or pharmaceutical compositions of the invention are useful in the treatment of a variety of diseases mediated by epidermal growth factor receptor kinase (EGFR).
- EGFR epidermal growth factor receptor kinase
- the disease mediated by EGFR is various cancers.
- the cancer includes, but is not limited to, non-small cell lung cancer, breast cancer, glioma, prostate cancer, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, colon cancer, Skin cancer, leukemia, lymphoma, gastric cancer, multiple myeloma or solid tumor.
- EGFR includes its wild type as well as various variants which cause disease. These variants include, but are not limited to, variants comprising the following mutations: T790M, L858R, L861Q, or L858R/T790M.
- the invention also encompasses truncated forms of EGFR that cause disease.
- the compounds of the invention, or pharmaceutical compositions thereof are useful in the treatment of a variety of diseases mediated by EGFR wild-type or various variants thereof that cause disease, including various cancers as described above, or inhibition of EGFR wild-type Or its biological activity that can cause various variants of the disease.
- the crude compound 5 (54 g, 0.15 mol) was dissolved in DMF (500 mL), and DBU (40.2 g, 0.26 mol) was added at room temperature, and the mixture was heated to 90 ° C for 3 hours.
- the reaction solution was cooled to room temperature, poured slowly into ice water, and the solid was evaporated, filtered, and the filter cake was washed twice with water and dried to give 47 g of a yellow solid.
- Compound 11b was prepared in the same manner as Compound 11a except that N,N,N'-trimethylethylenediamine was replaced by 4-methylpiperazine.
- 1 H NMR 400MHz, CDCl 3 ): ⁇ 8.23 (s, 1H), 6.52 (s, 1H), 3.98 (s, 3H), 3.20-3.10 (m, 4H), 2.69-2.59 (m, 4H) , 2.40 (s, 3H); MS (ESI) (m/z): [M+H] + 330.0.
- Compound 14b was prepared in the same manner as Compound 14a except that Compound 13a was replaced with Compound 13b.
- Compound 11c was prepared in the same manner as Compound 11a except that N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylpiperidin-4-amine.
- Compound 12c was prepared in the same manner as Compound 12a except that Compound 11a was replaced with Compound 11c.
- Compound 14c was prepared in the same manner as Compound 14a except that Compound 13a was replaced with Compound 13c.
- Compound 14d was prepared in the same manner as Compound 14a except that Compound 13a was replaced with Compound 13d.
- Compound 11e was prepared in the same manner as Compound 11a except that N,N,N'-trimethylethylenediamine was replaced by 5-methyl-2,5-diazaspiro[3.4]octane.
- Compound 14e was prepared in the same manner as Compound 14a except that Compound 13a was replaced with Compound 13e.
- Compound 18a was prepared in the same manner as Compound 11a except that Compound 10 was replaced with Compound 17.
- Compound 19a was prepared in the same manner as Compound 12a except that Compound 11a was replaced with Compound 18a.
- Compound 20a was prepared in the same manner as Compound 13a except that Compound 12a was replaced with Compound 19a.
- Compound 21a was prepared in the same manner as Compound 14a except that Compound 13a was replaced with Compound 20a.
- Compound 18b was prepared in the same manner as Compound 11a except that Compound 10 was replaced with Compound 17, and N,N,N'-trimethylethylenediamine was replaced by 4-methylpiperazine.
- Compound 19b was prepared in the same manner as Compound 12a except that Compound 11a was replaced with Compound 18b.
- Compound 21b was prepared in the same manner as Compound 14a except that Compound 13a was replaced with Compound 20b.
- Compound 18c was prepared in the same manner as Compound 11a except that Compound 10 was replaced with Compound 17, N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylazetidin-3-amine. .
- Compound 21c was prepared in the same manner as Compound 14a except that Compound 13a was replaced with Compound 20c.
- Compound 18d was prepared in the same manner as Compound 11a except that Compound 10 was replaced with Compound 17, and N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylpiperidin-4-amine.
- Compound 21d was prepared in the same manner as Compound 14a except that Compound 13a was replaced with Compound 20d.
- Compound 21e was prepared in the same manner as Compound 14a except that Compound 13a was replaced with Compound 20e.
- Compound 21f was prepared in the same manner as Compound 14a except that Compound 13a was replaced with Compound 20f.
- N,N-diisopropylethylamine (280 mg, 2.14 mmol) and N,N were added sequentially to a solution of Compound 28 (650 mg, 1.65 mmol) in N,N-dimethylacetamide (15 mL).
- N'-trimethylethylenediamine (202 mg, 1.98 mmol).
- the mixture was heated to 70 ° C for 6 hours, and after completion of the reaction, ethyl acetate and water were added. After stirring well, the mixture was filtered over Celite, and the organic layer was washed with brine, and then dried and concentrated to give a dark solid compound 29a (450 mg, 57%).
- Compound 29b was prepared in the same manner as Compound 29a except that N,N,N'-trimethylethylenediamine was replaced by 4-methylpiperazine. MS (ESI) (m / z ): [M + H] + 475.1.
- Compound 30b was prepared in the same manner as Compound 30a except that Compound 29a was replaced by Compound 29b.
- Compound 31b was prepared in the same manner as Compound 31a except that Compound 30a was replaced with Compound 30b.
- Compound 29c was prepared in the same manner as Compound 29a except that N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylazetidin-3-amine.
- Compound 31c was prepared in the same manner as Compound 31a except that Compound 30a was replaced by Compound 30c.
- Compound 29d was prepared in the same manner as Compound 29a except that N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylpiperidin-4-amine.
- Compound 30d was prepared in the same manner as Compound 30a except that Compound 29a was replaced by Compound 29d.
- Compound 31d was prepared in the same manner as Compound 31a except that Compound 30a was replaced by Compound 30d.
- Compound 31e was prepared in the same manner as Compound 31a except that Compound 30a was replaced with Compound 30e.
- Compound 29f was prepared in the same manner as Compound 29a except that N,N,N'-trimethylethylenediamine was replaced by 5-methyl-2,5-diazaspiro[3.4]octane.
- Compound 30f was prepared in the same manner as Compound 30a except that Compound 29a was replaced by Compound 29f.
- Compound 31f was prepared in the same manner as Compound 31a except that Compound 30a was replaced by Compound 30f.
- Compound 37b was prepared in the same manner as Compound 37a except that N,N,N'-trimethylethylenediamine was replaced by 4-methylpiperazine. MS (ESI) (m / z ): [M + H] + 511.2.
- Compound 38b was prepared in the same manner as Compound 38a except that Compound 37a was replaced with Compound 37b.
- Compound 39b was prepared in the same manner as Compound 39a except that Compound 38a was replaced with Compound 38b.
- Compound 37c was prepared in the same manner as Compound 37a except that N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylazetidin-3-amine.
- Compound 37d was prepared in the same manner as Compound 37a except that N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylpiperidin-4-amine.
- Compound 38d was prepared in the same manner as Compound 38a except that Compound 37a was replaced with Compound 37d.
- Compound 39d was prepared in the same manner as Compound 39a except that Compound 38a was replaced with Compound 38d.
- Compound 39e was prepared in the same manner as Compound 39a except that Compound 38a was replaced with Compound 38e.
- Compound 37f was prepared in the same manner as Compound 37a except that N,N,N'-trimethylethylenediamine was replaced by 5-methyl-2,5-diazaspiro[3.4]octane.
- Compound 38f was prepared in the same manner as Compound 38a except that Compound 37a was replaced by Compound 37f.
- 1 H NMR (400 MHz, CDCl 3 ): 8.63 - 8.59 (m, 1 H), 8.43 (d, J 5.2 Hz, 1H), 8.24 - 8.16 (m, 2H), 7.93 (s, 1H), 7.69-7.
- Compound 39f was prepared in the same manner as Compound 39a except that Compound 38a was replaced by Compound 38f.
- Compound 48b was prepared in the same manner as Compound 48a except that Compound 27 was replaced with Compound 35. MS (ESI) (m / z ): [M + H] + 437.1.
- the compound 51b was prepared in the same manner as the compound 51a except that the compound 50a was replaced with the compound 50b.
- Compound 49c was prepared in the same manner as Compound 49a except that Compound 48a was replaced by Compound 48b and N,N,N'-trimethylethylenediamine was replaced by 4-methylpiperazine.
- Compound 51c was prepared in the same manner as Compound 51a except that Compound 50a was changed to Compound 50c.
- Compound 49d was prepared in the same manner as Compound 49a except that Compound 48a was replaced by Compound 48b, N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylazetidin-3-amine. .
- Compound 50d was prepared in the same manner as Compound 50a except that Compound 49a was changed to Compound 49d.
- Compound 51d was prepared in the same manner as Compound 51a except that Compound 50a was changed to Compound 50d.
- Compound 49e was prepared in the same manner as Compound 49a except that Compound 48a was replaced by Compound 48b and N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylpiperidin-4-amine.
- Compound 51e was prepared in the same manner as Compound 51a except that Compound 50a was changed to Compound 50e.
- Compound 51f was prepared in the same manner as Compound 51a except that Compound 50a was changed to Compound 50f.
- Compound 78c was prepared in the same manner as Compound 78a except that N,N,N'-trimethylethylenediamine was replaced by 4-methylpiperazine.
- Compound 78d was prepared in the same manner as Compound 78a except that N,N,N'-trimethylethylenediamine was replaced by N,N-dimethylazetidin-3-amine.
- Compound 79b was prepared in the same manner as Compound 79a except that Compound 78a was changed to Compound 78b.
- Compound 80b was prepared in the same manner as Compound 80a except that Compound 79a was replaced by Compound 79b.
- Compound 80c was prepared in the same manner as Compound 80a except that Compound 79a was changed to Compound 79c.
- 1 H NMR (400MHz, CDCl 3 ): ⁇ 10.94 (s, 1H), 9.59 (s, 1H), 8.86-8.48 (m, 3H), 7.95-7.76 (m, 2H), 7.41-7.25 (m, 2H), 6.82 (s, 1H), 6.62 (s, 1H), 6.51-6.47 (m, 1H), 6.37-6.30 (m, 1H), 5.81 (d, J 10.3 Hz, 1H), 3.90 (s) , 3H), 3.06-3.00 (m, 4H), 2.88-2.80 (m, 4H), 2.51 (s, 3H); MS (ESI) (m/z): [M+H] + 485.2.
- Compound 80d was prepared in the same manner as Compound 80a except that Compound 79a was changed to Compound 79d.
- Compound 80e was prepared in the same manner as Compound 80a except that Compound 79a was changed to Compound 79e.
- Compound 80f was prepared in the same manner as Compound 80a except that Compound 79a was changed to Compound 79f.
- Example 38 N-(4-(Difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-methyl-) 1H-pyrrolo[2,3-b]pyridin-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (Compound 85)
- Compound 89 was prepared in the same manner as Compound 85 except that Compound 84 was replaced with Compound 88.
- 1 H NMR (400MHz, CDCl 3 ): ⁇ 10.23 (s, 1H), 9.74 (s, 2H), 9.61 (s, 1H), 8.73 (s, 1H), 8.61 (s, 1H), 7.98 (s , 1H), 7.88-7.86 (m, 1H), 7.38 (m, 2H), 6.70-6.36 (m, 2H), 5.76 (d, J 10.7 Hz, 1H), 3.93 (s, 3H), 2.93 ( s, 2H), 2.77 (s, 3H), 2.33 (s, 8H); MS (ESI) (m/z): [M+H] + 488.2.
- Compound 94d was prepared in the same manner as Compound 94a except that 3-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine was replaced by 3-bromopyrazolo[1,5-a]pyrimidine. .
- Compound 96d was prepared in the same manner as Compound 96a except that Compound 95a was replaced by Compound 95d.
- Compound 97b was prepared in the same manner as Compound 97a except that Compound 96a was replaced by Compound 96b.
- 1 H NMR 400 MHz, CD 3 OD
- ⁇ 8.58 (s, 1H), 8.18-8.11 (m, 1H), 7.61 (d, J 5.3 Hz, 1H), 7.21.
- Compound 97d was prepared in the same manner as Compound 97a except that Compound 96a was replaced by Compound 96d.
- Compound 102 was prepared in the same manner as Compound 96a except that Compound 95a was replaced by Compound 101.
- the MTT cell proliferation assay is described below.
- H1975 non-small cell lung cancer cells, EGFR L858K/T790M
- ⁇ 431 human epidermal carcinoma cells, EGFR wild type cells were purchased from the ATCC cell bank.
- the growth medium of H1975 cells was RPMI-1640 (GIBCO, A10491-065), 10% fetal bovine serum.
- the growth medium of A431 cells was DMEM (GIBCO, 11995-065), 10% fetal bovine serum.
- the effect of the compound on the proliferation activity of tumor cells was examined by CellTiter-Glo assay. Tumor cells were exposed to the treatment conditions for 72 h, and the cell density used in each cell line was adjusted according to the 72 h growth curve of the cells. Ten concentration gradients (0.5 nM - 10 ⁇ M) were set for the compounds to be tested, and three sets of parallel controls were used for each concentration value.
- the cells in the logarithmic growth phase were trypsinized to prepare a cell suspension, which was counted by a Roche counter and diluted appropriately with complete medium to a final concentration of 1 to 2 x 10 3 cells/mL.
- the cells were seeded in a 384-well plate at 22.6 ⁇ L per well, and 3 sets of parallel were set, and cultured overnight at 37 ° C in a 5% CO 2 incubator.
- the compound was dissolved in DMSO to prepare a mother liquor at a concentration of 10 ⁇ mol/L, and then the compound was serially diluted with a BRAVO instrument, and the concentrations of the compounds were gradually diluted to 10, 3.33, 1.11, 0.37, 0.123, 0.041, 0.0137, 0.00457, 0.00152, respectively. , 0.0005 ⁇ mol/L.
- 2 ⁇ L of the compound solution was added to 18 ⁇ L of the medium, and after thorough mixing, 2 ⁇ L of the compound and medium mixed solution was added to 18 ⁇ L of the medium, and the mixture was thoroughly mixed.
- 2.4 ⁇ L of the mixture was added to a 384-well plate.
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Abstract
Description
Claims (21)
- 式(I)所示的化合物或其药学上可接受的盐、或其溶剂化物:其中,X选自碳,Y选自碳,Z选自C-Ra,R1选自甲氧基;或X选自氮,Y选自碳,Z选自C-Rb,R1选自甲氧基或二氟甲氧基;或X选自氮,Y选自氮,Z选自C-Rc,R1选自甲氧基或二氟甲氧基;或X选自氮,Y选自氮,Z选自C-Rd,R1选自二氟甲氧基;Ra选自3-甲基-1H-吲唑-1-基、1-甲基-1H-吡咯并[2,3-b]吡啶-3-基、1-甲基-1H-噻吩并[3,2-c]吡唑-3-基、1-甲基-1H-吡唑并[4,3-b]吡啶-3-基、吡唑并[1,5-a]嘧啶-3-基或咪唑并[1,2-a]吡啶-3-基;Rb选自苯并[d]异恶唑-3-基、1-甲基-1H-吡咯并[3,2-b]吡啶-3-基、2,4-二甲基-4H-噻吩并[3,2-b]吡咯-6-基、2,5,6-三甲基-6H-噻吩并[2,3-b]吡咯-4-基或1-甲基-1H-噻吩并[3,2-c]吡唑-3-基;Rc选自1H-苯并[d]咪唑-1-基、1H-吲哚-7-基或1-甲基-1H-吲哚-7-基;Rd选自1-甲基-1H-吡咯并[2,3-b]吡啶-3-基;R2选自(2-(二甲氨基)乙基)(甲基)氨基、4-甲基哌嗪-1-基、3-(二甲氨基)氮杂环丁-1-基、4-(二甲氨基)哌啶-1-基、(S)-2-((二甲氨基)甲基)吡咯烷-1-基或5-甲基-2,5-二氮杂螺[3.4]辛-2-基。
- 根据权利要求1所述的化合物或其药学上可接受的盐、或其溶剂化物,其具有式(III)所示的结构,其中,Rb选自苯并[d]异恶唑-3-基、1-甲基-1H-吡咯并[3,2-b]吡啶-3-基、2,4-二甲基-4H-噻吩并[3,2-b]吡咯-6-基、2,5,6-三甲基-6H-噻吩并[2,3-b]吡咯-4-基或1-甲基-1H-噻吩并[3,2-c]吡唑-3-基;R1选自甲氧基或二氟甲氧基;R2选自(2-(二甲氨基)乙基)(甲基)氨基、4-甲基哌嗪-1-基、3-(二甲氨基)氮杂环丁-1-基、4-(二甲氨基)哌啶-1-基、(S)-2-((二甲氨基)甲基)吡咯烷-1-基或5-甲基-2,5-二氮杂螺[3.4]辛-2-基。
- 根据权利要求3所述的化合物或其药学上可接受的盐、或其溶剂化物,其特征在于,Rb选自苯并[d]异恶唑-3-基、1-甲基-1H-吡咯并[3,2-b]吡啶-3-基或1-甲基-1H-噻吩并[3,2-c]吡唑-3-基。
- 根据权利要求4所述的化合物或其药学上可接受的盐、或其溶剂化物,其特征在于,Rc为1H-吲哚-7-基。
- 根据权利要求1~7中任一项所述的化合物或其药学上可接受的盐、或其溶剂化物,其特征在于,R2为(2-(二甲氨基)乙基)(甲基)氨基。
- 根据权利要求1~5中任一项所述的化合物或其药学上可接受的盐、或其溶剂化物,其特征在于,所述式(I)所示的化合物选自以下化合物中的任意一种:N-(5-((4-(苯并[d]异恶唑-3-基)嘧啶-2-基)氨基)-4-(二氟甲氧基)-2-((2-(二甲氨基)乙基)(甲基)氨基)苯基)丙烯酰胺、N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吡咯并[3,2-b]吡啶-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺、N-(4-(二氟甲氧基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-5-((4-(1-甲基-1H-吡咯并[3,2-b]吡啶-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺、N-(4-(二氟甲氧基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-5-((4-(1-甲基-1H- 噻吩并[3,2-c]吡咯-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺、N-(5-((4-(1H-吲哚-7-基)-1,3,5-三嗪-2-基)氨基)-4-(二氟甲氧基)-2-((2-(二甲氨基)乙基)(甲基)氨基)苯基)丙烯酰胺、N-(4-(二氟甲氧基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-5-((4-(1-甲基-1H-吡咯并[2,3-b]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺、N-(5-((4-(苯并[d]异恶唑-3-基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺、N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-噻吩并[3,2-c]吡咯-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺、或N-(5-((4-(1H-吲哚-7-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺。
- 根据权利要求1~9中任一项所述的化合物或其药学上可接受的盐、或其溶剂化物,其用于治疗癌症。
- 根据权利要求10所述的化合物或其药学上可接受的盐、或其溶剂化物,所述癌症包括非小细胞肺癌、乳腺癌、神经胶质细胞瘤、前列腺癌、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肝癌、肾癌、胰腺癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌、多发性骨髓癌或实体瘤。
- 一种药物组合物,包含根据权利要求1~11中任一项所述的化合物或其药学上可接受的盐、或其溶剂化物以及药学上可接受的稀释剂和/或载体。
- 根据权利要求1~11中任一项所述的化合物或其药学上可接受的盐、或其溶剂化物作为药物的用途。
- 根据权利要求1~11中任一项所述的化合物或其药学上可接受的盐、或其溶剂化物在制备治疗癌症的药物中的用途。
- 根据权利要求14所述的用途,其特征在于,所述癌症包括非小细胞肺癌、乳腺癌、神经胶质细胞瘤、前列腺癌、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肝癌、肾癌、胰腺癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌、多发性骨髓癌或实体瘤。
- 在需要治疗的温血动物例如人中产生抗癌作用的方法,其包括:向所述动物给药有效量的根据权利要求1~11中任一项所述的化合物或其药学上可接受的盐、或其溶剂化物。
- 根据权利要求1~11中任一项所述的化合物或其药学上可接受的盐、 或其溶剂化物和附加的抗肿瘤物质的用途,用于癌症的同时,独立或序贯治疗。
- 根据权利要求18所述的方法,其特征在于,所述有机溶剂包括二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
- 根据权利要求18或19所述的方法,其特征在于,所述羧酸或羧酸衍生物包括丙烯酸、丙烯酰氯或丙烯酸酯。
- 根据权利要求18~20中任一项所述的方法,其特征在于,所述式(VI)所示的化合物选自以下化合物中的任意一种:N4-(4-(4-苯并[d]异恶唑-3-基)嘧啶-2-基)-N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲苯-1,2,4-三胺、N4-(4-(苯并[d]异恶唑-3-基)嘧啶-2-基)-5-(二氟甲氧基)-N1-(2-(二甲氨基)乙基)-N1-甲苯-1,2,4-三胺、N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲基-N4-(4-(1-甲基-1H-吡咯并[3,2-b]吡啶-3-基)嘧啶-2-基)苯-1,2,4-三胺、5-(二氟甲氧基)-N1-(2-(二甲氨基)乙基)-N1-甲基-N4-(4-(1-甲基-1H-吡咯并[3,2-b]吡啶-3-基)嘧啶-2-基)苯-1,2,4-三胺、N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲基-N4-(4-(1-甲基-1H-噻吩并[3,2-c]吡唑-3-基)嘧啶-2-基)苯-1,2,4-三胺、5-(二氟甲氧基)-N1-(2-(二甲氨基)乙基)-N1-甲基-N4-(4-(1-甲基-1H-噻吩并[3,2-c]吡唑-3-基)嘧啶-2-基)苯-1,2,4-三胺、N4-(4-(1H-吲哚-7基)-1,3,5-三嗪-2-基)-N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲苯-1,2,4-三胺、N4-(4-(1H-吲哚-7基)-1,3,5-三嗪-2-基)-5-(二氟甲氧基)-N1-(2-(二甲氨基)乙基)-N1-甲苯-1,2,4-三胺或5-(二氟甲氧基)-N1-(2-(二甲氨基)乙基)-N1-甲基-N4-(4-(1-甲基-1H-吡咯并[2,3-b]吡啶-3-基)-1,3,5-三嗪-2- 基)苯-1,2,4-三胺。
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CN108707139A (zh) * | 2017-06-13 | 2018-10-26 | 北京浦润奥生物科技有限责任公司 | 氨基嘧啶类化合物及其制备方法和应用 |
JP2021516694A (ja) * | 2018-03-23 | 2021-07-08 | ウーシー ショアンリャン バイオテクノロジー カンパニー,リミティド | 医薬組成物、その製造方法及び使用 |
JP7095108B2 (ja) | 2018-03-23 | 2022-07-04 | ウーシー ショアンリャン バイオテクノロジー カンパニー,リミティド | 医薬組成物、その製造方法及び使用 |
US11786527B2 (en) | 2018-03-23 | 2023-10-17 | Wuxi Shuangliang Biotechnology Co., Ltd. | Pharmaceutical composition and preparation method therefor and uses thereof |
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EP3345906B1 (en) | 2022-05-25 |
JP6606278B2 (ja) | 2019-11-13 |
EP3345906A4 (en) | 2020-11-04 |
CN106132957A (zh) | 2016-11-16 |
KR102051609B1 (ko) | 2019-12-03 |
TWI601718B (zh) | 2017-10-11 |
US20180208585A1 (en) | 2018-07-26 |
AU2015407300B2 (en) | 2019-06-20 |
EP3345906A1 (en) | 2018-07-11 |
KR20180028517A (ko) | 2018-03-16 |
AU2015407300A1 (en) | 2018-04-19 |
TW201711997A (en) | 2017-04-01 |
US10377747B2 (en) | 2019-08-13 |
CN106132957B (zh) | 2018-06-12 |
JP2018525431A (ja) | 2018-09-06 |
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