CN113880804A - 新型苯并咪唑化合物 - Google Patents
新型苯并咪唑化合物 Download PDFInfo
- Publication number
- CN113880804A CN113880804A CN202010629495.XA CN202010629495A CN113880804A CN 113880804 A CN113880804 A CN 113880804A CN 202010629495 A CN202010629495 A CN 202010629495A CN 113880804 A CN113880804 A CN 113880804A
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- China
- Prior art keywords
- membered
- heterocycloalkyl
- alkyl
- following
- general formula
- Prior art date
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- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract description 45
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract description 45
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000013078 crystal Substances 0.000 claims abstract description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 88
- -1 R5is-H Inorganic materials 0.000 claims description 38
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 125000006529 (C3-C6) alkyl group Chemical group 0.000 claims description 8
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- 239000004480 active ingredient Substances 0.000 claims description 5
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
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- 125000004432 carbon atom Chemical group C* 0.000 description 8
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
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- 125000000217 alkyl group Chemical group 0.000 description 6
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- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
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- 239000000460 chlorine Chemical group 0.000 description 5
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- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
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- 230000001028 anti-proliverative effect Effects 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 4
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
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- 125000001424 substituent group Chemical group 0.000 description 4
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
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Classifications
-
- 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
- C07D401/02—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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- 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
- C07D471/10—Spiro-condensed systems
Abstract
本发明涉及一类式(1)所示的化合物及其制备方法,及式(1)化合物及其各异构体、各晶型、药学上可接受的盐作为EGFR抑制剂在抗肿瘤等EGFR相关疾病的药物制备中的用途。
Description
技术领域
本发明属涉及药物化学领域,更具体而言,涉及一类苯并咪唑化合物,及其制备方法和该类化合物作为EGFR抑制剂在制备抗肿瘤药物中的用途。
背景技术
肺癌是常见的恶性肿瘤之一,每年全球新发肺癌病例数约在160万,因肺癌导致的死亡患者每年约在140万。而其中,非小细胞肺癌(non-small cell lung cancer,NSCLC)约占肺癌总数的80%-85%左右(Nature,2018,553,446–454)。EGFR蛋白家族是一类蛋白激酶,负责传导促有丝分裂信号,在生长发育中发挥了重要的作用。大量的体外肿瘤细胞,动物模型以及人类肿瘤样本的分析和研究表明EGFR家族蛋白的突变导致人类肿瘤发展,是多种癌症发生和发展的重要诱因之一。因此靶向和抑制EGFR突变蛋白的活性是治疗相关肿瘤的重要手段。研究显示EGFR基因突变在大约12到47%的非小细胞肺癌中能够被发现。在非小细胞肺癌中,两类最常见的EGFR基因突变为外显子19缺失(del19)和在外显子21中的L858R错译(L858 missense mutation)突变。这两类突变会导致EGFR蛋白不依赖配体而持续激活。虽然具有EGFR蛋白Del19或L858R突变的NSCLC患者对于EGFR蛋白激酶抑制剂(EGFRTKI)例如erlotinib、gefitinib、afatinib或osimertinib的靶向治疗更为敏感,能够在临床上获得较高的(60-85%左右)的客观缓解率(objective response rate,ORR),但是这一响应通常不会持续太久,大多数使用第一代或第二代EGFR TKIs的患者会在约11个月时发生疾病进展。耐药分析显示在大约50-70%耐药患者中,耐药分子机制是EGFR基因获得第二种突变,称为T790M突变(T790M+)(Cancer Discov.2012,2,872-5)。这一二次突变使第一代和第二代EGFR TKIs对于突变肿瘤细胞失去抑制活性。osimertinib作为第三代共价EGFRTKI,被开发用来治疗具有EGFR del19和L858R突变并伴随或不伴随T790M突变的肿瘤。虽然osimertinib针对T790M突变导致的耐药具有较高的响应率,然而,大约70%的患者最终也会发生耐药,疾病会在大约10个月后再次进展(Lung Cancer.2017,108,228-231)。对第三代EGFR TKI耐药的分子机制研究显示,在大约20-40%经历osimertinib治疗并复发的病人中,一个主要的耐药机制是EGFR基因获得第三重突变,即C797S突变。而且,在经过第三代EGFR TKI治疗后,具有EGFR del19/L858R T790M C797S突变体的患者已不能再对第一代、第二代或第三代EGFR TKIs响应。2015年Thress等人首次报道了基于15例患者对于osimertinib的耐药分析,发现其中约有40%的耐药由C797S突变而来(Nature Medicine,2015,21,560-562)。2017年ASCO,Piotrowska和周彩存各报道了23例和99例患者耐药分析,两者的分析结果都显示大约有22%左右的耐药由C797S突变引起。所以靶向抑制EGFRdel19/L858R T790M C797S突变能够克服osimertinib耐药,但目前还未有上市的EGFR TKI能够抑制EGFR del19/L858R T790M C797S突变体,所以研究和发现第四代EGFR TKI来满足这一尚未被满足的临床需求非常迫切。
EGFR del19/L858R T790M C797S突变体作为经第三代EGFR TKI治疗后新浮现的EGFR突变体,目前的研究还不是很多。目前只有少数第四代EGFR TKI被报道能够抑制EGFRdel19/L858R T790M C797S突变体。比如Boehringer Ingelheim报道了一类大环化合物BI-4020具有抗EGFR del19/L858R T790M C797S突变体活性以及体内抗肿瘤活性(J MedChem.2019,62,10272-10293)。而专利WO2019/015655中,报道了一类芳基磷氧化合物具有抗EGFR del19/L858R T790M C797S突变体活性以及体内抗肿瘤活性。其通式A及代表化合物B(专利中实施例41)结构如下(式中各符号的定义请参照该专利):
目前,研究和发现具有针对EGFR del19/L858R T790M C797S突变活性好、安全并且药代动力学性质优良的化合物存在迫切的需求。
发明内容
本发明旨在提供一类结构通式如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物:
式(1)中:
R1为(C3-C6)烷基、(C3-C6)环烷基或(4-7元)杂环烷基,其中所述(C3-C6)烷基、(C3-C6)环烷基、(4-7元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-OH、卤素、(C1-C6)烷基和(C1-C6)烷氧基;
R2为-H或者卤素;
R3为-H、卤素、-CN、-NH2、-NR3aR3b、(C1-C4)烷基、(C1-C4)卤代烷基、(C2-C4)烯基或(C2-C4)炔基;
R4为苯基、(5-6元)杂芳基或9元杂芳基,其中所述苯基、(5-6元)杂芳基或9元杂芳基各自独立任选被1个或多个下列基团取代:-H、卤素、-OH、-CN、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)卤代烷基、-O-(C1-C6)烷基、-O-(C3-C6)环烷基、-O-(C1-C6)卤代烷基、-NR4aR4b、-C(O)NHR4aR4b和-(CH2)mNR4aR4b;
当R2为-H时,R5为-(CH2)n-(3-11元)杂环烷基、-O-(CH2)m-(4-9元)杂环烷基、-O-(CH2)m-NR5aR5b、(C1-C6)烷氧基或(C1-C6)卤代烷氧基,其中所述(3-11元)杂环烷基各自独立被1个或多个下列基团取代:-R5c、-(CH2)m-NR5aR5b、-N(R4a)-(CH2)m-NR5aR5b、-O-(CH2)m-NR5aR5b和-O-(CH2)m-OR5a,和其中所述(4-9元)杂环烷基、(C1-C6)烷氧基或(C1-C6)卤代烷氧基各自独立任选被1个或多个下列基团取代:-H、-CN、-OH、(C1-C6)烷基、-(C1-C6)环烷基、-NR5aR5b和卤素;
当R2为卤素时,R5为-H、卤素、-(CH2)n-(3-11元)杂环烷基、-O-(CH2)m-(4-9元)杂环烷基、-O-(CH2)m-NR5aR5b、(C1-C6)烷氧基、(C1-C6)卤代烷氧基、-NR5aR5b、-N(R4a)-(CH2)m-NR5aR5b或(C1-C6)烷基,其中所述(3-11元)杂环烷基各自独立任选被1个或多个下列基团取代:(C1-C4)烷基、(C1-C4)烷氧基、(C3-C6)环烷基、-NR5aR5b、-(CH2)m-NR5aR5b、-(CH2)m-OR5a、-N(R4a)-(CH2)m-NR5aR5b、-O-(CH2)m-NR5aR5b和-O-(CH2)m-OR5a和-R5c,和其中所述(4-9元)杂环烷基、(C1-C6)烷氧基、(C1-C6)烷基或(C1-C6)卤代烷氧基各自独立任选被1个或多个下列基团取代:-H、-CN、-OH、(C1-C6)烷基、-(C1-C6)环烷基、-NR5aR5b和卤素;
R6为-H、卤素、-(CH2)n-(3-11元)杂环烷基、-O-(CH2)m-(4-9元)杂环烷基、-O-(CH2)m-NR5aR5b、(C1-C6)烷氧基、(C1-C6)卤代烷氧基、-NR5aR5b、-N(R4a)-(CH2)m-NR5aR5b或(C1-C6)烷基,其中所述(3-11元)杂环烷基各自独立任选被1个或多个下列基团取代:(C1-C4)烷基、(C1-C4)烷氧基、(C3-C6)环烷基、-NR5aR5b、-(CH2)m-NR5aR5b、-(CH2)m-OR5a、-N(R4a)-(CH2)m-NR5aR5b、-O-(CH2)m-NR5aR5b和-O-(CH2)m-OR5a和-R5c,和其中所述(4-9元)杂环烷基、(C1-C6)烷氧基、(C1-C6)卤代烷氧基或(C1-C6)烷基各自独立任选被1个或多个下列基团取代:-H、-CN、-OH、(C1-C6)烷基、-(C1-C6)环烷基、-NR5aR5b和卤素;
R7为-H或者卤素;
R3a和R3b各自独立地为-H或(C1-C4)烷基;
R4a和R4b各自独立地为-H或(C1-C6)烷基;
R5a和R5b各自独立地为-H、(C1-C6)烷基或(C3-C6)环烷基,或R5a和R5b与其连接的N原子能够共同组成一个(3-11元)杂环烷基,此杂环烷基各自独立任选被1个或多个下列基团取代:-H、-(C1-C6)烷基和卤素;
R5c为(3-11元)杂环烷基,此杂环烷基各自独立任选被1个或多个下列基团取代:-H、-(C1-C6)烷基、-(C1-C6)环烷基、卤素和-CD3;
m为1或2的整数;和
n为0、1或2的整数。
在另一优选例中,其中所述通式(1)中,R1为(C3-C6)烷基、(C3-C6)环烷基或(4-7元)杂环烷基,其中所述(C3-C6)烷基、(C3-C6)环烷基、(4-7元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-OH、-F、-CH3和-OCH3。
在另一优选例中,其中所述通式(1)中,R1为:
在另一优选例中,其中所述通式(1)中,R2为-H或者-F。
在另一优选例中,其中所述通式(1)中,R3为-H、-F、-CN、-NH2、-N(CH3)2、-CH3、-CH2CH3、-CF3、-CHF2或-C≡CH。
在另一优选例中,其中所述通式(1)中,R4为苯基、(5-6元)杂芳基或9元杂芳基,其中所述苯基、(5-6元)杂芳基或9元杂芳基各自独立任选被1个或多个下列基团取代:-H、-F、-Cl、-OH、-CN、-CH3、-OCH3、-N(CH3)2、和-NH2。
在另一优选例中,其中所述通式(1)中,R4为:
在另一优选例中,其中所述通式(1)中,R2为-H,和R5为(4-10元)杂环烷基、-(CH2)-(4-10元)杂环烷基、-O-(CH2)-(4-9元)杂环烷基、-O-(CH2)2-(4-9元)杂环烷基、-O-(CH2)2-N(CH3)2、-O-(CH2)2-N(CH2CH3)2或-OCH3,其中所述(4-10元)杂环烷基为: 所述此(4-10元)杂环烷基各自独立被1个或多个下列基团取代: 和其中所述(4-9元)杂环烷基为: 所述此(4-9元)杂环烷基各自独立被1个或多个下列基团取代:-H、-F、-CH3、-CN、OH、-OCH3和-N(CH3)2。
在另一优选例中,其中所述通式(1)中,R2为-H,和R5为:
在另一优选例中,其中所述通式(1)中,R2为-F,和R5为-H、-F、-Cl、(4-10元)杂环烷基、-(CH2)-(4-10元)杂环烷基、-O-(CH2)-(4-9元)杂环烷基、-O-(CH2)2-(4-9元)杂环烷基、-O-(CH2)2-N(CH3)2、-O-(CH2)2-N(CH2CH3)2、-OCH3、-N(CH2CH3)2、-NH-(CH2)2-N(CH3)2、-N(CH3)-(CH2)2-N(CH3)2或(C1-C6)烷基,其中所述(4-10元)杂环烷基为: 所述此(4-10元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-F、-CH3、-CN、-OH、-OCH3、-N(CH3)2、 和其中所述(4-9元)杂环烷基为 所述此(4-9元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-F、-CH3、-CN、-OH、-OCH3和-N(CH3)2。
在另一优选例中,其中所述通式(1)中,R2为-F,和R5为:
-H、-F、-Cl、-OCH3、-N(CH3)2、-O-(CH2)2-N(CH3)2、-O-(CH2)2-N(CH2CH3)2、-N(CH2CH3)2、-NH-(CH2)2-N(CH3)2、-N(CH3)-(CH2)2-N(CH3)2、
在另一优选例中,其中所述通式(1)中,R6为-H、-F、-Cl、(4-10元)杂环烷基、-(CH2)-(4-10元)杂环烷基、-O-(CH2)-(4-9元)杂环烷基、-O-(CH2)2-(4-9元)杂环烷基、-O-(CH2)2-N(CH3)2、-O-(CH2)2-N(CH2CH3)2、-OCH3、-N(CH2CH3)2、-NH-(CH2)2-N(CH3)2、-N(CH3)-(CH2)2-N(CH3)2或(C1-C6)烷基,其中所述(4-10元)杂环烷基为: 所述此(4-10元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-F、-CH3、-CN、OH、-OCH3、-N(CH3)2、 和其中所述(4-9元)杂环烷基为: 所述此(4-9元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-F、-CH3、-CN、-OH、-OCH3和-N(CH3)2。
在另一优选例中,其中所述通式(1)中,6为:
-H、-F、-Cl、-OCH3、-N(CH3)2、-O-(CH2)2-N(CH3)2、-O-(CH2)2-N(CH2CH3)2、-N(CH2CH3)2、-NH-(CH2)2-N(CH3)2、-N(CH3)-(CH2)2-N(CH3)2、
在另一优选例中,其中所述通式(1)中,R7为-H、-F或-Cl。
在各种不同实施方式中,本发明代表性化合物具有以下结构之一:
本发明的另一个目的是提供了一种药物组合物,它含有药理上可接受的赋形剂或载体,以及本发明通式(1)化合物、或其各异构体、药学上可接受的无机或有机盐做为活性成分。
本发明的再一个目的提供了本发明的上述化合物、或其各异构体、药学上可接受的无机或有机盐或上述药物组合物用于制备治疗EGFR突变相关疾病药物中的应用。
本发明的再一个目的提供了本发明的上述化合物、或其各异构体、药学上可接受的无机或有机盐或上述药物组合物用于制备治疗EGFR突变相关疾病中的应用。
本发明的再一个目的还提供治疗EGFR突变相关疾病的方法,包括对受试者给与治疗有效量上述化合物、或其各异构体、药学上可接受的无机或有机盐或上述药物组合物。
通过合成和仔细研究了多类涉及具有EGFR抑制作用的新化合物,发明人发现在通式(1)化合物中,当R2、R5或R6为如上文所定义基团时,化合物意外地具有很强的EGFRdel19 /T790M/C797S和EGFRL858R/T790M/C797S抑制活性,并且对于野生型EGFR WT有较高的选择性。
应理解,本发明的前述一般性描述和以下详细描述都是示例性和说明性的,旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明通式(1)化合物的制备方法,但这些具体方法不对本发明构成任何限制。
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外,在此提到的溶剂,温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成,包括发现于March,ADVANCED ORGANIC CHEMISTRY4th Ed.,(Wiley 1992);Carey和Sundberg,ADVANCED ORGANIC CHEMISTRY 4th Ed.,Vols.A和B(Plenum 2000,2001),Green和Wuts,PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rdEd.,(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面,本文所述的化合物根据工艺中公知的方法。然而方法的条件,例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易的进行。一方面,本发明还提供了一种所述的通式(1)所示化合物的制备方法,其采用下列一般反应流程1、一般反应流程2或一般反应流程3制备:
一般反应流程1
通式(1)化合物的实施方式可根据一般反应流程1制备,其中R1、R3、R4、R5、R6和R7如上文中所定义,X表示溴或氯,B表示硼酸、硼酸酯或三氟硼酸盐。如一般反应流程1所示,化合物1-1和R4-B发生偶联反应生成化合物1-2,化合物1-2通过水解反应生成中间体1-3,化合物1-4通过还原反应生成化合物1-5,化合物1-5进行关环反应生成中间体1-6,中间体1-6与中间体1-3偶联缩合得到目标化合物1-7。
一般反应流程2
通式(1)化合物的实施方式可根据一般反应流程1制备,其中R1、R3、R4、R5、R6和R7如上文中所定义,X表示溴或氯,B表示硼酸、硼酸酯或三氟硼酸盐。如一般反应流程1所示,化合物2-1和R4-B发生偶联反应生成化合物2-2,化合物2-2通过水解反应生成中间体2-3,化合物2-4通过还原反应生成化合物2-5,化合物2-5进行关环反应生成中间体2-6,中间体2-6与中间体2-3偶联缩合得到目标化合物2-7。
化合物的进一步形式
“药学上可接受”这里指一种物质,如载体或稀释液,不会使化合物的生物活性或性质消失,且相对无毒,如,给予个体某物质,不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式,该形式不会引起对给药有机体的重要的刺激,且不会使化合物的生物活性和性质消失。在某些具体方面,药学上可接受的盐是通过式(1)化合物与酸反应获得,如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式,尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂,且是在与药学上可接受溶剂如水,乙醇等,结晶化过程中选择性形成的。当溶剂是水时形成水合物,或当溶剂是乙醇时形成醇化物。式(1)化合物的溶剂化物按照本文所述的方法,很方便的制得或形成。举例说明,式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得,使用的有机溶剂包括但不限于,四氢呋喃、丙酮、乙醇或甲醇。此外,在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之,对于在此提供的化合物和方法为目的,溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中,式(1)化合物被制备成不同的形式,包括但不限于,无定形,粉碎形和毫微-粒度形式。此外,式(1)化合物包括结晶型,也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射图、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂,结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面,式(1)化合物可能存在手性中心和/或轴手性,并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体,并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(3H)、碘-125(125I)和C-14(14C)。又例如,可用重氢取代氢原子形成氘代化合物,氘与碳构成的键比普通氢和碳构成的键更坚固,相比于未氘代药物,通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包含在本发明的范围之内。
术语
如果无另外说明,用于本发明申请,包括说明书和权利要求书中的术语,定义如下。必须注意,在说明书和所附的权利要求书中,如果文中无另外清楚指示,单数形式“一个”包括复数意义。如果无另外说明,使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中,如果无另外说明,使用“或”或“和”指“和/或”。
除非另有规定,“烷基”指饱和的脂肪烃基团,包括1至14个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基,例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用,“烷基”包括未取代和取代的烷基,尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH3、CH3CH2、CF3、CHF2、CF3CH2、CF3(CH3)CH、i-Pr、n-Pr、i-Bu、n-Bu或t-Bu。
除非另有规定,“烯基”指含有碳-碳双键的不饱和脂肪烃基团,包括1至14个碳原子的直链或支链基团。优选含有1至4个碳原子的低级烯基,例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。
除非另有规定,“炔基”指含有碳-碳叁键的不饱和脂肪烃基团,包括1至14个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烯基,例如乙炔基、1-丙炔基或1-丁炔基。
除非另有规定,“环烷基”指3至14元全碳单环脂肪烃基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。例如,环丙基、环丁基、环戊基、环己烷、环己二烯等。
除非另有规定,“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基,如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用,“烷氧基”包括未取代和取代的烷氧基,尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH3、OCF3、CHF2O、CF3CH2O、i-PrO、n-PrO、i-BuO、n-BuO或t-BuO。
除非另有规定,“芳基”指碳氢芳香基团,芳基是单环或多环的,例如单环芳基环与一个或多个碳环芳香基团稠和。芳基的例子包括但不限于,苯基、萘基和菲基。
除非另有规定,“亚芳基”指二价的如上所定义的芳基。亚芳基的例子包括但不限于,亚苯基、亚萘基和亚菲基。
除非另有规定,“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团,杂芳基是单环或多环的,例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环基基团稠和。杂芳基的例子包括但不限于,吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、喹啉基、异喹啉基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基和吡咯并嘧啶基。
除非另有规定,“亚杂芳基”指二价的如上所定义的杂芳基。
除非另有规定,“杂环烷基”指含有一个或多个杂原子(O、S或N)的饱和或部分不饱和环体系基团,其中氮和硫原子任选地被氧化,氮原子任选地被季铵化,作为环原子。除非另有说明,“杂环烷基”的环体系可以是单环、双环、螺环或多环的环体系。“杂环烷基”可以通过一个以上环碳或杂原子连接于分子的其余部分。“杂环烷基”的例子包括但不限于吡咯烷、哌啶、N-甲基哌啶、四氢咪唑、吡唑烷、丁内酰胺、戊内酰胺、咪唑啉酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、嘧啶-2,4(1H,3H)-二酮、1,4-二氧六环、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环、2-氮杂螺[3.3]庚烷等。
除非另有规定,“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代,也就是说,以任意组合的方式被F、Cl、Br或I取代,优选被F或Cl取代。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
当一个连接基团的数量为0时,比如-(CH2)0-,表示该连接基团为单键。
当其中一个变量选自化学键时,表示其连接的两个基团直接相连,比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。
特定药学及医学术语
术语“可接受的”,如本文所用,指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用,包括缓和、抑制或改善疾病的症状或状况;抑制并发症的产生;改善或预防潜在代谢综合症;抑制疾病或症状的产生,如控制疾病或情况的发展;减轻疾病或症状;使疾病或症状减退;减轻由疾病或症状引起的并发症,或预防或治疗由疾病或症状引起的征兆。如本文所用,某一化合物或药物组合物,给药后,可以使某一疾病、症状或情况得到改善,尤指其严重度得到改善,延迟发病,减缓病情进展,或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药,可以归因于或与给药有关的情况。
“活性成分”指通式(1)所示化合物,以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性),并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心,取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体,并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用,且都是指当施用于个体(人类或动物)时,能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物,或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值,此处已尽可能精确地呈现具体实施例中的相关数值。然而,任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处,“约”通常是指实际数值在一特定数值或范围的正负10%、5%、1%或0.5%之内。或者是,“约”一词代表实际数值落在平均值的可接受标准误差之内,视本领域技术人员的考虑而定。除了实验例之外,或除非另有明确的说明,当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此,除非另有相反的说明,本说明书与附随权利要求书所揭示的数值参数皆为约略的数值,且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义,此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外,在不和上下文冲突的情形下,本说明书所用的单数名词涵盖该名词的复数型;而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明提供了使用本发明化合物或药物组合物治疗疾病的方法,包括但不限于涉及EGFR突变的病况(例如癌症)。
在一些事实方案中,提供了用于癌症治疗的方法,该方法包括给予有需要的个体有效量的任何前述的保护结构式(1)化合物的药物组合物。在一些实施方案中,癌症由EGFR突变介导。在其它实施方案中,该癌症是肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、乳腺癌、尿路上皮癌、前列腺癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂,其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时,可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势,使本发明的内容变得十分明了。在此应理解,下述的详细说明及实例描述了具体的实施例,仅用于参考。在阅读了本发明的说明内容后,本领域的技术人员可对本发明作各种改动或修改,这些等价形势同样落于本申请所限定的范围。
所有实施例中,1H-NMR用Varian Mercury 400核磁共振仪记录,化学位移以δ(ppm)表示;分离用硅胶未说明均为200-300目,洗脱液的配比均为体积比。
本发明采用下述缩略词:CDCl3代表氘代氯仿;EtOAc代表乙酸乙酯;Hexane代表正己烷;MeCN代表乙腈;DCM代表二氯甲烷;DIPEA代表二异丙基乙基胺;Dioxane代表1,4-二氧六环;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EDCI代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺;h代表小时;HOBt代表1-羟基苯并三氮唑;K3PO4代表磷酸钾;m-CPBA代表间氯过氧苯甲酸;MeOH代表甲醇;min代表分钟;MS代表质谱;NaH代表氢化钠;NMP代表1-甲基吡咯烷-2-酮;NMR代表核磁共振;POCl3代表三氯氧磷;SOCl2代表二氯亚砜;TEA代表三乙胺;TFA(CF3COOH)代表三氟乙酸;TLC代表薄层色谱;THF代表四氢呋喃。
合成方法A:
使用合成方法A进行具体实施例1:N-(1-(2-羟基-2-甲基丙基)-6-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-1H-苯并[d]咪唑-2-基)-4'-甲氧基-6-甲基-[2,3'-联吡啶]-4-甲酰胺:
步骤1:4'-甲氧基-6-甲基-[2,3'-联吡啶]-4-羧酸甲酯(化合物int_2)的合成:
将4-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)吡啶(2.35g,10mmol),2-氯-6-甲基异烟酸甲酯(1.85g,10mmol),Pd(dppf)Cl2(732mg,1mmol),溶于1,4-二氧六环中(50mL),加入碳酸钾(4.0M,20mmol,5mL),氩气保护下,升温80℃反应过夜,LC-MS监测反应完毕,加入乙酸乙酯(150mL),水(100mL),分液,有机相浓缩,柱层析得到棕色固体2.1g,收率81%。
ESI-MS m/z:259[M+H]+.
步骤2:4'-甲氧基-6-甲基-[2,3'-联吡啶]-4-羧酸(化合物int_3)的合成:
将4'-甲氧基-6-甲基-[2,3'-联吡啶]-4-羧酸甲酯(2.0g,7.7mmol)溶于甲醇、四氢呋喃和水的混合溶剂(1:1:1,15mL)中,加入氢氧化锂水合物(1.96g,46.5mmol),室温搅拌反应3h,LC-MS监测反应完毕,冰浴下浓盐酸调pH至约5~6,析出固体,过滤,滤饼干燥,得到浅黄色固体1.0g,收率53%。
ESI-MS m/z:245[M+H]+.
步骤3:1-((5-氟-2-硝基苯基)氨基)-2-甲基丙烷-2-醇(化合物int_5)的合成:
将1-氨基-2-甲基丙烷-2-醇(5.88g,66mmol),2,4-二氟-1-硝基苯(10g,62.8mmol)溶于DMF(300mL)中,加入DIPEA(24.33g,188.6mmol),于60℃反应3h,LC-MS监测反应完毕,直接浓缩柱层析得到黄色固体12g,收率83%。
ESI-MS m/z:229[M+H]+.
步骤4:1-甲基-1-((5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2-硝基苯基)氨基)丙烷-2-醇(化合物int_6)的合成:
将1-((5-氟-2-硝基苯基)氨基)-2-甲基丙烷-2-醇(3g,13.15mmol),1-甲基-4-(哌啶-4-基)哌嗪(2.41g,13.15mmol)溶于DMF(60mL)中,加入碳酸钾(3.63g,26.29mmol),于120℃反应6h,LC-MS监测反应完毕,过滤,有机相浓缩,柱层析得到棕色固体4g,收率78%。
ESI-MS m/z:392[M+H]+.
步骤5:1-((2-氨基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-2-甲基丙烷-2-醇(化合物int_7)的合成:
将1-甲基-1-((5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2-硝基苯基)氨基)丙烷-2-醇(4g,10.22mmol)溶于甲醇、四氢呋喃混合液(1:1,300mL)中,加入Pd/C(800mg),通入氢气,室温反应过夜,LC-MS监测反应完毕,过滤,有机相浓缩,得到棕色固体3.2g,收率86%。
ESI-MS m/z:362[M+H]+.
步骤6:1-(2-氨基-6-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2-甲基丙烷-2-醇(化合物int_8)的合成:
将1-((2-氨基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-2-甲基丙烷-2-醇(1g,2.77mmol)溶于二氯甲烷(20mL)和乙醇(20mL)的混合溶剂中,冰浴,滴加溴化氰的二氯甲烷(4mL)溶液,室温搅拌反应过夜,LC-MS监测反应完毕,有机相浓缩,直接反相柱层析,得到浅黄色固体320mg,收率30%。
ESI-MS m/z:387[M+H]+.
步骤7:N-(1-(2-羟基-2-甲基丙基)-6-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-1H-苯并[d]咪唑-2-基)-4'-甲氧基-6-甲基-[2,3'-联吡啶]-4-甲酰胺(化合物1)的合成:
将1-(2-氨基-6-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2-甲基丙烷-2-醇(100mg,0.26mmol),4'-甲氧基-6-甲基-[2,3'-联吡啶]-4-羧酸(63mg,0.26mmol),TEA(131mg,1.29mmol),HOBt(52mg,0.39mol)溶于DMF(5mL)中,加入EDCI(75mg,0.39mmol),室温反应过夜,LC-MS监测反应完毕,制备液相色谱纯化,得到浅黄色固体10mg,收率7%。
1H NMR(400MHz,CDCl3)δ:8.87(s,1H),8.51(d,J=5.8Hz,1H),8.27(s,1H),7.82(d,J=1.4Hz,1H),7.24(d,J=7.3Hz,2H),6.96–6.90(m,2H),6.83(d,J=2.1Hz,1H),5.38–5.24(m,1H),4.23(s,2H),3.96(s,3H),3.69(d,J=12.2Hz,2H),3.30-2.95(m,6H),2.78(t,J=11.9Hz,3H),2.68(d,J=12.0Hz,6H),2.03-1.95(m,2H),1.85-1.60(m,4H),1.34(s,6H);ESI-MS m/z:613[M+H]+.
合成方法B:
使用合成方法B进行具体实施例2:3-氟-N-(1-(2-羟基-2-甲基丙基)-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-1H-苯并[d]咪唑-2-基)-4'-甲氧基-6-甲基-[2,3'-联二吡啶]-4-甲酰胺的合成:
步骤1:2-溴-5-氟异烟酸甲酯(化合物int_2)的合成:
往1L单口瓶中加入2-溴-5-氟异烟酸(14g,63.64mmol)和MeOH(200mL),冷却至0-5℃,分批加入SOCl2(37.85g,318.19mmol)后,室温反应过夜。反应液浓缩得到固体,将固体溶解于水中,用饱和NaHCO3调pH值至9,水相用用乙酸乙酯(1000mL*2)萃取,合并有机相,有机相用食盐水洗,无水硫酸钠干燥,过滤,浓缩得白色固体(13.8g,收率:92.6%)。
ESI-MS m/z:233[M+H]+.
步骤2:5-氟-2-甲基异烟酸甲酯(化合物int_3)的合成:
往100mL单口瓶中加入2-溴-5-氟异烟酸甲酯(13.8g,58.97mmol),Pd(dppf)Cl2(2.16g,2.95mmol),碳酸钾(16.30g,117.94mmol),三甲基硼氧六环(14.81g,117.94mmol)和Dioxane(150mL),氮气保护下90℃反应过夜。反应液过滤,滤液浓缩得到粗品。粗品经过柱层析纯化得白色固体产物(9.90g,收率:99%)。
ESI-MS m/z:170[M+H]+.
步骤3:5-氟-4-(甲氧基羰基)-2-甲基吡啶1-氧化物(化合物int_4)的合成:
往500mL单口瓶中加入5-氟-2-甲基异烟酸甲酯(9.90g,58.53mmol),m-CPBA(20.20g,117.05mmol)和DCM(150mL),加完25℃搅拌2h,反应液减压浓缩得到粗品。粗品经柱层析纯化得到黄色固体产物(8.50g,收率:78.4%)。ESI-MS m/z:186[M+H]+.
步骤4:2-氯-3-氟-6-甲基异烟酸甲酯(化合物int_5)的合成:
往250mL单口瓶中加入5-氟-4-(甲氧基羰基)-2-甲基吡啶1-氧化物(8.50g,45.91mmol)和POCl3(126mL),80℃反应2h。将反应液减压浓缩,水相用DCM(100mL*3)萃取,合并有机相,有机相用食盐水洗,无水硫酸钠干燥,过滤,浓缩得粗品,粗品经柱层析纯化得到黄色固体产物(5.20g,收率:25.54%)。
ESI-MS m/z:204[M+H]+.
步骤5:3-氟-4'-甲氧基-6-甲基-[2,3'-联二吡啶]-4-羧酸甲酯(化合物int_6)的合成:
将4-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)吡啶(3.60g,17.68mmol),2-氯-3-氟-6-甲基异烟酸甲酯(3.00g,14.73mmol),Pd(dppf)Cl2(539.08mg,0.74mmol),溶于1,4-二氧六环中(20mL),加入碳酸钾(4.07g,29.47mmol),氩气保护下,升温80℃反应过夜,LC-MS监测反应完毕,加入乙酸乙酯(150mL),水(100mL),分液,有机相浓缩,柱层析得到棕色固体3.0g,收率73.7%。ESI-MS m/z:277[M+H]+.
步骤6:3-氟-4'-甲氧基-6-甲基-[2,3'-联二吡啶]-4-羧酸(化合物int_7)的合成:
将3-氟-4'-甲氧基-6-甲基-[2,3'-联二吡啶]-4-羧酸甲酯(3.00g,10.86mmol)溶于甲醇、四氢呋喃和水的混合溶剂(1:1:1,15mL)中,加入氢氧化锂水合物(2.73g,65.16mmol),室温搅拌反应2h,LC-MS监测反应完毕,加入水(30mL),水相用DCM(200mL*3)萃取,弃去有机相,水相在冰浴下用浓盐酸调pH至约5~6,水相用DCM(200mL*3)萃取,合并有机相,有机相用食盐水洗,无水硫酸钠干燥,过滤,浓缩得粗品,粗品经在乙醇中重结晶得到灰色固体产物(630mg,收率:17.4%)。
1H NMR(400MHz,DMSO)δ:8.58(d,J=5.8Hz,1H),8.39(s,1H),7.67(d,J=5.0Hz,1H),7.24(d,J=6.0Hz,1H);ESI-MS m/z:263[M+H]+.
步骤7:1-((4-氟-2-硝基苯基)氨基)-2-甲基丙基-2-醇(化合物int_9)的合成:
将1-氨基-2-甲基丙烷-2-醇(5.88g,66mmol),1,4-二氟-2-硝基苯(10g,62.8mmol)溶于DMF(300mL)中,加入DIPEA(24.33g,188.6mmol),于60℃反应3h,LC-MS监测反应完毕,直接浓缩柱层析得到黄色固体10g,收率70%。
ESI-MS m/z:229[M+H]+.
步骤8:2-甲基l-1-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2-硝基苯基)氨基)丙基-2-醇(化合物int_10)的合成:
将1-((4-氟-2-硝基苯基)氨基)-2-甲基丙基-2-醇(3g,13.15mmol),1-甲基-4-(哌啶-4-基)哌嗪(2.41g,13.15mmol)溶于DMF(60mL)中,加入碳酸钾(3.63g,26.29mmol),于120℃反应6h,LC-MS监测反应完毕,过滤,有机相浓缩,柱层析得到棕色固体4.1g,收率80.3%。
ESI-MS m/z:392[M+H]+.
步骤9:1-((2-氨基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-2-甲基丙基-2-醇(化合物int_11)的合成:
将2-甲基l-1-((4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2-硝基苯基)氨基)丙基-2-醇(4g,10.22mmol)溶于甲醇、四氢呋喃混合液(1:1,300mL)中,加入Pd/C(800mg),通入氢气,室温反应过夜,LC-MS监测反应完毕,过滤,有机相浓缩,得到棕色固体3.0g,收率81.3%。
ESI-MS m/z:362[M+H]+.
步骤10:1-(2-氨基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2-甲基丙基-2-醇(化合物int_12)的合成:
将1-((2-氨基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-2-甲基丙基-2-醇(1g,2.77mmol)溶于二氯甲烷(20mL)和乙醇(20mL)的混合溶剂中,冰浴,滴加溴化氰的二氯甲烷(4mL)溶液,室温搅拌反应过夜,LC-MS监测反应完毕,有机相浓缩,直接反相柱层析,得到浅黄色固体300mg,收率28%。
ESI-MS m/z:387[M+H]+.
步骤11:3-氟-N-(1-(2-羟基-2-甲基丙基)-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-1H-苯并[d]咪唑-2-基)-4'-甲氧基-6-甲基-[2,3'-联二吡啶]-4-甲酰胺(化合物2)的合成:
将1-(2-氨基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-1H-苯并[d]咪唑-1-基)-2-甲基丙基-2-醇(100mg,0.26mmol),3-氟-4'-甲氧基-6-甲基-[2,3'-联二吡啶]-4-羧酸(68mg,0.26mmol),TEA(131mg,1.29mmol),HOBt(52mg,0.39mol)溶于DMF(5mL)中,加入EDCI(75mg,0.39mmol),室温反应过夜,LC-MS监测反应完毕,制备液相色谱纯化,得到浅黄色固体15mg,收率9.2%。
ESI-MS m/z:631[M+H]+.
实施例1化合物3-332的合成
使用合成方法A或合成方法B,采用不同原料,可以得到表1中目标化合物3-332。
表1
实施例2本发明化合物对EGFR(del19/T790M/C797S)、EGFR(L858R/T790M/C797S)或EGFR(WT)酶的抑制活性的检测
运用HTRF方法测定化合物对EGFR(del19/T790M/C797S)、EGFR(L858R/T790M/C797S)或EGFR(WT)酶活的抑制作用。具体如下。
将WT或者突变型EGFR蛋白与梯度稀释的化合物在28℃孵育10分钟后加入biotin-标记的通用酪氨酸激酶底物(TK)和ATP,在室温反应40分钟。终止反应后加入针对TK的Eu3+-Cryptate标记抗体和streptavidin-XL665,在室温孵育60分钟。通过检测615nm和665nm的发光,计算665/615的比值,定量TK底物磷酸化的水平。与对照组相比,计算化合物抑制百分比和IC50。结果见下列表2。
表2.本发明化合物对EGFR(del19/T790M/C797S)、EGFR(L858R/T790M/C797S)或EGFR(WT)的抑制活性
+表示抑制率小于或等于20%
++表示抑制率为20%至50%
+++表示抑制率大于50%。
从表2数据可知,本发明化合物对EGFR(del19/T790M/C797S)和EGFR(L858R/T790M/C797S)的酶活性有较好的抑制活性,且对EGFR(WT)有较好的选择性。
实施例3本发明化合物对Ba/F3(EGFRdel19/T790M/C797S)三突变细胞和A431(EGFR WT)细胞的抗增殖活性
3000个携带EGFR(del19/T790M/C797S)的Ba/F3细胞,或者2000个A431细胞种植于384孔板中,生长一天后,加入梯度稀释的化合物(Ba/F3细胞最高500nM,A431细胞最高10uM)。加入化合物三天后,加入Cell Titer Glow评价细胞生长,计算化合物抑制细胞生长的百分率和IC50值,结果见下列表3。
表3.本发明化合物对Ba/F3(EGFRdel19/T790M/C797S)三突变细胞和A431野生型(EGFRWT)细胞的抗增殖活性
从表3数据可知,本发明绝大多数化合物对Ba/F3(EGFRdel19/T790M/C797S)三突变细胞的抗增殖活性都小于200nM,可见当R2、R5或R6为如上文所定义基团时,化合物都具有很强的Ba/F3(EGFRdel19/T790M/C797S)三突变细胞的抗增殖活性。
Claims (16)
1.一种结构如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物:
式(1)中:
R1为(C3-C6)烷基、(C3-C6)环烷基或(4-7元)杂环烷基,其中所述(C3-C6)烷基、(C3-C6)环烷基、(4-7元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-OH、卤素、(C1-C6)烷基和(C1-C6)烷氧基;
R2为-H或者卤素;
R3为-H、卤素、-CN、-NH2、-NR3aR3b、(C1-C4)烷基、(C1-C4)卤代烷基、(C2-C4)烯基或(C2-C4)炔基;
R4为苯基、(5-6元)杂芳基或9元杂芳基,其中所述苯基、(5-6元)杂芳基或9元杂芳基各自独立任选被1个或多个下列基团取代:-H、卤素、-OH、-CN、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)卤代烷基、-O-(C1-C6)烷基、-O-(C3-C6)环烷基、-O-(C1-C6)卤代烷基、-NR4aR4b、-C(O)NHR4aR4b和-(CH2)mNR4aR4b;
当R2为-H时,R5为-(CH2)n-(3-11元)杂环烷基、-O-(CH2)m-(4-9元)杂环烷基、-O-(CH2)m-NR5aR5b、(C1-C6)烷氧基或(C1-C6)卤代烷氧基,其中所述(3-11元)杂环烷基各自独立被1个或多个下列基团取代:-R5c、-(CH2)m-NR5aR5b、-N(R4a)-(CH2)m-NR5aR5b、-O-(CH2)m-NR5aR5b和-O-(CH2)m-OR5a,和其中所述(4-9元)杂环烷基、(C1-C6)烷氧基或(C1-C6)卤代烷氧基各自独立任选被1个或多个下列基团取代:-H、-CN、-OH、(C1-C6)烷基、-(C1-C6)环烷基、-NR5aR5b和卤素;
当R2为卤素时,R5为-H、卤素、-(CH2)n-(3-11元)杂环烷基、-O-(CH2)m-(4-9元)杂环烷基、-O-(CH2)m-NR5aR5b、(C1-C6)烷氧基、(C1-C6)卤代烷氧基、-NR5aR5b、-N(R4a)-(CH2)m-NR5aR5b或(C1-C6)烷基,其中所述(3-11元)杂环烷基各自独立任选被1个或多个下列基团取代:(C1-C4)烷基、(C1-C4)烷氧基、(C3-C6)环烷基、-NR5aR5b、-(CH2)m-NR5aR5b、-(CH2)m-OR5a、-N(R4a)-(CH2)m-NR5aR5b、-O-(CH2)m-NR5aR5b和-O-(CH2)m-OR5a和-R5c,和其中所述(4-9元)杂环烷基、(C1-C6)烷氧基、(C1-C6)烷基或(C1-C6)卤代烷氧基各自独立任选被1个或多个下列基团取代:-H、-CN、-OH、(C1-C6)烷基、-(C1-C6)环烷基、-NR5aR5b和卤素;
R6为-H、卤素、-(CH2)n-(3-11元)杂环烷基、-O-(CH2)m-(4-9元)杂环烷基、-O-(CH2)m-NR5aR5b、(C1-C6)烷氧基、(C1-C6)卤代烷氧基、-NR5aR5b、-N(R4a)-(CH2)m-NR5aR5b或(C1-C6)烷基,其中所述(3-11元)杂环烷基各自独立任选被1个或多个下列基团取代:(C1-C4)烷基、(C1-C4)烷氧基、(C3-C6)环烷基、-NR5aR5b、-(CH2)m-NR5aR5b、-(CH2)m-OR5a、-N(R4a)-(CH2)m-NR5aR5b、-O-(CH2)m-NR5aR5b和-O-(CH2)m-OR5a和-R5c,和其中所述(4-9元)杂环烷基、(C1-C6)烷氧基、(C1-C6)卤代烷氧基或(C1-C6)烷基各自独立任选被1个或多个下列基团取代:-H、-CN、-OH、(C1-C6)烷基、-(C1-C6)环烷基、-NR5aR5b和卤素;
R7为-H或者卤素;
R3a和R3b各自独立地为-H或(C1-C4)烷基;
R4a和R4b各自独立地为-H或(C1-C6)烷基;
R5a和R5b各自独立地为-H、(C1-C6)烷基或(C3-C6)环烷基,或R5a和R5b与其连接的N原子能够共同组成一个(3-11元)杂环烷基,此杂环烷基各自独立任选被1个或多个下列基团取代:-H、-(C1-C6)烷基和卤素;
R5c为(3-11元)杂环烷基,此杂环烷基各自独立任选被1个或多个下列基团取代:-H、-(C1-C6)烷基、-(C1-C6)环烷基、卤素和-CD3;
m为1或2的整数;和
n为0、1或2的整数。
2.如权利要求1所述的化合物,其中所述通式(1)中,R1为(C3-C6)烷基、(C3-C6)环烷基或(4-7元)杂环烷基,其中所述(C3-C6)烷基、(C3-C6)环烷基、(4-7元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-OH、-F、-CH3和-OCH3。
4.如权利要求1-3所述的化合物,其中所述通式(1)中,R2为-H或者-F。
5.如权利要求1-4所述的化合物,其中所述通式(1)中,R3为-H、-F、-CN、-NH2、-N(CH3)2、-CH3、-CH2CH3、-CF3、-CHF2或-C≡CH。
6.如权利要求1-5所述的化合物,其中所述通式(1)中,R4为苯基、(5-6元)杂芳基或9元杂芳基,其中所述苯基、(5-6元)杂芳基或9元杂芳基各自独立任选被1个或多个下列基团取代:-H、-F、-Cl、-OH、-CN、-CH3、-OCH3、-N(CH3)2、和-NH2。
10.如权利要求1-7所述的化合物,其中所述通式(1)中,R2为-F,和R5为-H、-F、-Cl、(4-10元)杂环烷基、-(CH2)-(4-10元)杂环烷基、-O-(CH2)-(4-9元)杂环烷基、-O-(CH2)2-(4-9元)杂环烷基、-O-(CH2)2-N(CH3)2、-O-(CH2)2-N(CH2CH3)2、-OCH3、-N(CH2CH3)2、-NH-(CH2)2-N(CH3)2、-N(CH3)-(CH2)2-N(CH3)2或(C1-C6)烷基,其中所述(4-10元)杂环烷基为: 所述此(4-10元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-F、-CH3、-CN、-OH、-OCH3、-N(CH3)2、 和其中所述(4-9元)杂环烷基为: 所述此(4-9元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-F、-CH3、-CN、-OH、-OCH3和-N(CH3)2。
12.如权利要求1-11所述的化合物,其中所述通式(1)中,R6为-H、-F、-Cl、(4-10元)杂环烷基、-(CH2)-(4-10元)杂环烷基、-O-(CH2)-(4-9元)杂环烷基、-O-(CH2)2-(4-9元)杂环烷基、-O-(CH2)2-N(CH3)2、-O-(CH2)2-N(CH2CH3)2、-OCH3、-N(CH2CH3)2、-NH-(CH2)2-N(CH3)2、-N(CH3)-(CH2)2-N(CH3)2或(C1-C6)烷基,其中所述(4-10元)杂环烷基为: 所述此(4-10元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-F、-CH3、-CN、-OH、-OCH3、-N(CH3)2、 和其中所述(4-9元)杂环烷基为: 所述此(4-9元)杂环烷基各自独立任选被1个或多个下列基团取代:-H、-F、-CH3、-CN、-OH、-OCH3和-N(CH3)2。
14.如权利要求1-13所述的化合物,其中所述通式(1)中,R7为-H、-F或-Cl。
16.一种用于治疗、调节和/或预防与EGFR突变蛋白相关的疾病的药物组合物,其特征在于,它含有药学上可接受的赋形剂或载体,以及作为活性成分的权利要求1-15任一项所述的化合物、或其各异构体、药学上可接受的盐、水合物或溶剂合物。
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