WO2022135590A1 - 一类嘧啶并杂环类化合物、制备方法和用途 - Google Patents
一类嘧啶并杂环类化合物、制备方法和用途 Download PDFInfo
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- WO2022135590A1 WO2022135590A1 PCT/CN2021/141359 CN2021141359W WO2022135590A1 WO 2022135590 A1 WO2022135590 A1 WO 2022135590A1 CN 2021141359 W CN2021141359 W CN 2021141359W WO 2022135590 A1 WO2022135590 A1 WO 2022135590A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- membered
- compound
- heterocycloalkyl
- mmol
- Prior art date
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- 238000002360 preparation method Methods 0.000 title abstract description 10
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- -1 hydroxy, amino Chemical group 0.000 claims description 74
- 125000003118 aryl group Chemical group 0.000 claims description 65
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 58
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- 150000002431 hydrogen Chemical class 0.000 claims description 28
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- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 239000011988 third-generation catalyst Substances 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- 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
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
Description
Claims (10)
- 一种如通式(I-1)或(I-2)所示的嘧啶并杂环类化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药,式中:R 1独立地选自C 1-C 10烷基、C 1-C 10卤代烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 12环烷基、C 4-C 12环烯基、3-12元杂环烷基、5-12元的芳基或5-12元杂芳基、-OC 1-C 10烷基、-NHC 1-C 10烷基、-N(C 1-C 10烷基)(C 1-C 10烷基)、-NH(C 3-C 12环烷基)、-NH(3-12元杂环烷基)、-O(C 3-C 12环烷基)、-O(3-12元杂环烷基)、-SC 1-C 10烷基、-SOC 1-C 10烷基、-SO 2C 1-C 10烷基、碳环或含杂原子的螺环/桥环/稠环,其中,所述的C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 12环烷基、C 4-C 12环烯基、3-12元杂环烷基、5-12元的芳基或5-12元杂芳基、碳环或含杂原子的螺环/桥环/稠环,可以任选地被1-3个Rn取代;或者上述两个Rn可以通过碳链或者杂原子构成3-12元的饱和或部分不饱和,或芳香的环系;所述的Rn选自氢、氘、卤素、氰基、硝基、酰胺、磺酰胺、羟基、氨基、脲基、磷酰基、烷基磷氧基、烷基硅基、C 1-C 6烷基、C 1-C 6烷氧基、卤代烷基、卤代烷氧基、C 1-C 6单烷基氨基、C 1-C 6双烷基氨基、烯基、炔基、3-8元环烷基或杂环烷基、C 1-C 6烷基-S-、C 1-C 6烷基-SO-、C 1-C 6烷基-SO 2-等;R 2a和R 2b分别独立地选自氢、氘、卤素、C 1-C 6烷基、3-8元环烷基或杂环烷基;并且R 2a和R 2b或者R 2a与Ar上的取代基R m可以通过碳链或杂原子形成3-8元饱和或部分不饱和或不饱和环系;R 3和R 4分别独立地为H、氘、卤素、羟基、氨基、氰基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷胺基、3-8元环烷基或杂环烷基、C 2-C 4烯基、C 2-C 4炔基、5-10元芳香环或芳香杂环基;Y和Z分别独立地选自N或CR 5,R 5选自氢、氘、卤素、氰基、C 1-C 6烷基,3-8元环烷基或杂环烷基;Ar选自5-12元的单环或双环的芳基或杂芳基,上述芳基或杂芳基可以被一个或多个R m取代,R m选自下组:氢、氘、卤素、氰基、硝基、取代或未取代的酰胺、取代或未取代的磺酰胺、羟基、 氨基、脲基、磷酰基、烷基磷氧基、烷基硅基、C 1-C 10烷基、C 1-C 10烷氧基、C 1-C 10烷氧基烷基、C 1-C 10卤代烷基、C 1-C 10卤代烷氧基、C 1-C 10卤代烷氧基烷基、C 1-C 10单烷基氨基、C 1-C 10双烷基氨基、C 1-C 10单烷基氨基烷基、C 1-C 10双烷基氨基烷基、C 1-C 10烯基、C 1-C 10炔基、3-12元环烷基或杂环烷基、3-12元环烷基或杂环烷基烷基、C 1-C 10烷基-S-、C 1-C 10烷基-SO-、C 1-C 10烷基-SO 2-、取代或未取代的5-12元的芳基或杂芳基等,或者上述两个R m可以通过碳链或者杂原子构成3-12元的饱和或部分不饱和,或芳香的环系;上述的任一基团上的一个或多个氢原子可以被选自下组的取代基取代:包括但不限于氘、卤素、羟基、C 1-C 3烷基、C 1-C 3卤代烷基、3-6元环烷基或杂环烷基、氧代基(=O)、C 1-C 3烷氧基、C 1-C 10单烷基氨基烷基、C 1-C 10双烷基氨基烷基、3-6元环烷基C1-C3烷基-、3-6元杂环烷基C1-C3烷基-、氨基3-6元环烷基-、氨基3-6元杂环烷基-、C(=O)(3-6元杂环基)C 1-C 3烷基、C(=O)C 1-C 3烷基、C(=O)C 1-C 10单烷基氨基烷基、C(=O)C 1-C 10双烷基氨基烷基、C(=O)C 1-C 3烷基、C(=O)氨基C 1-C 10单烷基OH、C(=O)氨基C 1-C 10双烷基OH;其中,所述的杂芳基包含1-3个选自下组的杂原子:N、O、P或S,所述的杂环烷基包含1-3个选自下组的杂原子:N、O、P或S,所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
- 如权利要求1或2所述的化合物,其为通式(III-1)-(III-12)所示的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药:其中,Ar 1优选自5-6元的芳香或杂芳香环系,并且上述环系可以被1-5个选自下组的取代基取代:氢、氘、卤素、氰基、硝基、取代或未取代的酰胺、取代或未取代的磺酰胺、羟基、氨基、脲基、磷酰基、烷基磷氧基、烷基硅基、C 1-C 10烷基、C 1-C 10烷氧基、C 1-C 10烷氧基烷基、C 1-C 10卤代烷基、C 1-C 10卤代烷氧基、C 1-C 10卤代烷氧基烷基、C 1-C 10单烷基氨基、C 1-C 10双烷基氨基、C 1-C 10单烷基氨基烷基、C 1-C 10双烷基氨基烷基、C 1-C 10烯基、C 1-C 10炔基、3-12元环烷基或杂环烷基、3-12元环烷基或杂环烷基烷基、C 1-C 10烷基-S-、C 1-C 10烷基-SO-、C 1-C 10烷基-SO 2-、取代或未取代的5-12元的芳基或杂芳基等;R 6独立地选自1-5个选自下组的取代基:氢、氘、卤素、氰基、硝基、取代或未取代的酰胺、取代或未取代的磺酰胺、羟基、氨基、脲基、磷酰基、烷基磷氧基、烷基硅基、C 1-C 10烷基、C 1-C 10烷氧基、C 1-C 10烷氧基烷基、C 1-C 10卤代烷基、C 1-C 10卤代烷氧基、C 1-C 10卤代烷氧基烷基、C 1-C 10单烷基氨基、C 1-C 10双烷基氨基、C 1-C 10单烷基氨基烷基、C 1-C 10双烷基氨基烷基、C 1-C 10烯基、C 1-C 10炔基、3-12元环烷基或杂环烷基、3-12元环烷基或杂环烷基烷基、C 1-C 10烷基-S-、C 1-C 10烷基-SO-、C 1-C 10烷基-SO 2-、取代或未取代的5-12元的芳基或杂芳基等等;R 1、R 4、Y、Z的范围如权利要求1、2所定义。
- 如权利要求1-3中任一项所述的化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药,其特征在于,所述R 1选自如下基团:其中一个或多个R c分别独立地选自氢、氘、卤素、-C 1-C 6烷基、-OC 1-C 6烷基、氰基、羟基、氨基、-SC 1-C 6烷基、-SOC 1-C 6烷基、-SO 2C 1-C 6烷基、-COC 1-C 6烷基、-COOC 1-C 6烷基、-CONHC 1-C 6烷基、-CON(C 1-C 6烷基)(C 1-C 6烷基)、3-6元环烷基或杂环烷基、5-10元芳基或杂芳基、-C 1-C 6卤代烷基、-C 1-C 6卤代烷氧基、-C 1-C 6氘代烷基、-C 1-C 6氘代烷氧基、-O-3-6元环烷基或杂环烷基、-C 1-C 6烷基OC 1-C 6烷基、-C 1-C 6烷基NHC 1-C 6烷基、-C 1-C 6烷基OH、-C 1-C 6烷基N(C 1-C 6烷基)(C 1-C 6烷基)、-C 1-C 6烷基3-6元环烷基、-C 1-C 6烷基3-6元杂环烷基、C(=O)(3-6元杂环基)C 1-C 3烷基、C(=O)氨基C 1-C 6双烷基OH并且任意两个Rc之间可以通过碳链或者杂原子形成3~10元饱和或部分不饱和碳环或杂环;R d独立地选自-C 1-C 6烷基、-C 1-C 6烷基OC 1-C 6烷基、-C 1-C 6烷基SC 1-C 6烷基、-C 1-C 6烷基SOC 1-C 6烷基、-C 1-C 6烷基SO 2C 1-C 6烷基、-COC 1-C 6烷基、-COOC 1-C 6烷基、-CONHC 1-C 6烷基、-CON(C 1-C 6烷基)(C 1-C 6烷基)、3-6元环烷基或杂环烷基、5-10元芳基或杂芳基、-C 1-C 6卤代烷基、-C 1-C 6卤代烷氧基、-C 1-C 6氘代烷基、-C 1-C 6氘代烷氧基-C 1-C 6烷基、-C 1-C 6烷基O-3-6元环烷基或杂环烷基、-C 1-C 6烷基NHC 1-C 6烷基、-C 1-C 6烷基OH、-C 1-C 6烷基N(C 1-C 6烷基)(C 1-C 6烷基)等。
- 如权利要求1-8中任一项所述的式I化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药的用途,其特征在于,用于制备治疗与Ras蛋白活性或表达或突变相关的疾病的药物,特别是肿瘤的治疗药 物。所述的肿瘤独立地选自肺癌、胰腺癌、肝癌、结直肠癌、胆管癌、脑癌、白血病、淋巴癌、黑色素瘤、甲状腺癌、鼻咽癌等。
- 包含如权利要求1-8中任一项所述的式I化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药组成的药物组合物,其特征在于,所述的药物组合物包括:(i)有效量的式I化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药;和(ii)药学上可接受的载体。
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