CN115190762A - 新的取代的磺酰脲和磺酰亚胺脲衍生物 - Google Patents
新的取代的磺酰脲和磺酰亚胺脲衍生物 Download PDFInfo
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- CN115190762A CN115190762A CN202180017484.9A CN202180017484A CN115190762A CN 115190762 A CN115190762 A CN 115190762A CN 202180017484 A CN202180017484 A CN 202180017484A CN 115190762 A CN115190762 A CN 115190762A
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- carbamoyl
- indacen
- hexahydro
- ene
- prop
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
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- 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
- A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—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 sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/52—Y being a hetero atom
- C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
- C07C311/55—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
- C07C381/10—Compounds containing sulfur atoms doubly-bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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Abstract
本发明涉及新的通式(I)的化合物,其药物可接受的盐、药物可接受的溶剂化物、对映异构体、非对映异构体和多晶型物。本发明还涉及用于制备本发明化合物的方法,包含所述化合物的药物组合物以及本发明化合物属于NOD样受体家族(NLR)蛋白NLRP3调节剂的家族所带来的用途。因此,本发明涉及新的NLRP3调节剂以及新的抑制剂化合物在治疗涉及白介素1β活性的疾病或病症中的用途。
Description
发明领域
本发明涉及新的通式(I)的化合物,其药物可接受的盐、药物可接受的溶剂化物、对映异构体、非对映异构体和多晶型物。本发明还涉及用于制备本发明化合物的方法,包含所述化合物的药物组合物以及本发明化合物属于NOD样受体家族(NLR)蛋白NLRP3调节剂的家族所带来的用途。因此,本发明涉及新的NLRP3调节剂以及新的抑制剂化合物在治疗涉及白介素1β活性的疾病或病况中的用途。
背景技术
NOD样受体家族(NLR)蛋白NLRP3是感知多种病原体、环境来源和宿主来源因子的胞内信号传导分子。(Wen等人,Immunity.2013;39:432–441)。NLRP3的激活导致与含有CARD的细胞凋亡相关的斑点样蛋白(ASC)结合。ASC转而与半胱氨酸蛋白酶胱天蛋白酶-1(caspase-1)相互作用,形成称为炎性小体(inflammasome)的复合物。这导致胱天蛋白酶-1的激活,这将促炎性细胞因子IL-1β和IL-18裂解成其激活形式,并介导称为细胞焦亡(pyroptosis)的炎性细胞死亡类型。其它胞内模式识别受体(PRR)也能够形成炎性小体。这些包括其它NLR家族成员,例如NLRP1和NLRC4,以及非NLR PRR,例如双链DNA(dsDNA)传感器黑色素瘤缺乏因子2(AIM2)和干扰素,伽马诱导蛋白16(interferon inducible protein16,IFI16)(Latz等人,Nat Rev Immunol.2013;13:397-411)。NLRP3依赖性IL-1β加工也可通过胱天蛋白酶-1下游的间接、非规范的途径激活(Lamkanfi等人,Cell.2014;157:1013-1022)。
炎性小体成分例如NLRP3、ASC和胱天蛋白酶-1在肝的免疫细胞,包括库普弗细胞(Kupffer cell)、浸润性巨噬细胞、肝细胞和肝星状细胞中表达。炎性小体的激活依赖于两个连续的信号。信号1由TLR和IL-1R信号传导驱动,包括包含NLRP3、ASC、促胱天蛋白酶-1、促IL-1β和促IL-18的成分蛋白的表达。信号2由危险信号(DAMPS)提供,在NASH发生过程中,危险信号主要由应激的或濒死的肝细胞释放或经由“渗漏的”肠道(PAMP)释放。这个过程导致炎性小体成分的寡聚化和促胱天蛋白酶-1的裂解,导致激活的促炎性细胞因子的释放。
NLRP3炎性小体通过激活胱天蛋白酶-1导致促炎性细胞因子白介素-1β(IL-1β)和白介素-18(IL-18)的加工和释放,充当炎性反应的关键介质。NLRP3炎性小体是炎性过程的组成部分,并且其异常激活在遗传性疾患(例如罕见周期性发热综合征、冷吡啉相关周期性综合征(CAPS)、肿瘤坏死因子受体相关周期性综合征(TRAPS))和复杂疾病(例如多发性硬化,2型糖尿病,动脉粥样硬化,哮喘,痛风性关节炎和包括阿尔茨海默病和其它脑疾病的炎性中枢神经***(CNS)疾病)中是致病性的。(Masters等人,Annu Rev Immunol.2009;27:621–668;Strowig等人,Nature 2012,481,278-286;Guo等人,Nat.Med.2015,21,677;Ising等人,Nature 2019,575,669–673)
炎症是对感染和损伤的基本的宿主反应。对促炎性细胞因子白介素-1β(IL-1β)的调节是宿主对感染反应的核心,当其被不当激活时也引起组织损伤。(Dinarello等人,Nat.Rev.Drug Discovery 2012,11,633-652.)NLRP3炎性小体激活在包括促炎性信号传导的诱导、肝细胞损伤和细胞死亡以及负责胶原沉积和肝纤维化的肝星状细胞(HSC)的活化的每个组成部分中都发挥着关键作用。特别地,从NAFLD到NASH的转换与NLRP3-炎性小体激活和包括含有羧基端CARD的细胞凋亡相关斑点样蛋白(ASC)、胱天蛋白酶-1(CASP-1)和泛连接蛋白的炎性小体相关成分的表达增加相关。(Mridha等人,Journal of Hepatology,2017,66(5),1037-1046)
目前对于NLRP3相关疾病的治疗包括靶向IL-1的生物剂。这些是重组IL-1受体拮抗剂阿那白滞素(Anakinra)、中和IL-1β抗体康纳单抗(Canakinumab)和可溶性诱饵IL-1受体利纳西普(Rilonacept)。
使用NLRP3炎性小体抑制剂抑制IL-1β和IL-18将是细胞因子风暴期间的有效治疗,并且可能是用于疾病如严重急性呼吸综合征(SARS)、中东呼吸综合征(MERS)、西班牙流感、COVID19(冠状病毒病2019)、丙型肝炎病毒、基肯尼亚病毒、甲型流感病毒、1型单纯疱疹病毒和日本脑炎病毒的合理的治疗选择,其中高水平的白介素(IL)-1β和/或IL-18与炎症和发病机制有关(Lancet 2020,395,(10223),497-506;The FASEB Journal 2020,33,8865-6677)。
Wipo专利申请第WO98/32733、WO2001/019390、WO2014/190015、WO2016/123229、WO2016/131098号公开了作为NLRP3炎性小体抑制剂的磺酰脲衍生物和相关化合物。WO2017/017469公开了某些作为NLRP3炎性小体抑制剂的环状二芳基硼衍生物用于治疗其中涉及白介素1β活性的疾病或病况。最近的一些专利申请,例如WO2017/031161、WO2017/079352、WO2017/129897、WO2017/184623、WO2018/225018、WO2019/043610、WO2019/023147、WO2019/068772、WO2020/035466、WO2020/208249、WO2020/035465、WO2020/254697,也公开了某些类别的作为NLRP3抑制剂的化合物。
我们在本文公开了新的通式(I)的化合物,所述化合物是NLRP3调节剂,用于预防和治疗由NLRP3介导的疾病状态或其中涉及白介素1β活性的病况,包括炎症、痛风性关节炎、2型糖尿病、动脉粥样硬化和肝纤维化。更特别地,本发明的实施方案可用作治疗多种病理性病况的治疗剂,所述病理性病况包括(但不限于)淋巴瘤、自身免疫疾病、异种免疫疾病、炎性疾病、癌症和神经退行性疾病或病况。
发明内容
本发明公开了新的如通式(I)定义的化合物,所述化合物是NLRP3调节剂,用于预防和治疗由NLRP3介导的疾病状态以及治疗其中涉及白介素1β活性的疾病或病况。本发明化合物通过抑制NLRP3可用于治疗人或动物体。因此,本发明化合物适合用于预防和治疗由NLRP3介导的疾病状态。
本发明的实施方案
本发明的实施方案提供了新的由通式(I)表示的化合物、其互变异构形式、其对映异构体、其非对映异构体、其立体异构体、其药物可接受的盐和含有它们或它们的混合物的药物组合物。
在本发明的另一实施方案中,提供了药物组合物,所述药物组合物包含通式(I)的化合物、其互变异构形式、其对映异构体、其非对映异构体、其立体异构体、其药物可接受的盐或其混合物与适合的载体、溶剂、稀释剂和通常用于制备此类组合物的其它溶媒的组合。
在另一实施方案中,提供了本发明化合物作为NLRP3调节剂的用途,其通过向哺乳动物施用治疗有效且无毒的量的通式(I)的化合物或其药物可接受的组合物。
在又一实施方案中,本发明的式(I)的化合物可以与一种或多种适合的药物活性剂组合使用。
在另一实施方案中,提供了用于制备新的本发明化合物的方法。
具体实施方式
因此,本发明涉及通式(I)的化合物
其互变异构形式、其立体异构体、其对映异构体、其药物可接受的盐和含有它们的药物组合物,其中
R1和R2中的每一个在每次出现时独立地表示氢、卤素、卤代烷基、氰基、任选取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C3-C7)环烷基、(C1-C6)烷基SO2(C1-C6)烷基、(C1-C6)烷基N(C1-C6)烷基、(C1-C6)烷基N(C3-C7)环烷基、芳基、杂芳基、杂环基、苄基、叔丁氧基羰基、硫醇、巯基烷基、SO2(C1-C6)烷基、SO2(C3-C7)环烷基、SO2-芳基、SO2-杂环基、(C1-C6)硫代烷基、(C1-C6)硫代烷氧基、(C1-C6)烷基SO2NH2、-CONH2、-CO(C1-C6)烷基、-CO(C1-C6)卤代烷基、CO(O)(C1-C6)烷基、-CO-芳基、-CO-杂芳基、-CO-杂环基、4至7元杂环、7至14元双环杂环体系、任选地具有一个或多个杂原子的桥环或螺环体系;或者R1、R2和N一起可以形成饱和或部分饱和的3至8元杂环体系、7至14元双环杂环体系、任选地具有一个或多个杂原子的桥环或螺环体系;
R3和R4中的每一个在每次出现时表示氢、卤素、卤代烷基、氰基、硝基、酰胺、磺酰胺、酰基、羟基、任选取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C6)环烷基、(C1-C6)烷氧基、SO2(C1-C6)烷基、硫醇、巯基烷基苄基、芳基、杂芳基、杂环基;或者R3和R4可以形成键;
X是O、N-R6;R6在每次出现时独立地表示氢、羟基、卤素、硝基、氰基、卤代烷基、任选取代的选自以下的基团:(C1-C10)烷基、(C1-C10)烷氧基、(C3-C10)环烷基、(C2-C10)烯基、(C2-C10)炔基、SO2(C1-C6)烷基、硫醇、硫代烷基、硫代烷氧基、SO2(C1-C6)烷基、SO(C1-C6)烷基、苄基、芳基、杂芳基、杂环基;
n独立地选自整数0至3;
R5在每次出现时独立地表示氢、卤素、卤代烷基、氰基、任选取代的选自以下的基团:(C1-C6)烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C3-C7)环烷基、苄基、芳基、杂芳基、杂环基、硫醇、硫代烷基、硫代烷氧基、SO2(C1-C6)烷基、SO(C1-C6)烷基、任选地具有一个或多个杂原子的桥环或螺环体系;
“A”选自以下环系
其中X、Y、Z在每次出现时独立地表示C、N、S、SO2和O,其可以被任选地取代;
R7、R8、R9、R10、R11和R12在每次出现时独立地选自氢、卤素、氰基、酰胺、磺酰胺、酰基、羟基、任选取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C6)环烷基、(C1-C6)烷氧基、苄基、芳基、杂芳基、杂环基;或者R8和R9、R9和R10、R10和R11以及R11和R12中的每一个在可能的情况下可以一起形成含有0至2个选自N、O和S(O)p的另外的杂原子的4至7元饱和或部分饱和的环;p=1至2。
当任何上述定义的基团被取代时,对其的取代可选自上述的那些或可选自氢、羟基、氰基、卤代、卤代烷基、卤代烷氧基、烷基硫代、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C10)环烷基、C1-(C1-C6)烷氧基、芳基、杂环基、杂芳基、-COR11、-CSR11、C(O)OR11、C(O)-R11、-C(O)-NR11R12、-C(S)-NR11R12、-SO2R11基团,其中R11和R12中的每一个独立地选自氢、任选取代的选自以下的基团:(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C7)环烷基、芳基、杂芳基、杂环基基团;
在优选实施方案中,R3和R4中的每一个在每次出现时独立地选自氢、卤素、任选取代的选自以下的基团:(C1-C6)烷基;
在优选实施方案中,R5每次出现时独立地表示氢、卤素、任选取代的选自以下的基团:(C1-C6)烷基;
在优选实施方案中,R6每次出现时独立地表示氢、氰基;
在优选实施方案中,R7、R8、R9、R10、R11和R12中的每一个在每次出现时独立地选自氢、卤素、羟基、任选取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基;
在优选实施方案中,以上描述的基团、基可以选自:
“烷基”以及具有前缀“烷”的其它基团,例如烷氧基和烷酰基,意指如本领域技术人员所熟知的,其可进一步被氧原子取代的碳链,其可进一步是直链或支链的、及其组合,除非碳链另有定义。烷基基团的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、己基等,在指定的碳原子数允许的情况下,例如C3-10,术语烷基还包括环烷基,以及与环烷基结构组合的直链或支链烷基链的组合。当没有指定碳原子数时,意指C1-6。取代的烷基包括被一个或多个选自以下的部分取代的烷基:卤代(例如,Cl、F、Br和I);卤代烷基(例如,CF3、2-Br-乙基、CH2F、CH2Cl、CH2CF3或CF2CF3);羟基;氨基;羧酸酯;羧酰胺基;烷基氨基;芳基氨基;烷氧基;芳氧基;硝基;叠氮基;氰基;硫代;磺酸;硫酸酯;膦酸;磷酸酯和膦酸酯以及在“任选取代的”的定义下描述的那些。
“烯基”意指含有至少一个碳-碳双键的碳链,并且其可以是直链的或支链的或其组合,除非碳链另有定义。烯基的实例包括但不限于乙烯基、烯丙基、异丙烯基、己烯基、戊烯基、庚烯基、1-丙烯基、2-丁烯基、2-甲基-2-丁烯基等,在指定的碳原子数允许的情况下,例如C5-10,术语烯基还包括环烯基以及直链、支链和环状结构的组合。当没有指定碳原子数时,意指C2-6。
“炔基”意指含有至少一个碳-碳叁键的碳链,并且其可以是直链的或支链的或其组合。炔基的实例包括乙炔基、炔丙基、3-甲基-1-戊炔基等。当没有指定碳原子数时,意指。
单独使用或与其它基团组合使用的“硫代烷基”基团表示与式-SR’(硫及其氧化形式)(其中R’表示氢、烷基或芳基基团)的基团连接的如上所定义的烷基基团,例如硫代甲基、甲基硫代甲基、苯基硫代甲基等,其可以任选地被取代。
如本文所用,“碳环”或“碳环残基”旨在意指任何稳定的单环或双环或三环,其中任一个可以是饱和的、部分不饱和的或芳香族的。此类碳环的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基、环辛基、[3.3.0]二环辛烷、[4.3.0]二环壬烷、[4.4.0]二环癸烷(十氢化萘)、[2.2.2]二环辛烷、芴基、苯基、萘基、茚满基、金刚烷基或四氢萘基(四氢化萘)。在更广泛的观点中,术语碳环旨在包括(在适用的情况下)表示环烷基、苯基以及其它饱和、部分饱和或芳香族的残基的基团;
术语“环烷基”和“环烯基”是指任选取代的、饱和的和不饱和的单环、双环或三环碳基团。在适当的情况下,环烷基或环烯基可以具有指定的碳原子数,例如,C3-C6环烷基或环烯基在其范围内包括具有3、4、5或6个碳原子的碳环基团。此类取代基的实例可选自环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等。取代的环烷基或环烯基包括被一个或多个选自以下的部分取代:卤代(例如,Cl、F、Br和I);卤代烷基(例如,CF3、2-Br-乙基、CH2F、CH2Cl、CH2CF3或CF2CF3);羟基;氨基;羧酸酯;羧酰胺基;烷基氨基;芳基氨基;烷氧基;芳氧基;硝基;叠氮基;氰基;硫代;磺酸;硫酸酯;膦酸;磷酸酯和膦酸酯以及在“任选取代的”的定义下描述的那些。
“烷氧基”是指指定碳原子数的直链或支链烷氧化物。
“芳基”意指含有碳环原子的单环或多环芳香族环系。优选的芳基是单环或双环6至10元芳香族环系。苯基和萘基是优选的芳基。
“杂环基”是指饱和的、部分饱和的或不饱和的芳香族或非芳香族的单环、双环或三环基团,其含有一个或多个选自氮、硫和氧的杂原子,进一步任选地包括硫的氧化形式,即SO和SO2。杂环基体系可以经由任何数量的碳原子或杂原子的基团连接至其它部分,并且可以是饱和的和不饱和的。杂环的实例包括四氢呋喃(THF)、二氢呋喃、1,4-二氧六环、吗啉、1,4-二噻烷、哌嗪、哌啶、1,3-二氧戊环、咪唑啉、咪唑烷、吡咯烷、吡咯啉、四氢吡喃、二氢吡喃、氧硫杂环戊烷、二硫杂环戊烷、1,3-二氧六环、1,3-二噻烷、氧硫杂环己烷、硫代吗啉等。术语“杂环烷基”是指与如上文所定义的烷基基团连接的如上文所定义的杂环基团;
“杂芳基”意指含有至少一个选自O、S和N的环杂原子的芳香族或部分芳香族的杂环。因此,杂芳基包括与其它种类的环,例如芳基、环烷基和非芳香族的杂环稠合的杂芳基。杂芳基基团的实例包括:吡咯基、异噁唑基、异噻唑基、吡唑基、吡啶基、噁唑基、噁二唑基、噻二唑基、噻唑基、咪唑基、***基、四唑基、呋喃基、三嗪基、噻吩基、嘧啶基、苯并异噁唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、二氢苯并呋喃基、吲哚啉基、哒嗪基、吲唑基、异吲哚基、二氢苯并噻吩基、吲哚啉基、哒嗪基、吲唑基、异吲哚基、二氢苯并噻吩基、吲哚嗪基、噌啉基、酞嗪基、喹唑啉基、萘啶基、咔唑基、苯并二氧戊环基、喹喔啉基、嘌呤基、呋吖基、异苄基呋喃基、苯并咪唑基、苯并呋喃基、苯并噻吩基、喹啉基、吲哚基、异喹啉基、二苯并呋喃基等。对于杂环基和杂芳基基团,包括含有形成1至3个环的3至15个碳原子的环和环体系。
术语“卤代烷基”意指其中至少一个氢被卤素原子替代的烷基结构。在其中两个或更多个氢原子被卤素原子替代的某些实施方案中,卤素原子全部彼此相同。
“卤代烷氧基”基团选自与氧原子直接连接的如上文所定义的合适的卤代烷基,更优选选自氟甲氧基、氯甲氧基、氟乙氧基、氯乙氧基等的基团;
在其中两个或更多个氢原子被卤素原子替代的某些其它实施方案中,卤素原子并非全部彼此相同。
“芳氧基烷基”意指被如本文所定义的芳氧基基团取代的烷基。
“芳氧基芳基”意指被如本文所定义的芳氧基基团取代的芳基。
“芳氧基杂芳基”意指被如本文所定义的芳氧基基团取代的杂芳基。
“卤代/卤素”是指氟、氯、溴、碘。通常优选氯和氟。
在这些基团上的合适的基团和取代基可以选自在说明书中任何地方描述的那些。
如本文所用的术语“取代的”意指指定原子上的任一个或多个氢被选择的指定基团替代,条件是不超过指定原子的正常化合价,并且取代产生稳定的化合物。如本文所用的术语“取代的”意指指定原子上的任一个或多个氢被选择的指定基团替代,条件是不超过指定原子的正常化合价,并且取代产生稳定的化合物。
“药物可接受的盐”是指所公开的化合物的衍生物,其中母体化合物通过制备其酸或碱盐而被修饰。药物可接受的盐的实例包括但不限于碱性残基的无机或有机酸盐。此类常规无毒盐包括但不限于衍生自无机酸和有机酸的那些盐,所述无机酸和有机酸选自1,2-乙二磺酸、2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、重碳酸、碳酸、柠檬酸、乙二胺四乙酸、乙二磺酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、乙醇酰氨苯胂酸(glycollyarsanilic)、己基间苯二酚酸、海巴酸、氢溴酸、盐酸、氢碘酸、羟基马来酸、羟基萘甲酸、羟乙基磺酸、乳酸、乳糖酸、月桂基磺酸、马来酸、苹果酸、扁桃酸、甲磺酸、萘磺酸、硝酸、草酸、扑酸、泛酸、苯乙酸、磷酸、聚半乳糖醛酸、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、磺胺酸、硫酸、单宁酸、酒石酸和甲苯磺酸。
术语“任选的”或“任选地”意指随后描述的事件或情形可能发生或可能不发生,并且该描述包括该事件或情形发生的情况以及该事件或情形不发生的情况。例如,任选取代的烷基是指“烷基”或“取代的烷基”。此外,任选取代的基团包括未取代的基团。
除非在说明书中另有说明,本文描述的结构还意指包括区别仅在于一个或多个同位素富集的原子的存在的化合物。
特别有用的化合物可以选自但不限于以下:
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(异丙基氨基)丙-1-烯-1-磺酰胺;
(E)-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(丙基)氨基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(丙基氨基)丙-1-烯-1-磺酰胺;
(E)-3-((环丙基甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-3-((环丙基甲基)(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-3-(乙基(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(N-甲基甲基磺酰胺基)丙-1-烯-1-磺酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)-N-甲基环丙烷磺酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)-N-甲基环己烷磺酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)环己烷磺酰胺;
(E)-3-((环己基甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-3-((环己基甲基)(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)-N-甲基环己烷甲酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)-N-甲基乙酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)-N-甲基环丙烷甲酰胺;
(E)-N-((2,6-二异丙基苯基)氨基甲酰基)-3-(二甲基氨基)丙-1-烯-1-磺酰胺;
(E)-N-((2,6-二异丙基-4-甲基苯基)氨基甲酰基)-3-(二甲基氨基)丙-1-烯-1-磺酰胺;
(E)-3-(二甲基氨基)-N-((4-氟-2,6-二异丙基苯基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(苯基)氨基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(苯基氨基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(噻唑-2-基氨基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(噻唑-2-基)氨基)丙-1-烯-1-磺酰胺;
(E)-N'-氰基-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-3-(乙基(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-3-((环丙基甲基)(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-3-((环丙基甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-3-(二甲基氨基)-N-((4-氟-2,6-二异丙基苯基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-3-((环丙基甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-3-((环丙基甲基)(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-3-(二甲基氨基)-N-((4-氟-2,6-二异丙基苯基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-N'-甲基丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(氧杂环丁烷-3-基)氨基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(氧杂环丁烷-3-基氨基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(氧杂环丁烷-3-基氨基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(氧杂环丁烷-3-基氨基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(5-(甲基磺酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(3,4,5,6-四氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(5-(甲基磺酰基)-3,4,5,6-四氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺。
或上述任何化合物的药物可接受的盐。
以下是在本发明化合物的制备的描述中使用的缩写列表:
μg:微克
1H NMR:质子核磁共振
bs:宽单峰
CDC13:氘代氯仿
CHC13:氯仿
d:双峰
DAMP:损伤相关分子模式;
DBU:1,8-二氮杂双环(5.4.0)十一碳-7-烯
DCM:二氯甲烷
dd:双重双峰
DMAC:N,N-(二甲基乙酰胺)
DMAP:4-(二甲基氨基)吡啶
DMF:N,N-二甲基甲酰胺
DMSO:二甲基亚砜
dt:双重三峰
EDTA:乙二胺四乙酸
EtOAc:乙酸乙酯
EtOH:乙醇
HCl(g):氯化氢(气体)
IL1β:白细胞介素1β
K2CO3:碳酸钾
m:多重峰
MeOH:甲醇
mmol:毫摩尔
MS:质谱
N2:氮气
Na2CO3:碳酸钠
ng:纳克
NIS:N-碘代琥珀酰亚胺
PAMP:病原体相关分子模式;
PMA=佛波醇12-肉豆蔻酸酯13-乙酸酯
POCI3:磷酰氯
RM:反应混合物
r.t,RT:室温
s:单峰
t:三峰
td:三重双峰
THF:四氢呋喃
TLC:薄层色谱
TLR:Toll样受体。
TNFα:肿瘤坏死因子α
用于制备的一般方法
本发明的新化合物可以使用以下描述的反应和技术,以及有机合成领域技术人员已知的常规技术或本领域技术人员所理解的其变化形式来制备。
反应可以在适于所用试剂和材料且适于受影响进行转化的溶剂中进行。优选的方法包括但不限于以下描述的那些方法,其中所有符号如前文所定义,除非以下另有定义。
通式(I)的化合物可以如以下方案中所述连同在本领域技术人员的范围内适当的修改/变化来制备。
方案1
其中‘A’、R1、R2、R3、R4和R5如前文所定义。化合物(2)可以通过本领域技术人员熟悉的多种方法使用试剂如Boc酸酐由可商购的甲磺酰胺(1)制备。在合适的条件和合适的溶剂下用二苯基次膦酰氯处理化合物(2),得到化合物(3)(参考Synthesis 2003,15,2321-24)。在合适的条件下,在碱(如氢化钠)和合适的溶剂的存在下,用醛或酮衍生物(4)处理化合物(3),得到化合物(5),其可以在合适的条件下脱保护,得到化合物(6)。在合适的条件下,在碱(如氢化钠)和合适的溶剂的存在下,用异氰酸酯衍生物(7)处理化合物(6),得到化合物(8)。将化合物(8)的保护基脱保护,随后用适当的取代的醛或酮处理或用烷基卤化物处理得到式(I)的化合物。
进行如以上所述的方法步骤所需的具体反应条件、溶剂和其它参数都在本领域技术人员的能力范围内。
通过描述实施本发明的优选方式的以下非限制性实施例进一步说明本发明。这些不以任何方式限制本发明的范围。
实施例中给出的1H NMR光谱数据(见下文)使用400MHz光谱仪(Bruker AVANCE-400)记录并以δ标度报告。除非另有说明,用于NMR的溶剂是CDCl3,使用TMS作为内标。
实施例-1
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(异丙基氨基)丙-1-烯-1-磺酰胺的制备
中间体-1a:(E)-((3-((叔丁氧基羰基)氨基)丙-1-烯-1-基)磺酰基)氨基甲酸叔丁酯的制备
250mL、三颈、圆底的烧瓶配备有磁搅拌器、N2气囊、保温袋、干冰浴。在氮气气氛下,将((二苯基磷酰基)甲基)磺酰基氨基甲酸叔丁酯(Synthesis 2003,15,2321-24)(1当量)溶解在DMF(100ml)中。将其冷却至-20℃并添加NaH(2.2当量)。将其逐渐温热至25℃并搅拌30分钟。再次冷却至-20℃,并在-20℃下逐滴添加(2-氧代乙基)氨基甲酸叔丁酯(CASNo.:89711-08-0)(1.2当量)的DMF溶液,历时1小时。在添加后,将反应混合物温热至室温,并再搅拌17小时。将反应混合物冷却至0℃,并用饱和柠檬酸溶液(30mL)和水(200mL)酸化。用乙酸乙酯萃取反应混合物,收集有机层并干燥,得到(E)-((3-((叔丁氧基羰基)氨基)丙-1-烯-1-基)磺酰基)氨基甲酸叔丁酯(25%产率)。
1H NMR(400MHz,DMSO-d6):δ=11.28(s,1H),7.29(t,J=5.6Hz,1H),6.76–6.70(m,1H),6.58(d,J=15.2Hz,1H),3.88–3.70(m,2H),1.41(s,9H),1.39(s,9H);MS(TOF):m/z(%)=359.1603(80%)(M+Na)+,335.1516(100%)(M-1)
中间体-1b:(E)-((3-((叔丁氧基羰基)氨基)-3-甲基丁-1-烯-1-基)磺酰基)氨基甲酸叔丁酯的制备
中间体-1b也根据用于合成中间体-1a所描述的程序使用(2-甲基-1-氧代丙-2-基)氨基甲酸叔丁酯(CAS No.:109608-77-7)制备。
1H NMR(400MHz,DMSO-d6):δ=11.25(s,1H),7.07(s,1H),6.84(d,J=15.6Hz,1H),6.45(d,J=15.2Hz,1H),1.41(s,9H),1.37(s,9H),1.31(s,6H);MS(TOF):m/z(%)=363.1556(80%)(M+Na)+。
中间体-2a:(E)-(3-氨磺酰基烯丙基)氨基甲酸叔丁酯的制备
将中间体1(当量)溶解在DMSO(30ml)中并加热至80℃持续2小时(通过TLC监测起始材料的消失)。将反应冷却,倒入水(100ml)中并用EtOAc(3x 100ml)萃取。将溶剂真空浓缩并通过硅胶柱色谱(50%EtOAc:正己烷)纯化,得到产物(E)-(3-氨磺酰基烯丙基)氨基甲酸叔丁酯(89%产率)。
1H NMR(400MHz,DMSO-d6):δ=7.24(t,J=5.6Hz,1H),6.99(s,2H),6.49–6.38(m,2H),3.74–3.71(m,2H),1.39(s,9H);MS(TOF):m/z(%)=259.0998(100%)(M+Na)+,2.350928(40%)(M-1)。
中间体-2b:(E)-(2-甲基-4-氨磺酰基丁-3-烯-2-基)氨基甲酸叔丁酯的制备
中间体-2b也根据用于合成中间体-2a所描述的程序使用(E)-((3-((叔丁氧基羰基)氨基)-3-甲基丁-1-烯-1-基)磺酰基)氨基甲酸叔丁酯制备。
1H NMR(400MHz,DMSO-d6):δ=6.96(s,3H),6.60(d,J=15.2Hz,1H),6.27(d,J=15.2Hz,1H),1.39(s,9H),1.30(s,6H);MS(TOF):m/z(%)=287.1022(50%)(M+Na)+。
中间体-3:(E)-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)氨基甲酸叔丁酯的制备。
在0℃下,向磺酰胺[中间体2](1当量)的DMF(220ml)溶液中添加DBU(2.2当量)。使反应温热至室温,并搅拌30分钟。在0℃下分批添加4-异氰酸基-1,2,3,5,6,7-六氢-s-引达省(1.2当量)分批添加),将反应温热至室温,并搅拌过夜。使用50%柠檬酸水溶液将反应物酸化至pH=2.0,用水(1500ml)稀释,通过布氏漏斗过滤沉淀物并干燥,得到产物(76%产率)。
1H NMR(400MHz,DMSO-d6):δ=10.49(brs,1H),8.09(s,1H),7.28(t,J=5.6Hz,1H),6.96(s,1H),6.78–6.72(m,1H),6.67(d,J=15.6Hz,1H),3.96–3.85(m,2H),2.81(t,J=7.2Hz,4H),2.01(t,J=7.2Hz,4H),2.01–1.94(m,4H),1.42(s,9H);MS(ESI):m/z(%)=434.1724(100%)(M-1)。
中间体-4:(E)-3-氨基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺2,2,2-三氟乙酸盐的制备
在0℃下,向中间体3(1当量)的DCM(2.5ml)溶液中添加TFA(10当量)。将反应温热至室温,并再搅拌3小时。将反应混合物真空浓缩并纯化,得到产物。
1H NMR(400MHz,DMSO-d6):δ=10.87(brs,1H),8.14(s,1H),8.02(s,3H),7.05(d,J=15.2Hz,1H),6.97(s,1H),6.80–6.74(m,1H),3.89–3.69(m,2H),2.81(t,J=7.2Hz,4H),2.01(t,J=7.2Hz,4H),2.01–1.94(m,4H);MS(ESI):m/z(%)=336.1316(100%)(M+H)+,334.1172(100%)(M-1)。
实施例-1
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(异丙基氨基)丙-1-烯-1-磺酰胺
在室温下向中间体4(1当量)的MeOH(7.0mL)溶液中添加三乙胺(2.5当量),并搅拌5分钟。在室温下添加丙酮(3.5当量),并搅拌2小时。此后,在0℃分批用NaCNBH3(1.5当量)处理反应混合物,然后使反应混合物温热至室温,搅拌过夜。将反应混合物通过制备型HPLC纯化,得到纯产物。
1H NMR(400MHz,DMSO-d6):δ=8.28(br s,1H),7.51(s,1H),6.97(d,J=15.6Hz,1H),6.80(s,1H),6.36–6.29(m,1H),3.64(d,J=6.4Hz,2H),3.20–3.14(m,1H),2.77(t,J=7.6Hz,4H),2.70(t,J=7.2Hz,4H),1.96–1.88(m,4H),1.16(d,J=6.4Hz,6H);MS(ESI):m/z(%)=378.1787(100%)(M+H)+,376.1640(100%)(M-1)。
使用适当的起始材料和实施例1中所述方法的适当修改,包括适当添加和/或删除可能必要的步骤(这在本领域技术人员的范围内),以类似的方式制备以下化合物。
实施例-2
(E)-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺
在室温下向中间体4(1当量)的MeOH(7.0mL)溶液中添加三乙胺(2.5当量),并搅拌5分钟。在室温下添加多聚甲醛(5当量),并搅拌2小时。此后,在0℃分批用NaCNBH3(2.5当量)处理反应混合物,然后使反应混合物温热至室温,搅拌过夜。将反应混合物通过制备型HPLC纯化,得到纯产物。
1H NMR(400MHz,DMSO-d6):δ=10.22(brs,1H),7.94(s,1H),6.91(s,1H),6.86(d,J=15.2Hz,1H),6.62–6.55(m,1H),3.27(t,J=6.0Hz,2H),2.79(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.30(s,6H),1.99–1.91(m,4H);MS(ESI):m/z(%)=364.1513(100%)(M+H)+。
实施例-3
(E)-3-氨基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺2,2,2-三氟乙酸盐
1H NMR(400MHz,DMSO-d6):δ=10.87(brs,1H),8.14(s,1H),8.02(s,3H),7.05(d,J=15.2Hz,1H),6.97(s,1H),6.80–6.74(m,1H),3.89–3.69(m,2H),2.81(t,J=7.2Hz,4H),2.01(t,J=7.2Hz,4H),2.01–1.94(m,4H);MS(TOF):m/z(%)=336.1316(100%)(M+H)+,334.1172(100%)(M-1)。
实施例-4
(E)-3-(二丙基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.27(brs,1H),8.02(s,1H),6.94(s,1H),6.88(d,J=15.2Hz,1H),6.67–6.37(m,1H),3.45–3.28(m,2H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.41(t,J=6.8Hz,4H),2.00–1.92(m,4H),1.45–1.36(m,4H),0.82(t,J=7.2Hz,6H);MS(TOF):m/z(%)=420.2633(100%)(M+H)+,418.2245(100%)(M-1)。
实施例-5
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(异丙基(甲基)氨基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.89(s,1H),6.90–6.86(m,2H),6.61–6.54(m,1H),3.60–3.37(m,2H),3.02–2.99(m,1H),2.79(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.27(s,3H),1.99–1.91(m,4H),1.01(d,J=6.8Hz,6H);MS(TOF):m/z(%)=392.1983(100%)(M+H)+,390.1817(100%)(M-1)。
实施例-6
(E)-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.88(s,1H),6.90(s,1H),6.71(d,J=15.6Hz,1H),6.60(d,J=15.2Hz,1H),2.77(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.32(s,6H),1.98–1.91(m,4H),1.21(s,6H);MS(TOF):m/z(%)=392.1992(100%)(M+H)+,390.1819(100%)(M-1)。
实施例-7
(E)-(4-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=9.05(s,1H),7.81(s,1H),6.95(s,1H),6.89(s,1H),6.72(d,J=16.0Hz,1H),6.56(d,J=15.2Hz,1H),2.79(t,J=7.2Hz,4H),2.79(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),1.98–1.91(m,4H),1.36(s,9H),1.21(s,6H);MS(TOF):m/z(%)=462.2029(100%)(M-1)。
实施例-8
(E)-3-氨基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰胺2,2,2-三氟乙酸盐
1H NMR(400MHz,DMSO-d6):δ=10.90(brs,1H),8.42(s,1H),8.32(s,1H),7.81(s,1H),6.97–6.86(m,3H),2.81(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.01–1.90(m,4H),1.41(s,6H);MS(TOF):m/z(%)=364.1659(100%)(M+H)+,364.1659(10%)(M-1)。
实施例-9
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-((四氢-2H-吡喃-4-基)氨基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.68(s,1H),6.93(d,J=15.2Hz,1H),6.85(s,1H),6.52–6.46(m,1H),3.85–3.82(m,2H),3.60(d,J=5.6Hz,2H),3.26–3.20(m,2H),3.04–2.90(m,1H),2.78(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),1.97–1.90(m,4H),1.84–1.81(m,2H),1.42–1.34(m,2H);MS(TOF):m/z(%)=420.1931(100%)(M+H)+。
实施例-10
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-((1-甲基哌啶-4-基)氨基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.61(s,1H),6.88(d,J=15.6Hz,1H),6.85(s,1H),6.42(dt,J=15.2Hz,J=6.0Hz,1H),3.51(d,J=5.6Hz,2H),2.92–2.89(m,2H),2.80(t,J=7.2Hz,4H),2.72(t,J=7.2Hz,4H),2.29(s,3H),2.21–2.08(m,2H),2.01–1.94(m,4H),1.93–1.87(m,3H),1.48–1.40(m,2H);MS(TOF):m/z(%)=433.2725(100%)(M+H)+,431.2362(20%)(M-1)。
实施例-11
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-((四氢-2H-硫代吡喃-4-基)氨基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.74(s,1H),6.92(d,J=15.2Hz,1H),6.87(s,1H),6.54–6.51(m,1H),3.57(d,J=5.2Hz,2H),2.79(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),2.67–2.63(m,2H),2.57–2.51(m,3H),2.18–2.16(m,2H),1.99–1.92(m,4H),1.52–1.42(m,2H);MS(TOF):m/z(%)=436.2359(100%)(M+H)+,434.1904(50%)(M-1)。
实施例-12
((E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(异丙基氨基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.55(s,1H),6.83–6.80(m,2H),6.47(d,J=16.0Hz,1H),3.23–3.14(m,1H),2.77(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),1.96–1.89(m,4H),1.37(s,6H),1.13(d,J=6.4Hz,6H);MS(TOF):m/z(%)=406.2135(100%)(M+H)+,404.1985(30%)(M-1)。
实施例-13
(E)-3-(环己基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.58(s,1H),6.81–6.77(m,2H),6.48(d,J=15.2Hz,1H),2.82–2.80(m,1H),2.75(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),1.94–1.87(m,4H),1.82–1.73(m,2H),1.67–1.52(m,2H),1.49–1.41(m,1H),1.32(s,6H),1.21–1.11(m,4H),1.03–1.01(m,1H);MS(TOF):m/z(%)=446.2445(100%)(M+H)+,444.2301(300%)(M-1).
实施例-14
((E)-3-氨基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.93(brs,2H),7.39(s,1H),6.85(d,J=15.6Hz,1H),6.76(s,1H),6.36(d,J=15.6Hz,1H),2.74(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),1.93–1.85(m,4H),1.31(m,6H);MS(TOF):m/z(%)=364.1665(100%)(M+H)+,362.1531(10%)(M-1)。
实施例-15
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(1-甲基哌啶-4-基)氨基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.65(s,1H),6.83(s,1H),6.71(d,J=15.6Hz,1H),6.39–6.32(m,1H),3.18(d,J=5.2Hz,2H),2.93–2.90(m,2H),2.78(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.24(s,3H),2.17–2.12(m,4H),1.97–1.91(m,6H),1.71–1.68(m,2H),1.54–1.46(m,2H);MS(TOF):m/z(%)=447.2401(100%)(M+H)+,445.2269(20%)(M-1)。
实施例-16
(E)-3-(二乙基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.68(s,1H),6.90(s,1H),6.67(d,J=15.6Hz,1H),6.60(d,J=15.6Hz,1H),2.80(t,J=7.2Hz,4H),2.72(t,J=7.2Hz,4H),2.64–2.54(m,4H),1.99–1.92(m,4H),1.19(s,6H),1.00(t,J=6.4Hz,6H);MS(TOF):m/z(%)=420.2287(100%)(M+H)+,418.2140(20%)(M-1)。
实施例-17
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(哌啶-1-基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.85(s,1H),6.88(s,1H),6.79(d,J=15.6Hz,1H),6.52(d,J=3.6Hz,1H),2.79(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),1.93(d,J=13.6Hz,7H),1.51(m,4H),1.39(m,4H);MS(ESI):m/z(%)=404.19(100%)(M+1)。
实施例-18
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(吡咯烷-1-基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.22(s,1H),7.82(s,1H),7.00(s,1H),6.91(d,J=15.6Hz,1H),6.57(d,J=8.4Hz,1H),3.47(m,3H),2.79(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),1.95(m,4H),1.76(s,4H);MS(ESI):m/z(%)=390.18(100%)(M+1)。
实施例-19
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(四氢-2H-吡喃-4-基)氨基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.28(brs,1H),8.02(s,1H),6.92(s,1H),6.84(d,J=15.2Hz,1H),6.71–6.58(m,1H),3.85–3.82(m,2H),3.48–3.29(m,2H),3.23–3.17(m,2H),2.78(t,J=7.2Hz,4H),2.65(t,J=7.2Hz,4H),2.59–2.54(m,1H),2.19(s,3H),1.98–1.90(m,4H),1.64–1.61(m,2H),1.45–1.34(m,2H);MS(TOF):m/z(%)=434.2078(100%)(M+H)+,432.1949(30%)(M-1)。
实施例-20
(E)-3-(乙基(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.87(s,1H),6.70(d,J=15.6Hz,1H),6.89(s,1H),6.59(d,J=15.2Hz,1H),2.78(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.49–2.50(m,2H),2.28(s,3H),1.98–1.90(m,4H),1.19(s,6H),1.01(t,J=6.8Hz,3H);MS(TOF):m/z(%)=406.2131(100%)(M+H)+,404.1986(100%)(M-1)。
实施例-21
(E)-3-(环丁基(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.33(brs,1H),7.97(s,1H),6.97(s,1H),6.77–6.58(m,2H),3.52–3.37(m,1H),2.79(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.81(s,3H),1.99–1.87(m,8H),1.59–1.40(m,2H),1.15(s,6H);MS(TOF):m/z(%)=432.2295(100%)(M+H)+,430.2140(100%)(M-1)。
实施例-22
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(四氢-2H-硫代吡喃-4-基)氨基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.05(s,1H),6.94(s,1H),6.84(d,J=15.2Hz,1H),6.68(dt,J=14.8Hz,J=5.6Hz,1H),3.33–3.31(m,2H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.61–2.52(m,5H),2.20(s,1H),2.00–1.91(m,6H),1.61–1.50(m,2H);MS(TOF):m/z(%)=450.1869(100%)(M+H)+,448.1711(50%)(M-1)。
实施例-23
(E)-3-(环丁基(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.21(s,1H),6.93(s,1H),6.71–6.86(m,2H),3.64–3.61(m,1H),2.80(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.33(s,3H),1.99–1.91(m,4H),1.72–1.60(m,2H),1.59–1.45(m,4H),1.41–1.10(m,8H);MS(TOF):m/z(%)=446.2457(100%)(M+H)+,444.2307(40%)(M-1)。
实施例-24
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(异丙基(甲基)氨基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.94(s,1H),6.92(s,1H),6.75–6.59(m,2H),3.34–3.21(m,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.20(s,3H),1.99–1.92(m,8H),1.22(s,6H),0.98(d,J=6.4Hz,6H);MS(TOF):m/z(%)=420.2871(100%)(M+H)+,418.2452(100%)(M-1)。
实施例-25
(E)-3-((环丙基甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.49(s,1H),6.81(s,1H),6.77(d,J=15.6Hz,1H),6.38(d,J=15.6Hz,1H),2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.65(d,J=7.2Hz,2H),1.96–1.89(m,4H),1.34(s,6H),0.97–0.89(m,1H),0.54–0.48(m,2H),0.30–0.22(m,2H);MS(TOF):m/z(%)=418.2132(100%)(M+H)+,416.1982(30%)(M-1)。
实施例-26
(E)-3-(环丁基(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.49(brs,1H),8.02(s,1H),6.93(s,1H),6.85(d,J=15.2Hz,1H),6.69–6.63(m,1H),3.14(d,J=5.6Hz,2H),2.99–2.91(m,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.09(s,3H),2.01–1.90(m,8H),1.85–1.75(m,2H),1.65–1.51(m,2H);MS(TOF):m/z(%)=404.1974(100%)(M+H)+,402.1866(10%)(M-1)。
实施例-27
(E)-3-(二环丁基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.31(brs,1H),8.07(s,1H),6.95(s,1H),6.86(d,J=15.2Hz,1H),6.78–6.72(m,1H),3.29–3.21(m,2H),3.20–3.05(m,2H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.00–1.76(m,12H),1.60–1.44(m,4H);MS(TOF):m/z(%)=444.2285(100%)(M+H)+,442.2158(30%)(M-1)。
实施例-28
(Z)-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.52(brs,1H),8.12(s,1H),7.19–7.16(m,1H),6.96(s,1H),6.51(dt,J=11.2Hz,J=2.4Hz,1H),6.30–6.23(m,1H),4.10–4.09(m,2H),2.81(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),2.01–1.91(m,4H),1.38(s,9H);MS(TOF):m/z(%)=436.1961(5%)(M+H)+,458.1747(40%)(M+Na),434.1802(5%)(M-1)。
实施例-29
(Z)-3-氨基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺2,2,2-三氟乙酸盐
1H NMR(400MHz,DMSO-d6):δ=10.96(brs,1H),8.52(s,1H),8.00(s,3H),6.97(s,1H),6.74(d,J=11.2Hz,1H),6.40–6.34(m,1H),4.19–4.05(m,2H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.07–1.94(m,4H);MS(TOF):m/z(%)=336.1851(100%)(M+H)+,334.1538(30%)(M-1)。
实施例-30
(Z)-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=11.21(brs,1H),8.08(s,1H),6.84(s,1H),6.57(d,J=11.2Hz,1H),6.24–6.17(m,1H),3.95(d,J=7.6Hz,2H),2.77(t,J=7.2Hz,4H),2.70–2.68(m,10H),1.99–1.86(m,4H);MS(TOF):m/z(%)=364.2137(100%)(M+H)+,362.1824(10%)(M-1)。
实施例-31
(E)-((3-(二甲基氨基)-3-甲基丁-1-烯-1-基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)酰胺钠
1H NMR(400MHz,DMSO-d6):δ=7.36(s,1H),6.77(s,1H),6.51(d,J=15.6Hz,1H),6.23(d,J=15.6Hz,1H),2.76(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.11(s,1H),1.94–1.87(m,4H),1.06(s,6H);MS(TOF):m/z(%)=392.1987(100%)(M+H)+,390.1841(20%)(M-1)。
实施例-32
(E)-((3-(二甲基氨基)丙-1-烯-1-基)磺酰基)((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)酰胺钠
1H NMR(400MHz,DMSO-d6):δ=7.36(s,1H),6.77(s,1H),6.62(d,J=15.2Hz,1H),6.18(dt,J=15.2Hz,J=6.4Hz,1H),2.91(dd,J=6.4Hz,J=1.2Hz,2H),2.76(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.13(s,6H),1.96–1.70(m,4H);MS(TOF):m/z(%)=364.1676(100%)(M+H)+,362.1552(5%)(M-1)。
实施例-33
(E)-3-((3-氨基丙基)(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺。
1H NMR(400MHz,DMSO-d6):δ=7.47(s,1H),6.79(s,1H),6.64(d,J=15.2Hz,1H),6.27–6.20(m,1H),3.03(d,J=6.0Hz,2H),2.80–2.75(m,6H),2.68(t,J=7.2Hz,4H),2.38(t,J=6.4Hz,2H),2.10(s,3H),1.95–1.88(m,4H),1.68–1.63(m,2H);MS(TOF):m/z(%)=407.2104(100%)(M+H)+,405.2004(10%)(M-1)-。
实施例-34
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(哌啶-1-基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.02(s,1H),7.15(m,3H),6.95(d,J=11.2Hz,2H),6.65(m,6H),6.47(t,J=3.6Hz,1H),4.18(d,J=3.2Hz,2H),2.91(t,J=2.4Hz,4H),2.79(t,J=7.2Hz,4H),2.65(t,J=7.2Hz,4H),1.983(m,4H);MS(ESI):m/z(%)=426.18(100%)(M+1)。
实施例-35
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(异丁基(甲基)氨基)-3-甲基丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.34(brs,1H),8.04(s,1H),6.94(s,1H),6.72(d,J=15.6Hz,1H),6.66(d,J=15.2Hz,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.14(s,3H),2.10–2.08(m,2H),2.00–1.92(m,4H),1.68–1.61(m,1H),1.13(s,6H),0.82(d,J=6.8Hz,3H);MS(TOF):m/z(%)=434.3021(100%)(M+H)+,432.2628(20%)(M-1)。
实施例-36
(E)-3-(二甲基氨基)-N-((1,2,3,7-四氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.21(bs,1H),7.16(s,1H),6.87(d,J=15.2Hz,1H),6.80(d,J=5.6Hz,1H),6.69-6.51(m,1H),6.40(d,J=5.6Hz,1H),3.30-3.28(m,4H),2.87(t,J=7.2Hz,2H),2.74(t,J=7.2Hz,2H),2.32(s,6H),2.02-1.95(m,2H);MS(TOF):m/z(%)=362.15(100%)(M+H)+。
实施例-37
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基-3-(甲基磺酰胺基)丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=10.47(brs,1H),8.10(s,1H),7.42(s,1H),6.96(s,1H),6.89(d,J=15.2Hz,1H),6.75(d,J=15.2Hz,1H),2.99(s,3H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.01–1.93(m,4H),1.40(s,6H);MS(TOF):m/z(%)=442.1452(100%)(M+H)+,440.1309(20%)(M-1)。
实施例-38
(E)-3-(二甲基氨基)-N-((1,2,3,5-四氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.11(bs,1H),7.10(s,1H),6.88(d,J=15.2Hz,1H),6.83(d,J=5.6Hz,1H),6.61-6.52(m,1H),6.50(d,J=5.2Hz,1H),3.32-3.26(m,4H),2.87(t,J=7.2Hz,2H),2.76(t,J=7.2Hz,2H),2.34(s,6H),2.03-1.95(m,2H);MS(TOF):m/z(%)=362.15(100%)(M+H)+。
实施例-39
(E)-3-(二丙基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.96(s,1H),6.92(s,1H),3.32(t,J=7.2Hz,4H),2.80(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.63(t,J=7.2Hz,2H),2.50–2.45(m,2H),2.00–1.91(m,4H),1.86–1.82(m,2H),1.46–1.40(m,4H),0.84(d,J=7.2Hz,6H);MS(TOF):m/z(%)=422.2451(100%)(M+H)+,420.2326(20%)(M-1)。
实施例-40
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-((2-甲基-2-(吡咯烷-1-基)丙基)氨基)丙-1-烯-1-磺酰胺.
1H NMR(400MHz,DMSO-d6):δ=7.48(s,1H),6.77(s,1H),6.69(d,J=15.2Hz,1H),6.27–6.22(m,1H),3.25–3.24(m,2H),2.76(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.64–2.60(m,4H),2.45(s,2H),1.95–1.89(m,4H),1.67–1.65(m,4H),1.01(s,6H);MS(TOF):m/z(%)=461.2562(100%)(M+H)+,459.2421(30%)(M-1)-。
实施例-41
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(2-甲基-2-(吡咯烷-1-基)丙基)氨基)丙-1-烯-1-磺酰胺。
1H NMR(400MHz,DMSO-d6):δ=7.48(s,1H),6.77(s,1H),6.69(d,J=15.2Hz,1H),6.27–6.22(m,1H),3.25–3.24(m,2H),2.76(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.64–2.60(m,4H),2.45(s,2H),2.19(s,3H),1.95–1.89(m,4H),1.67–1.65(m,4H),1.01(s,6H);MS(TOF):m/z(%)=475.2717(100%)(M+H)+,473.2633(30%)(M-1)-。
实施例-42
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基-3-(吡咯烷-1-基)丁-1-烯-1-磺酰胺。
1H NMR(400MHz,DMSO-d6):δ=7.79(s,1H),6.87(s,1H),6.76(d,J=15.6Hz,1H),6.61(d,J=15.6Hz,1H),2.78(t,J=7.2Hz,8H),2.68(t,J=7.2Hz,4H),1.96(t,J=7.2Hz,4H),1.71(br s,4H),1.28(s,6H);MS(TOF):m/z(%)=418.2295(100%)(M+H)+。
实施例-43
(E)-4-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.85(s,1H),6.90(s,1H),6.74(d,J=15.2Hz,1H),6.58–6.51(m,1H),2.79(t,J=7.2Hz,2H),2.72–2.65(m,6H),2.46–2.43(m,2H),2.30(s,6H),1.97–1.91(m,4H);MS(TOF):m/z(%)=378.1834(100%)(M+H)+,376.1680(100%)(M-1)-;
实施例-44
(E)-4-氨基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丁-1-烯-1-磺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.46(s,1H),6.79(s,1H),6.58(d,J=15.2Hz,1H),6.26–6.19(m,1H),2.88(t,J=7.2Hz,2H),2.76(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.40–2.33(m,2H),1.96–1.89(m,4H);MS(TOF):m/z(%)=350.1945(100%)(M+H)+,348.1652(10%)(M-1)-。
实施例45
(E)-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=10.49(br s,1H),8.09(s,1H),7.28(t,J=5.6Hz,1H),6.96(s,1H),6.78–6.72(m,1H),6.67(d,J=15.6Hz,1H),3.96–3.85(m,2H),2.81(t,J=7.2Hz,4H),2.01(t,J=7.2Hz,4H),2.01–1.94(m,4H),1.42(s,9H)。
方案2:
其中“A”、R1、R2、R3、R4和R5如前文所定义。化合物6的合成如前文所述。用合适的保护基如取代的甲硅烷基氯保护6的胺基,得到9。在合适的条件和合适的溶剂下用三苯基膦和六氯乙烷处理化合物9,随后用氨处理,得到化合物10。在合适的条件(碱(如丁基锂或氢化钠)和合适的溶剂)下,用异氰酸酯衍生物(7)处理化合物10,得到11。在合适的条件下用合适的试剂对化合物11进行脱保护,然后与烷基溴反应,得到12。化合物12的脱保护,随后在适合的条件下,在碱(如氢化钠)和适合的溶剂的存在下,在适合的条件下用烷基溴或醛或酮衍生物处理,得到式(I”)的化合物。
进行如以上所述的方法步骤所需的具体反应条件、溶剂和其它参数都在本领域技术人员的能力范围内。
通过描述实施本发明的优选方式的以下非限制性实施例进一步说明本发明。这些不以任何方式限制本发明的范围。
实施例中给出的1H NMR光谱数据(见下文)使用400MHz光谱仪(Bruker AVANCE-400)记录并以δ标度报告。除非另有说明,用于NMR的溶剂是CDCl3,使用TMS作为内标。
实施例-49
(E)-N'-氰基-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰亚胺酰胺的制备
中间体-5:(E)-(4-(N-(叔丁基二苯基甲硅烷基)氨磺酰基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯的制备
在室温下,向(E)-(2-甲基-4-氨磺酰基丁-3-烯-2-基)氨基甲酸叔丁酯(5g,18.92mmol)的THF(50ml)溶液中添加三乙胺(6.59ml,47.3mmol)。将反应混合物在50℃下搅拌0.5小时。在50℃下逐滴添加TBDPS-Cl(6.07ml,23.64mmol)。将反应混合物在50℃下搅拌16小时。在50℃加入另外的三乙胺(6.59ml,47.3mmol)和TBDPS-Cl(6.07ml,23.64mmol)。将反应混合物在50℃下搅拌16小时。将反应混合物蒸发,得到粗产物。将粗产物通过柱色谱纯化,使用EtOAc:己烷作为洗脱剂,得到(E)-(4-(N-(叔丁基二苯基甲硅烷基)氨磺酰基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯(4g,7.96mmol,42.1%产率)。
1H NMR(400MHz,DMSO-d6):δ=7.77-7.70(m,5H),7.48-7.40(m,6H),6.97(bs,1H),6.97(d,J=14.8Hz,1H),6.14(d,J=15.2Hz,1H),1.38(s,9H),1.24(s,6H),0.95(s,9H);MS(TOF):m/z(%)=525.22(20%)(M+Na)+
中间体-6:(E)-(4-(N-(叔丁基二苯基甲硅烷基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯的制备
在氮气气氛下,将三苯基膦(0.678g,2.59mmol)和全氟乙烷(0.612g,2.59mmol)的干氯仿(10mL)溶液加热至70℃,持续6小时。将固体ppt冷却至室温并添加三乙胺(0.491ml,3.52mmol),搅拌10分钟。冷却至0℃并且添加(E)-(4-(N-(叔丁基二苯基甲硅烷基)氨磺酰基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯(1g,1.989mmol)的CHCl3(10mL)溶液,将其在0℃下搅拌30分钟,并在0℃下用氨气吹扫1小时。蒸发溶剂,得到粗产物。将粗产物通过柱色谱纯化,使用EtOAc:己烷作为洗脱剂,得到(E)-(4-(N-(叔丁基二苯基甲硅烷基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯(0.9g,1.794mmol,90%产率)。
1H NMR(400MHz,DMSO-d6):δ=7.76-7.73(m,4H),7.38-7.31(m,6H),6.86(bs,1H),6.51(s,2H),6.62(d,J=14.8Hz,1H),6.34(d,J=15.2Hz,1H),1.40(s,9H),1.26-1.18(m,6H),1.04(s,9H);MS(TOF):m/z(%)=502.24(100%)(M+H)+。
中间体-7:(E)-(4-(N'-(叔丁基二苯基甲硅烷基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯
在氮气气氛下,在0℃下向(E)-(4-(N-(叔丁基二苯基甲硅烷基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯(0.4g,0.797mmol)的THF(4ml)溶液中添加NaH(0.070g,1.754mmol)。将反应混合物再搅拌30分钟,然后在室温下再搅拌30分钟。一次性添加4-异氰酸基-1,2,3,5,6,7-六氢-s-引达省(0.191g,0.957mmol)的THF溶液。将所得悬浮液在室温下再搅拌2小时。将反应混合物用30%柠檬酸溶液酸化并添加水。将水层用乙酸乙酯萃取。将合并的有机层经Na2SO4干燥,蒸发溶剂,并将残余物通过使用EtOAc:己烷的柱色谱纯化,得到(E)-(4-(N'-(叔丁基二苯基甲硅烷基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯(0.335g,0.478mmol,60%产率)。
1H NMR(400MHz,DMSO-d6):δ=9.78(s,1H),8.00(s,1H),7.75-7.74(m,4H),7.39-7.34(m,6H),6.96-6.93(m,2H),6.84(d,J=14.8Hz,1H),6.64(d,J=15.2Hz,1H)2.79(t,J=7.2Hz,4H),2.62(t,J=7.2Hz,4H),1.99-1.91(m,4H),1.41(s,9H),1.26(s,6H),1.04(s,9H);MS(ESI):m/z(%)=701.35(100%)(M+H)+。
中间体-8:(E)-(4-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯的制备
向(E)-(4-(N'-(叔丁基二苯基甲硅烷基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯(3.4g,4.85mmol)的乙酸异丙酯(34ml)溶液中添加柠檬酸(19.40ml,48.5mmol)。将反应混合物在室温下搅拌48小时。减压浓缩反应混合物,过滤固体产物,得到粗产物。将粗产物通过使用EtOAc:己烷的柱色谱纯化,得到(E)-(4-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯(1.2g,2.59mmol,53.5%产率)。
1H NMR(400MHz,DMSO-d6):δ=8.29(bs,1H),7.19(s,1H),7.00(bs,1H),6.87(s,1H),6.73(d,J=16.0Hz,1H),6.60(d,J=15.2Hz,1H),2.78(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),1.99-1.90(m,4H),1.38(s,9H),1.32(s,6H);MS(TOF):m/z(%)=463.29(100%)(M+H)+。
中间体-9:(E)-(4-(N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯的制备
在室温下向(E)-(4-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯(0.180g,0.389mmol)的DMF(4ml)溶液中添加三乙胺(0.217ml,1.556mmol)和溴化氰(0.082g,0.778mmol),并将反应混合物在室温下搅拌17小时。将反应混合物通过制备型HPLC纯化,得到(E)-(4-(N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯(0.080g,0.164mmol,42.2%产率)。
1H NMR(400MHz,DMSO-d6):δ=7.86(bs,1H),6.90(bs,1H),6.83(s,1H),6.65(d,J=15.6Hz,1H),6.47(d,J=15.2Hz,1H),2.77(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),1.96-1.88(m,4H),1.37(s,9H),1.30(s,6H);MS(TOF):m/z(%)=488.23(100%)(M+H)+。
中间体-10:(E)-3-氨基-N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰亚胺酰胺的制备
将(E)-(4-(N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯(0.55g,1.128mmol)和HCl在二氧六环(3.76ml,11.28mmol,4M)中的混合物在室温下搅拌1小时。蒸发溶剂,得到粗产物。将粗产物通过制备型HPLC纯化,得到(E)-3-氨基-N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰亚胺酰胺(0.095g,0.245mmol,21.74%产率)。
1H NMR(400MHz,DMSO-d6):δ=7.93(bs,1H),6.84-6.80(m,2H),6.56(d,J=15.2Hz,1H),2.77(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),1.95-1.88(m,4H),1.34(s,6H);MS(TOF):m/z(%)=388.17(100%)(M+H)+。
实施例-49
(E)-N'-氰基-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰亚胺酰胺
在室温下向(E)-3-氨基-N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰亚胺酰胺(0.085g,0.219mmol)的MeOH(2ml)溶液中添加三乙胺(0.037ml,0.263mmol)、多聚甲醛(0.023g,0.768mmol)和氰基三氢硼酸钠(0.034g,0.548mmol)。将反应混合物在室温下搅拌16小时。蒸发溶剂,所得粗产物通过制备型HPLC纯化,得到(E)-N'-氰基-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰亚胺酰胺(0.042g,0.101mmol,46.1%产率)。
1H NMR(400MHz,DMSO-d6):δ=9.70(bs,1H),8.07(bs,1H),6.90(d,J=15.2Hz,1H),6.83(s,1H),6.52(d,J=15.6Hz,1H),2.78-2.75(m,10H),2.69(t,J=7.2Hz,4H),1.98-1.88(m,4H),1.45(s,6H);MS(TOF):m/z(%)=416.21(100%)(M+H)+。
使用适当的起始材料和实施例1中所述方法的适当修改,包括适当添加和/或删除可能必要的步骤(这在本领域技术人员的范围内),以类似的方式制备以下化合物。
实施例-46
(E)-(4-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=8.29(bs,1H),7.19(s,1H),7.00(bs,1H),6.87(s,1H),6.73(d,J=16.0Hz,1H),6.60(d,J=15.2Hz,1H),2.78(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),1.99-1.90(m,4H),1.38(s,9H),1.32(s,6H);MS(TOF):m/z(%)=463.29(100%)(M+H)+。
实施例-47
(E)-(4-(N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)磺酰亚胺酰胺基)-2-甲基丁-3-烯-2-基)氨基甲酸叔丁酯
1H NMR(400MHz,DMSO-d6):δ=7.86(bs,1H),6.90(bs,1H),6.83(s,1H),6.65(d,J=15.6Hz,1H),6.47(d,J=15.2Hz,1H),2.77(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),1.96-1.88(m,4H),1.37(s,9H),1.30(s,6H);MS(TOF):m/z(%)=488.23(100%)(M+H)+。
实施例-48
(E)-3-氨基-N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰亚胺酰胺
1H NMR(400MHz,DMSO-d6):δ=7.93(bs,1H),6.84-6.80(m,2H),6.56(d,J=15.2Hz,1H),2.77(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),1.95-1.88(m,4H),1.34(s,6H);MS(TOF):m/z(%)=388.17(100%)(M+H)+。
实施例-49
(E)-N'-氰基-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰亚胺酰胺
1H NMR(400MHz,DMSO-d6):δ=9.70(bs,1H),8.07(bs,1H),6.90(d,J=15.2Hz,1H),6.83(s,1H),6.52(d,J=15.6Hz,1H),2.78-2.75(m,10H),2.69(t,J=7.2Hz,4H),1.98-1.88(m,4H),1.45(s,6H);MS(TOF):m/z(%)=416.21(100%)(M+H)+。
实施例-50
(E)-3-氨基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-甲基丁-1-烯-1-磺酰亚胺酰胺
1H NMR(400MHz,DMSO-d6):δ=8.28(bs,1H),6.87(s,1H),6.72-6.64(m,2H),2.78(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),1.97-1.90(m,4H),1.30(s,6H);MS(TOF):m/z(%)=363.18(100%)(M+H)+。
生物活性:
体外测定:
用PMA(100ng/ml)分化THP1单核细胞并在5%CO2的存在下在37℃下孵育20小时。在96孔组织培养板的每孔中铺板2×105个分化细胞。使用500ng/ml脂多糖引发(primed)细胞,并在相同条件下孵育4小时。然后用各种浓度的化合物处理细胞30分钟,随后用5mM ATP处理1小时。收集上清液并通过IL-1b(Mabtech Cat#3415-1H-20)或TNF-a(Mabtech;Cat#3510-1H-20)检测试剂盒分析。使用GraphPad Prism V7.0分析数据。构建剂量响应曲线(DRC)以通过使用非线性回归分析将细胞存活百分比数据拟合至GraphPad Prism来确定IC50值。代表性化合物的体外IL-1β抑制活性(IC50)列于表1中。
表1
化合物 | IC<sub>50</sub>(nM) |
实施例1 | 43 |
实施例2 | 3.2 |
实施例5 | 20 |
实施例6 | 5.6 |
实施例18 | 6.6 |
实施例20 | 9.9 |
实施例21 | 6.0 |
实施例24 | 7.5 |
实施例35 | 11 |
实施例36 | 9.6 |
实施例38 | 3.6 |
实施例42 | 12.6 |
实施例47 | 3.8 |
实施例48 | 12 |
实施例49 | 6.5 |
体内功效研究:
测试化合物在大鼠小鼠、口服给药途径中的体内功效的证明。
动物
所有的动物实验在雌性大鼠和小鼠中进行,内部饲养。将动物以每笼6只动物的组,饲养一周,以便使它们适应饲养所条件(25±4℃,60-65%相对湿度,12:12h光:暗循环,在7.30am开始光照)。所有的动物实验根据“Zydus Research Center animal ethicalcommittee”批准后的国际有效指南进行。
体内LPS和ATP诱导的IL-1β测定:
雌性C57小鼠(6-8周)接受腹膜内注射50μg/小鼠的在PBS中的脂多糖(LPS)。立即用测试化合物或载体处理动物。在LPS注射2小时后,经由腹膜内途径向动物施用12.5mg/小鼠的溶于PBS的ATP。在ATP注射30分钟后,收集血清用于通过ELISA评估IL-1β。
本发明的新化合物可以通过熟知的技术和方法以及浓度与合适的赋形剂组合配制成合适的药物可接受的组合物。
式(I)的化合物或含有它们的药物组合物可用作抑制NLRP3活性的药物,并适用于人和其它温血动物,并且可以通过口服、局部或肠胃外给药。
因此,包含本发明的化合物的药物组合物可以包含合适的粘合剂、合适的填充剂和/或稀释剂以及可能需要的任何其它合适的试剂。任选地,药物组合物可以适当地用合适的包衣剂包衣。
本发明的化合物(I)是NLRP3抑制剂并且可用于治疗由NLRP3介导的疾病状态,优选其中涉及白介素1β活性的疾病或病症以及相关疾患。
在药物组合物及其单位剂型中的活性组分(即,根据本发明的式(I)的化合物)的量可以根据具体应用方法、具体化合物的效力和所需浓度而广泛地改变或调节。通常,活性组分的量将是组合物的0.5重量%至90重量%。
本发明的式(I)化合物可以单独使用或与一种或多种熟练的医学从业者可以容易地鉴定的其它治疗剂组合使用。此类其它治疗剂可以根据所治疗的疾病的类型、严重程度、患者服用的其它药物等来选择。因此,例如,对于类风湿性关节炎的治疗,一种或多种DMARD可以与本发明的化合物组合使用。
在一个实施方案中,本发明的式(I)的化合物可以与一种或多种选自以下治疗剂的适合的药物活性剂以任意组合组合使用。白细胞介素-1β的抑制剂(例如利纳西普(rilonacept)、康纳单抗(canakinumab)和阿那白滞素(anakinra));免疫抑制剂(例如,甲氨蝶呤、巯嘌呤、环磷酰胺)、代谢紊乱药物、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白(例如,英夫利昔单抗(Infliximab)、依那西普(etanercept))、干扰素-13、干扰素、白介素-2、抗组胺剂、β-激动剂、BTK抑制剂、抗胆碱能药、抗癌剂或它们的合适的药物可接受的盐。与非酒精性脂肪性肝炎(NASH)和纤维化药物、抗癌抗生素、激素、芳香酶抑制剂、抗体、细胞因子、疫苗、药物偶联物、丝裂原活化蛋白激酶信号传导抑制剂(例如:Bay43-9006)、Syk抑制剂、mTOR抑制剂、抗体(Rituxan)和BCR/ABL拮抗剂组合使用的其它实例。
本发明的组合物还与其它活性成分组合使用。为了治疗沙粒病毒科病毒感染,优选地,其它活性治疗剂对沙粒病毒科病毒感染,特别是拉沙病毒(Lassa virus)和胡宁病毒(Junin virus)感染具有活性。这些其它活性治疗剂的非限制性实例是利巴韦林(Ribavirin)、法韦吡韦(Favipiravir)(也称为T-705或Avigan)、T-705单磷酸酯、T-705二磷酸酯、T-705三磷酸酯、ST-193及其混合物。RNA依赖性RNA聚合酶(RDRP)调节剂,例如瑞德西韦(Remdesivir)。本发明的化合物和组合物还旨在与对患有沙粒病毒科病毒感染的患者提供的一般护理一起使用,包括肠胃外流体(包括右旋糖盐水和林格氏乳酸盐)和营养,抗生素(包括甲硝唑和头孢菌素抗生素,例如头孢曲松和头孢呋辛)和/或抗真菌预防,解热镇痛药物,止吐药(例如甲氧氯普胺)和/或止泻药,维生素和矿物质补充剂(包括维生素C或/和K以及硫酸锌),抗炎剂(例如布洛芬),抗炎和免疫抑制剂(例如***);止痛药物,以及用于患者人群中其它常见疾病的药物,例如抗疟药(包括蒿甲醚和青蒿琥酯-苯芴醇组合疗法),伤寒药(包括喹诺酮类抗生素,例如环丙沙星,大环内酯类抗生素,例如阿奇霉素,头孢菌素类抗生素,例如头孢曲松,或氨基青霉素类,例如氨苄青霉素),或志贺菌病。
虽然本发明已经就其具体实施方案进行了描述,但某些修改和等同对于本领域技术人员而言是显而易见的,并且旨在包括在本发明的范围内。
Claims (11)
1.具有通式(I)的结构的化合物:
其互变异构形式、其立体异构体、其对映异构体、其药物可接受的盐和含有它们的药物组合物,其中
R1和R2中的每一个在每次出现时独立地表示氢、卤素、卤代烷基、氰基、任选取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C3-C7)环烷基、(C1-C6)烷基SO2(C1-C6)烷基、(C1-C6)烷基N(C1-C6)烷基、(C1-C6)烷基N(C3-C7)环烷基、芳基、杂芳基、杂环基、苄基、叔丁氧基羰基、硫醇、巯基烷基、SO2(C1-C6)烷基、SO2(C3-C7)环烷基、SO2-芳基、SO2-杂环基、(C1-C6)硫代烷基、(C1-C6)硫代烷氧基、(C1-C6)烷基SO2NH2、-CONH2、-CO(C1-C6)烷基、-CO(C1-C6)卤代烷基、CO(O)(C1-C6)烷基、-CO-芳基、-CO-杂芳基、-CO-杂环基、4至7元杂环、7至14元双环杂环体系、任选地具有一个或多个杂原子的桥环或螺环体系;或者R1、R2和N一起可以形成饱和或部分饱和的3至8元杂环体系、7至14元双环杂环体系、任选地具有一个或多个杂原子的桥环或螺环体系;
R3和R4中的每一个在每次出现时表示氢、卤素、卤代烷基、氰基、硝基、酰胺、磺酰胺、酰基、羟基、任选取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C6)环烷基、(C1-C6)烷氧基、SO2(C1-C6)烷基、硫醇、巯基烷基苄基、芳基、杂芳基、杂环基;或者R3和R4可以形成键;
X是O、N-R6;其中R6在每次出现时独立地表示氢、羟基、卤素、硝基、氰基、卤代烷基、任选取代的选自以下的基团:(C1-C10)烷基、(C1-C10)烷氧基、(C3-C10)环烷基、(C2-C10)烯基、(C2-C10)炔基、SO2(C1-C6)烷基、硫醇、硫代烷基、硫代烷氧基、SO2(C1-C6)烷基、SO(C1-C6)烷基、苄基、芳基、杂芳基、杂环基;
n独立地选自整数0至3;
R5在每次出现时独立地表示氢、卤素、卤代烷基、氰基、任选取代的选自以下的基团:(C1-C6)烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C3-C7)环烷基、苄基、芳基、杂芳基、杂环基、硫醇、硫代烷基、硫代烷氧基、SO2(C1-C6)烷基、SO(C1-C6)烷基、任选地具有一个或多个杂原子的桥环或螺环体系;
“A”选自以下环系
其中X、Y、Z在每次出现时独立地表示C、N、S、SO2和O,其可以被任选地取代;
R7、R8、R9、R10、R11和R12中的每一个在每次出现时独立地选自氢、卤素、氰基、酰胺、磺酰胺、酰基、羟基、任选取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C6)环烷基、(C1-C6)烷氧基、苄基、芳基、杂芳基、杂环基;或者R8和R9、R9和R10、R10和R11以及R11和R12中的每一个在可能的情况下可以一起形成含有0至2个选自N、O和S(O)p的另外的杂原子的4至7元饱和或部分饱和的环;p=1至2。
2.如权利要求1所述的化合物,其中R3和R4在每次出现时独立地选自氢、卤素、任选取代的选自以下的基团:(C1-C6)烷基。
3.如权利要求1所述的化合物,其中R5在每次出现时独立地选自氢、卤素、任选取代的选自以下的基团:(C1-C6)烷基。
4.如权利要求1所述的化合物,其中R6在每次出现时独立地选自任选取代的选自以下的基团:氢、氰基。
5.如权利要求1所述的化合物,其中R7、R8、R9、R10、R11和R12中的每一个在每次出现时独立地选自氢、卤素、任选取代的选自以下的基团:(C1-C6)烷基、(C1-C6)卤代烷基。
6.如前述权利要求中任一项所述的化合物,其中当任何以上基团被取代时,所述取代选自氢、羟基、氰基、卤代、卤代烷基、卤代烷氧基、烷基硫代、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C10)环烷基、C1-(C1-C6)烷氧基、芳基、杂环基、杂芳基、-COR11、-CSR11、C(O)OR11、C(O)-R11、-C(O)-NR11R12、-C(S)-NR11R12、-SO2R11基团,其中R11和R12中的每一个独立地选自氢、任选取代的选自以下的基团:(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C7)环烷基、芳基、杂芳基、杂环基基团。
7.如权利要求1所述的化合物,其选自:
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(异丙基氨基)丙-1-烯-1-磺酰胺;
(E)-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(丙基)氨基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(丙基氨基)丙-1-烯-1-磺酰胺;
(E)-3-((环丙基甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-3-((环丙基甲基)(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-3-(乙基(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(N-甲基甲基磺酰胺基)丙-1-烯-1-磺酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)-N-甲基环丙烷磺酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)-N-甲基环己烷磺酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)环己烷磺酰胺;
(E)-3-((环己基甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-3-((环己基甲基)(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)-N-甲基环己烷甲酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)-N-甲基乙酰胺;
(E)-N-(3-(N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)氨磺酰基)烯丙基)-N-甲基环丙烷甲酰胺;
(E)-N-((2,6-二异丙基苯基)氨基甲酰基)-3-(二甲基氨基)丙-1-烯-1-磺酰胺;
(E)-N-((2,6-二异丙基-4-甲基苯基)氨基甲酰基)-3-(二甲基氨基)丙-1-烯-1-磺酰胺;
(E)-3-(二甲基氨基)-N-((4-氟-2,6-二异丙基苯基)氨基甲酰基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(苯基)氨基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(苯基氨基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(噻唑-2-基氨基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(噻唑-2-基)氨基)丙-1-烯-1-磺酰胺;
(E)-N'-氰基-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-3-(乙基(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-3-((环丙基甲基)(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-3-((环丙基甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-3-(二甲基氨基)-N-((4-氟-2,6-二异丙基苯基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-3-((环丙基甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-3-((环丙基甲基)(甲基)氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-3-(二甲基氨基)-N-((4-氟-2,6-二异丙基苯基)氨基甲酰基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-3-(二甲基氨基)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-N'-甲基丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(甲基(氧杂环丁烷-3-基)氨基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N'-氰基-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(氧杂环丁烷-3-基氨基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(氧杂环丁烷-3-基氨基)丙-1-烯-1-磺酰亚胺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(氧杂环丁烷-3-基氨基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(5-(甲基磺酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(3,4,5,6-四氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺;
(E)-N-((1,2,3,5,6,7-六氢-s-引达省-4-基)氨基甲酰基)-3-(5-(甲基磺酰基)-3,4,5,6-四氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-1-磺酰胺
或上述任何化合物的药物可接受的盐。
8.药物组合物,其包含治疗有效量的前述权利要求中任一项所述的式(I)的化合物和任选的一种或多种药物可接受的载体、稀释剂或赋形剂。
9.通过NLRP3调节剂用药治疗疾病以及治疗其中涉及白介素1β活性和白介素-18(IL-18)的疾病或病症的方法,所述方法包括向有需要的患者施用有效量的前述权利要求中任一项所述的式(I)的化合物或其合适的药物组合物。
10.前述权利要求中任一项所述的式(I)的化合物或其药物组合物适于治疗疾病的用途,其中所述NLRP3调节剂具有病理生理学功能。
11.如权利要求8所述的药物组合物,其与一种或多种选自以下的合适的药物活性剂组合使用:白介素-1β抑制剂;免疫抑制剂;代谢紊乱药物,糖皮质激素,非甾体抗炎药,COX-2特异性抑制剂,抗炎药,TNF-α结合蛋白,干扰素-13,干扰素,白介素-2,抗组胺剂,β-激动剂,BTK抑制剂,抗胆碱能药,抗癌剂或它们的合适的药物可接受的盐,非酒精性脂肪性肝炎(NASH)和纤维化药物,抗癌药物,抗生素,激素,芳香酶抑制剂,丝裂原活化蛋白激酶信号传导的抑制剂,Syk抑制剂,mTOR抑制剂,BCR/ABL拮抗剂,沙粒病毒科病毒感染,特别是拉沙病毒和胡宁病毒感染,抗生素和/或抗真菌预防,解热镇痛药物,止吐和/或止泻剂,维生素和矿物质补充剂,抗炎剂,抗炎和免疫抑制剂,止痛药和用于患者人群中其它常见疾病的药物,抗疟药和头孢菌素类抗生素。
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WO2019043610A1 (en) * | 2017-08-31 | 2019-03-07 | Cadila Healthcare Limited | NEW SUBSTITUTED SULFONYLUREA DERIVATIVES |
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