WO2019062949A1 - 具有erk激酶抑制活性的化合物及其用途 - Google Patents

具有erk激酶抑制活性的化合物及其用途 Download PDF

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WO2019062949A1
WO2019062949A1 PCT/CN2018/108762 CN2018108762W WO2019062949A1 WO 2019062949 A1 WO2019062949 A1 WO 2019062949A1 CN 2018108762 W CN2018108762 W CN 2018108762W WO 2019062949 A1 WO2019062949 A1 WO 2019062949A1
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alkyl
group
optionally substituted
compound
independently selected
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PCT/CN2018/108762
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English (en)
French (fr)
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李磊
耿美玉
黄颖
丁健
张琼
黄敏
唐帅
沈宁
陈奕
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上海海和药物研究开发有限公司
中国科学院上海药物研究所
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Priority to MX2020003240A priority Critical patent/MX2020003240A/es
Priority to JP2020539131A priority patent/JP7216105B2/ja
Priority to NZ763197A priority patent/NZ763197A/en
Priority to EP18862819.2A priority patent/EP3702354B1/en
Application filed by 上海海和药物研究开发有限公司, 中国科学院上海药物研究所 filed Critical 上海海和药物研究开发有限公司
Priority to CA3080623A priority patent/CA3080623C/en
Priority to AU2018339722A priority patent/AU2018339722B2/en
Priority to KR1020207012147A priority patent/KR20200078510A/ko
Priority to BR112020006294-4A priority patent/BR112020006294A2/pt
Priority to IL273655A priority patent/IL273655B2/en
Priority to US16/652,148 priority patent/US11465984B2/en
Priority to CN201880001907.6A priority patent/CN109863147A/zh
Priority to SG11202002968UA priority patent/SG11202002968UA/en
Priority to EA202090888A priority patent/EA202090888A1/ru
Publication of WO2019062949A1 publication Critical patent/WO2019062949A1/zh
Priority to ZA2020/01823A priority patent/ZA202001823B/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry.
  • the present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, which is used as an extracellular signal-regulated kinase (extracellular signal-regulated kinase) , ERK) pathway regulators, particularly as inhibitors of ERK kinases, such as ERK1 and/or ERK2 kinase.
  • extracellular signal-regulated kinase extracellular signal-regulated kinase
  • ERK extracellular signal-regulated kinase pathway regulators
  • the Ras-Raf-MEK-ERK pathway is a mitogen activated protein kinase (MAPK) signaling pathway that regulates cell proliferation, differentiation and apoptosis. Mutations in this pathway exist in more than one-third of all human cancers, so in recent years, nodulin on this pathway has become a hot spot for cancer-targeted drug development.
  • the specific B-Raf inhibitors vemurafenib and dabrafenib were approved by the US FDA for melanoma treatment in 2011 and 2013, respectively.
  • the MEK1/2 inhibitor trametinib (trametinib) was approved by the US FDA for the treatment of melanoma in 2013.
  • vemurafenib was combined with the MEK inhibitor cobimetinib to be approved by the US FDA for the treatment of B-Raf V600E or V600K mutations in melanoma.
  • the US FDA also approved the combination of darafini and trimetinib for the treatment of B-Raf V600E mutant non-small cell lung cancer.
  • inhibition of these upstream pathway nodes has its limitations. Tumors can rapidly develop resistance to B-Raf and MEK inhibitors.
  • the mechanisms of drug resistance include point mutations, protein polymorphism changes, and protein peptide chain length changes. This is a great challenge for developing the next generation of drugs for Raf and MEK.
  • activated ERK can transmit extracellular signals to the nucleus, promote phosphorylation of cytoplasmic target proteins or regulate the activity of other protein kinases, thereby regulating gene expression. Its importance is unquestionable in the development of oncology drugs. Especially in the current targeted therapy of most MAPK upstream, most of the drug resistance phenomenon appears. ERK inhibitors may become more effective treatment because they are less likely to produce acquired drug resistance. Since ERK was discovered in the 1990s, there has been a lot of extensive and in-depth research, but so far no ERK inhibitor has been approved for marketing. Currently leading internationally is the highly selective ERK inhibitor BVD-523 (Ulixertinib) in phase 2 clinical.
  • Patent application WO 2017/114510 A1 discloses a series of ERK inhibitors, but the inventors of the present application have found that in this patent application, some compounds, especially having a structure The compounds have poor chemical stability and are prone to impurities, especially when exposed to alkaline conditions. Such properties of the compounds pose certain difficulties for drug development; some have structures.
  • a compound in which R 3 is a halogen, an unsubstituted alkyl group, a halogenated alkyl group, a halogenated alkyl group or the like has good chemical stability, also has good solubility and permeability, and has both an enzyme test and a cell test.
  • ERK kinase inhibits activity and has good pharmacokinetic parameters, and is particularly suitable for drug development.
  • the invention provides novel ERK kinase inhibitors. Specifically, the present invention provides the following embodiments:
  • Embodiment 1 A compound of Formula (I), or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate thereof, or a pharmaceutically acceptable salt thereof,
  • X 1 is selected from the group consisting of: CR 9a and N;
  • X 2 is selected from the group consisting of: CR 9b and N;
  • X 3 is selected from the group consisting of: CR 9c and N; and at most one of X 1 , X 2 and X 3 is N;
  • Y 1 and Y 2 are each independently selected from: CR 9 ' and N;
  • R 9a , R 9b and R 9c are each independently selected from: H, D, halogen, -OH, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl Carbonyl, optionally substituted alkoxycarbonyl, optionally substituted cycloalkyl, amino, optionally substituted mono or di(alkyl)amino and -CONR a R b ;
  • R 9 ' is selected from the group consisting of: H, D, halogen, -OH, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylcarbonyl, optionally substituted alkane An oxycarbonyl group, an optionally substituted cycloalkyl group, an amino group, an optionally substituted mono or di(alkyl)amino group, and CONR a R b ;
  • R 1 is selected from the group consisting of: H and D;
  • R 2 is selected from the group consisting of an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, or R 2 together with X 1 to form an optionally substituted heterocyclic group;
  • R 3 is selected from the group consisting of: halogen and optionally substituted alkyl
  • R 4 is selected from the group consisting of: H, D, optionally substituted alkyl, optionally substituted alkoxy, -CO(CR 10 R 11 ) m R 12 , -SO 2 (CR 10 R 11 ) m R 12 , -CONR 13 (CR 10 R 11 ) m R 12 , -COO(CR 10 R 11 ) m R 12 , -CR 13 R 13 '(CR 10 R 11 ) m R 12 and C 1-8 alkylcarbonyl- Where m is 0, 1, 2 or 3, and wherein
  • R 10 and R 11 are each independently selected from: H, D, halogen, optionally substituted alkyl and optionally substituted alkoxy; or R 10 is bonded to R 11 to form an optionally substituted cycloalkyl. , cycloalkenyl, aryl, heteroaryl and heterocyclic;
  • R 12 are each independently selected from the group consisting of: H, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, and an optionally substituted hetero Aryl; and
  • R 13 and R 13 ' are each independently selected from: H and an optionally substituted alkyl; or R 13 and R 13 ' together with an adjacent carbon form an optionally substituted cycloalkyl, cycloalkenyl and hetero Ring base
  • R 5 , R 6 , R 7 and R 8 are each independently selected from: -H, -D, halogen, -OH, amino, cyano, optionally substituted alkyl, optionally substituted alkoxy, -(CH 2 ) 0-3 CONR a R b , -(CH 2 ) 0-3 COOH, an optionally substituted cycloalkyl group and an optionally substituted heterocyclic group; or R 5 , R 6 , R 7 And any two of R 8 together with an adjacent carbon form an optionally substituted cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic group;
  • R a and R b are each independently selected from the group consisting of: H, D, and optionally substituted alkyl;
  • the optional substituents are independently selected from: deuterium (D), halogen, -OH, a mercapto group, a cyano group, -CD 3, -C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, 3-8 membered cycloalkyl, aryl, 3-8 membered heterocyclyl, heteroaryl, aryl-C 1 -C 6 alkyl-, heteroaryl-C 1 -C 6 alkane -C 1 -C 6 haloalkyl-, -OC 1 -C 6 alkyl, -OC 2 -C 6 alkenyl, -OC 1 -C 6 alkylphenyl, -C 1 -C 6 alkyl- OH, -C 1 -C 6 alkyl-SH, -C 1 -C 6 alkyl-OC 1 -C 6 alkyl, -OC 1 -C 6 hal
  • Embodiment 2 The compound of Embodiment 1 or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate thereof or pharmaceutically acceptable thereof Salt, which is characterized by:
  • X 1 is selected from the group consisting of: CR 9a and N;
  • X 2 is selected from the group consisting of: CR 9b and N;
  • X 3 is selected from the group consisting of: CR 9c and N; and at most one of X 1 , X 2 and X 3 is N;
  • Y 1 and Y 2 are each independently selected from: CR 9 ' and N;
  • R 9a , R 9b and R 9c are each independently selected from: H, D, halogen, -OH, cyano, optionally substituted C 1-3 alkyl, optionally substituted C 1-3 alkoxy , optionally substituted C 1-3 alkylcarbonyl, optionally substituted C 1-3 alkoxycarbonyl, optionally substituted C 3-8 cycloalkyl, amino, optionally substituted s- Or a di-(C 1-3 alkyl)amino group and -CONR a R b ;
  • R 9 ' is selected from the group consisting of: H, D, halogen, -OH, cyano, optionally substituted C 1-3 alkyl, optionally substituted C 1-3 alkoxy, optionally substituted C 1 -3 alkylcarbonyl, optionally substituted C 1-3 alkoxycarbonyl, optionally substituted C 3-8 cycloalkyl, amino, optionally substituted mono- or di-(C 1-3 Alkyl)amino and CONR a R b ;
  • R 1 is selected from the group consisting of: H and D;
  • R 2 is selected from the group consisting of an optionally substituted C 1-8 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted 3-8 membered heterocyclic group, and optionally substituted 6- a 12-membered aryl group and an optionally substituted 5-12 membered heteroaryl group such as a 5-7 membered heteroaryl group, or R 2 and X 1 are taken together to form an optionally substituted 3-8 membered heterocyclic group;
  • R 3 is selected from the group consisting of: halogen and C 1-8 alkyl optionally substituted with one or more substituents independently selected from D and halogen;
  • R 4 is selected from the group consisting of: H, D, optionally substituted C 1-8 alkyl, optionally substituted C 1-8 alkoxy, -CO(CR 10 R 11 ) m R 12 , -SO 2 ( CR 10 R 11 ) m R 12 , -CONR 13 (CR 10 R 11 ) m R 12 , -COO(CR 10 R 11 ) m R 12 , -CR 13 R 13 '(CR 10 R 11 ) m R 12 and C 1-8 alkylcarbonyl-; wherein m is 0, 1, 2 or 3, and wherein
  • R 10 and R 11 are each independently selected from: H, D, halogen, optionally substituted C 1-8 alkyl, and optionally substituted C 1-8 alkoxy, or R 10 is bonded to R 11 An optionally substituted cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic group;
  • R 12 is each independently selected from: H, optionally substituted C 1-3 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally a substituted 6-12 membered aryl group and an optionally substituted 5-12 membered heteroaryl group such as a 5-7 membered heteroaryl group;
  • R 13 and R 13 ' are each independently selected from: H and optionally substituted C 1-3 alkyl; or R 13 and R 13 ' together with adjacent carbons form an optionally substituted C 3-8 ring An alkyl group, a C 4-8 cycloalkenyl group, and a C 5-8 heterocyclic group;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from: -H, -D, halogen, -OH, amino, cyano, optionally substituted C 1-3 alkyl, optionally substituted C 1-3 alkoxy, -(CH 2 ) 0-3 CONR a R b , -(CH 2 ) 0-3 COOH, optionally substituted C 3-8 cycloalkyl, and optionally substituted 3 An 8- to 8-membered heterocyclic group; or any two of R 5 , R 6 , R 7 and R 8 together with an adjacent carbon form an optionally substituted cycloalkyl, cycloalkenyl, aryl, heteroaryl group and Heterocyclic group;
  • R a and R b are each independently selected from the group consisting of: H, D, and optionally substituted C 1-3 alkyl.
  • R 9a , R 9b and R 9c are each independently selected from the group consisting of: H, D, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, —OH, cyano, halogen, amino, Mono- or di-(C 1-3 alkyl)amino, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl and C 3-8 cycloalkyl; preferably, R 9a , R 9b and R 9c are each independently selected from: H, D and C 1-3 alkyl; more preferably, R 9a , R 9b and R 9c are each independently selected from: H and D;
  • Y 1 is CR 9 '
  • Y 2 is CR 9 '
  • R 9 ' is selected from H, D, halogen and C 1-3 alkyl; more preferably, Y 1 is CR 9 ' and Y 2 is CR 9 ', and wherein R 9 'is H, D, F or methyl;
  • Y 1 is CR 9 ', Y 2 is N, and wherein R 9 ' is selected from H, D, halogen and C 1-3 alkyl; more preferably, Y 1 is CR 9 ', Y 2 is N, and wherein R 9 'is H, D, F or methyl;
  • Y 1 is N, Y 2 is CR 9 ', and wherein R 9 ' is selected from H, D, halogen, and C 1-3 alkyl; more preferably, Y 1 is N, Y 2 is CR 9 ', and wherein R 9 'is H, D, F or methyl;
  • Y 1 is N and Y 2 is N.
  • Embodiment 5 The compound of Embodiment 1 or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate thereof or pharmaceutically acceptable thereof Salt, characterized in that the compound has the structure shown in formula Ie:
  • X 1 is selected from the group consisting of CR 9a and N, wherein R 9a is selected from the group consisting of H, D, halogen, -OH, cyano, C 1-3 alkyl, C 1- 3- haloalkyl, C 1-3 alkoxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 3-8 cycloalkyl, amino and mono- or di-(C 1-3 alkane
  • X 1 is selected from the group consisting of CR 9a and N, wherein R 9a is selected from the group consisting of H, D and C 1-3 alkyl; more preferably, X 1 is selected from the group consisting of CH, CD and N.
  • R 2 is selected from the group consisting of an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted 3-8 membered heterocyclic group, and an optionally substituted 5- 12 yuan heteroaryl group such as a 5-7 membered heteroaryl, wherein the optional substituent is one or more groups independently selected from D, halogen, hydroxy, -CD 3, C 1-6 alkyl and hydroxy C 1- a substituent of a 6 alkyl group, preferably one or more substituents independently selected from the group consisting of D, halogen, hydroxy, -CD 3 , -CH 3 and -CH 2 OH;
  • R 2 is selected from: C 1-6 alkyl optionally substituted by one or more hydroxy groups, C 3-8 cycloalkyl optionally substituted by one or more hydroxy groups, 3-8 membered heterocyclic group, and optionally a 5-12 membered heteroaryl group substituted with one or more -CD 3 , C 1-6 alkyl and hydroxy C 1-6 alkyl groups such as a 5-7 membered heteroaryl;
  • R 2 is selected from the group consisting of: C 1-4 alkyl, They are optionally substituted by one or more substituents independently selected from the group consisting of D, halogen, hydroxy, C 1-4 alkyl, -CD 3 and hydroxy C 1-4 alkyl, preferably by one or more independently Substituent substitution selected from D, halogen, hydroxy, -CH 3 , -CD 3 and -CH 2 OH;
  • R 2 is selected from the group consisting of: isopropyl
  • R 2 is selected from
  • R 2 is selected from
  • R 3 is selected from the group consisting of halogen and C 1-6 alkyl optionally substituted by one or more substituents independently selected from D or halogen; or, R 3 is selected from Halogen and a C 1-3 alkyl group optionally substituted by one or more substituents independently selected from D or halogen; or, R 3 is selected from halogen and C 1-6 alkyl; or R 3 is selected from fluorine, Chlorine, bromine, iodine, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CF 3 , -CHF 2 , CF 3 CH 2 - and CD 3 -; Alternatively, R 3 is selected from the group consisting of fluorine, chlorine, and
  • R 4 is selected from -CO(CR 10 R 11 ) m R 12 and -CR 13 R 13 '(CR 10 R 11 ) m R 12 ; wherein m is 0, 1, 2 or 3, and wherein
  • R 10 and R 11 are each independently selected from H, D and C 1-4 alkyl optionally substituted by hydroxy;
  • R 12 are each independently selected from: an optionally substituted 6-12 membered aryl group and an optionally substituted 5-12 membered heteroaryl group such as a 5-7 membered heteroaryl group;
  • R 13 and R 13 ' are each independently selected from the group consisting of H, C 1-3 alkyl and C 1-3 haloalkyl.
  • Embodiment 10 The compound of Embodiment 9 or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate thereof or pharmaceutically acceptable thereof Salts, characterized in that R 12 are each independently selected from an optionally substituted 6-12 membered aryl group and an optionally substituted 5-12 membered heteroaryl group such as a 5-7 membered heteroaryl group, optionally A substituent is one or more substituents independently selected from the group consisting of D, halogen, C 1-4 alkyl, cyano and C 3-8 heterocyclyl-(CH 2 ) 0-4 - (eg morpholine) Such as morpholino, piperazinyl, tetrahydropyranyl such as tetrahydropyran-4-yl, morpholinylmethyl such as morpholinomethyl or piperazinylmethyl);
  • R 12 is selected from the group consisting of: an optionally substituted phenyl group and an optionally substituted pyridyl group such as pyridin-3-yl, wherein the optional substituent is one or more substituents independently selected from the group consisting of: D, halogen, C 1-4 alkyl (such as methyl or ethyl), cyano and C 3-8 heterocyclyl-(CH 2 ) 0-4 - (eg morpholino such as morpholino, piperazine a pyridyl group, a tetrahydropyranyl group such as tetrahydropyran-4-yl, morpholinylmethyl such as morpholinomethyl or piperazinylmethyl);
  • R 12 is selected from: Wherein Rc is selected from halogen such as fluorine or chlorine, C 1-4 alkyl such as methyl, Wherein R d is selected from H, C 1-4 alkyl such as methyl or ethyl and Wherein R e is selected from the group consisting of halogens such as fluorine and chlorine, and p is 1 or 2; Wherein R f is selected from:
  • R 4 is selected from -CO(CR 10 R 11 ) m R 12 , wherein m is 0, 1, 2 or 3, and wherein
  • R 10 and R 11 are each independently selected from H;
  • R 12 is selected from
  • R 4 is selected from -CO(CR 10 R 11 ) m R 12 , wherein m is 0, 1, 2 or 3, and wherein R 10 and R 11 are each independently selected From H;
  • R 12 is selected from the group consisting of 2-cyanophenyl, 5-chloro-2-fluorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5- Fluorophenyl, 2,5-difluorophenyl, 3-chloropyridin-2-yl, 6-chloropyridin-2-yl, 3-chloropyridin-4-yl or 4-chloropyridin-3-yl.
  • R 5 , R 6 , R 7 and R 8 are each independently selected from: -H, -D, halogen, -OH, amino, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, -(CH 2 ) 0-3 CONR a R b , -(CH 2 ) 0-3 COOH, optionally substituted C 3-8 cycloalkyl, and optionally substituted 3
  • An 8- to 8-membered heterocyclic group wherein the optional substituent is one or more substituents independently selected from the group consisting of D, -OH, -OC 1 -C 6 alkyl, and NH 2 , and wherein R a And R b are each independently selected from the group consisting of H, D and C 1-3 alkyl;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from H, C 1-6 alkyl optionally substituted by hydroxy or -OC 1 -C 6 alkyl;
  • R 5 and R 6 are each independently selected from H or C 1-6 alkyl; and R 7 and R 8 are each independently selected from H and C optionally substituted by hydroxy or -OC 1 -C 6 alkyl 1-6 alkyl;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from -H, -CH 3 and -CH 2 OH;
  • R 5 , R 6 and R 7 are H
  • R 8 is H, -CH 3 or -CH 2 OH.
  • Embodiment 14 Compounds selected from the examples P1-P20, P23-P25, P28-51, P53-P64:
  • the invention also provides a pharmaceutical composition comprising the above novel compound, the use of the above novel compound, and a method of treatment using the novel compound described above:
  • Embodiment 16 A pharmaceutical composition comprising a compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
  • Embodiment 18 A method of non-therapeutic inhibition of ERK kinase activity, the method comprising: contacting an effective amount of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, with ERK kinase, thereby inhibiting ERK kinase.
  • the invention also provides intermediates for the preparation of the novel compounds described above (e.g., intermediate 1-82, particularly intermediate 25 disclosed herein) and methods (e.g., the methods illustrated in Figures 1-4, Especially the method of Figure 3):
  • Embodiment 19 A compound having the following structure (4-(7-fluorodihydropurin-5-yl)pyridin-2-yl)(1-methyl-1H-pyrazol-5-yl)carbamic acid tert-butyl An ester or a stereoisomer thereof, a racemate, a geometric isomer, a tautomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof:
  • Embodiment 20 The compound of formula (I) as described in embodiment 1, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate thereof or A method of a pharmaceutically acceptable salt, the compound of formula (I) being a compound of formula C3:
  • the method comprises the following steps:
  • Embodiment 21 The method of Embodiment 20, wherein the amide coupling reaction is carried out in the presence of a condensation reagent and a base in an inert solvent.
  • the inert solvent is selected from the group consisting of ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, dichloro Methane, 1,2-dichloroethane, N-methyl-2-pyrrolidone or a combination thereof.
  • condensation reagent is selected from the group consisting of: 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azobenzotriazole (HOAT), hexafluorophosphate Benzotriazol-1-yl-oxytripyrrolidinium oxime (PyBOP), benzotriazol-1-tris(trimethylamino)-hexafluorophosphate (BOP), 1,1-carbonyldiimidazole (CDI) ), 1-propylphosphoric anhydride (T 3 P), 1-ethyl-3-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (EDC ⁇ HCl), N,N-II Cyclohexylcarbodiimide (DCC), acetic anhydride, acetyl chloride, oxalyl chloride, 2-(7-oxidized benzotriazole)-N,N,N',N'-tetramethyluron
  • the base is selected from the group consisting of: triethylamine, DIPEA, pyridine, 2,4-dimethylpyridine, NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , One or more of NaHCO 3 , Cs 2 CO 3 , Na 3 PO 4 or K 3 PO 4 .
  • the acid is selected from one or more of the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, formic acid, and phosphoric acid.
  • a short cross (“-") between two letters or symbols indicates the attachment site of the substituent.
  • -O(C 1-3 alkyl) refers to a C 1-3 alkyl group attached to the remainder of the molecule through an oxygen atom.
  • "-" can be omitted.
  • the wavy line indicates the point of attachment of the group to the rest of the molecule.
  • alkyl refers to a straight chain having from 1 to 8 carbon atoms, for example having from 1 to 6 carbon atoms, for example having from 1 to 4 carbon atoms, for example having 1, 2 or 3 carbon atoms or Branched saturated monovalent hydrocarbon groups.
  • C 1-8 alkyl means an alkyl group having 1-8 carbon atoms.
  • C 1-4 alkyl means an alkyl group having 1 to 4 carbon atoms;
  • C 1-3 alkyl means an alkyl group having 1 to 3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), n-propyl (“n-Pr”), isopropyl (“i-Pr”), n-butyl ( “n-Bu”), isobutyl (“i-Bu”), sec-butyl (“s-Bu”), tert-butyl (“t-Bu”), and the like.
  • Me methyl
  • Et ethyl
  • i-Pr isopropyl
  • n-Bu isobutyl
  • i-Bu isobutyl
  • sec-butyl sec-butyl
  • s-Bu sec-butyl
  • t-Bu tert-butyl
  • C carbon-carbon double bonds
  • C 2-6 alkenyl means an alkenyl group having 2 to 6 carbon atoms containing 1 or 2, preferably 1 carbon-carbon double bond.
  • C 2-3 alkenyl means an alkenyl group having 2-3 carbon atoms containing one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, 2-propenyl and 2-butenyl.
  • alkynyl refers to a radical having from 2 to 8 carbon atoms, for example 2 to 6 carbon atoms, containing one or more, for example 1, 2 or 3 carbon-carbon triple bonds (C ⁇ C).
  • C ⁇ C carbon-carbon triple bonds
  • a linear or branched monovalent hydrocarbon group of 2 to 4 carbon atoms For example, "C 2-6 alkynyl” means an alkynyl group having 2 to 6 carbon atoms containing 1 or 2, preferably 1 carbon-carbon triple bond.
  • C 2-3 alkynyl means an alkynyl group having 2-3 carbon atoms containing one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.
  • alkoxy refers to the group -O-alkyl, wherein alkyl is as defined above.
  • C 1-8 alkoxy means -OC 1-8 alkyl, that is, an alkoxy group having 1-8 carbon atoms.
  • C 1-3 alkoxy means -OC 1-3 alkyl, that is, an alkoxy group having 1 to 3 carbon atoms.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like. This definition applies regardless of whether the term "alkoxy" is used alone or as part of another group.
  • halo refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I), preferably fluorine and chlorine, most preferably fluorine.
  • haloalkyl refers to an alkyl radical, as defined herein, wherein one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen, and when more than one hydrogen atom is halogenated In the case of atom substitution, the halogen atoms may be the same or different from each other. Examples of haloalkyl include, but are not limited to -CF 3, -CHF 2, -CH 2 CF 3 and the like.
  • hydroxy refers to the group -OH.
  • mercapto refers to the group -SH.
  • cyano refers to the group -CN.
  • carboxy refers to the group -C(O)-OH, which may also be referred to as -COOH.
  • carbonyl refers to the group -C(O)-, which may also be referred to as -CO-.
  • amino refers to the group -NH 2 .
  • alkylamino or “monoalkylamino” as used herein, refers to the group alkyl-NH-, wherein alkyl is as defined herein.
  • dialkylamino refers to the group (alkyl) 2 -N-, wherein alkyl is as defined herein.
  • alkylcarbonyl refers to an alkyl group attached to the other group through a carbonyl group, ie, alkyl-C(O)-, wherein alkyl is as defined herein.
  • alkoxycarbonyl refers to an alkoxy group attached to the other group through a carbonyl group, ie, alkoxy-C(O)-, wherein alkoxy is as defined herein.
  • nitro refers to the group -NO 2 .
  • cycloalkyl refers to a saturated monovalent monocyclic or bicyclic hydrocarbon group having from 3 to 12 ring carbon atoms, for example having from 3 to 8 ring carbon atoms, for example having from 3 to 6 ring carbon atoms.
  • C 3-8 cycloalkyl means a cycloalkyl group having 3 to 8 ring carbon atoms.
  • C 3-6 cycloalkyl means a cycloalkyl group having 3 to 6 ring carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkenyl refers to a cycloalkyl group, as defined herein, containing one or more double bonds, for example 1, 2, 3 or 4 double bonds, the ring of which is non-aromatic ring.
  • C 3-8 cycloalkenyl means a cycloalkenyl group having 3 to 8 ring carbon atoms.
  • C 3-6 cycloalkenyl means a cycloalkenyl group having 3 to 6 ring carbon atoms.
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • heterocyclyl or “heterocyclic” or “heterocycle” as used herein, refers to having from 3 to 20 ring atoms, for example having from 3 to 12 ring atoms, for example from 3 to 8 ring atoms, for example 3- a 6 ring atomic monocyclic, bicyclic or tricyclic, saturated and partially unsaturated non-aromatic ring comprising, in addition to 1-4, for example 1-3, for example 1 or 2, for example 1 In addition to the heteroatoms selected from O, S and N, it also contains at least one carbon atom.
  • the "heterocyclyl” or “heterocyclic” or “heterocycle” refers to a monocyclic ring having from 3 to 8 ring atoms, for example 3, 4, 5 or 6 ring atoms, in addition to Including from 1 to 4, for example 1 to 3, for example 1 or 2, for example 1 hetero atom selected from O, S and N, further comprising at least one carbon atom.
  • the "heterocyclyl” or “heterocyclic” or “heterocycle” comprises 0, 1, 2 or 3 double bonds.
  • Any nitrogen or sulfur heteroatom may optionally be oxidized (eg, NO, SO, SO 2 ), and any nitrogen heteroatom may optionally be quaternized (eg, [NR 4 ] + Cl ⁇ , [NR 4 ] + OH - ).
  • the heterocyclic group having 3 to 8 ring atoms is also abbreviated as a 3-8 membered heterocyclic group, and a heterocyclic group having another carbon number can also be similarly expressed.
  • heterocyclic groups include, but are not limited to, oxiranyl, aziridine, thietyl, azetidinyl, oxetanyl, thietane, 1,2 -dithietyl, 1,3-dithiot-butyl, pyrrolidinyl (pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), dihydro-1H -pyrrolyl, dihydrofuranyl, tetrahydrofuranyl (eg tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrafluorofuran-4-yl), dihydrothienyl, tetrahydrothiophenyl, imidazolidinyl, piperidine Base, piperazinyl (eg piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl
  • Examples of 5-membered heterocyclic groups containing a sulfur or oxygen atom and 1 to 3 nitrogen atoms are: thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1, 3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, Azolyl, for example Zin-2-yl, and Diazolyl, such as 1,3,4- Diazol-5-yl and 1,2,4- Diazol-5-yl.
  • Examples of the 5-membered ring heterocyclic group having 2 to 4 nitrogen atoms include: an imidazolyl group such as imidazol-2-yl; a triazolyl group such as 1,3,4-triazol-5-yl; 1,2 , 3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl.
  • An example of a benzo-fused 5-membered heterocyclic group is benzo. Zyridin-2-yl, benzothiazol-2-yl and benzimidazol-2-yl.
  • An exemplary 6-membered heterocyclic group contains 1 to 3 nitrogen atoms and optionally contains a sulfur or oxygen atom, for example, a pyridyl group such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; pyrimidine a group such as pyrimidin-2-yl and pyrimidin-4-yl; a triazinyl group such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, In particular, pyridazin-3-yl, and pyrazinyl.
  • a pyridyl group such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl
  • pyrimidine a group such as pyrimidin-2-yl and pyrimidin-4-yl
  • a triazinyl group such as 1,3,4-triazin-2-yl
  • Pyridine N-oxides and pyridazine N-oxides as well as pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazinyl and 1,3,4-triazin-2-yl are additional heterocyclic groups Example.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, ie, -alkyl-OH, wherein alkyl is as defined herein.
  • alkyl is as defined herein.
  • groups include, but are not limited to, hydroxymethyl, hydroxyethyl (eg, 2-hydroxyethyl, 1-hydroxyethyl), hydroxypropyl (eg, 1-hydroxypropan-2-yl, 1-hydroxypropyl) 3-yl, 1-hydroxyprop-1-yl, etc.), hydroxybutyl (e.g., 4-hydroxybutan-2-yl, etc.).
  • aryl refers to a compound having 6 to 14 ring carbon atoms, for example having 6 to 12 ring carbon atoms, for example, having 6 to 10 ring carbon atoms, fused by one or more rings.
  • aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, preferably phenyl and naphthyl.
  • heteroaryl as used herein means:
  • a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, for example having 6 ring atoms, which comprises one or more, for example 1, 2 or 3, for example 1 or 2, independently selected from the ring.
  • a ring heteroatom of N, O and S eg N
  • the remaining ring atoms being carbon atoms;
  • a bicyclic aromatic hydrocarbon group having 8 to 12 ring atoms, for example having 9 or 10 ring atoms, which contains one or more, for example 1, 2, 3 or 4, for example 1 or 2, independently in the ring
  • a ring heteroatom selected from the group consisting of N, O and S (e.g., N), the remaining ring atoms being carbon atoms, at least one of which is an aromatic ring.
  • Heteroaryl also includes those heteroaryl groups wherein the N ring heteroatom is in the form of an N-oxide, such as an N-oxypyrimidinyl group.
  • the ring heteroatoms in the above heteroaryl are N atoms, and such heteroaryl groups are referred to as "nitrogen-containing heteroaryl groups.”
  • the nitrogen-containing heteroaryl group also includes those heteroaryl groups in which the N-ring hetero atom is in the form of an N-oxide, such as an N-oxidized pyridyl group.
  • the nitrogen-containing heteroaryl group is a monocyclic heteroaryl group having 5 ring atoms, which contains 1 or 2 N hetero atoms in the ring, and the remaining ring atoms are carbon atoms; for example, the nitrogen-containing hetero
  • the aryl group is a monocyclic heteroaryl group having 6 ring atoms, which contains 1, 2 or 3 hetero atoms in the ring, and the remaining ring atoms are carbon atoms.
  • heteroaryl groups include, but are not limited to, pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl), N-oxidized pyridine Pyrazinyl; pyrimidinyl; pyrazolyl (eg, pyrazol-5-yl, pyrazol-1-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl) ; imidazolyl; Azolyl Azyl; thiazolyl; isothiazolyl; thiadiazolyl; tetrazolyl; triazolyl; thienyl; furyl; pyranyl; pyrrolyl; pyridazinyl; benzo[d]thiazolyl; Di-dioxolyl, such as benzo[d][1,3]d)
  • nitrogen-containing heteroaryl group thereof examples include, but are not limited to, pyrrolyl; pyrazolyl; imidazolyl; pyridyl; pyrazinyl; pyrimidinyl, N-oxypyrimidinyl; pyridazinyl; pyrrolopyrimidyl, for example Pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; indenyl, for example 9H-indenyl and 7H-indenyl; quinolinyl; indenyl; Azolyl.
  • aryl or “aromatic” follows the Huckle's rule, where the number of ⁇ electrons is equal to 4n+2, n is zero or any positive integer of up to 6.
  • substitution pattern means that the substitution pattern, event, or circumstance described subsequently may or may not occur, and that the description includes the occurrence of the substitution pattern and The case where the substitution mode does not occur.
  • “optionally substituted alkyl” includes “unsubstituted alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any spatially impractical, chemically incorrect, synthetically infeasible And/or an inherently unstable substitution pattern.
  • a chemically correct and stable compound means that the compound is sufficiently stable to be separated from the reaction mixture and to determine the chemical structure of the compound, and can then be formulated into at least a practically useful formulation.
  • substituted or “substituted by” as used herein, unless the substituent is specifically recited, means that one or more hydrogen atoms on a given atom or group are independently or more, e.g., three or four substituents, the substituents are independently selected from: deuterium (D), halogen, -OH, a mercapto group, a cyano group, -CD 3, -C 1 -C 6 alkyl (preferably -C 1-3 alkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl (preferably 3-8 membered cycloalkyl), aryl, heterocyclic (preferably a 3-8 membered heterocyclic group), a heteroaryl group, an aryl-C 1 -C 6 alkyl group, a heteroaryl-C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group
  • pharmaceutically acceptable refers to a non-toxic, biologically tolerable, suitable for administration to an individual.
  • pharmaceutically acceptable salt refers to a non-toxic, biologically tolerated acid addition or base addition salt of a compound of formula (I) suitable for administration to an individual, including but It is not limited to an acid addition salt of a compound of the formula (I) with an inorganic acid, such as a hydrochloride, a hydrobromide, a carbonate, a hydrogencarbonate, a phosphate, a sulfate, a sulfite, a nitrate, etc.
  • an inorganic acid such as a hydrochloride, a hydrobromide, a carbonate, a hydrogencarbonate, a phosphate, a sulfate, a sulfite, a nitrate, etc.
  • an acid addition salt of a compound of formula (I) with an organic acid such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citric acid Salt, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate and with HOOC-(CH 2 ) n - A salt formed of an alkanedicarboxylic acid of COOH (wherein n is 0-4).
  • “Pharmaceutically acceptable salt” also includes the base addition salts of the compounds of formula (I) bearing an acidic group with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.
  • the free base form thereof can be obtained by alkalizing a solution of the acid addition salt.
  • the acid addition salt thereof particularly the pharmaceutically acceptable acid addition salt
  • the acid addition salt thereof can be dissolved in the appropriate base by conventional procedures for the preparation of the acid addition salt from the basic compound. The solvent is obtained by treating the solution with an acid.
  • solvates means a solvent addition form comprising a stoichiometric or non-stoichiometric solvent. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrate is formed by one or more molecules of water and one molecule of said substance, wherein water retains its molecular state of H 2 O, such a combination can form one or more hydrates, such as hemihydrate, Hydrates and dihydrates.
  • prodrug refers to an active or inactive compound that is chemically modified by the physiological action of the body, such as hydrolysis, metabolism, etc., to the compound of the invention after administration to an individual.
  • the suitability and techniques involved in the preparation and use of prodrugs are well known to those skilled in the art.
  • Exemplary prodrugs are, for example, esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols.
  • Suitable prodrugs are generally pharmaceutically acceptable ester derivatives which can be converted to the parent carboxylic acid by solvolysis under physiological conditions, such as lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, singles a - or a di-substituted lower alkyl ester such as ⁇ -(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl ester, ⁇ -(lower alkanoyloxy, Lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as pivaloyloxymethyl ester, etc., are conventionally used in the art.
  • the compounds of formula (I) may contain one or more chiral centers, and thus two or more stereoisomers are present.
  • the compounds of the invention may exist as individual stereoisomers (eg, enantiomers, diastereomers) and mixtures thereof in any ratio, such as racemates, and where appropriate, It may exist in the form of its tautomers and geometric isomers.
  • stereoisomer refers to a compound having the same chemical composition but differing in the spatial arrangement of the atoms or groups. Stereoisomers include enantiomers, diastereomers, conformers, and the like.
  • enantiomer refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.
  • diastereomer refers to a stereoisomer having two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties or biological activity. Mixtures of diastereomers can be separated by high resolution analytical methods such as electrophoresis and chromatography such as HPLC.
  • the prefixes d and l or (+) and (-) are used to indicate the sign of the plane-polarized light of the compound, where (-) or l indicates that the compound is left-handed.
  • Compounds with a prefix of (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they mirror each other. Particular stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur in the absence of stereoselectivity or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers that are not optically active.
  • the racemic mixture can be used in its own form or split into individual isomers.
  • a stereochemically pure compound or a mixture of one or more isomers can be obtained by resolution.
  • Methods for separating isomers are well known (see Allinger N. L. and Eliel E. L., "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using a chiral adsorbent.
  • Individual isomers in chiral form can be prepared from chiral precursors.
  • it may be by a single enantiomer with a chiral acid (eg, 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.)
  • a chiral acid eg, 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.
  • the racemate can be covalently attached to a chiral compound (auxiliary) to give the diastereomer which can be separated by chromatography or fractional crystallization, after which The chiral auxiliary is removed chemically to give the pure enantiomer.
  • formational isomer refers to an isomer of a molecule in which a covalent bond compound is bonded by a single bond, in which the atom or group is located in a different position, such as a half-chair conformation of cyclopentane. Isomers and envelope conformers.
  • tautomer or "tautomeric form” as used herein, refers to structural isomers of different energies that are interconvertible via low energy barriers.
  • proton tautomers also known as proton transfer tautomers
  • Valence bond tautomers include interconversions by recombination of some bonded electrons.
  • geometric isomer as used herein is an isomer which is caused by a single bond of a double bond or a ring carbon atom which cannot be freely rotated, and is also called a cis-trans isomer.
  • the substituent group is located on the same side of the plane as cis.
  • the isomer, located on the opposite side of the plane, is the trans isomer.
  • treating refers to the administration of one or more drug substances, particularly a compound of formula (I) as described herein, and/or pharmaceutically acceptable thereof to an individual having or having symptoms of the disease. Salt for curing, alleviating, alleviating, altering, treating, ameliorating, improving or affecting the disease or the symptoms of the disease.
  • the disease is cancer.
  • prevention refers to the administration of one or more drug substances, particularly a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, to an individual having a constitution predisposed to the disease.
  • the disease is a disease associated with an ERK kinase, such as ERK1 and/or ERK2 kinase.
  • the disease is a disease associated with high expression or high activity of an ERK kinase such as ERK1 and/or ERK2 kinase.
  • the disease is cancer or a tumor.
  • cancer refers to a physiological condition in a mammal that is typically characterized by unregulated cell growth.
  • cancers include blastoma, glioma, sarcoma, seminoma, glioblastoma, melanoma, leukemia and bone marrow or lymphoid malignancies.
  • More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma) and lung cancer, including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma.
  • NSCLC non-small cell lung cancer
  • cancers include skin cancer, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral vestibular cancer, pharyngeal cancer, lip cancer, tongue cancer, oral cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, Gastric cancer, gastrointestinal cancer, small intestine cancer, colon cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary cancer , gallbladder adenocarcinoma, thyroid cancer, papillary carcinoma, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penile cancer, bone cancer, multiple bone marrow Tumor, B cell lymphoma, central nervous system cancer, brain cancer, head and neck cancer, Hodg
  • Examples also include myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, myelofibrosis such as primary myelofibrosis, acute myeloid leukemia, and chronic myelogenous leukemia (CML).
  • myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, myelofibrosis such as primary myelofibrosis, acute myeloid leukemia, and chronic myelogenous leukemia (CML).
  • myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, myelofibrosis such as primary myelofibrosis, acute myeloid leukemia, and chronic myelogenous leukemia (CML).
  • CML chronic myelogenous leukemia
  • the terms “treating”, “contacting” and “reacting” mean adding or mixing two or more agents under appropriate conditions to produce the products shown and/or desired. It will be understood that the reaction to produce the indicated and/or desired products may not necessarily come directly from the combination of the two agents initially added, ie one or more intermediates may be present in the mixture, among these The body ultimately results in the formation of the products shown and/or desired.
  • the term "effective amount” as used herein refers to an amount that is generally sufficient to produce a beneficial effect on an individual.
  • Conventional influencing factors eg, mode of administration, pharmacokinetics of the compound, severity and duration of the disease, history of the individual, health status of the individual, individual
  • the effective amount of the compound of the present invention is determined by the degree of response to the drug, and the like.
  • inhibitor refers to a decrease in the baseline activity of a biological activity or process.
  • inhibiting ERK activity means an ERK activity relative to the absence of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the presence of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
  • a decrease in ERK activity caused by direct or indirect response.
  • the decrease in activity may be caused by a direct interaction of a compound of formula (I), or a pharmaceutically acceptable salt thereof, with ERK as described herein, or by a compound of formula (I) as described herein and/or pharmaceutically acceptable thereto
  • the accepted salt interacts with one or more other factors to affect the ERK activity.
  • the term "individual” as used herein refers to both mammals and non-mammals. Mammal refers to any member of mammals including, but not limited to: humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats and pigs; Livestock, such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs; Examples of non-mammals include, but are not limited to, birds and the like.
  • the term "individual” does not define a particular age or gender. In some embodiments, the individual is a human.
  • the compound of the formula (I) of the present invention or a stereoisomer, a racemate, a geometric isomer, a tautomer, a prodrug, a hydrate, a solvate thereof or a pharmaceutically acceptable salt thereof may be passed through Methods, including the methods given below, the methods given in the examples, or methods analogous thereto are prepared. Suitable general synthetic schemes are depicted below. Suitable reaction conditions for each reaction step are known to those skilled in the art. The starting materials are commercially available or can be prepared by methods below, methods analogous to those given below, or methods known in the art. Each variable in the formula has the same meaning as above, unless otherwise stated.
  • Figure 1 shows a general synthetic scheme A for the synthesis of the compounds of the invention.
  • Figure 2 shows a general synthetic scheme B for the synthesis of the compounds of the invention.
  • Figure 3 shows a general synthetic scheme C for the synthesis of the compounds of the invention.
  • Figure 4 shows a general synthetic scheme D for the synthesis of the compounds of the invention.
  • the protecting groups of the sensitive or reactive groups e.g., amino, hydroxyl, and carboxyl groups
  • the protecting group is treated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 5th edition, Wiley, New York 2014). These groups are removed at a convenient stage of compound synthesis using methods well known to those skilled in the art. The method and the choice of reaction conditions and their order of execution should be consistent with the preparation of the compound of formula (I).
  • amino protecting groups include carbamates, amides, alkyl and aryl groups, and imines, as well as many N-heteroatom derivatives, which can be removed to regenerate the desired amine groups.
  • Particular amino protecting groups are Pmb (p-methoxybenzyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) and Cbz (benzyloxycarbonyl). Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protecting Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, Inc., 1999.
  • hydroxy protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silyl ether (eg, TBS, TBDPS) groups. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., 1999.
  • Examples of the carboxy protecting group include an ester group and a heterocyclic group.
  • the ester derivative of the carboxylic acid group can be used to block or protect the carboxylic acid group when reacted on other functional groups of the compound.
  • Examples of such ester groups include substituted arylalkyl groups, including substituted benzyl groups such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl 2,4-Dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxy Alkyl or alkyl substituted alkyl ester such as methyl, ethyl, tert-butylallyl or tert-amyl, triphenylmethyl (trityl), 4-methoxy III Benzyl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-pheny
  • compound C2 is prepared by reacting compound C1 with a carboxylic acid. This is achieved by carrying out an amide coupling reaction.
  • the amide coupling reaction is carried out in an inert solvent. More preferably, the amide coupling reaction is carried out in an inert solvent in the presence of a condensation reagent and a base.
  • the inert solvent is preferably selected from the group consisting of ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane, N -Methyl-2-pyrrolidone or a combination thereof.
  • the condensation reagent is preferably selected from the group consisting of 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azobenzotriazole (HOAT), benzotriazol-1-yl-oxygen hexafluorophosphate Pyryl pyrrolidinium (PyBOP), benzotriazole-1-tris(trimethylamino)-hexafluorophosphate (BOP), 1,1-carbonyldiimidazole (CDI), 1-propylphosphoric anhydride (T 3 P), 1-ethyl-3-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (EDC ⁇ HCl), N,N-dicyclohexylcarbodiimide (DCC), Acetic anhydride, acetyl chloride, oxalyl chloride, 2-(7-oxidized benzotriazole)-N,N,N',N'-tetramethyluronium (HATU), O-(benzo
  • the base is preferably selected from the group consisting of: triethylamine, DIPEA, pyridine, 2,4-dimethylpyridine, NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , Cs 2 CO 3 , Na 3 One or more of PO 4 or K 3 PO 4 ; more preferably DIPEA.
  • the amide coupling reaction is carried out at a temperature from room temperature to reflux.
  • the reaction time of the amide coupling reaction is from 0.5 to 24 hours.
  • the compound C3 can be prepared by deprotecting compound C2.
  • the deprotection is carried out in an inert solvent.
  • the inert solvent is preferably selected from the group consisting of ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane, N -Methyl-2-pyrrolidone or a combination thereof.
  • the deprotection is carried out in the presence of an acid.
  • the acid is preferably selected from one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, formic acid, and phosphoric acid.
  • the deprotection is carried out at a temperature of from -10 °C to 80 °C.
  • the deprotection is carried out for 0.5 to 24 hours.
  • the compounds of the invention are useful in the treatment of diseases associated with ERK kinases such as ERK1 and/or ERK2 kinase, such as diseases associated with high expression or high activity of ERK kinases such as ERK1 and/or ERK2 kinase, such as tumors and cancer. More specifically, the tumor and cancer are selected, for example, from blastoma, glioma, sarcoma, seminoma, glioblastoma, melanoma, leukemia and bone marrow or lymphoid malignancies.
  • cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma) and lung cancer, including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma.
  • squamous cell carcinoma e.g., epithelial squamous cell carcinoma
  • lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma.
  • cancers include skin cancer, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral vestibular cancer, pharyngeal cancer, lip cancer, tongue cancer, oral cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, Gastric cancer, gastrointestinal cancer, small intestine cancer, colon cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary cancer , gallbladder adenocarcinoma, thyroid cancer, papillary carcinoma, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penile cancer, bone cancer, multiple bone marrow Tumor, B cell lymphoma, central nervous system cancer, brain cancer, head and neck cancer, Hodg
  • Examples also include myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, myelofibrosis such as primary myelofibrosis, acute myeloid leukemia, and chronic myelogenous leukemia (CML).
  • myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, myelofibrosis such as primary myelofibrosis, acute myeloid leukemia, and chronic myelogenous leukemia (CML).
  • myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, myelofibrosis such as primary myelofibrosis, acute myeloid leukemia, and chronic myelogenous leukemia (CML).
  • CML chronic myelogenous leukemia
  • the compounds of the invention may be administered to an individual in the form of a pharmaceutical composition, which may optionally comprise one or more pharmaceutically acceptable excipients.
  • the compounds of the invention may be administered by a variety of known routes including oral, rectal, intragastric, intracranial and parenteral administration, such as intravenous, intramuscular, intranasal, intradermal, subcutaneous, and the like. Particularly preferred are oral, intranasal and parenteral administration.
  • routes of administration different pharmaceutical formulations are required, some of which may require the application of a protective coating to the pharmaceutical formulation to prevent degradation of the compounds of the invention, for example, in the digestive tract.
  • the compounds of the invention may be formulated as syrups, infusions or injections, sprays, tablets, capsules, lozenges, liposomes, suppositories, and the like.
  • Particularly preferred pharmaceutical forms for the administration of the compounds of the invention are in a form suitable for injectable use, including sterile aqueous solutions or dispersions, and sterile powders for the preparation of sterile injectable solutions or dispersions.
  • the final solution or dispersion form must be sterile and fluid.
  • such solutions or dispersions will contain a solvent or dispersion medium containing, for example, a water-buffered aqueous solution such as a biocompatible buffer, ethanol, a polyol such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof , surfactant or vegetable oil.
  • the compounds of the invention may also be formulated as liposomes, especially liposomes for parenteral administration. Liposomes provide the advantage of increased half-life in circulation (if compared to free drug) and extended, more uniform release of the encapsulated drug.
  • Sterilization of infusions and injections can be accomplished by art-recognized techniques including, but not limited to, the addition of preservatives such as antibacterial or antifungal agents, such as paraben, chlorobutanol, phenol, sorbic acid or Thiomersal.
  • preservatives such as antibacterial or antifungal agents, such as paraben, chlorobutanol, phenol, sorbic acid or Thiomersal.
  • isotonic agents such as sugars or salts, especially sodium chloride, may also be incorporated into the infusion and injectable solutions.
  • a sterile injectable solution containing one or more of the compounds of the present invention is accomplished by incorporating the desired amount of each compound into a suitable solvent, as appropriate, with the various ingredients listed above, and then sterilizing. In order to obtain a sterile powder, the above solution is vacuum dried or freeze dried as needed.
  • Preferred diluents of the invention are water, physiologically acceptable buffers, physiologically acceptable buffered saline solutions or salt solutions.
  • Preferred carriers are cocoa butter and vitebesole.
  • Excipients that can be used with the various pharmaceutical forms of the compounds of the invention can be selected from the following non-limiting list:
  • binders such as lactose, mannitol, crystalline sorbitol, hydrogen phosphate, sugar, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, and the like;
  • lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerides and sodium stearyl fumarate;
  • a disintegrating agent such as starch, croscarmellose, sodium methylcellulose, agar, bentonite, alginic acid, carboxymethylcellulose, polyvinylpyrrolidone or the like.
  • the formulation is for oral administration and the formulation comprises one or more or all of the following ingredients: pregelatinized starch, talc, polyvinylpyrrolidone K30, croscarmellose sodium, hard Sodium fatty acid sodium fumarate, gelatin, titanium dioxide, sorbitol, monosodium citrate, xanthan gum, titanium dioxide, flavoring agent, sodium benzoate and sodium saccharin.
  • the compounds of the invention are administered intranasally, either as a dry powder inhaler or from the use of suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoro
  • suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoro
  • an alkane such as 1,1,1,2-tetrafluoroethane (HFA 134A TM ) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA TM )
  • HFA 134A TM 1,1,1,2,3,3,3-heptafluoropropane
  • CO 227EA TM 1,1,1,2,3,3,3-heptafluoropropane
  • the pressurized container, pump, nebulizer or nebulizer may contain a solution or suspension of a compound of the invention, for example a solution or suspension using ethanol and a propellant as a solvent, which may also contain a lubricant, for example Yamanate trioleate.
  • a typical dosage range for the compounds of the invention is from 0.001 to 1000 mg of active ingredient per kilogram of body weight per day.
  • the dose can be administered once or several times a day.
  • the determination of the appropriate dosage will be determined by the attending physician as appropriate, depending on the type of the disease to be treated and its severity, the health and prior medical history of the individual, the common drug, the particular compound administered, and the route of administration.
  • the amount of the compound of the present invention may be used in excess of the dosage range as needed.
  • Figure 1 shows a general synthetic scheme A for the synthesis of compounds of the invention wherein each variable is as defined herein.
  • Figure 2 shows a general synthetic scheme B for the synthesis of compounds of the invention, wherein the variables are as defined herein.
  • Figure 3 shows a general synthetic scheme C for the synthesis of compounds of the invention, wherein the variables are as defined herein.
  • Figure 4 shows a general synthetic scheme D for the synthesis of compounds of the invention, wherein the variables are as defined herein.
  • 1 H-NMR spectra were recorded on a Bluker AVHD 400 MHz or Bluker AVHD 500 MHz type nuclear magnetic resonance apparatus; 13 C-NMR spectra were recorded on a Bluker AVHD 500 MHz or Bluker AVHD 600 MHz type nuclear magnetic resonance apparatus, chemical shift Expressed in ⁇ (ppm); mass spectra were recorded with Waters UPLC H-Class + QDa (ESI) and Agilent 1260_6120 (ESI) mass spectrometer; reverse phase preparative HPLC separation was a fully automated purification system (XBridge) guided by Waters UV Prep C18 5 ⁇ m OBD column).
  • ESI Waters UPLC H-Class + QDa
  • ESI Agilent 1260_6120
  • N,N-dimethylformamide (10 mL), Intermediate 3 (1.7 g, 0.0079 mol), Compound 9 (1.23 g, 0.007 mol) and N, N were added to a dry 250 mL round bottom flask at room temperature.
  • Diisopropylethylamine (3.69 g, 0.028 mol) was replaced with nitrogen three times, gradually warmed to 50 ° C, and 1-propylphosphonic anhydride (56 mL, 50% ethyl acetate solution) was added to react for 0.5 hour. After the TLC reaction was completed, the mixture was concentrated under reduced pressure, and the residue was evaporated tojjjjjjjj LCMS: m/z 368.8 / 370.8 (M+H).
  • Ethyl acetoacetate (46) (6.1 g, 0.047 mol), potassium carbonate (8.7 g, 0.063 mol), 1,3-difluoro-2-nitro group were sequentially added to a dry 100 mL round bottom flask at room temperature.
  • Benzene (5 g, 0.031 mol) and N,N-dimethylformamide (20 mL) were warmed to 50 ° C and stirred for 2 hr.
  • the compound 84 (200.0 mg, 1.23 mmol) was added to tetrahydrofuran (15 mL), and the mixture was stirred for three times, and then cooled to 0 ° C, and lithium aluminum hydride (140.0 mg, 3.69 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 2 hours. . After completion of the reaction, water (20 mL) was added dropwise, and ethyl acetate (20 mL) was evaporated. Purification of 1:8) gave 7-fluoro-3-methyl-1H-indole 85 (130.0 mg, pale yellow oil).
  • the sodium hydroxide aqueous solution was adjusted to pH 8-9, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in 20 mL of ethanol, and triethylamine (692 mg, 6.85 mmol) Silver benzoate (197 mg, 0.86 mmol) was added in portions at room temperature, stirred for 10 minutes, and heated. The reaction was stirred at 80 ° C for ten minutes, cooled to room temperature, suction filtered, and the filtrate was concentrated.
  • intermediates 65 and 83 were synthesized from the corresponding starting materials in the table below:
  • Example P8 Analogously to the preparation of Example P8, according to the general synthetic scheme B given in Figure 2, the intermediates 11, 53 or a boronate ester intermediate similar to the intermediate 11 were synthesized to give Examples P10-P16, P32, P34. , P36, P44, P47-51, P53 and P58-59:
  • Examples P45-46 and P61 were synthesized using Intermediate 25 or an intermediate similar thereto according to the general synthetic scheme C given in Figure 3:
  • Example P64 was obtained analogously to the preparation of Example P60 using an intermediate similar to Intermediate 25.
  • Step 7 Resolution of Compound P60 to prepare compounds P62 and P63
  • Ultra-high performance liquid chromatography system including pump, autosampler, detector and column oven
  • Compound P9 was formulated into a solution having a concentration of 0.2 mg/ml in a different buffer system using PEG400 for dissolution. Solutions of solutions of different pH are prepared as follows:
  • Preparation method Weigh A107, add prescription amount of PEG400 and Solutol HS-15, vortex to obtain a clear solution, and then add a prescription amount of pH 1.2 diluted hydrochloric acid to obtain.
  • Solution prescription 10% PEG400 + 5% Solutol HS-15 + 85% pH 6.8 phosphate buffer
  • Preparation method Weigh A107, add prescription amount of PEG400 and Solutol HS-15, vortex to obtain a clear solution, and then add a prescribed amount of pH 6.8 phosphate buffer to mix and obtain.
  • Solution prescription 10% PEG400 + 5% Solutol HS-15 + 85% pH 7.4 phosphate buffer
  • Preparation method Weigh A107, add the prescribed amount of PEG400 and Solutol HS-15, vortex to obtain a clear solution, and then add a prescribed amount of pH 7.4 phosphate buffer to mix and obtain.
  • the half-inhibitory activity (IC 50 value) of the compound of the present invention against ERK2 kinase was determined in this example.
  • Enzyme Extracellular signal-regulated kinase ERK2 kinase (PV3595, Invitrogen)
  • Kit Z'- Protein Kinase Assay Kit - Ser/Thr 3Peptide (PV3176, Invitrogen)
  • Kit Composition Substrate Z'-LYTE TM Ser/Thr 3 Peptide (PV3200)
  • Microplate reader Multi-function microplate reader PerkinElmer En
  • Microplate 384-well black shallow well plate (6008269, PerkinElmer)
  • Substrate Z'-LYTE TM Ser/Thr 3 Peptide, phosphorylated substrate Z'-LYTE TM Ser/Thr 3 Phospho-peptide, 1X kinase buffer (5X kinase buffer diluted 5 times with ultrapure water), ATP , Developer Development Reagent A, Development Buffer Development Buffer, Terminator Stop Reagent, etc. are equilibrated to room temperature to prepare for loading.
  • the screening concentration for detecting the effect of the compound of the present invention on ERK enzyme activity was 3 fold dilution from 1 ⁇ M (positive drug from 0.2 ⁇ M), 7 concentrations were diluted, and 4% DMSO was used as a cosolvent.
  • the inhibition rate of each well was calculated from the fully active pores and the background signal wells.
  • the data analysis method is as follows:
  • Percent phosphorylation 1 - ⁇ (emission ratio ⁇ F 100% - C 100% ) / [C 0% - C 100% + emission ratio ⁇ (F 100% - F 0% )] ⁇ ⁇ 100
  • Inhibitor percentage 100 x (1 - % phosphorylation of test compound well / % phosphorylation of control inhibited by 0%)
  • emission ratio ratio of 445 nm emission to 520 nm emission in the sample
  • inhibitory activity data (IC 50 ) of the compounds of the present invention against ERK2 kinase activity are shown in the following table, wherein:
  • A represents an IC 50 of the compound is less than or equal to 10 nM
  • B represents an IC 50 of the compound greater than 10 nM but less than 100 nM;
  • C IC 50 of the compound represented by 100nM or greater but less than 1 ⁇ M.
  • the IC 50 values of the compounds P5, P9, P10, P18, P42, P59 and P60 of the present invention were 8.2 nM, 3.3 nM, 6.1 nM, 3.0 nM, 2.7 nM, 4.8 nM, respectively. And 10nM.
  • the proliferation inhibitory activity (IC 50 value) of the representative compound of the present invention and the representative compound of WO2017/114510A1 against human melanoma cell line A375 was measured.
  • Detection reagent sulforomindamine B SRB (S9012, Sigma)
  • Microplate reader Full-wavelength microplate microplate reader (SpectraMax 190, Molecular Devices)
  • Cells in logarithmic growth phase were inoculated into 96-well cell culture plates at a suitable density (3500/well) at 90 ⁇ L per well. After incubating at 37 ° C overnight in a carbon dioxide incubator, 10 ⁇ L of different concentrations of compounds were added for 72 hours, each The concentration was set to three replicate wells, and the corresponding concentration of physiological saline vehicle control and cell-free zero-adjustment were set. After the end of the reaction, the cells were de-cultured, added with 10% (w/v) trichloroacetic acid (100 ⁇ L/well) and fixed at 4 ° C for 1 hour, then rinsed five times with distilled water, placed in an oven and dried, and SRB was added to each well.
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader. The experiment was repeated twice.
  • the permeability of the compound P9 of the present invention and the compound A107 of WO2017/114510A1 was measured using the Caco-2 cell in vitro drug absorption model in this example.
  • Petri dish 10cm culture dish (430167, Corning)
  • Non-essential amino acids (M7145, Sigma)
  • the medium is high glucose DMEM medium supplemented with 10% fetal bovine serum, 1% glutamine, 1 % non-essential amino acids, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin.
  • the fluorescent marker Lucifer Yellow verifies the integrity of the Caco-2 cell monolayer. After the cell monolayer was grown for 21 days, Lucifer Yellow (100 ⁇ g/ml) 200 ⁇ L was added to the apical side (AP side), and the base end (basolateral side, BL side) was added with HBS solution 800 ⁇ L at 37 ° C, 5% CO. After culturing for 1.5 hours in the incubator of 2 , the sample was taken, and the absorbance at a wavelength of 485-535 nm was detected, and the amount of leakage was calculated, generally not exceeding 0.4%. Blank HBSS solution was used as a blank control.
  • the drug was simultaneously transported from the apical side (AP side) ⁇ basal side (BL side) and BL side ⁇ AP side of Caco-2 cell layer.
  • a mother liquor of the compound was prepared in DMSO at a concentration of 10 mM.
  • the apparent permeability coefficient P app (apparent permeability coefficients) of the drug through the Caco-2 cell model is calculated by the following formula (1):
  • V A is the receiving side volume
  • Area is the membrane area (cm 2 )
  • Time is the reaction time
  • [drug] acceptor is the receiving side drug concentration
  • [drug] initial donor is the drug side drug concentration.
  • the compound P9 of the present invention has a significantly higher apparent permeability coefficient (Papp, in the Caco-2 permeability test compared to the A107 compound in WO2017/114510A1. Apical to Basal); Papp>2 ⁇ 10 -6 is known to be a highly permeable drug (for example, see Journal of Pharmacological and Toxicological Methods 44 (2000) 235-249), and compound P9 is significantly higher than this index, while A107 Below this indicator.
  • the A107 has a higher Efflux Ratio and the P90 has a lower Efflux Ratio. Therefore, P9 has better permeability and is expected to have better intestinal absorption properties and better oral absorption in vivo.
  • thermodynamic solubility of the compounds of the invention was determined in this example
  • PH6.8 9900 ⁇ L HBSS+100 ⁇ L HEPS+5 ⁇ L 2N NaOH
  • PH7.4 DPBS adjusted to pH 2.0 with 2N HCl
  • the sample was centrifuged for 30 min, and the supernatant was transferred to a new EP tube and centrifuged for 30 min.
  • the sample was diluted 100-fold with ACN/H 2 O (V/V, 1:1).
  • Multi-reaction monitoring (MRM) mode
  • test sample was prepared in accordance with the concentration of pure free base.
  • IV Intravenous
  • mice Forty male SPF-class ICR mice (mice) were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., and 30 healthy ICR mice with good physical examination and no abnormality were used for the study. Animal weight: 20.12-25.56g .
  • Blood was collected by cardiac puncture after euthanasia or carbon dioxide (CO 2 ), and about 0.20 ml (mL) was collected for each sample. Heparin sodium was anticoagulated and collected on ice.
  • Collection time points of intravenous and oral administration groups 5, 15 and 30 min, 1, 2, 4, 6, 8, and 24 h before and after administration, as shown in the following table:
  • Plasma samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C). The collected plasma was stored at -80 °C prior to analysis.
  • the biological samples of the test samples were analyzed by LC-MS/MS.
  • the analysis method used was found in (1.7), and the LLOQ of the samples was 1 ng/mL.
  • the standard curve and the quality control samples were analyzed during the sample detection.
  • the pharmacokinetic parameters were calculated by using WinNonlin 7.0, and the parameters such as AUC 0-t , AUC 0- ⁇ , MRT 0- ⁇ , C max , T max , and T 1/2 were provided and their average values were obtained. Value and standard deviation.
  • samples taken prior to reaching C max should be calculated as zero values when calculating the pharmacokinetic parameters. Samples at the sampling point should be incapable of quantification (BLQ) after C max is reached.
  • Ultra Performance Liquid Chromatography System Waters, ACQUITY UPLC
  • ACQUITY UPLC Binary Solvent Manager
  • Sample Manager ACQUITY UPLC Autosampler Mod.
  • High-throughput Sample Organizer ACQUTIY UPLC Sample
  • ACQUITY UPLC Column Heater HT ACQUITY UPLC
  • Mass spectrometer (API 4000, Applied Biosystems, USA), electrospray ionization source (ESI), tandem quadrupole mass analyzer.
  • the data processing system is Analyst Software (Applied Biosystems, Inc., software version number 1.5.1).
  • Microanalytical balance (XP26, METTLER TOLEDO Instruments (Shanghai) Co., Ltd.); vortex oscillator (SI-A256, Scientific Industries, Inc.); small benchtop high-speed refrigerated centrifuge (5417R, Eppendorf); ultrapure Water machine (Millipore); pipette (Eppendorf).
  • the liquid phase conditions are as follows:
  • the mass spectrometry conditions are as follows:
  • test substance was weighed, and after methanol was completely dissolved, it was formulated into a stock solution having a concentration of 569,000 ng/mL.
  • a certain amount of stock solution was taken and diluted with methanol to a working solution having a concentration of 200,000 ng/mL.
  • a certain amount of 200,000 ng/mL standard solution was taken and added to a certain amount of blank plasma in a ratio of 1:39 to prepare a standard curve sample having a concentration of 5000 ng/mL.
  • a standard curve sample of 5000 ng/mL was taken and sequentially diluted with blank plasma to obtain 1000, 500, 100, 50, 10, 5, 1 ng/mL standard curve samples and 800, 200, 2.5 ng/mL quality control samples.
  • the specific preparation process is shown in Table I.
  • mice pharmacokinetic data of the representative compound in WO2017/114510A1 and the compound P9 of the present invention are as follows.
  • the compound P9 of the present invention has a significantly higher drug area under the curve (AUC) in mice compared to the compound of WO2017/114510A1. , and lower in vivo clearance (CLz), good bioavailability, so it is predicted that this compound has better oral absorption and better drug-forming properties.

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Abstract

一种式(I)的化合物。其中各变量如说明书中所定义。所述化合物是ERK激酶、例如ERK1和/或ERK2激酶的抑制剂。还涉及所述化合物的用途和制备方法以及包含所述化合物的药物组合物。

Description

具有ERK激酶抑制活性的化合物及其用途 技术领域
本发明属于药物化学领域。具体地,本发明涉及新的化合物或其药学上可接受的盐,以及含有所述化合物或其药学上可接受的盐的药物组合物,它们用作细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)通路的调节剂,特别是用作ERK激酶,例如ERK1和/或ERK2激酶的抑制剂。
背景技术
Ras-Raf-MEK-ERK通路是一条有丝分裂原活化蛋白激酶(mitogen activated protein kinase,MAPK)信号通路,其调控着细胞的增殖、分化和凋亡等诸多功能。该通路的突变存在于所有人类癌症的三分之一以上,因此近年来该通路上的节点蛋白成为癌症靶向药物研发的热点。特异性的B-Raf抑制剂威罗菲尼(vemurafenib)和达拉菲尼(dabrafenib)分别于2011年和2013年被美国FDA批准用于黑色素瘤的治疗。MEK1/2抑制剂曲美替尼(trametinib)于2013年被美国FDA批准用于黑色素瘤的治疗。2015年威罗菲尼与MEK抑制剂考比替尼(cobimetinib)联用被美国FDA批准用于治疗B-Raf V600E或V600K突变的黑色素瘤。2017年美国FDA还批准了达拉菲尼与曲美替尼联合用药用于治疗B-Raf V600E突变型非小细胞肺癌。然而抑制这些上游通路节点有其局限性,肿瘤对B-Raf和MEK抑制剂可以快速地产生抗药性,抗药性产生的机制包括点突变、蛋白多聚形式改变和蛋白肽链长度改变等多种方式,这对于开发下一代针对Raf、MEK的药物是极大的挑战。同时,作为MAPK的末端关键节点,活化的ERK能将胞外信号传递至细胞核,促进细胞质靶蛋白的磷酸化或调节其它蛋白激酶的活性,进而调节基因表达。其重要性在肿瘤药物的开发中是毋庸置疑的。尤其当目前大多数MAPK上游的靶向治疗中最终大多出现了耐药现象而ERK抑制剂将可能因为较不易产生获得性耐药而成为更有效的治疗手段。从ERK于20世纪90年代被发现以来,已经有了很多广泛而深入的研究,但迄今为止还没有ERK抑制剂作为药物被批准上市。目前在国际上领先的是在处于2期临床的高选择性ERK抑制剂BVD-523(Ulixertinib)。2017年初有报道显示每天两次600mg的BVD-523在病人上具有可接受的安全性,并且在具有NRAS突变的黑色素瘤、BRAF V600和非V600突变体实体瘤(包括黑色素瘤、多形性胶质母细胞瘤、脑转移癌、胆囊腺癌和头颈部肿瘤)的病人中产生持久的疗效。这些数据进一步地支持了ERK抑制剂的临床开发。
综上所述,可以预计ERK抑制剂作为单药或联合用药在肿瘤领域中将有广泛的前景,本领域也迫切需要研发出新的ERK抑制剂。专利申请WO2017/114510A1公开了一系列ERK抑制剂,但是本申请的发明人发现,在该专利申请中,一些化合物、尤其是具有结构
Figure PCTCN2018108762-appb-000001
的化合物化学稳定性较差,容易生成杂质,尤其是当遇到碱性条件时更是如此,该类化合物 的此类性质给药物开发带来了一定的难度;一些具有结构
Figure PCTCN2018108762-appb-000002
化合物、其中R基团是氨基、羧基或酰胺基等的化合物尽管在初步的体外测试中活性较好,但是其药代动力学参数不理想,给药物开发带来一定困难。简言之,专利申请WO2017/114510A1所公开的一些化合物在综合评估(例如在化学稳定性和/或药代动力学性质等方面)中显示出一定的药物开发难度。因此,需要通过综合评估寻找更适合药物开发的高选择性的具有ERK激酶抑制活性的化合物。
发明内容
本发明的发明人经过反复的实验研究,最终发现包含母核结构
Figure PCTCN2018108762-appb-000003
且其中R 3是卤素、未取代的烷基、卤代烷基、氘代烷基等的化合物具有良好的化学稳定性,也具有较好的溶解性和渗透性,在酶试验和细胞试验中均具有ERK激酶抑制活性,并且具有良好的药代动力学参数,特别适合用于药物开发。
实施方案
一方面,本发明提供了新的ERK激酶抑制剂。具体地,本发明提供了如下的实施方案:
实施方案1.式(I)化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,
Figure PCTCN2018108762-appb-000004
式中,
X 1选自:CR 9a和N;
X 2选自:CR 9b和N;
X 3选自:CR 9c和N;且X 1、X 2和X 3至多一个为N;
Y 1和Y 2各自独立地选自:CR 9’和N;
R 9a、R 9b和R 9c各自独立地选自:H、D、卤素、-OH、氰基、任选被取代的烷基、任选被取代的烷氧基、任选被取代的烷基羰基、任选被取代的烷氧基羰基、任选被取代的环烷基、氨基、任选被取代的单或二(烷基)氨基和-CONR aR b
R 9’选自:H、D、卤素、-OH、氰基、任选被取代的烷基、任选被取代的烷氧基、任选 被取代的烷基羰基、任选被取代的烷氧基羰基、任选被取代的环烷基、氨基、任选被取代的单或二(烷基)氨基和CONR aR b
R 1选自:H和D;
R 2选自:任选被取代的烷基、任选被取代的环烷基、任选被取代的杂环基、任选被取代的芳基和任选被取代的杂芳基,或者R 2与X 1共同形成任选被取代的杂环基;
R 3选自:卤素和任选被取代的烷基;
R 4选自:H、D、任选被取代的烷基、任选被取代的烷氧基、-CO(CR 10R 11) mR 12、-SO 2(CR 10R 11) mR 12、-CONR 13(CR 10R 11) mR 12、-COO(CR 10R 11) mR 12、-CR 13R 13’(CR 10R 11) mR 12和C 1-8烷基羰基-;其中m为0、1、2或3,且其中
R 10和R 11各自独立地选自:H、D、卤素、任选被取代的烷基和任选被取代的烷氧基;或者R 10与R 11相连形成任选被取代的环烷基、环烯基、芳基、杂芳基和杂环基;且
R 12各自独立地选自:H、任选被取代的烷基、任选被取代的环烷基、任选被取代的杂环基、任选被取代的芳基和任选被取代的杂芳基;和
R 13和R 13’各自独立地选自:H和任选被取代的烷基;或者R 13和R 13’与相邻的碳一起形成任选被取代的环烷基、环烯基和杂环基;
R 5、R 6、R 7和R 8各自独立地选自:-H、-D、卤素、-OH、氨基、氰基、任选被取代的烷基、任选被取代的烷氧基、-(CH 2) 0-3CONR aR b、-(CH 2) 0-3COOH、任选被取代的环烷基和任选被取代的杂环基;或者R 5、R 6、R 7和R 8中任意两个与相邻的碳一起形成任选被取代的环烷基、环烯基、芳基、杂芳基和杂环基;且
R a和R b各自独立地选自:H、D和任选被取代的烷基;
其中任选的取代基独立地选自:氘(D)、卤素、-OH、巯基、氰基、-CD 3、-C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、3-8元环烷基、芳基、3-8元杂环基、杂芳基、芳基-C 1-C 6烷基-、杂芳基-C 1-C 6烷基-、C 1-C 6卤代烷基-、-OC 1-C 6烷基、-OC 2-C 6烯基、-OC 1-C 6烷基苯基、-C 1-C 6烷基-OH、-C 1-C 6烷基-SH、-C 1-C 6烷基-O-C 1-C 6烷基、-OC 1-C 6卤代烷基、-NH 2、-C 1-C 6烷基-NH 2、-N(C 1-C 6烷基) 2、-NH(C 1-C 6烷基)、-N(C 1-C 6烷基)(C 1-C 6烷基苯基)、-NH(C 1-C 6烷基苯基)、硝基、-C(O)-OH、-C(O)OC 1-C 6烷基、-CONRiRii(其中Ri和Rii是H、D和C 1-6烷基)、-NHC(O)(C 1-C 6烷基)、-NHC(O)(苯基)、-N(C 1-C 6烷基)C(O)(C 1-C 6烷基)、-N(C 1-C 6烷基)C(O)(苯基)、-C(O)C 1-C 6烷基、-C(O)-5-7元杂芳基)、-C(O)C 1-C 6烷基苯基、-C(O)C 1-C 6卤代烷基、-OC(O)C 1-C 6烷基、-S(O) 2-C 1-C 6烷基、-S(O)-C 1-C 6烷基、-S(O) 2-苯基、-S(O) 2-C 1-C 6卤代烷基、-S(O) 2NH 2、-S(O) 2NH(C 1-C 6烷基)、-S(O) 2NH(苯基)、-NHS(O) 2(C 1-C 6烷基)、-NHS(O) 2(苯基)和-NHS(O) 2(C 1-C 6卤代烷基),其中所述的烷基、环烷基、苯基、芳基、杂环基和杂芳基中的每一个任选被一个或多个选自以下的取代基进一步取代:卤素、-OH、-NH 2、环烷基、3-8元杂环基、C 1-C 4烷基、C 1-C 4卤代烷基-、-OC 1-C 4烷基、-C 1-C 4烷基-OH、-C 1-C 4烷基-O-C 1-C 4烷基、-OC 1-C 4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC 1-C 6烷基、-CON(C 1-C 6烷基) 2、-CONH(C 1-C 6烷基)、-CONH 2、-NHC(O)(C 1-C 6烷基)、-NH(C 1-C 6烷基)C(O)(C 1-C 6烷基)、-SO 2(C 1-C 6烷基)、-SO 2(苯基)、-SO 2(C 1-C 6卤代烷基)、-SO 2NH 2、-SO 2NH(C 1-C 6烷基)、-SO 2NH(苯 基)、-NHSO 2(C 1-C 6烷基)、-NHSO 2(苯基)和-NHSO 2(C 1-C 6卤代烷基),条件是,所述化合物不是2-(2-氯吡啶-3-基)-1-(7-氟-2-(羟甲基)-5-(2-(异丙基氨基)嘧啶-4-基)二氢吲哚-1-基)乙-1-酮。
实施方案2.如实施方案1所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:
X 1选自:CR 9a和N;
X 2选自:CR 9b和N;
X 3选自:CR 9c和N;且X 1、X 2和X 3至多一个为N;
Y 1和Y 2各自独立地选自:CR 9’和N;
R 9a、R 9b和R 9c各自独立地选自:H、D、卤素、-OH、氰基、任选被取代的C 1-3烷基、任选被取代的C 1-3烷氧基、任选被取代的C 1-3烷基羰基、任选被取代的C 1-3烷氧基羰基、任选被取代的C 3-8环烷基、氨基、任选被取代的单-或二-(C 1-3烷基)氨基和-CONR aR b
R 9’选自:H、D、卤素、-OH、氰基、任选被取代的C 1-3烷基、任选被取代的C 1-3烷氧基、任选被取代的C 1-3烷基羰基、任选被取代的C 1-3烷氧基羰基、任选被取代的C 3-8环烷基、氨基、任选被取代的单-或二-(C 1-3烷基)氨基和CONR aR b
R 1选自:H和D;
R 2选自:任选被取代的C 1-8烷基、任选被取代的C 3-8环烷基、任选被取代的3-8元杂环基、任选被取代的6-12元芳基和任选被取代的5-12元杂芳基如5-7元杂芳基,或者R 2与X 1共同形成任选被取代的3-8元杂环基;
R 3选自:卤素和任选被一个或多个独立地选自D和卤素的取代基取代的C 1-8烷基;
R 4选自:H、D、任选被取代的C 1-8烷基、任选被取代的C 1-8烷氧基、-CO(CR 10R 11) mR 12、-SO 2(CR 10R 11) mR 12、-CONR 13(CR 10R 11) mR 12、-COO(CR 10R 11) mR 12、-CR 13R 13’(CR 10R 11) mR 12和C 1-8烷基羰基-;其中m为0、1、2或3,且其中
R 10和R 11各自独立地选自:H、D、卤素、任选被取代的C 1-8烷基和任选被取代的C 1-8烷氧基,或者R 10与R 11相连形成任选被取代的环烷基、环烯基、芳基、杂芳基和杂环基;且
R 12各自独立地选自:H、任选被取代的C 1-3烷基、任选被取代的C 3-8环烷基、任选被取代的3-8元杂环基、任选被取代的6-12元芳基和任选被取代的5-12元杂芳基如5-7元杂芳基;和
R 13和R 13’各自独立地选自:H和任选被取代的C 1-3烷基;或者R 13和R 13’与相邻的碳一起形成任选被取代的C 3-8环烷基、C 4-8环烯基和C 5-8杂环基;
R 5、R 6、R 7和R 8各自独立地选自:-H、-D、卤素、-OH、氨基、氰基、任选被取代的C 1-3烷基、任选被取代的C 1-3烷氧基、-(CH 2) 0-3CONR aR b、-(CH 2) 0-3COOH、任选被取代的C 3-8环烷基和任选被取代的3-8元杂环基;或者R 5、R 6、R 7和R 8中任意两个与相邻的碳一起形成任选被取代的环烷基、环烯基、芳基、杂芳基和杂环基;且
R a和R b各自独立地选自:H、D和任选被取代的C 1-3烷基。
实施方案3.如实施方案1至2中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于,所述化合物具有式Ia、Ib、Ic或Id所示的结构:
Figure PCTCN2018108762-appb-000005
R 9a、R 9b和R 9c各自独立地选自:H、D、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、-OH、氰基、卤素、氨基、单-或二-(C 1-3烷基)氨基、C 1-3烷基羰基、C 1-3烷氧基羰基和C 3-8环烷基;优选地,R 9a、R 9b和R 9c各自独立地选自:H、D和C 1-3烷基;更优选地,R 9a、R 9b和R 9c各自独立地选自:H和D;且
其它变量如实施方案1或2中所定义。
实施方案4.如实施方案1至3中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:
Y 1为CR 9’,Y 2为CR 9’,且其中R 9’选自H、D、卤素和C 1-3烷基;更优选地,Y 1为CR 9’,Y 2为CR 9’,且其中R 9’为H、D、F或甲基;
或者
Y 1为CR 9’,Y 2为N,且其中R 9’选自H、D、卤素和C 1-3烷基;更优选地,Y 1为CR 9’,Y 2为N,且其中R 9’为H、D、F或甲基;
或者
Y 1为N,Y 2为CR 9’,且其中R 9’选自H、D、卤素和C 1-3烷基;更优选地,Y 1为N,Y 2为CR 9’,且其中R 9’为H、D、F或甲基;
或者
Y 1为N,且Y 2为N。
实施方案5.如实施方案1所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于,所述化合物具有式Ie所示的结构:
Figure PCTCN2018108762-appb-000006
其中各变量如权利要求1中所定义。
实施方案6.如实施方案1、2和5中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:X 1选自CR 9a和N,其中R 9a选自H、D、卤素、-OH、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3烷基羰基、C 1-3烷氧基羰基、C 3-8环烷基、氨基和单-或二-(C 1-3烷基)氨基;优选地,X 1选自CR 9a和N,其中R 9a选自H、D和C 1-3烷基;更优选地,X 1选自CH、CD和N。
实施方案7.如实施方案1和5中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:
R 2选自:任选被取代的C 1-6烷基、任选被取代的C 3-8环烷基、任选被取代的3-8元杂环基和任选被取代的5-12元杂芳基如5-7元杂芳基,其中任选的取代基是一个或多个独立地选自D、卤素、羟基、-CD 3、C 1-6烷基和羟基C 1-6烷基的取代基,优选是一个或多个独立地选自D、卤素、羟基、-CD 3、-CH 3和-CH 2OH的取代基;
或者
R 2选自:任选被一个或多个羟基取代的C 1-6烷基、任选被一个或多个羟基取代的C 3-8环烷基、3-8元杂环基和任选被一个或多个-CD 3、C 1-6烷基和羟基C 1-6烷基取代的5-12元杂芳基如5-7元杂芳基;
或者
R 2选自:C 1-4烷基、
Figure PCTCN2018108762-appb-000007
它们任选地被一个或多个独立地选自D、卤素、羟基、C 1-4烷基、-CD 3和羟基C 1-4烷基的取代基取代,优选被一个或多个独立地选自D、卤素、羟基、-CH 3、-CD 3和-CH 2OH的取代基取代;
或者
R 2选自:异丙基,
Figure PCTCN2018108762-appb-000008
Figure PCTCN2018108762-appb-000009
或者
R 2选自
Figure PCTCN2018108762-appb-000010
或者
R 2选自
Figure PCTCN2018108762-appb-000011
实施方案8.如实施方案1至7中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:R 3选自卤素和任选被一个或多个独立地选自D或卤素的取代基取代的C 1-6烷基;或者,R 3选自卤素和任选被一个或多个独立地选自D或卤素的取代基取代的C 1-3烷基;或者,R 3选自卤素和C 1-6烷基;或者R 3选自氟、氯、溴、碘、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-CH 2CH 2CH 3、-CF 3、-CHF 2、CF 3CH 2-和CD 3-;或者,R 3选自氟、氯和-CH 3;或者,R 3为氟。
实施方案9.如实施方案1至8中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:
R 4选自-CO(CR 10R 11) mR 12和-CR 13R 13’(CR 10R 11) mR 12;其中m为0、1、2或3,且其中
R 10和R 11各自独立地选自H、D和任选被羟基取代的C 1-4烷基;
R 12各自独立地选自:任选被取代的6-12元芳基和任选被取代的5-12元杂芳基如5-7元杂芳基;
R 13和R 13’各自独立地选自:H、C 1-3烷基和C 1-3卤代烷基。
实施方案10.如实施方案9所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:R 12各自独立地选自任选被取代的6-12元芳基和任选被取代的5-12元杂芳基如5-7元杂芳基,其中任选的取代基是一个或多个独立地选自如下的取代基:D、卤素、C 1-4烷基、氰基和C 3-8杂环基-(CH 2) 0-4-(例如吗啉基如吗啉代基、哌嗪基、四氢吡喃基如四氢吡喃-4-基、吗啉基甲基如吗啉代基甲基或哌嗪基甲基);
或者,R 12选自:任选被取代的苯基和任选被取代的吡啶基如吡啶-3-基,其中任选的取代基是一个或多个独立地选自如下的取代基取代:D、卤素、C 1-4烷基(如甲基或乙基)、氰基和C 3-8杂环基-(CH 2) 0-4-(例如吗啉基如吗啉代基、哌嗪基、四氢吡喃基如四氢吡喃-4-基、吗啉基甲基如吗啉代基甲基或哌嗪基甲基);
或者,R 12选自:
Figure PCTCN2018108762-appb-000012
其中Rc选自卤素如氟或氯、C 1-4烷基如甲基、
Figure PCTCN2018108762-appb-000013
Figure PCTCN2018108762-appb-000014
其中R d选自H、C 1-4烷基如甲基或乙基和
Figure PCTCN2018108762-appb-000015
其中R e选自卤素如氟和氯,且p为1或2;和
Figure PCTCN2018108762-appb-000016
其中R f选自
Figure PCTCN2018108762-appb-000017
Figure PCTCN2018108762-appb-000018
实施方案11.如实施方案1至8中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:R 4选自-CO(CR 10R 11) mR 12,其中m为0、1、2或3,且其中
R 10和R 11各自独立地选自H;且
R 12选自
Figure PCTCN2018108762-appb-000019
实施方案12.如实施方案1至8中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:R 4选自-CO(CR 10R 11) mR 12,其中m为0、1、2或3,且其中R 10和R 11各自独立地选自H;R 12选自2-氰基苯基、5-氯-2-氟苯基、2-氯-3-氟苯基、2-氯-4-氟苯基、2-氯-5-氟苯基、2,5-二氟苯基、3-氯吡啶-2-基、6-氯吡啶-2-基、3-氯吡啶-4-基或4-氯吡啶-3-基。
实施方案13.如实施方案1至12中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于,
R 5、R 6、R 7和R 8各自独立地选自:-H、-D、卤素、-OH、氨基、氰基、任选被取代的C 1-6烷基、任选被取代的C 1-6烷氧基、-(CH 2) 0-3CONR aR b、-(CH 2) 0-3COOH、任选被取代的C 3-8环烷基和任选被取代的3-8元杂环基,其中任选的取代基是一个或多个独立地选自如下基团的取代基:D、-OH、-OC 1-C 6烷基和NH 2,且其中R a和R b各自独立地选自H、D和C 1-3烷基;
或者,R 5、R 6、R 7和R 8各自独立地选自H、任选被羟基或-OC 1-C 6烷基取代的C 1-6烷基;
或者,R 5和R 6各自独立地选自H或C 1-6烷基;且R 7和R 8各自独立地选自H和任选被羟基或-OC 1-C 6烷基取代的C 1-6烷基;
或者,R 5、R 6、R 7和R 8各自独立地选自-H、-CH 3和-CH 2OH;
或者,R 5、R 6和R 7为H,且R 8为H、-CH 3或-CH 2OH。
实施方案14.选自实施例P1-P20、P23-P25、P28-51、P53-P64的化合物:
Figure PCTCN2018108762-appb-000020
Figure PCTCN2018108762-appb-000021
Figure PCTCN2018108762-appb-000022
Figure PCTCN2018108762-appb-000023
Figure PCTCN2018108762-appb-000024
Figure PCTCN2018108762-appb-000025
Figure PCTCN2018108762-appb-000026
Figure PCTCN2018108762-appb-000027
Figure PCTCN2018108762-appb-000028
或其药学上可接受的盐。
另一方面,本发明还提供了包含上述新化合物的药物组合物、上述新化合物的用途和使用上述新化合物的治疗方法:
实施方案15.如实施方案1-14中任一项所述的化合物或其药学上可接受的盐,其用作药物。
实施方案16.药物组合物,包含如实施方案1-14中任一项所述的化合物或其药学上可接受的盐,并且任选地包含药学上可接受的载体。
实施方案17.如实施方案1-14中任一项所述的化合物或其药学上可接受的盐在制备用于预防和/或治疗与ERK激酶相关的疾病的药剂或用作ERK激酶抑制剂的产品中的用途。
实施方案18.非治疗性地抑制ERK激酶活性的方法,该方法包括将有效量的权利要求1-14中任一项所述的化合物或其药学上可接受的盐与ERK激酶接触,从而抑制ERK激酶。
另一方面,本发明还提供了制备上述新化合物的中间体(例如,本发明公开的中间体1-82,特别是中间体25)和方法(例如,图1-4中所示的方法,特别是图3的方法):
实施方案19.具有如下结构的化合物(4-(7-氟二氢吲哚-5-基)吡啶-2-基)(1-甲基-1H-比唑-5-基)氨基甲酸叔丁酯或其立体异构体、外消旋体、几何异构体、互变异构体、水合物、溶剂化物或其药学上可接受的盐:
Figure PCTCN2018108762-appb-000029
实施方案20.制备如实施方案1所述的式(I)化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐的方法,所述式(I)化合物是式C3的化合物:
Figure PCTCN2018108762-appb-000030
其中X 1、R 2、R 3、R 10、R 11、R 12和m如实施方案1中所定义,
该方法包括如下步骤:
(a)使式C1的化合物
Figure PCTCN2018108762-appb-000031
与化合物
Figure PCTCN2018108762-appb-000032
进行酰胺偶联反应,生成式C2的化合物,
Figure PCTCN2018108762-appb-000033
(b)当式C2的化合物为Boc保护时,使其脱保护,生成式C3的化合物,
Figure PCTCN2018108762-appb-000034
实施方案21.实施方案20的方法,其中所述酰胺偶联反应在缩合试剂和碱的存在下、在惰性溶剂中进行。
实施方案22.实施方案20的方法,其中所述脱保护在酸存在下、在惰性溶剂中进行。
实施方案23.实施方案21或22的方法,其中所述惰性溶剂选自:乙酸乙酯、四氢呋喃、甲基四氢呋喃、乙腈、二甲基亚砜、N,N-二甲基甲酰胺、二氯甲烷、1,2-二氯乙烷、N-甲基-2-吡咯烷酮或其组合。
实施方案24.实施方案21的方法,其中所述缩合试剂选自:1-羟基苯并三氮唑(HOBT)、1-羟基-7-偶氮苯并三氮唑(HOAT)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基鏻(PyBOP)、苯并三唑-1-三(三甲氨基)-六氟磷酸酯(BOP)、1,1-羰基二咪唑(CDI)、1-丙基磷酸酐(T 3P)、1-乙基-3-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)、N,N-二环己基碳二亚胺(DCC)、醋酸酐、乙酰氯、草酰氯、六氟磷酸2-(7-氧化苯并三唑)-N,N,N’,N’-四甲基脲鎓(HATU)、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸季铵盐(HBTU)中的一种或多种。
实施方案25.实施方案21的方法,其中所述碱选自:三乙胺、DIPEA、吡啶、2,4-二甲基吡啶、NaOH、KOH、LiOH、Na 2CO 3、K 2CO 3、NaHCO 3、Cs 2CO 3、Na 3PO 4或K 3PO 4中的一种或多种。
实施方案26.实施方案20的方法,其中所述酰胺偶联反应在室温至回流的温度下进行 0.5~24h。
实施方案27.实施方案22的方法,其中所述酸选自:盐酸、硫酸、三氟乙酸、乙酸、甲酸、磷酸中的一种或多种。
实施方案28.实施方案20的方法,其中所述脱保护在-10℃至80℃的温度下0.5~24h。
定义
本申请中所用的下列术语和符号具有如下所述的含义,其所处的上下文中另有说明的除外。
不在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如,-O(C 1-3烷基)是指通过氧原子与分子的其余部分连接的C 1-3烷基。然而,当取代基的连接位点对本领域技术人员来说是显而易见的时候,例如,卤素取代基,“-”可以被省略。
当基团带有波浪线
Figure PCTCN2018108762-appb-000035
时,波浪线表示该基团与分子其它部分的连接点。
本文所用的术语“烷基”是指具有1-8个碳原子、例如具有1-6个碳原子、例如具有1-4个碳原子、例如具有1、2或3个碳原子的直链或支链的饱和一价烃基。例如,“C 1-8烷基”表示具有1-8个碳原子的烷基。类似地,“C 1-4烷基”表示具有1-4个碳原子的烷基;“C 1-3烷基”表示具有1-3个碳原子的烷基。烷基的例子包括但不限于甲基(“Me”)、乙基(“Et”)、正丙基(“n-Pr”)、异丙基(“i-Pr”)、正丁基(“n-Bu”)、异丁基(“i-Bu”)、仲丁基(“s-Bu”)、叔丁基(“t-Bu”)等。无论术语“烷基”单独使用,还是作为其它基团例如卤代烷基、烷氧基等的一部分,均适用该定义。
本文所用的术语“烯基”是指含有一个或多个、例如1、2或3个碳碳双键(C=C)的、具有2-8个碳原子、例如具有2-6个碳原子、例如具有2、3或4个碳原子的直链或支链的一价烃基。例如,“C 2-6烯基”表示含有1或2个、优选1个碳碳双键的、具有2-6个碳原子的烯基。类似地,“C 2-3烯基”表示含有1个碳碳双键的、具有2-3个碳原子的烯基。烯基的例子包括但不限于乙烯基、2-丙烯基和2-丁烯基。
本文所用的术语“炔基”是指含有一个或多个、例如1、2或3个碳碳三键(C≡C)的、具有2-8个碳原子、例如2-6个碳原子、例如2-4个碳原子的直链或支链的一价烃基。例如,“C 2-6炔基”表示含有1或2个、优选1个碳碳三键的、具有2-6个碳原子的炔基。类似地,“C 2-3炔基”表示含有1个碳碳三键的、具有2-3个碳原子的炔基。炔基的例子包括但不限于乙炔基、2-丙炔基和2-丁炔基。
本文所用的术语“烷氧基”是指基团-O-烷基,其中烷基如上文所定义。例如,“C 1-8烷氧基”表示-O-C 1-8烷基,即,具有1-8个碳原子的烷氧基。类似地,“C 1-3烷氧基”表示-O-C 1-3烷基,即,具有1-3个碳原子的烷氧基。烷氧基的例子包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基和己氧基等。无论术语“烷氧基”单独使用,还是作为其它基团的一部分,均适用该定义。
本文所用的术语“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I),优选氟和氯,最优选氟。
本文所用的术语“卤代烷基”是指其中一个或多个氢原子、例如1、2、3、4或5个氢原子被卤素替代的本文所定义的烷基,并且当超过一个氢原子被卤素原子替代时,所述卤素原子可以彼此相同或不同。卤代烷基的例子包括但不限于-CF 3、-CHF 2、-CH 2CF 3等。
本文所述的术语“羟基”是指基团-OH。
本文所用的术语“巯基”是指基团-SH。
本文所用的术语“氰基”是指基团-CN。
本文所用的术语“羧基”是指基团-C(O)-OH,也可表示为-COOH。
本文所用的术语“羰基”是指基团-C(O)-,也可表示为-CO-。
本文所用的术语“氢”是指基团-H。
本文所用的符号“D”是指氘。
本文所用的术语“氨基”是指基团-NH 2
本文所用的术语“烷基氨基”或“单烷基氨基”是指基团烷基-NH-,其中烷基如本文所定义。
本文所用的术语“二烷基氨基”是指基团(烷基) 2-N-,其中烷基如本文所定义。
本文所用的术语“烷基羰基”是指通过羰基与其它基团连接的烷基,即,烷基-C(O)-,其中烷基如本文所定义。
本文所用的术语“烷氧基羰基”是指通过羰基与其它基团连接的烷氧基,即,烷氧基-C(O)-,其中烷氧基如本文所定义。
本文所用的术语“氧代”是指基团=O。
本文所用的术语“硝基”是指基团-NO 2
本文所用的术语“环烷基”是指具有3-12个环碳原子、例如具有3-8个环碳原子、例如具有3-6个环碳原子的饱和的一价单环或二环烃基。例如,“C 3-8环烷基”表示具有3-8个环碳原子的环烷基。类似地,“C 3-6环烷基”表示具有3-6个环碳原子的环烷基。环烷基的例子包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
本文所用的术语“环烯基”是指含有一个或多个双键、例如1、2、3或4个双键的本文所定义的环烷基,所述环烯基的环是非芳族的环。例如,“C 3-8环烯基”表示具有3-8个环碳原子的环烯基。类似地,“C 3-6环烯基”表示具有3-6个环碳原子的环烯基。环烯基的例子包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基和环辛烯基。
本文所用的术语“杂环基”或“杂环的”或“杂环”是指具有3-20个环原子、例如具有3-12个环原子、例如3-8个环原子、例如3-6个环原子的单环、二环或三环的、饱和的和部分不饱和的非芳族环,其除了包含1-4个、例如1-3个、例如1或2个、例如1个选自O、S和N的杂原子外,还包含至少一个碳原子。在一个实例中,所述“杂环基”或“杂环的”或“杂环”是指具有3至8个环原子、例如3、4、5或6个环原子的单环,其除了包含1-4个、例如1-3个、例如1或2个、例如1个选自O、S和N的杂原子外,还包含至少一个碳原子。在一个实例中,所述“杂环基”或“杂环的”或“杂环”包含0、1、2或3个双键。任何氮或硫杂原子可以任选被氧化(例如,NO、SO、SO 2),并且任何氮杂原子可以任选被季铵化(例如[NR 4] +Cl -、[NR 4] +OH -)。具有3-8个环原子的杂环基也简称为3-8元杂环基,具有其它碳原子数的杂环基 也可以类似地简要表述。杂环基的实例包括但不限于环氧乙烷基、氮丙啶基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、1,2-二硫杂环丁烷基、1,3-二硫杂环丁基、吡咯烷基(吡咯烷-1-基、吡咯烷-2-基、吡咯烷-3-基)、二氢-1H-吡咯基、二氢呋喃基、四氢呋喃基(例如四氢呋喃-2-基、四氢呋喃-3-基、四氟呋喃-4-基)、二氢噻吩基、四氢噻吩基、咪唑烷基、哌啶基、哌嗪基(例如哌嗪-1-基、哌嗪-2-基、哌嗪-3-基、哌嗪-4-基)、异喹啉基、四氢异喹啉基、吗啉基(例如吗啉代(即吗啉-1-基)、吗啉-2-基、吗啉-3-基)、硫吗啉基、1,1-二氧代-硫吗啉基、二氢吡喃基、四氢吡喃基(例如四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-基)、六氢噻喃基、六氢嘧啶基、氧杂氮杂环己烷基(oxazinanyl)、噻嗪烷基(thiazinanyl)、氧杂硫杂环己烷基(thioxanyl)、高哌嗪基(homopiperazinyl)、高哌啶基(homopiperidinyl)、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂
Figure PCTCN2018108762-appb-000036
氧杂氮杂环庚烷基、二氮杂环庚烷基、1,4-二氮杂环庚烷基、二氮杂
Figure PCTCN2018108762-appb-000037
基、硫氮杂
Figure PCTCN2018108762-appb-000038
基、硫杂氮杂环庚烷基、四氢噻喃基、
Figure PCTCN2018108762-appb-000039
唑烷基、噻唑烷基、异噻唑烷基、1,1-二氧代异噻唑烷酮基、
Figure PCTCN2018108762-appb-000040
唑烷酮基、咪唑烷酮基、4,5,6,7-四氢[2H]吲唑基、四氢苯并咪唑基、4,5,6,7-四氢苯并[d]咪唑基、1,6-二氢咪唑并[4,5-d]吡咯并[2,3-b]吡啶基、噻嗪基、
Figure PCTCN2018108762-appb-000041
嗪基、噻二嗪基、
Figure PCTCN2018108762-appb-000042
二嗪基、二噻嗪基、二
Figure PCTCN2018108762-appb-000043
嗪基、
Figure PCTCN2018108762-appb-000044
噻嗪基、噻三嗪基(thiatriazinyl)、
Figure PCTCN2018108762-appb-000045
三嗪基(oxatriazinyl)、二噻二嗪基(dithiadiazinyl)、咪唑啉基、二氢嘧啶基、四氢嘧啶基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、噻喃基、2H-吡喃基、4H-吡喃基、二
Figure PCTCN2018108762-appb-000046
烷基、1,3-二氧戊环基、吡唑啉基、吡唑烷基、二噻烷基、二硫戊环基、嘧啶酮基、嘧啶二酮基、嘧啶-2,4-二酮基、哌嗪酮基、哌嗪二酮基、吡唑烷基咪唑啉基、3-氮杂二环[3.1.0]己烷基、3,6-二氮杂二环[3.1.1]庚烷基、6-氮杂二环[3.1.1]庚烷基、3-氮杂二环[3.1.1]庚烷基、3-氮杂二环[4.1.0]庚烷基、氮杂二环[2.2.2]己烷基、2-氮杂二环[3.2.1]辛烷基、8-氮杂二环[3.2.1]辛烷基、2-氮杂二环[2.2.2]辛烷基、8-氮杂二环[2.2.2]辛烷基、7-氧杂二环[2.2.1]庚烷、氮杂螺[3.5]壬烷基、氮杂螺[2.5]辛烷基、氮杂螺[4.5]癸烷基、1-氮杂螺[4.5]癸烷-2-酮基、氮杂螺[5.5]十一烷基、四氢吲哚基、八氢吲哚基、四氢异吲哚基、四氢吲唑基、1,1-二氧代六氢噻喃基。含有硫或氧原子和1至3个氮原子的5元杂环基的实例是:噻唑基,包括噻唑-2-基和噻唑-2-基N-氧化物,噻二唑基,包括1,3,4-噻二唑-5-基和1,2,4-噻二唑-5-基,
Figure PCTCN2018108762-appb-000047
唑基,例如
Figure PCTCN2018108762-appb-000048
唑-2-基,和
Figure PCTCN2018108762-appb-000049
二唑基,例如1,3,4-
Figure PCTCN2018108762-appb-000050
二唑-5-基和1,2,4-
Figure PCTCN2018108762-appb-000051
二唑-5-基。含有2-4个氮原子的5-元环杂环基的实例包括:咪唑基,例如咪唑-2-基;三唑基,例如1,3,4-三唑-5-基;1,2,3-三唑-5-基、1,2,4-三唑-5-基,和四唑基,例如1H-四唑-5-基。苯并稠合的5元杂环基的实例是苯并
Figure PCTCN2018108762-appb-000052
唑-2-基、苯并噻唑-2-基和苯并咪唑-2-基。举例性的6元杂环基含有1至3个氮原子,并任选含有硫或氧原子,例如:吡啶基,例如吡啶-2-基、吡啶-3-基和吡啶-4-基;嘧啶基,例如嘧啶-2-基和嘧啶-4-基;三嗪基,例如1,3,4-三嗪-2-基和1,3,5-三嗪-4-基;哒嗪基,特别是哒嗪-3-基,和吡嗪基。吡啶N-氧化物和哒嗪N-氧化物以及吡啶基、嘧啶-2-基、嘧啶-4-基、哒嗪基和1,3,4-三嗪-2-基是另外的杂环基实例。
本文所用的术语“羟基烷基”是指被羟基取代的烷基,即-烷基-OH,其中烷基如本文所定义。这类基团的实例包括但不限于羟基甲基、羟基乙基(例如2-羟基乙基、1-羟基乙基)、羟基丙基(例如1-羟基丙-2-基、1-羟基丙-3-基、1-羟基丙-1-基等)、羟基丁基(例如4-羟基丁-2-基等)。
本文所用的术语“芳基”是指由一个环或多个环稠合组成的具有6-14个环碳原子、例如具有6-12个环碳原子、例如具有6-10个环碳原子的碳环烃基,其中至少一个环是芳族环。芳基的例子包括但不限于苯基、萘基、1,2,3,4-四氢萘基、茚基,优选苯基和萘基。
本文所用的术语“杂芳基”是指:
具有5、6或7个环原子、例如具有6个环原子的单环芳族烃基,其在环中包含一个或多个、例如1、2或3个、例如1或2个独立地选自N、O和S(例如N)的环杂原子,其余环原子是碳原子;和
具有8-12个环原子、例如具有9或10个环原子的二环芳族烃基,其在环中包含一个或多个、例如1、2、3或4个、例如1或2个独立地选自N、O和S(例如N)的环杂原子,其余环原子是碳原子,其中至少一个环是芳族环。
当杂芳基中的S和O原子的总数超过1时,这些S和O杂原子彼此不相邻。
杂芳基也包括其中的N环杂原子是N-氧化物形式的那些杂芳基,例如N-氧化嘧啶基。
在一些实施方案中,上述杂芳基中的环杂原子是N原子,这类杂芳基称为“含氮杂芳基”。含氮杂芳基也包括其中的N环杂原子是N-氧化物形式的那些杂芳基,例如N-氧化吡啶基。例如,所述含氮杂芳基是具有5个环原子的单环杂芳基,其在环中包含1或2个N杂原子,其余环原子是碳原子;又例如,所述含氮杂芳基是具有6个环原子的单环杂芳基,其在环中包含1、2或3个杂原子,其余环原子是碳原子。
杂芳基的例子包括但不限于:吡啶基(例如,吡啶-2-基、吡啶-3-基、吡啶-4-基、吡啶-5-基、吡啶-6-基)、N-氧化吡啶基;吡嗪基;嘧啶基;吡唑基(例如,吡唑-5-基、吡唑-1-基、吡唑-2-基、吡唑-3-基、吡唑-4-基);咪唑基;
Figure PCTCN2018108762-appb-000053
唑基;异
Figure PCTCN2018108762-appb-000054
唑基;噻唑基;异噻唑基;噻二唑基;四唑基;三唑基;噻吩基;呋喃基;吡喃基;吡咯基;哒嗪基;苯并[d]噻唑基;苯并间二氧杂环戊烯基,例如苯并[d][1,3]间二氧杂环戊烯基;苯并
Figure PCTCN2018108762-appb-000055
唑基,例如苯并[d]
Figure PCTCN2018108762-appb-000056
唑基;咪唑并吡啶基,例如咪唑并[1,2-a]吡啶基;三唑并吡啶基,例如[1,2,4]三唑并[4,3-a]吡啶基和[1,2,4]三唑并[1,5-a]吡啶基;吲唑基;2H-吲唑基;吡咯并嘧啶基,例如吡咯并[3,4-d]嘧啶基、7H-吡咯并[2,3-d]嘧啶基;吡唑并嘧啶基,例如吡唑并[1,5-a]嘧啶基;四唑并吡啶基,例如四唑并[1,5-a]吡啶基;苯并噻吩基;苯并呋喃基;苯并咪唑啉基;吲哚基;吲哚啉基;嘌呤基,例如9H-嘌呤基和7H-嘌呤基;喹啉基;异喹啉基;1,2,3,4-四氢喹啉基和5,6,7,8-四氢异喹啉基。
其中的含氮杂芳基的实例包括但不限于:吡咯基;吡唑基;咪唑基;吡啶基;吡嗪基;嘧啶基、N-氧化嘧啶基;哒嗪基;吡咯并嘧啶基,例如吡咯并[3,4-d]嘧啶基、7H-吡咯并[2,3-d]嘧啶基;嘌呤基,例如9H-嘌呤基和7H-嘌呤基;喹啉基;吲哚基;以及吲唑基。
如本文所用,“芳基”或“芳族的”遵循休克尔规则(Hückel′s rule),其中π电子数等于4n+2,n为零或任何最多为6的正整数。
本文所用的术语“任选”、“任选的”或“任选地”意指随后描述的取代模式、事件或情况可以发生或可以不发生,并且该描述包括所述取代模式发生的情形以及所述取代模式不发生的情形。例如,“任选被取代的烷基”包括本文定义的“未取代的烷基”和“被取代的烷基”。本领域技术人员应当理解的是,对于含有一个或多个取代基的任意基团而言,所述基团不包括任 何在空间上不切实际的、化学上不正确的、合成上不可行的和/或内在不稳定的取代模式。
本文所用的术语“被取代的”或“被……取代”意指给定原子或基团上的一个或多个氢原子被一个或多个选自给定的取代基组的取代基替换,条件是不超过该给定原子的正常化合价。当取代基是氧代(即=O)时,则单个原子上的两个氢原子被氧替换。只有当取代基和/或变量的组合导致化学上正确的且稳定的化合物时,这类组合才是允许的。化学上正确的且稳定的化合物意味着化合物足够稳定,以至于能从反应混合物中被分离出来并能确定化合物的化学结构,并且随后能被配制成至少具有实际效用的制剂。例如,在没有明确列出取代基的情况下,本文所用的术语“被取代的”或“被……取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代,所述取代基独立地选自:氘(D)、卤素、-OH、巯基、氰基、-CD 3、-C 1-C 6烷基(优选-C 1-3烷基)、C 2-C 6烯基、C 2-C 6炔基、环烷基(优选3-8元环烷基)、芳基、杂环基(优选3-8元杂环基)、杂芳基、芳基-C 1-C 6烷基-、杂芳基-C 1-C 6烷基-、C 1-C 6卤代烷基-、-OC 1-C 6烷基(优选-OC 1-C 3烷基)、-OC 2-C 6烯基、-OC 1-C 6烷基苯基、-C 1-C 6烷基-OH(优选-C 1-C 4烷基-OH)、-C 1-C 6烷基-SH、-C 1-C 6烷基-O-C 1-C 6烷基、-OC 1-C 6卤代烷基、-NH 2、-C 1-C 6烷基-NH 2(优选-C 1-C 3烷基-NH 2)、-N(C 1-C 6烷基) 2(优选-N(C 1-C 3烷基) 2)、-NH(C 1-C 6烷基)(优选-NH(C 1-C 3烷基))、-N(C 1-C 6烷基)(C 1-C 6烷基苯基)、-NH(C 1-C 6烷基苯基)、硝基、-C(O)-OH、-C(O)OC 1-C 6烷基(优选-C(O)OC 1-C 3烷基)、-CONRiRii(其中Ri和Rii是H、D和C 1-6烷基,优选C 1-3烷基)、-NHC(O)(C 1-C 6烷基)、-NHC(O)(苯基)、-N(C 1-C 6烷基)C(O)(C 1-C 6烷基)、-N(C 1-C 6烷基)C(O)(苯基)、-C(O)C 1-C 6烷基、-C(O)杂芳基(优选-C(O)-5-7元杂芳基)、-C(O)C 1-C 6烷基苯基、-C(O)C 1-C 6卤代烷基、-OC(O)C 1-C 6烷基(优选-OC(O)C 1-C 3烷基)、-S(O) 2-C 1-C 6烷基、-S(O)-C 1-C 6烷基、-S(O) 2-苯基、-S(O) 2-C 1-C 6卤代烷基、-S(O) 2NH 2、-S(O) 2NH(C 1-C 6烷基)、-S(O) 2NH(苯基)、-NHS(O) 2(C 1-C 6烷基)、-NHS(O) 2(苯基)和-NHS(O) 2(C 1-C 6卤代烷基),其中所述的烷基、环烷基、苯基、芳基、杂环基和杂芳基中的每一个任选被一个或多个选自以下的取代基进一步取代:卤素、-OH、-NH 2、环烷基、3-8元杂环基、C 1-C 4烷基、C 1-C 4卤代烷基-、-OC 1-C 4烷基、-C 1-C 4烷基-OH、-C 1-C 4烷基-O-C 1-C 4烷基、-OC 1-C 4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC 1-C 6烷基、-CON(C 1-C 6烷基) 2、-CONH(C 1-C 6烷基)、-CONH 2、-NHC(O)(C 1-C 6烷基)、-NH(C 1-C 6烷基)C(O)(C 1-C 6烷基)、-SO 2(C 1-C 6烷基)、-SO 2(苯基)、-SO 2(C 1-C 6卤代烷基)、-SO 2NH 2、-SO 2NH(C 1-C 6烷基)、-SO 2NH(苯基)、-NHSO 2(C 1-C 6烷基)、-NHSO 2(苯基)和-NHSO 2(C 1-C 6卤代烷基)。当一个原子或基团被多个取代基取代时,所述取代基可以相同或不同。
本文所用的术语“药学上可接受的”指的是无毒的、生物学上可耐受的,适合给个体施用的。
本文所用的术语“药学上可接受的盐”指的是无毒的、生物学上可耐受的适合给个体施用的式(I)的化合物的酸加成盐或碱加成盐,包括但不限于:式(I)的化合物与无机酸形成的酸加成盐,例如盐酸盐、氢溴酸盐、碳酸盐、碳酸氢盐、磷酸盐、硫酸盐、亚硫酸盐、硝酸盐等;以及式(I)的化合物与有机酸形成的酸加成盐,例如甲酸盐、乙酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙 磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和与式HOOC-(CH 2) n-COOH(其中n是0-4)的链烷二羧酸形成的盐等。“药学上可接受的盐”也包括带有酸性基团的式(I)的化合物与药学上可接受的阳离子例如钠、钾、钙、铝、锂和铵形成的碱加成盐。
此外,如果本文所述的化合物是以酸加成盐的形式得到的,其游离碱形式可以通过碱化该酸加成盐的溶液获得。相反地,如果产物是游离碱形式,则其酸加成盐、特别是药学上可接受的酸加成盐可以按照由碱性化合物制备酸加成盐的常规操作通过将游离碱溶于合适的溶剂并且用酸处理该溶液来得到。本领域技术人员无需过多实验即可确定各种可用来制备无毒的药学上可接受的酸加成盐的合成方法。
本发明的化合物可以以溶剂化物的形式存在。术语“溶剂化物”意指包含化学计量的或非化学计量的溶剂的溶剂加成形式。如果溶剂是水,则形成的溶剂化物是水合物,当溶剂是乙醇时,则形成的溶剂化物是乙醇合物。水合物是通过一个或多个分子的水与一分子所述物质形成的,其中水保留其H 2O的分子状态,这样的组合能形成一种或多种水合物,例如半水合物、一水合物和二水合物。
本文所用的术语“前药”是指施用于个体后通过体内生理学作用如水解、代谢等被化学修饰成本发明的化合物的有活性或无活性的化合物。制备和使用前药中所涉及的适合性和技术是本领域技术人员所公知的。举例性的前药有例如游离羧酸的酯和硫醇的S-酰基衍生物和醇或酚的O-酰基衍生物。适合的前药通常是可在生理条件下通过溶剂解转化成母体羧酸的药学上可接受的酯衍生物,例如低级烷基酯、环烃基酯、低级链烯基酯、苄基酯、单-或二-取代的低级烷基酯,如ω-(氨基、单-或二-低级烷基氨基、羧基、低级烷氧基羰基)-低级烷基酯、α-(低级烷酰基氧基、低级烷氧基羰基或二-低级烷基氨基羰基)-低级烷基酯,如新戊酰基氧基甲基酯等,它们在本领域中是常规使用的。
本领域技术人员应当理解的是,一些式(I)的化合物可以包含一个或多个手性中心,因此存在两个或更多个立体异构体。因此,本发明的化合物可以以单个立体异构体(例如对映异构体、非对映异构体)及其任意比例的混合物例如外消旋体的形式存在,以及在适当的情况下,可以以其互变异构体和几何异构体的形式存在。
本文所用的术语“立体异构体”是指具有相同化学构成、但在原子或基团的空间排列方面不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体等。
本文所用的术语“对映异构体”是指化合物的彼此是不可重叠的镜像的两种立体异构体。
本文所用的术语“非对映异构体”是指具有两个或更多个手性中心并且其分子彼此不是镜像的立体异构体。非对映异构体具有不同的物理性质,例如熔点、沸点、光谱性质或生物活性。非对映异构体的混合物可以用高分辨率分析方法例如电泳和色谱例如HPLC分离。
立体化学定义和惯例可遵循S.P.Parker编辑,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;和Eliel,E.和Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994。许多有机化合物以光学活性形式存在,即,它们具有旋转平面偏振光的平面的能力。在描述光学活性化合物时,前缀D和L或者R和S用于表示分子关于其手性中心的绝对构型。前缀d和l或者(+)和(-)用于表示化 合物旋转平面偏振光的符号,其中(-)或l表示该化合物是左旋的。带有(+)或d的前缀的化合物是右旋的。对于给定的化学结构,除了它们彼此互为镜像之外,这些立体异构体是相同的。特定的立体异构体也可以称为对映异构体,这类异构体的混合物通常称为对映异构体混合物。对映异构体的50∶50混合物被称为外消旋混合物或外消旋体,其可以出现在化学反应或方法中没有立体选择性或立体特异性的情况中。术语“外消旋混合物”和“外消旋体”是指不具有光学活性的两种对映异构体的等摩尔混合物。
外消旋混合物可以以其本身的形式使用或者拆分成单个异构体使用。通过拆分可以得到立体化学上的纯的化合物或者富集一种或多种异构体的混合物。分离异构体的方法是众所周知的(参见Allinger N.L.和Eliel E.L.,″Topics in Stereochemistry″,第6卷,Wiley Interscience,1971),包括物理方法,例如使用手性吸附剂的色谱法。可以由手性前体制备得到手性形式的单个异构体。或者,可以通过与手性酸(例如10-樟脑磺酸、樟脑酸、α-溴樟脑酸、酒石酸、二乙酰基酒石酸、苹果酸、吡咯烷酮-5-羧酸等的单个对映异构体)形成非对映异构体盐而由混合物化学分离得到单个异构体,将所述的盐分级结晶,然后游离出拆分的碱中的一个或两个,任选地重复这一过程,从而得到一个或两个基本上不包含另一种异构体的异构体,即光学纯度以重量计为例如至少91%、92%、93%、94%、95%、96%、97%、98%、99%或99.5%的所需的立体异构体。或者,如本领域技术人员所熟知的,可以将外消旋体共价连接到手性化合物(辅助物)上,得到非对映异构体,可通过色谱法或分级结晶法将其分离,之后化学除去手性辅助物,得到纯的对映异构体。
本文所用的术语“构象异构体”是指以单键连接的共价键化合物的分子中,原子或基团所处空间位置不同而形成的异构体,例如环戊烷的半椅式构象异构体和信封式构象异构体。
本文所用的术语术语“互变异构体”或“互变异构形式”是指经由低能量障碍可相互转化的不同能量的结构异构体。例如,质子互变异构体(也称为质子转移互变异构体)包括通过质子迁移进行的相互转化,例如酮-烯醇和亚胺-烯胺异构化。价键互变异构体包括通过一些键合电子的重组进行的相互转化。
本文所用的术语“几何异构体”是因双键或环碳原子的单键不能自由旋转而引起的异构体,又称顺反异构体,取代基团位于平面的同侧为顺式异构体,位于平面的对侧为反式异构体。
本文所用的术语“治疗”是指给患有疾病或者具有所述疾病的症状的个体施用一种或多种药物物质、特别是本文所述的式(I)化合物和/或其药学上可接受的盐,用以治愈、缓解、减轻、改变、医治、改善、改进或影响所述疾病或者所述疾病的症状。在一些实施方案中,所述疾病是癌症。
本文所用的术语“预防”是指给具有易患所述疾病的体质的个体施用一种或多种药物物质、特别是本文所述的式(I)化合物和/或其药学上可接受的盐,用以防止个体罹患该疾病。在一些实施方案中,所述疾病是与ERK激酶如ERK1和/或ERK2激酶相关的疾病。在进一步的实施方案中,所述疾病是与ERK激酶如ERK1和/或ERK2激酶高表达或高活性相关的疾病。在进一步的实施方案中,所述疾病是癌症或肿瘤。
本文所用的术语“癌症”、“癌”和“肿瘤”是指哺乳动物的典型特征在于不受调节的细胞生长的生理学状况。所述癌症的实例包括胚细胞瘤、胶质瘤、肉瘤、精原细胞瘤、成胶质细胞瘤、黑色素瘤、白血病和骨髓或淋巴样恶性病。此类癌症的更具体的实例包括鳞状细胞癌(例如,上皮鳞状细胞癌)和肺癌,包括小细胞肺癌、非小细胞肺癌(NSCLC)、肺腺癌和肺鳞状细胞癌。另外的癌症包括皮肤癌、角化棘皮瘤、滤泡型癌、多毛细胞白血病、口腔前庭癌、咽癌、唇癌、舌癌、口癌、唾液腺癌、食道癌、喉癌、肝细胞癌、胃癌、胃肠癌、小肠癌、大肠癌、胰腺癌、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、直肠癌、结肠直肠癌、泌尿生殖系统癌、胆道癌、胆囊腺癌、甲状腺癌、乳头状癌、子宫内膜癌、子宫癌、唾液腺癌、肾癌、前列腺癌、睾丸癌、外阴癌、腹膜癌、肛门癌、阴茎癌、骨癌、多发性骨髓瘤、B细胞淋巴瘤、中枢神经系统癌、脑癌、头颈癌、霍奇金淋巴瘤。实例还包括骨髓增生性障碍例如真性红细胞增多症、原发性血小板增多症、骨髓纤维化例如原发性骨髓纤维化、急性髓性白血病和慢性髓性白血病(CML)。
当涉及化学反应时,术语“处理”、“接触”和“反应”意指在适当的条件下加入或混合两种或更多种试剂,以产生所示的和/或所需的产物。应当理解的是,产生所示的和/或所需的产物的反应可能不一定直接来自最初加入的两种试剂的组合,即,在混合物中可能存在生成的一个或多个中间体,这些中间体最终导致了所示的和/或所需的产物的形成。
本文所用的术语“有效量”是指通常足以对个体产生有益效果的量。可以通过常规方法(例如建模、剂量递增研究或临床试验)结合常规影响因素(例如给药方式、化合物的药代动力学、疾病的严重程度和病程、个体的病史、个体的健康状况、个体对药物的响应程度等)来确定本发明的化合物的有效量。
术语“抑制”是指生物活动或过程的基线活性的降低。术语“抑制ERK活性”是指相对于不存在式(I)化合物或其药学上可接受的盐时的ERK活性,对存在本文所述的式(I)化合物或其药学上可接受的盐的直接或间接响应导致的ERK活性的降低。活性的降低可以是由本文所述的式(I)化合物或其药学上可接受的盐与ERK直接相互作用引起的,或者是由本文所述的式(I)化合物和/或其药学上可接受的盐与一种或多种其它因子相互作用进而影响ERK活性引起的。
本文所用的术语“个体”是指哺乳动物和非哺乳动物。哺乳动物是指哺乳类的任何成员,其包括但不限于:人;非人灵长类动物,如黑猩猩及其它猿类和猴类物种;农场动物,如牛、马、绵羊、山羊和猪;家畜,如兔、狗和猫;实验室动物,包括啮齿类动物,如大鼠、小鼠和豚鼠;等等。非哺乳动物的例子包括但不限于鸟等。术语“个体”并不限定特定的年龄或性别。在一些实施方案中,个体是人。
一般而言,术语“约”在本文中用于将所给出的数值调整至高于或低于该数值20%。
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
通用合成方法
本发明的式(I)化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水 合物、溶剂化物或其药学上可接受的盐可以通过多种方法、包括下文给出的方法、实施例中给出的方法或与之类似的方法制备。下文描绘了适宜的通用合成方案。对于各反应步骤而言适当的反应条件是本领域技术人员已知的。原料可购买获得,或者可以通过下文的方法、与下文给出的方法类似的方法或本领域已知的方法制得。通式中的各变量具有与上文相同的含义,另有说明除外。
本发明的化合物的通用合成方法参见附图1-4。
图1显示了用于合成本发明的化合物的通用合成方案A。
图2显示了用于合成本发明的化合物的通用合成方案B。
图3显示了用于合成本发明的化合物的通用合成方案C。
图4显示了用于合成本发明的化合物的通用合成方案D。
在这些方案中,充分理解的是:当有必要时,按照通用原则或化学使用敏感性或反应活性基团(例如氨基、羟基和羧基)的保护基,以防止其发生不希望的化学反应。按照有机合成的标准方法(T.W.Greene和P.G.M.Wuts,″Protective Groups in Organic Synthesis″,第5版,Wiley,纽约2014)处理保护基。在化合物合成的方便阶段采用本领域技术人员熟知的方法除去这些基团。方法以及反应条件及其执行顺序的选择应当与式(I)化合物的制备相一致。
氨基保护基的实例包括氨基甲酸酯、酰胺、烷基和芳基,和亚胺,以及许多N-杂原子衍生物,其可以被除去以再生所需的胺基团。特定的氨基保护基是Pmb(对甲氧基苄基)、Boc(叔丁氧基羰基)、Fmoc(9-芴基甲氧基羰基)和Cbz(苄氧基羰基)。这些基团的另外的实例见于T.W.Greene和P.G.M.Wuts,“Protecting Groups in Organic Synthesis”,第3版,John Wiley&Sons,Inc.,1999中。
羟基保护基的实例包括四氢吡喃基氧基、苯甲酰基、乙酰氧基、氨基甲酰基氧基、苄基和硅烷基醚(例如,TBS、TBDPS)基团。这些基团的另外的实例见于T.W.Greene和P.G.M.Wuts,“Protecting Groups in Organic Synthesis,第3版,John Wiley&Sons,Inc.,1999。
羧基保护基的实例包括酯基和杂环基。羧酸基团的酯衍生物可在化合物的其它官能团上进行反应时用于封闭或保护羧酸基团。这类酯基团的实例包括:被取代的芳基烷基,包括被取代的苄基,例如4-硝基苄基、4-甲氧基苄基、3,4-二甲氧基苄基、2,4-二甲氧基苄基、2,4,6-三甲氧基苄基、2,4,6-三甲基苄基、五甲基苄基、3,4-亚甲二氧基苄基;烷基或被取代的烷基酯,例如甲基、乙基、叔丁基烯丙基或叔戊基、三苯基甲基(三苯甲基)、4-甲氧基三苯甲基、4,4’-二甲氧基三苯甲基、4,4’,4”-三甲氧基三苯甲基、2-苯基丙-2-基;硫代酸酯,例如叔丁基硫代酸酯;硅烷基酯,例如三甲基硅烷基酯、叔丁基二甲基硅烷基酯(TBSO)等。这些基团的另外的实例可见于T.W.Greene和P.G.M.Wuts,″Protective Groups in Organic Synthesis″,第5版,Wiley,纽约2014中。
本领域技术人员能认识到式(I)化合物中是否存在立体中心。因此,当希望化合物是单独的对映异构体或非对映异构体时,其可以通过立体选择合成或通过拆分终产物或任意方便的中间体来获得。终产物、中间体或原料的拆分可以通过本领域已知的任意适宜方法来进行。参见例如E.L.Eliel,S.H.Wilen和L.N.Mander的“Stereochemistry of Organic Compounds” (Wiley-Interscience,1994)。
在图3和实施方案20的方法中,化合物C2的制备通过使化合物C1与羧酸
Figure PCTCN2018108762-appb-000057
进行酰胺偶联反应来实现。
优选地,所述酰胺偶联反应在惰性溶剂中进行。更优选地,所述酰胺偶联反应在缩合试剂和碱的存在下、在惰性溶剂中下。
所述惰性溶剂优选选自:乙酸乙酯、四氢呋喃、甲基四氢呋喃、乙腈、二甲基亚砜、N,N-二甲基甲酰胺、二氯甲烷、1,2-二氯乙烷、N-甲基-2-吡咯烷酮或其组合。
所述缩合试剂优选选自:1-羟基苯并三氮唑(HOBT)、1-羟基-7-偶氮苯并三氮唑(HOAT)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基鏻(PyBOP)、苯并三唑-1-三(三甲氨基)-六氟磷酸酯(BOP)、1,1-羰基二咪唑(CDI)、1-丙基磷酸酐(T 3P)、1-乙基-3-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)、N,N-二环己基碳二亚胺(DCC)、醋酸酐、乙酰氯、草酰氯、六氟磷酸2-(7-氧化苯并三唑)-N,N,N’,N’-四甲基脲鎓(HATU)、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸季铵盐(HBTU)中的一种或多种,更优选为T 3P。
所述碱优选选自:三乙胺、DIPEA、吡啶、2,4-二甲基吡啶、NaOH、KOH、LiOH、Na 2CO 3、K 2CO 3、NaHCO 3、Cs 2CO 3、Na 3PO 4或K 3PO 4中的一种或多种;更优选为DIPEA。
优选地,所述酰胺偶联反应在室温至回流的温度下进行。
优选地,所述酰胺偶联反应的反应时间为0.5~24h。
在图3和实施方案20的方法中,当式C2的化合物为Boc保护时,可以通过将化合物C2进行脱保护制备得到化合C3。
优选地,所述脱保护在惰性溶剂中进行。所述惰性溶剂优选选自:乙酸乙酯、四氢呋喃、甲基四氢呋喃、乙腈、二甲基亚砜、N,N-二甲基甲酰胺、二氯甲烷、1,2-二氯乙烷、N-甲基-2-吡咯烷酮或其组合。
优选地,所述脱保护在酸存在下进行。所述酸优选选自:盐酸、硫酸、三氟乙酸、乙酸、甲酸、磷酸中的一种或多种。
优选地,所述脱保护在-10℃至80℃的温度下进行。
优选地,所述脱保护进行0.5~24h。
功效和施用
本发明的化合物可用于治疗与ERK激酶如ERK1和/或ERK2激酶相关的疾病,例如与ERK激酶如ERK1和/或ERK2激酶高表达或高活性相关的疾病,例如肿瘤和癌症。更具体地,所述肿瘤和癌症选自例如胚细胞瘤、胶质瘤、肉瘤、精原细胞瘤、成胶质细胞瘤、黑色素瘤、白血病和骨髓或淋巴样恶性病。此类癌症的更具体的实例包括鳞状细胞癌(例如,上皮鳞状细胞癌)和肺癌,包括小细胞肺癌、非小细胞肺癌(NSCLC)、肺腺癌和肺鳞状细胞癌。另外的癌症包括皮肤癌、角化棘皮瘤、滤泡型癌、多毛细胞白血病、口腔前庭癌、咽癌、唇癌、舌癌、口癌、唾液腺癌、食道癌、喉癌、肝细胞癌、胃癌、胃肠癌、小肠癌、大肠癌、胰腺癌、宫 颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、直肠癌、结肠直肠癌、泌尿生殖系统癌、胆道癌、胆囊腺癌、甲状腺癌、乳头状癌、子宫内膜癌、子宫癌、唾液腺癌、肾癌、前列腺癌、睾丸癌、外阴癌、腹膜癌、肛门癌、阴茎癌、骨癌、多发性骨髓瘤、B细胞淋巴瘤、中枢神经系统癌、脑癌、头颈癌、霍奇金淋巴瘤。实例还包括骨髓增生性障碍例如真性红细胞增多症、原发性血小板增多症、骨髓纤维化例如原发性骨髓纤维化、急性髓性白血病和慢性髓性白血病(CML)。
本发明的化合物可以以药物组合物的形式施用于个体,所述药物组合物可任选包含一种或多种药学上可接受的赋形剂。
本发明的化合物可以通过各种已知的途径施用,包括口服、直肠、胃内、颅内和肠胃外施用,例如静脉内、肌内、鼻内、真皮内、皮下,以及类似的施用途径。特别优选的是口服、鼻内和肠胃外施用。根据施用途径的不同,需要不同的药物制剂,这些施用途径中的一些可能需要给药物制剂涂敷保护性包衣以防止本发明的化合物在例如消化道内降解。
本发明的化合物可以被配制成糖浆、输液或注射液、喷雾剂、片剂、胶囊、锭剂、脂质体、栓剂等。
用于施用本发明的化合物的特别优选的药物形式是适合注射使用的形式,包括无菌的水性溶液或分散体和用于即时制备无菌注射溶液或分散体的无菌粉末。在所有情况中,最终的溶液或分散体形式必须是无菌的并且是流体。典型地,这类溶液或分散体将包含溶剂或分散介质,其含有例如水-缓冲水溶液例如生物相容性的缓冲剂、乙醇、多元醇例如甘油、丙二醇、聚乙二醇、其适合的混合物,表面活性剂或植物油。本发明的化合物也可以被配制成脂质体,特别是用于肠胃外施用的脂质体。脂质体提供在循环中半衰期增加的优点(如果与游离药物相比)以及所包裹的药物的延长的更均匀的释放。
输液和注射液的灭菌可以通过本领域公认的技术来实现,包括但不限于加入防腐剂如抗细菌剂或抗真菌剂,例如尼泊金酯、三氯叔丁醇、苯酚、山梨酸或硫柳汞。此外,还可以在输液和注射液中掺入等张剂,例如糖或盐,特别是氯化钠。
含有一种或多种本发明的化合物的无菌注射液的生产通过以下方法完成:将所需量的各化合物掺入酌情具有上面列出的各种成分的适宜溶剂中,然后灭菌。为了获得无菌粉末,将上述溶液按照需要真空干燥或冷冻干燥。本发明的优选的稀释剂是水、生理学上可接受的缓冲剂、生理学上可接受的缓冲盐溶液或盐溶液。优选的载体是可可脂和vitebesole。
可以与本发明的化合物的各种药物形式一起使用的赋形剂可选自下面的非限制性列表:
a)粘合剂,例如乳糖、甘露醇、结晶山梨醇、磷酸氢盐、糖、微晶纤维素、羧甲基纤维素、羟乙基纤维素、聚乙烯吡咯烷酮等;
b)润滑剂,例如硬脂酸镁、滑石粉、硬脂酸钙、硬脂酸锌、硬脂酸、氢化植物油、亮氨酸、甘油酯和硬脂酰醇富马酸钠;
c)崩解剂,例如淀粉、交联羧甲基纤维素、甲基纤维素钠、琼脂、膨润土、海藻酸、羧甲基纤维素、聚乙烯吡咯烷酮等。
在一个实施方案中,制剂用于口服施用,并且制剂包含下列成分中的一种或多种或全部: 预胶化淀粉、滑石粉、聚乙烯吡咯烷酮K30、交联羧甲基纤维素钠、硬脂酰醇富马酸钠、明胶、二氧化钛、山梨醇、柠檬酸一钠、黄原胶、二氧化钛、矫味剂、苯甲酸钠和糖精钠。
在一个实施方案中,本发明的化合物被鼻内施用,其可以以干粉末吸入器或来自使用适合的抛射剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氢氟烷如1,1,1,2-四氟乙烷(HFA134A TM)或1,1,1,2,3,3,3-七氟丙烷(HFA 227EA TM)、二氧化碳、或其它适合的气体的加压容器、泵、喷雾器或雾化器中的喷雾剂的形式被施用。所述的加压容器、泵、喷雾器或雾化器可以含有本发明的化合物的溶液或混悬液,例如使用乙醇和抛射剂作为溶剂的溶液或混悬液,其还可以含有润滑剂,例如三油酸山梨坦。
本发明的化合物的典型的剂量范围是0.001-1000mg活性成分/公斤体重/天。所述剂量可以每日一次或分多次给予。适宜剂量的确定由主治医师根据要治疗的疾病的种类及其严重性、个体的健康状况和既往病史、共用药物、所施用的具体化合物、和施用途径等酌情确定。根据需要,本发明的化合物的用量可以超出该剂量范围。
应理解,在本发明范围内,本发明的上述各技术方案中定义的技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
除非结构式明显存在错误,否则当本发明的任意化合物的化学名称与所给出的结构式不一致时,以结构式为准。
如本领域技术人员能够清楚理解的,为了简便,在本申请所给出的一些化合物结构式中并非所有氢原子均被明确地标示出来。当化合物中的碳原子或氮原子存在空余化合价时,其表示存在未标示出的氢。例如,在下文中实施例P12的化合物用结构式
Figure PCTCN2018108762-appb-000058
描述,其中在嘧啶环与吡唑环之间的氮原子上省略了一个氢原子。本领域技术人员可以理解,该结构式与结构式
Figure PCTCN2018108762-appb-000059
表示相同的化合物。
附图说明
图1显示了用于合成本发明的化合物的通用合成方案A,其中各变量如本文所定义。
图2显示了用于合成本发明的化合物的通用合成方案B,其中各变量如本文所定义。
图3显示了用于合成本发明的化合物的通用合成方案C,其中各变量如本文所定义。
图4显示了用于合成本发明的化合物的通用合成方案D,其中各变量如本文所定义。
实施例
提供下面的实施例以进一步阐述本发明。应理解,这些实施例仅用于举例说明本发明,而不用于限制本发明的范围。
下列实施例中未注明具体条件的实验方法均可以按照这类反应的常规条件进行或者按照制造厂商所建议的条件进行。除非另有说明,否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
在下列实施例中, 1H-NMR谱是用Bluker AVHD 400MHz或Bluker AVHD 500MHz型核磁共振仪记录的; 13C-NMR谱是用Bluker AVHD 500MHz或Bluker AVHD 600MHz型核磁共振仪记录的,化学位移以δ(ppm)表示;质谱是用Waters UPLC H-Class+QDa(ESI)与Agilent 1260_6120(ESI)型质谱仪记录的;反相制备型HPLC分离是用Waters UV引导的全自动纯化系统(XBridge Prep C18 5μm OBD柱)进行的。
实施例中所用的缩写含义如下:
iPrOH             异丙醇
EtOH              乙醇
DCM               二氯甲烷
TFA或CF 3COOH      三氟乙酸
MeOH              甲醇
NaOH              氢氧化钠
HCl               氯化氢或盐酸
TEA               三乙胺
Raney Ni          阮内镍
dioxane           二噁烷,二氧六环
NaH               氢化钠
H 2O               水
Pd/C              钯/炭
H 2                氢气
N 2                氮气
HATU              六氟磷酸2-(7-氧化苯并三唑)-N,N,N’,N’-四甲基脲鎓
DMF               N,N-二甲基甲酰胺
THF               四氢呋喃
Boc 2O             二碳酸二叔丁酯
Boc               叔丁氧基羰基
NBS               N-溴代琥珀酰亚胺
NCS               N-氯代琥珀酰亚胺
NIS               N-碘代琥珀酰亚胺
MeCN或CH 3CN       乙腈
DIPEA或DIEA        N,N-二异丙基乙胺
NaBH 4              硼氢化钠
AcOH               醋酸
Ac 2O               醋酸酐
AcCl               乙酰氯
NaBH 3CN或NaBH 3(CN) 氰基硼氢化钠
K 2CO 3              碳酸钾
Cs 2CO 3             碳酸铯
NaHCO 3             碳酸氢钠
nBuLi              正丁基锂
LiAlH 4             氢化铝锂
Pd(dppf)Cl 2或PdCl 2(dppf) 1,1’-双(二苯基膦基)二茂铁]二氯化钯
PdCl 2(PPh 3) 2        双三苯基膦二氯化钯
KOAc               醋酸钾
Fumaronitrile      富马酸腈
P(nBu) 3            三正丁基膦
LDA                二异丙基氨基锂
LiOH               氢氧化锂
MeI                碘甲烷
EtI                碘乙烷
(CH 2O) n            多聚甲醛
HCO 2H或FA          甲酸
CH 3COCl            乙酰氯
HPLC               高效液相色谱法
CH 3COOK或AcOK      醋酸钾
t-BuONa            叔丁醇钠
DMSO               二甲基亚砜
h                  小时
min                分钟
DMAP               4-二甲氨基吡啶
r.t.或RT           室温
T 3P                1-丙基磷酸酐
DMEA               N,N-二甲基乙醇胺
POCl 3              三氯氧磷
                  ℃摄氏度
EA                乙酸乙酯
Bu 4NBr 3            四丁基三溴化铵
CuI                碘化亚铜
Mg                 镁
Py                 吡啶
TLC                薄层色谱法
LCMS               液相色谱法-质谱法联用
TBS                叔丁基二甲基硅烷基
TBSCl              叔丁基二甲基氯硅烷
BPin 2              双(频哪醇合)二硼
PE                 石油醚
MW                 微波
DEA                二乙胺
HEP                正庚烷
IPA                异丙醇
HEX                正己烷
中间体的合成
中间体4:7-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚(4)的合成
Figure PCTCN2018108762-appb-000060
步骤1. 7-氟二氢吲哚(2)的合成
Figure PCTCN2018108762-appb-000061
在干燥的50mL圆底烧瓶中室温下加入化合物1(5000mg,37mmol)和AcOH(30mL),0℃下,分批加入NaBH 3CN(5813mg,92.49mmol),加完室温下搅拌3小时。TLC板检测反应完毕后,减压浓缩,加入100mL水,0℃下,用2mol/L的氢氧化钠水溶液调节pH至9,搅拌1小时,再升温至25℃,搅拌1小时。乙酸乙酯萃取,干燥,过滤,滤液蒸干,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯/石油醚=1/50至1/10)纯化所得残余物,得到中间体2 7-氟二氢吲哚(4.0g,灰白色固体),产率:78.4%。LCMS:m/z 138.1(M+H)。
步骤2. 5-溴-7-氟二氢吲哚(3)的合成
Figure PCTCN2018108762-appb-000062
方法一:
在0℃下,在干燥的250mL圆底烧瓶中,向中间体2(4.0g,29.19mmol)的乙腈(100mL)溶液中缓慢加入NBS(5.2g,29.19mmol),然后升至室温,搅拌2小时。反应完毕后,减压浓缩,加入100mL水,用乙酸乙酯萃取(150mL×3),合并有机相。用饱和碳酸氢钠水溶液和饱和食盐水洗涤(100mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶8)纯化所得残余物,得到中间体3(5.0g,淡紫色固体),产率:80.6%。LCMS:m/z 215.9(M+H)。
方法二:
向在冰水浴中的100mL烧瓶中加入化合物2(9.8g,0.072mol)、二氯甲烷(100mL),分批加入四丁基三溴化铵(34.5g,0.072mol),自然升至室温,在室温下搅拌反应4小时。反应完毕后,减压浓缩,缓慢加入饱和碳酸氢钠水溶液调节pH至6-7,乙酸乙酯萃取(50mL×4),合并有机相,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶15)纯化所得残余物,得到5-溴-7-氟二氢吲哚3(9.5g,灰白色固体)。LCMS:m/z 215.9(M+H).
步骤3. 7-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-二氢吲哚(4)的合成
Figure PCTCN2018108762-appb-000063
在室温下向干燥的50mL单口瓶中加入中间体3(600mg,2.777mmol)、双(频哪醇合)二硼(1410mg,5.554mmol)、Pd(dppf)Cl 2(243mg,0.333mmol)、醋酸钾(545mg,5.554mmol)和1,4-二氧六环(4mL),氮气置换3次。搅拌加热至110℃,反应3小时。LCMS检测反应完毕后,过滤,滤液减压浓缩后用硅胶柱色谱法以洗脱剂体系(EA/PE=2%-10%)纯化所得残余物,得到产物中间体4,7-氟-5-(4,4,5,5-四甲基-[1,3,2]二氧硼环戊烷-2-基)-2,3-二氢-1H-吲哚(600mg,黄色固体),产率:82.1%,纯度约90%。LCMS:m/z 264.1(M+H)。
中间体7:4-溴-N-(1-甲基-1H-吡唑-5-基)吡啶-2-胺(7)的合成
Figure PCTCN2018108762-appb-000064
在室温下,向干燥的250mL圆底烧瓶中加入化合物6(4.2g,23.86mmol)、化合物5(2.8g, 28.83mmol)、叔丁醇钠(4.6g,47.8mmol)和DMSO(60ml)。氮气置换3次,125℃搅拌回流反应24小时。LC/MS检测反应完毕后,EA(50mL*3)萃取,饱和食盐水(30mL)洗涤后,干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(PE∶EA=3∶7)纯化所得残留物,得到中间体7(2.1g,淡黄色固体),收率:40%。LCMS:m/z 253.0/255.0(M+H)。
中间体8:(4-溴吡啶-2-基)(1-甲基-1H-吡唑-5-基)氨基甲酸叔丁酯(8)的合成
Figure PCTCN2018108762-appb-000065
在室温下,向干燥的100mL圆底烧瓶中加入中间体7(500mg,1.976mmol)、DMAP(67mg,0.593mmol)、DIPEA(766mg,5.928mmol)和DMF(5ml),室温搅拌溶解后,缓慢加入Boc 2O(1299mg,5.928mmol)后室温反应3小时。反应完毕后,用EA萃取,合并有机相。饱和食盐水溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯/石油醚=15/85至70/30)纯化所得混合物,得中间体8(626mg,淡黄色固体),产率:88%。LCMS:m/z 352.9(M+H)。
中间体13:1-(5-(2-溴嘧啶-4-基)-7-氟二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(13)的合成
Figure PCTCN2018108762-appb-000066
步骤1. 1-(5-溴-7-氟二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(10)的合成
Figure PCTCN2018108762-appb-000067
在室温下,向干燥的250mL圆底烧瓶中加入N,N-二甲基甲酰胺(10mL)、中间体3(1.7g,0.0079mol)、化合物9(1.23g,0.007mol)和N,N-二异丙基乙胺(3.69g,0.028mol),置换氮气3次, 逐渐升温至50℃,加入1-丙基磷酸酐(56mL,50%的乙酸乙酯溶液)反应0.5小时。TLC检测反应完毕后,减压浓缩,残余物倒入冰水中,析出固体,过滤得到中间体10(2.7g,浅黄色固体),产率93%。LCMS:m/z 368.8/370.8(M+H)。
步骤2. 2-(2-氯吡啶-3-基)-1-(7-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(11)的合成
Figure PCTCN2018108762-appb-000068
在室温下,向干燥的100mL圆底烧瓶中加入中间体10(2g,0.0054mol)、双(频哪醇合)二硼(2.0g,0.0079mol)、醋酸钾(1.59g,0.016mol)和1,4-二氧六环(36mL),置换氮气1次,加入Pd(dppf)Cl 2(442mg,0.0005mol),氮气置换3次,加热至90℃,搅拌反应4小时。LCMS监测反应完毕后,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶3)纯化所得残余物,得到中间体11(1.5g,浅黄色固体),产率:68%。LCMS:m/z 417.1(M+H)。
步骤3. 1-(5-(2-溴嘧啶-4-基)-7-氟二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(13)的合成
Figure PCTCN2018108762-appb-000069
在室温下,向干燥的100mL圆底烧瓶中加入中间体11(200mg,0.48mmol)、2,4-二溴嘧啶(126mg,0.53mmol)、碳酸钾(200mg,1.44mmol)、(1,1-双(二苯基膦基)二茂铁)二氯化钯(70mg,0.096mmol)和1,4-二氧六环与水的混合溶剂(4∶1,10.0mL)。氮气置换3次,升温至60℃,搅拌2小时。反应完毕后,减压浓缩,加入100mL水,用乙酸乙酯萃取(150mL×3),合并有机相。无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶1)纯化所得残余物,得到产物13(140mg,淡黄色固体),产率:65.0%。LCMS:m/z 446.8(M+H)。
中间体17:4-氯-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺(17)的合成
Figure PCTCN2018108762-appb-000070
步骤1. 2-(1-甲基-1H-吡唑-5-基)氨基-嘧啶-4(3H)-酮(16)的合成
Figure PCTCN2018108762-appb-000071
在室温下,向干燥的50mL圆底烧瓶中加入化合物14(7.8g,80mmol)、化合物15(5.72g,40mmol)和三甲基乙酸(28.6g)。开动搅拌,慢慢加热至150℃,反应40小时。LCMS检测反应完毕后,降至室温,加入30mL二氯甲烷及5mL甲醇,使反应混合物溶解完全,加入硅胶拌样,用硅胶柱色谱法以洗脱剂体系(二氯甲烷∶甲醇=3∶2)纯化得到中间体16(5g,黄色固体),产率:65.8%。LCMS:m/z 191.9(M+H)。
步骤2. 4-氯-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺(17)的合成
Figure PCTCN2018108762-appb-000072
在室温下,向干燥的250mL圆底烧瓶中加入中间体16(5g,26.1mmol)、三氯氧磷(10mL,109.2mmol)和乙腈(100.0mL)。升温至100℃,搅拌2小时。反应完毕后,减压浓缩,加入100毫升水淬灭,用乙酸乙酯萃取(60mL×3),合并有机相。饱和食盐水洗涤(40mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=3∶2)纯化所得残余物,得到中间体17(2.9g,浅黄色固体),产率:53.7%。LCMS:m/z 209.9(M+H)。 1H-NMR(CDCl3,400MHz):8.27(d,J=5.2Hz,1H),7.53(br,1H),7.48(d,J=5.2Hz,1H),6.80(d,J=5.6Hz,1H),6.28(d,J=5.6Hz,1H),3.77(s,3H).
中间体23:1-(7-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(23)的合成
Figure PCTCN2018108762-appb-000073
步骤1. 1-(5-溴-二氢吲哚-1-基)乙-1-酮(19)的合成
Figure PCTCN2018108762-appb-000074
在室温下,向干燥的50mL圆底烧瓶中加入化合物18(1500mg,7.57mmol)、DCM(20mL)、Et 3N(1915mg,18.93mmol)和DMAP(30mg),0℃下分批加入乙酰氯(1188mg,15.14mmol),加完室温下搅拌3小时。0℃下,倒入水中,搅拌1小时。DCM萃取,干燥,过滤,蒸干,得到中间体19(1.75g,黄色固体),产率:96.3%。LCMS:m/z 240.0/242.0(M+H)。
步骤2. 1-(5-溴-7-氯-二氢吲哚-1-基)乙-1-酮(20)
Figure PCTCN2018108762-appb-000075
在室温下,向干燥的50mL圆底烧瓶中加入中间体19(1600mg,14.58mmol)、乙腈(30mL)和NCS(979mg,7.33mmol),加完后70℃下搅拌18小时。倒入水(20mL)中,EA萃取,干燥,过滤,滤液蒸干,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯/石油醚=1/50至1/10)纯化所得残余物,得到中间体20(1.2g,黄色液体),产率:65.6%。LCMS:m/z 274.0/276.0(M+H)。
步骤3. 5-溴-7-氯-二氢吲哚(21)的合成
Figure PCTCN2018108762-appb-000076
在室温下,向干燥的50mL单口瓶中加入中间体20(1200mg,4.37mmol)、一水合氢氧化锂(550mg,13.11mmol)、以及甲醇(15mL)与水(8mL),搅拌加热至70℃,反应18小时。LCMS检测反应完毕后,EA萃取,洗涤,干燥,过滤,滤液减压浓缩后用硅胶柱色谱法以洗脱剂体系(EA/PE=2%-10%)纯化所得残余物,得中间体21(700mg,黄色固体),产率:68.9%,纯度约80%。LCMS:m/z 232.0(M+H)。
步骤4. 7-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-二氢吲哚(22)的合成
Figure PCTCN2018108762-appb-000077
在室温下,向干燥的50mL单口瓶中加入中间体21(600mg,2.581mmol)、双(频哪醇合)二硼(852mg,3.354mmol)、Pd(dppf)Cl 2(188mg,0.2581mmol)、醋酸钾(329mg,3.354mmol)和1,4- 二氧六环(5mL),氮气置换3次。搅拌加热至100℃,反应3小时。LCMS检测反应完毕后,过滤,滤液减压浓缩后用硅胶柱色谱法以洗脱剂体系(EA/PE=2%-10%)纯化所得残余物,得中间体22(480mg,黄色固体),产率:66.67%,纯度约80%。LCMS:m/z 280.1(M+H)。
步骤5.中间体1-(7-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(23)的合成
Figure PCTCN2018108762-appb-000078
在室温下,向干燥的25mL单口瓶中加入中间体22(440mg,1.574mmol)、化合物9(540mg,3.147mmol)、Et 3N(318mg,3.147mmol)、HATU(1193mg,3.147mmol)和THF(8mL),于氮气保护下32℃搅拌18小时。LCMS检测反应完毕后,EA萃取,水洗涤,干燥,蒸干,粗产品用硅胶柱色谱法以洗脱剂体系(EA/PE 10-40%)纯化,得到中间体23(290mg,黄色固体),产率:42.58%。LCMS:m/z 434.1(M+H)。
中间体31:2-(2-氯吡啶-3-基)-1-(7-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(31)的合成
Figure PCTCN2018108762-appb-000079
步骤1. 7-甲基二氢吲哚(28)的合成
Figure PCTCN2018108762-appb-000080
在0℃下,向干燥的250mL圆底烧瓶中加入化合物277-甲基-1H-吲哚(2.0g,15.27mmol)、氰基硼氢化钠(2.9g,45.81mmol)和冰醋酸(40mL),升至室温,搅拌反应3小时。TLC板检测反应完毕后,减压浓缩,加入100mL水,用2mol/L的氢氧化钠水溶液调节pH至9,乙酸乙 酯(100mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,用快速柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶5)纯化所得残余物,得到中间体28 7-甲基二氢吲哚(1.5g,灰白色固体),产率:75.3%。LCMS:m/z 134.1(M+H)。
步骤2. 5-溴-7-甲基二氢吲哚(29)的合成
Figure PCTCN2018108762-appb-000081
在室温下,向干燥的100mL圆底烧瓶中加入中间体28 7-甲基二氢吲哚(120mg,0.902mmol)、四丁基三溴化铵(464mg,0.902mmol)和二氯甲烷(10.0mL),搅拌反应30分钟。LCMS监测反应完毕后,减压浓缩,加入100mL水,乙酸乙酯萃取(150mL×3),合并有机相,饱和食盐水洗涤(100mL),无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶5)纯化所得残余物,得到中间体29 5-溴-7-甲基二氢吲哚(200mg,淡紫色固体),产率:80.6%。LCMS:m/z 211.9(M+H)。
步骤3. 1-(5-溴-7-甲基二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(30)的合成
Figure PCTCN2018108762-appb-000082
在干燥的100mL圆底烧瓶中加入中间体29(80mg,0.38mmol)、化合物9 2-(2-氯吡啶-3-基)乙酸(67mg,0.38mmol)、N,N-二异丙基乙胺(0.25mL,1.52mmol)、T 3P(1.208g,50%(wt%)的乙酸乙酯溶液(1.9mmol))和N,N-二甲基甲酰胺(5.0mL),室温搅拌反应30分钟。反应完毕后,加入100mL水,乙酸乙酯萃取(150mL×3),合并有机相,饱和食盐水洗涤(100mL×6),无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶5)纯化所得残余物,得到中间体30 1-(5-溴-7-甲基二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(50mg,灰白色固体),产率:36.3%。LCMS:m/z 364.8(M+H)。
步骤4. 2-(2-氯吡啶-3-基)-1-(7-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(31)的合成
Figure PCTCN2018108762-appb-000083
在室温下,向干燥的100mL圆底烧瓶中加入中间体30 1-(5-溴-7-甲基二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(400mg,1.09mmol)、双(频哪醇合)二硼(1.38g,5.43mmol)、醋酸钾(233mg,3.27mmol)、(1,1-双(二苯基膦基)二茂铁)二氯化钯(70mg,0.11mmol)和1,4-二氧六环(20.0mL),氮气置换5次,升温至90℃,搅拌反应过夜。LCMS监测反应完毕后,减压浓缩,加入100mL水,乙酸乙酯萃取(150mL×3),合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶10)纯化所得残余物,得到中间体31 2-(2-氯吡啶-3-基)-1-(7-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(200mg,白色固体),产率:44.0%。LCMS:m/z 413.0(M+H)。
中间体53:2-(2-氯吡啶-3-基)-1-(7-氟-2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮的合成
Figure PCTCN2018108762-appb-000084
步骤1. 2-(3-氟-2-硝基苯基)-3-氧代丁酸乙酯(47)的合成
Figure PCTCN2018108762-appb-000085
在室温下,向干燥的100mL圆底烧瓶中依次加入乙酰乙酸乙酯(46)(6.1g,0.047mol)、碳酸钾(8.7g,0.063mol)、1,3-二氟-2-硝基苯(5g,0.031mol)、N,N-二甲基甲酰胺(20mL),升温至50℃,搅拌反应2小时。TLC监测反应结束后,加入水(100mL)稀释,乙酸乙酯萃取(80mL×3),合并有机相,饱和食盐水洗(300mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析法(乙酸乙酯∶石油醚=1∶100)纯化所得残余物,得到2-(3-氟-2-硝基苯基)-3-氧代丁酸乙酯47(2.8g,浅黄色油状物),产率:33%。 1H NMR(CDCl 3,300MHz):13.07(s,1H),7.58-7.40(m,1H),7.30-7.19(m,1H),7.16-7.01(m,1H),4.31-4.00(m,2H),1.87(s,3H).1.18(t,J=7.2Hz,3H).
步骤2. 1-(3-氟-2-硝基苯基)丙烷-2-酮(48)的合成
Figure PCTCN2018108762-appb-000086
在室温下,向干燥的100mL圆底烧瓶中加入2-(3-氟-2-硝基苯基)-3-氧代丁酸乙酯(2.8g,0.01mol)、醋酸(20mL)、50%的硫酸(20mL),升温至100℃,搅拌反应4小时。TLC监测反应结束后,加入水(100mL)稀释,乙酸乙酯萃取(80mL×3),合并有机相,饱和碳酸氢钠水溶液洗涤(200mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析法(乙酸乙酯∶石油醚=1∶5)纯化,得到1-(3-氟-2-硝基苯基)丙烷-2-酮48(1.86g,浅黄色油状物),产率:91%。 1H NMR(DMSO-d 6,300MHz):7.73-7.63(m,1H),7.57-7.48(m,1H),7.31(d,J=7.5Hz,1H),4.13(s,3H),2.51(s,2H).
步骤3. 7-氟-2-甲基-1H-吲哚(49)的合成
Figure PCTCN2018108762-appb-000087
在干燥的100mL圆底烧瓶中依次加入蒸馏水(32mL)、连二亚硫酸钠(13.2g,0.076mol),滴加1-(3-氟-2-硝基苯基)丙烷-2-酮(1.5g,0.0076mmol)的1,4二氧六环溶液(3.4mL),室温下搅拌反应2小时。TLC监测反应结束后,加入水(80mL)稀释,乙酸乙酯萃取(60mL×3),合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析法(纯石油醚)纯化,得到7-氟-2-甲基-1H-吲哚49(250mg,白色固体),产率:22%。 1H NMR(DMSO-d 6,300MHz):11.34(s,1H),7.21(d,J=6.9Hz,1H),6.93-6.72(m,2H),6.19(s,1H),2.39(s,3H).
步骤4. 7-氟-2-甲基二氢吲哚(50)的合成
Figure PCTCN2018108762-appb-000088
在干燥的100mL圆底烧瓶中冰浴下依次加入7-氟-2-甲基-1H-吲哚49(1.8g,12.08mmol)、醋酸(20mL)、氰基硼氢化钠(2.28g,36.19mmol),缓慢升至室温,搅拌反应2小时。TLC监测反应结束后,减压浓缩,向所得残余物加入乙酸乙酯(100mL)溶解,饱和碳酸氢钠水溶液洗涤(80mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析法(乙酸乙酯∶石油醚=1∶70)纯化所得残余物,得到7-氟-2-甲基二氢吲哚50(1.4g,无色油状物),产率:77%。LCMS:m/z 152.1(M+H)。
步骤5. 5-溴-7-氟-2-甲基二氢吲哚(51)的合成
Figure PCTCN2018108762-appb-000089
向在冰浴中的干燥的100mL圆底烧瓶中依次加入7-氟-2-甲基二氢吲哚50(1.4g,9.27mmol)、乙腈(20mL)、N-溴代琥珀酰亚胺(1.65g,9.27mmol),逐渐升到室温,搅拌反应2小时。TLC监测反应结束后,减压浓缩,用柱层析法(乙酸乙酯∶石油醚=1∶70)纯化所得残余物,得到产物5-溴-7-氟-2-甲基二氢吲哚51(1.5g,浅黄色油状物),产率:71%。LCMS:m/z 229.9/231.9(M+H).
步骤6. 1-(5-溴-7-氟-2-甲基二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(52)的合成
Figure PCTCN2018108762-appb-000090
在室温下,向干燥的100mL圆底烧瓶中依次加入5-溴-7-氟-2-甲基二氢吲哚7(1.0g,4.35mmol)、2-(2-氯吡啶-3-基)乙酸(748mg,4.35mmol)、N,N-二甲基甲酰胺(10mL)、N,N-二异丙基乙胺(2.24g,17.36mmol),置换氮气3次,升温至50℃,加入1-丙基磷酸酐(26mL,50%的乙酸乙酯溶液),搅拌反应0.5小时。TLC监测反应完毕后,减压浓缩,残余物倒入冰水中,析出固体,过滤,滤饼干燥,得到1-(5-溴-7-氟-2-甲基二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮52(1.5g,浅棕色固体),产率90%。LCMS:m/z 382.8/384.8(M+H)。
步骤7. 2-(2-氯吡啶-3-基)-1-(7-氟-2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(53)的合成
Figure PCTCN2018108762-appb-000091
在室温下,向干燥的100mL圆底烧瓶中依次加入1-(5-溴-7-氟-2-甲基二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(52)(500mg,1.3mmol)、双(频哪醇合)二硼(496mg,1.95mmol)、醋酸钾(383mg,3.9mmol)和1,4-二氧六环(20mL),置换氮气1次,加入[1,1’-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(10.6mg,0.013mol),置换氮气3次,加热至90℃,搅拌反应3小时。LCMS监测反应完毕后,减压浓缩,用柱层析法(乙酸乙酯∶石油醚=1∶3)纯化所得残余物,得到2-(2-氯吡啶-3-基)-1-(7-氟-2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮53(450mg,无色油状物),产率:80%。LCMS:m/z 430.9(M+H)。
中间体70:2-(2-氯吡啶-3-基)-1-(4,7-二氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(70)的合成
Figure PCTCN2018108762-appb-000092
步骤1. 5-溴-4,7-二氟-1H-吲哚(67)的合成
Figure PCTCN2018108762-appb-000093
将乙烯基溴化镁(45.6mL,45.6mmol)加入四氢呋喃(50mL)中,氮气保护下冷至-78℃,滴加化合物66(3.9g,15.2mmol,溶于50mL四氢呋喃中),加毕,搅拌反应2小时,反应完毕后,缓慢加入饱和氯化铵水溶液(20mL),乙酸乙酯萃取(20mL×3),合并有机相,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶8)纯化所得残余物,得到5-溴-4,7-二 氟-1H-吲哚67(1.47g,淡黄色油状物),产率:38.7%。
1H NMR(CD 30D,300MHz):7.29(d,J=3.0Hz,1H),7.01-6.97(m,1H),6.60-6.54(m,1H).
步骤2. 5-溴-4,7-二氟-二氢吲哚(68)的合成
Figure PCTCN2018108762-appb-000094
向在冰水浴中的50mL圆底烧瓶中依次加入化合物67(1.45g,6.28mmol)和冰醋酸(20mL),历经约30分钟分批加入氰基硼氢化钠(0.87g,12.6mol),室温下搅拌16小时。反应完毕后,冰水浴冷却,向其中缓慢加入碳酸氢钠饱和溶液调节至pH 6-7,用乙酸乙酯萃取(10mL×3),合并有机相,无水硫酸钠干燥,过滤,滤液浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶6)纯化所得残余物,得到5-溴-4,7-二氟-二氢吲哚68(0.43g,淡黄色油状物),产率:30.0%。LCMS:m/z 234.0/236.0(M+H).
步骤3. 1-(5-溴-4,7-二氟-二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(69)的合成
Figure PCTCN2018108762-appb-000095
在室温下,向100mL烧瓶中依次加入化合物68(0.43mg,0.1.85mol)、乙酸乙酯(10mL)、化合物9(0.35g,2.04mmol)、T 3P(50%的乙酸乙酯溶液,W/W,2.83g,3.71mmol)、二异丙基乙基胺(0.48g,3.71mmol),室温下搅拌反应3小时。反应完毕后,缓慢加入饱和碳酸氢钠水溶液调节pH至6-7,乙酸乙酯萃取(10mL×4),合并有机相,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶3)纯化所得残余物,得到1-(5-溴-4,7-二氟-二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮69(0.56g,淡黄色油状物),产率:78.2%。LCMS:m/z 386.9/388.9(M+H).
步骤4. 2-(2-氯吡啶-3-基)-1-(4,7-二氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(70)的合成
Figure PCTCN2018108762-appb-000096
在干燥的100mL圆底烧瓶中依次向1,4-二氧六环(10mL)中加入化合物69(0.27g,0.69mmol)、双(频哪醇合)二硼(0.23g,0.89mol)、醋酸钾(0.10g,1.02mmol)、(1,1′-双(二苯基膦基)二茂铁)二氯化钯(0.028g,0.89mmol),氮气置换3次,升温至90℃,搅拌反应16小时。反应完毕后,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶3)纯化所得残余物,得到2-(2-氯吡啶-3-基)-1-(4,7-二氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮70(0.18g,淡黄色固体),粗产品。LCMS:m/z 434.7/436.8(M+H).
中间体77:2-(2-氯吡啶-3-基)-1-(6,7-二氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(77)的合成
Figure PCTCN2018108762-appb-000097
步骤1. 4-溴-2,3-二氟-6-碘苯胺(72)的合成
Figure PCTCN2018108762-appb-000098
在100mL圆底烧瓶中依次加入化合物71(0.85g,4.1mmol)、冰醋酸(15mL)、N-碘代琥珀酰亚胺(0.97g,4.31mmol),加毕,室温下搅拌反应3小时,反应完毕后,减压浓缩,向所得残余物中加入饱和碳酸氢钠水溶液调节pH至6-7,乙酸乙酯萃取(20mL×3),合并有机相,减压浓缩,所得残余物用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶10)纯化,得到4-溴-2,3-二氟-6-碘苯胺72(1.30g,淡黄色固体),产率:95%。LCMS:m/z 333.9/335.8(M+H)。
步骤2. 4-溴-2,3-二氟-6-((三甲基硅烷基)乙炔基)苯胺(73)的合成
Figure PCTCN2018108762-appb-000099
在100mL圆底烧瓶中依次加入化合物72(1.30g,3.91mmol)、三乙胺(20mL)、碘化亚铜(37.2mg,0.20mol)、乙炔基三甲基硅烷(460mg,4.69mmol)、双三苯基膦二氯化钯(137mg,0.20mmol),室温下搅拌反应16小时。反应完毕后,减压浓缩,所得残余物用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶10)纯化,得到4-溴-2,3-二氟-6-((三甲基硅烷基)乙炔基)苯胺73(1.02g,浅黄色油状物),产率:86.2%。 1H NMR(DMSO-d 6,400MHz):δ7.32(d,J=7.2,1H),5.86(s,2H),0.25(s,9H).
步骤3. 5-溴-6,7-二氟-1H-吲哚(74)的合成
Figure PCTCN2018108762-appb-000100
在50mL茄形瓶中加入化合物73(0.85g,2.80mmol)、N,N-二甲基甲酰胺(2mL)、碘化亚铜(1.07g,5.61mmol),氮气保护下加热至100℃,搅拌反应4小时。反应完毕后,冷至室温,向反应液中加入水(20mL),乙酸乙酯萃取(20mL×3),合并有机相,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶6)纯化所得残余物,得到5-溴-6,7-二氟-1H-吲哚74(560mg,淡黄色油状物),产率:86%。 1H NMR(DMSO-d 6,400MHz):812.46(s,1H),7.74-7.70(m,1H),7.51(s,1H),3.36(d,J=5.6Hz,1H).
步骤4. 5-溴-6,7-二氟-二氢吲哚(75)的合成
Figure PCTCN2018108762-appb-000101
向在冰水浴中的50mL圆底烧瓶中依次加入化合物74(0.56g,2.42mmol)和冰醋酸(10mL),历经约30分钟分批加入氰基硼氢化钠(0.35g,4.85mmol),,室温下搅拌反应16小时。反应完毕后,加冰水浴,向其中缓慢加入碳酸氢钠饱和溶液调节至pH 6-7,然后用乙酸乙酯萃取(10mL×3),合并有机相,无水硫酸钠干燥,过滤,滤液浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶6)纯化所得残余物,得到5-溴-6,7-二氟-二氢吲哚75(0.23g),淡黄色油状粗品。LCMS:m/z 233.9/235.9(M+H);RT=1.470min(2.5min).
步骤5. 1-(5-溴-6,7-二氟-二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(76)的合成
Figure PCTCN2018108762-appb-000102
在室温下,在100mL烧瓶中依次加入化合物75(0.23mg,0.99mmol)、乙酸乙酯(10mL)、化合物9(0.20g,1.18mmol)、T 3P(50%的乙酸乙酯溶液,W/W,1.26g,1.98mmol)、二异丙基乙基胺(0.38g,2.96mmol),室温下搅拌反应3小时。反应完毕后,缓慢加入饱和碳酸氢钠水溶液调节pH至6-7,乙酸乙酯萃取(10mL×4),合并有机相,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶3)纯化所得残余物,得到1-(5-溴-6,7-二氟-二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮76(0.10g,淡黄色油状物),产率:26.2%。LCMS:m/z 386.9/388.9(M+H);RT=1.427min(2.5min).
步骤6. 2-(2-氯吡啶-3-基)-1-(6,7-二氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(77)的合成
Figure PCTCN2018108762-appb-000103
在干燥的50mL圆底烧瓶中依次向1,4-二氧六环(10ml)中加入化合物76(0.10g,0.26mmol)、双(频哪醇合)二硼(0.079g,0.31mmol)、醋酸钾(0.038g,0.39mmol)、(1,1′-双(二苯基膦基)二茂铁)二氯化钯(0.011g,0.013mmol),氮气置换3次,升温至90℃,搅拌反应5小时。反应完毕后,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶3)纯化所得残余物,得到2-(2-氯吡啶-3-基)-1-(6,7-二氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮77(0.065g,淡黄色固体),粗产品。LCMS:m/z 435.1/437.1(M+H).
中间体89:2-(2-氯吡啶-3-基)-1-(7-氟-3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(89)的合成
Figure PCTCN2018108762-appb-000104
步骤1. 7-氟-3-甲基-1H-吲哚(85)的合成
Figure PCTCN2018108762-appb-000105
将化合物84(200.0mg,1.23mmol)加入四氢呋喃(15mL)中,置换氮气三次,冷却至0℃,加入氢化铝锂(140.0mg,3.69mmol),加毕,自然升至室温,搅拌反应2小时。反应完毕后,缓慢滴加水(20mL),乙酸乙酯萃取(20mL×3),合并有机相,减压浓缩,所得残余物用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶8)纯化,得到7-氟-3-甲基-1H-吲哚85(130.0mg,淡黄色油状物),产率:71.0%。
1H NMR(DMSO-d 6,400MHz):δ11.21(s,1H),7.29(d,J=7.6Hz,1H),7.17(s,1H),6.97-6.87(m,2H).
步骤2. 7-氟-3-甲基-二氢吲哚(86)的合成
Figure PCTCN2018108762-appb-000106
向冰水浴中的50mL圆底烧瓶中依次加入化合物85(819.0mg,5.49mmol)和冰醋酸(20mL),历经约30分钟分批加入氰基硼氢化钠(691.0mg,10.99mol),升温至室温,搅拌反应16小时。反应完毕后,冰水浴冷却,向其中缓慢加入碳酸氢钠饱和溶液调节pH至6-7,乙酸乙酯萃取(10mL×3),合并有机相,无水硫酸钠干燥,过滤,滤液浓缩,所得残余物用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶6)纯化,得到7-氟-3-甲基-二氢吲哚86(49.0mg,淡黄色油状物)。LCMS:m/z 152.0(M+H)。
步骤3. 5-溴-7-氟-3-甲基-二氢吲哚(87)的合成
Figure PCTCN2018108762-appb-000107
冰水浴下,在50mL烧瓶中加入化合物86(49.0mg,0.324mmol)、二氯甲烷(5mL),分批加入N-溴代琥珀酰亚胺(63mg,0.356mmol),室温下搅拌反应4小时。反应完毕后,室温下减压浓缩,缓慢加入饱和碳酸氢钠水溶液调节pH至6-7,乙酸乙酯萃取(10mL×4),合并有机相,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶5)纯化所得残余物,得到5-溴-7-氟-3-甲基-二氢吲哚87(61.0mg,淡黄色固体),产率:82.0%。LCMS:m/z 229.8/231.8(M+H).
步骤4. 1-(5-溴-7-氟-3-甲基-二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(88)的合成
Figure PCTCN2018108762-appb-000108
在室温下,向50mL烧瓶中依次加入化合物87(61.0mg,0.266mol)、乙酸乙酯(5mL)、T 3P(50%的乙酸乙酯溶液,W/W,406.0mg,0.53mmol)、二异丙基乙基胺(103.0mg,0.80mmol),搅拌反应3小时。反应完毕后,缓慢加入饱和碳酸氢钠水溶液调节pH至6-7,乙酸乙酯萃取(10mL×4),合并有机相,减压除去溶剂,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶3)纯化所得残余物,得到1-(5-溴-7-氟-3-甲基-二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮88(79.0mg,淡黄色油状物),产率:78.0%。LCMS:m/z 382.5/384.6(M+H).
步骤5. 2-(2-氯吡啶-3-基)-1-(7-氟-3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)乙-1-酮(89)的合成
Figure PCTCN2018108762-appb-000109
在干燥的50mL圆底烧瓶中依次向1,4-二氧六环(10ml)中加入化合物88(45.0mg,0.12mmol)、双(频哪醇合)二硼(36.0mg,0.14mmol)、醋酸钾(17.3mg,0.18mmol)、(1,1′-双(二苯基膦)二茂铁)二氯化钯(4.8mg,0.0058mmol),置换氮气3次,升温至90℃,搅拌反应3小时。反应完毕后,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶3)纯化所得残余物,得到2-(2-氯吡啶-3-基)-1-(7-氟-3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二 氢吲哚-1-基)乙-1-酮89(36.0mg,浅棕色固体)收率:76.0%。LCMS:m/z 430.8/432.8(M+H).
中间体57:2-(2-氯-4-氟-吡啶-3-基)乙酸(57)的合成
Figure PCTCN2018108762-appb-000110
步骤1. 2-(2-氯-4-氟吡啶-3-基)乙酸乙酯(56)的合成
Figure PCTCN2018108762-appb-000111
在室温下,向50mL圆底烧瓶中依次加入化合物54(1.0g,5.71mmol)、二氯甲烷(25mL)、N,N-二甲基甲酰胺(1mL),然后向其中滴加草酰氯(0.90g,7.14mmol)的二氯甲烷溶液(10mL),滴毕,室温下搅拌反应1小时,减压浓缩,向所得残余物中加入15mL无水四氢呋喃,冰水浴下将其滴加入化合物55(2M正己烷溶液,5.2mL,10.3mmol)和三乙胺(1.04g,10.3mmol)在乙腈和四氢呋喃(20mL∶20mL)中的混合液中,滴毕,在0℃下搅拌反应1小时,然后放入冰箱冷冻层放置16小时,加入乙酸乙酯(100mL)稀释,水洗,有机相用0.5mmol/L的盐酸调节pH值至4-5,室温下搅拌5分钟,然后用1mol/L的氢氧化钠水溶液调节pH至8-9,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物溶于20mL乙醇中,加入三乙胺(692mg,6.85mmol),室温下分批加入苯甲酸银(silver benzoate)(197mg,0.86mmol),搅拌10分钟,加热至80℃,搅拌反应十分钟,冷却至室温,抽滤,滤液浓缩,所得残余物用柱层析法以洗脱剂体系(乙酸乙酯∶石油醚=1∶7)纯化,得到2-(2-氯-4-氟吡啶-3-基)乙酸乙酯56(250mg,无色油状物),产率:20.0%。LCMS:m/z 217.8/219.8(M+H).
步骤2. 2-(2-氯-4-氟-吡啶-3-基)乙酸(57)的合成
Figure PCTCN2018108762-appb-000112
在室温下将化合物56(250mg,1.15mmol)溶于四氢呋喃中(10mL),加入氢氧化锂的水溶液(10mL,0.5mol/L),室温下搅拌反应1小时。LCMS监测反应完毕后,加入乙酸乙酯(10mL),水相用0.5mol/L稀盐酸调节pH至3-4,抽滤,滤饼用水洗涤,干燥,得到2-(2-氯-4-氟-吡啶-3-基)乙酸57(220mg,粗品,淡黄色油状物)。LCMS:m/z 189.9/191.9(M+H).
类似于中间体57的制备,由下表中对应原料,合成得到了中间体65和83:
Figure PCTCN2018108762-appb-000113
中间体82:3-(2-氯吡啶-3-基)丙酸(82)的合成
Figure PCTCN2018108762-appb-000114
步骤1.(E)-3-(2-氯吡啶-3-基)丙烯酸乙酯(80)的合成
Figure PCTCN2018108762-appb-000115
向在冰浴中的干燥的100mL圆底烧瓶中加入化合物79(634mg,4.46mmol)、四氢呋喃(50mL)、氢化钠(357mg,8.93mmol),在冰浴中搅拌0.5小时,加入化合物78(1000mg,4.46mmol),逐渐升温到室温,搅拌1小时,反应体系用LCMS监控,饱和氯化铵水溶液淬灭,乙酸乙酯(50mL×3)萃取,有机相干燥浓缩,用硅胶柱层析法(石油醚∶乙酸乙酯=5∶1)纯化所得残余物,得到(E)-3-(2-氯吡啶-3-基)丙烯酸乙酯80(300mg,白色固体)。产率:20%。LCMS:m/z 212.0(M+H)。
步骤2. 3-(2-氯吡啶-3-基)丙酸乙酯(81)的合成
Figure PCTCN2018108762-appb-000116
在室温下,向干燥的100mL圆底烧瓶中加入化合物80(300mg,1.4mmol)、甲醇(12mL)、 水(3mL)、氯化亚铜(140mg,1.4mmol)、硼氢化钠(54mg,1.4mmol),该反应在0℃搅拌1小时后,再加入硼氢化钠(54mg,1.4mmol),反应体系逐渐升温到室温搅拌1小时,LCMS监控该反应完成。反应用冰水淬灭,乙酸乙酯(50mL*3)萃取,有机相干燥浓缩,用硅胶柱层析法(石油醚∶乙酸乙酯=5∶1)纯化所得残余物,得到3-(2-氯吡啶-3-基)丙酸乙酯81(260mg,白色固体)。产率:86%。LCMS:m/z 214.0(M+H).
步骤3. 3-(2-氯吡啶-3-基)丙酸(82)的合成
Figure PCTCN2018108762-appb-000117
在室温下,向干燥的100mL圆底烧瓶中加入化合物81(260mg,1.21mmol)、氢氧化锂一水合物(153mg,3.64mmol)、四氢呋喃(20mL)、甲醇(4mL)、水(4mL),搅拌反应2小时,TLC监控该反应完成。浓缩反应体系,冻干,得到3-(2-氯吡啶-3-基)丙酸82(300mg白色固体),将其不经纯化即直接用于下一步。LCMS:m/z 185.9(M+H).
实施例:
实施例P1:
化合物2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-羟基丙-2-基)氨基)嘧啶-4-基)二氢吲哚-1-基)乙-1-酮(P1)的合成
Figure PCTCN2018108762-appb-000118
在室温下,向干燥的100mL圆底烧瓶中加入中间体13(100mg,0.22mmol)、DL-氨基丙醇(84mg,1.10mmol)和DMSO(0.5mL),升温至90℃,搅拌1小时。反应完毕后,减压浓缩,加入100mL水,用乙酸乙酯萃取(150mL×3),合并有机相。无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯)纯化所得残余物,得到产物P1(10mg,白色固体),产率:10.0%。LCMS:m/z 441.9(M+H)。
1H-NMR(DMSO-d6,,400MHz):δ8.334(s,1H),8.333(d,J=10.4Hz,1H),7.91(s,1H),7.76(m,3H),7.84(m,1H),7.83(d,J=10.4Hz,1H),7.43(dd,J=7.6Hz,5.2Hz,1H),7.14(d,J=5.2Hz,1H),6.85(d,J=8.0Hz,1H),4.71(t,J=5.6Hz,1H),4.29(t,J=8.0Hz,2H),4.08(s,2H),3.50(m,1H),3.31(m,2H),3.23(t,J=8.4Hz,2H),1.16(d,J=6.4Hz,2H).
类似于实施例P1的制备,按照图1中给出的通用合成方案A,由中间体13和相应的胺制备得到实施例P2-P7:
Figure PCTCN2018108762-appb-000119
Figure PCTCN2018108762-appb-000120
实施例P8:
2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-羟基丙-2-基)氨基)吡啶-4-基)二氢吲哚-1-基)乙-1-酮(P8)的合成
Figure PCTCN2018108762-appb-000121
步骤1. 2-((4-溴吡啶-2-基)氨基)丙-1-醇(24)的合成
Figure PCTCN2018108762-appb-000122
在干燥的20mL微波反应瓶中加入二甲基亚砜(8mL)、化合物4-溴-2-氟吡啶(1g,0.0057mol)、化合物2-氨基丙醇(0.65g,0.0085mol)和N,N-二异丙基乙胺(1.1g,0.0085mol),升温至140℃,搅拌反应0.5小时。LCMS监测反应结束后,反应液倒入水(10mL)中,乙酸乙酯萃取(10mL×3),合并有机相,饱和食盐水洗涤(10mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,将残余物用快速色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶1)纯化,得到化合物24 2-((4- 溴吡啶-2-基)氨基)丙-1-醇(0.8g,黄色固体)产率:61%。LCMS:m/z 230.8/232.8(M+H)。
步骤2. 2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-羟基丙-2-基)氨基)吡啶-4-基)二氢吲哚-1-基)乙-1-酮(P8)的合成
Figure PCTCN2018108762-appb-000123
在室温下,向干燥的100mL圆底烧瓶中加入中间体24(0.05g,0.00021mol)、K 2CO 3(0.058g,0.00042mol)、中间体11(0.108g,0.00026mol)、Pd(dppf)Cl 2(15mg,0.000021mol)、1,4-二氧六环(20mL)和蒸馏水(2mL),置换氮气3次,在氮气保护下升温至80℃,搅拌5小时。反应结束后,减压浓缩,粗品用薄层色谱法(乙酸乙酯)纯化,得到化合物P8(0.04g,白色固体),产率:43%。LCMS:m/z 440.7(M+H)。
1H-NMR(DMSO-d 6,400MHz):δ8.34(d,J=3.6Hz,1H),7.98(d,J=5.8Hz,1H),7.89(d,J=6.8Hz,1H),7.51(s,1H),7.45-7.40(m,2H),6.96(br s,1H),6.88(br s,1H),4.91(br s,1H),4.28(t,J=7.8Hz,2H),4.08(s,2H),4.05-3.96(m,1H),3.52-3.44(m,1H),3.37(s,1H),3.22(t,J=7.8Hz,2H),1.15(d,J=6.5Hz,3H).
类似于实施例P8的制备,按照图2中给出的通用合成方案B,利用中间体11、53或类似于中间体11的硼酸酯中间体合成得到了实施例P10-P16、P32、P34、P36、P44、P47-51、P53和P58-59:
Figure PCTCN2018108762-appb-000124
Figure PCTCN2018108762-appb-000125
Figure PCTCN2018108762-appb-000126
Figure PCTCN2018108762-appb-000127
Figure PCTCN2018108762-appb-000128
Figure PCTCN2018108762-appb-000129
实施例P9:
2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)乙 -1-酮(P9)的合成
Figure PCTCN2018108762-appb-000130
步骤1.(4-(7-氟二氢吲哚-5-基)吡啶-2-基)(1-甲基-1H-吡唑-5-基)氨基甲酸叔丁酯(25)的合成
Figure PCTCN2018108762-appb-000131
方法一:在室温下,向干燥的50mL圆底烧瓶中加入中间体4(600mg,2.279mmol)、1,4-二氧六环(4mL)和水(0.8mL)、中间体8(563mg,1.595mmol)、Pd(dppf)Cl 2(167mg,0.2279mmol)和碳酸氢钠(383mg,4.56mmol),氮气置换3次。升温至75℃,搅拌2小时。反应完毕后,趁热过滤,减压蒸馏得粗品,粗品用硅胶柱色谱法以洗脱剂体系(乙酸乙酯/石油醚=1/5至3/1)纯化,得到中间体25(4-(7-氟二氢吲哚-5-基)吡啶-2-基)(1-甲基-1H-吡唑-5-基)氨基甲酸叔丁酯(620mg,固体),产率:60.45%。 1H NMR(400MHz,DMSO)δ8.27(d,J=5.2Hz,1H),7.85(d,J=1.2Hz,1H),7.49(dd,J=5.2,1.6Hz,1H),7.43(s,1H),7.41-7.36(m,2H),6.18(d,J=2.0Hz,1H),6.14(s,1H),3.70(s,3H),3.57(t,J=8.8Hz,2H),3.08(t,J=8.8Hz,2H),1.41(s,9H).LCMS:m/z 410.2(M+H)。
方法二:在室温下,向干燥的250mL圆底烧瓶中依次加入中间体8(0.984g,2.80mmol)、中间体4(0.88g,2.90mol)、三乙胺(1.19g,12mmol)、1,4-二氧六环(15mL)、蒸馏水(3mL),再加入Pd(dppf)Cl 2(240mg,0.3mol),置换氮气3次,升温至70℃,搅拌反应16小时。LCMS监测反应结束后,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶3~1∶5)纯化所得残余物,得到中间体25(4-(7-氟二氢吲哚-5-基)吡啶-2-基)(1-甲基-1H-吡唑-5-基)氨基甲酸叔丁酯)(1.0g,固体,产率88%)。LCMS:m/z 410.1(M+H)。
方法三:向圆底烧瓶(50mL)中,依次加入中间体8(1.80g)、中间体4(2.15g.),甲基四氢呋喃(15mL),三乙胺(2.06g),纯水(3.6g)和Pd(ddpf)Cl 2(1.25g),氮气置换三次,控制温度在65~75℃,反应约15小时。取样送HPLC检测反应结束后,减压浓缩;加入MTBE和自来水,搅拌溶解;硅藻土抽滤,洗涤滤饼;合并滤液,分层;有机层用自来水洗两次。合并滤液减压浓缩后,滴加正庚烷,降温打浆。减压抽滤,滤饼用甲基叔丁基醚淋洗。滤饼减压烘干,得到中间体25(4-(7-氟二氢吲哚-5-基)吡啶-2-基)(1-甲基-1H-吡唑-5-基)氨基甲酸叔丁酯)1.72g。LCMS:m/z 410.1(M+H)。
步骤2.(4-(1-(2-(2-氯吡啶-3-基)乙酰基)-7-氟二氢吲哚-5-基)吡啶-2-基)(1-甲基-1H-吡唑-5-基) 氨基甲酸酯(26)的合成
Figure PCTCN2018108762-appb-000132
方法一:在室温下,向干燥的25mL圆底烧瓶中加入化合物9 2-氯吡啶-3-乙酸(493mg,2.876mmol)、Ac 2O(285mg,2.80mmol)和THF(3mL),该反应在75℃下,反应1小时后,再加入中间体25(620mg,1.514mmol)、THF(2mL)、DMF(1mL)和吡啶(240mg,3.028mmol),氮气置换3次。升温至70℃,搅拌3小时。反应完毕后,加入甲醇(2mL),减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯/石油醚=1/4至DCM∶MeOH=30/1)纯化所得残余物,得到中间体26(400mg,淡黄色固体),产率:46.9%。LCMS:m/z 564.2(M+H)。
方法二:在室温下向1000mL圆底烧瓶中依次加入化合物25(1.682g,4.1mmol)、二异丙基乙基胺(2.121g,16.4mmol)、化合物9(0.843g,4.9mol)、乙酸乙酯(20mL)、1-丙基磷酸酐(50%的乙酸乙酯溶液,6.54g,10mmol),加毕,室温下搅拌反应5小时。LCMS监测反应完毕后,加入饱和碳酸氢钠水溶液中和调节pH至7-8,乙酸乙酯萃取(50mL×3),合并有机相,无水硫酸钠干燥,抽滤,滤液减压浓缩,得到(4-(1-(2-(2-氯吡啶-3-基)乙酰基)-7-氟二氢吲哚-5-基)吡啶-2-基)(1-甲基-1氢-吡唑-5-基)氨基甲酸叔丁酯(26)(2.033g,浅黄色油状物,粗产品)。LCMS:m/z 562.5/564.5(M+H).
步骤3. 2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)乙-1-酮(P9)的合成
Figure PCTCN2018108762-appb-000133
方法一:在干燥的25mL单口瓶中室温下加入中间体26(350mg,0.622mmol)、TFA(709mg,6.22mmol)、乙腈(5mL)和H 2O(0.5mL),于氮气保护下40℃搅拌8小时。LCMS检测反应完毕后,粗产品用制备型液相色谱法纯化,得到产物P9 2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)乙-1-酮(135mg,黄色固体),产率:46.9%。LCMS:m/z 463.1(M+H)。
1H-NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.35(dd,J=4.8,1.6Hz,1H),8.17(d,J=5.6Hz,1H),7.88(dd,J=7.2,1.2Hz,1H),7.50(s,1H),7.45-7.41(m,2H),7.34(d,J=1.2Hz,1H),7.10(d,J=5.2Hz,1H),7.02(s,1H),6.28(d,J=1.2Hz,1H),4.28(t,J=8.0Hz,2H),4.08(s,2H),3.69(s,3H),3.21(t,J=8.0Hz,2H).
方法二:在干燥的50mL圆底烧瓶中,依次加入二氯甲烷(15mL)和中间体26(2.033g,3.6 mmol),然后缓慢加入三氟乙酸(4ml),室温下搅拌反应过夜。LCMS监测反应结束后,滴加饱和碳酸钠水溶液,调节pH至7-8,分液,二氯甲烷(50mL×3)萃取,合并有机相,减压浓缩,搅拌下向混悬液中滴加水(20mL);冰浴搅拌1-2小时;抽滤,水(10mL)洗涤滤饼一次;滤饼减压烘干得到P9(2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-甲基-1氢-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)乙烷-1-酮)1.63g。LCMS:m/z 463.1(M+H)。
类似于实施例P9的制备,按照图3中给出的通用合成方案C,利用中间体25或与其类似的中间体合成得到了实施例P45-46和P61:
Figure PCTCN2018108762-appb-000134
实施例P17:
1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-1-基)-2-(2-氟苯基)乙-1-酮(P17)的合成
Figure PCTCN2018108762-appb-000135
步骤1.N-4-(7-氟二氢吲哚-5-基)-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-基胺(32)的合成
Figure PCTCN2018108762-appb-000136
在室温下,向干燥的100mL圆底烧瓶中加入化合物4 7-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚(900mg,3.80mmol)、化合物17 4-氯-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺(800mg,3.80mmol)、碳酸钾(1.1g,7.60mmol)、(1,1-双(二苯基膦基)二茂铁)二氯化钯(278mg,0.38mmol)和1,4-二氧六环(20.0mL),置换氮气5次,升温至80℃,搅拌反应过夜。反应完毕后,减压浓缩,加入100mL水,乙酸乙酯萃取(150mL×3),合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶10)纯化所得残余物,得到中间体32 N-4-(7-氟二氢吲哚-5-基)-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-基胺(150mg,白色固体),产率:12.0%。
LCMS:m/z 311.0(M+H)。
步骤2. 1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-1-基)-2-(2-氟苯基)乙-1-酮(P17)的合成
Figure PCTCN2018108762-appb-000137
在室温下,向干燥的100mL圆底烧瓶中加入化合物32 N-4-(7-氟二氢吲哚-5-基)-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-基胺(50mg,0.16mmol)、化合物33 2-(2-氟苯基)乙酸(25mg,0.16mmol)、N,N-二异丙基乙胺(0.1mL,0.64mmol)、1-丙基磷酸酐(407mg,50%(wt%)的乙酸乙酯溶液(0.64mmol)和N,N-二甲基甲酰胺(1.0mL),搅拌反应30分钟。反应完毕后,减压浓缩,加入100mL水,乙酸乙酯萃取(150mL×3),合并有机相,饱和食盐水(50mL×5)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶1) 纯化所得残余物,得到产物P17 1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-1-基)-2-(2-氟苯基)乙-1-酮(16.7mg,淡黄色固体),产率:20.0%。LCMS:m/z 447.0(M+H)。
1H NMR(DMSO-d6,400MHz):δ9.48(s,1H),8.51(d,J=5.2Hz,1H),7.91(s,1H),7.83(d,J=12.4Hz,1H),7.46(d,J=5.2Hz,1H),7.41-7.31(m,3H),7.19(q,J=7.6Hz,2H),6.29(s,1H),4.26(t,J=8.0Hz,2H),3.98(s,2H),3.70(s,3H),3.23(t,J=8.0Hz,2H).
按照图3中给出的通用合成方案C,利用中间体32或与其类似的中间体合成如下实施例P18-P20、P23-P25、P28-31、P33、P37-39和P54-57:
Figure PCTCN2018108762-appb-000138
Figure PCTCN2018108762-appb-000139
Figure PCTCN2018108762-appb-000140
Figure PCTCN2018108762-appb-000141
Figure PCTCN2018108762-appb-000142
实施例P35:
Figure PCTCN2018108762-appb-000143
步骤1. 1-甲基-5-硝基-1H-吡唑-3-甲酸甲酯(59)的合成
Figure PCTCN2018108762-appb-000144
向在冰水浴中的100mL圆底烧瓶中依次加入化合物58(5.0g,12.74mmol)、碳酸钾(1.94g,14.0mmol)、N,N-二甲基甲酰胺(50mL),缓慢滴加碘甲烷(3.80g,26.75mmol)的N,N-二甲基甲酰胺溶液(10mL),滴毕,搅拌反应16小时。反应完毕后,加入水(150mL),乙酸乙酯萃取(50mL×3),合并有机相,饱和食盐水洗涤((30mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物用柱层析法以洗脱剂体系(乙酸乙酯∶石油醚=1∶20)纯化,得到1-甲基-5-硝基-1H-吡唑-3-甲酸甲酯59(1.0g,白色固体),产率:17.0%。LCMS:m/z 185.9(M+H)
步骤2. 5-氨基-1-甲基-1H-吡唑-3-甲酸甲酯(60)的合成
Figure PCTCN2018108762-appb-000145
在室温下,将化合物59(200mg,1.081mmol)溶于甲醇(10mL)中,加入Pd/C(10%,90mg),在1个大气压的氢气环境下搅拌反应4小时。LCMS监测反应完毕后,抽滤,滤液减压浓缩,得到5-氨基-1-甲基-1H-吡唑-3-甲酸甲酯60(145mg,淡黄色油状物)。产率:87.0%。LCMS:m/z 156(M+H).
步骤3. 5-((4-溴吡啶-2-基)氨基)-1-甲基-1H-吡唑-3-甲酸甲酯(61)的合成
Figure PCTCN2018108762-appb-000146
在室温下,向50mL圆底烧瓶中依次加入化合物60(650mg,4.19mmol)、N,N-二甲基甲酰胺(10mL),分批加入氢化钠(335mg,8.38mmol),搅拌反应0.5小时,加入2-溴-4-氟吡啶(1.47g,8.387mmol),搅拌反应16小时。LCMS监测反应完毕后,加入水(30mL),乙酸乙酯萃取(10mL×5),合并有机相,饱和食盐水洗涤(20mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物用柱层析法以洗脱剂体系(乙酸乙酯∶石油醚=1∶4)纯化,得到5-((4-溴吡啶-2-基)氨基)-1-甲基-1H-吡唑-3-甲酸甲酯61(130mg,浅黄色固体),产率:10%。LCMS:m/z 310.9/312.9(M+H).
步骤4.(5-((4-溴吡啶-2-基)氨基)-1-甲基-1H-吡唑-3-基)甲醇(62)的合成
Figure PCTCN2018108762-appb-000147
在室温下,将化合物61(130mg,0.418mmol)溶解在无水甲醇(25mL)中,分批加入硼氢化钠(156mg,4.18mmol),加毕,室温下搅拌反应2小时,减压浓缩,所得残余物用柱层析法以洗脱剂体系(乙酸乙酯∶石油醚=4∶1)纯化,得到(5-((4-溴吡啶-2-基)氨基)-1-甲基-1H-吡唑-3-基)甲醇62(100mg,白色胶状物),产率:85%。LCMS:m/z 282.9/284.9(M+H).
步骤5.N-(3-(((叔丁基二甲基硅烷基)氧基)甲基)-1-甲基-1H-吡唑-5-基)-N-(4-溴吡啶-2-基)-胺(63)的合成
Figure PCTCN2018108762-appb-000148
在室温下,向50mL圆底烧瓶中依次加入化合物62(100mg,0.355mmol)、叔丁基二甲基氯硅烷(532mg,3.55mmol)、三乙胺(358mg,3.55mmol)、4-二甲氨基吡啶(4.33mg,0.036mmol)、二氯甲烷(10mL),置换氮气三次,室温下搅拌反应16小时。反应完毕后,加入水(30mL),乙酸乙酯萃取(10mL×3),合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,用硅 胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=1∶5)纯化所得残余物,得到N-(3-(((叔-丁基二甲基硅烷基)氧基)甲基)-1-甲基-1H-吡唑-5-基)-N-(4-溴吡啶-2-基)-胺63(50mg,淡黄色油状物),产率:33.0%。LCMS:m/z 396.9/398.9(M+H).
步骤6. 1-(5-(2-((3-(((叔丁基二甲基硅烷基)氧基)甲基)-1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)-7-氟二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮(64)的合成
Figure PCTCN2018108762-appb-000149
在室温下向50mL圆底烧瓶中依次加入化合物63(50mg,0.126mmol)、1,4-二氧六环(10mL)、PdCl 2(dppf)(9.2mg,0.0126mmol)、碳酸钾(26.1mg,0.189mmol)、化合物11(52.5mg,0.126mmol),置换氮气三次,升温至80℃,搅拌反应3小时。反应完毕后,减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯∶石油醚=5∶1)纯化所得残余物,得到1-(5-(2-((3-(((叔-丁基二甲基硅烷基)氧基)甲基)-1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)-7-氟二氢吲哚-1-基)-2-(2-氯吡啶-3-基)乙-1-酮64(60mg,浅黄色油状物),产率:78.5%。LCMS:m/z 606.5/608.5,(M+H)
步骤7. 2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((3-(羟甲基)-1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)乙-1-酮(P35)的合成
Figure PCTCN2018108762-appb-000150
在室温下向50mL烧瓶中依次加入化合物64(60mg,0.099mmol)、三氟乙酸(2mL)、二氯甲烷(10mL),室温下搅拌反应1小时。反应完毕后,减压浓缩,缓慢加入饱和碳酸氢钠水溶液(15mL),用乙酸乙酯萃取(10mL×5),合并有机相,减压浓缩,用制备液相色谱法(色谱柱:-Gemini-C18 150x 21.2mm,5um;流动相:ACN-H 2O(0.1%FA),梯度:10-60)纯化所得残余物,得到2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((3-(羟甲基)-1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)乙-1-酮P35(12mg,浅黄色固体),产率:25%。
1H-NMR(CD3OD,400MHz):8.33(d,J=3.2Hz,1H),8.15(d,J=5.6Hz,1H),7.90(d,J=7.6Hz,1H),7.51(s,1H),7.44-7.38(m,2H),7.12(d,J=5.6Hz,1H),6.99(s,1H),6.31(s,1H),4.56(s,2H),4.37(t,J=7.6Hz,2H),4.14(s,2H),3.73(s,3H),3.28(t,J=7.2Hz,2H).LCMS:m/z  492.9/494.9(M+H)
实施例P60:2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)-2-羟基乙-1-酮(P60)的合成
Figure PCTCN2018108762-appb-000151
步骤1. 2-(2-氯吡啶-3-基)-2-羟基乙酸乙酯(91)的合成
Figure PCTCN2018108762-appb-000152
向在冰浴中的干燥的250mL圆底烧瓶中加入化合物90(6.0g,0.031mol)、四氢呋喃(100mL)、异丙基氯化锂氯化镁(31mL,40.3mol),置换氮气3次,自然升至室温,搅拌反应3小时。冰水浴冷却,加入化合物2(3.2g,0.031mol),逐渐升至室温,搅拌反应2小时,反应体系用饱和的氯化铵(100mL)淬灭,乙酸乙酯(80mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析法(乙酸乙酯∶石油醚=1∶10)纯化所得残余物,得到2-(2-氯吡啶-3-基)-2-羟基乙酸乙酯91(1.4g,浅黄色油状物),产率:21%。LCMS:m/z 216.0(M+H).
步骤2. 2-((叔丁基二甲基硅烷基)氧基)-2-(2-氯吡啶-3-基)乙酸乙酯(92)的合成
Figure PCTCN2018108762-appb-000153
在室温下,向干燥的100mL圆底烧瓶中加入化合物91(800mg,3.7mmol)、二氯甲烷(50mL)、叔丁基二甲基氯硅烷(2796mg,18.5mmol)、4-二甲氨基吡啶(452mg,3.7mmol)、三乙胺(3740mg,37.0mmol),置换氮气3次,室温下搅拌反应18小时。反应完毕后,加入冰水(100mL)淬灭,二氯甲烷(60mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析法(乙酸乙酯∶石油醚=1∶20)纯化所得残余物,得到2-((叔丁基二甲基硅烷基)氧 基)-2-(2-氯吡啶-3-基)乙酸乙酯92(640mg,无色油),产率:52%。LCMS:m/z 330.0(M+H).
步骤3. 2-((叔丁基二甲基硅烷基)氧基)-2-(2-氯吡啶-3-基)乙酸(93)的合成
Figure PCTCN2018108762-appb-000154
在干燥的100mL圆底烧瓶中室温下加入化合物92(640mg,1.94mmol)、氢氧化锂一水合物(244mg,5.81mmol)、四氢呋喃(20mL)、水(4mL),搅拌反应2小时。过滤,滤液减压浓缩,用1N的盐酸水溶液调节pH至7,有固体析出,过滤并干燥,得到2-((叔丁基二甲基硅烷基)氧基)-2-(2-氯吡啶-3-基)乙酸93(180mg,白色固体),产率:31%。LCMS:m/z 302.0(M+H)。
步骤4.N-(4-(1-(2-((叔丁基二甲基硅基)氧基)-2-(2-氯吡啶-3-基)乙酰基)-7-氟吲哚-5-基)吡啶-2-基)-N-(1-甲基-1H-吡唑-5-基)氨基甲酸叔丁酯(94)的合成
Figure PCTCN2018108762-appb-000155
向在冰浴中的干燥的100mL圆底烧瓶中加入化合物93(243mg,0.6mmol)、化合物25(180mg,0.6mmol)、三氯氧磷(273mg,1.8mmol)和吡啶(20mL),逐渐升到室温,搅拌反应3小时。加入冰水(50mL)稀释,乙酸乙酯(50mL×3)萃取,合并有机相,减压浓缩,用制备TLC(乙酸乙酯∶石油醚=1∶3)纯化所得残余物,得到N-(4-(1-(2-((叔丁基二甲基硅基)氧基)-2-(2-氯吡啶-3-基)乙酰基)-7-氟吲哚-5-基)吡啶-2-基)-N-(1-甲基-1H-吡唑-5-基)氨基甲酸叔丁酯94(250mg),产率:61%。LCMS:m/z 692.5(M+H).
步骤5. 2-((叔丁基二甲基硅烷基)氧基)-2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)乙-1-酮(95)的合成
Figure PCTCN2018108762-appb-000156
在干燥的100mL圆底烧瓶中室温下加入化合物94(250mg,0.36mmol)、二氯甲烷(20mL)和三氟乙酸(5mL),室温下搅拌反应2小时。冰浴冷却,用碳酸氢钠饱和水溶液(50mL)中和, 二氯甲烷(30mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,得到2-((叔丁基二甲基硅烷基)氧基)-2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)乙-1-酮95(200mg,无色油状物),产率:93%。LCMS:m/z 593.1(M+H)
步骤6. 2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)-2-羟基乙-1-酮(P60)的合成
Figure PCTCN2018108762-appb-000157
在干燥的100mL圆底烧瓶中室温下加入化合物95(200mg,0.34mmol)、四氢呋喃(4mL)、四丁基氟化铵(1N的THF溶液,4mL),室温搅拌反应1小时。用水(50mL)稀释,乙酸乙酯(30mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析法(乙酸乙酯∶石油醚=1∶20)纯化所得残余物,得到2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)-2-羟基乙-1-酮P60(120mg,白色固体),用乙酸乙酯∶正己烷=1∶2重结晶,得到2-(2-氯吡啶-3-基)-1-(7-氟-5-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)二氢吲哚-1-基)-2-羟基乙-1-酮P60(55mg,白色固体),产率:34%。
1H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.38(dd,J=2.0,4.8Hz,1H),8.16(d,J=5.6Hz,1H),8.02(dd,J=2.0,7.6Hz,1H),7.55-7.47(m,2H),7.41(d,J=12Hz,1H),7.34(d,J=1.6Hz,1H),7.09(dd,J=1.2,5.2Hz,1H),7.01(s,1H),6.63(d,J=6.8Hz,1H),6.27(d,J=2.0Hz,1H),5.77(d,J=6.4Hz,1H),4.42-4.33(m,1H),4.24-4.14(m,1H),3.68(s,3H),3.27-3.20(m,1H).
LCMS:m/z 479.0(M+H).
类似于实施例P60的制备方法,利用与中间体25类似的中间体合成得到了实施例P64:
Figure PCTCN2018108762-appb-000158
步骤7:化合物P60的拆分制得化合物P62和P63
Figure PCTCN2018108762-appb-000159
拆分条件:
手性柱:AD-H,0.46cm I.D.X15cm L
流动相:HEP∶IPA(0.1%DEA)=60∶40
流速:0.5mL
检测波长:UV 254nm
柱温:25℃
第一个出峰所得化合物(Peak1),编号P62
1H NMR(400MHz,DMSO)δ8.81(s,1H),8.38(dd,J=4.8,1.8Hz,1H),8.16(d,J=5.4Hz,1H),8.02(dd,J=7.6,1.6Hz,1H),7.52(dd,J=7.6,4.8Hz,1H),7.48(s,1H),7.40(d,J=12.0Hz,1H),7.34(d,J=1.8Hz,1H),7.09(d,J=4.2Hz,1H),7.00(s,1H),6.61(s,1H),6.27(d,J=1.6Hz,1H),5.77(d,J=6.6Hz,1H),4.37-4.41(m,1H),4.26-4.14(m,1H),3.68(s,3H),3.22(dd,J=13.4,7.2Hz,,2H).
.LCMS:m/z 479.0(M+H).
第二个出峰所得化合物(Peak2),编号P63
1H NMR(400MHz,DMSO)δ8.81(s,1H),8.38(dd,J=4.8,1.8Hz,1H),8.16(d,J=5.4Hz,1H),8.02(dd,J=7.6,1.8Hz,1H),7.52(dd,J=7.6,4.8Hz,1H),7.48(s,1H),7.40(d,J=12.0Hz, 1H),7.34(d,J=1.8Hz,1H),7.09(dd,J=5.4,1.6Hz,1H),7.00(s,1H),6.61(d,J=6.8Hz,1H),6.27(d,J=1.8Hz,1H),5.77(d,J=6.8Hz,1H),4.43-4.35(m,1H),4.25-4.15(m,1H),3.68(s,3H),3.22(dd,J=13.4,7.2Hz,2H).
LCMS:m/z 479.0(M+H).
实施例P40和P41.化合物P53的拆分制得P40和P41
Figure PCTCN2018108762-appb-000160
拆分条件:
手性柱:chiralpak-OJ,0.46cm I.D.×25cm L
流动相:HEX-EtOH(0.2%DEA)=50∶50
流速:0.8mL
检测波长:UV 214/254nm
柱温:40℃
第一个出峰所得化合物(Peak1),编号P40
1H NMR(CD 3OD,400MHz):8.34(d,J=4.8Hz,1H),7.98(d,J=5.6Hz,1H),7.90(d,J=7.6Hz,1H),7.51(s,1H),7.44-7.38(m,2H),6.94-6.92(m,1H),6.79(s,1H),4.51-4.48(m,1H),4.37(t,J=8Hz,2H),4.30-4.27(m,1H),4.14(s,2H),3.28(t,J=7.6Hz,2H),2.41-2.38(m,2H),2.35-2.31(m,2H).
LCMS:m/z 452.8/454.9(M+H)
第二个出峰所得化合物(Peak2),编号P41
1H NMR(CD 3OD,400MHz):8.33(d,J=4.8Hz,1H),7.97(d,J=6Hz,1H),7.90(d,J=7.6Hz,1H),7.53(s,1H),7.43-7.40(m,2H),6.96(d,J=5.6Hz,1H),6.84(s,1H),4.37(t,J=7.6Hz,2H),4.14(s,2H),4.10-4.03(m,1H),3.85-3.77(m,1H),3.29(t,J=8Hz,2H),2.91-2.85(m,2H),1.92-1.85(m,2H).
LCMS:m/z 452.8/454.9(M+H)
实施例P42和P43.化合物P16的拆分制得P42和P43
Figure PCTCN2018108762-appb-000161
拆分条件:
手性柱:OJ,0.46cm I.D.*25cm L
流动相:正己烷∶乙醇(0.2%二乙胺)=50∶50
流速:0.8mL
检测波长:UV 214/254nm
柱温:40℃
第一个出峰所得化合物(Peak1),编号P42
1H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.34(d,J=3.2Hz,1H),8.16(d,J=5.2Hz,1H),7.89(d,J=7.6Hz,1H),7.52(s,1H),7.49-7.41(m,2H),7.34(d,J=1.4Hz,1H),7.10(d,J=5.4Hz,1H),7.01(s,1H),6.28(s,1H),4.97-4.89(m,1H),4.18(d,J=16.8Hz,1H),3.96(d,J=16.8Hz,1H),3.68(s,3H),3.57-3.51(m,1H),2.72(d,J=16.0Hz,1H),1.27(d,J=6.4Hz,3H).LCMS:m/z 476.9(M+H).
第二个出峰所得化合物(Peak2),编号P43
1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.34(d,J=3.6Hz,1H),8.16(d,J=5.4Hz,1H),7.89(d,J=6.8Hz,1H),7.52(s,1H),7.48-7.41(m,2H),7.34(s,1H),7.10(d,J=5.4Hz,1H),7.01(s,1H),6.27(s,1H),4.98-4.89(m,1H),4.18(d,J=16.8Hz,1H),3.96(d,J=16.8Hz,1H),3.68(s,3H),3.57-3.51(m,1H),2.72(d,J=16.0Hz,1H),1.27(d,J=6.4Hz,3H).
LCMS:m/z 476.9(M+H).
效果实施例I:化学稳定性试验
1.化学稳定性试验中用于检测的手段和条件
检测方法:超高效液相色谱法(UPLC)
色谱条件:
系统:        超高效液相色谱系统,包括泵、自动进样器、检测器和柱温箱
色谱柱:      Waters Acquity UPLC BEH C18(2.1*50mm,1.7μm)
检测器:      PDA检测器
检测波长:    225nm
流动相:      A:0.05%的三氟乙酸水溶液
B:乙腈
Figure PCTCN2018108762-appb-000162
流速:        0.4ml/min
柱温:        40℃
进样体积:    2μl
2.本发明的化合物的化学稳定性考察
(1).受试化合物P9的溶液的配制
采用PEG400助溶,将化合物P9在不同缓冲体系中配制成浓度为0.2mg/ml的溶液,用于化学稳定性研究。不同pH的溶液的如下处方配制:
Figure PCTCN2018108762-appb-000163
化学稳定性试验条件:将化合物P9的不同pH值的溶液在37℃下放置24小时,分别于0、4、8、12、14和24小时用HPLC测定化合物P9的含量。
(2).受试化合物P9在不同pH的溶液中的化学稳定性试验结果
Figure PCTCN2018108762-appb-000164
(3).结论
研究结果显示,化合物P9在pH 2.0、pH 6.8、pH 7.4的溶液中,于37℃放置24h后,均无明显杂质增长,化学稳定性良好。
3.对比化合物的化学稳定性考察
类似地,用上述方法测试了WO2017/114510A1中的化合物A107在pH 1.2、pH 6.8、pH 7.4的溶液中的化学稳定性。
(1).化合物A107的溶液的配制
(1.1).A107处方溶液(pH1.2):
溶液处方:10%PEG400+5%Solutol HS-15+85%pH1.2稀盐酸
溶液浓度:0.2mg/ml
配制方法:称取A107,加入处方量的PEG400和Solutol HS-15,涡旋得澄清溶液,再加入处方量的pH1.2稀盐酸混匀即得。
(1.2).A107处方溶液(pH6.8):
溶液处方:10%PEG400+5%Solutol HS-15+85%pH6.8磷酸盐缓冲液
溶液浓度:0.2mg/ml
配制方法:称取A107,加入处方量的PEG400和Solutol HS-15,涡旋得澄清溶液,再加入处方量的pH6.8磷酸盐缓冲液混匀即得。
(1.3).A107处方溶液(pH7.4):
溶液处方:10%PEG400+5%Solutol HS-15+85%pH7.4磷酸盐缓冲液
溶液浓度:0.2mg/ml
配制方法:称取A107,加入处方量的PEG400和Solutol HS-15,涡旋得澄清溶液,再加入处方量的pH7.4磷酸盐缓冲液混匀即得。
(2)化合物A107在不同pH下的化学稳定性测试实验结果如下:
Figure PCTCN2018108762-appb-000165
上表中的实验结果显示,WO2017/114510A1中的化合物A107在pH 1.2、pH 6.8、pH 7.4的溶液中,于37℃放置24h后,杂质显著增长,在酸性、中性、弱碱性条件下化学稳定性均较差。
效果实施例II:体外酶活性测定
在本实施例中测定了本发明的化合物对ERK2激酶的半数抑制活性(IC 50值)
(1).材料与仪器:
酶:           细胞外信号调节激酶ERK2激酶(PV3595,Invitrogen)
试剂盒:       Z′-
Figure PCTCN2018108762-appb-000166
蛋白激酶分析试剂盒-Ser/Thr 3Peptide(PV3176,Invitrogen)
试剂盒成分:   底物Z′-LYTE TM Ser/Thr 3 Peptide(PV3200)
               磷酸化底物Z′-LYTE TM Ser/Thr 3 Phospho-peptide(PV3215)
               5X激酶缓冲液:250mM HEPES(pH 7.5),50mM MgCl 2
               5mM EGTA,0.05%BRIJ-35(PV3189,Invitrogen)
               ATP(PV3227,Invitrogen)
               显影剂Development Reagent A(PV3295,Invitrogen)
               显影缓冲液Development Buffer(P3127,Invitrogen)
               终止剂Stop Reagent(P3094,Invitrogen)
酶标仪:       多功能酶标仪PerkinElmer En
Figure PCTCN2018108762-appb-000167
微孔板:       384孔黑色浅孔板(6008269,PerkinElmer)
(2).试验方法:
将底物Z′-LYTE TM Ser/Thr 3 Peptide、磷酸化底物Z′-LYTE TM Ser/Thr 3 Phospho-peptide、1X激酶缓冲液(5X激酶缓冲液用超纯水稀释5倍)、ATP、显影剂Development Reagent A、显影缓冲液Development Buffer、终止剂Stop Reagent等平衡至室温准备加样。检测本发明的化合物对ERK酶活性影响的筛选浓度从1μM(阳性药从0.2μM)开始3倍梯度稀释,共稀释7个浓度,使用4%DMSO作为共溶剂。在384孔板中,加入5μL酶体系(50mM HEPES pH 7.5,1mM EGTA,10mM MgCl 2,0.01%Brij-35,4uM底物,0.8ng/μL酶)、2.5μL化合物、2.5uL 400nM ATP,室温避光孵育60min。反应完成后,向所有反应孔中加入5μl经显影缓冲液(Development Buffer)稀释的显影剂A(Development Reagent A),室温避光孵育60min。每孔加入5μL终止剂终止反应。用多功能酶标仪PerkinElmer En
Figure PCTCN2018108762-appb-000168
检测荧光信号(激发光波长为400nm,发射光波长为460nm、528nm)。
通过全活性孔和背景信号孔计算出每个孔的抑制率,数据分析方法如下:
磷酸化百分比=1-{(发射比×F 100%-C 100%)/[C 0%-C 100%+发射比×(F 100%-F 0%)]}×100
抑制剂百分比=100×(1-受试化合物孔的磷酸化百分比/0%抑制的对照的磷酸化百分比)
其中:发射比=样品中445nm发射光与520nm发射光比值
F 100%=100%磷酸化底物对照孔中520nm发射荧光平均值
F 0%=0%磷酸化底物对照孔中520nm发射荧光平均值
C 100%=100%磷酸化底物对照孔中445nm发射荧光平均值
C 0%=0%磷酸化底物对照孔中445nm发射荧光平均值实验平行重复两次。通过一系列不同浓度下受试化合物对激酶的抑制数值计算IC 50值。
(3).实验结果
本发明的化合物对ERK2激酶活性的抑制活性数据(IC 50)如下表中所示,其中:
A:代表化合物的IC 50小于或等于10nM;
B:代表化合物的IC 50大于10nM但是小于100nM;
C:代表化合物的IC 50大于或等于100nM但是小于1μM。
本发明的化合物对ERK2激酶活性的抑制活性数据
化合物编号 ERK2 IC 50
P1 C
P2 B
P3 B
P4 B
P5 A
P6 B
P7 B
P8 C
P9 A
P10 A
P11 B
P12 B
P13 C
P14 B
P17 B
P18 A
P19 C
P28 B
P29 B
P30 B
P31 A
P32 A
P33 B
P34 B
P35 B
P36 B
P37 B
P38 B
P39 C
P40 B
P41 B
P43 B
P44 B
P45 A
P46 A
P47 A
P48 A
P49 A
P50 C
P53 C
P54 B
P55 B
P56 B
P57 C
P58 A
P61 B
更具体地,在本实施例中,本发明的化合物P5、P9、P10、P18、P42、P59和P60的IC 50值分别为8.2nM、3.3nM、6.1nM、3.0nM、2.7nM、4.8nM和10nM。
效果实施例III:体外细胞活性研究
在本实施例中测定了本发明的化合物P9与WO2017/114510A1中的代表化合物对人类黑色素瘤细胞株A375的增殖抑制活性(IC 50值)
(1).材料与仪器:
细胞:       人黑色素瘤细胞株A375(CRL-1619 TM,ATCC)
检测试剂:   磺酰罗单明B SRB(S9012,Sigma)
培养板:     96孔细胞培养板(3599,Corning)
酶标仪:     全波长式微孔板酶标仪(SpectraMax 190,Molecular Devices)
(2).试验方法:
处于对数生长期的细胞按合适密度(3500/孔)接种至96孔细胞培养板,每孔90μL,在二氧化碳恒温箱内37℃培养过夜后,加入10μL不同浓度的化合物作用72小时,每个浓度设三复孔,并设相应浓度的生理盐水溶媒对照及无细胞调零孔。作用结束后,细胞去培养液,加入10%(w/v)三氯乙酸(100μL/孔)于4℃固定1小时,随后用蒸馏水冲洗五次,放于烘箱中干燥后,每 孔加入SRB溶液(4mg/mL,溶于1%冰乙酸)100μL,室温下孵育染色15min后,用1%冰乙酸冲洗五次洗去未结合的SRB,放于烘箱中干燥后,每孔加入10mM Tris溶液150μL,用全波长式微孔板酶标仪SpectraMax 190测定560nm波长下的光密度(OD值)。按以下公式计算药物对肿瘤细胞生长的抑制率:
Figure PCTCN2018108762-appb-000169
IC 50值采用酶标仪随机附带软件以四参数法回归求得。实验重复两次。
实验结果如下表中所示。
WO2017/114510A1中的代表化合物与本发明的化合物P9的细胞活性数据比较
Figure PCTCN2018108762-appb-000170
以上实验结果显示,本发明的化合物P9的活性显著高于WO2017/114510A1中的代表化合物。
效果实施例IV:渗透性研究
在本实施例中应用Caco-2细胞体外药物吸收模型测定了本发明的化合物P9以及WO2017/114510A1中的化合物A107的渗透性。
(1).材料与仪器:
细胞:          人肠癌Caco2(HTB-37,ATCC)
培养皿:        10cm培养皿(430167,Corning)
                Millicell-24细胞培养板(PSHT010R5,Millipore)
缓冲液:        PBS(14190,Invitrogen)
                HEPES(H0887,Sigma)
                HBSS(H8264,Sigma)
细胞培养相关:  高糖DMEM培养基(L0103-500,Biowest)
                胎牛血清(S1810-500,Biowest)
                胰蛋白酶(255200-056,Invitrogen)
                非必需氨基酸(M7145,Sigma)
                 青、链霉素(B-13234,GIBCO)
                 丙酮酸钠(11360-070,Invitrogen)
                 L-谷氨酰胺(25030-081,Invitrogen)
相关试剂:       荧光黄(L0144,Sigma)
                 普萘洛尔(P831800,Sigma)
                 秋水仙碱(C9754,Sigma)
                 阿替洛尔(A7655,Sigma)
仪器:           液相色谱(Waters Acquity UPLC I-class,Waters)
                 质谱(Waters xevo TQ-S MS/MS,Waters)
                 电阻仪(Millicell-ERS,Thermo)
                 微孔板读板机(Infinite Pro,Tecan)
(2).试验方法:
Caco-2细胞单层模型的建立
1)复苏Caco-2细胞。在37℃,5-6%的CO 2和95%相对湿度培养箱中培养在10em培养皿中,培养基采用高糖DMEM培养基,其中添加10%胎牛血清、1%谷氨酰胺、1%非必需氨基酸、100U/mL青霉素、100μg/mL链霉素。
2)细胞密度达到80-90%时用胰酶消化,离心,弃上清,用6毫升完全培养基重悬细胞,并计数3次。
3)1000转,离心5分钟收集细胞,稀释细胞悬液,将细胞按2×10 5/mL的浓度接种于Millicell-24孔板,每孔400μL,基底侧加入培养液800μL,在37℃,5%CO 2的培养箱中培养。
4)细胞接种72小时后换液,以后隔天换液。培养21天。
Caco-2单层细胞的评价
1)经过21天的培养后,通过测量细胞生长过程中的跨膜电阻来评估每一孔的Caco-2单层细胞的完整性。
2)标志物渗漏检查
荧光标记物Lucifer Yellow验证Caco-2细胞单层的完整性。细胞单层生长到21d后,在细胞层顶端(apical side,AP侧)加入Lucifer Yellow(100ìg/ml)200μL,基底端(basolateral side,BL侧)加入HBSS液800μL,在37℃,5%CO 2的培养箱中培养1.5h后取样,检测波长485-535nm处吸光值,计算漏出量,一般不超过0.4%。采用空白HBSS液为空白对照。
双侧转运实验
在相同条件下,同时测定药物从Caco-2细胞层顶端(apical side,AP侧)→基底端(basolateral side,BL侧)和BL侧→AP侧转运。
1)以DMSO配制化合物的母液,浓度为10mM。
2)以HBSS溶液稀释母液至工作浓度20μM。
3)用HBSS冲洗细胞3次,用细胞电位仪测定TEER值。
4)分别在细胞两侧加入对照化合物或待测化合物和HBSS,顶端AP侧400μL/孔,基底端BL侧800μL/孔
5)置于37℃,5%CO2的培养箱中培养1.5h后分别收集AP侧及BL侧的样品。
(3).数据分析:
药物透过Caco-2细胞模型的表观渗透系数P app(apparent permeability coefficients)按下式(1)计算:
Papp=(V A/(Area×Time))×([drug] acceptor/[drug] initial donor)        (1)
其中V A为接收侧体积,Area为膜面积(cm 2),Time为反应时间,[drug] acceptor为接收侧药物浓度,[drug] initial donor为给药侧药物浓度。
实验结果如下表中所示。
Figure PCTCN2018108762-appb-000171
根据这些渗透性参数的测定结果,可以看出,与WO2017/114510A1中的A107化合物相比,本发明的化合物P9在Caco-2渗透性试验中,具有显著更高的表观渗透系数(Papp,Apical to Basal);已知Papp>2×10 -6属于渗透性好的药物(例如,参见Journal of Pharmacological and Toxicological Methods 44(2000)235-249),化合物P9显著高于这一指标,而A107低于这一指标。A107的外排率(Efflux Ratio)较高,而P9的外排率(Efflux Ratio)较低。因此P9具有更好的渗透性,可预计其在体内具有更好的经肠吸收性质和更好的口服吸收程度。
效果实施例V:溶解度测定
在本实施例中测定了本发明的化合物的热力学溶解度
(1).试剂和材料:
名称 供应商 货号/批号
DPBS Corning R21-031-CV
HBSS Sigma RNBC5907
ACN Merck JA054630
NaOH 国药集团 20120515
HCl 国药集团 20160503
384孔板 Greiner B16093FV
DMSO Merck K42958652 225
(2)仪器与设备:
名称 来源
恒温混匀仪 Eppendorf
离心机 Eppendorf 5424R型离心机,Eppendorf
离心机 Eppendorf 5810R型离心机,Eppendorf
封板机 Plate Loc封板机,Agilent
震荡器 IKA MS3数显型振荡器,IKA
液相色谱 Waters ACQUITY I-Class System,Waters
PH计 Sartorius PB-10,Sartorius
涡流机 MS3数显型涡流机,IKA
分析天平 赛多利斯MSE125P-100-DA型分析天平
MS/MS系统 Waters ACQUITY XEVO TQ-S(ESI源),Waters
(3)实验方法
不同pH值的空白基质:
PH7.4:DPBS
PH6.8:9900μL HBSS+100μL HEPS+5μL 2N NaOH
PH7.4:DPBS用2N HCl调PH至2.0
实验孵育:
称取约3mg化合物,分别加入500μL空白基质,于37℃环境下摇24h。
样品处理:
孵育结束后的样品,离心30min,上清液转移至新的EP管中,继续离心30min。
离心结束后将样品用ACN/H 2O(V/V,1∶1)稀释100倍。
用ACN/H 2O(V/V,1∶1)配置线性,线性浓度范围12.5nM-1mM
生物分析:
所有样品,与水按体积比1∶1混匀,4000rpm离心5min,LC-MS/MS分析。
分析方法:
色谱方法:
分析柱:Acquity BEH C18(1.7μm;2.1x 50mm,Waters)
流动相A:0.1%FA在H 2O中的溶液
流动相B:0.1%FA在CAN/MEOH(9∶1,V/V)中的溶液
梯度:如下表所示
时间(h) 流速(mL/min) A% B% 曲线(h)
开始时 0.5 80 20 开始时
1.2 0.5 40 60 6
1.5 0.5 10 90 6
2.0 0.5 80 20 1
MS/MS系统
采用多反应监测(MRM)模式:
化合物 离子化模式 MRM
本发明的化合物P9 ESI,positive 463.047>307.588
(4)实验结果
Figure PCTCN2018108762-appb-000172
以上结果显示,在考察的三种pH值下,本发明的化合物P9比WO2017/114510A1中的化合物具有大得多的溶解度,利于配制成药物。
效果实施例VI:动物模型中的药代动力学研究
在本实施例中测定了本发明的化合物P9以及WO2017/114510A1中的代表化合物在小鼠体内的药代动力学参数。
(1)单次静脉注射(IV)和口服(PO)给予ICR小鼠体内药代动力学研究方案
(1.1)供试品的制备
供试品配制为按照纯游离碱的浓度计算。
静脉注射(IV)
准确称取适量受试物,加入适量的处方辅料(5%DMSO+5%Solutol+90%生理盐水),使完全溶解后,制得浓度为0.2mg/mL的给药溶液,用于静脉注射给药。
灌胃口服(PO)
准确称取适量受试物,加入适量的处方辅料(0.4%甲基纤维素(粘度:400cps)),使充分混匀后,制得浓度为1mg/mL的给药溶液,用于口服给药。
(1.2)动物接收与适应
从上海西普尔-必凯实验动物有限公司购入40只雄性SPF级ICR小鼠(mice),其中体检合格、无异常的30只健康ICR小鼠用于该研究,动物体重:20.12-25.56g。
(1.3)动物给药
雄性ICR小鼠30只,按下表进行实验。
Figure PCTCN2018108762-appb-000173
注*:所有动物给药前禁食10-14小时,给药后2小时恢复给食。
(1.4)样品采集与处理
经眼眶或二氧化碳(CO 2)安乐死后经心脏穿刺采血,每个样品采集约0.20毫升(mL),肝素钠抗凝,采集后放置冰上。
静脉及口服给药组的采集时间点:给药前及给药后5、15和30min,1、2、4、6、8和24h,具体如下表所示:
Figure PCTCN2018108762-appb-000174
血液样本采集后置于冰上,离心分离血浆(离心条件:8000转/分钟,6分钟,2-8℃)。收集的血浆分析前存放于-80℃。
供试品的生物样品采用LC-MS/MS进行分析,所采用的分析方法见(1.7)项,样品检测的LLOQ为1ng/mL,样品检测过程中随行标准曲线及质控样品的分析。
(1.5)动物处置
试验结束后,按照机构SOP对所有动物实施安乐死。
(1.6)药物代谢动力学分析
根据药物的血药浓度数据,运用WinNonlin 7.0计算药代动力学参数,提供AUC 0-t、AUC 0-∞、MRT 0-∞、C max、T max、和T 1/2等参数及其平均值和标准差。
对于浓度低于定量下限的样品,在进行药代动力学参数计算时,在达到C max以前取样的样品应以零值计算,在达到C max以后取样点样品应以无法定量(BLQ)计算。
(1.7)分析方法
a.仪器设备
LC-MS/MS
超高效液相色谱系统(Waters公司,ACQUITY UPLC),包括二元溶剂管理器(ACQUITY UPLC Binary Solvent Manager)、样品管理器(ACQUITY UPLC Autosampler Mod.)、高通量样品组织管理器(ACQUTIY UPLC Sample Organizer)、高温柱温箱(ACQUITY UPLC Column  Heater HT)。
质谱仪(API 4000,美国应用生物系统公司),电喷雾离子源(ESI),串联四极杆质量分析器。
数据处理系统为Analyst软件(美国应用生物系统公司,软件版本号1.5.1)。
微量分析天平(XP26,梅特勒-托利多仪器(上海)有限公司);涡旋振荡器(SI-A256,Scientific Industries,Inc.);小型台式高速冷冻离心机(5417R,Eppendorf);超纯水机(Millipore);移液器(Eppendorf)。
试剂
甲醇(Burdick&Jackson,HPLC)、乙腈(Burdick&Jackson,HPLC)、甲酸(J&K)、超纯水。
b.LC-MS/MS条件
液相条件如下:
色谱柱:ACQUITY UPLC HSS T3 1.8μm(50mm×2.10mm)
流动相:
时间(min) A(%) B(%)
0.00 80 20
0.40 10 90
0.80 10 90
0.81 80 20
1.20 80 20
A:0.1%甲酸水溶液    B:0.1%甲酸甲醇溶液
柱温:40℃                         自动进样器温度:4℃
流速:500μL/min                     进样量:1μL
质谱条件如下:
扫描模式:正离子多反应监测模式
Figure PCTCN2018108762-appb-000175
c.标准曲线样品及质控样品的制备
称取一定量受试物,加甲醇使完全溶解后,配制成浓度为569,000ng/mL的储备液。取一定量的储备液,用甲醇稀释成浓度为200,000ng/mL的工作溶液。取一定量的200,000ng/mL标准溶液,按照1∶39的比例,加入到一定量的空白血浆中,制得浓度为5000ng/mL的标准曲线样品。取5000ng/mL的标准曲线样品,用空白血浆依次稀释得到1000、500、100、50、10、5、1ng/mL标准曲线样品和800、200、2.5ng/mL的质控样品。具体制备过程见表I。
表I标准曲线样品及QC样品的制备表
Figure PCTCN2018108762-appb-000176
内标工作液:吸取一定量的浓度为767,000ng/mL的甲苯磺丁脲储备液至一定体积的容量瓶中,用甲醇定容至刻度后混匀,制得浓度为200ng/mL的内标工作溶液。
d.血浆样品处理
取50μL样品(标曲/质控/生物样品)至1.5mL离心管中,加入250μL内标溶液(空白不加内标补加相同体积的甲醇),涡旋混匀。14000转/分钟,离心5分钟。取200μL上清液,加入到相应的96孔进样板中,LC-MS/MS进样分析。
(2)实验结果
WO2017/114510A1中的代表化合物与本发明的化合物P9的小鼠药代动力学数据比较如下。
Figure PCTCN2018108762-appb-000177
Figure PCTCN2018108762-appb-000178
根据这些小鼠体内药代动力学参数的测定结果,可以看出,与WO2017/114510A1中的化合物相比,本发明的化合物P9在小鼠中具有显著更高的药时曲线下面积(AUC),以及更低的体内清除率(CLz),生物利用度好,因此预测本化合物具有更好的口服吸收和更好的成药性。
制剂实施例I
准确称取适量化合物P9,加入5%DMSO+5%Solutol+90%生理盐水等,使完全溶解后,制得浓度为0.2mg/mL的给药溶液,无菌过滤,用于静脉注射给药;
制剂实施例II
准确称取适量化合物P9,加入0.4%甲基纤维素(粘度:400cps)等至终体积,使充分混匀后,制得浓度为1mg/mL的给药溶液,用于口服给药。
通过引用将本发明中所提及的所有参考文献均完整合并入本文,就如同每一篇文献均单独列出一样。应理解,在阅读了本发明的公开内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落入本申请所附权利要求书所限定的范围内。

Claims (28)

  1. 式(I)化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,
    Figure PCTCN2018108762-appb-100001
    式中,
    X 1选自:CR 9a和N;
    X 2选自:CR 9b和N;
    X 3选自:CR 9c和N;且X 1、X 2和X 3至多一个为N;
    Y 1和Y 2各自独立地选自:CR 9’和N;
    R 9a、R 9b和R 9c各自独立地选自:H、D、卤素、-OH、氰基、任选被取代的烷基、任选被取代的烷氧基、任选被取代的烷基羰基、任选被取代的烷氧基羰基、任选被取代的环烷基、氨基、任选被取代的单或二(烷基)氨基和-CONR aR b
    R 9’选自:H、D、卤素、-OH、氰基、任选被取代的烷基、任选被取代的烷氧基、任选被取代的烷基羰基、任选被取代的烷氧基羰基、任选被取代的环烷基、氨基、任选被取代的单或二(烷基)氨基和CONR aR b
    R 1选自:H和D;
    R 2选自:任选被取代的烷基、任选被取代的环烷基、任选被取代的杂环基、任选被取代的芳基和任选被取代的杂芳基,或者R 2与X 1共同形成任选被取代的杂环基;
    R 3选自:卤素和任选被取代的烷基;
    R 4选自:H、D、任选被取代的烷基、任选被取代的烷氧基、-CO(CR 10R 11) mR 12、-SO 2(CR 10R 11) mR 12、-CONR 13(CR 10R 11) mR 12、-COO(CR 10R 11) mR 12、-CR 13R 13’(CR 10R 11) mR 12和C 1-8烷基羰基-;其中m为0、1、2或3,且其中
    R 10和R 11各自独立地选自:H、D、卤素、任选被取代的烷基和任选被取代的烷氧基;或者R 10与R 11相连形成任选被取代的环烷基、环烯基、芳基、杂芳基和杂环基;且
    R 12各自独立地选自:H、任选被取代的烷基、任选被取代的环烷基、任选被取代的杂环基、任选被取代的芳基和任选被取代的杂芳基;和
    R 13和R 13’各自独立地选自:H和任选被取代的烷基;或者R 13和R 13’与相邻的碳一起形成任选被取代的环烷基、环烯基和杂环基;
    R 5、R 6、R 7和R 8各自独立地选自:-H、-D、卤素、-OH、氨基、氰基、任选被取代的 烷基、任选被取代的烷氧基、-(CH 2) 0-3CONR aR b、-(CH 2) 0-3COOH、任选被取代的环烷基和任选被取代的杂环基;或者R 5、R 6、R 7和R 8中任意两个与相邻的碳一起形成任选被取代的环烷基、环烯基、芳基、杂芳基和杂环基;且
    R a和R b各自独立地选自:H、D和任选被取代的烷基;
    其中任选的取代基独立地选自:氘(D)、卤素、-OH、巯基、氰基、-CD 3、-C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、3-8元环烷基、芳基、3-8元杂环基、杂芳基、芳基-C 1-C 6烷基-、杂芳基-C 1-C 6烷基-、C 1-C 6卤代烷基-、-OC 1-C 6烷基、-OC 2-C 6烯基、-OC 1-C 6烷基苯基、-C 1-C 6烷基-OH、-C 1-C 6烷基-SH、-C 1-C 6烷基-O-C 1-C 6烷基、-OC 1-C 6卤代烷基、-NH 2、-C 1-C 6烷基-NH 2、-N(C 1-C 6烷基) 2、-NH(C 1-C 6烷基)、-N(C 1-C 6烷基)(C 1-C 6烷基苯基)、-NH(C 1-C 6烷基苯基)、硝基、-C(O)-OH、-C(O)OC 1-C 6烷基、-CONRiRii(其中Ri和Rii是H、D和C 1-6烷基)、-NHC(O)(C 1-C 6烷基)、-NHC(O)(苯基)、-N(C 1-C 6烷基)C(O)(C 1-C 6烷基)、-N(C 1-C 6烷基)C(O)(苯基)、-C(O)C 1-C 6烷基、-C(O)-5-7元杂芳基)、-C(O)C 1-C 6烷基苯基、-C(O)C 1-C 6卤代烷基、-OC(O)C 1-C 6烷基、-S(O) 2-C 1-C 6烷基、-S(O)-C 1-C 6烷基、-S(O) 2-苯基、-S(O) 2-C 1-C 6卤代烷基、-S(O) 2NH 2、-S(O) 2NH(C 1-C 6烷基)、-S(O) 2NH(苯基)、-NHS(O) 2(C 1-C 6烷基)、-NHS(O) 2(苯基)和-NHS(O) 2(C 1-C 6卤代烷基),其中所述的烷基、环烷基、苯基、芳基、杂环基和杂芳基中的每一个任选被一个或多个选自以下的取代基进一步取代:卤素、-OH、-NH 2、环烷基、3-8元杂环基、C 1-C 4烷基、C 1-C 4卤代烷基-、-OC 1-C 4烷基、-C 1-C 4烷基-OH、-C 1-C 4烷基-O-C 1-C 4烷基、-OC 1-C 4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC 1-C 6烷基、-CON(C 1-C 6烷基) 2、-CONH(C 1-C 6烷基)、-CONH 2、-NHC(O)(C 1-C 6烷基)、-NH(C 1-C 6烷基)C(O)(C 1-C 6烷基)、-SO 2(C 1-C 6烷基)、-SO 2(苯基)、-SO 2(C 1-C 6卤代烷基)、-SO 2NH 2、-SO 2NH(C 1-C 6烷基)、-SO 2NH(苯基)、-NHSO 2(C 1-C 6烷基)、-NHSO 2(苯基)和-NHSO 2(C 1-C 6卤代烷基),条件是,所述化合物不是2-(2-氯吡啶-3-基)-1-(7-氟-2-(羟甲基)-5-(2-(异丙基氨基)嘧啶-4-基)二氢吲哚-1-基)乙-1-酮。
  2. 如权利要求1所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:
    X 1选自:CR 9a和N;
    X 2选自:CR 9b和N;
    X 3选自:CR 9c和N;且X 1、X 2和X 3至多一个为N;
    Y 1和Y 2各自独立地选自:CR 9’和N;
    R 9a、R 9b和R 9c各自独立地选自:H、D、卤素、-OH、氰基、任选被取代的C 1-3烷基、任选被取代的C 1-3烷氧基、任选被取代的C 1-3烷基羰基、任选被取代的C 1-3烷氧基羰基、任选被取代的C 3-8环烷基、氨基、任选被取代的单-或二-(C 1-3烷基)氨基和-CONR aR b
    R 9’选自:H、D、卤素、-OH、氰基、任选被取代的C 1-3烷基、任选被取代的C 1-3烷氧基、任选被取代的C 1-3烷基羰基、任选被取代的C 1-3烷氧基羰基、任选被取代的C 3-8环烷基、氨基、任选被取代的单-或二-(C 1-3烷基)氨基和CONR aR b
    R 1选自:H和D;
    R 2选自:任选被取代的C 1-8烷基、任选被取代的C 3-8环烷基、任选被取代的3-8元杂环基、任选被取代的6-12元芳基和任选被取代的5-12元杂芳基如5-7元杂芳基,或者R 2与X 1共同形成任选被取代的3-8元杂环基;
    R 3选自:卤素和任选被一个或多个独立地选自D和卤素的取代基取代的C 1-8烷基;
    R 4选自:H、D、任选被取代的C 1-8烷基、任选被取代的C 1-8烷氧基、-CO(CR 10R 11) mR 12、-SO 2(CR 10R 11) mR 12、-CONR 13(CR 10R 11) mR 12、-COO(CR 10R 11) mR 12、-CR 13R 13’(CR 10R 11) mR 12和C 1-8烷基羰基-;其中m为0、1、2或3,且其中
    R 10和R 11各自独立地选自:H、D、卤素、任选被取代的C 1-8烷基和任选被取代的C 1-8烷氧基,或者R 10与R 11相连形成任选被取代的环烷基、环烯基、芳基、杂芳基和杂环基;且
    R 12各自独立地选自:H、任选被取代的C 1-3烷基、任选被取代的C 3-8环烷基、任选被取代的3-8元杂环基、任选被取代的6-12元芳基和任选被取代的5-12元杂芳基如5-7元杂芳基;和
    R 13和R 13’各自独立地选自:H和任选被取代的C 1-3烷基;或者R 13和R 13’与相邻的碳一起形成任选被取代的C 3-8环烷基、C 4-8环烯基和C 5-8杂环基;
    R 5、R 6、R 7和R 8各自独立地选自:-H、-D、卤素、-OH、氨基、氰基、任选被取代的C 1-3烷基、任选被取代的C 1-3烷氧基、-(CH 2) 0-3CONR aR b、-(CH 2) 0-3COOH、任选被取代的C 3-8环烷基和任选被取代的3-8元杂环基;或者R 5、R 6、R 7和R 8中任意两个与相邻的碳一起形成任选被取代的环烷基、环烯基、芳基、杂芳基和杂环基;且
    R a和R b各自独立地选自:H、D和任选被取代的C 1-3烷基。
  3. 如权利要求1至2中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于,所述化合物具有式Ia、Ib、Ic或Id所示的结构:
    Figure PCTCN2018108762-appb-100002
    R 9a、R 9b和R 9c各自独立地选自:H、D、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、-OH、氰基、卤素、氨基、单-或二-(C 1-3烷基)氨基、C 1-3烷基羰基、C 1-3烷氧基羰基和C 3-8环烷基;优选地,R 9a、R 9b和R 9c各自独立地选自:H、D和C 1-3烷基;更优选地,R 9a、R 9b和R 9c各自独立地选自:H和D;且
    其它变量如权利要求1或2中所定义。
  4. 如权利要求1至3中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:
    Y 1为CR 9’,Y 2为CR 9’,且其中R 9’选自H、D、卤素和C 1-3烷基;更优选地,Y 1为CR 9’,Y 2为CR 9’,且其中R 9’为H、D、F或甲基;
    或者
    Y 1为CR 9’,Y 2为N,且其中R 9’选自H、D、卤素和C 1-3烷基;更优选地,Y 1为CR 9’,Y 2为N,且其中R 9’为H、D、F或甲基;
    或者
    Y 1为N,Y 2为CR 9’,且其中R 9’选自H、D、卤素和C 1-3烷基;更优选地,Y 1为N,Y 2为CR 9’,且其中R 9’为H、D、F或甲基;
    或者
    Y 1为N,且Y 2为N。
  5. 如权利要求1所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于,所述化合物具有式Ie所示的结构:
    Figure PCTCN2018108762-appb-100003
    其中各变量如权利要求1中所定义。
  6. 如权利要求1、2和5中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:X 1选自CR 9a和N,其中R 9a选自H、D、卤素、-OH、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3烷基羰基、C 1-3烷氧基羰基、C 3-8环烷基、氨基和单-或二-(C 1-3烷基)氨基;优选地,X 1选自CR 9a和N,其中R 9a选自H、D和C 1-3烷基;更优选地,X 1选自CH、CD和N。
  7. 如权利要求1和5中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:
    R 2选自:任选被取代的C 1-6烷基、任选被取代的C 3-8环烷基、任选被取代的3-8元杂环基和任选被取代的5-12元杂芳基如5-7元杂芳基,其中任选的取代基是一个或多个独立地选自D、卤素、羟基、-CD 3、C 1-6烷基和羟基C 1-6烷基的取代基,优选是一个或多个独立地选自D、卤素、羟基、-CD 3、-CH 3和-CH 2OH的取代基;
    或者
    R 2选自:任选被一个或多个羟基取代的C 1-6烷基、任选被一个或多个羟基取代的C 3-8环烷基、3-8元杂环基和任选被一个或多个-CD 3、C 1-6烷基和羟基C 1-6烷基取代的5-12元杂芳 基如5-7元杂芳基;
    或者
    R 2选自:C 1-4烷基、
    Figure PCTCN2018108762-appb-100004
    它们任选地被一个或多个独立地选自D、卤素、羟基、C 1-4烷基、-CD 3和羟基C 1-4烷基的取代基取代,优选被一个或多个独立地选自D、卤素、羟基、-CH 3、-CD 3和-CH 2OH的取代基取代;
    或者
    R 2选自:异丙基,
    Figure PCTCN2018108762-appb-100005
    Figure PCTCN2018108762-appb-100006
    或者
    R 2选自
    Figure PCTCN2018108762-appb-100007
    或者
    R 2选自
    Figure PCTCN2018108762-appb-100008
  8. 如权利要求1至7中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:R 3选自卤素和任选被一个或多个独立地选自D或卤素的取代基取代的C 1-6烷基;或者,R 3选自卤素和任选被一个或多个独立地选自D或卤素的取代基取代的C 1-3烷基;或者,R 3选自卤素和C 1-6烷基;或者R 3选自氟、氯、溴、碘、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-CH 2CH 2CH 3、-CF 3、-CHF 2、CF 3CH 2-和CD 3-;或者,R 3选自氟、氯和-CH 3;或者,R 3为氟。
  9. 如权利要求1至8中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:
    R 4选自-CO(CR 10R 11) mR 12和-CR 13R 13’(CR 10R 11) mR 12;其中m为0、1、2或3,且其中
    R 10和R 11各自独立地选自H、D和任选被羟基取代的C 1-4烷基;
    R 12各自独立地选自:任选被取代的6-12元芳基和任选被取代的5-12元杂芳基如5-7元杂芳基;
    R 13和R 13’各自独立地选自:H、C 1-3烷基和C 1-3卤代烷基。
  10. 如权利要求9所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:R 12各自独立地选自任选被取代的6-12元芳基和任选被取代的5-12元杂芳基如5-7元杂芳基,其中任选的取代基是一个或多个独立地选自如下的取代基:D、卤素、C 1-4烷基、氰基和C 3-8杂环基-(CH 2) 0-4-(例如吗啉基如吗啉代基、哌嗪基、四氢吡喃基如四氢吡喃-4-基、吗啉基甲基如吗啉代基甲基或哌嗪基甲基);
    或者,R 12选自:任选被取代的苯基和任选被取代的吡啶基如吡啶-3-基,其中任选的取代基是一个或多个独立地选自如下的取代基取代:D、卤素、C 1-4烷基(如甲基或乙基)、氰基和C 3-8杂环基-(CH 2) 0-4-(例如吗啉基如吗啉代基、哌嗪基、四氢吡喃基如四氢吡喃-4-基、吗啉基甲基如吗啉代基甲基或哌嗪基甲基);
    或者,R 12选自:
    Figure PCTCN2018108762-appb-100009
    其中Rc选自卤素如氟或氯、C 1-4烷基如甲基、
    Figure PCTCN2018108762-appb-100010
    Figure PCTCN2018108762-appb-100011
    其中R d选自H、C 1-4烷基如甲基或乙基和
    Figure PCTCN2018108762-appb-100012
    Figure PCTCN2018108762-appb-100013
    其中R e选自卤素如氟和氯,且p为1或2;和
    Figure PCTCN2018108762-appb-100014
    其中R f选自
    Figure PCTCN2018108762-appb-100015
    Figure PCTCN2018108762-appb-100016
  11. 如权利要求1至8中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:R 4选自-CO(CR 10R 11) mR 12,其中m为0、1、2或3,且其中
    R 10和R 11各自独立地选自H;且
    R 12选自
  12. 如权利要求1至8中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于:R 4选自-CO(CR 10R 11) mR 12,其中m为0、1、2或3,且其中R 10和R 11各自独立地选自H;R 12选自2-氰基苯基、5-氯-2-氟苯基、2-氯-3-氟苯基、2-氯-4-氟苯基、2-氯-5-氟苯基、2,5-二氟苯基、3-氯吡啶-2-基、6-氯吡啶-2-基、3-氯吡啶-4-基或4-氯吡啶-3-基。
  13. 如权利要求1至12中任一项所述的化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,其特征在于,
    R 5、R 6、R 7和R 8各自独立地选自:-H、-D、卤素、-OH、氨基、氰基、任选被取代的C 1-6烷基、任选被取代的C 1-6烷氧基、-(CH 2) 0-3CONR aR b、-(CH 2) 0-3COOH、任选被取代的C 3-8环烷基和任选被取代的3-8元杂环基,其中任选的取代基是一个或多个独立地选自如下基团的取代基:D、-OH、-OC 1-C 6烷基和NH 2,且其中R a和R b各自独立地选自H、D和C 1-3烷基;
    或者,R 5、R 6、R 7和R 8各自独立地选自H、任选被羟基或-OC 1-C 6烷基取代的C 1-6烷基;
    或者,R 5和R 6各自独立地选自H或C 1-6烷基;且R 7和R 8各自独立地选自H和任选被羟基或-OC 1-C 6烷基取代的C 1-6烷基;
    或者,R 5、R 6、R 7和R 8各自独立地选自-H、-CH 3和-CH 2OH;
    或者,R 5、R 6和R 7为H,且R 8为H、-CH 3或-CH 2OH。
  14. 选自实施例P1-P20、P23-P25、P28-51、P53-P64的化合物或其药学上可接受的盐。
  15. 如实施方案1-14中任一项所述的化合物或其药学上可接受的盐,其用作药物。
  16. 药物组合物,包含如权利要求1-14中任一项所述的化合物或其药学上可接受的盐,并且任选地包含药学上可接受的载体。
  17. 如权利要求1-14中任一项所述的化合物或其药学上可接受的盐在制备用于预防和/或治疗与ERK激酶相关的疾病的药剂或用作ERK激酶抑制剂的产品中的用途。
  18. 非治疗性地抑制ERK激酶活性的方法,该方法包括将有效量的权利要求1-14中任一项所述的化合物或其药学上可接受的盐与ERK激酶接触,从而抑制ERK激酶。
  19. 具有如下结构的化合物(4-(7-氟二氢吲哚-5-基)吡啶-2-基)(1-甲基-1H-吡唑-5-基)氨基甲酸叔丁酯或其立体异构体、外消旋体、几何异构体、互变异构体、水合物、溶剂化物或其药学上可接受的盐:
    Figure PCTCN2018108762-appb-100018
  20. 制备如权利要求1所述的式(I)化合物或其立体异构体、外消旋体、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐的方法,所述式(I)化合物是式C3的化合物:
    Figure PCTCN2018108762-appb-100019
    其中X 1、R 2、R 3、R 10、R 11、R 12和m如权利要求1中所定义,
    该方法包括如下步骤:
    (a)使式C1的化合物
    Figure PCTCN2018108762-appb-100020
    与化合物
    Figure PCTCN2018108762-appb-100021
    进行酰胺偶联反应,生成式C2的化合物,
    Figure PCTCN2018108762-appb-100022
    (b)当式C2的化合物为Boc保护时,使其脱保护,生成式C3的化合物,
    Figure PCTCN2018108762-appb-100023
  21. 权利要求20的方法,其中所述酰胺偶联反应在缩合试剂和碱的存在下、在惰性溶剂中进行。
  22. 权利要求20的方法,其中所述脱保护在酸存在下、在惰性溶剂中进行。
  23. 权利要求21或22的方法,其中所述惰性溶剂选自:乙酸乙酯、四氢呋喃、甲基四氢呋喃、乙腈、二甲基亚砜、N,N-二甲基甲酰胺、二氯甲烷、1,2-二氯乙烷、N-甲基-2-吡咯烷酮或其组合。
  24. 权利要求21的方法,其中所述缩合试剂选自:1-羟基苯并三氮唑(HOBT)、1-羟基-7-偶氮苯并三氮唑(HOAT)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基鏻(PyBOP)、苯并三唑-1-三(三甲氨基)-六氟磷酸酯(BOP)、1,1-羰基二咪唑(CDI)、1-丙基磷酸酐(T 3P)、1-乙基-3-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HC1)、N,N-二环己基碳二亚胺(DCC)、醋酸酐、乙酰氯、草酰氯、六氟磷酸2-(7-氧化苯并三唑)-N,N,N’,N’-四甲基脲鎓(HATU)、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸季铵盐(HBTU)中的一种或多种。
  25. 权利要求21的方法,其中所述碱选自:三乙胺、DIPEA、吡啶、2,4-二甲基吡啶、NaOH、KOH、LiOH、Na 2CO 3、K 2CO 3、NaHCO 3、Cs 2CO 3、Na 3PO 4或K 3PO 4中的一种或多种。
  26. 权利要求20的方法,其中所述酰胺偶联反应在室温至回流的温度下进行0.5~24h。
  27. 权利要求22的方法,其中所述酸选自:盐酸、硫酸、三氟乙酸、乙酸、甲酸、磷酸中的一种或多种。
  28. 权利要求20的方法,其中所述脱保护在-10℃至80℃的温度下0.5~24h。
PCT/CN2018/108762 2017-09-30 2018-09-29 具有erk激酶抑制活性的化合物及其用途 WO2019062949A1 (zh)

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AU2018339722A AU2018339722B2 (en) 2017-09-30 2018-09-29 Compound having ERK kinase inhibitory activity and use thereof
NZ763197A NZ763197A (en) 2017-09-30 2018-09-29 Compound having erk kinase inhibitory activity and use thereof
EP18862819.2A EP3702354B1 (en) 2017-09-30 2018-09-29 Compound having erk kinase inhibitory activity and use thereof
BR112020006294-4A BR112020006294A2 (pt) 2017-09-30 2018-09-29 composto com atividade inibidora da erk quinase e seu uso
CA3080623A CA3080623C (en) 2017-09-30 2018-09-29 Compound having erk kinase inhibitory activity and use thereof
JP2020539131A JP7216105B2 (ja) 2017-09-30 2018-09-29 Erkキナーゼ阻害活性を有する化合物及びその使用
KR1020207012147A KR20200078510A (ko) 2017-09-30 2018-09-29 Erk 키나제 억제 활성을 갖는 화합물 및 그의 용도
MX2020003240A MX2020003240A (es) 2017-09-30 2018-09-29 Compuesto que tiene actividad inhibidora de la quinasa erk y su uso.
IL273655A IL273655B2 (en) 2017-09-30 2018-09-29 A compound with erk kinase inhibitory activity and its use
US16/652,148 US11465984B2 (en) 2017-09-30 2018-09-29 Compound having ERK kinase inhibitory activity and use thereof
CN201880001907.6A CN109863147A (zh) 2017-09-30 2018-09-29 具有erk激酶抑制活性的化合物及其用途
SG11202002968UA SG11202002968UA (en) 2017-09-30 2018-09-29 Compound having erk kinase inhibitory activity and use thereof
EA202090888A EA202090888A1 (ru) 2017-09-30 2018-09-29 Соединение, обладающее активностью по ингибированию erk киназы, и его применение
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