WO2017088723A1 - 一类取代三唑并哌嗪类parp抑制剂及其制备方法和用途 - Google Patents

一类取代三唑并哌嗪类parp抑制剂及其制备方法和用途 Download PDF

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WO2017088723A1
WO2017088723A1 PCT/CN2016/106707 CN2016106707W WO2017088723A1 WO 2017088723 A1 WO2017088723 A1 WO 2017088723A1 CN 2016106707 W CN2016106707 W CN 2016106707W WO 2017088723 A1 WO2017088723 A1 WO 2017088723A1
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substituted
compound
group
unsubstituted
halogen
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PCT/CN2016/106707
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French (fr)
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张翱
缪泽鸿
王平原
宋姗姗
宋子兰
宦霞娟
樊州龙
丁健
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中国科学院上海药物研究所
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Priority to AU2016359511A priority Critical patent/AU2016359511B2/en
Priority to CN201680070846.XA priority patent/CN108290897A/zh
Priority to JP2018526769A priority patent/JP6634519B2/ja
Priority to EP16867946.2A priority patent/EP3381919A4/en
Publication of WO2017088723A1 publication Critical patent/WO2017088723A1/zh
Priority to US15/987,458 priority patent/US10597399B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of compounds of the novel PARP inhibitors having the structure of the substituted triazolopyipazines represented by the following general formula (I), stereoisomers thereof, preparation methods thereof, intermediates thereof and preparation thereof for prevention and treatment Uses in PARP-related disease drugs, including various ischemic diseases, neurodegenerative diseases, and cancers.
  • PARP1 Poly ADP-ribose polymerase
  • PARP Poly(ADP-ribose) polymerase
  • NAD + nicotinamide adenine dinucleotide
  • PARP glandular Ribose diphosphate ribose aggregates at a specific site of various important proteins including PARP itself to form poly(ADP-ribose), PAR, which regulates the function of proteins and plays a role in the repair of DNA single-strand break damage. play a key role in.
  • PARP is a family of nuclear enzyme proteins that catalyze the synthesis of poly ADP-ribose. So far, 18 subtypes of their families have been isolated and identified, including: PARP-1, PARP-2, PARP-3, vPARP (PARP-4), Tankyrase-1 (PARP-5), Tankyrase -2 (PARP-5b), PARP-6, tiPARP (PARP-7), PARP-8, PARP-10, PARP-11, PARP-12, ZAP (PARP-13), BAL-1 (PARP-9) , BAL-2 (PARP-14), BAL-3 (PARP-15), PARP-16, PARG.
  • PARP-1 was the first member of the PARP family to be discovered and the most well-characterized, and its activity accounted for more than 90% of the total PARP activity in cells. It is a polypeptide chain of molecular weight 116kDa composed of 1014 amino acids. It includes three major functional domains: the N-terminal DNA binding domain (DBD), the self-modifying domain (AMD), and the C-terminal catalytic domain.
  • the DNA binding domain (DBD) contains two zinc finger structures and one nuclear localization sequence, which are involved in the recognition of DNA gaps.
  • the first zinc finger structure recognizes DNA single-strand and double-strand damage, and its mutation can be significant.
  • the activity of the PARP enzyme is reduced; the second zinc finger structure can only participate in the identification of DNA single strand damage.
  • the self-modifying domain contains 15 highly conserved glutamate residues as a target for self-ADP ribosylation, which is the major regulatory site.
  • the C-terminal catalytic domain is the basis for the conversion of NAD + to ADP ribose.
  • PARP-2 and PARP-1 have the highest degree of homology with 69% homology. Therefore, the currently reported PARP-1 inhibitors have comparable inhibitory activity against PARP-2.
  • PARP and BRCA are the major involved enzymes for base excision repair and homologous recombination repair, respectively.
  • BRCA1 and BRCA2 two subtypes of BRCA, often mutate and lose the ability to repair DNA damage.
  • Cell repair mainly achieves damage repair through base-repair repair of PARP enzyme. Blocking the function of PARP to repair DNA damage will cause apoptosis of cancer cells and enable cancer to be effectively treated.
  • the BRCA1 gene mutation rate is 45% in the high-incidence family of breast cancer, and the BRCA1 gene mutation rate is as high as 90% in the family with high incidence of breast cancer and ovarian cancer.
  • Some sporadic breast cancer also has BRCA1 gene mutation.
  • BRCA1/2 mutations are also found in other solid tumors such as ovarian cancer.
  • Bryant and Framer reported the use of PARP inhibitors alone in BRCA1/2-mediated homologous recombination-repairing cells, thereby inhibiting PARP-mediated base excision repair (BER) pathways. It eventually leads to synthetic lethality of tumor cells. This suggests that PARP inhibitors may be used alone to treat certain tumors.
  • the acceptor domain binds to the ADP site of the poly ADP-ribose chain.
  • the supply domain binds to NAD + , and this site can also be divided into three sub-binding domains, namely the nicotinamide-ribose binding site (NI site), the phosphate binding site (PH site), and the adenosine-ribose binding site (AD site).
  • nicotinamide such as AZD2281 (olaparib/KU-59436) developed by AstraZeneca Pharmaceuticals.
  • An oral PARP small molecule inhibitor has shown good development prospects in the treatment of ovarian cancer, breast cancer and solid tumors in combination with drugs such as cisplatin, carboplatin and paclitaxel, and is currently on the market.
  • the selective and inhibitory activity of the compound AZD2281 on PARP1 was weak, the effective dose of the inhibitory activity at the cellular level was 200 nM, and the in vivo dose above 100 mg showed significant antitumor activity.
  • the clinical daily dose is also as high as 400 mg (50 mg capsules, 8 capsules).
  • the in vivo time and half-life are shorter ( ⁇ 1 hour) and the bioavailability is lower ( ⁇ 15%).
  • the metabolite of compound AZD2281 is mainly the oxidation and removal of acyl groups of piperazine in the hydrophilic region of the molecule. Therefore, the research team introduced the structurally stable piperazine triazine fragment A in the early stage and optimized by the piperazine substituent.
  • the introduction of a methyl group is effective to increase the stability of the piperazine substituent moiety and to reduce the production of toxic products (CN103570725A). Based on this, the present invention further optimizes the triazine fragment based on the PARP enzyme and small molecule mode of action, and found that the aryl, heteroaryl or heterocycloalkyl substituted derivative B has higher activity.
  • An object of the present invention is to provide a substituted triazolopiperazine compound represented by the formula (I), a tautomer, an enantiomer, a diastereomer, a racemate, a metabolite, a metabolic precursor. , pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof.
  • Another object of the invention is to provide a process for the preparation of such compounds.
  • Another object of the invention is to provide an important intermediate for such compounds.
  • Another object of the present invention is to provide a compound of the formula (I) and a stereoisomer thereof.
  • a further object of the present invention is to provide a use of such a compound for the preparation of a medicament for preventing and treating a disease associated with PARP (ribose poly ADP-ribose polymerase), and a disease associated with PARP (ribose poly ADP-ribose polymerase) That is, various ischemic diseases (brain, umbilical cord, heart, digestive tract, retina, etc.), neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, muscular dystrophy, etc.) and cancer (breast, ovary) Cancer, liver cancer, melanoma, prostate cancer, colon cancer, stomach cancer and solid tumors, etc.).
  • ischemic diseases brain, umbilical cord, heart, digestive tract, retina, etc.
  • neurodegenerative diseases Parkinson's disease, Alzheimer's disease, muscular dystrophy, etc.
  • cancer breast, ovary
  • the present invention provides a substituted triazolopyrazine compound represented by the following formula (I), a tautomer, an enantiomer, a diastereomer, a racemate, a metabolite, a metabolic precursor, and a drug. Salts, esters, prodrugs or hydrates thereof:
  • a and B are each independently hydrogen or a substituted or unsubstituted C1-C8 alkyl group, wherein the substitution means substitution with one or more substituents selected from the group consisting of halogen, cyano, nitro, Hydroxyl and amino groups;
  • a and B together with the attached carbon atom form a substituted or unsubstituted C4-C8 aliphatic ring, a substituted or unsubstituted C6-C10 aromatic ring, substituted or unsubstituted containing 1-3 selected from N, a 4-8 membered heterocyclic ring of O and S atoms, or a substituted or unsubstituted 5-8 membered aromatic heterocyclic ring containing 1-3 selected from N, O and S atoms, wherein said substitution means selected from Substituted by one or more substituents: halogen, cyano, nitro, hydroxy and amino;
  • X is hydrogen, halogen, hydroxy or cyano
  • R is halogen, COOR 1 , substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heteroaryl ring, substituted or unsubstituted aromatic ring, wherein the heterocyclic ring, heteroaryl ring, said substitution in the aromatic ring means selected from Substituted by one or more substituents: substituted or unsubstituted C1-C8 alkyl, halogen, cyano, nitro, hydroxy, amino, C1-C6 alkoxy, C2-C6 alkylcarbonyl, C2-C6 An alkoxycarbonyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C6-C10 aryl group, wherein the substitution in the substituted C1-C8 alkyl group means one or more selected from the group consisting of Substituted by a substituent: halogen, cyano, nitro, hydroxy, amino;
  • R 1 is selected from a hydrogen atom, a C1-C8 alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, wherein said said substitution means substitution by one or more substituents selected from the group consisting of :C1-C8 alkyl, halogen, cyano, nitro, hydroxy, amino, C1-C6 alkoxy, C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkenyl, C2-C6 alkyne Base and C6-C10 aryl.
  • a and B are each independently hydrogen or a C1-C4 alkyl group
  • X is hydrogen, halogen, hydroxy or cyano
  • R is a halogen, COOR 1 , a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted aromatic ring, wherein the heterocyclic ring, the heteroaryl ring, the substituted ring in the aromatic ring means selected from the following Substituted by one or more substituents: substituted or unsubstituted C1-C4 alkyl, halogen, cyano, nitro, hydroxy, amino, C1-C4 alkoxy, C2-C4 alkylcarbonyl, C2-C4 alkane Oxycarbonyl, C2-C4 alkenyl, C2-C4 alkynyl and phenyl, wherein said substitution in said substituted C1-C4 alkyl means substituted by one or more substituents selected from : halogen, cyano, nitro, hydroxy, amino;
  • R 1 is selected from a hydrogen atom, a C1-C4 alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, wherein the substitution means substitution with one or more substituents selected from C1: -C4 alkyl, halogen, cyano, nitro, hydroxy, amino, C1-C4 alkoxy, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkenyl, C2-C4 alkynyl and Phenyl.
  • a and B are each independently hydrogen or methyl
  • a and B together with the attached carbon atoms form a benzene ring
  • X is hydrogen or halogen
  • R is halogen, COOR 1 , substituted or unsubstituted phenyl, substituted or unsubstituted 5 to 6-membered heterocyclic ring, substituted or unsubstituted 5 to 6-membered aromatic heterocyclic ring; the substitution means one selected from the group consisting of or Substituted by various substituents: methyl, halogen, trifluoromethyl, methoxy, hydroxymethyl;
  • R 1 is selected from a hydrogen atom, a methyl group, and an ethyl group.
  • the halogen may be fluorine, chlorine, bromine or iodine
  • the alkyl group is preferably a C1-C8 aliphatic alkyl group, and may be a linear alkyl group, a branched alkyl group, a spirocycloalkyl group, a fused cycloalkyl group, a bridged cycloalkyl group, an olefin alkyl group, an alkyne group, or a ring.
  • the alkenyl group may be an alkenyl group of 2 to 10 carbons such as a vinyl group, a propenyl group, a butenyl group, a styryl group, a phenylpropenyl group;
  • the alkynyl group may be an alkynyl group of 2 to 10 carbons, such as an ethynyl group, a propynyl group, a butynyl group, a phenylethynyl group, a phenylpropynyl group;
  • the cycloalkyl group may be a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl group comprises from 3 to 10 One carbon atom.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • the spiro group refers to a 5- to 20-membered polycyclic group sharing a carbon atom (spiro atom) between the single rings, which may contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include
  • the fused cycloalkyl group means 5 to 20 members, and each ring in the system shares an adjacent carbon atomic all-carbon polycyclic group with other rings in the system, wherein one or more rings may contain one or more Double keys, but none of them have a complete ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl groups include
  • the bridged cycloalkyl group means 5 to 20 members, and any two rings share two all-carbon polycyclic groups of carbon atoms which are not directly bonded, and these may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring.
  • the heterocyclic group refers to a saturated or partially saturated monocyclic or polycyclic cyclic hydrocarbon substituent including a 3 to 12 membered atom containing one or more heteroatoms (nitrogen, oxygen, sulfur) saturated or unsaturated.
  • Monocyclic, cyclo, spiro, fused, bridged, etc. including but not limited to morpholine, piperidine, piperazine, N-alkyl or acyl substituted piperazine ring, homopiperazine ring, N-alkyl or acyl substituted homopiperazine ring, pyrrole, tetrahydropyrrole, 7H-indole, and the like.
  • the aryl group refers to a 6 to 10 membered all-carbon monocyclic or fused polycyclic (ie, a ring sharing a pair of adjacent carbon atoms) groups having a polycyclic group of a conjugated ⁇ -electron system.
  • phenyl and naphthyl For example phenyl and naphthyl.
  • the aryl ring may be fused to a heterocyclic, heteroaryl or cycloalkyl ring, non-limiting examples containing benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzo Pyrazole, quinoline, benzopyrene, benzodihydrofuran.
  • the heteroaryl group refers to a heteroaromatic system comprising from 1 to 4 heteroatoms, from 5 to 14 atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably a 5- to 10-membered ring.
  • the heteroaryl group is preferably a 5- or 6-membered ring such as a furyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group or the like.
  • the heteroaryl group can be fused to an aryl group, a heterocyclic group or a cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring.
  • triazolopiperazines of formula I may also exist in the form of tautomers.
  • the tautomeric form of the substituted triazolopyipazine compound represented by the formula (I) may include, but is not limited to, a structure represented by the following formula (II), wherein X, A, B, and R are as defined above. Description:
  • Typical compounds of the invention include, but are not limited to, the following compounds:
  • the compound S and the compound D are subjected to a condensation reaction to obtain a substituted triazolopyrazine compound represented by the formula (I); preferably, the compound S and the compound D are carried out in a suitable solvent in the presence of a condensing agent and a suitable base.
  • the catalyst can also be used as needed.
  • Compound D can be prepared by the following reaction route:
  • the compound D1 and the compound D2 are dissolved in a C1-C5 alcohol, ground with an oxidizing agent, and then the ground powder is dissolved in dichloromethane, washed, concentrated, and then dissolved in a C1-C5 alcohol, a catalyst is added, and hydrogen is introduced. Compound D is produced.
  • the C1-C5 alcohol is selected from one or more of methanol, ethanol, isopropanol, n-propanol, tert-butanol and n-butanol, preferably from one of methanol and ethanol Or a plurality, optimally selected from the group consisting of: the oxidizing agent is selected from one or more of [bis(trifluoroacetoxy)iodo]benzene and iodobenzene diacetic acid; and the catalyst is selected from the group consisting of palladium/carbon. One or more of Raney nickel and platinum carbon.
  • the compound S and the compound D are carried out in a suitable solvent in the presence of a condensing agent and a suitable base, and a catalyst may be added as needed;
  • the condensing agent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide ( DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or its hydrochloride (EDC or EDC.HCl), carbonyl diimidazole (CDI), N, N'- Diisopropylcarbodiimide (DIC), O-[2-oxo-1(2H)-pyridyl]-N,N,N',N'-tetramethyluronium tetrafluoroborate, O- Benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azobenzotriazole)-N,N
  • a preferred preparation method may include the following steps:
  • the obtained compound can be further converted by a hydrolysis reaction or the like.
  • R is a C2-C4 alkoxycarbonyl-substituted heterocyclic ring, a C2-C4 alkoxycarbonyl-substituted heteroaryl ring, or a C2-C4 alkoxycarbonyl-substituted aromatic ring
  • it may undergo a hydrolysis reaction to form an unsubstituted group.
  • a precursor, a pharmaceutically acceptable salt, an ester, a prodrug or a hydrate thereof as a novel highly selective PARP1 inhibitor for the preparation and use thereof for prevention and/or treatment with PARP (poly ADP-ribose polymerase)
  • PARP poly ADP-ribose polymerase
  • drugs for related diseases namely various ischemic diseases (brain, umbilical cord, heart, digestive tract, retina, etc.), neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, muscular dystrophy) Etc.) and cancer (breast cancer, ovarian cancer, liver cancer, melanoma, prostate cancer, colon cancer, gastric cancer, and other solid tumors, etc.).
  • a pharmaceutical composition comprising a therapeutically effective amount of a substituted triazolopyrazine compound of the formula (I), a tautomer thereof, an enantiomer thereof, One or more of a diastereomer, a racemate, a metabolite, a metabolic precursor, a pharmaceutically acceptable salt, an ester, a prodrug or a hydrate thereof, and optionally further comprising a pharmaceutically acceptable carrier Or an excipient.
  • a PARP1 inhibitor comprising a therapeutically effective amount of the formula (I) Substituted triazolopyipazine compounds, tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, pharmaceutically acceptable salts, esters, prodrugs or One or more of its hydrates, and may optionally further comprise a pharmaceutically acceptable carrier or excipient.
  • Figure 1 is an HPLC chromatogram of Compound S13
  • Figure 2 is a HPLC chromatogram of the compound S13-(-);
  • Figure 3 is a HPLC chromatogram of the compound S13-(+).
  • HBTU is benzotriene Azole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIPEA is diisopropylethylamine
  • DMF is N,N-dimethylformamide.
  • the starting materials D1-1 (1 eq) and D2 (1 eq) were dissolved in ethanol, and stirred at room temperature overnight. After the reaction was completed, the solvent was removed, and the mixture was ground for 2 minutes by adding iodobenzenediacetic acid (1.5 eq), and then the ground powder was used. Dissolve in dichloromethane, wash the dichloromethane solution with saturated sodium sulfite solution, wash with saturated brine, concentrate and spin dry, then dissolve with ethanol, add palladium / carbon (0.1 eq), pass hydrogen, react at 50 ° C for 12 hours, complete reaction After that, the palladium/carbon was filtered off and dried to give the amine 1-1.
  • the intermediate S1 was dissolved in ethanol, and then 6N hydrochloric acid was added thereto, and the mixture was stirred at room temperature overnight, then the solvent was evaporated, and then aqueous ammonia was stirred for 30 minutes. After completion of the reaction, aqueous ammonia was removed and column chromatography gave white solid S3.
  • the S4 synthesis method is the same as that of S3, and the raw material S1 is replaced with S2.
  • the synthesis of the starting material 8-1 is the same as that of 1-1, and the raw material D1-1 is replaced by D1-6.
  • the synthesis of the starting material 10-1 is the same as that of 1-1, and the raw material D1-1 is replaced by D1-8.
  • the synthesis of the starting material 14-1 is the same as that of 1-1, and the raw material D1-1 is replaced by D1-12.
  • the synthesis of the starting material 15-1 is the same as that of 1-1, and the raw material D1-1 is replaced by D1-13.
  • the synthesis of the starting material 19-1 is as follows: D2 (1 eq) is dissolved in trimethyl orthoformate and refluxed overnight. After the reaction is completed, the solvent is removed, dissolved in dichloromethane, and then N-iodosuccinyl is added.
  • the imine (1 eq) was reacted at room temperature for 1 hour, a 1N hydrochloric acid solution was added, the methylene chloride layer was separated, and the methylene chloride layer was washed with brine, dried over anhydrous sodium sulfate, filtered, filtered, Dissolve, add palladium/carbon (0.1 eq), pass hydrogen, react at 50 ° C overnight, after completion of the reaction, filter off palladium / carbon, spin dry to obtain amine 19-1.
  • the synthesis of the starting material 20-1 is the same as that of 1-1, and the raw material D1-1 is replaced by D1-17.
  • the synthesis of the starting material 21-1 is the same as that of 1-1, and the raw material D1-1 is replaced by D1-18.
  • the S23 synthesis method is the same as that of S1, and the compound 1-1 is replaced with the compound 13-1, and the compound Sa is replaced with the compound Sb.
  • the S28 synthesis method is the same as that of S1, and the compound 1-1 is replaced with the compound 13-1, and the compound Sa is replaced with the compound Sc.
  • the S30 synthesis method is the same as that of S1, and the compound 1-1 is replaced with the compound 15-1, and the compound Sa is replaced with the compound Sd.
  • the S31 synthesis method is the same as that of S1, and the compound 1-1 is replaced with the compound 15-1, and the compound Sa is replaced with the compound Se.
  • the S32 synthesis method is the same as that of S1, and the compound 1-1 is replaced with the compound 13-1, and the compound Sa is replaced with the compound Se.
  • the full-length plasmid of PARP1 was amplified by PCR, digested, ligated and transformed into DH5a to obtain HTb-PARP1 positive clones. After extraction and restriction enzyme digestion, the cells were transformed into DH10Bac, and then Bacmid/PARP was identified by PCR and sequencing. Transfection of TNI was performed. The virus was collected, the cells were lysed, and the PARP1 protein was purified by affinity chromatography and identified by Western blotting.
  • the substrate histone, NAD + and DNA and the expressed PARP1 enzyme are coated, placed in a 96-well plate reaction system, optimized and finally determined various reaction conditions, and the reaction product PAR is reacted with PAR mAb, and after adding the secondary antibody, The OD value was read with a microplate reader, and the degree of inhibition of PARP1 enzyme activity was calculated accordingly, as shown in Table 1.
  • AZD2281 (Olapani) is the first PARP inhibitor listed in the international pharmaceutical company AstraZeneca in 2014, which is a positive control in this test.
  • the compound of the present invention can be used as a potent novel PARP-1 inhibitor for the prevention and treatment of diseases associated with PARP (ribose poly ADP-ribose polymerase), such as ischemic diseases, neurodegenerative diseases, and cancer.
  • diseases associated with PARP ribose poly ADP-ribose polymerase
  • Figure 1 is an HPLC chromatogram of Compound S13
  • Figure 2 is a HPLC chromatogram of the compound S13-(-);
  • Figure 3 is a HPLC chromatogram of the compound S13-(+).
  • the new compound not only has high activity at the PARP1 enzyme level, but also has a strong inhibitory effect on the proliferation of BRCA-deficient MDA-MB-436 and Capan-1 cells. Most of the compound activity is positive compound AZD2281. 10 times more.
  • such an aromatic ring- or aromatic heterocyclic-substituted triazolopiperazine compound represented by the compound S13 has an extremely high PARP1 enzyme inhibitory activity, and the cell activity is also significantly higher than that of the positive compound AZD2281.
  • the presence of a methyl substituent on the ring also significantly increases the selectivity of the compound for the telomerase TNKS1 and TNKS2, with a low risk of cardiotoxicity. Therefore, these compounds are useful as novel high-selective ribose poly ADP-ribose polymerase-1 (PARP1) inhibitors for the prevention and/or treatment of PARP-related diseases.
  • PARP1 novel high-selective ribose poly ADP-ribose polymerase-1

Abstract

本发明涉及一类由如通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体和可药用的盐、酯、前药或其水合物，其制备方法，中间体及其在制备预防和治疗与PARP相关疾病的药物中的用途，所述与PARP相关疾病包括各种缺血性的疾病、神经退行性疾病和癌症。

Description

一类取代三唑并哌嗪类PARP抑制剂及其制备方法和用途 技术领域
本发明涉及一类由如下通式(I)表示的具有取代三唑并哌嗪类结构的新型PARP抑制剂的化合物、其立体异构体、其制备方法、中间体及其在制备预防和治疗与PARP相关疾病药物中的用途，所述与PARP相关疾病包括各种缺血性的疾病、神经退行性疾病和癌症。
背景技术
1、PARP家族和结构特征
聚腺苷二磷酸核糖聚合酶(PARP)，自1963年Chambon及其小组首次发现距今已有50年的历史，其在损伤修复和维持基因组的稳定性方面的重要作用引起了众多学者的关注。其中，PARP1发现最早、结构最典型、研究最多，它在DNA修复、细胞凋亡和增殖分化等方面发挥着关键作用，经常被认为是“DNA的守护天使”。聚腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase,PARP]存在于真核细胞中，催化NAD+(烟酰胺腺嘌呤二核苷酸)释放腺苷二磷酸核糖，并进一步催化腺苷二磷酸核糖在多种重要蛋白包括PARP本身的特定位点聚合形成聚腺苷二磷酸核糖[Poly(ADP-ribose)，PAR]，调控蛋白的功能，在DNA单链断裂损伤修复过程中发挥关键作用。
PARP是一类催化聚腺苷二磷酸核糖合成的细胞核酶蛋白家族。到目前为止，其家族中的18个亚型被陆续分离、鉴定出来，包含：PARP-1、PARP-2、PARP-3、vPARP(PARP-4)、Tankyrase-1(PARP-5)、Tankyrase-2(PARP-5b)、PARP-6、tiPARP(PARP-7)、PARP-8、PARP-10、PARP-11、PARP-12、ZAP(PARP-13)、BAL-1(PARP-9)、BAL-2(PARP-14)、BAL-3(PARP-15)、PARP-16、PARG。其中PARP-1是最早被发现，也是特性了解最清楚的PARP家族成员，其活性占到细胞中PARP总酶活性的90％以上。它是由1014个氨基酸组成的一条分子量为116kDa的多肽链。包括三个主要的功能性结构域：N端的DNA结合域(DBD)，自身修饰域(AMD)和C端的催化域。DNA的结合域(DBD)包含两个锌指结构和一个核定位序列，这两个锌指结构参与识别DNA缺口，第一个锌指结构识别DNA单链和双链损伤，它的突变能够显著降低PARP酶的活性；第二个锌指结构只能参与识别DNA单链的损伤。自身修饰域(AMD)含有15个高度保守的谷氨酸残基作 为自身ADP核糖基化的靶点，它是主要的调节部位。C端的催化域是把NAD+转化为ADP核糖的基础。
在PARP家族中，PARP-2和PARP-1的同源程度最高，具有69％的同源性。因此，目前报道的PARP-1抑制剂均对PARP-2具有相当的抑制活性。
2、PARP与疾病的治疗
在正常情况下，细胞主要通过碱基切处修复或同源重组来修复DNA损伤。PARP和BRCA分别是碱基切除修复和同源重组修复的主要参与酶。在多数卵巢癌和三阴性乳腺癌病人中，BRCA的两个亚型BRCA1和BRCA2往往发生突变而失去修复DNA损伤的能力，细胞修复主要通过PARP酶参与的碱基切补修复实现损伤修复，若阻断PARP修复DNA损伤的功能，将引起癌细胞的凋亡，使癌症得到有效治疗。据统计，在乳腺癌高发家族中BRCA1基因突变率达45％，在乳腺癌与卵巢癌均高发的家族中BRCA1基因突变率高达90％，部分散发性乳腺癌也有BRCA1基因突变。此外，BRCA1/2突变还见于卵巢癌等其它实体瘤。2005年Bryant和Framer分别报道了对BRCA1/2介导的同源重组修复功能缺失的细胞单独使用PARP抑制剂，从而对PARP介导的碱基切除修复(base excision repair,BER)通路产生抑制作用，最终导致肿瘤细胞协同致死(synthetic lethality)。这暗示着PARP抑制剂可能存在单独用于治疗某些肿瘤的可能，这一研究成果迅速引起了医药公司和学术界的广泛关注，由此开启了以PARP抑制剂作为高选择性抗肿瘤药物研发的新时代。目前，PARP1已成为近年来抗肿瘤药物研究的前沿分子靶标。
3、PARP抑制剂
Armin等以PARP的底物NAD+为模板进行研究发现PARP-1的催化活性部位可以大致分为供给和接受两个域。接受域与聚腺苷二磷酸核糖链的ADP部位结合。供给域与NAD+结合，此部位还可以分成三个亚结合域，分别为烟酰胺-核糖结合部位(NI site)、磷酸结合部位(PH site)和腺苷-核糖结合部位(AD site)。大部分的PARP抑制剂都是与PARP的NI site相互作用，竞争性抑制NAD+的，因此与烟酰胺的结构具有相似性,如阿斯利康制药公司开发的AZD2281(olaparib/KU-59436)就是一种口服PARP小分子抑制剂，在与顺铂、卡铂、紫杉醇等药物联用治疗卵巢癌、乳腺癌和实体瘤的研究中显示了良好的开发前景，目前已经上市。
Figure PCTCN2016106707-appb-000001
然而，化合物AZD2281对PARP1的选择性和抑制活性较弱，在细胞水平的抑制活性的有效剂量在200nM，体内剂量在100mg以上才显示明显的抗肿瘤活性。临床上每日剂量也高达400mg(50mg胶囊，8粒)。体内作用时间和半衰期较短(<1小时)，生物利用率也较低(<15％)。化合物AZD2281的代谢产物主要是分子亲水区的哌嗪氧化和脱除酰基，因此，本研究团队在前期中通过引入结构稳定的哌嗪并三嗪片段A，并通过哌嗪取代基的优化发现引入甲基可有效增加哌嗪取代基部分的稳定性和降低毒性产物的产生(CN103570725A)。基于此，本发明基于PARP酶和小分子作用模式进一步对三嗪片段进行优化，发现芳基、杂芳基或杂环烷基取代衍生物B具有较高的活性。
发明内容
本发明的一个目的是提供通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物。
本发明的另一目的是提供该类化合物的制备方法。
本发明的另一目的是提供该类化合物的重要中间体。
本发明的另一目的是提供包含通式(I)化合物和其立体异构体。
本发明的又一目的是提供该类化合物在制备预防和治疗与PARP(核糖多聚ADP-核糖聚合酶)相关疾病的药物中的用途，与PARP(核糖多聚ADP-核糖聚合酶)相关疾病即各种缺血性的疾病(大脑、脐带、心脏、消化管、视网膜等)、神经退行性疾病(帕金森氏症、阿尔茨海默病、肌肉萎缩症等)和癌症(乳腺癌、卵巢癌、肝癌、黑素瘤、前列腺癌、结肠癌、胃癌和实体瘤等)。
本发明提供如下通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物：
Figure PCTCN2016106707-appb-000002
其中，
Y为
Figure PCTCN2016106707-appb-000003
或者
Figure PCTCN2016106707-appb-000004
A和B各自独立地为氢或者取代或未取代的C1-C8烷基，其中，所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
或者，A和B与相连接的碳原子一起形成取代或未取代的C4-C8脂族环，取代或未取代的C6-C10芳环，取代或未取代的含有1-3个选自N、O和S原子的4-8元杂环，或者取代或未取代的含有1-3个选自N、O和S原子的5-8元芳杂环，其中，所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
X为氢、卤素、羟基或氰基；
R为卤素，COOR1，取代或未取代杂环，取代或未取代杂芳环，取代或未取代芳环，其中杂环，杂芳环，芳环中的所述取代是指被选自如下的一种或多种取代基所取代：取代或未取代的C1-C8烷基、卤素、氰基、硝基、羟基、氨基、C1-C6烷氧基、C2-C6烷羰基、C2-C6烷氧羰基、C2-C6链烯基、C2-C6炔基和C6-C10芳基，其中所述的取代的C1-C8烷基中的取代是指被选自如下的一种或多种的取代基所取代：卤素、氰基、硝基、羟基、氨基；
R1选自氢原子、C1-C8烷基、取代或未取代芳基或者取代或未取代杂环基，其中所述所述取代是指被选自如下的一种或多种取代基所取代：C1-C8烷基、卤素、氰基、硝基、羟基、氨基、C1-C6烷氧基、C2-C6烷羰基、C2-C6烷氧羰基、C2-C6链烯基、C2-C6炔基和C6-C10芳基。
进一步优选地，在通式(I)化合物中，
Y为
Figure PCTCN2016106707-appb-000005
或者
Figure PCTCN2016106707-appb-000006
A和B各自独立地为氢或C1-C4烷基；
或者，A和B与相连接的碳原子一起形成取代或未取代的C4-C6脂族环或者取代或未取代的C6-C8芳环，其中，所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
X为氢、卤素、羟基或氰基；
R为卤素，COOR1，取代或未取代杂环，取代或未取代杂芳环，取代或未取代芳环，其中杂环，杂芳环，芳环中所述取代是指被选自如下的一种或多种取代基所取代：取代或未取代的C1-C4烷基、卤素、氰基、硝基、羟基、氨基、C1-C4烷氧基、C2-C4烷羰基、C2-C4烷氧羰基、C2-C4链烯基、C2-C4炔基和苯基，其中所述的取代的C1-C4烷基中所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基、氨基；
R1选自氢原子、C1-C4烷基、取代或未取代芳基或者取代或未取代杂环基，其中所述取代是指被选自如下的一种或多种取代基所取代：C1-C4烷基、卤素、氰基、硝基、羟基、氨基、C1-C4烷氧基、C2-C4烷羰基、C2-C4烷氧羰基、C2-C4链烯基、C2-C4炔基和苯基。
特别优选地，在通式(I)化合物中，
Y为
Figure PCTCN2016106707-appb-000007
或者
Figure PCTCN2016106707-appb-000008
A和B各自独立地为氢或甲基；
或者，A和B与相连接的碳原子一起形成苯环；
X为氢或卤素；
R为卤素，COOR1，取代或未取代苯基、取代或未取代5至6元杂环、取代或未取代5至6元芳杂环；所述取代是指被选自如下的一种或多种取代基所取代：甲基、卤素、三氟甲基、甲氧基、羟甲基；
R1选自氢原子、甲基、乙基。
在本发明中，所述卤素可以为氟、氯、溴、碘；
所述烷基优选为C1～C8脂肪族烷基，可以是直链烷基、支链烷基、螺环烷基、稠环烷基、桥环烷基、烯烷基、炔烷基、环烷基、环烯基、环炔基、烷氧烷基、烷氧酰基烷基、环烷基烷基，非限制性地包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、烯丙基、炔丙基、环丁烯基、环己烯基；
所述烯基可以为2-10个碳的烯基，如乙烯基、丙烯基、丁烯基、苯乙烯基、苯丙烯基；
所述炔基可以为2-10个碳的炔基，如乙炔基、丙炔基、丁炔基、苯乙炔基、苯丙炔基；
所述环烷基可以为饱和或者部分不饱和单环或多环环状烃取代基，其中包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基包含3至10个碳原子。单环环烷基非限制实施例包含环丙基、环丁基、环戊烯基、环己基、环辛基等。多环环烷基包括螺环、稠环和桥环的环烷基。
所述螺环基指5至20元，单环之间共用一个碳原子(螺原子)的多环基团，这些可以含有一个或者多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制实施例包含
Figure PCTCN2016106707-appb-000009
所述稠环烷基指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环极有完全的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或者三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实施例包含
Figure PCTCN2016106707-appb-000010
所述桥环烷基指5至20元，任意两个环公用两个不直接连接的碳原子的全碳多环基团，这些可以包含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或者多环桥环烷基，优选为双环、三环或四环，更优选为双环或者三环。
所述杂环基指饱和或部分饱和单环或者多环环状烃取代基，其中包括3至12元原子，其中含有一个或多个杂原子(氮、氧、硫)的饱和或者非饱和的单环、并环、螺环、稠环、桥环等，包含但不局限于吗啉环，哌啶环，哌嗪环，N-烷基或酰基取代的哌嗪环，高哌嗪环，N-烷基或酰基取代的高哌嗪环，吡咯，四氢吡咯，7H-嘌呤等。
所述芳基指6至10元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环基团。例如苯基和萘基。所述芳基环可以稠合与杂环基、杂芳基或环烷基环上，非限制性实施例含苯并咪唑、苯并噻唑、苯并恶唑、苯并异恶唑、苯并吡唑、喹啉、苯并吲哚、苯并二氢呋喃。
所述杂芳基指包含1至4个杂原子，5至14个原子的杂芳族体系，其中杂原子包括氧、硫和氮。优选为5至10元环。杂芳基优选为是5元或6元环，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述的杂芳基可以稠合于芳基、杂环基或者环烷基环上，其中与母体结构连接在一起的环为杂芳基环。
本领域普通技术人员可以理解，通式I表示的三唑并哌嗪类化合物还可存在互变异构体的形式。
当Y为
Figure PCTCN2016106707-appb-000011
时，通式(I)表示的取代三唑并哌嗪类化合物的互变形式可包括但不限于由如下通式(II)表示的结构，其中X、A、B、R的定义同前所述：
Figure PCTCN2016106707-appb-000012
本发明的典型化合物包括，但不限于以下化合物：
Figure PCTCN2016106707-appb-000013
Figure PCTCN2016106707-appb-000014
Figure PCTCN2016106707-appb-000015
Figure PCTCN2016106707-appb-000016
Figure PCTCN2016106707-appb-000017
Figure PCTCN2016106707-appb-000018
通式(I)所示的取代三唑并哌嗪类化合物的制备方法，其反应路线如下：
Figure PCTCN2016106707-appb-000019
其中，X，Y，R的定义与前述相同；
化合物S与化合物D经缩合反应得到通式(I)所示的取代三唑并哌嗪类化合物；优选的，化合物S与化合物D在缩合剂和合适的碱存在下，在合适的溶剂中进行；还可根据需要使用催化剂。
其中，
原料S的合成参考文献J.Med.Chem.2008,51,6581–6591,Bioorg.Med.Chem.Lett.2010,20,1100-1105,或Bioorg.Med.Chem.Lett.2008,18,3942-3945,CN201110082475。原料D的合成参考文献Green.Chem.2004,6,156-157,J.Med.Chem.2008,51,589–602。
化合物D可通过如下反应路线制备得到：
Figure PCTCN2016106707-appb-000020
将化合物D1与化合物D2溶于C1-C5醇中，加入氧化剂研磨，然后将研磨后的粉末用二氯甲烷溶解，洗涤后浓缩，然后用C1-C5醇溶解，加入催化剂，通入氢气，反应生成化合物D。
一种具体的制备通式(I)所示的取代三唑并哌嗪类化合物的方法如下：
Figure PCTCN2016106707-appb-000021
Figure PCTCN2016106707-appb-000022
(1)将化合物D1与化合物D2溶于C1-C5醇中，室温搅拌过夜，反应完全后，旋除溶剂，加入氧化剂研磨，然后将研磨后的粉末用二氯甲烷溶解，用饱和亚硫酸钠溶液洗涤二氯甲烷溶液，饱和食盐水洗，浓缩旋干，然后用C1-C5醇溶解，加入催化剂，通入氢气，0至80摄氏度下反应1-48小时，反应完全后，滤除催化剂，旋干，得到胺D；其中，所述的C1-C5醇选自甲醇，乙醇，异丙醇，正丙醇，叔丁醇和正丁醇中的一种或多种，优选自甲醇和乙醇中的一种或多种，最优选自乙醇；所述的氧化剂选自[双(三氟乙酰氧基)碘]苯和碘苯二乙酸中的一种或多种；所述的催化剂选自钯/碳，雷尼镍和铂碳中的一种或多种。
(2)化合物S与化合物D在缩合剂和合适的碱存在下，在合适的溶剂中进行，可根据需要加入催化剂；所述缩合剂选自N,N'-二环己基碳二亚胺(DCC)、N-(3-二甲氨基丙基)-N'-乙基碳二亚胺或其盐酸盐(EDC或EDC.HCl)，碳酰二咪唑(CDI)、N,N'-二异丙基碳二亚胺(DIC)、O-[2-氧-1(2H)-吡啶基]-N,N,N',N'-四甲基脲四氟硼酸酯、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)、O-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、O-(6-氯-1H-苯并三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)和六氟磷酸苯并三唑-1-基-氧基三吡咯烷基(PyBOP)中的一种或多种，优选自苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯，O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯和O-[2-氧-1(2H)-吡啶基]-N,N,N',N'-四甲基脲四氟硼酸酯中的一种或多种；所述碱选自三乙胺、二乙胺、三正丁胺、三丙基胺、二异丙基胺、二异丙基乙胺(DIPEA)、三甲胺、吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶、哌啶、吡咯烷、喹啉、吗啉、N-甲基吗啉(NMM)、N-乙基吗啉、N-甲基哌啶、二异丙基胺、二异丙基乙胺、1,8-二氮杂环[5,4,0]十一烯-7和1,5-二氮杂二环[4.3.0]-壬-5-烯中的一种或多种，优选自三乙胺和二异丙基乙胺中的一种或多种；反应溶剂选自苯、二甲苯、甲苯、二氯甲烷、氯仿、四氯化碳、四氢呋喃、2-甲基四氢呋喃、乙醚、丙酮、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二甲基乙酰胺、乙腈、二甲亚砜中的一种或多种， 更优选为二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的一种或多种；所述催化剂选自1-羟基-苯并三氮唑(HOBt)和4-二甲基氨基吡啶(DMAP)中的一种或多种；反应温度选自-10℃～100℃，优选自15℃～40℃之间；反应时间选自1-48小时，优选自6-24小时。
具体的，一种优选的制备方法可以包括如下步骤：
(1)将化合物D1(1eq)与化合物D2(1eq)溶于乙醇中，室温搅拌过夜，反应完全后，旋除溶剂，加入碘苯二乙酸(1.5eq)研磨2分钟，然后将研磨后的粉末用二氯甲烷溶解，用饱和亚硫酸钠溶液洗涤二氯甲烷溶液，饱和食盐水洗，浓缩旋干，然后用乙醇溶解，加入钯/碳(0.1eq)，通入氢气，50摄氏度下反应12小时，反应完全后，滤除钯/碳，旋干，得到胺D；
(2)将化合物S(1eq)与化合物D(1eq)溶于DMF中，冰浴下依次加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯、二异丙基乙胺，逐渐升温至室温反应12小时；于冰浴下加入水，用二氯甲烷萃取，二氯甲烷层用饱和食盐水洗，干燥，蒸除溶剂，通过柱色谱分离得到通式(I)表示的取代三唑并哌嗪类化合物。
所制得的化合物还可以经过水解反应等进一步发生转化。比如：当R为C2-C4烷氧羰基取代的杂环、C2-C4烷氧羰基取代的杂芳环、或C2-C4烷氧羰基取代的芳环时，可以经过水解反应，分别生成未取代的杂环、未取代的杂芳环、或未取代的芳环。
本发明的再一个方面还提供了通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物的用途，其作为新型高选择性PARP1抑制剂，在制备用于预防和/或治疗与PARP(聚腺苷二磷酸核糖聚合酶)相关疾病的药物中的用途，即各种缺血性的疾病(大脑、脐带、心脏、消化管、视网膜等)、神经退行性疾病(帕金森氏症、阿尔兹海默病、肌肉萎缩症等)和癌症(乳腺癌、卵巢癌、肝癌、黑素瘤、前列腺癌、结肠癌、胃癌和其它实体瘤等)。
在本发明的又一个方面，提供了一种药物组合物，其包含治疗有效量的通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物中的一种或多种，并可任选进一步包含药学上可接受的载体或赋形剂。
在本发明的又一个方面，提供了一种PARP1抑制剂，其包含治疗有效量的通式(I) 所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物中的一种或多种，并可任选进一步包含药学上可接受的载体或赋形剂。
附图说明
图1为化合物S13的HPLC谱图；
图2为化合物S13-(-)HPLC谱图；
图3为化合物S13-(+)HPLC谱图。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但这些实施例并不限制本发明的范围。
一、制备实施例
1H-NMR用Varian MercuryAMX300型仪测定；MS用VG ZAB-HS或VG-7070型仪测定，除注明外均为EI源(70ev)；所有溶剂在使用前均经过重新蒸馏，所使用的无水溶剂均是按标准方法干燥处理获得；除说明外，所有反应均是在氮气保护下进行并TLC跟踪，后处理时均经饱和氯化钠水溶液洗涤和无水硫酸钠干燥过程；产品的纯化除说明外均使用硅胶(200～300目)柱色谱法；其中硅胶(200～300目)由青岛海洋化工厂生产，GF254薄层硅胶板由烟台江友硅胶开发有限公司生产。
1化合物S1的合成
Figure PCTCN2016106707-appb-000023
其中，原料S-a的合成参考文献J.Med.Chem.2008,51,6581–6591，原料1-1的合成参考文献Green.Chem.2004,6,156-157,J.Med.Chem.2008,51,589–602，HBTU是苯并三 氮唑-N,N,N',N'-四甲基脲六氟磷酸酯，DIPEA是二异丙基乙胺，DMF是N,N-二甲基甲酰胺。
将原料D1-1(1eq)与D2(1eq)溶于乙醇中，室温搅拌过夜，反应完全后，旋除溶剂，加入碘苯二乙酸(1.5eq)研磨2分钟，然后将研磨后的粉末用二氯甲烷溶解，用饱和亚硫酸钠溶液洗涤二氯甲烷溶液，饱和食盐水洗，浓缩旋干，然后用乙醇溶解，加入钯/碳(0.1eq)，通入氢气，50摄氏度下反应12小时，反应完全后，滤除钯/碳，旋干，得到胺1-1。1H NMR(300MHz,Chloroform-d)δ4.32–4.00(m,4H),3.17(dd,J＝13.3,4.2Hz,1H),3.04(d,J＝12.5Hz,1H),2.79(d,J＝31.5Hz,2H),2.07(s,2H),1.94–1.75(m,3H),1.50–1.39(m,9H).
将中间体S(1eq)与3-环丙基-5-甲基-5,6,7,8-四氢[1,2,4]三唑[4,3-a]哌嗪(胺1-1)(1eq)溶于DMF中，冰水浴下，依次加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(1.5eq)，DIPEA(2eq)，逐渐升温至室温反应12小时。于冰浴下加入水，用二氯甲烷萃取3次，合并二氯甲烷层，并用饱和食盐水洗二氯甲烷层，干燥，蒸除溶剂，柱层析得白色固体S1。1H NMR(300MHz,Chloroform-d)δ11.07(s,1H),8.43(d,J＝7.3Hz,1H),7.71(dt,J＝19.3,7.3Hz,3H),7.32(d,J＝8.4Hz,2H),7.07(d,J＝8.8Hz,1H),4.85(d,J＝15.5Hz,2H),4.50(d,J＝47.4Hz,2H),4.24(d,J＝21.6Hz,4H),3.37(d,J＝13.7Hz,1H),2.86(s,3H),2.13–1.67(m,5H),1.44(s,9H).
2化合物S2的合成
Figure PCTCN2016106707-appb-000024
其中原料2-1的合成方法与1-1相同，将原料D1-1替换为D1-2。2-1的分析数据：1H NMR(300MHz,Chloroform-d)δ5.09(dd,J＝6.7,3.2Hz,1H),4.47–3.78(m,5H),3.27– 2.89(m,2H),1.80(s,3H),1.49(d,J＝42.3Hz,15H).
S2合成方法与S1相同，将化合物1-1替换为化合物2-1。S2的分析数据：1H NMR(300MHz,Chloroform-d)δ10.66(s,1H),8.44(d,J＝7.3Hz,1H),7.94–7.59(m,3H),7.34(d,J＝6.0Hz,2H),7.07(t,J＝8.8Hz,1H),5.18–5.03(m,1H),4.85(d,J＝15.8Hz,2H),4.69–4.39(m,2H),4.28(s,3H),4.04(s,1H),3.30(d,J＝14.0Hz,1H),1.75(d,J＝14.5Hz,4H),1.59–0.98(m,14H).
3化合物S3的合成
Figure PCTCN2016106707-appb-000025
将中间体S1溶于乙醇中，然后加入6N的盐酸，室温搅拌过夜，然后旋除溶剂，加入氨水搅拌30分钟，反应结束后旋除氨水，柱层析得到白色固体S3。1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),8.26(d,J＝7.8Hz,1H),8.11–7.75(m,3H),7.61–7.22(m,3H),5.42(d,J＝17.4Hz,0.5H),4.88–4.47(m,4H),4.36(s,2H),3.95–3.60(m,8H),3.50(s,0.5H),1.25–1.00(m,3H).
4化合物S4的合成
Figure PCTCN2016106707-appb-000026
S4合成方法与S3相同，将原料S1替换为S2。S4的分析数据：1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),8.26(d,J＝7.7Hz,1H),8.09–7.75(m,3H),7.65–7.19(m,3H),5.39(d,J＝17.9Hz,1H),4.85–4.44(m,3H),4.35(s,2H),3.41(dd,J＝81.2,18.2Hz,4H),3.04(s,2H),2.30(s,6H),1.40–0.96(m,3H).
5化合物S5的合成
Figure PCTCN2016106707-appb-000027
其中原料5-1的合成与1-1相同，将原料D1-1替换为D1-3。5-1的分析数据：1H NMR(300MHz,Chloroform-d)δ5.05(d,J＝7.8Hz,1H),4.29(d,J＝17.3Hz,2H),4.05(d,J＝16.7Hz,1H),3.87–3.64(m,2H),3.45(s,1H),3.18–2.96(m,2H),1.91(s,4H),1.42(s,9H).
S5合成方法与S1相同，将化合物1-1替换为化合物5-1。S5的分析数据：1H NMR(300MHz,Chloroform-d)δ10.49(d,J＝18.1Hz,1H),8.44(d,J＝7.2Hz,1H),7.89–7.55(m,3H),7.33(s,2H),7.07(t,J＝8.6Hz,1H),5.15–4.75(m,2H),4.54(s,2H),4.27(d,J＝4.6Hz,2H),3.73–3.23(m,3H),2.08(d,J＝73.5Hz,5H),1.62–1.05(m,14H).
6化合物S6的合成
Figure PCTCN2016106707-appb-000028
其中原料6-1的合成与1-1相同，将原料D1-1替换为D1-4。6-1的分析数据：1H NMR(300MHz,Chloroform-d)δ5.05(d,J＝7.8Hz,1H),4.29(d,J＝17.3Hz,2H),4.05(d,J＝16.7Hz,1H),3.87–3.64(m,2H),3.45(s,1H),3.18–2.96(m,2H),1.91(s,4H),1.42(s,9H).
S6合成方法与S1相同，将化合物1-1替换为化合物6-1。S6的分析数据：1H NMR(300MHz,Chloroform-d)δ10.41(s,1H),8.44(d,J＝7.4Hz,1H),7.97–7.56(m,3H),7.34(s,2H),7.07(t,J＝9.1Hz,1H),5.11–4.81(m,2H),4.56(s,2H),4.27(s,2H),3.55(d,J＝46.4Hz,3H),2.09(d,J＝72.1Hz,5H),1.49(q,J＝48.1,43.8Hz,14H).
7化合物S7的合成
Figure PCTCN2016106707-appb-000029
其中原料7-1的合成与1-1相同，将原料D1-1替换为D1-5。7-1的分析数据：1H NMR(300MHz,Chloroform-d)δ7.16(ddt,J＝4.8,3.1,1.6Hz,2H),6.83(td,J＝3.5,1.8Hz,1H),4.26(dd,J＝8.1,3.9Hz,1H),4.02(d,J＝16.4Hz,1H),3.79(dd,J＝16.7,2.0Hz,1H),3.15(q,J＝1.6Hz,2H),3.05–2.90(m,1H),2.77(d,J＝13.5Hz,1H),1.06(dd,J＝6.5,1.8Hz,3H).
S7合成方法与S1相同，将化合物1-1替换为化合物7-1。S7的分析数据：1H NMR(300MHz,Chloroform-d)δ11.02(s,1H),8.44(d,J＝7.5Hz,1H),7.87–7.64(m,3H),7.62–7.30(m,4H),7.25–6.95(m,2H),5.08–4.51(m,4H),4.28(s,2H),3.47(dd,J＝13.7,4.0Hz,1H),1.43(d,J＝6.5Hz,3H).
8化合物S8的合成
Figure PCTCN2016106707-appb-000030
其中原料8-1的合成与1-1相同，将原料D1-1替换为D1-6。8-1的分析数据：1H NMR(300MHz,Chloroform-d)δ11.38(s,1H),8.47(s,1H),7.69(s,1H),4.38(s,1H),4.28(d,J＝16.4Hz,1H),4.04(d,J＝16.4Hz,1H),3.65(q,J＝6.9Hz,1H),3.21(dd,J＝13.4,4.3Hz,1H),3.03(d,J＝13.3Hz,1H),1.33(d,J＝6.5Hz,3H).
S8合成方法与S1相同，将化合物1-1替换为化合物8-1。S8的分析数据：1H NMR(300MHz,Chloroform-d)δ11.38(s,1H),10.98(s,1H),8.39(d,J＝7.3Hz,1H),7.71(d,J＝7.6Hz,4H),7.30(d,J＝6.1Hz,1H),7.05(t,J＝9.0Hz,1H),5.50–5.19(m,1H),4.89(t,J＝14.5Hz,1H),4.57(d,J＝16.9Hz,1H),4.24(s,2H),3.58–3.37(m,1H),1.19(s,3H).
9化合物S9的合成
Figure PCTCN2016106707-appb-000031
其中原料9-1的合成与1-1相同，将原料D1-1替换为D1-7。9-1的分析数据：1H NMR(300MHz,Chloroform-d)δ11.38(s,1H),7.70(d,J＝26.7Hz,2H),4.38(s,1H),4.28(d,J＝16.4Hz,1H),4.04(d,J＝16.4Hz,1H),3.65(q,J＝6.9Hz,1H),3.21(dd,J＝13.4,4.3Hz,1H),3.03(d,J＝13.3Hz,1H),1.33(d,J＝6.5Hz,3H).
S9合成方法与S1相同，将化合物1-1替换为化合物9-1。S9的分析数据：1H NMR(300MHz,Chloroform-d)δ13.28(s,3H),8.54–8.37(m,3H),7.74(dt,J＝17.9,5.3Hz,9H),7.30(d,J＝22.8Hz,9H),7.08(t,J＝8.6Hz,3H),5.09–4.91(m,4H),4.67(d,J＝16.9Hz,3H),4.32(s,6H),3.67(d,J＝15.9Hz,4H),3.40(d,J＝13.7Hz,2H),3.18–3.01(m,4H),1.46(s,9H).
10化合物S10的合成
Figure PCTCN2016106707-appb-000032
其中原料10-1的合成与1-1相同，将原料D1-1替换为D1-8。10-1的分析数据：1H NMR(300MHz,Chloroform-d)δ7.85(s,1H),7.76(s,1H),4.38(s,1H),4.28(d,J＝16.4Hz,1H),4.04(d,J＝16.4Hz,1H),3.92(d,J＝1.3Hz,3H),3.65(q,J＝6.9Hz,1H),3.21(dd,J＝13.4,4.3Hz,1H),3.03(d,J＝13.3Hz,1H),1.33(d,J＝6.5Hz,3H).
S10合成方法与S1相同，将化合物1-1替换为化合物10-1。S10的分析数据：1H NMR(300MHz,Chloroform-d)δ10.56(s,1H),8.41(dd,J＝7.6,1.8Hz,1H),7.79–7.61(m,3H),7.31(d,J＝6.3Hz,2H),7.13–6.91(m,3H),5.52(s,0.5H),4.96–4.84(m,1H),4.68–4.52(m,1H),4.24(s,2H),4.07(d,J＝3.4Hz,3H),3.61(s,0.5H),3.40–3.30(m,1H),1.39(d,J＝6.5Hz,3H).
11化合物S11的合成
Figure PCTCN2016106707-appb-000033
其中原料11-1的合成与1-1相同，将原料D1-1替换为D1-9。11-1的分析数据：1H NMR(300MHz,Chloroform-d)δ7.74–7.65(m,1H),7.56–7.38(m,2H),4.60–4.46(m,1H),4.29(d,J＝16.4Hz,1H),4.09(d,J＝16.4Hz,1H),3.28(dd,J＝13.4,4.3Hz,1H),3.03(dd,J＝13.4,2.8Hz,1H),2.21(d,J＝27.6Hz,2H),1.28(d,J＝6.5Hz,3H).
S11合成方法与S1相同，将化合物1-1替换为化合物11-1。S11的分析数据：1H NMR(300MHz,Chloroform-d)δ10.84(d,J＝61.1Hz,1H),8.87(d,J＝16.6Hz,1H),8.40(d,J＝7.6Hz,1H),8.17(d,J＝33.4Hz,1H),7.68(dd,J＝16.2,7.5Hz,3H),7.32(s,2H),7.05(t,J＝8.8Hz,1H),5.69(d,J＝18.3Hz,0.5H),5.16–4.76(m,2H),4.79–4.48(m,2H),4.24(s,2H),3.71(s,0.5H),3.44(d,J＝13.7Hz,1H),1.41(d,J＝6.6Hz,3H).
12化合物S12的合成
Figure PCTCN2016106707-appb-000034
其中原料12-1的合成与1-1相同，将原料D1-1替换为D1-10。12-1的分析数据：1H NMR(300MHz,Chloroform-d)δ7.85(d,J＝3.3Hz,1H),7.37(d,J＝3.2Hz,1H),5.18–5.01(m,1H),4.36(d,J＝16.8Hz,1H),4.09(d,J＝16.8Hz,1H),3.26–3.01(m,2H),1.86(s, 2H),1.44(d,J＝6.5Hz,3H).
S12合成方法与S1相同，将化合物1-1替换为化合物12-1。S12的分析数据：1H NMR(300MHz,Chloroform-d)δ10.85(d,J＝51.2Hz,1H),8.46(d,J＝7.5Hz,1H),7.76(dq,J＝15.3,8.4,7.3Hz,4H),7.60–7.28(m,4H),7.10(t,J＝8.8Hz,1H),5.64(d,J＝17.8Hz,0.5H),4.99–4.62(m,3H),4.30(s,2H),3.71(s,0.5H),3.62–3.43(m,1H),1.39(d,J＝6.6Hz,3H).
13化合物S13的合成
Figure PCTCN2016106707-appb-000035
其中原料13-1的合成与1-1相同，将原料D1-1替换为D1-11。13-1的分析数据：1H NMR(300MHz,Chloroform-d)δ7.50(d,J＝2.0Hz,1H),7.20(d,J＝1.6Hz,1H),7.00(d,J＝3.4Hz,1H),6.50(dd,J＝3.4,1.8Hz,1H),4.68(ddd,J＝6.8,4.4,2.2Hz,1H),4.27(d,J＝3.3Hz,1H),4.03(d,J＝5.2Hz,1H),3.64(d,J＝7.0Hz,1H),3.17(d,J＝4.2Hz,1H),3.03(d,J＝10.3Hz,1H),1.34(d,J＝6.5Hz,3H).
S13合成方法与S1相同，将化合物1-1替换为化合物13-1。S13的分析数据：1H NMR(300MHz,DMSO-d6)δ12.60(s,1H),8.69(dd,J＝19.2,4.9Hz,1H),8.22(dd,J＝19.7,7.6Hz,2H),7.91(dt,J＝41.6,8.0Hz,4H),7.57–7.38(m,3H),7.29(t,J＝9.0Hz,1H),5.50(d,J＝16.9Hz,1H),5.26(s,1H),4.87–4.54(m,2H),4.36(d,J＝5.1Hz,2H),3.87–3.73(m,1H),3.56(d,J＝13.8Hz,1H),1.42–1.04(m,3H).
14化合物S14的合成
Figure PCTCN2016106707-appb-000036
其中原料14-1的合成与1-1相同，将原料D1-1替换为D1-12。14-1的分析数据：1H NMR(300MHz,Chloroform-d)δ7.85(s,1H),7.76(s,1H),4.38(s,1H),4.28(d,J＝16.4Hz,1H),4.04(d,J＝16.4Hz,1H),3.92(d,J＝1.3Hz,3H),3.65(q,J＝6.9Hz,1H),3.21(dd,J＝13.4,4.3Hz,1H),3.03(d,J＝13.3Hz,1H),1.33(d,J＝6.5Hz,3H).
S14合成方法与S1相同，将化合物1-1替换为化合物14-1。S14的分析数据：1H NMR(300MHz,Chloroform-d)δ10.74(s,1H),8.45(d,J＝7.5Hz,1H),8.09–7.64(m,5H),7.35(d,J＝6.4Hz,2H),7.10(t,J＝8.8Hz,1H),5.71(d,J＝17.8Hz,0.5H),5.03–4.84(m,2H),4.62(d,J＝19.3Hz,2H),4.30(s,2H),3.98(d,J＝10.8Hz,3H),3.71(s,0.5H),3.56–3.41(m,1H),1.43(d,J＝6.5Hz,2H),1.22(d,J＝9.3Hz,1H).
15化合物S15的合成
Figure PCTCN2016106707-appb-000037
其中原料15-1的合成与1-1相同，将原料D1-1替换为D1-13。15-1的分析数据：1H NMR(300MHz,Chloroform-d)δ6.82(s,2H),4.47(dt,J＝7.8,4.3Hz,1H),4.26(d,J＝16.2Hz,1H),4.12(d,J＝16.1Hz,1H),3.86(d,J＝3.9Hz,9H),3.32(dd,J＝13.4,4.5Hz,1H), 2.97(dd,J＝13.3,3.5Hz,1H),2.09(s,2H),1.15(d,J＝6.5Hz,3H).
S15合成方法与S1相同，将化合物1-1替换为化合物15-1。S15的分析数据：1H NMR(300MHz,DMSO-d6)δ12.61(s,1H),8.25(d,J＝7.7Hz,1H),8.08(dd,J＝11.8,3.3Hz,1H),7.98–7.80(m,3H),7.63–7.38(m,2H),7.29(t,J＝9.2Hz,1H),5.55(d,J＝17.7Hz,0.5H),5.28(s,0.5H),5.07(s,0.5H),4.86–4.70(m,1H),4.60(d,J＝17.9Hz,0.5H),4.47–4.24(m,2H),3.81(d,J＝12.8Hz,0.5H),3.57(t,J＝15.0Hz,1H),1.60–0.99(m,3H).
16化合物S16的合成
Figure PCTCN2016106707-appb-000038
其中原料16-1的合成与1-1相同，将原料D1-1替换为D1-14。16-1的分析数据：1H NMR(300MHz,Chloroform-d)δ8.25(d,J＝7.2Hz,1H),7.30(d,J＝5.7Hz,1H),6.65(s,1H),4.26(dd,J＝8.1,3.9Hz,1H),4.02(d,J＝16.4Hz,1H),3.79(dd,J＝16.7,2.0Hz,1H),3.15(q,J＝1.6Hz,2H),3.05–2.90(m,1H),2.77(d,J＝13.5Hz,1H),1.06(dd,J＝6.5,1.8Hz,3H).
S16合成方法与S1相同，将化合物1-1替换为化合物16-1。S16的分析数据：1H NMR(300MHz,Chloroform-d)δ10.41(s,1H),8.46(d,J＝7.1Hz,1H),7.81–7.67(m,3H),7.36(d,J＝5.7Hz,2H),7.17–7.03(m,2H),6.59(s,1H),5.75(d,J＝17.9Hz,0.5H),5.12–4.54(m,4H),4.30(s,2H),3.71(s,0.5H),3.53–3.38(m,1H),1.47(d,J＝6.5Hz,3H).
17化合物S17的合成
Figure PCTCN2016106707-appb-000039
其中原料17-1的合成与1-1相同，将原料D1-1替换为D1-15。17-1的分析数据：1H NMR(300MHz,Chloroform-d)δ4.70(ddd,J＝8.9,7.5,1.5Hz,1H),4.30(d,J＝16.7Hz,1H),4.08(dd,J＝16.7,1.5Hz,1H),3.14(dd,J＝13.4,4.0Hz,1H),3.04(d,J＝13.6Hz,1H),1.56(dd,J＝6.6,1.5Hz,3H),1.43(s,6H).
S17合成方法与S1相同，将化合物1-1替换为化合物17-1。S17的分析数据：1H NMR(300MHz,Chloroform-d)δ10.63(d,J＝32.0Hz,1H),8.52–8.35(m,1H),7.90–7.61(m,3H),7.46–7.29(m,2H),7.15–7.01(m,1H),5.61(d,J＝18.1Hz,0.5H),5.14(t,J＝7.1Hz,1H),4.97–4.59(m,4H),4.40(td,J＝7.9,6.7,2.4Hz,1H),4.28(s,2H),3.63(s,0.5H),3.35(d,J＝13.8Hz,1H),1.64(d,J＝44.0Hz,3H),1.53–1.32(m,6H).
18化合物S18的合成
Figure PCTCN2016106707-appb-000040
其中原料18-1的合成与1-1相同，将原料D1-1替换为D1-16。18-1的分析数据：1H NMR(300MHz,Chloroform-d)δ6.92(d,J＝3.4Hz,1H),6.40(d,J＝3.4Hz,1H),4.72(s,1H),4.66(s,2H),4.31(d,J＝16.6Hz,1H),4.08(d,J＝16.5Hz,1H),3.47(d,J＝0.9Hz,1H),3.24 (dd,J＝13.5,4.3Hz,1H),3.06(dd,J＝13.2,2.2Hz,1H),1.39(d,J＝6.5Hz,3H).
S18合成方法与S1相同，将化合物1-1替换为化合物18-1。S18的分析数据：1H NMR(300MHz,Chloroform-d)δ11.11(d,J＝113.9Hz,1H),8.38(d,J＝7.8Hz,1H),7.69(d,J＝12.7Hz,3H),7.30(s,2H),7.13–6.86(m,2H),6.34(d,J＝21.2Hz,1H),5.61(d,J＝18.3Hz,0.5H),5.00–4.52(m,4H),4.23(s,2H),3.56(s,0.5H),3.39(d,J＝19.8Hz,1H),2.79(d,J＝14.4Hz,1H),1.51–1.07(m,3H).
19化合物S19的合成
Figure PCTCN2016106707-appb-000041
其中原料19-1的合成按以下步骤：D2(1eq)溶于原甲酸三甲酯中，回流过夜，反应完全后，旋除溶剂，加入二氯甲烷溶解，然后加入N-碘代丁二酰亚胺(1eq)，室温反应1小时，加入1N的盐酸溶液，分出二氯甲烷层，用饱和食盐水洗涤二氯甲烷层，无水硫酸钠干燥，抽滤，滤液旋干，然后用乙醇溶解，加入钯/碳(0.1eq)，通入氢气，50摄氏度下反应过夜，反应完全后，滤除钯/碳，旋干，得到胺19-1。19-1的分析数据：1H NMR(300MHz,Chloroform-d)δ4.56(s,1H),4.51–4.38(m,1H),4.22(d,J＝16.8Hz,1H),3.31–3.21(m,1H),3.13(d,J＝13.9Hz,1H),1.89–1.40(m,3H).
S19合成方法与S1相同，将化合物1-1替换为化合物19-1。S19的分析数据：1H NMR(300MHz,Chloroform-d)δ10.42(d,J＝43.6Hz,1H),8.45(d,J＝6.7Hz,1H),7.85–7.64(m,3H),7.36(dd,J＝13.9,4.8Hz,2H),7.08(t,J＝8.9Hz,1H),5.80(d,J＝17.8Hz,0.5H),4.94(t,J＝16.2Hz,2H),4.63–4.48(m,1H),4.28(s,2H),3.71(s,0.5H),3.34(d,J＝14.0Hz,1H),1.48(d,J＝6.6Hz,2H),1.23(s,1H).
20化合物S20的合成
Figure PCTCN2016106707-appb-000042
其中原料20-1的合成与1-1相同，将原料D1-1替换为D1-17。20-1的分析数据：1H NMR(300MHz,Chloroform-d)δ9.50(s,1H),8.59-8.65(m,2H),5.18–5.01(m,1H),4.36(d,J＝16.8Hz,1H),4.09(d,J＝16.8Hz,1H),3.26–3.01(m,2H),1.44(d,J＝6.5Hz,3H).
S20合成方法与S1相同，将化合物1-1替换为化合物20-1。S20的分析数据：1H NMR(300MHz,Chloroform-d)δ10.82(d,J＝29.8Hz,1H),9.59(s,1H),8.88–8.34(m,3H),7.94–7.62(m,3H),7.38(d,J＝5.9Hz,2H),7.11(t,J＝8.8Hz,1H),5.80(s,0.5H),5.55(s,1H),4.99(t,J＝13.6Hz,1H),4.69(d,J＝17.9Hz,1H),4.31(s,2H),3.73(s,0.5H),3.54–3.39(m,1H),1.47(d,J＝6.3Hz,2H),1.26(s,1H).
21化合物S21的合成
Figure PCTCN2016106707-appb-000043
其中原料21-1的合成与1-1相同，将原料D1-1替换为D1-18。21-1的分析数据：1H NMR(300MHz,Chloroform-d)δ6.82(s,2H),4.47(dt,J＝7.8,4.3Hz,1H),4.26(d,J＝16.2Hz,1H),4.12(d,J＝16.1Hz,1H),3.86(d,J＝3.9Hz,9H),3.32(dd,J＝13.4,4.5Hz,1H),2.97(dd,J＝13.3,3.5Hz,1H),1.15(d,J＝6.5Hz,3H).
S21合成方法与S1相同，将化合物1-1替换为化合物21-1。S21的分析数据：1H NMR(300MHz,Chloroform-d)δ10.84(d,J＝33.7Hz,1H),8.46(d,J＝7.4Hz,1H),7.75(dt,J＝16.7,8.0Hz,3H),7.36(d,J＝6.1Hz,2H),7.11(t,J＝8.7Hz,1H),6.83(d,J＝10.7Hz,2H),5.57(d,J＝18.0Hz,0.5H),4.91(d,J＝16.7Hz,1H),4.68(d,J＝16.7Hz,2H),4.30(s,2H),3.90(d,J＝3.3Hz,9H),3.71(d,J＝16.2Hz,1.5H),1.28(d,J＝6.5Hz,3H).
22化合物S22的合成
Figure PCTCN2016106707-appb-000044
原料S-b的合成参考文献Bioorg.Med.Chem.Lett.2010,20,1100-1105.
S22合成方法与S1相同，将化合物1-1替换为化合物15-1，将化合物S-a替换为化合物S-b。S22的分析数据：1H NMR(300MHz,Chloroform-d)δ11.96(s,1H),7.88(d,J＝3.2Hz,1H),7.41(d,J＝3.3Hz,1H),7.26(t,J＝7.2Hz,2H),7.06(dd,J＝9.3,5.1Hz,2H),6.83(d,J＝9.7Hz,1H),5.77(d,J＝18.3Hz,0.5H),5.40(d,J＝7.1Hz,1H),5.27(s,0.5H),4.93(d,J＝15.4Hz,1.5H),4.65(d,J＝18.7Hz,1H),3.86(s,2H),3.69(d,J＝3.0Hz,0.5H),3.34(d,J＝3.7Hz,1H),1.47(d,J＝6.5Hz,3H).
Figure PCTCN2016106707-appb-000045
23化合物S23的合成
S23合成方法与S1相同，将化合物1-1替换为化合物13-1，将化合物S-a替换为化合物S-b。S23的分析数据：1H NMR(300MHz,Chloroform-d)δ12.01(s,1H),8.58(d,J＝5.0Hz,1H),8.24(d,J＝7.9Hz,1H),7.76(dd,J＝8.8,6.9Hz,1H),7.27(dt,J＝14.5,5.6Hz,2H),7.05(dt,J＝7.9,3.6Hz,2H),6.83(d,J＝9.7Hz,1H),5.68(d,J＝10.7Hz,0.5H),4.91(t,J＝ 14.0Hz,1H),4.65(dd,J＝17.6,10.8Hz,1H),3.86(s,2H),3.67(s,0.5H),3.39(dd,J＝13.8,3.8Hz,1H),1.39(d,J＝6.5Hz,3H).
24化合物S24的合成
Figure PCTCN2016106707-appb-000046
其中原料24-1的合成与1-1相同，将原料D1-1替换为D1-19。24-1的分析数据：1H NMR(300MHz,Chloroform-d)δ5.09–5.01(m,1H),4.36(m,3H),4.11(d,J＝16.4Hz,1H),3.22–3.01(m,2H),1.87(m,2H),1.45(d,J＝6.5Hz,3H),1.33(t,J＝4.2Hz,3H).
S24合成方法与S1相同，将化合物1-1替换为化合物24-1。S24的分析数据：1H NMR(300MHz,DMSO-d6)δ12.59(s,1H),8.36–8.10(m,1H),8.04–7.68(m,3H),7.44(dd,J＝32.6,6.3Hz,2H),7.30(t,J＝8.9Hz,1H),5.50(d,J＝17.8Hz,0.5H),5.03(s,0.5H),4.90–4.51(m,2.5H),4.37(d,J＝9.7Hz,4H),3.66(s,0.5H),3.53(d,J＝14.1Hz,1H),1.51–1.26(m,4H),1.08(s,2H).
25化合物S25的合成
Figure PCTCN2016106707-appb-000047
将S24用于四氢呋喃和水中的，然后加入氢氧化锂(4eq)的水溶液，室温搅拌过夜，TLC检测反应完全后，用3N的盐酸调节pH值等于3，有固体析出，抽滤，固体水洗，乙醇洗，烘干得到白色固体S25。S25的分析数据：1H NMR(300MHz,DMSO-d6)δ12.58 (s,1H),8.64(d,J＝6.5Hz,1H),8.26(d,J＝7.6Hz,1H),8.04–7.77(m,3H),7.45(s,2H),7.29(d,J＝10.0Hz,1H),5.01(s,0.5H),4.85(s,0.5H),4.58(s,1H),4.46(s,0.5H),4.34(s,2H),4.25(s,0.5H),4.12(s,0.5H),3.90–3.78(m,0.5H),3.66(d,J＝13.9Hz,1H),1.47–1.14(m,3H).
26化合物S26的合成
Figure PCTCN2016106707-appb-000048
其中原料26-1的合成与1-1相同，将原料D1-1替换为D1-20。26-1的分析数据：1H NMR(300MHz,Chloroform-d)δ7.87(d,J＝3.5Hz,1H),5.09(s,1H),4.43(d,J＝6.9Hz,1H),4.29(d,J＝6.1Hz,1H),3.12–2.99(m,1H),2.90(d,J＝12.4Hz,1H),1.38(dd,J＝5.7,2.1Hz,3H).
S26合成方法与S1相同，将化合物1-1替换为化合物26-1。S26的分析数据：1H NMR(300MHz,Chloroform-d)δ10.40(s,1H),8.50–8.32(m,1H),7.69-7.74(m,4H),7.29(d,J＝5.4Hz,2H),6.91(t,J＝7.2Hz,1H),5.81(d,J＝18.3Hz,0.5H),5.30(s,1H),5.24(s,0.5H),5.03–4.81(m,1H),4.57(t,J＝19.4Hz,1H),4.29(s,2H),3.69(s,0.5H),3.31(s,0.5H),1.42(d,J＝6.5Hz,3H).
27化合物S27的合成
Figure PCTCN2016106707-appb-000049
原料S-c的合成参考文献Bioorg.Med.Chem.Lett.2008,18,3942-3945。
S27合成方法与S1相同，将化合物1-1替换为化合物15-1，将化合物S-a替换为化 合物S-c。S27的分析数据：1H NMR(300MHz,Chloroform-d)δ8.13(d,J＝7.5Hz,1H),7.93–7.78(m,1H),7.45(ddt,J＝14.7,11.2,6.7Hz,5H),7.20–7.13(m,1H),7.04(t,J＝7.6Hz,1H),6.95(d,J＝8.4Hz,1H),6.03–5.71(m,1H),5.40(d,J＝7.4Hz,1H),5.25(s,0.5H),5.14(d,J＝3.9Hz,2H),5.02–4.87(m,1H),4.63(dd,J＝24.8,17.8Hz,1H),3.66(d,J＝15.5Hz,0.5H),3.39(dd,J＝14.2,3.7Hz,1H),1.59–1.28(m,3H).
28化合物S28的合成
Figure PCTCN2016106707-appb-000050
S28合成方法与S1相同，将化合物1-1替换为化合物13-1，将化合物S-a替换为化合物S-c。S28的分析数据：1H NMR(300MHz,Chloroform-d)δ8.55(d,J＝28.1Hz,1H),8.26(d,J＝8.0Hz,1H),8.14(d,J＝7.6Hz,1H),7.84–7.70(m,1H),7.45(dt,J＝24.6,8.6Hz,4H),7.30(t,J＝6.3Hz,1H),7.19(d,J＝9.2Hz,1H),7.12–6.88(m,2H),5.75(d,J＝37.6Hz,2.5H),5.14(d,J＝3.2Hz,2H),5.01–4.81(m,2H),4.67(dd,J＝17.5,10.8Hz,1H),3.68(d,J＝11.3Hz,0.5H),3.42(dd,J＝13.4,4.2Hz,1H),1.52–1.23(m,3H).
29化合物S29的合成
Figure PCTCN2016106707-appb-000051
原料S-d的合成参考文献Bioorg.Med.Chem.Lett.2010,20,1100-1105.
S29合成方法与S1相同，将化合物13-1替换为化合物13-1，将化合物S-a替换为化合物S-d。S29的分析数据：1H NMR(300MHz,Chloroform-d)δ12.28(s,1H),8.51(dd,J＝33.3,4.9Hz,1H),8.23(t,J＝7.5Hz,1H),7.74(t,J＝7.9Hz,1H),7.37–7.14(m,3H),7.03(t,J＝8.8Hz,1H),5.76–5.50(m,1H),4.89(t,J＝14.0Hz,1.5H),4.63(dd,J＝17.7,11.0Hz,1H),3.80(s,2H),3.66(s,0.5H),3.38(q,J＝6.6,5.0Hz,1H),2.07(s,3H),1.31(dd,J＝41.6,6.5Hz,3H).
30化合物S30的合成
Figure PCTCN2016106707-appb-000052
S30合成方法与S1相同，将化合物1-1替换为化合物15-1，将化合物S-a替换为化合物S-d。S30的分析数据：1H NMR(300MHz,Chloroform-d)δ12.14(s,1H),7.83(dd,J＝26.0,3.2Hz,1H),7.39(dd,J＝8.0,3.4Hz,1H),7.31–7.18(m,2H),7.04(t,J＝8.7Hz,1H),6.89(d,J＝1.5Hz,1H),5.76(d,J＝18.3Hz,0.5H),5.44–5.20(m,1H),4.92(d,J＝15.5Hz,2H),4.72–4.51(m,1H),3.81(s,2H),3.69(s,0.5H),3.42–3.32(m,1H),2.08(d,J＝1.2Hz,3H),1.46(d,J＝6.5Hz,3H).
31化合物S31的合成
Figure PCTCN2016106707-appb-000053
原料S-e的合成参考文献Bioorg.Med.Chem.Lett.2010,20,1100-1105.
S31合成方法与S1相同，将化合物1-1替换为化合物15-1，将化合物S-a替换为化合物S-e。S31的分析数据：1H NMR(300MHz,Chloroform-d)δ11.54(d,J＝63.5Hz,1H),7.89(d,J＝3.0Hz,1H),7.42(d,J＝3.1Hz,1H),7.20(s,2H),7.04(t,J＝8.7Hz,1H),5.78(d,J＝18.4Hz,0.5H),5.32(d,J＝49.4Hz,1H),4.94(d,J＝15.5Hz,1H),4.62(t,J＝16.3Hz,1H),3.90(s,2H),3.70(s,0.5H),3.36(d,J＝14.0Hz,1H),2.04(d,J＝23.2Hz,6H),1.48(d,J＝6.4Hz,3H).
32化合物S32的合成
Figure PCTCN2016106707-appb-000054
S32合成方法与S1相同，将化合物1-1替换为化合物13-1，将化合物S-a替换为化合物S-e。S32的分析数据：1H NMR(300MHz,Chloroform-d)δ11.34(s,1H),8.54(d,J＝30.9Hz,1H),8.26(d,J＝8.4Hz,1H),7.77(t,J＝8.0Hz,1H),7.25(d,J＝19.7Hz,2H),7.04(t,J＝8.8Hz,1H),5.68(s,1H),4.91(t,J＝13.4Hz,1.5H),4.76–4.57(m,1H),3.90(s,2H),3.68(s,0.5H),3.39(d,J＝13.8Hz,1H),2.04(d,J＝23.3Hz,6H),1.40(d,J＝6.4Hz,3H).
33化合物S33的合成
Figure PCTCN2016106707-appb-000055
其中原料33-1的合成与1-1相同，将原料D-1替换为D1-21。33-1的分析数据：1H NMR(300MHz,Chloroform-d)δ1H NMR(300MHz,Chloroform-d)δ8.43(d,J＝4.5Hz,1H),7.55(dd,J＝10.0,8.3Hz,1H),7.41–7.26(m,1H),5.09(dt,J＝6.7,3.3Hz,1H),4.33(d,J＝16.6Hz,1H),4.13(d,J＝16.6Hz,1H),3.24(dd,J＝13.5,4.4Hz,1H),2.98(dd,J＝13.5,2.7Hz,1H),1.19(d,J＝6.8Hz,3H).
S33合成方法与S1相同，将化合物1-1替换为化合物33-1。S33的分析数据：1H NMR(300MHz,Chloroform-d)δ10.65(d,J＝12.4Hz,1H),8.43(dd,J＝19.3,6.1Hz,2H),7.87–7.52(m,4H),7.45–7.26(m,3H),7.04(t,J＝8.9Hz,1H),5.68(d,J＝17.6Hz,0.5H),5.45(s,1H),5.25(s,1H),4.94(d,J＝17.1Hz,1H),4.86–4.61(m,2H),4.24(s,2H),3.65(s,0.5H),3.46(d,J＝14.1Hz,1H),1.32(d,J＝6.5Hz,3H).
34化合物S34的合成
Figure PCTCN2016106707-appb-000056
其中原料34-1的合成与1-1相同，将原料D-1替换为D1-22。34-1的分析数据：1H NMR(300MHz,Chloroform-d)δ8.56(d,J＝5.0Hz,1H),8.25(d,J＝8.1Hz,1H),7.75(d,J＝1.7Hz,1H),7.26(dd,J＝7.7,4.8Hz,1H),5.35(s,1H),4.36(d,J＝16.6Hz,1H),4.12(d,J＝16.7Hz,1H),3.28–3.17(m,1H),3.12–3.00(m,1H),1.34(d,J＝6.5Hz,3H).
S34合成方法与S1相同，将化合物1-1替换为化合物34-1。S34的分析数据：1H NMR(300MHz,Chloroform-d)δ10.87(d,J＝22.5Hz,1H),8.58(d,J＝4.9Hz,1H),8.40(d,J＝7.3Hz,1H),8.23(dd,J＝14.8,7.0Hz,1H),7.71(tt,J＝12.5,7.2Hz,4H),7.32(d,J＝7.5Hz,3H),7.03(t,J＝9.1Hz,1H),5.66(s,0.5H),5.48(s,0.5H),4.90(t,J＝14.1Hz,1.5H),4.62(d,J＝17.8Hz,1H),4.24(s,2H),3.66(s,0.5H),3.46–3.32(m,1H),1.40(t,J＝4.6Hz,3H).
35化合物S35的合成
Figure PCTCN2016106707-appb-000057
其中原料35-1的合成与1-1相同，将原料D-1替换为D1-23。35-1的分析数据：1H NMR(300MHz,Chloroform-d)δ8.84(d,J＝2.3Hz,1H),8.70–8.61(m,1H),8.53(d,J＝2.8Hz, 0H),7.98(dt,J＝7.9,2.0Hz,1H),7.76(dt,J＝8.8,2.3Hz,0H),7.39(dd,J＝7.9,4.9Hz,1H),4.48(tt,J＝6.6,3.9Hz,1H),4.27(dd,J＝16.4,2.6Hz,1H),4.12(d,J＝16.3Hz,1H),3.30(ddd,J＝13.4,4.5,2.6Hz,1H),2.98(ddd,J＝13.5,5.7,3.5Hz,1H),1.19–1.10(m,3H).
S35合成方法与S1相同，将化合物1-1替换为化合物35-1。S35的分析数据：1H NMR(300MHz,Chloroform-d)δ10.25(s,1H),8.80–8.49(m,2H),8.40(d,J＝7.5Hz,1H),7.88–7.56(m,4H),7.31(d,J＝6.3Hz,2H),7.07(t,J＝8.9Hz,1H),4.93–4.57(m,3.5H),4.24(s,2H),3.62(d,J＝13.0Hz,2H),2.91(d,J＝48.3Hz,1.5H),1.27(d,J＝6.5Hz,3H).
36化合物S36的合成
Figure PCTCN2016106707-appb-000058
其中原料36-1的合成与1-1相同，将原料D-1替换为D1-24。36-1的分析数据：1H NMR(300MHz,Chloroform-d)δ7.88(d,J＝7.4Hz,1H),7.64(s,1H),6.74(d,J＝8.3Hz,1H),5.31(s,1H),4.36(d,J＝16.6Hz,1H),4.12(d,J＝16.6Hz,1H),3.89(d,J＝1.5Hz,3H),3.24(dd,J＝13.5,4.1Hz,1H),3.06(d,J＝13.4Hz,1H),1.41(d,J＝6.6Hz,3H).
S36合成方法与S1相同，将化合物1-1替换为化合物36-1。S36的分析数据：1H NMR(300MHz,Chloroform-d)δ10.63(d,J＝16.9Hz,1H),8.47–8.33(m,1H),7.89(d,J＝7.2Hz,1H),7.69(dq,J＝18.3,7.4,6.5Hz,4H),7.31(d,J＝6.0Hz,2H),7.05(t,J＝8.8Hz,1H),6.77(d,J＝8.4Hz,1H),5.73(d,J＝18.3Hz,0.5H),5.61(s,1H),5.42(s,0.5H),4.91(t,J＝13.7Hz,1H),4.62(d,J＝17.6Hz,1H),4.24(s,2H),3.85(d,J＝39.4Hz,3H),3.67(s,0.5H),3.41(d,J＝12.2Hz,1H),1.52–1.25(m,3H).
37化合物S37的合成
Figure PCTCN2016106707-appb-000059
其中原料37-1的合成与1-1相同，将原料D-1替换为D1-25。37-1的分析数据：1H NMR(300MHz,Chloroform-d)δ8.02(d,J＝7.9Hz,1H),7.62(t,J＝7.8Hz,1H),7.10(d,J＝7.7Hz,1H),5.35(t,J＝6.0Hz,1H),4.34(d,J＝16.6Hz,1H),4.09(d,J＝16.6Hz,1H),3.20(dd,J＝13.5,4.1Hz,1H),3.04(d,J＝13.5Hz,1H),2.50(s,3H),1.35(d,J＝6.5Hz,3H).
S37合成方法与S1相同，将化合物1-1替换为化合物37-1。S37的分析数据：1H NMR(300MHz,Chloroform-d)δ10.45(d,J＝15.0Hz,1H),8.48–8.32(m,1H),8.05(d,J＝8.2Hz,1H),7.85–7.52(m,4H),7.31(t,J＝5.8Hz,2H),7.09(dt,J＝25.4,8.7Hz,2H),5.69(d,J＝11.8Hz,1H),4.91(t,J＝15.1Hz,1.5H),4.61(d,J＝18.5Hz,1H),4.24(s,2H),3.66(s,0.5H),3.46–3.29(m,1H),2.54(s,3H),1.42(d,J＝6.4Hz,3H).
38化合物S38的合成
Figure PCTCN2016106707-appb-000060
其中原料38-1的合成与1-1相同，将原料D-1替换为D1-26。38-1的分析数据：1H NMR(300MHz,Chloroform-d)δ8.16(dd,J＝7.6,2.2Hz,1H),7.85(q,J＝8.0Hz,1H),6.90(dd,J＝8.2,2.8Hz,1H),5.25(ddd,J＝8.9,4.3,2.2Hz,1H),4.35(dd,J＝16.7,1.0Hz,1H),4.10(d, J＝16.7Hz,1H),3.20(dd,J＝13.5,4.1Hz,1H),3.06(dt,J＝13.5,1.4Hz,1H),1.38(d,J＝6.5Hz,3H).
S38合成方法与S1相同，将化合物1-1替换为化合物38-1。S38的分析数据：1H NMR(300MHz,Chloroform-d)δ10.54(s,1H),8.40(dd,J＝7.3,1.9Hz,1H),8.18(d,J＝7.4Hz,1H),7.88(d,J＝7.9Hz,1H),7.80–7.57(m,3H),7.31(d,J＝6.0Hz,2H),7.04(t,J＝9.0Hz,1H),6.95(d,J＝8.6Hz,1H),5.75(d,J＝18.2Hz,0H),5.56(s,0.5H),5.39(s,1H),5.01–4.84(m,1H),4.61(d,J＝18.9Hz,1H),4.24(s,2H),3.66(s,0.5H),3.37(d,J＝13.7Hz,1H),1.43(d,J＝6.5Hz,2H).
39化合物S39的合成
Figure PCTCN2016106707-appb-000061
其中原料39-1的合成与1-1相同，将原料D-1替换为D1-27。39-1的分析数据：1H NMR(300MHz,Chloroform-d)δ7.78(q,J＝0.9Hz,1H),5.04(ddd,J＝6.1,4.0,1.8Hz,1H),4.38(dd,J＝16.8,0.9Hz,1H),4.10(d,J＝16.8Hz,1H),3.27–3.04(m,2H),1.47(d,J＝6.4Hz,3H).
S39合成方法与S1相同，将化合物1-1替换为化合物39-1。S39的分析数据：1H NMR(300MHz,Chloroform-d)δ10.60(d,J＝15.1Hz,1H),8.50–8.32(m,1H),7.73(ddd,J＝23.0,18.8,6.5Hz,4H),7.32(d,J＝6.0Hz,2H),7.05(t,J＝8.9Hz,1H),5.84(d,J＝18.3Hz,0.5H),5.34(s,1H),5.14(s,0.5H),5.05–4.87(m,1H),4.59(t,J＝19.4Hz,1H),4.25(s,2H),3.68(s,0.5H),3.44–3.31(m,0.5H),1.48(d,J＝6.5Hz,3H).
二、试验实施例
1、ELISA高通量PARP1抑制剂分子水平评价
利用PARP1全长质粒，经PCR扩增、酶切、连接、转化到DH5a，获得HTb-PARP1阳性克隆；经抽提、酶切鉴定，转化到DH10Bac后PCR、测序鉴定Bacmid/PARP，转染TNI，收集病毒、裂解细胞，用亲和层析法纯化PARP1蛋白、Western blotting鉴定。将底物组蛋白、NAD+和DNA以及表达的PARP1酶进行包被、置于96孔板反应体系、优化并最终确定各种反应条件，反应产物PAR用PAR单抗反应，加入二抗后，用酶标仪读取OD值，并据此计算PARP1酶活性抑制程度，如表一所示。其中，AZD2281(奥拉帕尼)为国际制药公司阿斯利康2014年上市的第一个PARP抑制剂，在本试验中为阳性对照。
表一、化合物在分子水平对PARP1酶活性的抑制作用
Figure PCTCN2016106707-appb-000062
Figure PCTCN2016106707-appb-000063
Figure PCTCN2016106707-appb-000064
Figure PCTCN2016106707-appb-000065
Figure PCTCN2016106707-appb-000066
Figure PCTCN2016106707-appb-000067
从表一我们可以看到，绝大多数的化合物在分子水平对PARP1酶表现出高亲和力，对PARP表现出显著抑制活性，全部的化合物抑制率浓度为纳摩尔级(<100nM)，绝大多数化合物对PARP的抑制活性强于阳性化合物，最好化合物甚至达到1nM以下，是阳性化合物AZD-2281的50倍。因此，本发明的化合物可以作为强效新型的PARP-1抑制剂，用于预防和治疗与PARP(核糖多聚ADP-核糖聚合酶)相关疾病，如缺血性的疾病、神经退行性疾病以及癌症。
2、化合物手性拆分
由于化合物大多具有1-2个手性中心，我们通过手性制备液相色谱对它们进行拆分，得到相应的光学异构体。例如化合物S13的两个对映异构体均显示较高的PARP1酶抑制活性，其中(+)-S13的活性比(-)-S13的活性高出两倍，表明(+)-异构体与PARP酶的结合更好。具体结果如下：
1)拆分条件：
手性柱：CHIRALPAK IA
手性柱尺寸：0.46cm I.D.×15cm L
流动相：Hexane/IPA＝40/60(v/v)流速：1ml/min
检测波长：UV 254nm
2)手性HPLC谱图：参看图1-3。
图1为化合物S13的HPLC谱图；
图2为化合物S13-(-)HPLC谱图；
图3为化合物S13-(+)HPLC谱图。
3)对映异构体的PARP1酶抑制活性，见表二：
表二：S13及其对应异构体的PARP1酶抑制活性
Figure PCTCN2016106707-appb-000068
3、代表性化合物细胞活性测试
紧接着我们采用CCK-8法和SRB法，以AZD2281为阳性对照，初步评价化合物对MDA-MB-436和Capan-1细胞的增殖抑制作用，结果见表三。
表三.化合物对MDA-MB-436和Capan-1细胞的增殖抑制作用
Figure PCTCN2016106707-appb-000069
Figure PCTCN2016106707-appb-000070
从上面结果可以看出，新化合物不仅在PARP1酶水平具有高活性，对BRCA缺陷的MDA-MB-436和Capan-1细胞的增殖有很强的抑制作用，绝大部分化合物活性是阳性化合物AZD2281的10倍以上。
4、代表性化合物S13与AZD2281对不同肿瘤细胞增殖生长抑制作用的比较
为进一步明确新化合物与AZD2281可能的比较优势，我们对代表性化合物S13与AZD2281对不同肿瘤细胞增殖生长抑制作用进行了平行对比，结果见表四。该结果显示，对四种不同组织来源的肿瘤细胞，S13的增殖生长抑制作用均强于AZD2281，最强达628倍。
表四.化合物S13与AZD2281对不同肿瘤细胞增殖生长抑制作用
Figure PCTCN2016106707-appb-000071
Figure PCTCN2016106707-appb-000072
5，化合物对AZD2281耐药细胞的抗增殖活性
与AZD2281相比，本系列化合物显示了较高的活性。为了研究这些化合物对AZD2281的耐药是否也有效，我们测试了化合物S13对AZD2281的耐药细胞抗增殖能力，结果见表五。将AZD2281在Capan-1亲本和耐药细胞中的IC50进行比较，AZD2281表现出约14倍的耐药性，而化合物S13的IC50仍维持在0.256nM以下，可见本发明的化合物对耐药细胞也具有高活性，具有优异的开发前景。
表五.化合物S13与AZD2281对亲本和耐药肿瘤细胞增殖生长抑制作用
Figure PCTCN2016106707-appb-000073
6.化合物对钾离子通道hERG的抑制活性
为评价新化合物是否具有较好的安全性，尤其是对心脏毒性相关的钾离子通道hERG 的抑制活性，我们进一步评价了这些化合物对hERG的抑制活性，结果见表六：
表六.化合物对钾离子通道hERG的抑制作用
Figure PCTCN2016106707-appb-000074
可见，这类化合物无论是消旋体还是立体异构体，都不对钾离子通道hERG产生抑制作用，因而心脏毒性的风险较低。
综上所述，以化合物S13为代表的这类含芳环或者芳杂环取代的三唑并哌嗪类化合物具有极高的PARP1酶抑制活性，细胞活性也明显高于阳性化合物AZD2281。同时，保留环上甲基取代基的存在也明显提高了化合物对端粒酶TNKS1和TNKS2的选择性，心脏毒性风险小。因此，这些化合物作为新型高选择性核糖多聚ADP-核糖聚合酶-1(PARP1)抑制剂可用于预防和/或治疗与PARP相关疾病。

Claims (10)

  1. 一种通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物：
    Figure PCTCN2016106707-appb-100001
    其中，
    Y为
    Figure PCTCN2016106707-appb-100002
    或
    Figure PCTCN2016106707-appb-100003
    A和B各自独立地为氢或者取代或未取代的C1-C8烷基，其中，所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
    或者，A和B与相连接的碳原子一起形成取代或未取代的C4-C8脂族环，取代或未取代的C6-C10芳环，取代或未取代的含有1-3个选自N、O和S原子的4-8元杂环，或者取代或未取代的含有1-3个选自N、O和S原子的5-8元芳杂环，其中，所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
    X为氢、卤素、羟基或氰基；
    R为卤素，COOR1，取代或未取代杂环，取代或未取代杂芳环，取代或未取代芳环，其中杂环，杂芳环，芳环中的所述取代是指被选自如下的一种或多种取代基所取代：取代或未取代的C1-C8烷基、卤素、氰基、硝基、羟基、氨基、C1-C6烷氧基、C2-C6烷羰基、C2-C6烷氧羰基、C2-C6链烯基、C2-C6炔基和C6-C10芳基，其中所述的取代的C1-C8烷基中的取代是指被选自如下的一种或多种的取代基所取代：卤素、氰基、硝基、羟基、氨基；
    R1选自氢原子、C1-C8烷基、取代或未取代芳基或者取代或未取代杂环基，其中所述所述取代是指被选自如下的一种或多种取代基所取代：C1-C8烷基、卤素、氰基、硝基、羟基、氨基、C1-C6烷氧基、C2-C6烷羰基、C2-C6烷氧羰基、C2-C6链烯基、C2-C6炔 基和C6-C10芳基。
  2. 如权利要求1所述的通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物，
    其中，
    Y为
    Figure PCTCN2016106707-appb-100004
    或
    Figure PCTCN2016106707-appb-100005
    A和B各自独立地为氢或C1-C4烷基；
    或者，A和B与相连接的碳原子一起形成取代或未取代的C4-C6脂族环或者取代或未取代的C6-C8芳环，其中，所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
    X为氢、卤素、羟基或氰基；
    R为卤素，COOR1，取代或未取代杂环，取代或未取代杂芳环，取代或未取代芳环，其中杂环，杂芳环，芳环中所述取代是指被选自如下的一种或多种取代基所取代：取代或未取代的C1-C4烷基、卤素、氰基、硝基、羟基、氨基、C1-C4烷氧基、C2-C4烷羰基、C2-C4烷氧羰基、C2-C4链烯基、C2-C4炔基和苯基，其中所述的取代的C1-C4烷基中所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基、氨基；
    R1选自氢原子、C1-C4烷基、取代或未取代芳基或者取代或未取代杂环基，其中所述取代是指被选自如下的一种或多种取代基所取代：C1-C4烷基、卤素、氰基、硝基、羟基、氨基、C1-C4烷氧基、C2-C4烷羰基、C2-C4烷氧羰基、C2-C4链烯基、C2-C4炔基和苯基。
  3. 如权利要求1所述的通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物，
    其中，
    Y为
    Figure PCTCN2016106707-appb-100006
    或
    Figure PCTCN2016106707-appb-100007
    A和B各自独立地为氢或甲基；
    或者，A和B与相连接的碳原子一起形成苯环；
    X为氢或卤素；
    R为卤素，COOR1，取代或未取代苯基、取代或未取代5至6元杂环、取代或未取代5至6元芳杂环；所述取代是指被选自如下的一种或多种取代基所取代：甲基、卤素、三氟甲基、甲氧基、羟甲基；
    R1选自氢原子、甲基、乙基。
  4. 如权利要求1所述的通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物，其中，所述的互变异构体，具有如下通式(II)表示的结构，其中X、A、B、R的定义同权利要求1所述：
    Figure PCTCN2016106707-appb-100008
  5. 如权利要求1所述的通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物，其中，所述的通式(I)所示的取代三唑并哌嗪类化合物选自：
    Figure PCTCN2016106707-appb-100009
    Figure PCTCN2016106707-appb-100010
    Figure PCTCN2016106707-appb-100011
    Figure PCTCN2016106707-appb-100012
    Figure PCTCN2016106707-appb-100013
    Figure PCTCN2016106707-appb-100014
  6. 权利要求1-5中任一项所述的通式(I)所示的取代三唑并哌嗪类化合物的制备方法，其反应路线如下：
    Figure PCTCN2016106707-appb-100015
    其中，X，Y，R的定义与相对应的权利要求相同；
    化合物S与化合物D经缩合反应得到通式(I)所示的取代三唑并哌嗪类化合物；优选的，化合物S与化合物D在缩合剂和合适的碱存在下，在合适的溶剂中进行。
  7. 权利要求1-5中任一项所述的通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物作为高选择性PARP1抑制剂的用途。
  8. 权利要求1-5中任一项所述的通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物在制备用于预防和/或治疗与PARP相关疾病的药物中的用途。
  9. 如权利要求8所述的用途，其特征在于：所述与PARP相关疾病包括缺血性的疾病、神经退行性疾病和癌症；其中，所述缺血性的疾病包括大脑、脐带、心脏、消化管、视网膜缺血性疾病，所述神经退行性疾病包括帕金森氏症、阿尔兹海默病、肌肉萎缩症，所述癌症包括乳腺癌、卵巢癌、肝癌、黑素瘤、前列腺癌、结肠癌、胃癌和其它实体瘤。
  10. 一种药物组合物，其包含治疗有效量的权利要求1-5中任一项所述的通式(I)所示的取代三唑并哌嗪类化合物、其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、可药用的盐、酯、前药或其水合物中的一种或多种。
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