WO2019091492A1 - 用作iap抑制剂的smac模拟物及其用途 - Google Patents

用作iap抑制剂的smac模拟物及其用途 Download PDF

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Publication number
WO2019091492A1
WO2019091492A1 PCT/CN2018/115256 CN2018115256W WO2019091492A1 WO 2019091492 A1 WO2019091492 A1 WO 2019091492A1 CN 2018115256 W CN2018115256 W CN 2018115256W WO 2019091492 A1 WO2019091492 A1 WO 2019091492A1
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group
compound
alkyl
pharmaceutically acceptable
acceptable salt
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PCT/CN2018/115256
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English (en)
French (fr)
Inventor
刘迎春
徐招兵
胡利红
丁照中
朱兴训
胡国平
黎健
陈曙辉
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南京明德新药研发股份有限公司
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Priority to EA202091169A priority Critical patent/EA202091169A1/ru
Priority to JP2020526193A priority patent/JP7257397B2/ja
Priority to ES18875727T priority patent/ES2927195T3/es
Priority to PL18875727.2T priority patent/PL3712162T3/pl
Priority to BR112020009369-6A priority patent/BR112020009369A2/pt
Priority to CA3082437A priority patent/CA3082437A1/en
Priority to DK18875727.2T priority patent/DK3712162T3/da
Priority to EP18875727.2A priority patent/EP3712162B1/en
Application filed by 南京明德新药研发股份有限公司 filed Critical 南京明德新药研发股份有限公司
Priority to US16/763,746 priority patent/US11358950B2/en
Priority to CN201880070118.8A priority patent/CN111247161B/zh
Priority to KR1020207015888A priority patent/KR20200081456A/ko
Priority to AU2018364218A priority patent/AU2018364218B2/en
Priority to SG11202004377XA priority patent/SG11202004377XA/en
Priority to CN202210145394.4A priority patent/CN114685602A/zh
Publication of WO2019091492A1 publication Critical patent/WO2019091492A1/zh
Priority to IL274598A priority patent/IL274598A/en
Priority to ZA2020/03178A priority patent/ZA202003178B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • 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
    • A61K31/40—Heterocyclic 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
    • A61K31/403—Heterocyclic 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
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention describes compounds that inhibit IAP (inhibitor of apoptosis proteins), their preparation, and their use in the treatment of various diseases.
  • the compounds of the invention are useful in the treatment of cancer, autoimmune diseases and other diseases involving defects in apoptosis.
  • Programmed cell death plays a key role in regulating cell numbers and clearing stressed or damaged cells from normal tissues.
  • the apoptotic signaling network mechanisms inherent in most cell types provide a major barrier against the development and progression of human cancer.
  • Most current cancer therapies include chemotherapy, radiation therapy, and immunotherapy, all of which work by indirectly inducing apoptosis in cancer cells.
  • chemotherapy, radiation therapy, and immunotherapy all of which work by indirectly inducing apoptosis in cancer cells.
  • the inability of cancer cells to perform apoptosis procedures due to defects in normal apoptotic mechanisms is often associated with increased resistance to apoptosis induced by chemotherapy, radiation therapy, or immunotherapy. Therefore, targeting a key negative regulator that plays an important role in directly inhibiting cancer cell apoptosis will be a promising therapeutic strategy for new anticancer drug designs.
  • Bcl-2 family proteins such as two potent anti-apoptotic molecules, Bcl-2 and Bcl-XL proteins.
  • IAPs apoptosis proteins
  • XIAP X-linked inhibitor of apoptosis
  • caspase-3, caspase-7 and caspase-9 apoptosis by blocking the death receptor pathway.
  • the substrate NIK NF- ⁇ B-inducing kinase
  • NIK NF- ⁇ B-inducing kinase
  • the accumulated NIK activates NF through non-canonical pathways.
  • ⁇ B Activation of NF- ⁇ B promotes TNF ⁇ secretion, and TNF ⁇ binds to TNF-R1 (TNF receptor1) to initiate death receptor pathway.
  • RIPK1 receptor interacting protein kinase 1, receptor-interacting protein kinase 1
  • FADD Fas-associated death domin, Fas-related death domain
  • caspase-8 caspase-8
  • a number of drug molecules have entered the clinic and are actively progressing, such as LCL-161, Debio 1143, BI-891065 and ASTX-660.
  • X 1 is selected from the group consisting of C(R 5 ) and N;
  • X 2 is selected from the group consisting of C(R 6 ), N, O and S;
  • L is selected from the group consisting of a single bond and -O-;
  • the C 1-5 alkyl group, C 1-5 heteroalkyl group, phenyl group, 5- to 6-membered heteroaryl group or 5- to 6-membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R;
  • the alkyl group is optionally substituted with 1, 2 or 3 R;
  • R 3 and R 7 are each independently selected from H, halogen and C 1-4 alkyl, and the C 1-4 alkyl group is optionally substituted by 1, 2 or 3 R;
  • R 4 is selected from the group consisting of H, phenyl and 5- to 6-membered heteroaryl
  • R 5 is selected from the group consisting of H and halogen
  • R 6 is selected from H, halogen, C 1-4 alkyl, C 1-4 heteroalkyl, CN and COOH, and the C 1-4 alkyl or C 1-4 heteroalkyl is optionally 1, 2 or 3 R substitutions;
  • the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • X 1 , X 2 , L, R 1 , R 2 , R 3 , R 4 and R 7 are as defined above.
  • X 2 above is selected from the group consisting of C(R 6 ) and N.
  • the above X 2 is selected from the group consisting of C(H), C(Cl), C(CH 3 ), and N.
  • the thio group, C 1-5 acyl group, C 1-5 sulfonyl group, phenyl group, 5- to 6-membered heterocycloalkyl group or 5- to 6-membered heteroaryl group may be optionally substituted by 1, 2 or 3 R groups.
  • R 1 is selected from
  • R 2 is selected from the group consisting of H, halogen, C 1-4 alkyl, and C 1-4 alkyl-O-, said C 1-4 alkyl or C 1-4 alkyl- O- is optionally substituted with 1, 2 or 3 halogens.
  • R 2 is selected from the group consisting of H, F, Cl, Br, CF 3 , OCF 3 .
  • R 3 and R 7 above are each independently selected from the group consisting of H, F, and Cl.
  • R 4 is selected from the group consisting of H and
  • R 5 is selected from the group consisting of H and Cl.
  • R 6 above is selected from the group consisting of H, Cl, and CH 3 .
  • X 2 is selected from the group consisting of C(R 6 ) and N, and other variables are as defined above.
  • the above X 2 is selected from the group consisting of C(H), C(Cl), C(CH 3 ), and N, and other variables are as defined above.
  • R 2 is selected from the group consisting of H, halogen, C 1-4 alkyl, and C 1-4 alkyl-O-, said C 1-4 alkyl or C 1-4 alkyl- O- is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined above.
  • R 2 above is selected from the group consisting of H, F, Cl, Br, CF 3 , OCF 3 , and other variables are as defined above.
  • R 3 and R 7 above are each independently selected from the group consisting of H, F, and Cl, and other variables are as defined above.
  • R 4 is selected from the group consisting of H and Other variables are as defined above.
  • R 5 above is selected from the group consisting of H and Cl, and other variables are as defined above.
  • R 6 above is selected from the group consisting of H, Cl, and CH 3 , and other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from
  • R 2 , R 3 and R 7 are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from
  • R 2 , R 3 and R 7 are as defined above.
  • the invention also provides a compound or a pharmaceutically acceptable salt thereof, selected from
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of an IAP inhibitor.
  • the present invention provides a method of treating a disease which is beneficial for IAP inhibition, comprising administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof, and the above Pharmaceutical composition.
  • the present invention provides the use of the above compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof as described above for the treatment of a disease which benefits from IAP inhibition.
  • the present invention provides the above compound or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the use as a medicament is used as a medicament for treating a disease that benefits from IAP inhibition.
  • the above IAP inhibitor refers to a cIAP1 inhibitor.
  • the above IAP inhibitor or cIAP1 inhibitor is a medicament for treating cancer.
  • the cancer described above is breast cancer.
  • the compounds of the invention are SMAC mimetics, have an antagonistic effect on cIAP1, and are selective for cIAP1 and XIAP.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a relatively acidic functional group is contained in the compound of the present invention
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts. Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are non-mirrored.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the compound of the invention when the compound of the invention is an isomer, there is “enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomer enriched” ".
  • the term “enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refers to one of the isomers or enantiomers
  • the content is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96 or more. %, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or 99.9% or more.
  • the compound of the invention when the compound of the invention is an isomer, there is an “isomer excess” or an “enantiomeric excess”.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable such as R
  • R When it occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, any combination of variables and/or variants thereof is permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in conjunction with another term, is represented by a number of carbon atoms and at least A stable, linear, branched or cyclic hydrocarbon radical consisting of a hetero atom or a combination thereof.
  • heteroalkyl by itself or in conjunction with another term, refers to a stable straight or branched alkyl radical or composition thereof consisting of a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including the position at which the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy).
  • alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • heterocycloalkyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkyl”, respectively, and further, in the case of the "heterocycloalkyl", a heteroatom may occupy a heterocycloalkyl group.
  • the heterocycloalkyl group is a 4-6 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkane.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetra Hydropyranyl, piperidinyl, piperazinyl, morpholinyl, dioxoalkyl, dithiaalkyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2- Thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or oxetanyl,
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • alkylamino refers to -NH-alkyl.
  • alkylthio refers to -S-alkyl.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms.
  • the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • C n-n+m or C n -C n+m includes any one of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range of n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n to n
  • the +m element indicates that the number of atoms on the ring is n to n+m, for example, the 3-12 element ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
  • a 10-membered ring, a 11-membered ring, and a 12-membered ring and includes any one of n to n+m, for example, a 3-12-membered ring including a 3-6-membered ring, a 3-9-membered ring, and a 5-6-membered ring. Ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • DMF stands for N,N-dimethylformamide
  • DMA stands for N,N-dimethylacetamide
  • TEA stands for triethylamine
  • DIPEA stands for N,N-diisopropyl B Amine
  • Pd(dppf)Cl 2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • Pd 2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium
  • DPPF Represents 1,1'-bisdiphenylphosphinoferrocene
  • NBS stands for N-bromosuccinimide
  • POCl 3 stands for phosphorus oxychloride
  • HOBt stands for 1-hydroxybenzotriazole
  • HATU stands for 2-( 7-Oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • EDCI stands
  • the compound (A) is deprotected under acidic conditions (such as a hydrogen chloride / ethyl acetate solution) to give the compound (B).
  • acidic conditions such as a hydrogen chloride / ethyl acetate solution
  • Compound (B) and compound (C) undergo an acid amine condensation reaction to obtain compound (D).
  • the reaction requires a suitable condensing agent (such as HOBt), a suitable dehydrating agent (such as EDCI), and a suitable base. (such as DIPEA).
  • Compound (D) is then deprotected under acidic conditions (such as hydrogen chloride / ethyl acetate solution) to give the compound of formula (I).
  • the compound (G) can be produced by a substitution reaction of the compound (E) with the compound (F), which requires a suitable base (such as potassium carbonate), and according to the reaction scheme 2, the reaction is more Preference is given to performing at high temperatures.
  • Compound (G) is deprotected under acidic conditions (such as hydrogen chloride / ethyl acetate solution) to give compound (H).
  • Compound (A) can be prepared by acid amine condensation reaction of compound (H) with compound (I), which requires a suitable condensing agent (such as HOBt), a suitable dehydrating agent (such as EDCI), a suitable base (such as DIPEA). .
  • Reaction Scheme 3 prepares compound (A), where X 1 is N and X 2 is CCl,
  • the compound (K) can be produced by an acid amine condensation reaction of the compound (J) with the compound (I), which requires a suitable condensing agent (such as HATU), and a suitable base (such as DIPEA).
  • Compound (K) is reacted with p-toluenesulfonyl chloride under basic conditions (such as TEA) to give compound (L).
  • the compound (A) can be produced by subjecting the compound (L) to the compound (E) by a substitution reaction under basic conditions such as potassium carbonate, and the reaction is more preferably carried out at a high temperature according to the reaction scheme 2.
  • Reaction Scheme 4 prepares compound (E), where X 1 is N and X 2 is C,
  • the compound (E) when R 1 is CH 3 CO- or CH 3 CH(CH 3 )CO-, the compound (E) may form a FC acyl group from the compound (V) and the corresponding acid halide or acid anhydride.
  • the reaction is prepared by a suitable catalyst (such as aluminum trichloride).
  • the compound (E) can be prepared by reacting the compound (V) with a cyanating reagent which requires a suitable cyanating agent such as chlorosulfonyl isocyanate, according to Reaction Scheme 4, the reaction More preferred to proceed at low temperatures.
  • a cyanating reagent which requires a suitable cyanating agent such as chlorosulfonyl isocyanate, according to Reaction Scheme 4, the reaction More preferred to proceed at low temperatures.
  • R 1 is -CONH 2
  • the compound (V) is reacted with a cyanating reagent to obtain a compound (W) which requires a suitable cyanating agent (such as chlorosulfonyl isocyanate).
  • a suitable cyanating agent such as chlorosulfonyl isocyanate
  • the reaction is carried out. More preferred to proceed at low temperatures.
  • Compound (E) can be produced by subjecting compound (W) to hydrolysis under basic conditions, which requires a suitable base such as potassium carbonate, a suitable solvent such as an ethanol/hydrogen peroxide mixed solvent.
  • compound (E) can be prepared by sulfonylation of compound (V) with methanesulfonyl chloride under basic conditions, which requires a suitable base (such as potassium t-butoxide).
  • a suitable catalyst such as a solution of triethylborane in tetrahydrofuran, depending on reaction scheme 4, prefers to proceed at low temperatures.
  • Compound (E) can be prepared by reacting compound (X) with dimethylamine, which requires a suitable catalyst (such as sodium cyanide), a suitable oxidizing agent (such as manganese dioxide).
  • a suitable catalyst such as sodium cyanide
  • a suitable oxidizing agent such as manganese dioxide
  • R 1 When the compound (V) is halogenated with a brominated reagent, the compound (Y) is obtained, which requires a suitable bromine reagent (such as NBS).
  • Compound (E) can be prepared by Suzuki coupling reaction of compound (Y) with the corresponding boronic acid or boric acid ester, which requires a suitable catalyst (such as Pd(dppf)Cl 2 ), a suitable base (such as potassium phosphate), according to In Reaction Scheme 4, the reaction is more preferred to proceed at elevated temperatures.
  • R 1 When the compound (V) is halogenated with an iodo reagent to obtain an intermediate compound, the reaction requires a suitable iodo reagent (such as elemental iodine), and then the intermediate compound is reacted with Boc 2 O to obtain a compound (Z).
  • a suitable catalyst such as DMAP
  • a suitable base such as TEA
  • Compound (E) can be prepared by Ullmann coupling reaction of compound (Z) with the corresponding saturated aza five-membered ring compound, which requires a suitable catalyst (such as cuprous iodide), a suitable ligand (such as N, N- Dimethylethylenediamine), a suitable base (such as cesium carbonate), according to Reaction Scheme 4, the reaction is more preferred to proceed at elevated temperatures.
  • a suitable catalyst such as cuprous iodide
  • a suitable ligand such as N, N- Dimethylethylenediamine
  • a suitable base such as cesium carbonate
  • step 1
  • step 1
  • Example 3 The preparation method of Example 3 is referred to Example 1.
  • 1 H NMR 400MHz, CD 3 OD
  • ⁇ 8.57 s, 1H
  • 8.41 s, 1H
  • 4.64 - 4.54 m, 2H
  • LCMS m/z: 535.2 (M+1).
  • Example 4 The preparation method of Example 4 is referred to Example 1.
  • Example 5 The preparation method of Example 5 is referred to Example 1.
  • Example 6 The preparation method of Example 6 is referred to Example 1.
  • Example 7 The preparation method of Example 7 is referred to Example 1.
  • Example 9 The preparation method of Example 9 is referred to Example 1.
  • Example 10 The preparation method of Example 10 is referred to Example 1.
  • step 1
  • the preparation method of the compound 12-5 refers to the compound 1-4.
  • the preparation method of the compound 12-6 refers to the compound 1-8.
  • the preparation method of the compound 12-7 refers to the compound 1-10.
  • Example 1 The method for preparing the hydrochloride salt of Example 13 is referred to Example 1.
  • step 1
  • the preparation method of the compound 14-6 refers to the compound 1-5.
  • the preparation method of the compound 14-8 refers to the compound 1-8.
  • the preparation method of the compound 14-9 refers to the compound 1-10.
  • Example 14 The preparation method of Example 14 is referred to Example 1.
  • step 1
  • the preparation method of the compound 16-2 refers to the compound 1-4.
  • the preparation method of the compound 16-6 refers to the compound 1-5.
  • the preparation method of the compound 16-7 refers to the compound 1-7.
  • the preparation method of the compound 16-8 refers to the compound 1-8.
  • the preparation method of the compound 16-9 refers to the compound 1-10.
  • Example 16 The preparation method of Example 16 is referred to Example 1.
  • Example 17 The preparation method of Example 17 is referred to Example 16 and Example 1.
  • Example 18 The preparation method of Example 18 is referred to Example 16 and Example 1.
  • Example 19 The preparation method of Example 19 is referred to Example 14.
  • 1 H NMR 400 MHz, CD 3 OD
  • step 1
  • the preparation method of the compound 20-2 refers to the compound 1-4.
  • the preparation method of the compound 20-3 refers to the compound 1-5.
  • the preparation method of the compound 20-4 refers to the compound 1-7.
  • the preparation method of the compound 20-5 refers to the compound 1-8.
  • the preparation method of the compound 20-6 refers to the compound 1-10.
  • Example 20 The preparation method of Example 20 is referred to Example 1.
  • Example 21 The preparation method of Example 21 is referred to Example 20.
  • 1 H NMR 400 MHz, CD 3 OD
  • step 1
  • Example 22 The preparation method of Example 22 is referred to Example 1.
  • step 1
  • the preparation method of the compound 23-6 refers to the compound 1-5.
  • the preparation method of the compound 23-7 refers to the compound 1-7.
  • the preparation method of the compound 23-8 refers to the compound 1-8.
  • the preparation method of the compound 23-9 refers to the compound 1-10.
  • Example 23 The preparation method of Example 23 is referred to Example 1.
  • Example 24 The preparation method of Example 24 is referred to Example 1.
  • 1 H NMR 400MHz, CD 3 OD
  • ⁇ 8.36-8.23 m, 2H
  • 4.60-4.44 m, 3H
  • 4.21-4.05 m, 1H
  • 3.97-3.77 m, 2H
  • 3.44 (spt, J 6.8 Hz, 1H)
  • 2.23 - 2.07 m, 1H
  • 2.06-1.96 m, 1H
  • 1.85-1.64 m, 8H
  • 1.27-1.05 m, 10H
  • LCMS ESI
  • step 1
  • the preparation method of the compound 25-4 refers to the compound 1-4.
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.43 - 7.24 (m, 5H), 7.22 - 7.13 (m, 1H), 7.13 - 7.07 (m, 1H), 7.05 - 6.97 (m, 1H), 4.49 - 4.36 (m, 1H), 4.31-4.24 (m, 1H), 3.50-3.33 (m, 1H), 3.26-3.11 (m, 1H), 2.35 (s, 3H), 1.95-1.85 (m, 1H), 1.83 -1.71 (m, 2H), 1.59-1.46 (m, 11H); LCMS (ESI) m/z: 431.3 (M+23).
  • the preparation method of the compound 25-6 refers to the compound 1-7.
  • the preparation method of the compound 25-7 refers to the compound 1-8.
  • the preparation method of the compound 25-8 refers to the compound 1-10.
  • Example 25 The preparation method of Example 25 is referred to Compound Example 1.
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 26 The preparation method of Example 26 is referred to Example 25.
  • 1 H NMR 400 MHz, CD 3 OD
  • step 1
  • the preparation method of the compound 28-5 refers to the compound 1-4.
  • the preparation method of the compound 28-6 refers to the compound 1-5.
  • the preparation method of the compound 28-7 refers to the compound 1-7.
  • the preparation method of the compound 28-8 refers to the compound 1-8.
  • the preparation method of the compound 28-9 refers to the compound 1-10.
  • Example 28 The preparation method of Example 28 is referred to Example 1.
  • Example 29 The preparation method of Example 29 is referred to Example 28.
  • 1 H NMR 400MHz, CD 3 OD
  • Example 30 The preparation method of Example 30 is referred to Example 28.
  • 1 H NMR 400MHz, CD 3 OD
  • step 1
  • the preparation method of the compound 31-8 is referred to the compound 1-5.
  • the preparation method of the compound 31-9 refers to the compound 1-7.
  • the preparation method of the compound 31-10 is referred to the compound 1-8.
  • Example 31 The preparation method of Example 31 is referred to Example 1.
  • the compounds of the invention are IAP inhibitors.
  • the IC 50 as used herein refers to the concentration of the corresponding reagent when a certain reagent is used to produce 50% maximal inhibition.
  • Test buffer system (cIAP1 BIR3 or XIAP BIR3 buffer): 100 mM potassium phosphate, pH 7.5, 0.1% BSA, 0.005% Triton X-100 and 1% dimethyl sulfoxide.
  • Probe ARPFAQ-K(5-FAM)-NH 2 .
  • cIAP1-BIR3-his RBC Cat#APT-11-370, the BIR3 domain of human cIAP1 (covering amino acids 258 to 363; cIAP1 BIR3) was expressed and purified as a GST-fusion protein from E. coli.
  • XIAP-BIR3-his RBC Cat#APT-11-374, BIR3 domain of XIAP (covering amino acids 255 to 356; XIAP BIR3) was expressed and purified from Escherichia coli (E. coli) as a GST-fusion protein.
  • Reaction conditions 5 nM ARPFAQ-K (5-FAM)-NH 2, 20 nM cIAP1 BIR3 and 30 nM XIAP BIR3.
  • the compounds of the invention exhibit cIAP1 BIR3 binding activity and are selective for cIAP1 and XIAP.
  • test compound is made to a high concentration of 10 ⁇ M, and the test compound is diluted 5 times, and each compound is diluted by 10 concentration gradients), and then the cell plate is returned to the carbon dioxide incubator for cultivation. 7 days.
  • the compounds of the invention have MDA-MB-231 cell anti-proliferative activity.
  • Example 1 3.7 74.7 70.0
  • Example 2 5.0 29.9 54.8
  • Example 3 1.0 18.1 16.0
  • Example 4 2.6 97.0 220.0
  • Example 5 2.6 95.9 75.0
  • Example 6 58.3 9.3 497.0
  • Example 8 5.6 40.3 75.0
  • Example 9 5.7 20.0 26.0
  • Example 10 4.5 27.2 32.4
  • Example 11 5.2 139.0 74.8
  • Example 13 5.0 30.6 44.3
  • Example 14 6.2 49.9 57.7
  • Example 15 4.0 258.0 93.0
  • Example 16 8.4 346.0 109.3
  • Example 17 1.9 80.7 79.0
  • Example 18 5.1 42.5 22.5
  • Example 19 4.6 129.0 43.1
  • Example 20 1.1 53.9 75.0
  • Example 21 4.2 37.4 16.4
  • Example 22 3.0 42.0 85.0
  • Example 23 4.6 21.3 45.2
  • Example 24 4.1 19.2 73.0
  • Example 25 6.8 20
  • mice Female, 6-8 weeks, weighing approximately 18-22 grams, maintained the mice in a special pathogen free environment and in a single ventilated cage (3 mice per cage). All cages, bedding and water are disinfected prior to use. All animals are free to access a standard certified commercial laboratory diet. A total of 48 mice purchased from Shanghai BK Laboratory Animal Co., Ltd. were used for the study. Tumor cells (10 x 10 6 in 0.2 ml phosphate buffer) were implanted subcutaneously in the right flank of each mouse for tumor growth. Dosing begins when the average tumor volume reaches approximately 147 cubic millimeters. The test compound was orally administered daily at a dose of 30 mg/kg.
  • the anti-tumor efficacy is determined by dividing the average tumor-increased volume of the treated animals by the average tumor-increased volume of the untreated animals.
  • the compounds of the invention exhibit potency.
  • mice Female, 6-8 weeks, weighing approximately 18-22 grams, maintained the mice in a special pathogen free environment and in a single ventilated cage (3 mice per cage). All cages, bedding and water are disinfected prior to use. All animals are free to access a standard certified commercial laboratory diet. A total of 48 mice purchased from Shanghai BK Laboratory Animal Co., Ltd. were used for the study. Tumor cells (10 x 10 6 in 0.2 ml phosphate buffer) were implanted subcutaneously in the right flank of each mouse for tumor growth. Dosing begins when the average tumor volume reaches about 110 cubic millimeters. The test compound was orally administered daily at a dose of 30 mg/kg.
  • the anti-tumor efficacy is determined by dividing the average tumor-increased volume of the treated animals by the average tumor-increased volume of the untreated animals.
  • the compounds of the invention exhibited better pharmacodynamic effects.

Abstract

一类用作IAP抑制剂的SMAC模拟物，具体公开了式(I)所示的化合物、其异构体及其药学上可接受的盐。所述IAP抑制剂是治疗癌症，特别是乳腺癌的药物。

Description

用作IAP抑制剂的SMAC模拟物及其用途
相关申请的交叉引用
本申请要求于2017年11月13日向中国国家知识产权局提交的第201711117079.6号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本发明描述了抑制IAP(凋亡抑制蛋白，inhibitor of apoptosis proteins)的化合物，其制备过程，及其在治疗多种疾病中的用途。本发明的化合物用于治疗癌症、自身免疫性疾病和其他涉及细胞凋亡缺陷的疾病。
背景技术
程序性细胞死亡在调节细胞数量和从正常组织中清除应激或受损细胞方面起关键作用。实际上，大部分细胞类型中所固有的凋亡信号传导网络机制提供了抗人类癌症发展和恶化的主要屏障。然而，所有癌细胞的共同性在于它们无法执行凋亡程序，并由于正常凋亡机制的缺失而缺乏适当的凋亡。目前大多数癌症疗法包括化疗、放射疗法和免疫疗法，均通过间接诱导癌细胞凋亡发挥作用。因而，癌细胞由于正常凋亡机制的缺陷而无法执行凋亡程序通常与对化疗、放射疗法或免疫疗法诱导的细胞凋亡的抗性增强有关。因此，以直接抑制癌细胞凋亡中扮演了重要角色的关键负调控因子为目标将成为极有希望的用于新的抗癌药物设计的治疗策略。
目前已经确认了两类重要的细胞凋亡的负调节因子。第一类调节因子是Bcl-2族蛋白，例如两个有效的抗凋亡分子，Bcl-2和Bcl-XL蛋白。
细胞凋亡的第二类重要的负调节因子是细胞凋亡蛋白的抑制剂(IAPs)。IAP最初在杆状病毒中由于其能够取代P35蛋白质功能而被发现。这类蛋白包括：XIAP、cIAP1、cIAP2、ML-IAP、ILP-2、NAIP、Apollon和Survivin。其中X染色体连锁的细胞凋亡抑制剂(XIAP)通过直接抑制半胱天冬酶-3，半胱天冬酶-7和半胱天冬酶-9，起到对抗凋亡的作用。cIAPs则主要是通过阻断死亡受体通路抑制凋亡，随着cIAPs的降解，其底物NIK(NF-κB-inducing kinase)免于被降解而积聚，积聚的NIK通过非经典通路激活NF-κB；NF-κB的激活促进TNFα分泌，TNFα与TNF-R1(TNF receptor1)结合启动死亡受体通路，由于cIAPs的降解，RIPK1(receptor interacting protein kinase 1，受体相互作用蛋白激酶1)的分泌也会增加，其与FADD(Fas-associated death domin，Fas相关的死亡结构域)和caspase-8(半胱天冬酶-8)一起形成促凋亡RIPK1-FADD-caspase-8复合物，然后半胱天冬酶-3激活，导致细胞凋亡。
已在多种恶性疾病中观察到由11q21-q23区(其涵盖两种基因)的频繁染色体扩增而导致的cIAP1及cIAP2的过表达，该多种恶性疾病包括神经胚细胞瘤、肾细胞癌、结直肠癌及胃癌等。
目前已有多个药物分子进入临床并且进展积极，如LCL-161,Debio 1143,BI-891065及ASTX-660等。
发明内容
本发明提供式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2018115256-appb-000001
其中，
X 1选自C(R 5)和N；
X 2选自C(R 6)、N、O和S；
Figure PCTCN2018115256-appb-000002
分别独立地选自单键和双键；
L选自单键和-O-；
R 1选自-C(＝O)NH 2、CN、C 1-5烷基、C 1-5杂烷基、苯基、5～6元杂芳基和5～6元杂环烷基，所述C 1-5烷基、C 1-5杂烷基、苯基、5～6元杂芳基或5～6元杂环烷基任选被1、2或则3个R取代；
R 2选自H、卤素、CN、COOH、-C(＝O)NH 2、C 1-4烷基和C 1-4杂烷基，所述C 1-4烷基或C 1-4杂烷基任选被1、2或3个R取代；
R 3和R 7分别独立地选自H、卤素和C 1-4烷基，所述C 1-4烷基任选被1、2或3个R取代；
R 4选自H、苯基和5～6元杂芳基；
R 5选自H和卤素；
R 6选自H、卤素、C 1-4烷基、C 1-4杂烷基、CN和COOH，所述C 1-4烷基或C 1-4杂烷基任选被1、2或3个R取代；
R选自卤素、OH、CN、CH 3、CH 3CH 2、CH 3CH 2CH 2、CH(CH 3) 2、OCH 3、OCF 3、CHF 2、CH 2F和NH 2；所述C 1-4杂烷基、C 1-5杂烷基、5～6元杂环烷基和5～6元杂芳基分别包含1、2或者3个独立选自-NH-、-O-、-S-、N、-C(＝O)O-、-C(＝O)-、-C(＝O)NH-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-、-C(＝NH)-、-S(＝O) 2NH-、-S(＝O)NH-和-NHC(＝O)NH-的杂原子和杂原子团。
在本发明的一些方案中，上述化合物或其药学上可接受的盐选自
Figure PCTCN2018115256-appb-000003
其中，
Figure PCTCN2018115256-appb-000004
X 1、X 2、L、R 1、R 2、R 3、R 4和R 7如上述所定义。
在本发明的一些方案中，上述X 2选自C(R 6)和N。
在本发明的一些方案中，上述X 2选自C(H)、C(Cl)、C(CH 3)和N。
在本发明的一些方案中，上述R 1选自-C(＝O)NH 2、CN、C 1-5烷基、C 1-5烷氧基、C 1-5烷氨基、C 1-5烷硫基、C 1-5酰基、C 1-5磺酰基、苯基、含有1-2个独立地选自N或O原子的任选被1个氧代的5～6元杂环烷基和含有1-2个独立地选自N原子的5～6元杂芳基，所述C 1-5烷基、C 1-5烷氧基、C 1-5烷氨基、C 1-5烷硫基、C 1-5酰基、C 1-5磺酰基、苯基、5～6元杂环烷基或5～6元杂芳基任选被1、2或则3个R取代。
在本发明的一些方案中，上述R 1选自-C(＝O)NH 2、CN、CH 3、CH 3CH 2、C 1-5烷基-C(＝O)-、C 1-4烷基-C(＝O)-、C 1-5烷基-S(＝O) 2-、C 1-5烷基-N(H)C(＝O)-、C 1-4烷基-N(H)C(＝O)-、(C 1-2烷基) 2-N-C(＝O)-、苯基、
Figure PCTCN2018115256-appb-000005
所述CH 3、CH 3CH 2、C 1-5烷基-C(＝O)-、C 1-4烷基-C(＝O)-、C 1-5烷基-S(＝O) 2-、C 1-5烷基-N(H)C(＝O)-、C 1-4烷基-N(H)C(＝O)-、(C 1-2烷基) 2-N-C(＝O)-、苯基、
Figure PCTCN2018115256-appb-000006
任选被1、2或则3个R取代。
在本发明的一些方案中，上述R 1选自
Figure PCTCN2018115256-appb-000007
Figure PCTCN2018115256-appb-000008
在本发明的一些方案中，上述R 2选自H、卤素、C 1-4烷基和C 1-4烷基-O-，所述C 1-4烷基或C 1-4烷基-O-任选被1、2或3个卤素取代。
在本发明的一些方案中，上述R 2选自H、F、Cl、Br、CF 3、OCF 3。
在本发明的一些方案中，上述R 3和R 7分别独立地选自H、F和Cl。
在本发明的一些方案中，上述R 4选自H和
Figure PCTCN2018115256-appb-000009
在本发明的一些方案中，上述R 5选自H和Cl。
在本发明的一些方案中，上述R 6选自H、Cl和CH 3。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018115256-appb-000010
选自
Figure PCTCN2018115256-appb-000011
Figure PCTCN2018115256-appb-000012
在本发明的一些方案中，上述结构单元
Figure PCTCN2018115256-appb-000013
选自
Figure PCTCN2018115256-appb-000014
在本发明的一些方案中，上述X 2选自C(R 6)和N，其他变量如上述所定义。
在本发明的一些方案中，上述X 2选自C(H)、C(Cl)、C(CH 3)和N，其他变量如上述所定义。
在本发明的一些方案中，上述R 1选自-C(＝O)NH 2、CN、C 1-5烷基、C 1-5烷氧基、C 1-5烷氨基、C 1-5烷硫基、C 1-5酰基、C 1-5磺酰基、苯基、含有1-2个独立地选自N或O原子的任选被1个氧代的5～6元 杂环烷基和含有1-2个独立地选自N原子的5～6元杂芳基，所述C 1-5烷基、C 1-5烷氧基、C 1-5烷氨基、C 1-5烷硫基、C 1-5酰基、C 1-5磺酰基、苯基、5～6元杂环烷基或5～6元杂芳基任选被1、2或则3个R取代，其他变量如上述所定义。
在本发明的一些方案中，上述R 1选自-C(＝O)NH 2、CN、CH 3、CH 3CH 2、C 1-5烷基-C(＝O)-、C 1-4烷基-C(＝O)-、C 1-5烷基-S(＝O) 2-、C 1-5烷基-N(H)C(＝O)-、C 1-4烷基-N(H)C(＝O)-、(C 1-2烷基) 2-N-C(＝O)-、苯基、
Figure PCTCN2018115256-appb-000015
所述CH 3、CH 3CH 2、C 1-5烷基-C(＝O)-、C 1-4烷基-C(＝O)-、C 1-5烷基-S(＝O) 2-、C 1-5烷基-N(H)C(＝O)-、C 1-4烷基-N(H)C(＝O)-、(C 1-2烷基) 2-N-C(＝O)-、苯基、
Figure PCTCN2018115256-appb-000016
任选被1、2或则3个R取代，其他变量如上述所定义。
在本发明的一些方案中，上述R 2选自H、卤素、C 1-4烷基和C 1-4烷基-O-，所述C 1-4烷基或C 1-4烷基-O-任选被1、2或3个卤素取代，其他变量如上述所定义。
在本发明的一些方案中，上述R 2选自H、F、Cl、Br、CF 3、OCF 3，其他变量如上述所定义。
在本发明的一些方案中，上述R 3和R 7分别独立地选自H、F和Cl，其他变量如上述所定义。
在本发明的一些方案中，上述R 4选自H和
Figure PCTCN2018115256-appb-000017
其他变量如上述所定义。
在本发明的一些方案中，上述R 5选自H和Cl，其他变量如上述所定义。
在本发明的一些方案中，上述R 6选自H、Cl和CH 3，其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018115256-appb-000018
选自
Figure PCTCN2018115256-appb-000019
Figure PCTCN2018115256-appb-000020
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018115256-appb-000021
选自
Figure PCTCN2018115256-appb-000022
Figure PCTCN2018115256-appb-000023
其他变量如上述所定义。
本发明还有一些方案是由上述各变量任意组合而来。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，选自
Figure PCTCN2018115256-appb-000024
其中，R 2、R 3和R 7如上述所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，选自
Figure PCTCN2018115256-appb-000025
其中，R 2、R 3和R 7如上述所定义。
本发明还提供化合物或其药学上所接受的盐，选自
Figure PCTCN2018115256-appb-000026
Figure PCTCN2018115256-appb-000027
Figure PCTCN2018115256-appb-000028
Figure PCTCN2018115256-appb-000029
在本发明的一些方案中，上述化合物或其药学上可接受的盐，选自
Figure PCTCN2018115256-appb-000030
Figure PCTCN2018115256-appb-000031
Figure PCTCN2018115256-appb-000032
Figure PCTCN2018115256-appb-000033
本发明还提供一种药物组合物，包括治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供上述化合物或其药学上可接受的盐或者上述药物组合物在制备IAP抑制剂中的应用。
另一方面，本发明还提供一种治疗受益于IAP抑制的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的上述化合物或其药学上可接受的盐及其上述药物组合物。
另一方面，本发明还提供上述化合物或其药学上可接受的盐及其上述药物组合物在治疗受益于IAP抑制的疾病中的应用。
另一方面，本发明还提供作为药物使用的上述化合物或其药学上可接受的盐。在本发明的部分实施方案中，所述作为药物使用指作为作为治疗受益于IAP抑制的疾病的药物使用。
在本发明的一些方案中，上述IAP抑制剂指cIAP1抑制剂。
在本发明的一些方案中，上述IAP抑制剂或cIAP1抑制剂是治疗癌症的药物。
在本发明的一些方案中，上述癌症是乳腺癌。
技术效果
本发明化合物为SMAC模拟物，对cIAP1具有拮抗作用，而且对cIAP1和XIAP具有选择性。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关 系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2018115256-appb-000034
和楔形虚线键
Figure PCTCN2018115256-appb-000035
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2018115256-appb-000036
和直形虚线键
Figure PCTCN2018115256-appb-000037
表示立体中心的相对构型，用波浪线
Figure PCTCN2018115256-appb-000038
表示楔形实线键
Figure PCTCN2018115256-appb-000039
或楔形虚线键
Figure PCTCN2018115256-appb-000040
或用波浪线
Figure PCTCN2018115256-appb-000041
表示直形实线键
Figure PCTCN2018115256-appb-000042
和直形虚线键
Figure PCTCN2018115256-appb-000043
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，本发明化合物当是异构体时，存在“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”。所述术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，本发明化合物当是异构体时，存在“异构体过量”或“对映体过量”。所述术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R、
Figure PCTCN2018115256-appb-000044
)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，任何变量和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2018115256-appb-000045
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018115256-appb-000046
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018115256-appb-000047
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018115256-appb-000048
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、 苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示由一定数目的碳原子和至少一个杂原子组成的，稳定的直链、支链或环状的烃原子团或其组合。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示由一定数目的碳原子和至少一个杂原子组成的，稳定的直链或支链的烷基原子团或其组合物。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、 -CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“杂环烷基”本身或者与其他术语联合分别表示环化的“杂烷基”，此外，就该“杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。在一些实施方案中，所述杂环烷基为4～6元杂环烷基；在另一些实施方案中，所述杂环烷基为5～6元杂环烷。杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、二恶烷基、二噻烷基、异恶唑烷基、异噻唑烷基、1,2-恶嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或氧杂环庚烷基、
Figure PCTCN2018115256-appb-000049
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
除非另有规定，术语“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6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、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“烷基氨基”指-NH-烷基。
除非另有规定，术语“烷硫基”指-S-烷基。
除非另有规定，术语“酰基”指烷基-C(＝O)-。
除非另有规定，术语“烷基磺酰基”指烷基-S(＝O) 2-。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起 或共价连接。
除非另有规定，术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方 式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：DMF代表N,N-二甲基甲酰胺；DMA代表N,N-二甲基乙酰胺；TEA代表三乙胺；DIPEA代表N,N-二异丙基乙胺；Pd(dppf)Cl 2代表[1,1'-双(二苯基磷)二茂铁]二氯化钯；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；DPPF代表1,1’-双二苯基膦二茂铁；NBS代表N-溴代丁二酰亚胺；POCl 3代表三氯氧磷；HOBt代表1-羟基苯并三唑；HATU代表2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；DIAD代表偶氮二甲酸二异丙酯；Boc 2O代表二碳酸二叔丁酯；ODPH代表O-二苯基膦羟胺。
化合物经手工或者
Figure PCTCN2018115256-appb-000050
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
反应流程1制备式I所示化合物，
Figure PCTCN2018115256-appb-000051
在反应流程1所示的反应中，化合物(A)在酸性条件(比如氯化氢/乙酸乙酯溶液)下脱保护得到化合物(B)。化合物(B)与化合物(C)发生酸胺缩合反应得到化合物(D)，根据反应流程1，该反应需要合适的缩合剂(比如HOBt)，合适的脱水剂(比如EDCI)，以及合适的碱(比如DIPEA)。然后化合物(D)在酸性条件(比如氯化氢/乙酸乙酯溶液)下脱保护得到式(I)所示化合物。
反应流程2制备化合物(A)，X 2不是CCl，
Figure PCTCN2018115256-appb-000052
在反应流程2所示的反应中，化合物(G)可以由化合物(E)与化合物(F)发生取代反应制备，该反应需要合适的碱(比如碳酸钾)，根据反应流程2，该反应更偏好于在高温下进行。化合物(G)在酸性条件(比如氯化氢/乙酸乙酯溶液)下脱保护得到化合物(H)。化合物(A)可以由化合物(H)与化合物(I)发生酸胺缩合反应制备，该反应需要合适的缩合剂(比如HOBt)，合适的脱水剂(比如EDCI)，合适的碱(比如DIPEA)。
反应流程3制备化合物(A)，此处X 1是N，X 2是CCl，
Figure PCTCN2018115256-appb-000053
在反应流程3所示的反应中，化合物(K)可以由化合物(J)与化合物(I)发生酸胺缩合反应制备，该反应需要合适的缩合剂(比如HATU)，以及合适的碱(比如DIPEA)。化合物(K)在碱性条件(比如TEA)下与对甲苯磺酰氯反应得到化合物(L)。化合物(A)可以由化合物(L)与化合物(E)在碱性条件(比如碳酸钾)下发生取代反应制备，根据反应流程2，该反应更偏好于在高温下进行。
反应流程4制备化合物(E)，此处X 1是N，X 2是C，
Figure PCTCN2018115256-appb-000054
在反应流程4所示的反应中，当R 1是CH 3CO-或CH 3CH(CH 3)CO-时，化合物(E)可由化合物(V)与相对应的酰卤或酸酐发生F-C酰基化反应制备，该反应需要合适的催化剂(比如三氯化铝)。
当R 1是-CN时，化合物(E)可由化合物(V)与氰基化试剂发生反应制备，该反应需要合适的氰基化试剂(比如氯磺酰异氰酸酯)，根据反应流程4，该反应更偏好于在低温下进行。
当R 1是-CONH 2时，化合物(V)与氰基化试剂发生反应得到化合物(W)，该反应需要合适的氰基化试剂(比如氯磺酰异氰酸酯)，根据反应流程4，该反应更偏好于在低温下进行。化合物(E)可由化合物(W)在碱性条件下发生水解反应制备，该反应需要合适的碱(比如碳酸钾)，合适的溶剂(比如乙醇/双氧水混合溶剂)。
当R 1是CH 3SO 2-时，化合物(E)可由化合物(V)与甲烷磺酰氯在碱性条件下发生磺酰化反应制备，该反应需要合适的碱(比如叔丁醇钾)，合适的催化剂(比如三乙基硼烷的四氢呋喃溶液)，根据反应流程4，该反应更偏好于在低温下进行。
当R 1是CH 3N(CH 3)CO-时，化合物(V)与POCl 3和DMF发生Vilsmeier-Haack反应得到化合物(X)。化合物(E)可由化合物(X)与二甲胺发生反应制备，该反应需要合适的催化剂(比如氰化钠)， 合适的氧化剂(比如二氧化锰)。
当R 1是
Figure PCTCN2018115256-appb-000055
时，化合物(V)与溴代试剂发生卤化反应得到化合物(Y)，该反应需要合适的溴代试剂(比如NBS)。化合物(E)可由化合物(Y)与相应的硼酸或硼酸酯发生Suzuki偶联反应制备，该反应需要合适的催化剂(比如Pd(dppf)Cl 2)，合适的碱(比如磷酸钾)，根据反应流程4，该反应更偏好于在高温下进行。
当R 1是
Figure PCTCN2018115256-appb-000056
时，化合物(V)与碘代试剂发生卤化反应得到中间体化合物，该反应需要合适的碘代试剂(比如单质碘)，然后该中间体化合物与Boc 2O反应得到化合物(Z)，该反应需要合适的催化剂(比如DMAP)，合适的碱(比如TEA)。化合物(E)可由化合物(Z)与相应的饱和氮杂五元环化合物发生Ullmann偶联反应制备，该反应需要合适的催化剂(比如碘化亚铜)，合适的配体(比如N,N-二甲基乙二胺)，合适的碱(比如碳酸铯)，根据反应流程4，该反应更偏好于在高温下进行。
实施例1
Figure PCTCN2018115256-appb-000057
第1步：
在15℃下，向氯化铵(7.92克，148毫摩尔，5.17毫升，4.0当量)的1,2-二氯乙烷(100毫升)悬浊液中滴加醋酸酐(7.55克，74毫摩尔，6.93毫升，2.0当量)，混合物在15℃下搅拌30分钟，向混合物中加入化合物1-1(5.0克，37毫摩尔，1.0当量)的1,2-二氯乙烷(50毫升)溶液，混合物在15℃搅 拌2小时。向反应液中加入三氯化铝(9.87克，74毫摩尔，2.0当量)，反应液由非均相变为均相，向反应液中再加入醋酸酐(3.78克，37毫摩尔，3.47毫升，1.0当量)，反应液在15℃下搅拌30分钟。LCMS显示原料反应完全。反应液缓慢倒入冰水(200毫升)中，得到的混合物用乙酸乙酯(100毫升×2)萃取，合并有机相用食盐水(100毫升)洗涤后分液，减压浓缩，得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝10：1到1：1)纯化，得到化合物1-2。LCMS(ESI)m/z:178.1(M+1).
第2步：
向化合物1-2(1.36克，6.67毫摩尔，1.0当量)的DMF(20毫升)溶液中加入化合物1-3(7.11克，20.01毫摩尔，3.0当量)和碳酸钾(4.61克，33.35毫摩尔，5.0当量)，在氮气保护下，将得到的混合物加热至100℃，反应15小时。LCMS显示原料没有反应完全，将反应液加热至120℃，反应2小时，LCMS显示反应完全。向反应液中加入水(30毫升)，得到的混合物用乙酸乙酯(30毫升×3)萃取。将合并的有机相用食盐水(30毫升)洗涤后浓缩，得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝10：1到3：1)纯化，得到化合物1-4。LCMS(ESI)m/z:361.1(M+1).
第3步:
在0℃下，向化合物1-4(2.0克，3.71毫摩尔，1.0当量)的乙酸乙酯(20毫升)溶液中加入氯化氢/乙酸乙酯溶液(4.0摩尔/升，20毫升，21.57当量)，得到的反应液在15℃下搅拌1小时，大量固体析出，LCMS显示反应完全。将反应液过滤，滤饼用乙酸乙酯(10毫升)洗涤后干燥，得到化合物1-5，粗品直接用于下一步。 1H NMR(400MHz,DMSO-d 6)δ8.75(s,1H),7.90-7.79(m,2H),7.17(dt,J＝9.2,2.6Hz,1H),4.84-4.58(m,2H),3.36-3.20(m,1H),3.19-3.04(m,1H),2.44(d,J＝2.8Hz,4H),2.18-2.06(m,1H),2.02(br dd,J＝7.9,5.5Hz,1H),1.88(td,J＝12.6,7.9Hz,1H),1.80-1.67(m,1H)；LCMS(ESI)m/z:261.1(M+1).
第4步:
向化合物1-5(1.0克，3.37毫摩尔，1.0当量)的二氯甲烷(30毫升)溶液中加入化合物1-6(1.30克，5.05毫摩尔，1.5当量)，HOBt(500.85毫克，3.71毫摩尔，1.1当量)，EDCI(710.56毫克，3.71毫摩尔，1.1当量)和DIPEA(1.31克，10.11毫摩尔，1.76毫升，3当量)，将得到的混合物在15℃下反应16小时。LCMS显示反应完全。将反应液倒入水(50毫升)中，得到的混合物用二氯甲烷(50毫升×3)萃取。合并的有机相浓缩，得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝10：1到1：1)纯化，得到化合物1-7。LCMS(ESI)m/z:500.2(M+1).
第5步：
在0℃下，向化合物1-7(1.75克，3.39毫摩尔，1.0当量)的乙酸乙酯(20毫升)溶液中加入氯化氢/乙酸乙酯(4.0摩尔/升，20毫升，23.61当量)，混合物在15℃下反应1小时，LCMS显示反应完全。将反应液浓缩，得到化合物1-8，粗品直接用于下一步。LCMS(ESI)m/z:400.1(M+1).
第6步：
向化合物1-8(1.5克，3.44毫摩尔，1.0当量)的二氯甲烷(30毫升)溶液中加入化合物1-9(1.05克，5.16毫摩尔，1.5当量)，HOBt(511.41毫克，3.78毫摩尔，1.1当量)，EDCI(725.54毫克，3.78毫摩尔，1.1当量)和DIPEA(1.33克，10.32毫摩尔，1.8毫升，3当量)，将得到的反应液在15℃下反应14小时。LCMS显示反应完全。将反应液倒入水(50毫升)中，得到的混合物用二氯甲烷(50毫升 ×3)萃取，将合并的有机相浓缩。得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝2：1到1：4)纯化，得到化合物1-10。LCMS(ESI)m/z:585.3(M+1).
第7步：
在0℃下，向化合物1-10(1.30克，2.22毫摩尔，1.0当量)的乙酸乙酯(20毫升)溶液中加入氯化氢/乙酸乙酯(4.0摩尔/升，18.57毫升，33.41当量)，将得到的混合物在15℃下反应1小时。LCMS显示反应完全。将反应液浓缩，得到的残余物通过制备的HPLC(盐酸体系，流动相：水(0.05％盐酸)-乙腈，梯度：乙腈15％-25％)纯化，得到实施例1的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.28(s,1H),7.87(dd,J＝9.7,2.4Hz,1H),7.78(dd,J＝8.9,4.2Hz,1H),7.04(dt,J＝9.0,2.4Hz,1H),4.56-4.42(m,3H),4.14-4.02(m,1H),3.95(q,J＝6.8Hz,1H),3.83(q,J＝8.4Hz,1H),3.77-3.66(m,1H),2.67(s,3H),2.50(s,3H),2.25-2.09(m,1H),2.03-1.93(m,1H),1.85-1.64(m,9H),1.51(d,J＝7.0Hz,3H),1.33-1.01(m,6H)；LCMS(ESI)m/z:485.2(M+1).
实施例2
Figure PCTCN2018115256-appb-000058
第1步：
在15℃下，向氯化铵(3.53克，65.97毫摩尔，2.31毫升，2.0当量)的1,2-二氯乙烷(10毫升)悬浊液中滴加醋酸酐(6.73克，65.97毫摩尔，6.18毫升，2.0当量)，混合物在15℃下搅拌15分钟，向混合物中加入化合物2-1(5.0克，32.98毫摩尔，1.0当量)，混合物在15℃搅拌2小时。向反应液中加入三氯化铝(8.80克，65.97毫摩尔，2.0当量)，反应液在15℃下搅拌30分钟，向反应液中再加入醋酸酐(3.37克，32.98毫摩尔，3.09毫升，1.0当量)，反应液在15℃下搅拌15分钟。LCMS显示原料反应完全。反应液缓慢倒入冰水中，得到的混合物用乙酸乙酯(100毫升*3)萃取，萃取液用Na 2SO 4 干燥，减压浓缩，得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝1：1)纯化，得到化合物2-2。LCMS(ESI)m/z:194.1(M+1).
第2步：
向化合物1-3(7.54克，20.66毫摩尔，2.0当量)的DMF(70毫升)溶液中加入化合物2-2(2.00克，10.33毫摩尔，1.0当量)和碳酸钾(7.14克，51.65毫摩尔，5.0当量)，混合物加热在100℃下搅拌12小时。向反应液中加入水(300毫升)和乙酸乙酯(300毫升)，有机相用食盐水(100毫升)洗涤，Na 2SO 4干燥，过滤，减压浓缩得到化合物2-3。LCMS(ESI)m/z:377.0(M+1).
第3步:
向化合物2-3(2.4克，3.07毫摩尔，1.0当量)的二氧六环(20毫升)溶液中加入氯化氢/二氧六环溶液(4.0摩尔/升，20毫升，26.04当量)，得到的反应液在15℃下搅拌10小时，LCMS显示反应完全。将反应液过滤，滤饼用乙酸乙酯(10毫升*3)洗涤后干燥，得到化合物2-4，粗品直接用于下一步。LCMS(ESI)m/z:277.1(M+1).
第4步:
向化合物1-6(625.81毫克，2.43毫摩尔，1.1当量)的DMF(5毫升)的溶液中加入DIPEA(857.20毫克，6.63毫摩尔，1.16毫升，3当量)和HATU(1.01克，2.65毫摩尔，1.2当量)，混合物在15℃下搅拌30分钟，化合物2-4(700毫克，2.21毫摩尔，1.0当量，盐酸盐)加入到反应液中，反应混合物在15℃下搅拌1.5小时。向反应液中加入水(30毫升)和乙酸乙酯(40毫升)，有机相用柠檬酸(20毫升，10％水溶液)和食盐水(20毫升)洗涤，Na 2SO 4干燥，过滤，减压浓缩得到化合物2-5。LCMS(ESI)m/z:516.2(M+1).
第5步：
向化合物2-5(1.10克，2.13毫摩尔，1.0当量)的二氧六环(10毫升)溶液中加入氯化氢/二氧六环(4.0摩尔/升，18.33毫升，34.40当量)，混合物在15℃下反应1.5小时。将反应液过滤，滤饼用乙酸乙酯(20毫升)洗涤后干燥，得到化合物2-6。LCMS(ESI)m/z:416.2(M+1).
第6步：
向化合物1-9(188.50毫克，927.48微摩尔，1.1当量)的DMF(5毫升)的溶液中加入DIPEA(326.91毫克，2.53毫摩尔，440.58微升，3当量)，HATU(384.71毫克，1.01毫摩尔，1.2当量)和化合物2-6(500毫克，843.16微摩尔，1.0当量，盐酸盐)，反应混合物在15℃下搅拌1小时。向反应液中加入水(30毫升)和乙酸乙酯(20毫升)，有机相用柠檬酸(20毫升，10％水溶液)和食盐水(20毫升)洗涤，Na 2SO 4干燥，过滤，减压浓缩得到化合物2-7，粗品直接用于下一步。LCMS(ESI)m/z:601.1(M+1).
第7步：
在0℃下，向化合物2-7(500毫克，787.28微摩尔，1.0当量)的二氯甲烷(10毫升)溶液中加入三氟乙酸(3毫升)，将得到的混合物在0℃下反应1小时。LCMS显示反应完全。将反应液浓缩，得到的残余物通过制备的HPLC(盐酸)纯化，得到实施例2的盐酸盐。LCMS(ESI)m/z:501.4(M+1). 1H NMR(400MHz,DMSO-d 6)δ9.50(br s,1H),8.88(br d,J＝5.3Hz,1H),8.78(d,J＝8.2Hz,1H),8.47(s,1H),8.15(d,J＝2.1Hz,1H),7.89(d,J＝8.8Hz,1H),7.32(dd,J＝2.1,8.7Hz,1H),4.48-4.33(m,3H),4.10(br dd, J＝14.8,9.9Hz,1H),3.90-3.90(m,1H),3.73-3.54(m,2H),2.46-2.45(m,1H),2.44(s,3H),2.16-2.01(m,1H),1.97-1.81(m,1H),1.79-1.52(m,9H),1.34(d,J＝6.8Hz,3H),1.27-0.87(m,6H).
实施例3
Figure PCTCN2018115256-appb-000059
实施例3的制备方法参考实施例1。 1H NMR(400MHz,CD 3OD)δ8.57(s,1H),8.41(s,1H),7.97(d,J＝8.7Hz,1H),7.55(dd,J＝8.7,1.6Hz,1H),4.64-4.54(m,2H),4.48(d,J＝7.7Hz,1H),4.25-4.12(m,1H),3.95-3.81(m,2H),3.79-3.69(m,1H),2.67(s,3H),2.55(s,3H),2.26-2.12(m,1H),2.09-1.97(m,1H),1.91-1.59(m,9H),1.50(d,J＝7.0Hz,3H),1.36-0.97(m,6H)；LCMS(ESI)m/z:535.2(M+1).
实施例4
Figure PCTCN2018115256-appb-000060
实施例4的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.32(br s,1H),8.85(br d,J＝5.9Hz,1H),8.78(br d,J＝8.2Hz,1H),8.45(s,1H),7.88(d,J＝7.1Hz,1H),7.31-7.20(m,2H),4.48-4.36(m,3H),4.14-4.04(m,1H),3.92-3.81(m,1H),3.73-3.64(m,1H),3.63-3.56(m,1H),2.49-2.45(m,4H),2.17-2.02(m,1H),1.96-1.84(m,1H),1.81-1.56(m,9H),1.34(d,J＝6.8Hz,3H),1.27-0.95(m,6H)；LCMS(ESI)m/z:501.4(M+1).
实施例5
Figure PCTCN2018115256-appb-000061
实施例5的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.50(br s,1H),8.96-8.85(m,1H),8.82(d,J＝8.3Hz,1H),8.45(s,1H),8.15(d,J＝8.5Hz,1H),8.00(d,J＝1.6Hz,1H),7.24(dd,J＝8.5,1.8Hz,1H),4.47-4.35(m,3H),4.08(dd,J＝14.5,9.9Hz,1H),3.89-3.80(m,1H),3.74-3.66(m,1H),3.64-3.56(m,1H),2.46(br s,1H),2.44(s,3H),2.18-2.05(m,1H),1.96-1.84(m,1H),1.79-1.57(m,9H),1.35(d,J＝6.8Hz,3H),1.27-0.95(m,6H)；LCMS(ESI)m/z:501.4(M+1).
实施例6
Figure PCTCN2018115256-appb-000062
实施例6的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.30(br s,1H),8.80(br s,1H),8.59(br d,J＝7.8Hz,1H),8.39(br s,1H),8.19(br d,J＝7.8Hz,1H),7.37-7.07(m,2H),4.87-4.59(m,2H),4.57-4.29(m,2H),3.79(br s,1H),3.65(br s,2H),2.43(br s,7H),2.16-1.23(m,13H),1.21-0.73(m,5H)；LCMS(ESI)m/z:501.3(M+1).
实施例7
Figure PCTCN2018115256-appb-000063
实施例7的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.60-9.44(m,1H),8.97-8.84(m,1H),8.79(br d,J＝8.2Hz,1H),8.46(s,1H),8.31(d,J＝1.8Hz,1H),7.84(d,J＝8.8Hz,1H),7.43(dd,J＝8.8,2.0Hz,1H),4.47-4.35(m,3H),4.18-3.98(m,1H),3.85(br d,J＝4.8Hz,1H),3.73-3.64(m,1H),2.47-2.42(m,6H),2.17-2.02(m,1H),1.98-1.85(m,1H),1.81-1.52(m,9H),1.34(d,J＝6.8Hz,3H),1.21-0.98(m,5H)；LCMS(ESI)m/z:547.2(M+1).
实施例8
Figure PCTCN2018115256-appb-000064
实施例8的制备方法参考实施例1， 1H NMR(400MHz,DMSO-d 6)δ9.60-9.48(m,1H),8.96-8.83(m,1H),8.79(d,J＝8.3Hz,1H),8.53(s,1H),8.28(s,1H),8.20(s,1H),4.48-4.32(m,3H),4.11(br dd,J＝13.3,8.2Hz,1H),3.83-3.77(m,1H),3.73-3.65(m,1H),3.64-3.52(m,1H),2.47-2.43(m,6H),2.21-2.03(m,1H),1.96-1.84(m,1H),1.77-1.72(m,2H),1.67-1.55(m,5H),1.34(d,J＝6.8Hz,3H),1.26-0.86(m,6H)；LCMS(ESI)m/z:535.3(M+1).
实施例9
Figure PCTCN2018115256-appb-000065
实施例9的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ0.89-1.27(m,6H)1.34(d,J＝6.85Hz,3H),1.58-1.70(m,5H),1.73-1.80(m,2H),1.86-1.97(m,1H),2.05-2.19(m,1H),2.42-2.47(m,6H),3.50-3.74(m,2H),3.79-3.91(m,1H),4.11(dd,J＝13.75,8.50Hz,1H),4.26-4.46(m,3H),7.98(d,J＝10.15Hz,1H),8.19-8.24(m,1H),8.49(s,1H),8.75(d,J＝8.19Hz,1H),8.86(br d,J＝5.62Hz,1H),9.43(br s,1H)；LCMS(ESI)m/z:519.3(M+1).
实施例10
Figure PCTCN2018115256-appb-000066
实施例10的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.63-9.35(m,1H),8.88(br d,J＝5.3Hz,1H),8.76(br d,J＝8.1Hz,1H),8.55-8.43(m,1H),7.73(d,J＝8.8Hz,1H),7.41(dd,J＝8.4,6.7Hz,1H),4.47-4.29(m,3H),4.19-4.05(m,1H),3.95-3.78(m,1H),3.16(s,3H),2.47-2.43(m,5H),2.21-2.02(m,1H),1.90(br d,J＝3.3Hz,1H),1.84-1.46(m,9H),1.33(br d,J＝6.7Hz,3H),1.22-0.91(m,5H)；LCMS(ESI)m/z:519.3(M+1).
实施例11
Figure PCTCN2018115256-appb-000067
实施例11的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ0.96-1.19(m,5H),1.30-1.42(m,3H),1.53-1.80(m,1H),1.53-1.82(m,7H),1.90(br s,1H),2.02-2.17(m,1H),2.41-2.48(m,6H),3.57-3.63(m,1H),3.83-3.91(m,1H),4.07-4.19(m,1H),4.37-4.46(m,2H),7.28(br d,J＝8.19Hz,1H),7.97(d,J＝8.93Hz,1H),8.03-8.13(m,1H),8.55(s,1H),8.79(br d,J＝7.95Hz,1H),8.90(br s,1H),9.60(br d,J＝5.01Hz,1H)；LCMS(ESI)m/z:551.3(M+1).
实施例12
Figure PCTCN2018115256-appb-000068
第1步：
向化合物12-1(1.0克，9.89毫摩尔，0.96毫升，1.0当量)的二氯甲烷(20毫升)溶液中加入化合物1-6(2.54克，9.89毫摩尔，1.0当量)，HATU(3.76克，9.89毫摩尔，1.0当量)和DIPEA(3.83克，29.66毫摩尔，5.17毫升，3.0当量)。将混合物在30℃下反应2.0小时。TLC(石油醚：乙酸乙酯＝1：1)检测原料反应完全。将反应液倒入水(100毫升)中，并用乙酸乙酯(50毫升×2)萃取，将合并的有机相浓缩。得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝5：1到1：1)纯化，得到化合物12-2。 1H NMR(400MHz,CDCl 3)δ5.21(br d,J＝9.0Hz,1H),4.75(br d,J＝6.4Hz,1H),4.31-4.18(m,2H),3.95-3.78(m,1H),3.69-3.61(m,1H),3.60-3.52(m,1H),3.47(td,J＝10.2,7.3Hz,1H),2.12-2.03(m,2H),1.96-1.80(m,3H),1.69-1.51(m,5H),1.41(s,9H),1.22-0.97(m,6H)；LCMS(ESI)m/z:341.2(M+1).
第2步：
向化合物12-2(1.80克，5.29毫摩尔，1.0当量)的二氯甲烷(40毫升)溶液中加入TEA(1.60克，15.86毫摩尔，2.21毫升，3.0当量)和对甲苯磺酰氯(1.21克，6.34毫摩尔，1.20当量)。将得到的混合物在30℃下反应2.0小时。LCMS检测显示原料反应不完，向反应液中加入水(100毫升)，分液，得到的有机相用饱和食盐水(100毫升)洗涤，有机相浓缩，得到化合物12-3。粗品直接用于下一步。LCMS(ESI)m/z:495.3(M+1).
第3步：
化合物12-5的制备方法参考化合物1-4。LCMS(ESI)m/z:550.2(M+1).
第4步：
化合物12-6的制备方法参考化合物1-8。LCMS(ESI)m/z:450.2(M+1).
第5步：
化合物12-7的制备方法参考化合物1-10。LCMS(ESI)m/z:635.3(M+1).
第6步：
实施例12的盐酸盐制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.31(br s,1H),8.87(br d,J＝8.2Hz,2H),8.21(d,J＝1.6Hz,1H),7.93(d,J＝8.8Hz,1H),7.40(dd,J＝8.8,1.7Hz,1H),4.57-4.29(m,3H),4.28-4.11(m,1H),3.82(br s,2H),2.60(s,3H),2.11-1.93(m,2H),1.81-1.51(m,8H),1.44-0.90(m,12H)；LCMS(ESI)m/z:535.2(M+1).
实施例13
Figure PCTCN2018115256-appb-000069
实施例13的盐酸盐制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ0.92-1.16(m,5H)，1.33(br d,J＝6.72Hz,3H),1.47-1.68(m,8H),1.91(br d,J＝6.48Hz,1H),2.16-2.32(m,1H),2.44(br t,J＝5.01Hz,3H),2.53(s,3H),2.80(s,3H),3.59-3.63(m,1H),3.65-3.72(m,1H),3.85(br dd,J＝11.55,6.79Hz,1H),4.17-4.45(m,4H),7.23(dd,J＝8.68,1.59Hz,1H),7.80(d,J＝8.80Hz,1H),8.02(d,J＝1.71Hz,1H),8.73(br d,J＝8.19Hz,1H),8.86(br s,1H),9.45(br s,1H)；LCMS(ESI)m/z:515.2(M+1).
实施例14
Figure PCTCN2018115256-appb-000070
第1步：
在0℃下，向化合物14-1(4克，26.22毫摩尔，1.0当量)的DMA(100毫升)溶液中加入碘(13.31克，52.43毫摩尔，10.56毫升，2.0当量)，氢氧化钾(5.88克，104.86毫摩尔，4当量)。将得到的混合物在20℃下反应12小时。LCMS显示反应完全。向反应液中加入饱和亚硫酸钠水溶液(200毫升)，得到的混合物用乙酸乙酯(200毫升×2)萃取，将合并的有机相用饱和食盐水(200毫升)洗涤后浓缩。得到的残余物用石油醚(5毫升)打浆，得到化合物14-2。 1H NMR(400MHz,DMSO-d 6)δ13.71(br s,1H),7.60(d,J＝8.8Hz,1H),7.47-7.38(m,2H).
第2步：
化合物14-3的制备方法参考化合物1-4。 1H NMR(400MHz,DMSO-d 6)δ7.66(d,J＝8.9Hz,1H), 7.54-7.41(m,2H),4.56-4.41(m,2H),4.23-4.05(m,1H),3.29-3.01(m,2H),1.93-1.57(m,4H),1.37(br s,5H),1.11(br s,4H)；LCMS(ESI)m/z:484.1(M+23).
第3步：
在氮气保护下，向化合物14-3(4.80克，10.21毫摩尔，1.0当量)的DMF(100毫升)溶液中加入氰化锌(0.72克，6.12毫摩尔，0.388毫升，0.6当量)，Pd 2(dba) 3(0.93克，1.02毫摩尔，0.1当量)，锌粉(1.33克，20.42毫摩尔，2.0当量)和DPPF(1.13克，2.04毫摩尔，0.2当量)，将得到的混合物加热至100℃，反应2小时。LCMS显示反应完全。反应液冷却后过滤，滤饼用乙酸乙酯(50毫升)洗涤，滤液浓缩。得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝10：1到3：1)纯化，得到化合物14-4。LCMS(ESI)m/z:383.2(M+23).
第4步：
在0℃下，向化合物14-4(0.8克，2.22毫摩尔，1当量)的四氢呋喃(20毫升)溶液中加入甲基溴化镁(3摩尔/升，1.48毫升，2当量)，将得到的混合物在20℃下反应2小时。LCMS显示反应完全。将反应液缓慢倒入水(100毫升)中，并用乙酸乙酯(50毫升×2)萃取，合并的有机相经饱和食盐水(100毫升)洗涤后分液，有机相浓缩，得到化合物14-5。粗品直接用于下一步。LCMS(ESI)m/z:378.1(M+1).
第5步：
化合物14-6的制备方法参考化合物1-5。LCMS(ESI)m/z:278.1(M+1).
第6步：
化合物14-7的制备方法参考化合物1-7。LCMS(ESI)m/z:539.4(M+23).
第7步：
化合物14-8的制备方法参考化合物1-8。LCMS(ESI)m/z:417.1(M+1).
第8步：
化合物14-9的制备方法参考化合物1-10。LCMS(ESI)m/z:624.3(M+23).
第9步：
实施例14的制备方法参考实施例1. 1H NMR(400MHz,DMSO-d 6)δ9.06-8.79(m,2H),8.70(br d,J＝8.2Hz,1H),8.17-8.10(m,1H),7.97(br d,J＝8.9Hz,1H),7.56(br d,J＝8.7Hz,1H),4.71(br dd,J＝13.2,3.8Hz,1H),4.58-4.44(m,2H),4.38(br t,J＝7.6Hz,1H),3.85(br d,J＝5.1Hz,2H),2.62(s,3H),1.92-1.74(m,5H),1.72-1.49(m,8H),1.31(br d,J＝6.7Hz,3H),1.13(br d,J＝13.7Hz,4H),1.04-0.91(m,2H)；LCMS(ESI)m/z:502.1(M+1).
实施例15
Figure PCTCN2018115256-appb-000071
实施例15的制备方法参考实施例14. 1H NMR(400MHz,DMSO-d 6)δ9.56(br s,1H),8.87(br s,1H),8.80-8.60(m,1H),8.14-7.94(m,1H),7.85-7.68(m,1H),7.58-7.40(m,1H),4.78-4.30(m,4H),3.96-3.74(m,1H),3.64-3.58(m,2H),2.61(s,1H),2.47-2.38(m,3H),1.94-1.52(m,11H),1.39-1.26(m,3H),1.24-0.87(m,6H)；LCMS(ESI)m/z:486.3(M+1).
实施例16
Figure PCTCN2018115256-appb-000072
第1步：
化合物16-2的制备方法参考化合物1-4。LCMS(ESI)m/z:336.2(M+1).
第2步：
在-20℃下，向化合物16-2的DMF(20毫升)溶液中加入化合物16-3(997.86毫克7.05毫摩尔，612.18微升，1.5当量)，得到的混合物在0℃下搅拌2小时。TLC显示原料为反应完全。在-20℃下，向上述反应液中补加1.5毫升化合物16-3(2.44克，17.28毫摩尔，1.5毫升，3.68当量)，得到的混合物在0℃下搅拌0.5小时。LC-MS显示原料反应完全。向反应混合物中加入水(50毫升)，得到的混合物过滤，滤饼用水(20毫升×2)洗涤后真空干燥。得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝50：1至10：1)纯化，得到化合物16-3。 1H NMR(400MHz,DMSO-d 6)δ0.98(br s,5H),1.14-1.31(m,4H),1.80(br d,J＝17.85Hz,4H),3.17-3.31(m,2H),4.12-4.30(m,2H),4.35-4.44(m,1H),8.24-8.39(m,1H),8.42-8.57(m,2H)；LCMS(ESI)m/z:361.1(M+1).
第3步：
化合物16-5的制备方法参考化合物14-5。LCMS(ESI)m/z:378.2(M+1).
第4步：
化合物16-6的制备方法参考化合物1-5。LCMS(ESI)m/z:278.0(M+1).
第5步：
化合物16-7的制备方法参考化合物1-7。LCMS(ESI)m/z:539.4(M+23).
第6步：
化合物16-8的制备方法参考化合物1-8。LCMS(ESI)m/z:417.3(M+1).
第7步：
化合物16-9的制备方法参考化合物1-10。LCMS(ESI)m/z:624.1(M+23).
第8步：
实施例16的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ1.02-1.14(m,6H),1.35-1.49(m,2H),1.58(br s,4H),1.66-1.80(m,4H),1.87(br d,J＝6.72Hz,2H),2.09-2.20(m,3H),2.46(s,3H),2.93(dt,J＝13.57,6.79Hz,1H),3.54(br d,J＝9.90Hz,2H),3.62-3.70(m,1H),4.21-4.41(m,2H),4.48(br dd,J＝13.51,7.03Hz,1H),4.68(br d,J＝3.18Hz,1H),7.80(br d,J＝8.80Hz,1H),8.32-8.40(m,1H),8.40-8.47(m,1H),8.55-8.66(m,1H)；LCMS(ESI)m/z:502.1(M+1).
实施例17
Figure PCTCN2018115256-appb-000073
实施例17的制备方法参考实施例16和实施例1。 1H NMR(400MHz,CD 3OD)δ8.53(br d,J＝7.6Hz,1H),8.06(s,1H),7.88(dd,J＝8.9,4.2Hz,1H),7.32(dd,J＝8.8,2.3Hz,1H),7.14(dt,J＝9.1,2.3Hz,1H),4.57-4.45(m,3H),4.21-4.08(m,1H),3.92(q,J＝6.8Hz,1H),3.86-3.78(m,1H),3.76-3.65(m,1H),2.67(s,3H),2.22-2.07(m,1H),2.04-1.96(m,1H),1.83-1.63(m,8H),1.50(d,J＝6.8Hz,3H),1.3-1.02(m,6H)；LCMS(ESI)m/z:468.2(M+1).
实施例18
Figure PCTCN2018115256-appb-000074
实施例18的制备方法参考实施例16和实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.60-9.41(m,1H),8.86(br d,J＝4.6Hz,1H),8.69(d,J＝8.3Hz,1H),8.37(s,1H),7.94(d,J＝8.8Hz,1H),7.66(d,J＝1.8Hz,1H),7.39(dd,J＝8.8,2.0Hz,1H),4.41(br d,J＝2.8Hz,1H),4.38(br d,J＝6.5Hz,1H),4.23-4.12(m,1H),3.88-3.79(m,1H),3.70-3.53(m,2H),2.44(br t,J＝5.1Hz,3H),2.15-2.01(m,1H),1.90(br d,J＝4.3Hz,1H),1.75-1.52(m,8H),1.32(d,J＝6.8Hz,3H),1.25-0.89(m,6H)；LCMS(ESI)m/z:484..4(M+1).
实施例19
Figure PCTCN2018115256-appb-000075
实施例19的制备方法参考实施例14。 1H NMR(400MHz,CD 3OD)δ7.93(d,J＝9.0Hz,1H),7.83(d,J＝1.1Hz,1H),7.54(dd,J＝8.9,1.5Hz,1H),4.77-4.70(m,1H),4.68-4.61(m,1H),4.57(br s,1H),4.48(br d,J＝7.0Hz,1H),3.88(q,J＝7.0Hz,1H),3.84-3.74(m,1H),3.65-3.54(m,1H),2.68-2.62(m,3H),1.97-1.85(m,3H),1.83-1.66(m,7H),1.47(d,J＝7.0Hz,3H),1.37-1.00(m,5H)；LCMS(ESI)m/z:485.1(M+1).
实施例20
Figure PCTCN2018115256-appb-000076
第1步：
在氮气保护下，向化合物1-1(1.0克，7.40毫摩尔，1.0当量)的四氢呋喃(20毫升)中加入叔丁醇钾(0.91克，8.14毫摩尔，1.1当量)，将混合物在15℃下反应0.5小时后，向反应液中缓慢加入三乙基硼烷的四氢呋喃溶液(1摩尔/升，8.14毫升，1.1当量)。将反应液继续在15℃下反应0.5小时，再向反应液中加入甲烷磺酰氯(0.93克，8.14毫摩尔，0.63毫升，1.1当量)。将反应液在-15℃反应10小时。LCMS显示反应完全。向反应体系中加入饱和氯化铵水溶液(100毫升)，得到的混合物用乙酸乙酯(100毫升×2)萃取，合并的有机相浓缩，得到化合物20-1。LCMS(ESI)m/z:214.0(M+1).
第2步：
化合物20-2的制备方法参考化合物1-4。LCMS(ESI)m/z:397.1(M+1).
第3步：
化合物20-3的制备方法参考化合物1-5。LCMS(ESI)m/z:297.1(M+1).
第4步：
化合物20-4的制备方法参考化合物1-7。LCMS(ESI)m/z:558.1(M+23).
第5步：
化合物20-5的制备方法参考化合物1-8。
第6步：
化合物20-6的制备方法参考化合物1-10。LCMS(ESI)m/z:643.4(M+23).
第7步：
实施例20的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.61-9.37(m,1H),8.96-8.83(m,1H),8.79(d,J＝8.2Hz,1H),8.23-8.19(m,1H),7.98(dd,J＝9.2,4.4Hz,1H),7.52(dd,J＝9.4,2.5Hz,1H),7.26(dt,J＝9.2,2.5Hz,1H),4.51-4.32(m,3H),4.15(dd,J＝13.2,8.6Hz,1H),3.98-3.79(m,1H),3.20(s,3H),2.46(t,J＝5.3Hz,3H),2.08(td,J＝12.2,8.7Hz,1H),1.95-1.82(m,1H),1.77-1.49(m,9H),1.37-1.30(m,3H),1.26-0.91(m,6H)；LCMS(ESI)m/z:521.3(M+1).
实施例21
Figure PCTCN2018115256-appb-000077
实施例21的制备方法参考实施例20。 1H NMR(400MHz,CD 3OD)δ8.03(s,1H),7.91-7.80(m,2H),7.32(dd,J＝8.7,1.9Hz,1H),4.59-4.43(m,2H),4.21-4.10(m,1H),3.94(q,J＝6.8Hz,1H),3.82(q,J＝8.5Hz,1H),3.74-3.63(m,1H),3.18(s,3H),2.67(s,3H),2.16-2.02(m,1H),2.01-1.94(m,1H),1.85-1.72(m,6H),1.71-1.59(m,2H),1.50(d,J＝7.0Hz,3H),1.34-1.01(m,6H)；LCMS(ESI)m/z:537.1(M+1).
实施例22
Figure PCTCN2018115256-appb-000078
第1步：
向化合物17-8(175毫克，308.27微摩尔，1.0当量)的乙醇(8毫升)溶液中加入碳酸钾(85.21毫克，616.53微摩尔，2.0当量)，双氧水(9.44克，83.26毫摩尔，8毫升，浓度为30％，270.09当量)， 得到的反应液在50℃下反应1小时。LCMS显示反应完全。向反应液中加入水(40毫升)，得到的混合物用乙酸乙酯(30毫升)萃取，合并的有机相用饱和食盐水(20毫升)洗涤，经无水硫酸钠干燥后过滤，滤液减压浓缩，得到化合物22-2。LCMS(ESI)m/z:586.6(M+1).
第2步：
实施例22的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.48(br s,1H),8.88(br s,1H),8.81(br d,J＝7.9Hz,1H),8.16(s,1H),7.87-7.78(m,2H),7.13-7.06(m,1H),4.44-4.36(m,2H),4.32(br d,J＝4.1Hz,1H),4.03(br dd,J＝13.5,9.6Hz,1H),3.86(br d,J＝4.9Hz,2H),3.63-3.53(m,1H),2.44(br s,1H),2.15-2.02(m,1H),1.91(br s,1H),1.77-1.58(m,9H),1.35(br d,J＝6.8Hz,3H),1.21-0.99(m,6H)；LCMS(ESI)m/z:486.5(M+1).
实施例23
Figure PCTCN2018115256-appb-000079
第1步：
在0℃下，在30分钟内向DMF(8.55克，116.97毫摩尔，9毫升，5.91当量)溶液中缓慢滴加POCl 3(3.96克，25.83毫摩尔，2.40毫升，1.31当量)。向混合液中滴加化合物23-1(3.0克，19.79毫摩尔，1.0当量)的DMF(3毫升)溶液，将得到的混合物在25℃搅拌1小时。TLC(石油醚：乙酸乙酯＝3：1)和LC-MS显示原料反应完全。将反应液缓慢倒入水(150毫升)中，用10％的NaOH溶液调节混合液的pH至9，然后用乙酸乙酯萃取(200毫升×2)。将合并的有机相用饱和食盐水(100毫升×2)洗涤，经无水硫酸钠干燥后浓缩，得到化合物23-2。 1H NMR(400MHz,DMSO-d 6)δ7.28(dd,J＝8.66,2.13Hz,1H),7.54(d,J＝8.66Hz,1H),8.06(d,J＝2.01Hz,1H),8.36(s,1H),9.93(s,1H),12.29(br s,1H)；LCMS(ESI)m/z:180.1(M+1).
第2步：
向化合物23-2(3克，16.70毫摩尔，1.0当量)和氰化钠(163.72毫克，3.34毫摩尔，0.2当量)的DMF(30毫升)溶液中加入化合物23-3(2摩尔/升，33.41毫升，4.0当量)，将得到的混合物在30℃下搅拌10分钟。向混合物中分批加入二氧化锰(36.30克，417.59毫摩尔，25.0当量)，得到的混合物在30℃下继续搅拌14小时。LCMS显示原料反应完全。将反应混合物过滤，滤饼用乙酸乙酯(100毫升×2)洗涤。将合并的有机相依次用饱和硫酸亚铁溶液(50毫升×2)和食盐水(100毫升)洗涤，经无水硫酸钠干燥后浓缩，得到化合物23-4，粗品直接用于下一步。LCMS(ESI)m/z:223.2(M+1).
第3步：
化合物23-5的制备方法参考化合物1-4。LCMS(ESI)m/z:406.0(M+1).
第4步：
化合物23-6的制备方法参考化合物1-5。 1H NMR(400MHz,DMSO-d 6)δ1.62-1.77(m,1H),1.80-1.92(m,1H),1.94-2.04(m,1H),2.06-2.17(m,1H),3.04-3.15(m,6H)3.20-3.31(m,1H),3.86(br s,1H),4.52-4.56(m,1H),4.61(br dd,J＝14.87,5.08Hz,2H),4.69-4.77(m,1H),4.69-4.77(m,1H),7.26(dd,J＝8.72,2.07Hz,1H),7.79(d,J＝8.78Hz,1H),7.90(d,J＝2.01Hz,1H),8.26(s,1H),9.35(br s,1H),10.04(br s,1H)；LCMS(ESI)m/z:306.1(M+1).
第5步：
化合物23-7的制备方法参考化合物1-7。LCMS(ESI)m/z:545.4(M+1)
第6步：
化合物23-8的制备方法参考化合物1-8。LCMS(ESI)m/z:445.0(M+1).
第7步：
化合物23-9的制备方法参考化合物1-10。LCMS(ESI)m/z:630.3(M+1).
第8步：
实施例23的制备方法参考实施例1。 1H NMR(400MHz,CD 3OD)δ1.00-1.30(m,5H),1.47-1.54(m,3H),1.61(br d,J＝12.23Hz,1H),1.65-1.87(m,7H),1.99(br s,1H),2.06-2.23(m,1H),2.64-2.71(m,3H),3.1-3.30(m,6H),3.72(br d,J＝6.48Hz,1H),3.83(q,J＝8.48Hz,1H),3.90-4.02(m,1H),4.09-4.20(m,1H),4.46(br d,J＝7.46Hz,1H),4.51-4.62(m,2H),7.24-7.30(m,1H),7.74(s,1H),7.80(d,J＝9.05Hz,1H),7.92(br s,1H)；LCMS(ESI)m/z:530.3(M+1).
实施例24
Figure PCTCN2018115256-appb-000080
实施例24的制备方法参考实施例1。 1H NMR(400MHz,CD 3OD)δ8.36-8.23(m,2H),7.79(d,J＝8.8Hz,1H),7.27(dd,J＝8.8,2.0Hz,1H),4.60-4.44(m,3H),4.21-4.05(m,1H),3.97-3.77(m,2H),3.71(qd,J＝10.0,4.0Hz,1H),3.44(spt,J＝6.8Hz,1H),2.67(s,3H),2.23-2.07(m,1H),2.06-1.96(m,1H),1.85-1.64(m,8H),1.50(d,J＝7.1Hz,3H),1.27-1.05(m,10H)；LCMS(ESI)m/z:551.3(M+23).
实施例25
Figure PCTCN2018115256-appb-000081
第1步：
向化合物1-1(0.2克，1.48毫摩尔，1.0当量)的DMF(2毫升)溶液中分批加入NBS(276.58毫克，1.55毫摩尔，1.05当量)，得到的混合物在15℃搅拌1小时。TLC(石油醚：乙酸乙酯＝3：1)显示原料反应完全，LCMS显示有产物生成。向反应液中加入饱和的亚硫酸钠溶液(2毫升)，混合物用乙酸乙酯(2毫升×3)萃取。将合并的有机相浓缩，得到化合物25-1，粗品直接用于下一步。LCMS(ESI)m/z:211.9(M-1).
第2步：
在氮气保护下，向化合物25-1(1.5克，7.01毫摩尔，1.0当量)的四氢呋喃(18毫升)和水(3.0毫升)的混合溶液中加入化合物25-2(1.91克，14.02毫摩尔，2.0当量)、磷酸钾(2.98克，14.02毫摩尔，2.0当量)和Pd(dppf)Cl 2(512.80毫克，700.82微摩尔，0.1当量)，将得到的混合物加热至80℃，搅拌16小时。LCMS显示原料反应完全。将反应液用无水硫酸钠干燥后过滤，滤液减压浓缩，得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝1：0到5：1)纯化，得到化合物25-3。 1H NMR(400MHz,DMSO-d 6)δ8.07-7.86(m,1H),7.52(d,J＝2.4Hz,1H),7.46-7.40(m,1H),7.37-7.30(m,1H),7.26-7.21(m,2H),7.13-7.05(m,2H),6.99(dt,J＝9.1,2.3,1H),2.29(s,3H)；LCMS(ESI)m/z:224.0(M-1).
第3步：
化合物25-4的制备方法参考化合物1-4。 1H NMR(400MHz,CDCl 3)δ7.43-7.24(m,5H),7.22-7.13(m,1H),7.13-7.07(m,1H),7.05-6.97(m,1H),4.49-4.36(m,1H),4.31-4.24(m,1H),3.50-3.33(m,1H),3.26-3.11(m,1H),2.35(s,3H),1.95-1.85(m,1H),1.83-1.71(m,2H),1.59-1.46(m,11H)；LCMS(ESI)m/z:431.3(M+23).
第4步：
化合物25-5的制备方法参考化合物1-5。LCMS(ESI)m/z:309.2(M+1).
第5步：
化合物25-6的制备方法参考化合物1-7。LCMS(ESI)m/z:548.1(M+1).
第6步：
化合物25-7的制备方法参考化合物1-8。LCMS(ESI)m/z:448.2(M+1).
第7步：
化合物25-8的制备方法参考化合物1-10。LCMS(ESI)m/z:633(M+1).
第8步：
实施例25的制备方法参考化合物实施例1。 1H NMR(400MHz,CD 3OD)δ7.70(dd,J＝8.9,4.1Hz,1H),7.31(dd,J＝4.7,3.2Hz,2H),7.27(s,1H),7.25-7.19(m,2H),7.03-6.94(m,2H),4.62-4.47(m,3H),4.21-4.07(m,1H),3.97-3.88(m,1H),3.86-3.74(m,1H),3.70-3.59(m,1H),2.68(s,3H),2.28(s,3H),2.09-1.57(m,11H),1.52(d,J＝6.9Hz,3H),1.39-1.02(m,6H)；LCMS(ESI)m/z:533.2(M+1).
实施例26
Figure PCTCN2018115256-appb-000082
实施例26的制备方法参考实施例25。 1H NMR(400MHz,CD 3OD)δ8.23-8.14(m,1H),8.03-7.93(m,1H),7.88(dd,J＝8.9,4.3Hz,1H),7.39(br d,J＝9.4Hz,1H),7.12(dt,J＝9.1,2.4Hz,1H),6.94-6.85(m,1H),4.65-4.56(m,2H),4.48(d,J＝7.5Hz,1H),4.25-4.08(m,4H),4.00-3.91(m,1H),3.90-3.80(m,1H),3.79-3.68(m,1H),2.67(s,3H),2.30-2.13(m,1H),2.05-1.95(m,1H),1.90-1.60(m,8H),1.51(d,J＝7.0Hz,3H),1.38-1.01(m,6H)；LCMS(ESI)m/z:523.3(M+1).
实施例27
Figure PCTCN2018115256-appb-000083
实施例27制备方法参考实施例25。 1H NMR(400MHz,DMSO-d 6)δ7.83-7.95(m,2H),7.82(s,1H),7.53-7.59(m,1H),7.47-7.53(m,1H),7.29(dd,J＝8.78,2.01Hz,1H),6.48(d,J＝1.76Hz,1H),4.34-4.53(m,3H),4.10(dd,J＝13.05,8.03Hz,1H),3.86-3.89(m,3H),3.61(br d,J＝8.03Hz,2H),2.97(q,J＝6.69Hz, 1H),2.17(s,3H),1.98-2.07(m,1H),1.78-1.92(m,2H),1.51-1.77(m,9H),1.14(br s,1H),1.09(d,J＝6.78Hz,4H),0.89-1.04(m,2H)；LCMS(ESI)m/z:539.3(M+1).
实施例28
Figure PCTCN2018115256-appb-000084
第1步：
在20℃下，向化合物23-1(1.0克，6.60毫摩尔，1.0当量)的DMF(20毫升)溶液中加入碘(1.67克，6.60毫摩尔，1.0当量)的DMF(20毫升)溶液和氢氧化钾(0.92克，16.49毫摩尔，2.5当量)，将得到的混合物在20℃下搅拌反应1小时。TLC(石油醚：乙酸乙酯＝3：1)检测原料反应完全。将反应液缓慢倒入饱和亚硫酸钠水溶液(100毫升)中，然后用乙酸乙酯(100毫升)萃取。合并的有机相用饱和食盐水(100毫升)洗涤后浓缩，得到化合物28-1。粗品直接用于下一步。LCMS(ESI)m/z:277.9(M+1).
第2步：
向化合物28-1(1.5克，5.41毫摩尔，1.0当量)的二氯甲烷(50毫升)溶液中加入Boc 2O(1.42克，6.49毫摩尔，1.49毫升，1.2当量)，TEA(1.64克，16.22毫摩尔，1当量)和DMAP(66毫克，0.54毫摩尔，0.1当量)。将得到的混合物在20℃下搅拌反应10小时。TLC(石油醚：乙酸乙酯＝10：1)检测原料反应完全。将反应浓缩，得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝20：1到10：1)纯化，得到化合物28-2。 1H NMR(400MHz,DMSO-d 6)δ8.01(d,J＝8.8Hz,1H),7.91(s,1H),7.39(dd,J＝8.8,2.0Hz,1H),7.30(d,J＝1.8Hz,1H),1.61(s,9H)；LCMS(ESI)m/z:378.0(M+1).
第3步：
在氮气保护下，向化合物28-2(1.5克，3.97毫摩尔，1.0当量)的二氧六环(40毫升)溶液中加入化合物28-3(1.01克，11.92毫摩尔，0.91毫升，3.0当量)，碘化亚铜(0.37毫克，1.99毫摩尔，0.5当量)，碳酸铯(3.88克，11.92毫摩尔，3.0当量)，N,N-二甲基乙二胺(0.35克，3.97毫摩尔，1.0当 量)。将反应液加热至80℃，反应2.0小时。LCMS显示原料反应完全。将反应液冷却到20℃，过滤，滤饼用乙酸乙酯(50毫升)洗涤，滤液浓缩。得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝5：1到1：1)纯化，得到化合物28-4. 1H NMR(400MHz,CDCl 3)δ8.97(br s,1H),7.53(d,J＝1.8Hz,1H),7.19-7.01(m,3H),3.92(t,J＝7.0Hz,2H),2.64(t,J＝8.2Hz,2H),2.32-2.24(m,2H)；LCMS(ESI)m/z:234.1(M+1).
第4步：
化合物28-5的制备方法参考化合物1-4。 1H NMR(400MHz,CDCl 3)δ7.61(br d,J＝6.1Hz,1H),7.48(br d,J＝8.7Hz,1H),7.44-7.38(m,1H),7.32(br d,J＝8.7Hz,1H),7.15(dd,J＝8.8,1.9Hz,1H),4.22-4.13(m,1H),3.98(br t,J＝7.0Hz,2H),3.45-3.15(m,2H),2.95(s,1H),2.87(s,1H),2.59(t,J＝8.1Hz,2H),2.30-2.16(m,2H),1.93-1.65(m,4H),1.50(s,10H)；LCMS(ESI)m/z:418.2(M+1).
第5步：
化合物28-6的制备方法参考化合物1-5。LCMS(ESI)m/z:318.1(M+1).
第6步：
化合物28-7的制备方法参考化合物1-7。LCMS(ESI)m/z:557.3(M+1).
第7步：
化合物28-8的制备方法参考化合物1-8。LCMS(ESI)m/z:457.2(M+1).
第8步：
化合物28-9的制备方法参考化合物1-10。LCMS(ESI)m/z:642.3(M+1).
第9步：
实施例28的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.41(br s,1H),9.08-8.72(m,2H),7.84-7.49(m,3H),7.26-7.09(m,1H),4.51-4.23(m,3H),4.10-3.79(m,4H),3.72-3.51(m,1H),2.46(br s,6H),2.14(br d,J＝6.0Hz,2H),1.95(br s,1H),1.90-1.54(m,9H),1.35(br d,J＝6.2Hz,3H),1.29-0.94(m,6H)；LCMS(ESI)m/z:542.3(M+1).
实施例29
Figure PCTCN2018115256-appb-000085
实施例29的制备方法参考实施例28。 1H NMR(400MHz,CD 3OD)δ7.67(d,J＝8.8Hz,1H),7.57(d,J＝1.8Hz,1H),7.31(s,1H),7.15(dd,J＝8.7,1.9Hz,1H),4.59-4.38(m,4H),4.08-3.98(m,1H),3.96-3.90(m,1H),3.88-3.81(m,2H),3.81-3.74(m,1H),3.72-3.64(m,1H),3.61-3.53(m,2H),2.89(s,4H),2.67(s,3H),1.93(br d,J＝9.7Hz,2H),1.88-1.66(m,9H),1.52-1.49(m,3H),1.36-1.08(m,6H)；LCMS(ESI)m/z:557.3(M+1).
实施例30
Figure PCTCN2018115256-appb-000086
实施例30的制备方法参考实施例28。 1H NMR(400MHz,CD 3OD)δ7.70(d,J＝8.8Hz,1H),7.63(d,J＝2.0Hz,1H),7.45(s,1H),7.21-7.14(m,1H),4.60-4.55(m,2H),4.54-4.43(m,3H),4.12(dt,J＝8.1,3.5Hz,2H),4.07-3.98(m,1H),3.97-3.89(m,1H),3.84-3.75(m,1H),3.73-3.64(m,1H),2.67(s,3H),2.00-1.89(m,2H),1.87-1.76(m,6H),1.71(br d,J＝10.8Hz,2H),1.51(d,J＝7.0Hz,3H),1.36-1.06(m,6H)；LCMS(ESI)m/z:544.3(M+1).
实施例31
Figure PCTCN2018115256-appb-000087
第1步：
向化合物31-1(10克，43.24毫摩尔，1.0当量)的DMF(100毫升)溶液中加入碳酸钾(17.93克，129.73毫摩尔，3.0当量)和碘甲烷(9.21克，64.87毫摩尔，4.04毫升，1.5当量)，将得到的混合物在15℃下反应5小时。TLC(石油醚：乙酸乙酯＝1：1)显示反应完全。向反应液中加入水(100毫升)，得到的混合物用乙酸乙酯(100毫升×2)萃取。将合并的有机相用饱和食盐水(100毫升×3)洗涤后浓缩，得到化合物31-2。粗品直接用于下一步。
第2步：
在氮气保护下，向化合物31-2(9.0克，36.69毫摩尔，1.0当量)的四氢呋喃(150毫升)溶液中加入苯酚(3.8克，40.36毫摩尔，3.55毫升，1.1当量)，三苯基膦(10.59克，40.36毫摩尔，1.1当量)和DIAD(8.16克，40.36毫摩尔，7.85毫升，1.1当量)。将得到的混合物在15℃下搅拌12小时。LCMS显示反应完全。将反应液浓缩，向得到的残余物中加入水(100毫升)、乙酸乙酯(200毫升)，分液。有机相用饱和食盐水(100毫升×2)洗涤后浓缩，得到化合物31-3。粗品直接用于下一步。LCMS(ESI)m/z:322.2(M+1).
第3步：
在0℃下，向化合物31-3(9克，28.01毫摩尔，1.0当量)的四氢呋喃(100毫升)溶液中加入四氢铝锂(1.59克，42.01毫摩尔，1.5当量)，将得到的混合物在15℃下反应2小时。LCMS显示反应完全。依次向反应液中滴加水(3毫升)，30％氢氧化钠溶液(6毫升)，水(3毫升)淬灭反应。将得到的混合物过滤，滤饼用乙酸乙酯(100毫升)洗涤，滤液浓缩。得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝10：到2：1)纯化，得到化合物31-4。LCMS(ESI)m/z:316.2(M+23).
第4步：
在0℃下，向化合物31-4(5克，17.04毫摩尔，1.0当量)的二氯甲烷(150毫升)溶液中加入吡啶(4.04克，51.13毫摩尔，4.13毫升，3.0当量)和对甲苯磺酰氯(6.50克，34.09毫摩尔，2.0当量)，将得到的混合物在15℃下搅拌10小时。LCMS显示反应完全。将反应液浓缩，得到的残余物通过硅胶柱层析(石油醚：乙酸乙酯＝20：1到3：1)纯化，得到化合物31-5。LCMS(ESI)m/z:470.2(M+23).
第5步：
化合物31-7的制备方法参考化合物1-4。LCMS(ESI)m/z:453.1(M+1).
第6步：
化合物31-8的制备方法参考化合物1-5。
第7步：
化合物31-9的制备方法参考化合物1-7。LCMS(ESI)m/z:592.1(M+1).
第8步：
化合物31-10的制备方法参考化合物1-8。
第9步：
化合物31-11的制备方法参考化合物1-10。LCMS(ESI)m/z:677.2(M+1).
第10步：
实施例31的制备方法参考实施例1。 1H NMR(400MHz,DMSO-d 6)δ9.60-9.34(m,1H),8.98-8.83(m, 1H),8.80(d,J＝7.8Hz,1H),7.98(s,1H),7.83(dd,J＝9.8,2.6Hz,1H),7.73(dd,J＝9.0,4.5Hz,1H),7.44-7.34(m,2H),7.15-7.08(m,3H),7.07-7.01(m,1H),5.22(br s,1H),4.73-4.56(m,2H),4.37(t,J＝7.6Hz,1H),4.33-4.22(m,1H),4.10(dd,J＝11.8,4.6Hz,1H),3.93-3.83(m,2H),2.45(br t,J＝5.2Hz,4H),2.31(s,3H),2.21-2.09(m,1H),2.00(br d,J＝14.2Hz,1H),1.71-1.55(m,6H),1.35(d,J＝6.8Hz,3H),1.22-0.92(m,6H)；LCMS(ESI)m/z:577.2(M+1).
本发明涉及的化合物是IAP抑制剂。以下实验结果证实本专利申请列举的化合物是IAP抑制剂并且可作为潜在的抗癌药。此处用到的IC 50是指使用某种试剂产生50％最大抑制时对应该试剂的浓度。
实验例一：cIAP1 BIR3和XIAP BIR3结合实验
实验材料：
测试缓冲体系(cIAP1 BIR3或XIAP BIR3的缓冲液)：100mM磷酸钾，pH 7.5,0.1％BSA,0.005％曲拉通X-100和1％二甲基亚砜。
探针：ARPFAQ-K(5-FAM)-NH 2。
靶标：
cIAP1-BIR3-his:RBC Cat#APT-11-370，人类cIAP1的BIR3域(涵盖氨基酸258至363；cIAP1 BIR3)作为GST-融合蛋白自大肠杆菌(E.coli)表达及纯化。
XIAP-BIR3-his:RBC Cat#APT-11-374，XIAP的BIR3域(涵盖氨基酸255至356；XIAP BIR3)作为GST-融合蛋白自大肠杆菌(E.coli)表达及纯化。
反应条件：5nM ARPFAQ-K(5-FAM)-NH 2,20nM cIAP1 BIR3和30nM XIAP BIR3。
实验步骤：
首先制备cIAP1 BIR3或XIAP BIR3的新鲜缓冲液，加入2倍cIAP1 BIR3或XIAP BIR3溶液，再通过声学技术将100％DMSO溶解的待测化合物加入到cIAP1 BIR3或XIAP BIR3的缓冲溶液中，然后再加入2倍探针，室温下黑暗中混合孵化60分钟，测量荧光偏振和计算mP值，最后得到IC 50值。
实验结果：
如表1所示。
实验结论：
本发明化合物表现出cIAP1 BIR3结合活性，而且对cIAP1 和XIAP具有选择性。
实验例二：体外细胞活性测试
实验材料：
RPMI 1640培养基(Invitrogen-22400089)，胎牛血清(Invitrogen-10099141)，Trypsin，0.05％(1X)with EDTA 4Na(Invitrogen-25300062)，发光法细胞活力检测试剂盒(Promega-G7573)，杜氏磷酸盐缓冲液(HyClone-SH30028.01B)，384孔板(Corning-6007680)。Envision多标记分析仪。
实验方法：
1、向384微孔板的孔中加30μL MDA-MB-231细胞悬液，其中包含250个MDA-MB-231细胞。
2、加入20μL受试化合物(受试化合物做高浓度为10μM，对受试化合物进行5倍梯度稀释，将每个化合物稀释10个浓度梯度)，然后将细胞板放回到二氧化碳培养箱中培养7天。
3、将细胞板在室温下平放30分钟。
4、向细胞板中加入每孔20μL的Promega CellTiter-Glo试剂。
5、10分钟后采用Envision多标记分析仪读数。
实验结果：见表1。
实验结论：
本发明化合物具有MDA-MB-231细胞抗增殖活性。
表1
受试化合物 cIAP1 BIR3 IC 50(nM) XIAP BIR3 IC 50(nM) MDA-MB-231细胞IC 50(nM)
实施例1 3.7 74.7 70.0
实施例2 5.0 29.9 54.8
实施例3 1.0 18.1 16.0
实施例4 2.6 97.0 220.0
实施例5 2.6 95.9 75.0
实施例6 58.3 9.3 497.0
实施例7 4.9 45.0 16.6
实施例8 5.6 40.3 75.0
实施例9 5.7 20.0 26.0
实施例10 4.5 27.2 32.4
实施例11 5.2 139.0 74.8
实施例13 5.0 30.6 44.3
实施例14 6.2 49.9 57.7
实施例15 4.0 258.0 93.0
实施例16 8.4 346.0 109.3
实施例17 1.9 80.7 79.0
实施例18 5.1 42.5 22.5
实施例19 4.6 129.0 43.1
实施例20 1.1 53.9 75.0
实施例21 4.2 37.4 16.4
实施例22 3.0 42.0 85.0
实施例23 4.6 21.3 45.2
实施例24 4.1 19.2 73.0
实施例25 6.8 208.0 1153.0
实施例26 1.1 60.0 181.0
实施例27 4.4 46.4 282.1
实施例28 5.2 27.3 36.7
实施例29 6.1 31.4 134.0
实施例30 4.4 21.6 47.6
实施例31 3.7 49.1 1461.0
实验例三：体内药效研究1
在皮下植入MDA-MB-231三阴性乳腺癌患者来源的基于人源肿瘤细胞系的异种移植(CDX)BALB/c裸小鼠上进行体内药效实验
实验操作：
BALB/c裸鼠，雌性，6-8周，体重约18-22克，将小鼠保持在一个特殊的无病原体的环境中，且在单个通风笼中(3只小鼠每笼)。所有的笼子，铺垫和水在使用前进行消毒。所有的动物都可以自由获取标准认证的商业实验室饮食。共有48只购于上海西普尔必凯实验动物有限公司(Shanghai BK Laboratory Animal Co.,LTD)的小鼠用于研究。每只小鼠在右胁腹皮下植入肿瘤细胞(10×10 6在0.2毫升磷酸盐缓冲液中)，用于肿瘤的生长。当平均肿瘤体积达到约147立方毫米时开始给药。将试验化合物每日口服给药，给药剂量为30毫克/公斤。肿瘤体积每3天用二维卡尺测量，体积以立方毫米计量，通过以下公式计算：V＝0.5a×b 2，其中a和b分别是肿瘤的长径和短径。抗肿瘤药效是通过用化合物处理过的动物的平均肿瘤增加体积除以未处理过动物的平均肿瘤增加体积来确定。
实验结果：见表2。
实验结论：
在MDA-MB-231三阴性乳腺癌CDX体内药效模型中，本发明化合物展现药效。
表2
Figure PCTCN2018115256-appb-000088
实验例四：体内药效研究2
在皮下植入MDA-MB-231三阴性乳腺癌患者来源的基于人源肿瘤细胞系的异种移植(CDX)BALB/c裸小鼠上进行体内药效实验。
实验操作：
BALB/c裸鼠，雌性，6-8周，体重约18-22克，将小鼠保持在一个特殊的无病原体的环境中，且在单个通风笼中(3只小鼠每笼)。所有的笼子，铺垫和水在使用前进行消毒。所有的动物都可以自由获取标准认证的商业实验室饮食。共有48只购于上海西普尔必凯实验动物有限公司(Shanghai BK Laboratory Animal Co.,LTD)的小鼠用于研究。每只小鼠在右胁腹皮下植入肿瘤细胞(10×10 6在0.2毫升磷酸盐缓冲液中)，用于肿瘤的生长。当平均肿瘤体积达到约110立方毫米时开始给药。将试验化合物每日口服给药，给药剂量为30毫克/公斤。肿瘤体积每3天用二维卡尺测量，体积以立方毫米计量，通过以下公式计算：V＝0.5a×b 2，其中a和b分别是肿瘤的长径和短径。抗肿瘤药效是通过用化合物处理过的动物的平均肿瘤增加体积除以未处理过动物的平均肿瘤增加体积来确定。
实验结论：
在MDA-MB-231三阴性乳腺癌CDX体内药效模型中，本发明化合物展现较好的药效。
表3
Figure PCTCN2018115256-appb-000089
Figure PCTCN2018115256-appb-000090

Claims (22)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2018115256-appb-100001
    其中，
    X 1选自C(R 5)和N；
    X 2选自C(R 6)、N、O和S；
    Figure PCTCN2018115256-appb-100002
    分别独立地选自单键和双键；
    L选自单键和-O-；
    R 1选自-C(＝O)NH 2、CN、C 1-5烷基、C 1-5杂烷基、苯基、5～6元杂芳基和5～6元杂环烷基，所述C 1-5烷基、C 1-5杂烷基、苯基、5～6元杂芳基或5～6元杂环烷基任选被1、2或3个R取代；
    R 2选自H、卤素、CN、COOH、-C(＝O)NH 2、C 1-4烷基和C 1-4杂烷基，所述C 1-4烷基或C 1-4杂烷基任选被1、2或3个R取代；
    R 3和R 7分别独立地选自H、卤素和C 1-4烷基，所述C 1-4烷基任选被1、2或3个R取代；
    R 4选自H、苯基和5～6元杂芳基；
    R 5选自H和卤素；
    R 6选自H、卤素、C 1-4烷基、C 1-4杂烷基、CN和COOH，所述C 1-4烷基或C 1-4杂烷基任选被1、2或3个R取代；
    R选自卤素、OH、CN、CH 3、CH 3CH 2、CH 3CH 2CH 2、CH(CH 3) 2、OCH 3、OCF 3、CHF 2、CH 2F和NH 2；所述C 1-4杂烷基、C 1-5杂烷基、5～6元杂环烷基和5～6元杂芳基分别包含1、2或者3个独立选自-NH-、-O-、-S-、N、-C(＝O)O-、-C(＝O)-、-C(＝O)NH-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-、-C(＝NH)-、-S(＝O) 2NH-、-S(＝O)NH-和-NHC(＝O)NH-的杂原子或杂原子团。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，选自
    Figure PCTCN2018115256-appb-100003
    其中，
    Figure PCTCN2018115256-appb-100004
    X 1、X 2、L、R 1、R 2、R 3、R 4和R 7如权利要求1所定义。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，X 2选自C(R 6)和N。
  4. 根据权利要求3所述的化合物或其药学上可接受的盐，其中，X 2选自C(H)、C(Cl)、C(CH 3)和N。
  5. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 1选自-C(＝O)NH 2、CN、CH 3、CH 3CH 2、C 1-5烷基-C(＝O)-、C 1-4烷基-C(＝O)-、C 1-5烷基-S(＝O) 2-、C 1-5烷基-N(H)C(＝O)-、C 1-4烷基-N(H)C(＝O)-、(C 1-2烷基) 2-N-C(＝O)-、苯基、
    Figure PCTCN2018115256-appb-100005
    所述CH 3、CH 3CH 2、C 1-5烷基-C(＝O)-、C 1-4烷基-C(＝O)-、C 1-5烷基-S(＝O) 2-、C 1-5烷基-N(H)C(＝O)-、C 1-4烷基-N(H)C(＝O)-、(C 1-2烷基) 2-N-C(＝O)-、苯基、
    Figure PCTCN2018115256-appb-100006
    任选被1、2或3个R取代。
  6. 根据权利要求5所述的化合物或其药学上可接受的盐，其中，R 1选自
    Figure PCTCN2018115256-appb-100007
    Figure PCTCN2018115256-appb-100008
  7. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 2选自H、卤素、C 1-4烷基和C 1- 4烷基-O-，所述C 1-4烷基或C 1-4烷基-O-任选被1、2或3个卤素取代。
  8. 根据权利要求7所述的化合物或其药学上可接受的盐，其中，R 2选自H、F、Cl、Br、CF 3、OCF 3。
  9. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 3和R 7分别独立地选自H、F和Cl。
  10. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 4选自H和
    Figure PCTCN2018115256-appb-100009
  11. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 5选自H和Cl。
  12. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 6选自H、Cl和CH 3。
  13. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018115256-appb-100010
    选自
    Figure PCTCN2018115256-appb-100011
  14. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018115256-appb-100012
    选自
    Figure PCTCN2018115256-appb-100013
  15. 根据权利要求1、7～9任意一项所述的化合物或其药学上可接受的盐，选自
    Figure PCTCN2018115256-appb-100014
    其中，R 2、R 3和R 7如权利要求1～2、7～9所定义。
  16. 根据权利要求2或15所述的化合物或其药学上可接受的盐，选自
    Figure PCTCN2018115256-appb-100015
    其中，R 2、R 3和R 7如权利要求2或15所定义。
  17. 化合物或其药学上所接受的盐，选自
    Figure PCTCN2018115256-appb-100016
    Figure PCTCN2018115256-appb-100017
    Figure PCTCN2018115256-appb-100018
    Figure PCTCN2018115256-appb-100019
  18. 根据权利要求17所述的化合物或其药学上可接受的盐，选自
    Figure PCTCN2018115256-appb-100020
    Figure PCTCN2018115256-appb-100021
    Figure PCTCN2018115256-appb-100022
    Figure PCTCN2018115256-appb-100023
  19. 一种药物组合物，包括治疗有效量的根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  20. 根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐或者权利要求19所述的组合物 在制备IAP抑制剂中的应用。
  21. 根据权利要求20所述的应用，其中IAP抑制剂是治疗癌症的药物。
  22. 根据权利要求21所述的应用，其中所述癌症是乳腺癌。
PCT/CN2018/115256 2017-11-13 2018-11-13 用作iap抑制剂的smac模拟物及其用途 WO2019091492A1 (zh)

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