WO2019120121A1 - 用于抑制激酶活性的二苯氨基嘧啶类化合物 - Google Patents

用于抑制激酶活性的二苯氨基嘧啶类化合物 Download PDF

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WO2019120121A1
WO2019120121A1 PCT/CN2018/120618 CN2018120618W WO2019120121A1 WO 2019120121 A1 WO2019120121 A1 WO 2019120121A1 CN 2018120618 W CN2018120618 W CN 2018120618W WO 2019120121 A1 WO2019120121 A1 WO 2019120121A1
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group
optionally substituted
compound
alkyl
membered
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PCT/CN2018/120618
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English (en)
French (fr)
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王义汉
李焕银
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深圳市塔吉瑞生物医药有限公司
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Priority to US16/954,246 priority Critical patent/US11254696B2/en
Priority to EP18890509.5A priority patent/EP3715343B1/en
Priority to JP2020534864A priority patent/JP7043098B2/ja
Publication of WO2019120121A1 publication Critical patent/WO2019120121A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the invention belongs to the field of medical technology.
  • the present invention relates to diphenylaminopyrimidine compounds which have an inhibitory effect on protein tyrosine kinases, pharmaceutical compositions containing them, and processes for their preparation and use.
  • Anaplastic lymphoma kinase is a receptor-type protein tyrosine kinase belonging to the insulin receptor superfamily. It was discovered in 1994 by Morris and Shiota as a product of chromosomal rearrangement from Anaplastic large cell lymphoma (ALCL). The most common fusion method is the NPM (Nucleophosmin) gene on chromosome 5. ALK gene fusion on chromosome 2. NPM-ALK fusion proteins were detected in nearly 75% of ALCL-positive ALCL patients. In subsequent studies, different ALK fusion forms were found in a wide variety of cancers, including inflammatory myofibroblastic tumors. And diffuse large B-cell lymphoma.
  • EML4-ALK gene-positive patients generally do not carry the epidermal growth factor receptor (EGFR) or the Kirsten rat sarcoma virus (KRAS) mutation, which makes the EML4-ALK fusion gene A unique molecular target for non-small cell lung cancer.
  • EGFR epidermal growth factor receptor
  • KRAS Kirsten rat sarcoma virus
  • amplification or point mutations of the ALK gene have been found in Neuroblastomas, anaplastic thyroid cancer, and ovarian cancer.
  • crizotinib achieved an objective response rate of 60-74% and a good median progression-free survival (8-11 months) in ALK+NSCLC patients, most patients developed disease recurrence after 1 year of treatment. That is, acquired resistance is produced. Acquired resistance mechanisms of crizotinib have also been identified, including gains in ALK fusion genes, activation of signaling pathways, secondary mutations in the ALK kinase region, and other mechanisms.
  • second-generation ALK inhibitors have been effective in overcoming the deficiencies of resistance to crizotinib, such as ceritinib (Zykadia, Novartis) and erlotinib (Alectinib, Alecensa, Roche).
  • crizotinib such as ceritinib (Zykadia, Novartis) and erlotinib (Alectinib, Alecensa, Roche).
  • these second-generation inhibitors are effective in overcoming most of the crizotinib-resistant mutations, they are still ineffective for some mutations, such as ceratinib versus F1174C/V, erlotinib versus I1171N/T/S and They still have no effect on the G1202R. Therefore, it is very urgent to develop new, more effective and safe ALK inhibitors.
  • the present invention provides a novel diphenylaminopyrimidine compound and a pharmaceutical composition comprising the same, a preparation method and use thereof, which have better ALK kinase inhibitory activity and high selectivity for the drug resistance mutation L1196M, and can be used for It treats, prevents, and alleviates ALK kinase-mediated diseases.
  • R 1 and R 2 are independently selected from H, halogen, -CN, -NO 2 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted a C 1 -C 6 alkoxy group, an optionally substituted C 3 -C 10 carbocyclic group or an optionally substituted 3 to 10 membered heterocyclic group; or R 1 and R 2 may form a fused with the atom to which they are attached 5 to 7 yuan ring;
  • Linker W is selected from
  • R 3 is selected from H, halogen, -CN, -NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy;
  • R 4 is selected from H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl
  • R 5 and R 6 are independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 alkoxy, optionally a substituted C 3 -C 10 carbocyclic group or an optionally substituted 3 to 10 membered heterocyclic group; or R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted 3 to 10 membered heterocyclic group;
  • R 7 is selected from an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 1 -C 6 haloalkoxy group, an optionally substituted C 2 -C 6 alkenyloxy group or an optionally substituted 3 ⁇ 7-membered cycloalkyloxy group;
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the present invention provides a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention to form a pharmaceutical composition.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.
  • the invention provides a method of treating a cancer-related disorder resulting from an ALK mutation in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention.
  • the cancer is selected from the group consisting of non-small cell lung cancer, breast cancer, neurological tumors (such as glioblastoma and neuroblastoma); esophageal cancer, soft tissue cancer (such as rhabdomyosarcoma, etc.); Forms of lymphoma, such as non-Hodgkin's lymphoma (NHL) known as anaplastic large cell lymphoma (ALCL); various forms of leukemia.
  • NHL non-Hodgkin's lymphoma
  • ACL anaplastic large cell lymphoma
  • the non-small cell lung cancer is an ALK positive non-small cell lung cancer.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.
  • C 1 -C 6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 - C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 C 4 -C 6 , C 4 -C 5 and C 5 -C 6 alkyl.
  • C 1 -C 6 alkyl refers to a straight or branched saturated hydrocarbon group having from 1 to 6 carbon atoms, also referred to herein as “lower alkyl.” In some embodiments, a C 1 -C 4 alkyl group is particularly preferred.
  • alkyl group examples include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), uncle Butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
  • each of the alkyl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"); For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • the alkyl group is unsubstituted C 1 -C 6 alkyl (e.g., -CH 3). In some embodiments, the alkyl group is a substituted C 1 -C 6 alkyl.
  • C 2 -C 6 alkenyl refers to a straight or branched chain hydrocarbon radical having from 2 to 6 carbon atoms and one or more carbon-carbon double bonds (eg, 1, 2 or 3 carbon-carbon double bonds) group.
  • One or more carbon-carbon double bonds may be internal (eg, in 2-butenyl) or end (eg, in 1-butenyl).
  • C2-4 alkenyl is particularly preferred.
  • alkenyl group examples include, but are not limited to, vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-propen-2-yl (C 3 ), 1- Butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ),and many more.
  • each of the alkenyl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"); For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • an alkenyl group is an unsubstituted C 2-6 alkenyl group.
  • an alkenyl group is a substituted C 2-6 alkenyl group.
  • C 2 -C 6 alkynyl means having from 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (eg, 1, 2 or 3 carbon-carbon triple bonds), and optionally one or more A linear or branched hydrocarbon group of a carbon-carbon double bond (for example, 1, 2 or 3 carbon-carbon double bonds).
  • a C2-4 alkynyl group is particularly preferred.
  • an alkynyl group does not contain any double bonds.
  • the one or more carbon oxime bonds may be internal (eg, in 2-butynyl) or end (eg, in 1-butynyl).
  • alkynyl group examples include, but are not limited to, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2- Butynyl (C 4 ), pentynyl (C 5 ), 3-methylbut-1-ynyl (C 5 ), hexynyl (C 6 ), and the like.
  • each of the alkynyl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"); For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • an alkynyl group is an unsubstituted C 2-6 alkynyl group.
  • an alkynyl group is a substituted C 2-6 alkynyl group.
  • C 1 -C 6 alkoxy refers to the group -OR wherein R is a substituted or unsubstituted C 1 -C 6 alkyl group. In some embodiments, a C 1 -C 4 alkoxy group is particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, N-Hexyloxy and 1,2-dimethylbutoxy.
  • C 1 -C 6 alkylthio refers to the group -SR wherein R is optionally substituted C 1 -C 6 alkyl.
  • a C 1 -C 4 alkylthio group is particularly preferred.
  • the C 1 -C 6 alkylthio group includes, but is not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, sec-butylthio, N-pentylthio, n-hexylthio and 1,2-dimethylbutylthio.
  • C 1 -C 6 alkylamino refers to the group -NHR or -NR 2 wherein R is optionally substituted C 1 -C 6 alkyl.
  • a C 1 -C 4 alkylamino group is particularly preferred.
  • the C 1 -C 6 alkylamino group includes, but is not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, t-butylamino, dimethylamino, methylethylamino and diethylamino.
  • Halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • the halo group is F, -Cl or Br.
  • the halogen group is F or Cl.
  • the halogen group is F.
  • C 1 -C 6 haloalkyl and “C 1 -C 6 haloalkoxy” mean the above-mentioned “C 1 -C 6 alkyl” and "C 1 -C 6 alkoxy", which are one or Multiple halogen groups are substituted.
  • a C 1 -C 4 haloalkyl group is particularly preferred, more preferably a C 1 -C 2 haloalkyl group.
  • a C 1 -C 4 haloalkoxy group is particularly preferred, more preferably a C 1 -C 2 haloalkoxy group.
  • Exemplary haloalkyl groups include, but the are not limited to: -CF 3, -CH 2 F, -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • Exemplary haloalkoxy groups include, but are not limited to, -OCH 2 F, -OCHF 2 , -OCF 3 , and the like.
  • C 3 -C 8 carbocyclic group or "3 to 8 membered carbocyclic group” means a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms and zero hetero atoms.
  • a C 5 -C 8 carbocyclic group, a non-aromatic cyclic hydrocarbon group having 5 to 8 ring carbon atoms and zero heteroatoms is preferred.
  • a 5-membered carbocyclic group is preferred, which is a non-aromatic cyclic hydrocarbon group having 5 ring carbon atoms and zero heteroatoms.
  • Carbocyclyl also includes ring systems wherein the above carbocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclic ring, and in such cases, the number of carbons continues to be represented The number of carbons in the carbocyclic system.
  • carbocyclic groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclopentadienyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and Cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl ( C 8 ), bicyclo [2.2.1] heptyl (C 7 ), bicyclo [2.2.2] octyl (C 8 ), and the
  • each of the carbocyclic groups is independently optionally substituted, ie, unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclic group"").
  • the carbocyclic group is unsubstituted C 3 -C 8 carbocyclyl.
  • the carbocyclyl is substituted with C 3 -C 8 carbocyclyl.
  • 3 to 8 membered heterocyclic group means a 3 to 8 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms, wherein each hetero atom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, Phosphorus and silicon, wherein carbon, nitrogen, sulfur and phosphorus atoms may also exist in their oxidation state, such as C(O), S(O), S(O) 2 , P(O) and the like.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • a 4- to 7-membered heterocyclic group is preferred, which is a 4 to 7 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms.
  • a 5- to 8-membered heterocyclic group is preferred, which is a 5 to 8 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms.
  • a 4 to 6 membered heterocyclyl group is preferred, which is a 4 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms.
  • a 5- to 6-membered heterocyclic group is preferred, which is a 5 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms.
  • a 5-membered heterocyclic group is more preferred, which is a 5-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms.
  • the cyclic group contains 1 to 3 (more preferably 1 or 2) ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably nitrogen or oxygen.
  • each of the heterocyclic groups is independently optionally substituted, that is, unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic ring"base").
  • the heterocyclyl is an unsubstituted 3-8 membered heterocyclyl.
  • a heterocyclic group is a substituted 3-8 membered heterocyclyl.
  • the heterocyclic group further includes a ring system in which the above heterocyclic ring is fused to one or more carbocyclic groups, wherein the point of attachment is on the carbocyclic ring, or wherein the above heterocyclic ring is bonded to one or more aryl groups or A heteroaryl fused ring system wherein the point of attachment is on a heterocyclyl ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclic groups containing one hetero atom include, but are not limited to, aziridine, oxacyclopropane, thicyclopropyl.
  • Exemplary 4-membered heterocyclic groups containing one hetero atom include, but are not limited to, azetidinyl, oxetanyl and thietane.
  • Exemplary 5-membered heterocyclic groups containing one hetero atom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolyl, oxathiolanyl, oxathiolanyl (1,2-oxothio) Cyclopentenyl, 1,3-oxathiolanyl, dithiolanyl, dihydropyrazolyl, dihydroimidazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrogen Oxazolyl, dihydroisoxazolyl, dihydrooxadiazolyl and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 6-membered heterocyclic groups containing one hetero atom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, tetrahydropyridyl and thiacyclohexane.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dihydropyrazinyl, piperazinyl, morpholinyl, dithianyl, dioxoalkyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl.
  • Exemplary 7-membered heterocyclic groups containing one or two heteroatoms include, but are not limited to, azepanyl, diazepanyl, oxacycloheptyl, and thienyl.
  • Exemplary 8-membered heterocyclic groups containing one or two heteroatoms include, but are not limited to, azacyclooctyl, oxacyclooctyl, thietane, octahydrocyclopentadienyl [ c] pyrrolyl and octahydropyrrolo[3,4-c]pyrrolyl.
  • Exemplary 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocyclyl) fused to a C6 aryl ring include, but are not limited to, indanyl, isoindoline , dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclic groups fused to a C 6 aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and many more.
  • C 6 -C 14 aryl or “6 to 14-membered aromatic ring group” means a monocyclic or polycyclic ring having 6 to 14 ring carbon atoms and zero hetero atoms provided in the aromatic ring system (for example, a bicyclic or tricyclic) 4n+2 aromatic ring system (eg, having 6, 10 or 14 ⁇ electrons shared in a cyclic arrangement) ("C 6-14 aryl”).
  • an aryl group having six ring carbon atoms "C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (" C10 aryl”; for example, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • an aryl group has fourteen ring carbon atoms (" C14 aryl”; for example, fluorenyl).
  • C 6 -C 14 aryl also includes ring systems in which the above aryl ring is fused to one or more carbocyclic or heterocyclic groups, wherein the atomic group or point of attachment is On the aryl ring, in this case, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system.
  • Typical aryl groups include, but are not limited to, those derived from acetaminophen, decene, acephenanthrylene, hydrazine, hydrazine, benzene, quinone, acetophenone, fluoranthene, anthracene, hexacene, and hexyl Fen, hexene, asymmetric introduction, symmetric introduction, indole, anthraquinone, naphthalene, octabenzene, octene, octene, egg benzene, penta-2,4-diene, pentacene , pentylene, penfen, hydrazine, phenalene, phenanthrene, anthracene, heptarene, anthracene, quercetin, jade red, benzophenanthrene and quinone.
  • the aryl group includes a phenyl group, a naphthyl group, an anthracenyl group, and a tetrahydronaphthyl group.
  • each of the aryl groups is independently optionally substituted, that is, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").
  • the aryl group is an unsubstituted C 6-14 aryl group.
  • the aryl group is a substituted C 6-14 aryl group.
  • 5 to 10 membered heteroaryl means a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms (for example, having a ring-like arrangement) a group of 6 or 10 ⁇ electrons, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • a 5-membered heteroaryl is preferred, which is a 5-membered monocyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms (eg, having 6 shared in a cyclic arrangement)
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems wherein the above heteroaryl ring is fused to one or more carbocyclic or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case a carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system.
  • each of the heteroaryl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl" base").
  • the heteroaryl is an unsubstituted 5 to 10 membered heteroaryl.
  • the heteroaryl is a substituted 5 to 10 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyrrolyl, furyl and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one hetero atom include, but are not limited to, azepandinyl, oxepanethylene, and thiephenylene.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, mercapto, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Pyridazinyl and fluorenyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, acridinyl, quinolyl, isoquinolinyl, fluorenyl, quinoxalinyl, pyridazinyl and quinazolinyl .
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl as defined herein are optionally substituted groups.
  • substituted whether or not preceded by the term “optionally”, means that at least one hydrogen present on a group (eg, a carbon or nitrogen atom) is substituted with an allowable substituent, for example, when substituted.
  • Substituents that result in stable compounds for example, compounds that do not spontaneously undergo a transition (eg, by rearrangement, cyclization, elimination, or other reaction).
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, The substituents at one position are the same or different.
  • substituted includes substitutions made with all of the permissible substituents of the organic compound that result in the formation of any of the substituents described herein.
  • a hetero atom such as nitrogen can have a hydrogen substituent and/or any suitable substituent described herein that satisfies the valence of the hetero atom and results in the formation of a stable moiety.
  • Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R aa groups are bonded to form a heterocyclyl or a heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R dd groups Substitute
  • Each of R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R cc groups are bonded to form a heterocycle a hetero or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R Substituting dd group;
  • Each of R ee is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon The cyclo, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;
  • Each of R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ff groups are bonded to form a heterocyclic group Or a heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R gg Group substitution
  • pharmaceutically acceptable salt means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases.
  • non-toxic acid addition salts are salts of amino and inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids, such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed using methods used in the art, for example, an ion exchange method.
  • amino and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed using methods used in the art, for example, an ion exchange method.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • Further pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed using counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Subjects for administration include, but are not limited to, humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young Adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or condition (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. Delay or minimize.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.
  • a compound of the invention refers to a pharmaceutically acceptable salt, crystalline form, prodrug, metabolite, hydrate, solvate, stereoisomer or isotope derivative of a compound of formula (I) below. Things.
  • the invention relates to a compound of formula (I):
  • R 1 and R 2 are independently selected from H, halogen, -CN, -NO 2 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted a C 1 -C 6 alkoxy group, an optionally substituted C 3 -C 10 carbocyclic group or an optionally substituted 3 to 10 membered heterocyclic group; or R 1 and R 2 may form a fused with the atom to which they are attached 5 to 7 yuan ring;
  • Linker W is selected from
  • R 3 is selected from H, halogen, -CN, -NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy;
  • R 4 is selected from H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl
  • R 5 and R 6 are independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 alkoxy, optionally a substituted C 3 -C 10 carbocyclic group or an optionally substituted 3 to 10 membered heterocyclic group; or R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted 3 to 10 membered heterocyclic group;
  • R 7 is selected from an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 1 -C 6 haloalkoxy group, an optionally substituted C 2 -C 6 alkenyloxy group or an optionally substituted 3 ⁇ 7-membered cycloalkyloxy group;
  • R 1 is independently selected from H, halogen, -CN, -NO 2 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 a haloalkyl group, an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 3 -C 10 carbocyclic group or an optionally substituted 3 to 10 membered heterocyclic group; preferably, R 1 is selected from H, Halogen, -CN, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C a 10 carbocyclic group or an optionally substituted 3 to 10 membered heterocyclic group; preferably, R 1 is selected from the group consisting of H, F, Cl, Br, methyl, ethyl, isopropyl, -CH 2 F,
  • R 2 is independently selected from H, halogen, -CN, -NO 2 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 a haloalkyl group, an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 3 -C 10 carbocyclic group or an optionally substituted 3 to 10 membered heterocyclic group; preferably, R 2 is selected from H, Halogen, -CN, -NO 2 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy; preferably, R 2 is selected from H, F, Cl, Br, -CN, -NO 2 , -OH or methyl; more preferably, R 2 is selected from H.
  • the atoms to which R 1 and R 2 are attached may form a fused 5- to 7-membered ring; preferably, R 1 and R 2 may form a fused with the carbon atom to which they are attached.
  • the linker W is selected from
  • W is selected from
  • W is selected from
  • R 5 and R 6 are independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 a -C 6 alkoxy group, an optionally substituted C 3 -C 10 carbocyclic group or an optionally substituted 3 to 10 membered heterocyclic group; or R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted a 3 to 10 membered heterocyclic group; preferably, R 5 and R 6 are independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 carbocyclic group or optionally substituted a 3 to 10 membered heterocyclic group; or R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted 3 to 10 membered heterocyclic group; more preferably, R 5 and R 6 are independently selected from H, Methyl or ethyl
  • -W-NR 5 R 6 is selected from the group consisting of:
  • -W-NR 5 R 6 is selected from:
  • R 7 is selected from an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 1 -C 6 haloalkoxy group, an optionally substituted C 2 -C 6 alkenyl group An oxy group or an optionally substituted 3- to 7-membered cycloalkyloxy group; preferably, R 7 is selected from an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 1 -C 6 haloalkoxy group;
  • R 2 is selected from -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , -OCH 2 F or -OCH 2 CF 3; more preferably, R 2 is selected from -OCH 3, -OCH (CH 3) 2 or -OCH 2 CF 3; most preferably, R 2 is selected from -OCH 3, -OCH (CH
  • the invention relates to compounds of formula (IIa)-(IIm):
  • R 5 , R 6 , R 7 , R 8 and W are as defined above.
  • the invention relates to compounds of formula (IIa)-(IIm):
  • W is selected from a C 1 -C 6 alkylene group, a C 3 -C 10 carbocyclic group, a 3 to 10 membered heterocyclylene group, and the atom to which the W is bonded to the benzene ring must be C; Optionally substituted by one or more R 3 ;
  • R 3 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1-6 alkoxy;
  • R 5 and R 6 are independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 alkoxy, optionally a substituted C 3 -C 10 carbocyclic group or an optionally substituted 3 to 10 membered heterocyclic group; or R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted 3 to 10 membered heterocyclic group;
  • R 7 is selected from an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 1 -C 6 haloalkoxy group or an optionally substituted 3 to 7 membered cycloalkyloxy group;
  • R 8 is selected from H, halogen or C 1 -C 6 alkyl
  • W is selected from C 1 -C 6 alkylene, C 3 -C 10 carbocyclylene, 3 to 10 membered heterocyclylene, wherein the atom to which the phenyl ring is attached must be C; The group thereof is optionally substituted by one or more R 3 ; wherein R 3 is selected from H or C 1 -C 6 alkyl;
  • W is selected from a C 1 -C 6 alkylene group, which is optionally substituted by one more than one R 3 ; wherein R 3 is selected from H or C 1 -C 6 alkyl; preferably, W is selected from - CH 2 -, -CH 2 CH 2 -, -C(CH 3 )H-, -C(CH 3 ) 2 -, -C(CH 3 )HCH 2 -, -C(CH 3 ) 2 CH 2 -, -C(CH 3 )HC(CH 3 )H- or -C(CH 3 ) 2 C(CH 3 ) 2 -;
  • W is selected from a C 3 -C 10 carbocyclic group, which is optionally substituted by one or more R 3 ; wherein R 3 is selected from H or C 1 -C 6 alkyl; preferably, W is selected from
  • W is selected from a 3 to 10 membered heterocyclylene group, and the atom to which the W is attached to the phenyl ring must be C; which is optionally substituted with one or more R 3 ; wherein R 3 is selected from H or C 1- C 6 alkyl; preferably, W is selected from Its * indicates that it is attached to the benzene ring, and # indicates that it is attached to the N atom.
  • R 5 and R 6 are independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted 3 To a 10-membered heterocyclic group; or R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted 3 to 10 membered heterocyclic group;
  • R 5 and R 6 are independently selected from H or an optionally substituted C 1 -C 6 alkyl group; or R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted 3 to 10 membered heterocyclic ring base;
  • -W-NR 5 R 6 is selected from:
  • -W-NR 5 R 6 is selected from:
  • R 7 is selected from an optionally substituted C 1 -C 6 alkoxy group; preferably, R 7 is selected from -OCH 3 .
  • R 8 is selected from H or C 1 -C 6 alkyl; preferably, R 8 is selected from H or methyl.
  • the invention relates to a compound of formula (IIa):
  • W is selected from C 1 -C 6 alkylene; the group thereof is optionally substituted by one or more R 3 ;
  • R 3 is selected from H or C 1 -C 6 alkyl
  • R 5 and R 6 are independently selected from H or an optionally substituted C 1 -C 6 alkyl group; or R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted 5 to 6 membered heterocyclic group;
  • R 7 is selected from the group consisting of an optionally substituted C 1 -C 6 alkoxy group
  • R 8 is selected from H or C 1 -C 6 alkyl
  • W is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -C(CH 3 )H-, -C(CH 3 ) 2 -, -C(CH 3 )HCH 2 -, -C(CH 3 ) 2 CH 2 -, -C(CH 3 )HC(CH 3 )H- or -C(CH 3 ) 2 C(CH 3 ) 2 -;
  • R 5 and R 6 are independently selected from H or optionally substituted C 1 -C 6 alkyl; preferably, R 5 and R 6 are independently selected from H or methyl; R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted 5 to 6 membered heterocyclic group; preferably, R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted piperidine ring , piperazine ring or morpholine ring.
  • -W-NR 5 R 6 is selected from:
  • R 7 is selected from an optionally substituted C 1 -C 6 alkoxy group; preferably, R 7 is selected from -OCH 3 .
  • R 8 is selected from H or C 1 -C 6 alkyl; preferably, R 8 is selected from H or methyl.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the invention also includes all suitable isotopic derivatives of the compounds of the invention.
  • An isotope derivative of a compound of the invention is defined as wherein at least one atom is replaced by an atom having the same atomic number but differing in atomic mass from the atomic mass typically found in nature.
  • isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. 18 F, 31 P, 32 P, 35 S and 36 Cl.
  • isotopic derivatives of the compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • Deuterated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with isotopes e.g., hydrazine, i.e., 2 H
  • Isotopic derivatives of the compounds of the invention can generally be prepared by conventional procedures, for example by descriptive methods or by the preparations described in the Examples below, using appropriate isotopic derivatives of the appropriate reagents.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may be in an amorphous or crystalline form.
  • the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • the term "crystalline form" refers to a crystalline form (or a salt, hydrate or solvate thereof) of a compound in a particular crystal packing arrangement. All crystal forms have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can result in a crystalline form that predominates. Various crystal forms of the compounds can be prepared by crystallization under different conditions.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound which is converted in vivo to an active form thereof having a medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduction This article serves as a reference.
  • a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of formula (I) in vivo.
  • Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound.
  • Prodrugs include, for example, compounds of the invention wherein a hydroxy, amine or sulfhydryl group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amine or sulfhydryl group.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol, mercapto and amine functional groups of the compounds of formula (I).
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.
  • compositions, formulations and kits are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • the pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles which do not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum white) Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene - Block poly
  • kits e.g., pharmaceutical packs.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents) Suitable container).
  • first and second containers eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents
  • kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent.
  • a compound of the invention provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.
  • formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention.
  • the invention is not limited to the following pharmaceutical compositions.
  • Exemplary Formulation 1 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 0.3-30 mg tablets (each tablet contains 0.1-10 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 2 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 30-90 mg tablet (each tablet contains 10-30 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 3 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 4-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 150-240 mg tablet (each tablet contains 50-80 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 5 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 240-270 mg tablets (each tablet contains 80-90 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 6-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a tablet of 270-450 mg (each tablet contains 90-150 mg of active compound) in a tablet press.
  • Exemplary Formulation 7-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 450-900 mg tablets (each tablet contains 150-300 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 8-Capsule The compound of the present invention in dry powder form can be mixed with a starch diluent in a weight ratio of about 1:1. The mixture was filled into 250 mg capsules (each capsule containing 125 mg of active compound).
  • Exemplary Formulation 9-Liquid The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended, passed through a No. 10 mesh U.S. sieve, and then It was mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then, sufficient water can be added to give a total volume of 5 mL.
  • Exemplary Formulation 10 - Injection The compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.
  • the pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration. , intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician. .
  • the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.
  • long-term administration can also be administered chronically.
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject.
  • chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within a therapeutic window.
  • a pharmaceutical composition of the present invention can be further delivered using various methods of administration.
  • a pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose that causes a slow release of the active ingredient, while a bolus that is delivered directly to the vein (eg, via IV IV drip) ) can be delivered more quickly, so that the concentration of the active ingredient in the blood is rapidly increased to an effective level.
  • the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.
  • Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration.
  • a carrier or excipient and a processing aid is provided in unit dosage form for ease of precise dosing.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, water Methyl salicylate or orange flavoring.
  • a binder for example, microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn star
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active component When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base.
  • the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and generally include other ingredients for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
  • transdermal administration can be accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials as well as processing techniques and the like are set forth in Remington's Pharmaceutical Sciences, 17 th edition , 1985, Mack Publishing Company, Easton, in Section 8 Pennsylvania, herein incorporated by reference in this document.
  • the compounds of the invention may also be administered in sustained release form or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention further relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation comprises hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic derivative thereof, or a given to a subject in need of treatment.
  • Pharmaceutical The pharmaceutical composition of the invention is used to treat cancer.
  • the cancer is an ALK-driven cancer.
  • the cancer is non-small cell lung cancer.
  • a “therapeutically effective amount” is an amount effective to detect the growth or spread of killing or inhibiting cancer cells; the size or number of weights; or other measure of the level, stage, progression or severity of cancer. The exact amount required can vary from subject to subject, depending on the race, age and general health of the subject, the severity of the disease, the particular anticancer agent, its mode of administration, combination therapy with other therapies, and the like.
  • various compounds disclosed herein inhibit tyrosine kinase activity of ALK, fak, and c-met, particularly tyrosine kinases believed to mediate the growth, progression, and/or metastasis of cancer.
  • a variety of compounds as disclosed herein have also been found to have potent in vitro activity against cancer cell lines. Thus, such compounds are useful in the treatment of cancer, including solid tumors as well as lymphomas, and include cancers that are resistant to other therapies.
  • the cancer is an ALK-driven cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is an ALK positive NSCLC. In some embodiments, the cancer is a locally advanced or metastatic ALK-positive NSCLC. In some embodiments, the cancer/patient has been previously treated with crizotinib or another tyrosine kinase inhibitor. In some embodiments, the cancer/patient has not previously been treated with an ALK inhibitor.
  • NSCLC non-small cell lung cancer
  • the cancer is an ALK positive NSCLC.
  • the cancer is a locally advanced or metastatic ALK-positive NSCLC.
  • the cancer/patient has been previously treated with crizotinib or another tyrosine kinase inhibitor. In some embodiments, the cancer/patient has not previously been treated with an ALK inhibitor.
  • Such cancers include, but are not limited to, breast cancer, non-small cell lung cancer, neurological tumors (such as glioblastoma and neuroblastoma); esophageal cancer, soft tissue cancer (such as rhabdomyosarcoma, etc.); various forms of lymphoma, Non-Hodgkin's lymphoma (NHL) such as known as anaplastic large cell lymphoma (ALCL); various forms of leukemia; and includes cancers mediated by ALK or c-met.
  • NDL Non-Hodgkin's lymphoma
  • ACL anaplastic large cell lymphoma
  • leukemia includes cancers mediated by ALK or c-met.
  • Anaplastic lymphoma kinase is a transmembrane receptor tyrosine kinase that belongs to the insulin receptor subfamily.
  • the ALK receptor tyrosine kinase was originally identified for its involvement in human non-Hodgkin's lymphoma subtypes known as anaplastic large cell lymphoma (ALCL).
  • ALK typically has a restricted distribution in mammalian cells and is found to be at a significant level in the nervous system only during embryonic development, indicating the role of ALK in brain development.
  • normal ALK In addition to its role in normal development, expression of full-length normal ALK has been detected in cell lines derived from various tumors, such as glioblastoma, neuroectodermal tumors, and glioblastoma, and breast. Cancer and melanoma lines.
  • translocations affect the ALK gene, leading to expression of the original cell fusion kinase, the most common of which is NPM-ALK.
  • NPM-ALK anaplastic large cell lymphoma
  • ACL anaplastic large cell lymphoma
  • NMP nucleolar phosphoprotein
  • This mutant protein, NPM-ALK has a constitutively active tyrosine kinase domain that is responsible for its carcinogenic properties by activating downstream effectors.
  • ALK positive lymphoid cancer cells The constitutively activated chimeric ALK has been shown to be present in approximately 60% of inflammatory myofibroblastic tumors (IMTs), a slow-growing sarcoma that primarily affects children and young adults. Furthermore, current reports have described the appearance of the variant ALK fusion TPM4-ALK in the case of esophageal squamous cell carcinoma (SCC).
  • IMTs myofibroblastic tumors
  • SCC esophageal squamous cell carcinoma
  • ALK is one of the few examples of RTKs involved in neoplasia in both non-hematopoietic malignancies and hematopoietic malignancies.
  • EML4 thorny animal microtubule-associated protein-like 4
  • ALK anaplastic lymphoma kinase
  • an ALK inhibitor can create a durable cure when used as a single therapeutic agent or in combination with current chemotherapy for ALCL, IMT, proliferative disorders, glioblastoma, and other possible solid tumors cited herein, Or as a single therapeutic agent can be used to prevent the maintenance of relapse in patients in need of such treatment.
  • a compound as disclosed herein can be administered as part of a therapeutic regimen wherein the compound is the only active agent, or in combination with one or more other therapeutic agents that are part of a combination therapy.
  • the therapeutic agent being administered can be formulated to simultaneously or sequentially administer separate compositions at different time points (eg, within 72 hours, 48 hours, or 24 hours of each other), Alternatively, the therapeutic agents can be formulated together as a single pharmaceutical composition and administered simultaneously.
  • administration of a compound of the invention may be mediated by at least one additional treatment known to those skilled in the art for preventing or treating cancer, such as radiation therapy or cytostatics, cytotoxic agents, other anticancer agents, and other drugs. Symptoms of cancer or any side effects of drugs.
  • additional therapeutic agents include agents suitable for immunotherapy (such as, for example, PD-1 or PDL-1 inhibitors), anti-angiogenic agents (such as, for example, bevacizumab), and/or chemotherapy.
  • such combination products employ a compound as disclosed herein in an acceptable dosage range.
  • the compounds as disclosed herein can be administered sequentially with other anticancer or cytotoxic agents.
  • the compounds as disclosed herein can be administered prior to, concurrently with, or subsequent to the administration of other anticancer or cytotoxic agents.
  • a typical chemotherapy regimen consists of a DNA alkylating agent, a DNA intercalating agent, a CDK inhibitor, or a microtubule poison.
  • the dose of chemotherapy used is just below the maximum tolerated dose, and thus dose limiting toxicity typically includes nausea, vomiting, diarrhea, hair loss, neutropenia, and the like.
  • antineoplastic agents are available for commercial use, clinical evaluation, and preclinical development, which can be selected for treatment of cancer by combination chemotherapy.
  • antineoplastic agents There are several major classes of such antineoplastic agents, namely, antibiotic agents, alkylating agents, antimetabolites, antihormonal agents, immunizing agents, interferon-type agents, and a class of confounding agents.
  • an anticancer alkylating agent or an intercalating agent eg, nitrogen mustard, chlorambucil, cyclophosphamide, melphalan, and ifosfamide
  • Antimetabolites eg methotrexate
  • anti-caking agents or pyrimidine antagonists eg 5-fluorouracil, cytarabine and gemcitabine
  • spindle inhibitors eg vinblastine, vincristine, vinorelbine
  • podophyllotoxin eg etoposide, irinotecan, topotecan
  • antibiotics eg doxorubicin, bleomycin and mitomycin
  • nitrosoureas eg Camo) Statin, lomustine
  • inorganic ions such as cisplatin, carboplatin, oxaliplatin or oxiplatin
  • enzymes such as asparaginase
  • Proteasome inhibitors eg, sputum, other proteasome inhibition and (eg Src, Bcr/Abl, kdr, flt3, aurora-2, glycogen synthase kinase 3 (GSK-3), EGFR) Enzymes (such as Iressa, Tarceva, etc.), VEGF-R kinases, inhibitors of PDGF-R kinase, etc.; antibodies, soluble receptors or other receptor antagonists that are resistant to receptors or hormones involved in cancer ( Including receptors such as EGFR, ErbB2, VEGFR, PDGFR and IGF-R; and drugs such as Herceptin, Avastin, Erbitux, etc.) Examples of other therapeutic agents include, but are not limited to, sterol, alemtuzmab, hexa Melamine, amifostine, nastrozole, antibodies against prostate-specific membrane antigens (eg MLN-591,
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • Example 8 and Example 9 (2-((5-chloro-2-((4-(dimethylamino)ethyl)-2-methoxyphenyl)amino)pyrimidin-4-yl) ) amino) Phenyl) dimethylphosphine oxide (compound T-8) and (2-((5-chloro-2-((4-(1-(methylamino)ethyl)-2-methoxyphenyl)) Amino)pyrimidin-4-yl) Preparation of amino)phenyl)dimethylphosphine oxide (Compound T-9).
  • tetrabutylammonium nitrate (6.7 g, 21.94 mmol), 18-crown-6 (845 mg, 3.2 mmol) and dichloromethane (30 mL) were added, and the mixture was stirred and cooled.
  • TFAA 13 mL was added dropwise under a nitrogen atmosphere, stirred for 15 minutes, and a solution of compound 23 (4.0 g, 22.86 mmol) in dichloromethane (10 mL) was added dropwise, and the mixture was applied dropwise. hour.
  • the reaction was quenched with water (30 mL) EtOAc (EtOAc)EtOAc.
  • Example 11 and Example 12 (2-((5-chloro-2-(2-methoxy-4-(2-methyl-1-(methylamino)propan-2-yl)phenyl)) Amino)pyrimidine 4-yl)amino)phenyl)dimethylphosphine oxide (compound T-11) and (2-((5-chloro-2-((4-(1-(dimethylamino))-2-) Propane-2-yl)-2- Preparation of methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (Compound T-12).
  • Example 14 and Example 15 (2-((5-chloro-2-((4-(2-methylamino)propan-2-yl)-2-methoxyphenyl)amino)pyrimidine- 4-base) Amino)phenyl)dimethylphosphine oxide (compound T-14) and (2-((5-chloro-2-((2-methoxy-4-(2-(methylamino))propane-2-) Phenyl)amino) Preparation of pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (Compound T-15).
  • Example 17 and Example 18 (2-((5-chloro-2-((4-(1-methylamino)propan-2-yl)-2-methoxyphenyl)amino)pyrimidine- 4-base) Amino)phenyl)dimethylphosphine oxide (compound T-17) and (2-((5-chloro-2-((2-methoxy-4-(1-(methylamino))propane-2-) Phenyl)ammonia Preparation of pyrimido-4-yl)amino)phenyl)dimethylphosphine oxide (Compound T-18).
  • Example 20 and Example 21 (2-((5-chloro-2-((4-(2-(dimethylamino)ethyl)-2-methoxy-5-methylphenyl)amino)) Pyrimidine-4- (amino)phenyl)dimethylphosphine oxide (compound T-20) and (2-((5-chloro-2-((2-methoxy-5-methyl-4-(2-)) Amino)ethyl)phenyl) Preparation of amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (Compound T-21).
  • the compounds of the invention were evaluated in a number of tests to determine their biological activity. For example, the ability of a compound of the invention to inhibit a variety of protein kinases of interest can be tested. Some of the compounds tested showed potent inhibitory activity against ALK kinase.
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. Compounds were diluted to 0.1 mM in DMSO (100 times the final concentration of the dilution) before use and diluted in 3 folds at 11 concentrations. Dilute to 4 times the final concentration of the dilution solution with the buffer.
  • the compounds of the present invention were tested in the above kinase inhibition assay and found to have potent activity against ALK and ALK [L1196M].
  • the results for the representative example compounds are summarized in Table 1 below.
  • the in vitro antiproliferative activity of the compounds of the present invention against three cells cultured in vitro was examined by the CellTiter-Glo method.
  • the experimental results show that the compound of the present invention has a strong inhibitory effect on the in vitro proliferation of EML4-ALK and EML4-ALK L1196M mutant cells cultured in vitro.
  • BaF3parental contains 10 ng/ml IL-3, 0% fetal bovine serum, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin in RPMI1640 medium
  • Reagents and consumables RPMI-1640 (GIBCO, catalog number A10491-01); fetal bovine serum (GIBCO, catalog number 10099141); 0.25% trypsin-EDTA (GIBCO, catalog number 25200); penicillin-streptomycin, liquid ( GIBCO, Cat. No. 15140-122); DMSO (Sigma, Cat. No. D2650); CellTiter-Glo Test Kit (Promega, Cat. No. G7572), 96-well plate (Corning, Cat. No. 3365).
  • the cells in the logarithmic growth phase were diluted with the culture medium to a specific cell concentration, and 90 ⁇ l of the cell suspension was added to the 96-well plate to bring the cell density to the specified concentration. Incubate overnight at 37 ° C in a 5% carbon dioxide gas incubator.
  • the compounds of the present invention were tested in the above cytotoxicity assay and found to have potent activity against Ba/F3ALK and Ba/F3 ALK [L1196M] and superior selectivity to cellular Ba/F3parental.
  • the results of the inhibition of in vitro proliferation of cancer cells by representative examples are summarized in Table 2 below, wherein A represents IC 50 ⁇ 25 nM, B represents an IC 50 of 25-50 nM, and C represents an IC 50 of 50-100 nM, and D represents The IC 50 is 100-200 nM, E represents an IC 50 of 200-1000 nM, and E represents an IC 50 ⁇ 1000 nM.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

Abstract

一种对蛋白酪氨酸激酶具有抑制作用的二苯氨基嘧啶类化合物，其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物，包含它们的药物组合物，以及它们的制备和用途被公开。该化合物的结构如式（I）所示，其可用于治疗ALK介导的癌症相关病症，例如非小细胞肺癌、乳腺癌、神经肿瘤、食道癌、软组织癌、淋巴瘤或白血病。

Description

用于抑制激酶活性的二苯氨基嘧啶类化合物 技术领域
本发明属于医药技术领域。具体地，本发明涉及对蛋白酪氨酸激酶具有抑制作用的二苯氨基嘧啶类化合物，包含它们的药物组合物，以及它们的制备方法和用途。
背景技术
间变性淋巴激瘤酶(Anaplastic lymphoma kinase,ALK)是一种受体型蛋白质酪氨酸激酶，隶属于胰岛素受体超级家族。1994年由Morris和Shiota等从间变性大细胞淋巴瘤(Anaplastic large cell lymphoma,ALCL)中作为染色体重排的产物而被发现，最常见的融合方式是5号染色体上的NPM(Nucleophosmin)基因与2号染色体上ALK基因融合。将近75％的ALK呈阳性的ALCL患者中检测到NPM-ALK融合蛋白，在后续的一些研究中发现，在很多种癌症中都发现了不同的ALK融合形式，这其中包括炎性肌纤维母细胞瘤和弥漫大B细胞淋巴瘤。尽管如此，ALK激酶作为一个有效抗肿瘤药物靶点的重要性并没有完全被承认。直到2007年，Soda等发现EML4-ALK融合蛋白在非小细胞肺癌(non-small-cell lung cancer,NSCLC)中的占有几率为5％，ALK激酶作为一个抗肿瘤药物的靶点的重要性才凸显出来。这是因为全球癌症患者的数量非常巨大，其中肺癌居首，美国每年新发ALK阳性肺癌病例超过8000，而中国每年有超过6.5万的新发病例，而且全球肺癌5年存活率仅为15％。吸引眼球的是，EML4-ALK基因阳性患者一般不携带表皮生长因子受体(Epidermal growth factor receptor,EGFR)或鼠Kirsten肉瘤病毒(Kirsten rat sarcoma virus,KRAS)突变，这使得EML4-ALK融合基因成为非小细胞肺癌独特的分子靶点。除此之外，人们在神经母细胞瘤(Neuroblastomas)、甲状腺未分化癌(anaplastic thyroid cancer)和卵巢癌(ovarian cancer)中发现ALK基因的扩增或点突变。
首个针对ALK融合基因的小分子抑制剂克唑替尼(Crizotinib,Xalkori)是辉瑞研制的，属第一代ALK抑制剂。然而，尽管克唑替尼在ALK+NSCLC患者获得60-74％的客观应答率和良好的中位无进展生存期(8-11个月)，大部分患者在治疗1年后出现疾病复发，即产生获得性耐药。克唑替尼的获得性耐药机制也已经被鉴定，包括ALK融合基因的增益，信号传导旁路的激活，ALK激酶区域的二次突变和其他机制。大约40％ALK阳性患者在一开始接收克唑替尼治疗时就无客观应答，1/3克唑替尼耐药患者会发生二次突变，诱发继发性耐药。
有数个第二代ALK抑制剂能够有效克服对克唑替尼治疗耐药的不足，如色瑞替尼(Ceritinib,Zykadia,诺华制药)和艾乐替尼(Alectinib,Alecensa,罗氏制药)。然而，虽然这些第二代抑制剂能有效克服大部分克唑替尼耐药突变，但是仍然对有些突变无效，比如色瑞替尼对F1174C/V，艾乐替尼对I1171N/T/S和它们对G1202R仍然没有疗效。因此非常迫切需要开发新型的，更加有效安全的ALK抑制剂。
发明内容
本发明提供了一种新的二苯氨基嘧啶类化合物及包含它们的药物组合物、制备方法和用途，其具有更好地ALK激酶抑制活性，以及对于耐药突变L1196M的高选择性，可用于治疗、预防以及缓解ALK激酶介导的疾病。
对此，本发明采用的技术方案如下：
本发明的第一方面，提供了式(I)化合物：
Figure PCTCN2018120618-appb-000001
其中，
R 1和R 2独立地选自H、卤素、-CN、-NO 2、-OH、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 1和R 2与它们相连的原子可形成稠合的5～7元环；
连接基W选自
1)C 1-C 6亚烷基、C 1-C 6亚烯基、C 1-C 6亚炔基、C 3-C 8亚碳环基、3至10元亚杂环基、C 6-C 14芳基或5至10元杂芳基；其中W与苯环所连接的原子必须为C；其中所述基团任选被一个或多个R 3取代；
2)-C(＝O)-、-C(＝O)O-、-C(＝O)N(R 4)-；
R 3选自H、卤素、-CN、-NO 2、氧代基、C 1-C 6烷基、C 1-C 6卤代烷基或C 1-C 6烷氧基；
R 4选自H、C 1-C 6烷基或C 1-C 6卤代烷基；
R 5和R 6独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的3至10元杂环基；
R 7选自任选取代的C 1-C 6烷氧基、任选取代的C 1-C 6卤代烷氧基、任选取代的C 2-C 6烯基氧基或任选取代的3～7元环烷基氧基；
R 8选自H、卤素、-R、-CN、-NO 2、-OH、-SH、-C(＝O)R、-C(＝O)OR、-C(＝O)NRR、-NR 2、-NRC(＝O)R、-NRC(＝O)OR、-NRC(＝O)NRR、-NRS(＝O)R、-NRS(＝O)NRR、-NRS(＝O) 2R、-NRS(＝O) 2NRR、-OR、-OC(＝O)R、-OC(＝O)NRR、-S(＝O)R、-S(＝O)OR、-S(＝O)NRR、-S(＝O) 2R、-S(＝O) 2OR、-S(＝O) 2NRR、-SC(＝O)R、-SC(＝O)OR或-SC(＝O)NRR，只要化学允许；其中R独立地为H、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烯基、C 1-C 6炔基、C 3-C 10碳环基、3至10元杂环基、C 6-C 14芳基或5至10元杂芳基；两个相邻的R可一起形成任选取代的C 3-C 10碳环基、任选取代的5至8元杂环基、任选取代的C 6-C 14芳基或任选取代的5至10杂芳基；
或其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。在具体实施方案中，本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中，本发明化合物以治疗有效量提供。在具体实施方案中，本发明化合物以预防有效量提供。
在另一方面，本发明提供了一种如上所述的药物组合物的制备方法，包括以下步骤：将药学上可接受的赋形剂与本发明化合物进行混合，从而形成药物组合物。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物，其还含有其他治疗剂。
在另一方面，本发明提供了在需要其的受试者中治疗ALK突变导致的癌症相关病症的方法，所述方法包括给予受试者有效剂量的本发明化合物。在具体的实施方案中，所述癌症选自非小细胞肺 癌、乳腺癌、神经肿瘤(诸如胶质母细胞瘤和神经母细胞瘤)；食道癌、软组织癌(诸如横纹肌肉瘤等)；各种形式的淋巴瘤，诸如已知为间变性大细胞淋巴瘤(ALCL)的非霍奇金氏淋巴瘤(NHL)；各种形式的白血病。在优选实施方案中，非小细胞肺癌为ALK阳性的非小细胞肺癌。在具体实施方案中，口服、皮下、静脉内或肌肉内给药所述化合物。在具体实施方案中，长期给药所述化合物。
由随后的具体实施方式、实施例和权利要求，本发明的其他目的和优点将对于本领域技术人员显而易见。
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C 1-C 6烷基”包括C 1、C 2、C 3、C 4、C 5、C 6、C 1-C 6、C 1-C 5、C 1-C 4、C 1-C 3、C 1-C 2、C 2-C 6、C 2-C 5、C 2-C 4、C 2-C 3、C 3-C 6、C 3-C 5、C 3-C 4、C 4-C 6、C 4-C 5和C 5-C 6烷基。
应该理解，当本文描述时，任何下面所定义的基团可以被许多取代基取代，而且相应的定义在下面列出的它们的范围内，包括取代的基团。除非另作说明，否则，术语“取代”如下面所定义。
“C 1-C 6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团，本文也称为“低级烷基”。在一些实施方案中，C 1-C 4烷基是特别优选的。所述烷基的实例包括但不限于：甲基(C 1)、乙基(C 2)、正丙基(C 3)、异丙基(C 3)、正丁基(C 4)、叔丁基(C 4)、仲丁基(C 4)、异丁基(C 4)、正戊基(C 5)、3-戊基(C 5)、戊基(C 5)、新戊基(C 5)、3-甲基-2-丁基(C 5)、叔戊基(C 5)和正己基(C 6)。除非另作说明，否则，烷基的每个独立地任选被取代，即，未取代(“未取代的烷基”)或被一个或多个取代基取代(“取代的烷基”)；例如，1至5个取代基、1至3个取代基或1个取代基。在一些实施方案中，烷基是未取代的C 1-C 6烷基(例如，-CH 3)。在一些实施方案中，烷基是取代的C 1-C 6烷基。
“C 2-C 6烯基”是指具有2至6个碳原子和一个或多个碳-碳双键(例如，1、2或3个碳-碳双键)的直链或支链烃基团。一个或多个碳-碳双键可以在内部(例如，在2-丁烯基中)或端部(例如，在1-丁烯基中)。在一些实施方案中，C 2-4烯基是特别优选的。所述烯基的实例包括但不限于：乙烯基(C 2)、1-丙烯基(C 3)、2-丙烯基(C 3)、1-丙烯-2-基(C 3)、1-丁烯基(C 4)、2-丁烯基(C 4)、丁二烯基(C 4)、戊烯基(C 5)、戊二烯基(C 5)、己烯基(C 6)，等等。除非另作说明，否则，烯基的每个独立地任选被取代，即，未取代(“未取代的烯基”)或被一个或多个取代基取代(“取代的烯基”)；例如，1至5个取代基、1至3个取代基或1个取代基。在一些实施方案中，烯基是未取代的C 2-6烯基。在一些实施方案中，烯基 是取代的C 2-6烯基。
“C 2-C 6炔基”是指具有2至6个碳原子、一个或多个碳-碳叁键(例如，1、2或3个碳-碳叁键)以及任选一个或多个碳-碳双键(例如，1、2或3个碳-碳双键)的直链或支链烃基团。在一些实施方案中，C 2-4炔基是特别优选的。在一些实施方案中，炔基不含有任何双键。一个或多个碳叁键可以在内部(例如，在2-丁炔基中)或端部(例如，在1-丁炔基中)。所述炔基的实例包括但不限于：乙炔基(C 2)、1-丙炔基(C 3)、2-丙炔基(C 3)、1-丁炔基(C 4)、2-丁炔基(C 4)、戊炔基(C 5)、3-甲基丁-1-炔基(C 5)、己炔基(C 6)，等等。除非另作说明，否则，炔基的每个独立地任选被取代，即，未取代(“未取代的炔基”)或被一个或多个取代基取代(“取代的炔基”)；例如，1至5个取代基、1至3个取代基或1个取代基。在一些实施方案中，炔基是未取代的C 2-6炔基。在一些实施方案中，炔基是取代的C 2-6炔基。
“C 1-C 6烷氧基”是指基团-OR，其中，R为取代或未取代的C 1-C 6烷基。在一些实施方案中，C 1-C 4烷氧基是特别优选的。具体的所述烷氧基包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基和1,2-二甲基丁氧基。
“C 1-C 6烷硫基”是指基团-SR，其中，R为任选取代的C 1-C 6烷基。在一些实施方案中，C 1-C 4烷硫基是特别优选的。具体的所述C 1-C 6烷硫基包括但不限于：甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、叔丁硫基、仲丁硫基、正戊硫基、正己硫基和1,2-二甲基丁硫基。
“C 1-C 6烷氨基”是指基团-NHR或者-NR 2，其中，R为任选取代的C 1-C 6烷基。在一些实施方案中，C 1-C 4烷氨基是特别优选的。具体的所述C 1-C 6烷氨基包括但不限于：甲氨基、乙氨基、正丙氨基、异丙氨基、正丁氨基、叔丁氨基、二甲氨基、甲乙氨基和二乙氨基。
“C 1-C 6烷酰基”是指基团-(＝O)R，其中，R为任选取代的C 1-C 6烷基。在一些实施方案中，C 1-C 4烷酰基是特别优选的。示例性的所述C 1-C 6烷酰基包括但不限于：-(＝O)CH 3、-(＝O)CH 2CH 3、-(＝O)CH 2CH 2CH 3和-(＝O)CH(CH 3) 2。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。在一些实施方案中，卤素基团是F、-Cl或Br。在一些实施方案中，卤素基团是F或Cl。在一些实施方案中，卤素基团是F。
因此，“C 1-C 6卤代烷基”和“C 1-C 6卤代烷氧基”是指上述“C 1-C 6烷基”和“C 1-C 6烷氧基”，其被一个或多个卤素基团取代。在一些实施方案中，C 1-C 4卤代烷基是特别优选的，更优选C 1-C 2卤代烷基。在一些实施方案中，C 1-C 4卤代烷氧基是特别优选的，更优选C 1-C 2卤代烷氧基。示例性的所述卤代烷基包括但不限于：-CF 3、-CH 2F、-CHF 2、-CHFCH 2F、-CH 2CHF 2、-CF 2CF 3、-CCl 3、-CH 2Cl、-CHCl 2、2,2,2-三氟-1,1-二甲基-乙基，等等。示例性的所述卤代烷氧基包括但不限于：-OCH 2F、-OCHF 2、-OCF 3，等等。
“C 3-C 8碳环基”或“3至8元碳环基”是指具有3至8个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，优选C 5-C 8碳环基，具有5至8个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，优选C 3-C 6碳环基，具有3至6个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，优选5元碳环基，其为具有5个环碳原子和零个杂原子的非芳香环烃基团。碳环基还包括其中上述碳环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在碳环基环上，且在这样的情况中，碳的数目继续表示碳环基体系中的碳的数目。示例性的所述碳环基包括但不限于：环丙基(C 3)、环丙烯基(C 3)、环丁基(C 4)、环丁烯基(C 4)、环戊基(C 5)、环戊烯基(C 5)、环戊二烯基(C 5)、环己基(C 6)、环己烯基(C 6)、环已二烯基(C 6)，以及环庚基(C 7)、环庚烯基(C 7)、环庚二烯基(C 7)、环庚三烯基(C 7)、环辛基(C 8)、环辛烯基(C 8)、二环[2.2.1]庚基(C 7)、二环[2.2.2]辛基(C 8)，等等。除非另作说明，否则碳环基的每个独立地为任选取代的，即，未取代(“未取代的碳环基”)或被一个或多个取代基取代(“取代的碳环基”)。在一些实施方案中，碳环基是未取代的C 3-C 8碳环基。在一些实施方案中，碳环基是取代的C 3-C 8碳环基。
“3至8元杂环基”是指具有环碳原子和1至3个环杂原子的3至8元非芳香环系，其中每个杂原子独立地选自氮、氧、硫、硼、磷和硅，其中碳、氮、硫和磷原子还可以其氧化态存在，如C(O)、S(O)、S(O) 2、P(O)等。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，优选4至7元杂环基，其为具有环碳原子和1至3个环杂原子的4至7元非芳香环系。在一些实施方案中，优选5至8元杂环基，其为具有环碳原子和1至3个环杂原子的5至8元非芳香环系。在一些实施方案中，优选4至6元杂环基，其为具有环碳原子和1至3个环杂原子的4至6元非芳香环系。在一些实施方案中，优选5至6元杂环基，其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。在一些实施方案中，更优选5元杂环基，其为具有环碳原子和1至3个环杂原子的5元非芳香环系。在一些实施方案中，上述3至8元杂环基、4至7元杂环基、5至8元杂环基、4至6元杂环基、5至6元杂环基和5元杂环基含有1至3个(更优选1或2个)选自氮、氧和硫(优选氮或氧)的环杂原子。除非另作说明，否则，杂环基的每个独立地为任选取代的，即，未取代(“未取代的杂环基”)或被一个或多个取代基取代(“取代的杂环基”)。在一些实施方案中，杂环基是未取代的3-8元杂环基。在一些实施方案中，杂环基是取代的3-8元杂环基。杂环基还包括其中上述杂环基环与一个或多个碳环基稠合的环体系，其中连接点在碳环基环上，或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基。示例性的含有一个杂原子的 4元杂环基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于：四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于：二氧杂环戊烷基、氧硫杂环戊烷基、氧硫杂环戊烯基(1,2-氧硫杂环戊烯基、1,3-氧硫杂环戊烯基)、二硫杂环戊烷基、二氢吡唑基、二氢咪唑基、二氢噻唑基、二氢异噻唑基、二氢噁唑基、二氢异噁唑基、二氢噁二唑基和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于：***啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于：哌啶基、四氢吡喃基、二氢吡啶基、四氢吡啶基和硫杂环己烷基。示例性的包含两个杂原子的6元杂环基包括但不限于：二氢吡嗪基、哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于：六氢三嗪基。示例性的含有一个或两个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、二氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的包含一个或两个杂原子的8元杂环基包括但不限于：氮杂环辛烷基、氧杂环辛烷基、硫杂环辛烷基、八氢环戊二烯并[c]吡咯基和八氢吡咯并[3,4-c]吡咯基。示例性的与C 6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与C 6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。
“C 6-C 14芳基”或“6至14元芳环基”是指具有提供在芳族环系中的6-14个环碳原子和零个杂原子的单环或多环的(例如，双环或三环)4n+2芳族环体系(例如，具有以环状排列共享的6、10或14个π电子)的基团(“C 6-14芳基”)。在一些实施方案中，芳基具有六个环碳原子(“C 6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C 10芳基”；例如，萘基，例如，1-萘基和2-萘基)。在一些实施方案中，芳基具有十四个环碳原子(“C 14芳基”；例如，蒽基)。“C 6-C 14芳基”还包括这样的环***，在这种环***中，上述芳基环与一个或多个碳环基或杂环基稠合，其中，原子团或连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环***中的碳原子数目。典型的芳基包括但不限于衍生自以下的基团：醋蒽烯、苊烯、醋菲烯(acephenanthrylene)、蒽、薁、苯、屈、晕苯、荧蒽、芴、并六苯、己芬、己搭烯、不对称引达省、对称引达省、茚满、茚、萘、并八苯、辛芬、辛搭烯、卵苯、戊-2,4-二烯、并五苯、戊搭烯、戊芬、苝、非那烯、菲、苉、七曜烯、芘、皮蒽、玉红省、苯并菲和联三萘。具体地说，芳基包括苯基、萘基、茚基和四氢萘基。除非另作说明，否则，芳基的每个独立地任选被取代，即，未取代(“未取代的芳基”)或被一个或多个取代基取代(“取代的芳基”)。在一些实施方案中，芳基是未取代的C 6-14芳基。在一些实施方案中，芳基是取代 的C 6-14芳基。
“5至10元杂芳基”是指具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在一些实施方案中，优选5元杂芳基，其为具有环碳原子和1-4个环杂原子的5元单环4n+2芳族环体系(例如，具有以环状排列共享的6个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环***在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个碳环基或杂环基稠合的环***，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环***中的碳原子数目。除非另作说明，否则，杂芳基的每个独立地任选被取代的，即，未取代(“未取代的杂芳基”)或被一个或多个取代基取代(“取代的杂芳基”)。在一些实施方案中，杂芳基是未取代的5至10元杂芳基。在一些实施方案中，杂芳基是取代的5至10元杂芳基。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：***基、噁二唑基和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并***基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。
本文定义的烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基等为任选取代的基团。通常，术语“取代的”，不论前面是否有术语“任选”，是指存在于基团(例如，碳或氮原子)上的至少一个氢被可允许的取代基取代，例如，在取代时产生稳定的化合物的取代基，例如，不自发地进行转变(例如通过重排、环化、消除或其它反应)的化合物。除非另外说明，否则，“取代的”基团在所述基团的一个或多个可取代的位置处具有取代基，且当在任何给定结构中的一个以上的位置被取代时，在每个位置处的取代基是相同或不同的。术语“取代的”包括用有机化合物的所有可允许的取代基(导致形成稳定化合物的本文描述的任何取代基)进行的取代。对于本发明，杂原子例如氮可具有氢取代基和/ 或本文描述的任何合适的取代基，其满足杂原子的化合价且导致形成稳定的部分。
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OR aa、-ON(R bb) 2、-N(R bb) 2、-N(R bb) 3 +X -、-N(OR cc)R bb、-SH、-SR aa、-SSR cc、-C(＝O)R aa、-CO 2H、-CHO、-C(OR cc) 2、-CO 2R aa、-OC(＝O)R aa、-OCO 2R aa、-C(＝O)N(R bb) 2、-OC(＝O)N(R bb) 2、-NR bbC(＝O)R aa、-NR bbCO 2R aa、-NR bbC(＝O)N(R bb) 2、-C(＝NR bb)R aa、-C(＝NR bb)OR aa、-OC(＝NR bb)R aa、-OC(＝NR bb)OR aa、-C(＝NR bb)N(R bb) 2、-OC(＝NR bb)N(R bb) 2、-NR bbC(＝NR bb)N(R bb) 2、-C(＝O)NR bbSO 2R aa、-NR bbSO 2R aa、-SO 2N(R bb) 2、-SO 2R aa、-SO 2OR aa、-OSO 2R aa、-S(＝O)R aa、-OS(＝O)R aa、-Si(R aa) 3、-OSi(R aa) 3、-C(＝S)N(R bb) 2、-C(＝O)SR aa、-C(＝S)SR aa、-SC(＝S)SR aa、-SC(＝O)SR aa、-OC(＝O)SR aa、-SC(＝O)OR aa、-SC(＝O)R aa、-P(＝O) 2R aa、-OP(＝O) 2R aa、-P(＝O)(R aa) 2、-OP(＝O)(R aa) 2、-OP(＝O)(OR cc) 2、-P(＝O) 2N(R bb) 2、-OP(＝O) 2N(R bb) 2、-P(＝O)(NR bb) 2、-OP(＝O)(NR bb) 2、-NR bbP(＝O)(OR cc) 2、-NR bbP(＝O)(NR bb) 2、-P(R cc) 2、-P(R cc) 3、-OP(R cc) 2、-OP(R cc) 3、-B(R aa) 2、-B(OR cc) 2、-BR aa(OR cc)、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(R bb) 2、＝NNR bbC(＝O)R aa、＝NNR bbC(＝O)OR aa、＝NNR bbS(＝O) 2R aa、＝NR bb或＝NOR cc取代；
R aa的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R aa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
R bb的每个独立地选自：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR cc、-SOR aa、-C(＝S)N(R cc) 2、-C(＝O)SR cc、-C(＝S)SR cc、-P(＝O) 2R aa、-P(＝O)(R aa) 2、-P(＝O) 2N(R cc) 2、-P(＝O)(NR cc) 2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R bb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
R cc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R cc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
R dd的每个独立地选自：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OR ee、-ON(R ff) 2、-N(R ff) 2,、-N(R ff) 3 +X -、-N(OR ee)R ff、-SH、-SR ee、-SSR ee、-C(＝O)R ee、-CO 2H、-CO 2R ee、-OC(＝O)R ee、-OCO 2R ee、 -C(＝O)N(R ff) 2、-OC(＝O)N(R ff) 2、-NR ffC(＝O)R ee、-NR ffCO 2R ee、-NR ffC(＝O)N(R ff) 2、-C(＝NR ff)OR ee、-OC(＝NR ff)R ee、-OC(＝NR ff)OR ee、-C(＝NR ff)N(R ff) 2、-OC(＝NR ff)N(R ff) 2、-NR ffC(＝NR ff)N(R ff) 2、-NR ffSO 2R ee、-SO 2N(R ff) 2、-SO 2R ee、-SO 2OR ee、-OSO 2R ee、-S(＝O)R ee、-Si(R ee) 3、-OSi(R ee) 3、-C(＝S)N(R ff) 2、-C(＝O)SR ee、-C(＝S)SR ee、-SC(＝S)SR ee、-P(＝O) 2R ee、-P(＝O)(R ee) 2、-OP(＝O)(R ee) 2、-OP(＝O)(OR ee) 2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代，或者两个偕R dd取代基可结合以形成＝O或＝S；
R ee的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代；
R ff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R ff基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代；
R gg的每个独立地是：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OC 1-6烷基、-ON(C 1-6烷基) 2、-N(C 1-6烷基) 2、-N(C 1-6烷基) 3 +X -、-NH(C 1-6烷基) 2 +X -、-NH 2(C 1-6烷基) +X -、-NH 3 +X -、-N(OC 1-6烷基)(C 1-6烷基)、-N(OH)(C 1-6烷基)、-NH(OH)、-SH、-SC 1-6烷基、-SS(C 1-6烷基)、-C(＝O)(C 1-6烷基)、-CO 2H、-CO 2(C 1-6烷基)、-OC(＝O)(C 1-6烷基)、-OCO 2(C 1-6烷基)、-C(＝O)NH 2、-C(＝O)N(C 1-6烷基) 2、-OC(＝O)NH(C 1-6烷基)、-NHC(＝O)(C 1-6烷基)、-N(C 1-6烷基)C(＝O)(C 1-6烷基)、-NHCO 2(C 1-6烷基)、-NHC(＝O)N(C 1-6烷基) 2、-NHC(＝O)NH(C 1-6烷基)、-NHC(＝O)NH 2、-C(＝NH)O(C 1-6烷基)、-OC(＝NH)(C 1-6烷基)、-OC(＝NH)OC 1-6烷基、-C(＝NH)N(C 1-6烷基) 2、-C(＝NH)NH(C 1-6烷基)、-C(＝NH)NH 2、-OC(＝NH)N(C 1-6烷基) 2、-OC(NH)NH(C 1-6烷基)、-OC(NH)NH 2、-NHC(NH)N(C 1-6烷基) 2、-NHC(＝NH)NH 2、-NHSO 2(C 1-6烷基)、-SO 2N(C 1-6烷基) 2、-SO 2NH(C 1-6烷基)、-SO 2NH 2、-SO 2C 1-6烷基、-SO 2OC 1-6烷基、-OSO 2C 1-6烷基、-SOC 1-6烷基、-Si(C 1-6烷基) 3、-OSi(C 1-6烷基) 3、-C(＝S)N(C 1-6烷基) 2、C(＝S)NH(C 1-6烷基)、C(＝S)NH 2、-C(＝O)S(C 1-6烷基)、-C(＝S)SC 1-6烷基、-SC(＝S)SC 1-6烷基、-P(＝O) 2(C 1-6烷基)、-P(＝O)(C 1-6烷基) 2、-OP(＝O)(C 1-6烷基) 2、-OP(＝O)(OC 1-6烷基) 2、C 1-6烷基、C 1-6全卤代烷基、C 2-6烯基、C 2-6炔基、C 3-10碳环基、C 6-10芳基、3-10元杂环基、5-10元杂芳基；或者两个偕R gg取代基可结合形成＝O或＝S；其中，X -为反离子。
示例性的氮原子上取代基包括但不局限于：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR bb)R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、 -SO 2R cc、-SO 2OR cc、-SOR aa、-C(＝S)N(R cc) 2、-C(＝O)SR cc、-C(＝S)SR cc、-P(＝O) 2R aa、-P(＝O)(R aa) 2、-P(＝O) 2N(R cc) 2、-P(＝O)(NR cc) 2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者连接至氮原子的两个R cc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代，且其中R aa、R bb、R cc和R dd如上所述。
其它定义
术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、***反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适无机和有机酸和碱的盐。药学上可接受的无毒酸加成盐的实例是氨基与无机酸形成的盐，例如盐酸、氢溴酸、磷酸、硫酸和高氯酸，或与有机酸形成的盐，例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸，或使用本领域使用的方法形成的盐，例如，离子交换方法。其它药学上可接受的盐包括：已二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐，等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N +(C 1-4烷基) 4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐，等等。如果合适的话，进一步的药学上可接受的盐包括使用反离子形成的无毒的铵盐、季铵盐和胺阳离子，反离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药物动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗和预防性治疗有效量。
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的数量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化。化合物的治疗有效量是指单独使用或与其它疗法联用的治疗剂的数量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效能的数量。
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的数量，或足以预防与疾病、障碍或病症有关的一或多种症状的数量，或防止疾病、障碍或病症复发的数量。化合物的预防有效量是指单独使用或与其它药剂联用的治疗剂的数量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的数量，或增强其它预防药剂的预防效能的数量。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如，本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药，或与另一治疗剂一起呈单一单位剂型同时给药。
具体实施方式
化合物
本文中，“本发明化合物”指的是以下的式(I)的化合物其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物。
在一个实施方案中，本发明涉及式(I)化合物：
Figure PCTCN2018120618-appb-000002
其中，
R 1和R 2独立地选自H、卤素、-CN、-NO 2、-OH、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 1和R 2与它们相连的原子可形成稠合的5～7元环；
连接基W选自
1)C 1-C 6亚烷基、C 1-C 6亚烯基、C 1-C 6亚炔基、C 3-C 8亚碳环基、3至10元亚杂环基、C 6-C 14芳基或5至10元杂芳基；其中W与苯环所连接的原子必须为C；其中所述基团任选被一个或多个R 3取代；
2)-C(＝O)-、-C(＝O)O-、-C(＝O)N(R 4)-；
R 3选自H、卤素、-CN、-NO 2、氧代基、C 1-C 6烷基、C 1-C 6卤代烷基或C 1-C 6烷氧基；
R 4选自H、C 1-C 6烷基或C 1-C 6卤代烷基；
R 5和R 6独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的3至10元杂环基；
R 7选自任选取代的C 1-C 6烷氧基、任选取代的C 1-C 6卤代烷氧基、任选取代的C 2-C 6烯基氧基或任选取代的3～7元环烷基氧基；
R 8选自H、卤素、-R、-CN、-NO 2、-OH、-SH、-C(＝O)R、-C(＝O)OR、-C(＝O)NRR、-NR 2、-NRC(＝O)R、 -NRC(＝O)OR、-NRC(＝O)NRR、-NRS(＝O)R、-NRS(＝O)NRR、-NRS(＝O) 2R、-NRS(＝O) 2NRR、-OR、-OC(＝O)R、-OC(＝O)NRR、-S(＝O)R、-S(＝O)OR、-S(＝O)NRR、-S(＝O) 2R、-S(＝O) 2OR、-S(＝O) 2NRR、-SC(＝O)R、-SC(＝O)OR或-SC(＝O)NRR，只要化学允许；其中R独立地为H、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烯基、C 1-C 6炔基、C 3-C 10碳环基、3至10元杂环基、C 6-C 14芳基或5至10元杂芳基；两个相邻的R可一起形成任选取代的C 3-C 10碳环基、任选取代的5至8元杂环基、任选取代的C 6-C 14芳基或任选取代的5至10杂芳基；
或其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物。
在该实施方案中，优选地，R 1独立地选自H、卤素、-CN、-NO 2、-OH、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；优选地，R 1选自H、卤素、-CN、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；优选地，R 1选自H、F、Cl、Br、甲基、乙基、异丙基、-CH 2F、-CHF 2、甲氧基、异丙氧基、环丙基或环氧乙烷基；更优选地，R 1选自H、F、Cl、甲基、异丙基或环丙基；更优选地R 1选自Cl。
在该实施方案中，优选地，R 2独立地选自H、卤素、-CN、-NO 2、-OH、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；优选地，R 2选自H、卤素、-CN、-NO 2、-OH、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基；优选地，R 2选自H、F、Cl、Br、-CN、-NO 2、-OH或甲基；更优选地，R 2选自H。
在该实施方案中，优选地，R 1和R 2与它们相连的原子可形成稠合的5～7元环；优选地，R 1和R 2与和它们相连的碳原子可形成稠合的5～7元芳基环，其含有0～2个选自N、O和S的杂原子；优选地，R 1和R 2与和它们相连的碳原子可形成稠合的5元芳基环，其含有0～2个选自N和S的杂原子；优选地，R 1和R 2与和它们相连的碳原子可形成稠合的吡咯环、吡唑环、咪唑环、噻吩环或呋喃环。
在该实施方案中，优选地，连接基W选自
1)C 1-C 6亚烷基、C 1-C 6亚烯基、C 1-C 6亚炔基、C 3-C 8亚碳环基、3至10元亚杂环基、C 6-C 14芳基或5至10元杂芳基；其中W与苯环所连接的原子必须为C；其中所述基团任选被一个或多个R 3取代；
2)-C(＝O)-、-C(＝O)O-、-C(＝O)N(R 4)-；
优选地，W选自
1)C 1-C 6亚烷基、C 3-C 10亚碳环基、3至10元亚杂环基，其W与苯环所连接的原子必须为C，其所述基团任选被一个或多个R 3取代；
2)-C(＝O)-、-C(＝O)O-、-C(＝O)N(R 4)-；
更优选地，W选自
1)-CH 2-、-CH 2CH 2-、-C(CH 3)H-、-C(CH 3) 2-、-C(CH 3)HCH 2-、-C(CH 3) 2CH 2-、-C(CH 3)HC(CH 3)H-、-C(CH 3) 2C(CH 3) 2-、
Figure PCTCN2018120618-appb-000003
其*表示与苯环相连，#表示与N原子相连；
2)-C(＝O)-。
在该实施方案中，优选地，R 5和R 6独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的3至10元杂环基；优选地，R 5和R 6独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的3至10元杂环基；更优选地，R 5和R 6独立地选自H、甲基或乙基，或者R 5和R 6与它们相连的氮原子一起形成任选取代的3元、4元、5元或6元杂环基。
在该实施方案中，优选地，-W-NR 5R 6选自：
Figure PCTCN2018120618-appb-000004
Figure PCTCN2018120618-appb-000005
优选地，-W-NR 5R 6选自：
Figure PCTCN2018120618-appb-000006
在该实施方案中，优选地，R 7选自任选取代的C 1-C 6烷氧基、任选取代的C 1-C 6卤代烷氧基、任选取代的C 2-C 6烯基氧基或任选取代的3～7元环烷基氧基；优选地，R 7选自任选取代的C 1-C 6烷氧基、任选取代的C 1-C 6卤代烷氧基；优选地，R 2选自-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2、-OCF 3、-OCHF 2、-OCH 2F或-OCH 2CF 3；更优选地，R 2选自-OCH 3、-OCH(CH 3) 2或-OCH 2CF 3；最优选地，R 2选自-OCH 3。
在该实施方案中，优选地，R 8选自H、卤素、-R、-CN、-NO 2、-OH、-SH、-C(＝O)R、-C(＝O)OR、-C(＝O)NRR、-NR 2、-NRC(＝O)R、-NRC(＝O)OR、-NRC(＝O)NRR、-NRS(＝O)R、-NRS(＝O)NRR、-NRS(＝O) 2R、-NRS(＝O) 2NRR、-OR、-OC(＝O)R、-OC(＝O)NRR、-S(＝O)R、-S(＝O)OR、-S(＝O)NRR、-S(＝O) 2R、-S(＝O) 2OR、-S(＝O) 2NRR、-SC(＝O)R、-SC(＝O)OR或-SC(＝O)NRR，只要化学允许；其中R独立地为H、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烯基、C 1-C 6炔基、C 3-C 10碳环基、3至10元杂环基、C 6-C 14芳基或5至10元杂芳基；两个相邻的R可一起形成任选取代的C 3-C 10碳环基、任选取代的5至8元杂环基、任选取代的C 6-C 14芳基或任选取代的5至10杂芳基；R 8选自H、R、卤素、-CN、-C(＝O)R、-C(＝O)OR、-C(＝O)NRR、-NR 2、-NRC(＝O)R、-NRC(＝O)OR、-NRC(＝O)NRR、-OR、-OC(＝O)R、-OC(＝O)NRR，只要化学允许；其中R独立地为H、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6烯基、C 1-C 6炔基、C 3-C 10碳环基或3至10元杂环基；两个相邻的R可一起形成任选取代的C 3-C 10碳环基、任选取代的5至8元杂环基；优选地，R 8选自H、F、Cl、Br、甲基、-C(＝O)CH 3、-C(＝O)OCH 3、-C(＝O)N(CH 3) 2、-N(CH 3) 2、-N(CH 3)C(＝O)(CH＝CH 2)或-OC(＝O)N(CH 3) 2；更优选地，优选地，R 8选自H或甲基。
在另一个实施方案中，本发明涉及式(IIa)-(IIm)化合物：
Figure PCTCN2018120618-appb-000007
其中，R 5、R 6、R 7、R 8和W如上文所定义。
在另一个优选地实施方案中，本发明涉及式(IIa)-(IIm)化合物：
Figure PCTCN2018120618-appb-000008
Figure PCTCN2018120618-appb-000009
其中，
W选自C 1-C 6亚烷基、C 3-C 10亚碳环基、3至10元亚杂环基，其W与苯环所连接的原子必须为C；其所述基团任选被一个或多个R 3取代；
R 3选自H、C 1-C 6烷基、C 1-C 6卤代烷基或C 1-6烷氧基；
R 5和R 6独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的3至10元杂环基；
R 7选自任选取代的C 1-C 6烷氧基、任选取代的C 1-C 6卤代烷氧基或任选取代的3～7元环烷基氧基；
R 8选自H、卤素或C 1-C 6烷基；
或其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物。
在一些实施方案中，W选自C 1-C 6亚烷基、C 3-C 10亚碳环基、3至10元亚杂环基，其W与苯环所连接的原子必须为C；其所述基团任选被一个或多个R 3取代；其中，R 3选自H或C 1-C 6烷基；
优选地，W选自C 1-C 6亚烷基，其任选地被一个多个R 3取代；其中，R 3选自H或C 1-C 6烷基；优选地，W选自-CH 2-、-CH 2CH 2-、-C(CH 3)H-、-C(CH 3) 2-、-C(CH 3)HCH 2-、-C(CH 3) 2CH 2-、-C(CH 3)HC(CH 3)H-或-C(CH 3) 2C(CH 3) 2-；
优选地，W选自C 3-C 10亚碳环基，其任选地被一个或多个R 3取代；其中，R 3选自H或C 1-C 6烷基；优选地，W选自
Figure PCTCN2018120618-appb-000010
优选地，W选自3至10元亚杂环基，且W与苯环所连接的原子必须为C；其任选地被一个或多个R 3取代；其中，R 3选自H或C 1-C 6烷基；优选地，W选自
Figure PCTCN2018120618-appb-000011
其*表示与苯环相连，#表示与N原子相连。
在一些实施方案中，优选地，R 5和R 6独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的3至10元杂环基；
优选地，R 5和R 6独立地选自H或任选取代的C 1-C 6烷基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的3至10元杂环基；
在一些实施方案中，优选地，-W-NR 5R 6选自：
Figure PCTCN2018120618-appb-000012
Figure PCTCN2018120618-appb-000013
优选地，-W-NR 5R 6选自：
Figure PCTCN2018120618-appb-000014
Figure PCTCN2018120618-appb-000015
在一些实施方案中，优选地，R 7选自任选取代的C 1-C 6烷氧基；优选地，R 7选自-OCH 3。
在一些实施方案中，优选地，R 8选自H或C 1-C 6烷基；优选地，R 8选自H或甲基。
在另一个优选地实施方案中，本发明涉及式(IIa)化合物：
Figure PCTCN2018120618-appb-000016
其中，
W选自C 1-C 6亚烷基；其所述基团任选被一个或多个R 3取代；
R 3选自H或C 1-C 6烷基；
R 5和R 6独立地选自H或任选取代的C 1-C 6烷基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的5至6元杂环基；
R 7选自任选取代的C 1-C 6烷氧基；
R 8选自H或C 1-C 6烷基；
或其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物。
在一些实施方案中，优选地，W选自-CH 2-、-CH 2CH 2-、-C(CH 3)H-、-C(CH 3) 2-、-C(CH 3)HCH 2-、-C(CH 3) 2CH 2-、-C(CH 3)HC(CH 3)H-或-C(CH 3) 2C(CH 3) 2-；
在一些实施方案中，优选地，R 5和R 6独立地选自H或任选取代的C 1-C 6烷基；优选地，R 5和R 6独立地选自H或甲基；优选地，R 5和R 6与它们相连的氮原子一起形成任选取代的5至6元杂环基；优选地，R 5和R 6与它们相连的氮原子一起形成任选取代的哌啶环、哌嗪环或吗啉环。
在一些实施方案中，优选地，-W-NR 5R 6选自：
Figure PCTCN2018120618-appb-000017
Figure PCTCN2018120618-appb-000018
在一些实施方案中，优选地，R 7选自任选取代的C 1-C 6烷氧基；优选地，R 7选自-OCH 3。
在一些实施方案中，优选地，R 8选自H或C 1-C 6烷基；优选地，R 8选自H或甲基。
在最优选地实施方案中，上述式(I)、(IIa)-(IIm)化合物为以下化合物：
Figure PCTCN2018120618-appb-000019
Figure PCTCN2018120618-appb-000020
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本发明也包括本发明化合物的所有合适的同位素衍生物。本发明化合物的同位素衍生物的定义为其中至少一个原子被具有相同原子数但原子质量与自然界中通常发现的原子质量不同的原子代替。可以掺入本发明化合物中的同位素的实例包括氢、碳、氮、氧、氟和氯的同位素，例如分别为 2H、 3H、 13C、 14C、 15N、 17O、 18O、 18F、 31P、 32P、 35S和 36Cl。本发明化合物的一些同位素衍生物，例如其中掺入放射性同位素如 3H或 14C的那些，可用于药物和/或底物组织分布研究。氚化(即 3H)和碳-14(即 14C)同位素因其易于制备和可检测性而为特别优选的。此外，用同位素(例如氘，即 2H)取代可以提供由于更大的代谢稳定性而得到的一些治疗优点，例如增加的体内半衰期或减少的剂量需要，并且因此在一些情况下可以是优选的。本发明化合物的同位素衍生物通常可以通过如下制备：常规程序例如通过说明性方法或通过下文实施例中描述的制备，其使用合适试剂的适当同位素衍生物。
本发明化合物或其药学上可接受的盐可以是无定形或结晶形式。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“晶型”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种晶型物可在不同的条件下通过结晶制备。
本领域技术人员将理解，许多有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。
前药为任何共价键合的载体，当将这种前药给予患者时，其在体内释放式(I)化合物。通常通过修饰官能团来制备前药，修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括，例如，其中羟基、胺或巯基与任意基团键合的本发明化合物，当将其给予患者时，可以裂解形成羟基、胺或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的醇、巯基和胺官能团的乙酸酯、甲酸酯和苯甲酸酯衍生物。另外，在羧酸(-COOH)的情况下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。
药物组合物、制剂和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的活性组分。在一些实施方案中，所述药物组合物包含治疗有效量的活性组分。在一些实施方案中，所述药物组合物包含预防有效量的活性组分。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载 剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
下列制剂实施例说明可根据本发明制备的代表性的药物组合物。然而，本发明不限于下列药物组合物。
示例性的制剂1-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为0.3-30mg片剂(每个片剂含有0.1-10mg活性化合物)。
示例性的制剂2-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为30-90mg片剂(每个片剂含有10-30mg活性化合物)。
示例性的制剂3-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为90-150mg片剂(每个片剂含有30-50mg活性化合物)。
示例性的制剂4-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为150-240mg片剂(每个片剂含有50-80mg活性化合物)。
示例性的制剂5-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为240-270mg片剂(每个片剂含有80-90mg活性化合物)。
示例性的制剂6-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为270-450mg片剂(每个片剂 含有90-150mg活性化合物)。
示例性的制剂7-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为450-900mg片剂(每个片剂含有150-300mg活性化合物)。
示例性的制剂8-胶囊剂：可以将干粉形式的本发明化合物与淀粉稀释剂以约1:1的重量比混合。将该混合物填充到250mg胶囊中(每个胶囊含有125mg活性化合物)。
示例性的制剂9-液体：可以将本发明化合物(125mg)与蔗糖(1.75g)和黄原胶(4mg)混合，且可将得到的混合物共混，通过No.10筛目美国筛，然后与预先制备的微晶纤维素和羧甲基纤维素钠(11:89，50mg)的水溶液混合。将苯甲酸钠(10mg)、调味剂和着色剂用水稀释，并在搅拌下加入。然后，可以加入充足的水，得到5mL的总体积。
示例性的制剂10-注射剂：可以将本发明化合物溶解或悬浮在缓冲无菌盐水可注射的水性介质中，达到约5mg/mL的浓度。
给药
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、***给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定 水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington’s Pharmaceutical Sciences,17 th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药***中给予。代表性的持续释放材料的描述可在Remington’s Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
治疗方法
本发明提供了给需要治疗的受试者给药本发明化合物，或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素衍生物，或给药本发明所述的药物组合物用于治疗癌症。在一些实施方案中，癌症是ALK驱动的癌症。在一些实施方案中，癌症是非小细胞肺癌。
“治疗有效量”是有效检测杀死或抑制癌症细胞的生长或扩散；重量的大小或数目；或癌症的水平、阶段、进展或严重程度的其它度量的量。所需的精确量可根据对象不同而改变，这取决于对象的种族、年龄和总体健康状况、疾病的严重程度、特定的抗癌剂、其施用模式、与其它疗法的联合治疗等。
本文公开了具有生物性质的化合物，所述生物性质使得它们成为用于治疗或调控可涉及激酶的疾病、此类疾病的症状或者由激酶介导的其它生理学事件的影响的目标。例如本文公开的多种化合物可抑制ALK、fak和c-met的酪氨酸激酶活性，尤其据信介导癌症的生长、发展和/或转移的酪氨酸激酶。还发现如本文公开的多种化合物针对癌症细胞系具有有效的体外活性。因此，此类化合物用于治疗癌症(包括实体瘤以及淋巴瘤且包括得其它疗法有抗性的癌症)的目标。
在一些实施方案中，癌症是ALK驱动的癌症。在一些实施方案中，癌症是非小细胞肺癌(NSCLC)。在一些实施方案中，癌症是ALK阳性的NSCLC。在一些实施方案中，癌症是局部晚期或转移性ALK阳性NSCLC。在一些实施方案中，癌症/患者之前已经用克唑替尼或另一种酪氨酸激酶抑制剂治疗。在一些实施方案中，癌症/患者之前未用ALK抑制剂治疗。
此类癌症包括但不限于乳腺癌、非小细胞肺癌、神经肿瘤(诸如胶质母细胞瘤和神经母细胞瘤)；食道癌、软组织癌(诸如横纹肌肉瘤等)；各种形式的淋巴瘤，诸如已知为间变性大细胞淋巴瘤(ALCL)的非霍奇金氏淋巴瘤(NHL)；各种形式的白血病；且包括为ALK或c-met介导的癌症。
间变性淋巴瘤激酶(ALK)是跨细胞膜受体酪氨酸激酶，其属于胰岛素受体亚家族。ALK受体酪氨酸激酶(RTK)由于其参与已知为间变性大细胞淋巴瘤(ALCL)的人非霍奇金氏淋巴瘤亚型而被最初鉴别。ALK通常在哺乳动物细胞中具有受限的分布，发现其在胚胎发育期间仅在神经***中处于显著水平，表明了ALK在脑发育中的作用。
除了其在正常发育中的作用之外，已在源自多种肿瘤的细胞系中检测到全长正常ALK的表达，诸如神经胶母细胞瘤、神经外胚层肿瘤和胶质母细胞瘤以及乳腺癌和黑素瘤系。
与其它RTK一样，易位影响ALK基因，从而导致原细胞融合激酶表达，其最常见的是NPM-ALK。例如，约百分之六十的间变性大细胞淋巴瘤(ALCL)与产生由核仁磷酸蛋白(NMP)ALK的胞内结构域组成的融合蛋白的染色体突变相关。这种突变体蛋白，NPM-ALK，具有组成型活性酪氨酸激酶结构域，所述结构域通过激活下游效应子负责其致癌性质。实验数据已经证明组成型活性ALK的异常表达直接涉及ALCL的发病并且ALK的此种抑制可显著阻碍ALK阳性淋巴癌细胞的生长。组成型激活的嵌合ALK已证明存在于约60％的炎性肌纤维母细胞瘤(IMT)(一种缓慢生长的肉瘤，其主要影响儿童和年轻人)中。此外，当前报道已经描述在食管的鳞状细胞癌(SCC)的情况下出现了变型ALK融合体TPM4-ALK。因此，ALK是涉及非造血***恶性肿瘤和造血***恶性肿瘤两者中的瘤形成的RTK的少数实例之一。最近，已显示染色体2p内的倒置导致非小细胞肺癌细胞中包含刺皮动物微管相关蛋白一样4(EML4)基因和间变性淋巴瘤激酶(ALK)基因的一部分的融合基因形成。
在一些实施方案中，ALK抑制剂当作为单一治疗剂或与当前化疗组合用于ALCL、IMT、增殖性病症、胶质母细胞瘤和本文引用的其它可能的实体肿瘤时可创造出持久治愈，或者作为单一治疗剂可用于预防在需要此类治疗的患者中复发的维持作用中。
如本文公开的化合物可作为其中化合物是唯一的活性药剂的治疗方案的一部分施用，或与作为组合疗法的一部分的一种或多种其它治疗剂联用。当作为组合疗法的一种组分施用时，可将正在施用的治疗剂配制为在不同的时间点(如在彼此72小时、48小时或24小时内)同时或依序施用单独的组合物，或可将治疗剂一起配制为单一药物组合物并同时施用。
因此，本发明化合物的施用可结合本领域技术人员已知的预防或治疗癌症的至少一种另外的治疗(诸如放射疗法或细胞抑制剂、细胞毒性剂、其他抗癌剂和其它药物)以缓解癌症的症状或任何药物副作用。另外的治疗剂的非限制性实例包括适用于免疫疗法的药剂(诸如，例如PD-1或PDL-1抑制剂)、抗血管新生的药剂(诸如，例如贝伐单抗)和/或化疗的药剂。
如果配制为固定剂量，此类组合产物采用在可接受的剂量范围内的如本文公开的化合物。当组合制剂适当时，如本文公开的化合物可与其它抗癌剂或细胞毒性剂依序施用。如本文公开的化合物可在其它抗癌剂或细胞毒性剂施用之前、同时或之后施用。
当前，原发性肿瘤的标准治疗由手术切除、随后适当时放射或化疗组成，且通常静脉内施用。通常的化疗方案由DNA烷基化剂、DNA嵌入剂、CDK抑制剂或微管毒药组成。所用的化疗剂量刚好低于最大耐受剂量，且因此剂量限制毒性通常包括恶心、呕吐、腹泻、掉发、嗜中性粒细胞减少症等。
存在大量的抗肿瘤药可用于商业用途、临床评价和临床前开发，其可经选择通过组合药物化疗用于治疗癌症。并且存在数种主要类别的此类抗肿瘤药，即抗生素型药剂、烷基化剂、抗代谢剂、抗激素剂、免疫剂、干扰素型药剂和一类的混杂药剂。
其它治疗剂的实例包括但不限于一种或多种下述药物：抗癌烷化剂或嵌入试剂(如氮芥、苯丁酸氮芥、环磷酰胺、美法仑和异环磷酰胺)；抗代谢物(如甲氨蝶呤)；嘌呤抗结剂或嘧啶拮抗剂(如5-氟尿嘧啶、阿糖胞苷和吉西他滨)；纺锤体抑制剂(如长春碱、长春新碱、长春瑞滨河紫杉醇)；鬼臼毒素(如依托泊苷、伊立替康、托泊替康)；抗生素(如多柔比星、博莱霉素和丝裂霉素)；亚硝基脲类(如卡莫司汀、洛莫司汀)；无机离子(如顺铂、卡铂、奥沙利铂或oxiplatin)；酶(如天冬酰胺酶)；激素(如他莫西芬、亮丙瑞林、氟他胺或甲地孕酮)；mTOR抑制剂(如西罗莫司(雷帕霉素)、Temsiroliumus(CCI779)、依维莫司(RAD001)、AP23573或公开于美国专利7091213中的其他化合物)；蛋白酶体抑制剂(如万珂、其他蛋白酶体抑制及(如Src、Bcr/Abl、kdr、flt3、aurora-2、 糖原合成酶激酶3(GSK-3)、EGFR激酶(如易瑞沙、特罗凯等)、VEGF-R激酶、PDGF-R激酶等的抑制剂)；抗体、可溶性受体或抵抗癌症中涉及的受体或激素的其它受体拮抗剂(包括受体如EGFR、ErbB2、VEGFR、PDGFR和IGF-R；和药物如赫赛汀、阿瓦斯丁、爱必妥等)等等。其它治疗药物的实例包括但不限于嘌醇、alemtuzmab、六甲密胺、氨磷汀、nastrozole、对抗***特异性膜抗原的抗体(如MLN-591、MLN591RL和MLN2704)、三氧化二砷、贝沙罗汀、博莱霉素、白消安、卡培他滨、Giadel Wafer、塞来考西、苯丁酸氮芥、顺铂-肾上腺素凝胶、克拉曲滨、阿糖胞苷脂质体、柔红霉素脂质体、柔红霉素、红比霉素、右雷佐生、多西紫杉醇、多柔比星、Elliott’sB溶液、表柔比星、磷雌氮芥、磷酸依托泊苷、依西美坦、氟达拉滨、5-FU、氟维司群、吉西他滨、吉姆单抗-奥佐米星、醋酸戈舍瑞林、羟基脲、伊达比星、去甲氧柔红霉素、异环磷酰胺、甲磺酸伊马替尼、伊立替康(或其它拓扑异构酶抑制剂，包括抗体如MLN576(XR11576))、来曲唑、亚叶酸钙、亚叶酸钙左旋咪唑、脂质体柔红霉素、美法仑、L-PAM、美司钠、甲氨蝶呤、甲氧沙林、丝裂霉素C、米托蒽醌、MLN518或MLN608(或其它flt-3受体酪氨酸激酶、PDFG-R或c-kit的抑制剂)、itoxantrone、紫杉醇、培加酶、喷他司丁、利妥西单抗、滑石、他莫昔芬、temozolamide、替尼泊昔、VM-26、托泊替康、托瑞米芬、2C4(或干扰HER2-介导的信号的其它抗体)、维甲酸、ATRA、戊柔比星、长春瑞滨、或氨羟二磷酸二钠、唑来二磷酸二钠或其它二磷酸盐。
实施例
下面结合具体实施例，作进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～100℃，优选0℃～80℃)下进行。反应时间通常为0.1-60小时，优选地为0.5-24小时。
实施例1(2-((5-氯-2-((4-((二甲基氨基)甲基)-2-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧 化膦(化合物T-1)的制备。
Figure PCTCN2018120618-appb-000021
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000022
步骤1 化合物2的合成
依次往配有磁力搅拌的50mL单口烧瓶中加入化合物1(0.6g，3.0mmol)和甲醇(15mL)，搅拌溶清，缓慢滴加入浓硫酸(1mL)，加完后升温到回流，氮气氛下保温搅拌反应3小时。冷却到室温，加入水(40mL)淬灭反应，二氯甲烷萃取(40mLx2)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩无色液体0.52g，收率82.1％。LC-MS(APCI):m/z＝212.1(M+1) +.
步骤2 化合物3的合成
依次往配有磁力搅拌的50mL单口烧瓶中加入化合物2(0.5g，2.37mmol)和无水THF(15mL)，搅拌溶清，冰水浴冷却，缓慢加入氢化锂铝(LiAlH 4，90mg，2.37mmol)，氮气氛下保温搅拌反应1小时。加入十水硫酸钠(10g)淬灭反应，搅拌5分钟，加入二氯甲烷(40mL)稀释，过滤，二氯甲烷(10mL)洗涤滤饼，无水硫酸钠干燥，过滤，浓缩得白色固体0.4g，收率92.2％。LC-MS(APCI):m/z＝184.1(M+1) +.
步骤3 化合物4的合成
向配有磁力搅拌的100mL单口瓶中依次加化合物3(400mg，2.18mmol)和二氯甲烷(DCM，10mL),搅拌溶清，加入Dess-Martin氧化剂(904mg，2.18mmol)，反应混合物氮气氛下室温搅拌反应1小时。加入水(20mL)淬灭反应，生成的固体过滤，水相二氯甲烷萃取(20mLx2)，合并有机相，水洗(30mLx2)，无色硫酸钠干燥，浓缩并过硅胶柱得白色固体300mg，收率74.9％。LC-MS(APCI):m/z＝182.1(M+1) +.
步骤4 化合物5的合成
向配有磁力搅拌的50mL单口瓶中依次加化合物4(181mg,1.0mmol)和甲醇(5ml)，搅拌溶清，滴加入二甲胺的四氢呋喃溶液(1mL，2.0mmol，2M)和冰醋酸(1滴)，氮气氛下室温搅拌反应十分钟，缓慢滴加入NaBH 3CN(150mg,2.5mmol)，室温搅拌反应1小时。加入水(5mL)淬灭反应，乙酸乙酯萃取(15mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体126mg，收率60.0％。LC-MS(APCI):m/z＝211.1(M+1) +.
步骤5 化合物6的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中加入化合物5(126mg，0.6mmol)和乙醇/水(8mL，3/1)，搅拌溶清，加入还原铁粉(3.6mmol，202mg)和氯化铵(0.6mmol，32mg)，氮气氛下升温回流并保温反应1小时。冷却到室温，过滤，乙醇(5mL)洗涤滤饼，浓缩去除有机溶剂，二氯甲烷萃取(10mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得棕色固体80mg，收率74.1％。LC-MS(APCI):m/z＝181.1(M+1) +.
步骤6 化合物T-1的合成
向配有磁力搅拌跟冷凝管的25mL单口瓶中加入化合物6(80mg，0.44mmol)、化合物7(138mg，0.44mmol)和乙二醇单甲醚(3mL)，搅拌溶清，滴加入氯化氢的异丙醇溶液(0.66mmol，0.13mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(10mL)和饱和碳酸氢钠(5mL)，二氯甲烷萃取(15mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体100mg，收率为49.5％。LC-MS(APCI):m/z＝460.2(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ/ppm:11.17(s,1H),8.47-8.43(m,1H),8.14(s,1H),8.12(s,1H),7.71(d,J＝8.0Hz,1H),7.58-7.53(m,1H),7.39(t,J＝8.0Hz,1H),7.13(t,J＝8.0Hz,1H),6.97(s,1H),6.81(d,J＝8.0Hz,1H),3.80(s,3H),2.17(s,6H),1.78(s,3H),1.75(s,3H).
实施例2(2-((2-((4-(2-氨基乙基)-2-甲氧基苯基)氨基)-5-氯嘧啶-4-基)氨基)苯基)二甲基氧化膦 (化合物T-2)的制备。
Figure PCTCN2018120618-appb-000023
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000024
步骤1 化合物10的合成
依次往配有磁力搅拌的250mL单口烧瓶中加入化合物8(5.1g，30mmol)和无水DMSO(40mL)，氮气氛下搅拌溶清并冷却到0℃，缓慢加入NaH(3.6g，90mmol，60％)，0℃搅拌反应半小时，缓慢滴加入化合物9(11.6g，90mmol)的DMSO溶液(10mL)，滴毕，拆去冰浴，反应混合物升温到100℃并保温搅拌反应3小时。冷却到室温，加入水(50mL)，乙酸乙酯萃取(50mLx3)，合并有机相，水洗(60mLx2)，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体8.3g，收率98.1％。LC-MS(APCI):m/z＝282.1(M-1) -.
步骤2 化合物11的合成
依次往配有磁力搅拌的250mL单口烧瓶中加入化合物10(2.83g，10mmol)和DMSO(50mL)，搅拌溶清，加入NaCl(1.17g，20mmol)和水(0.18g，10mmol)，反应混合物升温到120℃并保温搅拌反应3小时。冷却到室温，加入水(80mL)，乙酸乙酯萃取(50mLx3)，合并有机相，水洗(60mLx2)，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体1.9g，收率84.1％。LC-MS(APCI):m/z＝224.1(M-1) -.
步骤3 化合物12的合成
依次往配有磁力搅拌的250mL单口烧瓶中加入化合物11(1.9g，8.4mmol)和无水THF(50mL)，搅拌溶清，冰水浴冷却，缓慢加入LiAlH 4(320mg，8.4mmol)，氮气氛下保温搅拌反应1小时。加入十水硫酸钠(20g)淬灭反应，搅拌5分钟，加入二氯甲烷(60mL)稀释，过滤，二氯甲烷(10mL)洗涤滤饼，无水硫酸钠干燥，过滤，浓缩得白色固体1.3g，收率79.0％。LC-MS(APCI): m/z＝198.1(M+1) +.
步骤4 化合物13的合成
向配有磁力搅拌和冷凝管的100mL单口瓶中加入化合物12(1.3g，6.6mmol)和乙醇/水(40mL，3/1)，搅拌溶清，加入还原铁粉(39.6mmol，2.23g)和氯化铵(6.6mmol，350mg)，氮气氛下升温回流并保温反应1小时。冷却到室温，过滤，乙醇(10mL)洗涤滤饼，浓缩去除有机溶剂，二氯甲烷萃取(30mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩得棕色固体850mg，收率77.1％。LC-MS(APCI):m/z＝168.1(M+1) +.
步骤6 化合物14的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中加入化合物13(850mg，5.09mmol)、化合物7(1.6g，5.09mmol)和乙二醇单甲醚(10mL)，搅拌溶清，滴加入氯化氢的异丙醇溶液(7.64mmol，1.53mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(30mL)和饱和碳酸氢钠(20mL)，二氯甲烷萃取(50mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体1.2g，收率为52.9％。LC-MS(APCI):m/z＝447.2(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ/ppm:11.16(s,1H),8.46-8.43(m,1H),8.11(s,1H),8.07(s,1H),7.62(d,J＝8.0Hz,1H),7.58-7.51(m,1H),7.39(t,J＝8.0Hz,1H),7.12(t,J＝8.0Hz,1H),6.90(s,1H),6.73(d,J＝8.0Hz,1H),4.62(t,J＝4.8Hz,1H),3.77(s,3H),3.61(q,J＝4.8Hz,2H),2.71(t,J＝5.6Hz,2H),1.77(s,3H),1.74(s,3H).
步骤7 化合物15的合成
向配有磁力搅拌和冷凝管的100mL单口瓶中加入化合物14(1.7g，3.8mmol)和无水二氯甲烷(20mL)，搅拌溶清，加入CBr 4(4.1mmol，1.36g)，氮气氛下冷却到0℃，加入三苯基膦(TPP，1.08g，4.1mmol)，加完后拆去冰浴，室温搅拌反应1h。减压蒸除溶剂，残留物过硅胶柱得白色固体960mg，收率49.5％。LC-MS(APCI):m/z＝509.1,511.1(M+1) +.
步骤8 化合物T-2的合成
向配有磁力搅拌的50mL单口瓶中加入化合物15(102mg，0.2mmol)和乙腈(2mL)，搅拌溶清，加入氨水(3mL)，氮气氛室温搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体60mg，收率67.4％。LC-MS(APCI):m/z＝446.1(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ/ppm:11.19(s,1H),8.49-8.46(m,1H),8.15(s,1H),8.10(s,1H),7.96(br s,2H),7.77(d,J＝8.0Hz,1H),7.61-7.55(m,1H),7.45(t,J＝8.0Hz,1H),7.16(t,J＝8.0Hz,1H),6.97(s,1H),6.78(d,J＝8.0Hz,1H),3.84(s,3H),3.06(t,J＝8.0Hz,2H),2.88(t,J＝8.0Hz,2H),1.80(s,3H),1.76(s,3H).
实施例3(2-((5-氯-2-((4-(2-(二甲基氨基)乙基)-2-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基 氧化膦(化合物T-3)的制备。
Figure PCTCN2018120618-appb-000025
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000026
向配有磁力搅拌的50mL单口瓶中加入化合物15(102mg，0.2mmol)和乙腈(2mL)，搅拌溶清，加入二甲胺的四氢呋喃溶液(5mL)，氮气氛室温搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体60mg，收率63.4％。LC-MS(APCI):m/z＝474.2(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ/ppm:11.19(s,1H),8.48-8.45(m,1H),8.14(s,1H),8.12(s,1H),7.71(d,J＝8.0Hz,1H),7.60-7.56(m,1H),7.44(t,J＝8.0Hz,1H),7.15(t,J＝8.0Hz,1H),6.99(s,1H),6.79(d,J＝8.0Hz,1H),3.82(s,3H),3.04-3.00(m,2H),2.95-2.89(m,2H),2.60(s,6H),1.80(s,3H),1.76(s,3H).
实施例4(2-((5-氯-2-((2-甲氧基-4-(2-(哌啶-1-基)乙基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧 化膦(化合物T-4)的制备。
Figure PCTCN2018120618-appb-000027
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000028
向配有磁力搅拌的50mL单口瓶中加入化合物15(102mg，0.2mmol)和乙腈(2mL)，搅拌溶清，加入哌啶(51mg，0.6mmol)，氮气氛室温搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体60mg，收率58.5％。LC-MS(APCI):m/z＝514.2(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ/ppm:11.19(s,1H),8.48-8.45(m,1H),8.14(s,1H),8.12(s,1H),7.69(d,J＝8.0Hz,1H),7.60-7.56(m,1H),7.43(t,J＝8.0Hz,1H),7.15(t,J＝8.0Hz,1H),6.97(s,1H),6.78(d,J＝8.0Hz,1H),3.81(s,3H),3.38-3.36(m,2H),2.91-2.62(m,6H),1.80(s,3H),1.76(s,3H),1.69-1.62(m,4H),1.49-1.45(m,2H).
实施例5(2-((5-氯-2-((2-甲氧基-4-(2-(4-甲基哌嗪-1-基)乙基)苯基)氨基)嘧啶-4-基)氨基)苯基)二 甲基氧化膦(化合物T-5)的制备。
Figure PCTCN2018120618-appb-000029
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000030
向配有磁力搅拌的50mL单口瓶中加入化合物15(102mg，0.2mmol)和乙腈(2mL)，搅拌溶清，加入N-甲基哌嗪(60mg，0.6mmol)，氮气氛室温搅拌反应过夜。减压蒸除溶剂，残留物过 硅胶柱得白色固体60mg，收率56.8％。LC-MS(APCI):m/z＝514.2(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ/ppm:11.18(s,1H),8.48-8.45(m,1H),8.13(s,1H),8.10(s,1H),7.64(d,J＝8.0Hz,1H),7.59-7.54(m,1H),7.41(t,J＝8.0Hz,1H),7.14(t,J＝8.0Hz,1H),6.96(s,1H),6.76(d,J＝8.0Hz,1H),3.80(s,3H),3.38-3.30(m,4H),2.74(t,J＝8.0Hz,2H),2.59-2.52(m,4H),2.50-2.47(m,2H),2.26(s,3H),1.79(s,3H),1.76(s,3H).
实施例6(2-((5-氯-2-((2-甲氧基-4-(2-吗啉乙基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦 (化合物T-6)的制备。
Figure PCTCN2018120618-appb-000031
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000032
向配有磁力搅拌的50mL单口瓶中加入化合物15(102mg，0.2mmol)和乙腈(2mL)，搅拌溶清，加入吗啉(52mg，0.6mmol)，氮气氛室温搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体60mg，收率58.2％。LC-MS(APCI):m/z＝516.2(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ/ppm:11.18(s,1H),8.48-8.45(m,1H),8.13(s,1H),8.10(s,1H),7.64(d,J＝8.0Hz,1H),7.59-7.54(m,1H),7.41(t,J＝8.0Hz,1H),7.14(t,J＝8.0Hz,1H),6.96(s,1H),6.76(d,J＝8.0Hz,1H),3.80(s,3H),3.60(t,J＝8.4Hz,4H),2.74(t,J＝8.0Hz,2H),2.54(t,J＝8.0Hz,2H),2.45(t,J＝8.0Hz,4H),1.79(s,3H),1.76(s,3H).
实施例7(2-((2-((4-(1-氨基乙基)-2-甲氧基苯基)氨基)-5-氯嘧啶-4-基)氨基)苯基)二甲基氧化膦 (化合物T-7)的制备。
Figure PCTCN2018120618-appb-000033
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000034
步骤1 化合物17的合成
依次往配有磁力搅拌的100mL三口烧瓶中加入化合物1(2.75g，13.95mmol)和无水THF(20mL)，氮气氛下搅拌溶清并冷却到0℃，滴加入无水DMF(3滴)，然后缓慢滴加入草酰氯的二氯甲烷溶液(16.74mmol，8.37mL，2M)，滴毕，拆去冰浴，室温下搅拌反应1小时。减压蒸除溶剂，并溶于甲苯(40mL)中，搅拌及氮气氛下加入MgCl 2(927mg，9.74mmol)和三乙胺(3.38g，334.4mmol)，再缓慢加入化合物9(2.21g，16.7mmol)，反应混合物室温下搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得淡黄色固体1.68g，收率61.7％。LC-MS(APCI):m/z＝196.1(M+1) +.
步骤2 化合物18的合成
向配有磁力搅拌的20mL微波管中加入化合物17(500mg，2.56mmol)和乙醇(10mL)，搅拌溶清，加入醋酸铵(1.97g，25.62mmol)和NaBH 3CN(322mg，5.12mmol)，反应混合物置于微波反应器中升温到120℃，搅拌反应10分钟。冷却到室温，蒸除溶剂，残留物过硅胶柱得无色油状 物500mg，收率99.5％。LC-MS(APCI):m/z＝197.1(M+1) +.
步骤3 化合物19的合成
向配有磁力搅拌的50mL单口瓶中加入化合物18(500mg，2.55mmol)和二氯甲烷(10mL)，搅拌溶清，加入三乙胺(1.29g，12.74mmol)，冰水浴冷却下滴加入三氟乙酸酐(TFAA，1.07g，5.1mmol)，滴毕，拆去冰浴，氮气氛下室温搅拌反应30分钟。减压蒸除溶剂，残留物过硅胶柱得淡黄色固体230mg，收率30.9％。LC-MS(APCI):m/z＝293.2(M+1) +. 1H NMR(300MHz,CDCl 3)δ(ppm):7.88(d,J＝6.3Hz,1H),7.04(d,J＝1.2Hz,1H),6.99(dd,J＝6.6Hz,J＝1.2Hz,1H),5.16(t,J＝5.4Hz,1H),3.99(s,3H),1.63(t,J＝5.4Hz,3H).
步骤4 化合物20的合成
向配有磁力搅拌的50mL单口瓶中加入化合物19(230mg，0.79mmol)和甲醇(10mL)，搅拌溶清，加入Pd/C(50mg，60％)，抽真空并氢气置换三次，氢气球氛下室温搅拌反应过夜。滤除催化剂，甲醇(5mL)洗涤滤饼，蒸除溶剂得黄色固体180mg，收率87.2％LC-MS(APCI):m/z＝263.2(M+1) +.
步骤5 化合物21的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中加入化合物20(180mg，0.69mmol)、化合物7(239mg，0.75mmol)和乙二醇单甲醚(3mL)，搅拌溶清，滴加入氯化氢的异丙醇溶液(1.03mmol，0.21mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(10mL)和饱和碳酸氢钠(5mL)，二氯甲烷萃取(20mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体0.3g，收率为80.6％。LC-MS(APCI):m/z＝542.2(M+1) +.
步骤6 化合物T-7的合成
向配有磁力搅拌的50mL单口瓶中加入化合物21(300mg，0.55mmol)和THF/MeOH/H 2O(2mL/1mL/1mL)，搅拌溶清，加入一水合氢氧化锂(LiOH·H 2O，116mg，2.77mmol)，反应混合物室温下搅拌反应过夜。加入水(10mL)，二氯甲烷萃取(15mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体0.2g，收率为81.0％。LC-MS(APCI):m/z＝446.3(M+1) +. 1H NMR(300MHz,DMSO-d 6)δ(ppm):11.19(s,1H),8.47(dd,J＝6.3Hz,J＝3.3Hz,1H),8.15(s,2H),8.03(br s,2H),7.84(d,J＝6.3Hz,1H),7.56(dd,J＝10.2Hz,J＝5.7Hz,1H),7.48(t,J＝5.7Hz,1H),7.26(s,1H),7.15(t,J＝5.4Hz,1H),6.399(d,J＝6.0Hz,1H),4.33(d,J＝5.1Hz,1H),3.84(s,3H),1.76(d,J＝9.9Hz,6H),1.50(d,J＝5.1Hz,3H).
实施例8和实施例9(2-((5-氯-2-((4-(1-(二甲基氨基)乙基)-2-甲氧基苯基)氨基)嘧啶-4-基)氨基) 苯基)二甲基氧化膦(化合物T-8)和(2-((5-氯-2-((4-(1-(甲基氨基)乙基)-2-甲氧基苯基)氨基)嘧啶-4-基) 氨基)苯基)二甲基氧化膦(化合物T-9)的制备。
Figure PCTCN2018120618-appb-000035
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000036
向配有磁力搅拌的50mL单口瓶中加入化合物T-7(110mg，0.25mmol)和甲醇(5mL)，搅拌溶清，加入甲醛(14mg，0.17mmol)和冰醋酸(1滴)，氮气氛下搅拌反应10分钟。冷却到0℃，加入NaBH 3CN(15mg，0.25mmol)，反应混合物室温下搅拌反应1小时。加入水(10mL)淬灭反应，二氯甲烷萃取(15mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得T-8，白色固体30mg，收率为25.7％。LC-MS(APCI):m/z＝474.2(M+1) +. 1H NMR(300MHz,CDCl 3)δ(ppm):10.87(s,1H),8.58(dd,J＝6.6Hz,J＝3.3Hz,1H),8.41(d,J＝6.3Hz,1H),8.15(s,1H),7.61-7.55(m,2H),7.34-7.31(m,2H),7.18(t,J＝5.4Hz,1H),6.87(d,J＝6.3Hz,1H),4.00(s,3H),3.87(s,1H),2.59(s,6H),1.85(s,J＝9.9Hz,6H),1.68(s,3H)；
残留物过硅胶柱得T-9为白色固体17mg，收率15％。LC-MS(APCI):m/z＝460.2(M+1) +. 1H NMR(300MHz,CDCl 3)δ(ppm):10.84(s,1H),8.56(dd,J＝6.3z,J＝3.0z,1H),8.42(d,J＝6.3Hz,1H),8.14(s,1H),7.62-7.58(m,2H),7.36-7.27(m,2H),7.19(dd,J1＝5.4Hz,J2＝0.9Hz,1H),6.91(d,J＝6.3Hz,1H),4.08(d,J＝5.1Hz,1H),4.01(s,3H),2.45(s,3H),1.87-1.83(m,9H).
实施例10(2-((2-((4-(1-氨基-2-甲基丙基-2-基)-2-甲氧基苯基)氨基)-5-氯嘧啶-4-基)氨基)苯基)二 甲基氧化膦(化合物T-10)的制备。
Figure PCTCN2018120618-appb-000037
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000038
步骤1 化合物23的合成
向配有磁力搅拌的50mL单口瓶中加入化合物22(2g，13.6mmol)和THF(40mL)，搅拌溶清，冷却到0℃，加入叔丁醇钾(4.7g，40.8mmol)，搅拌10分钟，滴加入碘甲烷(5.8g，40.8mmol)，滴毕，拆去冰浴，氮气氛下室温搅拌反应过夜。加入水(60mL)淬灭反应，乙酸乙酯萃取(40mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体1.84g，收率为77.3％。LC-MS(APCI):m/z＝176.2(M+1) +.
步骤2 化合物24的合成
向配有磁力搅拌的50mL单口瓶中加入四丁基硝酸铵(6.7g，21.94mmol)、18-冠醚-6(845mg，3.2mmol)和二氯甲烷(30mL)，搅拌溶清，冷却到0℃，氮气氛下滴加入TFAA(13mL)，搅拌15分钟，滴加入化合物23(4.0g，22.86mmol)的二氯甲烷溶液(10mL)，滴毕，拆去冰浴，室温下搅拌反应2小时。加入水(30mL)和饱和碳酸氢钠水液(30mL)淬灭反应，搅拌5分钟，分出有机层，水相二氯甲烷萃取(40mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得无水油状物3.1g，收率为61.6％。LC-MS(APCI):m/z＝221.1(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):7.87(d,J＝8.8Hz,1H),7.23(d,J＝2.0Hz,1H),7.09(dd,J＝8.8Hz,J＝2.0Hz,1H),4.00(s,3H),1.76(s,6H).
步骤3 化合物25的合成
向配有磁力搅拌和冷凝管的100mL单口瓶中加入化合物24(3.2g，14.9mmol)和乙醇/水(60mL，3/1)，搅拌溶清，加入还原铁粉(70.5mmol，3.2g)和氯化铵(14.9mmol，790mg)，氮气氛下升温回流并保温反应1小时。冷却到室温，过滤，乙醇(10mL)洗涤滤饼，浓缩去除有机溶剂，二氯甲烷萃取(50mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩得棕色固体2.6g，收率91.8％。LC-MS(APCI):m/z＝191.1(M+1) +.
步骤4 化合物26的合成
向配有磁力搅拌跟冷凝管的50mL单口瓶中加入化合物25(1.5g，7.9mmol)、化合物7(2.5g，7.9mmol)和乙二醇单甲醚(15mL)，搅拌溶清，滴加入氯化氢的异丙醇溶液(11.8mmol，2.4mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(30mL)和饱和碳酸氢钠(30mL)，二氯甲烷萃取(40mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体1.2g，收率为32.4％。LC-MS(APCI):m/z＝470.1(M+1) +.
步骤5 化合物T-10的合成
向配有磁力搅拌跟冷凝管的50mL单口瓶中加入化合物26(1.2g，2.56mmol)和THF(10mL)，搅拌溶清，滴加入硼烷四氢呋喃溶液(8mL，8.0mmol，1M)，氮气氛下升温到回流并保温搅拌反应4小时。冷却到室温，减压蒸除溶剂，残留物过硅胶柱得白色固体460mg，收率为38.0％。LC-MS(APCI):m/z＝474.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):10.82(s,1H),8.59-8.55(m,1H),8.29(d,J＝8.4Hz,1H),8.08(s,1H),7.58(t,J＝8.4Hz,1H),7.50(s,1H),7.33-7.30(m,1H),7.17-7.14(m,1H),6.88-6.85(m,2H),3.91(s,3H),3.05(s,2H),1.85(s,3H),1.82(s,3H),1.45(s,6H).
实施例11和实施例12(2-((5-氯-2-((2-甲氧基-4-(2-甲基-1-(甲基氨基)丙烷-2-基)苯基)氨基)嘧啶 -4-基)氨基)苯基)二甲基氧化膦(化合物T-11)和(2-((5-氯-2-((4-(1-(二甲基氨基)-2-甲基丙烷-2-基)-2- 甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(化合物T-12)的制备。
Figure PCTCN2018120618-appb-000039
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000040
向配有磁力搅拌的50mL单口瓶中加入化合物T-10(300mg，0.63mmol)和甲醇(10mL)，搅拌溶清，加入甲醛(15mg，0.5mmol)和冰醋酸(1滴)，氮气氛下搅拌反应10分钟。冷却到0℃，加入NaBH 3CN(40mg，0.63mmol)，反应混合物室温下搅拌反应1小时。加入水(20mL)淬灭反应，二氯甲烷萃取(20mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得T-11，白色固体50mg，收率为16.3％。LC-MS(APCI):m/z＝488.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):10.87(s,1H),8.61-8.58(m,1H),8.40(d,J＝8.4Hz,1H),8.14(s,1H),7.59-7.55(m,2H),7.35-7.30(m,1H),7.22-7.17(m,1H),7.03(d,J＝2.0Hz,1H),6.93(dd,J＝8.0Hz,J＝2.0Hz,1H),4.00(s,3H),3.15(s,2H),2.50(s,3H),1.87(s,3H),1.84(s,3H),1.61(s,6H)；
以及残留物过硅胶柱得T-12为白色固体150mg，收率30.0％。LC-MS(APCI):m/z＝502.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):10.87(s,1H),8.61-8.58(m,1H),8.40(d,J＝8.4Hz,1H),8.14(s,1H),7.59-7.55(m,2H),7.35-7.30(m,1H),7.22-7.17(m,1H),7.03(d,J＝2.0Hz,1H),6.93(dd,J＝8.0Hz,J＝2.0Hz,1H),4.00(s,3H),3.15(s,2H),2.50(s,6H),1.87(s,3H),1.84(s,3H),1.61(s,6H).
实施例13(2-((2-((4-(2-氨基丙烷-2-基)-2-甲氧基苯基)氨基)-5-氯嘧啶-4-基)氨基)苯基)二甲基氧 化膦(化合物T-13)的制备。
Figure PCTCN2018120618-appb-000041
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000042
步骤1 化合物27的合成
向配有磁力搅拌的50mL单口瓶中加入化合物26(1.6g，3.41mmol)和水(10mL)，搅拌下加入浓硫酸(10mL)，反应液氮气氛下升温到100℃，保温搅拌反应过夜。冷却到室温，NaOH水液(2M)调pH～5，二氯甲烷萃取(40mLx3)合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体850mg，收率为51.1％。LC-MS(APCI):m/z＝487.2(M-1)-.
步骤2 化合物T-13的合成
向配有磁力搅拌的50mL单口瓶中加入化合物27(200mg，0.41mmol)和二氯甲烷(10mL)，搅拌溶清，加入三乙胺(0.53mL，0.53mmol)，氮气氛下搅拌反应15分钟，加入叠氮磷酸二苯酯(DPPA，147mg，0.53mmol)，室温下继续搅拌反应3小时。减压蒸除溶剂，并溶于甲苯(10mL)中，升温回流2小时，冷却到室温，加入盐酸(20mL，6M)，并再次回流反应3小时。冷却到室温，氨水调pH～10，乙酸乙酯萃取(30mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体110mg，收率为58.4％。LC-MS(APCI):m/z＝460.2(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ(ppm):11.20(s,1H),8.50-8.47(m,1H),8.25-8.15(m,4H),7.83(d,J＝8.8Hz,1H),7.60-7.55(m,1H),7.50(t,J＝8.0Hz,1H),7.30(s,1H),7.15(t,J＝8.0Hz,1H),7.03(dd,J＝8.8Hz.J＝2.0Hz,1H),3.87(s,3H),1.79(s,3H),1.75(s,3H),1.63(s,6H).
实施例14和实施例15(2-((5-氯-2-((4-(2-(二甲基氨基)丙烷-2-基)-2-甲氧基苯基)氨基)嘧啶-4-基) 氨基)苯基)二甲基氧化膦(化合物T-14)和(2-((5-氯-2-((2-甲氧基-4-(2-(甲基氨基)丙烷-2-基)苯基)氨基) 嘧啶-4-基)氨基)苯基)二甲基氧化膦(化合物T-15)的制备。
Figure PCTCN2018120618-appb-000043
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000044
向配有磁力搅拌的50mL单口瓶中加入化合物T-13(300mg，0.65mmol)和甲醇(10mL)，搅拌溶清，加入甲醛(15mg，0.5mmol)和冰醋酸(1滴)，氮气氛下搅拌反应10分钟。冷却到0℃，加入NaBH 3CN(42mg，0.65mmol)，反应混合物室温下搅拌反应1小时。加入水(20mL)淬灭反应，二氯甲烷萃取(20mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得T-14，白色固体150mg，收率为30.0％。LC-MS(APCI):m/z＝488.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):10.87(s,1H),8.58-8.57(m,1H),8.42(d,J＝8.4Hz,1H),8.14(s,1H),7.82(br s,1H),7.61(s,1H),7.56(t,J＝8.0Hz,1H),7.31-7.28(m,1H),7.17(t,J＝8.0Hz,1H),6.98(dd,J＝8.4Hz,J＝2.0Hz,1H),4.08(s,3H),2.62(s,6H),1.85(s,3H),1.82(s,3H),1.81(s,6H)；
以及残留物过硅胶柱得T-15为白色固体50mg，收率15.0％。LC-MS(APCI):m/z＝474.2(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ(ppm):11.20(s,1H),9.53(br s,1H),8.47-8.44(m,1H),8.21(s,1H),8.18(s,1H),7.88(d,J＝8.4Hz,1H),7.60-7.55(m,1H),7.51(t,J＝8.0Hz,1H),7.42(s,1H),7.16(t,J＝8.0Hz,1H),7.07(dd,J＝8.8Hz.J＝2.0Hz,1H),3.89(s,3H),2.22(s,3H),1.79(s,3H),1.75(s,3H),1.69(s,6H).
实施例16(2-((2-((4-(1-氨基丙烷-2-基)-2-甲氧基苯基)氨基)-5-氯嘧啶-4-基)氨基)苯基)二甲基氧 化膦(化合物T-16)的制备。
Figure PCTCN2018120618-appb-000045
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000046
步骤1 化合物28的合成
向配有磁力搅拌的50mL单口瓶中加入化合物22(4g，27.2mmol)和THF(40mL)，搅拌溶清，冷却到-10℃，滴加入LiHMDS(29.92mL，29.92mmol，1M)，搅拌10分钟，滴加入碘甲烷(4.3g，29.92mmol)，滴毕，0℃氮气氛下室温搅拌反应过夜。加入水(60mL)淬灭反应，乙酸乙酯萃取(40mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体3.2g，收率为73.5％。LC-MS(APCI):m/z＝176.2(M+1) +. 1H NMR(400MHz,CDCl3)δ(ppm):7.33-7.28(m,1H),6.96-6.87(m,3H),3.89(q,J＝7.2Hz,1H),3.84(s,3H),1.87(d,J＝7.2Hz,3H).
步骤2 化合物29的合成
向配有磁力搅拌的50mL单口瓶中加入四丁基硝酸铵(6.7g，21.94mmol)、18-冠醚-6(845mg，3.2mmol)和二氯甲烷(30mL)，搅拌溶清，冷却到0℃，氮气氛下滴加入TFAA(13mL)，搅拌15分钟，滴加入化合物28(3.7g，22.86mmol)的二氯甲烷溶液(10mL)，滴毕，拆去冰浴，室温下搅拌反应2小时。加入水(30mL)和饱和碳酸氢钠水液(30mL)淬灭反应，搅拌5分钟，分出有机层，水相二氯甲烷萃取(40mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得无水油状物3.1g，收率为68.6％。LC-MS(APCI):m/z＝207.1(M+1) +.
步骤3 化合物30的合成
向配有磁力搅拌和冷凝管的100mL单口瓶中加入化合物29(3.1g，14.9mmol)和乙醇/水(60mL，3/1)，搅拌溶清，加入还原铁粉(70.5mmol，3.2g)和氯化铵(14.9mmol，790mg)，氮气氛下升温回流并保温反应1小时。冷却到室温，过滤，乙醇(10mL)洗涤滤饼，浓缩去除有机溶剂， 二氯甲烷萃取(50mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩得棕色固体2.4g，收率91.5％。LC-MS(APCI):m/z＝177.1(M+1) +.
步骤4 化合物31的合成
向配有磁力搅拌跟冷凝管的50mL单口瓶中加入化合物30(1.4g，7.9mmol)、化合物7(2.5g，7.9mmol)和乙二醇单甲醚(15mL)，搅拌溶清，滴加入氯化氢的异丙醇溶液(11.8mmol，2.4mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(30mL)和饱和碳酸氢钠(30mL)，二氯甲烷萃取(40mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体1.2g，收率为33.4％。LC-MS(APCI):m/z＝456.1(M+1) +.
步骤5 化合物T-16的合成
向配有磁力搅拌跟冷凝管的50mL单口瓶中加入化合物31(1.2g，2.64mmol)和THF(10mL)，搅拌溶清，滴加入硼烷四氢呋喃溶液(8mL，8.0mmol，1M)，氮气氛下升温到回流并保温搅拌反应4小时。冷却到室温，减压蒸除溶剂，残留物过硅胶柱得白色固体460mg，收率为37.8％。LC-MS(APCI):m/z＝460.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):10.77(s,1H),8.55-8.52(m,1H),8.19(d,J＝8.8Hz,1H),8.02(s,1H),7.53(t,J＝8.0Hz,1H),7.42(s,1H),7.29-7.25(m,1H),7.16-7.14(m,1H),6.79-6.77(m,2H),3.89(s,3H),3.18-3.15(m,2H),3.05-3.02(m,1H),1.84(d,J＝1.6Hz,3H),1.80(d,J＝1.6Hz,3H),1.36(d,J＝6.4Hz,3H).
实施例17和实施例18(2-((5-氯-2-((4-(1-(二甲基氨基)丙烷-2-基)-2-甲氧基苯基)氨基)嘧啶-4-基) 氨基)苯基)二甲基氧化膦(化合物T-17)和(2-((5-氯-2-((2-甲氧基-4-(1-(甲基氨基)丙烷-2-基)苯基)氨 基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(化合物T-18)的制备。
Figure PCTCN2018120618-appb-000047
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000048
向配有磁力搅拌的50mL单口瓶中加入化合物T-16(300mg，0.65mmol)和甲醇(10mL)，搅拌溶清，加入甲醛(15mg，0.5mmol)和冰醋酸(1滴)，氮气氛下搅拌反应10分钟。冷却到0℃，加入NaBH 3CN(42mg，0.65mmol)，反应混合物室温下搅拌反应1小时。加入水(20mL)淬灭反应，二氯甲烷萃取(20mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得T-17，白色固体150mg，收率为30.0％。LC-MS(APCI):m/z＝488.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):10.85(s,1H),8.60-8.58(m,1H),8.34(d,J＝8.4Hz,1H),8.13(s,1H),7.56(t,J＝8.0Hz,1H),7.52(s,1H),7.35-7.29(m,1H),7.21-7.16(m,1H),6.87(s,1H),6.82-6.79(m,1H),3.94(s,3H),3.37-3.32(m,1H),3.10-3.02(m,1H),2.96-2.94(m,1H),2.59(s,6H),1.87(s,3H),1.84(s,3H),1.41(d,J＝6.4Hz,3H)；
以及残留物过硅胶柱得T-18为白色固体50mg，收率15.0％。LC-MS(APCI):m/z＝474.2(M+1) +.1H NMR(400MHz,CDCl 3)δ(ppm):10.85(s,1H),8.60-8.58(m,1H),8.34(d,J＝8.4Hz,1H),8.13(s,1H),7.56(t,J＝8.0Hz,1H),7.52(s,1H),7.35-7.29(m,1H),7.21-7.16(m,1H),6.87(s,1H),6.82-6.79(m,1H),3.94(s,3H),3.37-3.32(m,1H),3.10-3.02(m,1H),2.96-2.94(m,1H),2.59(s,3H),1.87(s,3H),1.84(s,3H),1.41(d,J＝6.4Hz,3H).
实施例19(2-((2-((4-(2-氨基乙基)-2-甲氧基-5-甲基苯基)氨基)-5-氯嘧啶-4-基)氨基)苯基)二甲基 氧化膦(化合物T-19)的制备。
Figure PCTCN2018120618-appb-000049
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000050
步骤1 化合物34的合成
向配有磁力搅拌的50mL单口瓶中加入NaOH(2.7g，67.1mmol)和DMSO(10mL)，冷却到0℃，滴加入化合物32(1.12g，6.71mmol)和化合物33(1.0g，6.71mmol)的DMSO(10mL)，滴毕，反应混合物氮气氛下继续搅拌反应2小时。加入水(50mL)淬灭反应，乙酸乙酯萃取(40mLx3)，水洗(60mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱白色固体1.3g，收率为94.2％。LC-MS(APCI):m/z＝207.1(M+1) +.
步骤2 化合物35的合成
向配有磁力搅拌和冷凝管的100mL单口瓶中加入化合物34(3.1g，14.9mmol)和乙醇/水(60mL，3/1)，搅拌溶清，加入还原铁粉(70.5mmol，3.2g)和氯化铵(14.9mmol，790mg)，氮气氛下升温回流并保温反应1小时。冷却到室温，过滤，乙醇(10mL)洗涤滤饼，浓缩去除有机溶剂，二氯甲烷萃取(50mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩得棕色固体2.4g，收率91.5％。LC-MS(APCI):m/z＝177.1(M+1) +.
步骤3 化合物36的合成
向配有磁力搅拌跟冷凝管的50mL单口瓶中加入化合物35(1.4g，7.9mmol)、化合物7(2.5g，7.9mmol)和乙二醇单甲醚(15mL)，搅拌溶清，滴加入氯化氢的异丙醇溶液(11.8mmol，2.4mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(30mL)和饱和碳酸氢钠(30mL)，二氯甲烷萃取(40mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体1.2g，收率为33.4％。LC-MS(APCI):m/z＝456.1(M+1) +.
步骤4 化合物T-19的合成
向配有磁力搅拌跟冷凝管的50mL单口瓶中加入化合物31(1.2g，2.64mmol)和THF(10mL)，搅拌溶清，滴加入硼烷四氢呋喃溶液(8mL，8.0mmol，1M)，氮气氛下升温到回流并保温搅拌反 应4小时。冷却到室温，减压蒸除溶剂，残留物过硅胶柱得白色固体460mg，收率为37.8％。LC-MS(APCI):m/z＝460.2(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ(ppm):8.47-8.44(m,1H),8.14(s,1H),8.04(s,1H),7.60-7.55(m,2H),7.41(t,J＝8.0Hz,1H),7.16-7.13(m,2H),6.86(s,1H),3.80(s,3H),2.94(t,J＝8.4Hz,2H),2.81(t,J＝8.4Hz,2H),2.17(s,3H),1.79(s,3H),1.76(s,3H).
实施例20和实施例21(2-((5-氯-2-((4-(2-(二甲基氨基)乙基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4- 基)氨基)苯基)二甲基氧化膦(化合物T-20)和(2-((5-氯-2-((2-甲氧基-5-甲基-4-(2-(甲基氨基)乙基)苯基) 氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(化合物T-21)的制备。
Figure PCTCN2018120618-appb-000051
采用以下路线进行合成：
Figure PCTCN2018120618-appb-000052
向配有磁力搅拌的50mL单口瓶中加入化合物T-19(300mg，0.65mmol)和甲醇(10mL)，搅拌溶清，加入甲醛(15mg，0.5mmol)和冰醋酸(1滴)，氮气氛下搅拌反应10分钟。冷却到0℃，加入NaBH 3CN(42mg，0.65mmol)，反应混合物室温下搅拌反应1小时。加入水(20mL)淬灭反应，二氯甲烷萃取(20mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得T-20，白色固体150mg，收率为30.0％。LC-MS(APCI):m/z＝488.2(M+1) +. 1H NMR(400MHz,CDCl3)δ(ppm):10.79(s,1H),8.59-8.56(m,1H),8.09-8.08(m,2H),7.48(t,J＝8.0Hz,1H),7.43(s,1H),7.30-7.27(m,1H),7.14-7.10(m,1H),6.68(s,1H),6.82-6.79(m,1H),3.84(s,3H),2.98-2.94(m,2H),2.80-2.73(m,2H),2.58(s,6H),2.20(s,3H),1.83(s,3H),1.81(s,3H)；
以及残留物过硅胶柱得T-21为白色固体50mg，收率15.0％。LC-MS(APCI):m/z＝474.2(M+1) +.10.76(s,1H),8.59-8.56(m,1H),8.09-8.08(m,2H),7.48(t,J＝8.0Hz,1H),7.43(s,1H),7.30-7.27(m,1H), 7.14-7.10(m,1H),6.68(s,1H),6.82-6.79(m,1H),3.84(s,3H),2.98-2.94(m,2H),2.80-2.73(m,2H),2.55(s,3H),2.20(s,3H),1.83(s,3H),1.81(s,3H).
实施例22化合物的生物评价。
对本发明的化合物在多个测试中进行评价以确定它们的生物学活性。例如，可测试本发明化合物抑制多种关注的蛋白激酶的能力。一些测试的化合物对ALK激酶显示出强效的抑制活性。
(1)激酶抑制作用评价
化合物配制：受试化合物溶于DMSO配成20mM母液。使用前将化合物在DMSO中稀释成0.1mM(100倍终浓度的稀释液)，并做3倍梯度稀释，11个浓度。加药时用缓冲液稀释成4倍终浓度的稀释液。
激酶检测：配制缓冲液后，将酶与预先稀释配制的不同浓度化合物混合，室温放置30分钟，每个浓度双复孔。加入对应底物及ATP，室温反应60分钟(其中设置阴阳性对照)。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。根据XLfit5软件进行数据分析及拟图。通过该公式(IC50＝[(ABS测试-ABS开始)/(ABS对照-ABS开始)]x 100)计算IC 50值。其中A表示IC 50≤2nM，B表示IC 50为2-5nM，C表示IC 50为5-10nM。
在上述激酶抑制实验中测试了本发明化合物，发现本发明化合物对ALK和ALK[L1196M]具有强效的活性。代表性实施例化合物的结果归纳于如下表1中。
表1：
Figure PCTCN2018120618-appb-000053
Figure PCTCN2018120618-appb-000054
(2)细胞毒性实验
采用CellTiter-Glo方法检测了本发明化合物对体外培养的3株细胞的体外抗增殖活性。实验结果表明本发明化合物对体外培养的EML4-ALK及EML4-ALK L1196M突变细胞的体外增殖具有很强的抑制作用。
细胞系：BaF3parental；BaF3[EML4-ALK](来自药明康德)和BaF3[EML4-ALK L1196M](来自药明康德)；其中，BaF3parental用含10ng/ml IL-3、0％胎牛血清、100U/ml青霉素、100μg/ml链霉素的RPMI1640培养基培养，BaF3[EML4-ALK]和BaF3[EML4-ALK L1196M]用含10％胎牛血清、100U/ml青霉素、100μg/ml链霉素的RPMI1640培养基培养。
试剂和耗材：RPMI-1640(GIBCO,目录号A10491-01)；胎牛血清(GIBCO,目录号10099141)；0.25％胰蛋白酶-EDTA(GIBCO,目录号25200)；青霉素-链霉素,液体(GIBCO,目录号15140-122)；DMSO(Sigma,目录号D2650)；CellTiter-Glo测试试剂盒(Promega，目录号G7572)，96孔板(Corning,目录号3365)。
具体实验方法：
1、用DMSO溶解被受试化合物溶解形成储存液并进行梯度稀释，得到10倍工作浓度溶液。
2、将处于对数生长期的细胞用培养液稀释调整至特定细胞浓度，添加90μl细胞悬液至96孔板中，使细胞密度达到指定的浓度。置于37℃、5％二氧化碳气体培养箱中培养过夜。
3、在已接种细胞的96孔板中每孔加入10μl药物溶液。被测化合物最高浓度为20μM，10个浓度，3倍梯度稀释，双复孔。
4、细胞继续培养72小时后，CellTiter-Glo检测细胞活力。用GraphPad Prism软件制作量效曲线并计算IC 50。
在上述细胞毒性实验中测试了本发明化合物，发现本发明化合物对Ba/F3ALK和Ba/F3 ALK[L1196M]具有强效的活性以及优于细胞Ba/F3parental的优异选择性。代表性实施例对癌细胞的体外增殖的抑制作用的结果归纳于下表2中，其中A表示IC 50≤25nM，B表示IC 50为25-50nM，C表示IC 50为50-100nM，D表示IC 50为100-200nM，E表示IC 50为200-1000nM，并且E表示IC 50≥1000nM。
表2
Figure PCTCN2018120618-appb-000055
(3)代谢稳定性评价
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；大鼠肝微粒体：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的实施例化合物的粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH7.4)的配制：取预先配好的150mL的0.5M磷酸二氢钾和700mL的 0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。
配制NADPH再生***溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸***和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL SD大鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体或者大鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生***置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生***溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生***溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS***检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t 1/2和CL int，其中V/M即等于1/蛋白浓度。
Figure PCTCN2018120618-appb-000056
对本发明化合物，评价其在人和大鼠肝微粒体的代谢稳定性。作为代谢稳定性的指标的半衰期及肝固有清除率如下表3所示。本发明化合物可以明显改善代谢稳定性。
表3
Figure PCTCN2018120618-appb-000057
Figure PCTCN2018120618-appb-000058
(4)大鼠药代动力学实验
6只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组3只，经静脉或口服单个剂量的化合物(口服10mg/kg)，比较其药代动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入***后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL 1％肝素盐溶液。使用前，试管于60℃烘干过夜。在最后一个时间点血样采集完成之后，大鼠***麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
实验表明，本发明化合物在动物体内具有更好的药代动力学性质，因此具有更好的药效学和治理效果。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (13)

  1. 式(I)所示化合物，
    Figure PCTCN2018120618-appb-100001
    其中，
    R 1和R 2独立地选自H、卤素、-CN、-NO 2、-OH、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 1和R 2与它们相连的原子可形成稠合的5～7元环；
    连接基W选自
    1)C 1-C 6亚烷基、C 1-C 6亚烯基、C 1-C 6亚炔基、C 3-C 8亚碳环基、3至10元亚杂环基、C 6-C 14芳基或5至10元杂芳基；其中W与苯环所连接的原子必须为C；其中所述基团任选被一个或多个R 3取代；
    2)-C(＝O)-、-C(＝O)O-、-C(＝O)N(R 4)-；
    R 3选自H、卤素、-CN、-NO 2、氧代基、C 1-C 6烷基、C 1-C 6卤代烷基或C 1-C 6烷氧基；
    R 4选自H、C 1-C 6烷基或C 1-C 6卤代烷基；
    R 5和R 6独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的3至10元杂环基；
    R 7选自任选取代的C 1-C 6烷氧基、任选取代的C 1-C 6卤代烷氧基、任选取代的C 2-C 6烯基氧基或任选取代的3～7元环烷基氧基；
    R 8选自H、卤素、-R、-CN、-NO 2、-OH、-SH、-C(＝O)R、-C(＝O)OR、-C(＝O)NRR、-NR 2、-NRC(＝O)R、-NRC(＝O)OR、-NRC(＝O)NRR、-NRS(＝O)R、-NRS(＝O)NRR、-NRS(＝O) 2R、-NRS(＝O) 2NRR、-OR、-OC(＝O)R、-OC(＝O)NRR、-S(＝O)R、-S(＝O)OR、-S(＝O)NRR、-S(＝O) 2R、-S(＝O) 2OR、-S(＝O) 2NRR、-SC(＝O)R、-SC(＝O)OR或-SC(＝O)NRR，只要化学允许；其中R独立地为H、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烯基、C 1-C 6炔基、C 3-C 10碳环基、3至10元杂环基、C 6-C 14芳基或5至10元杂芳基；两个相邻的R可一起形成任选取代的C 3-C 10碳环基、任选取代的5至8元杂环基、任选取代的C 6-C 14芳基或任选取代的5至10杂芳基；
    或其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物。
  2. 根据权利要求1所述的化合物，其中
    R 1选自H、卤素、-CN、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；优选地，R 1选自H、F、Cl、Br、甲基、乙基、异丙基、-CH 2F、-CHF 2、甲氧基、异丙氧基、环丙基或环氧乙烷基；更优选地，R 1选自H、F、Cl、甲基、异丙基或环丙基；更优选地R 1选自Cl；
    R 2选自H、卤素、-CN、-NO 2、-OH、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基；优选地，R 2选自H、F、Cl、Br、-CN、-NO 2、-OH或甲基；更优选地，R 2选自H；
    或者，R 1和R 2与和它们相连的碳原子可形成稠合的5～7元芳基环，其含有0～2个选自N、O和S的杂原子；优选地，R 1和R 2与和它们相连的碳原子可形成稠合的5元芳基环，其含有0～2个选自N和S的杂原子。
  3. 根据权利要求2所述的化合物，其选自下式化合物：
    Figure PCTCN2018120618-appb-100002
    Figure PCTCN2018120618-appb-100003
    其中，
    W选自C 1-C 6亚烷基、C 3-C 10亚碳环基、3至10元亚杂环基，其W与苯环所连接的原子必须为C；其所述基团任选被一个或多个R 3取代；
    R 3选自H、C 1-C 6烷基、C 1-C 6卤代烷基或C 1-6烷氧基；
    R 5和R 6独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 1-C 6卤代烷基、任选取代的C 1-C 6烷氧基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的3至10元杂环基；
    R 7选自任选取代的C 1-C 6烷氧基、任选取代的C 1-C 6卤代烷氧基或任选取代的3～7元环烷基氧基；
    R 8选自H、卤素或C 1-C 6烷基；
    或其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物。
  4. 根据权利要求1-3中任一项所述的化合物，其中W选自-CH 2-、-CH 2CH 2-、-C(CH 3)H-、-C(CH 3) 2-、-C(CH 3)HCH 2-、-C(CH 3) 2CH 2-、-C(CH 3)HC(CH 3)H-、-C(CH 3) 2C(CH 3) 2-、
    Figure PCTCN2018120618-appb-100004
    Figure PCTCN2018120618-appb-100005
    其*表示与苯环相连，#表示与N原子相连。
  5. 根据权利要求1-4中任一项所述的化合物，其中
    R 5和R 6独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 3-C 10碳环基或任选取代的3至10元杂环基；或者R 5和R 6与它们相连的氮原子一起形成任选取代的3至10元杂环基。
  6. 根据权利要求1-5中任一项所述的化合物，其中
    -W-NR 5R 6选自：
    Figure PCTCN2018120618-appb-100006
    Figure PCTCN2018120618-appb-100007
    优选地，-W-NR 5R 6选自：
    Figure PCTCN2018120618-appb-100008
  7. 根据权利要求1-6中任一项所述的化合物，其中R 7选自-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2、-OCF 3、-OCHF 2、-OCH 2F或-OCH 2CF 3；优选地，R 7选自-OCH 3、-OCH(CH 3) 2或-OCH 2CF 3；优选地，R 7选自-OCH 3。
  8. 根据权利要求1-7中任一项所述的化合物，其中R 8选自H或C 1-C 6烷基；
    优选地，优选地，R 8选自H或甲基。
  9. 根据权利要求1所述的化合物，其所述的化合物选自：
    Figure PCTCN2018120618-appb-100009
    Figure PCTCN2018120618-appb-100010
    或其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物。
  10. 药物组合物，其含有权利要求1-9中任一项所述的化合物或其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物，和药学上可接受的赋形剂。
  11. 一种如权利要求1-9中任一项所述的化合物或其药学上可接受的盐、晶型、前药、代谢物、水合物、溶剂合物、立体异构体或同位素衍生物，或权利要求10中的药物组合物在制备用于治疗ALK介导的癌症相关病症的药物中的用途。
  12. 根据权利要求11所述的用途，其中所述的癌症选自非小细胞肺癌、乳腺癌、神经肿瘤、食道癌、软组织癌、淋巴瘤或白血病。
  13. 根据权利要求12所述的用途，其中所述的非小细胞肺癌为ALK阳性的非小细胞肺癌；其中所述的淋巴瘤为间变性大细胞淋巴瘤。
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