WO2022012484A1 - 作为atr激酶抑制剂的吡唑并嘧啶化合物 - Google Patents

作为atr激酶抑制剂的吡唑并嘧啶化合物 Download PDF

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WO2022012484A1
WO2022012484A1 PCT/CN2021/105867 CN2021105867W WO2022012484A1 WO 2022012484 A1 WO2022012484 A1 WO 2022012484A1 CN 2021105867 W CN2021105867 W CN 2021105867W WO 2022012484 A1 WO2022012484 A1 WO 2022012484A1
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compound
alkyl
pharmaceutically acceptable
diastereomer
enantiomer
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PCT/CN2021/105867
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English (en)
French (fr)
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郑翔玲
赵焰平
王红军
刘彬
仲伟婷
徐慧芬
黄闯闯
李晶
刘伟娜
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北京泰德制药股份有限公司
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Priority to CA3185963A priority Critical patent/CA3185963A1/en
Priority to BR112023000654A priority patent/BR112023000654A2/pt
Priority to MX2023000577A priority patent/MX2023000577A/es
Priority to IL299804A priority patent/IL299804A/en
Priority to KR1020237004201A priority patent/KR20230039675A/ko
Priority to EP21843562.6A priority patent/EP4166556A1/en
Priority to US18/016,164 priority patent/US20230271968A1/en
Priority to AU2021310000A priority patent/AU2021310000A1/en
Priority to JP2023501863A priority patent/JP2023534676A/ja
Priority to CN202180048970.7A priority patent/CN115943145A/zh
Publication of WO2022012484A1 publication Critical patent/WO2022012484A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to pyrazolopyrimidine compounds that are inhibitors of ATR kinases. More specifically, the compounds of the present invention are useful in the treatment of ATR kinase mediated diseases such as proliferative diseases such as cancer. The present invention also provides pharmaceutical compositions of the compounds, their use for treating ATR kinase-mediated diseases, and their preparation.
  • ATR Alzheimer's disease telangiectasia and Rad3-related protein
  • ATR is a class of protein kinases involved in genome stability and DNA damage repair, and is a member of the PIKK family. Activation of ATR can be activated by stalled replication forks or by DNA single-strand damage (SSB). The activated ATR will recruit repair proteins or repair factors to repair the damaged site, delay the mitotic process (especially in the G2/M phase of mitosis), and stabilize the replication fork and ensure the stability of the genome.
  • SSB DNA single-strand damage
  • inhibition of ATR can be used in combination with radiotherapy or chemotherapeutic drugs to synergistically enhance the effect.
  • Widely used chemotherapy drugs include antimetabolites (eg, gemcitabine), DNA cross-linking agents (eg, cisplatin, carboplatin), alkylating agents (eg, temozolomide), topoisomerase inhibitors (eg, topotecan, irinotecan) )Wait.
  • antimetabolites eg, gemcitabine
  • DNA cross-linking agents eg, cisplatin, carboplatin
  • alkylating agents eg, temozolomide
  • topoisomerase inhibitors eg, topotecan, irinotecan
  • the present invention provides compounds of general formula (I) which are useful in the treatment of ATR kinase mediated diseases such as proliferative diseases such as cancer.
  • the present invention provides a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • X is CR X or N
  • Y is CR Y or N
  • R 1 , R 2 , R 3 , R 4 and R Y are independently selected from H, D, halogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R 1 and R 2 , R 3 and R 4 are connected to form a bond, C 1-6 alkylene group, C 2-6 alkenylene group or C 2-6 alkynylene group; wherein the group may be substituted by one or more D or halogen , until it is completely replaced;
  • R X is H, D, halogen, -CN, -NRR', -OR, -SR or C 1-6 alkyl, wherein the group may be substituted with one or more D or halogen, up to complete substitution;
  • Y is CR Y wherein R & lt Y, R 1 form together with the atom to which they C 3-5 cycloalkyl, or 3-5 membered heterocyclyl, wherein said group may be substituted with one or more halo or D replace until fully replaced;
  • Ring A is a C 3-7 cycloalkyl group, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group; A is absent or a cycloalkyl, and R a L a so connected; or ( R a ) m -ring AL- does not exist;
  • R a is independently selected from optionally substituted with R * is H, D, halo, -CN, -NRR ', - OR , -SR, -C (O) R, -C (O) OR, -C (O )NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, or 3-8 membered heterocyclyl, wherein the group may be substituted with one or more D or halogen until fully substituted ;
  • n 0, 1, 2, 3, 4 or 5;
  • Ring B is a 5-6 membered heteroaryl
  • R b is independently selected from H, D, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O optionally substituted with R* )NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, or 3-8 membered heterocyclyl, wherein the group may be substituted with one or more D or halogen until fully substituted ;
  • n 0, 1, 2, 3, 4 or 5;
  • Ring C is C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • L is a bond, -O-, -S-, -N(R)-, -C(O)-, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R 5 is H, D, halogen, -CN, -NRR', -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein the group may be One or more D or halogen substitutions up to complete substitution;
  • R 6 is H, D, halogen, -CN, -NRR', -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein the group may be One or more D or halogen substitutions up to complete substitution;
  • R* is H, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6 -10 aryl or 5-10 membered heteroaryl, wherein said group may be substituted with one or more D or halogen, up to full substitution;
  • R and R' are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R, R' and the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl group ; wherein the group may be substituted by one or more D or halogen up to complete substitution;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.
  • the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient, which also contain other therapeutic agents.
  • kits comprising a compound of the present invention, and other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment and/or prevention of ATR kinase mediated diseases.
  • the present invention provides a method of treating and/or preventing an ATR kinase mediated disease in a subject comprising administering to the subject a compound of the present invention or a composition of the present invention.
  • the present invention provides compounds of the present invention or compositions of the present invention for use in the treatment and/or prevention of ATR kinase mediated diseases.
  • the diseases include proliferative diseases (eg, cancer), especially solid tumors (eg, carcinomas and sarcomas) and leukemias and lymphomas, especially for eg breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate cancer and bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophagus cancer, ovarian cancer, pancreatic cancer, skin cancer, Testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, and leukemia [including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), etc.], multiple Myeloma and lymphoma.
  • proliferative diseases eg, cancer
  • solid tumors eg, carcinomas and sarcomas
  • leukemias and lymphomas especially for
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2, C 2-6, C 2-5, C 2-4, C 2-3, C 3-6, C 3-5, C 3-4, C 4-6, C 4-5 and C 5 -6 alkyl.
  • C 1-6 alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl groups are preferred. Examples of C 1-6 alkyl groups include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl base (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 ).
  • C 1-6 alkyl also includes heteroalkyl groups in which one or more (eg, 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkyl group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • Conventional abbreviations group comprising: Me (-CH 3), Et (-CH 2 CH 3), iPr (-CH (CH 3) 2), nPr (-CH 2 CH 2 CH 3), n-Bu (-CH 2 CH 2 CH 2 CH 3), or i-Bu (-CH 2 CH ( CH 3) 2).
  • C 2-6 alkenyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl groups are preferred. Examples of C 2-6 alkenyl groups include: vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • C 2-6 alkenyl also includes heteroalkenyl groups in which one or more (eg, 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkenyl group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-6 alkynyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl group are preferred. Examples of C 2-6 alkynyl groups 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 ), hexynyl (C 6 ), and the like.
  • C 2-6 alkynyl also includes heteroalkynyl groups in which one or more (eg, 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkynyl group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene refers to "C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkenyl” as defined above alkynyl" divalent group.
  • C 1-6 alkylene group refers to a divalent group formed by removing another hydrogen of a C 1-6 alkyl group, and may be a substituted or unsubstituted alkylene group. In some embodiments, C 1-4 alkylene groups are particularly preferred. Unsubstituted alkylene groups include, but the are not limited to: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 - ), butylene base (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -) ,etc.
  • substituted alkylene group e.g., substituted with one or more alkyl (meth) the alkylene group, including but not limited to: substituted methylene (-CH (CH 3) - , -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- ), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 ) -, - C (CH 3) 2 CH 2 CH 2 -, - CH 2 C (CH 3) 2 CH 2 -, - CH 2 CH 2 C (CH 3) 2 -), and the like.
  • substituted methylene -CH (CH 3) - , -C(CH 3 ) 2 -
  • C 2-6 alkynylene refers to a divalent group formed by removing another hydrogen of a C 2-6 alkynyl group, and may be a substituted or unsubstituted alkynylene group. In some embodiments, C 2-4 alkynylene groups are particularly preferred. Exemplary of the alkylene groups include, but are not limited to alkynyl: ethynylene (-C ⁇ C-), a substituted or unsubstituted alkylene group propynyl (-C ⁇ CCH 2 -), and the like.
  • C 1-6 alkoxy refers to the group -OR, wherein R is a substituted or unsubstituted C 1-6 alkyl group. In some embodiments, C 1-4 alkoxy is particularly preferred.
  • the specific alkoxy groups include but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy and 1,2-dimethylbutoxy.
  • An alkoxy group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • Halo or "halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • C 1-6 haloalkyl and “C 1-6 haloalkoxy” refer to the above-mentioned “C 1-6 alkyl” and “C 1-6 alkoxy", which are replaced by one or more halo groups group replaced.
  • C 1-4 haloalkyl is particularly preferred, more preferably C 1-2 haloalkyl.
  • C 1-4 haloalkoxy is particularly preferred, more preferably C 1-2 haloalkoxy.
  • 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 the are not limited to: -OCH 2 F, -OCHF 2, -OCF 3, and the like.
  • the haloalkyl and haloalkoxy groups can be substituted at any available point of attachment, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 3-7 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C3-5cycloalkyl is preferred. In other embodiments, C3-6cycloalkyl is preferred. In other embodiments, C5-6cycloalkyl is preferred. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to indicate The number of carbons in a cycloalkyl system.
  • cycloalkyl 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 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), and the like.
  • a cycloalkyl group may be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 3-11 membered heterocyclyl refers to a group of 3 to 11 membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, Sulfur, Boron, Phosphorus and Silicon.
  • the point of attachment may be a carbon or nitrogen atom as valence allows.
  • 3-9 membered heterocyclyl which is a 3- to 9-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms
  • 3-8 membered Heterocyclyl which is a 3- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms
  • a 3-6 membered heterocyclyl which is a ring carbon atom and 1 to 3 ring heteroatoms
  • preferably a 3-5 membered heterocyclic group which is a 3- to 5-membered non-aromatic ring system having ring carbon atoms and 1 to 2 ring heteroatoms
  • preferably a 4-8 membered heterocyclic group A cyclic group, which is a 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1
  • Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl ring is fused with one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or wherein the aforementioned heterocyclyl ring is fused with one or more aryl or Heteroaryl-fused ring systems wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to mean the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridine, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-diketone.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxa oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiahexyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclyl groups) fused to a C6 aryl ring include, but are not limited to: indoline, isoindolyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like.
  • Exemplary of the C 6 aryl ring fused to the 6-membered heterocyclic group include but are not limited to: tetrahydroquinolinyl, tetrahydro- isoquinolinyl, etc.
  • a heterocyclyl group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 6-10 aryl refers to a monocyclic or polycyclic (eg, bicyclic) 4n+2 aromatic ring system (eg, having a cyclic arrangement of 6-10 ring carbon atoms and zero heteroatoms) shared 6 or 10 pi electrons).
  • an aryl group having six ring carbon atoms ( "C 6 aryl”; e.g., phenyl).
  • aryl groups have ten ring carbon atoms (" C10 aryl”; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • Aryl also includes ring systems in which the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system.
  • An aryl group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 5-10 membered heteroaryl refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (eg, with 6 or 10 pi electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • the point of attachment may be a carbon or nitrogen atom as valence allows.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the carbon atom is The numbers continue to indicate the number of carbon atoms in the heteroaryl ring system.
  • 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom 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 (eg, 1,2,4-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 heteroatom 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 heteroatom include, but are not limited to, azacyclotrienyl, oxeptrienyl, and thiacyclotrienyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indanyl and purine groups.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • Heteroaryl groups can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • heteroaryl groups include: pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl ( 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyranyl, 2-furanyl, 3-furan, etc., 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl azolyl, thiazolyl, thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl).
  • Carbonyl whether used alone or in combination with other terms (eg, aminocarbonyl), is represented as -C(O)-.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, and the like, as defined herein, are optionally substituted groups.
  • Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or Heteroaryl rings in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R dd groups group replacement;
  • Each of Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two Rcc groups are combined to form a heterocycle yl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R dd group substitution;
  • R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon cyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;
  • Each of Rff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two Rff groups are combined to form a heterocyclyl group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently separated by 0, 1, 2, 3, 4, or 5 R gg group substitution;
  • cancer includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lips, Cancers of tongue, oral cavity, pharynx, small intestine, colorectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, Adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, hair cell carcinoma and leukemia.
  • treating refers to reversing, alleviating, inhibiting the progression or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the action of the verb treat, as just defined.
  • the term "pharmaceutically acceptable salts” refers to those carboxylates, amino acid addition salts of the compounds of the present invention which are suitable, within the scope of sound medical judgment, for use in contact with patient tissue without undue toxicity, Irritations, allergies, etc., commensurate with a reasonable benefit/risk ratio, are effective for their intended use, including (where possible) the zwitterionic forms of the compounds of the present invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
  • Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt.
  • the free acid can be regenerated by contacting the salt form with the acid in a conventional manner and isolating the free acid.
  • the free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the salts are nevertheless equivalent to their respective free acids.
  • Salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates prepared from inorganic acids Salts, chlorides, bromides, iodides, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like.
  • Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, lauryl acid salt, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, Mesylate, glucoheptonate, lactobionate, lauryl sulfonate and isethionate, etc.
  • Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, horse Acetate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, tosylate, phenylethyl acid salt, citrate, lactate, maleate, tartrate, mesylate, etc.
  • Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal based cations, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also encompassed are salts of amino acids, such as arginine, gluconate, galacturonate, etc. (see, eg, Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1- 19, incorporated herein by reference).
  • examples of amides include those derived from C l -C 6 alkyl esters wherein the alkyl group is a straight-chain or branched. Acceptable esters also include C 5 -C 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl ester. C 1 -C 4 alkyl esters are preferred. Esters of compounds of the present invention can be prepared according to conventional methods, eg: March's Advanced Organic Chemistry, 5 Edition" MB Smith & J. March, John Wiley & Sons, 2001.
  • non-toxic amides include those derived from ammonia, primary C 1 -C 6 alkyl amines and secondary C 1 -C 6 dialkyl amines amides, wherein alkyl is straight-chain or branched chain.
  • the amine may also be in the form of a 5- or 6-membered heterocyclic ring containing one nitrogen atom.
  • C 1 -C 3 alkyl primary amines and C 1 -C 2 dialkyl secondary amides are preferred amines.
  • Amides of the compounds of the present invention can be prepared according to conventional methods, eg: March's Advanced Organic Chemistry, 5 Edition", MB Smith & J. March, John Wiley & Sons, 2001.
  • Subjects for administration include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and/or non-human animals, eg, mammals, eg, primates (eg, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human", “patient” and “subject” are used interchangeably herein.
  • treatment includes the effect that occurs when a subject has a particular disease, disorder or condition, which reduces the severity of, or delays or slows down, the disease, disorder or condition or development of a disorder ("therapeutic treatment”), and also includes effects that occur before a subject begins to suffer from a particular disease, disorder or condition ("prophylactic treatment").
  • an "effective amount" of a compound refers to an amount sufficient to elicit a target biological response.
  • the effective amount of a compound of the present invention may vary depending on factors such as, for example, the biological objective, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the subject's Age health conditions and symptoms.
  • An effective amount includes a therapeutically effective amount and a prophylactically effective amount.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or cause one or more symptoms associated with the disease, disorder or condition The amount of delay or minimization.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent, 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 disorder, or enhances the therapeutic effect of other therapeutic agents.
  • a prophylactically effective amount of a compound as used herein is an amount sufficient to prevent a disease, disorder or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease , the amount of recurrence of the disorder or condition.
  • a prophylactically effective amount of a compound refers to that amount of a therapeutic agent, 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 overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.
  • Combination and related terms refer to the simultaneous or sequential administration of a compound of the present invention and another therapeutic agent.
  • the compounds of the present invention may be administered concurrently or sequentially with other therapeutic agents in separate unit dosage forms, or concurrently with other therapeutic agents in a single unit dosage form.
  • compounds of the present invention refers to the following compounds of formula (I) to formula (III) (including sub-formulae such as (I-1), (II-2), (III-3), etc.), Pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof.
  • the present invention relates to compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates thereof , polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • X is CR X or N
  • Y is CR Y or N
  • R 1 , R 2 , R 3 , R 4 and R Y are independently selected from H, D, halogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R 1 and R 2 , R 3 and R 4 are connected to form a bond, C 1-6 alkylene group, C 2-6 alkenylene group or C 2-6 alkynylene group; wherein the group may be substituted by one or more D or halogen , until it is completely replaced;
  • R X is H, D, halogen, -CN, -NRR', -OR, -SR or C 1-6 alkyl, wherein the group may be substituted with one or more D or halogen, up to complete substitution;
  • Y is CR Y wherein R & lt Y, R 1 form together with the atom to which they C 3-5 cycloalkyl, or 3-5 membered heterocyclyl, wherein said group may be substituted with one or more halo or D replace until fully replaced;
  • Ring A is a C 3-7 cycloalkyl group, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group; A is absent or a cycloalkyl, and R a L a so connected; or ( R a ) m -ring AL- does not exist;
  • R a is independently selected from optionally substituted with R * is H, D, halo, -CN, -NRR ', - OR , -SR, -C (O) R, -C (O) OR, -C (O )NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, or 3-8 membered heterocyclyl, wherein the group may be substituted with one or more D or halogen until fully substituted ;
  • n 0, 1, 2, 3, 4 or 5;
  • Ring B is a 5-6 membered heteroaryl
  • R b is independently selected from H, D, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O optionally substituted with R* )NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, or 3-8 membered heterocyclyl, wherein the group may be substituted with one or more D or halogen until fully substituted ;
  • n 0, 1, 2, 3, 4 or 5;
  • Ring C is C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • L is a bond, -O-, -S-, -N(R)-, -C(O)-, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • R 5 is H, D, halogen, -CN, -NRR', -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein the group may be One or more D or halogen substitutions up to complete substitution;
  • R 6 is H, D, halogen, -CN, -NRR', -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein the group may be One or more D or halogen substitutions up to complete substitution;
  • R* is H, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6 -10 aryl or 5-10 membered heteroaryl, wherein said group may be substituted with one or more D or halogen, up to full substitution;
  • R and R' are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R, R' and the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl group ; wherein the group may be substituted by one or more D or halogen up to complete substitution;
  • X is CR X; In another embodiment, X is CH; In another embodiment, X is N.
  • Y is CR Y; In another embodiment, Y is N.
  • R 1 is H; in another specific embodiment, R 1 is D; in another specific embodiment, R 1 is halogen; in another specific embodiment, R 1 is C 1-6 alkyl, such as (R)-C 1-6 alkyl, such as (R)-methyl; in another specific embodiment, R 1 is C 1-6 haloalkyl, such as (R)-C 1-6 haloalkyl; in another specific embodiment, R 1 is C 2-6 alkenyl; in another specific embodiment, R 1 is C 2-6 alkynyl.
  • R 2 is H; in another specific embodiment, R 2 is D; in another specific embodiment, R 2 is halogen; in another specific embodiment, R 2 is C 1-6 alkyl, such as (R)-C 1-6 alkyl, such as (R)-methyl; in another specific embodiment, R 2 is C 1-6 haloalkyl, such as (R)-C 1-6 haloalkyl; in another specific embodiment, R 2 is C 2-6 alkenyl; in another specific embodiment, R 2 is C 2-6 alkynyl.
  • R 3 is H; In another embodiment, R 3 is D; In another embodiment, R 3 is a halogen; In another embodiment, R 3 is C 1-6 alkyl, such as (R)-C 1-6 alkyl, such as (R)-methyl; in another specific embodiment, R 3 is C 1-6 haloalkyl, such as (R)-C 1-6 haloalkyl; in another specific embodiment, R 3 is C 2-6 alkenyl; in another specific embodiment, R 3 is C 2-6 alkynyl.
  • R 4 is H; In another particular embodiment, R 4 is D; In another particular embodiment, R 4 is a halogen; In another particular embodiment, R 4 is a C 1-6 alkyl, such as (R)-C 1-6 alkyl, such as (R)-methyl; in another specific embodiment, R 4 is C 1-6 haloalkyl, such as (R)-C 1-6 haloalkyl; in another specific embodiment, R 4 is C 2-6 alkenyl; in another specific embodiment, R 4 is C 2-6 alkynyl.
  • RY is H; in another specific embodiment, RY is D; in another specific embodiment, RY is halogen; in another specific embodiment, RY is C 1-6 alkyl, such as (R)-C 1-6 alkyl, such as (R)-methyl; in another specific embodiment, R Y is C 1-6 haloalkyl, such as (R)-C 1-6 haloalkyl; in another specific embodiment, R Y is C 2-6 alkenyl; in another specific embodiment, R Y is C 2-6 alkynyl.
  • At least one of R 1 and R 2 is C 1-6 alkyl, such as (R)-C 1-6 alkyl, such as (R)-methyl.
  • R 1 and R 2 , or R 3 and R 4 are linked to form a bond; in another specific embodiment, R 1 and R 2 , or R 3 and R 4 are linked to form C 1-6 an alkylene group such as methylene, ethylene or propylene; in another specific embodiment, R 1 and R 2 , or R 3 and R 4 are linked to form a C 2-6 alkenylene; in another In specific embodiments, R 1 and R 2 , or R 3 and R 4 are linked to form a C 2-6 alkynylene group.
  • the above groups may be substituted with one or more D or halogen up to full substitution.
  • the C 3-5 Cycloalkyl is cyclopropyl; in another specific embodiment, the C3-5 cycloalkyl is cyclobutyl; in another specific embodiment, the C3-5 cycloalkyl is cyclopentane group; in another particular embodiment, when Y when Y is CR, wherein R & lt Y, form a 3-5 membered heterocyclyl group R 1 together with the atom to which they are connected; in another embodiment, the 3- The 5-membered heterocyclic group is oxetanyl, aziridine or thiirane; in another specific embodiment, the 3-5 membered heterocyclic group is oxetanyl, azetidine cyclobutyl or thietanyl; in another specific embodiment, the 3-5
  • Ring A is absent; in another specific embodiment, Ring A is C 3-7 cycloalkyl; in another specific embodiment, Ring A is 4-7 membered heterocyclyl; In another specific embodiment, Ring A is a C6-10 aryl; in another specific embodiment, Ring A is a 5-10 membered heteroaryl.
  • Ring A is a 5-6 membered heteroaryl. In another specific embodiment, Ring A is a 4-7 membered heterocyclyl group, preferably selected from piperazinyl or piperidinyl.
  • Ring A is selected from Wherein, A 1 is CR a1 or N; A 2 is CR a2 or N; A 3 is CR a3 or N; A 4 is CR a4 or N; A 5 is CR a5 or N; R a1 , R a2 , R a3 , R a4 and R a5 are as defined above for R a.
  • (R a ) m -cyclic AL- is selected from
  • R a is independently selected from optionally substituted with R * is H, D, halo, -CN, -NRR ', - OR , -SR, -C (O) R, -C (O )OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl or 3-8 membered heterocyclyl, wherein the group may be replaced by one or more D or halogen, until completely substituted; in another embodiment, one of R a is H; in another embodiment, one of R a is D; in another embodiment, one of R a a halogen; in another particular embodiment, wherein R a is a -CN; in another particular embodiment, wherein
  • R a is independently selected from H, D, halo, -CN, -NRR ', - OR , -SR, -C (O) R, -C (O) OR, -C ( O) NRR', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein said groups may be substituted with one or more D up to complete deuterium generation.
  • Ring B is a 5-6 membered heteroaryl group such as pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl , triazolyl, pyridyl, pyrimidinyl or pyrazinyl; preferably pyrrolyl, furyl, thienyl, pyrazolyl or pyridyl; preferably pyrazolyl.
  • pyrrolyl, furyl, thienyl, pyrazolyl or pyridyl preferably pyrazolyl.
  • R b is independently selected from optionally substituted with R * is H, D, halo, -CN, -NRR ', - OR , -SR, -C (O) R, -C (O )OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl or 3-8 membered heterocyclyl, wherein the group may be replaced by one or more D or halogen substitution, until fully substituted; in another embodiment, one of R b is H; in another embodiment, one of R b is D; in another embodiment, one of R b a halogen; in another particular embodiment, wherein R b is a -CN; in another particular embodiment, wherein R b
  • R b is independently selected from H, D, halogen, -CN, -NRR', -OR, -SR, C 1-6 alkyl or C 1- optionally substituted with R* 6 haloalkyl.
  • Ring C is C 3-7 cycloalkyl; in another specific embodiment, Ring C is 4-7 membered heterocyclyl; in another specific embodiment, Ring C is C 6 -10 aryl; in another specific embodiment, Ring C is a 5-10 membered heteroaryl.
  • Ring C is 5-6 membered heteroaryl or phenyl; preferably pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole pyrazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl; preferably pyrazolyl .
  • Ring C is C 3-7 cycloalkyl or 4-7 membered heterocyclyl, preferably cyclopentyl or tetrahydropyranyl.
  • L is a bond; in another specific embodiment, L is -O-; in another specific embodiment, L is -S-; in another specific embodiment, L is - N(R)-; in another specific embodiment, L is -C(O)-; in another specific embodiment, L is C 1-6 alkylene; in another specific embodiment, L is C 2-6 alkenylene; in another specific embodiment, L is C 2-6 alkynylene.
  • L is a bond, -C(O)- or C 1-6 alkylene.
  • R 5 is H; In another particular embodiment, R 5 is D; In another particular embodiment, R 5 is a halogen; In another particular embodiment, R 5 is - the CN; in another particular embodiment, R 5 is -NRR '; in another particular embodiment, R 5 is -OR; in another particular embodiment, R 5 is -SR; in another particular embodiment In the scheme, R 5 is C 1-6 alkyl; In another specific embodiment, R 5 is C 2-6 alkenyl; In another specific embodiment, R 5 is C 2-6 alkynyl; In in another particular embodiment, R 5 may be substituted with one or more halo or D, until completely substituted.
  • R 6 is H; In another particular embodiment, R 6 is D; In another particular embodiment, R 6 is a halogen; In another particular embodiment, R 6 is - the CN; in another particular embodiment, R 6 is -NRR '; in another particular embodiment, R 6 is -OR; in another particular embodiment, R 6 is -SR; in another particular embodiment In the scheme, R 6 is C 1-6 alkyl; In another specific embodiment, R 6 is C 2-6 alkenyl; In another specific embodiment, R 6 is C 2-6 alkynyl; In in another particular embodiment, R 6 may be substituted with one or more halo or D, until completely substituted.
  • R* is H; in another specific embodiment, R* is halogen; in another specific embodiment, R* is -CN; in another specific embodiment, R* is -NRR'; in another specific embodiment, R* is -OR; in another specific embodiment, R* is -SR; in another specific embodiment, R* is -C(O)R; In another specific embodiment, R* is -C(O)OR; in another specific embodiment, R* is -C(O)NRR'; in another specific embodiment, R* is -OC (O)R'; in another specific embodiment, R* is -NRC(O)R'; in another specific embodiment, R* is -OC(O)NRR'; in another specific embodiment, R* is -NRC(O)NRR'; In another specific embodiment, R* is -S(O) p R; In another specific embodiment, R* is C 3-7 cycloalkyl In another specific embodiment, R* is 3-8 membered heterocyclyl; In another specific embodiment, R* is C 3-7
  • R and R' are independently H; in another specific embodiment, R and R' are independently C 1-6 alkyl; in another specific embodiment, R and R' are independently C 2-6 alkenyl; in another specific embodiment, R and R' are independently C 2-6 alkynyl; in another specific embodiment, R, R' and the nitrogen atom to which they are attached A 4-8 membered heterocyclyl is formed; in another specific embodiment, R and R' may be substituted with one or more D or halo, up to full substitution.
  • any technical solution in any of the above specific embodiments or any combination thereof may be combined with any technical solution in other specific embodiments or any combination thereof.
  • any technical solution of X or any combination thereof can be combined with Y, R 1 -R 6 , ring A, ring B, ring C, R a , R b , R*, m, n, p, R and R ' etc. or any combination thereof.
  • the present invention is intended to include all the combinations of these technical solutions, and is not listed one by one due to space limitations.
  • the present invention provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates thereof , hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general structure:
  • the present invention provides a compound of general formula (I-1) or (I-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, exo Racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • Ring C is C 3-7 cycloalkyl or 4-7 membered heterocyclic group; preferably cyclopentyl or tetrahydropyranyl;
  • Ring B is pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; preferably is pyrrolyl, furyl, thienyl, pyrazolyl or pyridyl;
  • R 5 is preferably H, D, halogen, -CN, -NRR', -OR, -SR, wherein the group may be substituted with one or more D or halogen, until fully substituted; preferably, R 5 is located in ring C On the C atom connected to the parent nucleus;
  • the present invention provides a compound of general formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate thereof compounds, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • Ring C is 5-6 membered heteroaryl or phenyl; preferably pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazole pyrazolyl, pyridyl, pyrimidinyl or pyrazinyl; preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl; preferably pyrazolyl;
  • the present invention provides the above-mentioned compound of general formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof , solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
  • Ring B is pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; preferably is pyrrolyl, furyl, thienyl, pyrazolyl or pyridyl;
  • the present invention provides a compound of general formula (II) or (II-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof Forms, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • Ring A is absent, C 3-7 cycloalkyl or 4-7 membered heterocyclyl
  • the present invention provides the above-mentioned compound of general formula (II) or (II-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, Racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
  • Ring A does not exist or is a 4-7 membered heterocyclic group; preferably piperidinyl or piperazinyl;
  • Ring B is pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; preferably is pyrrolyl, furyl, thienyl, pyrazolyl or pyridyl;
  • L is a bond, -O-, -S-, -N(R)-, -C(O)- or C 1-6 alkylene;
  • R 5 and R 6 are independently C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein said groups may be substituted with one or more D, until fully deuterated;
  • the present invention provides a compound of general formula (III) or (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic thereof Forms, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • Ring C is 5-6 membered heteroaryl or phenyl; preferably pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazole pyrazolyl, pyridyl, pyrimidinyl or pyrazinyl; preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl; preferably pyrazolyl;
  • the present invention provides the compound of general formula (III) or (III-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, Racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
  • Ring B is pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; preferably is pyrrolyl, furyl, thienyl, pyrazolyl or pyridyl;
  • the present invention provides a compound of general formula (III-2) or (III-3), or a pharmaceutically acceptable salt, enantiomer, diastereomer, exo Racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • a 1 is CR a1 or N;
  • a 2 is CR a2 or N;
  • a 5 is CR a5 or N;
  • the present invention provides the compound of general formula (III-3) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof , solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
  • a 3 is CR a3 or N
  • R a1 , R a2 , R a3 , R a5 , R 5 and R 6 are independently H, D, halogen, -CN, -OR, -SR, -NRR', -C(O)R, -C(O ) OR, -C(O)NRR' or C 1-6 alkyl, wherein said group may be substituted with one or more D or halogen, up to full substitution;
  • the present invention provides the compound of general formula (III-3) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof , solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
  • a 3 is CR a3 or N
  • R a1 , R a2 , R a3 and R a5 are independently selected from H, D, halogen, -CN, -OH, -C(O)NH 2 , C 1-6 alkyl or C 1-6 haloalkyl, wherein The group may be substituted with one or more D up to full deuteration;
  • R 5 and R 6 are independently C 1-6 alkyl or C 1-6 haloalkyl, wherein said groups may be substituted with one or more D until fully deuterated.
  • the present invention provides the compound of general formula (III-3) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof , solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
  • a 3 is CR a3 or N
  • R a1 is H or D
  • R a2 is H, D, halogen, -CN, -OH, -C(O)NH 2 , C 1-6 alkyl or C 1-6 haloalkyl;
  • R a3 is H, D or -OH
  • R a5 is H or D
  • R 5 is C 1-6 alkyl or C 1-6 haloalkyl; preferably methyl
  • R 6 is C 1-6 alkyl or C 1-6 haloalkyl; methyl is preferred.
  • the present invention provides a compound of general formula (III-3), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate thereof compounds, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • a 3 is CR a3 or N
  • R a1 , R a2 , R a3 , R a5 , R 5 and R 6 are independently H, D, halogen, -OR, -SR, -NRR', C 1-6 alkyl or C 1-6 haloalkyl, wherein the group may be substituted with one or more D, up to full deuteration;
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R, R' are formed with the nitrogen atom to which they are attached 4-8 membered heterocyclyl; wherein the group may be substituted with one or more Ds until fully deuterated.
  • the present invention provides the compound of general formula (III-3) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof , solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
  • a 3 is CR a3 or N
  • R a1 , R a2 , R a3 and R a5 are independently selected from H, D, halogen, -OH, C 1-6 alkyl or C 1-6 haloalkyl, wherein the groups may be replaced by one or more D Substitution until fully deuterated;
  • R 5 and R 6 are independently C 1-6 alkyl or C 1-6 haloalkyl, wherein said groups may be substituted with one or more D until fully deuterated.
  • the present invention provides the compound of general formula (III-3) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof , solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
  • a 3 is CR a3 or N
  • R a1 is H or D
  • R a2 is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R a3 is H, D or -OH
  • R a5 is H or D
  • R 5 is C 1-6 alkyl or C 1-6 haloalkyl; preferably methyl
  • R 6 is C 1-6 alkyl or C 1-6 haloalkyl; methyl is preferred.
  • the present invention provides a compound of general formula (III-4), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate thereof compounds, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • a 4 is CR a4 or N
  • R a1 , R a2 , R a4 , R a5 , R 5 and R 6 are independently H, D, halogen, -CN, -OR, -SR, -NRR', -C(O)R, -C(O ) OR, -C(O)NRR' or C 1-6 alkyl, wherein said group may be substituted with one or more D or halogen, up to full substitution;
  • the present invention provides the compound of general formula (III-4) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof , solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
  • a 4 is CR a4 or N
  • R a1 , R a2 , R a4 and R a5 are independently selected from H, D, halogen, -CN, -OH, -C(O)NH 2 , C 1-6 alkyl or C 1-6 haloalkyl, wherein The group may be substituted with one or more D up to full deuteration;
  • R 5 and R 6 are independently C 1-6 alkyl or C 1-6 haloalkyl, wherein said groups may be substituted with one or more D until fully deuterated.
  • the present invention provides the compound of general formula (III-4) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof , solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
  • a 4 is CR a4 or N
  • R a1 is H, D or halogen
  • R a2 is H, D, halogen, -CN, -OH, -C(O)NH 2 , C 1-6 alkyl or C 1-6 haloalkyl;
  • R a4 is H, D or -OH
  • R a5 is H or D
  • R 5 is C 1-6 alkyl or C 1-6 haloalkyl; preferably methyl
  • R 6 is C 1-6 alkyl or C 1-6 haloalkyl; methyl is preferred.
  • Preferred compounds of the present invention include, but are not limited to, the compounds listed below, or their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs Types, prodrugs or isotopic variants, and mixtures thereof:
  • the compounds of the present invention may contain one or more asymmetric centers, and thus may exist in various stereoisomeric, eg, enantiomeric and/or diastereomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (eg, cis and trans isomers), or may be in the form of a mixture of stereoisomers, Include racemic mixtures and mixtures enriched in one or more stereoisomers.
  • 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 chiral salts; or preferred isomers can be obtained by prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are called "solvates”. When the solvent is water, the complex is called a "hydrate”.
  • the present invention encompasses all solvates of the compounds of the present invention.
  • solvate refers to a solvent-bound compound or salt form thereof usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein can be prepared, eg, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • hydrate refers to a compound that is combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, for example, hydrates of the compounds of general formula available R ⁇ x H 2 O represented that the compound wherein R, and x is a number greater than 0.
  • a given compound can form more than one type of hydrate, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R 0.5H2 ) O)) and a multi-hydrate (x is a number greater than 1, e.g., dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)) .
  • the compounds of the present invention may be in amorphous or crystalline form (polymorph). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) of a particular crystal packing arrangement. All polymorphs 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 solvent, rate of crystallization, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically-labeled compounds that are equivalent to those described in formula (I), but with one or more atoms replaced by an atom having an atomic mass or mass number different from that normally found in nature. It may be introduced into compounds of the invention Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively, for example 2 H, 3 H, 13 C , 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention for example, introduction of a radioactive isotope (e.g. 3 H and 14 C), are useful in drug and / or substrate tissue distribution assays.
  • Tritium, ie 3 H, and carbon-14, ie 14 C isotopes are particularly preferred because of their ease of preparation and detection. Further, substituted with heavier isotopes such as deuterium, i.e.
  • Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents in carrying out the processes disclosed in the following Schemes and/or Examples and Preparations labeled reagents.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted in vivo to its active form 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, Vol. 14 of ACSSymposium Series, 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: solution limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each cited This article is for reference.
  • a prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo.
  • Prodrugs are typically prepared by modifying functional groups in a manner such that the modification can be cleaved, either by routine manipulation or in vivo, to yield the parent compound.
  • Prodrugs include, for example, compounds of the present invention wherein a hydroxyl, amino or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amino or sulfhydryl group.
  • prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxy, sulfhydryl and amino functional groups of compounds of formula (I).
  • esters such as methyl esters, ethyl esters, and the like can be used.
  • the esters themselves may be active and/or hydrolyzable under human in vivo conditions.
  • Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups which are readily cleaved in humans to release the parent acid or salt thereof.
  • the present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.
  • compositions, formulations and kits are provided.
  • the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a compound of the present invention.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention.
  • the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does 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 albumin).
  • buffer substances such as phosphates
  • glycine such as sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols and lanolin.
  • kits eg, pharmaceutical packages.
  • kits can include a compound of the present invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packs or other) containing the compounds of the present invention, other therapeutic agents. suitable container).
  • kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the present invention and/or other therapeutic agent.
  • a compound of the present invention and other therapeutic agent provided in a first container and a second container are combined to form one unit dosage form.
  • compositions provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration Drugs, administration via implants, or other modes of administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intrameningeal 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 depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
  • the compounds provided herein are administered to subjects at risk of developing the disorders, typically on the advice and supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a particular disorder typically include subjects with a family history of the disorder, or those subjects determined by genetic testing or screening to be particularly susceptible to developing the disorder.
  • Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over an extended period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, For example, the rest of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within a therapeutic window.
  • the pharmaceutical composition may be administered as a bolus injection, eg, in order 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, e.g., intramuscular or subcutaneous bolus doses provide slow release of the active ingredient, while bolus injections delivered directly into the vein (e.g., by IV infusion) ) can be delivered more rapidly, resulting in a rapid increase in the concentration of the active ingredient in the blood to an effective level.
  • the pharmaceutical composition may be administered as a continuous infusion, eg, by IV infusion, to provide a steady state concentration of the active ingredient in the body of the subject.
  • a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
  • Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, the compositions are presented 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 material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, and the like.
  • the compound will generally be the minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various components useful in forming the desired administration form. carriers or excipients and processing aids.
  • a typical regimen is one to five oral doses, especially two to four oral doses, typically three oral doses per day.
  • each dose provides about 0.01 to about 20 mg/kg of a compound of the invention, with preferred doses each providing about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.
  • transdermal doses are typically selected in amounts of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.
  • injection dose levels are in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour.
  • a preloaded bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be administered.
  • the maximum total dose cannot exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration can include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • Solid forms may include, for example, any of the following components, or compounds of similar properties: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or cornstarch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, water Methyl cylate or orange flavoring.
  • binders such as microcrystalline cellulose, tragacanth, or gelatin
  • excipients such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or cornstarch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically the minor component, often 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 ingredient When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base.
  • the active ingredient may be formulated in a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.
  • transdermal administration can be accomplished using reservoir or porous membrane types, or patches of various solid matrices.
  • compositions for oral administration, injection or topical administration are only representative. Additional materials and processing techniques, etc. are described in Section 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
  • the compounds of the present invention can also be administered in sustained release form, or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins consisting of 6, 7 and 8 ⁇ -1,4-linked glucose units, respectively, which optionally include a or more substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, a sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, eg, U.S. 5,376,645.
  • the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).
  • ATR kinases are known to play a role in tumorigenesis and many other diseases. We have found that compounds of formula (I) possess potent anti-tumor activity thought to be obtained by inhibiting ATR kinase.
  • the compounds of the present invention have value as antitumor agents.
  • the compounds of the present invention have value as anti-proliferative, apoptotic and/or anti-invasive agents in the suppression and/or treatment of solid and/or liquid neoplastic diseases.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumors that are susceptible to inhibition of ATR.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumors mediated by ATR alone or in part.
  • the compounds are useful for producing ATR enzyme inhibition in warm-blooded animals in need of such treatment.
  • inhibitors of ATR kinases are useful in the treatment of proliferative diseases such as cancers, especially solid tumors such as carcinomas and sarcomas, and leukemias and lymphomas, especially for the treatment of, eg, breast, colorectal, lung cancers including Small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate cancer and bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophagus cancer, ovarian cancer, pancreatic cancer , skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, and leukemia (including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), etc. ], multiple myeloma and lymphoma have therapeutic value.
  • proliferative diseases such as cancers, especially solid tumors such as carcinomas and sarcom
  • Anticancer effects useful for treating cancer in patients include, but are not limited to, antitumor effects, response rates, time to disease progression, and survival rates.
  • the anti-tumor effects of the treatment methods of the present invention include, but are not limited to, inhibition of tumor growth, retardation of tumor growth, regression of tumors, shrinkage of tumors, prolongation of tumor regeneration after cessation of treatment, and slowing of disease progression.
  • Anticancer effects include preventive treatment as well as treatment of existing disease.
  • ATR kinase inhibitors or pharmaceutically acceptable salts thereof are also useful in the treatment of patients with cancers including but not limited to blood cancers such as leukemia, multiple myeloma; lymphomas such as Hodgkin's disease, non-Hodgkin's Lymphomas (including mantle cell lymphomas) and myelodysplastic syndromes, and also solid tumors and their metastases, such as breast cancer, lung cancer (non-small cell lung cancer (NSCL), small cell lung cancer (SCLC), squamous cell carcinoma), endometrial carcinoma, tumors of the central nervous system (eg, glioma, dysplastic neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, Retinoblastoma, neuroblastoma, germ cell tumor and teratoma, gastrointestinal cancer (eg stomach cancer), esophagus cancer, hepatocellular (liver) cancer, bile
  • the compounds of the present invention and methods of treatment comprising administration or use of an ATR kinase inhibitor or a pharmaceutically acceptable salt thereof are expected to be particularly useful in the treatment of patients with lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, Patients with kidney cancer, gastric cancer, sarcoma, head and neck cancer, tumors of the central nervous system and their metastases, and for the treatment of patients with acute myeloid leukemia.
  • an effective amount of a compound of the present invention will generally be administered in single or multiple doses at an average daily dose of 0.01 mg to 50 mg compound/kg patient body weight, preferably 0.1 mg to 25 mg compound/kg patient body weight.
  • the compounds of the present invention can be administered to such patients in need of such treatment in a daily dosage range of from about 1 mg to about 3500 mg, preferably 10 mg to 1000 mg, per patient.
  • the daily dose per patient may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000mg.
  • Administration may be one or more times daily, weekly (or several days apart) or on an intermittent schedule.
  • the compound can be administered on a weekly basis (eg, every Monday), one or more times per day, indefinitely or for several weeks, eg, 4-10 weeks.
  • the compound may be administered daily for several days (eg, 2-10 days), followed by several days (eg, 1-30 days) with no administration of the compound, repeating the cycle indefinitely or a given number of times, eg, 4-10 cycle.
  • a compound of the invention may be administered daily for 5 days, followed by a 9-day break, then again daily for 5 days, then a 9-day break, and so on, repeating the cycle indefinitely or 4-10 times in total.
  • Treatment as defined herein may be applied as a sole therapy, or may include conventional surgery or radiation or chemotherapy in addition to the compounds of the present invention. Accordingly, the compounds of the present invention may also be used in combination with existing therapeutic agents for the treatment of cancer.
  • Suitable agents for use in combination include:
  • Antiproliferative/antineoplastic drugs and combinations thereof used in medical oncology such as alkylating agents (e.g. cisplatin, carboplatin, cyclophosphamide, chlorambucil, melphalan, chlorambucil, Busulfan and nitrosoureas); antimetabolites (eg, antifolates such as fluorouracils such as 5-fluorouracil and tegafur, raltitrexed, methotrexate urea, cytarabine, hydroxyurea, and gemcitabine); antineoplastic antibiotics (eg, anthracyclines such as adriamycin, bleomycin, doxorubicin, doxorubicin, Daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin) ; Antimitotic agents (eg, vinca alkaloids, such as vincris), such as
  • cytostatics such as anti-estrogens (eg tamoxifen, toremifene, raloxifene, droloxifene and idoxifene) (iodoxyfene), estrogen receptor down-regulators (eg, fulvestrant), anti-androgens (eg, bicalutamide, flutamide, nilutamide, and Cyproterone acetate), LHRH antagonists or LHRH agonists (eg, goserelin, leuprorelin, and buserelin), progestins (eg, megestrol acetate) , aromatase inhibitors (such as Anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride Amine (finasteride);
  • anti-estrogens eg tamoxifen, toremifene, raloxifene
  • anti-invasive agents eg c-Src kinase family inhibitors, such as AZD0530 and dasatinib
  • metalloproteinase inhibitors such as marimastat
  • urokinase-type plasminogen activator inhibitors of body function eg. c-Src kinase family inhibitors, such as AZD0530 and dasatinib
  • metalloproteinase inhibitors such as marimastat
  • urokinase-type plasminogen activator inhibitors of body function eg. c-Src kinase family inhibitors, such as AZD0530 and dasatinib
  • metalloproteinase inhibitors such as marimastat
  • urokinase-type plasminogen activator inhibitors of body function eg.g c-Src kinase family inhibitors, such as AZD0530 and dasatinib
  • Growth factor function inhibitors such as growth factor antibodies and growth factor receptor antibodies (such as the anti-erbB2 antibody trastuzumab [Herceptin TM ] and the anti-erbB1 antibody cetuximab [C225]); such inhibition Agents also include, for example, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (eg, EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib, and CI 1033; and erbB2 tyrosine kinases) inhibitors, such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib; inhibitors of serine/threonine kinases (eg, Ras/Raf signaling) Inhibitors, such as farnesyltransferase inhibitors, such as sorafenib (BA
  • anti-angiogenic agents such as those that inhibit the effects of vascular endothelial growth factor [eg, the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin TM ); and VEGF receptor tyrosine kinase inhibitors, such as ZD6474, AZD2171, vatalanib, and sunitinib, and compounds that act by other mechanisms (eg, linomide, inhibitors of integrin ⁇ v ⁇ 3 function, and angiostatins) ];
  • vascular endothelial growth factor eg, the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin TM )
  • VEGF receptor tyrosine kinase inhibitors such as ZD6474, AZD2171, vatalanib, and sunitinib, and compounds that act by other mechanisms (eg, linomide, inhibitors of integrin ⁇ v ⁇ 3 function,
  • vascular disrupting agents such as combretastatin
  • antisense therapies such as those directed against the targets listed above, such as ISIS 2503;
  • Gene therapy methods including methods of replacing abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2); GDEPT (gene-directed enzyme prodrug therapy) methods, such as the use of cytosine deaminase, thymidine those methods of glycoside kinase or bacterial nitroreductase; and methods of increasing patient tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and
  • immunotherapeutic methods including in vitro and in vivo methods to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines (eg, interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor); lowering T - methods of anergy; methods using transfected immune cells such as cytokine-transfected dendritic cells; methods using cytokine-transfected tumor cell lines and methods using anti-idiotype antibodies.
  • cytokines eg, interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor
  • intermediate a1 (15.9 mmol, 4.0 g) and intermediate 3,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester a2-1 (24.0 mmol, 5.3 g) were dissolved in 1,4-dioxane and water in 50 mL of mixture (v/v: 9/1).
  • Sodium carbonate 32 mmol, 3.39 g
  • Pd(dppf)Cl 2 1.6 mmol, 1.17 g
  • intermediate a3-1 (3.32mmol, 1.3g) and raw material a3-2 (4.98mmol, 1.38g) were dissolved in 20mL of a mixture of 1,4-dioxane and water (v/v : 9/1), sodium carbonate (6.64 mmol, 704 mg) and Pd(dppf)Cl 2 (0.33 mmol, 241 mg) were added, and the reaction was heated under microwave at 100° C. for 1 hour. The reaction was stopped, filtered, 40 mL of water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to obtain intermediate a3 (400 mg, yield: 26%).
  • intermediate a1 (1.63 mmol, 410 mg) was dissolved in 15 mL of anhydrous dichloromethane, N-iodosuccinimide NIS (1.79 mmol, 403 mg) was slowly added in portions, and stirring was continued for 2 hours. The reaction was stopped, 50 mL of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. Dry over anhydrous sodium sulfate to obtain intermediate a4-1 (700 mg, crude product). LC-MS: [M+H] + : 379.
  • intermediate a4-1 700 mg
  • raw material a3-2 2.44 mmol, 678 mg
  • 20 mL of a mixture of 1,4-dioxane and water (v/v: 9/1) , potassium carbonate (3.26 mmol, 451 mg) and Pd(dppf)Cl 2 (0.16 mmol, 117 mg) were added, and the reaction was heated under microwave at 100° C. for 1 hour.
  • the reaction was stopped, filtered, 40 mL of water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to obtain intermediate a4 (220 mg, two-step total yield: 34%).
  • the raw material a2-1 (2.25 mmol, 500 mg) was dissolved in 15 mL of DMF, NaH (4.5 mmol, 180 mg) was added in batches, and after stirring for 30 minutes, 4-((methylsulfonic acid) was slowly added Acyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (3.37mmol, 943mg), the temperature was raised to 90°C and the reaction was continued for 2 hours.
  • the starting material b6-1 (9.2 mmol, 2.0 g) and N-Boc-hydrazine (10.1 mmol, 1.33 g) were dissolved in 30 mL of acetic acid. After stirring for 5 minutes, NaBH 3 CN (27.6 mmol, 1.7 g) was slowly added, and the mixture was reacted at room temperature for 10 hours. The reaction was stopped, 80 mL of ice water was added to the system to quench the reaction, and the solvent was evaporated under reduced pressure. The pH of the system was adjusted to about 9 with saturated aqueous NaHCO 3 solution, and extracted with dichloromethane. Dry over anhydrous sodium sulfate to obtain crude intermediate b6-2 (a pair of diastereomers).
  • intermediate A1-3 (0.29 mmol, 180 mg) and thiophene-2-boronic acid pinacol ester A7-1 (0.58 mmol, 121 mg) were dissolved in 10 mL of 1,4-dioxane and water and mixed In the liquid (v/v: 9/1), potassium carbonate (0.87 mmol, 120 mg), Pd(dppf)Cl 2 (0.03 mmol, 22 mg) were added, and the reaction was heated at 95° C. for 2 hours.
  • intermediate a4 (0.25 mmol, 100 mg) and intermediate b6 (0.50 mmol, 211 mg) were dissolved in 10 mL of a mixture of 1,4-dioxane and water (v/v: 9/1) , potassium carbonate (0.50 mmol, 69 mg) and Pd(dppf)Cl 2 (0.03 mmol, 22 mg) were added.
  • the reaction was heated in the microwave at 100°C for 2 hours.
  • the reaction was stopped, filtered, 20 mL of water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by TLC chromatography to obtain compound A16-1 (60 mg, yield: 36%).
  • the intermediate b6 was replaced with its diastereomer b7 to obtain the target compound A16-II.
  • Example 14 ATR kinase activity assay:
  • a protein derived from p53 biotinylation was phosphorylated with ATR kinase (Eurofins, Cat. No. 14-952). This experiment utilizes time-resolved fluorescence to measure the amount of phosphorylated protein. The amount of phosphorylated protein was detected using an anti-p53-phospho-(serine 15)-K-specific antibody (Cisbio, Cat. No. 61GSTDLA) and a d2-labeled anti-GST antibody (Cisbio, Cat. No. 61P08KAE).
  • reaction buffer (20mM HEPES pH8.0, 1% glycerol, 0.01% Brij-35), dilution buffer (20mM HEPES pH8.0, 1% glycerol, 0.01% Brij-35, 5mM DTT and 1% BSA), stop solution (20mM HEPES pH8.0, 1% glycerol, 0.01% Brij-35, 250mM EDTA), assay buffer (50mM HEPES pH7.0, 150mM NaCl, 267mM KF , 0.1% sodium cholate, 0.01% Tween-20, 0.0125% sodium azide).
  • the reagents used above were purchased from Sigma or Invitrogen unless the manufacturer was specifically mentioned.
  • 4X serial dilutions of compound solutions were prepared in 1X reaction buffer to yield 9 different concentrations of compounds, and 2.5 [mu]L of 4X serial dilutions of compound solutions were added to a 384-well assay plate (784075, Greiner).
  • 4 ⁇ ATR/ATRIP working solution (12.8 ng/ ⁇ L) with dilution buffer and add 2.5 ⁇ L of 4 ⁇ ATR/ATRIP working solution to a 384-well assay plate.
  • Example 15 In vitro cell proliferation inhibition experiment:
  • TOV21G cells and MV4-11 cells were purchased from the American Type Culture Collection (American Type Culture Collection, ATCC).
  • TOV21G cells were cultured in MCDB105/M199 medium (containing 15% FBS), and the cells were used for experiments when the cell confluency reached more than 85%. About 1000 cells were seeded in each well of a 96-well culture plate, cultured for 24 hours, and the cells were treated by adding different concentrations of the compounds to be tested (0-10 ⁇ M). Blank wells (containing media only) and control wells (seeded cells without drug treatment) were set up.
  • MV-4-11 cells were cultured in IMDM medium (containing 20% FBS), about 10,000 cells were seeded in each well of a 96-well culture plate, and cells were treated by adding different concentrations of test compounds (0-10 ⁇ M). parallel holes. Blank wells (containing media only) and control wells (seeded cells without drug treatment) were set up. After culturing for 120 hours, add 40 ⁇ L of Cell Titer-Glo solution to each well, incubate in the dark for 20 min with shaking, transfer 100 ⁇ L from each well to a 96-well white plate, and read the luminescence value with a Biotek Synergy H1 multifunctional microplate reader.
  • Inhibition rate (%) 100% ⁇ (control well-test well)/(control well-blank well)
  • Proliferation assay results demonstrate that the test compound has efficacy in human tumor cells studied in order to reflect the IC 50 values (IC 50 of inhibition at a concentration of 50% of the maximum effect).
  • Liver microsome stability experiments were carried out on the compounds of the present invention.
  • the compounds to be tested (final concentration 2.0 nM) were co-incubated with human/mouse liver microsomes with or without the addition of NADPH, and the compound concentrations in the supernatants of the incubations were detected within 60 minutes. Results for representative compounds are as follows:
  • Example 17 Compound in vivo pharmacokinetic experiments:
  • mice Male ICR mice (3 mice/group) were given oral gavage at a dose of 10 mg/kg. Plasma samples were collected pre-dose (0 hours) and post-dose (0.25, 0.5, 1, 2, 4, 6, 8, 24 hours), LC/MS/analyzed and data collected on collected samples, collected The data were analyzed using Analyst v1.6.2 (AB Applied Biosystems Company, USA) software to calculate relevant pharmacokinetic parameters.
  • the compounds to be tested were diluted to 0.51 nM with 10 ⁇ M as the starting point (10 concentrations in total), and their effects on the kinases ATM 1 , DNA-PK 2 , PI3K ⁇ 3 , PI3K ⁇ 3 and mTOR 4 were determined respectively.
  • the inhibitory activity of the results are as follows:

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Abstract

公开了通式(I)化合物，它们可用于治疗ATR激酶介导的疾病，例如增生性疾病，例如癌症。还公开了通式(I)化合物的制备方法、药物组合物以及所述药物组合物用于治疗ATR激酶介导的疾病的用途。

Description

作为ATR激酶抑制剂的吡唑并嘧啶化合物 发明领域
本发明涉及作为ATR激酶的抑制剂的吡唑并嘧啶化合物。更具体地，本发明的化合物可有效用于ATR激酶介导的疾病，例如增生性疾病，例如癌症的治疗。本发明还提供所述化合物的药物组合物、其用于治疗ATR激酶介导的疾病的用途、及其制备。
背景技术
ATR(Ataxia telangiectasia and Rad3-related protein)是一类参与基因组稳定性及DNA损伤修复的蛋白激酶，属于PIKK家族成员。ATR的激活可被停滞的复制叉或者DNA单链损伤(SSB)所激活。激活的ATR将招募修复蛋白或修复因子对受损部位进行修复，延缓有丝分裂过程(特别在有丝分裂的G2/M期)，既稳定了复制叉，又保障了基因组的稳定性。
此外，大部分肿瘤细胞中的DNA损伤修复系统异常，通常缺失一定的修复通路(如p53或ATM的突变)，使得其更加依赖ATR来存活。而在正常细胞中，由于其健全完整的修复通路，单独抑制ATR激酶不会产生较大影响。因此，抑制ATR可能对癌症的治疗具有更显著的效果，而对正常细胞则不会产生较大毒副作用。
而且，ATR的抑制可同时与放疗或化疗药物联用来协同增强效果。广泛应用的化疗药物包括抗代谢药(如吉西他滨)，DNA交联剂(如顺铂、卡铂)、烷化剂(如替莫唑胺)，拓扑异构酶抑制剂(如拓扑替康、伊立替康)等。肿瘤细胞在受到化疗或放疗的影响时，会较大程度上激活ATR信号通路来修复受损的DNA。因此，利用放疗或化疗药治疗癌症时，同时对ATR进行抑制，可使得癌症的治疗效果大大增强。
到目前为止，仍无ATR抑制剂上市，因此发现更加有效且安全的ATR抑制剂仍十分必要。
发明内容
本发明提供通式(I)化合物，它们可用于治疗ATR激酶介导的疾病，例如增生性疾病，例如癌症。
在一个方面，本发明提供了通式(I)的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
Figure PCTCN2021105867-appb-000001
其中，
X为CR X或N；
Y为CR Y或N；
R 1、R 2、R 3、R 4和R Y独立地选自H、D、卤素、C 1-6烷基、C 2-6烯基或C 2-6炔基，或者R 1与R 2，R 3与R 4连接形成键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
其中R X为H、D、卤素、-CN、-NRR’、-OR、-SR或C 1-6烷基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
当Y为CR Y时，其中R Y、R 1与它们连接的原子一起形成C 3-5环烷基或3-5元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
环A为C 3-7环烷基、4-7元杂环基、C 6-10芳基或5-10元杂芳基；或者环A不存在，因此一个R a与L连接；或者(R a) m-环A-L-都不存在；
R a独立地选自任选被R*取代的H、D、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基或3-8元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
m＝0、1、2、3、4或5；
环B为5-6元杂芳基；
R b独立地选自任选被R*取代的H、D、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基或3-8元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
n＝0、1、2、3、4或5；
环C为C 3-7环烷基、4-7元杂环基、C 6-10芳基或5-10元杂芳基；
L为键、-O-、-S-、-N(R)-、-C(O)-、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R 5为H、D、卤素、-CN、-NRR’、-OR、-SR、C 1-6烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
R 6为H、D、卤素、-CN、-NRR’、-OR、-SR、C 1-6烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
R*为H、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
R和R’独立地选自H、C 1-6烷基、C 2-6烯基或C 2-6炔基，或者R、R’与它们连接的氮原子形成4-8元杂环基；其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
p＝1或2。
在另一个方面，本发明提供了一种药物组合物，所述药物组合物含有本发明化合物，和任选地药学上可接受的赋形剂。
在另一个方面，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 它治疗剂。
在另一个方面，本发明提供了包含本发明化合物，和其它治疗剂以及药学上可接受的载剂、佐剂或媒剂的试剂盒。
在另一个方面，本发明提供了本发明化合物在制备用于治疗和/或预防ATR激酶介导的疾病的药物中的用途。
在另一个方面，本发明提供了在受试者中治疗和/或预防ATR激酶介导的疾病的方法，包括向所述受试者给药本发明化合物或本发明组合物。
在另一个方面，本发明提供了本发明化合物或本发明组合物，其用于治疗和/或预防ATR激酶介导的疾病。
在具体实施方案中，所述疾病包括增生性疾病(如癌症)，尤其实体瘤(如癌和肉瘤)及白血病和淋巴癌，尤其对于例如乳腺癌、结肠直肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)和前列腺癌及胆管癌、骨癌、膀胱癌、头及颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、子宫颈癌和外阴癌、以及白血病[包括急性淋巴细胞白血病(ALL)、慢性髓细胞源性白血病(CML)以及急性髓细胞白血病(AML)等]、多发性骨髓瘤和淋巴癌。
由随后的具体实施方案、实施例和权利要求，本发明的其它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 1-6烷基”包括C 1、C 2、C 3、C 4、C 5、C 6、C 1-6、C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-5、C 2-4、C 2-3、C 3-6、C 3-5、C 3-4、C 4-6、C 4-5和C 5-6烷基。
“C 1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团。在一些实施方案中，C 1-4烷基是优选的。C 1-6烷基的例子包括：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)。术语“C 1-6烷基”还包括杂烷基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。常规烷基缩写包括：Me(-CH 3)、Et(-CH 2CH 3)、iPr(-CH(CH 3) 2)、nPr(-CH 2CH 2CH 3)、n-Bu(-CH 2CH 2CH 2CH 3)或i-Bu(-CH 2CH(CH 3) 2)。
“C 2-6烯基”是指具有2至6个碳原子和至少一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烯基是优选的。C 2-6烯基的例子包括：乙烯基(C 2)、1-丙烯基(C 3)、2-丙烯基(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。术语“C 2-6烯基”还包括杂烯基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烯基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C 2-6炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团。在一些实施方案中，C 2-4炔基是优选的。C 2-6炔基的例子包括但不限于：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)、己炔基(C 6)，等等。术语“C 2-6炔基”还包括杂炔基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。炔基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基”指的是上述定义的“C 1-6烷基、C 2-6烯基或C 2-6炔基”的二价基团。
“C 1-6亚烷基”是指除去C 1-6烷基的另一个氢而形成的二价基团，并且可以是取代或未取代的亚烷基。在一些实施方案中，C 1-4亚烷基是特别优选的。未取代的所述亚烷基包括但不限于：亚甲基(-CH 2-)、亚乙基(-CH 2CH 2-)、亚丙基(-CH 2CH 2CH 2-)、亚丁基(-CH 2CH 2CH 2CH 2-)、亚戊基(-CH 2CH 2CH 2CH 2CH 2-)、亚己基(-CH 2CH 2CH 2CH 2CH 2CH 2-)，等等。示例性的取代的所述亚烷基，例如，被一个或多个烷基(甲基)取代的所述亚烷基，包括但不限于：取代的亚甲基(-CH(CH 3)-、-C(CH 3) 2-)、取代的亚乙基(-CH(CH 3)CH 2-、-CH 2CH(CH 3)-、-C(CH 3) 2CH 2-、-CH 2C(CH 3) 2-)、取代的亚丙基(-CH(CH 3)CH 2CH 2-、-CH 2CH(CH 3)CH 2-、-CH 2CH 2CH(CH 3)-、-C(CH 3) 2CH 2CH 2-、-CH 2C(CH 3) 2CH 2-、-CH 2CH 2C(CH 3) 2-)，等等。
“C 2-6亚烯基”是指除去C 2-6烯基的另一个氢而形成的二价基团，并且可以是取代或未取代的亚烯基。在一些实施方案中，C 2-4亚烯基是特别优选的。示例性的未取代的所述亚烯基包括但不限于：亚乙烯基(-CH＝CH-)和亚丙烯基(例如，-CH＝CHCH 2-、-CH 2-CH＝CH-)。示例性的取代的所述亚烯基，例如，被一个或多个烷基(甲基)取代的亚烯基，包括但不限于：取代的亚乙基(-C(CH 3)＝CH-、-CH＝C(CH 3)-)、取代的亚丙烯基(-C(CH 3)＝CHCH 2-、-CH＝C(CH 3)CH 2-、-CH＝CHCH(CH 3)-、-CH＝CHC(CH 3) 2-、-CH(CH 3)-CH＝CH-、-C(CH 3) 2-CH＝CH-、-CH 2-C(CH 3)＝CH-、-CH 2-CH＝C(CH 3)-)，等等。
“C 2-6亚炔基”是指除去C 2-6炔基的另一个氢而形成的二价基团，并且可以是取代或未取代的亚炔基。在一些实施方案中，C 2-4亚炔基是特别优选的。示例性的所述亚炔基包括但不限于：亚乙炔基(-C≡C-)、取代或未取代的亚丙炔基(-C≡CCH 2-)，等等。
“C 1-6烷氧基”是指基团-OR，其中，R为取代或未取代的C 1-6烷基。在一些实施方案中，C 1-4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。烷氧基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。
因此，“C 1-6卤代烷基”和“C 1-6卤代烷氧基”是指上述“C 1-6烷基”和“C 1-6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 1-4卤代烷基是特别优选的，更优选C 1-2卤代烷基。在一些实施方案中，C 1-4卤代烷氧基是特别优选的，更优选C 1-2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。卤代烷基和卤代烷氧基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。
“C 3-7环烷基”是指具有3至7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，C 3-5环 烷基是优选的。在另一些实施方案中，C 3-6环烷基是优选的。在另一些实施方案中，C 5-6环烷基是优选的。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于：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)、环己基(C 6)、环己烯基(C 6)、环已二烯基(C 6)、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)，等等。环烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“3-11元杂环基”是指具有环碳原子和1至5个环杂原子的3至11元非芳香环系的基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。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3-9元杂环基，其为具有环碳原子和1至5个环杂原子的3至9元非芳香环系；在一些实施方案中，优选3-8元杂环基，其为具有环碳原子和1至4个环杂原子的3至8元非芳香环系；优选3-6元杂环基，其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系；优选3-5元杂环基，其为具有环碳原子和1至2个环杂原子的3至5元非芳香环系；优选4-8元杂环基，其为具有环碳原子和1至3个环杂原子的4至8元非芳香环系；优选4-7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；更优选5-6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。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系，其中连接点在环烷基环上，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(thiorenyl)。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(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)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：三唑啉基、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、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于：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(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。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。杂环基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C 6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如，双环)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。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)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统，而且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系统中的碳原子数目。芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“5-10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。杂芳基双环系统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环烷基或杂环基稠合的环系统，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系统中的碳原子数目。在一些实施方案中，5-6元杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。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：三唑基、噁二唑基(例如，1,2,4-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、苯并三唑基、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。杂芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
优选的杂芳基的具体例子包括：吡咯基、咪唑基、吡唑基、2-吡啶基、3-吡啶基、4-吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基(4H-l,2,4-三唑基、1H-1,2,3-三唑基、2H-l,2,3-三唑基、吡喃基、2-呋喃基、3-呋喃等、2-噻吩基、3-噻吩基、噁唑基、异噁唑基、噁唑基(1,2,4-噁唑基、1,3,4-噁唑基、1,2,5-噁唑基、噻唑基、噻二唑基(1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基)。
“羰基”无论单独使用或与其他术语连用(如氨基羰基)，表示为-C(O)-。
“氧代”表示＝O。
“硫代”表示＝S。
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。
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卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 7碳环基、C 6-C 10芳基、C 3-C 7杂环基、C 5-C 10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“癌症”包括但不限于下列癌症：乳腺、卵巢、子宫颈、前列腺、睾丸、食道、胃、皮肤、肺、骨、结肠、胰腺、甲状腺、胆道、颊腔与咽(口)、唇、舌、口腔、咽、小肠、结肠直肠、大肠、直肠、脑与中枢神经系统的癌症、成胶质细胞瘤、神经母细胞瘤、角化棘皮瘤、表皮样癌、大细胞癌、腺癌、腺瘤、滤泡癌、未分化的癌、乳头状癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、霍奇金氏病、毛细胞癌和白血病。
本文所用的术语“治疗”涉及逆转、减轻、抑制该术语适用的障碍或病症的进展或者预防之，或者这类障碍或病症的一种或多种症状。本文所用的名词“治疗”涉及动词治疗的动作，后者是如刚才所定义的。
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐，它们在可靠的医学判断范围内适用于与患者组织接触，不会产生不恰当的毒性、刺激作用、变态反应等，与合理的益处/风险比相称，就它们的预期应用而言是有效的，包括(可能的话)本发明化合物的两性离子形式。
药学上可接受的碱加成盐是与金属或胺生成的，例如碱金属与碱土金属氢氧化物或有机胺。用作阳离子的金属的实例有钠、钾、镁、钙等。适合的胺的实例有N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因。
酸性化合物的碱加成盐可以这样制备，按照常规方式使游离酸形式与足量所需的碱接触，生成盐。按照常规方式使盐形式与酸接触，再分离游离酸，可以使游离酸再生。游离酸形式在某些物理性质上多少不同于它们各自的盐形式，例如在极性溶剂中的溶解度，但是出于本发明的目的，盐还是等价于它们各自的游离酸。
盐可以是从无机酸制备的硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物，酸例如盐酸、硝酸、硫酸、氢溴酸、氢碘酸、磷酸等。代表性盐包括：氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、月桂基磺酸盐和羟乙磺酸盐等。盐也可以是从有机酸制备的，例如脂肪族一元与二元羧酸、苯基取代的烷酸、羟基烷酸、烷二酸、芳香族酸、脂肪族与芳香族磺酸等。代表性盐包括乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盆、甲基苯甲酸盐、二硝基苯甲酸盐、萘甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐等。药学上可接受的盐可以包括基于碱金属与碱土金属的阳离子，例如钠、锂、钾、钙、镁等，以及无毒的铵、季铵和胺阳离子，包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。还涵盖氨基酸的盐，例如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等(例如参见Berge S.M.et al.，"Pharmaceutical Salts,”J.Pharm.Sci.，1977；66:1-19，引入此作为参考)。
本发明化合物的药学上可接受的无毒酰胺的实例包括从C l-C 6烷基酯，其中烷基是直链或支链的。可接受的酯还包括C 5-C 7环烷基酯以及芳基烷基酯，例如但不限于苄基酯。C 1-C 4烷基酯是优选的。本发明化合物的酯可以按照常规方法制备，例如：March's Advanced Organic Chemistry,5 Edition”M.B.Smith&J.March,John Wiley&Sons，2001。
本发明化合物的药学上可接受的无毒性酰胺的实例包括从氨、伯C 1-C 6烷基胺和仲C 1-C 6二烷基胺衍生的酰胺，其中烷基是直链或支链的。在仲胺的情况下，胺也可以是含有一个氮原子的5或6元杂环的形式。从氨、C 1-C 3烷基伯胺和C 1-C 2二烷基仲胺衍生的酰胺是优选的。本发明化合物的酰胺可以按照常规方法制备，例如：March's Advanced Organic Chemistry,5 Edition”，M.B.Smith&J.March,John Wiley&Sons，2001。
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。本文可互换使用术语“人”、“患者”和“受试者”。
“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”)，还包括在受 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、化合物的药代动力学、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。有效量包括治疗有效量和预防有效量。
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的量。化合物的治疗有效量是指单独使用或与其它疗法联用时，治疗剂的量，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果的量。
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、障碍或病症的量，或足以预防与疾病、障碍或病症有关的一或多种症状的量，或防止疾病、障碍或病症复发的量。化合物的预防有效量是指单独使用或与其它药剂联用时，治疗剂的量，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量，或增强其它预防药剂的预防效果的量。
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如，本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药，或与其它治疗剂一起在单一单位剂型中同时给药。
具体实施方案
本文中，“本发明化合物”指的是以下的式(I)至式(III)化合物(包括子通式，例如(I-1)、(II-2)、(III-3)等)、其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物。
本文中，化合物使用标准的命名法命名。具有非对称中心的化合物，应该明白(除非另有说明)所有的光学异构体及其混合物均包含在内。此外，除非另有规定，本发明所包括的所有异构体化合物与碳碳双键可能以Z和E的形式出现。在不同的互变异构形式存在的化合物，一个所述化合物并不局限于任何特定的互变异构体，而是旨在涵盖所有的互变异构形式。某些化合物所使用的一般公式，包括描述、变量。除非另有规定，在这样的公式中的每个变量被定义独立于任何其他变量和在每个发生时独立地定义了一个公式中的任何一个变量的多个变量。
在一个实施方案中，本发明涉及通式(I)的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
Figure PCTCN2021105867-appb-000002
其中，
X为CR X或N；
Y为CR Y或N；
R 1、R 2、R 3、R 4和R Y独立地选自H、D、卤素、C 1-6烷基、C 2-6烯基或C 2-6炔基，或者R 1与R 2，R 3与R 4连接形成键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
其中R X为H、D、卤素、-CN、-NRR’、-OR、-SR或C 1-6烷基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
当Y为CR Y时，其中R Y、R 1与它们连接的原子一起形成C 3-5环烷基或3-5元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
环A为C 3-7环烷基、4-7元杂环基、C 6-10芳基或5-10元杂芳基；或者环A不存在，因此一个R a与L连接；或者(R a) m-环A-L-都不存在；
R a独立地选自任选被R*取代的H、D、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基或3-8元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
m＝0、1、2、3、4或5；
环B为5-6元杂芳基；
R b独立地选自任选被R*取代的H、D、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基或3-8元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
n＝0、1、2、3、4或5；
环C为C 3-7环烷基、4-7元杂环基、C 6-10芳基或5-10元杂芳基；
L为键、-O-、-S-、-N(R)-、-C(O)-、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
R 5为H、D、卤素、-CN、-NRR’、-OR、-SR、C 1-6烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
R 6为H、D、卤素、-CN、-NRR’、-OR、-SR、C 1-6烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
R*为H、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
R和R’独立地选自H、C 1-6烷基、C 2-6烯基或C 2-6炔基，或者R、R’与它们连接的氮原子形成4-8元杂环基；其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
p＝1或2。
X和Y
在一个具体实施方案中，X为CR X；在另一个具体实施方案中，X为CH；在另一个具体实施方案中，X为N。
在一个具体实施方案中，Y为CR Y；在另一个具体实施方案中，Y为N。
R 1、R 2、R 3、R 4和R Y
在一个具体实施方案中，R 1为H；在另一个具体实施方案中，R 1为D；在另一个具体实施方案中，R 1为卤素；在另一个具体实施方案中，R 1为C 1-6烷基，例如(R)-C 1-6烷基，例如(R)-甲基；在另一个具体实施方案中，R 1为C 1-6卤代烷基，例如(R)-C 1-6卤代烷基；在另一个具体实施方案中，R 1为C 2-6烯基；在另一个具体实施方案中，R 1为C 2-6炔基。
在一个具体实施方案中，R 2为H；在另一个具体实施方案中，R 2为D；在另一个具体实施方案中，R 2为卤素；在另一个具体实施方案中，R 2为C 1-6烷基，例如(R)-C 1-6烷基，例如(R)-甲基；在另一个具体实施方案中，R 2为C 1-6卤代烷基，例如(R)-C 1-6卤代烷基；在另一个具体实施方案中，R 2为C 2-6烯基；在另一个具体实施方案中，R 2为C 2-6炔基。
在一个具体实施方案中，R 3为H；在另一个具体实施方案中，R 3为D；在另一个具体实施方案中，R 3为卤素；在另一个具体实施方案中，R 3为C 1-6烷基，例如(R)-C 1-6烷基，例如(R)-甲基；在另一个具体实施方案中，R 3为C 1-6卤代烷基，例如(R)-C 1-6卤代烷基；在另一个具体实施方案中，R 3为C 2-6烯基；在另一个具体实施方案中，R 3为C 2-6炔基。
在一个具体实施方案中，R 4为H；在另一个具体实施方案中，R 4为D；在另一个具体实施方案中，R 4为卤素；在另一个具体实施方案中，R 4为C 1-6烷基，例如(R)-C 1-6烷基，例如(R)-甲基；在另一个具体实施方案中，R 4为C 1-6卤代烷基，例如(R)-C 1-6卤代烷基；在另一个具体实施方案中，R 4为C 2-6烯基；在另一个具体实施方案中，R 4为C 2-6炔基。
在一个具体实施方案中，R Y为H；在另一个具体实施方案中，R Y为D；在另一个具体实施方案中，R Y为卤素；在另一个具体实施方案中，R Y为C 1-6烷基，例如(R)-C 1-6烷基，例如(R)-甲基；在另一个具体实施方案中，R Y为C 1-6卤代烷基，例如(R)-C 1-6卤代烷基；在另一个具体实施方案中，R Y为C 2-6烯基；在另一个具体实施方案中，R Y为C 2-6炔基。
在另一个具体实施方案中，R 1和R 2中至少一个为C 1-6烷基，例如(R)-C 1-6烷基，例如(R)-甲基。
在另一个具体实施方案中，R 1与R 2，或R 3与R 4连接形成键；在另一个具体实施方案中，R 1与R 2，或R 3与R 4连接形成C 1-6亚烷基，例如亚甲基、亚乙基或亚丙基；在另一个具体实施方案中，R 1与R 2，或R 3与R 4连接形成C 2-6亚烯基；在另一个具体实施方案中，R 1与R 2，或R 3与R 4连接形成C 2-6亚炔基。
在另一个具体实施方案中，上述基团可以被一个或多个D或卤素取代，直至完全取代。
在另一个具体实施方案中，当Y为CR Y时，其中R Y、R 1与它们连接的原子一起形成C 3-5环烷基；在另一个具体实施方案中，所述C 3-5环烷基为环丙基；在另一个具体实施方案中，所述C 3-5环烷基为环丁基；在另一个具体实施方案中，所述C 3-5环烷基为环戊基；在另一个具体实施方案中，当Y为CR Y时，其中R Y、R 1与它们连接的原子一起形成3-5元杂环基；在另一个具体实施方案中，所述3-5元杂环基为氧杂环丙基、 氮杂环丙基或硫杂环丙基；在另一个具体实施方案中，所述3-5元杂环基为氧杂环丁基、氮杂环丁基或硫杂环丁基；在另一个具体实施方案中，所述3-5元杂环基为四氢呋喃基、吡咯烷基或硫杂环戊基。在另一个具体实施方案中，所述C 3-5元环烷和3-5元杂环基可以被一个或多个D或卤素取代，直至完全取代。
环A
在一个具体实施方案中，环A不存在；在另一个具体实施方案中，环A为C 3-7环烷基；在另一个具体实施方案中，环A为4-7元杂环基；在另一个具体实施方案中，环A为C 6-10芳基；在另一个具体实施方案中，环A为5-10元杂芳基。
在另一个具体实施方案中，环A为5-6元杂芳基。在另一个具体实施方案中，环A为4-7元杂环基，优选选自哌嗪基或哌啶基。
在另一个具体实施方案中，环A选自
Figure PCTCN2021105867-appb-000003
其中，A 1为CR a1或N；A 2为CR a2或N；A 3为CR a3或N；A 4为CR a4或N；A 5为CR a5或N；R a1、R a2、R a3、R a4和R a5如上文针对R a所定义。
在另一个具体实施方案中，(R a) m-环A-L-选自
Figure PCTCN2021105867-appb-000004
Figure PCTCN2021105867-appb-000005
R a
在一个具体实施方案中，R a独立地选自任选被R*取代的H、D、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基或3-8元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；在另一个具体实施方案中，其中一个R a为H；在另一个具体实施方案中，其中一个R a为D；在另一个具体实施方案中，其中一个R a为卤素；在另一个具体实施方案中，其中一个R a为-CN；在另一个具体实施方案中，其中一个R a为-NRR’；在另一个具体实施方案中，其中一个R a为-OR；在另一个具体实施方案中， 其中一个R a为-SR；在另一个具体实施方案中，其中一个R a为-C(O)R；在另一个具体实施方案中，其中一个R a为-C(O)OR；在另一个具体实施方案中，其中一个R a为-C(O)NRR’；在另一个具体实施方案中，其中一个R a为-OC(O)R’；在另一个具体实施方案中，其中一个R a为-NRC(O)R’；在另一个具体实施方案中，其中一个R a为-OC(O)NRR’；在另一个具体实施方案中，其中一个R a为-NRC(O)NRR’；在另一个具体实施方案中，其中一个R a为-S(O) pR；在另一个具体实施方案中，其中一个R a为C 1-6烷基；在另一个具体实施方案中，其中一个R a为C 2-6烯基；在另一个具体实施方案中，其中一个R a为C 2-6炔基；在另一个具体实施方案中，其中一个R a为C 3-7环烷基；在另一个具体实施方案中，其中一个R a为3-8元杂环基；在另一个具体实施方案中，其中一个R a被一个、两个或三个R*取代；在另一个具体实施方案中，其中所述基团可以被一个或多个D或卤素取代，直至完全取代。
在另一个具体实施方案中，R a独立地选自H、D、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D取代，直至完全氘代。
m
在一个具体实施方案中，m＝0；在另一个具体实施方案中，m＝1；在另一个具体实施方案中，m＝2；在另一个具体实施方案中，m＝3；在另一个具体实施方案中，m＝4；在另一个具体实施方案中，m＝5。
环B
在一个具体实施方案中，环B为5-6元杂芳基，例如吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡咯基、呋喃基、噻吩基、吡唑基或吡啶基；优选为吡唑基。
R b
在一个具体实施方案中，R b独立地选自任选被R*取代的H、D、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基或3-8元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；在另一个具体实施方案中，其中一个R b为H；在另一个具体实施方案中，其中一个R b为D；在另一个具体实施方案中，其中一个R b为卤素；在另一个具体实施方案中，其中一个R b为-CN；在另一个具体实施方案中，其中一个R b为-NRR’；在另一个具体实施方案中，其中一个R b为-OR；在另一个具体实施方案中，其中一个R b为-SR；在另一个具体实施方案中，其中一个R b为-C(O)R；在另一个具体实施方案中，其中一个R b为-C(O)OR；在另一个具体实施方案中，其中一个R b为-C(O)NRR’；在另一个具体实施方案中，其中一个R b为-OC(O)R’；在另一个具体实施方案中，其中一个R b为-NRC(O)R’；在另一个具体实施方案中，其中一个R b为-OC(O)NRR’；在另一个具体实施方案中，其中一个R b为-NRC(O)NRR’；在另一个具体实施方案中，其中一个R b为-S(O) pR；在另一个具体实施方案中，其中一个R b为C 1-6烷基；在另一个具体实施方 案中，其中一个R b为C 2-6烯基；在另一个具体实施方案中，其中一个R b为C 2-6炔基；在另一个具体实施方案中，其中一个R b为C 3-7环烷基；在另一个具体实施方案中，其中一个R b为3-8元杂环基；在另一个具体实施方案中，其中一个R b被一个、两个或三个R*取代；在另一个具体实施方案中，其中所述基团可以被一个或多个D或卤素取代，直至完全取代。
在另一个具体实施方案中，R b独立地选自任选被R*取代的H、D、卤素、-CN、-NRR’、-OR、-SR、C 1-6烷基或C 1-6卤代烷基。
n
在一个具体实施方案中，n＝0；在另一个具体实施方案中，n＝1；在另一个具体实施方案中，n＝2；在另一个具体实施方案中，n＝3；在另一个具体实施方案中，n＝4；在另一个具体实施方案中，n＝5。
环C
在一个具体实施方案中，环C为C 3-7环烷基；在另一个具体实施方案中，环C为4-7元杂环基；在另一个具体实施方案中，环C为C 6-10芳基；在另一个具体实施方案中，环C为5-10元杂芳基。
在另一个具体实施方案中，环C为5-6元杂芳基或苯基；优选为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或三唑基；优选吡唑基。
在另一个具体实施方案中，环C为C 3-7环烷基或4-7元杂环基，优选环戊基或四氢吡喃基。
L
在一个具体实施方案中，L为键；在另一个具体实施方案中，L为-O-；在另一个具体实施方案中，L为-S-；在另一个具体实施方案中，L为-N(R)-；在另一个具体实施方案中，L为-C(O)-；在另一个具体实施方案中，L为C 1-6亚烷基；在另一个具体实施方案中，L为C 2-6亚烯基；在另一个具体实施方案中，L为C 2-6亚炔基。
在另一个具体实施方案中，L为键、-C(O)-或C 1-6亚烷基。
R 5
在一个具体实施方案中，R 5为H；在另一个具体实施方案中，R 5为D；在另一个具体实施方案中，R 5为卤素；在另一个具体实施方案中，R 5为-CN；在另一个具体实施方案中，R 5为-NRR’；在另一个具体实施方案中，R 5为-OR；在另一个具体实施方案中，R 5为-SR；在另一个具体实施方案中，R 5为C 1-6烷基；在另一个具体实施方案中，R 5为C 2-6烯基；在另一个具体实施方案中，R 5为C 2-6炔基；在另一个具体实施方案中，R 5可以被一个或多个D或卤素取代，直至完全取代。
R 6
在一个具体实施方案中，R 6为H；在另一个具体实施方案中，R 6为D；在另一个具体实施方案中，R 6为卤素；在另一个具体实施方案中，R 6为-CN；在另一个具体实施方案中，R 6为-NRR’；在另一个具体实施方案中，R 6为-OR；在另一个具体实施方案中，R 6为-SR；在另一个具体实施方案中，R 6为C 1-6烷基；在另一个具体实施方案中，R 6为C 2-6烯基；在另一个具体实施方案中，R 6为C 2-6炔基；在另一个具体实施方案中，R 6可以被一个或多个D或卤素取代，直至完全取代。
R*
在一个具体实施方案中，R*为H；在另一个具体实施方案中，R*为卤素；在另一个具体实施方案中，R*为-CN；在另一个具体实施方案中，R*为-NRR’；在另一个具体实施方案中，R*为-OR；在另一个具体实施方案中，R*为-SR；在另一个具体实施方案中，R*为-C(O)R；在另一个具体实施方案中，R*为-C(O)OR；在另一个具体实施方案中，R*为-C(O)NRR’；在另一个具体实施方案中，R*为-OC(O)R’；在另一个具体实施方案中，R*为-NRC(O)R’；在另一个具体实施方案中，R*为-OC(O)NRR’；在另一个具体实施方案中，R*为-NRC(O)NRR’；在另一个具体实施方案中，R*为-S(O) pR；在另一个具体实施方案中，R*为C 3-7环烷基；在另一个具体实施方案中，R*为3-8元杂环基；在另一个具体实施方案中，R*为C 6-10芳基；在另一个具体实施方案中，R*为5-10元杂芳基；在另一个具体实施方案中，R*可以被一个或多个D或卤素取代，直至完全取代。
R和R’
在一个具体实施方案中，R和R’独立地为H；在另一个具体实施方案中，R和R’独立地为C 1-6烷基；在另一个具体实施方案中，R和R’独立地为C 2-6烯基；在另一个具体实施方案中，R和R’独立地为C 2-6炔基；在另一个具体实施方案中，R、R’与它们连接的氮原子形成4-8元杂环基；在另一个具体实施方案中，R和R’可以被一个或多个D或卤素取代，直至完全取代。
p
在一个具体实施方案中，p＝1；在另一个具体实施方案中，p＝2。
以上任一具体实施方案中的任一技术方案或其任意组合，可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如，X的任一技术方案或其任意组合，可以与Y、R 1-R 6、环A、环B、环C、R a、R b、R*、m、n、p、R和R’等的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合，限于篇幅，不再一一列出。
在更具体的实施方案中，本发明提供了通式(I)的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有以下通式结构：
Figure PCTCN2021105867-appb-000006
其中，各基团如上下文所定义。
在更具体的实施方案中，本发明提供了通式(I-1)或(I-2)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
Figure PCTCN2021105867-appb-000007
其中，
环C为C 3-7环烷基或4-7元杂环基；优选环戊基或四氢吡喃基；
环B为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡咯基、呋喃基、噻吩基、吡唑基或吡啶基；
R 5优选H、D、卤素、-CN、-NRR’、-OR、-SR，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；优选地，R 5位于环C与母核相连的C原子上；
其他基团如上下文所定义。
在更具体的实施方案中，本发明提供了通式(I-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
Figure PCTCN2021105867-appb-000008
其中，
环C为5-6元杂芳基或苯基；优选为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或三唑基；优选吡唑基；
其他基团如上下文所定义。
在另一更具体的实施方案中，本发明提供了上述通式(I-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
环B为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡咯基、呋喃基、噻吩基、吡唑基或吡啶基；
其他基团如上下文所定义。
在更具体的实施方案中，本发明提供了通式(II)或(II-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
Figure PCTCN2021105867-appb-000009
其中，
环A为不存在、C 3-7环烷基或4-7元杂环基；
其他基团如上下文所定义。
在另一更具体的实施方案中，本发明提供了上述通式(II)或(II-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
环A不存在或为4-7元杂环基；优选哌啶基或哌嗪基；
环B为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡咯基、呋喃基、噻吩基、吡唑基或吡啶基；
L为键、-O-、-S-、-N(R)-、-C(O)-或C 1-6亚烷基；
R 5和R 6独立地为C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D取代，直至完全氘代；
其他基团如上下文所定义。
在更具体的实施方案中，本发明提供了通式(III)或(III-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
Figure PCTCN2021105867-appb-000010
其中，
环C为5-6元杂芳基或苯基；优选为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或三唑基；优选吡唑基；
其他基团如上下文所定义。
在另一更具体的实施方案中，本发明提供了上述通式(III)或(III-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
环B为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡咯基、呋喃基、噻吩基、吡唑基或吡啶基；
其他基团如上下文所定义。
在更具体的实施方案中，本发明提供了通式(III-2)或(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
Figure PCTCN2021105867-appb-000011
其中，
A 1为CR a1或N；A 2为CR a2或N；A 5为CR a5或N；
其他基团如上下文所定义。
在另一更具体的实施方案中，本发明提供了上述通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
A 3为CR a3或N；
R a1、R a2、R a3、R a5、R 5和R 6独立地为H、D、卤素、-CN、-OR、-SR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’或C 1-6烷基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
其他基团如上下文所定义。
在另一更具体的实施方案中，本发明提供了上述通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
A 3为CR a3或N；
R a1、R a2、R a3和R a5独立地选自H、D、卤素、-CN、-OH、-C(O)NH 2、C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代；
R 5和R 6独立地为C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代。
在另一更具体的实施方案中，本发明提供了上述通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
A 3为CR a3或N；
R a1为H或D；
R a2为H、D、卤素、-CN、-OH、-C(O)NH 2、C 1-6烷基或C 1-6卤代烷基；
R a3为H、D或-OH；
R a5为H或D；
R 5为C 1-6烷基或C 1-6卤代烷基；优选甲基；
R 6为C 1-6烷基或C 1-6卤代烷基；优选甲基。
在更具体的实施方案中，本发明提供了通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
Figure PCTCN2021105867-appb-000012
其中，
A 3为CR a3或N；
R a1、R a2、R a3、R a5、R 5和R 6独立地为H、D、卤素、-OR、-SR、-NRR’、C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代；
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，或者R、R’与它们连接的氮原子形成4-8元杂环基；其中所述基团可以被一个或多个D取代，直至完全氘代。
在另一更具体的实施方案中，本发明提供了上述通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
A 3为CR a3或N；
R a1、R a2、R a3和R a5独立地选自H、D、卤素、-OH、C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代；
R 5和R 6独立地为C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代。
在另一更具体的实施方案中，本发明提供了上述通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
A 3为CR a3或N；
R a1为H或D；
R a2为H、D、卤素、C 1-6烷基或C 1-6卤代烷基；
R a3为H、D或-OH；
R a5为H或D；
R 5为C 1-6烷基或C 1-6卤代烷基；优选甲基；
R 6为C 1-6烷基或C 1-6卤代烷基；优选甲基。
在更具体的实施方案中，本发明提供了通式(III-4)化合物，或其药学上可接受的盐、对映异构体、非对 映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
Figure PCTCN2021105867-appb-000013
其中，
A 4为CR a4或N；
R a1、R a2、R a4、R a5、R 5和R 6独立地为H、D、卤素、-CN、-OR、-SR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’或C 1-6烷基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
其他基团如上下文所定义。
在另一更具体的实施方案中，本发明提供了上述通式(III-4)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
A 4为CR a4或N；
R a1、R a2、R a4和R a5独立地选自H、D、卤素、-CN、-OH、-C(O)NH 2、C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代；
R 5和R 6独立地为C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代。
在另一更具体的实施方案中，本发明提供了上述通式(III-4)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
A 4为CR a4或N；
R a1为H、D或卤素；
R a2为H、D、卤素、-CN、-OH、-C(O)NH 2、C 1-6烷基或C 1-6卤代烷基；
R a4为H、D或-OH；
R a5为H或D；
R 5为C 1-6烷基或C 1-6卤代烷基；优选甲基；
R 6为C 1-6烷基或C 1-6卤代烷基；优选甲基。
优选的本发明化合物包括但不限于下面列举的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
Figure PCTCN2021105867-appb-000014
Figure PCTCN2021105867-appb-000015
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，包括外消旋体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。
本领域技术人员将理解，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。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H 2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5H 2O))和多水合物(x为大于1的数，例如，二水合物(R·2H 2O)和六水合物(R·6H 2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。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“多晶型物”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)。所有的多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。化合物的各种多晶型物可在不同 的条件下通过结晶制备。
本发明还包括同位素标记的化合物，它们等同于式(I)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。氚、即 3H和碳-14、即 14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即 2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
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本发明化合物，当将这种前药给予患者时，其在体内释放母体化合物。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、氨基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、氨基或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。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。
本发明还提供药物制剂，包含治疗有效量的式(I)化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋形剂。所有这些形式都属于本发明。
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本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。
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。
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、阴道给药、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,17th 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，或从持续释放给药系统中给予。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
如本文中所述，已知ATR激酶在肿瘤发生及许多其它疾病中起作用。我们已经发现式(I)化合物具有强有力的抗肿瘤活性，所述抗肿瘤活性被认为通过抑制ATR激酶获得。
从而，本发明化合物具有作为抗肿瘤药剂的价值。尤其，本发明化合物具有在实体和/或液体肿瘤疾病的遏制和/或治疗中作为抗增殖、凋亡和/或抗侵袭药剂的价值。尤其，预期本发明化合物有用于预防或治疗对抑制ATR敏感的那些肿瘤。此外，预期本发明化合物有用于预防或治疗单独或部分由ATR介导的那些肿瘤。因此，所述化合物可用于在需要此类治疗温血动物中产生ATR酶抑制作用。
如本文中所述，ATR激酶的抑制剂应对增生性疾病(如癌症)，尤其实体肿瘤(如癌和肉瘤)及白血病和淋巴癌的治疗，尤其对于例如乳腺癌、结肠直肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)和前列腺癌及胆管癌、骨癌、膀胱癌、头及颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、子宫颈癌和外阴癌、以及白血病[包括急性淋巴细胞白血病(ALL)、慢性髓细胞源性白血病(CML)以及急性髓细胞白血病(AML)等]、多发性骨髓瘤和淋巴癌的治疗具有治疗价值。
有用于治疗患者中的癌症的抗癌作用包括但不局限于抗肿瘤作用、响应率、疾病进展的时间及存活率。本发明治疗方法的抗肿瘤作用包括但不局限于肿瘤生长的抑制、肿瘤生长的延迟、肿瘤的退化、肿瘤的收缩、治疗停止后肿瘤再生长时间的延长及疾病进展的减慢。抗癌作用包括预防性治疗以及现存在疾病的治疗。
ATR激酶抑制剂或其药学上可接受的盐还有用于治疗癌症患者，所述癌症包括但不局限于血癌，如白血病、多发性骨髓瘤；淋巴瘤，如霍奇金病、非霍奇金淋巴瘤(包括套细胞淋巴瘤)和骨髓增生异常综合征，以及还有实体肿瘤及其转移灶(metastases)，如乳腺癌、肺癌(非小细胞肺癌(NSCL)、小细胞肺癌(SCLC)、鳞状细胞癌)、子宫内膜癌、中枢神经系统肿瘤(如胶质瘤、胚胎期发育不良性神经上皮肿瘤、多形性成胶质细胞瘤、混合型胶质瘤、髓母细胞瘤、成视网膜细胞瘤、成神经细胞瘤、生殖细胞瘤和畸胎瘤、胃肠道癌(如胃癌)、食道癌、肝细胞(肝)癌、胆管癌、结肠和直肠癌、小肠癌、胰腺癌、皮肤癌如黑素瘤(尤其转移性黑素瘤)、甲状腺癌、头及颈癌和唾液腺癌、前列腺癌、睾丸癌、卵巢癌、子宫颈癌、子宫癌、外阴癌、膀胱癌、肾癌(包括肾细胞癌、明细胞和肾嗜酸细胞瘤)、鳞状细胞癌、肉瘤如骨肉瘤、软骨肉瘤、平滑肌肉瘤、软组织肉瘤、尤因肉瘤、胃肠道间质瘤(GIST)、卡波西肉瘤和儿科癌如横纹肌肉瘤和成神经细胞瘤。
预期本发明化合物以及包括给予或使用ATR激酶抑制剂或其药学上可接受的盐的治疗方法特别有用于治疗患有肺癌、前列腺癌、黑素瘤、卵巢癌、乳腺癌、子宫内膜癌、肾癌、胃癌、肉瘤、头及颈癌、中枢神经系统的肿瘤及其转移灶的患者，还有用于治疗患有急性髓细胞白血病的患者。
本发明化合物的有效量通常在平均日剂量为0.01mg至50mg化合物/千克患者体重，优选0.1mg至25mg化合物/千克患者体重，以单次或多次给药。通常，本发明化合物可向该有此治疗需要的患者以每位患者约1mg至约3500mg的日剂量范围给药，优选10mg至1000mg。例如，每位患者的日剂量可为10、20、30、40、50、60、70、80、90、100、150、200、250、300、350、400、500、600、700、800、900或1000mg。可每天、每周(或间隔数天)或以间歇时间表，给药一次或多次。例如，可在每周的基础上(例如每周一)，每天给予所述化合物一次或多次，不定地或持续几周，例如4-10周。或者，可每天给药持续几天(例如2-10天)，然后几天(例如1-30天)不给药所述化合物，不定地重复该循环或重复给定的次数，例如4-10个循环。例如，本发明化合物可每天给药持续5天，然后间断9天，然后再每天给药持续5天，然后间断9天，以此类推，不定地重复该循环或共重复4-10次。
组合治疗
本文中定义的治疗可作为单独治疗应用，或除本发明化合物之外，可包括常规外科手术或放疗或化疗。因此，本发明化合物还可与用于治疗癌症的现有治疗药剂联合使用。
联合使用的合适的药剂包括：
(i)内科肿瘤学所用的抗增殖/抗肿瘤药物及其组合，如烷化剂(例如顺铂、卡铂、环磷酰胺、氮芥、美法仑(melphalan)、苯丁酸氮芥、白消安(Busulphan)和亚硝基脲)；抗代谢药(例如抗叶酸剂，如诸如5-氟尿嘧啶和替加氟(tegafur)之类的氟尿嘧啶、雷替曲塞(raltitrexed)、甲氨碟呤、阿糖胞苷、羟基脲和吉西他滨(gemcitabine))；抗肿瘤抗生素(例如蒽环类，如阿霉素(adriamycin)、博莱霉素(bleomycin)、多柔比星(doxorubicin)、道诺霉素(daunomycin)、表柔比星(epirubicin)、伊达比星(idarubicin)、丝裂霉素C(mitomycin-C)、放线菌素D(dactinomycin)和光神霉素(mithramycin))；抗有丝分裂药剂(例如长春花生物碱，如长春新碱、长春碱、长春地辛和长春瑞滨；和紫杉烷类，如紫杉醇和多西他赛(taxotere))；拓扑异构酶抑制剂(例如表鬼臼毒素，如依托泊苷(etoposide)和替尼泊苷(teniposide)、安吖啶(amsacrine)、拓扑替康(topotecan)和喜树碱(camptothecin))；和DNA损伤修复抑制剂(例如奥拉帕利(olaparib)，如芦卡帕利(rucaparib)和尼拉帕利(niraparib))；
(ii)细胞生长抑制剂，如抗雌激素(例如他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)和艾多昔芬(iodoxyfene))、雌激素受体下调剂(例如氟维司群(fulvestrant))、抗雄激素(例如比卡鲁胺(bicalutamide)、氟他胺(flutamide)、尼鲁米特(nilutamide)和乙酸环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林(goserelin)、亮丙瑞林(leuprorelin)和布舍瑞林(buserelin))、孕激素(例如乙酸甲地孕酮)、芳化酶抑制剂(例如阿那曲唑(Anastrozole)、来曲唑(letrozole)、伏氯唑(vorazole)和依西美坦(exemestane))和5α-还原酶的抑制剂，如非那雄胺(finasteride)；
(iii)抗侵袭药剂(例如c-Src激酶家族抑制剂，如AZD0530和达沙替尼)和金属蛋白酶抑制剂，如马立马司他(marimastat)；以及尿激酶型纤溶酶原激活物受体功能的抑制剂)；
(iv)生长因子功能抑制剂：例如生长因子抗体和生长因子受体抗体(例如抗erbB2抗体曲妥珠单抗[Herceptin TM]和抗erbBl抗体西妥昔单抗[C225])；此类抑制剂还包括例如酪氨酸激酶抑制剂，例如表皮生长 因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂，如吉非替尼、厄洛替尼和CI 1033；和erbB2酪氨酸激酶抑制剂，如拉帕替尼)；肝细胞生长因子家族的抑制剂；血小板衍生生长因子家族的抑制剂，如伊马替尼；丝氨酸/苏氨酸激酶的抑制剂(例如Ras/Raf信号传导抑制剂，如法尼基转移酶抑制剂，例如索拉非尼(BAY43-9006))和通过MEK和/或Akt激酶的细胞信号传导的抑制剂；
(v)抗血管生成药剂，如抑制血管内皮生长因子的作用的那些药剂[例如抗血管内皮细胞生长因子抗体贝伐珠单抗(Avastin TM)；和VEGF受体酪氨酸激酶抑制剂，如ZD6474、AZD2171、伐他拉尼(vatalanib)和舒尼替尼(sunitinib)，和通过其它机理起作用的化合物(例如利诺胺(linomide)、整联蛋白αvβ3功能抑制剂和血管生成抑制素)]；
(vi)血管破坏剂，如考布他汀(combretastatin)；
(vii)反义疗法，例如针对以上列出的靶标的那些，如ISIS 2503；
(viii)基因治疗方法，包括置换异常基因(如异常ρ53或异常BRCA1或BRCA2)的方法；GDEPT(基因导向的(gene-directed)酶前药治疗)方法，如使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的那些方法；和提高患者对化疗或放疗的耐受性的方法，如多药耐药性基因疗法；和
(ix)免疫治疗方法，包括提高患者的肿瘤细胞的免疫原性的体外和体内方法，如用细胞因子(如白介素2、白介素4或粒细胞-巨噬细胞集落刺激因子)转染；降低T-细胞麻痹(anergy)的方法；使用转染的免疫细胞(如细胞因子转染的树突细胞)的方法；使用细胞因子转染的肿瘤细胞系的方法和使用抗独特型抗体的方法。
实施例
本文所用的材料或试剂为可购买到的或由本领域通常已知的合成方法制备。以下反应路线例示了本发明化合物的具体合成方法。
具体如下：
关键中间体a1-a4的制备:
Figure PCTCN2021105867-appb-000016
将原料5,7-二氯吡唑并[1,5-a]嘧啶a1-1(53.2mmol,10g)溶于30mL 1N NaOH水溶液中，升温至90℃反应0.5小时，停止反应。冷却至室温，缓慢加入1N盐酸溶液调节pH至7，二氯甲烷萃取，无水Na 2SO 4干燥，得到中间体a1-2(9g，收率定量)，LC-MS:[M+H] +:170。
在微波反应瓶中加入中间体a1-2(47.3mmol,8g)和(R)-2-甲基吗啉(94.6mmol,9.56g)。30mL N-甲基吡咯烷酮NMP溶解后，190℃微波加热反应6小时。停止反应，减压蒸除溶剂，flash柱层析分离，得到中间体a1-3(6.4g，收率：58％)，LC-MS:[M+H] +:235。
在反应瓶中加入中间体a1-3(27.4mmol,6.4g)和三乙胺(54.8mmol，5.55g)，20mL三氯氧磷溶解。 升温至80℃搅拌2小时，停止反应。缓慢加入冰水100mL淬灭反应，滴加1N NaOH水溶液调节pH至8，二氯甲烷萃取，无水Na 2SO 4干燥，flash柱层析分离，得到中间体a1(4.4g，收率：64％)，LC-MS:[M+H] +:253。
Figure PCTCN2021105867-appb-000017
氮气保护下，将中间体a1(15.9mmol,4.0g)和中间体3,5-二甲基-1H-吡唑-4-硼酸频哪醇酯a2-1(24.0mmol,5.3g)溶于1,4-二氧六环和水的50mL混合液中(v/v:9/1)。加入碳酸钠(32mmol,3.39g)和Pd(dppf)Cl 2(1.6mmol,1.17g)，加热回流反应10小时。停止反应，过滤，减压蒸除溶剂，加水50mL，乙酸乙酯萃取，flash柱层析分离，得到中间体a2(3.2g，收率：65％)，LC-MS:[M+H] +:313。
Figure PCTCN2021105867-appb-000018
冰浴下，将中间体a2(10.25mmol,3.2g)溶于15mL无水二氯甲烷中，缓慢分批加入N-溴代琥珀酰亚胺NBS(10.3mmol,1.8g)，并继续搅拌2小时。停止反应，加入50mL饱和氯化铵水溶液，二氯甲烷萃取。无水硫酸钠干燥，flash柱层析分离，得中间体a3-1(3.9g，收率：98％)。LC-MS:[M+H] +:392。
氮气保护下，将中间体a3-1(3.32mmol,1.3g)和原料a3-2(4.98mmol,1.38g)溶于20mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钠(6.64mmol,704mg)和Pd(dppf)Cl 2(0.33mmol,241mg)，微波100℃下加热反应1小时。停止反应，过滤，向体系加水40mL，乙酸乙酯萃取，无水硫酸钠干燥，flash柱层析分离，得到中间体a3(400mg，收率：26％)。LC-MS:[M+H] +:463。
Figure PCTCN2021105867-appb-000019
冰浴下，将中间体a1(1.63mmol,410mg)溶于15mL无水二氯甲烷中，缓慢分批加入N-碘代琥珀酰亚胺NIS(1.79mmol,403mg)，并继续搅拌2小时。停止反应，加入50mL饱和氯化铵水溶液，二氯甲烷萃取。无水硫酸钠干燥，得中间体a4-1(700mg，粗品)。LC-MS:[M+H] +:379。
氮气保护下，将中间体a4-1(700mg)和原料a3-2(2.44mmol,678mg)溶于20mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钾(3.26mmol,451mg)和Pd(dppf)Cl 2(0.16mmol,117mg)，微波100℃ 下加热反应1小时。停止反应，过滤，向体系加水40mL，乙酸乙酯萃取，无水硫酸钠干燥，flash柱层析分离，得到中间体a4(220mg，两步总收率：34％)。LC-MS:[M+H] +:403。
关键中间体b1-b7的制备:
Figure PCTCN2021105867-appb-000020
在反应瓶中加入原料b1-1(36.7mmol,7g)，碳酸铯(92.1mmol,30.03g)，100mL DMF溶解，缓慢加入原料b1-2(36.8mmol,8.43g)。升温至80℃反应4小时后停止反应，缓慢加水300mL，乙酸乙酯萃取，无水Na 2SO 4干燥，flash柱层析分离，得到中间体b1-3(3.4g，收率：23％)和中间体b1-4(7.0g，收率：47％)，LC-MS:[M+H] +:413。
Figure PCTCN2021105867-appb-000021
在-78℃下，将中间体b1-3(6.3mmol,2.6g)溶于60mL无水THF中，逐滴加入丁基锂(3.0mL,2.5M)，30分钟后，加入异丙氧基硼酸频哪醇酯(9.5mmol,1.88mL)。-78℃继续反应3小时，加入150mL饱和氯化铵水溶液淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，得到粗品中间体b1。直接用于下一步反应。LC-MS:[M+H] +:460。
参照中间体b1的合成路线，以b1-4为原料，得到粗品中间体b2，LC-MS:[M+H] +:460。
Figure PCTCN2021105867-appb-000022
冰浴下，氮气保护下，将原料a2-1(2.25mmol,500mg)溶于15mL DMF中，分批加入NaH(4.5mmol,180mg)，搅拌30分钟后，缓慢加入4-((甲基磺酰基)氧基)哌啶-1-甲酸叔丁酯(3.37mmol,943mg)，升温至90℃继续反应2小时。停止反应，缓慢向体系加入50mL冰水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，得到粗品中间体b3，直接用于下一步反应。LC-MS:[M+H] +:406。
Figure PCTCN2021105867-appb-000023
氮气保护下，-78℃下，将原料b4-1(1.54mmol,150mg)溶于10mL无水THF中，逐滴加入正丁基锂(1.0mL,2.5M)，30分钟后，加入三甲基氯化锡(2.31mmol,462mg)。-78℃下继续反应3小时，停止反应，加入40mL饱和氯化铵水溶液淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，得到粗品中间体b4。直接用于下一步反应。LC-MS:[M+H] +:260。
Figure PCTCN2021105867-appb-000024
冰浴下，将原料a2-1(2.0mmol,444mg)，哌嗪-1-甲酸叔丁酯(3.0mmol,559mg)，DIEA(5.0mmol,645mg)溶于15mL四氢呋喃中。搅拌5分钟后，缓慢向体系加入三光气(4.0mmol,1.08g)，冰浴下继续搅拌2小时后停止反应。向该反应液加水40mL，二氯甲烷萃取，flash柱层析分离，得到中间体b5(180mg,收率：21％)。LC-MS:[M+H] +:435。
Figure PCTCN2021105867-appb-000025
将原料b6-1(9.2mmol,2.0g)和N-Boc-肼(10.1mmol,1.33g)溶于30mL醋酸中。搅拌5分钟后，缓慢加入NaBH 3CN(27.6mmol,1.7g)，室温下反应10小时。停止反应，向体系中加入80mL冰水淬灭反应，减压蒸除溶剂。用饱和NaHCO 3水溶液调体系pH至9左右，二氯甲烷萃取。无水硫酸钠干燥，得到粗品中间体b6-2(一对非对应异构体)。
在反应瓶中加入中间体b6-2(粗品)和乙酰丙酮(10.6mmol,1.1mL)，30mL醋酸溶解。向该混合物中缓慢加入3mL氢溴酸(45％)，室温反应2小时。停止反应，减压蒸除溶剂，得到粗品中间体b6-3(3.0g，粗品)。LC-MS:[M+H] +:198。
将粗品中间体b6-3(3.0g)、Boc酸酐(11.7mmol,2.5g)、三乙胺(23.4mmol,3.4mL)和DMAP(0.78mmol,95mg)溶于20mL四氢呋喃中，室温反应12小时。停止反应，加水100mL，乙酸乙酯萃取，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，得到黄色油状产品(2.4g)。将该黄色油状物溶于10mL DMF中并置于冰浴下，缓慢分批加入NBS(8.88mmol，1.58g)，室温反应8小时后，加入50mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，flash柱层析分离，得到中间体b6-4(1.2g，三步总收率：35％)和中间体b6-5(600mg，三步总收率：17％)。LC-MS:[M+H] +:377。
氮气保护下，在微波反应瓶中加入中间体b6-4(1.25mmol,470mg)，双联硼酸频那醇酯(2.34mmol,595mg)，DIEA(2.5mmol,323mg)和Pd(Amphos)Cl 2(0.13mmol,90mg)，16mL 2-甲基-四氢呋喃和甲醇的混合溶液溶解(v/v，1/1)。微波升温至100℃反应1小时后停止反应。过滤，加水30mL，乙酸乙酯萃取，flash柱层析分离，得到中间体b6(120mg,收率：23％)。LC-MS:[M+H] +:424。
参照中间体b6的合成，以b6-5为原料，合成中间体b7。LC-MS:[M+H] +:424。
实施例1：
Figure PCTCN2021105867-appb-000026
氮气保护下，将原料a1-1(1.06mmol,200mg)和中间体b1(1.59mmol,730mg)溶于10mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钠(2.12mmol,225mg)和Pd(dppf)Cl 2(0.1mmol,73mg)。95℃下加热反应3小时。停止反应，过滤，向体系加水40mL，乙酸乙酯萃取，无水硫酸钠干燥，flash柱层析分离，得到化合物A1-1(330mg，收率：64％)。LC-MS:[M+H] +:485。
将中间体A1-1(0.68mmol,330mg)和(R)-2-甲基吗啉(1.36mmol,138mg)溶于5mL DMSO中，加入KF(2.04mmol,118mg)，微波升温至150℃反应2小时。停止反应，加入30mL水，二氯甲烷萃取。无水硫酸钠干燥，flash柱层析分离，得到化合物A1-2(220mg，收率：59％)。LC-MS:[M+H] +:550。
冰浴下，将中间体A1-2(0.40mmol,220mg)溶于5mL无水二氯甲烷中，缓慢分批加入N-溴代琥珀酰亚胺NBS(0.40mmol,72mg)，并继续搅拌2小时。停止反应，加入20mL饱和氯化铵水溶液，二氯甲烷萃取。无水硫酸钠干燥，flash柱层析分离，得到化合物A1-3(140mg，收率：56％)。LC-MS:[M+H] +:629。
氮气保护下，将中间体A1-3(0.22mmol,140mg)和原料a3-2(0.33mmol,92mg)溶于5mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钾(0.44mmol,61mg)和Pd(dppf)Cl 2(0.02mmol,15mg)。95℃下加热反应2小时。停止反应，过滤，向体系加水20mL，乙酸乙酯萃取，无水硫酸钠干燥，flash柱层析分离，得到中间体A1-4(45mg，收率：29％)。LC-MS:[M+H] +:700。
将中间体A1-4(45mg)溶于5mL二氯甲烷中，加入3mL三氟乙酸，室温反应2小时。停止反应，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调节pH至10，二氯甲烷萃取，制备色谱分离，得到目标化合物A1(8mg,收率：24％)，LC-MS:[M+H] +:516。
参照实施例1路线合成如下化合物：
Figure PCTCN2021105867-appb-000027
实施例2：
Figure PCTCN2021105867-appb-000028
氮气保护下，将中间体a1(0.79mmol,200mg)和中间体b3(1.19mmol,粗品)溶于10mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钠(1.60mmol,170mg)和Pd(dppf)Cl 2(0.08mmol,59mg)。95℃下加热反应10小时。停止反应，过滤，向体系加水40mL，乙酸乙酯萃取，无水硫酸钠干燥，flash柱层析分离，得到化合物A3-1(230mg，收率：59％)。LC-MS:[M+H] +:496。
冰浴下，将中间体A3-1(0.46mmol,230mg)溶于15mL无水二氯甲烷中，缓慢分批加入N-溴代琥珀酰亚胺NBS(0.51mmol,90mg)，并继续搅拌2小时。停止反应，加入30mL饱和氯化铵水溶液，二氯甲烷萃取。无水硫酸钠干燥，flash柱层析分离，得化合物A3-2(220mg，收率：83％)。LC-MS:[M+H] +:575。
氮气保护下，将中间体A3-2(0.38mmol,220mg)和原料a3-2(0.76mmol,211mg)溶于10mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钾(0.76mmol,105mg)和Pd(dppf)Cl 2(0.038mmol,28mg)。微波100℃下加热反应2小时。停止反应，过滤，向体系加水30mL，乙酸乙酯萃取，无水硫酸钠干燥，flash柱层析分离，得到化合物A3-3(100mg，收率：41％)。LC-MS:[M+H] +:646。
将中间体A3-3(100mg)溶于6mL二氯甲烷中，加入3mL三氟乙酸，室温反应2小时。停止反应，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调节pH-10，二氯甲烷萃取，制备色谱分离，得到目标化合物A3(25mg,收率：35％)，LC-MS:[M+H] +:462。
参照实施例2路线合成如下化合物：
Figure PCTCN2021105867-appb-000029
Figure PCTCN2021105867-appb-000030
实施例3：
Figure PCTCN2021105867-appb-000031
氮气保护下，将中间体A1-3(0.32mmol,200mg)和原料四羟基二硼(0.64mmol,58mg)溶于10mL无水四氢呋喃中，加入DIEA(0.64mmol,83mg)和Pd(Amphos)Cl 2(0.03mmol,21mg)，微波95℃下加热反应2小时。停止反应，过滤，向体系加水30mL，乙酸乙酯萃取，无水硫酸钠干燥，得到粗品化合物A5-1。直接用于下一步反应。LC-MS:[M+H] +:594。
氮气保护下，将上步粗品中间体A5-1(150mg，粗品)和2-溴咪唑A5-2(0.25mmol,37mg)溶于10mL1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钾(0.5mmol,69mg)和Pd(dppf)Cl 2(0.025mmol,19mg)。微波110℃下加热反应2小时。停止反应，过滤，向体系加水30mL，乙酸乙酯萃取，无水硫酸钠干燥，flash柱层析分离，得到化合物A5-3(70mg，两步总收率：36％)。LC-MS:[M+H] +:616。
将中间体A5-3(70mg)溶于4mL二氯甲烷中，加入2mL三氟乙酸，室温反应2小时。停止反应，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调节pH至10，二氯甲烷萃取，制备色谱分离，得到目标化合物A5(30mg,收率：53％)，LC-MS:[M+H] +:516。
参照实施例3路线合成如下化合物：
Figure PCTCN2021105867-appb-000032
实施例4：
Figure PCTCN2021105867-appb-000033
氮气保护下，将中间体A1-3(0.29mmol,180mg)和噻吩-2-硼酸频哪醇酯A7-1(0.58mmol,121mg)溶于1,4-二氧六环和水的10mL混合液中(v/v:9/1)，加入碳酸钾(0.87mmol,120mg)，Pd(dppf)Cl 2(0.03mmol,22mg)，95℃加热反应2小时。停止反应，过滤，减压蒸除溶剂，加水30mL，乙酸乙酯萃取，flash柱层析分离，得到化合物A7-2(100mg，收率：55％)，LC-MS:[M+H] +:632。
将中间体A7-2(100mg)溶于5mL二氯甲烷中，加入2mL三氟乙酸，室温反应2小时。停止反应，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调节pH至10，二氯甲烷萃取，制备色谱分离，得到目标化合物A7(20mg,收率：25％)，LC-MS:[M+H] +:532。
(TFA盐)； 1H NMR(600MHz,DMSO-d 6)δ8.83(s,1H),8.44(s,1H),8.27(d,J＝11.8Hz,1H),7.44(t,J＝ 7.4Hz,1H),7.35(m,1H),7.08(m,1H),6.94(m,1H),4.73(s,1H),4.54(s,1H),4.25(d,J＝13.8Hz,1H),4.01(m,1H),3.78(m,1H),3.68(s,1H),3.59–3.53(m,1H),3.45(d,J＝12.5Hz,2H),3.26(m,3H),2.42–2.30(m,2H),2.23–1.97(m,5H),1.28(d,J＝6.9Hz,3H).
实施例5：
Figure PCTCN2021105867-appb-000034
氮气保护下，将中间体a1(0.59mmol,150mg)和中间体b4(1.54mmol,粗品)溶于10mL甲苯中，加入三乙胺(1.19mmol,120mg)和Pd(PPh 3) 2Cl 2(0.12mmol,84mg)。100℃下加热反应3小时。停止反应，过滤，向体系加水30mL，乙酸乙酯萃取，无水硫酸钠干燥，TLC色谱分离，得到化合物A8-1(120mg，收率：65％)。LC-MS:[M+H] +:314。
冰浴下，将中间体A8-1(0.38mmol,120mg)溶于8mL无水二氯甲烷中，缓慢分批加入N-溴代琥珀酰亚胺NBS(0.42mmol,75mg)，室温下搅拌2小时。停止反应，加入20mL饱和氯化铵水溶液，二氯甲烷萃取。无水硫酸钠干燥，得到化合物A8-2(200mg，粗品)。LC-MS:[M+H] +:393。
氮气保护下，将上步粗品中间体A8-2(200mg)和原料a3-2(0.57mmol,158mg)溶于10mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钾(0.76mmol,105mg)和Pd(dppf)Cl 2(0.04mmol,29mg)。微波100℃下加热反应2小时。停止反应，过滤，向体系加水40mL，乙酸乙酯萃取，无水硫酸钠干燥，TLC色谱分离，得到化合物A8-3(80mg，两步总收率：46％)。LC-MS:[M+H] +:464。
将中间体A8-3(80mg)溶于5mL二氯甲烷中，加入2mL三氟乙酸，室温反应2小时。停止反应，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调节pH至10，二氯甲烷萃取，制备色谱分离，得到目标化合物A8(27mg,收率：42％)，LC-MS:[M+H] +:380。
(TFA盐)； 1H NMR(400MHz,DMSO-d 6)δ8.30(s,1H),7.67(d,J＝1.8Hz,1H),7.05(s,1H),6.79(d,J＝2.0Hz,1H),4.57(d,J＝6.6Hz,1H),4.28(d,J＝13.2Hz,1H),4.02(d,J＝3.4Hz,1H),3.99(s,3H),3.79(d,J＝11.4Hz,1H),3.67(dd,J＝11.8,2.9Hz,1H),3.52(td,J＝11.8,2.9Hz,1H),3.33–3.23(m,1H),2.27(s,3H),1.29(d,J＝6.7Hz,3H).
实施例6：
Figure PCTCN2021105867-appb-000035
氮气保护下，在微波反应瓶中加入中间体a3(0.17mmol,80mg)，3-溴-5-氟-吡啶A9-1(0.34mmol,60mg)，磷酸钾(0.34mmol,72mg)和CuI(0.034mmol,7mg)，5mL DMF溶解。搅拌5分钟后，缓慢加入N,N-二甲基-1,2-环己二胺(0.07mmol,10mg)。微波升温至110℃反应1.5小时后停止反应，加水40mL，乙酸乙酯萃取，无水Na 2SO 4干燥，flash柱层析分离，得到化合物A9-2(50mg，收率：53％)，LC-MS:[M+H] +:558。
将中间体A9-2(50mg)溶于4mL二氯甲烷中，加入2mL三氟乙酸，室温反应2小时。停止反应，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调节pH至10，二氯甲烷萃取，制备色谱分离，得到目标化合物A9(28mg,收率：67％)，LC-MS:[M+H] +:474。
参照实施例6路线合成如下化合物：
Figure PCTCN2021105867-appb-000036
Figure PCTCN2021105867-appb-000037
Figure PCTCN2021105867-appb-000038
实施例7：
Figure PCTCN2021105867-appb-000039
氮气保护下，在微波反应瓶中加入中间体a3(0.15mmol,70mg)，3-溴-6-苄氧基-吡啶A14-1(0.30mmol,79mg)，磷酸钾(0.45mmol,95mg)和CuI(0.02mmol,4mg)，5mL N-甲基吡咯烷酮溶解。搅拌5分钟后，缓慢加入N,N-二甲基-1,2-环己二胺(0.03mmol,4.3mg)。升温至110℃反应10小时后停止反应，加水20mL，乙酸乙酯萃取，无水硫酸钠干燥，TLC色谱分离，得到化合物A14-2(70mg，收率：73％)，LC-MS:[M+H] +:646。
将中间体A14-2(70mg)溶于5mL甲醇中，加入3mL浓盐酸，升温至65℃反应2小时。停止反应，将反应液置于冰浴下，并向体系内缓慢加入饱和NaHCO 3水溶液，乙酸乙酯萃取，无水硫酸钠干燥，制备色谱分离，得到目标化合物A14(20mg,收率：39％)，LC-MS:[M+H] +:472。
(游离碱)； 1H NMR(400MHz,DMSO-d 6)δ8.27(s,1H),7.74(d,J＝2.9Hz,1H),7.62(dd,J＝9.5,3.0Hz,2H),6.77(d,J＝1.9Hz,1H),6.69(s,1H),6.49(d,J＝9.6Hz,1H),4.54(s,1H),4.26(d,J＝13.5Hz,1H),4.03–3.98(m,1H),3.78(d,J＝11.4Hz,1H),3.68(dd,J＝11.6,3.1Hz,1H),3.57–3.49(m,1H),3.30–3.22(m,1H),2.24(s,3H),2.20(s,3H),1.28(d,J＝6.6Hz,3H).
实施例8：
Figure PCTCN2021105867-appb-000040
氮气保护下，将中间体a1(0.79mmol,200mg)和中间体b5(1.19mmol,516mg)溶于15mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钾(1.60mmol,221mg)和Pd(dppf)Cl 2(0.08mmol,59mg)，95℃下加热反应10小时。停止反应，过滤，向体系加水40mL，乙酸乙酯萃取，无水硫酸钠干燥，flash柱层析分离，得到化合物A15-1(170mg，收率：41％)。LC-MS:[M+H] +:525。
冰浴下，将中间体A15-1(0.32mmol,170mg)溶于10mL无水二氯甲烷中，缓慢分批加入N-溴代琥珀酰亚胺NBS(0.35mmol,63mg)。室温下搅拌2小时，停止反应。加入20mL饱和氯化铵水溶液，二氯甲烷萃取。无水硫酸钠干燥，得化合物A15-2(200mg，粗品)。LC-MS:[M+H] +:604。
氮气保护下，将上步粗品中间体A15-2(200mg)和原料a3-2(0.64mmol,178mg)溶于10mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钾(0.64mmol,89mg)和Pd(dppf)Cl 2(0.03mmol,22mg)。微波100℃下加热反应2小时。停止反应，过滤，向体系加水20mL，乙酸乙酯萃取，无水硫酸钠干燥，TLC色谱分离，得到化合物A15-3(45mg，两步总收率：21％)。LC-MS:[M+H] +:675。
将中间体A15-3(45mg)溶于4mL二氯甲烷中，加入1.5mL三氟乙酸室温反应2小时。停止反应，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调节pH至10，二氯甲烷萃取，制备色谱分离，得到目标化合物A15(9mg,收率：30％)，LC-MS:[M+H] +:491。
(游离碱)； 1H NMR(400MHz,DMSO-d 6)δ8.26(s,2H),7.71(s,1H),7.51(s,1H),6.78(s,1H),6.69(s,1H),4.57(s,1H),4.27(s,1H),4.00(dd,J＝11.5,3.6Hz,1H),3.77(d,J＝11.4Hz,1H),3.67(dd,J＝11.3,3.1Hz,1H),3.56–3.37(m,5H),3.23(dd,J＝12.7,3.9Hz,1H),2.76(m,4H),2.32(s,3H),2.17(s,3H),1.27(d,J＝6.7Hz,3H).
实施例9：
Figure PCTCN2021105867-appb-000041
氮气保护下，将中间体a4(0.25mmol,100mg)和中间体b6(0.50mmol,211mg)溶于10mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钾(0.50mmol,69mg)和Pd(dppf)Cl 2(0.03mmol,22mg)。微波100℃下加热反应2小时。停止反应，过滤，向体系加水20mL，乙酸乙酯萃取，无水硫酸钠干燥，TLC色谱分离，得到化合物A16-1(60mg，收率：36％)。LC-MS:[M+H] +:664。
将中间体A16-1(60mg)溶于4mL二氯甲烷中，加入2mL三氟乙酸室温反应2小时。停止反应，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调节pH至10，二氯甲烷萃取，制备色谱分离，得到目标化合物A16-I(10mg,收率：23％)，LC-MS:[M+H] +:480。
(游离碱)；
参照化合物A16-I的合成路线，将中间体b6替换成其非对应异构体b7，得到目标化合物A16-II。
(游离碱)； 1H NMR(400MHz,DMSO-d 6)δ8.24(s,1H),7.59(s,1H),6.74(s,1H),6.64(s,1H),4.92–4.73(m,1H),4.56(s,1H),4.43(m,1H),4.27(d,J＝13.6Hz,1H),4.02–3.96(m,1H),3.76(d,J＝11.4Hz,1H),3.66(dd,J＝11.4,3.1Hz,1H),3.55–3.49(m,1H),3.44(dd,J＝7.0,5.0Hz,1H),3.25–3.18(m,1H),2.97(d,J＝12.5Hz,1H),2.68–2.61(m,2H),2.25(s,3H),2.16(s,3H),2.08(m,1H),1.92(m,1H),1.27(d,J＝6.7Hz,3H).
参照实施例9合成如下化合物：
Figure PCTCN2021105867-appb-000042
实施例10：
Figure PCTCN2021105867-appb-000043
将化合物A11(0.063mmol,30mg)溶于6mL水和乙腈的混合溶液中(v/v，5/1)中，加入二氧化锰(0.115mmol,10mg)。90℃下加热反应10小时。停止反应，过滤，flash柱层析分离，得到化合物A17(4mg，收率：13％)。LC-MS:[M+H] +:499。
(游离碱)； 1H NMR(400MHz,DMSO-d 6)δ9.11(d,J＝1.9Hz,1H),8.98(d,J＝2.4Hz,1H),8.42(t,J＝2.2Hz,1H),8.35(s,1H),8.28(s,1H),7.78(s,1H),7.60(s,1H),6.77(s,2H),4.56(d,J＝7.4Hz,1H),4.28(d,J＝13.4Hz,1H),4.05–3.97(m,1H),3.79(d,J＝11.5Hz,1H),3.69(m,1H),3.54(m,1H),3.28–3.22(m,1H),2.38(s,3H),2.26(s,3H),1.29(d,J＝6.7Hz,3H).
实施例11：
Figure PCTCN2021105867-appb-000044
氮气保护下，在反应瓶中加入中间体a3(0.17mmol,80mg)，2-溴乙醇A18-1(0.34mmol,43mg)，5mL DMF溶解。搅拌5分钟后，缓慢加入NaH(0.34mmol,14mg)。升温至50℃反应2小时后停止反应，加水40mL，乙酸乙酯萃取，无水Na 2SO 4干燥，TLC色谱分离，得到化合物A18-2(40mg，收率：47％)，LC-MS:[M+H] +:507。
将中间体A18-2(60mg)溶于5mL二氯甲烷中，加入2mL三氟乙酸，室温反应2小时。停止反应，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调节pH至10左右，二氯甲烷萃取，制备色谱分离，得到目标化合物A18(20mg,收率：40％)，LC-MS:[M+H] +:423。
(游离碱)； 1H NMR(400MHz,DMSO-d 6)δ12.66(br,1H),8.23(s,1H),7.58(s,1H),6.74(s,1H),6.58(s,1H),4.92(t,J＝5.3Hz,1H),4.54(d,J＝7.5Hz,1H),4.25(d,J＝13.6Hz,1H),4.10(t,J＝5.7Hz,2H),3.99(dd,J＝11.5,3.6Hz,1H),3.77(m,3H),3.67(dd,J＝11.5,3.1Hz,1H),3.52(td,J＝11.8,3.0Hz,1H),3.28–3.20(m, 1H),2.25(s,3H),2.13(s,3H),1.27(d,J＝6.7Hz,3H).
实施例12：
Figure PCTCN2021105867-appb-000045
氮气保护下，在微波反应瓶中加入中间体a3(0.19mmol,90mg)，3-溴-5-苄氧基-吡啶A19-1(0.38mmol,100mg)，磷酸钾(0.57mmol,120mg)和CuI(0.04mmol,8mg)，5mL DMF溶解。搅拌5分钟后，缓慢加入N,N-二甲基-1,2-环己二胺(0.04mmol,5mg)。升温至110℃反应10小时后停止反应，过滤，加水30mL，乙酸乙酯萃取，无水硫酸钠干燥，TLC色谱分离，得到化合物A19-2(85mg，收率：70％)，LC-MS:[M+H] +:646。
将中间体A19-2(0.13mmol,85mg)和Pd/C(9mg)混于4mL甲醇和乙酸乙酯的混合溶液中(v/v,3/1)，置换氢气(4atm)，升温至50℃反应2小时。停止反应，过滤，减压蒸除溶剂，得到粗品中间体A19-3。LC-MS:[M+H] +:556。
将粗品中间体A19-3溶于5mL二氯甲烷中，加入2mL三氟乙酸，室温反应2小时，停止反应。减压蒸除溶剂，向体系内缓慢加入10mL饱和NaHCO 3水溶液，二氯甲烷萃取，无水硫酸钠干燥，制备色谱分离，得到目标化合物A19(38mg,两步总收率：63％)，LC-MS:[M+H] +:472。
(游离碱)； 1H NMR(400MHz,DMSO-d 6)δ8.32–8.24(m,2H),8.22(d,J＝2.5Hz,1H),7.60(s,1H),7.36(t,J＝2.3Hz,1H),6.76(s,2H),4.56(d,J＝8.0Hz,1H),4.27(d,J＝13.5Hz,1H),4.01(dd,J＝11.4,3.6Hz,1H),3.79(d,J＝11.4Hz,1H),3.69(dd,J＝11.5,3.1Hz,1H),3.54(m,1H),3.27(m,1H),2.33(s,3H),2.23(s,3H),1.29(d,J＝6.7Hz,3H).
实施例13：
Figure PCTCN2021105867-appb-000046
-78℃下，氮气保护下，将中间体a1(1.59mmol,400mg)溶于15mL无水四氢呋喃中，逐滴加入正丁基锂(0.76mL,2.5M)。反应30分钟后，缓慢加入四氢吡喃-4-酮A20-1(1.75mmol,175mg),继续搅拌2小时后停止反应。向体系缓慢加入30mL饱和氯化铵水溶液，二氯甲烷萃取。无水硫酸钠干燥，TLC色谱分离，得化合物A20-2(100mg，收率：20％)。LC-MS:[M+H] +:319。
冰浴下，将中间体A20-2(0.31mmol,100mg)溶于10mL无水二氯甲烷中，缓慢分批加入N-碘代琥珀酰亚胺NIS(0.35mmol,79mg)。室温下搅拌2小时，停止反应。加入20mL饱和氯化铵水溶液，二氯甲烷萃取。无水硫酸钠干燥，得化合物A20-3(170mg，粗品)。LC-MS:[M+H] +:445。
氮气保护下，将上步粗品中间体A20-3(170mg)和原料a3-2(0.62mmol,172mg)溶于10mL 1,4-二氧六环和水的混合液中(v/v:9/1)，加入碳酸钾(0.64mmol,89mg)和Pd(dppf)Cl 2(0.03mmol,22mg)。微波100℃下加热反应2小时。停止反应，过滤，向体系加水20mL，乙酸乙酯萃取，无水硫酸钠干燥，TLC色谱分离，得到化合物A20-4(120mg，两步总收率：83％)。LC-MS:[M+H] +:467。
将中间体A20-4(120mg)溶于6mL二氯甲烷中，加入3mL三氟乙酸室温反应2小时。停止反应，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调节pH至10，二氯甲烷萃取，制备色谱分离，得到目标化合物A20(61mg,收率：61％)，LC-MS:[M+H] +:383。
(游离碱)； 1H NMR(400MHz,DMSO-d 6)δ12.68(br,1H),8.33(s,1H),7.70–7.52(m,1H),6.81(s,1H),6.73(s,1H),5.87(s,1H),4.58–4.45(m,1H),4.18(d,J＝13.3Hz,1H),4.01(dd,J＝11.4,3.6Hz,1H),3.81(t,J＝9.7Hz,5H),3.66(dd,J＝11.5,3.1Hz,1H),3.51(td,J＝11.8,2.9Hz,1H),3.25(dd,J＝12.8,3.8Hz,1H),3.01(td,J＝12.7,5.8Hz,2H),1.50(d,J＝11.8Hz,2H),1.28(d,J＝6.6Hz,3H).
实施例14：ATR激酶活性实验：
用ATR激酶磷酸化衍生自p53生物素化的蛋白(Eurofins，货号：14-952)。该实验利用时间分辨荧光测定磷酸化蛋白的量。利用抗-p53-phospho-(丝氨酸15)-K-特异性抗体(Cisbio，货号：61GSTDLA)和d2-标记的抗-GST抗体(Cisbio，货号：61P08KAE)来检测磷酸化蛋白的量。实验开始前，根据需要配制如下工作液：1×反应缓冲液(20mM HEPES PH8.0、1％甘油、0.01％Brij-35)，稀释缓冲液(20mM HEPES PH8.0、 1％甘油、0.01％Brij-35、5mM DTT和1％BSA)，终止液(20mM HEPES PH8.0、1％甘油、0.01％Brij-35、250mM EDTA)，检测缓冲液(50mM HEPES PH7.0、150mM NaCl、267mM KF、0.1％胆酸钠、0.01％Tween-20、0.0125％叠氮化钠)。上述所用试剂除特别提到生产商，其它试剂均购于Sigma或英潍捷基。
进行照如下操作：
用1×反应缓冲液制备4×梯度稀释化合物溶液，得到9个不同浓度的化合物，加2.5μL 4×梯度稀释化合物溶液到384孔分析板(784075，Greiner)。用1×反应缓冲液制备4×p53底物工作液(40nM)，加2.5μL4×p53底物工作液到384孔分析板中。用稀释缓冲液制备4×ATR/ATRIP工作液(12.8ng/μL)，加2.5μL4×ATR/ATRIP工作液至384孔分析板。用去离子水制备4×ATP工作液(2mM)，加2.5μL 4×ATP工作液到384孔分析板，在避光条件下室温培育30分钟。加5μL终止液到384分析板。最后加5μL检测混合物(0.084ng/μL的Anti-phospho-p53(ser15)-K和5ng/μL的Anti-GST-d2)到384孔分析板。室温孵育过夜，用ENVISION(Perkinelmer)仪器检测荧光信号(激发波长为320nm，发射波长为665nm和615nm)。通过各孔荧光强度值计算出每个孔中的抑制率：ER(Emission Ratio，发射光比率)＝(665nm处荧光强度/615nm处荧光强度)；抑制率＝(ER阳性-ER待测化合物)/(ER阳性-ER阴性)×100％，利用参数拟合标准软件(GraphPad Prism 6.0)计算化合物的IC 50数值。
实施例的激酶数据结果：
编号 ATR/IC50/nM 编号 ATR/IC50/nM
A1 70 A14 3
A2 33 A15 13
A3 184 A16-I 33
A4 74 A16-II 31
A6 17 A17 3
A7 12 A18 8
A8 84 A19 4
A9 2 A20 188
A10 3 A21 52
A11 9 A22 2
A12 2 A23 4
A13 2 A24 2
实施例15：体外细胞增殖抑制实验：
本实验通过检测化合物在肿瘤细胞系TOV21G(卵巢癌)和MV4-11(白血病)中对体外细胞活性的影响，研究化合物抑制细胞增殖的作用。
TOV21G细胞与MV4-11细胞均购于美国典型培养物保藏中心(American Type Culture Collection,ATCC)。
TOV21G细胞培养于MCDB105/M199培养基(含15％FBS)中，细胞融合度达到85％以上时，用于试验。96-孔培养板每孔接种约1000个细胞，培养24小时，加入不同浓度待测化合物(0-10μM)处理细胞，每组设置3个平行复孔。设置空白孔(只含有培养基)和对照孔(接种细胞，不用药物处理)。培养120小时，每孔加入40μL Cell Titer-Glo溶液(Promega,#G7573)，避光震荡孵育20min，每孔取100μL转移至96-孔白板中(Corning，#3917)，用Biotek Synergy H1多功能酶标仪读取发光值。
MV-4-11细胞培养于IMDM培养基(含有20％FBS)中，96-孔培养板每孔接种约10000个细胞，加入不同浓度待测化合物(0-10μM)处理细胞，每组设置3个平行复孔。设置空白孔(只含有培养基)和对照孔(接种细胞，不用药物处理)。培养120小时，每孔加入40μL Cell Titer-Glo溶液，避光震荡孵育20min，每孔取100μL转移至96-孔白板中，用Biotek Synergy H1多功能酶标仪读取发光值。
抑制率(％)＝100％×(对照孔-测试孔)/(对照孔-空白孔)
增殖试验结果证明测试化合物在研究的人肿瘤细胞中具有效力，以IC 50值反映(IC 50为在50％最大效力下的抑制浓度)。
CellTiter-Glo发光法细胞活性检测结果
Figure PCTCN2021105867-appb-000047
NT＝未测试
实施例16：化合物体外肝微粒体稳定性实验：
对本发明化合物进行肝微粒体稳定性实验研究。将待测化合物(终浓度2.0nM)在加入或不加入NADPH情况下与人/小鼠的肝微粒体进行共孵育，检测60分钟内孵育上清中的化合物浓度。代表性化合物的结果如下：
Figure PCTCN2021105867-appb-000048
实施例17：化合物体内药代动力学实验：
对本发明化合物进行体内药代动力学研究。
实验方法：
雄性ICR小鼠(3只/组)口服灌胃给药，给药剂量为10mg/kg。收集给药前(0小时)和给药后(0.25,0.5,1,2,4,6,8,24小时)的血浆样品，对收集的样品进行LC/MS/分析并采集数据，采集的分析数据用Analyst v1.6.2(AB Applied Biosystems Company,USA)软件计算相关药代动力学参数。
代表性化合物的结果如下：
Figure PCTCN2021105867-appb-000049
实施例18：化合物对于ATR激酶选择性研究：
对本发明化合物进行同家族(ATM，DNA-PK,PI3K,mTOR)抑制实验测试：
根据文献报道的实验方法，将待测化合物以10μM为起点，3倍稀释至0.51nM(共计10个浓度)，分别测定其对激酶ATM 1,DNA-PK 2,PI3Kα 3,PI3Kδ 3和mTOR 4的抑制活性，结果如下所示：
Figure PCTCN2021105867-appb-000050
以上结果表明该发明所述化合物对于ATR具有高度选择性，对于家族内其他激酶抑制活性较低。
参考文献：
[1]Discovery of Novel 3-Quinoline Carboxamides as Potent,Selective and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated(ATM)Kinase,J.Med.Chem.2016,56,6281-6292；
[2]The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one(AZD7648),a Potent and Selective DNA-Dependent Protein Kinase(DNA-PK)Inhibitor,J.Med.Chem.2020,63,3461-3471；
[3]WO2012044641；
[4]Discovery and SAR exploration of a novel series of imidazo[4,5-b]pyrazin-2-ones as potent and selective mTOR kinase inhibitors.Bioorg.Med.Chem.Lett.2011；21:6793-6799.
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 (37)

  1. 通式(I)的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
    Figure PCTCN2021105867-appb-100001
    其中，
    X为CR X或N；
    Y为CR Y或N；
    R 1、R 2、R 3、R 4和R Y独立地选自H、D、卤素、C 1-6烷基、C 2-6烯基或C 2-6炔基，或者R 1与R 2，R 3与R 4连接形成键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    其中R X为H、D、卤素、-CN、-NRR’、-OR、-SR或C 1-6烷基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    当Y为CR Y时，其中R Y、R 1与它们连接的原子一起形成C 3-5环烷基或3-5元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    环A为C 3-7环烷基、4-7元杂环基、C 6-10芳基或5-10元杂芳基；或者环A不存在，因此一个R a与L连接；或者(R a) m-环A-L-都不存在；
    R a独立地选自任选被R*取代的H、D、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基或3-8元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    m＝0、1、2、3、4或5；
    环B为5-6元杂芳基；
    R b独立地选自任选被R*取代的H、D、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基或3-8元杂环基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    n＝0、1、2、3、4或5；
    环C为C 3-7环烷基、4-7元杂环基、C 6-10芳基或5-10元杂芳基；
    L为键、-O-、-S-、-N(R)-、-C(O)-、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；
    R 5为H、D、卤素、-CN、-NRR’、-OR、-SR、C 1-6烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    R 6为H、D、卤素、-CN、-NRR’、-OR、-SR、C 1-6烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    R*为H、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) pR、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    R和R’独立地选自H、C 1-6烷基、C 2-6烯基或C 2-6炔基，或者R、R’与它们连接的氮原子形成4-8元杂环基；其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    p＝1或2。
  2. 权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R 1为C 1-6烷基，优选地为(R)-C 1-6烷基，更优选为(R)-甲基。
  3. 权利要求1或2的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，X为CR X，且R 2、R 3、R 4和R X为氢或D。
  4. 权利要求1-3中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，Y为N。
  5. 权利要求1-4中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，环A选自以下基团：
    Figure PCTCN2021105867-appb-100002
    其中，A 1为CR a1或N；A 2为CR a2或N；A 3为CR a3或N；A 4为CR a4或N；A 5为CR a5或N；
    R a1、R a2、R a3、R a4和R a5具有与权利要求1中R a相同的定义；
    优选地，(R a) m-环A-L-选自以下基团：
    Figure PCTCN2021105867-appb-100003
    Figure PCTCN2021105867-appb-100004
  6. 权利要求1-4中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，环A不存在或选自哌嗪基或哌啶基。
  7. 权利要求1-6中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R a独立地选自H、D、卤素、-CN、-NRR’、-OR、-SR、-C(O)R、-C(O)OR、-C(O)NRR’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D取代，直至完全氘代。
  8. 权利要求1-7中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，环B为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡咯基、呋喃基、噻吩基、吡唑基或吡啶基；优选为吡唑基。
  9. 权利要求1-8中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R b独立地选自任选被R*取代的H、D、卤素、-CN、-NRR’、-OR、-SR、C 1-6烷基或C 1-6卤代烷基；优选为H或D。
  10. 权利要求1-9中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，环C为5-6元杂芳基或苯基；优选为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或三唑基；优选吡唑基。
  11. 权利要求1-9中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，环C为C 3-7环烷基或4-7元杂环基。
  12. 权利要求1-11中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，L为键、-C(O)-或C 1-6亚烷基。
  13. 权利要求1-12中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R 5和R 6独立地为H、D、C 1-6烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代。
  14. 权利要求1-13中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有以下通式结构：
    Figure PCTCN2021105867-appb-100005
    其中，各基团具有与权利要求1-13中任一项相同的定义。
  15. 权利要求14的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为通式(I-1)或(I-2)化合物：
    Figure PCTCN2021105867-appb-100006
    其中，
    环C为C 3-7环烷基或4-7元杂环基；优选环戊基或四氢吡喃基；
    环B为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡咯基、呋喃基、噻吩基、吡唑基或吡啶基；
    R 5优选H、D、卤素、-CN、-NRR’、-OR、-SR，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；优选地，R 5位于环C与母核相连的C原子上；
    其他基团具有与权利要求1-13中任一项相同的定义。
  16. 权利要求14的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为通式(I-1)化合物：
    Figure PCTCN2021105867-appb-100007
    其中，
    环C为5-6元杂芳基或苯基；优选为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或三唑基；优选吡唑基；
    其他基团具有与权利要求1-13中任一项相同的定义。
  17. 权利要求16的通式(I-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
    环B为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡咯基、呋喃基、噻吩基、吡唑基或吡啶基；
    其他基团具有与权利要求1-13中任一项相同的定义。
  18. 权利要求14的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为通式(II)或(II-1)化合物：
    Figure PCTCN2021105867-appb-100008
    其中，
    环A为不存在、C 3-7环烷基或4-7元杂环基；
    其他基团具有与权利要求1-13中任一项相同的定义。
  19. 权利要求18的通式(II)或(II-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
    环A不存在或为4-7元杂环基；优选哌啶基或哌嗪基；
    环B为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡咯基、呋喃基、噻吩基、吡唑基或吡啶基；
    L为键、-O-、-S-、-N(R)-、-C(O)-或C 1-6亚烷基；
    R 5和R 6独立地为C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，其中所述基团可以被一个或多个D取代，直至完全氘代；
    其他基团具有与权利要求1-13中任一项相同的定义。
  20. 权利要求14的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为通式(III)或(III-1)化合物：
    Figure PCTCN2021105867-appb-100009
    其中，
    环C为5-6元杂芳基或苯基；优选为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或三唑基；优选吡唑基；
    其他基团具有与权利要求1-13中任一项相同的定义。
  21. 权利要求20的通式(III)或(III-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
    环B为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、吡啶基、嘧啶基或吡嗪基；优选为吡咯基、呋喃基、噻吩基、吡唑基或吡啶基；
    其他基团具有与权利要求1-13中任一项相同的定义。
  22. 权利要求14的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为通式(III-2)或(III-3)化合物：
    Figure PCTCN2021105867-appb-100010
    其中，
    A 1为CR a1或N；A 2为CR a2或N；A 5为CR a5或N；
    其他基团具有与权利要求1-13中任一项相同的定义。
  23. 权利要求22的通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
    A 3为CR a3或N；
    R a1、R a2、R a3、R a5、R 5和R 6独立地为H、D、卤素、-CN、-OR、-SR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’或C 1-6烷基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    其他基团具有与权利要求1-13中任一项相同的定义。
  24. 权利要求22的通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
    A 3为CR a3或N；
    R a1、R a2、R a3和R a5独立地选自H、D、卤素、-CN、-OH、-C(O)NH 2、C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代；
    R 5和R 6独立地为C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代。
  25. 权利要求22的通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
    A 3为CR a3或N；
    R a1为H或D；
    R a2为H、D、卤素、-CN、-OH、-C(O)NH 2、C 1-6烷基或C 1-6卤代烷基；
    R a3为H、D或-OH；
    R a5为H或D；
    R 5为C 1-6烷基或C 1-6卤代烷基；优选甲基；
    R 6为C 1-6烷基或C 1-6卤代烷基；优选甲基。
  26. 权利要求14的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为通式(III-3)化合物：
    Figure PCTCN2021105867-appb-100011
    其中，
    A 3为CR a3或N；
    R a1、R a2、R a3、R a5、R 5和R 6独立地为H、D、卤素、-OR、-SR、-NRR’、C 1-6烷基或C 1-6卤代烷基， 其中所述基团可以被一个或多个D取代，直至完全氘代；
    R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，或者R、R’与它们连接的氮原子形成4-8元杂环基；其中所述基团可以被一个或多个D取代，直至完全氘代。
  27. 权利要求26的通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
    A 3为CR a3或N；
    R a1、R a2、R a3和R a5独立地选自H、D、卤素、-OH、C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代；
    R 5和R 6独立地为C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代。
  28. 权利要求26的通式(III-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
    A 3为CR a3或N；
    R a1为H或D；
    R a2为H、D、卤素、C 1-6烷基或C 1-6卤代烷基；
    R a3为H、D或-OH；
    R a5为H或D；
    R 5为C 1-6烷基或C 1-6卤代烷基；优选甲基；
    R 6为C 1-6烷基或C 1-6卤代烷基；优选甲基。
  29. 权利要求14的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为通式(III-4)化合物：
    Figure PCTCN2021105867-appb-100012
    其中，
    A 4为CR a4或N；
    R a1、R a2、R a4、R a5、R 5和R 6独立地为H、D、卤素、-CN、-OR、-SR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’或C 1-6烷基，其中所述基团可以被一个或多个D或卤素取代，直至完全取代；
    其他基团具有与权利要求1-13中任一项相同的定义。
  30. 权利要求29的通式(III-4)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
    A 4为CR a4或N；
    R a1、R a2、R a4和R a5独立地选自H、D、卤素、-CN、-OH、-C(O)NH 2、C 1-6烷基或C 1-6卤代烷基，其中 所述基团可以被一个或多个D取代，直至完全氘代；
    R 5和R 6独立地为C 1-6烷基或C 1-6卤代烷基，其中所述基团可以被一个或多个D取代，直至完全氘代。
  31. 权利要求29的通式(III-4)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，
    A 4为CR a4或N；
    R a1为H、D或卤素；
    R a2为H、D、卤素、-CN、-OH、-C(O)NH 2、C 1-6烷基或C 1-6卤代烷基；
    R a4为H、D或-OH；
    R a5为H或D；
    R 5为C 1-6烷基或C 1-6卤代烷基；优选甲基；
    R 6为C 1-6烷基或C 1-6卤代烷基；优选甲基。
  32. 权利要求1的化合物，其选自：
    Figure PCTCN2021105867-appb-100013
    Figure PCTCN2021105867-appb-100014
  33. 药物组合物，其含有权利要求1-32中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。
  34. 权利要求1-32中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体在制备用于治疗和/或预防ATR激酶介导的疾病的药物中的用途。
  35. 一种在受试者中治疗和/或预防ATR激酶介导的疾病的方法，所述方法包括向所述受试者给药权利要求1-32中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体或权利要求33的药物组合物。
  36. 权利要求1-32中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体或权利要求33的药物组合物，其用于治疗和/或预防ATR激酶介导的疾病。
  37. 权利要求34的用途或权利要求35的方法或权利要求36的化合物或组合物的用途，其中所述ATR 激酶介导的疾病包括增生性疾病(如癌症)，尤其实体瘤(如癌和肉瘤)及白血病和淋巴癌，尤其对于例如乳腺癌、结肠直肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)和前列腺癌及胆管癌、骨癌、膀胱癌、头及颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、子宫颈癌和外阴癌、以及白血病[包括急性淋巴细胞白血病(ALL)、慢性髓细胞源性白血病(CML)以及急性髓细胞白血病(AML)等]、多发性骨髓瘤和淋巴癌。
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