WO2022223020A1 - Inhibitor targeting activated and inactivated kras g12d - Google Patents

Inhibitor targeting activated and inactivated kras g12d Download PDF

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WO2022223020A1
WO2022223020A1 PCT/CN2022/088438 CN2022088438W WO2022223020A1 WO 2022223020 A1 WO2022223020 A1 WO 2022223020A1 CN 2022088438 W CN2022088438 W CN 2022088438W WO 2022223020 A1 WO2022223020 A1 WO 2022223020A1
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halogen
alkyl
cancer
haloalkyl
compound
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PCT/CN2022/088438
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French (fr)
Chinese (zh)
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张永辉
尚言国
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清华大学
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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 the field of medicine, in particular, the present invention provides a compound capable of reversibly inhibiting KRAS G12D mutein, and a preparation method and application thereof.
  • Rat sarcoma homologous gene (rat sarcoma, RAS) is the first discovered oncogene (oncogene) with the highest mutation frequency.
  • oncogene As a "molecular switch", RAS protein regulates multiple signaling pathways related to cell proliferation and differentiation.
  • the common mutation sites of KRAS include G12, G13 and Q61, most of which are mutations at the G12 site, accounting for about 83%.
  • the common mutation types of KRAS G12 include G12D, G12V and G12C, and the number of cancer patients with KRAS G12D mutation is the largest.
  • KRAS G12D mutations accounted for 51%, 45%, and 17% of pancreatic ductal carcinoma, colorectal carcinoma, and lung adenocarcinoma, respectively (Schirripa, M., et al., KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population. Clin Colorectal Cancer 19, (2020) 219-225).
  • the carboxyl group of Asp 12 of KRAS G12D cannot be added to the double bond of acrylamide, so although covalent inhibitors have been successful on KRAS G12C protein, such small molecules obviously cannot bind to KRAS G12D.
  • the present invention designs and synthesizes an inhibitor that can form a non-covalent bond with KRAS G12D, and proves that the compound of the present invention can effectively inhibit the activity of KRAS G12D.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
  • X is -N(R)- or -CH(R*)-;
  • R is selected from H, -( CH2 ) 1-3 -halogen, -( CH2 ) 1-3 -OH, -( CH2 ) 1-3 -CN, -( CH2 ) 1-3 - NH2 , C 1-6 alkyl or C 1-6 haloalkyl;
  • R* is selected from -( CH2 ) 0-3 -halogen, -( CH2 ) 0-3 -OH, -( CH2 ) 0-3 -CN or -( CH2 ) 0-3 - NH2 ;
  • Y is N or CH
  • Y 1 is CR Y1a R Y1b ;
  • Y 2 is CR Y2a R Y2b ;
  • Y 3 is CR Y3a R Y3b or NR Y3c ;
  • R Y1a , R Y1b , R Y2a , R Y2b , R Y3a and R Y3b are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;
  • R Y3c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • a double bond can be formed between Y 3 and its adjacent Y 2 ;
  • R A is selected from H, C 6-10 aryl or 5-14 membered heteroaryl, optionally substituted with 1, 2, 3 or 4 R A1 ;
  • each R A1 is independently selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • L is selected from chemical bonds, -O-, -S- or -NH-;
  • R B is selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 membered aryl or 5-14 membered heteroaryl; it is optionally substituted with 1, 2, 3 or 4 R#;
  • R# is selected from H, -C 0-6 alkylene-halogen, -C 0-6 alkylene-CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, -C 0-6 alkylene-OR X , -C 0-6 alkylene-SR X , -C 0-6 alkylene-NR Y R Z , -C 0-6 Alkylene-C(O)R X , -C 0-6 alkylene-C(O)OR X , -C 0-6 alkylene-C(O)-NR Y R Z , -C 0- 6 alkylene-C 3-10 cycloalkyl, -C 0-6 alkylene-3-10 membered heterocyclic group, -C 0-6 alkylene-C 6-10 aryl or -C 0- 6 alkylene-5-14 membered heteroaryl; and R# is optional
  • R X is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R Y and R Z are independently selected from H, C 1-6 alkyl , C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R Y and R Z and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclic group;
  • R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d ) m -R';
  • R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -R";
  • R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
  • R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 are connected to form -(CR a R b ) n -;
  • R a is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R b is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R c is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R d is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R' is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e , -C(O)NR f R g , C 2- 6 alkenyl or C 2-6 alkynyl;
  • R" is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e , -C(O)NR f R g , C 2- 6 alkenyl or C 2-6 alkynyl;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R e is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R f and R g are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R f and R g and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclyl.
  • 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.
  • 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 KRAS G12D mutein mediated diseases.
  • the present invention provides a method of treating and/or preventing a KRAS G12D mutein-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 KRAS G12D mutein mediated diseases.
  • diseases treated by the present invention include cancers selected from the group consisting of acute myeloid leukemia, acute myeloid leukemia, juvenile cancer, childhood adrenocortical cancer, AIDS-related cancers such as lymphoma and Kaposi sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahe
  • Fig. 1 Analysis of the binding site of KRAS G12D protein and TH-Z 816.
  • Fig. 2 Analysis of the binding mode of TH-Z 816 to KRAS G12D protein.
  • 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 , C2-6 , C2-5 , C2-4 , C2-3 , C3-6 , C3-5 , C3-4 , C4-6 , C4-5 , and C5 -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 and C 1-2 alkyl 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.
  • alkyl abbreviations include: Me( -CH3 ), Et(-CH2CH3), iPr(-CH( CH3 ) 2 ), nPr ( -CH2CH2CH3 ) , n - Bu(-CH 2CH2CH2CH3 ) or i - Bu(-CH2CH ( CH3 ) 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, C2-4alkynyl groups 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.
  • C2-6alkynyl 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 group refers to a divalent group formed by removing another hydrogen of a C 1-6 alkyl group, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred.
  • the unsubstituted alkylene groups include, but are not limited to: methylene ( -CH2- ), ethylene ( -CH2CH2- ) , propylene ( -CH2CH2CH2- ) , 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 -) ,and many more.
  • alkylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to: substituted methylene groups (-CH( CH3 )- , -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 ( CH3 ) 2CH2CH2- , -CH2C ( CH3 ) 2CH2- , -CH2CH2C ( CH3 ) 2- ) , etc.
  • C 0-6 alkylene group refers to the chemical bond as well as the above-mentioned "C 1-6 alkylene group”.
  • alkenylene groups eg, alkenylene groups substituted with one or more alkyl (methyl) groups
  • C 2-6 alkynylene refers to a divalent group formed by removing another hydrogen of a C 2-6 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkynylene groups are particularly preferred. Exemplary such alkynylene groups include, but are not limited to: ethynylene (-C ⁇ C-), substituted or unsubstituted propynylene ( -C ⁇ CCH2- ), and the like.
  • Halo or "halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • C 1-6 haloalkyl refers to the aforementioned "C 1-6 alkyl" substituted with one or more halogen groups.
  • C 1-4 haloalkyl is particularly preferred, more preferably C 1-2 haloalkyl.
  • Exemplary such haloalkyl groups include, but are not limited to : -CF3 , -CH2F , -CHF2 , -CHFCH2F , -CH2CHF2 , -CF2CF3 , -CCl3 , -CH2Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • a haloalkyl group can be substituted at any available point of attachment, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, with C 5-6 cycloalkyl being more 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.
  • 3-12 membered heterocyclyl refers to a group of 3 to 12 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.
  • 4-12 membered heterocyclyl which is a 4- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms
  • 3-10 membered Heterocyclyl which is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms
  • a 3-8 membered heterocyclyl which is a ring carbon atom and 3- to 8-membered non-aromatic ring systems of 1 to 4 ring heteroatoms
  • Preferred is a 4-7 membered heterocyclyl, which is a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms
  • 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 6 -membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl groups) fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.
  • 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 has six ring carbon atoms (" C6 aryl”; eg, 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.
  • 5-14 membered heteroaryl refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (eg, with 6, 10 or 14 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.
  • 5-10 membered heteroaryl groups are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • 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.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the like, as defined herein, are optionally substituted groups.
  • Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or Heteroaryl rings in which each alkyl, alkenyl, alkynyl, cycloalkyl, 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, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rcc groups are combined to form a heterocycle radical or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R dd group substitution;
  • Each of R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, ring Alkyl, 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, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rff groups are combined to form a heterocyclyl group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R gg group substitution;
  • KRAS G12D refers to a mutant form of the mammalian KRAS protein that contains an amino acid substitution of aspartic acid for glycine at amino acid position 12.
  • 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, within the scope of sound medical judgment, are suitable 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 can 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 S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1- 19, incorporated herein by reference).
  • 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 suffers from 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.
  • an effective amount of a compound of the present invention may vary depending on factors such as, for example, the biological target, 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 to induce 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) (including sub-formulae such as formula (II), formula (V-2), etc.), pharmaceutically acceptable salts, enantiomers thereof Conformers, diastereomers, solvates, hydrates or isotopic variants, and mixtures thereof.
  • the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
  • X is -N(R)- or -CH(R*)-;
  • R is selected from H, -( CH2 ) 1-3 -halogen, -( CH2 ) 1-3 -OH, -( CH2 ) 1-3 -CN, -( CH2 ) 1-3 - NH2 , C 1-6 alkyl or C 1-6 haloalkyl;
  • R* is selected from -( CH2 ) 0-3 -halogen, -( CH2 ) 0-3 -OH, -( CH2 ) 0-3 -CN or -( CH2 ) 0-3 - NH2 ;
  • Y is N or CH
  • Y 1 is CR Y1a R Y1b ;
  • Y 2 is CR Y2a R Y2b ;
  • Y 3 is CR Y3a R Y3b or NR Y3c ;
  • R Y1a , R Y1b , R Y2a , R Y2b , R Y3a and R Y3b are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;
  • R Y3c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • a double bond can be formed between Y 3 and its adjacent Y 2 ;
  • R A is selected from H, C 6-10 aryl or 5-14 membered heteroaryl, optionally substituted with 1, 2, 3 or 4 R A1 ;
  • each R A1 is independently selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • L is selected from chemical bonds, -O-, -S- or -NH-;
  • R B is selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 membered aryl or 5-14 membered heteroaryl; it is optionally substituted with 1, 2, 3 or 4 R#;
  • R# is selected from H, -C 0-6 alkylene-halogen, -C 0-6 alkylene-CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, -C 0-6 alkylene-OR X , -C 0-6 alkylene-SR X , -C 0-6 alkylene-NR Y R Z , -C 0-6 Alkylene-C(O)R X , -C 0-6 alkylene-C(O)OR X , -C 0-6 alkylene-C(O)-NR Y R Z , -C 0- 6 alkylene-C 3-10 cycloalkyl, -C 0-6 alkylene-3-10 membered heterocyclic group, -C 0-6 alkylene-C 6-10 aryl or -C 0- 6 alkylene-5-14 membered heteroaryl; and R# is optional
  • R X is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R Y and R Z are independently selected from H, C 1-6 alkyl , C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R Y and R Z and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclic group;
  • R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d ) m -R';
  • R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -R";
  • R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
  • R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 are connected to form -(CR a R b ) n -;
  • R a is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R b is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R c is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R d is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R' is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e , -C(O)NR f R g , C 2- 6 alkenyl or C 2-6 alkynyl;
  • R" is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e , -C(O)NR f R g , C 2- 6 alkenyl or C 2-6 alkynyl;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R e is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R f and R g are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R f and R g and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclyl.
  • X is -N(R)-; in another specific embodiment, X is -NH-; in another specific embodiment, X is -NMe-; in a specific embodiment , X is -CH(R*)-; in another specific embodiment, X is -CH( NH2 )-; in another specific embodiment, X is -CH( CH2NH2 ) -; in another specific embodiment, X is -CH( CH2CH2NH2 ) - ; in another specific embodiment, X is -CH(OH)-; in another specific embodiment, X is -CH (CH2OH) - ; in another specific embodiment, X is -CH ( CH2CH2OH) - .
  • Y is N; in another specific embodiment, Y is CH.
  • Y 1 is CR Y1a R Y1b ; in another specific embodiment, Y 1 is CH 2 ; in another specific embodiment, (Y 1 ) r is CH 2 ; in another specific embodiment In embodiments, (Y 1 ) r is CH 2 CH 2 .
  • Y 2 is CR Y2a R Y2b ; in another specific embodiment, Y 2 is CH 2 ; in another specific embodiment, (Y 2 ) s is CH 2 ; in another specific embodiment In embodiments, (Y 2 ) s is a chemical bond.
  • R A is selected from H, C 6-10 aryl or 5-14 membered heteroaryl, which is optionally substituted with 1, 2, 3 or 4 R A1 ; in another embodiment
  • RA is H; in another specific embodiment, RA is C6-10 aryl, which is optionally substituted with 1, 2, 3 or 4 RAs ; in another specific embodiment , R A is phenyl, which is optionally substituted by 1, 2, 3 or 4 R A1 ; in another specific embodiment, R A is naphthyl, which is optionally substituted by 1, 2, 3 or 4 R A1 is substituted; in another specific embodiment, R A is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4 R A1 .
  • R A1 is H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkene
  • R A1 is H; in another specific embodiment, R A1 is halogen; in another specific embodiment, R A1 is -CN; In another specific embodiment, R A1 is -OR X ; in another specific embodiment, R A1 is -SR X ; in another specific embodiment, R A1 is -NR Y R Z ; in another specific embodiment
  • R A1 is C 1-6 alkyl; in another specific embodiment, R A1 is C 1-6 haloalkyl; in another specific embodiment, R A1 is C 2-6 alkenyl; In another specific embodiment, R A1 is C 2-6 alkynyl.
  • R A is selected from the following groups: preferred more preferred In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA is In another more specific embodiment, RA
  • L is a chemical bond; in another specific embodiment, L is -O-; in another specific embodiment, L is -S-; in another specific embodiment, L is - NH-.
  • R B is selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 membered aryl, or 5-14 membered heteroaryl, which are optionally substituted by 1, 2, 3 or 4 R# substitutions; in another particular embodiment, R B is H; in another particular embodiment, R B is halogen; in another particular embodiment, R B is -CN; In a specific embodiment, RB is -ORX ; in another specific embodiment, RB is -SRX ; in another specific embodiment, RB is -NRYRZ ; in another specific embodiment In, R B is C 1-6 alkyl, which is optionally substituted by 1, 2, 3 or 4 R#; in another specific embodiment, R B is C 1-6 alkyl,
  • -LR B is selected from H, Preferably H, In another more specific embodiment, -LR B is H; in another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment, -LR B is In another more specific embodiment,
  • R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d ) m -R'; in another specific embodiment, R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN, -CH 3 or -CH 2 -OH; in another specific embodiment, R 1 and R 2 are independently selected from -CH 3 or -CH 2 -OH; in another specific embodiment, one of R 1 and R 2 is -CH 3 or -CH 2 -OH; in another specific embodiment, one of R 1 and R 2 One is -CH 3 or -CH 2 -OH in the R configuration.
  • R 2' is H; in another specific embodiment, R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl.
  • R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or -( CRcRd ) m -R"; in another specific embodiment, R3 and R4 are independently selected from H, -CH2 - Cl, -CH2 - F, -CH2 - CN, -CH2CH2 - Cl, -CH2CH2 - F, -CH2CH2 -CN; In another specific embodiment, R3 and R4 are independently selected from H or -CH2 - CN.
  • R1 and R2 are linked to form -CH2- , -CH2CH2- or -CH2CH2CH2- , preferably -CH2CH2- or -CH2CH2CH 2 -, more preferably -CH 2 CH 2 -; in another more specific embodiment, R 3 and R 4 are linked to form -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, preferably -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, more preferably -CH 2 CH 2 -; in another more specific embodiment, R 1 and R 4 are linked to form -CH 2 -, -CH 2 CH 2- or -CH2CH2CH2- , preferably -CH2CH2- or -CH2CH2CH2- , more preferably -CH2CH2- ; in another more specific embodiment, R2 and R 3 is linked to form -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2
  • 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, Y 1 , Y 2 , Y 3 , r, s, R A , L, R B , R 1 , R 2 , R 2′ , R 3 , R 4 , p and q, 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 compound (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof , which has the following structure:
  • the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof :
  • X is -N(R)- or -CH(R*)-;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R* is selected from -(CH 2 ) 0-3 -NH 2 or -(CH 2 ) 0-3 -OH;
  • R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d ) m -R';
  • R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -R";
  • R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
  • R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R' is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e or -C(O)NR e R f ;
  • R" is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e or -C(O)NR e R f ;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R e is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R f and R g are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R f and R g and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclyl.
  • the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variation thereof body, of which,
  • X is -N(R)- or -CH(R*)-;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R* is selected from -(CH 2 ) 0-1 -NH 2 or -(CH 2 ) 0-1 -OH;
  • R 1 and R 2 are independently selected from H or -(CR c R d ) m -R';
  • R 3 and R 4 are independently selected from H or -(CR c R d ) m -R";
  • R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
  • R c is H
  • R d is H
  • R' is selected from H, halogen or -OH
  • R" is selected from H, halogen, -OH, -NH2 or -CN;
  • n 0, 1, 2, 3, 4, 5 or 6.
  • the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof :
  • R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d )-R';
  • R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -CN;
  • R is selected from H or halogen
  • R d is selected from H or halogen
  • R' is selected from H, halogen, -OH, -SH, -NH2 or -CN;
  • the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variation thereof body, of which,
  • R 1 and R 2 are independently selected from H or -(CR c R d )-R';
  • R 3 and R 4 are independently selected from H or -(CR c R d )-CN;
  • R c is H
  • R d is H
  • R' is selected from H or -OH.
  • the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof :
  • R 1 and R 2 is -(CR c R d )-R' and the other is selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d )-R';
  • R 3 and R 4 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d )-R";
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R' is selected from H, halogen, -OH, -SH, -NH2 or -CN;
  • R" is selected from halogen, -OH, -SH, -NH2 or -CN.
  • the present invention provides a compound of formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variation thereof body, of which,
  • R 1 and R 2 are -(CR c R d )-R', and the other is H;
  • R and R are independently selected from H or -(CR c R d ) -R";
  • R is selected from H, C 1-2 alkyl or C 1-2 haloalkyl
  • R c is H
  • R d is H
  • R' is selected from H or -OH
  • R" is -CN.
  • the present invention provides a compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof body, solvate, hydrate or isotopic variant:
  • R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is linked to form -(CR a R b ) n -, and the remaining R 1 and R 2 are independently selected from H or -(CR c R d ) m -R', the remaining R 3 and R 4 are independently selected from H or -(CR c R d ) m -R ";
  • R is H, C 1-6 alkyl or C 1-6 haloalkyl
  • R a is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R b is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R' is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
  • R" is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3.
  • the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Constructs, solvates, hydrates or isotopic variants, wherein,
  • R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 is respectively H, halogen, -CN, -OH or -NH 2 ;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R a is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R b is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • n 0, 1, 2, 3 or 4.
  • the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Conforms, solvates, hydrates or isotopic variants, wherein,
  • R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 is H;
  • R is selected from H, C 1-2 alkyl or C 1-2 haloalkyl
  • R a is H
  • R b is H
  • n 1, 2 or 3.
  • the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Conforms, solvates, hydrates or isotopic variants, wherein,
  • R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is linked to form -(CR a R b ) n -, and the remaining R 1 and R 2 are independently selected from H or -(CR c R d ) m -R', the remaining R 3 and R 4 are independently selected from H or -(CR c R d ) m -R ";
  • R is H
  • R a is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R b is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R' is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
  • R" is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
  • n 0, 1, 2 or 3;
  • n 2, 3 or 4.
  • the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Conforms, solvates, hydrates or isotopic variants, wherein,
  • R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, -CN, -OH or -NH 2 ;
  • R is H
  • R a is selected from H, halogen or C 1-4 alkyl
  • R b is selected from H, halogen or C 1-4 alkyl
  • n 2, 3 or 4.
  • the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Conforms, solvates, hydrates or isotopic variants, wherein,
  • R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 is H;
  • R is H
  • R a is H
  • R b is H
  • n 2 or 3.
  • the present invention provides the following compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates or isotopic variants thereof, wherein said The compound is selected from:
  • 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.
  • a hydrate of a compound can be represented, for example, by the general formula R ⁇ xH2O, where R is the compound and x is a number greater than zero.
  • 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 polyhydrates (x is a number greater than 1, eg, dihydrate (R ⁇ 2H2O) and hexahydrate (R ⁇ 6H2O)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1, for example, hemihydrate (R 0.5H2 ) O
  • polyhydrates x is a number greater than 1, eg, dihydrate (R ⁇ 2H2O) and hexahydrate (R ⁇ 6H2O)
  • 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 generally 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 (isotopic variants), which are equivalent to those described in formula (I), except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature replaced.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H , 13C , 11C , 14C , 15N , 18 , respectively O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • 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 A.C.S. Symposium 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 the 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.
  • 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%).
  • the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, Antihormones, angiogenesis inhibitors and antiandrogens.
  • the starting materials or reagents used herein are either commercially available or prepared by synthetic methods generally known in the art.
  • Step 2 Sodium hydride (80 mg, 60% purity, 2 mmol) was added to anhydrous tetrahydrofuran, and N-methyl-L-prolinol (230 mg, 2 mmol) was added dropwise under nitrogen protection at 0°C. After stirring for 30 min, compound 2 (290 mg, 1 mmol) was added dropwise. After warming up to room temperature, it was heated to 70 °C for 12 h.
  • Step 4 Pd 2 (dba) 3 (137 mg, 0.15 mmol) and BINAP (187 mg, 0.3 mmol) were dissolved in 4 mL of toluene, reacted under nitrogen protection at 100° C. for 30 min, and then cooled to room temperature.
  • Compound 4 (278 mg, 1 mmol), 1-bromo-8-methylnaphthalene (331 mg, 1.5 mmol) and sodium tert-butoxide (240 mg, 2.5 mmol) were first dissolved in 10 mL of toluene. Under nitrogen protection, catalyst and The ligand solution was reacted at 100°C for 18h.
  • Step 5 Sodium hydride (80 mg, 60% purity, 2 mmol) was added to 4 mL of anhydrous DMF, and ethanethiol (124 mg, 2 mmol) was slowly added dropwise at 0°C. After 30 min of reaction, compound 5 (418 mg, 1 mmol) was added dropwise. ) in 5 mL of DMF. Then the temperature was raised to 60 °C for 1 h, and then 1 mL of a saturated solution of NH 4 Cl was slowly added dropwise at 0 °C. After the reaction was stirred for 15 min, 20 mL of water was added to the mixture for quenching, and the mixture was extracted once with ethyl acetate and dichloromethane, respectively.
  • Step 1 Compound 8 (9.8 g, 146 mmol) was dissolved in a mixed solution of tBuOH/PE (15 mL/57.5 mL), and 23.3 g of Br was dissolved in 15 mL of tBuOH, and slowly added dropwise to the above mixed solution, 15 The reaction was carried out at °C for 30 min to obtain intermediate 9.
  • Step 2 Dissolve sodium metal (3.36 g, 146 mmol) in 85 mL of EtOH, slowly drop it into the reaction mixture of intermediate 9, and react at 15° C. for 2 h. It was quenched by adding water, extracted twice with ethyl acetate, and the organic phase was concentrated and purified by column to obtain compound 10 (10.6 g, 50%).
  • Step 3 Dissolve N,N-dibenzylethylenediamine (5.75g, 24mmol) in 50mL of toluene, add 4.85g of triethylamine, then dropwise add compound 10 at 0°C, return to room temperature, and react for 12h. After filtration, the solvent was removed and column purification gave compound 11 (3.2 g, 45%).
  • Step 4 Compound 11 (1.64 g, 5.36 mmol) was dissolved in 15 mL of DCE, 1-chloroethyl chloroformate (3.06 g, 21.4 mmol) was added dropwise at 0 °C, the temperature was raised to 84 °C, and the reaction was carried out for 2 days. Then 15 mL of methanol was added, and the reaction was carried out at 65 °C for 1 h. After the solvent was removed by rotary evaporation under negative pressure, the solid washed with methyl tert-butyl ether and filtered to obtain compound 12 (0.6 g, 56%).
  • Step 1 Compound 7 (536 mg, 1 mmol) was dissolved in 5 ml of dry DMF, DIPEA (258 mg, 2 mmol) was added, and various N-Boc protected amine fragments or amine fragments without N-Boc protection (1.05 mmol) were added , under the protection of nitrogen, react at 100 °C for 1 ⁇ 10h. After cooling, 20 mL of water was added, extracted twice with ethyl acetate, the organic phase was concentrated, and purified by column to obtain the N-Boc protected compound and the target compound without N-Boc protection (30-90% yield).
  • Step 2 The N-Boc protected compound (1 mmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 1 h. 10 mL of saturated Na 2 CO 3 solution was added, extracted twice with dichloromethane, the organic phase was concentrated, and purified by column to obtain the target compound (80% yield).
  • the plasmid with the target gene (KRAS4b G12D, with His tag, truncated sequence 1-169) was transferred into BL21 (DE3) competent E.coli, and transferred to the LB medium containing ampicillin resistance, Incubate at 37°C and 220rpm.
  • OD 600nm of the bacterial liquid is about 0.6
  • cool down to 16°C add 0.5mM IPTG (isopropyl- ⁇ -D-thiogalactoside) to the culture medium in the large flask, and cultivate at 16°C and 220rpm for about 24h .
  • the fermentation broth was centrifuged at 4°C and 6000 g for 10 min, and the supernatant was discarded.
  • Buffer A 25 mM Tris, 150 mM NaCl, 10 mM imidazole, pH 8.5.
  • the resuspended bacterial liquid was crushed in a high-pressure homogenizer at 4°C, and then centrifuged at 4°C at 16,000 g for 1 h at high speed. The supernatant was collected, and the sample was filtered with a 0.22 ⁇ m pore size filter membrane.
  • the Ni-NTA column was first regenerated with 0.1M NiSO 4 , and the excess Ni ions were washed away by equilibration with Buffer A. After the column was equilibrated, the sample was loaded, and the flow rate was 3 mL/min. After loading the sample, use Buffer A to wash away unbound proteins and impurities until the A280 value returns to a stable baseline, and a linear elution strategy is used, that is, Buffer A and Buffer B (25mM Tris, 150mM NaCl, 500mM imidazole, pH 8.5) Mix and collect 6 mL of eluate in each tube for protein electrophoresis analysis.
  • Buffer A and Buffer B 25mM Tris, 150mM NaCl, 500mM imidazole, pH 8.5
  • Tev enzyme was added to the eluate containing KRAS G12D to cut off the His-tagged thioredoxin in the N segment, and dialyzed in Buffer C (25mM Tris, 150mM NaCl, pH 8.5).
  • Buffer C 25mM Tris, 150mM NaCl, pH 8.5.
  • the second pass through the Ni-NTA column was the same. Since the thioredoxin containing the His tag was cut off by the Tev enzyme, the target protein could not be bound to the affinity chromatography column. Therefore, when passing through the Ni column for the second time, the unbound part was collected.
  • the eluate was analyzed by protein electrophoresis.
  • the protein sample buffer contains 25mM Tris, pH 8.5 and 150mM NaCl. First try two kits, Crystal Screen I and Crystal Screen II, to observe the ratio of precipitates, determine the protein concentration of 40mg/mL, and conduct electrophoresis of the concentrated protein. Analysis to verify purity.
  • crystals were grown in a constant temperature incubation chamber at a constant temperature of 22°C using the sitting drop vapor diffusion method. All the more than 1,000 conditions were initially screened and observed every two days to see if crystals had grown, and related records were made. It was found that the crystallization conditions of KRAS G12D were 0.2M sodium acetate, 0.1M Tris, pH 8.5, 26% (w/v) PEG 3350, and the relevant reagents were prepared and the crystallization conditions and protein concentrations were optimized.
  • the regular-shaped KRAS G12D crystals were collected by X-ray diffraction data. After the crystals were immersed in the compound TH Z 816 with a concentration of 2 mM for 6 h, the antifreeze was dipped, and 10% glycerol was added to the crystallization conditions. Data were collected and processed with related software such as HKL2000.
  • reaction buffer 40 mM HEPES-KOH, 10 mM MgCl2 , 1 mM DTT, pH 8.5
  • KRAS G12D mantGDP 2'/3'-O-(N-methylanthraniloyl)guanosine 5'-diphosphate
  • SOS cat protein and the GDP solution were pre-mixed, and then added to the KRAS protein solution to initiate the reaction.
  • the total system was 100 ⁇ L, and the final concentrations of each component were KRAS G12D mantGDP 2 ⁇ M, SOS cat 2 ⁇ M, and GDP 1 mM.
  • the fluorescence value was read immediately with a microplate reader (PerkinElmer, EnVision) (excitation wavelength 355 nm, emission wavelength 460 nm, read every 30 s, read continuously for 1 h).
  • the kinetic data obtained were fitted with the One phase decay equation or One phase association in the GraphPad Prism 7.0 software, and the rate k value was calculated and plotted against the compound concentration gradient to obtain the IC 50 curve.
  • PANC-1, Panc 04.03 and p53.2.1.1 cells were purchased from ATCC (American Type Culture Collection). 5000 cells (PANC-1 or Panc 04.03) were plated per well in 96-well plates (Nest, #701001) in DMEM (10% fetal bovine serum, 1% penicillin/streptomycin). After the cells were plated, they were cultured in an incubator for 24 hours, and then different concentrations of drugs were added to continue the culture for 24 hours. Subsequently, CCK-8 reagent (Biyuntian, C0042) was added and incubated for 1 h. Absorbance was measured at 450 nm with a microplate reader. The data were fitted with the [Inhibitor] vs.response --Variable slope (four parameters) model in GraphPad Prism 7.0 software, and IC50 values were calculated.
  • TH-Z 816 binds in a pocket formed under swtch II (residues 60-76 of RAS protein), namely the switch II pocket (SIIP). This is an allosteric site adjacent to the binding site for guanylate (GDP or GTP).
  • the electron cloud density (2F o -F c , 1 ⁇ ) near the compound is displayed, and it can be seen that it completely covers the small molecule backbone.
  • Figure 3 presents the spatial characteristics of the binding pocket: the spatial characteristics of the binding pocket around the piperazine ring are that the upper space is smaller, while the lower space is larger, the proximal space is larger, and the distal space is small, so the piperazine ring The methyl group on the top points down.

Abstract

A pyridopyrimidine compound, a pharmaceutical composition containing same, a preparation method therefor, and the use thereof, wherein the compound can target activated and inactivated KRAS G12D and serve as a reversible inhibitor of a KRAS G12D mutant protein.

Description

靶向活化与失活态KRAS G12D的抑制剂Inhibitors targeting activated and inactivated KRAS G12D 技术领域technical field
本发明涉及医药领域，具体地，本发明提供了能够可逆抑制KRAS G12D突变蛋白的化合物及其制备方法和应用。The present invention relates to the field of medicine, in particular, the present invention provides a compound capable of reversibly inhibiting KRAS G12D mutein, and a preparation method and application thereof.
背景技术Background technique
大鼠肉瘤同源基因(rat sarcoma,RAS)是第一个被发现的、突变频率最高的原癌基因(oncogene)。RAS蛋白作为“分子开关”调控着多个有关细胞增殖和分化的信号通路。Rat sarcoma homologous gene (rat sarcoma, RAS) is the first discovered oncogene (oncogene) with the highest mutation frequency. As a "molecular switch", RAS protein regulates multiple signaling pathways related to cell proliferation and differentiation.
KRAS常见的突变位点包括G12、G13和Q61，其中绝大部分是G12位点的突变，占比约为83％。KRAS G12常见的突变类型包括G12D、G12V和G12C，其中携带KRAS G12D突变的癌症患者数量是最多的。在胰腺导管癌、结直肠癌和肺腺癌中，KRAS G12D的突变分别占比51％、45％、17％(Schirripa,M.,et al.,KRAS G12C Metastatic Colorectal Cancer:Specific Features of a New Emerging Target Population.Clin Colorectal Cancer 19,(2020)219-225)。一项统计估算显示在美国和欧洲，每年新增的携带KRAS G12D突变的癌症患者高达18万(Baldus,S.E.,et al.,Prevalence and heterogeneity of KRAS,BRAF,and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases.Clin Cancer Res 16,(2010)790-799)。The common mutation sites of KRAS include G12, G13 and Q61, most of which are mutations at the G12 site, accounting for about 83%. The common mutation types of KRAS G12 include G12D, G12V and G12C, and the number of cancer patients with KRAS G12D mutation is the largest. KRAS G12D mutations accounted for 51%, 45%, and 17% of pancreatic ductal carcinoma, colorectal carcinoma, and lung adenocarcinoma, respectively (Schirripa, M., et al., KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population. Clin Colorectal Cancer 19, (2020) 219-225). A statistical estimate shows that in the United States and Europe there are as many as 180,000 new cancer patients with KRAS G12D mutations each year (Baldus, S.E., et al., Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res 16, (2010) 790-799).
此前三十年的时间里，所有靶向RAS的药物研发都失败了，其难点主要在于RAS蛋白的鸟苷酸结合口袋不适合成药，且表面没有其他较深的结合口袋。自从2013年，科学家在KRAS G12C突变蛋白中发现了一个可被小分子诱导形成的别构口袋后，医药界兴起了研发KRAS G12C共价抑制剂的热潮，然而临床意义更大的突变蛋白KRAS G12D的抑制剂却鲜有成功的案例报道。In the past three decades, all drug development targeting RAS has failed. The main difficulty is that the guanylate binding pocket of the RAS protein is not suitable for drug synthesis, and there are no other deeper binding pockets on the surface. Since scientists discovered an allosteric pocket in the KRAS G12C mutant protein that can be induced by small molecules in 2013, there has been an upsurge in the development of KRAS G12C covalent inhibitors in the pharmaceutical industry. However, the more clinically significant mutant protein KRAS G12D However, few successful case reports have been reported.
因此，本领域对于安全有效的KRAS G12D突变蛋白的抑制剂存在着迫切的需求。Therefore, there is an urgent need in the art for safe and effective inhibitors of KRAS G12D muteins.
发明内容SUMMARY OF THE INVENTION
与KRAS G12C不同，KRAS G12D的Asp 12的羧基无法与丙烯酰胺的 双键进行加成，因而虽然共价抑制剂在KRAS G12C蛋白上获得了成功，但这类小分子显然无法与KRAS G12D结合。面对该技术问题，本发明设计并合成了能与KRAS G12D形成非共价键结合的抑制剂，并且证明了本发明化合物能够有效抑制KRAS G12D的活性。Unlike KRAS G12C, the carboxyl group of Asp 12 of KRAS G12D cannot be added to the double bond of acrylamide, so although covalent inhibitors have been successful on KRAS G12C protein, such small molecules obviously cannot bind to KRAS G12D. Faced with this technical problem, the present invention designs and synthesizes an inhibitor that can form a non-covalent bond with KRAS G12D, and proves that the compound of the present invention can effectively inhibit the activity of KRAS G12D.
在一个方面，本发明提供了式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体：In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
Figure PCTCN2022088438-appb-000001
Figure PCTCN2022088438-appb-000001
其中，in,
X为-N(R)-或-CH(R*)-；X is -N(R)- or -CH(R*)-;
其中R选自H、-(CH 2) 1-3-卤素、-(CH 2) 1-3-OH、-(CH 2) 1-3-CN、-(CH 2) 1- 3-NH 2、C 1-6烷基或C 1-6卤代烷基； wherein R is selected from H, -( CH2 ) 1-3 -halogen, -( CH2 ) 1-3 -OH, -( CH2 ) 1-3 -CN, -( CH2 ) 1-3 - NH2 , C 1-6 alkyl or C 1-6 haloalkyl;
R*选自-(CH 2) 0-3-卤素、-(CH 2) 0-3-OH、-(CH 2) 0-3-CN或-(CH 2) 0-3-NH 2； R* is selected from -( CH2 ) 0-3 -halogen, -( CH2 ) 0-3 -OH, -( CH2 ) 0-3 -CN or -( CH2 ) 0-3 - NH2 ;
Y为N或CH；Y is N or CH;
Y 1为CR Y1aR Y1b； Y 1 is CR Y1a R Y1b ;
Y 2为CR Y2aR Y2b； Y 2 is CR Y2a R Y2b ;
Y 3为CR Y3aR Y3b或NR Y3c； Y 3 is CR Y3a R Y3b or NR Y3c ;
r＝1或2；r=1 or 2;
s＝0或1；s=0 or 1;
其中R Y1a、R Y1b、R Y2a、R Y2b、R Y3a和R Y3b独立地选自H、卤素、C 1- 6烷基或C 1-6卤代烷基； wherein R Y1a , R Y1b , R Y2a , R Y2b , R Y3a and R Y3b are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;
R Y3c选自H、C 1-6烷基或C 1-6卤代烷基； R Y3c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
或者Y 3和与之相邻的Y 2之间可以形成双键； Or a double bond can be formed between Y 3 and its adjacent Y 2 ;
R A选自H、C 6-10芳基或5-14元杂芳基，其任选地被1、2、3或4个R A1取代； R A is selected from H, C 6-10 aryl or 5-14 membered heteroaryl, optionally substituted with 1, 2, 3 or 4 R A1 ;
其中各个R A1独立地选自H、卤素、-CN、-OR X、-SR X、-NR YR Z、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； wherein each R A1 is independently selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
L选自化学键、-O-、-S-或-NH-；L is selected from chemical bonds, -O-, -S- or -NH-;
R B选自H、卤素、-CN、-OR X、-SR X、-NR YR Z、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元 杂芳基；其任选被1、2、3或4个R#取代； R B is selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 membered aryl or 5-14 membered heteroaryl; it is optionally substituted with 1, 2, 3 or 4 R#;
其中R#选自H、-C 0-6亚烷基-卤素、-C 0-6亚烷基-CN、C 1-6烷基、C 1- 6卤代烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-O-R X、-C 0-6亚烷基-S-R X、-C 0-6亚烷基-NR YR Z、-C 0-6亚烷基-C(O)R X、-C 0-6亚烷基-C(O)OR X、-C 0-6亚烷基-C(O)-NR YR Z、-C 0-6亚烷基-C 3-10环烷基、-C 0-6亚烷基-3-10元杂环基、-C 0-6亚烷基-C 6-10芳基或-C 0-6亚烷基-5-14元杂芳基；并且R#任选地被卤素、-OH、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 1- 6烷基或C 1-6卤代烷基取代； wherein R# is selected from H, -C 0-6 alkylene-halogen, -C 0-6 alkylene-CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, -C 0-6 alkylene-OR X , -C 0-6 alkylene-SR X , -C 0-6 alkylene-NR Y R Z , -C 0-6 Alkylene-C(O)R X , -C 0-6 alkylene-C(O)OR X , -C 0-6 alkylene-C(O)-NR Y R Z , -C 0- 6 alkylene-C 3-10 cycloalkyl, -C 0-6 alkylene-3-10 membered heterocyclic group, -C 0-6 alkylene-C 6-10 aryl or -C 0- 6 alkylene-5-14 membered heteroaryl; and R# is optionally halogen, -OH, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N (C 1-6 alkyl) 2 , C 1-6 alkyl or C 1-6 haloalkyl substitution;
其中R X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； wherein R X is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R Y和R Z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 Y和R Z以及它们连接的氮原子形成3-10元杂环基； R Y and R Z are independently selected from H, C 1-6 alkyl , C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R Y and R Z and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclic group;
R 1和R 2独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R’； R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d ) m -R';
R 3和R 4独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R”； R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -R";
R 2’为H，或者R 2、R 2’连同它们连接的碳原子形成C 3-6环烷基； R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
或者R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-； Or any one group of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 are connected to form -(CR a R b ) n -;
p＝0、1、2或3；p=0, 1, 2 or 3;
q＝0、1、2或3；q=0, 1, 2 or 3;
其中R a选自H、卤素、C 1-6烷基或C 1-6卤代烷基； wherein R a is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R b选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R b is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R c选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R c is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R d选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R d is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R’选自H、卤素、-OH、-SH、-NH 2、-CN、-C(O)R e、-C(O)OR e、-C(O)NR fR g、C 2-6烯基或C 2-6炔基； R' is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e , -C(O)NR f R g , C 2- 6 alkenyl or C 2-6 alkynyl;
R”选自H、卤素、-OH、-SH、-NH 2、-CN、-C(O)R e、-C(O)OR e、-C(O)NR fR g、C 2-6烯基或C 2-6炔基； R" is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e , -C(O)NR f R g , C 2- 6 alkenyl or C 2-6 alkynyl;
m＝0、1、2、3、4、5或6；m=0, 1, 2, 3, 4, 5 or 6;
n＝0、1、2、3、4、5或6；n=0, 1, 2, 3, 4, 5 or 6;
其中R e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； wherein R e is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R f和R g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 f和R g以及它们连接的氮原子形成3-10元杂环基。 R f and R g are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R f and R g and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclyl.
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。In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.
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。In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient, which also contain other therapeutic agents.
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KRAS G12D突变蛋白介导的疾病的药物中的用途。In another aspect, 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 KRAS G12D mutein mediated diseases.
在另一个方面，本发明提供了在受试者中治疗和/或预防KRAS G12D突变蛋白介导的疾病的方法，包括向所述受试者给药本发明化合物或本发明组合物。In another aspect, the present invention provides a method of treating and/or preventing a KRAS G12D mutein-mediated disease in a subject comprising administering to the subject a compound of the present invention or a composition of the present invention.
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KRAS G12D突变蛋白介导的疾病。In another aspect, the present invention provides compounds of the present invention or compositions of the present invention for use in the treatment and/or prevention of KRAS G12D mutein mediated diseases.
在具体实施方案中，本发明治疗的疾病包括选自以下的癌症：急性髓细胞样白血病、急性髓细胞样白血病、青少年癌症、儿童肾上腺皮质癌、AIDS相关的癌症(例如淋巴瘤和卡波西氏肉瘤)、肛门癌、阑尾癌、星形细胞瘤、非典型畸胎样、基底细胞癌、胆管癌、膀胱癌、骨癌、脑干神经胶质瘤、脑瘤、乳腺癌、支气管肿瘤、伯基特淋巴瘤、类癌瘤、非典型畸胎样、胚胎肿瘤、生殖细胞肿瘤、原发性淋巴瘤、宫颈癌、儿童癌症、脊索瘤、心脏肿瘤、慢性淋巴细胞性白血病(CLL)、慢性髓细胞性白血病(CML)、慢性骨髓增殖性病症、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T细胞淋巴瘤、肝外导管原位癌(DCIS)、胚胎肿瘤、CNS癌症、子宫内膜癌、室管膜瘤、食道癌、嗅神经母细胞瘤、尤文氏肉瘤、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌、骨骼的纤维组织细胞瘤、胆囊癌、胃癌、胃肠道类癌瘤、胃肠道间质瘤(GIST)、生殖细胞肿瘤、妊娠滋养细胞肿瘤、毛细胞白血病、头颈癌、心脏癌、肝癌、霍奇金氏淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞瘤、胰腺神经内分泌瘤、肾癌、喉癌、唇和口腔癌、肝癌、小叶原位癌(LCIS)、肺癌、淋巴瘤、转移性鳞状颈癌伴隐匿原发灶、中线道癌、口腔癌、多发性内分泌瘤综合征、多发性骨髓瘤/浆细胞瘤、蕈样真菌病、骨髓发育不良综合征、骨髓发育不良/骨髓增殖性瘤、多发性骨髓瘤、梅克尔细胞癌、恶性间皮瘤、骨骼的恶性纤维组织细胞瘤和骨肉瘤、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金氏淋巴瘤、非小细胞肺癌(NSCLC)、口腔癌、唇和口腔癌、口咽癌、卵巢癌、 胰腺癌、乳头瘤、副神经节瘤、鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、胸膜肺母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、移行性细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、皮肤癌、胃癌、小细胞肺癌、小肠癌、软组织肉瘤、细胞淋巴瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管的移行性细胞癌、滋养细胞肿瘤、儿童罕见的癌症、尿道癌、子宫肉瘤、阴道癌、外阴癌或病毒诱导的癌症。In specific embodiments, diseases treated by the present invention include cancers selected from the group consisting of acute myeloid leukemia, acute myeloid leukemia, juvenile cancer, childhood adrenocortical cancer, AIDS-related cancers such as lymphoma and Kaposi sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, uterus Endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, stomach Intestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular Melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, Midline cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplasia/myeloproliferative neoplasm, multiple myeloma, meke cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), Oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary Central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, cell lymphoma , testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancers .
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。Other objects and advantages of the present invention will be apparent to those skilled in the art from the ensuing detailed embodiments, examples and claims.
附图说明Description of drawings
图1 KRAS G12D蛋白与TH-Z 816的结合位点分析。Fig. 1 Analysis of the binding site of KRAS G12D protein and TH-Z 816.
图2 TH-Z 816与KRAS G12D蛋白的结合模式分析。Fig. 2 Analysis of the binding mode of TH-Z 816 to KRAS G12D protein.
图3 TH-Z 816的哌嗪环周围的蛋白空腔结构分析。Figure 3. Analysis of the protein cavity structure around the piperazine ring of TH-Z 816.
定义definition
化学定义chemical definition
下面更详细地描述具体官能团和化学术语的定义。Definitions of specific functional groups and chemical terms are described in more detail below.
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。 When numerical ranges are listed, each value and subranges within the range are intended to be included. For example, "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 , C2-6 , C2-5 , C2-4 , C2-3 , C3-6 , C3-5 , C3-4 , C4-6 , C4-5 , and C5 -6 alkyl.
“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烷基和C 1-2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 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 and C 1-2 alkyl 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 ). The term "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 alkyl abbreviations include: Me( -CH3 ), Et(-CH2CH3), iPr(-CH( CH3 ) 2 ), nPr ( -CH2CH2CH3 ) , n - Bu(-CH 2CH2CH2CH3 ) or i - Bu(-CH2CH ( CH3 ) 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 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. The term "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 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, C2-4alkynyl groups 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. The term "C2-6alkynyl" 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。在一些实施方案中，C 1-4亚烷基、C 2-4亚烷基和C 1-3亚烷基是优选的。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 1-6 alkylene group" refers to a divalent group formed by removing another hydrogen of a C 1-6 alkyl group, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred. The unsubstituted alkylene groups include, but are not limited to: methylene ( -CH2- ), ethylene ( -CH2CH2- ) , propylene ( -CH2CH2CH2- ) , 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 -) ,and many more. Exemplary substituted such alkylene groups, eg, such alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene groups (-CH( CH3 )- , -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 ( CH3 ) 2CH2CH2- , -CH2C ( CH3 ) 2CH2- , -CH2CH2C ( CH3 ) 2- ) , etc.
“C 0-6亚烷基”是指化学键以及上述“C 1-6亚烷基”。 The "C 0-6 alkylene group" refers to the chemical bond as well as the above-mentioned "C 1-6 alkylene group".
“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。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 alkenylene" refers to a divalent group formed by removing another hydrogen of a C 2-6 alkenyl, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkenylene groups are particularly preferred. Exemplary unsubstituted such alkenylene groups include, but are not limited to: vinylene (-CH=CH-) and propenylene (eg, -CH=CHCH2-, -CH2 - CH =CH-). Exemplary substituted such alkenylene groups, eg, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted ethylene groups (-C( CH3 )=CH- , -CH=C(CH 3 )-), substituted propenylene (-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-, -CH2 -CH=C( CH3 )-), and so on.
“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。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 2-6 alkynylene" refers to a divalent group formed by removing another hydrogen of a C 2-6 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkynylene groups are particularly preferred. Exemplary such alkynylene groups include, but are not limited to: ethynylene (-C≡C-), substituted or unsubstituted propynylene ( -C≡CCH2- ), and the like.
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
因此，“C 1-6卤代烷基”是指上述“C 1-6烷基”，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。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。卤代烷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。 Thus, "C 1-6 haloalkyl" refers to the aforementioned "C 1-6 alkyl" substituted with one or more halogen groups. In some embodiments, C 1-4 haloalkyl is particularly preferred, more preferably C 1-2 haloalkyl. Exemplary such haloalkyl groups include, but are not limited to : -CF3 , -CH2F , -CHF2 , -CHFCH2F , -CH2CHF2 , -CF2CF3 , -CCl3 , -CH2Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. A haloalkyl group can be substituted at any available point of attachment, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 3-10环烷基”是指具有3至10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 4-7环烷基和C 3-6环烷基是特别优选的，更优选C 5-6环烷基。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。 "C 3-10 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, with C 5-6 cycloalkyl being more 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. Exemplary such 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.
“3-12元杂环基”是指具有环碳原子和1至5个环杂原子的3至12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4-12元杂环基，其为具有环碳原子和1至5个环杂原子的4至12元非芳香环系；在一些实施方案中，优选3-10元杂环基，其为具有环碳原子和1至5个环杂原子的3至10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。 "3-12 membered heterocyclyl" refers to a group of 3 to 12 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. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence allows. In some embodiments, 4-12 membered heterocyclyl, which is a 4- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, is preferred; in some embodiments, 3-10 membered Heterocyclyl, which is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-8 membered heterocyclyl, which is a ring carbon atom and 3- to 8-membered non-aromatic ring systems of 1 to 4 ring heteroatoms; preferably 3-6 membered heterocyclyls, which are 3- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; Preferred is a 4-7 membered heterocyclyl, which is a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5-6 membered heterocyclyl, which is a A 5- to 6-membered non-aromatic ring system of 1 to 3 ring heteroatoms. 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 6 -membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl groups) fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more. 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。 "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). In some embodiments, an aryl group has six ring carbon atoms (" C6 aryl"; eg, phenyl). In some embodiments, 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.
“5-14元杂芳基”是指具有环碳原子和1-4个环杂原子的5-14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、10或14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，5-10元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系。在另一些实施方案中，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。"5-14 membered heteroaryl" refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (eg, with 6, 10 or 14 pi electrons) wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, 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. In some embodiments, 5-10 membered heteroaryl groups are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 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.
本文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the like, as defined herein, are optionally substituted groups.
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、环烷基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、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； Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2 , -N3 , -SO2H , -SO3H , -OH, -ORaa , -ON( Rbb ) 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 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , -NR bb C(=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 bb C(=NR bb )N(R bb ) 2 , -C(=O)NR bb SO 2 R aa , -NR bb SO 2 R aa , -SO 2 N(R bb ) 2 , -SO 2 R aa , -SO 2 OR aa , -OSO 2 R 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) 2 R aa , -OP(=O) 2 R aa , -P(=O)(R aa ) 2 , -OP(=O)(R aa ) 2 , -OP(=O)(OR cc ) 2 , -P( =O) 2 N(R bb ) 2 , -OP(=O) 2 N(R bb ) 2 , -P(=O)(NR bb ) 2 , -OP(=O)(NR bb ) 2 , - NR bb P(=O)(OR cc ) 2 , -NR bb P(=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 ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R dd groups replace;
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； Or two geminal hydrogens on a carbon atom are surrounded by groups =O, =S, =NN( Rbb ) 2 , = NNRbbC (=O) Raa , = NNRbbC (=O) ORaa , = NNR bb S(=O) 2 R aa , =NR bb or =NOR cc substitution;
R aa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、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、环烷基、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； Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or Heteroaryl rings in which each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R dd groups group replacement;
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、环烷基、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、环烷基、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； Each of R bb is independently selected from: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O ) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , alkyl, haloalkyl, alkene radical, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R bb groups combined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkyne radyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;
R cc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、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、环烷基、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； Each of Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rcc groups are combined to form a heterocycle radical or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R dd group substitution;
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、环烷基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、环烷基、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； Each of Rdd is independently selected from: halogen, -CN, -NO2 , -N3 , -SO2H, -SO3H , -OH, -ORee , -ON( Rff )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 2 H, -CO 2 Ree , -OC(=O) Ree , -OCO 2 Ree , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , - NRff C(=O) Ree,-NRffCO2Ree , -NRffC (=O)N( Rff ) 2 , -C (= NRff ) ORee , -OC(=NRff ) Ree , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff ) N(R ff ) 2 , -NR ff SO 2 Ree , -SO 2 N(R ff ) 2 , -SO 2 Ree , -SO 2 OR ee , -OSO 2 Ree , -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) 2 Re ee , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 , -OP(=O)(OR ee ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle aryl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two gem R dd substituents may combine to form =O or =S;
R ee的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、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； Each of R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
R ff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、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、环烷基、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； Each of Rff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rff groups are combined to form a heterocyclyl group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R gg group substitution;
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环烷基、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。 Each of Rgg is independently: halogen, -CN, -NO2 , -N3 , -SO2H , -SO3H , -OH , -OC1-6 alkyl, -ON( C1-6 alkyl) 2 , -N(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 3 + X - , -NH(C 1-6 alkyl) 2 + X - , -NH 2 (C 1-6 alkyl) + X - , -NH 3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl ), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C (=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl) C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , - NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1- 6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl) , -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH(C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl) 3 , -C(=S)N(C 1-6 alkyl) 2 , C (=S)NH(C 1-6 alkyl), C(=S)NH 2 , -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl , -SC(=S)SC 1-6 alkyl, -P(=O) 2 (C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2 , -OP(= O)(C 1-6 alkyl) 2 , -O P(=O)(OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 Cycloalkyl, C 6 -C 10 aryl, C 3 -C 7 heterocyclyl, C 5 -C 10 heteroaryl; or two gem R gg substituents may combine to form =O or =S; where X - for counter ions.
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、环烷基、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、环烷基、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。 Exemplary substituents on nitrogen include, but are not limited to: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N (R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O )( NRcc ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rcc groups attached to a nitrogen atom combine to form a heterocycle aryl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R The dd group is substituted and wherein R aa , R bb , R cc and R dd are as described above.
其它定义Other definitions
术语“KRAS G12D”是指哺乳动物KRAS蛋白的突变形式，其在12位氨基酸处含有天冬氨酸对甘氨酸的氨基酸取代。The term "KRAS G12D" refers to a mutant form of the mammalian KRAS protein that contains an amino acid substitution of aspartic acid for glycine at amino acid position 12.
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。The term "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.
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。The term "treating" as used herein 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. The term "treatment" as used herein refers to the action of the verb treat, as just defined.
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。As used herein, the term "pharmaceutically acceptable salts" refers to those carboxylates, amino acid addition salts of the compounds of the present invention which, within the scope of sound medical judgment, are suitable 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.
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。Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
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。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.
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)。Salts can 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 S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1- 19, incorporated herein by reference).
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”。"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. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.
“疾病”、“障碍”和“病症”在本文中可互换地使用。"Disease," "disorder," and "condition" are used interchangeably herein.
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”)。Unless otherwise specified, the term "treatment" as used herein includes the effect that occurs when a subject suffers from 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").
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。Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a target biological response. As will be understood by those of ordinary skill in the art, an effective amount of a compound of the present invention may vary depending on factors such as, for example, the biological target, 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.
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。Unless otherwise specified, 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 to induce 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.
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。Unless otherwise specified, 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.
“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。"Combination" and related terms refer to the simultaneous or sequential administration of a compound of the present invention and another therapeutic agent. For example, 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.
具体实施方案specific implementation
本文中，“本发明化合物”指的是以下的式(I)化合物(包括子通式，例如式(II)、式(V-2)等)、其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，以及它们的混合物。Herein, "compounds of the present invention" refers to the following compounds of formula (I) (including sub-formulae such as formula (II), formula (V-2), etc.), pharmaceutically acceptable salts, enantiomers thereof Conformers, diastereomers, solvates, hydrates or isotopic variants, and mixtures thereof.
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。Herein, compounds are named using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise stated) all optical isomers and mixtures thereof are included. Furthermore, all isomeric compounds and carbon-carbon double bonds encompassed by this invention may occur in the Z and E forms unless otherwise specified. Compounds exist in different tautomeric forms, and a said compound is not limited to any particular tautomer, but is intended to cover all tautomeric forms.
在一个实施方案中，本发明涉及式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体：In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
Figure PCTCN2022088438-appb-000002
Figure PCTCN2022088438-appb-000002
其中，in,
X为-N(R)-或-CH(R*)-；X is -N(R)- or -CH(R*)-;
其中R选自H、-(CH 2) 1-3-卤素、-(CH 2) 1-3-OH、-(CH 2) 1-3-CN、-(CH 2) 1- 3-NH 2、C 1-6烷基或C 1-6卤代烷基； wherein R is selected from H, -( CH2 ) 1-3 -halogen, -( CH2 ) 1-3 -OH, -( CH2 ) 1-3 -CN, -( CH2 ) 1-3 - NH2 , C 1-6 alkyl or C 1-6 haloalkyl;
R*选自-(CH 2) 0-3-卤素、-(CH 2) 0-3-OH、-(CH 2) 0-3-CN或-(CH 2) 0-3-NH 2； R* is selected from -( CH2 ) 0-3 -halogen, -( CH2 ) 0-3 -OH, -( CH2 ) 0-3 -CN or -( CH2 ) 0-3 - NH2 ;
Y为N或CH；Y is N or CH;
Y 1为CR Y1aR Y1b； Y 1 is CR Y1a R Y1b ;
Y 2为CR Y2aR Y2b； Y 2 is CR Y2a R Y2b ;
Y 3为CR Y3aR Y3b或NR Y3c； Y 3 is CR Y3a R Y3b or NR Y3c ;
r＝1或2；r=1 or 2;
s＝0或1；s=0 or 1;
其中R Y1a、R Y1b、R Y2a、R Y2b、R Y3a和R Y3b独立地选自H、卤素、C 1- 6烷基或C 1-6卤代烷基； wherein R Y1a , R Y1b , R Y2a , R Y2b , R Y3a and R Y3b are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;
R Y3c选自H、C 1-6烷基或C 1-6卤代烷基； R Y3c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
或者Y 3和与之相邻的Y 2之间可以形成双键； Or a double bond can be formed between Y 3 and its adjacent Y 2 ;
R A选自H、C 6-10芳基或5-14元杂芳基，其任选地被1、2、3或4个R A1取代； R A is selected from H, C 6-10 aryl or 5-14 membered heteroaryl, optionally substituted with 1, 2, 3 or 4 R A1 ;
其中各个R A1独立地选自H、卤素、-CN、-OR X、-SR X、-NR YR Z、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； wherein each R A1 is independently selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
L选自化学键、-O-、-S-或-NH-；L is selected from chemical bonds, -O-, -S- or -NH-;
R B选自H、卤素、-CN、-OR X、-SR X、-NR YR Z、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被1、2、3或4个R#取代； R B is selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 membered aryl or 5-14 membered heteroaryl; it is optionally substituted with 1, 2, 3 or 4 R#;
其中R#选自H、-C 0-6亚烷基-卤素、-C 0-6亚烷基-CN、C 1-6烷基、C 1- 6卤代烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-O-R X、-C 0-6亚烷基-S-R X、-C 0-6亚烷基-NR YR Z、-C 0-6亚烷基-C(O)R X、-C 0-6亚烷基-C(O)OR X、-C 0-6亚烷基-C(O)-NR YR Z、-C 0-6亚烷基-C 3-10环烷基、-C 0-6亚烷基-3-10元杂环基、-C 0-6亚烷基-C 6-10芳基或-C 0-6亚烷基-5-14元杂芳基；并且R#任选地被卤素、-OH、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 1- 6烷基或C 1-6卤代烷基取代； wherein R# is selected from H, -C 0-6 alkylene-halogen, -C 0-6 alkylene-CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, -C 0-6 alkylene-OR X , -C 0-6 alkylene-SR X , -C 0-6 alkylene-NR Y R Z , -C 0-6 Alkylene-C(O)R X , -C 0-6 alkylene-C(O)OR X , -C 0-6 alkylene-C(O)-NR Y R Z , -C 0- 6 alkylene-C 3-10 cycloalkyl, -C 0-6 alkylene-3-10 membered heterocyclic group, -C 0-6 alkylene-C 6-10 aryl or -C 0- 6 alkylene-5-14 membered heteroaryl; and R# is optionally halogen, -OH, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N (C 1-6 alkyl) 2 , C 1-6 alkyl or C 1-6 haloalkyl substitution;
其中R X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； wherein R X is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R Y和R Z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 Y和R Z以及它们连接的氮原子形成3-10元杂环基； R Y and R Z are independently selected from H, C 1-6 alkyl , C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R Y and R Z and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclic group;
R 1和R 2独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R’； R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d ) m -R';
R 3和R 4独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R”； R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -R";
R 2’为H，或者R 2、R 2’连同它们连接的碳原子形成C 3-6环烷基； R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
或者R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-； Or any one group of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 are connected to form -(CR a R b ) n -;
p＝0、1、2或3；p=0, 1, 2 or 3;
q＝0、1、2或3；q=0, 1, 2 or 3;
其中R a选自H、卤素、C 1-6烷基或C 1-6卤代烷基； wherein R a is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R b选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R b is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R c选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R c is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R d选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R d is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R’选自H、卤素、-OH、-SH、-NH 2、-CN、-C(O)R e、-C(O)OR e、-C(O)NR fR g、C 2-6烯基或C 2-6炔基； R' is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e , -C(O)NR f R g , C 2- 6 alkenyl or C 2-6 alkynyl;
R”选自H、卤素、-OH、-SH、-NH 2、-CN、-C(O)R e、-C(O)OR e、-C(O)NR fR g、C 2-6烯基或C 2-6炔基； R" is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e , -C(O)NR f R g , C 2- 6 alkenyl or C 2-6 alkynyl;
m＝0、1、2、3、4、5或6；m=0, 1, 2, 3, 4, 5 or 6;
n＝0、1、2、3、4、5或6；n=0, 1, 2, 3, 4, 5 or 6;
其中R e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； wherein R e is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R f和R g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 f和R g以及它们连接的氮原子形成3-10元杂环基。 R f and R g are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R f and R g and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclyl.
XX
在一个具体实施方案中，X为-N(R)-；在另一个具体实施方案中，X为-NH-；在另一个具体实施方案中，X为-NMe-；在一个具体实施方案中，X为-CH(R*)-；在另一个具体实施方案中，X为-CH(NH 2)-；在另一个具体实施方案中，X为-CH(CH 2NH 2)-；在另一个具体实施方案中，X为-CH(CH 2CH 2NH 2)-；在另一个具体实施方案中，X为-CH(OH)-；在另一个具体实施方案中，X为-CH(CH 2OH)-；在另一个具体实施方案中，X为-CH(CH 2CH 2OH)-。 In a specific embodiment, X is -N(R)-; in another specific embodiment, X is -NH-; in another specific embodiment, X is -NMe-; in a specific embodiment , X is -CH(R*)-; in another specific embodiment, X is -CH( NH2 )-; in another specific embodiment, X is -CH( CH2NH2 ) -; in In another specific embodiment, X is -CH( CH2CH2NH2 ) - ; in another specific embodiment, X is -CH(OH)-; in another specific embodiment, X is -CH (CH2OH) - ; in another specific embodiment, X is -CH ( CH2CH2OH) - .
YY
在一个具体实施方案中，Y为N；在另一个具体实施方案中，Y为CH。In one specific embodiment, Y is N; in another specific embodiment, Y is CH.
(Y 1) r (Y 1 ) r
在一个具体实施方案中，Y 1为CR Y1aR Y1b；在另一个具体实施方案中，Y 1为CH 2；在另一个具体实施方案中，(Y 1) r为CH 2；在另一个具体实施方案中，(Y 1) r为CH 2CH 2。 In one specific embodiment, Y 1 is CR Y1a R Y1b ; in another specific embodiment, Y 1 is CH 2 ; in another specific embodiment, (Y 1 ) r is CH 2 ; in another specific embodiment In embodiments, (Y 1 ) r is CH 2 CH 2 .
(Y 2) s (Y 2 ) s
在一个具体实施方案中，Y 2为CR Y2aR Y2b；在另一个具体实施方案中，Y 2为CH 2；在另一个具体实施方案中，(Y 2) s为CH 2；在另一个具体实施方案中，(Y 2) s为化学键。 In one specific embodiment, Y 2 is CR Y2a R Y2b ; in another specific embodiment, Y 2 is CH 2 ; in another specific embodiment, (Y 2 ) s is CH 2 ; in another specific embodiment In embodiments, (Y 2 ) s is a chemical bond.
Y 3 Y 3
在一个具体实施方案中，Y 3为CR Y3aR Y3b；在另一个具体实施方案中，Y 3为CH 2；在另一个具体实施方案中，Y 3为NR Y3c；在另一个具体实施方案 中，Y 3为NH；在另一个具体实施方案中，(Y 2) s-Y 3为CH 2CH 2；在另一个具体实施方案中，(Y 2) s-Y 3为CH＝CH；在另一个具体实施方案中，(Y 2) s-Y 3为CH 2NH；在另一个具体实施方案中，(Y 2) s-Y 3为CH＝N。 In one specific embodiment, Y3 is CR Y3a R Y3b ; in another specific embodiment, Y3 is CH2 ; in another specific embodiment, Y3 is NR Y3c ; in another specific embodiment , Y 3 is NH; in another specific embodiment, (Y 2 ) s -Y 3 is CH 2 CH 2 ; in another specific embodiment, (Y 2 ) s -Y 3 is CH=CH; in In another specific embodiment, ( Y2 ) s - Y3 is CH2NH ; in another specific embodiment, ( Y2 ) s - Y3 is CH=N.
在一个更具体实施方案中，
Figure PCTCN2022088438-appb-000003
选自以下母核：
Figure PCTCN2022088438-appb-000004
Figure PCTCN2022088438-appb-000005
Figure PCTCN2022088438-appb-000006
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000007
为
Figure PCTCN2022088438-appb-000008
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000009
为
Figure PCTCN2022088438-appb-000010
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000011
为
Figure PCTCN2022088438-appb-000012
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000013
为
Figure PCTCN2022088438-appb-000014
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000015
为
Figure PCTCN2022088438-appb-000016
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000017
为
Figure PCTCN2022088438-appb-000018
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000019
为
Figure PCTCN2022088438-appb-000020
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000021
为
Figure PCTCN2022088438-appb-000022
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000023
为
Figure PCTCN2022088438-appb-000024
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000025
为
Figure PCTCN2022088438-appb-000026
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000027
为
Figure PCTCN2022088438-appb-000028
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000029
为
Figure PCTCN2022088438-appb-000030
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000031
为
Figure PCTCN2022088438-appb-000032
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000033
为
Figure PCTCN2022088438-appb-000034
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000035
为
Figure PCTCN2022088438-appb-000036
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000037
为
Figure PCTCN2022088438-appb-000038
在另一个更具体实施方案中，
Figure PCTCN2022088438-appb-000039
为
Figure PCTCN2022088438-appb-000040
In a more specific embodiment,
Figure PCTCN2022088438-appb-000003
Select from the following parent nuclei:
Figure PCTCN2022088438-appb-000004
Figure PCTCN2022088438-appb-000005
Figure PCTCN2022088438-appb-000006
In another more specific embodiment,
Figure PCTCN2022088438-appb-000007
for
Figure PCTCN2022088438-appb-000008
In another more specific embodiment,
Figure PCTCN2022088438-appb-000009
for
Figure PCTCN2022088438-appb-000010
In another more specific embodiment,
Figure PCTCN2022088438-appb-000011
for
Figure PCTCN2022088438-appb-000012
In another more specific embodiment,
Figure PCTCN2022088438-appb-000013
for
Figure PCTCN2022088438-appb-000014
In another more specific embodiment,
Figure PCTCN2022088438-appb-000015
for
Figure PCTCN2022088438-appb-000016
In another more specific embodiment,
Figure PCTCN2022088438-appb-000017
for
Figure PCTCN2022088438-appb-000018
In another more specific embodiment,
Figure PCTCN2022088438-appb-000019
for
Figure PCTCN2022088438-appb-000020
In another more specific embodiment,
Figure PCTCN2022088438-appb-000021
for
Figure PCTCN2022088438-appb-000022
In another more specific embodiment,
Figure PCTCN2022088438-appb-000023
for
Figure PCTCN2022088438-appb-000024
In another more specific embodiment,
Figure PCTCN2022088438-appb-000025
for
Figure PCTCN2022088438-appb-000026
In another more specific embodiment,
Figure PCTCN2022088438-appb-000027
for
Figure PCTCN2022088438-appb-000028
In another more specific embodiment,
Figure PCTCN2022088438-appb-000029
for
Figure PCTCN2022088438-appb-000030
In another more specific embodiment,
Figure PCTCN2022088438-appb-000031
for
Figure PCTCN2022088438-appb-000032
In another more specific embodiment,
Figure PCTCN2022088438-appb-000033
for
Figure PCTCN2022088438-appb-000034
In another more specific embodiment,
Figure PCTCN2022088438-appb-000035
for
Figure PCTCN2022088438-appb-000036
In another more specific embodiment,
Figure PCTCN2022088438-appb-000037
for
Figure PCTCN2022088438-appb-000038
In another more specific embodiment,
Figure PCTCN2022088438-appb-000039
for
Figure PCTCN2022088438-appb-000040
R A R A
在一个具体实施方案中，R A选自H、C 6-10芳基或5-14元杂芳基，其任选地被1、2、3或4个R A1取代；在另一个具体实施方案中，R A为H；在另 一个具体实施方案中，R A为C 6-10芳基，其任选地被1、2、3或4个R A1取代；在另一个具体实施方案中，R A为苯基，其任选地被1、2、3或4个R A1取代；在另一个具体实施方案中，R A为萘基，其任选地被1、2、3或4个R A1取代；在另一个具体实施方案中，R A为5-14元杂芳基，其任选地被1、2、3或4个R A1取代。 In one embodiment, R A is selected from H, C 6-10 aryl or 5-14 membered heteroaryl, which is optionally substituted with 1, 2, 3 or 4 R A1 ; in another embodiment In the scheme, RA is H; in another specific embodiment, RA is C6-10 aryl, which is optionally substituted with 1, 2, 3 or 4 RAs ; in another specific embodiment , R A is phenyl, which is optionally substituted by 1, 2, 3 or 4 R A1 ; in another specific embodiment, R A is naphthyl, which is optionally substituted by 1, 2, 3 or 4 R A1 is substituted; in another specific embodiment, R A is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4 R A1 .
在一个具体实施方案中，R A1为H、卤素、-CN、-OR X、-SR X、-NR YR Z、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；在另一个具体实施方案中，R A1为H；在另一个具体实施方案中，R A1为卤素；在另一个具体实施方案中，R A1为-CN；在另一个具体实施方案中，R A1为-OR X；在另一个具体实施方案中，R A1为-SR X；在另一个具体实施方案中，R A1为-NR YR Z；在另一个具体实施方案中，R A1为C 1-6烷基；在另一个具体实施方案中，R A1为C 1-6卤代烷基；在另一个具体实施方案中，R A1为C 2-6烯基；在另一个具体实施方案中，R A1为C 2-6炔基。 In a specific embodiment, R A1 is H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkene In another specific embodiment, R A1 is H; in another specific embodiment, R A1 is halogen; in another specific embodiment, R A1 is -CN; In another specific embodiment, R A1 is -OR X ; in another specific embodiment, R A1 is -SR X ; in another specific embodiment, R A1 is -NR Y R Z ; in another specific embodiment In an embodiment, R A1 is C 1-6 alkyl; in another specific embodiment, R A1 is C 1-6 haloalkyl; in another specific embodiment, R A1 is C 2-6 alkenyl; In another specific embodiment, R A1 is C 2-6 alkynyl.
在一个更具体实施方案中，R A选自以下基团：
Figure PCTCN2022088438-appb-000041
Figure PCTCN2022088438-appb-000042
Figure PCTCN2022088438-appb-000043
优选
Figure PCTCN2022088438-appb-000044
Figure PCTCN2022088438-appb-000045
更优选
Figure PCTCN2022088438-appb-000046
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000047
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000048
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000049
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000050
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000051
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000052
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000053
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000054
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000055
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000056
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000057
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000058
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000059
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000060
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000061
在另一个更具体实施方案中，R A为
Figure PCTCN2022088438-appb-000062
In a more specific embodiment, R A is selected from the following groups:
Figure PCTCN2022088438-appb-000041
Figure PCTCN2022088438-appb-000042
Figure PCTCN2022088438-appb-000043
preferred
Figure PCTCN2022088438-appb-000044
Figure PCTCN2022088438-appb-000045
more preferred
Figure PCTCN2022088438-appb-000046
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000047
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000048
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000049
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000050
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000051
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000052
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000053
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000054
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000055
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000056
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000057
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000058
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000059
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000060
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000061
In another more specific embodiment, RA is
Figure PCTCN2022088438-appb-000062
LL
在一个具体实施方案中，L为化学键；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-NH-。In one specific embodiment, L is a chemical bond; in another specific embodiment, L is -O-; in another specific embodiment, L is -S-; in another specific embodiment, L is - NH-.
R B R B
在一个具体实施方案中，R B选自H、卤素、-CN、-OR X、-SR X、-NR YR Z、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基，其任选被1、2、3或4个R#取代；在另一个具体实施方案中，R B为H；在另一个具体实施方案中，R B为卤素；在另一个具体实施方案中，R B为-CN；在另一个具体实施方案中，R B为-OR X；在另一个具体实施方案中，R B为-SR X；在另一个具体实施方案中，R B为-NR YR Z；在 另一个具体实施方案中，R B为C 1-6烷基，其任选被1、2、3或4个R#取代；在另一个具体实施方案中，R B为C 1-6卤代烷基，其任选被1、2、3或4个R#取代；在另一个具体实施方案中，R B为C 2-6烯基，其任选被1、2、3或4个R#取代；在另一个具体实施方案中，R B为C 2-6炔基，其任选被1、2、3或4个R#取代；在另一个具体实施方案中，R B为C 3-10环烷基，其任选被1、2、3或4个R#取代；在另一个具体实施方案中，R B为3-10元杂环基，其任选被1、2、3或4个R#取代；在另一个具体实施方案中，R B为C 6-10芳基，其任选被1、2、3或4个R#取代；在另一个具体实施方案中，R B为5-14元杂芳基，其任选被1、2、3或4个R#取代。 In a specific embodiment, R B is selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 membered aryl, or 5-14 membered heteroaryl, which are optionally substituted by 1, 2, 3 or 4 R# substitutions; in another particular embodiment, R B is H; in another particular embodiment, R B is halogen; in another particular embodiment, R B is -CN; In a specific embodiment, RB is -ORX ; in another specific embodiment, RB is -SRX ; in another specific embodiment, RB is -NRYRZ ; in another specific embodiment In, R B is C 1-6 alkyl, which is optionally substituted by 1, 2, 3 or 4 R#; in another specific embodiment, R B is C 1-6 haloalkyl, which is optionally substituted by 1, 2, 3 or 4 R# substituted; in another specific embodiment, R B is C 2-6 alkenyl, which is optionally substituted with 1, 2, 3 or 4 R#; in another specific embodiment In an embodiment, R B is C 2-6 alkynyl, which is optionally substituted with 1, 2, 3 or 4 R#; in another specific embodiment, R B is C 3-10 cycloalkyl, which optionally substituted with 1, 2, 3 or 4 R#; in another specific embodiment, R B is a 3-10 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 R#; In another specific embodiment, R B is C 6-10 aryl, which is optionally substituted with 1, 2, 3 or 4 R#; in another specific embodiment, R B is a 5-14 membered hetero Aryl optionally substituted with 1, 2, 3 or 4 R#.
在一个更具体实施方案中，-L-R B选自H、
Figure PCTCN2022088438-appb-000063
Figure PCTCN2022088438-appb-000064
Figure PCTCN2022088438-appb-000065
优选H、
Figure PCTCN2022088438-appb-000066
Figure PCTCN2022088438-appb-000067
Figure PCTCN2022088438-appb-000068
在另一个更具体实施方案中，-L-R B为H；在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000069
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000070
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000071
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000072
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000073
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000074
在另一 个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000075
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000076
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000077
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000078
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000079
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000080
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000081
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000082
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000083
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000084
在另一个更具体实施方案中，-L-R B为
Figure PCTCN2022088438-appb-000085
In a more specific embodiment, -LR B is selected from H,
Figure PCTCN2022088438-appb-000063
Figure PCTCN2022088438-appb-000064
Figure PCTCN2022088438-appb-000065
Preferably H,
Figure PCTCN2022088438-appb-000066
Figure PCTCN2022088438-appb-000067
Figure PCTCN2022088438-appb-000068
In another more specific embodiment, -LR B is H; in another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000069
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000070
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000071
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000072
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000073
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000074
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000075
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000076
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000077
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000078
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000079
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000080
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000081
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000082
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000083
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000084
In another more specific embodiment, -LR B is
Figure PCTCN2022088438-appb-000085
R 1和R 2 R1 and R2
在一个具体实施方案中，R 1和R 2独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R’；在另一个具体实施方案中，R 1和R 2独立地选自H、卤素、-OH、-NH 2、-CN、-CH 3或-CH 2-OH；在另一个具体实施方案中，R 1和R 2独立地选自-CH 3或-CH 2-OH；在另一个具体实施方案中，R 1和R 2之一为-CH 3或-CH 2-OH；在另一个具体实施方案中，R 1和R 2之一为R构型的-CH 3或-CH 2-OH。 In one specific embodiment, R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d ) m -R'; in another specific embodiment, R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN, -CH 3 or -CH 2 -OH; in another specific embodiment, R 1 and R 2 are independently selected from -CH 3 or -CH 2 -OH; in another specific embodiment, one of R 1 and R 2 is -CH 3 or -CH 2 -OH; in another specific embodiment, one of R 1 and R 2 One is -CH 3 or -CH 2 -OH in the R configuration.
R 2’ R 2'
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、R 2’连同它们连接的碳原子形成C 3-6环烷基。 In one specific embodiment, R 2' is H; in another specific embodiment, R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl.
R 3和R 4 R3 and R4
在一个具体实施方案中，R 3和R 4独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R”；在另一个具体实施方案中，R 3和R 4独立地选自H、-CH 2-Cl、-CH 2-F、-CH 2-CN、-CH 2CH 2-Cl、-CH 2CH 2-F、-CH 2CH 2-CN；在另一个具体实施方案中，R 3和R 4独立地选自H或-CH 2-CN。 In one specific embodiment, R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or -( CRcRd ) m -R"; in another specific embodiment, R3 and R4 are independently selected from H, -CH2 - Cl, -CH2 - F, -CH2 - CN, -CH2CH2 - Cl, -CH2CH2 - F, -CH2CH2 -CN; In another specific embodiment, R3 and R4 are independently selected from H or -CH2 - CN.
在一个更具体实施方案中，R 1和R 2连接形成-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-，优选-CH 2CH 2-或-CH 2CH 2CH 2-，更优选-CH 2CH 2-；在另一个更具体实施方案中，R 3和R 4连接形成-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-，优选-CH 2CH 2-或-CH 2CH 2CH 2-，更优选-CH 2CH 2-；在另一个更具体实施方案中，R 1和R 4连接形成-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-，优选-CH 2CH 2-或-CH 2CH 2CH 2-，更优选-CH 2CH 2-；在另一个更具体实施方案中，R 2和R 3连接形成-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-，优选-CH 2CH 2-或-CH 2CH 2CH 2-，更优选-CH 2CH 2-。 In a more specific embodiment, R1 and R2 are linked to form -CH2- , -CH2CH2- or -CH2CH2CH2- , preferably -CH2CH2- or -CH2CH2CH 2 -, more preferably -CH 2 CH 2 -; in another more specific embodiment, R 3 and R 4 are linked to form -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, preferably -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, more preferably -CH 2 CH 2 -; in another more specific embodiment, R 1 and R 4 are linked to form -CH 2 -, -CH 2 CH 2- or -CH2CH2CH2- , preferably -CH2CH2- or -CH2CH2CH2- , more preferably -CH2CH2- ; in another more specific embodiment, R2 and R 3 is linked to form -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, preferably -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, more preferably -CH 2 CH 2 - .
p和qp and q
在一个具体实施方案中，p＝0；在另一个具体实施方案中，p＝1；在另一个具体实施方案中，p＝2；在另一个具体实施方案中，p＝3。In one specific embodiment, p=0; in another specific embodiment, p=1; in another specific embodiment, p=2; in another specific embodiment, p=3.
在一个具体实施方案中，q＝0；在另一个具体实施方案中，q＝1；在另一个具体实施方案中，q＝2；在另一个具体实施方案中，q＝3。In one specific embodiment, q=0; in another specific embodiment, q=1; in another specific embodiment, q=2; in another specific embodiment, q=3.
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、Y 1、Y 2、Y 3、r、s、R A、L、R B、R 1、R 2、R 2’、R 3、R 4、p和q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。 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. For example, any technical solution of X or any combination thereof can be combined with Y, Y 1 , Y 2 , Y 3 , r, s, R A , L, R B , R 1 , R 2 , R 2′ , R 3 , R 4 , p and q, 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.
在更具体的实施方案中，本发明提供了上述(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其具有以下结构：In a more specific embodiment, the present invention provides compound (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof , which has the following structure:
Figure PCTCN2022088438-appb-000086
Figure PCTCN2022088438-appb-000086
其中，各基团如上文所定义。where each group is as defined above.
在更具体的实施方案中，本发明提供了式(II)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体：In a more specific embodiment, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof :
Figure PCTCN2022088438-appb-000087
Figure PCTCN2022088438-appb-000087
其中，in,
X为-N(R)-或-CH(R*)-；X is -N(R)- or -CH(R*)-;
其中R选自H、C 1-6烷基或C 1-6卤代烷基； wherein R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R*选自-(CH 2) 0-3-NH 2或-(CH 2) 0-3-OH； R* is selected from -(CH 2 ) 0-3 -NH 2 or -(CH 2 ) 0-3 -OH;
R 1和R 2独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R’； R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d ) m -R';
R 3和R 4独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R”； R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -R";
R 2’为H，或者R 2、R 2’连同它们连接的碳原子形成C 3-6环烷基； R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
p＝0、1、2或3；p=0, 1, 2 or 3;
q＝0、1、2或3；q=0, 1, 2 or 3;
其中R c选自H、卤素、C 1-4烷基或C 1-4卤代烷基； wherein R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R d选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R’选自H、卤素、-OH、-SH、-NH 2、-CN、-C(O)R e、-C(O)OR e或-C(O)NR eR f； R' is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e or -C(O)NR e R f ;
R”选自H、卤素、-OH、-SH、-NH 2、-CN、-C(O)R e、-C(O)OR e或-C(O)NR eR f； R" is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e or -C(O)NR e R f ;
m＝0、1、2、3、4、5或6；m=0, 1, 2, 3, 4, 5 or 6;
其中R e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； wherein R e is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R f和R g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 f和R g以及它们连接的氮原子形成3-10元杂环基。 R f and R g are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R f and R g and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclyl.
在更具体的实施方案中，本发明提供了上述式(II)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中，In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variation thereof body, of which,
X为-N(R)-或-CH(R*)-；X is -N(R)- or -CH(R*)-;
其中R选自H、C 1-6烷基或C 1-6卤代烷基； wherein R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R*选自-(CH 2) 0-1-NH 2或-(CH 2) 0-1-OH； R* is selected from -(CH 2 ) 0-1 -NH 2 or -(CH 2 ) 0-1 -OH;
R 1和R 2独立地选自H或-(CR cR d) m-R’； R 1 and R 2 are independently selected from H or -(CR c R d ) m -R';
R 3和R 4独立地选自H或-(CR cR d) m-R”； R 3 and R 4 are independently selected from H or -(CR c R d ) m -R";
R 2’为H，或者R 2、R 2’连同它们连接的碳原子形成C 3-6环烷基； R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
p＝0、1或2；p=0, 1 or 2;
q＝0、1或2；q=0, 1 or 2;
其中R c为H； wherein R c is H;
R d为H； R d is H;
R’选自H、卤素或-OH；R' is selected from H, halogen or -OH;
R”选自H、卤素、-OH、-NH 2或-CN； R" is selected from H, halogen, -OH, -NH2 or -CN;
m＝0、1、2、3、4、5或6。m=0, 1, 2, 3, 4, 5 or 6.
在更具体的实施方案中，本发明提供了式(III)化合物，或其药学上可接 受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体：In a more specific embodiment, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof :
Figure PCTCN2022088438-appb-000088
Figure PCTCN2022088438-appb-000088
其中，in,
R 1和R 2独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d)-R’； R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d )-R';
R 3和R 4独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-CN； R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -CN;
p＝0、1、2或3；p=0, 1, 2 or 3;
q＝0、1、2或3；q=0, 1, 2 or 3;
其中R c选自H或卤素； wherein R is selected from H or halogen;
R d选自H或卤素； R d is selected from H or halogen;
R’选自H、卤素、-OH、-SH、-NH 2或-CN； R' is selected from H, halogen, -OH, -SH, -NH2 or -CN;
m＝1或2。m=1 or 2.
在更具体的实施方案中，本发明提供了上述式(III)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中，In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variation thereof body, of which,
R 1和R 2独立地选自H或-(CR cR d)-R’； R 1 and R 2 are independently selected from H or -(CR c R d )-R';
R 3和R 4独立地选自H或-(CR cR d)-CN； R 3 and R 4 are independently selected from H or -(CR c R d )-CN;
p＝1或2；p=1 or 2;
q＝1或2；q=1 or 2;
其中R c为H； wherein R c is H;
R d为H； R d is H;
R’选自H或-OH。R' is selected from H or -OH.
在更具体的实施方案中，本发明提供了式(IV)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体：In a more specific embodiment, the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof :
Figure PCTCN2022088438-appb-000089
Figure PCTCN2022088438-appb-000089
其中，in,
R 1和R 2之一为-(CR cR d)-R’，另一选自H、卤素、-OH、-NH 2、-CN或-(CR cR d)-R’； One of R 1 and R 2 is -(CR c R d )-R' and the other is selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d )-R';
R 3和R 4独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d)-R”； R 3 and R 4 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d )-R";
R选自H、C 1-6烷基或C 1-6卤代烷基； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
p＝0、1、2或3；p=0, 1, 2 or 3;
q＝0、1、2或3；q=0, 1, 2 or 3;
其中R c选自H、卤素、C 1-4烷基或C 1-4卤代烷基； wherein R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R d选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R’选自H、卤素、-OH、-SH、-NH 2或-CN； R' is selected from H, halogen, -OH, -SH, -NH2 or -CN;
R”选自卤素、-OH、-SH、-NH 2或-CN。 R" is selected from halogen, -OH, -SH, -NH2 or -CN.
在更具体的实施方案中，本发明提供了上述式(IV)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中，In a more specific embodiment, the present invention provides a compound of formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variation thereof body, of which,
R 1和R 2之一为-(CR cR d)-R’，另一为H； One of R 1 and R 2 is -(CR c R d )-R', and the other is H;
R 3和R 4独立地选自H或-(CR cR d)-R”； R and R are independently selected from H or -(CR c R d ) -R";
R选自H、C 1-2烷基或C 1-2卤代烷基； R is selected from H, C 1-2 alkyl or C 1-2 haloalkyl;
p＝1或2；p=1 or 2;
q＝1或2；q=1 or 2;
其中R c为H； wherein R c is H;
R d为H； R d is H;
R’选自H或-OH；R' is selected from H or -OH;
R”为-CN。R" is -CN.
在更具体的实施方案中，本发明提供了式(V)、(V-1)或(V-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、溶剂合物、水合物或同 位素变体：In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof body, solvate, hydrate or isotopic variant:
Figure PCTCN2022088438-appb-000090
Figure PCTCN2022088438-appb-000090
其中，in,
R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1和R 2独立地选自H或-(CR cR d) m-R’，其余的R 3和R 4独立地选自H或-(CR cR d) m-R”； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is linked to form -(CR a R b ) n -, and the remaining R 1 and R 2 are independently selected from H or -(CR c R d ) m -R', the remaining R 3 and R 4 are independently selected from H or -(CR c R d ) m -R ";
R为H、C 1-6烷基或C 1-6卤代烷基； R is H, C 1-6 alkyl or C 1-6 haloalkyl;
其中R a选自H、卤素、C 1-4烷基或C 1-4卤代烷基； wherein R a is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R b选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R b is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R c选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R d选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R’选自H、卤素、-CN、-OH、-NH 2、C 2-4烯基或C 2-4炔基； R' is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
R”选自H、卤素、-CN、-OH、-NH 2、C 2-4烯基或C 2-4炔基； R" is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
n＝0、1、2、3或4；n=0, 1, 2, 3 or 4;
m＝0、1、2或3。m=0, 1, 2 or 3.
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体，其中，In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Constructs, solvates, hydrates or isotopic variants, wherein,
R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1、R 2、R 3或R 4分别为H、卤素、-CN、-OH或-NH 2； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 is respectively H, halogen, -CN, -OH or -NH 2 ;
R选自H、C 1-6烷基或C 1-6卤代烷基； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中R a选自H、卤素、C 1-4烷基或C 1-4卤代烷基； wherein R a is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R b选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R b is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
n＝0、1、2、3或4。n=0, 1, 2, 3 or 4.
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体，其中，In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Conforms, solvates, hydrates or isotopic variants, wherein,
R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1、R 2、R 3或R 4为H； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 is H;
R选自H、C 1-2烷基或C 1-2卤代烷基； R is selected from H, C 1-2 alkyl or C 1-2 haloalkyl;
其中R a为H； where R a is H;
R b为H； R b is H;
n＝1、2或3。n=1, 2 or 3.
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体，其中，In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Conforms, solvates, hydrates or isotopic variants, wherein,
R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1和R 2独立地选自H或-(CR cR d) m-R’，其余的R 3和R 4独立地选自H或-(CR cR d) m-R”； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is linked to form -(CR a R b ) n -, and the remaining R 1 and R 2 are independently selected from H or -(CR c R d ) m -R', the remaining R 3 and R 4 are independently selected from H or -(CR c R d ) m -R ";
R为H；R is H;
其中R a选自H、卤素、C 1-4烷基或C 1-4卤代烷基； wherein R a is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R b选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R b is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R c选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R d选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R’选自H、卤素、-CN、-OH、-NH 2、C 2-4烯基或C 2-4炔基； R' is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
R”选自H、卤素、-CN、-OH、-NH 2、C 2-4烯基或C 2-4炔基； R" is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
m＝0、1、2或3；m=0, 1, 2 or 3;
n＝2、3或4。n=2, 3 or 4.
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体，其中，In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Conforms, solvates, hydrates or isotopic variants, wherein,
R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1、R 2、R 3或R 4分别独立地选自H、卤素、-CN、-OH或-NH 2； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, -CN, -OH or -NH 2 ;
R为H；R is H;
其中R a选自H、卤素或C 1-4烷基； wherein R a is selected from H, halogen or C 1-4 alkyl;
R b选自H、卤素或C 1-4烷基； R b is selected from H, halogen or C 1-4 alkyl;
n＝2、3或4。n=2, 3 or 4.
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体，其中，In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Conforms, solvates, hydrates or isotopic variants, wherein,
R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1、R 2、R 3或R 4为H； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 is H;
R为H；R is H;
其中R a为H； where R a is H;
R b为H； R b is H;
n＝2或3。n=2 or 3.
在更具体的实施方案中，本发明提供了以下化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中所述化合物选自：In more specific embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates or isotopic variants thereof, wherein said The compound is selected from:
Figure PCTCN2022088438-appb-000091
Figure PCTCN2022088438-appb-000091
Figure PCTCN2022088438-appb-000092
Figure PCTCN2022088438-appb-000092
Figure PCTCN2022088438-appb-000093
Figure PCTCN2022088438-appb-000093
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。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. For example, 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.
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。Those skilled in the art will understand that 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.
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。The term "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.
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·2 H 2O)和六水合物(R·6 H 2O))。 The term "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, a hydrate of a compound can be represented, for example, by the general formula R · xH2O, where R is the compound and x is a number greater than zero. 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 polyhydrates (x is a number greater than 1, eg, dihydrate (R · 2H2O) and hexahydrate (R · 6H2O)).
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。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. The term "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 generally 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.
本发明还包括同位素标记的化合物(同位素变体)，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。 The present invention also includes isotopically labeled compounds (isotopic variants), which are equivalent to those described in formula (I), except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature replaced. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H , 13C , 11C , 14C , 15N , 18 , respectively 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, such as those into which radioactive isotopes (eg, 3H and14C ) have been incorporated, 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. Furthermore, substitution with heavier isotopes, such as deuterium, ie, 2H, may be preferred in some circumstances because greater metabolic stability may provide therapeutic benefits, such as increased in vivo half - life or reduced dosage requirements. 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.
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。Furthermore, 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 A.C.S. Symposium 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.
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。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. Thus, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxy, sulfhydryl and amino functional groups of the compounds of formula (I). Additionally, in the case of carboxylic acids (-COOH), 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.
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。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.
药物组合物和试剂盒Pharmaceutical compositions and kits
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。In another aspect, 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. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.
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。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). protein), buffer substances (such as phosphates), glycine, 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.
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。The present invention also includes kits (eg, pharmaceutical packages). Provided 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). In some embodiments, provided 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. In some embodiments, 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.
给药dosing
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。The pharmaceutical 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. For example, 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.
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。Typically, 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. .
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。When used to prevent the disorders of the present invention, 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.
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。The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). 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. In some embodiments, 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.
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。Various methods of administration can be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, 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. In other embodiments, 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. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
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。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. The term "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. In such compositions, 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.
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。For oral doses, a typical regimen is one to five oral doses, especially two to four oral doses, typically three oral doses per day. Using these dosing patterns, 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.
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。In order to provide blood levels similar to, or lower than, the use of injectable doses, 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.
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。From about 1 to about 120 hours, especially 24 to 96 hours, injection dose levels are in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be administered. For human patients of 40 to 80 kg, the maximum total dose cannot exceed approximately 2 g/day.
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。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.
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。Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. In such compositions, as previously mentioned, 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.
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。Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, 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.
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。The compounds of the present invention may also be administered by transdermal devices. Thus, transdermal administration can be accomplished using reservoir or porous membrane types, or patches of various solid matrices.
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。The above-described components of 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.
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。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.
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％)。The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-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. In some embodiments, 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. In some embodiments, the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).
药物联用drug combination
目前本领域中已知的许多化学治疗剂可与本发明化合物组合使用。在一些实施方案中，化学治疗剂选自有丝分裂抑制剂、烷化剂、抗代谢物、嵌入抗生素、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、生物反应调节剂、抗激素、血管生成抑制剂和抗雄激素。Many chemotherapeutic agents currently known in the art can be used in combination with the compounds of the present invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, Antihormones, angiogenesis inhibitors and antiandrogens.
实施例Example
本文所用的原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。The starting materials or reagents used herein are either commercially available or prepared by synthetic methods generally known in the art.
中间体1-溴-8-甲基萘的合成Synthesis of Intermediate 1-Bromo-8-methylnaphthalene
Figure PCTCN2022088438-appb-000094
Figure PCTCN2022088438-appb-000094
将化合物1,8-二溴萘(1g，3.5mmol)溶于20mL四氢呋喃中，加入2.6mL 1.6M甲基锂的乙醚溶液，氮气保护下，0℃反应30min。然后缓慢滴加1mL碘甲烷，再室温反应3h。随后将反应混合物用冰水淬灭，再用石油醚萃取2次，有机相干燥后经硅胶柱分离(洗脱剂：石油醚)纯化得到化合物1-溴-8-甲基萘(386mg，50％收率)。Compound 1,8-dibromonaphthalene (1 g, 3.5 mmol) was dissolved in 20 mL of tetrahydrofuran, 2.6 mL of 1.6 M methyllithium in ether solution was added, and the reaction was carried out at 0 °C for 30 min under nitrogen protection. Then 1 mL of methyl iodide was slowly added dropwise, and the mixture was reacted at room temperature for 3 h. Then the reaction mixture was quenched with ice water, extracted twice with petroleum ether, and the organic phase was dried and purified by silica gel column separation (eluent: petroleum ether) to obtain compound 1-bromo-8-methylnaphthalene (386 mg, 50 % yield).
中间体化合物7的合成Synthesis of Intermediate Compound 7
Figure PCTCN2022088438-appb-000095
Figure PCTCN2022088438-appb-000095
步骤1：将金属钠(23mg，1mmol)溶于2mL无水甲醇中，室温反应15min，随后将甲醇钠溶液缓慢加入原料1(购自上海卓因生物科技有限公司，294mg，1mmol)的四氢呋喃溶液(5mL)中，室温反应2h。随后加入饱和NH 4Cl淬灭，并用乙酸乙酯萃取两次，有机相干燥后经硅胶柱分离(洗脱剂：石油醚：乙酸乙酯＝5:1)纯化得到化合物2(260mg，90％收率)。 Step 1: Dissolve sodium metal (23 mg, 1 mmol) in 2 mL of anhydrous methanol, react at room temperature for 15 min, then slowly add the sodium methoxide solution to the tetrahydrofuran solution of raw material 1 (purchased from Shanghai Zhuoyin Biotechnology Co., Ltd., 294 mg, 1 mmol). (5 mL), react at room temperature for 2 h. Then it was quenched by adding saturated NH 4 Cl, and extracted twice with ethyl acetate. The organic phase was dried and separated by silica gel column (eluent: petroleum ether: ethyl acetate=5:1) and purified to give compound 2 (260 mg, 90%) yield).
步骤2：将氢化钠(80mg，60％纯度，2mmol)加入无水四氢呋喃中，氮气保护、0℃条件下滴加N-甲基-L-脯氨醇(230mg，2mmol)。搅拌30min后，滴加化合物2(290mg，1mmol)。升温至室温后，加热至70℃反应12h。然后0℃条件下缓慢滴加1mL NH 4Cl饱和溶液，搅拌15min后，加入20mL NaHCO 3饱和溶液，再用乙酸乙酯萃取两次，浓缩有机相，经硅胶柱分离(洗脱剂：二氯甲烷：甲醇＝10:1)纯化得到化合物3(294mg，80％收率)。 Step 2: Sodium hydride (80 mg, 60% purity, 2 mmol) was added to anhydrous tetrahydrofuran, and N-methyl-L-prolinol (230 mg, 2 mmol) was added dropwise under nitrogen protection at 0°C. After stirring for 30 min, compound 2 (290 mg, 1 mmol) was added dropwise. After warming up to room temperature, it was heated to 70 °C for 12 h. Then 1 mL of NH 4 Cl saturated solution was slowly added dropwise at 0°C, and after stirring for 15 min, 20 mL of NaHCO 3 saturated solution was added, extracted twice with ethyl acetate, the organic phase was concentrated, and separated by silica gel column (eluent: dichloromethane) Methane:methanol=10:1) was purified to give compound 3 (294 mg, 80% yield).
步骤3：将化合物3(368mg，1mmol)溶于10mL甲醇中，加入30mg  Pd/C，在H 2、40℃条件下反应12h。过滤除去Pd/C，浓缩有机相，经硅胶柱分离(二氯甲烷：甲醇＝5:1)纯化得到化合物4(250mg，90％收率)。 Step 3: Compound 3 (368 mg, 1 mmol) was dissolved in 10 mL of methanol, 30 mg of Pd/C was added, and the reaction was carried out under the conditions of H 2 and 40° C. for 12 h. Pd/C was removed by filtration, the organic phase was concentrated, and purified by silica gel column separation (dichloromethane:methanol=5:1) to obtain compound 4 (250 mg, 90% yield).
步骤4：将Pd 2(dba) 3(137mg，0.15mmol)与BINAP(187mg，0.3mmol)溶于4mL甲苯中，在氮气保护、100℃条件下反应30min，随后冷却至室温。将化合物4(278mg，1mmol)与1-溴-8-甲基萘(331mg，1.5mmol)以及叔丁醇钠(240mg，2.5mmol)先溶于10mL甲苯中，在氮气保护下，加入催化剂与配体的溶液，再100℃反应18h。然后冷却至室温，加入40mL水，用乙酸乙酯萃取两次，浓缩有机相，经硅胶柱分离(洗脱剂：二氯甲烷：甲醇＝15:1)纯化得到化合物5(293mg，70％收率)。 Step 4: Pd 2 (dba) 3 (137 mg, 0.15 mmol) and BINAP (187 mg, 0.3 mmol) were dissolved in 4 mL of toluene, reacted under nitrogen protection at 100° C. for 30 min, and then cooled to room temperature. Compound 4 (278 mg, 1 mmol), 1-bromo-8-methylnaphthalene (331 mg, 1.5 mmol) and sodium tert-butoxide (240 mg, 2.5 mmol) were first dissolved in 10 mL of toluene. Under nitrogen protection, catalyst and The ligand solution was reacted at 100°C for 18h. Then cooled to room temperature, added 40 mL of water, extracted twice with ethyl acetate, concentrated the organic phase, separated by silica gel column (eluent: dichloromethane: methanol = 15: 1) and purified to obtain compound 5 (293 mg, 70% yield). Rate).
步骤5：将氢化钠(80mg，60％纯度，2mmol)加入4mL无水DMF中，0℃条件下缓慢滴加乙硫醇(124mg，2mmol)，反应30min之后，滴加化合物5(418mg，1mmol)的5mL DMF溶液。随后升温至60℃反应1h，然后在0℃条件下缓慢滴加1mL NH 4Cl饱和溶液。反应搅拌15min后，向混合物中加入20mL水进行淬灭，再用乙酸乙酯和二氯甲烷分别萃取一次，合并有机相，加入适量的无水硫酸镁进行干燥。然后过滤并浓缩溶液，粗品经硅胶柱分离(洗脱剂：二氯甲烷：甲醇＝10:1)纯化得到化合物6(384mg，95％收率)。 Step 5: Sodium hydride (80 mg, 60% purity, 2 mmol) was added to 4 mL of anhydrous DMF, and ethanethiol (124 mg, 2 mmol) was slowly added dropwise at 0°C. After 30 min of reaction, compound 5 (418 mg, 1 mmol) was added dropwise. ) in 5 mL of DMF. Then the temperature was raised to 60 °C for 1 h, and then 1 mL of a saturated solution of NH 4 Cl was slowly added dropwise at 0 °C. After the reaction was stirred for 15 min, 20 mL of water was added to the mixture for quenching, and the mixture was extracted once with ethyl acetate and dichloromethane, respectively. The organic phases were combined, and an appropriate amount of anhydrous magnesium sulfate was added for drying. The solution was then filtered and concentrated, and the crude product was purified by silica gel column separation (eluent: dichloromethane: methanol = 10: 1) to give compound 6 (384 mg, 95% yield).
步骤6：将化合物6(404mg，1mmol)溶于20mL无水二氯甲烷中，加入N-苯基双(三氟甲烷磺酰)亚胺(428mg，1.2mmol)和碳酸铯(423mg，1.3mmol)，氮气保护下，室温反应2h。然后过滤除去固体，浓缩有机相，经硅胶柱分离(石油醚：乙酸乙酯＝2:1)纯化得到化合物7(428mg，80％收率)。Step 6: Compound 6 (404 mg, 1 mmol) was dissolved in 20 mL of anhydrous dichloromethane, N-phenylbis(trifluoromethanesulfonyl)imide (428 mg, 1.2 mmol) and cesium carbonate (423 mg, 1.3 mmol) were added ) and reacted at room temperature for 2 h under nitrogen protection. Then the solid was removed by filtration, the organic phase was concentrated, and purified by silica gel column separation (petroleum ether:ethyl acetate=2:1) to obtain compound 7 (428 mg, 80% yield).
中间体化合物12的合成Synthesis of Intermediate Compound 12
Figure PCTCN2022088438-appb-000096
Figure PCTCN2022088438-appb-000096
步骤1：将化合物8(9.8g，146mmol)溶解于tBuOH/PE(15mL/57.5mL)的混合溶液中，再将23.3g Br 2溶解在15mL tBuOH中，缓慢滴加至上 述混合液中，15℃反应30min得到中间体9。 Step 1: Compound 8 (9.8 g, 146 mmol) was dissolved in a mixed solution of tBuOH/PE (15 mL/57.5 mL), and 23.3 g of Br was dissolved in 15 mL of tBuOH, and slowly added dropwise to the above mixed solution, 15 The reaction was carried out at °C for 30 min to obtain intermediate 9.
步骤2：将金属钠(3.36g，146mmol)溶解在85mL的EtOH中，缓慢滴加至中间体9的反应混合液中，15℃反应2h。加水淬灭，再用乙酸乙酯萃取两次，浓缩有机相，过柱纯化得到化合物10(10.6g，50％)。Step 2: Dissolve sodium metal (3.36 g, 146 mmol) in 85 mL of EtOH, slowly drop it into the reaction mixture of intermediate 9, and react at 15° C. for 2 h. It was quenched by adding water, extracted twice with ethyl acetate, and the organic phase was concentrated and purified by column to obtain compound 10 (10.6 g, 50%).
步骤3：将N,N-二苄基乙二胺(5.75g，24mmol)溶解在50mL甲苯中，加入4.85g三乙胺，随后0℃滴加化合物10，再恢复至室温，反应12h。过滤后除去溶剂，过柱纯化得到化合物11(3.2g，45％)。Step 3: Dissolve N,N-dibenzylethylenediamine (5.75g, 24mmol) in 50mL of toluene, add 4.85g of triethylamine, then dropwise add compound 10 at 0°C, return to room temperature, and react for 12h. After filtration, the solvent was removed and column purification gave compound 11 (3.2 g, 45%).
步骤4：将化合物11(1.64g，5.36mmo)溶解在15mL DCE中，0℃滴加氯甲酸1-氯乙基酯(3.06g,21.4mmol)，再升温至84℃，反应2天。再加入15mL甲醇，65℃反应1h。负压旋蒸除去溶剂后，再用甲基叔丁基醚洗涤固体，过滤后得到化合物12(0.6g,56％)。Step 4: Compound 11 (1.64 g, 5.36 mmol) was dissolved in 15 mL of DCE, 1-chloroethyl chloroformate (3.06 g, 21.4 mmol) was added dropwise at 0 °C, the temperature was raised to 84 °C, and the reaction was carried out for 2 days. Then 15 mL of methanol was added, and the reaction was carried out at 65 °C for 1 h. After the solvent was removed by rotary evaporation under negative pressure, the solid was washed with methyl tert-butyl ether and filtered to obtain compound 12 (0.6 g, 56%).
实施例1-38的合成Synthesis of Examples 1-38
使用以下反应路线合成本发明化合物。对于TH-Z 808、TH-Z 814、TH-Z 815、TH-Z 830、TH-Z 831和TH-Z 832这几个化合物，以中间体化合物7为起始原料，经过一步反应得到终产物。其他化合物还需要经过脱除保护基的一步反应，才得到终产物。Compounds of the present invention were synthesized using the following reaction schemes. For the compounds TH-Z 808, TH-Z 814, TH-Z 815, TH-Z 830, TH-Z 831 and TH-Z 832, the intermediate compound 7 was used as the starting material, and the final product was obtained after one-step reaction. product. Other compounds also need to undergo a one-step reaction of deprotection to obtain the final product.
Figure PCTCN2022088438-appb-000097
Figure PCTCN2022088438-appb-000097
通用的合成步骤如下：The general synthetic steps are as follows:
步骤1：将化合物7(536mg，1mmol)溶于5ml无水DMF中，加入DIPEA(258mg，2mmol)，以及各种N-Boc保护的胺片段或者无需N-Boc保护的胺片段(1.05mmol)，氮气保护下、100℃条件下反应1～10h。冷却 后，加20mL水，再用乙酸乙酯萃取两次，浓缩有机相，过柱纯化得到N-Boc保护的化合物以及无N-Boc保护的目标化合物(30～90％收率)。Step 1: Compound 7 (536 mg, 1 mmol) was dissolved in 5 ml of dry DMF, DIPEA (258 mg, 2 mmol) was added, and various N-Boc protected amine fragments or amine fragments without N-Boc protection (1.05 mmol) were added , under the protection of nitrogen, react at 100 ℃ for 1～10h. After cooling, 20 mL of water was added, extracted twice with ethyl acetate, the organic phase was concentrated, and purified by column to obtain the N-Boc protected compound and the target compound without N-Boc protection (30-90% yield).
步骤2：将N-Boc保护的化合物(1mmol)溶于2mL二氯甲烷中，加入1mL三氟乙酸，室温反应1h。加入10mL Na 2CO 3饱和溶液，再用二氯甲烷萃取两次，浓缩有机相，过柱纯化得到目标化合物(80％收率)。 Step 2: The N-Boc protected compound (1 mmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 1 h. 10 mL of saturated Na 2 CO 3 solution was added, extracted twice with dichloromethane, the organic phase was concentrated, and purified by column to obtain the target compound (80% yield).
Figure PCTCN2022088438-appb-000098
Figure PCTCN2022088438-appb-000098
Figure PCTCN2022088438-appb-000099
Figure PCTCN2022088438-appb-000099
Figure PCTCN2022088438-appb-000100
Figure PCTCN2022088438-appb-000100
Figure PCTCN2022088438-appb-000101
Figure PCTCN2022088438-appb-000101
Figure PCTCN2022088438-appb-000102
Figure PCTCN2022088438-appb-000102
Figure PCTCN2022088438-appb-000103
Figure PCTCN2022088438-appb-000103
Figure PCTCN2022088438-appb-000104
Figure PCTCN2022088438-appb-000104
Figure PCTCN2022088438-appb-000105
Figure PCTCN2022088438-appb-000105
Figure PCTCN2022088438-appb-000106
Figure PCTCN2022088438-appb-000106
Figure PCTCN2022088438-appb-000107
Figure PCTCN2022088438-appb-000107
Figure PCTCN2022088438-appb-000108
Figure PCTCN2022088438-appb-000108
Figure PCTCN2022088438-appb-000109
Figure PCTCN2022088438-appb-000109
Figure PCTCN2022088438-appb-000110
Figure PCTCN2022088438-appb-000110
生物活性测试Biological activity test
KRAS蛋白表达和纯化KRAS protein expression and purification
(1)蛋白表达和样品处理(1) Protein expression and sample processing
将带有目的基因(KRAS4b G12D，带有His标签，截短序列1-169)的质粒转入BL21(DE3)感受态的E.coli中，转接到含有氨苄抗性的LB培养基中，于37℃、220rpm条件下培养。当菌液OD 600nm约为0.6时，降温至16℃，向大瓶培养基中加入0.5mM IPTG(异丙基-β-D-硫代半乳糖苷)，于16℃、220rpm条件下培养约24h。将发酵液在4℃、6000g下离心10min，弃掉上清。用Buffer A(25mM Tris、150mM NaCl、10mM咪唑、pH 8.5)重悬菌体。将重悬后的菌液在4℃的高压匀浆破碎机内破碎，然后在4 ℃、16000g下高速离心1h，取上清液，样品用0.22μm孔径的滤膜过滤。The plasmid with the target gene (KRAS4b G12D, with His tag, truncated sequence 1-169) was transferred into BL21 (DE3) competent E.coli, and transferred to the LB medium containing ampicillin resistance, Incubate at 37°C and 220rpm. When the OD 600nm of the bacterial liquid is about 0.6, cool down to 16°C, add 0.5mM IPTG (isopropyl-β-D-thiogalactoside) to the culture medium in the large flask, and cultivate at 16°C and 220rpm for about 24h . The fermentation broth was centrifuged at 4°C and 6000 g for 10 min, and the supernatant was discarded. Resuspend the cells in Buffer A (25 mM Tris, 150 mM NaCl, 10 mM imidazole, pH 8.5). The resuspended bacterial liquid was crushed in a high-pressure homogenizer at 4°C, and then centrifuged at 4°C at 16,000 g for 1 h at high speed. The supernatant was collected, and the sample was filtered with a 0.22 μm pore size filter membrane.
(2)亲和层析分离(2) Affinity chromatography separation
先用0.1M NiSO 4再生Ni-NTA柱子，用Buffer A平衡洗去多余的Ni离子，柱平衡后开始上样，流速为3mL/min。上样结束后，再用Buffer A洗去未结合的蛋白和杂质至A280值回归到基线稳定后，采用线性洗脱策略即将Buffer A和Buffer B(25mM Tris、150mM NaCl、500mM咪唑、pH 8.5)混合，每管收集6mL洗脱液，进行蛋白电泳分析。 The Ni-NTA column was first regenerated with 0.1M NiSO 4 , and the excess Ni ions were washed away by equilibration with Buffer A. After the column was equilibrated, the sample was loaded, and the flow rate was 3 mL/min. After loading the sample, use Buffer A to wash away unbound proteins and impurities until the A280 value returns to a stable baseline, and a linear elution strategy is used, that is, Buffer A and Buffer B (25mM Tris, 150mM NaCl, 500mM imidazole, pH 8.5) Mix and collect 6 mL of eluate in each tube for protein electrophoresis analysis.
(3)Tev酶酶切和二次亲和层析分离(3) Tev enzyme digestion and secondary affinity chromatography separation
在含有KRAS G12D的洗脱液中加入适量的Tev酶，用来切掉N段含有His标签的硫氧还蛋白，同时透析在Buffer C(25mM Tris、150mM NaCl、pH 8.5)中。第二次同样过Ni-NTA柱，由于Tev酶切掉了含有His标签的硫氧还蛋白，目的蛋白无法与亲和层析柱结合，所以二次过Ni柱时，收集的是未结合部分的洗脱液，进行蛋白电泳分析。An appropriate amount of Tev enzyme was added to the eluate containing KRAS G12D to cut off the His-tagged thioredoxin in the N segment, and dialyzed in Buffer C (25mM Tris, 150mM NaCl, pH 8.5). The second pass through the Ni-NTA column was the same. Since the thioredoxin containing the His tag was cut off by the Tev enzyme, the target protein could not be bound to the affinity chromatography column. Therefore, when passing through the Ni column for the second time, the unbound part was collected. The eluate was analyzed by protein electrophoresis.
(4)KRAS G12D的浓缩，纯度和浓度的检验(4) Concentration, purity and concentration inspection of KRAS G12D
蛋白样品缓冲液含有25mM Tris、pH 8.5和150mM NaCl，先尝试两个试剂盒Crystal Screen I、Crystal Screen II点晶体观察沉淀的比例，确定蛋白浓度为40mg/mL，并且将浓缩后的蛋白进行电泳分析，验证纯度。The protein sample buffer contains 25mM Tris, pH 8.5 and 150mM NaCl. First try two kits, Crystal Screen I and Crystal Screen II, to observe the ratio of precipitates, determine the protein concentration of 40mg/mL, and conduct electrophoresis of the concentrated protein. Analysis to verify purity.
(5)KRAS G12D蛋白结晶条件的初步筛选和结晶条件优化(5) Preliminary screening and optimization of crystallization conditions for KRAS G12D protein
在96孔板上，利用坐滴气相扩散法在恒温22℃下恒温培育室内进行晶体培育。初筛全部的1000多个条件，每隔两天观察一次，看是否晶体有长出，并作相关记录。发现KRAS G12D的结晶条件为0.2M醋酸钠、0.1M Tris、pH 8.5、26％(w/v)PEG 3350，配制相关试剂并进行结晶条件浓度和蛋白浓度的优化。On a 96-well plate, crystals were grown in a constant temperature incubation chamber at a constant temperature of 22°C using the sitting drop vapor diffusion method. All the more than 1,000 conditions were initially screened and observed every two days to see if crystals had grown, and related records were made. It was found that the crystallization conditions of KRAS G12D were 0.2M sodium acetate, 0.1M Tris, pH 8.5, 26% (w/v) PEG 3350, and the relevant reagents were prepared and the crystallization conditions and protein concentrations were optimized.
(6)KRAS G12D的衍射数据的收集和数据处理(6) Collection and data processing of diffraction data of KRAS G12D
将形状规则的KRAS G12D晶体进行X-光衍射数据的收集，将晶体浸入浓度为2mM的化合物TH Z 816中6h后，沾取抗冻剂，结晶条件加10％甘油，进行X-射线衍射并收集数据，并用HKL2000等相关软件进行处理。The regular-shaped KRAS G12D crystals were collected by X-ray diffraction data. After the crystals were immersed in the compound TH Z 816 with a concentration of 2 mM for 6 h, the antifreeze was dipped, and 10% glycerol was added to the crystallization conditions. Data were collected and processed with related software such as HKL2000.
SOS cat催化的核苷酸交换实验 Nucleotide exchange experiments catalyzed by SOS cat
在黑色平底96孔板中(Corning，#3686)，将不同浓度的化合物(DMSO终浓度为4％)与反应缓冲液(40mM HEPES-KOH、10mM MgCl 2、1mM  DTT、pH 8.5)混合，随后加入KRAS G12D mantGDP(2′/3′-O-(N-甲基邻氨基苯甲酰基)鸟苷5′-二磷酸)混合并孵育10min。将SOS cat蛋白与GDP溶液预先混合后，再加入KRAS蛋白溶液中，启动反应。总体系为100μL，各组分终浓度为KRAS G12D mantGDP 2μM、SOS cat 2μM、GDP 1mM。 In black flat bottom 96-well plates (Corning, #3686), various concentrations of compounds (4% final DMSO) were mixed with reaction buffer (40 mM HEPES-KOH, 10 mM MgCl2 , 1 mM DTT, pH 8.5), followed by KRAS G12D mantGDP (2'/3'-O-(N-methylanthraniloyl)guanosine 5'-diphosphate) was added, mixed and incubated for 10 min. The SOS cat protein and the GDP solution were pre-mixed, and then added to the KRAS protein solution to initiate the reaction. The total system was 100 μL, and the final concentrations of each component were KRAS G12D mantGDP 2 μM, SOS cat 2 μM, and GDP 1 mM.
对于TH-Z 835抑制SOS cat催化的KRAS G12D mantGCP(均苯四酸二酐与联苯四胺合成的聚吡咙薄膜)的核苷酸置换实验。反应缓冲液不变，总体系为100μL，各组分终浓度为KRAS G12C mantGCP 3μM、SOS cat 4μM、GCP 2mM、TH-Z 835500μM。 Nucleotide replacement experiments for TH-Z 835 inhibition of SOS cat -catalyzed KRAS G12D mantGCP (polypyrrolidone film synthesized from pyromellitic dianhydride and biphenyltetramine). The reaction buffer was unchanged, the total system was 100 μL, and the final concentrations of each component were KRAS G12C mantGCP 3 μM, SOS cat 4 μM, GCP 2 mM, and TH-Z 835500 μM.
对于TH-Z 835抑制SOS cat催化的KRAS G12D GCP的核苷酸置换实验。反应缓冲液不变，总体系为100μL，各组分终浓度为KRAS G12C GCP 3μM、SOS cat 2μM、mantGCP 4μM、TH-Z 835 500μM。 Nucleotide substitution experiments for the inhibition of SOS cat -catalyzed KRAS G12D GCP by TH-Z 835. The reaction buffer was unchanged, the total system was 100 μL, and the final concentrations of each component were KRAS G12C GCP 3 μM, SOS cat 2 μM, mantGCP 4 μM, and TH-Z 835 500 μM.
反应启动之后，随即用酶标仪(PerkinElmer,EnVision)读取荧光值(激发波长355nm，发射波长460nm，每隔30s读取一次，连续读取1h)。将得到的动力学数据用GraphPad Prism 7.0软件中的One phase decay方程或者One phase association进行拟合，计算得到速率k值，并对应化合物浓度梯度作图，得到IC 50曲线。 After the reaction was started, the fluorescence value was read immediately with a microplate reader (PerkinElmer, EnVision) (excitation wavelength 355 nm, emission wavelength 460 nm, read every 30 s, read continuously for 1 h). The kinetic data obtained were fitted with the One phase decay equation or One phase association in the GraphPad Prism 7.0 software, and the rate k value was calculated and plotted against the compound concentration gradient to obtain the IC 50 curve.
实验结果如下表所示：The experimental results are shown in the following table:
Figure PCTCN2022088438-appb-000111
Figure PCTCN2022088438-appb-000111
Figure PCTCN2022088438-appb-000112
Figure PCTCN2022088438-appb-000112
Figure PCTCN2022088438-appb-000113
Figure PCTCN2022088438-appb-000113
Figure PCTCN2022088438-appb-000114
Figure PCTCN2022088438-appb-000114
本发明化合物对KRAS G12D突变肿瘤细胞的杀伤Killing of KRAS G12D mutant tumor cells by the compounds of the present invention
我们测试了三个代表性化合物对胰腺癌来源的PANC-1细胞和Panc 04.03细胞，以及p53.2.1.1细胞的杀伤作用。两种细胞的KRAS基因都是杂合的，即只有一个等位基因是G12D突变。We tested the killing effect of three representative compounds on pancreatic cancer-derived PANC-1 cells and Panc 04.03 cells, as well as p53.2.1.1 cells. Both cells were heterozygous for the KRAS gene, that is, only one allele was the G12D mutation.
PANC-1、Panc 04.03和p53.2.1.1细胞从ATCC(American Type Culture Collection)购买获得。在96孔板(Nest，#701001)中，每孔铺种5000个细胞(PANC-1或者Panc 04.03)，培养基为DMEM(10％胎牛血清，1％青霉素/链霉素)。细胞铺板后在培养箱中培养24h，再加入不同浓度的药物继续培养24h。随后加入CCK-8试剂(碧云天，C0042)，孵育1h。用酶标仪在450nm测定吸光值。将数据用GraphPad Prism 7.0软件中的[Inhibitor]vs.response --Variable slope(four parameters)模型进行拟合，并计算得到IC 50值。 PANC-1, Panc 04.03 and p53.2.1.1 cells were purchased from ATCC (American Type Culture Collection). 5000 cells (PANC-1 or Panc 04.03) were plated per well in 96-well plates (Nest, #701001) in DMEM (10% fetal bovine serum, 1% penicillin/streptomycin). After the cells were plated, they were cultured in an incubator for 24 hours, and then different concentrations of drugs were added to continue the culture for 24 hours. Subsequently, CCK-8 reagent (Biyuntian, C0042) was added and incubated for 1 h. Absorbance was measured at 450 nm with a microplate reader. The data were fitted with the [Inhibitor] vs.response --Variable slope (four parameters) model in GraphPad Prism 7.0 software, and IC50 values were calculated.
两种KRAS G12D抑制剂对三种细胞的杀伤作用Killing effects of two KRAS G12D inhibitors on three types of cells
Figure PCTCN2022088438-appb-000115
Figure PCTCN2022088438-appb-000115
TH-Z 816的晶体结构分析Crystal Structure Analysis of TH-Z 816
我们尝试将TH-Z 816与KRAS G12D蛋白进行晶体学实验，以期研究化合物的构效关系。We tried to conduct crystallographic experiments between TH-Z 816 and KRAS G12D protein in order to study the structure-activity relationship of the compounds.
我们用浸泡的方法得到了小分子与KRAS G12D蛋白的复合物晶体(图1)，并进行了解析。在结合位点观察晶体结构可以发现，TH-Z 816结合在swtch II(RAS蛋白60-76位残基)下方形成的口袋中，即switch II pocket(SIIP)。这是一个别构位点(allosteric site)，与鸟苷酸(GDP或GTP)的结合位点相邻。将化合物附近的电子云密度(2F o-F c，1σ)显示出来，可以看到它完整地覆盖在小分子骨架上。我们将KRAS G12D-TH-Z 816的晶体与KRAS G12C-MRTX849(PDB：6UT0)的晶体叠合对齐，可以发现，两个蛋白的整体构象非常相似，Cα的RMSD为
Figure PCTCN2022088438-appb-000116
We obtained the complex crystals of small molecules and KRAS G12D protein by soaking method (Fig. 1) and analyzed them. Observing the crystal structure of the binding site, it can be found that TH-Z 816 binds in a pocket formed under swtch II (residues 60-76 of RAS protein), namely the switch II pocket (SIIP). This is an allosteric site adjacent to the binding site for guanylate (GDP or GTP). The electron cloud density (2F o -F c , 1σ) near the compound is displayed, and it can be seen that it completely covers the small molecule backbone. We aligned the crystals of KRAS G12D-TH-Z 816 with the crystals of KRAS G12C-MRTX849 (PDB: 6UT0) and found that the overall conformations of the two proteins are very similar, and the RMSD of Cα is
Figure PCTCN2022088438-appb-000116
分析TH-Z 168与KRAS G12D蛋白的结合模式可以发现，极性相互作用有四组：Asp 12的羧基与哌嗪末端二级胺形成的盐桥作用；Gly 60的主链的O原子与哌嗪末端N原子形成的氢键作用；Glu 62的羧基与侧链带正电的N-甲基吡咯烷之间的静电吸引作用；His 95的N原子与核心骨架嘧啶环的N原子与之间的氢键。非极性相互作用主要包括小分子与周围残基的疏水作用(图2)。By analyzing the binding mode of TH-Z 168 and KRAS G12D protein, it can be found that there are four groups of polar interactions: the salt bridge formed by the carboxyl group of Asp 12 and the secondary amine at the end of piperazine; the O atom of the main chain of Gly 60 and piperazine The hydrogen bond formed by the terminal N atom of the oxazine; the electrostatic attraction between the carboxyl group of Glu 62 and the positively charged N-methylpyrrolidine in the side chain; the interaction between the N atom of His 95 and the N atom of the pyrimidine ring of the core skeleton of hydrogen bonds. Nonpolar interactions mainly consist of hydrophobic interactions of small molecules with surrounding residues (Figure 2).
值得注意的是，这些极性相互作用都是有方向性的，尤其是哌嗪末端N原子与周围氨基酸形成的氢键和盐桥相互作用，有较强的方向性，所以对于活性较好的小分子来说，哌嗪两端N原子的位置相对固定，其构象(TH-Z 816位扭船型)、与嘧啶环的夹角，都有一定的限制。It is worth noting that these polar interactions are all directional, especially the hydrogen bonds and salt bridge interactions between the N atom at the end of piperazine and the surrounding amino acids, which have strong directionality. For small molecules, the positions of the N atoms at both ends of piperazine are relatively fixed, and its conformation (TH-Z 816-position twist boat type) and the included angle with the pyrimidine ring have certain restrictions.
图3呈现了结合口袋的空间特点：哌嗪环周围结合口袋的空间特点是上方的空间体积较小，而下方的空间较大，近端空间较大，而远端空间小，所 以哌嗪环上的甲基指向下方。Figure 3 presents the spatial characteristics of the binding pocket: the spatial characteristics of the binding pocket around the piperazine ring are that the upper space is smaller, while the lower space is larger, the proximal space is larger, and the distal space is small, so the piperazine ring The methyl group on the top points down.
Figure PCTCN2022088438-appb-000117
Figure PCTCN2022088438-appb-000117
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。The above content is a further detailed description of the present invention in combination with specific preferred embodiments, and it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field of the present invention, without departing from the concept of the present invention, some simple deductions or substitutions can be made, which should be regarded as belonging to the protection scope of the present invention.

Claims (27)

  1. 式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体：A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
    Figure PCTCN2022088438-appb-100001
    Figure PCTCN2022088438-appb-100001
    其中，in,
    X为-N(R)-或-CH(R*)-；X is -N(R)- or -CH(R*)-;
    其中R选自H、-(CH 2) 1-3-卤素、-(CH 2) 1-3-OH、-(CH 2) 1-3-CN、-(CH 2) 1- 3-NH 2、C 1-6烷基或C 1-6卤代烷基； wherein R is selected from H, -( CH2 ) 1-3 -halogen, -( CH2 ) 1-3 -OH, -( CH2 ) 1-3 -CN, -( CH2 ) 1-3 - NH2 , C 1-6 alkyl or C 1-6 haloalkyl;
    R*选自-(CH 2) 0-3-卤素、-(CH 2) 0-3-OH、-(CH 2) 0-3-CN或-(CH 2) 0-3-NH 2； R* is selected from -( CH2 ) 0-3 -halogen, -( CH2 ) 0-3 -OH, -( CH2 ) 0-3 -CN or -( CH2 ) 0-3 - NH2 ;
    Y为N或CH；Y is N or CH;
    Y 1为CR Y1aR Y1b； Y 1 is CR Y1a R Y1b ;
    Y 2为CR Y2aR Y2b； Y 2 is CR Y2a R Y2b ;
    Y 3为CR Y3aR Y3b或NR Y3c； Y 3 is CR Y3a R Y3b or NR Y3c ;
    r＝1或2；r=1 or 2;
    s＝0或1；s=0 or 1;
    其中R Y1a、R Y1b、R Y2a、R Y2b、R Y3a和R Y3b独立地选自H、卤素、C 1- 6烷基或C 1-6卤代烷基； wherein R Y1a , R Y1b , R Y2a , R Y2b , R Y3a and R Y3b are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;
    R Y3c选自H、C 1-6烷基或C 1-6卤代烷基； R Y3c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    或者Y 3和与之相邻的Y 2之间可以形成双键； Or a double bond can be formed between Y 3 and its adjacent Y 2 ;
    R A选自H、C 6-10芳基或5-14元杂芳基，其任选地被1、2、3或4个R A1取代； R A is selected from H, C 6-10 aryl or 5-14 membered heteroaryl, optionally substituted with 1, 2, 3 or 4 R A1 ;
    其中各个R A1独立地选自H、卤素、-CN、-OR X、-SR X、-NR YR Z、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； wherein each R A1 is independently selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    L选自化学键、-O-、-S-或-NH-；L is selected from chemical bonds, -O-, -S- or -NH-;
    R B选自H、卤素、-CN、-OR X、-SR X、-NR YR Z、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被1、2、3或4个R#取代； R B is selected from H, halogen, -CN, -OR X , -SR X , -NR Y R Z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 membered aryl or 5-14 membered heteroaryl; it is optionally substituted with 1, 2, 3 or 4 R#;
    其中R#选自H、-C 0-6亚烷基-卤素、-C 0-6亚烷基-CN、C 1-6烷基、C 1- 6卤代烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-O-R X、-C 0-6亚烷基-S-R X、-C 0-6亚烷基-NR YR Z、-C 0-6亚烷基-C(O)R X、-C 0-6亚烷基-C(O)OR X、-C 0-6亚烷基-C(O)-NR YR Z、-C 0-6亚烷基-C 3-10环烷基、-C 0-6亚烷基-3-10元杂环基、-C 0-6亚烷基-C 6-10芳基或-C 0-6亚烷基-5-14元杂芳基；并且R#任选地被卤素、-OH、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 1- 6烷基或C 1-6卤代烷基取代； wherein R# is selected from H, -C 0-6 alkylene-halogen, -C 0-6 alkylene-CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, -C 0-6 alkylene-OR X , -C 0-6 alkylene-SR X , -C 0-6 alkylene-NR Y R Z , -C 0-6 Alkylene-C(O)R X , -C 0-6 alkylene-C(O)OR X , -C 0-6 alkylene-C(O)-NR Y R Z , -C 0- 6 alkylene-C 3-10 cycloalkyl, -C 0-6 alkylene-3-10 membered heterocyclic group, -C 0-6 alkylene-C 6-10 aryl or -C 0- 6 alkylene-5-14 membered heteroaryl; and R# is optionally halogen, -OH, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N (C 1-6 alkyl) 2 , C 1-6 alkyl or C 1-6 haloalkyl substitution;
    其中R X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； wherein R X is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R Y和R Z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 Y和R Z以及它们连接的氮原子形成3-10元杂环基； R Y and R Z are independently selected from H, C 1-6 alkyl , C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R Y and R Z and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclic group;
    R 1和R 2独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R’； R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d ) m -R';
    R 3和R 4独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R”； R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -R";
    R 2’为H，或者R 2、R 2’连同它们连接的碳原子形成C 3-6环烷基； R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
    或者R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-； Or any one group of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 are connected to form -(CR a R b ) n -;
    p＝0、1、2或3；p=0, 1, 2 or 3;
    q＝0、1、2或3；q=0, 1, 2 or 3;
    其中R a选自H、卤素、C 1-6烷基或C 1-6卤代烷基； wherein R a is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R b选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R b is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R c选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R c is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R d选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R d is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R’选自H、卤素、-OH、-SH、-NH 2、-CN、-C(O)R e、-C(O)OR e、-C(O)NR fR g、C 2-6烯基或C 2-6炔基； R' is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e , -C(O)NR f R g , C 2- 6 alkenyl or C 2-6 alkynyl;
    R”选自H、卤素、-OH、-SH、-NH 2、-CN、-C(O)R e、-C(O)OR e、-C(O)NR fR g、C 2-6烯基或C 2-6炔基； R" is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e , -C(O)NR f R g , C 2- 6 alkenyl or C 2-6 alkynyl;
    m＝0、1、2、3、4、5或6；m=0, 1, 2, 3, 4, 5 or 6;
    n＝0、1、2、3、4、5或6；n=0, 1, 2, 3, 4, 5 or 6;
    其中R e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； wherein R e is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R f和R g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 f和R g以及它们连接的氮原子形成3-10元杂环基。 R f and R g are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R f and R g and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclyl.
  2. 权利要求1的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof,
    其中
    Figure PCTCN2022088438-appb-100002
    选自以下母核：
    Figure PCTCN2022088438-appb-100003
    Figure PCTCN2022088438-appb-100004
    in
    Figure PCTCN2022088438-appb-100002
    Select from the following parent nuclei:
    Figure PCTCN2022088438-appb-100003
    Figure PCTCN2022088438-appb-100004
  3. 权利要求1或2的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof,
    其中R A选自以下基团：
    Figure PCTCN2022088438-appb-100005
    Figure PCTCN2022088438-appb-100006
    wherein R A is selected from the following groups:
    Figure PCTCN2022088438-appb-100005
    Figure PCTCN2022088438-appb-100006
  4. 权利要求1-3中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof,
    其中-L-R B选自H、
    Figure PCTCN2022088438-appb-100007
    wherein -LR B is selected from H,
    Figure PCTCN2022088438-appb-100007
    Figure PCTCN2022088438-appb-100008
    Figure PCTCN2022088438-appb-100008
  5. 权利要求1-4中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中，X为-N(R)-，并且其中R选自H、C 1-6烷基或C 1-6卤代烷基，X优选为-NH-。 A compound of formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein , X is -N(R)-, and wherein R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, X is preferably -NH-.
  6. 权利要求1-5中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中，R 1或R 2选自H、卤素、-OH、-NH 2、-CN、-CH 3或-CH 2-OH，优选-CH 3或-CH 2-OH；优选地，R 1和R 2之一为-CH 3或-CH 2-OH；优选地，R 1和R 2之一为R构型的-CH 3或-CH 2-OH。 A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein , R 1 or R 2 is selected from H, halogen, -OH, -NH 2 , -CN, -CH 3 or -CH 2 -OH, preferably -CH 3 or -CH 2 -OH; preferably, R 1 and R One of 2 is -CH 3 or -CH 2 -OH; preferably, one of R 1 and R 2 is -CH 3 or -CH 2 -OH in R configuration.
  7. 权利要求1-5中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中，R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-，优选-CH 2CH 2-或-CH 2CH 2CH 2-。 A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein , any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - , preferably -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  8. 权利要求1-7中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中，R 3和R 4独立地选自H、-CH 2-Cl、-CH 2-F、-CH 2-CN、-CH 2CH 2-Cl、-CH 2CH 2-F、-CH 2CH 2-CN，优选H或-CH 2-CN。 A compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein , R 3 and R 4 are independently selected from H, -CH 2 -Cl, -CH 2 -F, -CH 2 -CN, -CH 2 CH 2 -Cl, -CH 2 CH 2 -F, -CH 2 CH 2 -CN, preferably H or -CH2 -CN.
  9. 权利要求1-8中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其具有以下结构：A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, which has the following structure:
    Figure PCTCN2022088438-appb-100009
    Figure PCTCN2022088438-appb-100009
    Figure PCTCN2022088438-appb-100010
    Figure PCTCN2022088438-appb-100010
    其中，各基团如权利要求1-8中任一项所定义。wherein each group is as defined in any one of claims 1-8.
  10. 权利要求9的式(II)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体：The compound of formula (II) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
    Figure PCTCN2022088438-appb-100011
    Figure PCTCN2022088438-appb-100011
    其中，in,
    X为-N(R)-或-CH(R*)-；X is -N(R)- or -CH(R*)-;
    其中R选自H、C 1-6烷基或C 1-6卤代烷基； wherein R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R*选自-(CH 2) 0-3-NH 2或-(CH 2) 0-3-OH； R* is selected from -(CH 2 ) 0-3 -NH 2 or -(CH 2 ) 0-3 -OH;
    R 1和R 2独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R’； R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d ) m -R';
    R 3和R 4独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-R”； R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -R";
    R 2’为H，或者R 2、R 2’连同它们连接的碳原子形成C 3-6环烷基； R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
    p＝0、1、2或3；p=0, 1, 2 or 3;
    q＝0、1、2或3；q=0, 1, 2 or 3;
    其中R c选自H、卤素、C 1-4烷基或C 1-4卤代烷基； wherein R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R d选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R’选自H、卤素、-OH、-SH、-NH 2、-CN、-C(O)R e、-C(O)OR e或-C(O)NR eR f； R' is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e or -C(O)NR e R f ;
    R”选自H、卤素、-OH、-SH、-NH 2、-CN、-C(O)R e、-C(O)OR e或-C(O)NR eR f； R" is selected from H, halogen, -OH, -SH, -NH 2 , -CN, -C(O)R e , -C(O)OR e or -C(O)NR e R f ;
    m＝0、1、2、3、4、5或6；m=0, 1, 2, 3, 4, 5 or 6;
    其中R e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； wherein R e is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R f和R g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 f和R g以及它们连接的氮原子形成3-10元杂环基。 R f and R g are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R f and R g and the nitrogen to which they are attached Atoms form a 3-10 membered heterocyclyl.
  11. 权利要求10的式(II)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中，The compound of formula (II) of claim 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
    X为-N(R)-或-CH(R*)-；X is -N(R)- or -CH(R*)-;
    其中R选自H、C 1-6烷基或C 1-6卤代烷基； wherein R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R*选自-(CH 2) 0-1-NH 2或-(CH 2) 0-1-OH； R* is selected from -(CH 2 ) 0-1 -NH 2 or -(CH 2 ) 0-1 -OH;
    R 1和R 2独立地选自H或-(CR cR d) m-R’； R 1 and R 2 are independently selected from H or -(CR c R d ) m -R';
    R 3和R 4独立地选自H或-(CR cR d) m-R”； R 3 and R 4 are independently selected from H or -(CR c R d ) m -R";
    R 2’为H，或者R 2、R 2’连同它们连接的碳原子形成C 3-6环烷基； R 2' is H, or R 2 , R 2' together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;
    p＝0、1或2；p=0, 1 or 2;
    q＝0、1或2；q=0, 1 or 2;
    其中R c为H； wherein R c is H;
    R d为H； R d is H;
    R’选自H、卤素或-OH；R' is selected from H, halogen or -OH;
    R”选自H、卤素、-OH、-NH 2或-CN； R" is selected from H, halogen, -OH, -NH2 or -CN;
    m＝0、1、2、3、4、5或6。m=0, 1, 2, 3, 4, 5 or 6.
  12. 权利要求9的式(III)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体：The compound of formula (III) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
    Figure PCTCN2022088438-appb-100012
    Figure PCTCN2022088438-appb-100012
    其中，in,
    R 1和R 2独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d)-R’； R 1 and R 2 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d )-R';
    R 3和R 4独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d) m-CN； R3 and R4 are independently selected from H, halogen, -OH, -NH2 , -CN or - ( CRcRd ) m -CN;
    p＝0、1、2或3；p=0, 1, 2 or 3;
    q＝0、1、2或3；q=0, 1, 2 or 3;
    其中R c选自H或卤素； wherein R is selected from H or halogen;
    R d选自H或卤素； R d is selected from H or halogen;
    R’选自H、卤素、-OH、-SH、-NH 2或-CN； R' is selected from H, halogen, -OH, -SH, -NH2 or -CN;
    m＝1或2。m=1 or 2.
  13. 权利要求12的式(III)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中，The compound of formula (III) of claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
    R 1和R 2独立地选自H或-(CR cR d)-R’； R 1 and R 2 are independently selected from H or -(CR c R d )-R';
    R 3和R 4独立地选自H或-(CR cR d)-CN； R 3 and R 4 are independently selected from H or -(CR c R d )-CN;
    p＝1或2；p=1 or 2;
    q＝1或2；q=1 or 2;
    其中R c为H； wherein R c is H;
    R d为H； R d is H;
    R’选自H或-OH。R' is selected from H or -OH.
  14. 权利要求9的式(IV)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体：The compound of formula (IV) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
    Figure PCTCN2022088438-appb-100013
    Figure PCTCN2022088438-appb-100013
    其中，in,
    R 1和R 2之一为-(CR cR d)-R’，另一选自H、卤素、-OH、-NH 2、-CN或-(CR cR d)-R’； One of R 1 and R 2 is -(CR c R d )-R' and the other is selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d )-R';
    R 3和R 4独立地选自H、卤素、-OH、-NH 2、-CN或-(CR cR d)-R”； R 3 and R 4 are independently selected from H, halogen, -OH, -NH 2 , -CN or -(CR c R d )-R";
    R选自H、C 1-6烷基或C 1-6卤代烷基； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    p＝0、1、2或3；p=0, 1, 2 or 3;
    q＝0、1、2或3；q=0, 1, 2 or 3;
    其中R c选自H、卤素、C 1-4烷基或C 1-4卤代烷基； wherein R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R d选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R’选自H、卤素、-OH、-SH、-NH 2或-CN； R' is selected from H, halogen, -OH, -SH, -NH2 or -CN;
    R”选自卤素、-OH、-SH、-NH 2或-CN。 R" is selected from halogen, -OH, -SH, -NH2 or -CN.
  15. 权利要求14的式(IV)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中，The compound of formula (IV) of claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
    R 1和R 2之一为-(CR cR d)-R’，另一为H； One of R 1 and R 2 is -(CR c R d )-R', and the other is H;
    R 3和R 4独立地选自H或-(CR cR d)-R”； R and R are independently selected from H or -(CR c R d ) -R";
    R选自H、C 1-2烷基或C 1-2卤代烷基； R is selected from H, C 1-2 alkyl or C 1-2 haloalkyl;
    p＝1或2；p=1 or 2;
    q＝1或2；q=1 or 2;
    其中R c为H； wherein R c is H;
    R d为H； R d is H;
    R’选自H或-OH；R' is selected from H or -OH;
    R”为-CN。R" is -CN.
  16. 权利要求9的式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体：The compound of formula (V), (V-1) or (V-2) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate thereof or isotopic variants:
    Figure PCTCN2022088438-appb-100014
    Figure PCTCN2022088438-appb-100014
    其中，in,
    R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1和R 2独立地选自H或-(CR cR d) m-R’，其余的R 3和R 4独立地选自H或-(CR cR d) m-R”； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is linked to form -(CR a R b ) n -, and the remaining R 1 and R 2 are independently selected from H or -(CR c R d ) m -R', the remaining R 3 and R 4 are independently selected from H or -(CR c R d ) m -R ";
    R为H、C 1-6烷基或C 1-6卤代烷基； R is H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中R a选自H、卤素、C 1-4烷基或C 1-4卤代烷基； wherein R a is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R b选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R b is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R c选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R d选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R’选自H、卤素、-CN、-OH、-NH 2、C 2-4烯基或C 2-4炔基； R' is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
    R”选自H、卤素、-CN、-OH、-NH 2、C 2-4烯基或C 2-4炔基； R" is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
    n＝0、1、2、3或4；n=0, 1, 2, 3 or 4;
    m＝0、1、2或3。m=0, 1, 2 or 3.
  17. 权利要求16的式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体，其中，The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate thereof or isotopic variants, where,
    R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1、R 2、R 3或R 4分别为H、卤素、-CN、-OH或-NH 2； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 is respectively H, halogen, -CN, -OH or -NH 2 ;
    R选自H、C 1-6烷基或C 1-6卤代烷基； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中R a选自H、卤素、C 1-4烷基或C 1-4卤代烷基； wherein R a is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R b选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R b is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    n＝0、1、2、3或4。n=0, 1, 2, 3 or 4.
  18. 权利要求16的式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体，其中，The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate thereof or isotopic variants, where,
    R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1、R 2、R 3或R 4为H； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 is H;
    R选自H、C 1-2烷基或C 1-2卤代烷基； R is selected from H, C 1-2 alkyl or C 1-2 haloalkyl;
    其中R a为H； where R a is H;
    R b为H； R b is H;
    n＝1、2或3。n=1, 2 or 3.
  19. 权利要求16的式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体，其中，The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate thereof or isotopic variants, where,
    R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1和R 2独立地选自H或-(CR cR d) m-R’，其余的R 3和R 4独立地选自H或-(CR cR d) m-R”； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is linked to form -(CR a R b ) n -, and the remaining R 1 and R 2 are independently selected from H or -(CR c R d ) m -R', the remaining R 3 and R 4 are independently selected from H or -(CR c R d ) m -R ";
    R为H；R is H;
    其中R a选自H、卤素、C 1-4烷基或C 1-4卤代烷基； wherein R a is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R b选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R b is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R c选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R c is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R d选自H、卤素、C 1-4烷基或C 1-4卤代烷基； R d is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R’选自H、卤素、-CN、-OH、-NH 2、C 2-4烯基或C 2-4炔基； R' is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
    R”选自H、卤素、-CN、-OH、-NH 2、C 2-4烯基或C 2-4炔基； R" is selected from H, halogen, -CN, -OH, -NH 2 , C 2-4 alkenyl or C 2-4 alkynyl;
    m＝0、1、2或3；m=0, 1, 2 or 3;
    n＝2、3或4。n=2, 3 or 4.
  20. 权利要求16的式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体，其中，The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate thereof or isotopic variants, where,
    R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1、R 2、R 3或R 4分别独立地选自H、卤素、-CN、-OH或-NH 2； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, -CN, -OH or -NH 2 ;
    R为H；R is H;
    其中R a选自H、卤素或C 1-4烷基； wherein R a is selected from H, halogen or C 1-4 alkyl;
    R b选自H、卤素或C 1-4烷基； R b is selected from H, halogen or C 1-4 alkyl;
    n＝2、3或4。n=2, 3 or 4.
  21. 权利要求16的式(V)、(V-1)或(V-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、溶剂合物、水合物或同位素变体，其中，The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate thereof or isotopic variants, where,
    R 1和R 2、R 3和R 4、R 1和R 4、R 2和R 3中任一组连接形成-(CR aR b) n-，其余的R 1、R 2、R 3或R 4为H； Any one of R 1 and R 2 , R 3 and R 4 , R 1 and R 4 , R 2 and R 3 is connected to form -(CR a R b ) n -, and the remaining R 1 , R 2 , R 3 or R 4 is H;
    R为H；R is H;
    其中R a为H； where R a is H;
    R b为H； R b is H;
    n＝2或3。n=2 or 3.
  22. 权利要求1的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，其中所述化合物选自：The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein the compound is selected from the group consisting of:
    Figure PCTCN2022088438-appb-100015
    Figure PCTCN2022088438-appb-100015
    Figure PCTCN2022088438-appb-100016
    Figure PCTCN2022088438-appb-100016
    Figure PCTCN2022088438-appb-100017
    Figure PCTCN2022088438-appb-100017
    Figure PCTCN2022088438-appb-100018
    Figure PCTCN2022088438-appb-100018
  23. 药物组合物，其含有权利要求1-22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、溶剂合物、水合物或同位素变体，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。A pharmaceutical composition comprising a compound of any one of claims 1-22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof , and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.
  24. 权利要求1-22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、溶剂合物、水合物或同位素变体在制备用于治疗和/或预防KRAS G12D突变蛋白介导的疾病的药物中的用途。A compound of any one of claims 1-22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, in preparation for use in therapy and/or Or use in a medicament for the prevention of KRAS G12D mutant protein-mediated diseases.
  25. 一种在受试者中治疗和/或预防KRAS G12D突变蛋白介导的疾病的方法，所述方法包括向所述受试者给药权利要求1-22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、溶剂合物、水合物或同位素变体或权利要求23的药物组合物。A method of treating and/or preventing a KRAS G12D mutein-mediated disease in a subject, the method comprising administering to the subject a compound of any one of claims 1-22, or a pharmacy An acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant or the pharmaceutical composition of claim 23.
  26. 权利要求1-22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、溶剂合物、水合物或同位素变体或权利要求23的药物组合物，其用于治疗和/或预防KRAS G12D突变蛋白介导的疾病。The compound of any one of claims 1-22 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof or the pharmaceutical combination of claim 23 for the treatment and/or prevention of KRAS G12D mutant protein-mediated diseases.
  27. 权利要求24的用途或权利要求25的方法或权利要求26的化合物或组合物的用途，其中所述KRAS G12D突变蛋白介导的疾病选自急性髓细胞样白血病、急性髓细胞样白血病、青少年癌症、儿童肾上腺皮质癌、AIDS相关的癌症(例如淋巴瘤和卡波西氏肉瘤)、肛门癌、阑尾癌、星形细胞瘤、非典型畸胎样、基底细胞癌、胆管癌、膀胱癌、骨癌、脑干神经胶质瘤、脑瘤、乳腺癌、支气管肿瘤、伯基特淋巴瘤、类癌瘤、非典型畸胎样、胚胎肿瘤、生殖细胞肿瘤、原发性淋巴瘤、宫颈癌、儿童癌症、脊索瘤、心脏肿瘤、慢性淋巴细胞性白血病(CLL)、慢性髓细胞性白血病(CML)、慢性骨髓增殖性病症、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T细胞淋巴瘤、肝外导管原位癌(DCIS)、胚胎肿瘤、CNS癌症、子宫内膜癌、室管膜瘤、食道癌、嗅神经母细胞瘤、尤文氏肉瘤、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌、骨骼的纤维组织细胞瘤、胆囊癌、胃癌、胃肠道类癌瘤、胃肠道间质瘤(GIST)、生殖细胞肿瘤、妊娠滋养细胞肿瘤、毛细胞白血病、头颈癌、心脏癌、肝癌、 霍奇金氏淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞瘤、胰腺神经内分泌瘤、肾癌、喉癌、唇和口腔癌、肝癌、小叶原位癌(LCIS)、肺癌、淋巴瘤、转移性鳞状颈癌伴隐匿原发灶、中线道癌、口腔癌、多发性内分泌瘤综合征、多发性骨髓瘤/浆细胞瘤、蕈样真菌病、骨髓发育不良综合征、骨髓发育不良/骨髓增殖性瘤、多发性骨髓瘤、梅克尔细胞癌、恶性间皮瘤、骨骼的恶性纤维组织细胞瘤和骨肉瘤、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金氏淋巴瘤、非小细胞肺癌(NSCLC)、口腔癌、唇和口腔癌、口咽癌、卵巢癌、胰腺癌、乳头瘤、副神经节瘤、鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、胸膜肺母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、移行性细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、皮肤癌、胃癌、小细胞肺癌、小肠癌、软组织肉瘤、细胞淋巴瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管的移行性细胞癌、滋养细胞肿瘤、儿童罕见的癌症、尿道癌、子宫肉瘤、阴道癌、外阴癌或病毒诱导的癌症。The use of claim 24 or the method of claim 25 or the use of the compound or composition of claim 26, wherein the KRAS G12D mutein mediated disease is selected from the group consisting of acute myeloid leukemia, acute myeloid leukemia, juvenile cancer , childhood adrenocortical carcinoma, AIDS-related cancers (eg, lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone Carcinoma, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma , extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell Tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, Heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS) , lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasmacytoma, mycosis fungoides, myelodysplastic syndrome syndrome, myelodysplasia/myeloproliferative tumor, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and sinus cancer, nasopharyngeal carcinoma, neuroblastoma Tumor, Non-Hodgkin's Lymphoma, Non-Small Cell Lung Cancer (NSCLC), Oral Cancer, Lip and Mouth Cancer, Oropharyngeal Cancer, Ovarian Cancer, Pancreatic Cancer, Papilloma, Paraganglioma, Sinus and Nasal Cancer, Thyroid Para adenocarcinoma, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Skin cancer, gastric cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, cellular lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of renal pelvis and ureter, trophoblastic tumor, rare in children Cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer.
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