WO2024174980A1 - Composé contenant de la dihydrophtalazine et de l'alcényle et son utilisation - Google Patents

Composé contenant de la dihydrophtalazine et de l'alcényle et son utilisation Download PDF

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WO2024174980A1
WO2024174980A1 PCT/CN2024/077697 CN2024077697W WO2024174980A1 WO 2024174980 A1 WO2024174980 A1 WO 2024174980A1 CN 2024077697 W CN2024077697 W CN 2024077697W WO 2024174980 A1 WO2024174980 A1 WO 2024174980A1
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alkyl
optionally substituted
cycloalkyl
membered
halogen
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PCT/CN2024/077697
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English (en)
Chinese (zh)
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刘飞
严正磊
施伟
彭岩
徐宏江
顾佳佳
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正大天晴药业集团股份有限公司
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Publication of WO2024174980A1 publication Critical patent/WO2024174980A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present application relates to a compound containing dihydrophthalazine and an alkenyl group, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating related diseases (such as cancer).
  • Protein arginine N-methyltransferase is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the omega-nitrogen of the guanidino function of L-arginine residues in proteins (omega monomethylation) and transfers a second methyl group to the other omega-nitrogen, generating symmetric dimethylarginine (sDMA).
  • SAM S-adenosyl-L-methionine
  • sDMA symmetric dimethylarginine
  • PRMT5 forms a complex with MEP50 (methylosome protein 50), which is required for substrate recognition and orientation and for the histone 2A and histone 4 methyltransferase activities catalyzed by PRMT5.
  • MTAP methylthioadenosine phosphorylase
  • MTA-synergistic inhibition of PRMT5 activity would provide therapeutic benefit in a variety of cancers.
  • MTA-synergistic PRMT5 inhibitors that are able to inhibit PRMT5 activity in the presence of elevated MTA concentrations, particularly in MTAP-deficient cells.
  • the present application relates to a compound of formula I or a pharmaceutically acceptable salt thereof,
  • R 2 is each independently selected from halogen, CN, OH, NH 2 , optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 1-10 alkoxy, optionally substituted C 1-10 alkylNH- , optionally substituted (C 1-10 alkyl) 2 N-, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted 3-10 membered heterocycloalkenyl, -C(O)OR a , -OC(O)R a , -C(O)NHR a , -NHCOR a , -N(C 1-10 alkyl)COR a , -S(O)NHR a , -NHS(O)R a , -NHS(O) 2 R a , -N(C 1-6 alkyl)
  • Ra and Rb are each independently selected from H, C1-10 alkyl, C3-10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein the C1-10 alkyl, C3-10 cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more groups selected from OH, NH2 , CN or halogen;
  • W is selected from CH or N;
  • Ring A is selected from C 6-10 aryl, 5-15 membered heterocyclyl or 5-10 membered heteroaryl;
  • R 4 and R 5 are each independently selected from H, OH, NH 2 , CN, halogen, optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 1-10 alkoxy, optionally substituted C 3-10 cycloalkyl or optionally substituted 3-10 membered heterocycloalkyl;
  • Ring B is selected from C 3-15 cycloalkyl, C 6-15 aryl, 3-15 membered heterocyclyl or 5-10 membered heteroaryl;
  • R 6 is each independently selected from halogen, OH, NH 2 , CN, optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3-10 cycloalkyl , optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, or -XR;
  • X is selected from NH, N(C 1-10 alkyl), O or S;
  • R is selected from optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C 6-10 aryl or optionally substituted 5-10 membered heteroaryl;
  • n, q are independently selected from 0, 1, 2, 3, 4 or 5.
  • R 1 is selected from optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, or -CONHR a .
  • R 1 is selected from halogen, CN, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)NHR a or -CO 2 R a , and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , -C(O)R a , -CO 2 R a , -NHC(O)R a , -N(C 1-3 alkyl)C(O)R a , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylNH- or (C 1-3 alkyl) 2 N-.
  • R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)NHR a or -CO 2 R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , -C(O)R a , -CO 2 R a , -NHC(O)R a , -N(C 1-3 alkyl)C(O)R a , C 1-3 alkyl, C 1-3 alkylNH- or (C 1-3 alkyl) 2 N-.
  • R 1 is selected from C 1-3 alkyl, C 3-4 cycloalkyl , 3-4 membered heterocycloalkyl, -C(O)NHR a or -CO 2 R a , and the C 1-3 alkyl, C 3-4 cycloalkyl or 3-4 membered heterocycloalkyl is optionally substituted with one or more of the following groups: NH 2 , -C(O)R a , -CO 2 R a , -NHC(O)R a , -N(C 1-3 alkyl)C(O)R a , C 1-3 alkyl, C 1-3 alkylNH- or (C 1-3 alkyl) 2 N-.
  • R 1 is selected from C 1-3 alkyl, which is optionally substituted with one or more of the following groups: NH 2 , -NHC(O)R a , -N(C 1-3 alkyl)C(O)R a , C 1-3 alkylNH—, or (C 1-3 alkyl) 2 N—.
  • R 1 is selected from C 1-3 alkyl optionally substituted with one or more NH 2 .
  • R 1 is selected from -CH 2 NH 2 .
  • R2 is each independently selected from halogen, CN, OH, NH2 , optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkylNH-, optionally substituted ( C1-6 alkyl) 2N- , optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 3-6 membered heterocycloalkenyl, -C(O) ORa , -OC(O) Ra , -C(O) NHRa , -NHC(O) Ra , -N( C1-6 alkyl)C(O) Ra , -S(O) NHRa , -NHS(O) Ra , -NHS(O) 2Ra , -N( C1-6 alkyl)S(O) 2Ra ,
  • R 2 is each independently selected from halogen, CN, OH, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylNH—, (C 1-10 alkyl) 2 N—, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, -C(O)OR a , -OC(O)R a , -C ( O)NHR a , -NHCOR a , -N(C 1-6 alkyl)C(O)R a , -S(O)NHR a , -NHS(O)R a , -NHS(O) 2 R a , -N(C 1-6 alkyl)S(O) 2 R a or -C(O)R a , wherein the C 1-10 alkyl,
  • R 2 is each independently selected from halogen, CN, OH, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10 alkyl) 2 N-, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, -C(O)OR a , -OC(O)R a , -C(O)NHR a , -NHC(O)R a , -N(C 1-6 alkyl)C(O)R a or -C(O)R a , wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylNH-, (C 1-10 alkyl) 2 N-, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl
  • R 2 is each independently selected from halogen, CN, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylNH—, (C 1-6 alkyl) 2 N—, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, —NHC(O)R a , —N(C 1-3 alkyl)C(O)R a , or —C(O)R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylNH—, (C 1-6 alkyl) 2 N—, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , CHO,
  • R 2 is independently selected from halogen, CN, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl) 2 N- are optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , CHO, COOH, C 1-3 alkyl, C 1-3 alkoxy , C 1-3 alkylNH- or (C 1-3 alkyl) 2 N-.
  • R 2 is each independently selected from NH 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylNH— or (C 1-6 alkyl) 2 N—, wherein the C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylNH— or (C 1-6 alkyl) 2 N— is optionally substituted with one or more of the following groups: halogen, CN, OH or NH 2 .
  • R 2 is independently selected from halogen, NH 2 , C 1-4 alkyl NH- or (C 1-3 alkyl) 2 N-. In some embodiments, R 2 is independently selected from NH 2 , C 1-4 alkyl NH- or (C 1-3 alkyl) 2 N-.
  • R 2 is each independently selected from halogen, CN, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl , or C 2-4 alkynyl , which is optionally substituted with one or more of the following groups: halogen, CN, OH, or NH 2 .
  • R 2 is each independently selected from NH 2 , C 2-4 alkenyl, or C 2-4 alkynyl.
  • R 2 is selected from halogen or NH 2 .
  • R 2 is selected from Cl or NH 2 .
  • R 2 is selected from NH 2 .
  • Ra is selected from H, C1-6 alkyl , or C3-6 cycloalkyl, which is optionally substituted with one or more groups selected from OH, NH2 , CN, or halogen.
  • Ra is selected from H, C1-3 alkyl, or C3-4 cycloalkyl. In some embodiments, Ra is selected from H or C1-3 alkyl.
  • R b is selected from H, C 1-6 alkyl , or C 3-6 cycloalkyl, which is optionally substituted with one or more groups selected from OH, NH 2 , CN, or halogen.
  • R b is selected from H, C 1-3 alkyl, or C 3-4 cycloalkyl. In some embodiments, R b is selected from H or C 1-3 alkyl. In some embodiments, R b is selected from H.
  • n is selected from 0, 1 or 2. In some embodiments, m is selected from 0 or 1. In some embodiments, m is 0.
  • m is 1 and R 2 is Cl or NH 2 .
  • m is 1, W is CH, and R 2 is linked to W.
  • W is selected from CH.
  • ring A is selected from C 6-10 aryl or 5-10 membered heterocyclyl. In some embodiments, ring A is selected from 5-10 membered heterocyclyl. In some embodiments, ring A is selected from 5-10 membered heteroaryl. In some embodiments, ring A is selected from 5-6 membered heteroaryl. In some embodiments, ring A is selected from 5 membered heteroaryl. In some embodiments, ring A is selected from 5 membered heteroaryl. In some embodiments, ring A is selected from 5 membered heteroaryl containing N.
  • Ring A is selected from pyrazolyl. In some embodiments, Ring A is selected from
  • R 3 is each independently selected from OH, NH 2 , CN, halogen, C 1-4 alkyl, C 1-4 alkoxy, or C 3-4 cycloalkyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, or C 3-4 cycloalkyl is optionally substituted with one or more of the following groups: OH, NH 2 , CN, or halogen.
  • R 3 is each independently selected from C 1-4 alkyl or C 3-4 cycloalkyl, which is optionally substituted with one or more of the following groups: OH, NH 2 , CN, or halogen.
  • R 3 is each independently selected from C 1-3 alkyl or cyclopropyl, which is optionally substituted with one or more halogens.
  • R 3 is each independently selected from OH, NH 2 , CN, halogen, or C 1-6 alkyl. In some embodiments, R 3 is each independently selected from OH, NH 2 , CN, halogen, or C 1-3 alkyl. In some embodiments, R 3 is each independently selected from C 1-6 alkyl. In some embodiments, R 3 is each independently selected from C 1-3 alkyl.
  • R 3 is each independently selected from NH 2 or C 1-3 alkyl.
  • R 3 is each independently selected from NH 2 or methyl.
  • R 3 is each independently selected from methyl.
  • n is selected from 0, 1, 2, or 3. In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 1 or 2. In some embodiments, n is selected from 1.
  • n is 1 and R 3 is selected from NH 2 or C 1-3 alkyl. In some embodiments, n is 1 and R 3 is selected from NH 2 or methyl. In some embodiments, n is 1 and R 3 is methyl.
  • Ring A is selected from n is 1, R3 is NH2 or methyl and is connected to the nitrogen on ring A.
  • R 4 and R 5 are each independently selected from H, OH, NH 2 , CN, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl.
  • R4 and R5 are each independently selected from H, OH, NH2 , CN, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C3-10 cycloalkyl, or 3-10 membered heterocycloalkyl, wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C3-10 cycloalkyl, or 3-10 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, NH2 , -C(O) Ra , -C(O) ORa , -OC(O) Ra , -C(O) NHRa , -NHC(O) Ra , -S(O) NHRa , -NHS(O) Ra , -S(O) 2NHRa , -
  • R 4 and R 5 are each independently selected from H, OH, NH 2 , CN, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl, wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl , or 3-10 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , CHO, COOH, C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylNH—, or (C 1-10 alkyl) 2 N—.
  • R 4 and R 5 are each independently selected from H, OH, NH 2 , CN, halogen, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl, which is optionally substituted with one or more of the following groups: halogen, CN, OH, or NH 2 .
  • R 4 and R 5 are each independently selected from H, OH, NH 2 , CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, or C 3-4 cycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, or C 3-4 cycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, or NH 2 .
  • R 4 and R 5 are each independently selected from H, OH, NH 2 , CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, or C 3-4 cycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, or C 3-4 cycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, or NH 2 .
  • R4 and R5 are each independently selected from H, CN, C1-4 alkyl, C2-3 alkenyl, C1-3 alkoxy or C3-4 cycloalkyl, wherein the C1-4 alkyl, C2-3 alkenyl, C1-3 alkoxy or C3-4 cycloalkyl is optionally substituted with one or more fluorine atoms.
  • R4 and R5 are each independently selected from H, CN, -CH3 , -CH2CH3 , -CH ( CH3 ) 2 , -CH2CH ( CH3 ) 2 , cyclopropyl, -CHF2 , -CF3 , -OCH3 , -OCH2CH3 , -OCH( CH3 ) 2 , -OCF3 , or vinyl.
  • R 4 and R 5 are each independently selected from H, CN, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , or -OCH(CH 3 ) 2 .
  • R 4 is selected from H, OH, NH 2 , CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, or C 3-4 cycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, or C 3-4 cycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, or NH 2 .
  • R4 is selected from H, -CH3 , -CH2CH3 , -CH ( CH3 ) 2 , -CH2CH ( CH3 ) 2 , cyclopropyl, -CHF2 , -CF3 , -OCH3 , -OCH2CH3 , -OCH ( CH3 ) 2 , -OCF3 , or vinyl.
  • R 4 and R 5 are each independently selected from H, OH, NH 2 , CN, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy is optionally substituted with one or more of the following groups: halogen, CN, OH or NH 2 .
  • R 4 and R 5 are each independently selected from H, OH, NH 2 , CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy is optionally substituted with one or more of the following groups: halogen, CN, OH or NH 2 .
  • R 4 and R 5 are independently selected from H, OH, NH 2 , CN, halogen, C 1-6 alkyl, C 2-6 alkenyl or C 1-6 alkoxy, wherein the C 1-6 alkyl, C 2-6 alkenyl or C 1-6 alkoxy is optionally substituted with one or more of the following groups: halogen, CN, OH or NH 2 .
  • R 4 and R 5 are independently selected from H, CN, C 1-3 alkyl, C 2-3 alkenyl or C 1-3 alkoxy, and the C 1-3 alkyl, C 2-3 alkenyl or C 1-3 alkoxy is optionally substituted with one or more fluorine atoms.
  • R 4 and R 5 are independently selected from H, CN, -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 or vinyl.
  • R 4 is selected from H, -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 or vinyl.
  • R 4 is selected from C 1-10 alkyl.
  • R 4 is selected from C 1-6 alkyl.
  • R 4 is selected from C 1-3 alkyl.
  • R 4 is selected from -CH 3 or -CH 2 CH 3.
  • R 4 is H.
  • R 5 is selected from CN.
  • R 4 is selected from H, OH, NH 2 , CN, halogen, C 1-6 alkyl, C 2-6 alkenyl or C 1-6 alkoxy, wherein the C 1-6 alkyl, C 2-6 alkenyl or C 1-6 alkoxy is optionally substituted with one or more of the following groups: halogen, CN, OH or NH 2 , and R 5 is selected from CN.
  • R 4 is selected from H, OH, NH 2 , CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy or C 3-4 cycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy or C 3-4 cycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH or NH 2 , and R 5 is selected from CN.
  • R 4 is selected from H, -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , or vinyl, and R 5 is selected from CN.
  • R4 is selected from H, -CH3 , -CH2CH3 , -CH ( CH3 ) 2 , -CH2CH ( CH3 ) 2 , cyclopropyl , -CHF2 , -CF3 , -OCH3 , -OCH2CH3 , -OCH( CH3 ) 2 , -OCF3 , or vinyl, and R5 is selected from CN.
  • ring B is selected from C 3-10 cycloalkyl, C 6-10 aryl, or 3-12 membered heterocyclyl. In some embodiments, ring B is selected from C 3-10 cycloalkyl, C 6-10 aryl, or 3-10 membered heterocyclyl.
  • Ring B is selected from C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl.
  • ring B is selected from C 6-10 aryl or 5-10 membered heteroaryl. In some embodiments, ring B is selected from C 6 aryl, C 10 aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl.
  • ring B is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, naphthyl, indolyl, quinolyl or isoquinolyl.
  • ring B is selected from phenyl or naphthyl.
  • ring B is selected from pyridinyl, pyrimidinyl or isoquinolyl.
  • ring B is selected from phenyl, In some embodiments, Ring B is selected from phenyl, In some embodiments, Ring B is selected from phenyl.
  • R 6 is each independently selected from halogen, OH, NH 2 , CN, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 aryl, optionally substituted 5-6 membered heteroaryl, or -XR.
  • R 6 is each independently selected from halogen, OH, NH 2 , CN, or the following groups optionally substituted with one or more Re : C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or -XR;
  • R e is each independently selected from halogen, OH, CN, NH 2 , C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-10 cycloalkyl, 4-10 membered heterocycloalkylO—, -NHC 3-10 cycloalkyl, 3-10 membered heterocycloalkylNH—, -C(O)R a , -C(O)OR a , -OC(O)R a , -C(O)NHR a , -NHC(O)R a , -S(O)NHR a , -NHS(O)R a , -S(O) 2 NHR a or -NHS(O) 2 R a , wherein the C 1-10 alkyl, -OC 1-10 alkyl, C
  • R 6 is independently selected from halogen, OH, NH 2 , CN, or the following groups optionally substituted with one or more Re : C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-8 membered heteroaryl, or -XR, and Re is as defined in the present application.
  • R 6 is independently selected from halogen, OH, NH 2 , CN, or the following groups optionally substituted with one or more Re : C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, or -XR, and Re is as defined herein.
  • R 6 is independently selected from halogen, OH, NH 2 , CN, or the following groups optionally substituted with one or more Re : C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, or -XR, and Re is as defined herein.
  • R 6 is independently selected from halogen, OH, NH 2 , CN, or the following groups optionally substituted with one or more Re : C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OC 3-4 cycloalkyl, 3-6 membered heterocycloalkylO-, -O phenyl, 5-6 membered heteroarylO-, -NHC 3-4 cycloalkyl, 3-6 membered heterocycloalkylNH-, -NHphenyl or 5-6 membered heteroarylNH-, and Re is defined as in the present application.
  • R 6 is independently selected from halogen, OH, NH 2 , CN, or the following groups optionally substituted with one or more Re : C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OC 3-4 cycloalkyl, -O phenyl or -NH phenyl, and Re is as defined in the present application.
  • R 6 is independently selected from halogen, OH, NH 2 , CN, or the following groups optionally substituted with one or more Re : -CH 3 , -OCH 3 , cyclopropyl, pyrrolidinyl, piperazinyl, phenyl, pyridyl, pyrimidinyl, isoxazolyl, thienyl, pyrazolyl, -Ocyclopropyl, -Ophenyl, -NHphenyl, Re is as defined in the present application.
  • R 6 is independently selected from halogen (e.g., F), OH, or the following groups optionally substituted with one or more Re : -CH 3 , -OCH 3 , cyclopropyl, pyrrolidinyl (e.g., 1-pyrrolidinyl), piperazinyl (e.g., 1-piperazinyl), phenyl, pyridinyl (e.g., 3-pyridinyl, 2-pyridinyl, 4-pyridinyl), pyrimidinyl (e.g., 5-pyrimidinyl), isoxazolyl (e.g., 4-isoxazolyl), thienyl (e.g., 3-thienyl), pyrazolyl (e.g., 4-pyrazolyl), -Ocyclopropyl, -Ophenyl, -NHphenyl, and Re is as defined herein.
  • pyrrolidinyl e.g., 1-pyrrol
  • R e is each independently selected from halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, 4-6 membered heterocycloalkylO-, -NHC 3-6 cycloalkyl, or 3-6 membered heterocycloalkylNH-, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, 4-6 membered heterocycloalkylO-, C 3-6 cycloalkylNH-, or 3-6 membered heterocycloalkylNH- is optionally substituted with one or more of the following groups:
  • R e is each independently selected from halogen, OH, CN, NH 2 , C 1-6 alkyl, -OC 1-6 alkyl, 4-6 membered heterocycloalkyl, -OC 3-6 cycloalkyl or 3-6 membered heterocycloalkylNH-, and the C 1-6 alkyl, C 1-6 alkoxy, 4-6 membered heterocycloalkyl, -OC 3-6 cycloalkyl or 3-6 membered heterocycloalkylNH- is optionally substituted with one or more of the following groups: halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-.
  • R e is independently selected from halogen, OH, C 1-3 alkyl, C 1-3 alkoxy, 4-6 membered heterocycloalkyl, -OC 3-4 cycloalkyl or 3-4 membered heterocycloalkylNH-, and the C 1-3 alkyl, C 1-3 alkoxy, 4-6 membered heterocycloalkyl, -OC 3-4 cycloalkyl or 3-4 membered heterocycloalkylNH- is optionally substituted with one or more of the following groups: halogen, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylNH- or (C 1-3 alkyl) 2 N-.
  • R e is independently selected from halogen, OH, C 1-3 alkyl, C 1-3 alkoxy, 4-6 membered heterocycloalkyl, -OC 3-4 cycloalkyl or 3-4 membered heterocycloalkylNH-, and the C 1-3 alkyl, C 1-3 alkoxy, 4-6 membered heterocycloalkyl, -OC 3-4 cycloalkyl or 3-4 membered heterocycloalkylNH- is optionally substituted with one or more of the following groups: F, OH, C 1-3 alkyl, C 1-3 alkylNH- or (C 1-3 alkyl) 2 N-.
  • R e is independently selected from F, OH, C 1-3 alkyl, C 1-3 alkoxy, 4-6 membered heterocycloalkyl, -OC 3-4 cycloalkyl, or 3-4 membered heterocycloalkylNH-, wherein the 4-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: OH, CH 3 , or (CH 3 ) 2 N-.
  • R e is independently selected from F, OH, C 1-3 alkyl, C 1-3 alkoxy, oxetanyl (e.g., 3-oxetanyl), cyclobutyl), pyrrolidinyl (e.g., 1-pyrrolidinyl), piperidinyl, piperazinyl (e.g., 1-piperazinyl), morpholinyl (e.g., 1-morpholinyl), -Ocyclopropyl or oxetanylNH- (e.g., 3-oxetanylNH-), the pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, are optionally substituted with one or more of the following groups: OH, CH 3 or (CH 3 ) 2 N-.
  • Re is independently selected from F, OH, -CH 3 , -OCH 3 , piperazinyl (e.g., 1-piperazinyl), morpholinyl (e.g., 1-morpholinyl), Or -Ocyclopropyl.
  • R 6 is each independently selected from halogen, OH, NH 2 , CN, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or -XR, and the C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl are optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , CHO, COOH, C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylNH-, or (C 1-10 alkyl) 2 N-.
  • R 6 is independently selected from halogen, OH, NH 2 , CN, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or -OC 3-10 cycloalkyl, wherein the C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocycloalkyl, C 6-10 aryl , 5-10 membered heteroaryl, or -OC 3-10 cycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , CHO, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, or (C
  • R 6 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or -OC 3-6 cycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl , C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or -OC 3-6 cycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , C 1-6 alkyl or C 1-6 alkoxy.
  • R 6 is independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl or -OC 3-6 cycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl or -OC 3-6 cycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , C 1-3 alkyl or C 1-3 alkoxy.
  • R 6 is independently selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, 6-membered heteroaryl or -OC 3-4 cycloalkyl, and the C 1-3 alkyl, C 1-3 alkoxy , C 3-4 cycloalkyl, 6-membered heteroaryl or -OC 3-4 cycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH or NH 2 .
  • R 6 is independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5-10 membered heteroaryl or -OC 3-10 cycloalkyl.
  • R 6 is independently selected from fluorine, chlorine, bromine, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl or -OC 3-6 cycloalkyl.
  • R 6 is independently selected from fluorine, chlorine, bromine, C 1-3 alkyl, fluorine-substituted C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, 6-membered heteroaryl or -OC 3-4 cycloalkyl.
  • R 6 is independently selected from F, Cl, OH, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , cyclopropyl, pyridyl (3-pyridyl, 2-pyridyl, 4-pyridyl), pyrimidinyl (5-pyrimidinyl),
  • R 6 is independently selected from F, -CH 3 , -CF 3 , -OCH 3 , Cl, OH, -OCF 3 , cyclopropyl, pyridyl (3-pyridyl, 2-pyridyl, 4-pyridyl), pyrimidinyl (5-pyrimidinyl),
  • R 6 is independently selected from F, -CH 3 , -CF 3 , -OCH 3 , cyclopropyl, pyridyl, pyrimidinyl or
  • q is selected from 0, 1, 2 or 3.
  • Ring B is phenyl
  • q is 1
  • R 6 is located at the para position of the phenyl group.
  • X is selected from NH, N(C 1-6 alkyl), O, or S. In some embodiments, X is selected from NH, N(C 1-3 alkyl), O, or S.
  • X is selected from NH, O, or S. In some embodiments, X is selected from O. In some embodiments, X is selected from NH.
  • R is selected from optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 aryl, or optionally substituted 5-6 membered heteroaryl.
  • R is selected from optionally substituted C 3-6 cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.
  • R is selected from C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein the C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , CHO, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH—, or (C 1-6 alkyl) 2 N—.
  • R is selected from C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, which is optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , CHO, COOH, or C 1-6 alkyl.
  • R is selected from C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, which is optionally substituted with one or more of the following groups: halogen, CN, OH, NH 2 , or C 1-3 alkyl.
  • R is selected from C 3-6 cycloalkyl. In some embodiments, R is selected from C 3-4 cycloalkyl. In some embodiments, R is selected from cyclopropyl.
  • m, n, and q are each independently selected from 0, 1, 2, or 3.
  • the double bonds attached to Ring A and Ring B, respectively are in the Z configuration or the E configuration.
  • heterocycloalkyl and heterocycloalkenyl each independently contain 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, heterocycloalkyl and heterocycloalkenyl each independently contain 1 or 2 heteroatoms independently selected from N and O.
  • the heteroaryl group contains 1, 2, or 3 heteroatoms independently selected from N, O, and S.
  • the heterocyclyl contains 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocyclyl contains 1 or 2 heteroatoms independently selected from N and O.
  • the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.
  • the C 1-10 is selected from C 1-9 , C 1-8 , C 1-7 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 .
  • C 1-6 is selected from C 1-4 , C 1-3 , or C 1-2 .
  • the C 1-4 is selected from C 4 , C 3 , C 2 , or C 1.
  • the C 1-3 is selected from C 3 , C 2 , or C 1 .
  • the C 2-10 is selected from C 2-8 , C 2-6 , C 2-5 , C 2-4 , C 2-3 .
  • the C 2-6 is selected from C 2-4 , or C 2-3 .
  • the C 2-4 is selected from C 4 , C 3 , or C 2 .
  • the C 3-6 is selected from C 3-5 , C 3-4 , C 4-6 , C 4-5 , or C 5-6 .
  • the C 6-10 is selected from C 6-9 , C 6-8 , C 6-7 , C 7-10 , C 7-9 , C 7-8 , C 8-10 , C 8-9 , or C 9-10 .
  • the C 3-10 is selected from C 3-9 , C 3-8 , C 3-7, C 3-6 , C 3-5 , C 3-4 , C 4-10 , C 4-9 , C 4-8 , C 4-7 , C 4-6 , C 4-5 , C 5-10 , C 5-9 , C 5-8 , C 5-7 , C 5-6 , C 6-10 , C 6-9 , C 6-8 , C 6-7 , C 7-12 , C 7-10 , C 7-9 , C 7-8 , C 8-12 , C 8-10 , C 8-9 , C 9-12 , or C 9-10 .
  • the C 3-15 is selected from C 3-12 or C 3-10 .
  • the C 3-12 is selected from C 3-10 .
  • the C 6-12 is selected from C 6-10 .
  • the 3-6 yuan is selected from 3-5 yuan, 3-4 yuan, 4-6 yuan, 4-5 yuan, or 5-6 yuan.
  • the 5-10 yuan is selected from 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, 9-10 yuan.
  • the 3-10 yuan is selected from 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 3-4 yuan, 4-10 yuan, 4-9 yuan, 4-8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, 9-10 yuan.
  • the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some embodiments, the 3-12 yuan is selected from 3-10 yuan. In some embodiments, the 5-12 yuan is selected from 5-10 yuan.
  • the "optionally substituted” means that the group is substituted by one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents, including but not limited to the following substituents: halogen, OH, -SH, NH 2 , CN, nitro, nitroso, azido, sulfoxide, sulfone, sulfonamide, carboxyl, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl (e.g., alkoxy, alkylNH- or (alkyl) 2 N-, etc.), halo-hetero
  • the “optionally substituted” means that the group is substituted by one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents, including but not limited to the following substituents: halogen, OH, —SH, NH 2 , CN, nitro, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, C 1-10 alkyl, halo-C 1-10 alkyl, C 3-10 cycloalkyl, halo-C 3-10 cycloalkyl, C 2-10 alkenyl, halo-C 2-10 alkenyl, C 3-10 cycloalkenyl, halo-C 3-10 cycloalkenyl, C 2-10 alkynyl, halo-C 2-10 alkynyl, C 3-10 cycloalkynyl, halo-C 3-10 cycloalkynyl, C 1-10
  • substituents
  • the "optionally substituted” means that the group is substituted by one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents, including but not limited to the following substituents: halogen, CN, OH, NH2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylNH- or ( C1-6 alkyl) 2N- , CHO, COOH, -CO2Ra , -NHC(O) Ra or -N( C1-6 alkyl)C(O) Ra , Ra is selected from H, C1-6 alkyl or C3-6 cycloalkyl.
  • substituents including but not limited to the following substituents: halogen, CN, OH, NH2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylNH- or ( C1-6 alkyl) 2N- , CHO, COOH, -CO2Ra , -NHC(O) Ra or -N( C1-6 alkyl)C(O
  • the term "optionally substituted” means that the group is replaced by one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents, including but not limited to the following substituents: halogen, CN, OH, NH2 , C1-4 alkyl, C1-4 alkoxy, C1-4 alkylNH- or ( C1-3 alkyl) 2N- , CHO, COOH, -CO2Ra , -NHC (O) Ra or -N( C1-3 alkyl)C(O) Ra , Ra is selected from H, C1-4 alkyl or C3-6 cycloalkyl.
  • substituents including but not limited to the following substituents: halogen, CN, OH, NH2 , C1-4 alkyl, C1-4 alkoxy, C1-4 alkylNH- or ( C1-3 alkyl) 2N- , CHO, COOH, -CO2Ra , -NHC (O) Ra or -N( C1-3 alkyl)C(O
  • the compound of formula I or a pharmaceutically acceptable salt thereof is selected from a compound of formula IA or IB or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , m, W, ring A, R 3 , n, R 4 , R 5 , ring B, R 6 and q are as defined in the present application.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is selected from a compound of formula II, II-A, II-B or III or a pharmaceutically acceptable salt thereof,
  • R c is selected from H, C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C(O ) H, -C(O)C 1-10 alkyl, S(O)H, -S(O)C 1-10 alkyl, -S(O) 2 H, -S(O) 2 C 1-10 alkyl, -C(O)OH or -C(O)OC 1-10 alkyl; or, R c is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C(O)H, -C(O)C 1-6 alkyl, S(O)H, -S(O)C 1-6 alkyl, -S(O) 2 H, -S(O) 2 C 1-6 alkyl, -C(O)OH or -C(O)OC 1-6 alkyl; or, R c is selected from H, C 1-10
  • R 2 , m, R 3 , n, R 4 , R 5 , Ring B, R 6 and q are as defined in the present application.
  • R 6a are each independently selected from halogen, OH, NH 2 , CN, or the following groups which are optionally substituted: C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, or -OC 3-10 cycloalkyl;
  • j and k are independently selected from 0, 1, 2, 3 or 4;
  • Ring C is selected from C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl;
  • R e' is independently selected from halogen, OH, CN, NH 2 , C 1-10 alkyl, -OC 1-10 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-10 cycloalkyl, 4-10 membered heterocycloalkylO-, -NHC 3-10 cycloalkyl, 3-10 membered heterocycloalkylNH-, -C(O)R a , -C(O)OR a , -OC(O)R a , -C(O)NHR a , -NHC(O)R a , -S(O)NHR a , -NHS(O)R a , -S(O) 2 NHR a or -NHS(O) wherein the C 1-10 alkyl, -OC 1-10 alkyl, C 3-10 cycl
  • R 6a is independently selected from halogen, OH, NH 2 , CN, or C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or -OC 3-8 cycloalkyl optionally substituted with one or more halogen, OH, NH 2 , CN.
  • R 6a is independently selected from halogen, OH, NH 2 , CN, or the following groups optionally substituted with one or more of halogen, OH, NH 2 , CN: C 1-3 alkyl, C 1-3 alkoxy, or -OC 3-4 cycloalkyl.
  • Ring C is selected from phenyl, 5-6 membered heteroaryl, or 4-6 membered heterocycloalkyl.
  • ring C is selected from phenyl or 5-6 membered heterocycloalkyl. In some embodiments, ring C is selected from phenyl or 5 membered heterocycloalkyl. In some embodiments, ring C is selected from phenyl or pyrrolidinyl. In some embodiments, ring C is selected from phenyl. In some embodiments, ring C is selected from pyrrolidinyl.
  • R e' is each independently selected from halogen, OH, CN, NH 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, 4-6 membered heterocycloalkylO—, -NHC 3-6 cycloalkyl, or 3-6 membered heterocycloalkylNH—, wherein the C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, 4-6 membered heterocycloalkylO—, C 3-6 cycloalkylNH—, or 3-6 membered heterocycloalkylNH— is optionally substituted with one or more
  • R e' is each independently selected from halogen, OH, CN, NH 2 , C 1-6 alkyl, -OC 1-6 alkyl, 4-6-membered heterocycloalkyl, -OC 3-6 cycloalkyl, or 3-6-membered heterocycloalkylNH-, and the C 1-6 alkyl, -OC 1-6 alkyl, 4-6-membered heterocycloalkyl, -OC 3-6 cycloalkyl, or 3-6-membered heterocycloalkylNH- are optionally substituted with one or more of the following groups: halogen, OH, CN, NH 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 1-6 alkylNH-, or (C 1-6 alkyl) 2 N-.
  • R e' is independently selected from halogen, OH, C 1-3 alkyl, -OC 1-3 alkyl, 4-6 membered heterocycloalkyl, -OC 3-4 cycloalkyl or 3-4 membered heterocycloalkylNH-, and the C 1-3 alkyl, -OC 1-3 alkyl, 4-6 membered heterocycloalkyl, -OC 3-4 cycloalkyl or 3-4 membered heterocycloalkylNH- is optionally substituted with one or more of the following groups: F, OH, C 1-3 alkyl, C 1-3 alkylNH- or (C 1-3 alkyl) 2 N-.
  • Re ' is defined as Re .
  • Ring B is phenyl
  • ring B is phenyl
  • X t is attached to ring B at the para position.
  • Ring B is phenyl
  • Xt is a bond
  • Ring C is attached to Ring B at the para position.
  • Ring C is phenyl and Re' is located at the para or meta position.
  • the present application is not the following compound:
  • the present application relates to the following compounds or pharmaceutically acceptable salts thereof,
  • the present application relates to a pharmaceutical composition, which contains the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present application also includes a pharmaceutically acceptable excipient.
  • the present application relates to the use of the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing or treating a disease associated with PRMT5.
  • the present application relates to a method for treating or preventing a disease associated with PRMT5 in a mammal, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
  • the present application relates to a method for treating or preventing a disease associated with PRMT5, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a mammal, preferably a human being, in need of such treatment.
  • the present application relates to the use of the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating diseases related to PRMT5.
  • the present application relates to the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating or preventing a disease associated with PRMT5.
  • the compounds of the present application provide therapeutic benefits for various cancers as MTA-synergistic PRMT5 inhibitors, which negatively regulate the activity of MTA-bound PRMT5 in cells, particularly MTAP-deficient cells, or are used to treat various forms of MTAP-related cancers (or tumors).
  • the above-mentioned PRMT5-related diseases are selected from disorders that can be treated by degrading or inhibiting PRMT5 protein; in some specific embodiments, the above-mentioned PRMT5-related diseases are selected from cancer (or tumor); in some more specific schemes, the above-mentioned PRMT5-related diseases are selected from colon cancer.
  • the present application comprises the above-defined variables and embodiments thereof, and any combination thereof.
  • the compounds of the present application have good in vitro protein binding activity and have binding effects on hPRMT5 & hMEP50 (with MTA).
  • the compounds of the present application have at least one of the following beneficial effects: MTA synergistic PRMT5 inhibition;
  • the invention discloses a novel novel anti-tumor compound having proliferation inhibitory activity on HCT116MTAP-/- cells, and having selective inhibitory activity on HCT116MTAP-/- cells compared with HCT116WT; having stable metabolism in vitro, for example, stable metabolism in liver microsomes; having good in vivo pharmacokinetic properties (for example, T 1/2 or AUC) and in vivo efficacy (for example, having good in vivo tumor inhibitory activity); and having high plasma protein binding rate.
  • the "one or more” is selected from one, two, three, four, five or six. In some embodiments, the “one or more” is selected from one, two, or three. In some embodiments, the “one or more” is selected from one, or two.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • an ethyl group is "optionally” substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 , etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.
  • C mn means that the moiety has an integer number of carbon atoms in a given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • any variable e.g., R
  • its definition at each occurrence is independent. For example, if a group contains 2 R's, each R has independent options.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to an -OH group.
  • amino refers to a -NH2 group.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 , typically containing 1-12, 1-10, 1-8, 1-6, 1-4 or 1-3 carbon atoms.
  • the alkyl group may be straight chain or branched.
  • C1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl portion i.e., alkyl
  • alkyl of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.
  • alkoxy refers to an -O-alkyl group.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically containing 2-12, 2-10, 2-8, 2-6, 2-4 or 2-3 carbon atoms.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically containing 2-12, 2-10, 2-8, 2-6, 2-4 or 2-3 carbon atoms.
  • alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH3), 2-propynyl (-CH2-C ⁇ CH), 1,3-butadiynyl (-C ⁇ C-C ⁇ CH), etc.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 20 rings or 3 to 10 rings (e.g., 4 to 10 rings, 4 to 8 rings, 5 to 7 rings, 5 to 6 rings).
  • Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.
  • cycloalkyl refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 20 rings or 3 to 10 rings (e.g., 5 to 8 rings, 3 to 8 rings, 3 to 6 rings).
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring.
  • the heterocycle is typically a 3 to 20-membered ring, 3 to 15-membered ring, 3 to 10-membered ring, 3 to 7-membered ring, 3 to 6-membered ring, 3 to 5-membered ring or 3 to 4-membered ring containing 1 to 6 (or 1 to 3) heteroatoms independently selected from boron, sulfur, oxygen and/or nitrogen (preferably 1, 2 or 3 heteroatoms, preferably heteroatoms selected from nitrogen, oxygen and sulfur).
  • 3-membered heterocycloalkyl examples include, but are not limited to, oxirane, thioethane, and cyclonitroethane.
  • 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxadiazolyl, and thiadinyl.
  • 5-membered heterocycloalkyl examples include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl.
  • 6-membered heterocycloalkyl examples include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl.
  • 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • the monocyclic heterocycloalkyl has 5 or 6 ring atoms.
  • heterocycloalkenyl includes cycloalkenyl groups in which one or more carbon atoms (e.g., up to 3 carbon atoms, or up to 2 carbon atoms, or 1 carbon atom) are each independently replaced by boron, oxygen, S(O) or nitrogen, provided that at least one cycloalkenyl carbon-carbon double bond is retained.
  • the cyclic group which may exist as a monocyclic, bridged or spirocyclic ring, may be a 3-20-membered ring, a 3-15-membered ring, a 3-13-membered ring (e.g., a 5-13-membered ring, a 5-8-membered ring, a 3-10-membered ring).
  • heterocyclic radical refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spirocyclic ring.
  • the heterocyclic ring is generally 3 to 20 yuan (or 3 to 17 yuan, or 3 to 13 yuan, or 3 to 12 yuan, or 3 to 10 yuan, or 3 to 7 yuan, or 5 to 15 yuan, or 5 to 10 yuan) ring containing 1 to 6 (or 1 to 3) heteroatoms (preferably 1, 2 or 3 heteroatoms, preferably heteroatoms selected from nitrogen, oxygen and sulfur) independently selected from boron, sulfur, oxygen and/or nitrogen.
  • 1 to 6 or 1 to 3 heteroatoms (preferably 1, 2 or 3 heteroatoms, preferably heteroatoms selected from nitrogen, oxygen and sulfur) independently selected from boron, sulfur, oxygen and/or nitrogen.
  • heterocyclic radicals include but are not limited to oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.
  • the heterocyclyl group can be, for example, heterocycloalkenyl, heterocycloalkyl, or benzoheterocycloalkenyl (not fully saturated heteroaromatic).
  • aryl refers to an aromatic ring group of an all-carbon monocyclic or fused polycyclic ring having a conjugated ⁇ electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl, etc.
  • heteroaryl refers to a monocyclic or fused polycyclic system containing at least one (e.g., 1, 2 or 3) ring atom selected from nitrogen, oxygen, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryls have a single 4 to 8 ring, especially 5 to 8 rings or 5 to 6 rings, or contain 6 to 14, especially 6 to 10 or 5 to 10 ring atoms of a plurality of fused rings.
  • heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • treatment means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, including preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • terapéuticaally effective amount means an amount of the compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein.
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the double bond position Indicates that the structure can be E configuration and/or Z configuration, for example express Or the two are mixed in any proportion, and the above configurations or mixtures thereof are all included in the scope of this application.
  • salts with organic bases for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also referred to as prototropic tautomers
  • proton migration such as keto-enol and imine-enamine isomerizations.
  • the specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens.
  • Valence tautomers include interconversions by the reorganization of some bonding electrons.
  • the present application also includes isotope-labeled compounds of the present application that are identical to those described herein, but one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature.
  • isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, etc.
  • Certain isotopically labeled compounds of the present invention can be used in compound and/or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present invention can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an isotopically unlabeled reagent.
  • substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, wherein the deuterium substitution may be partial or full, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be separated in optically pure form or racemic form. Optically pure forms can be separated from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present invention or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, Inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or sugar-coated core.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
  • the dosage administered is 0.01 to 200 mg/kg body weight per day in single or divided doses.
  • the compounds of the present application can be prepared by a variety of synthesis methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.
  • the compounds of the present application can be prepared by the following routes in combination with techniques known in the art:
  • R 2 , m, R 3 , n, R 4 , R 5 , Ring B, R c , R 6 and q are as defined in the present application.
  • Pd(dppf)Cl 2 represents (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride; DCM represents dichloromethane; TFA represents trifluoroacetic acid; Pd(OAc) 2 represents palladium acetate; SPhos represents 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; EA represents ethyl acetate; Boc represents tert-butyloxycarbonyl; DMAC represents dimethylacetamide; EtOH represents ethanol; DMF represents N,N-dimethylformamide; PE represents petroleum ether; Pd 2 (dba) 3 represents tris(dibenzylideneacetone) dipalladium; Tf represents trifluoromethanesulfonyl; THF represents tetrahydrofuran; HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Oxalyl chloride (1.42 g) was added dropwise to a DCM (10 mL) solution of 3,4-dimethoxyphenylacetic acid (2.00 g) and DMF (37 mg) at 25°C. After reacting at room temperature for 1 hour, the reaction system became clear. After reacting for another hour, the solvent was concentrated to remove the solvent. The concentrate was dissolved in 15 mL of acetonitrile, and then dropped into 15 mL of 0°C ammonia water. After reacting at 0°C for 0.5 hours, most of the acetonitrile was removed by concentration. 20 mL of sodium carbonate aqueous solution was added, stirred and filtered, and the filter cake was washed with 20 mL of water. The filter cake was dried to obtain compound 4-1.
  • Trifluoroacetic anhydride (1.72 g) was added dropwise to a solution of compound 4-1 (1.00 g) and triethylamine (1.04 g) in DCM (20 mL) at 0°C. After reacting at room temperature (25°C) for 6 h, the reaction solution was washed with brine, dried and concentrated to obtain compound 4-2.
  • compound 12-1 (79.0 mg), compound 1-2 (100.0 mg), potassium carbonate (69.1 mg), dioxane (4.0 mL) and water (1.0 mL), Pd(dppf) Cl2 (21.8 mg) were added to the reaction bottle, and the temperature was raised to 75-85°C for 3 hours. After the reaction was complete, ethyl acetate (100.0 mL) and water (50.0 mL) were added for extraction, and the organic layer was washed with saturated sodium chloride and evaporated to dryness under reduced pressure to obtain compound 12-2.
  • intermediate 15-2 was replaced with 17-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0- 90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 17.
  • MS (ESI) m/z [M+H] + : 427.18.
  • intermediate 15-2 was replaced with 18-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 18.
  • intermediate 15-2 was replaced with 19-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 19.
  • intermediate 15-2 was replaced with 20-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 20.
  • MS (ESI) m/z[M+H] + : 433.13.
  • intermediate 13-2 was replaced with 21-1 to obtain intermediate 21-2.
  • intermediate 13-3 was replaced with 21-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 21.
  • MS (ESI) m/z[M+H] + : 477.19.
  • intermediate 13-2 was replaced with 22-1 to obtain intermediate 22-2.
  • intermediate 13-3 was replaced with 22-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 22.
  • intermediate 15-2 was replaced with 24-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 24.
  • MS (ESI) m/z[M+H] + : 397.20.
  • intermediate 15-2 was replaced with 25-5, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 25.
  • MS (ESI) m/z[M+H] + : 491.20.
  • intermediate 15-2 was replaced with 26-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 26.
  • MS (ESI) m/z[M+H] + : 473.15.
  • intermediate 15-2 was replaced with 27-5, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 27.
  • MS (ESI) m/z[M+H] + : 489.22.
  • intermediate 15-2 was replaced with 30-5, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 30.
  • MS (ESI) m/z[M+H] + : 475.22.
  • intermediate 23-2 was replaced with 31-1, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 31.
  • MS (ESI) m/z[M+H] + : 476.35.
  • the intermediate B1 (32.0 g) was dissolved in N,N-dimethylformamide dimethyl acetal (112 mL), and potassium tert-butoxide (1459 mg) was added; the reaction was carried out at 105-110°C for 5 h.
  • intermediate 23-2 was replaced with 32-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 32.
  • MS (ESI) m/z[M+H] + : 495.25.
  • intermediate 15-2 was replaced with 33-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 33.
  • MS (ESI) m/z[M+H] + : 467.22.
  • intermediate 15-2 was replaced with 34-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 34.
  • MS (ESI) m/z[M+H] + :491.23.
  • intermediate 15-2 was replaced with 35-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 35.
  • MS (ESI) m/z[M+H] + : 487.14.
  • intermediate 15-2 was replaced with 36-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 36.
  • MS (ESI) m/z[M+H] + :471.18.
  • intermediate 15-2 was replaced with 37-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 37.
  • MS (ESI) m/z[M+H] + :501.22.
  • intermediate 15-2 was replaced with 38-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 38.
  • MS (ESI) m/z[M+H] + :495.08.
  • intermediate 15-2 was replaced with 39-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 39.
  • MS (ESI) m/z[M+H] + : 471.17.
  • intermediate 13-3 was replaced with 41-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 41.
  • MS (ESI) m/z[M+H] + :503.14.
  • intermediate 13-3 was replaced with 42-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 42.
  • MS (ESI) m/z[M+H] + :517.16.
  • intermediate 15-2 was replaced with 43-5, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 43.
  • MS (ESI) m/z[M+H] + :505.18.
  • intermediate 15-2 was replaced with 44-5, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 44.
  • MS (ESI) m/z[M+H] + :505.16.
  • intermediate 15-2 was replaced with 45-5, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 45.
  • MS (ESI) m/z[M+H] + : 488.19.
  • intermediate 15-2 was replaced with 46-5, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 46.
  • MS (ESI) m/z[M+H] + :517.22.
  • intermediate 15-2 was replaced with 47-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 47.
  • MS (ESI) m/z[M+H] + :503.17.
  • intermediate 48-2 (6.0 g), triethylamine (4.6 g) and dichloromethane (100 mL) were added to the reaction bottle, the temperature was lowered to 0-5°C, trifluoromethanesulfonic anhydride (10.2 g) was added, the reaction temperature was naturally raised to 20°C and the reaction was continued for 2 h. After the reaction was completed, water and dichloromethane were added to the reaction solution for extraction, the organic layer was separated and concentrated, and the concentrate was separated by column chromatography to obtain intermediate 48-3 (6.3 g).
  • intermediate 48-3 (0.3 g), 2-fluorophenylboronic acid (90.4 mg), Pd(PPh 3 ) 4 (75.0 mg), tetrahydrofuran (5.0 mL), water and K 2 CO 3 (0.3 g) were added to the reaction bottle, the temperature was raised to 60-65°C and the reaction was continued for 4 h. After the reaction was completed, water and ethyl acetate were added to the reaction solution for extraction, the organic layer was separated and concentrated, and the concentrate was separated by column chromatography to obtain intermediate 48-4 (102.3 mg).
  • intermediate 15-2 was replaced with 48-5, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 48.
  • MS (ESI) m/z[M+H] + :505.18.
  • intermediate 15-2 was replaced with 49-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 49.
  • MS (ESI) m/z[M+H] + :505.21.
  • intermediate 15-2 was replaced with 50-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 50.
  • MS (ESI) m/z [M+H] + : 505.21.
  • intermediate 15-2 was replaced with 51-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 51.
  • MS (ESI) m/z [M+H] + : 517.21.
  • intermediate 15-2 was replaced with 52-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 52.
  • MS (ESI) m/z [M+H] + : 517.21.
  • intermediate 15-2 was replaced with 53-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 53.
  • MS (ESI) m/z [M+H] + : 517.21.
  • intermediate 15-2 was replaced with 54-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 54.
  • MS (ESI) m/z [M+H] + : 547.20.
  • intermediate 15-2 was replaced with 55-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 55.
  • MS (ESI) m/z [M+2H] 2+ : 244.72.
  • intermediate 15-2 was replaced with 56-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 56.
  • MS (ESI) m/z[M+2H] 2+ :244.69.
  • intermediate 15-2 was replaced with 58-5, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 58.
  • MS (ESI) m/z[M+H] + :547.25.
  • intermediate 15-2 was replaced with 59-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0- 90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 59.
  • MS (ESI) m/z [M+H] + : 523.18.
  • intermediate 15-2 was replaced with 60-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 60.
  • MS (ESI) m/z[M+H] + :572.22.
  • intermediate 15-2 was replaced with 61-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 61.
  • MS (ESI) m/z[M+H] + :572.26.
  • intermediate 15-2 was replaced with 62-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 62.
  • MS (ESI) m/z[M+2H] 2+ :286.26.
  • intermediate 15-2 was replaced with 63-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 63.
  • MS (ESI) m/z[M+2H] 2+ :293.27.
  • intermediate 15-2 was replaced with 64-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 64.
  • MS (ESI) m/z[M+H] + :543.19.
  • intermediate 15-2 was replaced with 65-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 65.
  • MS (ESI) m/z[M+H] + :543.22.
  • intermediate 15-2 was replaced with 66-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 66.
  • MS (ESI) m/z[M+H] + :547.24.
  • intermediate 15-2 was replaced with 67-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 67.
  • MS (ESI) m/z[M+H] + : 489.13.
  • intermediate 15-2 was replaced with 68-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0- 90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 68.
  • MS (ESI) m/z [M+H] + : 506.23.
  • intermediate 15-2 was replaced with 69-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 69.
  • MS (ESI) m/z[M+H] + : 493.21.
  • intermediate 15-2 was replaced with 70-2, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 70.
  • MS (ESI) m/z[M+H] + :491.27.
  • intermediate 15-2 was replaced with 71-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 71.
  • MS (ESI) m/z[M+2H] 2+ :286.63.
  • intermediate 15-2 was replaced with 72-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 72.
  • MS (ESI) m/z [M+2H] 2+ : 286.66.
  • intermediate 15-2 was replaced with 73-4, and purified by preparative liquid phase (liquid phase conditions: chromatographic column: YMC AQ C18 30 ⁇ 250 mm, 10 ⁇ m; mobile phase: A: acetonitrile, B: 0.1% acetic acid-water; gradient: 20% B-30% B (0-90 min); flow rate: 60 mL/min; wavelength: 254 nm) to obtain compound 73.
  • MS (ESI) m/z[M+H] + :558.24.

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Abstract

L'invention concerne un composé contenant de la dihydrophtalazine et de l'alcényle. La présente invention concerne spécifiquement un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation, une composition pharmaceutique contenant le composé, et son utilisation dans le traitement d'une maladie associée à une tumeur.
PCT/CN2024/077697 2023-02-21 2024-02-20 Composé contenant de la dihydrophtalazine et de l'alcényle et son utilisation WO2024174980A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022192745A1 (fr) * 2021-03-11 2022-09-15 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 coopératif à base de mta
WO2022216648A1 (fr) * 2021-04-08 2022-10-13 Mirati Therapeutics, Inc. Polythérapies faisant appel à des inhibiteurs de prmt5 pour le traitement du cancer
CN115521293A (zh) * 2022-10-11 2022-12-27 燕山大学 一类酰肼类发光染料及其制备方法和应用
CN116854668A (zh) * 2023-07-11 2023-10-10 中国药科大学 酞嗪酮类化合物及其药物组合物和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022192745A1 (fr) * 2021-03-11 2022-09-15 Mirati Therapeutics, Inc. Inhibiteurs de prmt5 coopératif à base de mta
WO2022216648A1 (fr) * 2021-04-08 2022-10-13 Mirati Therapeutics, Inc. Polythérapies faisant appel à des inhibiteurs de prmt5 pour le traitement du cancer
CN115521293A (zh) * 2022-10-11 2022-12-27 燕山大学 一类酰肼类发光染料及其制备方法和应用
CN116854668A (zh) * 2023-07-11 2023-10-10 中国药科大学 酞嗪酮类化合物及其药物组合物和应用

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