WO2022174765A1 - 作为Wee-1抑制剂的稠环化合物 - Google Patents

作为Wee-1抑制剂的稠环化合物 Download PDF

Info

Publication number
WO2022174765A1
WO2022174765A1 PCT/CN2022/076366 CN2022076366W WO2022174765A1 WO 2022174765 A1 WO2022174765 A1 WO 2022174765A1 CN 2022076366 W CN2022076366 W CN 2022076366W WO 2022174765 A1 WO2022174765 A1 WO 2022174765A1
Authority
WO
WIPO (PCT)
Prior art keywords
membered
cycloalkyl
heterocycloalkyl
alkyl
haloalkyl
Prior art date
Application number
PCT/CN2022/076366
Other languages
English (en)
French (fr)
Inventor
谢雨礼
吴应鸣
樊后兴
钱立晖
Original Assignee
微境生物医药科技(上海)有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 微境生物医药科技(上海)有限公司 filed Critical 微境生物医药科技(上海)有限公司
Priority to CN202280014506.0A priority Critical patent/CN116888107A/zh
Publication of WO2022174765A1 publication Critical patent/WO2022174765A1/zh

Links

Classifications

    • 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
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicinal chemistry, and more particularly, to a fused-ring compound with Wee1 kinase inhibitory effect, a preparation method thereof, and use of the compound in the preparation of antitumor drugs.
  • Wee-1 protein kinase is an important negative regulator of cell cycle checkpoints.
  • Cell cycle checkpoints include the G1 phase checkpoint for the transition from G1 (cell quiescence) to S phase (DNA synthesis phase), the G2 phase checkpoint for the transition from G2 (preparation for cell division) to M (cell division), and the M Spindle checkpoint for the transition from metaphase (mid-phase) to anaphase (anaphase).
  • Wee-1 protein kinase plays an important role in the G2 phase checkpoint.
  • the entry of cells into M phase depends on the kinase activity of CDK1.
  • Wee-1 inhibits the activity of CDK1 by phosphorylating Tyr 15 of CDK1 protein, preventing cells from entering M phase (cell division phase).
  • Polo kinase kinase phosphorylates Wee-1, activates the degradation of Wee-1 protein, and promotes cell entry into M phase. It can be seen that the Wee-1 kinase activity determines the activity of the G2 checkpoint, which in turn regulates the transition of cells from G2 to M phase [Cell Cycle, 2013.12(19):p.3159-64.].
  • Cell cycle checkpoints are mainly activated after DNA damage and play an important role in DNA repair in cells. Normal activation of cell cycle checkpoints arrests the cell cycle and promotes DNA repair. Inhibit the function of checkpoints, DNA damage cannot be repaired, and cells undergo apoptosis. Compared with normal cells, various tumor cells mainly rely on the activation of the G2 checkpoint to repair DNA damage and avoid apoptosis due to the impaired function of p53, an important protein of the G1 phase checkpoint. Therefore, inhibiting the G2 phase checkpoint can selectively kill tumor cells.
  • Wee-1 kinase determines the repair or death of tumor cells after DNA damage, and inhibition of Wee-1 activity can promote unrepaired tumor cells after DNA damage to enter M stage, induce apoptosis [Curr Clin Pharmacol, 2010.5(3):p.186-91.].
  • Wee-1 kinase may be involved in tumor occurrence and development.
  • Studies in in vitro cell models and in vivo animal models have shown that inhibiting Wee-1 activity while inducing DNA damage can significantly inhibit the growth of various tumors [Cancer Biol Ther, 2010.9(7):p.514-22.; Mol Cancer Ther, 2009.8(11):p.2992-3000.].
  • the present invention provides a compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • X is CH or N
  • Y is -H, halogen, -CN, -S(O) 2 R 6 , -P(O)(R 7 ) 2 , -C(O)NR 8 R 9 , (C1-C6) alkyl, (C1 -C6) haloalkyl, (C2-C6) alkynyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl group, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11) membered) heterocycloalkyl or (5-11 membered) heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, halogen, R8 , -
  • Z is a chemical bond, -CH 2 -, -O- or -NH-;
  • Ring A is (C6-C14) aryl, (5-14 membered) heteroaryl or (3-14 membered) heterocycloalkyl;
  • R 4a and R 5a are each independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl, wherein the (C1-C6) Alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, - D, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 and -S(O) 2 NR 8 R 9 ; or R 4a and R
  • R 4b and R 5b are each independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl, wherein the (C1-C6) Alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, - D, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 and -S(O) 2 NR 8 R 9 ; or R 4b and R
  • R 4c and R 5c are each independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl, wherein the (C1) -C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl can each independently be optionally substituted with 1, 2, 3 or 4 of the following groups:- H, -D, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O ) NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 and -S(O) 2 NR 8 R 9
  • R 4d is -H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl, wherein said (C1-C6) alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -D, halogen , R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR9C (O) R8 , -NR9S (O) 2R8 , -S (O) pR8 and -S
  • R 4e and R 5e are each independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl, wherein the (C1) -C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl can each independently be optionally substituted with 1, 2, 3 or 4 of the following groups:- H, -D, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O ) NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 and -S(O) 2 NR 8 R 9
  • R 4f and R 5f are each independently -H, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups : -H, -D, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C (O) NR8R9 , -NR9C (O) R8 , -NR9S ( O ) 2R8 , -S(O)pR8 and -S ( O ) 2NR8
  • R 4g is (C1-C3) alkyl or (C3-C6) cycloalkyl, wherein the (C1-C3) alkyl or (C3-C6) cycloalkyl can each independently optionally be replaced by 1, 2, 3 or 4 of the following groups: -H, -D, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C (O) NR8R9 , -NR9C (O) R8 , -NR9S (O) 2R8 , -S(O)pR8 and -S (O) 2NR8R9 ; _
  • Each R3 is independently -H, -D , halogen, R8 , -OH , - ( CH2 ) nOR8 , - ( CH2 ) nNR8R9 , -OR8 , -NR8R9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 , -S(O) 2 NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) ) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl
  • Ring B is (C5-C11) partially unsaturated cycloalkyl or (5-11 membered) partially unsaturated heterocycloalkyl;
  • X 2 is a chemical bond
  • X 3 is CH, N or CR c ;
  • X 4 is CH, N or CR d ;
  • X 5 is NR a or CH-R b ;
  • Each R2 is independently -H, -D , halogen, R8 , -OH , - ( CH2 ) nOR8 , - ( CH2 ) nNR8R9 , -OR8 , -NR8R9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 and -S(O) 2 NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) ) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl,
  • R a is -H, R 8 , -(CH 2 ) m OR 8 , -(CH 2 ) m NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) Cycloalkyl or (3-15 membered) heterocycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl or (3-15 membered) heteroalkyl Cycloalkyl can be optionally substituted with 1 , 2, 3 or 4 of the following groups: -H, -D, halogen, R8 , -OH, -( CH2 ) nOR8 , -( CH2 ) nNR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 ,
  • R b is -H, R 8 , -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) Cycloalkyl or (3-15 membered) heterocycloalkyl, wherein said R 8 , R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl or ( 3-15 membered) heterocycloalkyl can be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -D, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , - (CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O
  • R c and R d are each independently -H, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 , -S(O) 2 NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) Aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl, (C
  • R e is -H, -D, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11 membered)heterocycloalkyl or (5-11 membered)heteroaryl may each independently be optionally replaced by 1, 2,
  • R f1 , R f2 , R g1 and R g2 are each independently -H, -D, R 8 , -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -CN, (C1- C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11) membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkyne group, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11 membered)heterocycloalkyl or (5-11 membered)hetero
  • R 6 is (C1-C3) alkyl or (C3-C6) cycloalkyl
  • R 7 is (C1-C3) alkyl
  • R 8 and R 9 are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 8 and R 9 on the same nitrogen atom and the N atom to which they are attached can be jointly Composition (3-11 membered) heterocycloalkyl, wherein the (3-11 membered) heterocycloalkyl may be optionally substituted with 1 , 2, 3 or 4 of the following groups: -H, halogen, R10 and -OR 10 ;
  • R 10 is -H, (C1-C6) alkyl or (C3-C14) cycloalkyl;
  • R 11 and R 12 are each independently -H, (C1-C3) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl, or R 11 and R 12 on the same nitrogen atom and The N atoms to which they are attached can together form a (4-6 membered) heterocycloalkyl; and
  • p is an integer of 0, 1 or 2
  • q is an integer of 1, 2, 3 or 4
  • s is an integer of 1, 2, 3 or 4
  • n is an integer of 0, 1, 2 or 3
  • m is 1, An integer of 2 or 3.
  • Z is -NH- or a chemical bond.
  • Y is -H, -F, -Cl, -Br, -I, -CN, -S(O) 2 CH 3 , -P(O )( CH3 ) 2 , -C(O) NH2 , (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl, (C2-C3)alkynyl or (5) -6-membered) heteroaryl; wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C5) cycloalkyl, (C2-C3) alkynyl or (5-6 membered)
  • the heteroaryl groups can each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -CN, -CH3 and -OCH3 .
  • Y is -H, -F, -Cl, -Br, -I, -CN, -S(O) 2 CH 3 , -P(O )(CH 3 ) 2 , -C(O)NH 2 , -CH 3 , -CF 3 , Y is preferably -Br, -CN, -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , -C(O)NH 2 , -CF 3 , Y is more preferably -CN.
  • ring A is a (C6-C10) aryl group, a (5-10-membered) heteroaryl group or a (5-10-membered) heterocycloalkyl group.
  • Ring A is Ring A is preferably Ring A is more preferably Ring A is more preferably
  • R 4a and R 5a are each independently (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl, wherein (C1 -C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups:- H, -D, -F, -Cl, -Br, -I, -CH3 , -OH, -CH2OCH3 , -CH2N ( CH3 ) 2 , -OCH3 , -N( CH3 ) 2 and -CN; or the S atoms to which R 4a and R 5a are attached can together form a (4-6 membered) heterocycloalkyl,
  • R 1 when R 1 is , the structural unit for: preferably preferably more preferably
  • R 1 when R 1 is , wherein R 4b and R 5b are each independently (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl, wherein the (C1 -C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups:- H, -D, -F, -Cl, -Br, -I, -CH3 , -OH, -CH2OCH3 , -CH2N ( CH3 ) 2 , -OCH3 , -N( CH3 ) 2 and -CN; or the P atom to which R 4b and R 5b are attached can together form a (4-6 membered) heterocycloalkyl,
  • R 1 when R 1 is , the structural unit for: preferably more preferably
  • R 1 when R 1 is , wherein R 4c and R 5c are each independently -H, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl, wherein
  • the (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl groups may each independently be optionally replaced by 1, 2, 3 or 4 of the following groups Substitution: -H, -D, -F, -Cl, -Br, -I, -CH3 , -OH, -CH2OCH3 , -CH2N ( CH3 )2 , -OCH3 , -N( CH 3 ) 2 and -CN; or the carbon atoms to which R 4c and R 5c are attached can collectively form a (3-6 membered
  • R 1 is , the structural unit for: preferably
  • R 1 when R 1 is where R 4d is -H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl or (C3-C5)cycloalkyl, wherein the (C1-C3) Alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl or (C3-C5)cycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, - D, -F, -Cl, -Br, -I, -CH3 , -OH, -CH2OCH3 , -CH2N ( CH3 ) 2 , -OCH3 , -N( CH3 )2 and - CN; and R 5d is (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-
  • R 1 is , the structural unit for: preferably
  • R 1 when R 1 is , wherein R 4e and R 5e are each independently -H, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl, wherein all The (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl groups may each independently be optionally replaced by 1, 2, 3 or 4 of the following groups Substitution: -H, -D, -F, -Cl, -Br, -I, -CH3 , -OH, -CH2OCH3 , -CH2N ( CH3 )2 , -OCH3 , -N( CH 3 ) 2 and -CN; or R 4e and R 5e and the N atom to which they are attached can together form a (4-6 membere
  • R 1 is , the structural unit for: preferably
  • R 1 when R 1 is where R 4f and R 5f are each independently -H, halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl or (C3-C5)cycloalkyl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl may each independently be optionally replaced by 1, 2, 3 or 4 of the following Group substitution: -H, -D, -F, -Cl, -Br, -I, -CH3 , -OH, -CH2OCH3 , -CH2N ( CH3 )2 , -OCH3 , - N(CH 3 ) 2 and -CN; or R 4f and R 5f and the carbon atoms to which they are attached can together form a (3-6 membered)
  • R 1 is , the structural unit for:
  • R 1 when R 1 is , wherein R 4g is (C1-C3) alkyl or (C3-C5) cycloalkyl, wherein the (C1-C3) alkyl or (C3-C5) cycloalkyl can be independently optionally 1, 2, 3 or 4 of the following groups are substituted: -H, -F, -Cl, -Br, -I, -CH3 , -OH, -CH2OCH3 , -CH2N ( CH3 )2 , - OCH3 , -N( CH3 ) 2 and -CN.
  • R 1 is , the structural unit for: preferably
  • each R 3 is independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OR 11 , -NR 11 R 12 , -CN, -C(O)NR 11 R 12 , -NR 12 C(O)R 11 , -NR 12 S(O) 2 R 11 , -SR 11 , -S(O) 2 R 11 , -S(O) 2 NR 11 R 12 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl , (C2-C4) alkynyl, (C3-C6) cycloalkyl, phenyl, (4-8 membered) heterocycloalkyl or (5-6 membered) heteroaryl, wherein the (C1-C3) Alkyl, (C1
  • each R 3 is independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -N(CH 3 ) 2 , -CN, -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)N( CH3 ) 2 , -NHC(O) CH3 , -N( CH3 )-C(O) CH3 , -NHS(O) 2CH3 , -NCH3S ( O) 2CH3 , -SCH3 , -S(O) 2CH3 and -S(O ) 2NH2 , -S(O)2NH( CH3 ) , -S(O ) 2N ( CH3 ) 2 , R 3 is preferably
  • the structural unit for: preferably
  • ring B is (C5-C8) partially unsaturated cycloalkyl or (5-8 membered) partially unsaturated heterocycloalkyl; and R e is : -H, -D, -CH 3 , -OCH 3 or -CH 2 CH 3 .
  • X 1 is: preferably more preferably more preferably
  • X 2 is: a chemical bond, preferably chemical bonds, More preferably a chemical bond, More preferably a chemical bond or
  • X 5 is NR a
  • R a is -H, -(CH 2 ) 2 OR 11 , -(CH 2 ) 2 NR 11 R 12 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 membered) heterocycloalkyl, wherein the (C1-C3) alkyl, ( C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 membered) heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -D, - F, -OH, -CH 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF3 ,
  • R b is -H, -(CH 2 ) 2 OR 11 , -NR 11 R 12 , - (CH 2 ) 2 NR 11 R 12 , (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C6)cycloalkyl, or (4-7 membered)heterocycloalkyl, wherein R 11 , R 12 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 membered) heterocycloalkyl may be optionally replaced by 1, 2, 3 or 4 of the following groups are substituted: -H, -D, -F, -OH, -CH3 , -CH2OCH3 , - ( CH2 ) 2OCH3 , -OCH3 , -OCH2CH3 ,
  • X 5 is CH-R b
  • R b is: -H, -N(CH 3 ) 2 , -N(CD 3 ) 2 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 OH, -(CH 2 ) 2 N(CH 3 ) 2
  • X 3 is: CH, N or CR c , wherein the R c is: -H, -F, -Cl, -Br, -I, -OH, -CH 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -CH 2 N(CH 3 ) 2 , -(CH 2 ) 2 N(CH 3 ) 2 , -N(CH 3 ) 2 or -CN; preferably -H, -F, -Cl, -CH 3 , -OCH 3 , -OCF 3 , -N(CH 3 ) 2 or -CN; more preferably -H, -F, -CH 3 , or -OCH 3 .
  • X 4 is: CH, N or CR d , wherein the R d is: -H, -F, -Cl, -Br, -I, -OH, -CH 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -CH 2 N(CH 3 ) 2 , -(CH 2 ) 2 N(CH 3 ) 2 , -N(CH 3 ) 2 or -CN; preferably -H, -F, -Cl, -CH 3 , -OCH 3 , -OCF 3 , -N(CH 3 ) 2 or -CN; more preferably -H, -F, -CH 3 , or -OCH 3 .
  • each R 2 is independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OR 11 , -NR 11 R 12 , -CN, -C(O)NR 11 R 12 , -NR 12 C(O)R 11 , -NR 12 S(O) 2 R 11 , -SR 11 , -S(O) 2 R 11 , -S(O) 2 NR 11 R 12 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl , (C2-C4) alkynyl, (C3-C6) cycloalkyl, phenyl, (4-8 membered) heterocycloalkyl or (5-6 membered) heteroaryl, wherein the (C1-C3) Alkyl, (C1-C3) Alkyl, (C1-C
  • each R 2 is independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -NH 2 , -N(CH 3 ) 2 , -CN, -C(O)NH 2 , -C(O)NH ( CH 3 ), -C(O)N(CH 3 ) 2 , -NHC(O)CH 3 , -N(CH 3 )-C(O)CH 3 , -NHS(O) 2 CH 3 , -NCH 3 S(O) 2 CH 3 , -SCH 3 , -S(O) 2 CH 3 and -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N( CH 3 ) 2 , Preferred
  • the present invention provides the compound of general formula (2) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • A, B, Y, Z, R 1 , R 2 , R 3 , Re , X 1 , X 2 , X 3 , X 4 , X 5 , q, and s are as described above, and the specific implementation Examples are illustrated.
  • the present invention provides a compound of general formula (3a) or general formula (3b) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof Compound:
  • A, B, Y, R 1 , R 2 , R 3 , Re , X 1 , X 2 , X 3 , X 4 , X 5 , q and s are as described above, and in specific embodiments for example.
  • the present invention provides a compound of general formula (4a), general formula (4b) or general formula (4c) or each isomer, each crystal form, pharmaceutically acceptable Salt, Hydrate or Solvate:
  • B, Y, Z, R 1 , R 2 , R 3 , Re , X 1 , X 2 , X 3 , X 4 , X 5 , q, and s are as described above, and in specific embodiments for example.
  • the present invention provides a compound of general formula (5a), general formula (5b) or general formula (5c) or each isomer, each crystal form, pharmaceutically acceptable Salt, Hydrate or Solvate:
  • A, Y, Z, R 1 , R 2 , R 3 , Re , X 1 , X 2 , X 3 , X 4 , X 5 , q and s are as described above, and in specific embodiments for example.
  • the present invention provides the compound of general formula (6a), general formula (6b) or general formula (6c) or each isomer, each crystal form, pharmaceutically acceptable Salt, Hydrate or Solvate:
  • A, Y, Z, R 1 , R 2 , R 3 , Re , X 2 , X 5 , q, and s are as described above and illustrated in specific embodiments.
  • the present invention provides a formula as represented by general formula (7a), general formula (7b), general formula (7c), general formula (7d), general formula (7e) or general formula (7f).
  • Y, Z, R 1 , R 2 , R 3 , Re , X 2 , X 5 , q, and s are as described above, and are illustrated in specific examples.
  • representative compounds of the present invention have one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) of the present invention, or each of its isomers, Each crystal form, pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
  • Another object of the present invention provides the compound represented by the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition of the present invention Use in the preparation of medicines for treating, regulating or preventing diseases related to Wee-1 protein.
  • Still another object of the present invention also provides a method for treating, regulating or preventing related diseases mediated by Wee-1 protein, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, Or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above pharmaceutical composition.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques combined with methods incorporated herein.
  • the solvents, temperatures and other reaction conditions mentioned herein may vary.
  • Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources.
  • the compounds described herein and other related compounds with various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.
  • the compounds described herein are according to methods well known in the art. However, the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following general reaction scheme 1, 2, 3 or 4:
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , R 3 , Re , X 1 , X 2 , X 3 , X 4 , X 5 , X, Y, Z , s, q, ring A and ring B are as defined above, H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, and O represents oxygen.
  • R 1 , R 2 , R 3 , Re , X 1 , X 2 , X 3 , X 4 , X 5 , X, Y, Z , s, q, ring A and ring B are as defined above
  • H represents hydrogen
  • N represents nitrogen
  • Cl represents chlorine
  • S sulfur
  • O oxygen.
  • compounds 1-1 and 1-2 undergo a substitution reaction under basic conditions to form compound 1-3
  • compound 1-3 reacts with m-CPBA to form compound 1-4
  • compound 1-4 and 1-5 undergoes a substitution
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 2, wherein R 1 , R 2 , R 3 , Re , X 1 , X 2 , X 3 , X 4 , X 5 , X, Y, s , q, Ring A and Ring B are as defined above, H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, and O represents oxygen.
  • R 1 , R 2 , R 3 , Re , X 1 , X 2 , X 3 , X 4 , X 5 , X, Y, s , q, Ring A and Ring B are as defined above
  • H represents hydrogen
  • N represents nitrogen
  • Cl represents chlorine
  • S sulfur
  • O oxygen
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 3, wherein R 1 , R 2 , R 3 , Re , X 1 , X 2 , X 3 , X 4 , X 5 , X, Y, Z , s, q, A and B rings are as defined above, H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, O represents oxygen, B represents boronic acid, boronate or trifluoroborate, L 1 represents bromine or iodine.
  • compounds 3-1 and 3-2 undergo a substitution reaction under basic conditions to form compound 3-3
  • compound 3-3 and YB undergo a coupling reaction to form the target compound 3-4
  • compound 3- 4 reacts with m-CPBA to generate compound 3-5
  • compounds 3-5 and 3-6 undergo substitution reaction to generate target compound 3-7.
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 4, wherein R 1 , R 2 , R 3 , Re , X 1 , X 2 , X 3 , X 4 , X 5 , X, Y, s , q, Rings A and B are as defined above, H represents hydrogen , N represents nitrogen, Cl represents chlorine, S represents sulfur, O represents oxygen, and L2 represents bromine or chlorine.
  • compounds 4-1 and 4-2 undergo a substitution reaction under basic conditions to form compound 4-3
  • compound 4-3 reacts with m-CPBA to form compound 4-4
  • compound 4-4 and 4-5 undergoes a substitution reaction to generate the target compound 4-6.
  • “Pharmaceutically acceptable” as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.
  • pharmaceutically acceptable salt refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound of general formula (1) with an acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, etc.
  • propionic acid oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent.
  • the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms.
  • the compound of the general formula (1) includes a crystalline form and can also be a polymorph.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • compounds of general formula (1) may exist in chiral centers and/or axial chirality and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds Enantiomeric forms, and cis-trans isomers occur.
  • Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 ) CH , iPr , nPr , iBu , nBu or tBu .
  • alkylene refers to a divalent alkyl group as defined above.
  • alkylene groups include, but are not limited to, methylene and ethylene.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methpropenyl.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, are preferred.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), and if the carbocyclic ring contains at least one double bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl” alkenyl", or if the carbocycle contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”.
  • Cycloalkyl groups may include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic.
  • the cycloalkyl group is monocyclic or bicyclic.
  • the ring-forming carbon atoms of the cycloalkyl group can optionally be oxidized to form oxo or thiol groups.
  • Cycloalkyl also includes cycloalkylene.
  • the cycloalkyl group contains 0, 1 or 2 double bonds.
  • cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups).
  • cycloalkyl groups can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused to aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexane and the like.
  • alkoxy refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH3 , OCF3, CHF2O , CF3CH2O , i - PrO, n- PrO , i- BuO, n- BuO or t- BuO.
  • aryl refers to a hydrocarbon aromatic group that is monocyclic or polycyclic, eg, a monocyclic aryl ring fused with one or more carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N), which is monocyclic or polycyclic.
  • a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene pyridyl, pyrrolopyrimidinyl, 1H-pyrro[3,2-b]pyridyl, 1H-pyrro[2,3-c]pyridyl, 1H-pyrro[3,2-c]pyridyl, 1H- Pyrro[2,3-b]pyridyl,
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one independently selected from boron, phosphorus , nitrogen, sulfur, oxygen and phosphorus heteroatom ring members.
  • a partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl” if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond May be referred to as "heterocycloalkynyl".
  • Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (eg, having two fused or bridged rings) ring systems.
  • a heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • the ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (eg C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized.
  • a heterocycloalkyl group can be attached via a ring carbon atom or a ring heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds.
  • the heterocycloalkyl group contains 0 to 2 double bonds.
  • moieties having one or more aromatic rings fused to (ie, sharing a bond with) the heterocycloalkyl ring such as piperidine, morpholine, azacyclotriene or Benzo derivatives of thienyl and the like.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom, including a ring-forming atom of a fused aromatic ring.
  • heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyri
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen-substituted appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.
  • Substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • membered ring includes any cyclic structure.
  • membered is meant to denote the number of backbone atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific portion or functional group of a molecule.
  • a chemical moiety is generally considered to be a chemical entity contained in or attached to a molecule.
  • acceptable refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
  • treatment include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom.
  • a compound or pharmaceutical composition when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, the conditions attributable to or associated with the administration.
  • Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers.
  • the number of asymmetric centers that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides that the use of the compounds or pharmaceutical compositions of general formula (1) of the present invention can generally be used to inhibit Wee1 kinase, and thus can be used to treat one or more disorders associated with Wee1 kinase activity. Accordingly, in certain embodiments, the present invention provides methods for the treatment of Wee1 kinase-mediated disorders comprising the step of administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof .
  • methods for cancer treatment comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of general structural formula (1).
  • compounds of general formula (1) may be used in combination with other cancer therapeutics.
  • compounds of general formula (1) may be used in combination with gemcitabine.
  • the cancer is mediated by Weel kinase.
  • the cancer is a hematological cancer and solid tumor, including, but not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myelodysplastic syndrome) and Solid tumors (cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue cancers and osteosarcomas, and stromal tumors) and the like.
  • hematological malignancies leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myelodysplastic syndrome
  • Solid tumors cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue cancers and osteosarcomas, and stromal tumors
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective dose of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gelling substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity .
  • “Compatibility” as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • pharmacologically acceptable excipients or carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • (Boc) 2 O stands for di-tert-butyl dicarbonate; CDCl 3 stands for deuterated chloroform; EtOAc stands for ethyl acetate; Hexane stands for n-hexane; HPLC stands for high performance liquid chromatography; MeCN stands for acetonitrile ; DCM for dichloromethane; DIPEA for diisopropylethylamine; Dioxane for 1,4-dioxane; DMF for N,N-dimethylformamide; DMAP for 4-(dimethylamino)pyridine ; DMSO for dimethyl sulfoxide; hr for hours; IPA for isopropanol; min for minutes ; K2CO3 for potassium carbonate; KOAc for potassium acetate ; K3PO4 for potassium phosphate ; min for minutes; MeOH for methanol ; MS represents mass spectrum; MsOH represents methanes
  • Int_1-9-2 (50 g, 264 mmol) was dissolved in THF (500 mL), and n-BuLi (2.5 M, 275 mL) was slowly added dropwise at -23°C under nitrogen protection. DMF (48.3 g, 660 mmol, 50.8 mL) was then slowly added dropwise at -23°C. Then HCl solution (6M, 300 mL) was slowly added dropwise at 20°C. The reaction solution was diluted with 100 mL of water, extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to give a yellow solid (55 g, crude product). The crude product can be used directly in the next reaction.
  • int_1-9-4 (3.1 g, 19.2 mmol) was dissolved in H 2 SO 4 (300 mL), at 0° C., KNO 3 (17.9 g, 177 mmol) was slowly added within 3 hours, and the temperature was raised to room temperature and stirred for 2 hours . TLC detection showed that the reaction was complete.
  • the reaction solution was diluted with 500 mL of water, and a large amount of solid was precipitated, which was filtered to obtain a precipitate, which was dried to obtain a yellow solid (79 g, crude product). The crude product can be used directly in the next reaction.
  • Int_1-7 (334 mg, 1.0 mmol) was dissolved in dichloromethane (40 mL), m-CPBA (85%, 240 mg, 1.2 mmol) was added at room temperature, and the mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (335 mg, crude product). The crude product can be used directly in the next reaction.
  • Int_1-8 (335 mg, 0.95 mmol) was dissolved in DMF (20 mL), int_1-9 (242 mg, 1.2 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added, and the reaction solution was heated to 80° C. and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to give a white solid (160 mg, yield: 34%).
  • HPLC preparation method is as follows:
  • Int_1-9-2 (50 g, 264 mmol) was dissolved in THF (500 mL), and n-BuLi (2.5 M, 275 mL) was slowly added dropwise at -23°C under nitrogen protection. DMF (48.3 g, 660 mmol, 50.8 mL) was then slowly added dropwise at -23°C. Then HCl solution (6M, 300 mL) was slowly added dropwise at 20°C. The reaction solution was diluted with 100 mL of water, extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to give a yellow solid (55 g, crude product). The crude product can be used directly in the next reaction.
  • int_1-9-4 (3.1 g, 19.2 mmol) was dissolved in H 2 SO 4 (300 mL), at 0° C., KNO 3 (17.9 g, 177 mmol) was slowly added within 3 hours, and the temperature was raised to room temperature and stirred for 2 hours . TLC detection showed that the reaction was complete.
  • the reaction solution was diluted with 500 mL of water, and a large amount of solid was precipitated, which was filtered to obtain a precipitate, which was dried to obtain a yellow solid (79 g, crude product). The crude product can be used directly in the next reaction.
  • Step 7 Synthesis of compounds int_1-9A and int_1-9B:
  • the int_1-9 (1.5g, 7.41mmol) was subjected to chiral resolution by preparative supercritical fluid chromatography (prep SFC) (SFC chiral resolution conditions: instrument: Waters SFC350; chromatographic column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); mobile phase: A: CO 2 , B: IPA (0.1% NH 3 H 2 O); gradient: B%: 50%-50%; flow rate: 200 mL/min; The segment liquid was concentrated under reduced pressure and lyophilized to obtain yellow oil int_1-9A (peak 1,438 mg, yield: 29.20%) and yellow oil int_1-9B (peak 2,450 mg, yield: 30.00%).
  • prep SFC SFC chiral resolution conditions: instrument: Waters SFC350; chromatographic column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); mobile phase: A: CO 2 , B: IPA (0.1% NH 3 H 2 O); gradient: B%
  • Int_1-7 (334 mg, 1.0 mmol) was dissolved in dichloromethane (40 mL), m-CPBA (85%, 240 mg, 1.2 mmol) was added at room temperature, and the mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (335 mg, crude product). The crude product can be used directly in the next reaction.
  • Int_1-8 (100 mg, 0.28 mmol) was dissolved in DMF (5 mL), int_1-9A (57 mg, 0.28 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added, and the reaction solution was heated to 80° C. and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase column to give a white solid (70 mg, yield: 50%).
  • HPLC preparation method is as follows:
  • Int_1-9-2 (50 g, 264 mmol) was dissolved in THF (500 mL), and n-BuLi (2.5 M, 275 mL) was slowly added dropwise at -23°C under nitrogen protection. DMF (48.3 g, 660 mmol, 50.8 mL) was then slowly added dropwise at -23°C. Then HCl solution (6M, 300 mL) was slowly added dropwise at 20°C. The reaction solution was diluted with 100 mL of water, extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to give a yellow solid (55 g, crude product). The crude product can be used directly in the next reaction.
  • int_1-9-4 (3.1 g, 19.2 mmol) was dissolved in H 2 SO 4 (300 mL), at 0° C., KNO 3 (17.9 g, 177 mmol) was slowly added within 3 hours, and the temperature was raised to room temperature and stirred for 2 hours . TLC detection showed that the reaction was complete.
  • the reaction solution was diluted with 500 mL of water, and a large amount of solid was precipitated, which was filtered to obtain a precipitate, which was dried to obtain a yellow solid (79 g, crude product). The crude product can be used directly in the next reaction.
  • Step 7 Synthesis of compounds int_1-9A and int_1-9B:
  • the int_1-9 (1.5g, 7.41mmol) was subjected to chiral resolution by preparative supercritical fluid chromatography (prep SFC) (SFC chiral resolution conditions: instrument: Waters SFC350; chromatographic column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); mobile phase: A: CO 2 , B: IPA (0.1% NH 3 H 2 O); gradient: B%: 50%-50%,; flow rate: 200 mL/min; column temperature: 40° C.), the The fractionated liquid was concentrated under reduced pressure and lyophilized to obtain yellow oil int_1-9A (peak 1,438 mg, yield: 29.20%) and yellow oil int_1-9B (peak 2,450 mg, yield: 30.00%).
  • prep SFC SFC chiral resolution conditions: instrument: Waters SFC350; chromatographic column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); mobile phase: A: CO 2 , B: IPA (0.1%
  • Int_1-7 (334 mg, 1.0 mmol) was dissolved in dichloromethane (40 mL), m-CPBA (85%, 240 mg, 1.2 mmol) was added at room temperature, and the mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (335 mg, crude product). The crude product can be used directly in the next reaction.
  • Int_1-8 (100 mg, 0.28 mmol) was dissolved in DMF (5 mL), int_1-9B (57 mg, 0.28 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added, and the reaction solution was heated to 80° C. and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparation to give a white solid (75 mg, yield: 55%).
  • HPLC preparation method is as follows:
  • Int_1-9-1 (50 g, 324 mmol) was dissolved in methanol (500 mL), SOCl2 (77.2 g, 649 mmol, 47.1 mL) was added dropwise at 0 °C, and the mixture was warmed to room temperature for 16 hours. TLC detection showed that the reaction was complete. The reaction solution was concentrated by distillation under reduced pressure to obtain the crude product as a white solid (53.4 g, yield: 97.2%). The crude product can be used directly in the next reaction.
  • Int_64-1-2 (54.3 g, 315 mmol) was dissolved in DMF (500 mL), and K2CO3 (87.1 g , 630 mmol) and Int_64-1-3 (89.4 g, 662 mmol, 67.2 mL) were added under nitrogen protection. The mixture was raised to 60°C and reacted for 16 hours. TLC detection showed that the reaction was complete.
  • the organic phase was filtered and distilled under reduced pressure to obtain the crude product.
  • the crude product was dissolved in 200 mL of ethyl acetate, filtered and the filter cake was washed with ethyl acetate (20 mL*3), and the filtrate was concentrated to obtain the crude product.
  • the crude product was dispersed and diluted in 50 mL of dichloromethane, filtered and the filter cake was washed with dichloromethane (5 mL*3), and the filter cake was dried to obtain the product (3.5 g, crude product).
  • the product can be directly used in the next reaction.
  • the organic phase was filtered and distilled under reduced pressure to obtain the crude product.
  • the organic phase was filtered and distilled under reduced pressure to obtain the crude product.
  • the crude product was subjected to column chromatography ( 40g Silica Flash Column, Eluent of 0-80% Ethyl acetate/Petroleum ether gradient) to obtain the product (4 g, yield: 83.2%).
  • Int_1-7 (334 mg, 1.0 mmol) was dissolved in dichloromethane (40 mL), m-CPBA (85%, 240 mg, 1.2 mmol) was added at room temperature, and the mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (335 mg, crude product). The crude product can be used directly in the next reaction.
  • Int_1-8 (335 mg, 0.95 mmol) was dissolved in DMF (20 mL), int_64-1 (245 mg, 1.2 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added, and the reaction solution was heated to 80° C. and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to give a white solid (165 mg, yield: 35%).
  • Int_137-5 500 mg, 1.57 mmol was dissolved in dichloromethane (40 mL), m-CPBA (85%, 381.7 mg, 1.88 mmol) was added at room temperature, and the mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (500 mg, crude product). The crude product can be used directly in the next reaction.
  • Int_137-6 (100 mg, 0.298 mmol) was dissolved in DMF (5 mL), int_1-9 (60 mg, 0.298 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added, and the reaction solution was heated to 80° C. and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparation to give a white solid (65 mg, yield: 46%).
  • Int_137-5 500 mg, 1.57 mmol was dissolved in dichloromethane (40 ml), m-CPBA (85%, 381.7 mg, 1.88 mmol) was added at room temperature, and the mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (500 mg, crude product). The crude product can be used directly in the next reaction.
  • Int_137-6 (100 mg, 0.298 mmol) was dissolved in DMF (5 mL), int_1-9A (60 mg, 0.298 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added, and the reaction solution was heated to 80° C. and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparation to give a white solid (60 mg, yield: 42.5%).
  • Int_137-5 500 mg, 1.57 mmol was dissolved in dichloromethane (40 mL), m-CPBA (85%, 381.7 mg, 1.88 mmol) was added at room temperature, and the mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (500 mg, crude product). The crude product can be used directly in the next reaction.
  • Int_137-6 (100 mg, 0.298 mmol) was dissolved in DMF (5 mL), int_1-9B (60 mg, 0.298 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added, and the reaction solution was heated to 80° C. and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparation to give a white solid (70 mg, yield: 50%).
  • the target compounds 4-63, 65-94, 96-136 and 140-296 in Table 1 can be obtained.
  • the LC-MS analysis method is as follows:
  • the inhibitory effect of the compounds on the enzyme activity of recombinant protein Wee-1 was determined by HTRF method. details as follows.
  • DMSO or serially diluted compounds (up to 200nM, 1:5 serial dilution) and recombinant proteins were incubated in kinase buffer at 37°C for 30 minutes, followed by the addition of Fluorescein-PolyGAT and ATP, followed by the addition of substrates to initiate the reaction. After 90 minutes of reaction at room temperature, add antibody and detection solution, and continue to incubate at room temperature for 60 minutes, read the fluorescence value (excitation wavelength: 340nm, emission wavelengths 495 and 520nm. Calculate the 520nm/495nm fluorescence intensity ratio, compare with the DMSO group, and then Compound percent inhibition and IC50 were calculated. Results are shown in Table 3 below.
  • +++ means IC50 less than or equal to 10nM
  • 3000/well MIA PaCa-2 cells were plated in a 384-well plate, and after overnight adherence, DMSO or compounds with a maximum concentration of 5 ⁇ M, 1:5 serial dilution were added. Cell survival was assessed by measuring intracellular ATP content 72 hours after dosing. The percent inhibition of cell survival by the compounds compared to the DMSO group was calculated, and IC50 values were calculated, and the results are shown in Table 4 below.
  • compound IC50 (nM) compound IC50 (nM) 1 236 2 259 3 1090 4 968 5 1180 6 910 49 >5000 50 148 64 400 87 184 105 441 108 225 110 186 112 >5000 121 89 137 >5000 295 72 296 161
  • Example 299 In vitro anti-proliferative activity of the compound of the present invention combined with gemcitabine (Gemcitabine) on MIA PaCa-2 cells
  • compound IC50 (nM) compound IC50 (nM) 1 1.9 2 0.245 3 6.4 4 2.4 5 2.1 6 5.3 49 >100 50 >100 64 3.5 87 1.6 105 2.1 108 11 110 1.1 112 29 121 1.4 137 26 295 1.5 296 3.1
  • Example 300 In vivo efficacy study - mouse HT29 subcutaneous xenograft model
  • HT29 is a colon cancer cell.
  • Each nude mouse was inoculated with 5 ⁇ 10 6 HT29 cells subcutaneously, and when the tumor grew to 100-200 mm 3 , the compound was administered orally once a day alone or in combination with intraperitoneal injection of 15 mg/kg Gemcitabine once a week, twice a week and Tumor volume was measured at the dosing endpoint.
  • TGI tumor growth rate inhibition rate

Abstract

本发明公开了作为Wee-1抑制剂的稠环化合物。具体的，本发明涉及一种通式(1)所示的化合物及其制备方法，及通式(1)化合物及其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为Wee-1抑制剂在抗肿瘤药物制备中的用途。

Description

作为Wee-1抑制剂的稠环化合物
本申请要求申请日为2021/2/19的中国专利申请2021101958215和2022/2/9的中国专利申请2022101226828的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属涉及药物化学领域，更具体而言，涉及具有Wee1激酶抑制作用的稠环化合物，及其制备方法和该类化合物在抗肿瘤药物制备中的用途。
背景技术
Wee-1蛋白激酶是细胞周期检查点中重要的负调控蛋白。细胞周期检查点包括G1(细胞静息期)到S期(DNA合成期)转变的G1期检查点，G2(细胞***准备期)到M(细胞***期)期转变的G2期检查点以及M期metaphase(细胞***期中期)到anaphase(细胞***期后期)转变的纺锤体检查点。Wee-1蛋白激酶在G2期检查点中发挥了重要的作用。细胞进入M期依赖于CDK1激酶活性，Wee-1通过磷酸化CDK1蛋白的Tyr 15，抑制CDK1的活性，阻止细胞进入M期(细胞***期)。而Polo kinase激酶磷酸化Wee-1，激活Wee-1蛋白的降解，促进细胞进入M期。由此可见，Wee-1激酶活性决定了G2检查点的活性，进而调节细胞G2到M期的转变[Cell Cycle,2013.12(19):p.3159-64.]。
细胞周期检查点主要在DNA损伤后激活，对细胞中DNA的修复发挥了重要作用。细胞周期检查点的正常激活阻滞细胞周期促进DNA修复。抑制检查点的功能，DNA损伤无法修复，细胞发生凋亡。与正常细胞相比，多种肿瘤细胞由于G1期检查点重要蛋白p53蛋白的功能受损，主要依赖于G2期检查点的激活修复DNA损伤，规避凋亡。因此，抑制G2期检查点，可以选择性的杀伤肿瘤细胞。而Wee-1激酶活性在G2期检查点中的重要作用，提示Wee-1激酶决定了DNA损伤后肿瘤细胞的修复或死亡，抑制Wee-1活性可以促进DNA损伤后未修复的肿瘤细胞进入M期，诱发凋亡[Curr Clin Pharmacol,2010.5(3):p.186-91.]。
研究表明，除了在G2检查点中的作用以外，Wee-1还参与了DNA合成，DNA同源修复，染色体组蛋白翻译后修饰等与肿瘤发生和发展密切相关的功能[J Cell Biol,2011.194(4):p.567-79.]。在大量包括肝癌，乳腺癌，***，黑色素瘤和肺癌等肿瘤中[PLoS One,2009.4(4):p.e5120.；Hepatology,2003.37(3):p.534-43.；Mol Cancer,2014.13:p.72.]， Wee-1表达大大升高。而Wee-1的高表达与肿瘤的发展和预后较差成正相关，提示Wee-1激酶可能参与了肿瘤的发生和发展。体外细胞模型和体内动物模型的研究表明在诱发DNA损伤的同时抑制Wee-1活性能够显著抑制多种肿瘤的生长[Cancer Biol Ther,2010.9(7):p.514-22.；Mol Cancer Ther,2009.8(11):p.2992-3000.]。
因此，开发特异性的高活性Wee-1激酶的小分子抑制剂对于肿瘤治疗，尤其是靶向诸如P53缺失的G1检查点受损的肿瘤具有重要的临床价值。
发明内容
本发明提供了一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022076366-appb-000001
通式(1)中：
X为CH或N；
Y为-H、卤素、-CN、-S(O) 2R 6、-P(O)(R 7) 2、-C(O)NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)炔基、(C3-C14)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)炔基、(C3-C14)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8-、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
Z为化学键、-CH 2-、-O-或-NH-；
环A为(C6-C14)芳基、(5-14元)杂芳基或(3-14元)杂环烷基；
R 1为
Figure PCTCN2022076366-appb-000002
R 4a和R 5a各自独立地为(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立 任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4a和R 5a与其连接的S原子能够共同组成一个(4-7元)杂环烷基，其中所述(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
R 4b和R 5b各自独立地为(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4b和R 5b与其连接的P原子能够共同组成一个(4-7元)杂环烷基，其中所述(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
R 4c和R 5c各自独立地为-H、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4c和R 5c与其连接的碳原子能够共同组成一个(3-7元)环烷基，其中所述(3-7元)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
R 4d为-H、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；和R 5d为(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4d和R 5d与他们所连接的原子能够共同组成一个(4-7元)杂环烷基，其中所述(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
R 4e和R 5e各自独立地为-H、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4e和R 5e与其连接的N原子能够共同组成一个(4-7元)杂环烷基，其中所述(4-7元)杂 环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
R 4f和R 5f各自独立地为-H、卤素、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4f和R 5f与其连接的碳原子能够共同组成一个(3-7元)环烷基，其中所述(3-7元)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
R 4g为(C1-C3)烷基或(C3-C6)环烷基，其中所述(C1-C3)烷基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
每个R 3独立地为-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或相邻的2个R 3与他们所连接的原子能够共同组成(5-9元)杂环烷基或(C5-C9)环烷基，其中所述(5-9元)杂环烷基或(C5-C9)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
B环为(C5-C11)部分不饱和环烷基或(5-11元)部分不饱和杂环烷基；
X 1为
Figure PCTCN2022076366-appb-000003
X 2为化学键、
Figure PCTCN2022076366-appb-000004
X 3为CH、N或C-R c；
X 4为CH、N或C-R d；
X 5为N-R a或CH-R b；
每个R 2独立地为-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9、(C1-C6)烷基、 (C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或2个相邻的R 2与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，其中所述(5-7元)杂环烷基或(C3-C9)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或B环上同一个碳原子上的2个R 2与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 2和一个相邻的R e与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，其中所述(5-7元)杂环烷基或(C3-C9)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R a为-H、R 8、-(CH 2) mOR 8、-(CH 2) mNR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R b为-H、R 8、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基，其中所述R 8、R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R c和R d各自独立地为-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独 立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R e为-H、-D、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)卤代烷氧基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)卤代烷氧基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R f1、R f2、R g1和R g2各自独立地为-H、-D、R 8、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R f2和一个相邻的R e与他们所连接的原子能够共同组成(C3-C9)环烷基或(3-11元)杂环烷基，其中所述(C3-C9)环烷基或(3-11元)杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R 6为(C1-C3)烷基或(C3-C6)环烷基；
R 7为(C1-C3)烷基；
R 8和R 9各自独立地为-H、(C1-C6)烷基或(C3-C14)环烷基，或同一个氮原子上的R 8和R 9与他们所连接的N原子能够共同组成(3-11元)杂环烷基，其中所述(3-11元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 10和-OR 10；
R 10为-H、(C1-C6)烷基或(C3-C14)环烷基；
R 11和R 12各自独立地为-H、(C1-C3)烷基、(C1-C3)卤代烷基或(C3-C6)环烷基，或同一个氮原子上的R 11和R 12与他们所连接的N原子能够共同组成一个(4-6元)杂环烷基；和
p为0、1或2的整数，q为1、2、3或4的整数，s为1、2、3或4的整数，n为0、1、2或3的整数，m为1、2或3的整数。
在另一优选例中，其中所述通式(1)中，Z为-NH-或化学键。
在另一优选例中，其中所述通式(1)中，Y为-H、-F、-Cl、-Br、-I、-CN、-S(O) 2CH 3、-P(O)(CH 3) 2、-C(O)NH 2、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C5)环烷基、(C2-C3)炔基或(5-6元)杂芳基；其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C5)环烷基、(C2-C3)炔基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-CN、-CH 3和-OCH 3。
在另一优选例中，其中所述通式(1)中，Y为-H、-F、-Cl、-Br、-I、-CN、-S(O) 2CH 3、-P(O)(CH 3) 2、-C(O)NH 2、-CH 3、-CF 3、
Figure PCTCN2022076366-appb-000005
Figure PCTCN2022076366-appb-000006
Y优选为-Br、-CN、-S(O) 2CH 3、-P(O)(CH 3) 2、-C(O)NH 2、-CF 3、
Figure PCTCN2022076366-appb-000007
Figure PCTCN2022076366-appb-000008
Y更优选为-CN。
在另一优选例中，其中所述通式(1)中，环A为(C6-C10)芳基、(5-10元)杂芳基或(5-10元)杂环烷基。
在另一优选例中，其中所述通式(1)中，环A为
Figure PCTCN2022076366-appb-000009
Figure PCTCN2022076366-appb-000010
Figure PCTCN2022076366-appb-000011
环A优选为
Figure PCTCN2022076366-appb-000012
Figure PCTCN2022076366-appb-000013
环A更优选为
Figure PCTCN2022076366-appb-000014
环A更优选为
Figure PCTCN2022076366-appb-000015
在另一优选例中，其中所述通式(1)中，当R 1为
Figure PCTCN2022076366-appb-000016
时，其中R 4a和R 5a各自独立地为(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4a和R 5a与其连接的S原子能够共同组成一个(4-6元)杂环烷基，其中所述(4-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，当R 1为
Figure PCTCN2022076366-appb-000017
时，结构单元
Figure PCTCN2022076366-appb-000018
为：
Figure PCTCN2022076366-appb-000019
Figure PCTCN2022076366-appb-000020
优选为
Figure PCTCN2022076366-appb-000021
优选为
Figure PCTCN2022076366-appb-000022
更优选为
Figure PCTCN2022076366-appb-000023
在另一优选例中，其中所述通式(1)中，当R 1为
Figure PCTCN2022076366-appb-000024
时，其中R 4b和R 5b各自独立地为(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4b和R 5b与其连接的P原子能够共同组成一个(4-6元)杂环烷基，其中所述(4-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，当R 1为
Figure PCTCN2022076366-appb-000025
时，结构单元
Figure PCTCN2022076366-appb-000026
为：
Figure PCTCN2022076366-appb-000027
Figure PCTCN2022076366-appb-000028
优选为
Figure PCTCN2022076366-appb-000029
更优选为
Figure PCTCN2022076366-appb-000030
在另一优选例中，其中所述通式(1)中，当R 1为
Figure PCTCN2022076366-appb-000031
时，其中R 4c和R 5c各自独立地为-H、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4c和R 5c与其连接的碳原子能够共同组成一个(3-6元)环烷基，其中所述(3-6元)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、 -I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，R 1为
Figure PCTCN2022076366-appb-000032
时，结构单元
Figure PCTCN2022076366-appb-000033
为：
Figure PCTCN2022076366-appb-000034
Figure PCTCN2022076366-appb-000035
优选为
Figure PCTCN2022076366-appb-000036
在另一优选例中，其中所述通式(1)中，当R 1为
Figure PCTCN2022076366-appb-000037
时，其中R 4d为-H、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；和R 5d为(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4d和R 5d与他们所连接的原子能够共同组成一个(4-6元)杂环烷基，其中所述(4-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，R 1为
Figure PCTCN2022076366-appb-000038
时，结构单元
Figure PCTCN2022076366-appb-000039
为：
Figure PCTCN2022076366-appb-000040
优选为
Figure PCTCN2022076366-appb-000041
Figure PCTCN2022076366-appb-000042
在另一优选例中，其中所述通式(1)中，当R 1为
Figure PCTCN2022076366-appb-000043
时，其中R 4e和R 5e各自 独立地为-H、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4e和R 5e与其所连接的N原子能够共同组成一个(4-6元)杂环烷基，其中所述(4-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，R 1为
Figure PCTCN2022076366-appb-000044
时，结构单元
Figure PCTCN2022076366-appb-000045
为：
Figure PCTCN2022076366-appb-000046
优选为
Figure PCTCN2022076366-appb-000047
在另一优选例中，其中所述通式(1)中，当R 1为
Figure PCTCN2022076366-appb-000048
时，其中R 4f和R 5f各自独立地为-H、卤素、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4f和R 5f与其所连接的碳原子能够共同组成一个(3-6元)环烷基，其中所述(3-6元)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，R 1为
Figure PCTCN2022076366-appb-000049
时，结构单元
Figure PCTCN2022076366-appb-000050
为：
Figure PCTCN2022076366-appb-000051
在另一优选例中，其中所述通式(1)中，当R 1为
Figure PCTCN2022076366-appb-000052
时，其中R 4g为(C1-C3)烷基或(C3-C5)环烷基，其中所述(C1-C3)烷基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，R 1为
Figure PCTCN2022076366-appb-000053
时，结构单元
Figure PCTCN2022076366-appb-000054
为：
Figure PCTCN2022076366-appb-000055
优选为
Figure PCTCN2022076366-appb-000056
在另一优选例中，其中所述通式(1)中，每个R 3独立地为-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OR 11、-CH 2NR 11R 12、-OR 11、-NR 11R 12、-CN、-C(O)NR 11R 12、-NR 12C(O)R 11、-NR 12S(O) 2R 11、-SR 11、-S(O) 2R 11、-S(O) 2NR 11R 12、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、苯基、(4-8元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、苯基、(4-8元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-OH、-OCH 3、-N(CH 3) 2和-CN；或相邻的2个R 3与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C5-C7)环烷基，其中所述(5-7元)杂环烷基或(C5-C7)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，每个R 3独立地为：-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-OCF 3、-N(CH 3) 2、-CN、-C(O)NH 2、-C(O)NH(CH 3)、-C(O)N(CH 3) 2、-NHC(O)CH 3、-N(CH 3)-C(O)CH 3、-NHS(O) 2CH 3、-NCH 3S(O) 2CH 3、-SCH 3、-S(O) 2CH 3和-S(O) 2NH 2、-S(O) 2NH(CH 3)、-S(O) 2N(CH 3) 2、
Figure PCTCN2022076366-appb-000057
Figure PCTCN2022076366-appb-000058
Figure PCTCN2022076366-appb-000059
R 3优选为-H、-D、-F、-Cl、-Br、-OCH 3、-OCF 3、
Figure PCTCN2022076366-appb-000060
R 3更优选为-H、-D、-F、-Cl、-OCH 3、
Figure PCTCN2022076366-appb-000061
R 3更优选为-H、-D、-F、-Cl、 -OCH 3、
Figure PCTCN2022076366-appb-000062
q优选为1或2；q更优选为1。
在另一优选例中，其中所述通式(1)中，结构单元
Figure PCTCN2022076366-appb-000063
为：
Figure PCTCN2022076366-appb-000064
Figure PCTCN2022076366-appb-000065
Figure PCTCN2022076366-appb-000066
Figure PCTCN2022076366-appb-000067
Figure PCTCN2022076366-appb-000068
Figure PCTCN2022076366-appb-000069
优选为
Figure PCTCN2022076366-appb-000070
Figure PCTCN2022076366-appb-000071
在另一优选例中，其中所述通式(1)中，B环为(C5-C8)部分不饱和环烷基或(5-8元)部分不饱和杂环烷基；和R e为：-H、-D、-CH 3、-OCH 3或-CH 2CH 3。
在另一优选例中，其中所述通式(1)中，结构单元
Figure PCTCN2022076366-appb-000072
为：
Figure PCTCN2022076366-appb-000073
Figure PCTCN2022076366-appb-000074
Figure PCTCN2022076366-appb-000075
在另一优选例中，其中所述通式(1)中，X 1为：
Figure PCTCN2022076366-appb-000076
Figure PCTCN2022076366-appb-000077
Figure PCTCN2022076366-appb-000078
优选为
Figure PCTCN2022076366-appb-000079
Figure PCTCN2022076366-appb-000080
更优选为
Figure PCTCN2022076366-appb-000081
更优选为
Figure PCTCN2022076366-appb-000082
在另一优选例中，其中所述通式(1)中，X 2为：化学键、
Figure PCTCN2022076366-appb-000083
Figure PCTCN2022076366-appb-000084
Figure PCTCN2022076366-appb-000085
优选为化学键、
Figure PCTCN2022076366-appb-000086
Figure PCTCN2022076366-appb-000087
更优选为化学键、
Figure PCTCN2022076366-appb-000088
Figure PCTCN2022076366-appb-000089
更优选为化学键或
Figure PCTCN2022076366-appb-000090
在另一优选例中，其中所述通式(1)中，当X 5为N-R a时，其中R a为-H、-(CH 2) 2OR 11、-(CH 2) 2NR 11R 12、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
Figure PCTCN2022076366-appb-000091
-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，当X 5为N-R a时，其中R a为：-H、-(CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
Figure PCTCN2022076366-appb-000092
Figure PCTCN2022076366-appb-000093
Figure PCTCN2022076366-appb-000094
优选为-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
Figure PCTCN2022076366-appb-000095
Figure PCTCN2022076366-appb-000096
更优选为-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
Figure PCTCN2022076366-appb-000097
更优选为
Figure PCTCN2022076366-appb-000098
Figure PCTCN2022076366-appb-000099
更优选为
Figure PCTCN2022076366-appb-000100
在另一优选例中，其中所述通式(1)中，当X 5为CH-R b时，其中R b为-H、-(CH 2) 2OR 11、-NR 11R 12、-(CH 2) 2NR 11R 12、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述R 11、R 12、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
Figure PCTCN2022076366-appb-000101
-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，当X 5为CH-R b时，其中R b为：-H、-N(CH 3) 2、 -N(CD 3) 2、-(CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
Figure PCTCN2022076366-appb-000102
Figure PCTCN2022076366-appb-000103
Figure PCTCN2022076366-appb-000104
优选为-N(CH 3) 2、-N(CD 3) 2或
Figure PCTCN2022076366-appb-000105
更优选为-N(CH 3) 2。
在另一优选例中，其中所述通式(1)中，X 3为：CH、N或C-R c，其中所述R c为：-H、-F、-Cl、-Br、-I、-OH、-CH 3、-CH 2OCH 3、
Figure PCTCN2022076366-appb-000106
-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2或-CN；优选为-H、-F、-Cl、-CH 3、
Figure PCTCN2022076366-appb-000107
-OCH 3、-OCF 3、-N(CH 3) 2或-CN；更优选为-H、-F、-CH 3、
Figure PCTCN2022076366-appb-000108
或-OCH 3。
在另一优选例中，其中所述通式(1)中，X 4为：CH、N或C-R d，其中所述R d为：-H、-F、-Cl、-Br、-I、-OH、-CH 3、-CH 2OCH 3、
Figure PCTCN2022076366-appb-000109
-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2或-CN；优选为-H、-F、-Cl、-CH 3、
Figure PCTCN2022076366-appb-000110
-OCH 3、-OCF 3、-N(CH 3) 2或-CN；更优选为-H、-F、-CH 3、
Figure PCTCN2022076366-appb-000111
或-OCH 3。
在另一优选例中，其中所述通式(1)中，每个R 2独立地为-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OR 11、-CH 2NR 11R 12、-OR 11、-NR 11R 12、-CN、-C(O)NR 11R 12、-NR 12C(O)R 11、-NR 12S(O) 2R 11、-SR 11、-S(O) 2R 11、-S(O) 2NR 11R 12、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、苯基、(4-8元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、苯基、(4-8元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-OCH 3、-N(CH 3) 2和-CN；或2个相邻的R 2与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C6)环烷基，其中所述(5-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或B环上同一个碳原子上的2个R 2与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、- I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 2和一个相邻的R e与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C6)环烷基，其中所述(5-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，每个R 2独立地为：-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-OCF 3、-NH 2、-N(CH 3) 2、-CN、-C(O)NH 2、-C(O)NH(CH 3)、-C(O)N(CH 3) 2、-NHC(O)CH 3、-N(CH 3)-C(O)CH 3、-NHS(O) 2CH 3、-NCH 3S(O) 2CH 3、-SCH 3、-S(O) 2CH 3和-S(O) 2NH 2、-S(O) 2NH(CH 3)、-S(O) 2N(CH 3) 2、
Figure PCTCN2022076366-appb-000112
Figure PCTCN2022076366-appb-000113
Figure PCTCN2022076366-appb-000114
优选为-H、-D、-F、-Cl、-OH、-OCH 3、-OCF 3、-NH 2、-N(CH 3) 2、-CN、
Figure PCTCN2022076366-appb-000115
Figure PCTCN2022076366-appb-000116
更优选为-H、-F、-OH、-NH 2、
Figure PCTCN2022076366-appb-000117
s优选为1或2；s更优选为1；s更优选为2。
在另一优选例中，其中所述通式(1)中，结构单元
Figure PCTCN2022076366-appb-000118
为：
Figure PCTCN2022076366-appb-000119
Figure PCTCN2022076366-appb-000120
Figure PCTCN2022076366-appb-000121
Figure PCTCN2022076366-appb-000122
Figure PCTCN2022076366-appb-000123
Figure PCTCN2022076366-appb-000124
Figure PCTCN2022076366-appb-000125
Figure PCTCN2022076366-appb-000126
在本发明的一些实施例中，本发明提供了如通式(2)所述化合物或其各异构体、各晶 型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022076366-appb-000127
其中A、B、Y、Z、R 1、R 2、R 3、R e、X 1、X 2、X 3、X 4、X 5、q、s的定义如前所述，并在具体实施例中举例说明。
在本发明的一些实施例中，本发明提供了如通式(3a)或通式(3b)所述化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022076366-appb-000128
其中A、B、Y、R 1、R 2、R 3、R e、X 1、X 2、X 3、X 4、X 5、q、s的定义如前所述，并在具体实施例中举例说明。
在本发明的一些实施例中，本发明提供了如通式(4a)、通式(4b)或通式(4c)所述化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022076366-appb-000129
其中B、Y、Z、R 1、R 2、R 3、R e、X 1、X 2、X 3、X 4、X 5、q、s的定义如前所述，并在具体实施例中举例说明。
在本发明的一些实施例中，本发明提供了如通式(5a)、通式(5b)或通式(5c)所述化合物 或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022076366-appb-000130
其中A、Y、Z、R 1、R 2、R 3、R e、X 1、X 2、X 3、X 4、X 5、q、s的定义如前所述，并在具体实施例中举例说明。
在本发明的一些实施例中，本发明提供了如通式(6a)、通式(6b)或通式(6c)所述化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022076366-appb-000131
其中A、Y、Z、R 1、R 2、R 3、R e、X 2、X 5、q、s的定义如前所述，并在具体实施例中举例说明。
在本发明的一些实施例中，本发明提供了如通式(7a)、通式(7b)、通式(7c)、通式(7d)、通式(7e)或通式(7f)所述化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022076366-appb-000132
其中Y、Z、R 1、R 2、R 3、R e、X 2、X 5、q、s的定义如前所述，并在具体实施例中举例说明。
在各种不同实施方式中，本发明代表性化合物具有以下结构之一：
Figure PCTCN2022076366-appb-000133
Figure PCTCN2022076366-appb-000134
Figure PCTCN2022076366-appb-000135
Figure PCTCN2022076366-appb-000136
Figure PCTCN2022076366-appb-000137
Figure PCTCN2022076366-appb-000138
Figure PCTCN2022076366-appb-000139
Figure PCTCN2022076366-appb-000140
Figure PCTCN2022076366-appb-000141
Figure PCTCN2022076366-appb-000142
本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明通式(1)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
本发明的再一个目的提供了本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防与Wee-1蛋白相关疾病的药物中的应用。
本发明的再一个目的还提供治疗、调节或预防与Wee-1蛋白介导的相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。
通过合成和仔细研究了多类涉及具有Wee-1抑制作用的新化合物，发明人发现在通式(1)化合物中，化合物意外地具有很强的Wee-1抑制活性。
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC  CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其中通式(1)化合物可采用下列一般反应流程1、2、3或4制备：
一般反应流程1
Figure PCTCN2022076366-appb-000143
通式(1)化合物的实施方式可根据一般反应流程1制备，其中R 1、R 2、R 3、R e、X 1、X 2、X 3、X 4、X 5、X、Y、Z、s、q、A环和B环如上文中所定义，H表示氢，N表示氮，Cl表示氯，S表示硫，O表示氧。如一般反应流程1所示,化合物1-1和1-2在碱性条件下发生取代反应生成化合物1-3，化合物1-3与m-CPBA反应生成化合物1-4，化合物1- 4和1-5发生取代反应生成目标化合物1-6。
一般反应流程2
Figure PCTCN2022076366-appb-000144
通式(1)化合物的实施方式可根据一般反应流程2制备，其中R 1、R 2、R 3、R e、X 1、X 2、X 3、X 4、X 5、X、Y、s、q、A环和B环如上文中所定义，H表示氢，N表示氮，Cl表示氯，S表示硫，O表示氧。如一般反应流程2所示,化合物2-1和2-2在碱性条件下发生取代反应生成化合物2-3，化合物2-3与m-CPBA反应生成化合物2-4，化合物2-4和2-5发生取代反应生成目标化合物2-6。
一般反应流程3
Figure PCTCN2022076366-appb-000145
Figure PCTCN2022076366-appb-000146
通式(1)化合物的实施方式可根据一般反应流程3制备，其中R 1、R 2、R 3、R e、X 1、X 2、X 3、X 4、X 5、X、Y、Z、s、q、A环和B环如上文中所定义，H表示氢，N表示氮，Cl表示氯，S表示硫，O表示氧，B表示硼酸、硼酸酯或三氟硼酸盐，L 1表示溴或碘。如一般反应流程3所示,化合物3-1和3-2在碱性条件下发生取代反应生成化合物3-3，化合物3-3和Y-B发生偶联反应生成目标化合物3-4，化合物3-4与m-CPBA反应生成化合物3-5，化合物3-5和3-6发生取代反应生成目标化合物3-7。
一般反应流程4
Figure PCTCN2022076366-appb-000147
通式(1)化合物的实施方式可根据一般反应流程4制备，其中R 1、R 2、R 3、R e、X 1、X 2、X 3、X 4、X 5、X、Y、s、q、A环和B环如上文中所定义，H表示氢，N表示氮，Cl表示氯，S表示硫，O表示氧，L 2表示溴或氯。如一般反应流程4所示,化合物4-1和4-2在碱性条件下发生取代反应生成化合物4-3，化合物4-3与m-CPBA反应生成化合物4-4，化合物4-4和4-5发生取代反应生成目标化合物4-6。
化合物的进一步形式
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式(1)化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，通式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面，通式(1)化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋 光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)和C-14( 14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH 3、CH 3CH 2、CF 3、CHF 2、CF 3CH 2、CF 3(CH 3)CH、 iPr、 nPr、 iBu、 nBu或 tBu。
除非另有规定，“亚烷基”指二价的如上所定义的烷基。亚烷基基的例子包括但不限于，亚甲基和亚乙基。
除非另有规定，“烯基”指含有碳-碳双键的不饱和脂肪烃基团，包括1至14个碳原子的直链或支链基团。优选含有1至4个碳原子的低级烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。
除非另有规定，“炔基”指含有碳-碳叁键的不饱和脂肪烃基团，包括1至14个碳原子的直链和支链基团。优选含有1至4个碳原子的低级炔基，例如乙炔基、1-丙炔基或1-丁炔基。
除非另有规定，“环烷基”是指非芳香族烃环***(单环、双环或多环)，如果碳环含有至少一个双键，那么部分不饱和环烷基可被称为“环烯基”，或如果碳环含有至少一个三键，那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为单环的或双环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫离子 基。环烷基还包括亚环烷基。在一些实施方案中，环烷基含有0、1或2个双键。在一些实施方案中，环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中，环烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基和杂环烷基稠合。一些实施方案中，环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH 3、OCF 3、CHF 2O、CF 3CH 2O、 i-PrO、 n-PrO、 i-BuO、 n-BuO或 t-BuO。
除非另有规定，“芳基”指碳氢芳香基团，芳基是单环或多环的，例如单环芳基环与一个或多个碳环芳香基团稠和。芳基的例子包括但不限于，苯基、萘基和菲基。
除非另有规定，“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团，杂芳基是单环或多环的。例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环烷基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、***基、吡嗪基、喹啉基、异喹啉基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基、吡咯并嘧啶基、1H-吡咯[3,2-b]吡啶基、1H-吡咯[2,3-c]吡啶基、1H-吡咯[3,2-c]吡啶基、1H-吡咯[2,3-b]吡啶基、
Figure PCTCN2022076366-appb-000148
除非另有规定，“杂环烷基”指非芳香族环或环***，其可以任选地含有一个或多个亚烯基作为环结构的一部分，其具有至少一个独立地选自硼、磷、氮、硫、氧和磷的杂原子环成员。如果杂环烷基含有至少一个双键，那么部分不饱和杂环烷基可被称为“杂环烯基”，或如果杂环烷基含有至少一个三键，那么部分不饱和杂环烷基可被称为“杂环炔基”。杂环烷基可以包括单环、双环、螺环或多环(例如具有两个稠合或桥接环)环***。在一些实施例中，杂环烷基为具有1、2或3个独立地选自氮、硫和氧的杂原子的单环基团。杂环烷基的成环碳原子和杂原子可以任选地氧化以形成氧代或硫离子基或其他氧化键(例如C(O)、S(O)、C(S)或S(O)2、N-氧化物等)，或氮原子可以季铵化。杂环烷基可以经由成环碳原子或成环杂原子而连接。在一些实施例中，杂环烷基含有0至3个双键。在一些实 施例中，杂环烷基含有0至2个双键。杂环烷基的定义中还包括具有一个或多个与杂环烷基环稠合(即，与其共用键)的芳香族环的部分，例如哌啶、吗啉、氮杂环庚三烯或噻吩基等的苯并衍生物。含有稠合芳香族环的杂环烷基可以经由任何成环原子，包括稠合芳香族环的成环原子而连接。杂环烷基的实例包括但不限于氮杂环丁基、氮杂环庚基、二氢苯并呋喃基、二氢呋喃基、二氢吡喃基、N-吗啉基、3-氧杂-9-氮杂螺[5.5]十一烷基、1-氧杂-8-氮杂螺[4.5]癸烷基、哌啶基、哌嗪基、氧代哌嗪基、吡喃基、吡咯烷基、奎宁基、四氢呋喃基、四氢吡喃基、1,2,3,4-四氢喹啉基、莨菪烷基、4,5,6,7-四氢噻唑并[5,4-c]吡啶基、4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶、N-甲基哌啶基、四氢咪唑基、吡唑烷基、丁内酰胺基、戊内酰胺基、咪唑啉酮基、乙内酰脲基、二氧戊环基、邻苯二甲酰亚胺基、嘧啶-2,4(1H,3H)-二酮基、1,4-二氧六环基、吗啉基、硫代吗啉基、硫代吗啉-S-氧化物基、硫代吗啉-S,S-氧化物基、哌嗪基、吡喃基、吡啶酮基、3-吡咯啉基、噻喃基、吡喃酮基、四氢噻吩基、2-氮杂螺[3.3]庚烷基、吲哚啉基、
Figure PCTCN2022076366-appb-000149
Figure PCTCN2022076366-appb-000150
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
取代基“-O-CH 2-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的碳原子连接，比如：
Figure PCTCN2022076366-appb-000151
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为单键。
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。
术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。例如，环己基、吡啶基、吡喃基、噻喃基是六元环，环戊基、吡咯基、呋喃基和噻吩基是五元环。
术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。
除非另有说明，用楔形实线键
Figure PCTCN2022076366-appb-000152
和楔形虚线键
Figure PCTCN2022076366-appb-000153
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022076366-appb-000154
和直形虚线键
Figure PCTCN2022076366-appb-000155
表示立体中心的相对构型，用波浪线
Figure PCTCN2022076366-appb-000156
表示楔形实线键
Figure PCTCN2022076366-appb-000157
或楔形虚线键
Figure PCTCN2022076366-appb-000158
或用波浪线
Figure PCTCN2022076366-appb-000159
表示直形实线键
Figure PCTCN2022076366-appb-000160
或直形虚线键
Figure PCTCN2022076366-appb-000161
除非另有说明，用
Figure PCTCN2022076366-appb-000162
表示单键或双键。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。
“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解 此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明提供了使用本发明通式(1)化合物或药物组合物通常可用于抑制Wee1激酶，因此可用于治疗与Wee1激酶活性相关的一种或多种病症。因此，在某些实施方式中，本发明提供了用于治疗Wee1激酶介导的病症的方法，所述方法包括向有需要的患者施用本发明化合物、或其药学上可接受的组合物的步骤。
在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的包括结构通式(1)化合物的药物组合物。在一些实施例中，通式(1)化合物可与其它癌症治疗药物联合应用。在一些实施例中，通式(1)化合物可与吉西他滨(Gemcitabine)联合应用。在一些实施例中，癌症由Wee1激酶介导。在其它实施例中，该癌症是血液癌和实体瘤，包括但不限于，血液恶性肿瘤(白血病、淋巴瘤、骨髓瘤包括多发性骨髓瘤、骨髓异常增生综合症和骨髓增生姓综合症)和实体瘤(癌例如***、乳腺、肺、结肠、胰腺、肾、卵巢以及软组织癌和骨肉瘤，以及间质瘤)等。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2022076366-appb-000163
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗 氧化剂、防腐剂、无热原水等。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
具体实施方式
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中， 1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
本发明采用下述缩略词：(Boc) 2O代表二碳酸二叔丁酯；CDCl 3代表氘代氯仿；EtOAc代表乙酸乙酯；Hexane代表正己烷；HPLC代表高效液相色谱；MeCN代表乙腈；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；Dioxane代表1,4-二氧六环；DMF代表N,N-二甲基甲酰胺；DMAP代表4-(二甲氨基)吡啶；DMSO代表二甲亚砜；hr代表小时；IPA代表异丙醇；min代表分钟；K 2CO 3代表碳酸钾；KOAc代表醋酸钾；K 3PO 4代表磷酸钾；min代表分钟；MeOH代表甲醇；MS代表质谱；MsOH代表甲磺酸；m-CPBA代表间氯过氧苯甲酸；n-BuLi代表正丁基锂；NMR代表核磁共振；Pd/C代表钯碳；Pd(PPh 3) 4代表四三苯基膦钯；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯(0)；PE代表石油醚；TFA代表三氟乙酸；T 3P代表1-丙基磷酸酐；XantPhos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；TLC代表薄层色谱；XPhos代表2-二环己基磷-2′,4′,6′-三异丙基联苯。
实施例1 化合物1的合成
Figure PCTCN2022076366-appb-000164
步骤1：化合物int_1-9-2的合成:
Figure PCTCN2022076366-appb-000165
将Int_1-9-1(50g,284mmol)，甲胺盐酸盐(57.5g,851mmol)和TEA(144g,1.42mol,197mL)溶于乙腈(600mL)中，室温下滴加T 3P(217g,341mmol,203mL,50％purity)，加毕，加热到50℃反应16小时。反应液用1500mL乙酸乙酯稀释，并用NaHCO 3水溶液(400mL*3)洗涤，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物为白色固体(50g,收率：93.1％)。粗产物可直接用于下一步反应。
1H NMR:(400MHz,Chloroform-d)δ7.12-7.01(m,3H),6.10-5.71(m,1H),2.93(d,J＝4.9Hz,3H),2.83(br s,2H),2.79-2.71(m,2H),1.84-1.65(m,4H)
MS(ESI):190[M+H] +.
步骤2：化合物int_1-9-3的合成:
Figure PCTCN2022076366-appb-000166
Int_1-9-2(50g,264mmol)溶于THF(500mL)中，氮气保护下，在-23℃缓慢滴加n-BuLi(2.5M,275mL)。随后在-23℃缓慢滴加DMF(48.3g,660mmol,50.8mL)。然后在20℃缓慢滴加HCl溶液(6M,300mL)。反应液用100mL水稀释，乙酸乙酯(500mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压浓缩得到黄色固体(55g,粗产物)。粗产物可直接用于下一步反应。
1H NMR:(400MHz,Chloroform-d)δ8.36-8.20(m,1H),7.46-7.32(m,2H),6.84(s,1H),3.63-3.52(m,3H),2.99-2.92(m,3H),2.75-2.69(m,2H),2.01-1.90(m,2H)
MS(ESI):200[M+H] +.
步骤3：化合物int_1-9-4的合成:
Figure PCTCN2022076366-appb-000167
int_1-9-3(55g,276mmol)和20g钯碳悬浮于甲醇(800mL)中，氢气加压(50psi)下在30℃搅拌过夜。过滤除去钯碳，滤液减压浓缩，柱层析(SiO 2,PE/EtOAc＝1/0到3/1)得到黄色固体(38.5g,收率：69.3％)。
1H NMR:(400MHz,DMSO-d 6)δ7.71-7.62(m,1H),7.28-7.20(m,2H),3.42(dd,J＝5.6,11.9Hz,1H),3.25(t,J＝12.5Hz,1H),3.13-2.99(m,4H),2.87-2.69(m,2H),2.06-1.90(m,2H),1.75-1.61(m,1H),1.41-1.22(m,1H)
MS(ESI):202[M+H] +.
步骤4：化合物int_1-9-5的合成:
Figure PCTCN2022076366-appb-000168
int_1-9-4(3.1g,19.2mmol)溶于H 2SO 4(300mL)中，在0℃下，3小时内缓慢加入KNO 3(17.9g,177mmol)，加毕升至室温搅拌2小时。TLC检测显示反应完毕。反应液用500mL水稀释，大量固体析出，过滤得到沉淀物，干燥后得到黄色固体(79g,粗产物)。粗产物可直接用于下一步反应。
MS(ESI):247[M+H] +.
步骤5：化合物int_1-9-6的合成:
Figure PCTCN2022076366-appb-000169
int_1-9-5(4.9,19.9mmol)和钯碳(2g,19.9mmol,10％purity)悬浮于甲醇(100mL)中，氢气加压(50psi)下在25℃反应16小时。过滤除去钯碳，滤液减压浓缩，柱层析(SiO 2,PE/EtOAc＝1/0到1/2)得到黄色固体(1.44g,收率：33.5％)。
1H NMR:(400MHz,Chloroform-d)δ7.24(d,J＝2.3Hz,1H),6.56(d,J＝2.0Hz,1H),3.67(br s,2H),3.32-3.25(m,2H),3.19-3.13(m,3H),3.09-2.97(m,1H),2.81-2.65(m,2H),2.07-1.90(m,2H),1.78-1.62(m,1H),1.37-1.23(m,1H).
MS(ESI):217[M+H] +.
步骤6：化合物int_1-9的合成:
Figure PCTCN2022076366-appb-000170
int_1-9-6(7g,32.4mmol)溶于无水四氢呋喃(300ml)，在0℃加入LiAlH 4(6.14g,162mmol)。氮气保护下，混合物升温至25℃反应2小时。向反应液中缓慢加入水淬灭反应，期间保持反应液温度在0～10℃，反应液用800mL乙酸乙酯稀释，并用水(100mL*3)洗涤，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物，粗产物柱层析(SiO 2,DCM/(MeOH+1％NH 4OH)＝1/0到10/1)得到黄色油状物(6.25g,收率：95.5％)。
1H NMR:(400MHz,Chloroform-d)δ6.31(s,1H),6.21(s,1H),3.88(d,J＝15.1Hz,1H),3.62-3.34(br s,2H),3.26(d,J＝15.1Hz,1H),2.98-2.69(m,4H),2.42(s,3H),2.03(t,J＝10.7Hz, 1H),1.92(tdd,J＝3.4,6.5,13.1Hz,1H),1.88-1.75(m,2H),1.34-1.17(m,1H).
MS(ESI):203[M+H] +.
步骤7：化合物int_1-2的合成:
Figure PCTCN2022076366-appb-000171
将int_1-1(3.46g,20mmol)溶于二氯甲烷(100mL)中，加入DIPEA(5.2g,40mmol)，DMAP(1.22g,10mmol)，(Boc) 2O(4.8g,22mmol)，室温反应过夜，LC-MS监测显示反应结束。向反应液加入二氯甲烷(100mL)稀释，水洗(200mL)，2N稀盐酸洗(100mL)，碳酸氢钠水溶液洗(100mL)，水洗(100mL)，最后用饱和食盐水洗(100mL)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物为浅棕色胶状物(4.0g,收率：73％)。粗产物可直接用于下一步反应。
ESI-MS m/z:273[M+H] +。
步骤8：化合物int_1-4的合成:
Figure PCTCN2022076366-appb-000172
将int_1-2(4g,14.6mmol)，int_1-3(1.36g,14.6mmol)，碳酸铯(7.14g,161mmol)，Pd 2(dba) 3(668mg,0.73mmol)，Xantphos(845mg,1.46mmol)溶于1,4-二氧六环中(120ml)，混合液在85℃反应过夜。LC-MS监测显示反应结束。反应液过滤、减压蒸馏得到粗产物，粗产物柱层析(SiO 2,DCM:MeOH＝100:1到30:1)，得到淡黄色固体产物(2.7g,收率：65％)。
ESI-MS m/z:286[M+H] +
步骤9：化合物int_1-5的合成:
Figure PCTCN2022076366-appb-000173
将int_1-4(2.4g,8.41mmol)溶于二氯甲烷(30mL)中，加入三氟乙酸(10mL)，室温反应过夜，LC-MS监测显示反应结束。反应液直接减压浓缩得到灰黄色固体(1.6g,收率：100％)。粗产物可直接用于下一步反应。
ESI-MS m/z:186[M+H] +
步骤10：化合物int_1-7的合成:
Figure PCTCN2022076366-appb-000174
将int_1-6(2g,10.8mmol)，int_1-5(3.2g,10.8mmol)溶于异丙醇(5mL)中，加入DIPEA(5.57g,43.1mmol,7.51mL)，反应液升温至50℃，反应过夜，LC-MS监测显示反应结束。将反应液冷却至室温，析出白色固体，过滤，得到产物。将产物干燥，得到白色固体(1.2g,收率：33％)。
1H NMR:(400MHz,DMSO-d 6).δ9.80(s,1H),8.70(s,1H),7.58(t,J＝7.9Hz,1H),7.16(d,J＝7.8Hz,1H),6.44(d,J＝7.9Hz,1H),3.41(s,6H),2.49(s,3H)
ESI-MS m/z:335[M+H] +
步骤11：化合物int_1-8的合成:
Figure PCTCN2022076366-appb-000175
将int_1-7(334mg,1.0mmol)溶于二氯甲烷(40mL)，室温下加入m-CPBA(85％,240mg,1.2mmol)，室温搅拌半小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(335mg,粗产物)。粗产物可直接用于下一步反应。
ESI-MS m/z:351[M+H] +
步骤12：化合物1的合成:
Figure PCTCN2022076366-appb-000176
将int_1-8(335mg,0.95mmol)溶于DMF(20mL)，加入int_1-9(242mg,1.2mmol)和三氟乙酸(456.8mg,4.0mmol)，反应液加热至80℃搅拌10小时。LC-MS监测显示反应结束。反应液冷却至室温，将反应液减压浓缩得到粗产物。粗产物经过制备HPLC纯化得白色固体(160mg,收率：34％)。
1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.70(d,J＝8.0Hz,1H),7.59(s,1H),7.48(s,1H),7.26(s,1H),7.07(d,J＝8.6Hz,2H),6.57(dd,J＝8.0,0.7Hz,1H),3.92(d,J＝15.2Hz,1H),3.36(s,6H),3.32(d,J＝15.2Hz,1H),3.05-2.89(m,2H),2.79(ddt,J＝24.3,17.0,8.9Hz,2H),2.44(s,3H),2.08(t,J＝10.4Hz,1H),1.99-1.78(m,3H),1.37-1.18(m,1H).LC-MS:489[M+H] +
HPLC制备方法如下：
仪器:Agilent 1260 infinity 2
色谱柱:Waters Xbridge Prep C1819*250mm,5um OBD
柱温:25℃
检测波长:205nm/254nm
流动相A:H 2O(0.1％FA)
流动相B:MeCN
流速:20mL/min
梯度：0.00min–1.00min:5％B→5％B
1.01min–20.00min:5％B→40％B
20.00min–20.01min:40％B→95％B
20.01min–24.00min:95％B→95％B
24.00min–24.01min:95％B→5％B
24.01min–27.00min:5％B→5％B
实施例2 化合物2的合成
Figure PCTCN2022076366-appb-000177
步骤1：化合物int_1-9-2的合成:
Figure PCTCN2022076366-appb-000178
将Int_1-9-1(50g,284mmol)，甲胺盐酸盐(57.5g,851mmol)和TEA(144g,1.42mol,197mL)溶于乙腈(600mL)中，室温下滴加T 3P(217g,341mmol,203mL,50％purity)，加毕， 加热到50℃反应16小时。反应液用1500mL乙酸乙酯稀释，并用NaHCO 3水溶液(400mL*3)洗涤，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物为白色固体(50g,264mmol,收率：93.1％)。粗产物可直接用于下一步反应。
1H NMR:(400MHz,Chloroform-d)δ7.12-7.01(m,3H),6.10-5.71(m,1H),2.93(d,J＝4.9Hz,3H),2.83(br s,2H),2.79-2.71(m,2H),1.84-1.65(m,4H)
MS(ESI):190[M+H] +.
步骤2：化合物int_1-9-3的合成:
Figure PCTCN2022076366-appb-000179
Int_1-9-2(50g,264mmol)溶于THF(500mL)中，氮气保护下，在-23℃缓慢滴加n-BuLi(2.5M,275mL)。随后在-23℃缓慢滴加DMF(48.3g,660mmol,50.8mL)。然后在20℃缓慢滴加HCl溶液(6M,300mL)。反应液用100mL水稀释，乙酸乙酯(500mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压浓缩得到黄色固体(55g,粗产物)。粗产物可直接用于下一步反应。
1H NMR:(400MHz,Chloroform-d)δ8.36-8.20(m,1H),7.46-7.32(m,2H),6.84(s,1H),3.63-3.52(m,3H),2.99-2.92(m,3H),2.75-2.69(m,2H),2.01-1.90(m,2H)
MS(ESI):200[M+H] +.
步骤3：化合物int_1-9-4的合成:
Figure PCTCN2022076366-appb-000180
int_1-9-3(55g,276mmol)和20g钯碳悬浮于甲醇(800mL)中，氢气加压(50psi)下在30℃搅拌过夜。过滤除去钯碳，滤液减压浓缩，柱层析(SiO 2,PE/EtOAc＝1/0到3/1)得到黄色固体(38.5g,收率：69.3％)。
1H NMR:(400MHz,DMSO-d 6)δ7.71-7.62(m,1H),7.28-7.20(m,2H),3.42(dd,J＝5.6,11.9Hz,1H),3.25(t,J＝12.5Hz,1H),3.13-2.99(m,4H),2.87-2.69(m,2H),2.06-1.90(m,2H),1.75-1.61(m,1H),1.41-1.22(m,1H)
MS(ESI):202[M+H] +.
步骤4：化合物int_1-9-5的合成:
Figure PCTCN2022076366-appb-000181
int_1-9-4(3.1g,19.2mmol)溶于H 2SO 4(300mL)中，在0℃下，3小时内缓慢加入KNO 3(17.9g,177mmol)，加毕升至室温搅拌2小时。TLC检测显示反应完毕。反应液用500mL水稀释，大量固体析出，过滤得到沉淀物，干燥后得到黄色固体(79g,粗产物)。粗产物可直接用于下一步反应。
MS(ESI):247[M+H] +.
步骤5：化合物int_1-9-6的合成:
Figure PCTCN2022076366-appb-000182
int_1-9-5(4.9,19.9mmol)和钯碳(2g,19.9mmol,10％purity)悬浮于甲醇(100mL)中，氢气加压(50psi)下在25℃反应16小时。过滤除去钯碳，滤液减压浓缩，柱层析(SiO 2,PE/EtOAc＝1/0到1/2)得到黄色固体(1.44g,收率：33.5％)。
1H NMR:(400MHz,Chloroform-d)δ7.24(d,J＝2.3Hz,1H),6.56(d,J＝2.0Hz,1H),3.67(br s,2H),3.32-3.25(m,2H),3.19-3.13(m,3H),3.09-2.97(m,1H),2.81-2.65(m,2H),2.07-1.90(m,2H),1.78-1.62(m,1H),1.37-1.23(m,1H).
MS(ESI):217[M+H] +.
步骤6：化合物int_1-9的合成:
Figure PCTCN2022076366-appb-000183
int_1-9-6(7g,32.4mmol)溶于无水四氢呋喃(300mL)，在0℃加入LiAlH 4(6.14g,162mmol)。氮气保护下，混合物升温至25℃反应2小时。向反应液中缓慢加入水淬灭反应，期间保持反应液温度在0～10℃，反应液用800mL乙酸乙酯稀释，并用水(100mL*3)洗涤，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物，粗产物柱层析(SiO 2,DCM/(MeOH+1％NH 4OH)＝1/0到10/1)得到黄色油状物(6.25g,收率：95.5％)。
1H NMR:(400MHz,Chloroform-d)δ6.31(s,1H),6.21(s,1H),3.88(d,J＝15.1Hz,1H),3.62-3.34(br s,2H),3.26(d,J＝15.1Hz,1H),2.98-2.69(m,4H),2.42(s,3H),2.03(t,J＝10.7Hz,1H),1.92(tdd,J＝3.4,6.5,13.1Hz,1H),1.88-1.75(m,2H),1.34-1.17(m,1H).
MS(ESI):203[M+H] +.
步骤7：化合物int_1-9A和int_1-9B的合成:
Figure PCTCN2022076366-appb-000184
将int_1-9(1.5g,7.41mmol)用制备超临界流体色谱(prep SFC)进行手性拆分(SFC手性拆分条件：仪器：Waters SFC350；色谱柱：DAICEL CHIRALPAK AD(250mm*50mm,10um)；流动相：A:CO 2，B:IPA(0.1％NH 3H 2O)；梯度：B％:50％-50％；流速：200mL/min；柱温：40℃)，将分段液进行减压浓缩、冻干，得到黄色油状物int_1-9A(peak 1,438mg,收率：29.20％)和黄色油状物int_1-9B(peak 2,450mg,收率：30.00％)。
int_1-9A： 1H NMR:(400MHz,Chloroform-d)δ6.32(s,1H),6.22(s,1H),3.88(d,J＝15.1Hz,1H),3.48(br s,2H),3.26(br d,J＝15.1Hz,1H),2.93(dd,J＝4.6,10.5Hz,1H),2.90-2.80(m,1H),2.79-2.64(m,2H),2.42(s,3H),2.02(t,J＝10.7Hz,1H),1.92(dtd,J＝3.6,6.5,9.8Hz,1H),1.87-1.79(m,2H),1.36-1.15(m,1H)
MS(ESI):203[M+H] +.
int_1-9B： 1H NMR:(400MHz,Chloroform-d)δ6.32(s,1H),6.22(s,1H),3.87(d,J＝15.3Hz,1H),3.47(br s,2H),3.26(d,J＝15.1Hz,1H),2.93(dd,J＝4.8,10.6Hz,1H),2.89-2.80(m,1H),2.80-2.65(m,2H),2.42(s,3H),2.02(t,J＝10.7Hz,1H),1.97-1.88(m,1H),1.87-1.75(m,2H),1.35-1.17(m,1H)
MS(ESI):203[M+H] +.
步骤8：化合物int_1-2的合成:
Figure PCTCN2022076366-appb-000185
将int_1-1(3.46g,20mmol)溶于二氯甲烷(100mL)中，加入DIPEA(5.2g,40mmol)，DMAP(1.22g,10mmol)，(Boc) 2O(4.8g,22mmol)，室温反应过夜，LC-MS监测显示反应结束。向反应液加入二氯甲烷(100mL)稀释，水洗(200mL)，2N稀盐酸洗(100mL)，碳酸氢钠水溶液洗(100mL)，水洗(100mL)，最后用饱和食盐水洗(100mL)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物为浅棕色胶状物(4.0g,收率：73％)。粗产物可直接用于下一步反应。
ESI-MS m/z:273[M+H] +。
步骤9：化合物int_1-4的合成:
Figure PCTCN2022076366-appb-000186
将int_1-2(4g,14.6mmol)，int_1-3(1.36g,14.6mmol)，碳酸铯(7.14g,161mmol)，Pd 2(dba) 3(668mg,0.73mmol)，Xantphos(845mg,1.46mmol)溶于1,4-二氧六环中(120mL)，混合液在85℃反应过夜。LC-MS监测显示反应结束。反应液过滤、减压蒸馏得到粗产物，粗产物柱层析(SiO 2,DCM:MeOH＝100:1到30:1)，得到淡黄色固体产物(2.7g,收率：65％)。
ESI-MS m/z:286[M+H] +
步骤10：化合物int_1-5的合成:
Figure PCTCN2022076366-appb-000187
将int_1-4(2.4g,8.41mmol)溶于二氯甲烷(30mL)中，加入三氟乙酸(10mL)，室温反应过夜，LC-MS监测显示反应结束。反应液直接减压浓缩得到灰黄色固体(1.6g,收率：100％)。粗产物直接用于下一步反应。
ESI-MS m/z:186[M+H] +
步骤11：化合物int_1-7的合成:
Figure PCTCN2022076366-appb-000188
将int_1-6(2g,10.8mmol)，int_1-5(3.2g,10.8mmol)溶于异丙醇(5mL)中，加入DIPEA(5.57g,43.1mmol,7.51mL)，反应液升温至50℃，反应过夜，LC-MS监测显示反应结束。将反应液冷却至室温，析出白色固体，过滤，得到产物。将产物干燥，得到白色固体(1.2g,收率：33％)。
1H NMR:(400MHz,DMSO-d 6).δ9.80(s,1H),8.70(s,1H),7.58(t,J＝7.9Hz,1H),7.16(d,J＝7.8Hz,1H),6.44(d,J＝7.9Hz,1H),3.41(s,6H),2.49(s,3H)
ESI-MS m/z:335[M+H] +
步骤12：化合物int_1-8的合成:
Figure PCTCN2022076366-appb-000189
将int_1-7(334mg,1.0mmol)溶于二氯甲烷(40mL)，室温下加入m-CPBA(85％,240mg,1.2mmol)，室温搅拌半小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(335mg,粗产物)。粗产物可直接用于下一步反应。
ESI-MS m/z:351[M+H] +
步骤13：化合物2的合成:
Figure PCTCN2022076366-appb-000190
将int_1-8(100mg,0.28mmol)溶于DMF(5mL)，加入int_1-9A(57mg,0.28mmol)和三氟乙酸(456.8mg,4.0mmol)，反应液加热至80℃搅拌10小时。LC-MS监测显示反应结束。反应液冷却至室温，将反应液减压浓缩得到粗产物。粗产物经过反相柱纯化得白色固体(70mg,产率：50％)。
1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.70(d,J＝8.0Hz,1H),7.59(s,1H),7.48(s,1H),7.26(s,1H),7.07(d,J＝8.6Hz,2H),6.57(dd,J＝8.0,0.7Hz,1H),3.92(d,J＝15.2Hz,1H),3.36(s,6H),3.32(d,J＝15.2Hz,1H),3.05-2.89(m,2H),2.79(ddt,J＝24.3,17.0,8.9Hz,2H),2.44(s,3H),2.08(t,J＝10.4Hz,1H),1.99-1.78(m,3H),1.37-1.18(m,1H).
LC-MS:489[M+H] +
HPLC制备方法如下：
仪器:Agilent 1260infinity 2
色谱柱:Waters Xbridge Prep C1819*250mm,5um OBD
柱温:25℃
检测波长:205nm/254nm
流动相A:H 2O(0.1％FA)
流动相B:MeCN
流速:20mL/min
梯度：0.00min–1.00min:5％B→5％B
1.01min–20.00min:5％B→40％B
20.00min–20.01min:40％B→95％B
20.01min–24.00min:95％B→95％B
24.00min–24.01min:95％B→5％B
24.01min–27.00min:5％B→5％B
实施例3 化合物3的合成
Figure PCTCN2022076366-appb-000191
步骤1：化合物int_1-9-2的合成:
Figure PCTCN2022076366-appb-000192
将Int_1-9-1(50g,284mmol)，甲胺盐酸盐(57.5g,851mmol)和TEA(144g,1.42mol,197mL)溶于乙腈(600mL)中，室温下滴加T 3P(217g,341mmol,203mL,50％purity)，加毕，加热到50℃反应16小时。反应液用1500mL乙酸乙酯稀释，并用NaHCO 3水溶液(400mL*3)洗涤，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物为白色固体(50g,264mmol,收率：93.1％)。粗产物可直接用于下一步反应。
1H NMR:(400MHz,Chloroform-d)δ7.12-7.01(m,3H),6.10-5.71(m,1H),2.93(d,J＝4.9Hz,3H),2.83(br s,2H),2.79-2.71(m,2H),1.84-1.65(m,4H)
MS(ESI):190[M+H] +.
步骤2：化合物int_1-9-3的合成:
Figure PCTCN2022076366-appb-000193
Int_1-9-2(50g,264mmol)溶于THF(500mL)中，氮气保护下，在-23℃缓慢滴加n-BuLi(2.5M,275mL)。随后在-23℃缓慢滴加DMF(48.3g,660mmol,50.8mL)。然后在20℃缓慢滴加HCl溶液(6M,300mL)。反应液用100mL水稀释，乙酸乙酯(500mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压浓缩得到黄色固体(55g,粗产物)。粗产物可直接用于下一步反应。
1H NMR:(400MHz,Chloroform-d)δ8.36-8.20(m,1H),7.46-7.32(m,2H),6.84(s,1H),3.63-3.52(m,3H),2.99-2.92(m,3H),2.75-2.69(m,2H),2.01-1.90(m,2H)
MS(ESI):200[M+H] +.
步骤3：化合物int_1-9-4的合成:
Figure PCTCN2022076366-appb-000194
int_1-9-3(55g,276mmol)和20g钯碳悬浮于甲醇(800mL)中，氢气加压(50psi)下在30℃搅拌过夜。过滤除去钯碳，滤液减压浓缩，柱层析(SiO 2,PE/EtOAc＝1/0到3/1)得到黄色固体(38.5g,收率：69.3％)。
1H NMR:(400MHz,DMSO-d 6)δ7.71-7.62(m,1H),7.28-7.20(m,2H),3.42(dd,J＝5.6,11.9Hz,1H),3.25(t,J＝12.5Hz,1H),3.13-2.99(m,4H),2.87-2.69(m,2H),2.06-1.90(m,2H),1.75-1.61(m,1H),1.41-1.22(m,1H)
MS(ESI):202[M+H] +.
步骤4：化合物int_1-9-5的合成:
Figure PCTCN2022076366-appb-000195
int_1-9-4(3.1g,19.2mmol)溶于H 2SO 4(300mL)中，在0℃下，3小时内缓慢加入KNO 3(17.9g,177mmol)，加毕升至室温搅拌2小时。TLC检测显示反应完毕。反应液用500mL水稀释，大量固体析出，过滤得到沉淀物，干燥后得到黄色固体(79g,粗产物)。粗产物可直接用于下一步反应。
MS(ESI):247[M+H] +.
步骤5：化合物int_1-9-6的合成:
Figure PCTCN2022076366-appb-000196
int_1-9-5(4.9,19.9mmol)和钯碳(2g,19.9mmol,10％purity)悬浮于甲醇(100mL)中，氢气加压(50psi)下在25℃反应16小时。过滤除去钯碳，滤液减压浓缩，柱层析(SiO 2,PE/EtOAc＝1/0到1/2)得到黄色固体(1.44g,收率：33.5％)。
1H NMR:(400MHz,Chloroform-d)δ7.24(d,J＝2.3Hz,1H),6.56(d,J＝2.0Hz,1H),3.67(br s,2H),3.32-3.25(m,2H),3.19-3.13(m,3H),3.09-2.97(m,1H),2.81-2.65(m,2H),2.07-1.90(m,2H),1.78-1.62(m,1H),1.37-1.23(m,1H).
MS(ESI):217[M+H] +.
步骤6：化合物int_1-9的合成:
Figure PCTCN2022076366-appb-000197
int_1-9-6(7g,32.4mmol)溶于无水四氢呋喃(300mL)，在0℃加入LiAlH 4(6.14g,162mmol)。氮气保护下，混合物升温至25℃反应2小时。向反应液中缓慢加入水淬灭反应， 期间保持反应液温度在0～10℃，反应液用800mL乙酸乙酯稀释，并用水(100mL*3)洗涤，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物，粗产物柱层析(SiO 2,DCM/(MeOH+1％NH 4OH)＝1/0到10/1)得到黄色油状物(6.25g,收率：95.5％)。
1H NMR:(400MHz,Chloroform-d)δ6.31(s,1H),6.21(s,1H),3.88(d,J＝15.1Hz,1H),3.62-3.34(br s,2H),3.26(d,J＝15.1Hz,1H),2.98-2.69(m,4H),2.42(s,3H),2.03(t,J＝10.7Hz,1H),1.92(tdd,J＝3.4,6.5,13.1Hz,1H),1.88-1.75(m,2H),1.34-1.17(m,1H).
MS(ESI):203[M+H] +.
步骤7：化合物int_1-9A和int_1-9B的合成:
Figure PCTCN2022076366-appb-000198
将int_1-9(1.5g,7.41mmol)用制备超临界流体色谱(prep SFC)进行手性拆分(SFC手性拆分条件：仪器：Waters SFC350；色谱柱：DAICEL CHIRALPAK AD(250mm*50mm,10um)；流动相：A:CO 2，B:IPA(0.1％NH 3H 2O)；梯度：B％:50％-50％，；流速：200mL/min；柱温：40℃)，将分段液进行减压浓缩、冻干，得到黄色油状物int_1-9A(peak 1,438mg,收率：29.20％)和黄色油状物int_1-9B(peak 2,450mg,收率：30.00％)。
int_1-9A： 1H NMR:(400MHz,Chloroform-d)δ6.32(s,1H),6.22(s,1H),3.88(d,J＝15.1Hz,1H),3.48(br s,2H),3.26(br d,J＝15.1Hz,1H),2.93(dd,J＝4.6,10.5Hz,1H),2.90-2.80(m,1H),2.79-2.64(m,2H),2.42(s,3H),2.02(t,J＝10.7Hz,1H),1.92(dtd,J＝3.6,6.5,9.8Hz,1H),1.87-1.79(m,2H),1.36-1.15(m,1H)
MS(ESI):203[M+H] +.
int_1-9B： 1H NMR:(400MHz,Chloroform-d)δ6.32(s,1H),6.22(s,1H),3.87(d,J＝15.3Hz,1H),3.47(br s,2H),3.26(d,J＝15.1Hz,1H),2.93(dd,J＝4.8,10.6Hz,1H),2.89-2.80(m,1H),2.80-2.65(m,2H),2.42(s,3H),2.02(t,J＝10.7Hz,1H),1.97-1.88(m,1H),1.87-1.75(m,2H),1.35-1.17(m,1H)
MS(ESI):203[M+H] +.
步骤8：化合物int_1-2的合成:
Figure PCTCN2022076366-appb-000199
将int_1-1(3.46g,20mmol)溶于二氯甲烷(100mL)中，加入DIPEA(5.2g,40mmol)，DMAP(1.22g,10mmol)，(Boc) 2O(4.8g,22mmol)，室温反应过夜，LC-MS监测显示反应结束。向反应液加入二氯甲烷(100mL)稀释，水洗(200mL)，2N稀盐酸洗(100mL)，碳酸氢钠水溶液洗(100mL)，水洗(100mL)，最后用饱和食盐水洗(100mL)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物为浅棕色胶状物(4.0g,收率：73％)。粗产物可直接用于下一步反应。
ESI-MS m/z:273[M+H] +。
步骤9：化合物int_1-4的合成:
Figure PCTCN2022076366-appb-000200
将int_1-2(4g,14.6mmol)，int_1-3(1.36g,14.6mmol)，碳酸铯(7.14g,161mmol)，Pd 2(dba) 3(668mg,0.73mmol)，Xantphos(845mg,1.46mmol)溶于1,4-二氧六环中(120mL)，混合液在85℃反应过夜。LC-MS监测显示反应结束。反应液过滤、减压蒸馏得到粗产物，粗产物柱层析(SiO 2,DCM:MeOH＝100:1到30:1)，得到淡黄色固体产物(2.7g,收率：65％)。
ESI-MS m/z:286[M+H] +
步骤10：化合物int_1-5的合成:
Figure PCTCN2022076366-appb-000201
将int_1-4(2.4g,8.41mmol)溶于二氯甲烷(30mL)中，加入三氟乙酸(10mL)，室温反应过夜，LC-MS监测显示反应结束。反应液直接减压浓缩得到灰黄色固体(1.6g,收率：100％)。粗产物可直接用于下一步反应。
ESI-MS m/z:186[M+H] +
步骤11：化合物int_1-7的合成:
Figure PCTCN2022076366-appb-000202
将int_1-6(2g,10.8mmol)，int_1-5(3.2g,10.8mmol)溶于异丙醇(5mL)中，加入DIPEA(5.57g,43.1mmol,7.51mL)，反应液升温至50℃，反应过夜，LC-MS监测显示反应结束。将反应液冷却至室温，析出白色固体，过滤，得到产物。将产物干燥，得到白色固体(1.2g,收率：33％)。
1H NMR:(400MHz,DMSO-d 6).δ9.80(s,1H),8.70(s,1H),7.58(t,J＝7.9Hz,1H),7.16(d,J＝7.8Hz,1H),6.44(d,J＝7.9Hz,1H),3.41(s,6H),2.49(s,3H)
ESI-MS m/z:335[M+H] +
步骤12：化合物int_1-8的合成:
Figure PCTCN2022076366-appb-000203
将int_1-7(334mg,1.0mmol)溶于二氯甲烷(40mL)，室温下加入m-CPBA(85％,240mg,1.2mmol)，室温搅拌半小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(335mg,粗产物)。粗产物可直接用于下一步反应。
ESI-MS m/z:351[M+H] +
步骤13：化合物3的合成:
Figure PCTCN2022076366-appb-000204
将int_1-8(100mg,0.28mmol)溶于DMF(5mL)，加入int_1-9B(57mg,0.28mmol)和三氟乙酸(456.8mg,4.0mmol)，反应液加热至80℃搅拌10小时。LC-MS监测显示反应结束。反应液冷却至室温，将反应液减压浓缩得到粗产物。粗产物经过反相制备纯化得白色固体(75mg,产率：55％)。
1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.70(d,J＝8.0Hz,1H),7.59(s,1H),7.48(s,1H),7.26(s,1H),7.07(d,J＝8.6Hz,2H),6.57(dd,J＝8.0,0.7Hz,1H),3.92(d,J＝15.2Hz,1H),3.36(s,6H),3.32(d,J＝15.2Hz,1H),3.05-2.89(m,2H),2.79(ddt,J＝24.3,17.0,8.9Hz,2H),2.44(s,3H),2.08(t,J＝10.4Hz,1H),1.99-1.78(m,3H),1.37-1.18(m,1H).
LC-MS:489[M+H] +
HPLC制备方法如下：
仪器:Agilent 1260 infinity 2
色谱柱:Waters Xbridge Prep C1819*250mm,5um OBD
柱温:25℃
检测波长:205nm/254nm
流动相A:H 2O(0.1％FA)
流动相B:MeCN
流速:20mL/min
梯度：0.00min–1.00min:5％B→5％B
1.01min–20.00min:5％B→40％B
20.00min–20.01min:40％B→95％B
20.01min–24.00min:95％B→95％B
24.00min–24.01min:95％B→5％B
24.01min–27.00min:5％B→5％B
实施例4 化合物64的合成
Figure PCTCN2022076366-appb-000205
步骤1：化合物int_64-1-2的合成:
Figure PCTCN2022076366-appb-000206
将Int_1-9-1(50g,324mmol)溶于甲醇(500mL)中，0℃下滴加SOCl2(77.2g,649mmol,47.1mL)，加毕，混合物升至室温反应16小时。TLC检测显示反应完毕。反应液减压蒸 馏浓缩得到粗产物为白色固体(53.4g,收率：97.2％)。粗产物可直接用于下一步反应。
1H NMR:(400MHz,METHANOL-d4)δ6.92(d,J＝2.0Hz,2H),6.47(t,J＝2.3Hz,1H),3.89-3.80(m,3H)
步骤2：化合物int_64-1-4的合成:
Figure PCTCN2022076366-appb-000207
Int_64-1-2(54.3g,315mmol)溶于DMF(500mL)中，氮气保护下，加入K 2CO 3(87.1g,630mmol)和Int_64-1-3(89.4g,662mmol,67.2mL)。混合物升至60℃反应16小时。TLC检测显示反应完毕。反应液用800mL水稀释，乙酸乙酯(800mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压浓缩，柱层析(SiO 2,PE/THF＝10/1到5/1)得到黄色固体(23.1g,收率：32.3％)。
1H NMR:(400MHz,Chloroform-d)δ7.15(ddd,J＝1.3,2.2,6.7Hz,2H),6.62(t,J＝2.3Hz,1H),6.12(s,1H),5.88(tdd,J＝6.7,10.3,17.1Hz,1H),5.23-5.04(m,2H),4.02(t,J＝6.7Hz,2H),3.90(s,3H),2.53(q,J＝6.7Hz,2H)
步骤3：化合物int_64-1-5的合成:
Figure PCTCN2022076366-appb-000208
int_64-1-4(16g,72mmol)溶于THF(150mL)和H 2O(37mL)中，0℃下加入LiOH.H2O(15.1g,360mmol)，在30℃搅拌16小时。TLC检测显示反应完毕。反应液用200mL水以及200mL乙酸乙酯稀释，并用4N盐酸溶液将反应液的pH值调至2～3，乙酸乙酯(100mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压浓缩得到粗产物(12.1g,收率：80.7％)。粗产物可直接用于下一步反应。
1H NMR:(400MHz,METHANOL-d4)δ7.04(t,J＝2.1Hz,2H),6.57(t,J＝2.3Hz,1H),5.92(tdd,J＝6.7,10.3,17.1Hz,1H),5.26-5.03(m,2H),4.01(t,J＝6.6Hz,2H),2.51(q,J＝6.5Hz,2H)
步骤4：化合物int_64-1-6的合成:
Figure PCTCN2022076366-appb-000209
int_64-1-5(12g,57.6mmol)溶于DCM(120mL)中，在0℃下，缓慢加入(COCl)2(11.0g,86.5mmol,7.57mL)和两滴DMF，反应液在0℃搅拌2小时。反应液减压浓缩，得到黄色固体(16.8g,粗产物)。粗产物可直接用于下一步反应。
步骤5：化合物int_64-1-8的合成:
Figure PCTCN2022076366-appb-000210
int_64-1-6(18.3g,68.5mmol)溶于乙酸乙酯(120mL)和H 2O(60mL)中，加入K 2CO 3(31.6g,228mmol)，将混合液冷却到0℃，向混合液中加入int_64-1-7(16.8g,粗品)的乙酸乙酯溶液(50mL)。反应液升至室温反应16小时。TLC检测显示反应完毕。反应液用200mL水稀释，乙酸乙酯(100mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压浓缩得到粗产物，粗产物经过柱层析(SiO 2,PE/THF＝1/0到4/1)得到黄色油状物(24g,收率：41.1％)。
悬浮于甲醇(100mL)中，氢气加压(50psi)下在25℃反应16小时。过滤除去钯碳，滤液减压浓缩，柱层析(SiO 2,PE/EtOAc＝1/0到1/2)得到黄色固体(1.44g,收率：33.5％)。
MS(ESI):308[M+H] +.
步骤6：化合物int_64-1-9的合成:
Figure PCTCN2022076366-appb-000211
int_64-1-8(10.3g,13.8mmol)溶于乙腈(180ml)，氮气保护下，加入新戊酸铯(6.45g,27.6mmol)和二氯五甲基茂基合铑(III)(216mg,345umol)。氮气保护下，反应液在25℃反应 7小时。LC-MS检测显示反应完毕。反应液过滤并浓缩，粗产物溶于200mL乙酸乙酯和200mL水，乙酸乙酯(200mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物。粗产物溶于200mL乙酸乙酯，过滤并用乙酸乙酯(20mL*3)洗涤滤饼，滤液浓缩得到粗产物。粗产物分散稀释于50mL二氯甲烷，过滤并用二氯甲烷(5mL*3)洗涤滤饼，干燥滤饼得到产物(3.5g,粗产物)。产物可直接用于下一步反应。
1H NMR:(400MHz,METHANOL-d4)δ6.91(d,J＝2.4Hz,1H),6.39(d,J＝2.4Hz,1H),4.47-4.34(m,1H),4.17-4.00(m,1H),3.47(dd,J＝4.3,10.9Hz,1H),3.18-2.99(m,2H),2.10-1.98(m,1H),1.74-1.60(m,1H),1.74-1.60(m,1H)
MS(ESI):206[M+H] +.
步骤7：化合物int_64-1-10的合成:
Figure PCTCN2022076366-appb-000212
int_64-1-9(4.00g,19.5mmol)和K 2CO 3(5.39g,39.0mmol)溶于乙腈(40ml)，加入溴苄(4.00g,23.4mmol,2.78mL)。氮气保护下，反应液在40℃反应16小时。LC-MS检测显示反应完毕。反应液过滤并浓缩，粗产物溶于200mL水，乙酸乙酯(200mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物。粗产物经柱层析(SiO 2,PE/EtOAc＝1/1到1/3)得到黄色固体(5.2g,收率：89.0％)。
1H NMR:(400MHz,Chloroform-d)δ7.47-7.29(m,5H),6.61(d,J＝2.5Hz,1H),6.52(br d,J＝4.5Hz,1H),5.11-5.03(m,2H),4.49-4.38(m,1H),4.18-4.05(m,1H),3.55-3.43(m,1H),3.26-3.14(m,2H),2.04-1.97(m,1H),1.75(br dd,J＝3.1,12.2Hz,1H)
MS(ESI):296[M+H] +.
步骤8：化合物int_64-1-11的合成:
Figure PCTCN2022076366-appb-000213
int_64-1-10(5.20g,17.6mmol)溶于DMF(50ml)，氮气保护下，于0℃下加入钠氢(1.06 g,26.4mmol,60％purity)。反应液在0℃反应0.5小时，然后加入碘甲烷(2.75g,19.4mmol,1.21mL)。反应液升至20℃反应1小时。LC-MS检测显示反应完毕。反应液缓慢倒入100mL冰水中淬灭，并用乙酸乙酯(100mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物。粗产物经柱层析(SiO 2,PE/EtOAc＝2/1到1/1)得到产物(4.8g,收率：88.1％)。
1H NMR:(400MHz,Chloroform-d)δ7.46-7.31(m,5H),7.28(d,J＝2.5Hz,1H),6.57(d,J＝2.6Hz,1H),5.11-5.03(m,2H),4.55-4.33(m,1H),4.23-4.00(m,1H),3.43-3.30(m,2H),3.29-3.19(m,1H),3.15(s,3H),2.04-1.96(m,1H),1.81-1.68(m,1H)
MS(ESI):310[M+H] +.
步骤9：化合物int_64-1-12的合成:
Figure PCTCN2022076366-appb-000214
int_64-1-11(4.80g,15.5mmol)溶于乙醇(50ml)，加入Pd/C(991mg,931umol,10％purity)。反应液在氢气氛围下(15Psi)在20℃反应16小时。LC-MS检测显示反应完毕。反应液减压蒸馏得到产物(3.1g,收率：89.4％)。
1H NMR:(400MHz,METHANOL-d4)δ6.90(d,J＝2.3Hz,1H),6.36(d,J＝2.5Hz,1H),4.45-4.33(m,1H),4.09(ddd,J＝1.9,11.0,12.7Hz,1H),3.56-3.44(m,1H),3.27(d,J＝11.3Hz,1H),3.24-3.15(m,1H),3.12(s,3H),2.04(tdd,J＝2.2,4.8,13.4Hz,1H),1.73-1.60(m,1H)MS(ESI):220[M+H] +.
步骤10：化合物int_64-1-13的合成:
Figure PCTCN2022076366-appb-000215
int_64-1-12(3g,13.7mmol)和三乙胺(4.15g,41.1mmol,5.71mL)溶于二氯甲烷(20ml)和四氢呋喃(20mL)，在0℃下滴加Tf 2O(4.63g,16.42mmol,2.71mL)。反应液升至20℃反应3小时。LC-MS检测显示反应完毕。反应液缓慢倒入75mL冰水中淬灭，并用乙酸乙 酯(100mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物。粗产物经柱层析(
Figure PCTCN2022076366-appb-000216
40g
Figure PCTCN2022076366-appb-000217
Silica Flash Column,Eluent of 0～80％Ethyl acetate/Petroleum ether gradient)得到产物(4g,收率：83.2％)。
1H NMR(400MHz,Chloroform-d)δ＝7.51(d,J＝2.4Hz,1H),6.87(d,J＝2.4Hz,1H),4.59-4.50(m,1H),4.24-4.14(m,1H),3.53-3.27(m,4H),3.18(s,4H),2.15-2.04(m,1H),1.89-1.72(m,2H)
MS(ESI):352[M+H] +.
步骤11：化合物int_64-1-15的合成:
Figure PCTCN2022076366-appb-000218
int_64-1-13(3g,8.54mmol)和int_64-1-14(1.86g,10.3mmol,1.72mL)溶于甲苯(40ml)，加入Pd 2(dba) 3(782mg,854umol)，BINAP(532mg,854umol)和Cs 2CO 3(5.56g,17.1mmol)。氮气保护下，反应液升至100℃反应16小时。LC-MS检测显示反应完毕。反应液减压蒸馏得到粗产物。粗产物经柱层析(
Figure PCTCN2022076366-appb-000219
40g
Figure PCTCN2022076366-appb-000220
Silica Flash Column,Eluent of 0～70％Ethyl acetate/Petroleum ether gradient)得到产物(2g,收率：61.2％)。
MS(ESI):383[M+H] +.
步骤12：化合物int_64-1-16的合成:
Figure PCTCN2022076366-appb-000221
int_64-1-15(2g,5.23mmol)溶于二氯甲烷(40ml)，在0℃缓慢滴加盐酸二氧六环溶液(4M,1.31mL)。氮气保护下，反应液升至20℃反应2小时。LC-MS检测显示反应完毕。反应液减压蒸馏得到粗产物。粗产物经柱层析(
Figure PCTCN2022076366-appb-000222
20g
Figure PCTCN2022076366-appb-000223
Silica Flash Column,Eluent of 0～80％Ethyl acetate/Petroleum ether gradient(1％NH 3·H 2O))得到产物(0.9g,收率：78.9％)。
1H NMR(400MHz,DMSO-d 6)δ＝6.68(d,J＝2.2Hz,1H),6.12(d,J＝2.2Hz,1H),5.11(s,2H),4.37-4.28(m,1H),4.07-3.94(m,1H),3.49-3.38(m,1H),3.23-3.03(m,3H),2.99(s,3H),1.99-1.89(m,1H),1.59-1.46(m,1H)
MS(ESI):219[M+H] +.
步骤13：化合物int_64-1的合成:
Figure PCTCN2022076366-appb-000224
int_64-1-16(0.9g,4.12mmol)溶于四氢呋喃(30ml)，在0℃缓慢加入氢化锂铝(782mg,20.6mmol)。氮气保护下，反应液升至20℃反应16小时。LC-MS检测显示反应完毕。反应液在0℃用Na 2SO 4·H 2O(50g)淬灭，过滤，浓缩滤液得到粗产物。粗产物经柱层析(
Figure PCTCN2022076366-appb-000225
12g
Figure PCTCN2022076366-appb-000226
Silica Flash Column,Eluent of 0～10％MeOH/DCM(1％NH 3·H 2O)得到产物(0.7g,收率：83.1％)。
1H NMR(400MHz,Chloroform-d)δ＝6.01(d,J＝2.0Hz,1H),5.98(d,J＝2.0Hz,1H),4.46-4.35(m,1H),4.20(ddd,J＝2.4,10.6,12.8Hz,1H),3.91(d,J＝15.4Hz,1H),3.62-3.42(m,2H),3.23(d,J＝15.4Hz,1H),3.10-2.91(m,2H),2.45(s,4H),2.05-1.97(m,1H),1.86(tdd,J＝2.2,4.2,12.9Hz,1H),1.72-1.55(m,1H)
MS(ESI):205[M+H] +.
步骤14：化合物int_1-2的合成:
Figure PCTCN2022076366-appb-000227
将int_1-1(3.46g,20mmol)溶于二氯甲烷(100mL)中，加入DIPEA(5.2g,40mmol)，DMAP(1.22g,10mmol)，(Boc) 2O(4.8g,22mmol)，室温反应过夜，LC-MS监测显示反应结束。向反应液加入二氯甲烷(100mL)稀释，水洗(200mL)，2N稀盐酸洗(100mL)，碳酸氢钠水溶液洗(100mL)，水洗(100mL)，最后用饱和食盐水洗(100mL)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物为浅棕色胶状物(4.0g,收率：73％)。粗产物可直接用于下一步反应。
ESI-MS m/z:273[M+H] +。
步骤15：化合物int_1-4的合成:
Figure PCTCN2022076366-appb-000228
将int_1-2(4g,14.6mmol)，int_1-3(1.36g,14.6mmol)，碳酸铯(7.14g,161mmol)，Pd 2(dba) 3(668mg,0.73mmol)，Xantphos(845mg,1.46mmol)溶于1,4-二氧六环中(120ml)，混合液在85℃反应过夜。LC-MS监测显示反应结束。反应液过滤、减压蒸馏得到粗产物，粗产物柱层析(SiO 2,DCM:MeOH＝100:1到30:1)，得到淡黄色固体产物(2.7g,收率：65％)。
ESI-MS m/z:286[M+H] +
步骤16：化合物int_1-5的合成:
Figure PCTCN2022076366-appb-000229
将int_1-4(2.4g,8.41mmol)溶于二氯甲烷(30mL)中，加入三氟乙酸(10mL)，室温反应过夜，LC-MS监测显示反应结束。反应液直接减压浓缩得到灰黄色固体(1.6g,收率：100％)。粗产物可直接用于下一步反应。
ESI-MS m/z:186[M+H] +
步骤17：化合物int_1-7的合成:
Figure PCTCN2022076366-appb-000230
将int_1-6(2g,10.8mmol)，int_1-5(3.2g,10.8mmol)溶于异丙醇(5mL)中，加入DIPEA(5.57g,43.1mmol,7.51mL)，反应液升温至50℃，反应过夜，LC-MS监测显示反应结束。将反应液冷却至室温，析出白色固体，过滤，得到产物。将产物干燥，得到白色固体(1.2g,收率：33％)。
1H NMR:(400MHz,DMSO-d 6).δ9.80(s,1H),8.70(s,1H),7.58(t,J＝7.9Hz,1H),7.16(d,J＝7.8Hz,1H),6.44(d,J＝7.9Hz,1H),3.41(s,6H),2.49(s,3H)
ESI-MS m/z:335[M+H] +
步骤18：化合物int_1-8的合成:
Figure PCTCN2022076366-appb-000231
将int_1-7(334mg,1.0mmol)溶于二氯甲烷(40mL)，室温下加入m-CPBA(85％,240mg,1.2mmol)，室温搅拌半小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(335mg,粗产物)。粗产物可直接用于下一步反应。
ESI-MS m/z:351[M+H] +
步骤19：化合物64的合成:
Figure PCTCN2022076366-appb-000232
将int_1-8(335mg,0.95mmol)溶于DMF(20mL)，加入int_64-1(245mg,1.2mmol)和三氟乙酸(456.8mg,4.0mmol)，反应液加热至80℃搅拌10小时。LC-MS监测显示反应结束。反应液冷却至室温，将反应液减压浓缩得到粗产物。粗产物经过制备HPLC纯化得白色固体(165mg,收率：35％)。
1H NMR(400MHz,Chloroform-d)δ8.35(s,1H),7.71(d,J＝7.8Hz,1H),7.54(dd,J＝19.7,11.9Hz,2H),7.40(s,1H),6.84(d,J＝17.9Hz,2H),6.58(d,J＝7.8Hz,1H),4.45(d,J＝10.8Hz,1H),4.23(t,J＝11.7Hz,1H),4.05(d,J＝15.5Hz,1H),3.43(d,J＝33.4Hz,1H),3.36(s,6H),3.16(d,J＝10.3Hz,3H),2.52(s,3H),1.94(d,J＝13.0Hz,1H),1.67(d,J＝12.8Hz,1H).
LC-MS:491[M+H] +
实施例5 化合物95的合成
Figure PCTCN2022076366-appb-000233
步骤1：化合物int_1-2的合成:
Figure PCTCN2022076366-appb-000234
将int_1-1(3.46g,20mmol)溶于二氯甲烷(100mL)中，加入DIPEA(5.2g,40mmol)，DMAP(1.22g,10mmol)，(Boc) 2O(4.8g,22mmol)，室温反应过夜，LC-MS监测显示反应结束。向反应液加入二氯甲烷(100mL)稀释，水洗(200mL)，2N稀盐酸洗(100mL)，碳酸氢钠水溶液洗(100mL)，水洗(100mL)，最后用饱和食盐水洗(100mL)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物为浅棕色胶状物(4.0g,收率：73％)。粗产物可直接用于下一步反应。
ESI-MS m/z:273[M+H] +。
步骤2：化合物int_1-4的合成:
Figure PCTCN2022076366-appb-000235
将int_1-2(4g,14.6mmol)，int_1-3(1.36g,14.6mmol)，碳酸铯(7.14g,161mmol)，Pd 2(dba) 3(668mg,0.73mmol)，Xantphos(845mg,1.46mmol)溶于1,4-二氧六环中(120mL)，混合液在85℃反应过夜。LC-MS监测显示反应结束。反应液过滤、减压蒸馏得到粗产物，粗产物柱层析(SiO 2,DCM:MeOH＝100:1到30:1)，得到淡黄色固体产物(2.7g,收率：65％)。
ESI-MS m/z:286[M+H] +
步骤3：化合物int_1-5的合成:
Figure PCTCN2022076366-appb-000236
将int_1-4(2.4g,8.41mmol)溶于二氯甲烷(30mL)中，加入三氟乙酸(10mL)，室温反应过夜，LC-MS监测显示反应结束。反应液直接减压浓缩得到灰黄色固体(1.6g,收率：100％)。粗产物可直接用于下一步反应。
ESI-MS m/z:186[M+H] +
步骤4：化合物int_95-2的合成:
Figure PCTCN2022076366-appb-000237
将int_95-1(2g,8.35mmol)，int_1-5(1.55g,8.35mmol)溶于异丙醇(5mL)中，加入DIPEA(4.32g,33.4mmol,5.83mL)，反应液升温至80℃，反应过夜，LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得淡黄色固体(1.5g,收率：46.3％)。ESI-MS m/z:388[M+H] +
步骤5：化合物int_95-3的合成:
Figure PCTCN2022076366-appb-000238
将int_95-2(100mg,0.26mmol)，环丙基硼酸(45mg,0.52mmol)，磷酸钾(166mg,0.78mmol)溶解在甲苯(7.5mL)和水(0.5mL)的混合溶剂中，氩气置换三次，加入醋酸钯(7mg,0.03mmol)和三环己基膦(17mg,0.06mmol)，氩气保护下，加热到100℃搅拌16小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得淡黄色固体(61g,收率：67.1％)。
ESI-MS m/z:350[M+H] +
步骤6：化合物int_95-4的合成:
Figure PCTCN2022076366-appb-000239
将int_95-3(500mg,1.43mmol)溶于二氯甲烷(40mL)，室温下加入m-CPBA(85％,348.6mg,1.72mmol)，室温搅拌半小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(335mg,粗产物)。粗产物可直接用于下一步反应。
ESI-MS m/z:366[M+H] +
步骤7：化合物95的合成:
Figure PCTCN2022076366-appb-000240
将int_95-4(100mg,0.273mmol)溶于DMF(5mL)，加入int_1-9(57mg,0.28mmol)和三氟乙酸(456mg,4.0mmol)，反应液加热至80℃搅拌10小时。LC-MS监测显示反应结束。反应液冷却至室温，将反应液减压浓缩得到粗产物。粗产物经过反相制备纯化得白色固体(75mg,产率：55％)。
ESI-MS m/z:504[M+H] +
实施例6 化合物137的合成
Figure PCTCN2022076366-appb-000241
步骤1：化合物int_137-3的合成:
Figure PCTCN2022076366-appb-000242
将int_137-1(3g,12.7mmol)，int_137-2(4.94g,63.3mmol)，三乙胺(3.86g,38.1mmol)，Pd(PPh 3) 4(733.8mg,0.635mmol)溶于乙腈中(100ml)，混合液在70℃反应过夜。LC-MS监测显示反应结束。反应液过滤、减压蒸馏得到粗产物，粗产物经柱层析，得到淡黄色固体产物(1.8g,收率：60％)。
ESI-MS m/z:234[M+H] +
步骤2：化合物int_137-5的合成:
Figure PCTCN2022076366-appb-000243
将int_137-3(2g,8.5mmol)，int_137-4(1.42g,8.5mmol)溶于异丙醇(5mL)中，加入DIPEA(4.39g,34mmol,5.6mL)，反应液升温至50℃，反应过夜，LC-MS监测显示反应结束。将反应液冷却至室温，反应液过滤、减压蒸馏得到粗产物，粗产物经柱层析，得到黄色固体(1.3g,收率：48％)。
ESI-MS m/z:320[M+H] +
步骤3：化合物int_137-6的合成:
Figure PCTCN2022076366-appb-000244
将int_137-5(500mg,1.57mmol)溶于二氯甲烷(40mL)，室温下加入m-CPBA(85％,381.7mg,1.88mmol)，室温搅拌半小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(500mg,粗产物)。粗产物可直接用于下一步反应。
ESI-MS m/z:336[M+H] +
步骤4：化合物137的合成:
Figure PCTCN2022076366-appb-000245
将int_137-6(100mg,0.298mmol)溶于DMF(5mL)，加入int_1-9(60mg,0.298mmol)和三氟乙酸(456.8mg,4.0mmol)，反应液加热至80℃搅拌10小时。LC-MS监测显示反应结束。反应液冷却至室温，将反应液减压浓缩得到粗产物。粗产物经过反相制备纯化得白色固体(65mg,产率：46％)。
1H NMR(400MHz,DMSO-d6):δ9.93(s,1H),9.74(s,1H),8.58(s,1H),7.91(s,2H),7.67(t,J＝6.3Hz,1H),7.08(s,2H),3.70(s,1H),3.12(dd,J＝25.9,9.8Hz,1H),2.88(dd,J＝10.9,4.8Hz,1H),2.67(q,J＝19.8,16.3Hz,3H),2.29(s,3H),1.96-1.75(m,4H),1.63(d,J＝13.5Hz,6H),1.28-1.05(m,1H).
LC-MS:474[M+H] +
实施例7 化合物138的合成
Figure PCTCN2022076366-appb-000246
步骤1：化合物int_137-3的合成:
Figure PCTCN2022076366-appb-000247
将int_137-1(3g,12.7mmol)，int_137-2(4.94g,63.3mmol)，三乙胺(3.86g,38.1mmol)，Pd(PPh 3) 4(733.8mg,0.635mmol)溶于乙腈中(100ml)，混合液在70℃反应过夜。LC-MS监测显示反应结束。反应液过滤、减压蒸馏得到粗产物，粗产物经柱层析，得到淡黄色固体产物(1.8g,收率：60％)。
ESI-MS m/z:234[M+H] +
步骤2：化合物int_137-5的合成:
Figure PCTCN2022076366-appb-000248
将int_137-3(2g,8.5mmol)，int_137-4(1.42g,8.5mmol)溶于异丙醇(5mL)中，加入DIPEA(4.39g,34mmol,5.6mL)，反应液升温至50℃，反应过夜，LC-MS监测显示反应结束。将反应液冷却至室温，反应液过滤、减压蒸馏得到粗产物，粗产物经柱层析，得到黄色固体(1.3g,收率：48％)。
ESI-MS m/z:320[M+H] +
步骤3：化合物int_137-6的合成:
Figure PCTCN2022076366-appb-000249
将int_137-5(500mg,1.57mmol)溶于二氯甲烷(40ml)，室温下加入m-CPBA(85％,381.7mg,1.88mmol)，室温搅拌半小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(500mg,粗产物)。粗产物可直接用于下一步反应。
ESI-MS m/z:336[M+H] +
步骤4：化合物138的合成:
Figure PCTCN2022076366-appb-000250
将int_137-6(100mg,0.298mmol)溶于DMF(5mL)，加入int_1-9A(60mg,0.298mmol)和三氟乙酸(456.8mg,4.0mmol)，反应液加热至80℃搅拌10小时。LC-MS监测显示反应结束。反应液冷却至室温，将反应液减压浓缩得到粗产物。粗产物经过反相制备纯化得白色固体(60mg,产率：42.5％)。
1H NMR(400MHz,DMSO-d 6)δ9.93(s,1H),9.74(s,1H),8.58(s,1H),7.91(s,2H),7.67(t,J ＝6.3Hz,1H),7.08(s,2H),3.70(s,1H),3.12(dd,J＝25.9,9.8Hz,1H),2.88(dd,J＝10.9,4.8Hz,1H),2.67(q,J＝19.8,16.3Hz,3H),2.29(s,3H),1.96-1.75(m,4H),1.63(d,J＝13.5Hz,6H),1.28-1.05(m,1H).
LC-MS:474[M+H] +
实施例8 化合物139的合成
Figure PCTCN2022076366-appb-000251
步骤1：化合物int_137-3的合成:
Figure PCTCN2022076366-appb-000252
将int_137-1(3g,12.7mmol)，int_137-2(4.94g,63.3mmol)，三乙胺(3.86g,38.1mmol)，Pd(PPh 3) 4(733.8mg,0.635mmol)溶于乙腈中(100ml)，混合液在70℃反应过夜。LC-MS监测显示反应结束。反应液过滤、减压蒸馏得到粗产物，粗产物经柱层析，得到淡黄色固体产物(1.8g,收率：60％)。
ESI-MS m/z:234[M+H] +
步骤2：化合物int_137-5的合成:
Figure PCTCN2022076366-appb-000253
将int_137-3(2g,8.5mmol)，int_137-4(1.42g,8.5mmol)溶于异丙醇(5mL)中，加入DIPEA(4.39g,34mmol,5.6mL)，反应液升温至50℃，反应过夜，LC-MS监测显示反应结束。将反应液冷却至室温，反应液过滤、减压蒸馏得到粗产物，粗产物经柱层析，得到黄色固体(1.3g,收率：48％)。
ESI-MS m/z:320[M+H] +
步骤3：化合物int_137-6的合成:
Figure PCTCN2022076366-appb-000254
将int_137-5(500mg,1.57mmol)溶于二氯甲烷(40mL)，室温下加入m-CPBA(85％,381.7mg,1.88mmol)，室温搅拌半小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(500mg,粗产物)。粗产物可直接用于下一步反应。
ESI-MS m/z:336[M+H] +
步骤4：化合物139的合成:
Figure PCTCN2022076366-appb-000255
将int_137-6(100mg,0.298mmol)溶于DMF(5mL)，加入int_1-9B(60mg,0.298mmol)和三氟乙酸(456.8mg,4.0mmol)，反应液加热至80℃搅拌10小时。LC-MS监测显示反应结束。反应液冷却至室温，将反应液减压浓缩得到粗产物。粗产物经过反相制备纯化得白色固体(70mg,产率：50％)。
1H NMR(400MHz,DMSO-d 6)δ9.93(s,1H),9.74(s,1H),8.58(s,1H),7.91(s,2H),7.67(t,J＝6.3Hz,1H),7.08(s,2H),3.70(s,1H),3.12(dd,J＝25.9,9.8Hz,1H),2.88(dd,J＝10.9,4.8Hz,1H),2.67(q,J＝19.8,16.3Hz,3H),2.29(s,3H),1.96-1.75(m,4H),1.63(d,J＝13.5Hz,6H),1.28-1.05(m,1H).
LC-MS:474[M+H] +
实施例9-296化合物4-63，65-94，96-136，140-296的合成
使用上述合成方法，采用不同原料，可以得到表1中目标化合物4-63，65-94，96-136，140-296。
LC-MS分析方法如下：
仪器：Agilent,LC:1260 InfinityII+MS:G6125B
色谱柱：Welch:Core-shell 2.7um 4.3*50mm
柱温：30℃
波长：254nm/214nm
流动相A：H2O(0.1％甲酸)
流动相B：乙腈(0.1％甲酸)
梯度：
时间(min) 流速(mL/min) 流动相B％ 流动相A％
0 2 5 95
0.1 2 5 95
2.2 2 95 5
2.7 2 95 5
2.71 2 5 95
3 2 5 95
表1
Figure PCTCN2022076366-appb-000256
Figure PCTCN2022076366-appb-000257
Figure PCTCN2022076366-appb-000258
Figure PCTCN2022076366-appb-000259
Figure PCTCN2022076366-appb-000260
Figure PCTCN2022076366-appb-000261
Figure PCTCN2022076366-appb-000262
Figure PCTCN2022076366-appb-000263
Figure PCTCN2022076366-appb-000264
Figure PCTCN2022076366-appb-000265
Figure PCTCN2022076366-appb-000266
Figure PCTCN2022076366-appb-000267
Figure PCTCN2022076366-appb-000268
Figure PCTCN2022076366-appb-000269
Figure PCTCN2022076366-appb-000270
Figure PCTCN2022076366-appb-000271
表2.表1中部分化合物的核磁数据和LC-MS保留时间
Figure PCTCN2022076366-appb-000272
Figure PCTCN2022076366-appb-000273
Figure PCTCN2022076366-appb-000274
实施例297本发明化合物体外抑制重组蛋白Wee-1酶活试验
运用HTRF方法测定化合物对重组蛋白Wee-1酶活的抑制作用。具体如下。
DMSO或者梯度稀释的化合物(最高200nM,1:5梯度稀释)和重组蛋白在激酶缓冲液中37度孵育30分钟后，加入Fluorescein-PolyGAT和ATP后，加入底物启动反应。室温反应90分钟后，加入抗体和检测液，室温继续孵育60分钟后，读取荧光值(激发波长：340nm，发射波长495和520nm。计算520nm/495nm荧光强度比值，与DMSO组相比，进而计算化合物抑制百分比和IC 50。结果见下列表3。
表3.本发明化合物对重组蛋白Wee-1的抑制活性
化合物 (IC 50) 化合物 (IC 50) 化合物 (IC 50) 化合物 (IC 50)
1 +++ 2 +++ 3 +++ 4 +++
5 +++ 6 +++ 7 +++ 8 +++
9 +++ 10 +++ 11 +++ 12 +++
13 +++ 14 +++ 15 +++ 16 +++
17 +++ 18 +++ 19 +++ 20 +++
21 +++ 22 +++ 23 +++ 24 +++
25 +++ 26 +++ 27 +++ 28 +++
29 +++ 30 +++ 31 +++ 32 +++
33 +++ 34 +++ 35 +++ 36 +++
37 +++ 38 +++ 39 +++ 40 +++
41 +++ 42 +++ 43 +++ 44 +++
45 +++ 46 +++ 47 +++ 48 +++
49 ++ 50 ++ 51 ++ 52 ++
53 ++ 54 ++ 55 ++ 56 ++
57 +++ 58 +++ 59 +++ 60 +++
61 +++ 62 +++ 63 +++ 64 +++
65 +++ 66 +++ 67 +++ 68 +++
69 +++ 70 +++ 71 +++ 72 +++
73 +++ 74 +++ 75 +++ 76 +++
77 +++ 78 +++ 79 +++ 80 +++
81 +++ 82 +++ 83 +++ 84 +++
85 +++ 86 +++ 87 +++ 88 +++
89 +++ 90 +++ 91 +++ 92 +++
93 +++ 94 +++ 95 +++ 96 +++
97 +++ 98 +++ 99 +++ 100 +++
101 +++ 102 +++ 103 +++ 104 +++
105 +++ 106 +++ 107 +++ 108 +++
111 +++ 112 +++ 113 +++ 114 +++
115 +++ 116 +++ 117 +++ 118 +++
119 +++ 120 +++ 121 +++ 122 +++
123 +++ 124 +++ 125 +++ 126 +++
127 +++ 128 +++ 129 +++ 130 +++
131 +++ 132 +++ 133 +++ 134 +++
135 +++ 136 +++ 137 +++ 138 +++
139 +++ 279 +++ 280 +++ 289 +++
290 +++ 291 +++ 292 +++ 293 +++
294 +++ 295 +++ 296 +++    
+++表示IC 50小于或等于10nM
++表示IC 50为10nM至50nM
+表示IC 50大于50nM。
从表3数据可知，本发明化合物对重组蛋白Wee-1的酶活性有较好的抑制活性。
实施例298本发明化合物对MIA PaCa-2细胞的体外抗增殖活性
3000/孔MIA PaCa-2细胞铺于384孔板，过夜贴壁后，加入DMSO或者最高浓度为5μM,1:5梯度稀释的化合物。加药后72小时，通过测定细胞内ATP含量，评价细胞存活。与DMSO组相比计算化合物抑制细胞存活的百分比，计算IC 50值，结果见下列表4。
表4本发明化合物对MIA PaCa-2细胞的抗增殖活性
化合物 IC 50(nM) 化合物 IC 50(nM)
1 236 2 259
3 1090 4 968
5 1180 6 910
49 >5000 50 148
64 400 87 184
105 441 108 225
110 186 112 >5000
121 89 137 >5000
295 72 296 161
从表4数据可见本发明化合物对MIA PaCa-2细胞都具有较强的抗增殖活性。
实施例299本发明化合物联合吉西他滨(Gemcitabine)对MIA PaCa-2细胞的体外抗增殖 活性
3000个/孔MIA PaCa-2细胞铺于384孔板并加入20nM Gemcitabine，过夜贴壁后，加入DMSO或者最高浓度为100nM，1:5梯度稀释的化合物。加药后72小时，通过测定细胞内ATP含量，评价细胞存活。与DMSO组相比，计算化合物抑制细胞存活的百分比，进而计算IC 50值，结果见下列表5。
表5本发明化合物联合吉西他滨(Gemcitabine)对MIA PaCa-2细胞的体外抗增殖活性
化合物 IC 50(nM) 化合物 IC 50(nM)
1 1.9 2 0.245
3 6.4 4 2.4
5 2.1 6 5.3
49 >100 50 >100
64 3.5 87 1.6
105 2.1 108 11
110 1.1 112 29
121 1.4 137 26
295 1.5 296 3.1
从表5数据可见本发明化合物联合吉西他滨(Gemcitabine)对MIA PaCa-2细胞都具有较强的体外抗增殖活性。
实施例300体内药效研究–小鼠HT29皮下移植瘤模型
HT29为结肠癌细胞。每只裸小鼠皮下接种5X10 6个HT29细胞，待肿瘤长至100-200mm 3时，每天经口给药一次化合物单用或者和腹腔注射15mg/kg Gemcitabine一周一次联用，每周两次以及给药终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第18天肿瘤体积-给药组第一天肿瘤体积)/(溶媒对照组第18天肿瘤体积-给药组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。结果见表6和表7。
表6.小鼠HT29皮下移植瘤生长抑制率–单药
Figure PCTCN2022076366-appb-000275
表7.小鼠HT29皮下移植瘤生长抑制率–和15mg/kg Gemcitabine联用
Figure PCTCN2022076366-appb-000276
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (38)

  1. 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2022076366-appb-100001
    通式(1)中：
    X为CH或N；
    Y为-H、卤素、-CN、-S(O) 2R 6、-P(O)(R 7) 2、-C(O)NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)炔基、(C3-C14)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)炔基、(C3-C14)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8-、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    Z为化学键、-CH 2-、-O-或-NH-；
    环A为(C6-C14)芳基、(5-14元)杂芳基或(3-14元)杂环烷基；
    R 1为
    Figure PCTCN2022076366-appb-100002
    R 4a和R 5a各自独立地为(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4a和R 5a与其连接的S原子能够共同组成一个(4-7元)杂环烷基，其中所述(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
    R 4b和R 5b各自独立地为(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立 任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4b和R 5b与其连接的P原子能够共同组成一个(4-7元)杂环烷基，其中所述(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
    R 4c和R 5c各自独立地为-H、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4c和R 5c与其连接的碳原子能够共同组成一个(3-7元)环烷基，其中所述(3-7元)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
    R 4d为-H、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；和R 5d为(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4d和R 5d与他们所连接的原子能够共同组成一个(4-7元)杂环烷基，其中所述(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
    R 4e和R 5e各自独立地为-H、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4e和R 5e与其连接的N原子能够共同组成一个(4-7元)杂环烷基，其中所述(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
    R 4f和R 5f各自独立地为-H、卤素、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 4f和R 5f与其连接的碳原子能够共同组成一个(3-7元)环烷基，其中 所述(3-7元)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OR 8、-NR 8R 9和-CN；
    R 4g为(C1-C3)烷基或(C3-C6)环烷基，其中所述(C1-C3)烷基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    每个R 3独立地为-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或相邻的2个R 3与他们所连接的原子能够共同组成(5-9元)杂环烷基或(C5-C9)环烷基，其中所述(5-9元)杂环烷基或(C5-C9)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    B环为(C5-C11)部分不饱和环烷基或(5-11元)部分不饱和杂环烷基；
    X 1为
    Figure PCTCN2022076366-appb-100003
    X 2为化学键、
    Figure PCTCN2022076366-appb-100004
    X 3为CH、N或C-R c；
    X 4为CH、N或C-R d；
    X 5为N-R a或CH-R b；
    每个R 2独立地为-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、 -OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或2个相邻的R 2与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，其中所述(5-7元)杂环烷基或(C3-C9)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或B环上同一个碳原子上的2个R 2与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 2和一个相邻的R e与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，其中所述(5-7元)杂环烷基或(C3-C9)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R a为-H、R 8、-(CH 2) mOR 8、-(CH 2) mNR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R b为-H、R 8、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基，其中所述R 8、R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R c和R d各自独立地为-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R e为-H、-D、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)卤代烷氧基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11 元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)卤代烷氧基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R f1、R f2、R g1和R g2各自独立地为-H、-D、R 8、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R f2和一个相邻的R e与他们所连接的原子能够共同组成(C3-C9)环烷基或(3-11元)杂环烷基，其中所述(C3-C9)环烷基或(3-11元)杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R 6为(C1-C3)烷基或(C3-C6)环烷基；
    R 7为(C1-C3)烷基；
    R 8和R 9各自独立地为-H、(C1-C6)烷基或(C3-C14)环烷基，或同一个氮原子上的R 8和R 9与他们所连接的N原子能够共同组成(3-11元)杂环烷基，其中所述(3-11元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 10和-OR 10；
    R 10为-H、(C1-C6)烷基或(C3-C14)环烷基；
    R 11和R 12各自独立地为-H、(C1-C3)烷基、(C1-C3)卤代烷基或(C3-C6)环烷基，或同一个氮原子上的R 11和R 12与他们所连接的N原子能够共同组成一个(4-6元)杂环烷基；和
    p为0、1或2的整数，q为1、2、3或4的整数，s为1、2、3或4的整数，n为0、1、2或3的整数，m为1、2或3的整数。
  2. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Y为-H、-F、-Cl、-Br、-I、-CN、-S(O) 2CH 3、-P(O)(CH 3) 2、-C(O)NH 2、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C5)环烷基、(C2-C3)炔基或(5-6元)杂芳基；其中所述(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、 -CN、-CH 3和-OCH 3。
  3. 如权利要求2所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Y为：-H、-F、-Cl、-Br、-I、-CN、-S(O) 2CH 3、-P(O)(CH 3) 2、-C(O)NH 2、-CH 3、-CF 3、
    Figure PCTCN2022076366-appb-100005
  4. 如权利要求1-3中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，环A为(C6-C10)芳基、(5-10元)杂芳基或(5-10元)杂环烷基。
  5. 如权利要求4所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，环A为：
    Figure PCTCN2022076366-appb-100006
    Figure PCTCN2022076366-appb-100007
    Figure PCTCN2022076366-appb-100008
  6. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当R 1为
    Figure PCTCN2022076366-appb-100009
    时，其中R 4a和R 5a各自独立地为(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4a和R 5a与其连接的S原子能够共同组成一个(4-6元)杂环烷基，其中所述(4-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  7. 如权利要求6所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当R 1为
    Figure PCTCN2022076366-appb-100010
    时，结构单元
    Figure PCTCN2022076366-appb-100011
    为：
    Figure PCTCN2022076366-appb-100012
    Figure PCTCN2022076366-appb-100013
  8. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当R 1为
    Figure PCTCN2022076366-appb-100014
    时，其中R 4b和R 5b各自独立地为(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4b和R 5b与其连接的P原子能够共同组成一个(4-6元)杂环烷基，其中所述(4-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  9. 如权利要求8所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当R 1为
    Figure PCTCN2022076366-appb-100015
    时，结构单元
    Figure PCTCN2022076366-appb-100016
    为：
    Figure PCTCN2022076366-appb-100017
    Figure PCTCN2022076366-appb-100018
  10. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当R 1为
    Figure PCTCN2022076366-appb-100019
    时，其中R 4c和R 5c各自独立地为-H、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4c和R 5c与其连接的碳原子能够共同组成一个(3-6元)环烷基，其中所述(3-6元)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  11. 如权利要求10所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为
    Figure PCTCN2022076366-appb-100020
    时，结构单元
    Figure PCTCN2022076366-appb-100021
    为：
    Figure PCTCN2022076366-appb-100022
    Figure PCTCN2022076366-appb-100023
  12. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当R 1为
    Figure PCTCN2022076366-appb-100024
    时，其中R 4d为-H、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；和R 5d为(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4d和R 5d与他们所连接的原子能够共同组成一个(4-6元)杂环烷基，其中所述(4-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  13. 如权利要求12所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为
    Figure PCTCN2022076366-appb-100025
    时，结构单元
    Figure PCTCN2022076366-appb-100026
    为：
    Figure PCTCN2022076366-appb-100027
    Figure PCTCN2022076366-appb-100028
  14. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当R 1为
    Figure PCTCN2022076366-appb-100029
    时，其中R 4e和R 5e各自独立地为-H、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4e和R 5e与其所连接的N原子能够共同组成一个(4-6元)杂环烷基，其中所述(4-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  15. 如权利要求14所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为
    Figure PCTCN2022076366-appb-100030
    时，结构单元
    Figure PCTCN2022076366-appb-100031
    为：
    Figure PCTCN2022076366-appb-100032
  16. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当R 1为
    Figure PCTCN2022076366-appb-100033
    时，其中R 4f和R 5f各自独立地为-H、卤素、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 4f和R 5f与其所连接的碳原子能够共同组成一个(3-6元)环 烷基，其中所述(3-6元)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  17. 如权利要求16所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为
    Figure PCTCN2022076366-appb-100034
    时，结构单元
    Figure PCTCN2022076366-appb-100035
    为：
    Figure PCTCN2022076366-appb-100036
    Figure PCTCN2022076366-appb-100037
  18. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当R 1为
    Figure PCTCN2022076366-appb-100038
    时，其中R 4g为(C1-C3)烷基或(C3-C5)环烷基，其中所述(C1-C3)烷基或(C3-C5)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  19. 如权利要求18所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为
    Figure PCTCN2022076366-appb-100039
    时，结构单元
    Figure PCTCN2022076366-appb-100040
    为：
    Figure PCTCN2022076366-appb-100041
    Figure PCTCN2022076366-appb-100042
  20. 如权利要求1-19中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，每个R 3独立地为-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OR 11、-CH 2NR 11R 12、-OR 11、-NR 11R 12、-CN、-C(O)NR 11R 12、-NR 12C(O)R 11、-NR 12S(O) 2R 11、-SR 11、-S(O) 2R 11、-S(O) 2NR 11R 12、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、苯基、(4-8元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、苯基、 (4-8元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-OH、-OCH 3、-N(CH 3) 2和-CN；或相邻的2个R 3与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C5-C7)环烷基，其中所述(5-7元)杂环烷基或(C5-C7)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  21. 如权利要求20所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，每个R 3独立地为：-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-OCF 3、-N(CH 3) 2、-CN、-C(O)NH 2、-C(O)NH(CH 3)、-C(O)N(CH 3) 2、-NHC(O)CH 3、-N(CH 3)-C(O)CH 3、-NHS(O) 2CH 3、-NCH 3S(O) 2CH 3、-SCH 3、-S(O) 2CH 3和-S(O) 2NH 2、-S(O) 2NH(CH 3)、-S(O) 2N(CH 3) 2、
    Figure PCTCN2022076366-appb-100043
    Figure PCTCN2022076366-appb-100044
  22. 如权利要求1-21中任一项所述的化合物或其各异构体、各晶型、药学上可接受 的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元
    Figure PCTCN2022076366-appb-100045
    为
    Figure PCTCN2022076366-appb-100046
    Figure PCTCN2022076366-appb-100047
    Figure PCTCN2022076366-appb-100048
    Figure PCTCN2022076366-appb-100049
    Figure PCTCN2022076366-appb-100050
    Figure PCTCN2022076366-appb-100051
  23. 如权利要求1-22中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，B环为(C5-C8)部分不饱和环烷基或(5-8元)部分不饱和杂环烷基；和R e为：-H、-D、-CH 3、-OCH 3或-CH 2CH 3。
  24. 如权利要求23所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元
    Figure PCTCN2022076366-appb-100052
    为：
    Figure PCTCN2022076366-appb-100053
    Figure PCTCN2022076366-appb-100054
    Figure PCTCN2022076366-appb-100055
  25. 如权利要求1-24中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X 1为：
    Figure PCTCN2022076366-appb-100056
    Figure PCTCN2022076366-appb-100057
  26. 如权利要求1-25中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X 2为：化学键、
    Figure PCTCN2022076366-appb-100058
    Figure PCTCN2022076366-appb-100059
  27. 如权利要求1-26中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当X 5为N-R a时，其中R a为-H、-(CH 2) 2OR 11、-(CH 2) 2NR 11R 12、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
    Figure PCTCN2022076366-appb-100060
    -OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。
  28. 如权利要求27所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当X 5为N-R a时，其中R a为：-H、-(CH 2) 2OCH 3、- (CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
    Figure PCTCN2022076366-appb-100061
    Figure PCTCN2022076366-appb-100062
  29. 如权利要求1-26中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当X 5为CH-R b时，其中R b为-H、-(CH 2) 2OR 11、-NR 11R 12、-(CH 2) 2NR 11R 12、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述R 11、R 12、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
    Figure PCTCN2022076366-appb-100063
    -OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。
  30. 如权利要求29所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当X 5为CH-R b时，其中R b为：-H、-N(CH 3) 2、-N(CD 3) 2、-(CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
    Figure PCTCN2022076366-appb-100064
    Figure PCTCN2022076366-appb-100065
  31. 如权利要求1-30中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X 3为：CH、N或C-R c，其中所述R c为：-H、-F、-Cl、-Br、-I、-OH、-CH 3、-CH 2OCH 3、
    Figure PCTCN2022076366-appb-100066
    -(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2或-CN。
  32. 如权利要求1-31中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X 4为：CH、N或C-R d，其中所述R d为：-H、-F、-Cl、-Br、-I、-OH、-CH 3、-CH 2OCH 3、
    Figure PCTCN2022076366-appb-100067
    -(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2或-CN。
  33. 如权利要求1-32中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，每个R 2独立地为-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OR 11、-CH 2NR 11R 12、-OR 11、-NR 11R 12、-CN、-C(O)NR 11R 12、-NR 12C(O)R 11、-NR 12S(O) 2R 11、-SR 11、-S(O) 2R 11、-S(O) 2NR 11R 12、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、苯基、(4-8元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、苯基、(4-8元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-OCH 3、-N(CH 3) 2和-CN；或2个相邻的R 2与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C6)环烷基，其中所述(5-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或B环上同一个碳原子上的2个R 2与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 2和一个相邻的R e与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C6)环烷基，其中所述(5-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  34. 如权利要求33所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合 物或溶剂合物，其中所述通式(1)中，每个R 2独立地为：-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-OCF 3、-N(CH 3) 2、-CN、-C(O)NH 2、-C(O)NH(CH 3)、-C(O)N(CH 3) 2、-NHC(O)CH 3、-N(CH 3)-C(O)CH 3、-NHS(O) 2CH 3、-NCH 3S(O) 2CH 3、-SCH 3、-S(O) 2CH 3和-S(O) 2NH 2、-S(O) 2NH(CH 3)、-S(O) 2N(CH 3) 2、
    Figure PCTCN2022076366-appb-100068
    Figure PCTCN2022076366-appb-100069
  35. 如权利要求1-34中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元
    Figure PCTCN2022076366-appb-100070
    为：
    Figure PCTCN2022076366-appb-100071
    Figure PCTCN2022076366-appb-100072
    Figure PCTCN2022076366-appb-100073
    Figure PCTCN2022076366-appb-100074
    Figure PCTCN2022076366-appb-100075
  36. 如权利要求1-35中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2022076366-appb-100076
    Figure PCTCN2022076366-appb-100077
    Figure PCTCN2022076366-appb-100078
    Figure PCTCN2022076366-appb-100079
    Figure PCTCN2022076366-appb-100080
    Figure PCTCN2022076366-appb-100081
    Figure PCTCN2022076366-appb-100082
    Figure PCTCN2022076366-appb-100083
    Figure PCTCN2022076366-appb-100084
    Figure PCTCN2022076366-appb-100085
  37. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-36中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
  38. 一种如权利要求1-36中任一项所述的化合物、或其各异构体、各晶型、药学上 可接受的盐、水合物或溶剂合物或如权利要求37所述的药物组合物在制备治疗Wee-1抑制剂中的应用。
PCT/CN2022/076366 2021-02-19 2022-02-15 作为Wee-1抑制剂的稠环化合物 WO2022174765A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280014506.0A CN116888107A (zh) 2021-02-19 2022-02-15 作为Wee-1抑制剂的稠环化合物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202110195821.5 2021-02-19
CN202110195821 2021-02-19
CN202210122682.8 2022-02-09
CN202210122682 2022-02-09

Publications (1)

Publication Number Publication Date
WO2022174765A1 true WO2022174765A1 (zh) 2022-08-25

Family

ID=82931198

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/076366 WO2022174765A1 (zh) 2021-02-19 2022-02-15 作为Wee-1抑制剂的稠环化合物

Country Status (3)

Country Link
CN (1) CN116888107A (zh)
TW (1) TWI823255B (zh)
WO (1) WO2022174765A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023083299A1 (zh) * 2021-11-12 2023-05-19 微境生物医药科技(上海)有限公司 作为hpk1抑制剂的稠环化合物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101784551A (zh) * 2007-06-15 2010-07-21 万有制药株式会社 二环苯胺衍生物
CN103703005A (zh) * 2011-02-28 2014-04-02 艾伯维公司 激酶的三环抑制剂
CN110621316A (zh) * 2017-04-21 2019-12-27 Epizyme股份有限公司 用ehmt2抑制剂进行的组合疗法
CN112442049A (zh) * 2019-09-03 2021-03-05 微境生物医药科技(上海)有限公司 作为Wee1抑制剂的嘧啶衍生物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101784551A (zh) * 2007-06-15 2010-07-21 万有制药株式会社 二环苯胺衍生物
CN103703005A (zh) * 2011-02-28 2014-04-02 艾伯维公司 激酶的三环抑制剂
CN110621316A (zh) * 2017-04-21 2019-12-27 Epizyme股份有限公司 用ehmt2抑制剂进行的组合疗法
CN112442049A (zh) * 2019-09-03 2021-03-05 微境生物医药科技(上海)有限公司 作为Wee1抑制剂的嘧啶衍生物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG YUEQIAN, TU ZHENLIN;TANG WEIFANG;CHEN YADONG: "Research Progress in WEE1 Kinase and Its Inhibitors", PROGRESS IN PHARMACEUTICAL SCIENCES, CHINA PHARMACEUTICAL UNIVERSITY, CN, vol. 46, no. 1, 25 January 2022 (2022-01-25), CN , pages 71 - 80, XP055960611, ISSN: 1001-5094 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023083299A1 (zh) * 2021-11-12 2023-05-19 微境生物医药科技(上海)有限公司 作为hpk1抑制剂的稠环化合物

Also Published As

Publication number Publication date
TWI823255B (zh) 2023-11-21
TW202237596A (zh) 2022-10-01
CN116888107A (zh) 2023-10-13

Similar Documents

Publication Publication Date Title
CN115315427B (zh) Hpk1抑制剂及其制备方法和用途
WO2023280280A1 (zh) 作为KRas G12D抑制剂的稠环化合物
WO2021249519A1 (zh) 吡啶酮并嘧啶类衍生物、其制备方法及其在医药上的应用
CN113045569B (zh) 用作ret激酶抑制剂的化合物及其应用
WO2022174765A1 (zh) 作为Wee-1抑制剂的稠环化合物
AU2017341999A1 (en) Inhibitors of mutant isocitrate dehydrogenases and compositions and methods thereof
WO2022171088A1 (zh) 吡唑并[3,4-d]嘧啶-3-酮衍生物
WO2022228511A1 (zh) 作为Wee-1抑制剂的稠环化合物及其制备方法和用途
WO2022171126A1 (zh) 作为Wee-1抑制剂的稠环化合物
WO2023016417A1 (zh) 作为Wee-1抑制剂的1,2-二氢-3H-吡唑[3,4-d]嘧啶-3-酮化合物
WO2022228512A1 (zh) 作为Wee-1抑制剂的吡咯并嘧啶衍生物
WO2023280180A1 (zh) 作为Wee-1抑制剂的稠环化合物
WO2022174796A1 (zh) 作为Wee-1抑制剂的嘧啶化合物
WO2023045942A1 (zh) 作为Wee-1抑制剂的1,2-二氢-3H-吡唑[3,4-d]嘧啶-3-酮化合物
WO2023030388A1 (zh) 作为Wee-1抑制剂的5-氟-7H-吡咯并[2,3-d]嘧啶类化合物
WO2023083373A1 (zh) 作为Src抑制剂的化合物
WO2022262857A1 (zh) 芳基氧膦类化合物
WO2023143344A1 (zh) 新型egfr抑制剂
WO2022012593A1 (zh) 5，6-二氢吡嗪并[2，3-c]异喹啉化合物
WO2023051717A1 (zh) 作为shp2抑制剂的稠环化合物
WO2023160614A1 (zh) 作为fak抑制剂的化合物及其用途
WO2023134608A1 (zh) 作为hpk1抑制剂的稠环化合物
TW202306955A (zh) 作為atr抑制劑的萘啶衍生物及其製備方法
CN113880804A (zh) 新型苯并咪唑化合物
TW202146406A (zh) 新型吡嗪化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22755538

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280014506.0

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 18277987

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22755538

Country of ref document: EP

Kind code of ref document: A1