WO2024012549A1 - 一种嘧啶并五元杂环化合物、其制备方法和用途 - Google Patents

一种嘧啶并五元杂环化合物、其制备方法和用途 Download PDF

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WO2024012549A1
WO2024012549A1 PCT/CN2023/107377 CN2023107377W WO2024012549A1 WO 2024012549 A1 WO2024012549 A1 WO 2024012549A1 CN 2023107377 W CN2023107377 W CN 2023107377W WO 2024012549 A1 WO2024012549 A1 WO 2024012549A1
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alkyl
group
ring
optionally substituted
halogen
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PCT/CN2023/107377
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English (en)
French (fr)
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易磊
张禹
花海清
朱忠远
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映恩生物制药（苏州）有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry, and specifically relates to a pyrazolopyrimidinone compound used as a Wee1 inhibitor, its preparation method, pharmaceutical composition and its use in preventing and/or treating Wee1 kinase-related diseases.
  • the cell cycle is a highly regulated and controlled process.
  • the normal cell cycle has checkpoints at the G1/S transition, S phase and G2/M transition, allowing sufficient time for DNA damage repair. Due to TP53 mutations, many human cancer cells suffer from lack of regulation by the G1/S checkpoint and therefore rely heavily on G2/M checkpoint regulation.
  • Wee1 kinase is a key regulator of the G2/M checkpoint (C.J. Matheson, D.S. Backos, P. Reigan, Trends in Pharmacological Sciences, 2016, 37: 872).
  • tyrosine kinase that operates on tyrosine 15 (Y15 ) phosphorylates Cdk1 (also known as Cdc2), resulting in its functional inactivation.
  • Cdk1 recruits cyclins A and B to initiate mitosis.
  • Abolishing the G2 checkpoint through Wee1 inhibitors may selectively sensitize P53-deficient cancer cells to DNA damage and avoid affecting surrounding normal tissues.
  • Wee1 also regulates CDK activity in S phase and prevents the induction of DNA damage during normal S phase progression.
  • Wee1 plays a positive regulatory role in homologous recombination (HR) repair, which is an important pathway for DNA double-strand break repair.
  • HR homologous recombination
  • Wee1 is highly expressed in many cancers, including breast, lung, cervical, head and neck, ovarian, prostate, melanoma, leukemia, glioblastoma, medulloblastoma, and hepatocellular carcinoma. Furthermore, high expression of Wee1 is associated with poor prognosis in multiple types of cancer. Inhibiting Wee1 kinase activity and thereby removing G2/M checkpoint function is a potential strategy to drive tumor cells into unscheduled mitosis, thereby experiencing mitotic blockage and leading to cell death. This method, in which cells are forced to enter mitosis without completing DNA replication, is highly toxic to cells and represents a novel mechanism for inducing tumor cell death. Therefore, Wee1 inhibitors have good application prospects as drugs.
  • Wee1 inhibitors have been reported (for example: WO2007126122A1, WO2019173082A1, WO2018011569A1, WO2018162932A1, WO2018090939, WO2019074981, etc.), but there is still an urgent need for new Wee1 inhibitors in this field, especially Wee1 inhibitors with high activity and other excellent properties. , to meet clinical unmet drug needs.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof labeled compound, metabolite or prodrug,
  • a ring is selected from phenyl and 5-10 membered heteroaromatic rings; the A ring is optionally substituted by one or more R a ;
  • Each R a is independently selected from H, halogen, -OH, -CN, -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 Alkyl) 2 , -C 2-4 alkenyl, -C 2-4 alkynyl; the C 1-6 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl are each optionally replaced by a or multiple substituents selected from hydrogen, halogen, oxo, -OH, -CN, -NH 2 , -C 1-6 alkyl;
  • the C 1-6 alkyl group, C 3-12 cycloalkyl group, and 4-12-membered heterocyclic group are each optionally replaced by one or more halogen and oxo groups.
  • R b and R d are each independently selected from H, -C 1-6 alkyl, -C 3-6 cycloalkyl, 4-12 membered heterocyclyl; the C 1-6 alkyl, C 3-
  • Each of the 6- cycloalkyl group and the 4-12-membered heterocyclyl group is optionally replaced by one or more groups selected from halogen, oxo group, -OH, -CN, -NH 2 , -N(C 1-6 alkyl) 2 , -C 1-6 alkylene- OH , -OC 1-6 alkyl, -C 1-6 alkylene-NHC 1-6 alkyl, -C 1-6 alkylene-N(C 1- 6 alkyl) 2 substituent substitution;
  • R 2 is selected from hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, 4-8 membered heterocyclyl, benzene base, 5-6 membered heteroaryl; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, Phenyl and heteroaryl are each optionally substituted by one or more substituents selected from halogen, oxo, -OH, -CN, -NH 2 , -C 1-6 alkyl;
  • Ring B is selected from phenyl, 5-10 membered heteroaryl; the B ring is optionally substituted by one or more substituents selected from hydrogen, halogen, -CN, -OCH 3 ;
  • E ring is selected from -C 3-12 cycloalkyl, 4-12 membered heterocyclyl; the E ring is optionally substituted by one or more R c ;
  • Each R c is independently selected from hydrogen, halogen, -OH, oxo, cyano, -C 1-6 alkyl, -OC 1-6 alkyl;
  • X is selected from CH or N;
  • L 1 is selected from single bond, -C 1-6 alkylene-, -C 3-6 cycloalkylene-, -(3-6 membered heterocyclylene)-, -NHC(O)-S(O ) 2 -(C 1-6 alkylene)-, -C(O)C 1-6 alkylene-, -C(O)C 3-6 cycloalkylene-, -C(O)-( 3-6 membered heterocyclylene)- and -C(O)-, wherein each of the C 1-6 alkylene, 3-6 membered heterocyclylene and C 3-6 cycloalkylene is optionally Substituted with one or more substituents selected from hydrogen, halogen, oxo, -OH and amino;
  • R3 is selected from the following conditions:
  • R 3 is selected from cyano, -OC 1-6 alkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NHC(O)C 1-6 alkyl, -C(O)C 1-6 alkyl, -NHC(O)OC 1-6 alkyl, -S(O) 2 C 1-6 alkyl; the C 1-6 Each alkyl group is optionally substituted by one or more Substituted from hydrogen, halogen, -OH, cyano, -O-(C 1-6 alkyl) substituents;
  • R 3 is selected from halogen, amino, -OH, cyano, -halo C 1-6 alkyl, -S(O) 2 C 1-6 alkyl, -OC 1 -6 alkyl, -NHC 1-6 alkyl -N(C 1-6 alkyl) 2 , -NH-C(O)O(C 1-6 alkyl), -N(C 1-6 alkyl )-C(O)OC 1-6 alkyl, -OC(O)NH 2 , -OC(O)NHC 1-6 alkyl and -N(C 1-6 alkyl)C(O)C 1- 6 alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, oxo, -OH, amino and -O-(C 1-6 alkyl).
  • R 3 when L 1 is a single bond, R 3 can also be a cyano group.
  • R 3 is selected from -OC 1-6 alkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NHC (O)C 1-6 alkyl, -C(O)C 1-6 alkyl, -NHC(O)OC 1-6 alkyl, -S(O) 2 C 1-6 alkyl; the described Each C 1-6 alkyl group is optionally substituted with one or more substituents selected from hydrogen, halogen, -OH, cyano, -O-(C 1-6 alkyl).
  • the pharmaceutically acceptable form of the present invention is selected from the group consisting of pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope markers, metabolic substances or prodrugs.
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite thereof or prodrugs which,
  • Ring A is selected from phenyl, pyridyl, thienyl and pyrazolyl.
  • the ring A is optionally substituted by one or more R a , each R a is independently selected from H, F, Cl, - OH, -C 1-3 alkyl and -OC 1-3 alkyl, the C 1-3 alkyl is optionally substituted by one or more substituents selected from F, Cl, -OH and -CN;
  • a ring is selected from phenyl, and said phenyl is optionally substituted by one or more R a , each R a is independently selected from H, F, Cl, -OH, -C 1-3 Alkyl and -OC 1-3 alkyl, the C 1-3 alkyl is optionally substituted by one or more substituents selected from F, Cl, -OH and -CN;
  • the A ring is selected from phenyl, said phenyl is optionally substituted by one or more R a , R a is selected from H, F, Cl, -CH 3 , -OCH 3 and -CH 2 OH .
  • Ring A is preferably phenyl, more preferably
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite thereof Or a prodrug wherein R 1 is selected from C 1-6 alkyl, 4-6 membered heterocyclyl, C 4-6 cycloalkyl, -O-(4-6 membered heterocyclyl), -NH-(4 -6-membered heterocyclyl), -C(O)N(C 1-6 alkyl ) 2 , each of the 4-6-membered heterocyclyl and C 4-6 cycloalkyl is optionally replaced by one or more Selected from halogen, oxo group, -OH, -CN, -OCH 3 , -NH 2 , -N(C 1-3 alkyl) 2 , -C 1-3 alkyl, -halogenated C 1-3 alkyl base, -halogenated C 1-3 al
  • R 1 is selected from pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydropyridyl, morpholinyl and piperazinyl; the pyrrolidinyl, tetrahydropyranyl, piperidinyl, Tetrahydropyridyl, morpholinyl and piperazinyl are each optionally replaced by one or more selected from F, Cl, -OH, -CN, oxo, -OCH 3 , -NH 2 , -N(CH 3 ) 2 , -C 1-3 alkyl, -halogenated C 1-3 alkyl, -halogenated C 1-3 alkoxy , -C 1-3 alkylene -OH, -C 1-3 alkylene Substituted with substituents of -N(CH 3 ) 2 , -C(O)OC 1-3 alkyl and -S(O) 2 C 1-3 alkyl;
  • R 1 is selected from
  • R 1 is preferably a 4-12-membered heterocyclyl group, more preferably a 4-6-membered heterocyclyl group, and further preferably a 6-membered heterocyclyl group; the heterocyclyl group is optionally One or more -C 1-6 alkyl or -deuterated C 1-6 alkyl substituted, preferably optionally by one or more -C 1-3 alkyl or -deuterated C 1-3 alkyl is substituted, more preferably -CH 3 or -CD 3 is substituted.
  • the heteroatom in the heterocyclic group is selected from N, O and S, preferably N.
  • the number of heteroatoms in the heterocyclic group is 1, 2 or 3, preferably 1 or 2.
  • R 1 is preferably piperidinyl, tetrahydropyridinyl or piperazinyl, which is optionally replaced by one or more -C 1 -3 alkyl or -deuterated C 1-3 alkyl substituted; more preferably piperazinyl, which is optionally substituted by one or more -CH 3 or -CD 3 .
  • R1 is preferably selected from Preferably
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite thereof Or a prodrug wherein R 2 is selected from -CH 3 , -CH 2 CH 3 , cyclopropyl, isopropyl, allyl, propargyl, -CH 2 -cyclopropyl, -CH 2 CF 3 ; preferably Ground, R 2 is selected from allyl.
  • R 2 is preferably -C 2-6 alkenyl, more preferably -C 2-4 alkenyl, and further preferably allyl.
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite thereof Or a prodrug wherein the B ring is selected from phenyl, pyridyl, pyrimidinyl, thienyl and thiazolyl, and the B ring is optionally substituted by one or more substituents selected from hydrogen, halogen and -CN;
  • ring B is selected from pyridyl and phenyl.
  • ring B is preferably a 5-10-membered heteroaryl group, more preferably a 5-6-membered heteroaryl group, and further preferably a 6-membered heteroaryl group.
  • the heteroatom in the heteroaryl group is selected from N, O and S, preferably N.
  • the number of heteroatoms in the heteroaryl group is 1 or 2, preferably 1.
  • B ring is preferably pyrimidinyl or pyridyl, more preferably pyridyl, further preferably
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite thereof Or a prodrug wherein the E ring is selected from 4-6 membered heterocyclyl; the E ring is optionally substituted by one or more R c , each R c is independently selected from hydrogen, F, Cl, - OH, oxo group, -CN, -CH 3 , -OCH 3 ;
  • the E ring is selected from azetidinyl, pyrrolidinyl and piperidinyl.
  • E ring is preferably azetidinyl or pyrrolidinyl, more preferably It is further preferred to The E ring is optionally substituted by one or more R c , each R c is independently selected from H, F, Cl, -OH, -CN, -CH 3 , -OCH 3 .
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite thereof or a prodrug wherein L is selected from methylene, -C(O)-methylene-O- and -C(O)-; wherein said methylene is optionally replaced by one or more hydrogen , F, and -CH 3 substituents.
  • L 1 is preferably selected from a single bond, -C 1-6 alkylene-, -C 3-6 cycloalkylene-, and -C(O)-; said -C 1 -6 alkylene- is preferably -C 1-3 alkylene-, more preferably methylene; the -C 3-6 cycloalkylene- is preferably cyclopropane.
  • R 3 is selected from -OCH 3 , -NHCH 3 , -NHC(O)CH 3 , -C(O)CH 3 and -S(O) 2 CH 3 ;
  • R 3 is selected from F, amino, -OH, -CN, -CHF 2 , -CH 2 F, -S(O) 2 CH 3 , -OCH 3 , -OCHF 2 , -NH-C(O)OCH 3 ;
  • R 3 is selected from F, -OH, -CN, -NH 2 -CHF 2 , -S(O) 2 CH 3 and -CH 3 .
  • R3 is preferably selected from:
  • R 3 is selected from cyano, -OC 1-6 alkyl and -S(O) 2 C 1-6 alkyl, wherein the -OC 1-6 alkyl is optional is substituted by one or more substituents selected from halogen;
  • the -OC 1-6 alkyl group is preferably -O-halo C 1-3 alkyl group, more preferably -OCF 2 ;
  • the -S (O) 2 C 1-6 alkyl is preferably -S(O) 2 C 1-3 alkyl, more preferably -S(O) 2 CH 3 ;
  • L 1 is -C 1-6 alkylene-, -C 3-6 cycloalkylene- or -C(O)- (preferably -C 1-6 alkylene-, more preferably -C 1- 3 alkylene-),
  • R 3 is selected from halogen, amino, -OH, cyano, C 1-6 alkyl, -halo C 1-6 alkyl, -S(O) 2 C 1-6 alkyl and -OC 1-6 alkyl;
  • the -halogenated C 1-6 alkyl is preferably -halogenated C 1-3 alkyl, more preferably fluorinated C 1-3 alkyl, such as CHF 2 Or CH 2 F;
  • the -S(O) 2 C 1-6 alkyl group is preferably -S(O) 2 C 1-3 alkyl group, and more preferably -S(O) 2 CH 3 ;
  • the -OC 1-6 alkyl group is preferably -OC 1-3 alkyl group, and more preferably -
  • R 3 is selected from halogen, amino, -OH, cyano, C 1-6 alkyl, -halo C 1-6 alkyl, -S (O) 2 C 1-6 alkyl and -OC 1-6 alkyl; preferably halogen, amino, -OH, cyano, C 1-3 alkyl, -halo C 1-3 alkyl, -S (O) 2 C 1-3 alkyl and -OC 1-3 alkyl.
  • the structural units Preferably selected from More preferably
  • the structural units Preferably selected from
  • the structural units Preferably, the structural units
  • R 1 is as described in any one of the present invention.
  • E ring is selected from 4-6 membered heterocyclyl, and the E ring is optionally substituted by one or more R c , each R c is independently selected from hydrogen, F, Cl, -OH, oxo group , -CN, -CH 3 , -OCH 3 ;
  • the E ring is selected from azetidinyl, pyrrolidinyl and piperidinyl;
  • L 1 is as described in any one of the present invention.
  • R3 is as described in any one of the invention.
  • the E ring is preferably azetidinyl or pyrrolidinyl, more preferably More preferably The E ring is optionally substituted by one or more R c , each R c is independently selected from H, F, Cl, -OH, -CN, -CH 3 , -OCH 3 .
  • R a is selected from H, F, Cl, -OH, -CN, -C 1-3 alkyl and -OC 1-3 alkyl, the C 1-3 alkyl is optionally replaced by one or more selected from F, Cl, -OH and -CN substituents are substituted;
  • R 1-1 is selected from H, -C 1-6 alkylene-OH, -C 1-6 alkyl, -halo C 1-6 alkyl and -deuterated C 1-6 alkyl;
  • Ring E is selected from a 4-6 membered heterocyclyl group, the heteroatom of the 4-6 membered heterocyclyl group is N, and the number of heteroatoms is 1, 2 or 3;
  • the E ring is optionally substituted by one or more R c , each R c is independently selected from H, F, Cl, -OH, -CN, -C 1-6 alkylene -OH, -C 1- 6 alkyl and -halo C 1-6 alkyl;
  • R 3 is selected from -CN, -C(O)NH 2 , -OC(O)NH 2 , -OC 1-6 alkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NHC( O )C 1-6 alkyl, -C(O)C 1-6 alkyl, -NHC(O)OC 1-6 alkyl, -S(O) 2 C 1-6 alkyl, -C 1-6 alkyl S(O) 2 C 1-6 alkyl, -halo C 1-6 alkyl, -O-halo C 1-3 alkyl, C 1-6 alkyl-CN, C 1-6 alkyl-OH, C 1-6 alkyl-NH 2 , -C 1-6 alkyl OC 1-6 alkyl and -cyclopropyl-OH; each of the C 1-6 alkyl groups Optionally substituted with one or more substituents selected from hydrogen, halogen, -OH, amino and cyan
  • the compound of formula (I) or formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof isotope label, metabolite or prodrug, wherein R a is selected from H, F, Cl, -CH 3 , -CN, -OCH 3 and -CH 2 OH.
  • R 1-1 is selected from -C 1-6 alkyl and -deuterated C 1-6 alkyl; the -C 1-6 alkyl The group is preferably -C 1-3 alkyl, more preferably -CH 3 ; the -deuterated C 1-6 alkyl group is preferably - deuterated C 1-3 alkyl, more preferably -CD 3 .
  • the compound of formula (I) or formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof isotope label, metabolite or prodrug, wherein the E ring is selected from azetidinyl, pyrrolidinyl and piperidinyl.
  • the compound of formula (I) or formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof isotope label, metabolite or prodrug, wherein R c is each independently selected from hydrogen, F, Cl, -OH, -CN, -CH 3 , -OCH 3 and -CH 2 OH.
  • compounds of formula (I) or formula (I-2) or pharmaceutically acceptable salts, esters, stereoisomers thereof, Tautomers, polymorphs, solvates, isotopic labels, metabolites or prodrugs wherein R 3 is selected from -CN, -C(O)NH 2 , -OC(O)NH 2 , - OC 1-3 alkyl, -C 1-3 alkyl -OH, -S(O) 2 CH 3 , -CH 2 S(O) 2 CH 3 , -halogenated C 1-3 alkyl, -O- Halogenated C 1-3 alkyl, -C 1-3 alkyl-CN and -C 1-3 alkyl-OC 1-3 alkyl .
  • the compound of formula (I) or formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof isotope label, metabolite or prodrug, wherein R 3 is selected from -CN, -CH 2 OH, -CHF 2 , -CH 2 F and -CF 3 .
  • R a is selected from H, F, Cl, -CH 3 , -CN, -OCH 3 and -CH 2 OH;
  • R 1-1 is -CH 3 and -CD 3 ;
  • E ring is selected from azetidinyl, pyrrolidinyl and piperidinyl;
  • the E ring is optionally substituted by one or more R c , each R c is independently selected from hydrogen, F, Cl, -OH, -CN, -CH 3 , -OCH 3 and -CH 2 OH;
  • R 3 is selected from -CN, -C(O)NH 2 , -OC(O)NH 2 , -OC 1-3 alkyl, -C 1-3 alkyl -OH, -S(O) 2 CH 3 , -CH 2 S(O) 2 CH 3 , -halo C 1-3 alkyl, -O-halo C 1-3 alkyl, -C 1-3 alkyl-CN and -C 1-3 alkyl -OC 1-3 alkane; preferably, R 3 is selected from -CN, -CH 2 OH, -CHF 2 , -CH 2 F and -CF 3 .
  • R 1-1 , R c , R 3 and R a are as described in any one of the present invention.
  • R 1-1 is -CH 3 and -CD 3 ;
  • R a is selected from H, F, Cl, -CH 3 , -CN, -OCH 3 and -CH 2 OH;
  • R c is each independently selected from hydrogen, F, Cl, -OH, -CN, -CH 3 , -OCH 3 and -CH 2 OH;
  • R 3 is selected from -CN, -C(O)NH 2 , -OC(O)NH 2 , -OC 1-3 alkyl, -C 1-3 alkyl -OH, -S(O) 2 CH 3 , -CH 2 S(O) 2 CH 3 , -halo C 1-3 alkyl, -O-halo C 1-3 alkyl, -C 1-3 alkyl-CN and -C 1-3 alkyl -OC 1-3 alkane; preferably, R 3 is selected from -CN, -CH 2 OH, -CHF 2 , -CH 2 F and -CF 3 .
  • the compound of formula (I-2) or formula (I-3) or formula (I-4) or formula (I-5) or a pharmaceutically acceptable salt, ester, stereoisomer thereof Conforms, tautomers, polymorphs, solvates, isotopic labels, metabolites or prodrugs, the compound being selected from:
  • R c , R 3 and R a are as described in any one of the present invention.
  • formula (I-3-1) or formula (I-3-2) or formula (I-4-1) or formula (I-4-2) or formula (I-5 -1) A compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite or prodrug thereof, wherein,
  • R a is selected from H, F, Cl, -CH 3 , -CN, -OCH 3 and -CH 2 OH;
  • R c is each independently selected from hydrogen, F, Cl, -OH, -CN, -CH 3 , -OCH 3 and -CH 2 OH;
  • R 3 is selected from -CN, -C(O)NH 2 , -OC(O)NH 2 , -OC 1-3 alkyl, -C 1-3 alkyl -OH, -S(O) 2 CH 3 , -CH 2 S(O) 2 CH 3 , -halo C 1-3 alkyl, -O-halo C 1-3 alkyl, -C 1-3 alkyl-CN and -C 1-3 alkyl -OC 1-3 alkane.
  • R3 is selected from -CN, -CH2OH , -CHF2 , -CH2F and -CF3 .
  • R 3 is selected from cyano group, -OC 1-6 alkyl group, -NHC 1-6 alkyl group, -NHC(O)C 1-6 alkyl group, -C(O )C 1-6 alkyl, -NHC(O)OC 1-6 alkyl, -S(O) 2 C 1-6 alkyl; each of the C 1-6 alkyl groups is optionally replaced by one or more Substituted with a substituent selected from hydrogen, halogen, -OH, cyano, -O-(C 1-6 alkyl).
  • the compound is not the following compound:
  • the 5- to 10-membered heteroaromatic ring is preferably a 5- to 6-membered heteroaryl group, and more preferably is a pyridyl or pyrimidinyl group.
  • the halogen or halogen is preferably fluorine, chlorine or bromine, more preferably fluorine.
  • the -C 1-6 alkyl group is preferably -C 1-3 alkyl group, more preferably methyl, ethyl or isopropyl group.
  • the -OC 1-6 alkyl group is preferably -OC 1-3 alkyl group, and more preferably is a methoxy group.
  • the -NHC 1-6 alkyl group is preferably -NHC 1-3 alkyl group.
  • the -N(C 1-6 alkyl) 2 is preferably -N(C 1-3 alkyl) 2 .
  • the -NHC(O)C 1-6 alkyl group is preferably -NHC(O)C 1-3 alkyl group.
  • the -C 2-6 alkenyl group is preferably -C 2-4 alkenyl group, more preferably vinyl or propenyl group.
  • the -C 2-6 alkynyl group is preferably -C 2-4 alkynyl group, more preferably an ethynyl group or a propynyl group.
  • the -halogenated C 1-6 alkyl group is preferably -halogenated C 1-3 alkyl group, and more preferably -halogenated methyl or -halogenated ethyl group.
  • the -C 3-12 cycloalkyl group is preferably -C 3-8 cycloalkyl group, and more preferably is -C 3-6 cycloalkyl group.
  • the -4-12-membered heterocyclic group is preferably -4-8-membered heterocyclic group, more preferably -4-6-membered heterocyclic group, further preferably azebutinyl, pyridinyl Rrolidyl, piperidinyl or piperazinyl.
  • the -halo C 1-6 alkoxy group is preferably - halo C 1-3 alkoxy group, and more preferably - halomethoxy or -haloethoxy group.
  • the -C 1-6 alkylene- is preferably -C 1-3 alkylene-, more preferably -methylene, -ethylene or propylene.
  • the -C 3-6 cycloalkylene group - is preferably - cyclopropylene group.
  • the -NHC(O)-S(O) 2 -(C 1-6 alkylene)- is preferably -NHC(O)-S(O) 2 -(C 1-3 alkylene)-.
  • the -C(O)C 1-6 alkylene group- is preferably -C(O)C 1-3 alkylene group-.
  • the -C(O)C 1-6 alkyl group is preferably -C(O)C 1-3 alkyl group.
  • the -NHC(O)OC 1-6 alkyl group is preferably -NHC(O)OC 1-3 alkyl group.
  • the -S(O) 2 C 1-6 alkyl group is preferably -S(O) 2 C 1-3 alkyl group, and more preferably is -S(O) 2 CH 3 alkyl group.
  • the -NHC 1-6 alkyl-N(C 1-6 alkyl) 2 is preferably -NHC 1-3 alkyl-N(C 1-3 alkyl) 2 .
  • the -NH-C(O)O(C 1-6 alkyl) is preferably -NH-C(O)O(C 1-3 alkyl).
  • the -N(C 1-6 alkyl)-C(O)OC 1-6 alkyl group is preferably -N(C 1-3 alkyl)-C(O)OC 1-3 alkyl group.
  • the -OC(O)NHC 1-6 alkyl group is preferably -OC(O)NHC 1-3 alkyl group.
  • the -N(C 1-3 alkyl)C(O)C 1-3 alkyl group is preferably -N(C 1-3 alkyl)C(O)C 1-3 alkyl group.
  • the present invention provides the following compounds or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope labels, metabolites or prodrugs, and the compounds are selected from since:
  • the present invention provides a method for preparing a compound of formula (I), which method includes the following steps:
  • Compounds IN1-1 and IN1-2 are dissolved in organic solvents (such as DMF, DMSO, NMP, dioxane, dichloromethane, toluene, tetrahydrofuran, chloroform, acetonitrile, etc.) and in organic bases (such as Et 3 N, DIPEA, N-methylmorpholine, DBU, sodium hydride, etc.) or inorganic bases (such as potassium carbonate, cesium carbonate, etc.) through substitution reaction or metal catalysis (such as: Pd(PPh3) 4 , PdCl 2 (dpPf) 2 , etc.) to obtain compound IN1-3; 2.
  • organic solvents such as DMF, DMSO, NMP, dioxane, dichloromethane, toluene, tetrahydrofuran, chloroform, acetonitrile, etc.
  • organic bases such as Et 3 N, DIPEA, N-methylmorpholine, DBU, sodium hydride,
  • Compound IN1-3 first generates intermediates under the action of oxidants (such as: m-CPBA, potassium hydrogen persulfate, etc.) Sulfoxide is then substituted with compound IN1-4 in a base (such as Et 3 N, DIPEA, N-methylmorpholine, DBU, sodium hydride, etc.) to obtain the compound of formula (I).
  • oxidants such as: m-CPBA, potassium hydrogen persulfate, etc.
  • Sulfoxide is then substituted with compound IN1-4 in a base (such as Et 3 N, DIPEA, N-methylmorpholine, DBU, sodium hydride, etc.) to obtain the compound of formula (I).
  • LG 1 represents a halogen leaving group, and the remaining groups are as defined in formula (I).
  • LG 1 is preferably chlorine or bromine
  • the starting materials for the preparation method of the present invention can be obtained from commercial sources or can be prepared according to known methods.
  • reaction steps can be appropriately adjusted, and the protection/deprotection reaction steps can be added or omitted.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof , isotope labels, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
  • a further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which method includes combining the compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more Pharmaceutically acceptable carrier combination.
  • the pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier, and examples of suitable pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (2005).
  • the pharmaceutical composition may be administered in any form so long as it prevents, alleviates, prevents, or cures symptoms in human or animal patients.
  • various suitable dosage forms can be prepared according to the route of administration.
  • administration of a compound or pharmaceutical composition of the invention may be combined with additional treatments.
  • the additional treatment methods may be selected from, but are not limited to: radiotherapy, chemotherapy, immunotherapy, or combinations thereof.
  • the present invention also relates to a pharmaceutical preparation, which contains a compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention.
  • the formulation is in the form of a solid, semi-solid, liquid or gaseous formulation.
  • a further object of the present invention is to provide a product, for example in the form of a kit.
  • Article of manufacture as used herein is intended to include, but is not limited to, kits and packaging.
  • the article of manufacture of the invention comprises: (a) a first container; (b) a pharmaceutical composition in the first container, wherein the composition comprises: a first therapeutic agent, the first therapeutic agent comprising: a compound of the invention or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) optionally a package insert stating that the pharmaceutical composition may be used to treat a neoplastic condition (as defined below); and (d) a second container.
  • the first container is a container for containing a pharmaceutical composition. This container can be used for preparation, storage, shipping and/or individual/bulk sales.
  • the first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (eg for cream preparations), or any other container used for preparing, containing, storing or dispensing a pharmaceutical product.
  • the second container is a container for holding the first container and optional package inserts.
  • the second container include, but are not limited to, boxes (eg, paper or plastic boxes), boxes, cartons, bags (eg, paper or plastic bags), sachets, and sacks.
  • the package insert may be physically adhered to the exterior of the first container via ties, glue, staples, or other means of adhesion, or it may be placed on the outside of the first container.
  • the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferred that the package insert is physically adhered via zip ties, glue, staples or other means of adhesion. Alternatively, it may abut or contact the exterior of the second container without physical adhesion.
  • the package insert is a trademark, label, sign, etc., which lists information related to the pharmaceutical composition located in the first container.
  • the information listed is generally determined by the regulatory agency (eg, the United States Food and Drug Administration) governing the area in which the product is marketed.
  • the package insert specifically lists the indications for which the pharmaceutical composition is approved.
  • the package insert may be made of any material from which the information contained in or on it can be read.
  • the package insert is a printable material (eg paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (eg printed or applied).
  • the present invention provides the use of a compound described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating Wee1 kinase-related diseases.
  • the invention provides the use of a compound described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention in the preparation of a Wee1 inhibitor.
  • the Wee1 inhibitor can be used in vivo in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample to provide comparison, or prepared according to conventional methods in this field. into a kit that provides rapid detection of the inhibitory effect of Wee1.
  • the present invention provides the use of a compound described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of cancer.
  • the cancers include, but are not limited to, breast, colorectal, colon, lung, and prostate cancers, as well as cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, renal cancer, liver cancer, gastrointestinal cancer, Tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) ) and chronic myeloid leukemia (CML)), multiple myeloma, and lymphoma.
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphoblastic leukemia
  • CML chronic myeloid leukemia
  • the lung cancer is lung adenocarcinoma.
  • the colorectal cancer is colorectal adenocarcinoma.
  • the invention provides a method for preventing or treating Wee1 kinase-related diseases, the method comprising administering a compound as described herein or a pharmaceutically acceptable form thereof, or a medicament of the invention to an individual in need thereof. combination.
  • the present invention provides a compound as described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention for preventing or treating Wee1 kinase-related diseases.
  • the invention provides a method for preventing or treating a Wee1 kinase-related disease in combination with a compound as described herein, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention, in combination with an additional therapeutic method, the additional therapeutic method being Treatment methods include, but are not limited to: radiotherapy, chemotherapy, immunotherapy, or combinations thereof.
  • the Wee1 kinase-associated disease is a disease that is sensitive or responsive to Wee1 kinase inhibition.
  • the Wee1 kinase-associated disease is cancer.
  • the cancers include, but are not limited to, breast, colorectal, colon, lung, and prostate cancers, as well as cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, renal cancer, liver cancer, gastrointestinal cancer, Tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) ) and chronic myeloid leukemia (CML)), multiple myeloma, and lymphoma.
  • the lung cancer is lung adenocarcinoma.
  • the colorectal cancer is colorectal adenocarcinoma.
  • the compounds of the invention can be used in combination with chemoradiotherapy or immunotherapy to prevent or treat cancer.
  • Dosing regimens can be adjusted to provide the best desired response. For example, when administered in injectable form, a single bolus, bolus injection, and/or continuous infusion may be administered, among others. For example, several divided doses may be administered over time or may be proportionally reduced as the exigencies of the therapeutic situation indicate. or increase the dose. It is noted that dosage values may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. Generally, the dosage of treatment will vary depending on considerations such as: age, sex and general health of the patient to be treated; frequency of treatment and nature of the desired effect; extent of tissue damage; severity of symptoms Duration; and other variables that can be adjusted by individual physicians.
  • compositions according to the invention may also be provided in unit dosage form.
  • the present invention provides a new class of highly active Wee1 inhibitors that can achieve at least one of the following technical effects: (1) high inhibitory activity against Wee1 kinase; (2) excellent physical and chemical properties (such as solubility, physical and/or chemical stability); (3) excellent pharmacokinetic properties (such as good bioavailability, suitable half-life and duration of action); (4) excellent safety (lower toxicity and/or less side effects, wider therapeutic window), etc.
  • one or more may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) or more (species).
  • C 1-6 should be understood to encompass any subrange therein and every point value, such as C 2-5 , C 3-4 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , etc., and C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc.
  • C 3-10 should also be understood in a similar manner, e.g. to encompass any subranges and point values contained therein, such as C 3-9 , C 6-9 , C 6-8 , C 6- 7 , C 7-10 , C 7-9 , C 7-8 , C 8-9, etc.
  • the expression "3-10 yuan” should be understood to cover any sub-range and every point value therein, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan Yuan, 3-9 Yuan, 4-5 Yuan, 4-6 Yuan, 4-7 Yuan, 4-8 Yuan, 5-7 Yuan, 5-8 Yuan, 6-7 Yuan, etc. and 3, 4, 5, 6 , 7, 8, 9, 10 yuan, etc.
  • the expression "5-10 yuan” should also be understood in a similar manner, for example, it can cover any sub-range and point value included therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5- 9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc. and 5, 6, 7, 8, 9, 10 yuan, etc.
  • alkyl when used herein alone or in combination with other groups refers to a saturated straight or branched chain hydrocarbon group.
  • C 1-6 alkyl refers to a saturated straight or branched chain hydrocarbon radical having 1 to 6 carbon atoms (eg, 1, 2, 3, 4, 5 or 6 carbon atoms).
  • C 1- 6Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl wait.
  • alkenyl refers to a straight or branched hydrocarbon group containing one or more double bonds.
  • alkenyl groups include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, and the like.
  • C2-6 alkenyl groups with more than one double bond include butadienyl, pentadienyl, hexadienyl and hexatrienyl and branched forms thereof.
  • the position of the unsaturated bond (double bond) can be anywhere in the carbon chain.
  • alkynyl refers to an unsaturated straight or branched chain alkynyl group, such as ethynyl, 1-propynyl, propargyl, butynyl, and the like.
  • alkylene when used herein alone or in combination with other groups refers to a saturated straight or branched chain divalent hydrocarbon radical.
  • C 1-6 alkylene refers to a saturated linear or branched divalent hydrocarbon radical having 1 to 6 carbon atoms.
  • C 1-6 alkylene includes, for example, but is not limited to methylene, ethylene, propylene or butylene.
  • alkenylene refers to a linear or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon double bonds to which two Groups (or fragments) can be connected to the same carbon atom or to different carbon atoms.
  • C 2-6 alkenylene refers to an alkenylene group having 2 to 6 carbon atoms (e.g. wait).
  • alkynylene refers to a linear or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon triple bonds to which two Groups (or fragments) are connected to different carbon atoms.
  • C 2-6 alkynylene refers to an alkynylene group having 2 to 6 carbon atoms (e.g. wait).
  • alicyclic or "aliphatic hydrocarbon ring” refers to aliphatic hydrocarbons that are monocyclic or polycyclic (including fused rings, bridged rings, and spiro rings, such as bicyclic rings) Ring system, including cycloalkane ring, cycloalkene ring, cycloalkyne ring, etc.
  • cycloalkyl When used herein alone or in combination with other groups, the terms “cycloalkyl”, “carbocyclic” or “cycloalkylene” refer to saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-cyclic Aromatic hydrocarbon group.
  • Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cycloalkyl Pentene, cyclohexene, etc.; or bicyclic cycloalkyl, including fused ring, bridged ring or spiro ring, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl base, bicyclo[5.2.0]nonyl, decalinyl, etc.
  • C 3-12 cycloalkyl refers to a cycloalkyl group having 3 to 12 ring carbon atoms (eg, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12).
  • heterocycloalkyl refers to a saturated or partially saturated, monocyclic or polycyclic ring (such as a bicyclic ring, for example: a bridged ring, a bridged ring or spirocyclic) non-aromatic group, the ring atoms of which are composed of carbon atoms and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur.
  • a heterocycloalkyl group can be attached to the rest of the molecule through any ring atom if the valence bond requirements are met.
  • heterocycloalkyl refers to a heterocycloalkyl group having 3 to 8 ring atoms.
  • Common heterocycloalkyl groups include (but are not limited to) oxiranyl, oxocyclobutanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl , sulfolane, etc.
  • heteroaryl or “heteroaryl ring” refers to an aromatic ring having a conjugated pi electron system. Rings in which one or more (eg 1, 2 or 3) ring atoms are heteroatoms selected from N, O, P and S, and the remaining ring atoms are C. Heteroaryl or heteroaromatic rings can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group may contain 5-12 (eg, 5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, especially 5, 6, 9, 10 ring atoms. .
  • heteroaryl groups are, for example, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl, etc.; this term also covers the situation where the heteroaryl or heteroaromatic ring can optionally be further fused to the aryl or heteroaryl ring to form a fused ring.
  • haloalkyl refers to an alkyl group as described above, in which one or more hydrogen atoms are replaced by halogen.
  • C 1-6 haloalkyl refers to a C 1-6 alkyl group optionally substituted with one or more (eg, 1-3) halogens.
  • the halogens may be the same or different and may be located on the same or different C atoms.
  • haloalkyl groups are, for example, -CH 2 F, -CHF 2 , -CF 3 , -CCl 3 , -C 2 F 5 , -C 2 Cl 5 , -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 etc.
  • alkoxy when used herein alone or in combination with other groups means an alkyl group as described above with an oxygen atom attached to the parent molecular moiety.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, pentyloxy, and the like.
  • halogen when used herein alone or in combination with other groups refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • hydroxy refers to -OH.
  • cyano refers to -CN
  • nitro refers to -NO2 .
  • amino refers to -NH2 .
  • each independently used herein means that at least two groups (or fragments) present in the structure with the same or similar value ranges can have the same or different meanings under specific circumstances.
  • the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl.
  • the substituent Y can be either hydrogen, halogen, or Hydroxy, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl
  • substituted and its other variations herein means that one or more (such as 1, 2, 3 or 4) atoms or groups of atoms (such as hydrogen atoms) on the specified atom are replaced by other equivalents , provided that the normal valency of the specified atom or group of atoms in the current situation is not exceeded and that a stable compound can be formed. If an atom or group of atoms is described as “optionally substituted,” it may be either substituted or unsubstituted. Unless otherwise stated, the attachment point for a substituent herein may be from any suitable position on the substituent. When the bond in a substituent is shown as a chemical bond passing through two atoms connected to each other in the ring system, it means that the substituent can be connected to any ring-forming atom in the ring system.
  • Solid lines may be used in this article solid wedge or virtual wedge Draw the carbon-carbon bonds of the compounds of the invention.
  • the use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, a racemic mixture, etc.).
  • the use of solid or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to demonstrate that the stereoisomers shown exist. When present in a racemic mixture, solid and imaginary wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the present invention may be present as stereoisomers (which includes cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixture).
  • the compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereoisomers).
  • the invention also encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the present invention may exist in free form for therapeutic use, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs that can be directly administered to a patient in need thereof. Or indirectly provide the compound of the present invention or its metabolite. Therefore, when reference is made herein to "a compound of the invention", it is also intended to encompass the various derivative forms of the compound described above.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts.
  • Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts.
  • suitable salts see, for example, “Remington's Pharmaceutical Sciences”, Mack Publishing Company, Easton, Pa., (2005); and “Handbook of Pharmaceutical Salts: Properties, Selection” , and Use), Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.
  • esters means an ester derived from the compounds described herein, which includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the compound of the invention) .
  • the compounds of the present invention may themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural elements of the crystal lattice of the compounds a polar solvent, in particular such as water, methanol or ethanol.
  • a polar solvent in particular such as water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming nitrogen oxides because nitrogen requires available lone pairs of electrons to oxidize to oxides.
  • nitrogen-containing heterocycles capable of forming nitrogen oxides.
  • tertiary amines are capable of forming nitrogen oxides. Synthetic methods for the preparation of nitrogen oxides of heterocyclic and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl peroxybenzoic acid, etc.
  • peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl peroxybenzoic acid, etc.
  • Hydrogen oxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyldioxirane oxidize heterocycles and tertiary amines.
  • These methods for the preparation of nitrogen oxides have been extensively described and reviewed in the literature, see for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750 (A.R. Katritzky and A.J. Boulton, Eds., Academic Press) ; and G.W.H. Cheeseman and E.S.G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392 (A.R. Katritzky and A.J. Boulton, Eds., Academic Press).
  • metabolites of the compounds of the invention ie substances formed in the body upon administration of the compounds of the invention. Metabolites of compounds can be identified by techniques well known in the art, and their activity can be characterized by experimental methods. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce metabolites thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity when administered into or onto the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • the prodrugs of the present invention can be prepared, for example, by using a compound known to those skilled in the art as a "pro-moiety (e.g. "Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985)" are prepared by substituting certain parts of the appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming chemically protected forms of the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, which references are incorporated herein by reference.
  • the protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the present invention also encompasses methods of preparing the compounds described herein. It will be appreciated that the compounds of the present invention may be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for effecting the transformation.
  • active ingredient refers to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.
  • the term "effective amount” refers to an amount of an active ingredient that, when administered, will achieve the desired effect, such as alleviation of the condition being treated. one or more symptoms or to prevent the occurrence of a disease or its symptoms.
  • treat means reversing, alleviating, inhibiting, or preventing the progression of one or more symptoms of the disorder or condition to which such term applies. a disease or condition or one or more symptoms of such a disease or condition.
  • “Individual” as used herein includes humans or non-human animals.
  • Exemplary human subjects include human subjects (referred to as patients) suffering from a disease, such as those described herein, or normal subjects.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs , cats, cows, pigs, etc.).
  • MS Mass spectrometry
  • Thin layer chromatography purification uses GF 254 (0.4 ⁇ 0.5nm) silica gel plate produced in Yantai.
  • the reaction is monitored by thin layer chromatography (TLC) or liquid chromatography mass spectrometry (LC-MS), and the developing agent system used includes but is not limited to In: methylene chloride and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system.
  • TLC thin layer chromatography
  • LC-MS liquid chromatography mass spectrometry
  • the volume ratio of the solvent can be adjusted according to the polarity of the compound, or triethylamine, etc. can be added for adjustment.
  • Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase.
  • the eluent system includes but is not limited to the dichloromethane and methanol system and the n-hexane and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine, etc. can also be added for adjustment.
  • reaction temperature is room temperature (20°C to 30°C).
  • reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology, or Shanghai Shuya Pharmaceutical Technology.
  • Step 1 Preparation of 2-bromo-6-(3-((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)pyridine (compound A1-2)
  • Step 2 2-allyl-1-(6-(3-((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)pyridin-2-yl) Preparation of -6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound A1-4)
  • Step 4 2-allyl-1-(6-(3-(hydroxymethyl)azetidin-1-yl)pyridin-2-yl)-6-(4-(4-methylpiperidine) Azin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (preparation of compound A1)
  • ADP-Glo luminescent kit was used to examine the effects of different compounds on Wee1 enzyme activity.
  • the Wee1 enzyme was purchased from Carna bioscience, and Poly(Lys Tyr(4:1)) was used as the enzyme reaction substrate.
  • A427 cells the effect of each compound on cell proliferation was detected. Specifically, after incubation for 120 hours with gradient diluted compounds, The chemiluminescence cell viability assay (CTG method) evaluates and calculates the half inhibitory concentration (IC50) of the compound on these cell lines.
  • CCG method chemiluminescence cell viability assay
  • HT29 SNU5, SNU16, and A427 cells
  • CCG method evaluates and calculates the half inhibitory concentration (IC50) of the compound on these cell lines.
  • the compound A9S of the present invention reaches a higher exposure level in the systemic circulation of female and male mice at an injection dose of 1 mg/kg and an oral dose of 10 mg/Kg, and its comprehensive properties are significantly better than AZD1775, showing excellent Pharmacokinetic properties.
  • HEK 293 human embryonic kidney cells, purchased from Invitrogen: cells were cultured in a medium containing 85% DMEM, 10% dialyzed fetal calf serum, 0.1mM NEAA, 25mM HEPES, The cells were cultured in the culture medium of 100 U/mL penicillin-streptomycin, 5 ⁇ g/mL Blasticidin and 400 ⁇ g/mL Geneticin. The cells were cultured in a cell culture flask of 25 cm 2 , 5% CO 2 , and 37°C.
  • Cells were passaged approximately three times per week using TrypLE TM Express, maintaining at approximately 40% to 80% confluency. Before the experiment, cells were induced with doxycycline (1 ⁇ g/mL) for 48 hours. On the day of the experiment, the induced cells were resuspended and seeded in a 3.5cm cell culture dish containing a coverslip (5 ⁇ 10 5 cells/3.5cm cell culture dish) before use, and cultured in a medium without Blasticidin and Geneticin.
  • the passage number of the cell lines used for safety evaluation tests is less than 60.
  • test compounds were dissolved in DMSO and formulated at 30mM, 10mM, 3.33mM, 1.11mM and 0.37mM. Extracellular fluid was then added respectively, with the final concentrations of test compounds being 30 ⁇ M, 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M and 0.37 ⁇ M, and the final concentration of DMSO being 0.1%.
  • Test group Add different concentrations of the compounds to be tested into the microwell plate, add Luciferin-ME (100 ⁇ M), K 3 PO 4 (100mM) and CYP1A2 (0.01pmol/ ⁇ L) to each well, and pre-incubate at room temperature. 10 min, then add NADPH regeneration system, react at room temperature for 30 min, finally add an equal volume of detection buffer, incubate at room temperature for 20 min, and then perform chemiluminescence detection.
  • Luciferin-ME 100 ⁇ M
  • K 3 PO 4 100mM
  • CYP1A2 CYP1A2
  • Negative control group The experimental method is the same as that of the test group, except that the compound to be tested is not added.
  • Blank control group The experimental method is the same as that of the test group, except that the compound to be tested is not added, and CYP1A2 Membrance (0.01pmol/ ⁇ L) is used instead of CYP1A2.
  • Test group Add different concentrations of the compounds to be tested into the microwell plate, and add Luciferin-ME EGE (3 ⁇ M), K 3 PO 4 (100mM) and CYP2D6 (5nM) were pre-incubated at room temperature for 10 min, then the NADPH regeneration system was added, reacted at 37°C for 30 min, and finally an equal volume of detection buffer was added, incubated at room temperature for 20 min, and then Chemiluminescence detection.
  • Luciferin-ME EGE 3 ⁇ M
  • K 3 PO 4 100mM
  • CYP2D6 5nM
  • Negative control group The experimental method is the same as that of the test group, except that the compound to be tested is not added.
  • Blank control group The experimental method is the same as that of the test group, except that the compound to be tested is not added, and CYP2D6 Membrance (5nM) is used instead of CYP2D6.
  • Test group Add different concentrations of the compounds to be tested into the microwell plate, add Luciferin-IPA (3 ⁇ M), K 3 PO 4 (100mM) and CYP3A4 (2nM) to each well, pre-incubate at room temperature for 10 minutes, and then Add the NADPH regeneration system and react at room temperature for 30 minutes. Finally, add an equal volume of detection buffer and incubate at room temperature for 20 minutes, and then perform chemiluminescence detection.
  • Luciferin-IPA 3 ⁇ M
  • K 3 PO 4 100mM
  • CYP3A4 2nM
  • Negative control group The experimental method is the same as that of the test group, except that the compound to be tested is not added.
  • Blank control group The experimental method is the same as that of the test group, except that the compound to be tested is not added, and CYP3A4 Membrance (2nM) is used instead of CYP3A4.
  • Percent inhibition rate (1-(chemiluminescence signal value of the test compound concentration group-chemiluminescence signal value of the blank control group)/(chemiluminescence signal value of the negative control group-chemiluminescence signal value of the blank control group)) ⁇ 100%.

Abstract

涉及一种嘧啶并五元杂环化合物、其制备方法和用途，以及包含其的药物组合物。具体地，涉及式(I)所示的化合物或其药学上可接受的形式，其表现出较好的Wee1抑制活性，可以作为高效的Wee1抑制剂，用于预防和/或治疗Wee1相关疾病。

Description

一种嘧啶并五元杂环化合物、其制备方法和用途
本申请要求申请日为2022/7/15的中国专利申请2022108377886、申请日为2023/4/12的中国专利申请2023103912164的优先权和申请日为2023/7/10的中国专利申请2023108424468的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及药物化学领域，并且具体地涉及一种用作Wee1抑制剂的吡唑并嘧啶酮化合物、其制备方法、药物组合物及其用于预防和/或治疗Wee1激酶相关疾病中的用途。
背景技术
细胞周期是一个高度调节和控制的过程。正常细胞周期在G1/S转换、S期和G2/M转换处有检查点，为DNA损伤修复留出足够的时间。由于TP53突变，许多人类癌细胞受到G1/S检查点的缺乏调控，因此严重依赖G2/M检查点调控。Wee1激酶是G2/M检查点的关键调节因子(C.J.Matheson，D.S.Backos，P.Reigan，Trends in Pharmacological Sciences，2016，37：872)，属于非典型酪氨酸激酶，在酪氨酸15(Y15)上磷酸化Cdk1(也称为Cdc2)，导致其功能失活。Cdk1招募细胞周期蛋白A和B启动有丝分裂。通过Wee1抑制剂来废除G2检测点可能选择性的使P53缺陷性癌细胞对DNA损伤敏感，避免对周围正常组织产生影响。Wee1也调节S期的CDK活性，阻止正常的S期进程中DNA损伤的诱导。此外，Wee1在同源重组(HR)修复中起积极调节作用，同源重组修复是DNA双链断裂修复的重要路径。
Wee1在许多癌症中高度表达，包括乳腺癌、肺癌、宫颈癌、头颈癌、卵巢癌、前列腺癌、黑色素瘤、白血病、胶质母细胞瘤、髓母细胞瘤、肝细胞癌。此外，Wee1的高度表达与多种类型癌症的不良预后有关。抑制Wee1激酶活性从而移除G2/M检查点的功能是一种有潜力的策略来驱动肿瘤细胞进入到计划外的有丝分裂，从而经历有丝分裂障碍而导致细胞死亡。这种细胞未完成DNA复制而被迫进入有丝分裂的方式，对细胞的毒性很大，代表了一种新颖的诱导肿瘤细胞死亡的机制。因此，Wee1抑制剂作为药物具有良好的应用前景。
目前已经报道了一些Wee1抑制剂(例如：WO2007126122A1，WO2019173082A1，WO2018011569A1，WO2018162932A1，WO2018090939，WO2019074981等)，但本领域仍然亟需新的Wee1抑制剂，特别是具有高活性以及其他优异性质的Wee1抑制剂，以满足临床未满足的用药需求。
发明内容
第一方面，本发明提供式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，
其中，
A环选自苯基、5-10元杂芳环；所述的A环任选地被一个或多个Ra取代；
每一个Ra各自独立地选自H、卤素、-OH、-CN、-C1-6烷基、-OC1-6烷基、-NHC1-6烷基、-N(C1- 6烷基)2、-C2-4烯基、-C2-4炔基；所述的C1-6烷基、C2-4烯基、C2-4炔基各自任选地被一个或多个选自氢、卤素、氧代基、-OH、-CN、-NH2、-C1-6烷基的取代基取代；
R1选自卤素、-CN、C1-6烷基、卤代C1-6烷基、-C3-12环烷基、4-12元杂环基、-O-(4-12元杂环基)、-N(Rb)-(4-12元杂环基)、-C(O)(4-12元杂环基)、-C(O)NRbRd、-N＝S(O)RbRd；所述的C1-6烷基、C3-12环烷基、4-12元杂环基各自任选地被一个或多个选自卤素、氧代基、-CN、-ORb、-NRbRd、-C1- 6烷基、-卤代C1-6烷基、-卤代C1-6烷氧基、-C1-6亚烷基-ORb、-C1-6亚烷基-NRbRd、-C3-8环烷基、4-8元杂环基、-SRb、-C(O)Rb、-C(O)ORb、-C(O)NRbRd、-N(Rb)C(O)Rd、-N(Rb)C(O)ORd、-S(O)2Rd、-N(Rb)S(O)2Rd的取代基取代；进一步的，所述的C3-8环烷基、4-8元杂环基各自任选地被一个或多个选自卤素、氧代基、-OH、-CN、-C1-6烷基、-卤代C1-6烷基、-NHC1-6烷基、-N(C1-6烷基)2取代基取代；
Rb、Rd各自独立地选自H、-C1-6烷基、-C3-6环烷基、4-12元杂环基；所述的C1-6烷基、C3-6环烷基、4-12元杂环基各自任选地被一个或多个选自卤素、氧代基、-OH、-CN、-NH2、-N(C1-6烷基)2、-C1-6亚烷基-OH、-OC1-6烷基、-C1-6亚烷基-NHC1-6烷基、-C1-6亚烷基-N(C1-6烷基)2的取代基取代；
R2选自氢、卤素、-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、4-8元杂环基、苯基、5-6元杂芳基；所述的C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、4-8元杂环基、苯基、杂芳基各自任选地被一个或多个选自卤素、氧代基、-OH、-CN、-NH2、-C1-6烷基的取代基取代；
B环选自苯基、5-10元杂芳基；所述的B环任选地被一个或多个选自氢、卤素、-CN、-OCH3的取代基取代；
E环选自-C3-12环烷基、4-12元杂环基；所述的E环任选地被一个或多个Rc取代；
每一个Rc各自独立地选自氢、卤素、-OH、氧代基、氰基、-C1-6烷基、-OC1-6烷基；
X选自CH或者N；
L1选自单键、-C1-6亚烷基-、-C3-6亚环烷基-、-(3-6元亚杂环基)-、-NHC(O)-S(O)2-(C1-6亚烷基)-、-C(O)C1-6亚烷基-、-C(O)C3-6亚环烷基-、-C(O)-(3-6元亚杂环基)-和-C(O)-，其中所述C1-6亚烷基、3-6元亚杂环基和C3-6亚环烷基各自任选地被一个或多个选自氢、卤素、氧代基、-OH和氨基的取代基取代；
R3选自如下条件：
i)L1为单键时，R3选自氰基、-OC1-6烷基、-NHC1-6烷基、-N(C1-6烷基)2、-NHC(O)C1-6烷基、-C(O)C1-6烷基、-NHC(O)OC1-6烷基、-S(O)2C1-6烷基；所述的C1-6烷基各自任选地被一个或多个选 自氢、卤素、-OH、氰基、-O-(C1-6烷基)的取代基取代；
ii)L1不为单键时，R3选自卤素、氨基、-OH、氰基、-卤代C1-6烷基、-S(O)2C1-6烷基、-OC1-6烷基、-NHC1-6烷基-N(C1-6烷基)2、-NH-C(O)O(C1-6烷基)、-N(C1-6烷基)-C(O)OC1-6烷基、-OC(O)NH2、-OC(O)NHC1-6烷基和-N(C1-6烷基)C(O)C1-6烷基，其中所述C1-6烷基任选地被一个或多个选自卤素、氧代基、-OH、氨基和-O-(C1-6烷基)的取代基取代。
在本发明的一些实施方案中，L1为单键时，R3还可以为氰基。
在本发明的一些实施方案中，L1为单键时，R3选自-OC1-6烷基、-NHC1-6烷基、-N(C1-6烷基)2、-NHC(O)C1-6烷基、-C(O)C1-6烷基、-NHC(O)OC1-6烷基、-S(O)2C1-6烷基；所述的C1-6烷基各自任选地被一个或多个选自氢、卤素、-OH、氰基、-O-(C1-6烷基)的取代基取代。
本发明所述药学上可接受的形式选自药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、氮氧化物、同位素标记物、代谢物或前药。
在本发明的一些实施方案中，式(I)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，
A环选自苯基、吡啶基、噻吩基和吡唑基，所述的A环任选地被一个或多个Ra取代，每一个Ra各自独立地选自H、F、Cl、-OH、-C1-3烷基和-OC1-3烷基，所述C1-3烷基任选地被一个或多个选自F、Cl、-OH和-CN的取代基取代；
优选地，A环选自苯基，所述的苯基任选地被一个或多个Ra取代，每一个Ra各自独立地选自H、F、Cl、-OH、-C1-3烷基和-OC1-3烷基，所述C1-3烷基任选地被一个或多个选自F、Cl、-OH和-CN的取代基取代；
更优选地，A环选自苯基，所述的苯基任选地被一个或多个Ra取代，Ra选自H、F、Cl、-CH3、-OCH3和-CH2OH。
在本发明的一些实施方案中，A环优选为苯基，更优选为
在本发明的一些实施方案中，式(I)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中R1选自C1-6烷基、4-6元杂环基、C4-6环烷基、-O-(4-6元杂环基)、-NH-(4-6元杂环基)、-C(O)N(C1-6烷基)2，所述4-6元杂环基和C4- 6环烷基各自任选地被一个或多个选自卤素、氧代基、-OH、-CN、-OCH3、-NH2、-N(C1-3烷基)2、-C1-3烷基、-卤代C1-3烷基、-卤代C1-3烷氧基、-C1-3亚烷基-OH、-C1-3亚烷基-N(C1-3烷基)2、-C(O)OC1- 3烷基和-S(O)2C1-3烷基的取代基取代；
优选地，R1选自吡咯烷基、四氢吡喃基、哌啶基、四氢吡啶基、吗啉基和哌嗪基；所述吡咯烷基、四氢吡喃基、哌啶基、四氢吡啶基、吗啉基和哌嗪基各自任选地被一个或多个选自F、Cl、-OH、-CN、氧代基、-OCH3、-NH2、-N(CH3)2、-C1-3烷基、-卤代C1-3烷基、-卤代C1-3烷氧基、-C1-3亚烷基-OH、-C1-3亚烷基-N(CH3)2、-C(O)OC1-3烷基和-S(O)2C1-3烷基的取代基取代；
优选地，R1选自
在本发明的一些实施方案中，R1优选为4-12元杂环基，更优选为4-6元杂环基，进一步优选为6元杂环基；所述杂环基任选地被一个或多个-C1-6烷基或-氘代C1-6烷基取代，优选任选被一个或多 个-C1-3烷基或-氘代C1-3烷基取代，更优选被-CH3或-CD3取代。其中，所述杂环基中的杂原子选自N、O和S，优选为N。所述杂环基中的杂原子个数为1、2或3个，优选为1或2个。
在本发明的一些实施方案中，R1优选为哌啶基、四氢吡啶基或哌嗪基，所述哌啶基、四氢吡啶基或哌嗪基任选被一个或多个-C1-3烷基或-氘代C1-3烷基取代；更优选为哌嗪基，所述哌嗪基任选被一个或多个-CH3或-CD3取代。
在本发明的一些实施方案中，R1优选选自优选为
在本发明的一些实施方案中，式(I)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中R2选自-CH3、-CH2CH3、环丙基、异丙基、烯丙基、炔丙基、-CH2-环丙基、-CH2CF3；优选地，R2选自烯丙基。
在本发明的一些实施方案中，R2优选为-C2-6烯基，更优选为-C2-4烯基，进一步优选为烯丙基。
在本发明的一些实施方案中，式(I)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中B环选自苯基、吡啶基、嘧啶基、噻吩基和噻唑基，所述B环任选地被一个或多个选自氢、卤素和-CN的取代基取代；
优选地，B环选自吡啶基和苯基。
在本发明的一些实施方案中，B环优选为5-10元杂芳基，更优选为5-6元杂芳基，进一步优选为6元杂芳基。其中，所述杂芳基中的杂原子选自N、O和S，优选为N。所述杂芳基中的杂原子个数为1或2个，优选为1个。
在本发明的一些实施方案中，B环优选为嘧啶基或吡啶基，更优选为吡啶基，进一步优选为
在本发明的一些实施方案中，式(I)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中E环选自4-6元杂环基；所述的E环任选地被一个或多个Rc取代，每一个Rc各自独立地选自氢、F、Cl、-OH、氧代基、-CN、-CH3、-OCH3；
优选地，E环选自吖丁啶基、吡咯烷基和哌啶基。
在本发明的一些实施方案中，E环优选为吖丁啶基或吡咯烷基，更优选为进一步优选为所述的E环任选地被一个或多个Rc取代，每一个Rc各自独立地选自H、F、Cl、-OH、-CN、-CH3、-OCH3。
在本发明的一些实施方案中，式(I)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中L1选自亚甲基、-C(O)-亚甲基-O-和-C(O)-；其中所述亚甲基任选地被一个或多个选自氢、F、和-CH3的取代基取代。在本发明的一些实施方案中，L1优选选自单键、-C1-6亚烷基-、-C3-6亚环烷基-和-C(O)-；所述-C1-6亚烷基-优选为-C1-3亚烷基-，更优选为亚甲基；所述-C3-6亚环烷基-优选为亚环丙烷。
在本发明的一些实施方案中，式(I)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中R3选自：
i)L1为单键时，R3选自-OCH3、-NHCH3、-NHC(O)CH3、-C(O)CH3和-S(O)2CH3；
ii)L1不为单键时，R3选自F、氨基、-OH、-CN、-CHF2、-CH2F、-S(O)2CH3、-OCH3、-OCHF2、-NH-C(O)OCH3；优选地，R3选自F、-OH、-CN、-NH2-CHF2、-S(O)2CH3和-CH3。
在本发明的一些实施方案中，R3优选选自：
i)L1为单键时，R3选自氰基、-OC1-6烷基和-S(O)2C1-6烷基，其中所述的-OC1-6烷基任选地被一个或多个选自卤素的取代基取代；所述的-OC1-6烷基优选为-O-卤代C1-3烷基，更优选为-OCF2；所述的-S(O)2C1-6烷基优选为-S(O)2C1-3烷基，更优选为-S(O)2CH3；
ii)L1为-C1-6亚烷基-、-C3-6亚环烷基-或-C(O)-(优选-C1-6亚烷基-，更优选-C1-3亚烷基-)时，R3选自卤素、氨基、-OH、氰基、C1-6烷基、-卤代C1-6烷基、-S(O)2C1-6烷基和-OC1-6烷基；所述的-卤代C1-6烷基优选为-卤代C1-3烷基，更优选为氟代C1-3烷基，例如为CHF2或CH2F；所述的-S(O)2C1- 6烷基优选为-S(O)2C1-3烷基，更优选为-S(O)2CH3；所述的-OC1-6烷基优选为-OC1-3烷基，更优选为-OCH3。
在本发明的一些实施方案中，L1为亚甲基时，R3选自卤素、氨基、-OH、氰基、C1-6烷基、-卤代C1-6烷基、-S(O)2C1-6烷基和-OC1-6烷基；优选为卤素、氨基、-OH、氰基、C1-3烷基、-卤代C1-3烷基、-S(O)2C1-3烷基和-OC1-3烷基。
在本发明的一些实施方案中，结构单元优选选自更优选为
在本发明的一些实施方案中，结构单元优选选自
在本发明的一些实施方案中，结构单元为 优选为
在本发明的一些实施方案中，结构单元优选为
在本发明的一些实施方案中，式(I)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，所述化合物选自：
其中，R1如本发明任一项所述；
E环选自4-6元杂环基，所述的E环任选地被一个或多个Rc取代，每一个Rc各自独立地选自氢、F、Cl、-OH、氧代基、-CN、-CH3、-OCH3；优选地，E环选自吖丁啶基、吡咯烷基和哌啶基；
L1如本发明任一项所述；
R3如本发明任一项所述。
在本发明的一些实施方案中，式(I-1)化合物中，E环优选为吖丁啶基或吡咯烷基，更优选为 更优选为所述的E环任选地被一个或多个Rc取代，每一个Rc各自独立地选自H、F、Cl、-OH、-CN、-CH3、-OCH3。
在本发明的一些实施方案中，式(I)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，所述化合物选自：
其中，
Ra选自H、F、Cl、-OH、-CN、-C1-3烷基和-OC1-3烷基，所述C1-3烷基任选地被一个或多个选自F、Cl、-OH和-CN的取代基取代；
R1-1选自H、-C1-6亚烷基-OH、-C1-6烷基、-卤代C1-6烷基和-氘代C1-6烷基；
E环选自4-6元杂环基，所述4-6元杂环基的杂原子为N，杂原子个数为1个、2个或3个；
所述E环任选地被一个或多个Rc取代，Rc各自独立地选自H、F、Cl、-OH、-CN、-C1-6亚烷基-OH、-C1-6烷基和-卤代C1-6烷基；
R3选自-CN、-C(O)NH2、-OC(O)NH2、-OC1-6烷基、-NHC1-6烷基、-N(C1-6烷基)2、-NHC(O)C1- 6烷基、-C(O)C1-6烷基、-NHC(O)OC1-6烷基、-S(O)2C1-6烷基、-C1-6烷基S(O)2C1-6烷基、-卤代C1-6烷基、-O-卤代C1-3烷基、C1-6烷基-CN、C1-6烷基-OH、C1-6烷基-NH2、-C1-6烷基OC1-6烷基和-环丙基-OH；所述的C1-6烷基各自任选地被一个或多个选自氢、卤素、-OH、氨基和氰基的取代基取代。
在本发明的一些实施方案中，式(I)或式(I-2)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，Ra选自H、F、Cl、-CH3、-CN、-OCH3和-CH2OH。
在本发明的一些实施方案中，式(I-2)化合物中，R1-1选自-C1-6烷基和-氘代C1-6烷基；所述-C1-6烷基优选为-C1-3烷基，更优选为-CH3；所述-氘代C1-6烷基优选为-氘代C1-3烷基，更优选为-CD3。
在本发明的一些实施方案中，式(I)或式(I-2)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，R1-1为-CH3或-CD3。
在本发明的一些实施方案中，式(I)或式(I-2)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，E环选自吖丁啶基、吡咯烷基和哌啶基。
在本发明的一些实施方案中，式(I)或式(I-2)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，Rc各自独立地选自氢、F、Cl、-OH、-CN、-CH3、-OCH3和-CH2OH。
在本发明的一些实施方案中，式(I)或式(I-2)化合物或其药学上可接受的盐、酯、立体异构体、 互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，R3选自-CN、-C(O)NH2、-OC(O)NH2、-O-C1-3烷基、-C1-3烷基-OH、-S(O)2CH3、-CH2S(O)2CH3、-卤代C1-3烷基、-O-卤代C1- 3烷基、-C1-3烷基-CN和-C1-3烷基-O-C1-3烷基。
在本发明的一些实施方案中，式(I)或式(I-2)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，R3选自-CN、-CH2OH、-CHF2、-CH2F和-CF3。
在本发明的一些实施方案中，式(I-2)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，
Ra选自H、F、Cl、-CH3、-CN、-OCH3和-CH2OH；
R1-1为-CH3和-CD3；
E环选自吖丁啶基、吡咯烷基和哌啶基；
所述E环任选地被一个或多个Rc取代，Rc各自独立地选自氢、F、Cl、-OH、-CN、-CH3、-OCH3和-CH2OH；
R3选自-CN、-C(O)NH2、-OC(O)NH2、-O-C1-3烷基、-C1-3烷基-OH、-S(O)2CH3、-CH2S(O)2CH3、-卤代C1-3烷基、-O-卤代C1-3烷基、-C1-3烷基-CN和-C1-3烷基-O-C1-3烷；优选地，R3选自-CN、-CH2OH、-CHF2、-CH2F和-CF3。
在本发明的一些实施方案中，式(I-2)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，所述化合物选自：
其中，
R1-1、Rc、R3、Ra如本发明任一项所述。
在本发明的一些实施方案中，式(I-3)或式(I-4)或式(I-5)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，
R1-1为-CH3和-CD3；
Ra选自H、F、Cl、-CH3、-CN、-OCH3和-CH2OH；
Rc各自独立地选自氢、F、Cl、-OH、-CN、-CH3、-OCH3和-CH2OH；
R3选自-CN、-C(O)NH2、-OC(O)NH2、-O-C1-3烷基、-C1-3烷基-OH、-S(O)2CH3、-CH2S(O)2CH3、-卤代C1-3烷基、-O-卤代C1-3烷基、-C1-3烷基-CN和-C1-3烷基-O-C1-3烷；优选地，R3选自-CN、-CH2OH、-CHF2、-CH2F和-CF3。
在本发明的一些实施方案中，式(I-2)或式(I-3)或式(I-4)或式(I-5)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，所述化合物选自：
其中，Rc、R3、Ra如本发明任一项所述。
在本发明的一些实施方案中，式(I-3-1)或式(I-3-2)或式(I-4-1)或式(I-4-2)或式(I-5-1)化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，
Ra选自H、F、Cl、-CH3、-CN、-OCH3和-CH2OH；
Rc各自独立地选自氢、F、Cl、-OH、-CN、-CH3、-OCH3和-CH2OH；
R3选自-CN、-C(O)NH2、-OC(O)NH2、-O-C1-3烷基、-C1-3烷基-OH、-S(O)2CH3、-CH2S(O)2CH3、-卤代C1-3烷基、-O-卤代C1-3烷基、-C1-3烷基-CN和-C1-3烷基-O-C1-3烷。
优选地，R3选自-CN、-CH2OH、-CHF2、-CH2F和-CF3。
本发明中，L1为单键时，R3选自氰基、-OC1-6烷基、-NHC1-6烷基、-NHC(O)C1-6烷基、-C(O)C1- 6烷基、-NHC(O)OC1-6烷基、-S(O)2C1-6烷基；所述的C1-6烷基各自任选地被一个或多个选自氢、卤素、-OH、氰基、-O-(C1-6烷基)的取代基取代。
本发明中，所述化合物不为以下化合物：
本发明中，所述5-10元杂芳环优选为5-6元杂芳基，更优选为吡啶基或嘧啶基。
所述卤素或卤代优选为氟、氯或溴，更优选为氟。
所述-C1-6烷基优选为-C1-3烷基，更优选为甲基、乙基或异丙基。
所述-OC1-6烷基优选为-OC1-3烷基，更优选为甲氧基。
所述-NHC1-6烷基优选为-NHC1-3烷基。
所述-N(C1-6烷基)2优选为-N(C1-3烷基)2。
所述-NHC(O)C1-6烷基优选为-NHC(O)C1-3烷基。
所述-C2-6烯基优选为-C2-4烯基，更优选为乙烯基或丙烯基。
所述-C2-6炔基优选为-C2-4炔基，更优选为乙炔基或丙炔基。
所述-卤代C1-6烷基优选为-卤代C1-3烷基，更优选为-卤代甲基或-卤代乙基。
所述-C3-12环烷基优选为-C3-8环烷基，更优选为-C3-6环烷基。
所述-4-12元杂环基优选为-4-8元杂环基，更优选为-4-6元杂环基，进一步优选为吖丁啶基、吡 咯烷基、哌啶基或哌嗪基。
所述-卤代C1-6烷氧基优选为-卤代C1-3烷氧基，更优选为-卤代甲氧基或-卤代乙氧基。
所述-C1-6亚烷基-优选为-C1-3亚烷基-，更优选为-亚甲基、-亚乙基或亚丙基。
所述-C3-6亚环烷基-优选为-亚环丙基。
所述-NHC(O)-S(O)2-(C1-6亚烷基)-优选为-NHC(O)-S(O)2-(C1-3亚烷基)-。
所述-C(O)C1-6亚烷基-优选为-C(O)C1-3亚烷基-。
所述-C(O)C1-6烷基优选为-C(O)C1-3烷基。
所述-NHC(O)OC1-6烷基优选为-NHC(O)OC1-3烷基。
所述-S(O)2C1-6烷基优选为-S(O)2C1-3烷基，更优选为-S(O)2CH3烷基。
所述-NHC1-6烷基-N(C1-6烷基)2优选为-NHC1-3烷基-N(C1-3烷基)2。
所述-NH-C(O)O(C1-6烷基)优选为-NH-C(O)O(C1-3烷基)。
所述-N(C1-6烷基)-C(O)OC1-6烷基优选为-N(C1-3烷基)-C(O)OC1-3烷基。
所述-OC(O)NHC1-6烷基优选为-OC(O)NHC1-3烷基。
所述-N(C1-3烷基)C(O)C1-3烷基优选为-N(C1-3烷基)C(O)C1-3烷基。
本发明提供了如下化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，所述化合物选自：


又一方面，本发明提供式(I)化合物的制备方法，所述方法包括以下步骤：
1.化合物IN1-1与IN1-2经过在有机溶剂(如：DMF、DMSO、NMP、二氧六环、二氯甲烷、甲苯、四氢呋喃、氯仿、乙腈等)中，在有机碱(如：Et3N、DIPEA、N-甲基吗啉、DBU、氢化钠等)或无机碱(如：碳酸钾、碳酸铯等)存在下经过取代反应或者金属催化(如：Pd(PPh3)4、PdCl2(dpPf)2等)的偶联反应得到化合物IN1-3；2.化合物IN1-3先在氧化剂(如：m-CPBA、过硫酸氢钾等)作用下生成中间体 亚砜，随后与化合物IN1-4在碱(如：Et3N、DIPEA、N-甲基吗啉、DBU、氢化钠等)进行取代反应得到式(I)的化合物。
其中，LG1表示卤素离去基团，其余各基团如式(I)中所定义。
在本发明的一些实施例方案中，LG1优选为氯、溴；
本发明制备方法的起始原料可来自商业来源或可按照已知方法制备。
本领域技术人员应当理解，根据期望获得的产物结构，可适当地调整反应步骤的顺序，以及增加或省略保护/脱保护反应步骤。
又一方面，本发明提供了一种药物组合物，其包含本文所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，以及一种或多种药学上可接受的载体。
本发明的进一步的目的在于提供一种制备本发明的药物组合物的方法，所述方法包括将本发明所述化合物或其药学上可接受的形式、或者它们的混合物、与一种或多种药学上可接受的载体组合。
在本发明的药物组合物中可使用的药学上可接受的载体为药学上可接受的载体，适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(2005)中所述。
药物组合物可以以任意形式施用，只要其实现预防、减轻、防止或者治愈人类或动物患者的症状即可。例如，可根据给药途径制成各种适宜的剂型。
在另一些实施方案中，本发明的化合物或药物组合物的施用可以与另外的治疗方法组合。所述另外的治疗方法可以选自，但不限于：放射疗法、化疗疗法、免疫疗法，或其组合。
本发明还涉及一种药物制剂，其包本发明化合物或其药学上可接受的形式、或它们的混合物作为活性成分，或者本发明的药物组合物。在一些实施方案中，所述制剂的形式为固体制剂、半固体制剂、液体制剂或气态制剂。
本发明的进一步的目的在于提供一种制品，例如以试剂盒形式提供。本文所用的制品意图包括但不限于药盒和包装。本发明的制品包含：(a)第一容器；(b)位于第一容器中的药物组合物，其中所述组合物包含：第一治疗剂，所述第一治疗剂包括：本发明化合物或其药学上可接受的形式、或者它们的混合物；(c)任选存在的包装说明书，其说明所述药物组合物可用于治疗肿瘤病症(如下文所定义)；和(d)第二容器。
所述第一容器为用于容纳药物组合物的容器。此容器可用于制备、储存、运输和/或独立/批量销售。第一容器意图涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如用于乳膏制品)，或者用于制备、容纳、储存或分配药物产品的任何其它容器。
所述第二容器为用于容纳所述第一容器和任选包装说明书的容器。所述第二容器的实例包括但不限于盒(例如纸盒或塑料盒)、箱、纸箱、袋(例如纸袋或塑料袋)、小袋和粗布袋。所述包装说明书可经由扎带、胶水、U形钉或别的粘附方式物理粘附于所述第一容器的外部，或者其可放在所述第 二容器的内部，而无需与所述第一容器粘附的任何物理工具。或者，所述包装说明书位于所述第二容器的外面。当位于所述第二容器的外面时，优选的是所述包装说明书经由扎带、胶水、U形钉或别的粘附方式物理粘附。或者，其可邻接或接触所述第二容器的外部，而无需物理粘附。
所述包装说明书为商标、标签、标示等，其列举了与位于所述第一容器内的药物组合物相关的信息。所列出的信息通常由管辖待销售所述制品的区域的管理机构(例如美国食品与药品管理局)决定。优选所述包装说明书具体列出了所述药物组合物获准用于的适应症。所述包装说明书可由任何材料制成，可从所述材料上读取包含于其中或其上的信息。优选所述包装说明书为可印刷材料(例如纸、塑料、卡纸板、箔、胶粘纸或塑料等)，其上可形成(例如印刷或施涂)所需信息。
又一方面，本发明提供本文所述的化合物或其药学上可接受的形式、或者本发明的药物组合物在制备用于预防或治疗Wee1激酶相关疾病的药物中的用途。
又一方面，本发明提供本文所述的化合物或其药学上可接受的形式、或者本发明的药物组合物在制备Wee1抑制剂中的用途。在所述的用途中，所述的Wee1抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为Wee1的抑制效果提供快速检测。
又一方面，本发明提供本文所述的化合物或其药学上可接受的形式、或者本发明的药物组合物在制备治疗癌症的药物中的用途。在进一步的实施方案中，所述的癌症包括但不限于乳腺癌、结肠直肠癌、结肠癌、肺癌和前列腺癌，以及胆管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、宫颈癌和外阴癌，以及白血病(包括慢性淋巴细胞性白血病(CLL)、急性淋巴细胞性白血病(ALL)和慢性骨髓性白血病(CML))、多发性骨髓瘤和淋巴瘤。
在一些实施方案中，所述的肺癌为肺腺癌。所述的结肠直肠癌为结直肠腺癌。
又一方面，本发明提供一种用于预防或治疗Wee1激酶相关疾病的方法，所述方法包括向有需要的个体施用如本文所述化合物或其药学上可接受的形式、或者本发明的药物组合物。
又一方面，本发明提供如本文所述的化合物或其药学上可接受的形式、或者本发明的药物组合物，用于预防或治疗Wee1激酶相关疾病。
又一方面，本发明提供如本文所述的化合物或其药学上可接受的形式或者本发明的药物组合物与另外的治疗方法组合用于预防或治疗Wee1激酶相关疾病的方法，所述另外的治疗方法包括但不限于：放射疗法、化疗疗法，免疫疗法、或其组合。
在一些实施方案中，所述Wee1激酶相关疾病为对Wee1激酶抑制敏感或有响应的疾病。
在一些实施方案中，所述Wee1激酶相关疾病为癌症。在进一步的实施方案中，所述的癌症包括但不限于乳腺癌、结肠直肠癌、结肠癌、肺癌和前列腺癌，以及胆管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、宫颈癌和外阴癌，以及白血病(包括慢性淋巴细胞性白血病(CLL)、急性淋巴细胞性白血病(ALL)和慢性骨髓性白血病(CML))、多发性骨髓瘤和淋巴瘤。在一些实施方案中，所述的肺癌为肺腺癌。所述的结肠直肠癌为结直肠腺癌。
在进一步优选的实施方案中，本发明的化合物可以与放化疗或免疫疗法联用以预防或治疗癌症。
可调整给药方案以提供最佳所需响应。例如，以注射剂形式用药时，可给药单次推注、团注和/或连续输注，等等。例如，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少 或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。一般地，治疗的剂量是变化的，这取决于所考虑的事项，例如：待治疗患者的年龄、性别和一般健康状况；治疗的频率和想要的效果的性质；组织损伤的程度；症状的持续时间；以及可由各个医师调整的其它变量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。可以通过临床领域的普通技术人员容易地确定所述药物组合物的施用量和施用方案。例如，本发明的组合物或化合物可以以分剂量每天4次至每3天给药1次，给药量可以是例如0.01～1000mg/次。可以以一次或多次施用需要的剂量，以获得需要达到的结果。也可以以单位剂量形式提供根据本发明的药物组合物。
本发明提供一类新型的高活性Wee1抑制剂，能够实现下述至少一种技术效果：(1)对Wee1激酶的高抑制活性；(2)优异的物理化学性质(例如溶解度、物理和/或化学稳定性)；(3)优异的药物代谢动力学性质(例如良好的生物利用度、合适的半衰期和作用持续时间)；(4)优异的安全性(较低的毒性和/或较少的副作用，较宽的治疗窗)等。
一般术语和定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由...组成”的含义。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
除非另有声明，浓度以重量计，比例(包括百分比)以摩尔量计。
术语“一个(种)或多个(种)”或者类似的表述“至少一个(种)”可以表示例如1、2、3、4、5、6、7、8、9、10个(种)或更多个(种)。
当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围(以形式“约a至b”，或同等的，“大约a至b”，或同等的，“约a-b”)，应理解为表示涵盖于较宽范围中的每个数值和范围。
例如，表述“C1-6”应理解为涵盖其中的任意亚范围以及每个点值，例如C2-5、C3-4、C1-2、C1-3、C1-4、C1-5等，以及C1、C2、C3、C4、C5、C6等。例如，表述“C3-10”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C3-9、C6-9、C6-8、C6-7、C7-10、C7-9、C7-8、C8-9等以及C3、C4、C5、C6、C7、C8、C9、C10等。又例如，表述“3-10元”应理解为涵盖其中的任意亚范围以及的每个点值，例如3-4元、3-5元、3-6元、3-7元、3-8元、3-9元、4-5元、4-6元、4-7元、4-8元、5-7元、5-8元、6-7元等以及3、4、5、6、7、8、9、10元等。还例如，表述“5-10元”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如5-6元、5-7元、5-8元、5-9元、5-10元、6-7元、6-8元、6-9元、6-10元、7-8元等以及5、6、7、8、9、10元等。
在本文中单独或与其它基团组合使用时，术语“烷基”指饱和的直链或支链烃基。如本文中所使用，术语“C1-6烷基”指具有1-6个碳原子(例如1、2、3、4、5或6个碳原子)的饱和直链或支链烃基。“C1- 6烷基”为例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基等。
在本文中单独或与其它基团组合使用时，术语“烯基”是指含有一个或多个双键的直链或支链烃基。烯基的示例性实例包括烯丙基、高烯丙基、乙烯基、巴豆基、丁烯基、戊烯基和己烯基等。具有一个以上双键的C2-6链烯基的示例性实例包括丁二烯基、戊二烯基、己二烯基和己三烯基以及它们的支化形式。不饱和键(双键)的位置可以是在碳链的任何一个位置。
在本文中单独或与其它基团组合使用时，术语“炔基”是指不饱和直链或支链炔基，例如乙炔基、1-丙炔基、炔丙基、丁炔基等。
在本文中单独或与其它基团组合使用时，术语“亚烷基”指饱和的直链或支链的二价烃基。如本文中所使用，术语“C1-6亚烷基”指具有1-6个碳原子的饱和的直链或支链的二价烃基。“C1-6亚烷基”例如包括但不限于亚甲基、亚乙基、亚丙基或亚丁基等。
在本文中单独或与其他基团组合使用时，术语“亚烯基”是指具有一个或多个碳-碳双键的直链或支链的二价脂肪族烃基，其所连接的两个基团(或片段)既可以连接同一个碳原子，又可以连接不同的碳原子。例如，本文中所使用的术语“C2-6亚烯基”是指具有2-6个碳原子的亚烯基(如 等)。
在本文中单独或与其他基团组合使用时，术语“亚炔基”是指具有一个或多个碳-碳三键的直链或支链的二价脂肪族烃基，其所连接的两个基团(或片段)分别连接不同的碳原子。例如，本文中所使用的术语“C2-6亚炔基”是指具有2-6个碳原子的亚炔基(如等)。
在本文中单独或与其他基团组合使用时，术语“脂环”或“脂烃环”是指单环或多环(包括稠环、桥环和螺环，如双环)的脂肪族烃类环系，包括环烷环、环烯环和环炔环等。
在本文中单独或与其它基团组合使用时，术语“环烷基”、“碳环”或“亚环烷基”是指饱和或部分饱和的，单环或多环(诸如双环)的非芳香族烃基。常见的环烷基包括(但不限于)单环环烷基，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环丁烯、环戊烯、环己烯等；或双环环烷基，包括稠环、桥环或螺环，诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基、双环[5.2.0]壬基、十氢化萘基等。例如，“C3-12环烷基”指具有3-12个环碳原子(如3、4、5、6、7、8、9、10、11或12个)的环烷基。
在本文中单独或与其它基团组合使用时，术语“杂环烷基”或“杂环基”是指饱和或部分饱和的，单环或多环(诸如双环，例如：并环、桥环或螺环)的非芳香族基团，其环原子由碳原子以及至少一个(例如1、2、3或4个)选自氮、氧和硫的杂原子构成。如果满足价键要求，杂环烷基可以通过任意一个环原子与分子的其余部分连接。例如，“3-8元杂环烷基”是指具有3至8个环原子的杂环烷基。常见的杂环烷基包括(但不限于)环氧乙烷基、氧代环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基、高哌嗪基、环丁砜等。
在本文中单独或与其它基团组合使用时，术语“杂芳基”或“杂芳环”指具有共轭π电子系统的芳族 环，其中一个或多个(例如1、2或3个)环原子是选自N、O、P和S的杂原子，其余的环原子为C。杂芳基或杂芳环可以用环原子的数目表征。例如，5-12元杂芳基可以含有5-12个(例如5、6、7、8、9、10、11或12个)环原子，特别是含有5、6、9、10个环原子。杂芳基的实例为例如，噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、吡啶基、吡嗪基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等；该术语还涵盖杂芳基或杂芳环可任选地进一步稠合于芳基、或杂芳基环上，形成稠环的情况。
在本文中单独或与其它基团组合使用时，术语“卤代烷基”指上文所述的烷基，其中一个或多个氢原子被卤素代替。例如，术语“C1-6卤代烷基”指任选地被一个或多个(如1-3个)卤素取代的C1-6烷基。本领域技术人员应当理解，当卤素取代基多于一个时，卤素可以相同也可以不同，并且可以位于相同或不同的C原子上。卤代烷基的实例有例如-CH2F、-CHF2、-CF3、-CCl3、-C2F5、-C2Cl5、-CH2CF3、-CH2Cl或-CH2CH2CF3等。
在本文中单独或与其它基团组合使用时，术语“烷氧基”意指氧原子连接至母体分子部分的如上文所述的烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、正丁氧基、叔丁氧基、戊氧基等。
在本文中单独或与其他基团组合使用时，术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。在本文中单独或与其他基团组合使用时，术语“羟基”是指-OH。
在本文中单独或与其他基团组合使用时，术语“氰基”是指-CN。
在本文中单独或与其他基团组合使用时，术语“硝基”是指-NO2。
在本文中单独或与其他基团组合使用时，术语“氨基”是指-NH2。
在本文中单独或与其他基团组合使用时，术语“氧代基”是指＝O。
本文中所使用的术语“各自独立地”是指结构中存在的取值范围相同或相近的至少两个基团(或片段)可以在特定情形下具有相同或不同的含义。例如，取代基X和取代基Y各自独立地为氢、卤素、羟基、氰基、烷基或芳基，则当取代基X为氢时，取代基Y既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基；同理，当取代基Y为氢时，取代基X既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基
术语“取代”及其在本文中的其它变体形式是指所指定的原子上的一个或多个(如1、2、3或4个)原子或原子团(如氢原子)被其他等同物代替，条件是未超过所指定的原子或原子团在当前情况下的正常化合价，并且能够形成稳定的化合物。如果某一原子或原子团被描述为“任选地被......取代”，则其既可以被取代，又可以未被取代。除非另有说明，本文中取代基的连接位点可以来自取代基的任意适宜位置。当取代基中的连接键显示为穿过环系中相互连接的两个原子之间的化学键时，则表示该取代基可以连接该环系中的任意一个成环原子。
本文中可使用实线实楔形或虚楔形描绘本发明的化合物的碳-碳键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物可以以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及 其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明还涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。适合的酸加成盐由形成药学可接受盐的酸来形成。适合的碱加成盐由形成药学可接受盐的碱来形成。适合的盐的综述参见例如“Remington′s Pharmaceutical Sciences”，Mack Publishing Company，Easton，Pa.，(2005)；和“药用盐手册：性质、选择和应用”(Handbook of Pharmaceutical Salts：Properties，Selection，and Use)，Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本文所描述的化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成氮氧化物。本领域技术人员会识别能够形成氮氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成氮氧化物。用于制备杂环和叔胺的氮氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(mCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备氮氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist，Comprehensive Organic Synthesis，vol.7，pp 748-750(A.R.Katritzky和A.J.Boulton，Eds.，Academic Press)；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry，vol.22，pp 390-392(A.R.Katritzky和A.J.Boulton，Eds.，Academic Press)。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过试验的方法进行表征。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其它信息可参见“Pro-drugs as Novel Delivery  Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier，1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene & P.G.M.Wuts，Protective Groups in Organic Synthesis，John Wiley & Sons，2006中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
本发明还涵盖本文所述化合物的制备方法。应当理解，本发明的化合物可使用下文描述的方法以及合成有机化学领域中已知的合成方法或本领域技术人员所了解的其变化形式来合成。优选方法包括(但不限于)下文所述那些。反应可在适于所使用的试剂和材料且适合于实现转化的溶剂或溶剂混合物中进行。
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标病症或病况的一种或多种症状。
如本文中所使用的术语“有效量”(例如“治疗有效量”或“预防有效量”)指给药后会在一定程度上实现预期效果的活性成分的量，例如缓解所治疗病症的一种或多种症状或预防病症或其症状的出现。
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一种或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一种或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
具体实施方式
本发明包括所叙述特定实施方式的所有组合。本发明的进一步实施方式及可应用性的完整范畴将自下文所提供的详细描述变得显而易见。然而，应理解，尽管详细描述及特定实施例指示本发明的优选实施方式，但仅以说明的方式提供这些描述及实施例，因为本发明的精神及范畴内的各种改变及修改将自此详细描述对熟悉此项技术者变得显而易见。出于所有目的，包括引文在内的本文所引用的所有公开物、专利及专利申请将以引用的方式全部并入本文。
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例
以下列举实施例和试验例，进而详细地说明本发明，但它们不限制本发明的范围，另外在不脱离本发明的范围下可进行变化。
质谱(MS)的测定使用Agilent(ESI)质谱仪，生产商：Agilent，型号：Agilent 6120B。
制备高效液相色谱法(HPLC)使用岛津LC-8A制备液相色谱仪(YMC，ODS，250×20mm色谱柱)。
薄层色谱法纯化采用烟台产GF 254(0.4～0.5nm)硅胶板。
反应的监测采用薄层色谱法(TLC)或液相色谱质谱联用(LC-MS)，使用的展开剂体系包括但不限 于：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系以及石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，或者加入三乙胺等进行调节。
柱色谱法一般使用青岛海洋200～300目硅胶为固定相。洗脱剂体系包括但不限于二氯甲烷和甲醇体系以及正己烷和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺等进行调节。
如实施例中无特殊说明，则反应的温度为室温(20℃～30℃)。
除非特别指明，实施例中所使用的试剂购自Acros Organics、Aldrich Chemical Company、南京药石科技或者上海书亚医药科技等公司。
实施例1：化合物的制备
制备例1：2-烯丙基-1-(6-(3-(羟甲基)氮杂环丁-1-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基)氨基)-1，2-二氢-3H-吡唑并[3，4-d]嘧啶-3-酮(化合物A1的制备)
第一步：2-溴-6-(3-((叔丁基二苯基硅基)氧)甲基)氮杂环丁-1-基)吡啶(化合物A1-2)的制备
将A1-1(3.60g，11.08mmol)、2，6-二溴吡啶(2.62g，11.08mmol)、碳酸钾(3.06g，22.16mmol)加入到二氧六环(35mL)中，搅拌加热至80℃反应4hrs。TLC确认反应完全后，向反应液中加水，用乙酸乙酯萃取，合并有机相用盐水洗，饱和硫酸钠干燥，减压浓缩得到粗品，经柱层析纯化得到化合物A1-2(1.4g，收率26.2％)。
第二步：2-烯丙基-1-(6-(3-((叔丁基二苯基硅基)氧基)甲基)氮杂环丁-1-基)吡啶-2-基)-6-(甲硫基)-1，2-二氢-3H-吡唑并[3，4-d]嘧啶-3-酮(化合物A1-4)的制备
化合物A1-3(300mg，1.35mmol)、化合物A1-2(779mg，1.61mmol)，碘化亚铜(257mg，1.35mmol)、碳酸钾(279mg，2.02mmol)和N，N′-二甲基乙二胺(131mg，1.49mmol)加入到二氧六环(5ml)中，氮气保护下加热至95℃反应12小时。LCMS监测显示原料反应完全。反应液加入用水稀释，乙酸乙酯萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得到粗品，粗品经柱层析纯化得到化合物A1-4(400mg，47.6％)。
第三步：2-烯丙基-1-(6-(3-(叔丁基二苯基硅基)氧基)甲基)氮杂环丁-1-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基)氨基)-1，2-二氢-3H-吡唑并[3，4-d]嘧啶-3-酮(化合物A1-6)的制备
化合物A1-4(200mg，0.32mmol)溶于甲苯(2mL)中，25℃下加入间氯过氧苯甲酸(69mg， 0.32mmol，80％)，在该温度下反应1小时，随后加入化合物N，N-二异丙基乙胺(215.80mg，1.67mmol)和化合物A1-5(67mg，0.35mmol)，继续反应16小时。LCMS显示反应完全，反应液中加入水，用乙酸乙酯萃取，有机相用饱和氯化钠洗涤，无水硫酸钠干燥过滤，减压浓缩，粗品用硅胶柱纯化得到化合物A1-6(100mg，40％)。
第四步：2-烯丙基-1-(6-(3-(羟甲基)氮杂环丁-1-基)吡啶-2-基)-6-(4-(4-甲基哌嗪-1-基)苯基)氨基)-1，2-二氢-3H-吡唑并[3，4-d]嘧啶-3-酮(化合物A1的制备)
[1]化合物A1-6(100mg，0.13mmol)溶于甲醇(3mL)中，加入氟化氨(14.5mg，0.39mmol)后反应2小时，LCMS显示反应完全，反应液过滤后减压浓缩，粗品经制备高效液相色谱仪纯化得到化合物A1(10mg，14.5％)。
LCMS(ESI)m/z：528.1[M+H]+；
1H NMR(400MHz，CD3OD)δppm 8.79(s，1H)，7.70(t，J＝7.6Hz，1H)，7.59(br d，J＝8.8Hz，2H)，7.05(d，J＝7.6Hz，1H)，6.97(d，J＝9.2Hz，2H)，6.34(d，J＝8.0Hz，1H)，5.70-5.82(m，1H)，5.09(dd，J＝10.2，1.2Hz，1H)，5.01(dd，J＝17.2，1.2Hz，1H)，4.76(br d，J＝6.4Hz，2H)，4.11(t，J＝8.4Hz，2H)，3.82(dd，J＝8.4，5.2Hz，2H)，3.77(d，J＝6.4Hz，2H)，3.18-3.24(m，4H)，2.63-2.69(m，4H)，2.51-2.41(m，1H)，2.38(s，3H)。
制备例2：化合物A9S的制备
第一步：化合物A9S-2的制备
将A9S-1(0.36g，4.13mmol)、2，6-二溴吡啶(1g，4.13mmol)、碳酸钾(1.14g，8.26mmol)加入到二甲基亚砜(8mL)中，搅拌加热至80℃反应2小时。TLC确认反应完全后，向反应液中加水，用乙酸乙酯萃取，合并有机相用盐水洗，饱和硫酸钠干燥，减压浓缩得到粗品，经柱层析纯化得到化合物A9S-2(0.6g，收率60％)。
第二步：化合物A9S-3的制备
化合物A9S-2(600mg，2.47mmol)、化合物A1-3(548mg，2.47mmol)，碘化亚铜(48mg，0.25mmol)、碳酸钾(279mg，4.94mmol)加入到二氧六环(5ml)中，氮气保护下加热至95℃反应12小时。LCMS监测显示原料反应完全。反应液加入用水稀释，乙酸乙酯萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得到粗品，粗品经柱层析纯化得到化合物A9S-3(300mg，收率32％)。
第三步：化合物A9S的制备
化合物A9S-3(45mg，0.2mmol)溶于甲苯(2mL)中，25℃下加入m-CPBA(43mg，0.2mmol，80％)，在该温度下反应1小时，随后加入化合物N，N-二异丙基乙胺(168mg，1.3mmol)和化合物A1-5(100mg，0.26mmol)，继续反应16小时。LCMS显示反应完全，反应液中加入水，用乙酸乙酯萃取，有机相用饱和氯化钠洗涤，无水硫酸钠干燥过滤，减压浓缩，粗品经反向HPLC纯化得到化合物A9S(10mg，收率10％)。
LCMS(ESI)m/z：528.2[M+H]+；
1H NMR(400MHz，DMSO-d6)δ10.09(s，1H)，8.79(s，1H)，8.30(s，1H)，7.74(d，J＝8.2Hz，1H)，7.60(s，2H)，7.04(d，J＝7.6Hz，1H)，6.96-6.84(m，2H)，6.46(d，J＝8.2Hz，1H)，5.68(ddt，J＝16.4，10.2，5.8Hz，1H)，5.04(dt，J＝10.4，1.4Hz，1H)，4.92(dt，J＝17.2，1.6Hz，1H)，4.59(s，2H)，4.27(t，J＝7.0Hz，1H)，3.93-3.75(m，2H)，3.68(td，J＝5.8，5.2，3.2Hz，2H)，3.09(t，J＝5.0Hz，4H)，2.45(t，J＝5.0Hz，4H)，2.34-2.13(m，5H).
参照制备例1或者制备例2的方法合成以下化合物，




制备例3：参比化合物1和参比化合物2，依据专利WO2023072301中实施例131和实施例19的方法制备。
实施例2：Wee1酶活抑制实验
Wee1酶活性抑制实验中，采用ADP-Glo luminescent kit考察不同化合物对Wee1酶活的影响，其中Wee1酶购自Carna bioscience，Poly(Lys Tyr(4∶1))作为酶反应底物。化合物(最高浓度1000nM，3倍梯度稀释)与Wee1(2nM)孵育30min后，加入反应底物及ATP室温反应1h，加入ADP-Glo stop reagent，室温避光反应40min，加ADP-Glo kinase detection reagent，避光室温孵育1h，检测Luminescence发光值，计算化合物对酶活的半数抑制浓度。
表1.Wee1酶活抑制试验结果

++++：IC50＜1nM；+++：1nM＜IC50＜10nM；结果表明本申请的化合物具有较好的Wee1酶抑制活性。
实施例3：细胞增殖抑制实验一
在A427细胞中，检测各化合物对细胞增殖的影响。具体的，梯度稀释的化合物孵育120h后，化学发光细胞活率检测法(即CTG方法)评估并计算化合物对这几株细胞的半数抑制浓度(IC50)。
表2.化合物对不同细胞增殖活性抑制结果
++++：IC50＜200nM；+++：200nM＜IC50＜400nM；++＞400nM
结果表明本申请的化合物具有较好的细胞增殖抑制活性。
实施例4：细胞增殖抑制实验二
在HT29、SNU5、SNU16、A427细胞中，检测各化合物对细胞增殖的影响。具体的，梯度稀释的化合物孵育120h后，化学发光细胞活率检测法(即CTG方法)评估并计算化合物对这几株细胞的半数抑制浓度(IC50)。
表3.化合物对不同细胞增殖活性抑制结果
结果表明本申请的化合物与AZD1775相比，在HT29及SNU16细胞中具有较好的细胞增殖抑制活性。
实施例5：Balb/c小鼠药代动力学(PK)研究
分别通过静脉和灌胃两种给药方式向雌性及雄性Balb/c小鼠给药化合物A9S、AZD1775考察 药代动力学特性。静脉给药剂量是1mg/kg，药物溶剂为5％DMSO+5％Solutol+90％Saline；灌胃给药剂量是和10mg/kg，药物溶剂为0.5％MC(甲基纤维素钠)。静脉和灌胃给药后在不同时间点收集血液，血液采用EDTA.K2抗凝，于-80℃条件下保存。
血液或血浆样品经沉淀蛋白处理后进行LC-MS/MS分析。应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见下表4。
表4.化合物在雄性及雌性Balb/c小鼠体内血液中的药代动力学参数

注：“/”表示不存在
结论：本发明的化合物A9S在注射给药剂量1mg/kg和口服给药剂量10mg/Kg，化合物在雌性及雄性小鼠体循环中达到较高暴露量，综合性质显著优于AZD1775，表现出优良的药代动力学性质。
实施例6：生化hERG抑制试验
1.实验材料
稳定表达hERG通道(Cat.K1236)HEK 293(人胚胎肾细胞，购买自Invitrogen)稳定转染细胞系的培养：细胞在含85％DMEM、10％透析胎牛血清、0.1mM NEAA、25mM HEPES、100U/mL青霉素-链霉素、5μg/mL Blasticidin和400μg/mL Geneticin的培养基中培养，细胞在25cm2、5％CO2、37℃的细胞培养瓶中培养。使用TrypLETMExpress每周传代细胞约三次，保持在约40％至80％的融合度。实验前，用强力霉素(1μg/mL)诱导细胞48小时。实验当天，使用前将诱导细胞重悬并种于含盖玻片的3.5cm细胞培养皿(5×105细胞/3.5cm细胞培养皿)，在不含Blasticidin和Geneticin的培养基中培养。
注：用于安全性评价试验的细胞系传代数小于60。
2.测试化合物的工作溶液制备
化合物溶解于DMSO，配制为30mM、10mM、3.33mM、1.11mM和0.37mM。随后分别加入细胞外液，测试化合物终浓度为30μM、10μM、3.33μM、1.11μM和0.37μM，DMSO的终浓度为0.1％。
3.实验方案
1)取表面有大量单个HEK 293 hERG细胞均匀生长的盖玻片，放置于倒置显微镜上的连续记录池中，灌流细胞外液(大约每分钟1毫升)并持续记录，等待电流稳定。2)使用标准的全细胞记录模式记录单个细胞的HERG通道电流。首先将膜电压钳制在-80mV，给予细胞持续5s，+20mV电压刺激，以激活hERG钾通道，再复极化至-50mV，持续5s，产生外向尾电流，持续灌注待电流稳定，此时尾电流峰值即为对照电流值。3)接着灌流含待测药物的细胞外液并持续记录直到药物对hERG电流的抑制作用到达稳定状态，此时尾电流峰值即为加药后电流值。4)再次用细胞外溶液 灌注细胞，直到hERG电流回复或接近加药物之前的水平，则可以继续灌流测试其它浓度或药物。可在每个细胞上测试一种或多种化合物或药物浓度。5)以Dofetilide(TRC)作为实验中的阳性对照以保证所使用的细胞反应正常。
4.数据验收标准
以下标准用于确定数据的可接受性。
1)初始密封电阻＞1GΩ；
2)泄漏电流在任何时候都小于控制峰值尾电流的50％；
3)峰值尾部振幅＞250pA；
4)薄膜电阻Rm＞500MΩ；
5)接入电阻(Ra)＜15MΩ；
6)峰值电流的表观下降＜2.5％/min。
5.实验结果
表5.hERG抑制试验结果
结论：测试结果表明，相比于AZD1775、参比化合物1、参比化合物2，本发明的化合物对hERG钾通道的抑制作用很弱，具有较好的成药性。
实施例7：生化CYP酶(细胞色素P450)抑制试验
1、试验系统：
P450-GloTM CYP1A2 Screening System，(Promega)；
P450-GloTM CYP2D6 Screening System，(Promega)；
P450-GloTM CYP3A4 Screening System，(Promega)。
2、测试仪器：
BMG PHERAstar FS Luminescent。
3、试验方法：
分别按照试剂盒说明书进行试验，步骤如下：
3.1.对CYP1A2的抑制：
测试组：将不同浓度的待测化合物加入到微孔板中，向每孔中加入Luciferin-ME(100μM)、K3PO4(100mM)和CYP1A2(0.01pmol/μL)，在室温下预孵育10min，随后加入NADPH再生系统，在室温下反应30min，最后加入等体积的检测缓冲液，在室温下孵育20min，然后进行化学发光检测。
阴性对照组：实验方法同测试组，只是不加待测化合物。
空白对照组：实验方法同测试组，只是不加待测化合物，并且用CYP1A2 Membrance(0.01pmol/μL)代替CYP1A2。
3.2.对CYP2D6的抑制：
测试组：将不同浓度的待测化合物加入到微孔板中，向每孔中加入Luciferin-ME EGE(3μM)、 K3PO4(100mM)和CYP2D6(5nM)，在室温下预孵育10min，随后加入NADPH再生系统，在37℃下反应30min，最后加入等体积的检测缓冲液，在室温下孵育20min，然后进行化学发光检测。
阴性对照组：实验方法同测试组，只是不加待测化合物。
空白对照组：实验方法同测试组，只是不加待测化合物，并且用CYP2D6 Membrance(5nM)代替CYP2D6。
3.3.对CYP3A4的抑制：
测试组：将不同浓度的待测化合物加入到微孔板中，向每孔中加入Luciferin-IPA(3μM)、K3PO4(100mM)和CYP3A4(2nM)，在室温下预孵育10min，随后加入NADPH再生系统，在室温下反应30min，最后加入等体积的检测缓冲液，在室温下孵育20min，然后进行化学发光检测。
阴性对照组：实验方法同测试组，只是不加待测化合物。
空白对照组：实验方法同测试组，只是不加待测化合物，并且用CYP3A4 Membrance(2nM)代替CYP3A4。
4、数据处理：
百分比抑制率＝(1-(待测化合物浓度组的化学发光信号值-空白对照组的化学发光信号值)/(阴性对照组的化学发光信号值-空白对照组的化学发光信号值))×100％。
当百分比抑制率介于30-80％之间时，根据下述公式，估算化合物对CYP酶的半数抑制浓度(IC50)或范围：IC50＝X×(1-百分比抑制率)/百分比抑制率，其中X为化合物的测试浓度。
5、试验结果：
按照上述方法测定本发明化合物对三种CYP酶的抑制，结果如下表5中所示。
表5.CYP酶抑制试验结果
6、结论：
上述结果表明，本发明化合物对3种主要CYP酶亚型均无明显抑制作用，表明其潜在的药物相互作用可能性相对较低，优于参比化合物1及参比化合物2。
上述实施例不以任何方式限定本申请的方案。除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入。

Claims (17)

  1. 式(I)所示化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，
    其中，
    A环选自苯基、5-10元杂芳环；所述的A环任选地被一个或多个Ra取代；
    每一个Ra各自独立地选自H、卤素、-OH、-CN、-C1-6烷基、-OC1-6烷基、-NHC1-6烷基、-N(C1- 6烷基)2、-C2-4烯基、-C2-4炔基；所述的C1-6烷基、C2-4烯基、C2-4炔基各自任选地被一个或多个选自氢、卤素、氧代基、-OH、-CN、-NH2、-C1-6烷基的取代基取代；
    R1选自卤素、-CN、C1-6烷基、卤代C1-6烷基、-C3-12环烷基、4-12元杂环基、-O-(4-12元杂环基)、-N(Rb)-(4-12元杂环基)、-C(O)(4-12元杂环基)、-C(O)NRbRd、-N＝S(O)RbRdd；所述的C1-6烷基、C3-12环烷基、4-12元杂环基各自任选地被一个或多个选自卤素、氧代基、-CN、-ORb、-NRbRd、-C1- 6烷基、-卤代C1-6烷基、-卤代C1-6烷氧基、-C1-6亚烷基-ORb、-C1-6亚烷基-NRbRd、-C3-8环烷基、4-8元杂环基、-SRb、-C(O)Rb、-C(O)ORb、-C(O)NRbRd、-N(Rb)C(O)Rd、-N(Rb)C(O)ORd、-S(O)2Rd、-N(Rb)S(O)2Rd的取代基取代；进一步的，所述的C3-8环烷基、4-8元杂环基各自任选地被一个或多个选自卤素、氧代基、-OH、-CN、-C1-6烷基、-卤代C1-6烷基、-NHC1-6烷基、-N(C1-6烷基)2取代基取代；
    Rb、Rd各自独立地选自H、-C1-6烷基、-C3-6环烷基、4-12元杂环基；所述的C1-6烷基、C3-6环烷基、4-12元杂环基各自任选地被一个或多个选自卤素、氧代基、-OH、-CN、-NH2、-N(C1-6烷基)2、-C1-6亚烷基-OH、-OC1-6烷基、-C1-6亚烷基-NHC1-6烷基、-C1-6亚烷基-N(C1-6烷基)2的取代基取代；
    R2选自氢、卤素、-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、4-8元杂环基、苯基、5-6元杂芳基；所述的C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、4-8元杂环基、苯基、杂芳基各自任选地被一个或多个选自卤素、氧代基、-OH、-CN、-NH2、-C1-6烷基的取代基取代；
    B环选自苯基、5-10元杂芳基；所述的B环任选地被一个或多个选自氢、卤素、-CN、-OCH3的取代基取代；
    E环选自-C3-12环烷基、4-12元杂环基；所述的E环任选地被一个或多个Rc取代；
    每一个Rc各自独立地选自氢、卤素、-OH、氧代基、氰基、-C1-6烷基、-OC1-6烷基；
    X选自CH或者N；
    L1选自单键、-C1-6亚烷基-、-C3-6亚环烷基-、-(3-6元亚杂环基)-、-NHC(O)-S(O)2-(C1-6亚烷基)-、-C(O)C1-6亚烷基-、-C(O)C3-6亚环烷基-、-C(O)-(3-6元亚杂环基)-和-C(O)-，其中所述C1-6亚烷基、3-6元亚杂环基和C3-6亚环烷基各自任选地被一个或多个选自氢、卤素、氧代基、-OH和氨基的取代基取代；
    R3选自如下条件：
    i)L1为单键时，R3选自氰基、-OC1-6烷基、-NHC1-6烷基、-N(C1-6烷基)2、-NHC(O)C1-6烷基、-C(O)C1-6烷基、-NHC(O)OC1-6烷基、-S(O)2C1-6烷基；所述的C1-6烷基各自任选地被一个或多个选自氢、卤素、-OH、氰基、-O-(C1-6烷基)的取代基取代；
    ii)L1不为单键时，R3选自卤素、氨基、-OH、氰基、-卤代C1-6烷基、-S(O)2C1-6烷基、-OC1-6烷基、-NHC1-6烷基-N(C1-6烷基)2、-NH-C(O)O(C1-6烷基)、-N(C1-6烷基)-C(O)OC1-6烷基、-OC(O)NH2、-OC(O)NHC1-6烷基和-N(C1-6烷基)C(O)C1-6烷基，其中所述C1-6烷基任选地被一个或多个选自卤素、氧代基、-OH、氨基和-O-(C1-6烷基)的取代基取代。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中，
    A环选自苯基、吡啶基、噻吩基和吡唑基，所述的A环任选地被一个或多个Ra取代，每一个Ra各自独立地选自H、F、Cl、-OH、-C1-3烷基和-OC1-3烷基，所述C1-3烷基任选地被一个或多个选自F、Cl、-OH和-CN的取代基取代；
    优选地，A环选自苯基，所述的苯基任选地被一个或多个Ra取代，每一个Ra各自独立地选自H、F、Cl、-OH、-C1-3烷基和-OC1-3烷基，所述C1-3烷基任选地被一个或多个选自F、Cl、-OH和-CN的取代基取代；
    更优选地，A环选自苯基，所述的苯基任选地被一个或多个Ra取代，Ra选自H、F、Cl、-CH3、-OCH3和-CH2OH。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中R1选自C1-6烷基、4-6元杂环基、C4-6环烷基、-O-(4-6元杂环基)、-NH-(4-6元杂环基)、-C(O)N(C1-6烷基)2，所述4-6元杂环基和C4-6环烷基各自任选地被一个或多个选自卤素、氧代基、-OH、-CN、-OCH3、-NH2、-N(C1-3烷基)2、-C1-3烷基、-卤代C1-3烷基、-卤代C1-3烷氧基、-C1-3亚烷基-OH、-C1-3亚烷基-N(C1-3烷基)2、-C(O)OC1-3烷基和-S(O)2C1-3烷基的取代基取代；
    优选地，R1选自吡咯烷基、四氢吡喃基、哌啶基、四氢吡啶基、吗啉基和哌嗪基；所述吡咯烷基、四氢吡喃基、哌啶基、四氢吡啶基、吗啉基和哌嗪基各自任选地被一个或多个选自F、Cl、-OH、-CN、氧代基、-OCH3、-NH2、-N(CH3)2、-C1-3烷基、-卤代C1-3烷基、-卤代C1-3烷氧基、-C1-3亚烷基-OH、-C1-3亚烷基-N(CH3)2、-C(O)OC1-3烷基和-S(O)2C1-3烷基的取代基取代；
    优选地，R1选自
  4. 根据权利要求1-3中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中R2选自-CH3、-CH2CH3、环丙基、异丙基、烯丙基、炔丙基、-CH2-环丙基、-CH2CF3；优选地，R2选自烯丙基。
  5. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中B环选自苯基、吡啶基、嘧啶基、噻吩基和噻唑基，所述B环任选地被一个或多个选自氢、卤素和-CN的取代基取代；
    优选地，B环选自吡啶基和苯基。
  6. 根据权利要求1-5中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异 构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中E环选自4-6元杂环基；所述的E环任选地被一个或多个Rc取代，每一个Rc各自独立地选自氢、F、Cl、-OH、氧代基、-CN、-CH3、-OCH3；
    优选地，E环选自吖丁啶基、吡咯烷基和哌啶基。
  7. 根据权利要求1-6中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中L1选自亚甲基、-C(O)-亚甲基-O-和-C(O)-；其中所述亚甲基任选地被一个或多个选自氢、F、和-CH3的取代基取代。
  8. 根据权利要求1-7所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其中R3选自：
    i)L1为单键时，R3选自-OCH3、-NHCH3、-NHC(O)CH3、-C(O)CH3和-S(O)2CH3；ii)L1不为单键时，R3选自F、氨基、-OH、-CN、-CHF2、-CH2F、-S(O)2CH3、-OCH3、-OCHF2、-NH-C(O)OCH3；优选地，R3选自F、-OH、-CN、-NH2-CHF2、-S(O)2CH3和-CH3。
  9. 根据权利要求1-8中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，所述化合物选自：
    其中，
    R1如权利要求3所述；
    E环选自4-6元杂环基，所述的E环任选地被一个或多个Rc取代，每一个Rc各自独立地选自氢、F、Cl、-OH、氧代基、-CN、-CH3、-OCH3；优选地，E环选自吖丁啶基、吡咯烷基和哌啶基；
    L1如权利要求7所述；
    R3如权利要求8所述。
  10. 根据权利要求1所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，所述化合物选自：
    其中，
    E环选自4-6元杂环基，所述4-6元杂环基的杂原子为N，杂原子个数为1个、2个或3个；
    所述E环任选地被一个或多个Rc取代，Rc各自独立地选自H、F、Cl、-OH、-CN、-C1-6亚烷基-OH、-C1-6烷基和-卤代C1-6烷基；
    R3选自-CN、-C(O)NH2、-OC(O)NH2、-OC1-6烷基、-NHC1-6烷基、-N(C1-6烷基)2、-NHC(O)C1- 6烷基、-C(O)C1-6烷基、-NHC(O)OC1-6烷基、-S(O)2C1-6烷基、-C1-6烷基S(O)2C1-6烷基、-卤代C1-6烷基、-O-卤代C1-3烷基、C1-6烷基-CN、C1-6烷基-OH、C1-6烷基-NH2、-C1-6烷基OC1-6烷基和-环丙基-OH；所述的C1-6烷基各自任选地被一个或多个选自氢、卤素、-OH、氨基和氰基的取代基取代。
  11. 根据权利要求10所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，
    其中，
    Ra选自H、F、Cl、-CH3、-CN、-OCH3和-CH2OH；
    R1-1为-CH3或-CD3；
    E环选自吖丁啶基、吡咯烷基和哌啶基；
    所述E环任选地被一个或多个Rc取代，Rc各自独立地选自氢、F、Cl、-OH、-CN、-CH3、-OCH3和-CH2OH；
    R3选自-CN、-C(O)NH2、-OC(O)NH2、-O-C1-3烷基、-C1-3烷基-OH、-S(O)2CH3、-CH2S(O)2CH3、-卤代C1-3烷基、-O-卤代C1-3烷基、-C1-3烷基-CN和-C1-3烷基-O-C1-3烷基；优选地，R3选自-CN、-CH2OH、-CHF2、-CH2F和-CF3。
  12. 根据权利要求1-11任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其满足以下条件中的一种或多种：
    1)L1为单键，R3选自-OC1-6烷基、-NHC1-6烷基、-N(C1-6烷基)2、-NHC(O)C1-6烷基、-C(O)C1- 6烷基、-NHC(O)OC1-6烷基、-S(O)2C1-6烷基；所述的C1-6烷基各自任选地被一个或多个选自氢、卤素、-OH、氰基、-O-(C1-6烷基)的取代基取代；
    2)A环为苯基，优选为
    3)R1为4-12元杂环基，优选为4-6元杂环基，更优选为6元杂环基；所述杂环基任选地被一个或多个-C1-6烷基或-氘代C1-6烷基取代，优选任选被一个或多个-C1-3烷基或-氘代C1-3烷基取代，更优选被-CH3或-CD3取代；
    4)R2为-C2-6烯基，优选为-C2-4烯基，更优选为烯丙基；
    5)B环为5-10元杂芳基，优选为5-6元杂芳基，更优选为6元杂芳基，进一步优选为吡啶基，特别优选为
    6)E环为吖丁啶基或吡咯烷基，优选为更优选为所述的E环任选地被一个或多个Rc取代，每一个Rc各自独立地选自H、F、Cl、-OH、-CN、-CH3、-OCH3；
    7)L1选自单键、-C1-6亚烷基-、-C3-6亚环烷基-和-C(O)-；所述-C1-6亚烷基-优选为-C1-3亚烷基-，更优选为亚甲基；所述-C3-6亚环烷基-优选为亚环丙烷；
    8)R3选自：
    i)L1为单键时，R3选自氰基、-OC1-6烷基和-S(O)2C1-6烷基，其中所述的-OC1-6烷基任选地被一个或多个选自卤素的取代基取代；所述的-OC1-6烷基优选为-O-卤代C1-3烷基，更优选为-OCF2；所述的-S(O)2C1-6烷基优选为-S(O)2C1-3烷基，更优选为-S(O)2CH3；
    ii)L1为-C1-6亚烷基-、-C3-6亚环烷基-或-C(O)-，优选-C1-6亚烷基-，更优选-C1-3亚烷基-时，R3选自卤素、氨基、-OH、氰基、C1-6烷基、-卤代C1-6烷基、-S(O)2C1-6烷基和-OC1-6烷基；所述的-卤代C1-6烷基优选为-卤代C1-3烷基，更优选为氟代C1-3烷基，例如为CHF2或CH2F；所述的-S(O)2C1-6烷基优选为-S(O)2C1-3烷基，更优选为-S(O)2CH3；所述的-OC1-6烷基优选为-OC1-3烷基，更优选为-OCH3；
    9)式(I-2)化合物中，R1-1选自-C1-6烷基和-氘代C1-6烷基；所述-C1-6烷基优选为-C1-3烷基，更优选为-CH3；所述-氘代C1-6烷基优选为-氘代C1-3烷基，更优选为-CD3。
  13. 根据权利要求12所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，其满足以下条件中的一种或多种：
    1)L1为亚甲基，R3选自卤素、氨基、-OH、氰基、C1-6烷基、-卤代C1-6烷基、-S(O)2C1-6烷基和-OC1-6烷基；优选为卤素、氨基、-OH、氰基、C1-3烷基、-卤代C1-3烷基、-S(O)2C1-3烷基和-OC1-3烷基；
    2)R1为哌啶基、四氢吡啶基或哌嗪基，所述哌啶基、四氢吡啶基或哌嗪基任选被一个或多个-C1-3烷基或-氘代C1-3烷基取代；优选为哌嗪基，所述哌嗪基任选被一个或多个-CH3或-CD3取代；较佳地，R1选自优选为
    3)结构单元选自优选为
    4)结构单元选自
    5)结构单元为 优选为
    较佳地，结构单元为
  14. 根据权利要求1-13任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，所述化合物选自：
    其中：
    R1-1、Rc、R3、Ra如权利要求1-13任一项所述；
    较佳地，所述化合物选自：
    其中：
    Rc、R3、Ra如权利要求1-13任一项所述。
  15. 根据权利要求1所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，所述化合物选自：


  16. 一种药物组合物，其包含权利要求1-15中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、同位素标记物、代谢物或前药，以及一种或多种药学上可接受的载体。
  17. 根据权利要求1-15中任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、氮氧化物、同位素标记物、代谢物或前药或者根据权利要求16所述的药物组合物，在制备用于预防和/或治疗癌症的药物或制备Wee1抑制剂中的用途；优选地，所述癌症选自以下癌症中的一种或多种：乳腺癌、结肠直肠癌、结肠癌、肺癌、前列腺癌、胆管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、宫颈癌和外阴癌、白血病、多发性骨髓瘤和淋巴瘤。
PCT/CN2023/107377 2022-07-15 2023-07-14 一种嘧啶并五元杂环化合物、其制备方法和用途 WO2024012549A1 (zh)

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Publication number Priority date Publication date Assignee Title
CN101432284A (zh) * 2006-04-27 2009-05-13 万有制药株式会社 二氢吡唑并嘧啶酮衍生物
CN109422754A (zh) * 2017-08-24 2019-03-05 上海迪诺医药科技有限公司 吡唑并[3,4-d]嘧啶-3-酮衍生物、其药物组合物及应用
WO2019134539A1 (zh) * 2018-01-05 2019-07-11 四川科伦博泰生物医药股份有限公司 二氢吡唑酮并嘧啶类化合物及其制备方法和用途
WO2023072301A1 (zh) * 2021-11-01 2023-05-04 正大天晴药业集团股份有限公司 吡唑[3,4-d]嘧啶-3-酮类化合物及其医药用途
CN116462687A (zh) * 2022-01-18 2023-07-21 江苏天士力帝益药业有限公司 Wee1抑制剂及其制备和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101432284A (zh) * 2006-04-27 2009-05-13 万有制药株式会社 二氢吡唑并嘧啶酮衍生物
CN109422754A (zh) * 2017-08-24 2019-03-05 上海迪诺医药科技有限公司 吡唑并[3,4-d]嘧啶-3-酮衍生物、其药物组合物及应用
WO2019134539A1 (zh) * 2018-01-05 2019-07-11 四川科伦博泰生物医药股份有限公司 二氢吡唑酮并嘧啶类化合物及其制备方法和用途
WO2023072301A1 (zh) * 2021-11-01 2023-05-04 正大天晴药业集团股份有限公司 吡唑[3,4-d]嘧啶-3-酮类化合物及其医药用途
CN116462687A (zh) * 2022-01-18 2023-07-21 江苏天士力帝益药业有限公司 Wee1抑制剂及其制备和用途

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