A substituted heteropolycyclic compound, a method for preparing the same, and use thereof

Abstract

The present application belongs to the field of pharmaceutical chemistry, and relates to substituted heteropolycyclic compounds, pharmaceutical compositions containing the same and uses thereof. Specifically, the present application relates to a compound represented by formula (I), formula (II) or a pharmaceutically acceptable form thereof, which exhibits good Wee1 inhibitory activity and can be used as an efficient Wee1 inhibitor for preventing and / or treating Wee1 related diseases.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more particularly to a heterocyclic compound used as a Wee1 inhibitor, its preparation method, pharmaceutical composition, and its use in the prevention and / or treatment of Wee1 kinase-related diseases. Background Technology

[0002] The cell cycle is a highly regulated and controlled process. Normal cell cycles have 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 lack regulation of the G1 / S checkpoint and therefore heavily rely on G2 / M checkpoint regulation. Wee1 kinase is a key regulator of the G2 / M checkpoint (CJMatheson, DSBackos, P. Reigan, Trends in Pharmacological Sciences, 2016, 37:872), belonging to atypical tyrosine kinases. It phosphorylates Cdk1 (also known as Cdc2) at tyrosine 15 (Y15), leading to its inactivation. Cdk1 recruits cyclins A and B to initiate mitosis. Abolishing the G2 checkpoint through Wee1 inhibitors could selectively sensitize P53-deficient cancer cells to DNA damage, preventing impact on surrounding normal tissues. Wee1 also regulates CDK activity in S phase, preventing the induction of DNA damage during normal S phase progression. In addition, Wee1 plays an active regulatory role in homologous recombination (HR) repair, which is an important pathway for DNA double-strand break repair.

[0003] Wee1 is highly expressed in many cancers, including breast cancer, lung cancer, cervical cancer, head and neck cancer, ovarian cancer, prostate cancer, melanoma, leukemia, glioblastoma, medulloblastoma, and hepatocellular carcinoma. Furthermore, high Wee1 expression is associated with poor prognosis in various cancer types. Inhibiting Wee1 kinase activity to remove the G2 / M checkpoint is a promising strategy to drive tumor cells into unplanned mitosis, thereby causing mitotic arrest and cell death. This forced entry into mitosis before DNA replication is completed is highly cytotoxic and represents a novel mechanism for inducing tumor cell death. Therefore, Wee1 inhibitors show promising potential as drugs.

[0004] Several Wee1 inhibitors have been reported (e.g., WO2007126122A1, WO2019173082A1, WO2018011569A1, WO2018162932A1, WO2018090939, WO2019074981, etc.), but there is still an urgent need in the field for new Wee1 inhibitors, especially those with high activity and other excellent properties, to meet unmet clinical needs. Summary of the Invention

[0005] This application provides a Wee1 inhibitor or a pharmaceutically acceptable salt thereof, which may have one or more effects selected from the group consisting of: (1) having inhibitory activity against Wee1 enzyme activity; (2) having inhibitory activity against the in vitro proliferation of tumor cells, such as in A427, NCI-H1299, CAPAN-1, NCI-H82 cells; (3) having in vivo antitumor effect; (4) having good kinase selectivity; and (5) having good in vivo safety and good oral bioavailability.

[0006] In a first aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof:

[0007]

[0008] in,

[0009] Ring A is selected from phenyl or 5-6 membered heteroaromatic rings; said phenyl or 5-6 membered heteroaromatic ring is optionally surrounded by one or more R a replace;

[0010] R a Each is independently selected from H, halogen, hydroxyl group, -CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl or -N(C) 1-6 Alkyl)2, the C 1-6 Each alkyl group may optionally be substituted by one or more substituents selected from halogens, oxo groups, hydroxyl groups, -CN, and -NH2;

[0011] Ring B is selected from phenyl or 5-6-membered heteroaryl groups, wherein ring B is optionally surrounded by one or more R groups. b1 replace;

[0012] Ring E is selected from C 5-10 cycloalkyl or 5-10 membered heterocyclic groups; the C 5-10 cycloalkyl or 5-10 membered heterocyclic groups are each optionally surrounded by one or more Rb2 replace;

[0013] R b1 and R b2 Each is independently selected from H, halogen, oxo group, -CN, -OH, -OC. 1-6 Alkyl, -OC 3-8 cycloalkyl, -NH2, -NHC 1-6 Alkyl, -NHC 3-6 cycloalkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -COOC 1-6 Alkyl, -COC 1-6 Alkyl, -NHCOOC 1-6 Alkyl group, -S(O)2C 1-6 Alkyl group; the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 2-6 alkenyl, -C 2-6 Each of the alkynyl groups is optionally surrounded by one or more groups selected from halogen, oxo group, hydroxyl group, -CN, -NH2, -NHC 1-6 Alkyl, -NHC 3-6 cycloalkyl, -N(C) 1-6 Alkyl)2, -OC 1-6 Alkyl, -OC 3-8 cycloalkyl, -S(O)2C 1-6 Alkyl, 4-8 membered heterocyclic alkyl, C 3-8 Substitution of cyclic alkyl groups;

[0014] R 1 Selected from hydrogen, halogens, -C 1-6 Alkyl, -C 2-6 alkenyl or -C 2-6 alkynyl group, the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more radicals selected from halogens, oxo groups, -OH, -CN, -NH2, and -C. 1-6 Alkyl substituents;

[0015] The G ring is selected from phenyl, 5-10-membered heteroaryl, and 5-6-membered heterocyclic groups;

[0016] R 2 Each is independently selected from H, halogen, cyano, nitro, oxo, -C 1-6 Alkyl, -C 2-6 alkenyl, -C2-6 alkynyl group, -C 3-12 Cycloalkyl, 4-12 membered heterocyclic, 5-6 membered heteroaryl, -OR c -SR c -NR c R d -NR c COR d -NR c S(O)2R d -COR c -CONR c R d -S(O)2NR c R d -S(O)2NR c -N=S(O)R c R d The C mentioned 1-6 Alkyl, C 2-6 Olefins, C 2-6 Alkynes, C 3-12 The cycloalkyl group, 4-12-membered heterocyclic group, or 5-6-membered heteroaryl group is optionally surrounded by one or more groups selected from halogen, oxo group, hydroxyl group, -CN, -NH2, -C 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-CN, -Halogenated C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl, -C 1-6 Alkylene-S(O)2C 1-6 Alkyl substituents;

[0017] R c R d Each is independently selected from H and -C. 1-6 Alkyl, -C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4-12 membered heterocyclic group are each optionally substituted by one or more substituents selected from halogen, oxo group, hydroxyl group, -CN, -NH2;

[0018] Alternatively, R connected to two adjacent ring atoms respectively 2 Together with the atoms attached to it, they form C 5-8 cycloalkyl or 5-8 membered heterocyclic groups; the C 5-8 cycloalkyl or 5-8 membered heterocyclic groups are each optionally surrounded by one or more R 2a Replace, R 2aEach is independently selected from halogens, hydroxyl groups, -CN, -NH2, and -C. 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 alkylene -OH, -C 1-6 Alkylene-CN or -halogenated C 1-6 alkyl;

[0019] n is 0, 1, 2, 3, or 4.

[0020] In some embodiments of the present invention, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein R a Each is independently selected from H, F, Cl, -OH, -C 1-3 Alkyl and -OC 1-3 Alkyl, the C 1-3 The alkyl group is optionally surrounded by one or more elements selected from F, Cl, -OH, and -CN; preferably, R a Each is independently selected from H, F, Cl, -CH3, -CD3, -CHF2, -OCHF2, -OCH3, and -CH2OH; more preferably, R a Selected from H.

[0021] In some embodiments of the invention, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein ring A is selected from phenyl, pyridinyl, thiophene, or pyrazolyl, preferably phenyl, and each ring A is optionally surrounded by one or more R a Replace, each R a Each as defined herein. In some embodiments of the invention, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein ring A is selected from phenyl, pyridinyl, thiophene, or pyrazolyl, wherein the phenyl, pyridinyl, thiophene, and pyrazolyl groups are each optionally surrounded by one or more R groups. a Replace; each R a Each is independently selected from H, F, Cl, -OH, -C 1-3 Alkyl and -OC 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted by one or more substituents selected from F, Cl, -OH and -CN.

[0022] In some embodiments of the invention, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein ring A is selected from phenyl, and said phenyl is optionally surrounded by one or more R a Replace, each R a Each is independently selected from H, F, Cl, -OH, -C 1-3 Alkyl and -OC 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted by one or more substituents selected from F, Cl, -OH and -CN.

[0023] In some embodiments of the invention, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein ring A is selected from phenyl, and said phenyl is optionally surrounded by one or more R a Replace, each R a Each is independently selected from H, F, Cl, -CH3, -CD3, -CHF2, -OCHF2, -OCH3 and -CH2OH.

[0024] In some embodiments of the present invention, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, wherein ring A is selected from... Preferably, ring A is selected from

[0025] In some embodiments of the present invention, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein R b1 Each is independently selected from H, F, Cl, -OH, -C 1-3 Alkyl, -C 1-3 Alkoxy, -NH2, -N(C) 1-3 Alkyl)2, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -halogenated C 1-3 Alkoxy, -C 1-3 alkylene -OH, -C 1-3 Alkylene-N(C) 1-3 Alkyl group 2, -CN, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl, -C 1-3Alkylene (4-6 membered heterocyclic alkyl) and -COOC 1-3 Alkyl; preferably, R b1 Each is independently selected from H, F, Cl, -OH, -OCH3, -NH2, -N(CH3)2, -CH3, -CD3, cyclopropyl, isopropyl, -CH2-C 3-6 Cycloalkyl, -halomethyl, -halomethoxy, -CH2OH, -CH2-N(CH3)2, -CN or -COOCH3; more preferably, R b1 Each is independently selected from H, -CH3, -CD3, cyclopropyl, -CH2-cyclopropyl; more preferably, R b1 Selected from H, -CH3, -CD3; more preferably, R b1 Selected from H and -CH3.

[0026] In some embodiments of the invention, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein the B ring is selected from phenyl, imidazolyl, pyrazolyl, and pyrroleyl, preferably, the B ring is selected from imidazolyl, pyrazolyl, and pyrroleyl, preferably, the B ring is selected from pyrroleyl, preferably, the B ring is selected from pyrazolyl, preferably, the B ring is selected from imidazolyl, and each of the B rings is optionally surrounded by one or more R b1 Replace, each R b1 Each as defined in any of the items in this article.

[0027] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled substances, metabolites, or prodrugs thereof, wherein the B ring is selected from phenyl, imidazolyl, pyrazolyl, and pyrroleyl groups, and each of the B rings is optionally surrounded by one or more R groups. b1 Replace, R b1 Each is independently selected from H, F, Cl, -OH, -C 1-3 Alkyl, -C 1-3 Alkoxy, -NH2, -N(C) 1-3 Alkyl)2, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -halogenated C 1-3 Alkoxy, -C 1-3 alkylene -OH, -C 1-3 Alkylene-N(C) 1-3 Alkyl group 2, -CN, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl, -C 1-3Alkylene (4-6 membered heterocyclic alkyl) and -COOC 1-3 alkyl.

[0028] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof, wherein the B ring is selected from imidazole, pyrazol, and pyrrole groups, and each of the B rings is optionally surrounded by one or more R groups. b1 Replacement, preferably, R b1 Each is independently selected from H, -CH3, and -CD3.

[0029] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof, wherein R b2 Each is independently selected from H, halogen, oxo group, -OH, -C 1-3 Alkoxy, -NH2, -N(C) 1-3 Alkyl)2, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -halogenated C 1-3 Alkoxy, -C 1-3 alkylene -OH, -C 1-3 Alkylene-N(C) 1-3 Alkyl group 2, -CN, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl, -C 1-3 Alkylene (4-6 membered heterocyclic alkyl) and -COOC 1-3 Alkyl; preferably, R b2 Each group is independently selected from H, F, Cl, oxo group, -OH, -OCH3, -NH2, -N(CH3)2, -CH3, -CD3, cyclopropyl, isopropyl, and -CH2-C. 3-6 Cycloalkyl, -halomethyl, -halomethoxy, -CH2OH, -CH2-N(CH3)2, -CN or -COOCH3; more preferably, R b2 Each is independently selected from H, -CH3, -CD3, cyclopropyl, -CH2-cyclopropyl; more preferably, R b2 Each is independently selected from H, -CH3, and -CD3; more preferably, R b2 Selected from H and -CH3.

[0030] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof, wherein the E ring is selected from 5-6 membered heterocyclic groups, preferably selected from 1-pyrrololine, 2-pyrrololine, 3-pyrrololine, 2-pyrazoline, 2,5-dihydrofuran, 4,5-dihydro-1H-imidazolium, 1,2,3,6-tetrahydropyrazine, 2,3,4,5-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, more preferably selected from 3-pyrrololine and 1,2,3,6-tetrahydropyrazine, wherein each of the E rings is optionally surrounded by one or more R b2 Replace, each R b2 Each as defined in any of the items in this article.

[0031] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof, wherein the E ring is selected from 5-6 membered heterocyclic groups, and each of the E rings is optionally surrounded by one or more R groups. b2 Replace; R b2 Each is independently selected from H, halogen, oxo group, -OH, -C 1-3 Alkoxy, -NH2, -N(C) 1-3 Alkyl)2, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -halogenated C 1-3 Alkoxy, -C 1-3 alkylene -OH, -C 1-3 Alkylene-N(C) 1-3 Alkyl group 2, -CN, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl, -C 1-3 Alkylene (4-6 membered heterocyclic alkyl) and -COOC 1-3 alkyl.

[0032] In some embodiments of the invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled substances, metabolites, or prodrugs thereof, wherein the E ring is selected from 3-pyrrolidine and 1,2,3,6-tetrahydropyrazine, and each of the E rings is optionally surrounded by one or more R... b2 Replace, R b2 Each is independently selected from H, -CH3, -CD3, cyclopropyl, and -CH2-cyclopropyl.

[0033] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein... Selected from

[0034] R b2 As defined in any one of the claims of this invention.

[0035] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein... Selected from Among them, R b2 Selected from H, -CH3, and -CD3.

[0036] In some embodiments of the present invention, the compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein... Selected from R b1 As defined in any one of the claims of this invention.

[0037] In some embodiments of the present invention, the compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein, Selected from R b1 Selected from H, -CH3, and -CD3.

[0038] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope labels, metabolites, or prodrugs thereof, wherein R 1 Selected from -CH3, -CH2CH3, cyclopropyl, isopropyl, allyl, propyne, or -CH2CF3.

[0039] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof, wherein R 1 Selected from allyl.

[0040] In some embodiments of the present invention, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, wherein the G ring is selected from phenyl, pyridinyl, pyrimidinyl, thiopheneyl or thiazolyl.

[0041] In some embodiments of the present invention, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, wherein the G ring is selected from pyridyl.

[0042] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof, wherein R 2 Selected from H, F, Cl, -OH, -CN, -NH2, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 1-6 Alkyl or -N=S(O)(CH3)2, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclic group is optionally surrounded by one or more groups selected from halogen, oxo group, hydroxyl group, -CN, -NH2, -C 1-3 Alkyl, -C 1-3 alkylene -OH, -C 1-3 Alkylene-OC 1-3 Alkyl, -C 1-3 Alkylene-CN, -Halogenated C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, -C 1-3 Alkylene-S(O)2C 1-3 Alkyl substituents.

[0043] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof, wherein R 2 Selected from H, F, Cl, -OH, -CN, -NH2, -C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, acrylonitrile, oxadiazinyl, -N=S(O)(CH3)2, the C 1-3The alkyl, cyclopropyl, cyclobutyl, cyclopentyl, acridineyl, or oxadiazine group is optionally substituted by one or more substituents selected from F, Cl, oxo, hydroxyl, -CN, -NH2, -CH3, -CH2CH3, -CH2OH, -CH2OCH3, -CH2CN, -CF3, -CH2CF3, -S(O)2CH3, and -CH2S(O)2CH3.

[0044] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof, wherein R 2 Selected from H, F, Cl, -OH, -CN, -NH2, -CH3, -CH2CH3, -C(CH3)3, -CH2OH, -CH2CN, -CHF2, -CH2F, -CF3, -N=S(O)(CH3)2,

[0045] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled substances, metabolites, or prodrugs thereof, wherein... Selected from R 2 Each as defined in any one of the present invention.

[0046] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope labels, metabolites, or prodrugs thereof, wherein R 2a Selected from H, halogen, oxo group, hydroxyl group, -CN, -NH2, -C 1-3 Alkyl, -C 1-3 Alkylene -OH, -OC 1-3 Alkyl, -C 1-3 Alkylene-CN or -halogenated C 1-3 alkyl.

[0047] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope labels, metabolites, or prodrugs thereof, wherein R 2a Selected from H, halogen, oxo group, hydroxyl group, -CN, -NH2, -CH3, -CH2CH3, -CH2OH, -CH2CN, -CHF2, -CH2F, or -CF3. In some embodiments of the invention, R 2a Selected from hydroxyl and -CH2CH3.

[0048] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled substances, metabolites, or prodrugs thereof, wherein... for Among them, R 2a Each as defined in any one of the present invention.

[0049] In some embodiments of the present invention, compounds of formula (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled substances, metabolites, or prodrugs thereof, wherein... Selected from:

[0050]

[0051] In some embodiments of the present invention, compounds of formula (II-1) and (II-2), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof, wherein the compounds are selected from...

[0052]

[0053] Among them, ring B, ring E, and ring R a R 1 R 2 m and m are respectively defined as in any one of the present invention;

[0054] Preferably,

[0055] Ring B is selected from phenyl, imidazolyl, pyrazolyl, and pyrroleyl groups, wherein each of the phenyl, imidazolyl, pyrazolyl, and pyrroleyl groups is optionally surrounded by one or more R groups. b1 Replace, each R b1 Each is independently selected from H, F, Cl, -OH, -C 1-3 Alkyl, -C 1-3 Alkoxy, -NH2, -N(C) 1-3 Alkyl)2, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -halogenated C 1-3 Alkoxy, -C 1-3 alkylene -OH, -C 1-3 Alkylene-N(C) 1-3 Alkyl group 2, -CN, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl, -C1-3 Alkylene (4-6 membered heterocyclic alkyl) and -COOC 1-3 alkyl;

[0056] The E ring is selected from a 5-6 membered heterocyclic group, which is optionally surrounded by one or more R rings. b2 Replace, R b2 Each is independently selected from H, halogen, oxo group, -OH, -C 1-3 Alkoxy, -NH2, -N(C) 1-3 Alkyl)2, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -halogenated C 1-3 Alkoxy, -C 1-3 alkylene -OH, -C 1-3 Alkylene-N(C) 1-3 Alkyl group 2, -CN, -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl, -C 1-3 Alkylene (4-6 membered heterocyclic alkyl) and -COOC 1-3 alkyl;

[0057] R 1 Selected from -CH3, -CH2CH3, cyclopropyl, isopropyl, allyl, propargyl or -CH2CF3;

[0058] R 2 Each is independently selected from H, F, Cl, -OH, -CN, -NH2, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -OC 1-6 Alkyl or -N=S(O)(CH3)2, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclic group is optionally surrounded by one or more groups selected from halogen, oxo group, hydroxyl group, -CN, -NH2, -C 1-3 Alkyl, -C 1-3 alkylene -OH, -C 1-3 Alkylene-OC 1-3 Alkyl, -C 1-3 Alkylene-CN, -Halogenated C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, -C 1-3 Alkylene-S(O)2C 1-3 Alkyl substituents;

[0059] Or, two Rs 2 Together with the atoms attached to it, they form C 5-6cycloalkyl or 5-6 membered heterocyclic groups; the C 5-6 cycloalkyl or 5-6 membered heterocyclic groups are each optionally surrounded by one or more R 2a Replace, R 2a Each is independently selected from halogens, hydroxyl groups, -CN, -NH2, and -C. 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene-CN or -halogenated C 1-6 alkyl;

[0060] More preferably,

[0061] Ring B is selected from imidazole, pyrazol, and pyrrole, wherein each of the imidazole, pyrazol, and pyrrole groups is optionally surrounded by one or more R groups. b1 Replace, R b1 Each is independently selected from H, -CH3, -CD3, cyclopropyl, and -CH2-cyclopropyl;

[0062] The E ring is selected from 3-pyrrolidine and 1,2,3,6-tetrahydropyrazine, wherein the 3-pyrrolidine and 1,2,3,6-tetrahydropyrazine are each optionally surrounded by one or more R rings. b2 Replace, R b2 Each is independently selected from H, -CH3, -CD3, cyclopropyl, and -CH2-cyclopropyl;

[0063] m is selected from 0 or 1;

[0064] R 1 Selected from allyl;

[0065] R 2 Each is independently selected from F, Cl, -OH, -CN, -NH2, -C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, acrylonitrile, oxadiazinyl, -N=S(O)(CH3)2, the C 1-3 The alkyl, cyclopropyl, cyclobutyl, cyclopentyl, acridineyl, or oxadiazine group is each optionally substituted by one or more substituents selected from F, Cl, oxo, hydroxyl, -CN, -NH2, -CH3, -CH2CH3, -CH2OH, -CH2OCH3, -CH2CN, -CF3, -CH2CF3, -S(O)2CH3, and -CH2S(O)2CH3;

[0066] Or, two Rs 2 Together with the atoms attached to it, they form C 5-6 cycloalkyl or 5-6 membered heterocyclic groups; the C 5-6 cycloalkyl or 5-6 membered heterocyclic groups are each optionally surrounded by one or more R 2a Replace, R 2aEach is independently selected from F, Cl, hydroxyl, -CN, -NH2, -CH3, -CH2CH3, -CH2OH, -CH2CN, -CHF2, -CH2F, and -CF3.

[0067] This invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof, as shown below:

[0068]

[0069]

[0070] Those skilled in the art will understand that this invention covers compounds obtained by any combination of the various embodiments. Embodiments obtained by combining technical features or preferred technical features from one embodiment with technical features or preferred technical features from another embodiment are also included within the scope of this invention.

[0071] In another aspect, the present invention provides a method for preparing compounds of formula (I) and formula (II), the method comprising the following steps:

[0072] The preparation of compounds of formula (I) and formula (II) includes the following steps: 1. Compound IN1 and IN2 undergo a substitution reaction or coupling reaction to obtain compound IN3; 2. Compound IN3 first generates the intermediate sulfoxide under the action of an oxidant, and then undergoes a substitution reaction with compound IN4 or IN5 to obtain the compound of formula (I).

[0073]

[0074] Among them, LG 1 The group represents the halogen leaving group, and the other groups are as defined in formula (I).

[0075] In some embodiments of the present invention, LG 1 Chlorine and bromine are preferred.

[0076] The starting materials for the preparation method of the present invention can be from commercial sources or can be prepared according to known methods.

[0077] Those skilled in the art should understand that, depending on the desired product structure, the order of reaction steps can be appropriately adjusted, and protection / deprotection reaction steps can be added or omitted.

[0078] In another aspect, the present invention provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0079] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, the method comprising combining the compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0080] The pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention are pharmaceutically acceptable carriers, and examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0081] Pharmaceutical compositions can be administered in any form, as long as they achieve the purpose of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms depending on the route of administration.

[0082] In other embodiments, the administration of the compounds or pharmaceutical compositions of the present invention may be combined with other treatment methods. These other treatment methods may be selected from, but are not limited to, radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0083] This invention also relates to a pharmaceutical formulation comprising, as an active ingredient, a compound of the invention or a pharmaceutically acceptable form thereof, or a mixture thereof, a pharmaceutical composition of the invention. In some embodiments, the formulation is in the form of a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0084] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. The article of manufacture as used herein is intended to include, but is not limited to, medicine boxes and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition contained in the first container, wherein the composition comprises: a first therapeutic agent, the first therapeutic agent comprising: a compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) optionally present packaging instructions stating that the pharmaceutical composition may be used to treat oncological conditions (as defined below); and (d) a second container.

[0085] The first container is a container for containing a pharmaceutical composition. This container may be used for the preparation, storage, transportation, and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g. for cream products), or any other container for the preparation, containment, storage, or dispensing of pharmaceutical products.

[0086] The second container is a container for holding the first container and optional instruction manuals. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic boxes), cartons, cartons, bags (e.g., paper or plastic bags), sachets, and cloth bags. The instruction manuals may be physically attached to the outside of the first container by cable ties, glue, U-staples, or other adhesive methods, or they may be placed inside the second container without any physical means of attachment to the first container. Alternatively, the instruction manuals may be located outside the second container. When located outside the second container, it is preferable that the instruction manuals be physically attached by cable ties, glue, U-staples, or other adhesive methods. Alternatively, they may be adjacent to or in contact with the outside of the second container without physical attachment.

[0087] The packaging instructions, such as trademarks, labels, or markings, list information relating to the pharmaceutical composition contained within the first container. The listed information is typically determined by the regulatory authority governing the region where the product is to be sold (e.g., the U.S. Food and Drug Administration). Preferably, the packaging instructions specifically list the approved indications for which the pharmaceutical composition is used. The packaging instructions can be made of any material from which information contained therein or on the material can be read. Preferably, the packaging instructions are made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic) on which the desired information can be formed (e.g., printed or coated).

[0088] In another aspect, the present invention provides the use of the compounds described herein or in a pharmaceutically acceptable form thereof, or the pharmaceutical compositions of the present invention, in the preparation of medicaments for the prevention or treatment of Wee1 kinase-related diseases.

[0089] In another aspect, the present invention provides a method for preventing or treating Wee1 kinase-related diseases, the method comprising administering to an individual in need a compound as described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention.

[0090] In another aspect, the present invention provides compounds as described herein or in pharmaceutically acceptable forms thereof, or pharmaceutical compositions of the present invention, for the prevention or treatment of Wee1 kinase-related diseases.

[0091] In another aspect, the present invention provides a method for preventing or treating Wee1 kinase-related diseases by combining the compounds described herein or pharmaceutically acceptable forms thereof, or the pharmaceutical compositions of the present invention, with other treatment methods including, but not limited to, radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0092] In some implementations, the Wee1 kinase-related disease is a disease that is sensitive to or responsive to Wee1 kinase inhibition.

[0093] In some embodiments, the Wee1 kinase-related disease is cancer. In further embodiments, the cancer includes, but is not limited to, breast cancer, colorectal cancer, colon cancer, lung cancer, and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal 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.

[0094] In a further preferred embodiment, the compounds of the present invention can be used in combination with radiotherapy, chemotherapy, or immunotherapy to prevent or treat cancer.

[0095] Dosing regimens can be adjusted to provide the optimal required response. For example, when administered in injectable form, a single bolus, bolus, and / or continuous infusion can be given, etc. For example, several fractions can be administered over time, or the dose can be reduced or increased proportionally as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and can include single or multiple doses. Generally, the dosage of treatment is variable, depending on considerations such as: the age, sex, and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; the duration of symptoms; and other variables that can be adjusted by individual physicians. To further understand, for any particular individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition. The dosage and administration regimen of the pharmaceutical composition can be readily determined by a person skilled in the clinical field. For example, the compositions or compounds of the present invention can be administered in fractions from four times daily to once every three days, with dosages ranging from, for example, 0.01 to 1000 mg per dose. The required dose can be administered once or multiple times to achieve the desired results. The pharmaceutical compositions according to the invention can also be provided in unit dose form.

[0096] The present invention provides a novel 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 physicochemical properties (e.g., solubility, physical and / or chemical stability); (3) excellent pharmacokinetic properties (e.g., good bioavailability, suitable half-life and duration of action); (4) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0097] General terms and definitions

[0098] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0099] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0100] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0101] Unless otherwise stated, concentrations are by weight and proportions (including percentages) are by moles.

[0102] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0103] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form of “about a to b”, or equivalently, “approximately a to b”, or equivalently, “about ab”) should be understood to represent each numerical value and range encompassed within a wider range.

[0104] For example, the expression "C" 1-6 "This should be understood as encompassing any subrange and each point value, such as C." 2-5 C 3-4 C 1-2 C 1-3 C 1-4 C 1-5 And so on, as well as C1, C2, C3, C4, C5, C6, etc. For example, the expression "C 3-10 "It should also be understood in a similar way, for example, it can encompass any subrange and point value contained within it, such as C." 3-9 C 6-9 C 6-8 C 6-7 C 7-10 C 7-9 C 7-8 C 8-9And C3, C4, C5, C6, C7, C8, C9, C 10 For example, the expression "3-10 yuan" should be understood as encompassing any sub-range and each point value within it, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 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., as well as 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc. Similarly, the expression "5-10 yuan" should also be understood in a similar way, for example, it can encompass any sub-range and point value included within it, 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., as well as 5, 6, 7, 8, 9, 10 yuan, etc.

[0105] When used alone or in combination with other groups herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group. As used herein, the term "C" refers to a saturated straight-chain or branched hydrocarbon group. 1-6 "Alkyl" refers to a saturated straight-chain or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). "C" 1-6 "alkyl" can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl. The alkyl group in this invention may optionally be substituted with one or more substituents described herein.

[0106] When used alone or in combination with other groups herein, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group. As used herein, the term "C 1-6 "Alkylene" refers to a saturated, straight-chain or branched divalent hydrocarbon group having 1-6 carbon atoms. 1-6 "alkylene" includes, but is not limited to, methylene, ethylene, propylene, or butylene. The alkylene groups in this invention may optionally be substituted with one or more substituents described in this invention.

[0107] When used alone or in combination with other groups in this document, the term "alkenyl" refers to a straight-chain or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon double bonds, to which the two groups (or segments) may be attached, either to the same carbon atom or to different carbon atoms. For example, the term "C" as used herein... 2-6 "Alkenyl" refers to alkenyl groups having 2-6 carbon atoms (e.g., alkenyl groups). (etc.), which may be optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0108] When used alone or in combination with other groups in this document, the term "acetylenic" refers to a straight-chain or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, wherein the two groups (or segments) to which it is attached are respectively attached to different carbon atoms. For example, the term "C" as used herein... 2-6 "Imyynyl" refers to an ynyl group having 2-6 carbon atoms (e.g., (etc.), which may be optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0109] When used alone or in combination with other groups in this document, the terms “cycloalkyl,” “carbocyclic,” or “cycloalkylene” refer to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-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, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings, or spirocyclic groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, decahydronaphthyl, etc. For example, “C… 3-12 "Cycloalkyl" refers to a cycloalkyl group having 3 to 12 cyclic carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). The cycloalkyl or cycloalkylene groups in this invention may optionally be substituted with one or more substituents described in this invention.

[0110] When used alone or in combination with other groups herein, the term "heterocyclic group" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, e.g., fused, bridged, or spirocyclic) non-aromatic group whose ring atoms consist of a carbon atom and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocyclic group can be connected to the rest of the molecule via any one ring atom, provided the valence requirements are met. For example, "3-8 membered heterocyclic group" refers to a heterocyclic group having 3 to 8 ring atoms. Common heterocyclic groups include (but are not limited to) ethylene oxide, oxocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, sulfolane, etc. The heterocyclic, sub-heterocyclic, or heterocyclic groups in this invention may optionally be substituted with one or more substituents (e.g., oxo groups) described in this invention.

[0111] When used alone or in combination with other groups herein, the term "heteroaryl" or "heteroary ring" refers to a monocyclic and fused heterocyclic system having one or more conjugated π-electron systems, wherein one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P, and S, and the remaining ring atoms are C. Heteroaryl or heteroary rings can be characterized by the number of ring atoms. For example, 5-12 membered heteroaryl groups may contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 5, 6, 9, or 10 ring atoms. Examples of heteroaryl groups include, for example, thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, indole, etc.

[0112] When used alone or in combination with other groups in this document, the term "haloalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 "Halogenated alkyl" refers to a C-aryl group optionally substituted with one or more (e.g., 1-3) halogens. 1-6 Alkyl groups. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. Examples of alkyl halogens include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, or -CH2CH2CF3. The alkyl halogens in this invention are optionally substituted with one or more substituents described in this invention.

[0113] When used alone or in combination with other groups herein, the term "alkoxy" means an alkyl group to which an oxygen atom is attached to a portion of the parent molecule, as described above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and pentoxy.

[0114] When used alone or in combination with other groups in this document, the term "halogen" refers to fluorine (F), chlorine (Cl), and bromine (Br).

[0115] Or iodine (I). When used alone or in combination with other groups in this document, the term "hydroxyl" refers to -OH.

[0116] When used alone or in combination with other groups in this document, the term "cyano" refers to -CN.

[0117] When used alone or in combination with other groups in this document, the term "nitro" refers to -NO2.

[0118] When used alone or in combination with other groups in this document, the term "amino" refers to -NH2.

[0119] When used alone or in combination with other groups in this document, the term "oxo" refers to =O.

[0120] The term "independently" as used herein means that at least two groups (or segments) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent X and substituent Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0121] The term “substitution” and its other variant forms herein refer to the replacement of one or more (e.g., 1, 2, 3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) on a specified atom with other equivalents, provided that the replacement does not exceed the normal valence of the specified atom or group of atoms in the present case and results in the formation of a stable compound. If an atom or group of atoms is described as “optionally substituted…”, it may or may not be substituted. Unless otherwise stated, the linking site of a substituent herein may be any suitable position of the substituent. When the linking bond in a substituent is shown as a chemical bond between two atoms connected to each other in the ring system, it indicates that the substituent may be linked to any one of the cyclic atoms in the ring system.

[0122] Solid lines (-) and solid wedges can be used in this article. Or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention may exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0123] This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0124] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0125] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. A review of suitable salts can be found, for example, in “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 present invention are known to those skilled in the art.

[0126] As used herein, the term "ester" means an ester derived from the compounds described herein, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0127] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0128] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form nitrogen oxides because nitrogen requires available lone pairs of electrons to be oxidized. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming nitrogen oxides. They will also recognize that tertiary amines can form nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing 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 (AR. Katritzky and A.J. Boulton, Eds., Academic Press); and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392 (AR. Katritzky and A.J. Boulton, Eds., Academic Press).

[0129] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body upon administration of the compounds of this invention. Metabolites of the compounds can be identified using techniques known in the art, and their activity can be characterized by experimental methods. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0130] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding 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 invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0131] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0132] This invention also covers methods for preparing the compounds described herein. It should be understood that the compounds of this invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof understood by 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 achieving the conversion.

[0133] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat one or more symptoms of a target condition or disease.

[0134] As used herein, the term "effective amount" (e.g., "therapeutic effective amount" or "preventive effective amount") refers to the amount of active ingredient that, when administered, will achieve the desired effect to a certain extent, such as relieving one or more symptoms of the treated condition or preventing the occurrence of the condition or its symptoms.

[0135] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or inhibit the progression of a disease or condition to which such term is applied, or one or more symptoms of such a disease or condition, or to prevent such a disease or condition, or one or more symptoms of such a disease or condition.

[0136] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). Detailed Implementation

[0137] This invention includes all combinations of the specific embodiments described. Further embodiments of the invention and the full scope of its applicability will become apparent from the detailed description provided below. However, it should be understood that although the detailed description and specific embodiments indicate preferred embodiments of the invention, these descriptions and embodiments are provided by way of illustration only, as various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. For all purposes, all disclosures, patents, and patent applications cited herein, including in quotation marks, are incorporated herein by reference in their entirety.

[0138] For experimental methods in the following examples where specific conditions are not specified, follow conventional methods and conditions, or select according to the product instructions.

[0139] Example

[0140] The following examples and test cases illustrate the present invention in detail, but they do not limit the scope of the invention, and variations can be made without departing from the scope of the invention.

[0141] Mass spectrometry (MS) measurements were performed using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0142] The preparative high performance liquid chromatography (HPLC) method was performed using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250×20mm column).

[0143] Thin-layer chromatography purification was performed using GF 254 (0.4–0.5 nm) silica gel plates produced in Yantai.

[0144] The reaction was monitored using thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent systems used included, but were not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvent was adjusted according to the polarity of the compound, or by adding triethylamine, etc.

[0145] Column chromatography typically uses 200-300 mesh silica gel from Qingdao Ocean as the stationary phase. Eluent systems include, but are not limited to, dichloromethane and methanol systems and n-hexane and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0146] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~30℃).

[0147] Unless otherwise specified, the reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology, or Shanghai Shuya Pharmaceutical Technology, etc.

[0148] Intermediate preparation:

[0149] Preparation of intermediate 1:

[0150]

[0151] Step 1: Preparation of 2-(4-nitrophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester (compound Int1-2)

[0152] Compound Int1-1 (5 g, 23.9 mmol) was dissolved in N,N-dimethylformamide (50 mL), and p-fluoronitrobenzene (4.38 g, 31.1 mmol) and potassium carbonate (6.61 g, 47.9 mmol) were added. The mixture was heated to 80 °C and stirred for 12 hours. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound Int1-2 (3.30 g, 42% yield).

[0153] Step 2: Preparation of 2-(4-nitrophenyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (compound Int1-3)

[0154] An ethyl acetate solution (18 mL, 2 M) of hydrochloric acid was added to compound Int1-2 (3.00 g, 9.10 mmol), and the mixture was stirred at 25 °C for 2 hours. The reaction was confirmed to be complete by TLC. After concentration under reduced pressure, ethyl acetate and a saturated sodium bicarbonate solution were added to the residue. The mixture was stirred and separated. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered to obtain crude compound Int1-3 (1.8 g), which was used directly in the next reaction.

[0155] Step 3: Preparation of 5-methyl-2-(4-nitrophenyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (compound Int1-4)

[0156] Compound Int1-3 (1.30 g, 5.65 mmol) was dissolved in tetrahydrofuran (75 mL), followed by the addition of acetic acid (1.30 mL) and formaldehyde solution (1.89 g, 37%). The mixture was stirred at 25 °C for 1 hour, and then sodium borohydride acetate (5.98 g) was added, with stirring continuing for 4 hours. After the reaction was confirmed to be complete by TLC, the pH of the reaction solution was adjusted to approximately 8 with a saturated sodium bicarbonate solution. The solution was extracted twice with dichloromethane, and the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound Int1-4 (1.00 g), which was directly used in the next reaction step.

[0157] Step 4: Preparation of 4-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)aniline (compound Int1)

[0158] Compound Int1-4 (1.00 g, 4.09 mmol) was dissolved in ethanol (10 mL), and wet palladium on carbon (0.3 g, 10%) was added. The reaction solution was purged with hydrogen three times at 15 Psi and 30 °C, and stirred for 12 hours. The reaction was confirmed to be complete by TLC. The reaction solution was filtered, and the filter cake was washed twice with ethanol. The filtrate was concentrated under reduced pressure to obtain crude compound Int1 (0.60 g), which was then used directly in subsequent reactions.

[0159] Preparation of intermediate 2:

[0160]

[0161] Step 1: Preparation of 1-(4-nitrophenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylic acid tert-butyl ester (compound Int2-1)

[0162] Compound Int1-1 (5 g, 23.9 mmol) and p-fluoronitrobenzene (4.38 g, 31.1 mmol) were dissolved in anhydrous N,N-dimethylformamide (50 mL). The mixture was cooled to 0 °C, and solid NaH (1.43 g, 35.8 mmol, 60%) was slowly added. After the addition was complete, the reaction was maintained at this temperature for 2 h. After the reaction was confirmed to be complete by TLC, the reaction solution was slowly quenched with water, followed by extraction twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound Int2-1 (4.7 g, 60% yield).

[0163] Steps 2 to 4: Preparation of 4-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)aniline (compound Int2)

[0164] Compound Int2 was synthesized using a method similar to steps two through four of intermediate 1.

[0165] Preparation of intermediate 3:

[0166]

[0167] Step 1: Preparation of 3-bromo-5-methyl-4,5,6,7-tetrahydropyrazole[1,5-a]pyrazine (compound Int3-2): Int3-1 (400 mg, 2.0 mmol) was dissolved in methanol (12 mL) at 0 °C. HCHO (400 mg, 4 mmol, 30% aqueous solution) and CH3COONa (132 mg, 1.6 mmol) were added, and the mixture was stirred for 20 minutes. Then, NaBH3CN (101 mg, 1.6 mmol) was added to the mixture and stirred for 30 minutes. After concentration, the mixture was purified by column chromatography to obtain Int3-2 (280 mg, 65%).

[0168] Step 2: Preparation of tert-butyl (4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenyl)carbamate (compound Int3-3)

[0169] In3-2 (240 mg, 1.12 mmol) and 4-(N-Boc-amino)phenylboronic acid (264 mg, 1.12 mmol) were dissolved in dioxane (6 mL), and Pd(PPh3)4 (64 mg, 0.10 mmol) and saturated NaHCO3 solution (6 mL) were added. The reaction mixture was reacted at 100 °C for 3 hours under nitrogen protection. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed twice with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to give Int3-3 (146 mg, 40%).

[0170] Step 3: Preparation of 4-(5-methyl-4,5,6,7-tetrahydropyrazole[1,5-a]pyrazin-3-yl)aniline (compound Int3)

[0171] Int3-3 (146 mg, 0.44 mmol) was dissolved in dioxane hydrochloride (7 mL, 4 N) and stirred at 25 °C for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. Dichloromethane was added to the residue, and the pH was adjusted to 8 with saturated Na2CO3 aqueous solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude Int3 (100 mg), which was then used directly in the next reaction.

[0172] Preparation of intermediate 4:

[0173]

[0174] Step 1: Preparation of 7-(4-nitrophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (compound Int4-2) Compound Int4-1 (130 mg, 1.06 mmol) was dissolved in DMF (10 ml) with p-nitrofluorobenzene (447 mg, 3.17 mmol) and Cs₂CO₃ (1.03 g, 3.17 mmol) and stirred overnight at 120 °C. The reaction solution was diluted with water, extracted three times with ethyl acetate, and the organic phase was washed twice with brine. After drying the organic phase, it was evaporated to dryness and purified by column chromatography to obtain compound Int4-2 (130 mg, 50%).

[0175] Step 2: Preparation of 4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)aniline (compound Int4) Compound Int4-2 (110 mg, 0.45 mmol) was dissolved in wet palladium on carbon (50 mg, 10%) in MeOH (5 ml) and THF (5 ml) and stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was evaporated to dryness to give compound In4 (70 mg, 73%).

[0176] Compounds Int5 and Int6 were synthesized using the same methods as intermediates 1-4.

[0177] Example 1:

[0178] Preparation Example 1: 2-Allyl-1-(6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-6-((4-(5-methyl-5,6-dihydropyrrole[3,4-c])

[0179] Preparation of pyrazol-2(4H)-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 1)

[0180]

[0181] Step 1: Preparation of 2-allyl-1-(6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compounds 1-3)

[0182] Compounds 1-1 (15 g, 67.5 mmol) and 1-2 (17.50 g, 81.0 mmol) were dissolved in dioxane (225 mL) and N,N-dimethylethylenediamine (6.54 g, 74.2 mmol). Potassium carbonate (14 g, 101.4 mmol) and cuprous iodide (12.85 g, 67.5 mmol) were added under nitrogen atmosphere, and the reaction was carried out at 100 °C for 12 hours. After the reaction was confirmed to be complete by LCMS, the reaction solution was cooled to room temperature, water and ethyl acetate were added, the mixture was stirred, and the liquid was separated. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 1-3 (20 g, 82.9% yield). Step 2: Preparation of 2-allyl-1-(6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-6-((4-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 1)

[0183] Compounds 1-3 (100.0 mg, 0.28 mmol) were dissolved in toluene (3 mL), and m-chloroperoxybenzoic acid (78.2 mg, 0.38 mmol, 85%) was added. The mixture was stirred at 25 °C for 1 hour. Subsequently, compound Int1 (59.9 mg, 0.28 mmol) and DIPEA (108.0 mg, 0.84 mmol) were added, and the mixture was heated to 60 °C for 4 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to give compound 1 (26.7 mg, yield 24%).

[0184] MS(ESI) m / z: 524.2 [M+H] + .

[0185] 1HNMR (400MHz, DMSO-d6): δ8.90(s,1H),8.33–8.31(m,1H),8.04(t,J=7.6Hz,1H),7.89–7.84(m,2H),7.75–7.71(m,2H),7.62–7.51( m,2H),5.70–5.59(m,1H),4.97(d,J=8.8Hz,1H),4.81–4.78(m,2H),4.70–4.61(m,3H),4.48-4.16(m,2H),3.07(s,3H),1.43(s,6H).

[0186] Preparation Example 2: Preparation of 2-allyl-1-(6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-6-((4-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 2)

[0187]

[0188] Compound 2 was synthesized following the method in step 2 of Preparation Example 1.

[0189] MS(ESI) m / z: 524.2 [M+H] + .

[0190] 1 HNMR (400MHz, CD3OD): δ8.86(s,1H),8.03(t,J=7.6Hz,1H),7.88–7.85(m,2H),7.78(d,J=7.6Hz,1H),7.68(d,J=8.0Hz,1H),7.61(s,1H),7.55–7.5 1(m,2H),5.78–5.67(m,1H),5.04(dd,J=10.0Hz,1.2Hz,1H),4.97–4.89(m ,3H),4.81(d,J=6.0Hz,2H),4.68–4.27(m,2H),3.24(s,3H),1.57(s,6H).

[0191] Preparation Example 3: Preparation of 2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopentyl[b]pyridin-2-yl)-6-((4-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 3)

[0192]

[0193] Compound 3 was synthesized following the method described in Preparation Example 1.

[0194] MS(ESI) m / z: 550.3 [M+H] + .

[0195] 1 HNMR (400MHz, CD3OD): δ8.87(s,1H),8.14(s,1H),7.91–7.83(m,3H),7.75–7.72(m,1H),7.68–7. 66(m,1H),7.53(d,J=8.8Hz,1H),5.78–5.68(d,J=9.6Hz,1H),5.04(d,J=9.6Hz,1H),4.96–4.92(m ,2H),4.77–4.71(m,2H),4.68–4.50(m,3H),3.22(s,3H),3.14–3.04(m,1H),2.92–2.84(m,1H),2 .42–2.35(m,1H),2.20–2.13(m,1H),2.07–1.98(m,1H),1.91–1.82(m,1H),0.95(t,J=7.6Hz,3H).

[0196] Preparation Example 4: Preparation of 2-allyl-6-((4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)phenyl)amino)-1-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 27)

[0197]

[0198] Compound 27 was synthesized following the method described in step 2 of Preparation Example 1.

[0199] MS(ESI) m / z: 524.2 [M+H] + .

[0200] 1HNMR(400MHz,CD3OD)δ8.79(s,1H),7.97(t,J=7.86Hz,1H),7.75(d,J=7.86Hz,1H), 7.63(d,J=7.74Hz,1H),7.59(d,J=8.48Hz,2H),7.06(t,J=13.42Hz,4H),5.71(ddd, J=17.02,6.12,4.20Hz,1H),5.03(dd,J=10.20,1.02Hz,1H),4.94–4.88(m,1H),4.8 0(d,J=6.12Hz,2H),4.40(s,2H),4.17(s,2H),3.72(t,J=5.24Hz,2H),1.57(s,6H).

[0201] Preparation Example 5: Preparation of 2-allyl-6-((4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)phenyl)amino)-1-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 16)

[0202]

[0203] Compound 16 was synthesized following the method described in step 2 of Preparation Example 1.

[0204] MS(ESI) m / z: 538.2 [M+H] + .

[0205] 1 HNMR (400MHz, CDCl3) δ8.67 (s, 1H), 7.76 (t, J = 7.86Hz, 1H), 7.55 (dd, J = 14.80 ,7.68Hz,4H),7.36(d,J=7.68Hz,1H),7.26(s,2H),7.10(d,J=7.32Hz,2H),5. 56–5.42(m,1H),4.85(d,J=10.02Hz,1H),4.73(d,J=17.00Hz,1H),4.60(d,J= 5.48Hz,2H),4.26(s,2H),3.32(s,2H),3.15(s,2H),2.69(s,3H),1.39(s,6H).

[0206] Preparation Example 6: Preparation of 2-allyl-1-(6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-6-((4-(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 20)

[0207]

[0208] Compound 20 was synthesized following the method described in step 2 of Preparation Example 1.

[0209] MS(ESI) m / z: 538.2 [M+H] + .

[0210] 1 HNMR(400MHz,CD3OD)δ9.33(s,1H),8.53(s,1H),8.38(s,1H),8.12(t,J=7.88 Hz,1H),7.81(dd,J=7.88,1.5Hz,2H),7.32(d,J=8.58Hz,2H),6.80(t,J=10.72 Hz,2H),5.83–5.68(m,1H),5.06(d,J=9.42Hz,1H),4.95–4.89(m,3H),4.45(s, 2H), 4.24 (t, J = 5.16Hz, 2H), 3.01 (t, J = 5.18Hz, 2H), 2.60 (s, 3H), 1.57 (s, 6H).

[0211] Preparation Example 7: Preparation of 2-allyl-1-(6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-6-((4-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 1)

[0212]

[0213] Compound 21 was synthesized following the method of Preparation Example 1.

[0214] MS(ESI) m / z: 536.2 [M+H] + .

[0215] 1HNMR(400MHz,CD3OD)δ8.85(s,1H),7.99(t,J=7.86Hz,1H),7.80(d,J=8.58Hz,2H),7.71(dd,J= 19.18,7.86Hz,2H),7.42(d,J=8.58Hz,2H),7.01(s,1H),5.81–5.59(m,1H),5.04(d,J=10.20Hz ,1H),4.91(d,J=17.28Hz,2H),4.69(d,J=6.00Hz,2H),4.08(t,J=5.42Hz,2H),3.72(s,2H),2.9 1(t,J=5.46Hz,2H),2.53(s,3H),1.35(dd,J=7.42,4.40Hz,2H),1.21(dd,J=7.42,4.40Hz,2H).

[0216] Example 2: Wee1 enzyme activity inhibition experiment

[0217] In the Wee1 enzyme activity inhibition experiment, the effects of different compounds on Wee1 enzyme activity were investigated using the ADP-Glo ​​luminescent kit. Wee1 enzyme was purchased from Carna Bioscience, and Poly(Lys Tyr (4:1)) was used as the enzyme reaction substrate. After incubating the compound (maximum concentration 1000 nM, serially diluted 3-fold) with Wee1 (2 nM) for 30 min, the reaction substrate and ATP were added, and the reaction was carried out at room temperature for 1 h. Then, ADP-Glo ​​stop reagent was added, and the reaction was carried out at room temperature in the dark for 40 min. Finally, ADP-Glo ​​kinase detection reagent was added, and the reaction was carried out at room temperature in the dark for 1 h. Luminescence values ​​were measured, and the half-maximal inhibitory concentration (IC50) of the compound on enzyme activity was calculated. The experimental results are shown in Table 1.

[0218] Table 1. Results of Wee1 enzyme activity inhibition assay

[0219] Compound 1 2.10 Compound 2 1.80 Compound 3 2.80 Compound 20 4.61 Compound 21 3.31 Compound 27 1.86

[0220] The results show that the compound of this application has good Wee1 enzyme inhibitory activity.

[0221] Example 3: Cell proliferation inhibition experiment

[0222] The effects of various compounds on cell proliferation were examined in A427, NCI-H1299, CAPAN-1, and NCI-H82 cell lines. Specifically, after incubation with serially diluted compounds for 72 or 144 hours... The half-maximal inhibitory concentration (IC50) of the compound on these cell lines was assessed and calculated using a chemiluminescent cell viability assay (CTG method). The results are shown in Table 2.

[0223] Table 2. Inhibition of different cell proliferation activities by compounds

[0224]

[0225]

[0226] The results show that the compound of this application has good cell proliferation inhibitory activity.

[0227] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. The compounds shown in formula (I) or formula (II) or their pharmaceutically acceptable salts, 、 ； in, Ring A is selected from phenyl; the phenyl group is optionally surrounded by one or more R groups. a Replace; R a Each is independently selected from H, halogen, -CN, -C 1-6 Alkyl, the C 1-6 Each alkyl group may optionally be substituted by one or more substituents selected from halogens, hydroxyl groups, and -CN groups; The B ring is selected from 5-6 membered heteroaryl groups, and the B ring is optionally surrounded by one or more R groups. b1 replace; The E ring is selected from a 5-6 membered heterocyclic group; the 5-6 membered heterocyclic group is optionally surrounded by one or more R rings. b2 replace; R b1 and R b2 Each is independently selected from H and -C. 1-6 Alkyl or -CD3; R 1 Selected from -C 2-6 alkenyl; The G ring is selected from 5-10 membered heteroaryl groups; R 2 Each is independently selected from -C 1-6 Alkyl and -C 3-12 cycloalkyl, the C 1-6 Alkyl or C 3-12 Each cycloalkyl group is optionally surrounded by one or more elements selected from halogen, hydroxyl, -CN, -NH2, -C 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-CN or -halogenated C 1-6 Alkyl substituents; Alternatively, R connected to two adjacent ring atoms respectively 2 Together with the atoms attached to it, they form C 5-8 cycloalkyl; the C 5-8 cycloalkyl groups are optionally surrounded by one or more R 2a Replace, R 2a Each is independently selected from halogens, hydroxyl groups, -CN, -NH2, and -C. 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene-CN or -halogenated C 1-6 alkyl; n is 0, 1, 2, 3, or 4; The compounds shown in formulas (I) and (II) are not .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from phenyl, wherein the phenyl group is optionally surrounded by one or more R groups. a Replace, each R a Each is independently selected from H, F, Cl and -C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted by one or more substituents selected from F, Cl and -CN.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from , and .

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring B is selected from imidazole, pyrazol, and pyrrole, wherein each of the imidazole, pyrazol, and pyrrole groups is optionally surrounded by one or more R groups. b1 Replace, each R b1 Each is independently selected from H and -C. 1-3 Alkyl or -CD3.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, R b1 Each is independently selected from H, -CH3, or -CD3.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, The E ring is selected from a 5-6 membered heterocyclic group, which is optionally surrounded by one or more R rings. b2 Replace, R b2 Each is independently selected from H and -C. 1-3 Alkyl or -CD3.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein, The E ring is selected from 3-pyrrolidine and 1,2,3,6-tetrahydropyrazine, wherein the 3-pyrrolidine and 1,2,3,6-tetrahydropyrazine are each optionally surrounded by one or more R rings. b2 Replace, R b2 Each is independently selected from H, -CH3, or -CD3.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Selected from , , , , , , , , , , , , or R b2 Each is independent of the definition in claim 1.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Selected from , , , , , or , where R b2 Selected from H, -CH3 and -CD3.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Selected from , , , , , R b1 Each is independent of the definition in claim 1.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein, Selected from , , , , ;R b1 Selected from H, -CH3 and -CD3.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from allyl.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the G ring is selected from pyridinyl, pyrimidinyl, thienyl, or thiazolyl.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein the G ring is selected from pyridyl groups.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 2 Selected from -C 1-6 Alkyl or -C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 Each cycloalkyl group is optionally surrounded by one or more elements selected from halogen, hydroxyl, -CN, -NH2, -C 1-3 Alkyl, -C 1-3 alkylene -OH, -C 1-3 Alkylene-OC 1-3 Alkyl, -C 1-3 Alkylene-CN or -halogenated C 1-3 Alkyl substituents.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein, R 2 Selected from -C 1-3 Alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, wherein the C 1-3 The alkyl, cyclopropyl, cyclobutyl, or cyclopentyl groups are each optionally substituted by one or more substituents selected from F, Cl, hydroxyl, -CN, -NH2, -CH3, -CH2CH3, -CH2OH, -CH2OCH3, -CH2CN, -CF3, or -CH2CF3.

17. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein, R 2 Selected from -CH3, -CH2CH3, -C(CH3)3, -CH2OH, -CH2CN, -CHF2, -CH2F, -CF3, , and .

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Selected from , , or R 2 As defined in claim 1.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2a Selected from halogens, hydroxyl groups, -CN, -NH2, -C 1-3 Alkyl, -C 1-3 alkylene -OH, -C 1-3 Alkylene-CN or -halogenated C 1-3 alkyl.

20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R 2a It is selected from halogens, hydroxyl groups, -CN, -NH2, -CH3, -CH2CH3, -CH2OH, -CH2CN, -CHF2, -CH2F or -CF3.

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, for , where R 2a As defined in claim 1.

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Selected from: , , , , , , , or .

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from: 、 ； Among them, ring B, ring E, and ring R a R 1 and R 2 As defined in claim 1; m can be one or more.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein, Ring B is selected from imidazole, pyrazol, and pyrrole, wherein each of the imidazole, pyrazol, and pyrrole groups is optionally surrounded by one or more R groups. b1 Replace, each R b1 Each is independently selected from H or -C. 1-3 alkyl; The E ring is selected from a 5-6 membered heterocyclic group, which is optionally surrounded by one or more R rings. b2 Replace, R b2 Each is independently selected from H or -C. 1-3 alkyl; R 1 Selected from allyl; R 2 Each is independently selected from -C 1-3 Alkyl or -C 3-6 cycloalkyl, the C 1-3 Alkyl or C 3-6 Each cycloalkyl group is optionally substituted by one or more substituents selected from F, Cl, hydroxyl, -CN, -NH2, -CH3, -CH2CH3, -CH2OH, -CH2OCH3, -CH2CN, -CF3 or -CH2CF3; Or, two Rs 2 Together with the atoms attached to it, they form C 5-6 cycloalkyl; the C 5-6 Each cycloalkyl group is optionally surrounded by one or more R 2a Replace, R 2a Each is independently selected from halogens, hydroxyl groups, -CN, -NH2, and -C. 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene-CN or -halogenated C 1-6 alkyl.

25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 26. A pharmaceutical composition comprising the compound of any one of claims 1-25 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

27. Use of the compound of any one of claims 1-25 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 26, in the preparation of a medicament for the prevention and / or treatment of Wee1 kinase-related diseases.

28. The use according to claim 27, wherein, The Wee1 kinase-related disease is cancer.

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