CN116848118A - Pyrazolo [3,4-d ] pyrimidin-3-one derivatives as Wee-1 inhibitors - Google Patents

Pyrazolo [3,4-d ] pyrimidin-3-one derivatives as Wee-1 inhibitors Download PDF

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CN116848118A
CN116848118A CN202280012695.8A CN202280012695A CN116848118A CN 116848118 A CN116848118 A CN 116848118A CN 202280012695 A CN202280012695 A CN 202280012695A CN 116848118 A CN116848118 A CN 116848118A
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alkyl
cycloalkyl
substituted
heterocycloalkyl
halogen
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谢雨礼
樊后兴
钱立晖
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Wigen Biomedicine Technology Shanghai Co Ltd
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Wigen Biomedicine Technology Shanghai Co Ltd
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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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Abstract

The invention discloses pyrazolo [3,4-d ] as Wee-1 inhibitor]Pyrimidine-3-one derivatives. Specifically, the invention relates to a compound shown as a formula (1) and/or pharmaceutically acceptable salt thereof, a composition containing the compound shown as the formula (1) and/or pharmaceutically acceptable salt thereof, a preparation method and application of the compound as a Wee-1 inhibitor in preparation of antitumor drugs.

Description

Pyrazolo [3,4-d ] pyrimidin-3-one derivatives as Wee-1 inhibitors
The present application claims priority from China patent application 2021101796460 with the application date 2021/2/9. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The application relates to the field of pharmaceutical chemistry, in particular to a compound with a Wee-1 kinase inhibition effect, a preparation method thereof and application of the compound in preparation of antitumor drugs.
Background
Wee-1 protein kinase is an important negative regulatory protein in cell cycle checkpoints. Cell cycle checkpoints include the G1 phase checkpoint of the G1 (cell resting phase) to S phase (DNA synthesis phase) transition, the G2 phase checkpoint of the G2 (cell division preparation phase) to M (cell division phase) phase transition, and the spindle checkpoints of the M phase metanase to anaphase (cell division phase post-phase) transition. Wee-1 protein kinase plays an important role in the G2 phase checkpoint. The entry of cells into the M phase depends on CDK1 kinase activity, and Wee-1 inhibits CDK1 activity by phosphorylating Tyr15 of CDK1 protein, preventing cells from entering the M phase (cell division phase). While the Polo kinase phosphorylates Wee-1, activates the degradation of Wee-1 protein and promotes cells to enter M phase. As can be seen, wee-1 kinase activity determines the activity of the G2 checkpoint, which in turn regulates the G2 to M phase transition of cells.
Cell cycle checkpoints are activated mainly after DNA damage, playing an important role in the repair of DNA in cells. Normal activation of cell cycle checkpoints blocks the cell cycle to promote DNA repair. Inhibiting the function of check point, DNA damage can not be repaired, and cells undergo apoptosis. Compared with normal cells, the functions of p53 protein, which is an important protein of a G1 phase checkpoint, of various tumor cells are damaged, and DNA damage is repaired mainly by activating the G2 phase checkpoint, so that apoptosis is avoided. Thus, inhibition of the G2 phase checkpoint can selectively kill tumor cells. While the important role of the activity of the Wee-1 kinase in the G2 phase check point suggests that the Wee-1 kinase determines the repair or death of tumor cells after DNA damage, and inhibiting the activity of the Wee-1 can promote unrepaired tumor cells after DNA damage to enter the M phase and induce apoptosis.
Research shows that Wee-1 is involved in DNA synthesis, DNA homologous repair, post-translational modification of chromosomal histones, and other functions closely related to tumorigenesis and development, in addition to its role in the G2 checkpoint. Wee-1 expression is greatly elevated in a number of tumors including liver cancer, breast cancer, cervical cancer, melanoma, lung cancer, and the like. While the high expression of Wee-1 is positively correlated with the poor development and prognosis of tumors, suggesting that Wee-1 kinase may be involved in tumor development and progression. Studies in vitro cell models and in vivo animal models have shown that inhibiting Wee-1 activity while inducing DNA damage can significantly inhibit the growth of a variety of tumors.
Thus, the development of specific, high activity small molecule inhibitors of Wee-1 kinase would be of great clinical value for tumor therapy, especially in targeting tumors such as P53 deleted G1 checkpoints that are impaired.
Currently, the Wee-1 inhibitor AZD1775 (MK-1775, adavosertib) of AstraZeneca has entered the clinical phase 2 study, with more than 30 clinical trials being developed. Patents related to AZD1775 are US20070254892, WO2007126122, EP2213673, WO2008133866, WO2011034743, etc. Abbott and Abbvie have also been studied for Wee-1 inhibitors and related patents are mainly US2012220572, WO2013126656, WO2013012681, WO2013059485, WO2013013031, etc. Patents by Almac corporation for Wee-1 inhibitors include WO2014167347, WO2015019037, WO2015092431, WO2018011570, WO2018062932, WO2019138227, and the like. Wee-1 patents from Giraffharma include WO2019074979 and WO2019074981. Patents from Zeno corporation on Wee-1 research include WO2018028008 and WO2019173082.
The Wee-1 inhibitor still has some problems in research, the treatment effect of single drug is poor, and the cell activity of the combination with other chemotherapeutics is not strong enough, so that the clinical combination effect is not ideal. Drug resistance usually occurs in the late stage of targeted treatment, chemotherapy is a common means for treating advanced tumors, and single-use chemotherapy drugs often produce larger side effects and poor patient tolerance, so that the Wee-1 inhibitor with good combined effect of the invention and the chemotherapy drugs has very important significance.
Disclosure of Invention
The invention provides a compound shown as a general formula (1), an optical isomer or a pharmaceutically acceptable salt thereof:
in the general formula (1):
m is 0 or 1;
n is 0 or 1;
v is 1, 2 or 3;
w is N or CH;
R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
R 2a and R is 2b Independently H or C1-C3 alkyl, or R 2a And R is 2b Form, together with the C atom to which it is attached, a C3-C6 cycloalkyl group;
R 3a and R is 3b Independently H or C1-C3 alkyl, or R 3a And R is 3b Form, together with the C atom to which it is attached, a C3-C6 cycloalkyl group;
R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N (C1-C6 alkyl) 2 NH (C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or (4-12 membered) heterocycloalkyl, said C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl and (4-12 membered) heterocycloalkyl being optionally substituted by 1 to 3 of the following groups: H. halogen, OH, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy, or (4-7 membered) heterocycloalkyl;
R 5 And R is 6 Independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkeneRadicals, C2-C6 alkynyl and C3-C6 cycloalkyl radicals, or R 5 And R is 6 Together with the atoms to which they are attached form a (3-10 membered) heterocycloalkyl;
R 7 is H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl or halogen substituted C1-C6 alkoxy;
R 8 and R is 9 Is independently H, C-C6 alkyl or C3-C6 cycloalkyl, or R 8 And R is 9 Together with the N atom to which it is attached, form a (4-7 membered) heterocycloalkyl, which (4-7 membered) heterocycloalkyl may be substituted with 1-3 of the following groups: H. halogen, OH, CN or C1-C3 alkyl.
The invention provides a compound shown as a general formula (2), an optical isomer or a pharmaceutically acceptable salt thereof:
in the general formula (2):
m is 0 or 1;
n is 0 or 1;
v is 1, 2 or 3;
w is N or CH;
x is CH or N;
R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
R 2a and R is 2b Each independently is H or C1-C3 alkyl, or R 2a And R is 2b Form, together with the C atom to which it is attached, a C3-C6 cycloalkyl group;
R 3a and R is 3b Each independently is H or C1-C3 alkyl, or R 3a And R is 3b Form, together with the C atom to which it is attached, a C3-C6 cycloalkyl group;
R 4 Is H, halogen, CN, OR 10 C1-C6 alkyl, C1-C6 alkylOxy, N (C1-C6 alkyl) 2 NH (C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or (4-12 membered) heterocycloalkyl, wherein said C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl or (4-12 membered) heterocycloalkyl may be optionally substituted by 1-3 of: H. halogen, OH, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy, N (C1-C6 alkyl) 2 C1-C3 alkyl substituted C3-C6 cycloalkyl, halogen substituted C3-C6 cycloalkyl, CN substituted C3-C6 cycloalkyl, (4-7 membered) heterocycloalkyl or halogen substituted (4-7 membered) heterocycloalkyl;
R 5 and R is 6 Each independently is C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, or R 5 And R is 6 Together with the atoms to which they are attached form a (3-10 membered) heterocycloalkyl;
R 7 is H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl or halogen substituted C1-C6 alkoxy;
R 8 and R is 9 Each independently is H, C-C6 alkyl or C3-C6 cycloalkyl, or R 8 And R is 9 Together with the N atom to which it is attached, form a (4-7 membered) heterocycloalkyl, wherein said (4-7 membered) heterocycloalkyl may be substituted with 1-3 of the following groups: H. halogen, OH, CN or C1-C3 alkyl;
R 10 is a C3-C6 cycloalkyl or a (4-12 membered) heterocycloalkyl, wherein said C3-C6 cycloalkyl or (4-12 membered) heterocycloalkyl is optionally substituted with 1-3 of the following groups: h or C1-C3 alkyl.
The invention also provides a compound shown in the general formula (1A), an optical isomer or a pharmaceutically acceptable salt thereof:
in the general formula (1A):
m is 0 or 1;
n is 0 or 1;
v is 1, 2 or 3;
w is N or CH;
R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
R 5 and R is 6 Independently is C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, or R 5 And R is 6 Together with the atoms to which they are attached form a (3-10 membered) heterocycloalkyl;
R 7 is H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl or halogen substituted C1-C6 alkoxy;
R 8 and R is 9 Is independently H, C-C6 alkyl or C3-C6 cycloalkyl, or R 8 And R is 9 Together with the N atom to which it is attached, form a (4-7 membered) heterocycloalkyl, which (4-7 membered) heterocycloalkyl may be substituted with 1-3 of the following groups: H. halogen, OH, CN or C1-C3 alkyl.
In some embodiments of the invention, wherein R in the general formula (1) or the general formula (1A) 1 Is Me, et, R 1 Preferably isEt、
In some embodiments of the present invention, wherein in the general formula (1) or the general formula (1A),is that Preferably is
In some embodiments of the present invention, wherein R in the general formula (1) 4 Is Me, et, CF 3 、CHF 2 、F、Cl、Br、I、CN、OMe、OEt、CN、SMe、SEt、OCF 3 、NMe 2 、NHMe、 R 4 Preferably Me, et, CF 3 、CHF 2 、F、Cl、Br、I、CN、OMe、OEt、CN、SMe、SEt、OCF 3 、NMe 2 、NHMe、 R 4 More preferably Me, et, F, cl, CN, OMe, OEt, NMe 2 、
In some embodiments of the invention, wherein the compound has one of the following structures:
it is another object of the present invention to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) or (1A) of the present invention, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
Still another object of the present invention is to provide the use of the compound of the general formula (1) or the general formula (1A), an optical isomer thereof or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition of the present invention for preparing a medicament for treating, modulating or preventing a disease associated with Wee-1.
Still another object of the present invention is to provide a method for treating, modulating or preventing a disease associated with Wee-1 mediation, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) or the general formula (1A) of the present invention, an optical isomer thereof or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described above.
Through intensive researches, it is found that R in a compound with a structure shown as a general formula (1) or a general formula (1A) 4 In the case of alkyl, cycloalkyl or heterocycloalkyl, the compounds have strong Wee-1 inhibition activity and combined administration activity with the chemotherapeutic drug Gemcitabine (GMC), and the results show that the compounds of the invention can have better effects in clinical combination with the chemotherapeutic drug.
It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
Synthesis of Compounds
The process for preparing the compound of the general formula (1) or the general formula (1A) of the present invention is specifically described below, but these specific processes do not constitute any limitation on the present invention.
The compounds of formula (1) or formula (1A) described above may be synthesized using standard synthetic techniques or well known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials for the synthesis of the compounds may be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., vols.A and B (Plenum 2000, 2001), green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general method of preparation of the compounds may be varied by the use of appropriate reagents and conditions for introducing different groups into the formulae provided herein.
In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as the reactants, solvents, bases, amounts of the compounds used, reaction temperature, time required for the reaction, etc., are not limited to the explanation below. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a method for preparing the compound represented by the general formula (1) or the general formula (1A), wherein the compound represented by the general formula (1) or the general formula (1A) can be prepared by the following method a:
the method A comprises the following steps: first, the compound A1 and the compound A2 are subjected to a coupling reaction to generate a compound A3, the compound A3 is subjected to an oxidation reaction to generate a compound A4, and the compound A4 and the compound B3 are further reacted to generate a target compound A5.
W, R in the above reaction equation 1 、R 2a 、R 2b 、R 3a 、R 3b 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 The definitions of m, n and v are as described above, Z is Br, I or-B (OH) 2 E is
Further forms of the compounds
By "pharmaceutically acceptable" is meant herein a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and which is relatively non-toxic, e.g., administration of a material to an individual does not cause an undesired biological effect or interact in a deleterious manner with any of the components thereof in which it is contained.
The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered, and does not abrogate the biological activity and properties of the compound. In certain specific aspects, the pharmaceutically acceptable salts are obtained by reacting a compound of formula (1) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and other organic acids, and an acidic amino acid, e.g., aspartic acid, glutamic acid.
References to pharmaceutically acceptable salts are understood to include solvent-added forms or crystalline forms, particularly solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of formula (1) are conveniently prepared or formed in accordance with the methods described herein. For example, the hydrate of the compound of formula (1) is conveniently prepared by recrystallisation from a mixed solvent of water/organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, solvated forms are considered to correspond to unsolvated forms.
In other specific embodiments, the compounds of formula (1) are prepared in different forms including, but not limited to, amorphous, crushed and nano-sized forms. In addition, the compound of formula (1) includes crystalline forms and may also be polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.
In another aspect, the compounds of formula (1) may have chiral centers and/or axial chiralities and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric forms, and cis-trans isomeric forms. Each chiral center or axial chiral will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The compounds of the present application may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) And C-14% 14 C) A. The application relates to a method for producing a fibre-reinforced plastic composite As another example, deuteration may be formed by substituting a hydrogen atom with a heavy hydrogenIn the compound, the bond formed by deuterium and carbon is firmer than the bond formed by common hydrogen and carbon, and compared with a non-deuterated medicament, the deuterated medicament has the advantages of reducing toxic and side effects, improving medicament stability, enhancing curative effect, prolonging in-vivo half-life of the medicament and the like. All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.
Terminology
The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. It must be noted that, in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In the present application, the use of "or" and "means" and/or "unless otherwise indicated.
Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, particularly alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH 3 、CH 3 CH 2 、CF 3 、CHF 2 、CF 3 CH 2 、CF 3 (CH 3 )CH、 i Pr、 n Pr、 i Bu、 n Bu or t Bu。
Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.
Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, and includes straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl are preferred.
Unless otherwise specified, "alkynyl" refers to unsaturated aliphatic hydrocarbon groups containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, for example ethynyl, 1-propynyl or 1-butynyl.
Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), a partially unsaturated cycloalkyl may be referred to as "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring-forming carbon atoms of cycloalkyl groups may optionally be oxidized to form oxo or thioionic groups. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, cycloalkyl contains 0, 1, or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused to aryl and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, pinyl, carenyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexane, and the like.
Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxyRadicals, in particular alkoxy radicals substituted by one or more halogens. Preferred alkoxy groups are selected from OCH 3 、OCF 3 、CHF 2 O、CF 3 CH 2 O、 i- PrO、 n- PrO、 i- BuO、 n- BuO or t- BuO。
Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If the heterocycloalkyl group contains at least one double bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkenyl", or if the heterocycloalkyl group contains at least one triple bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can optionally be oxidized to form oxo or thioxo groups or other oxidized bonds (e.g., C (O), S (O), C (S) or S (O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains from 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are benzo derivatives having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, thienyl, or the like. The heterocycloalkyl group containing the fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro [5.5 ] ]Undecyl, 1-oxa-8-azaspiro [4.5 ]]Decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranylPyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3, 4-tetrahydroquinolinyl, tropanyl, 4,5,6, 7-tetrahydrothiazolo [5,4-c ]]Pyridyl, 4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyllactam, valerolactam, imidazolone, hydantoin, dioxolanyl, phthalimido, pyrimidine-2, 4 (1H, 3H) -dione, 1, 4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S, S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro [3.3 ]]Heptyl, indolinyl, and,
Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted with F, cl, br or I, preferably F or Cl, in any combination.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
Substituent "-O-CH 2 -O- "means that two oxygen atoms in the substituent are attached to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, such as:
when the number of one linking group is 0, such as- (CH) 2 ) 0 -it is meant that the linking group is a single bond.
When one of the variables is selected from a bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in X-L-Y represents a bond, it is indicated that the structure is in fact X-Y.
Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keysAnd straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy linesSolid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysOr straight dotted line key
Unless otherwise indicated, use ofRepresents a single bond or a double bond.
Specific pharmaceutical and medical terminology
The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.
The terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.
"active ingredient" refers to a compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the invention may contain one or more asymmetric centers (chiral centers or axial chiralities) and thus appear as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The terms "compound", "composition", "agent" or "pharmaceutical (medicine or medicament)" are used interchangeably herein and refer to a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic effects when administered to an individual (human or animal).
The term "administration (administered, administering or administeration)" as used herein refers to the administration of the compound or composition directly, or the administration of a prodrug (pro), derivative (derivative), or analog (analog) of the active compound, and the like.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the average value, as determined by one of ordinary skill in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, ratios of amounts, and the like) are to be understood to be modified by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties. At least these numerical parameters should be construed as indicating the number of significant digits and by applying ordinary rounding techniques.
Unless defined otherwise herein, the meanings of scientific and technical terms used herein are the same as commonly understood by one of ordinary skill in the art. Furthermore, as used in this specification, the singular noun encompasses the plural version of the noun without conflict with the context; plural nouns as used also encompasses singular versions of the noun.
Therapeutic use
The present invention provides methods of treating diseases using the compounds of formula (1) or formula (1A) or pharmaceutical compositions of the present invention, the compounds of formula (1) or formula (1A) or pharmaceutical compositions being generally useful for inhibiting the Wee-1 kinase and thus useful for treating one or more conditions associated with Wee-1 kinase activity. Thus, in certain embodiments, the present invention provides methods for treating a Wee-1 kinase mediated condition comprising the step of administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.
In some embodiments, there is provided a method for treating cancer, the method comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of formula (1) or formula (1A). In some embodiments, the cancer is mediated by Wee-1. In other embodiments, the cancer includes, but is not limited to, hematological malignancies (leukemias, lymphomas, myelomas including multiple myeloma, myelodysplastic syndrome, and myeloproliferative surname syndrome), and solid tumors (carcinomas such as prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue carcinomas and osteosarcomas, and stromal tumors), among others.
Route of administration
The compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated into a variety of formulations comprising a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific conditions such as age, illness and treatment course of the subject.
"pharmaceutically acceptable excipient or carrier" means: one or more compatible solidsA body or liquid filler or gel material which is suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soya oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying agents (e.g. tween ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The above-mentioned features of the application, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
Detailed Description
The details of the various specific aspects, features and advantages of the above-described compounds, methods, pharmaceutical compositions will be set forth in the following description in order to provide a thorough understanding of the present application. It is to be understood that the detailed description and examples, which follow, describe specific embodiments for reference only. Various changes and modifications to the present application will become apparent to those skilled in the art upon reading the description of the application, and such equivalents are intended to fall within the scope of the application.
In all examples, the melting point was determined with an X-4 melting point apparatus, with the thermometer uncorrected; 1 H-NMR was recorded on a Varian Mercury400 Nuclear magnetic resonance apparatus, chemical shifts being expressed as delta (ppm); the silica gel for separation is not illustrated as 200-300 meshes, and the ratio of the eluents is volume ratio.
The invention adopts the following abbreviations: CDCl 3 Represents deuterated chloroform; cuI stands for cuprous iodide; DCM represents dichloromethane; DIPEA stands for diisopropylethylamine; dioxane substitutionTable 1, 4-dioxane; EA represents ethyl acetate; etOH stands for ethanol; h represents hours; k (K) 2 CO 3 Represents potassium carbonate; LC-MS stands for liquid phase-mass spectrometry; m-CPBA represents m-chloroperoxybenzoic acid; mL stands for milliliter; meOH represents methanol; min represents minutes; MS stands for mass spectrum; naBH 3 CN represents sodium cyanoborohydride; NMR represents nuclear magnetic resonance; DEG C represents DEG C; PE represents petroleum ether; r.t. stands for room temperature; TEA represents triethylamine; TFA represents trifluoroacetic acid; THF represents tetrahydrofuran.
Preparation 1 2-allyl-1- (6- ((dimethyl (oxo) -lambda) 6 -sulfinimide) amino) pyridin-2-yl) -6- (methylthio) -1, 2-dihydro-3H-pyrazolo [3,4-d]Preparation of pyrimidin-3-one (intermediate A3-1)
Step 1: synthesis of Compound A0-1
Ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (13.5 g,58.06 mmol), tert-butyl 1-allylhydrazine-1-carboxylate (10 g,58.06 mmol), DIPEA (18.72 g,145.16 mmol) were dissolved in THF (300 mL), the reaction was heated under reflux overnight, LC-MS was monitored, the reaction was concentrated, the residue was dissolved with EA (200 mL), the organic phase was washed with water (150 mL), saturated brine (100 mL), dried, concentrated to give yellow oil A0-1 (21 g, yield 98%), ESI-MS m/z 369.1[ M+H ] ] + 。
Step 2: synthesis of Compound A1-1
A0-1 (21 g,57 mmol) was dissolved in DCM (70 mL), TFA (70 mL) was added, the reaction was allowed to proceed overnight at room temperature, monitored by LC-MS, and the reaction was complete. Directly concentrating, dissolving the residue with EtOH (120 mL), dropwise adding aqueous sodium hydroxide solution (6M, 66 mL) in ice bath, stirring at room temperature for 1h after the dropwise addition, monitoring by LC-MS, directly concentrating the reaction solution after the reaction, and subjecting the residue to column chromatography (DCM/MeOH=100/1 to 10.1) to obtain yellow solid A1-1 (10 g, yield 79%) and ESI-MS m/z:223.1[ M+H ]] + 。
Step 3: synthesis of Compound A3-1
A2-1 (2.5 g,10 mmol), A1-1 (2.22 g,10 mmol), cuI (1.9 g,10 mmol), K 2 CO 3 (2.07 g,15 mmol), N, N' -dimethylethylenediamine (970 mg,11 mmol) was dissolved in dioxane (100 mL), argon protected, the reaction was performed overnight at 80℃and LC-MS was monitored, the reaction was completed, filtered, the filtrate was concentrated, and the residue was subjected to column chromatography (DCM/MeOH=100/1 to 20/1) to give pale yellow solid A3-1 (1.95 g, yield 50%), ESI-MS m/z:391.1[ M+H] + 。
The intermediates A3-2 to A3-20 can be obtained by using different raw materials and similar synthesis of the intermediate A3-1.
TABLE 1 structural formulas of intermediates A3-2 to A3-20
Preparation example 2 6- (pyrrolidin-1-yl) -5,6,7, 8-tetrahydronaphthalen-2-amine (intermediate B3-1)
Step 1: synthesis of Compound B2-1
6-Nitro-3, 4-dihydronaphthalen-2 (1H) -one (1.7 g,8.9 mmol) in ClCH 2 CH 2 Cl (40 mL), pyrrolidine (1.264 g,17.8 mmol), HOAc (1.6 g,26.7 mmol) were added under argon protection in an ice-water bath 3 CN (1.6755 g,26.7 mmol), room temperature reverseThe reaction was terminated by monitoring with LC-MS overnight. Passing through reverse phase column to obtain pink solid product B2-1 (1.1 g, yield 50%), LC-MS:247.3[ M+H ]] + 。
Step 2: synthesis of Compound B3-1
B2-1 (492 mg,2.0 mmol) was dissolved in methanol (50 mL), pd/C was added, and the mixture was allowed to react overnight at room temperature. LC-MS monitoring and reaction was completed. Filtration and concentration gave brown solid B3-1 (372 mg, 86% yield), ESI-MS m/z:217.2[ M+H ]] + 。
Intermediates B3-2 to B3-47 can be obtained by synthesis of intermediate B3-1 using different starting materials.
TABLE 2 structural formulas of intermediates B3-2 to B3-47
Example 1 2-allyl-1- (6- ((dimethyl (oxo) -lambda) 6 -sulfinimide) amino) pyridin-2-yl) -6- ((6- (dimethylamino) -5,6,7, 8-tetrahydronaphthalen-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d]Synthesis of pyrimidin-3-one (compound 1)
A3-1 (500 mg,1.28 mmol) was dissolved in DCM (20 mL), m-CPBA (310 mg,1.8 mmol) was added and reacted at room temperature for 1h. LC-MS monitoring, after the reaction is finished, the system sodium bicarbonate saturated solution is washed, the organic phase is dried, spin-dried, and the ESI-MS m/z is 405.5[ M+H ] in the direct next step ] + 。
The intermediate obtained in the above step was dissolved in DMF (10 mL), B3-2 (243 mg,1.28 mmol), TFA (146 mg,1.28 mmol) was added and reacted at 80℃for 10h under argon. LC-MS monitoring and finishing the reaction. DCM (50 mL) was added for dilution, water (20 mL x 2) was washed, the organic phase dried, and the residue was chromatographed on silica gel (DCM/meoh=100/1 to 10/1) to give compound 1 (274 mg, 40% yield) as a pale yellow solid.
1 H NMR(400MHz,CDCl 3 )δ:8.76(s,1H),7.61(t,J＝7.9Hz,1H),7.45(s,2H),7.31(d,J＝7.8Hz,1H),7.17(dd,J＝8.3,2.3Hz,1H),6.99(d,J＝8.2Hz,1H),6.62(dd,J＝8.0,0.7Hz,1H),5.58(ddt,J＝16.6,10.2,6.3Hz,1H),4.98-4.91(m,1H),4.88-4.77(m,2H),3.26(s,6H),2.94-2.52(m,5H),2.32(s,6H),2.08(d,J＝11.1Hz,1H),1.65-1.48(m,1H),ESI-MS m/z:531.3[M+H] + 。
Examples 2-66 Synthesis of Compounds 2-66
In analogy to the synthesis of compound 1, intermediates A3-1 to A3-20 and B3-1 to B3-47 reacted to give the target compounds 2-66 in Table 3.
TABLE 3 Structure of Compounds 2-66
EXAMPLE 67 determination of the inhibition of Wee-1 enzymatic Activity by Compounds of the invention
After mixing the gradient diluted compound and enzyme, incubation is performed at room temperature (25 ℃) for 15 minutes, centrifugation is performed at 1000rpm for 1 minute, and 5. Mu.L of substrate is added to initiate the reaction. After 60 minutes of reaction at room temperature, 5. Mu.L of ADP-GLO reagent was added, and after 1 minute of mixing by centrifugation at 1000rpm, incubation was continued at room temperature for 60 minutes, and then 10. Mu.L of kinase detection reagent was added for 60 minutes to detect chemiluminescence. The percent inhibition of enzyme activity by the compound was calculated as compared to the DMSO group, and IC was calculated 50 。
TABLE 4 IC of the compounds of the invention that inhibit Wee-1 kinase Activity 50 (nM)
As can be seen from the data in Table 4, the compounds of the present invention have a strong inhibitory effect on Wee-1 kinase, R in the general formula (1) and the general formula (1A) 4 The compounds are H, alkyl, alkoxy or heterocycloalkyl, and have strong activity of inhibiting Wee-1 kinase, such as compound 1 and compound 9, and the activity is improved by about 2 times compared with a control drug MK-1775.
EXAMPLE 68 in vitro antiproliferative Activity of the Compounds of the invention against MIA PaCa-2 cells
3000/well MIA PaCa-2 cells were plated in 384 well plates and after overnight adherence, DMSO or a compound with a maximum concentration of 5. Mu.M, 1:5 gradient dilution was added. 72 hours after dosing by measuring cellsIntracellular ATP content, cell survival was assessed. The percent inhibition of cell survival by the compound was calculated as compared to DMSO group, IC was calculated 50 Values, results are shown in Table 5 below.
Example 69 in vitro antiproliferative Activity of the inventive Compounds in combination with Gemcitabine (GMC) on MIA PaCa-2 cells
3000 MIA PaCa-2 cells per well were plated in 384 well plates and 20nM Gemcitabine was added, after overnight adherence, DMSO or a 1:5 gradient of the diluted compound at a maximum concentration of 100nM was added. Cell survival was assessed 72 hours after dosing by measuring intracellular ATP content. The percent inhibition of cell survival by the compound was calculated compared to DMSO group, and IC was calculated 50 Values, results are shown in Table 5 below.
TABLE 5 antiproliferative activity of the compounds of the invention on MIA PaCa-2 cells alone or in combination with GMC
As can be seen from the data in Table 5, the compounds of the present invention have stronger antiproliferative activity on MIA PaCa-2 cells, e.g., the IC50 of the antiproliferative activity of compound 1 and compound 9 on MIA PaCa-2 cells is less than 100nM, which is improved by more than 10 times compared with the control drug MK-1775. In particular, the compounds of the invention have greater IC activity in combination with GMC, such as compound 48 and compound 52 50 Less than 2nM. The compound of the invention has strong combined activity with GMC, which indicates that the compound can have better effect in clinical combination with chemotherapeutics.
While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims (9)

  1. A compound represented by general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
    in the general formula (1):
    m is 0 or 1;
    n is 0 or 1;
    v is 1, 2 or 3;
    w is N or CH;
    R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
    R 2a And R is 2b Each independently is H or C1-C3 alkyl, or R 2a And R is 2b Form, together with the C atom to which it is attached, a C3-C6 cycloalkyl group;
    R 3a and R is 3b Each independently is H or C1-C3 alkyl, or R 3a And R is 3b Form, together with the C atom to which it is attached, a C3-C6 cycloalkyl group;
    R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N (C1-C6 alkyl) 2 NH (C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or (4-12 membered) heterocycloalkyl, wherein said C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl or (4-12 membered) heterocycloalkyl may be optionally substituted by 1-3 of: H. halogen, OH, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy or (4-7 membered) heterocycloalkyl;
    R 5 and R is 6 Each independently is C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, or R 5 And R is 6 Together with the atoms to which they are attached form a (3-10 membered) heterocycloalkyl;
    R 7 is H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl or halogen substituted C1-C6 alkoxy;
    R 8 And R is 9 Each independently is H, C-C6 alkyl or C3-C6 cycloalkyl, or R 8 And R is 9 Together with the N atom to which it is attached, form a (4-7 membered) heterocycloalkyl, wherein said (4-7 membered) heterocycloalkyl may be substituted with 1-3 of the following groups: H. halogen, OH, CN or C1-C3 alkyl.
  2. A compound represented by the general formula (2), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
    in the general formula (2):
    m is 0 or 1;
    n is 0 or 1;
    v is 1, 2 or 3;
    w is N or CH;
    x is CN or N;
    R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
    R 2a and R is 2b Each independently is H or C1-C3 alkyl, or R 2a And R is 2b Form, together with the C atom to which it is attached, a C3-C6 cycloalkyl group;
    R 3a and R is 3b Each independently is H or C1-C3 alkyl, or R 3a And R is 3b Form C3-C6 together with the C atom to which it is attachedCycloalkyl;
    R 4 is H, halogen, CN, OR 10 C1-C6 alkyl, C1-C6 alkoxy, N (C1-C6 alkyl) 2 NH (C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or (4-12 membered) heterocycloalkyl, wherein said C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl or (4-12 membered) heterocycloalkyl may be optionally substituted by 1-3 of: H. halogen, OH, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy, N (C1-C6 alkyl) 2 C1-C3 alkyl substituted C3-C6 cycloalkyl, halogen substituted C3-C6 cycloalkyl, CN substituted C3-C6 cycloalkyl, (4-7 membered) heterocycloalkyl or halogen substituted (4-7 membered) heterocycloalkyl;
    R 5 and R is 6 Each independently is C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, or R 5 And R is 6 Together with the atoms to which they are attached form a (3-10 membered) heterocycloalkyl;
    R 7 is H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl or halogen substituted C1-C6 alkoxy;
    R 8 and R is 9 Each independently is H, C-C6 alkyl or C3-C6 cycloalkyl, or R 8 And R is 9 Together with the N atom to which it is attached, form a (4-7 membered) heterocycloalkyl, wherein said (4-7 membered) heterocycloalkyl may be substituted with 1-3 of the following groups: H. halogen, OH, CN or C1-C3 alkyl;
    R 10 is a C3-C6 cycloalkyl or a (4-12 membered) heterocycloalkyl, wherein said C3-C6 cycloalkyl or (4-12 membered) heterocycloalkyl is optionally substituted with 1-3 of the following groups: h or C1-C3 alkyl.
  3. The compound of claim 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound structure is represented by general formula (1A):
    in the general formula (1A):
    m is 0 or 1;
    n is 0 or 1;
    v is 1, 2 or 3;
    W is N or CH;
    R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
    R 5 and R is 6 Each independently is C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, or R 5 And R is 6 Together with the atoms to which they are attached form a (3-10 membered) heterocycloalkyl;
    R 7 is H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl or halogen substituted C1-C6 alkoxy;
    R 8 and R is 9 Each independently is H, C-C6 alkyl or C3-C6 cycloalkyl, or R 8 And R is 9 Together with the N atom to which it is attached, form a (4-7 membered) heterocycloalkyl, wherein said (4-7 membered) heterocycloalkyl may be substituted with 1-3 of the following groups: H. halogen, OH, CN or C1-C3 alkyl.
  4. The compound according to any one of claims 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1) or the general formula (1A), R 1 Is Me, et,
  5. The compound, the optical isomer thereof or the pharmaceutically acceptable salt thereof according to any of claim 1 to 4, wherein in the general formula (1) or the general formula (1A),is that
  6. The compound according to claim 1 or 2, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), R 4 Is Me, et, CF 3 、CHF 2 、F、Cl、Br、I、CN、OMe、OEt、SMe、SEt、OCF 3 、NMe 2 、NHMe、
  7. The compound of any one of claims 1-6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:
  8. a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as an active ingredient, a compound according to any one of claims 1 to 7, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
  9. Use of a compound according to any one of claims 1 to 7, an optical isomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 8 in the manufacture of a medicament for treatment of a Wee-1 related disease.
CN202280012695.8A 2021-02-09 2022-02-09 Pyrazolo [3,4-d ] pyrimidin-3-one derivatives as Wee-1 inhibitors Pending CN116848118A (en)

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PE20080695A1 (en) * 2006-04-27 2008-06-28 Banyu Pharma Co Ltd DIHYDROPIRAZOLOPYRIMIDINONE DERIVATIVES AS KINASE WEEL INHIBITORS
WO2009054332A1 (en) * 2007-10-23 2009-04-30 Banyu Pharmaceutical Co., Ltd. Pyridone-substituted-dihydropyrazolopyrimidinone derivative
GB201612092D0 (en) * 2016-07-12 2016-08-24 Almac Discovery Ltd Pharmaceutical compounds
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US11299493B2 (en) * 2017-10-09 2022-04-12 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
US11261192B2 (en) * 2018-03-09 2022-03-01 Recurium Ip Holdings, Llc Substituted 1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidin-3-ones

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