Combination therapy comprising a myt1 inhibitor and a weel inhibitor

Abstract

The present application relates to the use of a combination of a Myt1 inhibitor and a Wee1 inhibitor in the treatment of cancer or induction of cell death. The synergistic effect of this combination results in a sub-therapeutic dosage or reduced dosing regimen of the Myt1 inhibitor, the Wee1 inhibitor, or both, relative to monotherapy with the Myt1 inhibitor or the Wee1 inhibitor alone.

Description

Technical Field

[0001] This invention relates to a therapy using a combination of a membrane-associated tyrosine and threonine-specific CDC2 inhibitory kinase (Myt1) (gene name PKMYT1) inhibitor and a Wee1 (gene name WEE1) inhibitor, for example, at a subtherapeutic dose or a reduced dosing schedule.

[0002] background DNA is constantly subjected to both endogenous (e.g., stalled replication forks, reactive oxygen species) and exogenous (e.g., UV radiation, ionizing radiation, chemicals) damage that can lead to DNA injury. Therefore, cells have developed complex mechanisms to counteract these harmful events, which would otherwise compromise genome integrity and lead to genomically unstable diseases such as cancer. These mechanisms are collectively known as the DNA Damage Response (DDR). A component of the entire DDR is the activation of various checkpoint pathways that regulate specific DNA repair mechanisms at different stages of the cell cycle, including the G1, S, G2, and mitotic checkpoints. Due to p53 mutations, most cancer cells have lost their G1 checkpoints and therefore rely on the G2 checkpoint for necessary DNA damage correction before entering mitosis and dividing into two daughter cells.

[0003] New anti-cancer treatments are needed, such as those utilizing small molecules, especially therapies that allow for targeted cancer therapy. Summary of the Invention

[0004] This disclosure provides a method for using a combination of a membrane-associated tyrosine and threonine-specific CDC2 inhibitory kinase (Myt1) inhibitor and a Wee1 inhibitor. Advantageously, the combination of the Myt1 inhibitor and the Wee1 inhibitor can synergistically treat cancer or induce cell death. Compared to monotherapy with either a Myt1 inhibitor or a Wee1 inhibitor alone, the synergistic effect can result in effective treatment with lower doses (e.g., subtherapeutic doses) of the Myt1 inhibitor, the Wee1 inhibitor, or both.

[0005] In a first aspect, this disclosure provides a method for treating cancer in a subject, the method comprising administering a dose of a Myt1 inhibitor and a dose of a Wee1 inhibitor to the subject in need of such treatment according to a dosing regimen; and (i) the dose of the Myt1 inhibitor is a therapeutically effective dose; (ii) the dose of the Myt1 inhibitor is a subtherapeutic dose; (iii) the dose of the Wee1 inhibitor is a subtherapeutic dose; (iv) the dosing regimen of the Myt1 inhibitor is a reduced-dose dosing regimen; or (v) the dosing regimen of the Wee1 inhibitor is a reduced-dose dosing regimen.

[0006] In a second aspect, this disclosure provides a method for inducing cell death in cancer cells, the method comprising contacting cells with a dose of a Myt1 inhibitor and a dose of a Wee1 inhibitor according to a dosing regimen; and (i) the dose of the Myt1 inhibitor is a therapeutically effective dose; (ii) the dose of the Myt1 inhibitor is a subtherapeutic dose; (iii) the dose of the Wee1 inhibitor is a subtherapeutic dose; (iv) the Myt1 inhibitor dosing regimen is a reduced-dose dosing regimen; or (v) the Wee1 inhibitor dosing regimen is a reduced-dose dosing regimen. In some embodiments, the cells are in a subject.

[0007] In some embodiments of the first or second aspect, the cancer is uterine cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, head and neck cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, thyroid cancer, melanoma, or endometrial cancer. In some embodiments, the cancer includes... KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c- MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF The mutation, amplification, or overexpression of the virus, or a previous or current HPV infection. In some implementations, cancer includes those previously identified as... KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF Cancer caused by mutations, amplifications, or overexpression of HPV, or by previous or current HPV infection.

[0008] In some implementation schemes, cancer includes CCNE1 Overexpression. In some implementations, cancers include uterine cancer, ovarian cancer, pancreatic cancer, mesothelioma, kidney cancer, bladder cancer, stomach cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, or endometrial cancer.

[0009] In some implementation schemes, cancer includes FBXW7 Mutation. In some implementations, cancer includes uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, stomach cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

[0010] In some implementation schemes, cancer includes KRAS Mutation. In some implementations, cancer includes... KRAS Overexpression. In some implementations, cancer includes colorectal cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, cervical cancer, or gastroesophageal cancer. In some implementations, cancer includes HRAS Mutation. In some implementations, the cancer includes kidney cancer, bladder cancer, head and neck cancer, or thyroid cancer. In some implementations, the cancer includes... NRAS Mutation. In some implementations, the cancer includes colorectal cancer, thyroid cancer, or melanoma.

[0011] In some implementations, replication stress biomarkers are PPP2R1A Mutations. In some implementations, cancer includes endometrial cancer, ovarian cancer, and uterine cancer.

[0012] In a third aspect, this disclosure provides a method for increasing CDK1 activity in cells, the method comprising contacting cells with a dose of a Myt1 inhibitor and a dose of a Wee1 inhibitor according to a dosing regimen; and (i) the dose of the Myt1 inhibitor is a therapeutically effective dose; (ii) the dose of the Myt1 inhibitor is a subtherapeutic dose; (iii) the dose of the Wee1 inhibitor is a subtherapeutic dose; (iv) the dosing regimen of the Myt1 inhibitor is a reduced-dose dosing regimen; or (v) the dosing regimen of the Wee1 inhibitor is a reduced-dose dosing regimen.

[0013] In a fourth aspect, this disclosure provides a method for inducing premature mitosis in cells, the method comprising contacting cells with a dose of a Myt1 inhibitor and a dose of a Wee1 inhibitor according to a dosing regimen; and (i) the dose of the Myt1 inhibitor is a therapeutically effective dose; (ii) the dose of the Myt1 inhibitor is a subtherapeutic dose; (iii) the dose of the Wee1 inhibitor is a subtherapeutic dose; (iv) the dosing regimen of the Myt1 inhibitor is a tapered dosing regimen; or (v) the dosing regimen of the Wee1 inhibitor is a tapered dosing regimen. In some embodiments of the third or fourth aspect, the cells are in a subject.

[0014] In some embodiments, the dose of the Myt1 inhibitor is up to 500 mg. In some embodiments, the dose of the Myt1 inhibitor is up to 250 mg. In some embodiments, the dose of the Myt1 inhibitor is up to 100 mg. In a specific embodiment, the dose of the Myt1 inhibitor is 80 mg. In other specific embodiments, the dose of the Myt1 inhibitor is 60 mg. In some embodiments, the dose reduction regimen of the Myt1 inhibitor includes a once-daily dose. In some embodiments, the dose reduction regimen of the Myt1 inhibitor includes a twice-daily dose. In some embodiments, the dose reduction regimen of the Myt1 inhibitor includes a 1 / 6 dosing regimen. In some embodiments, the dose reduction regimen of the Myt1 inhibitor includes a 2 / 5 dosing regimen. In some embodiments, the dose reduction regimen of the Myt1 inhibitor includes a 3 / 4 dosing regimen. In some embodiments, the dose reduction regimen of the Myt1 inhibitor includes a 5 / 2 dosing regimen. In some embodiments, the dose reduction regimen of the Myt1 inhibitor includes a 1-week dosing / 1-week off regimen. In some implementations, the dose reduction regimen for Myt1 inhibitors includes a dosing schedule of 2 weeks of dosing followed by 1 week of off-dosing.

[0015] In some embodiments, the dose of the Wee1 inhibitor is up to 520 mg. In some embodiments, the dose of the Wee1 inhibitor is up to 400 mg. In some embodiments, the dose of the Wee1 inhibitor is up to 200 mg. In some embodiments, the dose reduction regimen of the Wee1 inhibitor includes one dose once daily. In some embodiments, the dose reduction regimen of the Wee1 inhibitor includes one dose twice daily. In some embodiments, the dose reduction regimen of the Wee1 inhibitor includes a 1 / 6 dosing regimen. In some embodiments, the dose reduction regimen of the Wee1 inhibitor includes a 2 / 5 dosing regimen. In some embodiments, the dose reduction regimen of the Wee1 inhibitor includes a 3 / 4 dosing regimen. In some embodiments, the dose reduction regimen of the Wee1 inhibitor includes a 5 / 2 dosing regimen. In some embodiments, the dose reduction regimen of the Wee1 inhibitor includes a 1-week dosing / 1-week off regimen. In some embodiments, the dose reduction regimen of the Wee1 inhibitor includes a 2-week dosing / 1-week off regimen.

[0016] In some embodiments, the dose of the Myt1 inhibitor is a subtherapeutic dose, and the dose of the Wee1 inhibitor is a subtherapeutic dose. In some embodiments, the dosing regimen of the Myt1 inhibitor is a reduced-dose regimen, and the dosing regimen of the Wee1 inhibitor is a reduced-dose regimen.

[0017] In some embodiments, the dose of the Myt1 inhibitor is a therapeutically effective dose, and the dose of the Wee1 inhibitor is a subtherapeutic dose. In some embodiments, the dosing regimen for the Myt1 inhibitor is a reduced-dose regimen, and the dosing regimen for the Wee1 inhibitor is a reduced-dose regimen.

[0018] In some embodiments, the Wee1 inhibitor is administered as a pharmaceutical composition. In some embodiments, the Wee1 inhibitor is one of the following: Or a pharmaceutically acceptable salt thereof. In some embodiments, the Wee1 inhibitor is selected from compounds W1 to W3052. In a specific embodiment, the Wee1 inhibitor is Debio-0123 or a pharmaceutically acceptable salt thereof. In some embodiments, the Wee1 inhibitor binds to Wee1, thereby reducing the activity of Wee1. In some embodiments, the Wee1 inhibitor is PROTAC. In some embodiments, the Wee1 inhibitor is a molecular gel. In some embodiments, the Myt1 inhibitor is administered as a pharmaceutical composition.

[0019] In some implementations, the Myt1 inhibitor is a compound of formula (I): Or its pharmaceutically acceptable salt. in Each of X, Y, and Z is independently N or CR. 2 ; R 1 and each R 2 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, cyano, -N(R) 7 )2、-OR 7 -C(O)N(R) 8 )2、-SO2N(R 8 )2、-SO2R 7Aor -QR 7B Or R 1 With one Neighbor R 1 R 2 Combining to form optional C 3-6 Alkylene; R 3 and R 4 Each of them is independently an optional substitution of C. 1-6 Alkyl or halogen; R 5 Is it H or -N(R) 7 )2; R 6 It is -C(O)NH(R) 8 -C(O)R 7A or -SO2R 7A ; Each R 7 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl or -SO2R 7A Or two Rs 7 The groups, together with the atoms to which they are attached, combine to form optionally substituted C groups. 2-9 Heterocyclic groups; Each R 7A C is independently optional substitution 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; Each R 7B Independently, it is a hydroxyl group, or an optionally substituted C. 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 1-9 heteroaryl, -N(R) 7 )2、-C(O)N(R 8 )2、-SO2N(R 8 )2、-SO2R 7A Or optionally substituted alkoxy groups; Each R 8 Independently hydrogen, optionally substituted C 1-6Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two R 8 Together with the atoms to which they are attached, they combine to form optionally substituted C atoms. 2-9 Heterocyclic groups; Each R 8 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two R 8 Together with the atoms to which they are attached, they combine to form optionally substituted C atoms. 2-9 Heterocyclic groups; and Each Q is independently an optional substituted C. 1-6 Alkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 Heterocyclic or optionally substituted C 1-9 Hybrid aryl.

[0020] In some implementations, the compound is rich in the (IA)-restricted transisomer: Or its pharmaceutically acceptable salt.

[0021] In some implementations, X is CR 2 .

[0022] In some embodiments, the compound is a compound of formula (II): Or its pharmaceutically acceptable salt.

[0023] In some embodiments, the compound is rich in the (IIA)-restricted transisomer: Or its pharmaceutically acceptable salt.

[0024] In some embodiments, the compound is a compound of formula (III): Where R 2A It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, -N(R) 7 )2、-OR 7 -C(O)N(R) 8 )2、-SO2N(R 8 )2、-SO2R 7A or -QR 7B ; Or its pharmaceutically acceptable salt.

[0025] In some implementations, the compound is rich in the (IIIA)-restricted transisomer: Or its pharmaceutically acceptable salt. In some embodiments, R 2A It is hydrogen, and the C is optionally substituted. 1-6 Alkyl or halogen.

[0026] In some implementation schemes, R 3 C is an optional substitute 1-6 Alkyl group. In some embodiments, R 3 It is a halogen. In some implementations, R 4 C is an optional substitute 1-6 Alkyl group. In some embodiments, R 4 It is a halogen. In some implementations, the halogen is chlorine.

[0027] In some implementation schemes, R 2 It is hydrogen. In some implementations, R 2 C is an optional substitute 1-6 Alkyl group. In some embodiments, R 2 It is an optionally substituted methyl or optionally substituted isopropyl. In some embodiments, R2 It is halogen.

[0028] In some implementation schemes, R 1 It is hydrogen. In some implementations, R 1 It is a halogen. In some implementations, R 1 It is chlorine or bromine. In some implementations, R 1 C is an optional substitute 1-6 Alkyl group. In some embodiments, R 1 It is optionally substituted methyl, optionally substituted ethyl, optionally substituted isopropyl, or optionally substituted butyl. In some embodiments, R 1 C is an optional substitute 1-9 heteroaryl. In some implementations, R 1 It is 1,3-thiazolyl, 1,2-thiazolyl, 1,3-oxazolyl, benzo-1,3-thiazolyl, benzo-1,3-oxazolyl, indolyl, benzimidazolyl, pyridyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, or pyrazolyl, wherein R 1 The optional C can be replaced as is. 1-9 Substituent substitution as defined by heteroaryl groups. In some embodiments, R 1 C is an optional substitute 3-8 Cycloalkyl. In some embodiments, R 1 It is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R 1 The optional C can be replaced as is. 3-8 Substituents as defined by cycloalkyl groups. In some embodiments, R 1 C is an optional substitute 2-9 Heterocyclic group. In some implementations, R 1 It is 1,2,3,6-tetrahydropyridyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, oxa-aza-spiro[3,3]heptane or oxa-aza-bicyclo[3.2.1]octane, wherein R 1 The optional C can be replaced as is. 2-9 Substituent substitution as defined by the heterocyclic group. In some embodiments, R 1 C is an optional substitute 3-8 Cycloalkenyl. In some embodiments, R 1 It is an optionally substituted cyclohexenyl or optionally substituted cyclopentenyl. In some embodiments, R 1 C is an optional substitute 6-10 Aryl. In some implementations, R 1 It is an optionally substituted phenyl group. In some embodiments, R 1 Yes - QR 7B In some implementations, Q is an optional replacement for C. 2-6Ethyneyl group. In some embodiments, Q is an optionally substituted C. 1-6 Alkylene. In some embodiments, Q is an optionally substituted C. 6-10 Aromatic compounds. In some implementations, R 7B C is an optional substitute 2-9 Heterocyclic group. In some implementations, R 7B C is an optional substitute 6-10 Aryl. In some implementations, R 1 The group may be substituted by one, two, or three independently selected groups from the group consisting of: methyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, -C(O)NH2, -C(O)NH(Me), -C(O)N(Me)2, -(CH2). n -C(O)OH and -(CH2) n -C(O)Ot-Bu, where n is 0 or 1. In some implementations, R 1 It is -N(R) 7 )2. In some implementation schemes, R 1 It is diethylamino.

[0029] In some implementation schemes, R 5 It is hydrogen. In some implementations, R 5 It is -N(R) 7 )2. In some implementation schemes, R 5 It is -NH2. In some implementations, R 6 It is -C(O)NH(R) 8 In some implementations, R 6 It is -C(O)NH2. In some implementations, R 6 It is -C(O)NH(Me). In some implementations, R 6 Yes - SO2R 7A In some implementations, R 6 It is -SO2Me.

[0030] In some embodiments, the Myt1 inhibitor is a compound selected from compounds 1 to 328 and their pharmaceutically acceptable salts. In a specific embodiment, the Myt1 inhibitor is lunresertib or a pharmaceutically acceptable salt thereof.

[0031] In a particular implementation, the Myt1 inhibitor is lunresertib or a pharmaceutically acceptable salt thereof, and the Wee1 inhibitor is Debio-0123 or a pharmaceutically acceptable salt thereof.

[0032] definition As used herein, the term “abnormal” means different from normal. When used to describe activity, abnormal refers to an activity that is greater than or less than the average value of a normal control or a normal non-pathological control sample. Abnormal activity may refer to an amount of activity that causes disease, wherein returning abnormal activity to a normal or non-disease-related amount (e.g., by administering a compound or using methods as described herein) results in a reduction of disease or one or more disease symptoms.

[0033] As used herein, the term "acyl" signifies a group -C(=O)-R, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclic group. The acyl group may be optionally substituted, as described herein with respect to each corresponding R group.

[0034] As used herein, the term "adenocarcinoma" refers to a malignant tumor caused by glandular cells arranged along organs within an organism. Non-limiting examples of adenocarcinoma include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colorectal cancer.

[0035] As used herein, the term "alkanoyl" refers to a hydrogen or alkyl group attached to a parent molecule group via a carbonyl group, and is exemplified by a formyl group (i.e., a carboxyl aldehyde group), an acetyl group, a propionyl group, a butyryl group, and an isobutyryl group. An unsubstituted alkanoyl group contains 1 to 7 carbons. As described herein with respect to alkyl groups, an alkanoyl group can be unsubstituted or substituted (e.g., optionally substituted C1-7 alkanoyl groups). A terminal "-acyl" group can be added to another group defined herein, such as an aryl, cycloalkyl, and heterocyclic group, to define "aromatic acyl," "cycloalkanoyl," and "(heterocyclic)acyl." These groups represent carbonyl groups substituted with aryl, cycloalkyl, or heterocyclic groups, respectively. Each of "aromatic acyl," "cycloalkanoyl," and "(heterocyclic)acyl" can be optionally substituted, as defined herein with respect to "aryl," "cycloalkyl," or "heterocyclic," respectively.

[0036] As used herein, the term "alkenyl" refers to a non-cyclic monovalent straight-chain or branched hydrocarbon group containing one, two, or three carbon-carbon double bonds. Non-limiting examples of alkenyl groups include vinyl, propenyl, propenyl, 1-methylvinyl, butenyl, butenyl, butenyl, 3-methylpropenyl, 1-methylpropenyl, 2-methylpropenyl, and 1-methylpropenyl. Alkenyl groups may be optionally substituted as defined herein with respect to alkyl groups.

[0037] As used herein, the term "alkenyl" refers to a divalent alkenyl group. Optionally substituted alkenyl groups are those that have been optionally substituted as described herein with respect to alkenyl groups.

[0038] Unless otherwise specified, as used herein, the term "alkoxy" is expressed as a -OR chemical substituent, where R is C 1-6Alkyl group. In some embodiments, as defined herein, the alkyl group may be further substituted. The term “alkoxy” may be combined with other terms defined herein (e.g., aryl, cycloalkyl, or heterocyclic) to define “arylalkoxy,” “cycloalkylalkoxy,” and “(heterocyclic)alkoxy.” These groups respectively represent alkoxy groups substituted with aryl, cycloalkyl, or heterocyclic groups. Each of “arylalkoxy,” “cycloalkylalkoxy,” and “(heterocyclic)alkoxy” may be optionally substituted, as defined herein for each individual part.

[0039] As used herein, the term "alkoxyalkyl" represents a -LOR chemical substituent, where L is C. 1-6 Alkylene and R is C 1-6 Alkyl. Optionally substituted alkoxyalkyl is an alkoxyalkyl that has been optionally substituted as described herein with respect to alkyl.

[0040] Unless otherwise specified, as used herein, the term "alkyl" refers to a non-cyclic straight-chain or branched saturated hydrocarbon group having 1 to 12 carbons when unsubstituted. In some preferred embodiments, the unsubstituted alkyl group has 1 to 6 carbons. Alkyl groups are exemplified by methyl; ethyl; n-propyl and isopropyl; n-butyl, sec-butyl, isobutyl and tert-butyl; neopentyl, etc., and may optionally (where the valence allows) be substituted by one, two, three, or, in the case of an alkyl group having two or more carbons, by four or more substituents independently selected from the group consisting of: amino; alkoxy; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; haloyl; heterocyclic; (heterocyclic)oxy; heteroaryl; hydroxyl; nitro; thiol; silyl; cyano; alkylsulfonyl; alkylsulfinyl; alkylsulfoxide; =O; =S; -C(O)R or -SO2R (where R is amino); and =NR' (where R' is H, alkyl, aryl or heterocyclic). Each of the substituents may be unsubstituted itself or (where the valence allows) substituted with an unsubstituted substituent as defined herein for each respective group.

[0041] As used herein, the term "alkylene" refers to a divalent alkyl group. Optionally substituted alkylene groups are alkylene groups that have been optionally substituted as described herein with respect to alkyl groups.

[0042] As used herein, the term "alkylamino" refers to an amino group having the formula -N(R N1 )2 or -NHR N1 The group, wherein R N1 It is an alkyl group, as defined herein. As defined with respect to alkyl, the alkyl moiety of an alkylamino group may be optionally substituted. Each optional substituent on a substituted alkylamino group may be unsubstituted itself or (where the valence allows) substituted with an unsubstituted substituent as defined herein with respect to each corresponding group.

[0043] As used herein, the term "alkyl sulfide" represents a -S-(alkyl) group. As defined with respect to alkyl, the alkyl sulfide group may be optionally substituted.

[0044] As used herein, the term "alkylsulfonyl" represents the formula -S(O)2-(alkyl) group. As defined with respect to alkyl, the alkylsulfonyl group may be optionally substituted.

[0045] As used herein, the term "alkynyl" means a monovalent straight-chain or branched hydrocarbon group containing two to six carbon atoms and having at least one carbon-carbon triple bond, and is exemplified by ethynyl, 1-propynyl, etc. As defined with respect to alkyl groups, alkynyl groups can be unsubstituted or substituted (e.g., optionally substituted alkynyl groups).

[0046] As used herein, the term "ethynyl" refers to a divalent ethynyl group. Optionally substituted ethynyl groups are ethynyl groups that have been optionally substituted as described herein with respect to ethynyl groups.

[0047] As used herein, the term "amino" signifies -N(R) N1 )2, where if the amino group is unsubstituted, then the two R groups are... N1 All are H; or, if the amino group is substituted, each R N1 Independently, it is H, -OH, -NO2, -N(R) N2 )2、-SO2OR N2 -SO2R N2 -SOR N2 -C(O)OR N2 The group consisting of an N-protecting group, an alkyl group, an alkenyl group, an alkoxy group, an aryl group, an arylalkyl group, an aryloxy group, a cycloalkyl group, a cycloalkenyl group, a heteroalkyl group, or a heterocyclic group, provided that at least one R-protecting group is present. N1 Not H, and each of the R's N2 Independently, it is H, alkyl, or aryl. Each of the substituents may be unsubstituted or substituted by an unsubstituted substituent as defined herein for each respective group. In some embodiments, the amino group is an unsubstituted amino group (i.e., -NH2) or a substituted amino group (e.g., -NHR). N1 ), where R N1 Independently -OH, SO2OR N2 -SO2R N2 -SOR N2 -COOR N2 Optionally substituted alkyl or Optionally substituted aryl, and each R N2 It can be an optionally substituted alkyl or optionally substituted aryl group. In some embodiments, the substituted amino group can be an alkylamino group, wherein the alkyl group is optionally substituted as described herein with respect to alkyl. In some embodiments, the amino group is -NHR.N1 , where R N1 It is an alkyl group that is optionally substituted.

[0048] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic carbocyclic system having one or two aromatic rings. An aryl group may contain 6 to 10 carbon atoms. All atoms within an unsubstituted carbocyclic aryl group are carbon atoms. Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indene, indene, etc. An aryl group may be unsubstituted or substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfonyl; alkylsulfonyl; amino; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; cycloalkynyl; haloyl; heteroalkyl; heterocyclic; (heterocyclic)oxy; hydroxyl; nitro; thiol; silyl; -(CH2) n -C(O)OR A -C(O)R; and -SO2R, where R is an amino or alkyl group, R A It is H or alkyl, and n is 0 or 1. Each of the substituents may be unsubstituted or substituted by an unsubstituted substituent as defined herein for each respective group.

[0049] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. The aryl and alkyl moiety may be optionally substituted as separate groups as described herein.

[0050] As used herein, the term "arylene" refers to a divalent aryl group. Optionally substituted arylene groups are arylene groups that have been optionally substituted as described herein with respect to aryl groups.

[0051] Unless otherwise specified, as used herein, the term "aryloxy group" is expressed as -OR chemical substituent, where R is an aryl group. In optionally substituted aryloxy groups, the aryl group is optionally substituted, as described herein with respect to the aryl group.

[0052] As used herein, the term "azido" refers to the -N3 group.

[0053] As used in this article, the term “cancer” refers to all types of cancer, growths, or malignant tumors found in mammals (e.g., humans).

[0054] As used herein, the term "carbocyclic" refers to an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure in which the ring, whether aromatic or non-aromatic, is formed from carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloynyl, and certain aryl groups.

[0055] As used herein, the term "carbonyl" refers to a -C(O)- group.

[0056] As used in this article, the term “cancer” refers to a malignant new growth consisting of epithelial cells that tend to infiltrate surrounding tissues and metastasize.

[0057] As used herein, the term "cyano" refers to the -CN group.

[0058] As the interchangeable terms used in this article are… CCNE1 "and" "cyclin E1" refers to G1 / S specific cyclin E1 (gene name: CCNE1 Overexpression CCNE1 The cells (which may be referred to in this article as) CCNE1 -High cell count is higher than normal expression CCNE1 The cells showed higher CCNE1 Viable cells. For example, compared to diploid normal cells with 2 copies, CCNE1 Overexpression cells are those that express at least 3 copies. Therefore, cells expressing more than 3 copies... CCNE1 The cells are overexpressing CCNE1 Cells. The expression levels of gene products in cells can be identified (e.g., ...). CCNE1 mRNA transcript count or CCNE1 Protein levels are used to measure CCNE1 Overexpression.

[0059] As used interchangeably in this document, the terms "CDC25" and "CDC25 phosphatase" refer to the CDC25 family of phosphatase proteins that control cell division. The CDC25 phosphatase family excludes phosphorylation events on CDK proteins, such as those induced by Myt1 and Wee1. CDC25 and CDK1 participate in a positive feedback loop, where activation of one promotes activation of the other. CDC25 phosphatases are involved in regulating cell division, controlling the transition from G1 to S phase and from G2 to M phase. The CDC25 phosphatase family includes CDC25A (encoded by the CDC25A gene), CDC25B (encoded by the CDC25B gene), and CDC25C (encoded by the CDC25C gene).

[0060] As used herein, the term "CDK" refers to a family of cyclin-dependent kinases, such as cyclin-dependent kinase 4 (CDK4). CDK4 Gene-encoded cyclin-dependent kinase 6 (CDK6, by...) CDK6 Gene encoding) or cyclin-dependent kinase 12 (CDK12; by CDK12(Encoded by genes). CDK proteins interact with a variety of regulatory proteins via phosphorylation at prescribed sites, thereby activating or inhibiting the protein. Although they are most commonly associated with cyclins (e.g., cyclin A, cyclin B, cyclin C, cyclin D, cyclin E, cyclin F, cyclin G, cyclin H, cyclin I, cyclin J, cyclin K, cyclin L, cyclin O, cyclin P, cyclin T, and cyclin Y), CDK proteins are known to interact with and regulate a variety of other cell signaling proteins. Those with loss-of-function mutations... CDK Genes that fail to produce functional CDK proteins or produce reduced amounts of CDK proteins in cells.

[0061] As used herein, the term "CDK regulatory protein" refers to any polypeptide molecule that can be used as a regulator (e.g., inhibitor or activator) of CDK proteins. CDK regulatory proteins include proteins that inhibit CDK proteins (e.g., p16 and p14arf; both are derived from...). CDKN2A The gene encodes p16 and p14arf, both of which inhibit CDK proteins such as CDK4 and CDK6, and proteins that prevent CDK protein inhibition (e.g., CDC25A). CDC25A The gene encodes CDC25A (which prevents CDK protein repression by removing phosphorylation events on the CDK protein). Mutations in CDK regulatory proteins refer to gain-of-function or loss-of-function mutations in the genes encoding CDK regulatory proteins.

[0062] Unless otherwise specified, as used herein, the term "cycloalkenyl" refers to a non-aromatic carbocyclic group having at least one intracyclic double bond and three to ten carbons (e.g., C10, C20, C30, C40, C50, C60, C7 ...60, C60, C60, C60, 3-10 (Cycloalkenyl). Non-limiting examples of cycloalkenyl include cyclopropenyl-1-enyl, cyclopropenyl-2-enyl, cyclobutenyl-1-enyl, cyclobutenyl-1-enyl, cyclobutenyl-2-enyl, cyclopentenyl-1-enyl, cyclopentenyl-2-enyl, cyclopentenyl-3-enyl, norbornenyl-1-enyl, norbornenyl-2-enyl, norbornenyl-5-enyl, and norbornenyl-7-enyl. As described with respect to cycloalkyl, the cycloalkenyl can be unsubstituted or substituted (e.g., optionally substituted cycloalkenyl).

[0063] As used herein, the term "cycloalkenylalkyl" refers to an alkyl group substituted with a cycloalkenyl group, each as defined herein. The cycloalkenyl and alkyl moieties may be substituted as separate groups as defined herein.

[0064] As used herein, the term "cycloene imide" refers to a divalent cycloene group. Optionally substituted cycloene imide groups are those that have been optionally substituted as described herein with respect to cycloalkyl groups.

[0065] Unless otherwise specified, as used herein, the term "cycloalkoxy" is expressed as -OR chemical substituent, where R is a cycloalkyl group. In some embodiments, as defined herein, the cycloalkyl group may be further substituted.

[0066] Unless otherwise specified, as used herein, the term "cycloalkyl" refers to a cycloalkyl group having three to ten carbon atoms (e.g., C3-C10). 10 Cycloalkyl groups. Cycloalkyl groups can be monocyclic or bicyclic. Bicyclic cycloalkyl groups can be of the bicyclic [pq0]alkyl type, where p and q are each independently 1, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 2, 3, 4, 5, 6, 7, or 8. Alternatively, bicyclic cycloalkyl groups can include bridged cycloalkyl structures, such as bicyclic [pqr]alkyl groups, where r is 1, 2, or 3, and p and q are each independently 1, 2, 3, 4, 5, or 6, provided that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. Cycloalkyl groups can be spirocyclic groups, such as spiro [pq]alkyl groups, where p and q are each independently 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 4, 5, 6, 7, 8, or 9. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[2.2.1.]heptyl, 2-bicyclo[2.2.1.]heptyl, 5-bicyclo[2.2.1.]heptyl, 7-bicyclo[2.2.1.]heptyl and decahydronaphthyl. Cycloalkyl groups may be unsubstituted or substituted by one, two, three, four, or five independently selected substituents from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfonyl; alkylsulfonyl; amino; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; haloyl; heteroalkyl; heterocyclic; (heterocyclic)oxy; heteroaryl; hydroxyl; nitro; thiol; silyl; cyano; =O; =S; -SO2R (where R is an optionally substituted amino); =NR' (where R' is H, alkyl, aryl, or heterocyclic); and -CON(R A )2 (where each R A It is independently H or alkyl, or two Rs A Together with the atoms to which they are attached, they combine to form a heterocyclic group. Each of the substituents may be unsubstituted or substituted by an unsubstituted substituent as defined herein for each corresponding group.

[0067] As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl moiety may be optionally substituted as separate groups as described herein.

[0068] As used herein, the term "cycloalkylene" refers to a divalent cycloalkyl group. Optionally substituted cycloalkylene groups are substituted cycloalkylene groups as described herein with respect to cycloalkyl groups.

[0069] Unless otherwise stated, as used herein, the term "cycloynyl" refers to a monovalent carbon cyclic group having one or two carbon-carbon triple bonds and having eight to twelve carbons. A cycloynyl group may contain a transcyclic bond or bridge. Non-limiting examples of cycloynyl groups include cyclooctyynyl, cyclononyynyl, cyclodecyynyl, and cyclodecadiynyl. As defined with respect to cycloalkyl groups, a cycloynyl group may be unsubstituted or substituted (e.g., optionally substituted cycloynyl groups).

[0070] "Disease" or "symptom" refers to the state or health condition of a patient or subject who can be treated with the compounds or methods provided herein.

[0071] As used herein, the term "dosing schedule" or "dosing regime" refers to the frequency at which a pharmaceutical composition is administered to a subject. For example, a pharmaceutical composition may be administered once daily, twice daily, three times daily, once weekly, once monthly, etc. Dosing schedules may include a period of treatment followed by periods of reduced or no administration (e.g., an "on-off" dosing schedule). For example, a pharmaceutical composition may be administered according to a "3-day dosing, 4-day off" dosing schedule (3 / 4 dosing); a "5-day dosing, 2-day off" dosing schedule (5 / 2 dosing schedule); a "1-day dosing, 6-day off" dosing schedule (1 / 6 dosing); a "2-day dosing, 5-day off" dosing schedule (2 / 5 dosing); a "4-day dosing, 3-day off" dosing schedule (4 / 3 dosing); a "1-week dosing, 1-week off" dosing schedule; a "2-week dosing, 1-week off" dosing schedule; or a "3-week dosing, 2-week off" dosing schedule. Dosing-off dosing regimens may include multiple administrations per day for the active pharmaceutical ingredient (e.g., the active pharmaceutical ingredient may be administered twice daily in a 3 / 4 dosing regimen). In combination therapy, one or more active pharmaceutical ingredients may be administered according to different dosing regimens (e.g., the first active pharmaceutical ingredient is administered once daily, while the second active pharmaceutical ingredient is administered twice daily).

[0072] As used in this article, the term "EGFR" refers to the epidermal growth factor receptor protein (EGFR) produced by the epidermal growth factor receptor protein. EGFR (Gene-encoded). EGFR is a transmembrane glycoprotein with both extracellular and intracellular domains. The extracellular domain receives signals (e.g., in the form of signal peptides such as epidermal growth factor), leading to conformational or chemical changes in the intracellular domain. The intracellular domain can then interact with various cellular signaling pathways (e.g., the RAS / MAPK pathway). Loss-of-function mutations... EGFRGenes that fail to produce functional EGFR protein or produce reduced amounts of EGFR protein in cells.

[0073] As used in this article, the term "FBXW7" refers to the protein 7 transcript containing the F-box / WD repeat sequence (gene name: FBXW7 ). With inactivation mutations FBXW7 Genes that cannot produce functional FBXW7 protein in cells or produce reduced amounts of FBXW7 protein.

[0074] As used herein, the term "γ-H2AX" or "γH2AX" refers to the phosphorylated form of histone H2AX. Phosphorylation of H2AX is a known marker in the art for indicating the presence of double-strand breaks (DSBs) in DNA. Furthermore, as used herein, the term "pan-γH2AX" refers to the widespread presence of phosphorylated H2AX within cells. Induction of pan-γH2AX, as described herein, can be used as a marker indicating that cells are more likely to have undergone early mitosis.

[0075] As used herein, the term "halo" refers to a halogen selected from bromine, chlorine, iodine, and fluorine.

[0076] As used herein, the term "heteroalkyl" refers to an alkyl, alkenyl, or ynyl group consisting of one or two heteroatoms spaced once; spaced independently twice; spaced independently three times; or spaced independently four times. Each heteroatom is independently O, N, or S. In some embodiments, the heteroatom is O or N. No heteroalkyl group contains two consecutive oxygen or sulfur atoms. Heteroalkyl groups can be unsubstituted or substituted (e.g., optionally substituted heteroalkyl groups). When a heteroalkyl group is substituted and a substituent is bonded to a heteroatom, the substituent is selected based on the nature and valence of the heteroatom. Therefore, the substituents bonded to the heteroatom (where the valence allows) are selected from the group consisting of: =O, -N(R N2 )2、-SO2OR N3 -SO2R N2 -SOR N3 -COOR N3 ,N protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic or cyano, wherein each R N2 Independently, it is H, alkyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, or heterocyclic, and each R N3Independently, they are alkyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, or heterocyclic groups. Each of these substituents may be unsubstituted on its own or substituted by an unsubstituted substituent as defined herein for each respective group. When the heteroalkyl group is substituted and the substituent is bonded to a carbon atom, the substituent is selected from those described for the alkyl group, provided that the substituent bonded to the carbon atom of the heteroatom is not Cl, Br, or I. It should be understood that the carbon atom is located at the end of the heteroalkyl group.

[0077] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl moieties may be optionally substituted as separate groups as described herein.

[0078] As used herein, the term "hybrid aryl" refers to a divalent heteroaryl. Optionally substituted heteroaryl is a heteroaryl that has been optionally substituted as described herein with respect to heteroaryl.

[0079] As used herein, the term "heteroaryloxy group" refers to the structure -OR, where R is a heteroaryl group. As defined for heterocyclic groups, the heteroaryloxy group may be optionally substituted.

[0080] As used herein, the term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic, or tetracyclic system having fused, bridged, and / or spirocyclic 3, 4, 5, 6, 7, or 8-membered rings, wherein, unless otherwise specified, the ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a "heterocyclic group" is a monocyclic, bicyclic, tricyclic, or tetracyclic system having fused or bridged 5, 6, 7, or 8-membered rings, wherein, unless otherwise specified, the ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclic groups can be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclic groups have zero or one double bond, non-aromatic 6- and 7-membered heterocyclic groups have zero to two double bonds, and non-aromatic 8-membered heterocyclic groups have zero to two double bonds and / or zero or one carbon-carbon triple bond. Unless otherwise specified, heterocyclic groups contain 1 to 16 carbon atoms. Some heterocyclic groups can contain up to nine carbon atoms. Non-aromatic heterocyclic groups include pyrrolinyl, pyrrolylalkyl, pyrazolinyl, pyrazolylalkyl, imidazolinyl, imidazolinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, thiomorpholinyl, thiazolinyl, isothiazolyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, dihydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyranyl, dihydropyranyl, dithiazolinyl, etc. If a heterocyclic system has at least one aromatic resonance structure or at least one aromatic tautomer, then this structure is an aromatic heterocyclic group (i.e., a heteroaryl). Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophene, benzooxazolyl, furanyl, imidazolyl, indolyl, isoinzolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purine, pyrrole, pyridyl, pyrazinyl, pyrimidinyl, quinazolinyl, quinolinyl, thiadiazolyl (e.g., 1,3,4-thiadiazolyl), thiazolyl, thiophene, triazolyl, tetrazolyl, etc. The term "heterocyclic group" also refers to heterocyclic compounds having a bridged polycyclic structure in which one or more carbon atoms and / or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as quinidine, tropane, or diazabicyclo[2.2.2]octane. The term "heterocyclic group" includes bicyclic, tricyclic, and tetracyclic groups, wherein any of the aforementioned heterocycles is fused to one, two, or three carbon rings, such as aryl rings, cyclohexane rings, cyclohexene rings, cyclopentane rings, cyclopentene rings, or other monocyclic heterocycles. Examples of fused heterocyclic groups include 1,2,3,5,8,8a-hexahydroindoleazine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene.Heterocyclic groups can be unsubstituted or substituted by one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfonyl; alkylsulfonyl; amino; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; haloyl; heteroalkyl; heterocyclic; (heterocyclic)oxy; hydroxyl; nitro; thiol; silyl; cyano; -C(O)R or -SO2R (where R is amino or alkyl); =O; =S; =NR' (where R' is H, alkyl, aryl, or heterocyclic). Each of the substituents can be unsubstituted itself or substituted by an unsubstituted substituent as defined herein for each respective group.

[0081] As used herein, the term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, each as defined herein. The heterocyclic and alkyl moieties may be optionally substituted as separate groups as described herein.

[0082] As used herein, the term "subheterocyclic group" refers to a divalent heterocyclic group. Optionally substituted subheterocyclic groups are optionally substituted subheterocyclic groups as described herein with respect to heterocyclic groups.

[0083] Unless otherwise specified, as used herein, the term "(heterocyclic)oxy group" is expressed as -OR chemical substituent, where R is a heterocyclic group. The (heterocyclic)oxy group may be optionally substituted in the manner described for the heterocyclic group.

[0084] As used interchangeably in this document, the term "hydroxyl (hydroxyl and hydroxy)" refers to the -OH group.

[0085] As used herein, the term "HRAS" (or alternatively "Hras", "H-RAS" or "H-ras") refers to... HRAS (also known as " Hras " H-RAS "or" H-ras ") Gene-encoded proteins, peptides, or polypeptides. As used in this article, " HRAS "Mutation" refers to a change in the amino acid sequence of the HRAS protein. HRAS Mutations in genes. HRAS mutations are commonly found in thyroid cancer, bladder cancer, head and neck cancer, and kidney cancer.

[0086] As used herein, the term "KRAS" (or alternatively "Kras," "K-RAS," or "K-ras") refers to the protein, peptide, or polypeptide encoded by the KRAS gene (also known as Kras, K-RAS, or K-ras). Two common isoforms of the KRAS protein are known, isoform a (KRAS4A) and isoform b (KRAS4B), which are produced by alternative gene splicing. Unless otherwise stated, KRAS should be understood to refer to both isoforms. As used herein, KRAS "Mutation" refers to a change in the amino acid sequence of the KRAS protein. KRAS Mutations in genes. KRAS Mutations are commonly found in colorectal cancer, lung cancer, pancreatic cancer, gynecological cancers (such as uterine cancer, ovarian cancer, cervical cancer, etc.) and gastroesophageal cancer.

[0087] As used herein, the term “leukemia” broadly refers to a progressive malignant disease of the hematopoietic organs and is typically characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is usually classified clinically based on (1) the duration and characteristics of the disease—acute or chronic; (2) the cell type involved; bone marrow (myelopathic), lymphoid (lymphoid), or monocytic; and (3) an increase or non-increase in the number of abnormal cells in the blood—leukemic or non-leukemic (subleukemic).

[0088] As used in this article, the term "lymphoma" refers to cancer caused by immune-originating cells.

[0089] As used in this article, the term "melanoma" refers to a tumor caused by the melanocyte system of the skin and other organs.

[0090] As used herein, the term "molecular glue" refers to a class of molecules configured to force association between a first protein and a second protein, for example, by binding to the first protein, thereby influencing a chemical or conformational change in the first protein and promoting an interaction between the first and second proteins. Crucially, molecular glues promote association between two proteins that would otherwise have minimal to no interaction in the absence of molecular glues. Molecular glues can be specifically configured to induce binding between a first protein and a second protein.

[0091] As used herein, the term "MYC" refers to the MYC family of cell signaling proteins. The MYC family includes c-MYC, l-MYC, and n-MYC (represented by...). c-MYC, l-MYC and n-MYC Gene coding; collectively referred to as MYCMYC proteins perform a variety of regulatory processes in cellular function, many of which are related to cell division, cell proliferation, and DNA replication. MYC genes with gain-of-function mutations produce MYC proteins with enhanced activity (e.g., MYC proteins involved in signal transduction pathways in the absence of signals activating these pathways) or produce increased amounts of MYC proteins in the cell. MYC The gene for the protein. Overexpression. MYC The cells exhibit higher expression than normal. MYC Higher cell MYC Cells with gene activity. For example, overexpression. MYC Cells exhibiting at least three copies of a substance are diploid cells that, relative to normal diploid cells with two copies, are considered to have more than three copies of a substance. MYC Cells with high copy number are overexpressing MYC . cells. MYC Overexpression can be used to identify the expression level of gene products in cells (e.g., MYC The mRNA transcript count or MYC protein level is used for measurement.

[0092] As used in this article, the term "Myt1" refers to membrane-associated tyrosine and threonine-specific CDC2 inhibitory kinase (Myt1) (gene name PKMYT1).

[0093] As used herein, the term "Myt1 inhibitor" refers to the reduction of Myt1 activity upon contact with the enzyme Myt1, whether in vitro, in cell culture, or in vivo, to achieve a measured Myt1 IC50. 50 It is a compound with a molecular weight of 10 µM or less (e.g., 5 µM or less or 1 µM or less). For some Myt1 inhibitors, the Myt1 IC50 value is... 50 It can be 100 nM or less (e.g., 10 nM or less or 3 nM or less) and can be as low as 100 pM or 10 pM. Preferably, Myt1 IC 50 It is 1 nM to 1 µM (e.g., 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM). Even more preferably, Myt1 IC 50 Less than 20 nm (e.g., 1 nM to 20 nM).

[0094] As used in this article, the term "nitro" refers to the -NO2 group.

[0095] As used herein, the term "NRAS" (or alternatively "Nras", "N-RAS" or "N-ras") refers to the action of NRAS (also known as "N-RAS"). Nras " N-RAS "or" N-ras") Gene-encoded proteins, peptides, or polypeptides. As used in this article, " NRAS "Mutation" refers to a change in the amino acid sequence of the NRAS protein. NRAS Changes in genes. NRAS Mutations are commonly found in colorectal cancer, thyroid cancer, and melanoma.

[0096] As used herein, the term "oxo" refers to a divalent oxygen atom (e.g., an oxo structure can be represented as =O).

[0097] As used in this article, the term "Ph" refers to phenyl.

[0098] As used herein, the term "pharmaceutical composition" means a composition containing the compounds described herein, formulated with pharmaceutically acceptable excipients, and manufactured or marketed by a government regulatory agency as part of a treatment regimen for treating diseases in mammals. Pharmaceutical compositions may be formulated in unit dosage forms, for example, for oral administration (e.g., tablets, capsules, caplets, gelcaps, or syrups); for topical administration (e.g., as creams, gels, lotions, or ointments); for intravenous administration (e.g., as a sterile solution in a solvent system suitable for intravenous use, free of particulate emboli); or in any other formulation form described herein.

[0099] As used interchangeably herein, the terms "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable carrier" refer to any component other than the compounds described herein that has non-toxic and non-inflammatory properties in the patient body (e.g., a medium capable of suspending or dissolving an active compound). Excipients may include, for example: anti-adhesives, antioxidants, adhesives, coatings, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, flow enhancers (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydrates. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dialkali), calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium carboxyacetic acid starch, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0100] As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for use in contact with tissues in humans and animals, within the bounds of reasonable medical judgment, without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences References 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (edited by PH Stahl and CGWermuth), Wiley-VCH, 2008. The salts may be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, gluconate, glyceryl phosphate, hemisulfate, heptaate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0101] As used herein, the term "PIK3CA" refers to the catalytic subunit α of phosphatidylinositol-4,5-bisphosphate 3-kinase (or P110α; derived from...). PIK3CA Gene encoding the catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). PI3K plays an important role in cell signaling, such as the PI3K / AKT / mTOR pathway. Those with gain-of-function mutations... PIKC3A A gene is a gene that produces PIK3CA protein with enhanced activity (e.g., PIK3CA protein involved in signal transduction pathways in the absence of signals that activate signal transduction pathways) or produces an increased amount of PIK3CA protein in the cell.

[0102] As used herein, the term "PPP2R1A" refers to the Aα isotype of the 65kDa regulatory subunit of serine / threonine protein phosphatase 2A (composed of...). PPP2R1A (Gene encoding). PPP2R1A is the regulatory subunit of protein phosphatase 2 (PP2A), one of the four major Ser / Thr phosphatases. Wild-type PP2A is involved because of its role in regulating tumorigenesis by controlling phosphorylation events in cell signaling pathways. Loss-of-function mutations... PPP2R1A The gene is one that fails to produce functional PPP2R1A protein or produces a reduced amount of PPP2R1A protein in the cell.

[0103] As used in this article, the term "PTEN" refers to a phosphatase and tensin homolog protein (composed of...). PTEN (Gene-encoded). PTEN is a cell cycle-regulating phosphatase that plays a role in the regulation of multiple cell signaling pathways, such as the Akt / PKB signaling pathway. Loss-of-function mutations... PTEN Genes that fail to produce functional PTEN protein or produce reduced amounts of PTEN protein in cells.

[0104] As used in this article, the term "precancerous lesion" or "precancerous" refers to a non-malignant condition that has the potential to become malignant.

[0105] As used herein, the term "proteolytically targeted chimera" or alternatively, PROTAC, refers to a molecule comprising two covalently linked protein-binding moieties (e.g., at opposite ends of the molecule). One protein-binding moieties is configured to bind an E3 ubiquitin ligase and a target protein of interest (e.g., a replication-related protein, such as Wee1, as described herein), forming a ternary complex comprising the E3 ligase, the protein of interest, and the PROTAC. Forced association between the ligase and the target protein then triggers the degradation of the target protein. For example, a PROTAC may promote ubiquitination of the target protein by the E3 ubiquitin ligase. The ubiquitinated target protein is then recognized and degraded by the proteasome. Unlike conventional protein inhibitors, PROTAC molecules operate catalytically and are not consumed by degradation mechanisms. Therefore, they can be administered at significantly lower doses than conventional protein inhibitors. Furthermore, the binding moieties can be engineered to allow targeted formation of specific ternary complexes, thereby enabling highly targeted drug delivery.

[0106] As used herein, the term "protecting group" refers to a group intended to protect a hydroxyl, amino, or carbonyl group during chemical synthesis from participating in one or more undesirable reactions. As used herein, the term "O-protecting group" refers to a group intended to protect a hydroxyl or carbonyl group during chemical synthesis from participating in one or more undesirable reactions. As used herein, the term "N-protecting group" refers to a group intended to protect a nitrogen-containing (e.g., amino, amide, heterocyclic NH, or hydrazine) group during chemical synthesis from participating in one or more undesirable reactions. Commonly used O-protecting and N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Exemplary O-protecting groups and N-protecting groups include alkyl, aromatic, or carbamoyl groups, such as formyl, acetyl, propionyl, neopentyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, tert-butyldimethylsilyl, tri-isopropylsilyloxymethyl, 4,4'-dimethoxytriphenylmethyl, isobutyryl, phenoxyacetyl, 4-isopropylphenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl.

[0107] Exemplary O-protecting groups for protecting carbonyl groups include, but are not limited to: acetals, carbonyl esters, 1,3-dithianes, 1,3-dioxanes, 1,3-dioxolane, and 1,3-dithiopentane.

[0108] Other O-protecting groups include, but are not limited to: substituted alkyl, aryl, and arylalkyl ethers (e.g., triphenylmethyl ether; methylthiomethyl ether; methoxymethyl ether; benzyloxymethyl ether; silaneoxymethyl ether; 2,2,2-trichloroethoxymethyl ether; tetrahydropyranyl ether; tetrahydrofuranyl ether; ethoxyethyl ether; 1-[2-(trimethylsilyl)ethoxy]ethyl ether; 2-trimethylsilylethyl ether; tert-butyl ether; p-chlorophenyl ether, p-methoxyphenyl ether, p-nitrophenyl ether, benzyl ether, p-methoxybenzyl ether, and nitrobenzyl ether); silyl ethers (e.g., trimethylsilyl ether; triethylsilyl ether; triisopropylsilyl ether; dimethylisopropylsilyl ether; tert-butyldimethylsilyl ether; tert-butyldiphenylsilyl ether; tribenzylsilyl ether; triphenylsilyl ether and diphenylmethylsilyl ether); carbonates (e.g., methyl esters, methoxymethyl esters, 9-fluorenylmethyl esters; ethyl esters; 2,2,2-trichloroethyl esters; 2-(trimethylsilyl)ethyl esters; vinyl esters, allyl esters, nitrobenzene esters, benzyl esters; methoxybenzyl esters; 3,4-dimethoxybenzyl esters; and nitrobenzyl esters).

[0109] Other N-protecting groups include, but are not limited to, chiral auxiliaries, such as protected or unprotected D, L, or D,L-amino acids, such as alanine, leucine, phenylalanine, etc.; sulfonyl groups, such as benzyl sulfonyl, p-toluenesulfonyl, etc.; and groups that form carbamates, such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, α,α-Dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy, tert-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentoxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, etc.; arylalkyl groups, such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, benzyloxymethyl, etc.; silylalkyl acetal groups, such as [2-(trimethylsilyl)ethoxy]methyl; and silyl groups, such as trimethylsilyl, etc. Available N-protecting groups are formyl, acetyl, benzoyl, neopentyl, tert-butylacetyl, alanyl, benzyl, dimethoxybenzyl, [2-(trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), tert-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0110] As used herein, the term "RAS" (or alternatively "Ras", "RAS GTPase", or "Ras GTPase") refers to the RAS family of cell signaling proteins. The RAS family includes KRAS, HRAS, and NRAS (represented by KRAS, HRAS, and NRAS, respectively). KRAS, HRAS and NRAS Gene coding; collectively referred to as RAS (Genes). It has been observed that approximately 25% of cancers involve... RAS Gene mutations. Those with gain-of-function mutations. RAS Genes that produce RAS proteins with enhanced activity (e.g., RAS proteins involved in signal transduction pathways in the absence of signals activating the pathway) or that produce increased amounts of these proteins in the cell. RAS The gene for the protein. Some cancers disclosed herein may include or are characterized by... RAS Increased gene expression. Overexpression. RAS The cells express the gene more than normally. RAS Higher gene cell RAS Cells with gene activity. For example, overexpression. RAS Cells exhibiting at least three copies of a substance are diploid cells that, relative to normal diploid cells with two copies, are considered to have more than three copies of a substance. RAS Cells with high gene copy number are overexpressing RAS . cells. RAS Gene overexpression can be used to identify the expression levels of gene products in cells (e.g., RAS The mRNA transcript count or RAS protein level is used for measurement. In some implementations, RAS Gene overexpression can be KRAS Gene overexpression.

[0111] As used herein, the term "replication stress" refers to cells experiencing faster and / or uncontrolled cell division. Many cancers are characterized by biomarkers of replication stress, such as gene mutations (e.g., loss-of-function or gain-of-function mutations) or gene overexpression, which result in a shortened time spent by cells in the G1, S, or G2 phases of the cell cycle. Furthermore, therapeutic (e.g., chemotherapy) drugs can also be drivers of replication stress. Methods disclosed herein may include administering one or more replicative stress-inducing therapeutic agents (e.g., Myt inhibitors) to cancers with replication stress mutations.

[0112] As used herein, the term "reduced dosing regimen" refers to a dosing regimen that results in a lower frequency of administration of an active pharmaceutical composition relative to a second dosing regimen. For example, in combination therapy, the dosing regimen may be "reduced" relative to monotherapy. A "reduced" regimen may refer to a reduction in the number of daily administration events (e.g., once daily instead of twice daily) or an increase in the number of days of discontinuation (e.g., a 3 / 4 regimen instead of a 5 / 2 regimen). Compounds administered in combination therapy (e.g., MYT1 inhibitors, such as any of compounds 1 to 328; or Wee1 inhibitors, such as any of compounds W1 to W3052) may be provided in a reduced dosing regimen relative to monotherapy. Reduced dosing regimens may further include compounds at reduced doses (e.g., subtherapeutic doses).

[0113] The term "sarcoma" generally refers to a tumor composed of a substance similar to embryonic connective tissue and typically consists of tightly packed cells embedded in fibrous or isomorphic material.

[0114] As used herein, the term "subject" means a human or non-human animal (e.g., a mammal) that is determined by a qualified professional (e.g., a physician or nursing practitioner) to have or be at risk of having a disease or condition, with or without laboratory testing known in the art on samples from the subject. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases in which the symptom is excessive cell proliferation, such as cancer.

[0115] As used herein, the term "subtherapeutic dose" refers to a dose of active pharmaceutical ingredient, as a dose of pharmacologically active agent administered to a subject, that is functionally insufficient to elicit the intended pharmacological effect on its own, or that is quantitatively less than the established therapeutic dose of the active pharmaceutical ingredient (e.g., as described in publications referenced by those skilled in the art, such as manufacturer's recommendations, etc.). In the context of combination therapy, "subtherapeutic dose" is used to refer to a dose of active pharmaceutical ingredient that is less than the dose intended to elicit the intended pharmaceutical effect when the active pharmaceutical ingredient is administered as a monotherapy. Subtherapeutic doses can be defined relative to the amount of active pharmaceutical ingredient routinely administered (i.e., 75%, 50%, 40%, 30%, 20%, 10%, etc.).

[0116] The term "tautomer" refers to structural isomers that are readily interchangeable through proton migration. Tautomers are different chemical species that can be identified by their distinct spectroscopic properties, but they are generally not isolated individually. Non-limiting examples of tautomers include keto-enols, enamine-imines, amide-imines, nitroso-oximes, enone-alkynols, and amino acid-ammonium formates.

[0117] As used herein, “treatment” refers to the medical management of a subject aimed at improving, ameliorhyming, stabilizing, preventing, or curing a disease or symptom. This term includes active treatment (treatment involving the improvement of a disease or symptom); etiological treatment (treatment involving the cause of a related disease or symptom); palliative treatment (treatment designed to relieve symptoms of a disease or symptom); preventive treatment (treatment involving minimizing or partially or completely suppressing the development of a related disease or symptom); and supportive treatment (treatment used to complement another therapy).

[0118] As used herein, the term "Wee1" refers to a nuclear kinase belonging to the Ser / Thr family of protein kinases. This protein is encoded by the WEE1 gene. This protein catalyzes inhibitory tyrosine phosphorylation of CDC2 / cyclin B kinase and helps control when the cell enters mitosis by coordinating the transition between DNA replication and mitosis by protecting the cell nucleus from cytoplasmic activated CDC2 kinase. Inhibition of Wee1 (e.g., via Wee1 inhibitors) results in a reduction in daughter cell size.

[0119] As used herein, the term "Wee1 inhibitor" refers to a compound that reduces Wee1 activity upon exposure to the Wee1 enzyme, whether in vitro, in cell culture, or in animals, resulting in a measured Wee1 IC50 value. 50 The concentration is 10 µM or lower (e.g., 5 µM or lower or 1 µM or lower). For some Wee1 inhibitors, the Wee1 IC50 is... 50 It can be 100 nM or lower (e.g., 10 nM or lower, or 3 nM or lower), and can be as low as 100 pM or 10 pM. Preferably, Wee1 IC 50 The wavelength range is from 0.1 nM to 1 µM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Even more preferably, Wee1 IC 50 Less than 20 nM (e.g., 1 nM to 20 nM). As used herein, Wee1 inhibitors include compounds that reduce Wee1 activity upon application (e.g., by preventing Wee1 from binding to substrates (e.g., Cdk1) without degrading Wee1), and compounds that cause Wee1 degradation upon application. For example, Wee1 inhibitors can be compounds that induce intracellular proteolysis (e.g., proteolysis-targeting chimeric (PROTAC) molecules) or molecular gels (e.g., bifunctional molecules, each half of which interacts with the biological material). Brief description of the attached diagram Figure 1A This is a graph showing the viability of FT282 wild-type (WT) cells exposed to lunresertib (compound 182; 37 nM) monotherapy, Debio-0123 (123 nM) monotherapy, and lunresertib (37 nM) and Debio-0123 (123 nM) combination therapy.

[0121] Figure 1BThis demonstrates exposure to lunresertib (37 nM) monotherapy, Debio-0123 (123 nM) monotherapy, and combination therapy of lunresertib (37 nM) and Debio-0123 (123 nM). CCNE1 - A graph showing high cell viability.

[0122] Figure 1C This is a graph showing the viability of OVCAR3 cells exposed to lunresertib (37 nM) monotherapy, Debio-0123 (123 nM) monotherapy, and combination therapy of lunresertib (37 nM) and Debio-0123 (123 nM).

[0123] Figure 2A This is a scatter plot showing the percentage of FT282 WT cells with histone H2AX phosphorylation after exposure to lunresertib alone and in combination with two concentrations of Debio-0123 (250 nM and 1000 nM) at different concentrations of lunresertib.

[0124] Figure 2B This demonstrates the presence of histone H2AX phosphorylation after exposure to lunresertib alone and in combination with two concentrations of Debio-0123 (250 nM and 1000 nM) at different concentrations. CCNE1 - A scatter plot showing the percentage of high-performing cells.

[0125] Figure 2C This is a scatter plot showing the percentage of OVCAR3 cells with histone H2AX phosphorylation after exposure to lunresertib alone and in combination with two concentrations of Debio-0123 (250 nM and 1000 nM) at different concentrations of lunresertib.

[0126] Figure 3A The percentage of Thr14 phosphorylation in CDK1 after treatment with 1000 nM Debio-0123, 250 nM lunresertib, and combination therapy is shown.

[0127] Figure 3B The percentage of Tyr15 phosphorylation in CDK1 is shown after treatment with 1000 nM Debio-0123, 250 nM lunresertib, and combination therapy.

[0128] Figure 3CThe images show bands corresponding to CDK1-pT14, CDK1-pY15, and unphosphorylated CDK1 in a gel electrophoresis experiment. Actinin is shown as a control.

[0129] Figure 4A The percentage of Ser151 phosphorylation in CDC25B after treatment with 1000 nM Debio-0123, 250 nM lunresertib, and combination therapy is shown.

[0130] Figure 4B The images show bands corresponding to CDC25B-pS151 and unphosphorylated CDC25B in a gel electrophoresis experiment. Actin is shown as a control.

[0131] Figure 5A This figure shows the treatments in a pancreatic xenograft model. The treatments included lunresertib monotherapy (15 mg / kg twice daily (BID), 3 days dosing / 4 days off), Debio-0123 monotherapy (15 mg / kg BID, 3 days dosing / 4 days off), and a combination therapy of lunresertib (15 mg / kg BID, 3 days dosing / 4 days off) plus Debio-0123 (15 mg / kg BID, 3 days dosing / 4 days off). Both drugs were administered orally via tube feeding. Data showed changes in tumor volume over 24 treatment days. Treatment with both compounds began on day 1. Results are presented as mean ± SEM, N=6 / group, female NOD SCID mice.

[0132] Figure 5B This is a graph showing the change in body weight in mice bearing subcutaneous pancreatic tumors after 24 days of treatment with lunresertib and / or Debio-0123. Data show the percentage change in body weight over the 24 treatment days. Treatment with both compounds began on day 1. Results are presented as mean ± SEM, N=6 / group, female NOD SCID mice.

[0133] Figure 5CThis graph shows the treatments in a pancreatic xenograft model. Treatments included lunresertib monotherapy (15 mg / kg BID, 3 days / 4 days off), Debio-0123 monotherapy (15 mg / kg BID, 3 days / 4 days off), and a combination therapy of lunresertib (15 mg / kg BID, 3 days / 4 days off) plus Debio-0123 (15 mg / kg BID, 3 days / 4 days off). Both drugs were administered orally via tube feeding. Data showed tumor volume on day 22 of treatment. Results are presented as mean ± SEM, N=6 / group, female NOD SCID mice. Statistical significance was determined by one-way ANOVA (Brown-Forsythe and Welch ANOVA tests in GraphPad Prism v10); ns indicates no significance, *p<0.05; **p<0.01; ***p<0.001.

[0134] Figure 6A This is a graph showing the treatment in an ovarian xenograft model. Treatment included lunresertib monotherapy (5 mg / kg BID, 3 days dosing / 4 days off), Debio-0123 monotherapy (30 mg / kg BID, 3 days dosing / 4 days off), and a combination therapy of lunresertib (5 mg / kg BID, 3 days dosing / 4 days off) plus Debio-0123 (30 mg / kg BID, 3 days dosing / 4 days off). Both drugs were administered orally via tube feeding. Data showed changes in tumor volume over 45 treatment days. Treatment with both compounds began on day 1. Results are presented as mean ± SEM, N=8 / group, female SCID beige mice. Statistical significance was determined by one-way ANOVA (Brown-Forsythe and Welch ANOVA tests in GraphPad Prism v10).

[0135] Figure 6B Is it displayed as follows Figure 6A The graph shows the weight change in mice with subcutaneous ovarian tumors treated with lunresertib and / or Debio-0123 for 45 days. Both drugs were administered orally via tube feeding. Data show the percentage change in weight over the 45 treatment days. Treatment with both compounds began on day 1. Results are presented as mean ± SEM, N=8 / group, female SCID beige mice. Statistical significance was determined by one-way ANOVA (Brown-Forsythe and Welch ANOVA tests in GraphPad Prism v10).

[0136] Figure 6C This is a graph showing the tumor volume in mice with an ovarian xenograft model on day 31. Treatment included lunresertib monotherapy (5 mg / kg BID, 3 days on, 4 days off), Debio-0123 monotherapy (30 mg / kg BID, 3 days on, 4 days off), and a combination therapy of lunresertib (5 mg / kg BID, 3 days on, 4 days off) plus Debio-0123 (30 mg / kg BID, 3 days on, 4 days off). Both drugs were administered orally via tube feeding. Results are presented as mean ± SEM, N=8 / group, female SCID beige mice. Statistical significance was determined by one-way ANOVA (Brown-Forsythe and Welch ANOVA tests in GraphPadPrism v10); ns indicates no significance, *p<0.05; **p<0.01; ***p<0.001.

[0137] Detailed description Typically, the present invention provides a method for using a combination of Myt1 inhibitors and Wee1 inhibitors. Advantageously, the combination of Myt1 inhibitors and Wee1 inhibitors can act synergistically to treat cancer or induce cell death.

[0138] Myt1 inhibitors can be used to inhibit cells (e.g., the subject's cells (e.g., overexpression)). CCNE1 Myt1 may be present in cells with an inactivating mutation in the FBXW7 gene. Subjects may require treatment for diseases or conditions, such as cancer, characterized by excessive cell proliferation. Myt1 inhibitory activity can be used to treat subjects requiring cancer treatment.

[0139] Myt1 is a cell cycle-regulated kinase primarily located in the endoplasmic reticulum and Golgi complex. It is part of the Wee kinase family, which includes Wee1 and Wee1b. Myt1 and Wee1 are involved in the negative regulation of the CDK1-cyclin B complex, which promotes cell progression from G2 phase to the mitotic phase (M phase) of the cell cycle. During DNA damage, Myt1, along with Wee1 (which mediates only Tyr15 phosphorylation), drives phosphorylation on Thr14 of CDK1, thereby keeping the kinase complex inactive in G2 as part of the G2 checkpoint response and preventing entry into mitosis until the damage is repaired. Furthermore, it has been proposed that Myt1 interact directly with the CDK1-cyclin B complex in the cytoplasm and prevent their nuclear translocation, thereby inhibiting cell cycle progression.

[0140] Myt1 is considered a potentially important cancer target because it is essential in many cancer cells. Overexpression of Myt1 has been observed in various cancers, including hepatocellular carcinoma and clear cell renal cell carcinoma. Downregulation of Myt1 plays a minor role in undisturbed cells but a more prominent role in cells exposed to DNA damage. Furthermore, in addition to defective G1 checkpoint regulation, cells exhibiting high levels of replication stress may be particularly sensitive to loss of Myt1 function, as these cells are prone to premature mitosis, genomic material damage, and ultimately, mitotic failure.

[0141] Inhibitors of Myt1 are regulators of the G2-M transition and may be particularly useful in treating tumors with replication stress biomarkers, such as mutations (e.g., gain-of-function or loss-of-function mutations) or gene amplifications of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, l-MYC, n-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or previous or current human papillomavirus (HPV) infection, or combinations thereof.

[0142] Replication stress biomarkers Cancers treated by the methods of this disclosure may include, be characterized by, or be identified by replication stress biomarkers. In some embodiments, the replication stress biomarker is a mutation in a replication stress-related gene. In some embodiments, the replication stress biomarker is a gain-of-function mutation. In some embodiments, the replication stress biomarker is a loss-of-function mutation. In some embodiments, the replication stress biomarker is increased expression (i.e., gene amplification) of a replication stress-related gene. In some embodiments, the replication stress biomarker is decreased expression of a replication stress-related gene. In some embodiments, the cancer is characterized by resistance to inhibitors of replication-related proteins. In some embodiments, the replication stress biomarker is a mutation or gene amplification of a gene encoding a cell division signaling protein. In some implementations, replication stress biomarkers are mutations (e.g., gain-of-function or loss-of-function mutations) or gene amplifications of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, l-MYC, n-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or previous or current HPV infection.

[0143] RAS biomarkers RAS proteins (such as Kras) are composed of RAS proteins (e.g., Kras) KRAS Gene encoding), Hras (by) HRAS Gene encoding) and Nras (by NRAS The gene encodes a member of the small guanidine triphosphatases (GTPase) protein superfamily (e.g., Ras, Rho, Ran, Rab, and Arf GTPases). RAS proteins bind to GTP molecules, converting Ras protein to an "activated state" (Ras-GTP). The activated Ras-GTP complex can then dephosphorylate, converting Ras protein to an "inactive state" (Ras-GDP). Many cancers are highly associated with mutations in the RAS gene (e.g., uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, thyroid cancer, melanoma, and endometrial cancer) or RAS overexpression. Mutations in the RAS gene (e.g., gain-of-function mutations) or RAS overexpression disrupt cellular signaling, either preventing cells from transducing certain signals to the nucleus, stimulating cells in the absence of signals, or amplifying cellular responses to stimuli. This leads to prolonged activation of the RAS protein, and consequently, prolonged signal transduction (e.g., signals to continue cell division).

[0144] TP53 biomarker Transformation-associated protein 53 (also known as p53, tumor protein P53, cell tumor antigen p53, or Tp53; by...) TP53 Tp53 (encoded in the gene) is a regulatory protein associated with ensuring healthy cell division by preventing genomic mutations. It plays a role in activating DNA repair, preventing the transition to the mitotic stage of cell division, and initiating apoptosis in cells with sufficiently damaged DNA. Due to its role in active DNA repair, Tp53 is classified as a "tumor suppressor gene" and is commonly mutated in cancer cells. TP53 mutations are present in approximately 30% to 50% of ovarian, esophageal, colorectal, head and neck, and lung cancers. Therefore, TP53 mutations may be replication stress mutations. Thus, those carrying... TP53 Mutated cancers may be particularly sensitive to treatment with drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy. In some embodiments, cancers treated by the methods of this disclosure include TP53 Mutation. In some implementations, the TP53 mutation encodes Tp53. - / - .

[0145] CCNE1 biomarkers Cyclin E1 (by...) CCNE1The gene encodes E1, which is involved in the cell cycle transition from G1 to S phase. In late G1 phase, it complexes with cyclin-dependent kinase 2 (Cdk2) to promote the activation of the E2F transcription factor and entry into S phase. Cyclin E1 levels are tightly regulated during the normal cell cycle, accumulating during the G1 / S transition and being completely degraded at the end of S phase. Cyclin E1 is degraded by the cell cycle-dependent proteasome by SCF. FBW7 The ubiquitin ligase complex mediates the transition to S phase. Once activated in late G1, the cyclin E1 / Cdk2 complex promotes the transition to S phase via phosphorylation and inactivation of pRB and subsequent release of E2F transcription factors. S phase is promoted by E2F-mediated transcription of multiple genes involved in DNA replication, including the pre-replication complex subunits Orc1, Cdc6, Cdt1, and Mcm helicase factor. CCNE1 It is frequently amplified and / or overexpressed in human cancers. It has been reported that... CCNE1 Amplification occurs in a variety of cancer types, including ovarian cancer, breast cancer, uterine cancer, pancreatic cancer, bladder cancer, stomach cancer, esophageal cancer, and sarcoma.

[0146] CCNE1 Overexpression is thought to drive tumorigenesis by inducing genomic instability (e.g., increased origin excitation, defective nucleotide library, transcriptional replication conflict and / or fork instability). CCNE1 Overexpression of this substance has been shown to induce replication stress, characterized by slowing or halting of replication forks and loss of heterozygosity at vulnerable sites. CCNE1 The main mechanism by which overexpression induces replication stress is an increase in origin activation in early S phase, followed by depletion of replication factors, including the nucleotide pool. The overall reduction in replication proteins and nucleotides slows bifurcation progression and causes stagnation and subsequent collapse or reversal. Therefore, CCNE1 Amplification is a biomarker of replication stress. Therefore, those carrying... CCNE1 Mutation or characteristic is CCNE1 Cancers that overexpress Myt1 may be particularly sensitive to treatment with drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy.

[0147] In some implementation schemes, cancer may include CCNE1 Mutation, overexpression, or amplification. In some implementations, cancer includes at least one other replication stress biomarker (such as the replication stress biomarker described herein) and CCNE1 Mutation, overexpression, or amplification.

[0148] CDK12 biomarker Cyclin-dependent kinase 12 (Cdk12) CDK12Cdk12 (encoded in the gene) is a member of the cyclin-dependent kinase (Cdk) family of serine-threonine kinases. Cdk family kinases interact with a variety of regulatory proteins by phosphorylating specific sites on the protein, thereby activating or inhibiting the protein. Cdk proteins play a regulatory role in many stages of the cell cycle and in the transitions between them. The entire family is considered important for maintaining healthy cell division throughout the cell cycle. Cdk12 belongs to a subclass of Cdk proteins that is particularly effective in gene transcriptional regulation. Cdk12 is further involved in RNA splicing, translation, and DNA damage responses. Therefore, cancers carrying mutated Cdk12 proteins, or cancers characterized by reduced Cdk protein expression, may be particularly sensitive to treatment with drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy.

[0149] In some implementations, replication stress biomarkers are CDK12 Mutations. In some implementations, cancers treated by the methods of this disclosure include... CDK12 Mutation. In some implementations, CDK12 Mutation is a loss-of-function mutation.

[0150] CDK4 and CDK6 biomarkers Cyclin-dependent kinase 4 (Cdk4; encoded by the CDK4 gene) and cyclin-dependent kinase 6 (Cdk6; encoded by the CDK6 gene) are both members of the cyclin-dependent kinase (Cdk) family of serine-threonine kinases. Both Cdk4 and Cdk6 belong to a subclass of Cdk proteins that regulate cell cycle progression. Both Cdk4 and Cdk6 are highly involved in regulating the cell transition between G1 and S phases of the cell cycle. Therefore, CDK4 and CDK6 are common drug targets in cancer therapy because inhibiting Cdk4 or Cdk6 arrests cell development in the G1 phase, thereby preventing or slowing mitosis. Some cancers (e.g., those involving CDK4 or CDK6 mutations) have been found to be resistant to chemotherapy with Cdk4 or Cdk6 inhibitors. Therefore, cancers containing CDK4 or CDK6 mutations (or resistant to chemotherapy with Cdk4 or Cdk6 inhibitors) are under high replication stress and may therefore be particularly sensitive to drugs that induce replication stress. In some embodiments, the CDK4 mutation is a loss-of-function mutation. In some embodiments, the CDK6 mutation is a loss-of-function mutation. In some embodiments, the cancer treated by the methods of this disclosure includes a CDK4 mutation. In some embodiments, the cancer treated by the methods of this disclosure includes a CDK6 mutation. In some embodiments, the cancer to be treated is resistant to treatment with Cdk4 inhibitors, Cdk6 inhibitors, or CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, and abexicillin).

[0151] CDKN2A biomarker p16 (or p16INK4a) and p14arf (both encoded by the CDKN2A gene) are naturally occurring inhibitors of Cdk4 and Cdk6. Mutations in CDKN2A (particularly loss-of-function mutations) can lead to loss or reduction of function and may serve to increase the expression of Cdk4 and Cdk6, thus acting as replication stress mutations. Therefore, cancers carrying CDKN2A mutations may be particularly sensitive to treatment with drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy. In some embodiments, the replication stress biomarker is a CDKN2A mutation. In some embodiments, cancers treated by the methods of this disclosure include CDKN2A mutations. In some embodiments, the CDKN2A mutation is a loss-of-function mutation.

[0152] CDC25A biomarker M-phase inducer phosphatase 1 (Cdc25A; encoded by the CDC25A gene). Cdc25A is a regulatory protein phosphatase responsible for removing inhibitory phosphorylation events of Cdk proteins (particularly Cdk2, Cdk4, and Cdk6). Therefore, mutations in CDC25A (particularly gain-of-function mutations) can reduce Cdk protein phosphorylation, thereby increasing Cdk protein activity and placing cells under replication stress. Consequently, cancers carrying CDC25A mutations may be particularly sensitive to treatment with drugs that induce replication stress (e.g., Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy). In some embodiments, the replication stress biomarker is a CDC25A mutation. In some embodiments, cancers treated by the methods of this disclosure include those with gain-of-function CDC25A mutations.

[0153] EGFR biomarkers Epidermal growth factor receptor (Egfr, or Her1 or ErbB1; encoded by the EGFR gene) is a transmembrane glycoprotein comprising an extracellular domain capable of binding extracellular growth factors (e.g., epidermal growth factor (Egf), heparin-binding Efg-like growth factor (Hbegf), β-cytokinin (Btc), bimodalin (Areg), epithelial regulatory protein (Ereg), epidermal growth factor (Epgn), etc.) and an intracellular domain including a tyrosine kinase domain. The binding of extracellular growth factor proteins to the extracellular domain promotes a conformational change in the intracellular tyrosine kinase domain, which in turn activates intracellular signaling pathways, particularly those associated with cell division (e.g., the Ras / Mapk pathway). Through this mechanism, Egfr is used to transduce extracellular signals (e.g., signals from extracellular polypeptide growth factors) into intracellular signals (e.g., as part of the Ras / Mapk pathway) to promote cell division. Mutations in EGFR can lead to conformational changes in the tyrosine kinase domain, independent of any interaction with extracellular growth factor peptides, resulting in sustained activation of cellular signals that initiate cell division. EGFR mutations are common in many cancers, and are particularly prevalent in lung cancer. Therefore, cancers carrying EGFR mutations (e.g., gain-of-function mutations) may be particularly sensitive to treatment with drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy.

[0154] In some embodiments, the replication stress biomarker is an EGFR mutation. In some embodiments, the cancer treated by the methods of this disclosure includes an EGFR mutation. In some embodiments, the cancer treated by the methods of this disclosure includes a functionally acquired EGFR mutation.

[0155] FBXW7 biomarker Proteins containing at least one F-box domain (called F-box proteins; for example, the Fbxw7 protein encoded by the gene FBXW7), particularly FBXW7, are frequently mutated in various cancer types, including endometrial cancer, colorectal cancer, and gastric cancer, with a frequency ranging from 5% to 35%. Mutations have been observed in more aggressive subtypes of endometrial cancer. FBXW7 The driving mutations include the subtypes UCS (approximately 35%) and USC (approximately 25%). FBXW7 Cancer exhibits a diverse spectrum of loss-of-function mutations, including truncation mutations widespread across genes and missense mutations within cyclin E1 that recognizes the WD40 repeat sequence. Fbxw7 functions as a homodimer within the SCF complex, and many of the detrimental missense mutations within the WD40 repeat sequence are mostly heterozygous and dominant-negative. Notably, several recurring hotspot missense mutations have been identified within the WD40 repeat sequence, including R465, R479, and R505—all of which disrupt cyclin E1 binding and ubiquitination. Therefore, cancers carrying FBXW7 mutations may be particularly sensitive to treatment with drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy.

[0156] In some embodiments, the cancer may include an FBXW7 mutation (e.g., a loss-of-function mutation). In some embodiments, the cancer includes at least one other replication stress biomarker (e.g., the replication stress biomarker described herein) and an FBXW7 mutation.

[0157] c-MYC biomarkers The Myc family of cell signaling proteins includes c-Myc, l-Myc, and n-Myc. c-Myc, l-Myc, and n-Myc are encoded by the c-MYC, l-MYC, and n-MYC genes, respectively. MYC genes perform a variety of regulatory processes in cellular function, many of which are related to cell division, cell proliferation, and DNA replication. Myc proteins contribute to the regulation of almost 15% of all genes. Mutations in MYC genes, particularly in c-MYC, are common in cancers, where mutations lead to, for example, uncontrolled cell division. Many c-MYC-related cancers are generally considered untreatable, excluding conventional chemotherapy. However, cancers carrying mutations in genes encoding Myc proteins (e.g., c-MYC mutations) may be particularly sensitive to drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy.

[0158] In some embodiments, the replication stress biomarker is a c-MYC mutation. In some embodiments, the cancer treated by the methods of this disclosure includes a functionally acquired c-MYC mutation. In some embodiments, the cancer to be treated includes gene amplification of the c-MYC gene.

[0159] PIK3CA biomarker The catalytic subunit α of phosphatidylinositol-4,5-bisphosphate 3-kinase (Pik3ca, or P110α; encoded by the PIK3CA gene) is the catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase (Pi3k). Pik3ca uses ATP to phosphorylate phosphatidylinositol (PtdIns), such as PtdIns4P, PtdIns(3,4)P2, PtdIns(3,4,5)P3, and PtdIns(4,5)P2. PtdIns can then bind protein kinase B (PKB or AKT). Through this phosphorylation pathway, PI3K plays an important role in cell signaling, such as the Pi3k / Akt / mtor pathway. The Pi3k / Akt / mtor pathway is a key inducer of cell and tissue growth. Therefore, mutations in Pi3k, particularly gain-of-function mutations in the Pik3ca subunit, are associated with many cancers. For example, nearly one-third of breast and cervical cancers involve PIK3CA mutations. Furthermore, PIKC3A mutations can lead to a variety of genetic disorders causing excessive growth in body parts, collectively known as the Pik3ca overgrowth spectrum (PROS). Therefore, cancers carrying Pi3k gene mutations (e.g., Pik3ca subunit mutations) may be particularly sensitive to treatment with drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy.

[0160] In some embodiments, the replication stress biomarker is a mutation in the PI3K protein. In some embodiments, the replication stress biomarker is a PIK3CA mutation. In some embodiments, the cancer treated by the methods of this disclosure includes a functionally acquired PIK3CA mutation.

[0161] PPP2R1A biomarker The 65kDa regulatory subunit Aα isoform of serine / threonine protein phosphatase 2A (Ppp2r1a, encoded by the PPP2R1A gene) is a regulatory subunit of protein phosphatase 2 (Pp2a), one of the four major Ser / Thr phosphatases. Pp2a is broadly responsible for phosphorylation of several cell division signaling pathways. Pp2a is involved in its role in regulating tumorigenesis by controlling phosphorylation events in cell signaling pathways. Mutations in PPP2R1A (e.g., loss-of-function mutations) result in the loss of Pp2a's ability to regulate phosphorylation events, eliminating the critical biological response to oncogenic mutations. PPP2R1A mutations are common in endometrial, ovarian, and uterine cancers. Therefore, cancers carrying PPP2R1A mutations may be particularly sensitive to drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy.

[0162] In some embodiments, the replication stress biomarker is the PPP2R1A mutation. In some embodiments, the cancer treated by the methods of this disclosure includes the PPP2R1A mutation. In some embodiments, the cancer treated by the methods of this disclosure includes the loss-of-function PPP2R1A mutation.

[0163] PTEN biomarkers Phosphatase and tensin homolog (Pten; encoded by the PTEN gene) is a cell cycle-regulated phosphatase. Unlike many other protein tyrosine phosphatases, Pten preferentially dephosphorylates phosphatidylinositol substrates. Pten plays a role in the regulation of multiple cellular signaling pathways, including the Akt / Pkb signaling pathway. PTEN is commonly mutated in tumor cells (e.g., loss-of-function mutations). PTEN mutations are common in breast cancer, prostate cancer, bladder cancer, lung cancer, endometrial cancer, melanoma, and head and neck cancers. Therefore, cancers carrying PTEN mutations may be particularly sensitive to drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy.

[0164] In some embodiments, the replication stress biomarker is a PTEN mutation. In some embodiments, the cancers treated by the methods of this disclosure include PTEN mutations. In some embodiments, the cancers treated by the methods of this disclosure include loss-of-function PTEN mutations.

[0165] RB1 biomarker Retinoblastoma protein (RB, or alternatively pRB; encoded by the RB1 gene) is a cell cycle protein that inhibits cell cycle progression by binding to transcription factor proteins, such as the E2 promoter-binding protein dimerizing chaperone (E2F-DP) dimer, thereby preventing signal transduction therefrom. Once cells have grown sufficiently and / or received signals to initiate cell division, pRB is phosphorylated by CDK proteins, thereby inactivating pRB and allowing cell division to proceed. Cancers associated with RB1 mutations include brain cancer, bone cancer, muscle cancer, prostate cancer, uterine cancer, breast cancer, lung cancer, and melanoma. Mutations in RB1 (such as loss-of-function mutations) can lead to permanent inactivation of pRB, resulting in uncontrolled cell division. Therefore, cancers carrying RB1 mutations may be particularly sensitive to treatment with drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy.

[0166] In some embodiments, the replication stress biomarker is an RB1 mutation. In some embodiments, the cancers treated by the methods of this disclosure include loss-of-function RB1 mutations.

[0167] BRAF biomarkers The BRAF protein (encoded by the BRAF gene) is a member of the Raf protein family. The Raf protein family also includes Araf (encoded by the ARAF gene) and Craf (encoded by the CRAF gene). They play crucial roles in multiple cell signaling pathways, including the Ras / Mapk pathway. Raf protein is the second step in the Ras / Mapk pathway, therefore wild-type Raf protein needs to interact with Ras protein to transduce cellular signals. Similar to mutated Ras proteins (as described above), mutations in Raf protein often prevent the dephosphorylation of phosphorylated Raf complexes, leading to continuous cellular signaling for cell division, which may contribute to tumor development. Cancers associated with BRAF mutations include melanoma, leukemia, lymphoma, and lung cancer. Cancers carrying BRAF mutations may be particularly sensitive to drugs that induce replication stress, such as Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy.

[0168] In some embodiments, the replication stress biomarker is a BRAF mutation. In some embodiments, the cancer treated by the methods of this disclosure includes a BRAF mutation. In some embodiments, the cancer treated by the methods of this disclosure includes a functionally acquired BRAF mutation.

[0169] HPV biomarkers Human papillomavirus (HPV) is a DNA virus commonly associated with the development of cancer in subjects who have previously had the disease. HPV typically causes DNA damage (e.g., mutations, such as replication stress mutations) in subjects. Even after a subject has been cured of HPV (e.g., by removing viral particles from the subject or alleviating associated symptoms), DNA damage can still lead to tumor growth or cancer development in the subject. HPV infection is known to cause cervical cancer, penile cancer, vaginal cancer, vulvar cancer, colorectal cancer, and laryngeal cancer. In particular, some reports suggest that over 90% of cervical cancers are associated with prior or current HPV infection. Therefore, cancers associated with or resulting from HPV infection may be particularly sensitive to treatment with drugs that induce replication stress (e.g., Myt1 inhibitors, such as any of compounds 1 to 328, optionally administered as a combination therapy).

[0170] In some embodiments, the replication stress biomarker is HPV infection. In some embodiments, the cancer treated by the methods of this disclosure developed in a patient with a prior HPV infection. In some embodiments, the prior HPV infection resulted in DNA damage. In some embodiments, the DNA damage caused replication stress mutations. In some embodiments, the replication stress mutation is a CDKN2A mutation. In some embodiments, the cancer treated by the methods of this disclosure includes a loss-of-function CDKN2A mutation.

[0171] Myt1 inhibitors The compound used in the method of the present invention may be, for example, a compound of formula (I): Or its pharmaceutically acceptable salt. in Each of X, Y, and Z is independently N or CR. 2 ; R 1 and each R 2 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, cyano, -N(R) 7)2、-OR 7 -C(O)N(R) 8 )2、-SO2N(R 8 )2、-SO2R 7 A or -QR 7 B; or R 1 With a neighboring R 1 R 2 Combining to form optional C 3-6 Alkylene; R 3 and R 4 Each of them is independently an optional substitution of C. 1-6 Alkyl or halogen; R 5 Is it H or -N(R) 7 )2; R 6 It is -C(O)NH(R) 8 -C(O)R 7A or -SO2R 7A ; Each R 7 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl or -SO2R 7A Or two Rs 7 The groups, together with the atoms to which they are attached, combine to form optionally substituted C groups. 2-9 Heterocyclic groups; Each R 7A C is independently optional substitution 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; Each R 7B Independently, it is a hydroxyl group, or an optionally substituted C. 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 1-9 heteroaryl, -N(R) 7 )2、-C(O)N(R 8 )2、-SO2N(R 8 )2、-SO2R7A Or optionally substituted alkoxy groups; Each R 8 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two R 8 Together with the atoms to which they are attached, they combine to form optionally substituted C atoms. 2-9 Heterocyclic groups; and Each Q is independently hydrogen, with optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two R 8 Together with the atoms to which they are attached, they combine to form optionally substituted C atoms. 2-9 Heterocyclic groups; and Preferably, the compound of formula (I) is rich in the trans-restricted isomer of formula (IA): All variables are as described in this article.

[0172] The compound used in the method of the present invention may be, for example, a compound of formula (II): All variables are as described in this article.

[0173] Preferably, the compound of formula (II) is rich in the trans-resisted isomer of formula (IIA): All variables are as described in this article.

[0174] The compound used in the method of the present invention may be, for example, a compound of formula (III): Where R 2A It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, -N(R) 7 )2、-OR 7 -C(O)N(R) 8 )2、-SO2N(R 8 )2、-SO2R 7A or -QR 7B .

[0175] Preferably, the compound of formula (III) is rich in the trans-restricted isomer of formula (IIIA): .

[0176] The compounds used in the methods of the present invention may be, for example, the compounds listed in Table 1 below or their pharmaceutically acceptable salts.

[0177] Table 1

[0178] Further examples of Myt1 inhibitors include those described in International Patent Publications: WO 2023 / 174397, WO 2023 / 155871, WO 2023 / 155892, WO 2023 / 155870, WO 2023 / 174397, WO 2023 / 174329 and WO 2023 / 177356; and those described in U.S. Patent Applications: 17 / 937,977 and 17 / 961,103; the inhibitors thereof are incorporated herein by reference.

[0179] The methods disclosed herein include (where possible) individual diastereomers, enantiomers, epiomers, and transisomers of the compounds disclosed herein, as well as mixtures of their diastereomers and / or enantiomers, including racemic mixtures. While the specific stereochemistry disclosed herein is preferred, other stereoisomers, including diastereomers, enantiomers, epiomers, transisomers, and mixtures thereof, may also be used to treat Myt1-mediated diseases. Inactive or less active diastereomers and enantiomers may be used, for example, in scientific research related to receptors and activation mechanisms.

[0180] It should be understood that some molecules can exist in multiple tautomer forms. Although only one tautomer may be indicated in the examples, the present invention includes all tautomers.

[0181] The present invention also includes pharmaceutically acceptable salts of the compounds and pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers. The compounds are particularly useful for, for example, certain types of cancer and for slowing the progression of cancer when it develops in a patient.

[0182] The compounds disclosed herein can be used in pharmaceutical compositions comprising (a) one or more compounds or pharmaceutically acceptable salts thereof and (b) a pharmaceutically acceptable carrier. The compounds can be used in pharmaceutical compositions comprising one or more other active pharmaceutical ingredients. The compounds can also be used in pharmaceutical compositions in which the compounds disclosed herein or pharmaceutically acceptable salts thereof are the sole active ingredient.

[0183] In a preferred example, the Myt1 inhibitor is lunresertib (compound 182).

[0184] Optical isomers - diastereomers - geometric isomers - tautomers The compounds disclosed herein may contain, for example, one or more stereoisomeric source centers and may exist as racemates, racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers and / or enantiomers. This invention includes all such isomeric forms of the compounds disclosed herein. It is intended that all possible stereoisomers (e.g., enantiomers and / or diastereomers) of the compounds in mixture form and as pure or partially purified compounds be included within the scope of this invention (i.e., all possible combinations of stereoisomeric source centers as pure compounds or in mixture form).

[0185] Some of the compounds described herein may contain rotationally hindered bonds, allowing two separate rotational isomers or trans-isomers to be isolated and found to have potentially advantageous different biological activities. It is intended that all possible trans-isomers be included within the scope of this invention.

[0186] Some of the compounds described herein may contain olefinic double bonds, and unless otherwise specified, both E and Z geometric isomers are intended to be included.

[0187] Some of the compounds described herein may have different hydrogen attachment sites, a phenomenon known as tautomerism. Examples include ketones and their enol forms, termed keto-enol tautomers. Individual tautomers and mixtures thereof are covered by this invention.

[0188] The compounds disclosed herein that have one or more asymmetric centers can be isolated into diastereomers, enantiomers, etc., by methods well known in the art.

[0189] Alternatively, enantiomers and other compounds with chiral centers can be synthesized by stereotactic synthesis using optically pure starting materials and / or reagents with known configurations.

[0190] Metabolites – Prodrugs This invention includes therapeutically active metabolites, wherein the metabolites themselves fall within the scope of the claims. This invention also includes prodrugs, which are compounds converted into the claimed compound upon or after administration to a patient. In some cases, the claimed chemical structure of this application may itself be a prodrug.

[0191] Isotope-enriched derivatives This invention includes molecules enriched with isotopes at one or more sites within the molecule. Therefore, compounds enriched with deuterium fall within the scope of the claims.

[0192] Methods for preparing Myt1 inhibitors Methods for preparing Myt1 inhibitors are known in the art (see, for example, International Patent Publication No. WO 2022 / 213204, the entire of which is incorporated herein by reference).

[0193] Wee1 inhibitors Wee1 inhibitors can be compounds that, upon exposure to Wee1, whether in vitro, in cell cultures, or in animals, reduce the activity of Wee1, resulting in a measured Wee1 IC50 value. 50 The concentration is 10 µM or lower (e.g., 5 µM or lower or 1 µM or lower). For some Wee1 inhibitors, the Wee1 IC50 is... 50 It can be 100 nM or lower (e.g., 10 nM or lower, or 1 nM or lower), and can be as low as 100 pM or 10 pM. Preferably, Wee1 IC 50 The concentration is from 0.1 nM to 1000 nM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). In some embodiments, the Wee1 inhibitor is a Wee1 degrading agent (e.g., a protein hydrolysis-targeting chimera (PROTAC) or a molecular gel). The Wee1 inhibitor used in this invention can be, for example, a compound listed in Tables 2a-2g below or a pharmaceutically acceptable salt thereof.

[0194] Table 2a

[0195] Table 2b

[0196] Table 2c

[0197] Table 2d

[0198] Table 2e

[0199] Table 2f

[0200] Table 2g

[0201] Further examples of Wee1 inhibitors include: 6-(2-Chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2217); 2-Phenylino-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2218); 6-(2-Chlorophenyl)-2-(pyridin-4-ylamino)imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2219); 6-(2-Chlorophenyl)-2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2220); 6-(2-Chlorophenyl)-2-(5,6,7,8-tetrahydronaphth-2-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2221); 6-(2-Chlorophenyl)-2-{[3-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2222); 6-(2-Chlorophenyl)-2-[(4-cyclohexylphenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2223); 6-(2-Chlorophenyl)-2-{[4-(piperidin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2224); 6-(2-Chlorophenyl)-2-{[4-(pyrrolidone-1-ylmethyl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2225); 6-(2-Chlorophenyl)-2-{[4-(morpholin-4-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2226); 6-(2-Chlorophenyl)-2-{[3-(pyrrolidone-1-ylmethyl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2227); 2-[(1-acetyl-2,3-dihydro-1H-indol-6-yl)amino]-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2228); 2-{[4-(4-acetylpiperazin-1-yl)phenyl]amino}-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2229); 6-(2-Methylphenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2230); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-[2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2231); 6-(2-methoxyphenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2232); 6-(2-Chlorophenyl)-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2233); 6-(2-Chlorophenyl)-2-[(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2234); 6-(2-Chlorophenyl)-2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2235); tert-butyl 7-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-3,4-dihydroisoquinoline-2(1H)-carboxylate (W2236); 6-(2-Chlorophenyl)-2-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2237); 6-(2-Chlorophenyl)-2-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2238); 6-Allyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2239); 6-Cyclohexyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2240); 6-(2-Chlorophenyl)-9-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2241); 6-(2-Chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidino[5,4-e][1,2,4]triazolo[4,3-a]pyrimidin-5(6H)-one (W2242); 4-(2-Chlorophenyl)-1-methyl-8-methylthio-4H-2,3,4,7,9,9b-hexaaza-cyclopenta[a]naphthyl-5-one (W2243); 4-(2-Chlorophenyl)-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidino[5,4-e]tetrazolo[1,5-a]pyrimidin-5(4H)-one (W2244); 6-(2-Chlorophenyl)-2-({4-[4-(propyl-2-yl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2245); 6-(2-Chlorophenyl)-2-({4-[4-(cyclohexylmethyl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2246); 3-{[4-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]methyl}benzonitrile (W2247); 2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2248); 6-(2-Chlorophenyl)-2-({3-fluoro-4-[4-(propyl-2-yl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2249); 6-(2-Chlorophenyl)-2-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2250); 6-(2-Chlorophenyl)-2-({4-[2-(dimethylamino)ethoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2251); 6-(2-Chlorophenyl)-2-({4-[2-(morpholin-4-yl)ethoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2252); 6-(2-Chlorophenyl)-2-{[3-methyl-4-(4-methyl-1,4-diazacycloheptane-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2253); 6-(2-Chlorophenyl)-2-{[4-(1-methylpiperidin-4-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2254); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-phenylimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2255); 6-(2-chloro-4-methylphenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2256); 4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-N-cyclohexylbenzamide (W2257); 6-(2-Chlorophenyl)-2-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2258); 6-(2-Chlorophenyl)-2-{[4-(1H-pyrazol-4-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2259); 6-(2-Chlorophenyl)-2-({4-[2-(diethylamino)ethoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2260); 6-(2-Chlorophenyl)-2-{[4-(pyridin-3-yl)phenyl]amino}imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2261); 4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-N-(trans-4-hydroxycyclohexyl)benzamide (W2262); 4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-N-ethylbenzamide (W2263); 6-(2-Chlorophenyl)-2-({4-[(4-hydroxypiperidin-1-yl)carbonyl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2264); 4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-N-(pyridin-4-yl)benzamide (W2265); 6-(2-Chlorophenyl)-2-({4-[3-(diethylamino)propoxy]-3-fluorophenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2266); 6-(2-Chlorophenyl)-2-({3-fluoro-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2267); 6-(2-Chlorophenyl)-2-{[2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2268); 6-(2-Chlorophenyl)-2-[(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2269); 6-(3-hydroxy-2-methylphenyl)-2-(phenylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2270); 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2271); 2-[(4-aminophenyl)amino]-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2272); N-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)acetamide (W2273); N-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)cyclopentaneformamide (W2274); N-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)-4-hydroxycyclohexaneformamide (W2275); N-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)-1-methylpiperidin-4-carboxamide (W2276); N-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)pyridine-4-carboxamide (W2277); 6-(2,6-dimethylphenyl)-2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2278); 2-({4-[4-(3-chlorobenzyl)piperazin-1-yl]phenyl}amino)-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2279); 6-(2-Chlorophenyl)-2-({4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2280); 6-(2-Chlorophenyl)-2-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2281); 6-(2-Chlorophenyl)-2-({3-methoxy-4-[4-(propyl-2-yl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2282); 6-(2-Chlorophenyl)-2-({3-methoxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2283); 6-(3-hydroxyphenyl)-2-(phenylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2284); 6-(2-Chlorophenyl)-2-[(4-methylphenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2285); 6-(2-Chlorophenyl)-2-{[4-(piperidin-2-yl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2286); 6-(2-Chlorophenyl)-2-{[4-(pyrrolidone-2-yl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2287); 6-(2-Chlorophenyl)-2-{[4-(pyrrolidone-3-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2288); 6-(2,6-dichlorophenyl)-2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2289); 6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(4-methyl-1,4-diazacycloheptane-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2290); 6-(2-Chlorophenyl)-2-{[4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2291); 6-(2-Chlorophenyl)-2-({4-[(2S)-pyrrolidine-2-ylmethoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2292); 6-(2-Chlorophenyl)-2-({2-methyl-4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2293); 6-(2-Chlorophenyl)-2-{[4-(morpholin-4-ylmethyl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2294); 6-(2-Chlorophenyl)-2-{[4-(1H-imidazol-1-ylmethyl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2295); 6-(2-Chlorophenyl)-2-{[4-(1H-imidazol-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2296); 6-(2-Chlorophenyl)-2-{[6-(piperazin-1-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2297); 6-(2-Chlorophenyl)-2-({3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2298); 6-(2-Chlorophenyl)-2-({3-[3-(piperidin-1-yl)propoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2299); 6-(2,6-dichlorophenyl)-2-(phenylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2300); 6-(2-Chlorophenyl)-2-({3-methoxy-4-[2-(propyl-2-ylamino)ethoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2301); 6-(2-Chlorophenyl)-2-({3-chloro-4-[2-(propyl-2-amino)ethoxy]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2302); 6-(2-Chlorophenyl)-2-{[4-(hydroxymethyl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2303); 6-(2-Chlorophenyl)-2-{[4-(1H-pyrazol-1-ylmethyl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2304); 6-(2-chlorophenyl)-2-{[4-(1H-pyrazol-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2305); 6-(2-Chlorophenyl)-2-(2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2306); 2-[(2'-acetyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2307); 6-(2-Chlorophenyl)-2-[(1-Methyl-1,2,3,4-tetrahydroquinolin-6-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2308); 6-(2-Chlorophenyl)-2-({1-[2-(dimethylamino)ethyl]-2,3-dihydro-1H-indol-5-yl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2309); 6-(2-Chlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2310); 6-(2-chloro-6-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2311); 6-(2-chloro-6-fluorophenyl)-2-{[3-methyl-4-(4-methyl-1,4-diazacycloheptane-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2312); 6-(2-chloro-6-fluorophenyl)-2-[(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2313); 6-(2,6-difluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2314); 6-(2-Chlorophenyl)-2-{[2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2315); 6-(2-Chlorophenyl)-2-{[3-(hydroxymethyl)-4-(4-methyl-1,4-diazacycloheptane-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2316); 6-(2-Chlorophenyl)-2-{[4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2317); 6-(2-Chlorophenyl)-2-[(4-hydroxy-3-methylphenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2318); 6-(2-Chlorophenyl)-2-({4-[3-(diethylamino)propoxy]-3-methylphenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2319); 6-(2-Chlorophenyl)-2-{[3-methyl-4-(piperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2320); 6-(2-chlorophenyl)-2-{[4-(1,4-diazacycloheptane-1-yl)-3-methylphenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2321); 6-(2-Chlorophenyl)-2-(2,3,4,5-tetrahydro-1H-2-benzozaheptan-7-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2322); 6-(2-Chlorophenyl)-2-[(3-methyl-2,3,4,5-tetrahydro-1H-3-benzozaheptan-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2323); 6-(2-Chlorophenyl)-2-[(1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2324); 6-(2,6-dichlorophenyl)-2-(2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2325); 6-(2,6-dichlorophenyl)-2-{[3-methyl-4-(piperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2326); 6-(2,6-dichlorophenyl)-2-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2327); 6-(2-Chlorophenyl)-2-{[3-ethyl-4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2328); 6-(2-Chlorophenyl)-2-{[2-(cyclohexylmethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2329); 6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2330); 6-(2,6-dichlorophenyl)-2-({4-[4-(propyl-2-yl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2331); 6-(2,6-dichlorophenyl)-2-{[4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2332); 6-(2-Chlorophenyl)-2-{[2-(2-ethylbutyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2333); 6-(2,6-dichlorophenyl)-2-({4-[2-(4-methylpiperazin-1-yl)ethyl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2334); 6-(2,6-dichlorophenyl)-2-({1-[2-(dimethylamino)ethyl]-2,3-dihydro-1H-indol-5-yl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2335); 6-(2,6-dichlorophenyl)-2-{[3-ethyl-4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2336); 6-(2,6-dichlorophenyl)-2-{[3-(hydroxymethyl)-4-(4-methyl-1,4-diazacycloheptane-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2337); 6-(2,6-dichlorophenyl)-2-(1,2,3,4-tetrahydroisoquinoline-6-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2338); 6-(2,6-dichloro-4-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2339); 6-(2,6-dichloro-4-fluorophenyl)-2-{[3-methyl-4-(4-methyl-1,4-diazacycloheptane-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2340); 6-(2,6-dichloro-4-fluorophenyl)-2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2341); 6-(2,6-dichloro-4-fluorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2342); 6-(2,6-dichlorophenyl)-2-({4-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2343); 6-(2,6-dichlorophenyl)-2-({4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-fluorophenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2344); 6-(2,6-dichlorophenyl)-2-{[3,5-difluoro-4-(piperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2345); 6-(2-chlorophenyl)-2-{[2-(cyclopropylmethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2346); 6-(2-Chlorophenyl)-2-{[4,4-dimethyl-2-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2347); 6-(2-Chlorophenyl)-2-{[4,4-dimethyl-2-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2348); 6-(2-Chlorophenyl)-2-[(1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2349); 6-(2,6-dichlorophenyl)-2-{[4-(pyrrolidone-2-yl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2350); 6-(2,6-dichlorophenyl)-2-{[4-(piperidin-2-yl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2351); 2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2352); 6-(2,6-dichlorophenyl)-2-({3-methoxy-4-[4-(propyl-2-yl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2353); 6-(2-Chlorophenyl)-2-{[4-(4-hydroxypiperidin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2354); 6-(2-chloro-6-fluorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2355); 6-(2-chloro-6-fluorophenyl)-2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2356); 6-(2-chloro-6-fluorophenyl)-2-{[4-(1,4-diazacycloheptane-1-yl)-3-methylphenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2357); 2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]-6-(prop-2-yl)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2358); 6-(2,6-dichlorophenyl)-2-{[4-(3-oxopiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2359); 6-(2-Chlorophenyl)-2-{[4,4-dimethyl-2-(propyl-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2360); 6-(2-Chlorophenyl)-2-{[4,4-dimethyl-2-(4,4,4-trifluorobutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2361); 6-(2-Chlorophenyl)-2-[(1,1,2-trimethyl-2,3-dihydro-1H-isoindol-5-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2362); 6-(2-Chlorophenyl)-2-[(1,1,2,3,3-pentamethyl-2,3-dihydro-1H-isoindol-5-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2363); 6-(2,6-dichlorophenyl)-2-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2364); 6-(2,6-dichlorophenyl)-2-({4-[3-(diethylamino)propoxy]-3-fluorophenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2365); 6-(2,6-dichlorophenyl)-2-[(1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2366); 2-({4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl}amino)-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2367); 6-(2,6-dichlorophenyl)-2-[(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2368); 6-(2,6-dichlorophenyl)-2-{[4-(4,4-difluoropiperidin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2369); 6-(2,6-dichlorophenyl)-2-{[4-(3,3-difluoropiperidin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2370); 6-(2,6-dichlorophenyl)-2-({3-fluoro-4-[4-(propyl-2-yl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2371); 6-(2,6-dichlorophenyl)-2-{[4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2372); 6-(2-Chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)-3-(prop-2-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2373); 2-{[4-(4-acetylpiperazin-1-yl)phenyl]amino}-6-(2-chloro-6-fluorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2374); 6-(2-chloro-6-fluorophenyl)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2375); 6-(2,6-dichloro-4-fluorophenyl)-2-(2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2376); 6-(2-Chlorophenyl)-2-[(2-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2377); 6-(2-Chlorophenyl)-2-{[4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2378); 6-(2-chlorophenyl)-2-({2-[4-(1H-imidazol-1-yl)benzyl]-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2379); 2-({2-[(1-benzylpiperidin-4-yl)methyl]-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl}amino)-6-(2-chlorophenyl)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2380); 2-[(2'-acetyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]-6-(2,6-dichloro-4-fluorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2381); 6-(2,6-dichlorophenyl)-2-{[4-(4-hydroxypiperidin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2382); 2-[(4-cyclohexylphenyl)amino]-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2383); 6-(2,6-dichlorophenyl)-2-{[4-(pyrrolidone-3-yl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2384); 6-(2,6-dichlorophenyl)-2-{[4-(morpholin-4-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2385); 6-(2,6-dichlorophenyl)-2-{[4,4-dimethyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2386); 2-{[2'-(cyclopropylcarbonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}-6-(2,6-dichloro-4-fluorophenyl)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2387); 6-(2,6-dichloro-4-fluorophenyl)-2-{[2'-(methanesulfonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2388); 6-(2,6-dichloro-4-fluorophenyl)-2-{[6-(piperazin-1-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2389); 6-(2,6-dichlorophenyl)-2-{[4-(2-oxopiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2390); 2-({4-[(1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl}amino)-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2391); 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)-3-(prop-2-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2392); 6-(2,6-dichlorophenyl)-2-[(1,1,2,3,3-pentamethyl-2,3-dihydro-1H-isoindol-5-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2393); 6-(2,6-dichlorophenyl)-2-[(1,1,2-trimethyl-2,3-dihydro-1H-isoindol-5-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2394); (3aS,10aS)-8-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-2,3,3a,5,10,10a-hexahydropyrrolo[3,4-c][1]benzozaheptan-4(1H)-one (W2395); 6-(2,6-dichlorophenyl)-2-{[4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2396); 2-(1,2,3-benzothiadiazole-5-ylamino)-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2397); 2-(1,3-benzothiazo-6-ylamino)-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2398); 2-({4-[bis(2-methoxyethyl)amino]phenyl}amino)-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2399); 6-(2-Chlorophenyl)-2-[(3-cyclopropyl-2,3,4,5-tetrahydro-1H-3-benzozazepine-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2400); 6-(2-Chlorophenyl)-2-{[3-(2,2-difluoroethyl)-2,3,4,5-tetrahydro-1H-3-benzozaheptan-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2401); 6-(2-chloro-4,6-difluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2402); 6-(2-chloro-4,6-difluorophenyl)-2-[(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2403); 6-(2-chloro-4,6-difluorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2404); 6-(2-Chlorophenyl)-2-[(4-{[3-(morpholin-4-yl)propyl]amino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2405); 6-(2-Chlorophenyl)-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2406); 6-(2-Chlorophenyl)-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2407); 6-(2-Chlorophenyl)-2-[(4-{[2-(1-methylpyrrolidone-2-yl)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2408); 4-(dimethylamino)cyclohexyl4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}benzoate (W2409); 6-(2,6-dichlorophenyl)-2-(1H-indazol-5-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2410); 6-(2,6-dichlorophenyl)-2-({4-[(3S)-3-(propyl-2-yl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2411); 6-(2,6-dichlorophenyl)-2-[(4-{1-[1-(dimethylamino)-3-methylbutyl]cyclobutyl}phenyl)amino]imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2412); 6-(2,6-dichlorophenyl)-2-({4-[4-methyl-2-(methylamino)-1,3-thiazolyl-5-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2413); 6-(2,6-dichlorophenyl)-2-{[6-(piperazin-1-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2414); 6-(2,6-dichlorophenyl)-2-(1H-indazol-6-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2415); (1R)-octahydro-2H-quinazin-1-yl4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}benzoate (W2416); 2-[cyclopropyl(methyl)amino]ethyl 4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}benzoate (W2417); 6-(2,6-Dichlorophenyl)-2-[(4-{[(1R,5S)-7-ethyl-3,7-diazabicyclo[3.3.1]non-3-yl]carbonyl}phenyl)amino]imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2418); 6-(2-Chlorophenyl)-2-{[3,5-difluoro-4-(piperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2419); 6-(2-Chlorophenyl)-2-({4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2420); 2-(2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-ylamino)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2421); 6-(2,6-dichlorophenyl)-2-{[2'-(methylsulfonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2422); 2-[(2'-acetyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2423); 6-(2-Chlorophenyl)-2-{[4-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2424); 6-(2-chloro-6-fluorophenyl)-2-[(1,1,2-trimethyl-2,3-dihydro-1H-isoindol-5-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2425); 6-(2-chloro-6-fluorophenyl)-2-[(1,1,2,3,3-pentamethyl-2,3-dihydro-1H-isoindol-5-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2426); 6-(2-Chlorophenyl)-2-({4-[4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2427); 6-(2,6-dichloro-4-fluorophenyl)-2-[(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2428); 6-(2,6-dichlorophenyl)-2-[(4-oxo-1,4-dihydro-6-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2429); 2-{[4-(4-acetylpiperazin-1-yl)phenyl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2430); 6-(2,6-dichlorophenyl)-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2431); 4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}methyl benzoate (W2432); 6-(2-Chlorophenyl)-2-{[3,5-dichloro-4-(piperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2433); 6-(2-Chlorophenyl)-2-{[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2434); 6-(2-Chlorophenyl)-2-({4-[4-oxo-3-(prop-2-yl)-1,3-thiazolidin-2-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2435); 6-(2-Chlorophenyl)-2-{[4-(2,3-dihydroimidazo[2,1-b][1,3]thiazo-6-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2436); 6-(2-Chlorophenyl)-2-{[4-(5-methyl-4-oxo-1,3-thiazolidin-2-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2437); 6-(2-chlorophenyl)-2-{[4-(imidazo[2,1-b][1,3]thiazo-6-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2438); 6-(2-Chlorophenyl)-2-{[4-(3-oxo-2,3-dihydro-1H-indazol-7-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2439); 6-(2-chloro-6-fluorophenyl)-2-{[2'-(2,2-difluoroethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2440); 6-(2-chloro-6-fluorophenyl)-2-{[2'-(2-fluoroethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2441); 6-(2-chloro-6-fluorophenyl)-2-{[2-(diethylamino)-2,3-dihydro-1H-inden-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2442); 6-(2-chloro-6-fluorophenyl)-2-{[2-(cyclopropylamino)-2,3-dihydro-1H-indene-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2443); 6-(2-chloro-6-fluorophenyl)-2-(2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2444); 2-{[4-(1,4'-bipiperidin-1'-yl)phenyl]amino}-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2445); 6-(2-Chlorophenyl)-2-({4-[(3R)-3-(dimethylamino)pyrrolidone-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2446); 6-(2-Chlorophenyl)-2-({4-[3-(trifluoromethyl)piperidin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2447); 3-[4-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]propionitrile (W2448); 3-[(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)(cyclopropyl)amino]propionitrile (W2449); 6-(2-Chlorophenyl)-2-[(4-{[2-(dimethylamino)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2450); 1-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)piperidine-4-carboxamide (W2451); 6-(2-Chlorophenyl)-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2452); 6-(2,6-dichlorophenyl)-2-[(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2453); 4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-N-[4-(dimethylamino)cyclohexyl]benzamide (W2454); 4-{[6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-N-(1-methylpiperidin-4-yl)benzamide (W2455); 6-(2,6-dichlorophenyl)-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2456); 2-[(2'-acetyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]-6-(2-chloro-6-fluorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2457); 6-(2-chloro-6-fluorophenyl)-2-{[2'-(cyclopropylcarbonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2458); 6-(2-chloro-6-fluorophenyl)-2-{[2'-(methanesulfonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2459); 6-(2-Chloro-6-fluorophenyl)-2-({4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2460); 2-({4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]phenyl}amino)-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2461); 6-(2-Chlorophenyl)-2-[(4-{[2-(pyrrolidone-1-yl)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2462); 6-(2-Chlorophenyl)-2-({4-[4-(pyridin-2-yl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2463); 6-(2-Chlorophenyl)-2-[(4-{[2-(morpholin-4-yl)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2464); 6-(2-Chlorophenyl)-2-({4-[(2S)-2-(pyrrolidone-1-ylmethyl)pyrrolidone-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2465); 6-(2-Chlorophenyl)-2-[(4-{4-[3-(dimethylamino)propyl]piperazin-1-yl}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2466); 6-(2-Chlorophenyl)-2-({4-[(2R)-2-(methoxymethyl)pyrrolidone-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2467); 1-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)-N,N-diethylpiperidine-3-carboxamide (W2468); 6-(2-Chlorophenyl)-2-[(4-{[3-(2-oxopyrrolidone-1-yl)propyl]amino}phenyl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2469); 6-(2-Chlorophenyl)-2-({4-[4-(4-fluorophenyl)piperazin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2470); 6-(2-chloro-6-fluorophenyl)-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2471); 6-(2-chloro-6-fluorophenyl)-2-({2-[(3S)-3-fluoropyrrolidone-1-yl]-2,3-dihydro-1H-inden-5-yl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2472); 6-(2-chloro-6-fluorophenyl)-2-({2-[(2-fluoroethyl)amino]-2,3-dihydro-1H-inden-5-yl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2473); 6-(2-chloro-6-fluorophenyl)-2-{[2-(propylamino)-2,3-dihydro-1H-indene-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2474); 6-(2-chloro-6-fluorophenyl)-2-{[2-(pyrrolidin-1-yl)-2,3-dihydro-1H-inden-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2475); 6-(2-Chlorophenyl)-2-[(4-{4-[2-(dimethylamino)ethyl]piperazin-1-yl}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2476); 6-(2-Chlorophenyl)-2-[(4-{3-(dimethylamino)propylamino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2477); 6-(2-Chlorophenyl)-2-[(4-{2-(dimethylamino)ethylamino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2478); 6-(2-Chlorophenyl)-2-[(4-{2-(dimethylamino)ethylamino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2479); 6-(2-Chlorophenyl)-2-({4-[(2S)-2-(methoxymethyl)pyrrolidone-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2480); 6-(2-chloro-6-fluorophenyl)-2-{[2'-(2-methylpropionyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2481); 6-(2-chloro-6-fluorophenyl)-2-{[2'-(2,2-dimethylpropionyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2482); 6-(2-chloro-6-fluorophenyl)-2-{[2'-(cyclopentylcarbonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2483); 6-(2-Chlorophenyl)-2-[(4-{[2-(1H-imidazol-4-yl)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2484); 6-(2-Chlorophenyl)-2-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}phenyl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2485); 6-(2-Chlorophenyl)-2-{[4-(Thiomorpholin-4-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2486); 6-(2-Chlorophenyl)-2-[(4-{propyl-2-yl[2-(propyl-2-ylamino)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2487); 1-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)piperidine-3-carboxamide (W2488); 6-(2,6-dichlorophenyl)-2-[(4-{[2-(1-methylpyrrolidone-2-yl)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2489); 6-(2,6-dichlorophenyl)-2-{[2'-(2-methylpropionyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2490); 6-(2-Chlorophenyl)-2-{[4-(Thiomorpholin-4-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2491); 6-(2-Chlorophenyl)-2-[(4-{propyl-2-yl[2-(propyl-2-ylamino)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2492); 1-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)piperidine-3-carboxamide (W2493); 6-(2,6-dichlorophenyl)-2-[(4-{[2-(1-methylpyrrolidone-2-yl)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2494); 6-(2,6-dichlorophenyl)-2-{[2'-(2-methylpropionyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2495); 2-{[2'-(cyclopropylcarbonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2496); 6-(2,6-dichlorophenyl)-2-{[2'-(2,2-dimethylpropionyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2497); 6-(2-Chloro-6-fluorophenyl)-2-(5,6,7,8-tetrahydro-1,6-naphthidin-3-ylamino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2498); 6-(2-chloro-3-hydroxyphenyl)-2-(2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-ylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2499); 2-(2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-ylamino)-6-(4-hydroxy-2-methylphenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2500); 6-(2-chloro-6-fluorophenyl)-2-{[2-(2,2-difluoroethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2501); 6-(2-chloro-6-fluorophenyl)-2-{[2-(2-fluoroethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2502); 2-{[4-(1,4'-bipiperidin-1'-yl)phenyl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2503); 6-(2,6-dichlorophenyl)-2-({4-[(3R)-3-(dimethylamino)pyrrolidone-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2504); 6-(2,6-dichlorophenyl)-2-[(4-{[2-(dimethylamino)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2505); 2-{[2'-(cyclopropylsulfonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2506); 6-(2,6-dichlorophenyl)-2-{[2'-(prop-2-ylsulfonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2507); 6-(2,6-dichlorophenyl)-2-{[4-(1-methylpiperidin-4-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2508); 2-{[4-(2,7-diazaspiro[3.5]non-7-yl)phenyl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2509); 6-(2-Chlorophenyl)-2-({4-[2-(trifluoromethyl)pyrrolidin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2510); 6-(2-Chlorophenyl)-2-{[4-(piperidin-4-yloxy)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2511); 6-(2-Chlorophenyl)-2-{[4-(piperidin-4-ylmethyl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2512); 6-(2-Chlorophenyl)-2-{[4-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2513); 1-(4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}phenyl)-N-methylmethanesulfonamide (W2514); 4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-N,N-diethylbenzenesulfonamide (W2515); 2-{[2-(cyclopropylamino)-2,3-dihydro-1H-inden-5-yl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2516); 6-(2,6-dichlorophenyl)-2-({2-[(2-fluoroethyl)amino]-2,3-dihydro-1H-inden-5-yl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2517); 6-(2,6-dichlorophenyl)-2-{[2-(propylamino)-2,3-dihydro-1H-indene-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2518); 2-{[4-(2-acetyl-2,7-diazaspiro[3.5]non-7-yl)phenyl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2519); 6-(2,6-dichlorophenyl)-2-({4-[2-(methanesulfonyl)-2,7-diazaspiro[3.5]non-7-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2520); 7'-{[6-(2-chloro-6-fluorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-N-methyl-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-formamide (W2521); 7'-{[6-(2-chloro-6-fluorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-N-(propyl-2-yl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-formamide (W2522); 6-(2,6-dichlorophenyl)-2-{[2-(2-fluoroethyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2523); 6-(2,6-dichlorophenyl)-2-({4-[6-(methylsulfonyl)-2,6-diazaspiro[3.3]hept-2-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2524); 2-{[4-(2,6-diazaspiro[3.3]hept-2-yl)phenyl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2525); 6-(2,6-dichlorophenyl)-2-{[2-(pyrrolidin-1-yl)-2,3-dihydro-1H-inden-5-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2526); 6-(2,6-dichlorophenyl)-2-({2-[(3S)-3-fluoropyrrolidone-1-yl]-2,3-dihydro-1H-inden-5-yl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2527); 6-(2,6-dichlorophenyl)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2528); 6-(2,6-dichlorophenyl)-2-{[4-(piperidin-4-ylamino)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2529); 6-(2-chloro-6-fluorophenyl)-2-{[4-(1-methylpiperidin-4-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2530); 2-[(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-6-(2-chloro-6-fluorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2531); 6-(2-chloro-6-fluorophenyl)-2-{[2-(cyclopropylcarbonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2532); 6-(2-chloro-6-fluorophenyl)-2-{[4,4-dimethyl-2-(methanesulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2533); 2-{[4-(2,6-diazaspiro[3,4]oct-2-yl)phenyl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2534); 2-{[4-(2,7-diazaspiro[3,5]non-2-yl)phenyl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidico[5,4-e]pyrimidin-5(6H)-one (W2535); 6-(2,6-dichlorophenyl)-2-({4-[(3S)-3-(dimethylamino)pyrrolidone-1-yl]phenyl}amino)imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2536); 6-(2-chloro-6-fluorophenyl)-2-{[2-(hydroxyacetyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2537); 7-{[6-(2-chloro-6-fluorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-sulfonamide (W2538); 2-[(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2539); 6-(2,6-dichlorophenyl)-2-{[4,4-dimethyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2540); 6-(2,6-dichlorophenyl)-2-{[2-(ethylsulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2541); 2-({4-[(1-acetylpiperidin-4-yl)amino]phenyl}amino)-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidozo[5,4-e]pyrimidin-5(6H)-one (W2542); 6-(2,6-dichlorophenyl)-2-[(4-{[1-(methanesulfonyl)piperidin-4-yl]amino}phenyl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2543); 6-(2,6-dichlorophenyl)-2-{[4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2544); 6-(2,6-dichlorophenyl)-2-({4-[6-(methanesulfonyl)-2,6-diazaspiro[3,4]oct-2-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2545); 6-(2-Chlorophenyl)-2-({4-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2546); 6-(2,6-Dichlorophenyl)-2-({4-[(3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrolo-1(2H)-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2547); 6-(2,6-dichlorophenyl)-2-[(4-{2-(dimethylamino)ethylamino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2548); 6-(2,6-dichlorophenyl)-2-[(4-{propyl-2-yl[2-(propyl-2-ylamino)ethyl]amino}phenyl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2549); 2-[(2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino]-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2550); 6-(2,6-dichlorophenyl)-2-{[2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2551); 2-[(2-acetyl-1,2,3,4-tetrahydroisoquinoline-6-yl)amino]-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2552); 6-(2-Chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-thione (W2553); 6-(2-Chlorophenyl)-5-imino-N-[4-(4-methylpiperazin-1-yl)phenyl]-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-amine (W2554); 6-(2-Chlorophenyl)-2-[(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-thione (W2555); 6-(2-Chlorophenyl)-5-imino-N-(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-amine (W2556); 6-(3-Fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2557); 6-(3-Chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2558); 6-(2-Chlorophenyl)-2-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2559); 6-[2-chloro-4-(trifluoromethyl)phenyl]-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2560); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-[2-(trifluoromethoxy)phenyl]imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2561); 4-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}benzoic acid (W2562); 2-[(4-bromophenyl)amino]-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2563); 6-(3-Methoxy-2-methylphenyl)-2-(phenylamino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2564); 2-{[4-(1,4-diazacycloheptane-1-yl)-3-methylphenyl]amino}-6-(2,6-dichlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2565); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(prop-2-yl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2566); 6-(2-Chlorophenyl)-2-{[3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2567); 6-(2-Chlorophenyl)-2-{[4-(trifluoromethyl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2568); 6-(2-Chlorophenyl)-2-{[4-(1,3-thiazolyl-4-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2569); 6-(2-chlorophenyl)-2-{[4-(1,3-thiazolyl-2-yl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2570); 6-(2-chlorophenyl)-2-{[4-(1,8-naphthid-2-yl)phenyl]amino}imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2571); 6-(2-Chlorophenyl)-2-({4-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2572); 2-{[3-chloro-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]amino}-6-(2-chlorophenyl)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2573); 6-(2-Chlorophenyl)-2-{[3-chloro-4-(piperazin-1-yl)-5-(trifluoromethyl)phenyl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2574); 6-(2-Chlorophenyl)-2-[(2'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-thione (W2575); 2-{[7-{[6-(2-chlorophenyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-2-yl]amino}-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-yl]methyl}benzonitrile (W2576); 6-(2-Chlorophenyl)-2-{[4,4-dimethyl-2-(4-propoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]amino}imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2577); 6-(2-Chlorophenyl)-2-({2-[3-fluoro-5-(trifluoromethyl)benzyl]-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2578); 6-(2-Chlorophenyl)-2-[(4-{2-[(2R)-2-methylpyrrolidone-1-yl]ethyl}phenyl)amino]imidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2579); 6-(2-Chlorophenyl)-2-({4-[2-(morpholin-4-yl)-1,3-thiazolyl-4-yl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2580); 6-(2-Chlorophenyl)-2-({4-[2-(6-methylquinolin-2-yl)ethyl]phenyl}amino)imidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2581); 6-Allyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2582); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-[(1E)-prop-1-en-1-yl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2583); 6-Allyl-N-{4-[2-(diethylamino)ethoxy]phenyl}-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2584); 6-Allyl-N-cyclohexyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2585); 1-{6-[(6-allyl-5,5-dioxo-6H-pyrimidino[5,4-c][2,1]benzothiazin-2-yl)amino]-2,3-dihydro-1H-indol-1-yl}acetone (W2586); 6-[(6-allyl-5,5-dioxo-6H-pyrimidino[5,4-c][2,1]benzothiazin-2-yl)amino]-2H-1,4-benzoxazin-3(4H)-one (W2587); 6-Allyl-N-[4-(pyridin-4-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2588); 6-Allyl-N-(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2589); 6-Allyl-N-[4-(4-methylpiperidin-1-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2590); 1-(4-{4-[(6-allyl-5,5-dioxo-6H-pyrimidino[5,4-c][2,1]benzothiazin-2-yl)amino]phenyl}piperazin-1-yl)acetone(W2591); 6-Allyl-N-[4-(piperidin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2592); 6-Allyl-N-[2-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2593); 6-Allyl-N-(4-cyclohexylphenyl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2594); 6-Allyl-N-[4-(1H-imidazo[4,5-c]pyridin-2-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2595); 6-Allyl-N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2596); 6-Allyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2597); 6-Allyl-N-(5,6,7,8-tetrahydronaphthyl-2-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2598); 6-Allyl-N-[3-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2599); 6-Allyl-N-[4-(1-methylpiperidin-4-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2600); 6-Allyl-N-[4-(1H-benzimidazol-2-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2601); 6-Allyl-N-[4-(1-methyl-1H-benzimidazol-2-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2602); 6-Allyl-N-(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2603); 6-Allyl-N-[4-(pyrimidin-2-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2604); 6-Allyl-N-phenyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2605); 6-Allyl-N-[4-(piperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2606); 6-Allyl-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2607); 6-Allyl-N-(pyridin-4-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2608); 6-Allyl-N-(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2609); 6-Allyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2610); 6-Allyl-N-(1,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2611); 6-Allyl-N-[3-fluoro-4-(piperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2612); 6-Allyl-N-phenyl-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2613); 6-Allyl-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2614); 6-Allyl-N-[4-(piperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2615); 1-{6-[(6-allyl-5,5-dioxo-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazin-2-yl)amino]-2,3-dihydro-1H-indol-1-yl}acetone (W2616); 6-Allyl-N-[3-fluoro-4-(piperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2617); 6-Allyl-N-[4-(piperidin-4-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2618); 6-Allyl-N-(1,2,3,4-Tetrahydroquinolin-7-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2619); 6-Allyl-N-{4-[2-(diethylamino)ethoxy]phenyl}-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2620); 6-Allyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2621); 6-Allyl-N-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2622); 6-Allyl-N-[3-methyl-4-(piperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2623); {4-[(6-allyl-5,5-dioxo-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-yl)amino]phenyl}(4-methylpiperazin-1-yl)methyl ketone (W2624); 6-Allyl-N-[2-methyl-4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2625); 6-Allyl-N-[4-(pyrrolidine-3-yl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2626); 6-Allyl-N-(1,2,3,4-tetrahydroisoquinoline-6-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2627); 6-Allyl-N-(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2628); 6-Allyl-N-[4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2629); 6-Allyl-N-(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2630); 6-Allyl-N-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2631); 6-Allyl-N-[4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2632); 6-Allyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2633); 6-Allyl-N-[3-methyl-4-(4-methyl-1,4-diazacycloheptane-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2634); 6-Allyl-N-(2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2635); 6-Methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimidino[4,5-e]thieno[3,2-c][1,2]thiazin-2-amine 5,5-dioxide (W2636); 6-Methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2637); 6-Methyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2638); 6-Methyl-N-[4-(pyrrolidone-1-ylmethyl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2639); 6-Allyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-7-carboxylic acid 5,5-dioxide (W2640); 6-Allyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-7-carboxylic acid methyl ester 5,5-dioxide (W2641); 6-Allyl-N-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-7-carboxamide 5,5-dioxide (W2642); 6-Allyl-N-(2-hydroxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-7-carboxamide 5,5-dioxide (W2643); 6-Allyl-8-bromo-N-phenyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2644); 6-Allyl-8-bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2645); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2646); 8-Bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2647); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2648); N-[4-(4-methylpiperazin-1-yl)phenyl]-8-phenyl-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2649); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(pyridin-3-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2650); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1H-pyrazol-4-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2651); 4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxo-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazin-8-yl)benzamide (W2652); N-Cyclopropyl-4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxo-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazin-8-yl)benzamide (W2653); 8-(2-aminopyrimidin-5-yl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2654); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(3-thienyl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2655); 4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxo-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazin-8-yl)phenol (W2656); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(pyridin-4-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2657); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1H-pyrrolo[2,3-b]pyridin-3-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2658); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2659); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2660); 2-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxo-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazin-8-yl)prop-2-ol (W2661); N-Cyclohexyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2662); N-Methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2663); N,N-Dimethyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2664); N-(2-hydroxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2665); N-(2-methoxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2666); N-(trans-4-aminocyclohexyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2667); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-N-(pyridin-3-ylmethyl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2668); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-phenyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2669); 6-(3-Methylphenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2670); 6-(3,5-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2671); 6-[3,5-bis(trifluoromethyl)phenyl]-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2672); 8-(1H-imidazol-1-yl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2673); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1H-pyrrolo-1-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2674); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1H-1,2,4-triazol-1-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2675); 6-(2,6-dichlorobenzyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2676); 9-Bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2677); N-[4-(4-methylpiperazin-1-yl)phenyl]-9-phenyl-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2678); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-9-(pyridin-3-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2679); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-9-(pyridin-4-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2680); N-Methyl-3-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxo-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazin-9-yl)benzamide (W2681); 9-{2-[(dimethylamino)methyl]phenyl}-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2682); N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]-6-(prop-2-en-1-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2683); N-[5-(piperazin-1-yl)pyridin-2-yl]-6-(prop-2-en-1-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2684); 6-Allyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2685); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-[(1E)-prop-1-en-1-yl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2686); 6-Allyl-N-{4-[2-(diethylamino)ethoxy]phenyl}-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2687); 6-Allyl-N-cyclohexyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2688); 1-{6-[(6-allyl-5,5-dioxo-6H-pyrimidino[5,4-c][2,1]benzothiazin-2-yl)amino]-2,3-dihydro-1H-indol-1-yl}acetone (W2689); 6-[(6-allyl-5,5-dioxo-6H-pyrimidino[5,4-c][2,1]benzothiazin-2-yl)amino]-2H-1,4-benzoxazin-3(4H)-one (W2690); 6-Allyl-N-(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2691); 6-Allyl-N-[4-(4-methylpiperidin-1-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2692); 1-(4-{4-[(6-allyl-5,5-dioxo-6H-pyrimidino[5,4-c][2,1]benzothiazin-2-yl)amino]phenyl}piperazin-1-yl)acetone(W2693); 6-Allyl-N-[4-(piperidin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2694); 6-Allyl-N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2695); 6-Allyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2696); 6-Allyl-N-[3-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2697); 6-Allyl-N-[4-(1-methylpiperidin-4-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2698); 6-Allyl-N-(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2699); 6-Allyl-N-phenyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2700); 6-Allyl-N-[4-(piperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2701); 6-Allyl-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2702); 6-Allyl-N-(pyridin-4-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2703); 6-Allyl-N-(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2704); 6-Allyl-N-(1,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2705); 6-Allyl-N-[3-fluoro-4-(piperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2706); 6-Methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2707); 6-Methyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2708); 6-Methyl-N-[4-(pyrrolidone-1-ylmethyl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2709); 6-Allyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-7-carboxylic acid 5,5-dioxide (W2710); 6-Allyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-7-carboxylic acid methyl ester 5,5-dioxide (W2711); 6-Allyl-N-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-7-carboxamide 5,5-dioxide (W2712); 6-Allyl-N-(2-hydroxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-7-carboxamide 5,5-dioxide (W2713); 6-Allyl-8-bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2714); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2715); 8-Bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2716); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2717); N-[4-(4-methylpiperazin-1-yl)phenyl]-8-phenyl-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2718); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(pyridin-3-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2719); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1H-pyrazol-4-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2720); 4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxo-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazin-8-yl)benzamide (W2721); N-Cyclopropyl-4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxo-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazin-8-yl)benzamide (W2722); 8-(2-aminopyrimidin-5-yl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2723); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(3-thienyl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2724); 4-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxo-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazin-8-yl)phenol (W2725); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(pyridin-4-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2726); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1H-pyrrolo[2,3-b]pyridin-3-yl)-6H-pyrimido[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2727); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2728); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2729); 2-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,5-dioxo-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazin-8-yl)prop-2-ol (W2730); N-Cyclohexyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2731); N-Methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2732); N,N-Dimethyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2733); N-(2-hydroxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2734); N-(2-methoxyethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2735); N-(trans-4-aminocyclohexyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2736); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-propyl-N-(pyridin-3-ylmethyl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxamide 5,5-dioxide (W2737); 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-phenyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2738); 6-(3-Methylphenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6H-pyrimidino[5,4-c][2,1]benzothiazine-8-carboxylic acid methyl ester 5,5-dioxide (W2739); 8-(1H-imidazol-1-yl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2740); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1H-pyrrolo-1-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2741); N-[4-(4-methylpiperazin-1-yl)phenyl]-6-propyl-8-(1H-1,2,4-triazol-1-yl)-6H-pyrimidino[5,4-c][2,1]benzothiazine-2-amine 5,5-dioxide (W2742); 6-Allyl-N-(1,2,3,4-tetrahydroisoquinoline-7-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2743); 6-Allyl-N-[4-(piperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2744); 1-{6-[(6-allyl-5,5-dioxo-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazin-2-yl)amino]-2,3-dihydro-1H-indol-1-yl}acetone (W2745); 6-Allyl-N-[3-fluoro-4-(piperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2746); 6-Allyl-N-[4-(piperidin-4-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2747); 6-Allyl-N-(1,2,3,4-Tetrahydroquinolin-7-yl)-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2748); 6-Allyl-N-{4-[2-(diethylamino)ethoxy]phenyl}-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2749); 6-Allyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2750); 6-Allyl-N-[3-methyl-4-(piperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2751); {4-[(6-allyl-5,5-dioxo-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazin-2-yl)amino]phenyl}(4-methylpiperazin-1-yl)methyl ketone (W2752); 6-Allyl-N-[2-methyl-4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2753); 6-Allyl-N-[4-(pyrrolidine-3-yl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2754); 6-Allyl-N-(1,2,3,4-Tetrahydroisoquinoline-6-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2755); 6-Allyl-N-(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2756); 6-Allyl-N-[4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2757); 6-Allyl-N-(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2758); 6-Allyl-N-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2759); 6-Allyl-N-[4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazin-2-amine 5,5-dioxide (W2760); 6-Allyl-N-[4-(morpholin-4-yl)phenyl]-6H-pyrido[2,3-c]pyrimidino[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2761); 6-Allyl-N-[3-methyl-4-(4-methyl-1,4-diazacycloheptane-1-yl)phenyl]-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2762); 6-Allyl-N-(2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)-6H-pyrido[2,3-c]pyrimido[4,5-e][1,2]thiazine-2-amine 5,5-dioxide (W2763); 6-Methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-6H-pyrimidino[4,5-e]thieno[3,2-c][1,2]thiazin-2-amine 5,5-dioxide (W2764); 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2765); 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[2,3-d]pyrimidin-5(8H)-one (W2766); 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-7-phenylpyrido[2,3-d]pyrimidin-5(8H)-one (W2767); 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[2,3-d]pyrimidin-5(8H)-one (W2768); 6-(2-chlorophenyl)-8-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2769); 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8,9-dihydropyrimidino[4,5-e]indazine-5(7H)-one (W2770); 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-(pyridin-4-yl)pyrido[2,3-d]pyrimidin-5(8H)-one (W2771); 6-(2,6-dichlorophenyl)-8-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2772); 6-(2,6-dichlorophenyl)-8-(4-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2773); 8-Cyclopropyl-6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2774); 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidin-5(8H)-one (W2775); 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-(pyridin-4-ylmethyl)pyrido[2,3-d]pyrimidin-5(8H)-one (W2776); 6-(2,6-dichlorophenyl)-8-[2-(dimethylamino)ethyl]-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2777); 6-(2,6-dichlorophenyl)-8-methyl-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2778); 8-Cyclobutyl-6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2779); 6-(2,6-dichlorophenyl)-8-(2-hydroxy-2-methylpropyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2780); 8-Cyclopropyl-6-(2,6-dichlorophenyl)-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2781); 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2782); 6-(2,6-dichlorophenyl)-8-methyl-2-{[3-methyl-4-(4-methyl-1,4-diazacycloheptane-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2783); 6-(2,6-dichlorophenyl)-8-methyl-2-[(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2784); 6-(2,6-dichlorophenyl)-2-(2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-ylamino)-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2785); 6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2786); 8-Cyclopropyl-6-(2,6-dichlorophenyl)-2-[(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2787); 8-Cyclopropyl-6-(2,6-dichlorophenyl)-2-(2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-ylamino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2788); 8-Cyclopropyl-6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2789); 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-(propyl-2-yl)pyrido[2,3-d]pyrimidin-5(8H)-one (W2790); 6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-(oxecyclobutane-3-yl)pyrido[2,3-d]pyrimidin-5(8H)-one (W2791); 8-tert-butyl-6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2792); 6-(2,6-Dichlorophenyl)-8-(4-methoxybenzyl)-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2793); 6-(2,6-dichlorophenyl)-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2794); 6-(2,6-dichlorophenyl)-8-ethyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2795); 6-(2,6-dichlorophenyl)-8-ethyl-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2796); 6-(2-chloro-6-fluorophenyl)-8-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2797); 6-(2-chloro-6-fluorophenyl)-8-methyl-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2798); 6-(2-chloro-6-fluorophenyl)-8-(4-methoxybenzyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2799); 6-(2-Chloro-6-fluorophenyl)-8-(4-methoxybenzyl)-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2800); 6-(2-chloro-6-fluorophenyl)-8-cyclopropyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2801); 6-(2-chloro-6-fluorophenyl)-8-cyclopropyl-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2802); 6-(2-chloro-6-fluorophenyl)-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2803); 6-(2-chloro-6-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W28O4); 6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2805); 6-(2,6-dichlorophenyl)-2-[(2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2806); 6-(2,6-dichlorophenyl)-2-(2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-ylamino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2807); 6-(2,6-dichlorophenyl)-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2808); 6-(2,6-dichlorophenyl)-8-methyl-2-(1,2,3,4-tetrahydroisoquinoline-6-ylamino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2809); 6-(2,6-dichlorophenyl)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2810); 6-(2,6-dichlorophenyl)-8-methyl-2-{[4-(morpholin-4-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2811); 6-(2,6-dichlorophenyl)-2-(2,3-dihydro-1H-isoindol-5-ylamino)-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2812); 6-(2,6-dichlorophenyl)-8-methyl-2-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2813); 6-(2,6-dichlorophenyl)-8-methyl-2-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2814); 6-(2,6-dichlorophenyl)-8-methyl-2-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2815); 6-(2,6-dichlorophenyl)-8-methyl-2-[(2-methyl-2,3-dihydro-1H-isoindol-5-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2816); 6-(2,6-dichlorophenyl)-8-methyl-2-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2817); 5-{[6-(2,6-dichlorophenyl)-8-methyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-1H-isoindole-1,3(2H)-dione (W2818); 6-(2,6-dichlorophenyl)-8-methyl-2-{[2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2819); 6-(2,6-dichlorophenyl)-8-methyl-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-ylamino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2820); 6-(2,6-dichlorophenyl)-8-methyl-2-{[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2821); 6-(2,6-dichlorophenyl)-8-methyl-2-[(1,1,2-trimethyl-2,3-dihydro-1H-isoindol-5-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2822); 6-(2,6-dichlorophenyl)-8-methyl-2-({4-[(1-methylpiperidin-4-yl)amino]phenyl}amino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2823); 6-(2,6-dichlorophenyl)-2-({2-[4-(dimethylamino)piperidin-1-yl]pyrimidin-5-yl}amino)-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2824); 6-(2,6-dichlorophenyl)-8-methyl-2-({4-[(3R)-pyrrolidine-3-ylamino]phenyl}amino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2825); 6-(2,6-dichlorophenyl)-8-methyl-2-({4-[(3S)-pyrrolidine-3-ylamino]phenyl}amino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2826); 6-(2,6-dichlorophenyl)-2-[(1,1-dimethyl-2,3-dihydro-1H-isoindol-5-yl)amino]-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2827); 6-(2,6-dichlorophenyl)-8-methyl-2-{[4-(piperidin-4-ylamino)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2828); 6-(2,6-dichlorophenyl)-8-methyl-2-({4-[(1-methylpyrrolidin-3-yl)amino]phenyl}amino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2829); 6-(2,6-dichlorophenyl)-8-methyl-2-({4-[(1-methylpiperidin-4-yl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2830); 6-(2-chloro-6-fluorophenyl)-8-methyl-2-({4-[(1-methylpiperidin-4-yl)amino]phenyl}amino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2831); 6-(2-chloro-6-fluorophenyl)-8-methyl-2-[(1,1,2-trimethyl-2,3-dihydro-1H-isoindol-5-yl)amino]pyrido[2,3-d]pyrimidin-5(8H)-one (W2832); 5-{[6-(2,6-dichlorophenyl)-8-methyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-2-(4-methylpiperazin-1-yl)benzoate (W2833); 6-(2,6-dichlorophenyl)-2-({2-[4-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-5-yl}amino)-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2834); 6-(2-chloro-6-fluorophenyl)-8-methyl-2-{[4-(piperidin-4-ylamino)phenyl]amino}pyrido[2,3-d]pyrimidin-5(8H)-one (W2835); 6-(2-chloro-6-fluorophenyl)-8-methyl-2-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2836); 6-(2-chloro-6-fluorophenyl)-8-methyl-2-(1,2,3,4-tetrahydroisoquinoline-6-ylamino)pyrido[2,3-d]pyrimidin-5(8H)-one (W2837); 6-(2,6-dichlorophenyl)-2-[(4-{[trans-4-(dimethylamino)cyclohexyl]amino}phenyl)amino]-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2838); 6-(2,6-dichlorophenyl)-2-[(4-{[cis-4-(dimethylamino)cyclohexyl]amino}phenyl)amino]-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2839); 6-(2,6-dichlorophenyl)-2-[(4-{4-[3-(dimethylamino)propyl]piperazin-1-yl}phenyl)amino]-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2840); 6-(2,6-dichlorophenyl)-2-[(4-{4-[2-(dimethylamino)ethyl]piperazin-1-yl}phenyl)amino]-8-methylpyrido[2,3-d]pyrimidin-5(8H)-one (W2841); 6-(2-Chlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2842); 6-(2-chloro-6-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2843); 4-(2-Chlorophenyl)-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-2,4-dihydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one (W2844); 6-(2,6-dichlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2845); 6-(2-chloro-6-methylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2846); 6-(2-chloro-6-fluorophenyl)-2-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2847); 2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-6-(2-chloro-6-fluorophenyl)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2848); 6-(2-Chloro-6-fluorophenyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2849); 6-(2-chloro-6-fluorophenyl)-2-((2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2850); 6-(2-chloro-6-fluorophenyl)-2-((2′-methyl-2′,3′-dihydro-1′H-spiro(cyclopropane-1,4′-isoquinoline)-7′-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2851); 6-(2-Chloro-6-fluorophenyl)-2-((2′-acetyl-2′,3′-dihydro-1′H-spiro(cyclopropane-1,4′-isoquinoline)-7′-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2852); 6-(2,6-dichlorophenyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2853); 6-(2,6-dichlorophenyl)-2-((2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2854); 6-(2,6-Dichlorophenyl)-2-((2′-methyl-2′,3′-dihydro-1′H-spiro(cyclopropane-1,4′-isoquinoline)-7′-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2855); 6-(2,6-dimethylphenyl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2856); 6-(2,6-dimethylphenyl)-2-((2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2857); 6-(2,6-Dimethylphenyl)-2-((2′-methyl-2′,3′-dihydro-1′H-spiro(cyclopropane-1,4′-isoquinoline)-7′-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2858); 6-Isopropyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2859); 6-(tert-butyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2860); 6-Cyclopropyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2861); 6-Cyclohexyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2862); 6-Allyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2863); 2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-6-(thiophen-2-yl)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2864); 6-(furan-2-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2865); 2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-6-(1H-pyrrolo-2-yl)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2866); 6-(1H-imidazol-5-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2867); 6-(2-chloro-6-fluorophenyl)-8,8-dimethyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2868); 6-(2-chloro-6-fluorophenyl)-9,9-dimethyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2869); 6-(2-chloro-6-fluorophenyl)-2-((4-((2S,6R)-2,6-dimethylmorpholino)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2870); 6-(2-Chloro-6-fluorophenyl)-2-((4-(morpholinomethyl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2871); 6-(2-Chloro-6-fluorophenyl)-2-((4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2872); 6-(2-Chloro-6-fluorophenyl)-2-((4-((3S,5R)-4-isopropyl-3,5-dimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2873); 6-(2-chloro-6-fluorophenyl)-2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2874); 6-(2-chloro-6-fluorophenyl)-2-((2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2875); 6-(2-chloro-6-fluorophenyl)-2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2876); 6-(2-chloro-6-fluorophenyl)-2-((2-chloro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2877); 6-(2-chloro-6-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2878); 6-(2-Chloro-6-fluorophenyl)-2-((2-trifluoromethyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2879); 6-(2-chloro-6-fluorophenyl)-2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2880); 6-(2-Chloro-6-fluorophenyl)-2-((2-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2881); 6-(2-chloro-6-fluorophenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2882); 6-(2-chloro-6-fluorophenyl)-2-((3-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2883); 6-(2-chloro-6-fluorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2884); 2-((3-chloro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-6-(2-chloro-6-fluorophenyl)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2885); 6-(2-chloro-6-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2886); 6-(2-Chloro-6-fluorophenyl)-2-((3-trifluoromethyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2887); 6-(2-chloro-6-fluorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2888); 6-(2-Chloro-6-fluorophenyl)-2-((3-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2889); 6-(2-chloro-6-fluorophenyl)-2-((4-(4-isopropylpiperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2890); 6-(2-Chloro-6-fluorophenyl)-2-((4-((3S,5R)-4-isopropyl-3,5-dimethylpiperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2891); 6-(2-chloro-6-fluorophenyl)-2-((3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2892); 6-(2-chloro-6-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2893); 6-(2-chloro-6-fluorophenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2894); 6-(2-chloro-6-fluorophenyl)-2-((6-4-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2895); 6-(2-Chloro-6-fluorophenyl)-2-((2′-isopropyl-2′,3′-dihydro-1′H-spiro(cyclopropane-1,4′-isoquinoline)-7′-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2896); 6-(2-Chloro-6-fluorophenyl)-2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2897); 6-(2,6-difluorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2898); 6-(2-fluoro-6-(trifluoromethyl)phenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2899); 6-(2-fluoro-6-methylphenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2900); 6-(2,6-dichlorophenyl)-2-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2901); 6-(2,6-dichlorophenyl)-2-((4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2902); 6-(2,6-dichlorophenyl)-2-((4-((3S,5R)-4-isopropyl-3,5-dimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2903); 6-(2,6-dichlorophenyl)-2-((2-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2904); 6-(2,6-dichlorophenyl)-2-((2-chloro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2905); 6-(2,6-Dichlorophenyl)-2-((2-trifluoromethyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2906); 6-(2,6-dichlorophenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2907); 6-(2,6-dichlorophenyl)-2-((3-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2908); 6-(2,6-dichlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2909); 6-(2,6-dichlorophenyl)-2-((3-chloro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2910); 6-(2,6-dichlorophenyl)-2-((4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2911); 6-(2,6-dichlorophenyl)-2-((3-trifluoromethyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2912); 6-(2,6-dichlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2913); 6-(2,6-dichlorophenyl)-2-((4-(4-isopropylpiperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2914); 6-(2,6-dichlorophenyl)-2-((3-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2915); 6-(2,6-dichlorophenyl)-2-((4-((3S,5R)-4-isopropyl-3,5-dimethylpiperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2916); 6-(2,6-dichlorophenyl)-2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2917); 6-(2-chloro-6-(trifluoromethyl)phenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2918); 6-(2-chloro-6-methylphenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2919); 6-(2-chloro-6-methoxyphenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2920); 6-(2,6-dimethylphenyl)-2-((4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2921); 6-(4-Chlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2922); 6-(3-Chlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2923); 6-(2,4-Dichlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2924); 6-(2-chloro-4-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2925); 6-(2-chloro-3-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2926); 6-(2,5-Dichlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2927); 6-(2,3-Dichlorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2928); 6-(pyrimidin-2-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2929); 2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2930); 6-Cyclobutyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2931); 6-Cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2932); 6-Phenyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2933); 6-(pyridin-2-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2934); 6-(pyridin-3-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2935); 6-(pyridin-4-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one (W2936); 6-(2,6-difluorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2937); 6-(2,6-difluorophenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2938); 6-(2-chloro-6-fluorophenyl)-2-((4-(1H-imidazol-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2939); 6-(2-chloro-6-fluorophenyl)-2-((4-(4-methyl-1,4-diazacycloheptane-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2940); 6-(2-Chloro-6-fluorophenyl)-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2941); 6-(2-Chloro-6-fluorophenyl)-2-((4-(2-(dimethylamino)ethoxy)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2942); 6-(2-Chloro-6-fluorophenyl)-2-((4-(3-(dimethylamino)propoxy)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2943); 6-(2-Chloro-6-fluorophenyl)-2-((4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2944); 6-(2-Chloro-6-fluorophenyl)-2-((4-((2-(dimethylamino)ethyl)amino)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2945); 6-(2-Chloro-6-fluorophenyl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2946); 6-(2-Chloro-6-fluorophenyl)-2-((4-((3-(dimethylamino)propyl)amino)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2947); 6-(2-Chloro-6-fluorophenyl)-2-((4-((3-(dimethylamino)propyl)(methyl)amino)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2948); 6-(2-chloro-6-fluorophenyl)-2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2949); 6-(2-chloro-6-fluorophenyl)-2-((4-(methyl(1-methylpiperidin-4-yl)amino)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2950); 6-(2-chloro-6-fluorophenyl)-2-((4-(1-methylpiperidin-4-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2951); 6-(2-chloro-6-fluorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2952); 6-(2-chloro-6-fluorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2953); 6-(2-chloro-6-fluorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2954); 6-(2-Chloro-6-fluorophenyl)-2-((3-bromo-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2955); 6-(2-chloro-6-fluorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2956); 6-(2-chloro-6-fluorophenyl)-2-((3-fluoro-5-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2957); 6-(2-chloro-6-fluorophenyl)-2-((5-(4-methylpiperazin-1-yl)pyrazin-2-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2958); 6-(2-chloro-6-fluorophenyl)-2-((3,5-dichloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2959); 6-(2-chloro-6-fluorophenyl)-2-((3-fluoro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2960); 6-(2-chloro-6-fluorophenyl)-2-((3-fluoro-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2961); 6-(2-chloro-6-fluorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2962); 6-(2-chloro-6-fluorophenyl)-2-((3-chloro-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2963); 6-(2-chloro-6-fluorophenyl)-2-((3-bromo-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2964); 6-(2-chloro-6-fluorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2965); 6-(2-chloro-6-fluorophenyl)-2-((3-methoxy-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2966); 6-(2,6-dichlorophenyl)-2-((5-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2967); 6-(2,6-dichlorophenyl)-2-((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2968); 6-(2,6-dichlorophenyl)-2-((5-chloro-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2969); 6-(2,6-dichlorophenyl)-2-((2,4,4,5-tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2970); 6-(2,6-Dichlorophenyl)-2-((5′-chloro-2′-methyl-2′,3′-dihydro-1′H-spiro(cyclopropane-1,4′-isoquinoline)-7′-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2971); 6-(2,6-Dichlorophenyl)-2-((2′,5′-dimethyl-2′,3′-dihydro-1′H-spiro(cyclopropane-1,4′-isoquinoline)-7′-yl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2972); 6-(2,6-dichlorophenyl)-2-((3,5-dichloro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2973); 6-(2,6-dichlorophenyl)-2-((3-chloro-5-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2974); 6-(2,6-dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2975); 6-(2,6-dichlorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2976); 6-(2,6-dichlorophenyl)-2-((3-bromo-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2977); 6-(2,6-dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2978); 6-(2,6-dichlorophenyl)-2-((3,5-dichloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2979); 6-(2,6-dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-fluoro-5-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2980); 6-(2,6-dichlorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)-5-methoxyphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2981); 6-(2,6-dichlorophenyl)-2-((3-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2982); 6-(2,6-dichlorophenyl)-2-((3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2983); 6-(2,6-dichlorophenyl)-2-((3-chloro-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2984); 6-(2,6-dichlorophenyl)-2-((3-fluoro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2985); 6-(2,6-dichlorophenyl)-2-((3-fluoro-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2986); 6-(2,6-dichlorophenyl)-2-((3,5-dichloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2987); 6-(2,6-dichlorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2988); 6-(2,6-dichlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2989); 6-(2,6-dichlorophenyl)-2-((3-chloro-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2990); 6-(2,6-dichlorophenyl)-2-((3-bromo-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2991); 6-(2,6-dichlorophenyl)-2-((3-bromo-5-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2992); 6-(2,6-dichlorophenyl)-2-((3-bromo-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2993); 6-(2,6-dichlorophenyl)-2-((3-bromo-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2994); 6-(2,6-dichlorophenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2995); 6-(2,6-dichlorophenyl)-2-((3-methoxy-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2996); 6-(2-bromo-6-chlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-fluoro-5-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2997); 6-(2-bromo-6-chlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2998); 6-(2-bromo-6-chlorophenyl)-2-((3-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W2999); 6-(2-bromo-6-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3000); 6-(2-bromo-6-chlorophenyl)-2-((3,5-dichloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3001); 6-(2-bromo-6-chlorophenyl)-2-((3-fluoro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3002); 6-(2-bromo-6-chlorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3003); 6-(2-bromo-6-chlorophenyl)-2-((3-bromo-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3004); 6-(2-fluoro-6-methylphenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3005); 6-(2-fluoro-6-methylphenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3006); 6-(2-chloro-6-methylphenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-fluoro-5-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3007); 6-(2-chloro-6-methylphenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3008); 6-(2-chloro-6-methylphenyl)-2-((3,5-dichloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3009); 6-(2-chloro-6-methylphenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3010); 6-(2-chloro-6-methylphenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3011); 6-(2,6-dichlorophenyl)-2-((4-(piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3012); 6-(2,6-dichlorophenyl)-2-((3-chloro-4-(piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3013); 6-(2,6-dichlorophenyl)-2-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3014); 6-(2,6-dichlorophenyl)-2-((3-methoxy-4-(piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3015); 6-(2-chloro-6-fluorophenyl)-2-((3-(hydroxymethyl)-4-(piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3016); 6-(2,6-dichlorophenyl)-2-((3-(hydroxymethyl)-4-(piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3017); 6-(2,6-dichlorophenyl)-2-((3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3018); 6-(2,6-dichlorophenyl)-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3019); 6-(2,6-dichlorophenyl)-2-((4-morpholinophenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3020); 6-(2,6-dichlorophenyl)-2-((3-((methylamino)methyl)-4-morpholinophenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3021); 6-(2-bromo-6-chlorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3022); 6-(2,6-dimethylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one (W3023); 3-(2,6-dichlorophenyl)-2-methyl-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3024); 3-(2-chloro-6-methylphenyl)-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3025); 3-(2,6-dichlorophenyl)-7-((3-(hydroxymethyl)-4-(piperazin-1-yl)phenyl)amino)-2-methyl-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3026); 3-(2,6-dichlorophenyl)-2,2-dimethyl-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3027); 3-(2-chloro-6-fluorophenyl)-7-((3-(hydroxymethyl)-4-(piperazin-1-yl)phenyl)amino)-2-methyl-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3028); 3-(2-chloro-6-(hydroxymethyl)phenyl)-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3029); 3-(4-chloro-1H-pyrazol-5-yl)-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3030); 3-(2-chloro-6-(hydroxymethyl)phenyl)-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3031); 7-((1H-indol-5-yl)amino)-3-(2-chloro-6-(hydroxymethyl)phenyl)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3032); 3-(2,6-dichlorophenyl)-2-methyl-7-((2-(methanesulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3033); 7-((2-acetyl-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(2,6-dichlorophenyl)-2-methyl-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]thiazin-4-one (W3034); 3-(2,6-dichlorophenyl)-2-methyl-7-((2-(methanesulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]thiazin-4-one (W3035); 3-(2,6-dichlorophenyl)-2-methyl-7-((1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3036); 3-(2,6-dichlorophenyl)-7-((4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2-methyl-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3037); 3-(2,6-dichlorophenyl)-2-methyl-7-((2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3038); 3-(2-chloro-6-methylphenyl)-7-((1,1-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]thiazin-4-one (W3039); 3-(2-chloro-6-methylphenyl)-7-((1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]thiazin-4-one (W3040); 3-(2-chloro-6-methylphenyl)-7-((4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]thiazin-4-one (W3041); 3-(2-chloro-6-fluorophenyl)-7-((1,1-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-2-methyl-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3042); 6-((3-(2-chloro-6-methylphenyl)-4-oxo-3,4-dihydro-2H-pyrimidino[5,4-e][1,3]oxazin-7-yl)amino)-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinoline-8-carboxynitrile (W3043); 6-((3-(2-chloro-6-fluorophenyl)-2-methyl-4-oxo-3,4-dihydro-2H-pyrimidino[5,4-e][1,3]oxazin-7-yl)amino)-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinoline-8-carboxynitrile (W3044); 3-(2-chloro-6-methylphenyl)-7-((8-fluoro-1,1-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-2-methyl-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3045); 3-(2-chloro-6-methylphenyl)-7-((2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3046); 3-(2-chloro-6-methylphenyl)-7-((4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-2-methyl-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3047); 2-Acetyl-7-((3-(2-chloro-6-methylphenyl)-4-oxo-3,4-dihydro-2H-pyrimidino[5,4-e][1,3]oxazin-7-yl)amino)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-5-carboxynitrile (W3048); 3-(2-chloro-6-methylphenyl)-7-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3049); 3-(2,6-dichlorophenyl)-7-((4-(4-(dimethylamino)piperidin-1-yl)-3-methylphenyl)amino)-2-methyl-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]thiazin-4-one (W3050); 3-(2-chloro-6-fluorophenyl)-7-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-2-methyl-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]thiazin-4-one (W3051); 3-(2-chloro-6-fluorophenyl)-2-methyl-7-((4-((R)-2-methylpiperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3052); 3-(2,6-dichlorophenyl)-2-methyl-7-((4-((S)-2-methylpiperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3053); 3-(3,5-dichloropyridin-4-yl)-7-((4-(4-methylpiperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3054); 3-(3,5-dichloropyridin-4-yl)-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3055); 3-(2-oxo-1,2-dihydropyridin-4-yl)-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3056); 7-((4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-3-(2-oxo-1,2-dihydropyridin-4-yl)-2,3-dihydro-4H-pyrimidino[5,4-e][1,3]oxazin-4-one (W3057); Or its pharmaceutically acceptable salt.

[0202] Further examples of Wee1 inhibitors can be found, for example, in U.S. Patent Nos. 8,710,065; 8,716,297; 8,791,125; 9,181,239; 9,850,247; 11,332,473; 11,345,711; 11,208,413; 11,248,006; 11,613,545; and 11,261,192; and International Patent Publication Nos. WO 2019 / 028008; WO 2019 / 173082; WO 2020 / 210320; WO 2020 / 210377; WO 2020 / 192581; WO 2021 / 073491; WO 2021 / 207598; WO 2022 / 155202; WO 2022 / 188802; WO 2022 / 251224; and WO 2022 / 256680; all of their Wee1 inhibitors are incorporated herein by reference in their entirety.

[0203] Treatment The methods disclosed herein can be used to treat diseases or conditions that depend on the activity of membrane-associated tyrosine and threonine-specific CDC2 inhibitory kinase (Myt1) (gene name PKMYT1) (e.g., overexpression). CCNE1 Cancer, in FBXW7 Cancers with inactivating mutations in the gene, cancers with activating mutations in the RAS gene, cancers that overexpress RAS, or cancers with inactivating mutations in the PPP2R1A gene. The methods disclosed herein may include administering to a subject of need a therapeutically effective amount of a membrane-associated tyrosine and threonine-specific CDC2 inhibitory kinase (Myt1) inhibitor and a therapeutically effective amount of a WEE1 inhibitor. In some embodiments, the dose of the Myt1 inhibitor, the WEE1 inhibitor, or both may be a subtherapeutic dose relative to monotherapy.

[0204] The disease or symptom may present with symptoms of excessive cell proliferation. For example, the disease or symptom could be cancer (e.g., overexpression of certain substances). CCNE1 Cancer, in FBXW7 Cancers with inactivating mutations in the gene, cancers with activating mutations in the RAS gene, cancers that overexpress RAS, or cancers with inactivating mutations in the PPP2R1A gene.

[0205] High CCNE1 Cancers with an overexpression rate or associated with it include, for example, uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, bladder cancer, stomach cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, and endometrial cancer. Preferably, the cancer is uterine cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

[0206] FBXW7 lack or FBXW7 Cancers that cause or are associated with loss of function include, for example, uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, bladder cancer, stomach cancer, colorectal cancer, breast cancer, lung cancer, and esophageal cancer. Preferably, the cancer is uterine cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

[0207] Cancers that have or are associated with RAS activating mutations or high-incidence RAS overexpression include, for example, uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, breast cancer, esophageal cancer, lung cancer, thyroid cancer, melanoma, and endometrial cancer. In embodiments where the mutation is a KRAS mutation, the cancer is preferably lung cancer, pancreatic cancer, or colorectal cancer.

[0208] Cancers that have or are associated with PPP2R1A deficiency or loss of PPP2R1A function include, for example, endometrial cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, cervical cancer, head and neck cancer, stomach cancer, bladder cancer, laryngeal cancer, and pancreatic cancer.

[0209] The compounds disclosed herein may be administered via routes selected from the group consisting of: oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intravenous, intraspinal, intraspinal, intranasal, inhalation, intratumoral, and local administration.

[0210] In some embodiments, the Myt1 inhibitor is administered before the Wee1 inhibitor (e.g., within 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours). In some embodiments, the Myt1 inhibitor is administered after the Wee1 inhibitor (e.g., within 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours). In some embodiments, the Myt1 inhibitor is co-administered with the Wee1 inhibitor. In some embodiments, the Myt1 inhibitor is administered continuously daily. In some embodiments, the Myt1 inhibitor is administered intermittently (e.g., 1 day / week, 2 days / week, or 3 days / week). In some embodiments, the Wee1 inhibitor is administered continuously daily. In some embodiments, the Wee1 inhibitor is administered intermittently (e.g., 1 day / week, 2 days / week, or 3 days / week).

[0211] Pharmaceutical Composition The compounds used in the methods described herein are preferably formulated as pharmaceutical compositions for administration to human subjects in a biocompatible form suitable for in vivo administration. Pharmaceutical compositions typically comprise the compounds described herein and pharmaceutically acceptable excipients. Some pharmaceutical compositions may comprise one or more additional pharmaceutically active agents described herein.

[0212] The compounds described herein can also be used in the form of free bases; in the form of salts, zwitterions, solvates; or as prodrugs or pharmaceutical compositions thereof. All forms are within the scope of this invention. As those skilled in the art will understand, depending on the chosen route of administration, the compounds, their salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions may be administered to a patient in a variety of forms. The compounds used in the methods described herein can be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, via patch, pump, or percutaneously, and pharmaceutical compositions may be formulated accordingly. Parenterally administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and local administration. Parenterally administration can be performed by continuous infusion over a selected time period.

[0213] For human use, the compounds of the present invention can be administered alone or in combination with a drug carrier chosen with regard to the intended route of administration and standard pharmaceutical practice. Therefore, pharmaceutical compositions according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants, which facilitate the processing of the compounds of the present invention into pharmaceutically acceptable formulations.

[0214] The present invention also includes a method of administering a pharmaceutical composition which may contain one or more pharmaceutically acceptable carriers. In preparing the pharmaceutical compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in a carrier, such as a capsule, sachet, paper, or other container. When the excipient acts as a diluent, it can be a solid, semi-solid, or liquid material (e.g., physiological saline) that serves as a medium, carrier, or mediator of the active ingredient. Therefore, the composition can be in the form of tablets, powders, lozenges, capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending on the intended route of administration. The resulting composition may contain additional agents, such as preservatives.

[0215] Excipients or carriers are selected based on the method and route of administration. Suitable drug carriers and essential pharmaceutical ingredients for drug formulations are described in Remington: The Science and Practice of Pharmacy, 21st Edition, Gennaro, ed., Lippincott Williams & Wilkins (2005) and USP / NF (United States Pharmacopeia and National Formulary), which are well-known references in the field. Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Formulations may additionally include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, edited by Rowe et al., Pharmaceutical Press (2009).

[0216] These pharmaceutical compositions can be manufactured in conventional ways, for example, by conventional mixing, dissolving, granulation, sugar-coated pelleting, grinding, emulsification, encapsulation, embedding, or lyophilization processes. Methods known in the art for preparing formulations can be found, for example, in *Remington: The Science and Practice of Pharmacy*, 21st edition, Gennaro, ed., Lippincott Williams & Wilkins (2005) and *Encyclopedia of Pharmaceutical Technology*, ed., J. Swarbrick and JC Boylan, 1988–1999, Marcel Dekker, New York. The appropriate formulation depends on the chosen route of administration. Formulations and preparations of such compositions are well known to those skilled in the art of pharmaceutical formulation. In preparing formulations, the active compound may be ground to provide an appropriate particle size before being combined with other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size may be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0217] dose The dosage of the compound used in the methods described herein, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the route of administration; the recipient's age, health status, and weight; the nature and severity of symptoms; the frequency of treatment and the type of concurrent treatment (if any); and the clearance rate of the compound in the treated animal. Those skilled in the art can determine an appropriate dosage based on the above factors. The compound used in the methods described herein can be initially administered at a suitable dosage, which can be adjusted as needed based on clinical response. In some embodiments, the appropriate daily dose of the compound of the invention will be the amount of the minimum dose at which the compound effectively produces a therapeutic effect. In some embodiments, the effective dose is a subtherapeutic dose relative to a single therapy. Such an effective dose will generally depend on the factors described above.

[0218] The compounds disclosed herein can be administered to patients in a single dose or in multiple doses. When multiple doses are administered, the doses can be spaced out, for example, every 1-24 hours, 1-7 days, 1-4 weeks, or 1-12 months. The compounds can be administered according to a schedule or without a predetermined schedule. For example, the active compound can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times daily; every 2 days, every 3 days, every 4 days, every 5 days, or every 6 days; every week, 1, 2, 3, 4, 5, 6, or 7 times; every month, 1, 2, 3, 4, 5, or 6 times; or every year, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times. It should be understood that for any particular subject, the specific dosing regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0219] The compounds disclosed herein can be administered to patients in a single dose or multiple doses. When multiple doses are administered, the doses can be spaced apart from each other, for example, 1-24 hours, 1-7 days, 1-4 weeks, or 1-12 months. The compounds can be administered according to a schedule, or the compounds can be administered without a predetermined schedule. The active compound can be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times daily, every 2, 3, 4, 5, or 6 days, 1, 2, 3, 4, 5, 6, or 7 times weekly, 1, 2, 3, 4, 5, or 6 times monthly, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times annually. It should be understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0220] The monotherapy of the MYT1 inhibitor, the monotherapy of the Wee1 inhibitor, or both described herein include a therapeutically effective dose (i.e., at least the amount required to elicit the desired pharmacological effect). A therapeutically effective dose of the MYT1 inhibitor or Wee1 inhibitor can be, for example, between 0.05 mg and 3000 mg (e.g., compounds greater than 100 mg, compounds greater than 150 mg, compounds greater than 200 mg, compounds greater than 250 mg, compounds greater than 300 mg, etc.). In some embodiments, the dose may be calculated using the patient's weight.

[0221] Monotherapy or a single therapy of the MYT1 inhibitor or the Wee1 inhibitor described herein, or both, may be provided in a dosing regimen. The dosing regimen may include, for example, once daily, twice daily, every other day, etc., providing the MYT1 inhibitor or Wee1 inhibitor. The dosing regimen may include a period of time during which the dosing regimen is applied. In some embodiments, the dosing regimen may vary within this period. For example, in some embodiments, the dose of the compound of the invention is administered to the patient according to the dosing regimen over a period of 1-7 days; 1-12 weeks; or 1-3 months. In some embodiments, the compound is administered to the patient over a period of, for example, 4-11 months or 1-30 years. In some embodiments, the compound is administered to the patient at the onset of symptoms. In any of these embodiments, the amount of compound administered may vary during the period of administration. When the compound is administered daily, administration may occur, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times daily.

[0222] Subtherapeutic dose In some embodiments, Myt1 inhibitors, Wee1 inhibitors, or both may be administered at a subtherapeutic dose relative to monotherapy. The compound used in the methods described herein (e.g., a combination of a Myt1 inhibitor selected from compounds 1 to 328 and a Wee1 inhibitor selected from compounds W1 to W3052) may initially be administered independently at a suitable monotherapy dose (e.g., a therapeutically effective dose for monotherapy). The dose may then be reduced (e.g., reduced to a subtherapeutic dose) based on clinical response. Alternatively, the compound used in the methods described herein may be administered at a subtherapeutic dose. A subtherapeutic dose of either a Myt1 inhibitor or a Wee1 inhibitor may be administered in combination with a therapeutically effective dose of the other. The extent of dose reduction (i.e., the amount less than the therapeutically effective dose when the subtherapeutic dose is administered) will generally depend on, for example, the synergistic effect between the Myt1 inhibitor and the Wee1 inhibitor, and the factors described herein.

[0223] In some implementations, the subtherapeutic dose of the Myt1 inhibitor may be approximately half the effective therapeutic dose of the Myt1 inhibitor. In some implementations, the subtherapeutic dose of the Myt1 inhibitor may be, for example, up to 500 mg (e.g., up to 400 mg, up to 350 mg, up to 300 mg, up to 250 mg, up to 240 mg, up to 230 mg, up to 220 mg, up to 210 mg, up to 200 mg, up to 190 mg, up to 180 mg, up to 170 mg, up to 160 mg, up to 150 mg, up to 140 mg, up to 130 mg, up to 120 mg, up to 110 mg, up to 100 mg, etc.).

[0224] In some embodiments, the subtherapeutic dose of the Wee1 inhibitor may be approximately half the effective therapeutic dose of the Wee1 inhibitor. In some embodiments, the subtherapeutic dose of the Wee1 inhibitor is, for example, up to 600 mg (e.g., up to 550 mg, up to 500 mg, up to 450 mg, up to 400 mg, up to 350 mg, up to 300 mg, up to 250 mg, up to 200 mg, up to 175 mg, up to 150 mg, up to 125 mg, up to 100 mg, up to 75 mg, up to 50 mg, up to 40 mg, up to 30 mg, or up to 20 mg).

[0225] In some embodiments, the Myt1 inhibitor, Wee1 inhibitor, or both are administered continuously at a subtherapeutic dose. In some embodiments, the Myt1 inhibitor, Wee1 inhibitor, or both are administered at a subtherapeutic dose using a reduced-dose regimen (such as the reduced-dose regimen described herein).

[0226] Reduced dosing regimen In some embodiments, Myt1 inhibitors, Wee1 inhibitors, or both may be administered in a reduced-dose regimen relative to Myt1 inhibitors or Wee1 inhibitors as monotherapy. Therefore, any dosing regimen described herein can be a reduced-dose regimen if the Myt1 inhibitor or Wee1 inhibitor is provided at a reduced frequency relative to the monotherapy dose. For example, monotherapy with a Myt1 inhibitor may include a dose described herein provided once daily (e.g., a therapeutic dose or a subtherapeutic dose), monotherapy with a Wee1 inhibitor may include a dose described herein provided once daily (e.g., a therapeutic dose or a subtherapeutic dose), or both. In combination therapies of such embodiments, the dosing regimen of Myt1 inhibitors, Wee1 inhibitors, or both may be reduced, for example, to once every other day, once weekly, or an on-off dosing regimen. As a further example, monotherapy with a Myt1 inhibitor may include a dose described herein provided twice daily (e.g., a therapeutic dose or a subtherapeutic dose), monotherapy with a Wee1 inhibitor may include a dose described herein provided twice daily (e.g., a therapeutic dose or a subtherapeutic dose), or both. In combination therapies with such implementation schemes, Myt1 inhibitors, Wee1 inhibitors, or both can be reduced to, for example, once daily, once weekly, or on-off dosing regimens.

[0227] The compounds used in the methods described herein can be initiated with any suitable dosing regimen (e.g., once daily, twice daily, etc.), which can be adjusted (e.g., reduced) based on clinical response (e.g., changing to once every other day, or changing to an on-off dosing regimen). Alternatively, the compounds used in the methods described herein can be initiated with a reduced dosing regimen.

[0228] In some embodiments, the Myt1 inhibitor dosing regimen is a reduced-dose regimen. In some embodiments, the Wee1 inhibitor dosing regimen is a reduced-dose regimen. In some embodiments, both the Myt1 inhibitor and Wee1 dosing regimens are reduced-dose regimens. In some embodiments, a single dosing regimen may be maintained for the duration of treatment. In some embodiments, treatment may include changes to the dosing regimen. In some embodiments, the dosing regimen may include a reduced-dose regimen for the entire duration of treatment. In some embodiments, the dosing regimen may include a reduced-dose regimen for only a portion of the treatment.

[0229] In some embodiments, the dose of the Myt1 inhibitor or Wee1 inhibitor administered in a reduced-dose regimen is a therapeutically effective dose. In some embodiments, the dose of the Myt1 inhibitor or Wee1 inhibitor administered is a subtherapeutic dose. In some embodiments, the dose of the Myt1 inhibitor, Wee1 inhibitor, or both administered in a reduced-dose regimen is the dose described herein.

[0230] In some embodiments, the dose reduction regimen for Myt1 inhibitors includes intermittent dosing of the Myt1 inhibitor (e.g., 1 day, 2 days, or 3 days per week). In some embodiments, the dose reduction regimen for Wee1 inhibitors includes intermittent dosing of the Wee1 inhibitor (e.g., 1 day, 2 days, or 3 days per week). In some embodiments, the dose reduction regimen may be an on-off dosing regimen. In an on-off dosing regimen, the Myt1 inhibitor or Wee1 inhibitor is administered continuously for several days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, or 3 weeks), followed by several discontinuous days (e.g., no administration for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, or 3 weeks). Each day of administration of the active pharmaceutical ingredient in an on-off dosing regimen may include multiple administrations of the active pharmaceutical ingredient. For example, the dose reduction regimen can be a "3-day dosing, 4-day off" regimen (3 / 4 dosing); a "5-day dosing, 2-day off" regimen (5 / 2 dosing), a "1-day dosing, 6-day off" regimen (1 / 6 dosing), a "2-day dosing, 5-day off" regimen (2 / 5 dosing), a "4-day dosing, 3-day off" regimen (4 / 3 dosing), a "1-week dosing, 1-week off" regimen, a "2-week dosing, 1-week off" regimen, or a "3-week dosing, 2-week off" regimen. The dose reduction regimen can include the period of time during which it is applied. In some embodiments, this period can vary. For example, in some embodiments, the compound of the present invention is administered to the patient over a period of 1-7 days; 1-12 weeks; or 1-3 months. In some embodiments, the compound is administered to the patient over a period of, for example, 4-11 months or 1-30 years.

[0231] In some implementations, the Myt1 inhibitor and the Wee1 inhibitor are administered co-administered with a reduced dose regimen. In other implementations, the Myt1 inhibitor and the Wee1 inhibitor are administered separately with a reduced dose regimen.

[0232] In some implementation schemes, the dose reduction regimen for Myt1 inhibitors can be, for example, once daily; twice daily, three times daily, four times daily, five times daily, once every other day, once every three days, once weekly; once monthly; three days of treatment followed by four days of rest; five days of treatment followed by two days of rest; two weeks of treatment followed by one week of rest.

[0233] In some implementations, the dose reduction regimen for Wee1 inhibitors may be, for example, once daily; twice daily, three times daily, four times daily, five times daily, every other day, every three days, once weekly; once monthly; three days of treatment followed by four days off; five days of treatment followed by two days off; or two weeks of treatment followed by one week off. In some implementations, the dose reduction regimen for Wee1 inhibitors may include administration of the Wee1 inhibitor up to one day per week.

[0234] In some embodiments, the Myt1 inhibitor, Wee1 inhibitor, or both are administered at a therapeutic dose in a reduced-dose regimen. In some embodiments, the Myt1 inhibitor, Wee1 inhibitor, or both are administered at a subtherapeutic dose in a reduced-dose regimen.

[0235] preparation Compounds identified as capable of treating any of the conditions described herein using any of the methods described herein may be administered to patients or animals in unit dosage forms together with pharmaceutically acceptable diluents, carriers, or excipients. Chemical compounds used for such therapies may be produced and isolated using any standard techniques known to those skilled in the art of medicinal chemistry. Suitable formulations or compositions may be provided using routine pharmaceutical practices to administer the identified compounds to patients suffering from the disease or condition. Administration may be initiated before the patient experiences symptoms.

[0236] Exemplary routes of administration in the methods of this disclosure (e.g., the compounds or pharmaceutical compositions thereof described herein) include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intravenous, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. The compounds are ideally administered with a pharmaceutically acceptable carrier. Formulating pharmaceutical formulations of the compounds described herein for the treatment of the conditions described herein is also part of this invention. The pharmaceutical composition may be a fixed dose of a Wee1 inhibitor and a Myt1 inhibitor.

[0237] Formulations for oral administration The pharmaceutical compositions contemplated by this invention include those formulated for oral administration (“oral dosage forms”). Oral dosage forms may be, for example, tablets, capsules, liquid solutions or suspensions, powders, or liquid or solid crystals, containing an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient. These excipients can be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch (including potato starch), calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives (including microcrystalline cellulose), starch (including potato starch), croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginate, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-sticking agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0238] Formulations intended for oral administration may also be presented as chewable tablets, hard gelatin capsules (where the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin)) or soft gelatin capsules (where the active ingredient is mixed with an aqueous or oil medium (e.g., peanut oil, liquid paraffin, or olive oil)). Powders, granules, and pills may be prepared using the ingredients mentioned above under tablets and capsules, in a conventional manner using, for example, mixers, fluidized bed apparatus, or spray drying equipment.

[0239] Controlled-release compositions for oral administration can be constructed to release the active drug substance by controlling the dissolution and / or diffusion of the active pharmaceutical ingredient. Any of several strategies can be employed to obtain controlled-release and target plasma concentration versus time profiles. In one example, controlled release is achieved by appropriately selecting various formulation parameters and components, including, for example, various types of controlled-release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. In some embodiments, the composition comprises a biodegradable, pH- and / or temperature-sensitive polymer coating.

[0240] Controlled release through dissolution or diffusion can be achieved by appropriately coating a compound into tablet, capsule, pill, or granule formulation or by incorporating the compound into a suitable matrix. Controlled-release coatings may contain coating substances mentioned above and / or one or more of the following: shellac, beeswax, sugar wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3-butanediol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled-release matrix formulations, matrix materials may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbomer 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene and / or halogenated fluorocarbons.

[0241] The compounds and compositions of the present invention may be incorporated herein in liquid form for oral administration, including aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical carriers.

[0242] Preparations for parenteral administration The compounds described herein for use in the methods of this invention can be administered as pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulations as described herein. Pharmaceutical formulations can also be administered parenterally (intravenous, intramuscular, subcutaneous, etc.) in dosage forms or formulations containing conventionally non-toxic, pharmaceutically acceptable carriers and adjuvants. Specifically, formulations suitable for parenteral administration include: aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. For example, to prepare such compositions, the compounds of this invention can be dissolved or suspended in parenteral-acceptable liquid media. Acceptable media and solvents that can be used are water (adjusted to a suitable pH by adding appropriate amounts of hydrochloric acid, sodium hydroxide, or suitable buffers), 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. Aqueous formulations may also contain one or more preservatives, such as methylparaben, ethylparaben, or n-propylparaben. Further information on parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), which is incorporated herein by reference.

[0243] Parenteral preparations may be any of the five general types of preparations identified by USP-NF as suitable for parenteral administration: (1) Drug injection: a liquid preparation of an active pharmaceutical ingredient (e.g., the compound of the present invention) or a solution thereof; (2) Injectable drug: Active pharmaceutical ingredient (e.g., the compound of the present invention) in dry solid form, which will be combined with a suitable sterile medium for parenteral administration in the form of a drug injection solution; (3) Drug injection emulsion: a liquid preparation of an active pharmaceutical ingredient (e.g., the compound of the present invention) dissolved or dispersed in a suitable emulsion medium; (4) Drug injection suspension: a liquid preparation of an active pharmaceutical ingredient (e.g., the compound of the present invention) suspended in a suitable liquid medium; and (5) Injectable suspension: The active pharmaceutical ingredient (e.g., the compound of the present invention) is in dry solid form and will be combined with a suitable sterile medium for parenteral administration in the form of an injectable suspension.

[0244] Formulations intended for parenteral administration include solutions of compounds prepared in water with a surfactant (e.g., hydroxypropyl cellulose). Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, mixtures thereof (with or without alcohol), and in oils. Under normal storage and use conditions, these preparations may contain preservatives to prevent microbial growth. Routine procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Gennaro, editor, Lippincott Williams & Wilkins (2005) and The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0245] Formulations for parenteral administration may contain, for example, excipients, sterile water or saline, polyalkylene glycols (e.g., polyethylene glycol), plant-derived oils, or hydrogenated naphthalene. The release of the compound can be controlled using biocompatible, biodegradable lactide polymers, lactide / glycolic acid copolymers, or polyoxyethylene-polyoxypropylene copolymers. Other potentially available parenteral delivery systems for the compound include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients (e.g., lactose) or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or may be oily solutions administered as nasal drops or gels.

[0246] Parenteral formulations can be formulated for rapid release or sustained / prolonged release of compounds. Exemplary formulations for parenteral release of compounds include: aqueous solutions, reconstituted powders, cosolvent solutions, oil / water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymer gels. Example

[0247] The following examples are intended to illustrate the invention. They are not intended to limit the invention in any way.

[0248] Example 1: Subtherapeutic dose in Myt1 inhibitor / Wee1 inhibitor combination therapy The viability of cells exposed to a combination of lunresertib and Debio-0123 (a representative Wee1 inhibitor) was investigated. Lunresertib (at a concentration of 37 nM) and Debio-0123 (at a concentration of 123 nM) were applied to (1) wild-type cells ( Figure 1A (2) CCNE1 -High cell lines ( Figure 1B () and (3) OVCAR3 cell line ( Figure 1C The cell viability of wild-type cells did not change significantly with the addition of lunresertib or Debio-0123 (alone or in combination therapy) (100%, 104%, 87%, and 84% for mediators without lunresertib or Debio-0123, lunresertib monotherapy, Debio-0123 monotherapy, and combination therapy, respectively). CCNE1 - Cell viability of high-density cells (HDCs) and OVCAR3 cells was not significantly affected by monotherapy (68% and 72% for lunresertib monotherapy, and 98% and 99% for Debio-0123 monotherapy), indicating that monotherapy is subtherapeutic at current concentrations. However, combination therapy... CCNE1 - Near-complete lethality was observed in high-density cells and OVCAR3 cells (cell viability was 4% and 11%, respectively).

[0249] Next, at two concentrations of Debio-0123 (250 nM and 1000 nM), wild-type cells ( Figure 2A ), CCNE1 -High cell count ( Figure 2B ) and OVCAR3 cells ( Figure 2CThe dose-dependent effect of combination therapy on lunresertib was investigated. The efficacy of treatment was measured by the percentage of cells with induced pan-γ-H2AX. High synergistic effects were observed at low concentrations (<500 nM) of lunresertib. CCNE1 - In high-density cytokines, more than 80% of cells exhibited pan-γ-H2AX. Unexpectedly, comparable or even higher pan-γ-H2AX expression was observed at 250 nM Debio-0123 and 1000 nM Debio-0123, demonstrating very high synergistic effects. Similar results were observed in OVCAR3 cells.

[0250] Example 2: Study on the biological origin of subtherapeutic doses in Myt1 inhibitor / Wee1 inhibitor combination therapy To determine the origin of the observed synergistic effect between lunresertib and Debio-0123, CDK1 phosphorylation was measured in the presence of both lunresertib and Debio-0123. Figure 3A , Figure 3B and Figure 3C Phosphorylation of threonine at amino acid position 14 (CDK1-pT14) and tyrosine at amino acid position 15 (CDK1-pY15) was shown in cells exposed to lunresertib and Debio-0123 monotherapy and combination therapy. Debio-0123 alone decreased CDK1-pY15 and increased CDK1-pT14, while lunresertib decreased CDK1-pT14 and increased CDK1-pY15. Neither therapy alone completely reduced CDK1 phosphorylation. However, the combination therapy resulted in a reduction in the phosphorylation depth at both sites.

[0251] Further investigation was conducted to investigate the effects of combination therapy on the relevant CDC25 phosphatase family. CDC25 family phosphatases remove phosphorylation events induced by Myt1 and Wee1. Furthermore, CDC25 and CDK1 also function in a positive feedback loop (i.e., activation of one leads to activation of the other), resulting in robust CDK1 activation. Incomplete dephosphorylation of CDK1 in monotherapy with a MYT1 inhibitor may lead to incomplete activation of CDC25 phosphatases, and thus result in the partial activation of CDK1 observed with monotherapy. Results are summarized in... Figure 4A and Figure 4B middle.

[0252] Treatment with lunresertib alone led to increased phosphorylation of serine at amino acid position 151 of CDC25B (CDC25B-pS151), inhibiting phosphatase activity. Treatment with Debio-0123 alone also led to an increase in CDC25B-pS151. However, the combination therapy of lunresertib and Debio-0123 resulted in a net reduction in CDC25B phosphorylation (and therefore increased activity) compared to either monotherapy, further indicating that the increased efficacy of the combination therapy (and therefore treatment with subtherapeutic doses) is associated with decreased CDK1 phosphorylation (and therefore decreased CDC25 phosphorylation and increased activation).

[0253] Increased CDK1 activity drives treated cells into early mitosis (shortening the time cells remain in an inactive G2 state during the G2 checkpoint response), leading to early tumor cell death. Therefore, combination therapy of Myt1 inhibitors (such as lunresertib or another compound disclosed herein) and Wee1 inhibitors can treat cancer, even at subtherapeutic doses.

[0254] Example 3: Therapeutic efficacy study in xenograft model The efficacy of the following treatments was investigated: (i) Myt1 inhibitors as monotherapy, (ii) Wee1 inhibitors as monotherapy, and (iii) combination therapies comprising Myt1 inhibitors and Wee1 inhibitors. The Myt1 inhibitor used in these trials was lunresertib (see Table 1). The Wee1 inhibitor used in these trials was Debio-0123 (see Table 2a).

[0255] An in vivo efficacy study was conducted in a pancreatic (PSN) xenograft model. Changes in tumor volume were analyzed over 24 treatment days. Figure 5A and Figure 5C ) and changes in weight ( Figure 5B Both compounds were used to initiate treatment on day 1. Comparative analysis showed that the low-dose combination therapy containing lunresertib and Debio-0123 was superior to lunresertib monotherapy and Debio-0123 monotherapy. The combination of lunresertib and Debio-0123 resulted in 91% tumor growth inhibition (TGI) on day 22, while lunresertib monotherapy provided 40% TGI, and Debio-0123 monotherapy provided a non-significant 3% TGI reduction. Figure 5C ).

[0256] Another in vivo efficacy study was conducted in an ovarian (OVCAR3) xenograft model. Changes in tumor volume were analyzed over 45 treatment days. Figure 6A and Figure 6C ) and changes in weight ( Figure 6B Both compounds were used to initiate treatment on day 1. Comparative analysis showed that the low-dose combination therapy containing lunresertib and Debio-0123 was superior to lunresertib monotherapy and Debio-0123 monotherapy. The combination of lunresertib and Debio-0123 resulted in 64% tumor regression (TR) on day 31, while lunresertib monotherapy provided 31% TGI, and Debio-0123 monotherapy provided -5% non-significant TGI change. Figure 6C ).

[0257] List of implementation plans E1. A method of treating a subject with cancer, the method comprising administering, according to a dosing regimen, a dose of a membrane-associated tyrosine and threonine-specific CDC2 inhibitory kinase (Myt1) inhibitor and a dose of a Wee1 inhibitor to the subject in need; and (i) The dose of the Myt1 inhibitor is a subtherapeutic dose; (ii) The dose of the Wee1 inhibitor is a subtherapeutic dose; (iii) The administration regimen of the Myt1 inhibitor is a reduced-dose regimen; or (iv) The administration regimen of the Wee1 inhibitor is a reduced-dose administration regimen.

[0258] E2. A method for inducing cell death in cancer cells, the method comprising contacting the cells with a dose of a Myt1 inhibitor and a dose of a Wee1 inhibitor according to a dosing regimen; and (i) The dose of the Myt1 inhibitor is a subtherapeutic dose; (ii) The dose of the Wee1 inhibitor is a subtherapeutic dose; (iii) The administration regimen of the Myt1 inhibitor is a reduced-dose regimen; or (iv) The administration regimen of the Wee1 inhibitor is a reduced-dose administration regimen.

[0259] E3. The method of claim E2, wherein the cells are in the subject.

[0260] E4. The method according to any one of claims E1 to E3, wherein the cancer is uterine cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, head and neck cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, thyroid cancer, melanoma, or endometrial cancer.

[0261] E5. The method according to any one of claims E1 to E4, wherein the cancer includes KRAS, NRAS HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1 or BRAF The mutation, amplification, or overexpression of HPV, or previous or current HPV infection.

[0262] E6. The method according to any one of claims E1 to E4, wherein the cancer includes cancer previously identified as KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1 or BRAF Cancer caused by mutations, amplifications, or overexpression of HPV, or by previous or current HPV infection.

[0263] E7. The method according to claim E5 or claim E6, wherein the cancer includes CCNE1 Overexpression.

[0264] E8. The method according to claim E7, wherein the cancer includes uterine cancer, ovarian cancer, pancreatic cancer, mesothelioma, kidney cancer, bladder cancer, gastric cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, or endometrial cancer.

[0265] E9. The method according to claim E5 or claim E6, wherein the cancer includes FBXW7 mutation.

[0266] E10. The method of claim E9, wherein the cancer includes uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

[0267] E11. The method according to claim E5 or claim E6, wherein the cancer includes KRAS mutation.

[0268] E12. The method according to claim E5 or claim E6, wherein the cancer comprises KRAS Overexpression.

[0269] E13. The method according to claim E11 or claim E12, wherein the cancer includes colorectal cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, cervical cancer, or gastroesophageal cancer.

[0270] E14. The method according to claim E5 or claim E6, wherein the cancer comprises HRAS mutation.

[0271] E15. The method of claim E14, wherein the cancer includes kidney cancer, bladder cancer, head and neck cancer, or thyroid cancer.

[0272] E16. The method according to claim E5 or claim E6, wherein the cancer includes NRAS mutation.

[0273] E17. The method of claim E16, wherein the cancer includes colorectal cancer, thyroid cancer, or melanoma.

[0274] E18. The method according to claim E5 or claim E6, wherein the replication pressure biomarker is PPP2R1A mutation.

[0275] E19. The method of claim E18, wherein the cancer includes endometrial cancer, ovarian cancer, and uterine cancer.

[0276] E20. A method for increasing CDK1 activity in cells, the method comprising contacting the cells with a dose of a Myt1 inhibitor and a dose of a Wee1 inhibitor according to a dosing regimen; and (i) The dose of the Myt1 inhibitor is a subtherapeutic dose; (ii) The dose of the Wee1 inhibitor is a subtherapeutic dose; (iii) The administration regimen of the Myt1 inhibitor is a reduced-dose regimen; or (iv) The administration regimen of the Wee1 inhibitor is a reduced-dose administration regimen.

[0277] E21. A method for inducing premature mitosis in cells, the method comprising contacting the cells with a dose of a Myt1 inhibitor and a dose of a Wee1 inhibitor according to a dosing regimen; and (i) The dose of the Myt1 inhibitor is a subtherapeutic dose; (ii) The dose of the Wee1 inhibitor is a subtherapeutic dose; (iii) The administration regimen of the Myt1 inhibitor is a reduced-dose regimen; or (iv) The administration regimen of the Wee1 inhibitor is a reduced-dose administration regimen.

[0278] E22. The method according to claim E20 or E21, wherein the cells are in the subject.

[0279] E23. The method according to any one of claims E1 to E22, wherein the dose of the Myt1 inhibitor is up to 500 mg.

[0280] E24. The method according to any one of claims E1 to E23, wherein the dose of the Myt1 inhibitor is up to 240 mg.

[0281] E25. The method according to any one of claims E1 to E24, wherein the dose of the Myt1 inhibitor is up to 100 mg.

[0282] E26. The method according to any one of claims E1 to E25, wherein the dose reduction regimen of the Myt1 inhibitor comprises administering one dose once daily.

[0283] E27. The method according to any one of claims E1 to E25, wherein the dose reduction regimen of the Myt1 inhibitor comprises administering one dose twice daily.

[0284] E28. The method according to any one of claims E1 to E27, wherein the dose reduction regimen of the Myt1 inhibitor comprises a 1 / 6 dosing regimen.

[0285] E29. The method according to any one of claims E1 to E27, wherein the dose reduction regimen of the Myt1 inhibitor comprises a 2 / 5 dosing regimen.

[0286] E30. The method according to any one of claims E1 to E27, wherein the dose reduction regimen of the Myt1 inhibitor comprises a 3 / 4 dosing regimen.

[0287] E31. The method according to any one of claims E1 to E27, wherein the dose reduction regimen of the Myt1 inhibitor comprises a 5 / 2 dosing regimen.

[0288] E32. The method according to any one of claims E1 to E27, wherein the dose reduction regimen of the Myt1 inhibitor comprises a dosing regimen of 1 week on and 1 week off.

[0289] E33. The method according to any one of claims E1 to E27, wherein the dose reduction regimen of the Myt1 inhibitor comprises a dosing regimen of 2 weeks of dosing and 1 week of off-dosing.

[0290] E34. The method according to any one of claims E1 to E33, wherein the dose of the Wee1 inhibitor is up to 520 mg.

[0291] E35. The method according to any one of claims E1 to E34, wherein the dose of the Wee1 inhibitor is up to 400 mg.

[0292] E36. The method according to any one of claims E1 to E35, wherein the dose of the Wee1 inhibitor is up to 200 mg.

[0293] E37. The method according to any one of claims E1 to E36, wherein the reduced dosing regimen of the Wee1 inhibitor comprises administering one dose once daily.

[0294] E38. The method according to any one of claims E1 to E36, wherein the reduced dosing regimen of the Wee1 inhibitor comprises administering one dose twice daily.

[0295] E39. The method according to any one of claims E1 to E38, wherein the reduced dosing regimen of the Wee1 inhibitor comprises a 1 / 6 dosing regimen.

[0296] E40. The method according to any one of claims E1 to E38, wherein the reduced dosing regimen of the Wee1 inhibitor comprises a 2 / 5 dosing regimen.

[0297] E41. The method according to any one of claims E1 to E38, wherein the reduced dosing regimen of the Wee1 inhibitor comprises a 3 / 4 dosing regimen.

[0298] E42. The method according to any one of claims E1 to E38, wherein the reduced dosing regimen of the Wee1 inhibitor comprises a 5 / 2 dosing regimen.

[0299] E43. The method according to any one of claims E1 to E38, wherein the dose reduction regimen of the Wee1 inhibitor comprises a dosing regimen of 1 week dosing and 1 week off.

[0300] E44. The method according to any one of claims E1 to E38, wherein the dose reduction regimen of the Wee1 inhibitor comprises a dosing regimen of 1 week of dosing and 2 weeks of withdrawal.

[0301] E45. The method according to any one of claims E1 to E44, wherein the dose of the Myt1 inhibitor is a subtherapeutic dose, and the dose of the Wee1 inhibitor is a subtherapeutic dose.

[0302] E44. The method according to any one of claims E1 to E43, wherein the administration regimen of the Myt1 inhibitor is a reduced-dose administration regimen, and the administration regimen of the Wee1 inhibitor is a reduced-dose administration regimen.

[0303] E45. The method according to any one of claims E1 to E44, wherein the Wee1 inhibitor is administered as a pharmaceutical composition.

[0304] E46. The method according to any one of claims E1 to E45, wherein the Wee1 inhibitor is one of the following: Or its pharmaceutically acceptable salt.

[0305] E47. The method according to any one of claims E1 to E45, wherein the Wee1 inhibitor is selected from compounds W1 to W3052.

[0306] E48. The method according to any one of claims E1 to E45, wherein the Wee1 inhibitor binds to Wee1, thereby reducing the activity of Wee1.

[0307] E49. The method according to any one of claims E1 to E45, wherein the Wee1 inhibitor is PROTAC.

[0308] E50. The method according to any one of claims E1 to E45, wherein the Wee1 inhibitor is a molecular glue.

[0309] E51. The method according to any one of claims E1 to E50, wherein the Myt1 inhibitor is administered as a pharmaceutical composition.

[0310] E52. The method according to any one of claims E1 to E51, wherein the Myt1 inhibitor is a compound of formula (I): Or its pharmaceutically acceptable salt. in Each of X, Y, and Z is independently N or CR. 2 ; R 1 and each R 2 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, cyano, -N(R) 7 )2、-OR 7 -C(O)N(R) 8 )2、-SO2N(R 8 )2、-SO2R 7A or -QR 7B Or R 1 With one adjacent R 1 R 2 Combining to form optional C 3-6 Alkylene; R 3 and R 4 Each of them is independently an optional substitution of C. 1-6 Alkyl or halogen; R 5 Is it H or -N(R) 7 )2; R 6 It is -C(O)NH(R) 8 -C(O)R 7A or -SO2R 7A ; Each R 7 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl or -SO2R 7A Or two Rs 7 The groups, together with the atoms to which they are attached, combine to form optionally substituted C groups. 2-9 Heterocyclic groups; Each R 7A C is independently optional substitution 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; Each R 7B Independently, it is a hydroxyl group, or an optionally substituted C. 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9Heterocyclic groups, optionally substituted C 1-9 heteroaryl, -N(R) 7 )2、-C(O)N(R 8 )2、-SO2N(R 8 )2、-SO2R 7A Or optionally substituted alkoxy groups; Each R 8 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two Rs 8 Together with the atoms to which they are attached, they combine to form optionally substituted C atoms. 2-9 Heterocyclic groups; and Each Q is independently an optional substituted C. 1-6 Alkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 Heterocyclic or optionally substituted C 1-9 Hybrid aryl.

[0311] E53. The method according to claim E52, wherein the compound is rich in the (IA) transisomer: Or its pharmaceutically acceptable salt.

[0312] E54. The method according to claim E52 or E53, wherein X is CR 2 .

[0313] E55. The method according to claim E53, wherein the compound has formula (II): Or its pharmaceutically acceptable salt.

[0314] E56. The method of claim E53, wherein the compound is rich in the (IIA)-dependent transisomer: Or its pharmaceutically acceptable salt.

[0315] E56. The method according to claim E53, wherein the compound is rich in the (IIA) transisomer: Where R 2A It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, -N(R) 7 )2、-OR 7 -C(O)N(R) 8 )2、-SO2N(R 8 )2、-SO2R 7A or -QR 7B ; Or its pharmaceutically acceptable salt.

[0316] E58. The method according to claim E57, wherein the compound is rich in the (IIIA) transisomer: Or its pharmaceutically acceptable salt.

[0317] E59. The method according to claim E57 or E58, wherein R 2A It is hydrogen, and the C is optionally substituted. 1-6 Alkyl or halogen.

[0318] E60. The method according to any one of claims E52 to E59, wherein R 3 C is an optional substitute 1-6 alkyl.

[0319] E61. The method according to any one of claims E52 to E59, wherein R 3 It is halogen.

[0320] E62. The method according to any one of claims E52 to E61, wherein R 4 C is an optional substitute 1-6 alkyl.

[0321] E63. The method according to any one of claims E52 to E61, wherein R 4 It is halogen.

[0322] E64. The method of claim 63, wherein the halogen is chlorine.

[0323] E65. The method according to any one of claims E52 to E64, wherein R 2 It is hydrogen.

[0324] E66. The method according to any one of claims E52 to E64, wherein R 2 C is an optional substitute 1-6 alkyl.

[0325] E67. The method of claim 66, wherein R 2 It is either a substituted methyl group or an substituted isopropyl group.

[0326] E68. The method according to any one of claims E52 to E64, wherein R 2 It is halogen.

[0327] E69. The method according to any one of claims E52 to E68, wherein R 1 It is hydrogen.

[0328] E70. The method according to any one of claims E52 to E68, wherein R 1 It is halogen.

[0329] E71. The method according to claim E70, wherein R 1 It is chlorine or bromine.

[0330] E72. The method according to any one of claims E52 to E67, wherein R 1 C is an optional substitute 1-6 alkyl.

[0331] E73. The method according to claim E72, wherein R 1 It is optionally substituted methyl, optionally substituted ethyl, optionally substituted isopropyl or optionally substituted butyl.

[0332] E74. The method according to any one of claims E52 to E68, wherein R 1 C is an optional substitute 1-9 Mixed aromatic compounds.

[0333] E75. The method according to claim E74, wherein R 1It is 1,3-thiazolyl, 1,2-thiazolyl, 1,3-oxazolyl, benzo-1,3-thiazolyl, benzo-1,3-oxazolyl, indolyl, benzimidazolyl, pyridyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, or pyrazolyl, wherein R 1 The optional C can be replaced as is. 1-9 Substituent substitution as defined by heteroaryl groups.

[0334] E76. The method according to any one of claims E52 to E68, wherein R 1 C is an optional substitute 3-8 Cycloalkyl.

[0335] E77. The method according to claim E76, wherein R 1 It is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R 1 The optional C can be replaced as is. 3-8 Substituents as defined by cycloalkyl groups.

[0336] E78. The method according to any one of claims E53 to E68, wherein R 1 C is an optional substitute 2-9 Heterocyclic group.

[0337] E79. The method according to claim E78, wherein R 1 It is 1,2,3,6-tetrahydropyridyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, oxa-aza-spiro[3,3]heptane or oxa-aza-bicyclo[3.2.1]octane, wherein R 1 The optional C can be replaced as is. 2-9 Substituent substitution as defined by heterocyclic groups.

[0338] E80. The method according to any one of claims E52 to E68, wherein R 1 C is an optional substitute 3-8 Cycloalkenyl.

[0339] E81. The method of claim E80, wherein R 1 It is an optional substituted cyclohexenyl or an optional substituted cyclopentenyl.

[0340] E82. The method according to any one of claims E52 to E68, wherein R 1 C is an optional substitute 6-10 Aryl.

[0341] E83. The method according to claim E82, wherein R 1 It is an optional substituted phenyl group.

[0342] E84. The method according to any one of claims E52 to E68, wherein R 1 Yes - QR 7B .

[0343] E85. The method of claim 84, wherein Q is an optional substitution of C. 2-6 Alynyl group.

[0344] E86. The method of claim 84, wherein Q is an optional substitution of C. 1-6 Alkylene.

[0345] E87. The method of claim 84, wherein Q is an optionally substituted C. 6-10 Alpha-aryl.

[0346] E88. The method according to any one of claims E84 to E87, wherein R 7B C is an optional substitute 2-9 Heterocyclic group.

[0347] E89. The method according to any one of claims E84 to E87, wherein R 7B C is an optional substitute 6-10 Aryl.

[0348] E90. The method according to any one of claims E52 to E89, wherein R 1 The radical is selected independently by one, two, or three of the following groups: methyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, -C(O)NH2, -C(O)NH(Me), -C(O)N(Me)2, and -(CH2). n -C(O)OH and -(CH2) n The group substitution of -C(O)Ot-Bu, where n is 0 or 1.

[0349] E91. The method according to any one of claims E52 to E68, wherein R 1 It is -N(R) 7 )2.

[0350] E92. The method according to claim E91, wherein R 1 It is diethylamino.

[0351] E93. The method according to any one of claims E52 to E92, wherein R 5 It is hydrogen.

[0352] E94. The method according to any one of claims E52 to E92, wherein R 5 It is -N(R) 7 )2.

[0353] E95. The method according to claim E92, wherein R 5 It is -NH2.

[0354] E96. The method according to any one of claims E52 to E94, wherein R 6 It is -C(O)NH(R) 8 ).

[0355] E97. The method according to any one of claims E52 to E94, wherein R 6 It is -C(O)NH2.

[0356] E98. The method according to any one of claims E52 to E94, wherein R 6 It is -C(O)NH(Me).

[0357] E99. The method according to any one of claims E52 to E94, wherein R 6 Yes - SO2R 7A .

[0358] E100. The method according to claim E99, wherein R 6 It is -SO2Me.

[0359] E101. The method according to any one of claims E1 to E52, wherein the Myt1 inhibitor is a compound selected from compounds 1 to 328 and their pharmaceutically acceptable salts.

[0360] E102. The method according to any one of claims E1 to E52, wherein the Myt1 inhibitor is a compound as lunresertib or a pharmaceutically acceptable salt thereof.

[0361] Other implementation plans Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been described in conjunction with specific embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. Indeed, various modifications to the described modes of implementation that will be apparent to those skilled in the art are intended to fall within the scope of the invention.

[0362] Other embodiments are described in the claims.

Claims

1. A method of treating a subject with cancer, the method comprising administering, according to a dosing regimen, a dose of a membrane-associated tyrosine and threonine-specific CDC2 inhibitory kinase (Myt1) inhibitor to the subject in need, and, according to a dosing regimen, a dose of a Wee1 inhibitor; and (i) The dose of the Myt1 inhibitor is the therapeutically effective dose; (ii) The dose of the Myt1 inhibitor is a subtherapeutic dose; (iii) The dose of the Wee1 inhibitor is a subtherapeutic dose; (iv) The administration regimen of the Myt1 inhibitor is a reduced-dose regimen; or (v) The administration regimen of the Wee1 inhibitor is a reduced-dose regimen.

2. A method for inducing cell death in cancer cells, the method comprising contacting the cells with a dose of a MYT1 inhibitor and a dose of a Wee1 inhibitor according to a dosing regimen; and (i) The dose of the Myt1 inhibitor is the therapeutically effective dose; (ii) The dose of the Myt1 inhibitor is a subtherapeutic dose; (iii) The dose of the Wee1 inhibitor is a subtherapeutic dose; (iv) The administration regimen of the Myt1 inhibitor is a reduced-dose regimen; or (v) The administration regimen of the Wee1 inhibitor is a reduced-dose regimen.

3. The method of claim 2, wherein the cells are in the subject.

4. The method according to any one of claims 1 to 3, wherein the cancer is uterine cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, head and neck cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, thyroid cancer, melanoma, or endometrial cancer.

5. The method according to any one of claims 1 to 4, wherein the cancer includes KRAS, NRAS, HRAS, TP53 CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1 or BRAF The mutation, amplification, or overexpression of HPV, or previous or current HPV infection.

6. The method according to any one of claims 1 to 4, wherein the cancer includes cancer previously identified as KRAS, NRAS HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1 or BRAF Cancer caused by mutations, amplifications, or overexpression of HPV, or by previous or current HPV infection.

7. The method according to claim 5 or claim 6, wherein the cancer includes CCNE1 Overexpression.

8. The method of claim 7, wherein the cancer includes uterine cancer, ovarian cancer, pancreatic cancer, mesothelioma, kidney cancer, bladder cancer, gastric cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, or endometrial cancer.

9. The method according to claim 5 or claim 6, wherein the cancer includes FBXW7 mutation.

10. The method of claim 9, wherein the cancer includes uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

11. The method according to claim 5 or claim 6, wherein the cancer includes KRAS mutation.

12. The method according to claim 5 or claim 6, wherein the cancer comprises KRAS Overexpression.

13. The method according to claim 11 or claim 12, wherein the cancer includes colorectal cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, cervical cancer, or gastroesophageal cancer.

14. The method according to claim 5 or claim 6, wherein the cancer includes HRAS mutation.

15. The method of claim 14, wherein the cancer includes kidney cancer, bladder cancer, head and neck cancer, or thyroid cancer.

16. The method according to claim 5 or claim 6, wherein the cancer includes NRAS mutation.

17. The method of claim 16, wherein the cancer includes colorectal cancer, thyroid cancer, or melanoma.

18. The method according to claim 5 or claim 6, wherein the replication pressure biomarker is PPP2R1A mutation.

19. The method of claim 18, wherein the cancer includes endometrial cancer, ovarian cancer, and uterine cancer.

20. A method for increasing CDK1 activity in cells, the method comprising contacting the cells with a dose of a Myt1 inhibitor and a dose of a Wee1 inhibitor according to a dosing regimen; and (i) The dose of the Myt1 inhibitor is the therapeutically effective dose; (ii) The dose of the Myt1 inhibitor is a subtherapeutic dose; (iii) The dose of the Wee1 inhibitor is a subtherapeutic dose; (iv) The administration regimen of the Myt1 inhibitor is a reduced-dose regimen; or (v) The administration regimen of the Wee1 inhibitor is a reduced-dose regimen.

21. A method for inducing premature mitosis in cells, the method comprising contacting the cells with a dose of a Myt1 inhibitor and a dose of a Wee1 inhibitor according to a dosing regimen; and (i) The dose of the Myt1 inhibitor is the therapeutically effective dose. (ii) The dose of the Myt1 inhibitor is a subtherapeutic dose; (iii) The dose of the Wee1 inhibitor is a subtherapeutic dose; (iv) The administration regimen of the Myt1 inhibitor is a reduced-dose regimen; or (v) The administration regimen of the Wee1 inhibitor is a reduced-dose regimen.

22. The method of claim 20 or claim 21, wherein the cells are in the subject.

23. The method according to any one of claims 1 to 22, wherein the Myt1 inhibitor is administered as a pharmaceutical composition.

24. The method according to any one of claims 1 to 23, wherein the Myt1 inhibitor is a compound of formula (I): Or its pharmaceutically acceptable salt. in Each of X, Y, and Z is independently N or CR. 2 ; R 1 and each R 2 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, cyano, -N(R) 7 )2、-OR 7 -C(O)N(R) 8 )2、-SO2N(R 8 )2、-SO2R 7A or -QR 7B Or R 1 With one Neighbor R 1 R 2 Combining to form optional C 3-6 Alkylene; R 3 and R 4 Each of them is independently an optional substitution of C. 1-6 Alkyl or halogen; R 5 Is it H or -N(R) 7 )2; R 6 It is -C(O)NH(R) 8 -C(O)R 7A or -SO2R 7A ; Each R 7 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl or -SO2R 7A Or two Rs 7 The groups, together with the atoms to which they are attached, combine to form optionally substituted C groups. 2-9 Heterocyclic groups; Each R 7A C is independently optional substitution 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 6-10 Aryl; Each R 7B Independently, it is a hydroxyl group, or an optionally substituted C. 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 1-9 heteroaryl, -N(R) 7 )2、-C(O)N(R 8 )2、-SO2N(R 8 )2、-SO2R 7A Or optionally substituted alkoxy groups; Each R 8 Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl or optionally substituted C 1-9 heteroaryl; or two Rs 8 Together with the atoms to which they are attached, they combine to form optionally substituted C atoms. 2-9 Heterocyclic groups; and Each Q is independently an optional substituted C. 1-6 Alkylene, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Ethyne group, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted C 2-9 Heterocyclic or optionally substituted C 1-9 Hybrid aryl.

25. The method of claim 24, wherein the compound is rich in the (IA) transisomer: Or its pharmaceutically acceptable salt.

26. The method according to claim 24 or 25, wherein X is CR 2 .

27. The method according to claim 25, wherein the compound has formula (II): Or its pharmaceutically acceptable salt.

28. The method of claim 25, wherein the compound is rich in the (IIA)-restricted transisomer: Or its pharmaceutically acceptable salt.

29. The method according to claim 24, wherein the compound has formula (III): Where R 2A It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 2-9 Heterocyclic C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 Alkyl, halogen, -N(R) 7 )2、-OR 7 -C(O)N(R) 8 )2、-SO2N(R 8 )2、-SO2R 7A or -QR 7B ; Or its pharmaceutically acceptable salt.

30. The method of claim 29, wherein the compound is rich in the (IIIA)-restricted transisomer: Or its pharmaceutically acceptable salt.

31. The method according to claim 29 or 30, wherein R 2A It is hydrogen, and the C is optionally substituted. 1-6 Alkyl or halogen.

32. The method according to any one of claims 24 to 31, wherein R 3 C is an optional substitute 1-6 alkyl.

33. The method according to any one of claims 24 to 31, wherein R 3 It is halogen.

34. The method according to any one of claims 24 to 33, wherein R 4 C is an optional substitute 1-6 alkyl.

35. The method according to any one of claims 24 to 33, wherein R 4 It is halogen.

36. The method of claim 35, wherein the halogen is chlorine.

37. The method according to any one of claims 24 to 36, wherein R 2 It is hydrogen.

38. The method according to any one of claims 24 to 36, wherein R 2 C is an optional substitute 1-6 alkyl.

39. The method of claim 38, wherein R 2 It is either a substituted methyl group or an substituted isopropyl group.

40. The method according to any one of claims 24 to 36, wherein R 2 It is halogen.

41. The method according to any one of claims 24 to 40, wherein R 1 It is hydrogen.

42. The method according to any one of claims 24 to 40, wherein R 1 It is halogen.

43. The method of claim 42, wherein R 1 It is chlorine or bromine.

44. The method according to any one of claims 24 to 39, wherein R 1 C is an optional substitute 1-6 alkyl.

45. The method of claim 44, wherein R 1 It is optionally substituted methyl, optionally substituted ethyl, optionally substituted isopropyl or optionally substituted butyl.

46. ​​The method according to any one of claims 24 to 40, wherein R 1 C is an optional substitute 1-9 Mixed aromatic compounds.

47. The method of claim 46, wherein R 1 It is 1,3-thiazolyl, 1,2-thiazolyl, 1,3-oxazolyl, benzo-1,3-thiazolyl, benzo-1,3-oxazolyl, indolyl, benzimidazolyl, pyridyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, or pyrazolyl, wherein R 1 The optional C can be replaced as is. 1-9 Substituent substitution as defined by heteroaryl groups.

48. The method according to any one of claims 24 to 40, wherein R 1 C is an optional substitute 3-8 Cycloalkyl.

49. The method of claim 48, wherein R 1 It is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R 1 The optional C can be replaced as is. 3-8 Substituents as defined by cycloalkyl groups.

50. The method according to any one of claims 25 to 40, wherein R 1 C is an optional substitute 2-9 Heterocyclic group.

51. The method of claim 50, wherein R 1 It is 1,2,3,6-tetrahydropyridyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, oxa-aza-spiro[3,3]heptane or oxa-aza-bicyclo[3.2.1]octane, wherein R 1 The optional C can be replaced as is. 2-9 Substituent substitution as defined by heterocyclic groups.

52. The method according to any one of claims 24 to 40, wherein R 1 C is an optional substitute 3-8 Cycloalkenyl.

53. The method of claim 52, wherein R 1 It is an optionally substituted cyclohexenyl or optionally substituted cyclopentenyl.

54. The method according to any one of claims 24 to 40, wherein R 1 C is an optional substitute 6-10 Aryl.

55. The method of claim 54, wherein R 1 It is an optional substituted phenyl group.

56. The method according to any one of claims 24 to 40, wherein R 1 Yes - QR 7B .

57. The method of claim 56, wherein Q is an optionally substituted C. 2-6 Alynyl group.

58. The method of claim 56, wherein Q is an optionally substituted C. 1-6 Alkylene.

59. The method of claim 56, wherein Q is an optionally substituted C. 6-10 Alpha-aryl.

60. The method according to any one of claims 56 to 59, wherein R 7B C is an optional substitute 2-9 Heterocyclic group.

61. The method according to any one of claims 56 to 59, wherein R 7B C is an optional substitute 6-10 Aryl.

62. The method according to any one of claims 24 to 61, wherein R 1 The group may be substituted by one, two, or three independently selected groups from the group consisting of: methyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, -C(O)NH2, -C(O)NH(Me), -C(O)N(Me)2, -(CH2). n -C(O)OH and -(CH2) n -C(O)Ot-Bu, where n is 0 or 1.

63. The method according to any one of claims 24 to 40, wherein R 1 It is -N(R) 7 )2.

64. The method of claim 63, wherein R 1 It is diethylamino.

65. The method according to any one of claims 24 to 64, wherein R 5 It is hydrogen.

66. The method according to any one of claims 24 to 64, wherein R 5 It is -N(R) 7 )2.

67. The method of claim 64, wherein R 5 It is -NH2.

68. The method according to any one of claims 24 to 66, wherein R 6 It is -C(O)NH(R) 8 ).

69. The method according to any one of claims 24 to 66, wherein R 6 It is -C(O)NH2.

70. The method according to any one of claims 24 to 66, wherein R 6 It is -C(O)NH(Me).

71. The method according to any one of claims 24 to 66, wherein R 6 Yes - SO2R 7A .

72. The method of claim 71, wherein R 6 It is -SO2Me.

73. The method according to any one of claims 1 to 23, wherein the Myt1 inhibitor is a compound selected from compounds 1 to 328 and pharmaceutically acceptable salts thereof.

74. The method according to any one of claims 1 to 23, wherein the Myt1 inhibitor is lunresertib or a pharmaceutically acceptable salt thereof.

75. The method according to any one of claims 1 to 74, wherein the Wee1 inhibitor is administered as a pharmaceutical composition.

76. The method according to any one of claims 1 to 75, wherein the Wee1 inhibitor is one of the following: Or its pharmaceutically acceptable salt.

77. The method according to any one of claims 1 to 75, wherein the Wee1 inhibitor is selected from compounds W1 to W3052.

78. The method according to any one of claims 1 to 75, wherein the Wee1 inhibitor is Debio-0123 or a pharmaceutically acceptable salt thereof.

79. The method according to any one of claims 1 to 23, wherein the Myt1 inhibitor is lunresertib and the Wee1 inhibitor is Debio-0123.

80. The method according to any one of claims 1 to 76, wherein the Wee1 inhibitor binds to Wee1, thereby reducing the activity of Wee1.

81. The method according to any one of claims 1 to 75, wherein the Wee1 inhibitor is PROTAC.

82. The method according to any one of claims 1 to 75, wherein the Wee1 inhibitor is a molecular glue.

83. The method according to any one of claims 1 to 82, wherein the dose reduction regimen of the Myt1 inhibitor comprises administering one dose once daily.

84. The method according to any one of claims 1 to 82, wherein the dose reduction regimen of the Myt1 inhibitor comprises administering one dose twice daily.

85. The method according to any one of claims 1 to 84, wherein the dose reduction regimen of the Myt1 inhibitor comprises a 1 / 6 dosing regimen.

86. The method according to any one of claims 1 to 84, wherein the dose reduction regimen of the Myt1 inhibitor comprises a 2 / 5 dosing regimen.

87. The method according to any one of claims 1 to 84, wherein the dose reduction regimen of the Myt1 inhibitor comprises a 3 / 4 dosing regimen.

88. The method according to any one of claims 1 to 84, wherein the dose reduction regimen of the Myt1 inhibitor comprises a 5 / 2 dosing regimen.

89. The method according to any one of claims 1 to 84, wherein the dose reduction regimen of the Myt1 inhibitor comprises a dosing regimen of 1 week dosing and 1 week off.

90. The method according to any one of claims 1 to 84, wherein the dose reduction regimen of the Myt1 inhibitor comprises a dosing regimen of 2 weeks of dosing and 1 week of off-dosing.

91. The method according to any one of claims 1 to 90, wherein the reduced dosing regimen of the Wee1 inhibitor comprises administering one dose once daily.

92. The method according to any one of claims 1 to 90, wherein the reduced dosing regimen of the Wee1 inhibitor comprises administering one dose twice daily.

93. The method according to any one of claims 1 to 92, wherein the reduced dosing regimen of the Wee1 inhibitor comprises a 1 / 6 dosing regimen.

94. The method according to any one of claims 1 to 92, wherein the reduced dosing regimen of the Wee1 inhibitor comprises a 2 / 5 dosing regimen.

95. The method according to any one of claims 1 to 92, wherein the reduced dosing regimen of the Wee1 inhibitor comprises a 3 / 4 dosing regimen.

96. The method according to any one of claims 1 to 92, wherein the reduced dosing regimen of the Wee1 inhibitor comprises a 5 / 2 dosing regimen.

97. The method according to any one of claims 1 to 92, wherein the dose reduction regimen of the Wee1 inhibitor comprises a 1-week dosing / 1-week discontinuation dosing regimen.

98. The method according to any one of claims 1 to 92, wherein the dose reduction regimen of the Wee1 inhibitor comprises a 1-week dosing / 2-week discontinuation dosing regimen.

99. The method according to any one of claims 1 to 98, wherein the dose of the Myt1 inhibitor is a subtherapeutic dose, and the dose of the Wee1 inhibitor is a subtherapeutic dose.

100. The method according to any one of claims 1 to 98, wherein the dose of the Myt1 inhibitor is a therapeutically effective dose, and the dose of the Wee1 inhibitor is a subtherapeutic dose.

101. The method according to any one of claims 1 to 100, wherein the administration regimen of the Myt1 inhibitor is a reduced-dose administration regimen, and the administration regimen of the Wee1 inhibitor is a reduced-dose administration regimen.

Images